Twenty Things To Know About Deep Brain Stimulation, 1E (2015) (PDF) (UnitedVRG)

20 Things to Know about
DeepBrainStimulation
20 Things to Know about Deep

Brain Stimulation
E R W I N B . M O N T G O M E R Y, J R . , M D
M ED I CA L D I R EC TO R
G R EEN V I L L E N EU R O M O D U L AT I O NC EN T ER
T H E G R EEN V I L L E N EU R O M O D U L AT I O N S C H O L A R
I N N EU R O S C I EN C E A N D PH I LO S O PH Y
T H I EL C O L L EG E
G R EEN V I L L E , PA
1
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Library of Congress Cataloging-in-Publication Data
Montgomery, Erwin B., Jr., author.
20 things to know about deep brain stimulation / Erwin B. Montgomery, Jr.
p. ; cm.
Includes bibliographical references.
ISBN 9780199338825 (alk. paper)
I. Title.
[DNLM: 1. Deep Brain Stimulationmethods. 2. Mental Disorderstherapy. 3. Movement
Disorderstherapy. WL 368]
RC347
616.8dc23
2014029318
The science of medicine is a rapidly changing field. As new research and clinical experience broaden
our knowledge, changes in treatment and drug therapy occur. The author and publisher of this
work have checked with sources believed to be reliable in their efforts to provide information that
is accurate and complete and in accordance with the standards accepted at the time of publication.
However, in light of the possibility of human error or changes in the practice of medicine, neither
the author, nor the publisher, nor any other party who has been involved in the preparation or
publication of this work warrants that the information contained herein is in every respect accurate
or complete. Readers are encouraged to confirm the information contained herein with other
reliable sources and are strongly advised to check the product information sheet provided by the
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987654321
Printed in the United States of America
on acid-free paper
To Lyn Turkstra, whose unfailing support made every house a home,

and to Michael, David, and Pat, whose love was always
a source of comfort when needed most.
CONTENTS
Preface ix
1. What Is Deep Brain Stimulation? 1
2. Why Deep Brain Stimulation? 14
3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease 22
4. Identifying the Least Acceptable Deep Brain Stimulation Candidates Among
Patients with Parkinsons Disease 37
5. Postoperative Management of Patients with Parkinsons Disease 56
6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor 66
Patients with Essential Tremor 74
8. Postoperative Care for Essential Tremor 87
9. Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia 94
Patients with Dystonia 101
11. Postoperative Management of Patients with Dystonia 115
12. Deep Brain Stimulation Is Safe and Effective for Tourettes Syndrome 122
Patients with Tourettes Syndrome 130
14. Deep Brain Stimulation for Cerebellar Outflow Tremor 145
15. Deep Brain Stimulation for Hyperkinetic Disorders 156
16. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive
Disorder 171
17. Could Deep Brain Stimulation Be Effective in the Treatment of Posttraumatic
Stress Disorder? 186
18. Deep Brain Stimulation and Insights to Pathophysiology and Physiology 216
19. Ethical Issues of Deep Brain Stimulation 226
20. The Future of Deep Brain Stimulation 247
Index 261
PREFACE
T WO PL E AS
The First Plea

In 1998, a 26-year-old woman laid on an operating room table with a set of electrodes implanted in the ventral intermediate nucleus of the thalamus of her brain.
After the stimulation was turned on, her severe tremor due to her multiple sclerosis
went away. She then said, Now I can hold my baby. She had given birth three
months before. In 2000, a father with young children suffered from Parkinsons
disease. After deep brain stimulation (DBS), much to the consternation and relief
of his children, he could beat them in basketball. Whether by fate, providence, or
self-organizing physical universe, humankind was given a gift.
Since DBS, as currently practiced, was reported in 1979 for psychiatric disorders (Dieckmann 1979)and in 1980 for movement disorders (Cooper etal. 1980),
much or little has changed, depending on ones perspective. The technical prowess of modern science generated many observations of how the brain reacts to
DBS, but it is no further in understanding why DBS creates what even the most
jaded would have to admit are nearly miraculous changes in patients lives. In
many disorders, DBS has demonstrated its superiority over every other treatment
option. Indeed, in many ways DBS is revolutionary and, in the field of Parkinsons
disease, a breakthrough on par with the discovery of levodopa. One would think
that such a breakthrough would be enthusiastically embraced for the potential
insights into pathophysiology and physiology of the brain and for the benefit physicians and healthcare professionals now can provide to their patients. If only that
were the case.
At the American Academy of Neurology annual meeting in 2014, there was
not a single presentation on DBS, only a short course on DBS programming.
Since 1997, Icannot think of a single neurology resident who actively sought
to participate in the DBS clinic to the point of having knowledge and skills
in DBS even close to proficiency. Interestingly, no mention of Deep Brain
Stimulation or DBS is made in the Certification Examination in Neurology
2013 Content Blueprint published by the American Board of Neurology and
Psychiatry (2012).
x P reface
In my experience, the enthusiasm at potentially helping patients with severe

tremor secondary to multiple sclerosis at one institution led to many patients being
referred and, in my opinion, appropriately. In the10 subsequent years at other institutions, only a single patient with cerebellar outflow tremor was referred. Perhaps
the physicians at the first institution were overly enthusiastic while latter physicians
were appropriately skeptical. However, the fact remains that such disparities must
argue for a profound dissonance as both groups of physicians probably read the
same publications.
Even for disorders that are uncontroversial, such as Parkinsons disease, only
a fraction of patients who could benefit are being provided that option. One of
the most painful and difficult questions Ihave been confronted with is when the
patient asks why did her physician wait so long, make her suffer so much, before
referring her for DBS? However, Ican commiserate with those physicians. There
have been remarkable changes in the nearly 30years Ihave been practicing medicine and not all of them good or helpful. The continued increases in responsibilities accompanied by reductions in authority has hamstrung many physicians and
healthcare professionals. The shortage of physicians and increase in work hours
makes any discretionary time that could be devoted to gaining knowledge and
skills to provide DBS challenging and requires no small amount of self-sacrifice.
When confronted with spending what little discretionary time and intellectual
capital they have on continuing education, physicians and healthcare professionals
do not choose DBS, which faces unfavorable odds when competing with epilepsy,
headache, and other more common disorders and treatments for the physicians
and healthcare professionals attention. Yet it is the patient whose suffering could
be alleviated with DBS that is paying the price. The answer to the dilemma of
providing all patients the care that they need, particularly as it relates to DBS, is
unclear. But what is clear is that the answer will not come unless the proper questions are asked.
I wish that every physician and healthcare professional could have the experience of seeing one of their patientswhom they have suffered with as no
medications helpeddramatically improve with the turning on of an electrical
switch. However, Iam not so nave to think that this is sufficient. Consequently,
there is no choice but to remind everyone of the current situation in a clear-eyed,
unrelenting analysis, remind each and every one of their obligations, and hope
for the best.
Anyone who recognizes that it is a privilege to be a physician and healthcare
professional also will recognize its obligations. Those obligations are to beneficence, that is, to do good, and are articulated in the Hippocratic Oath, the Oath
of Maimonides, and the Geneva Declaration that most physicians swear to. In
addition, physicians have an obligation to beneficence because it is extremely
rare that a physicians education and training were paid for by the physician
but rather subsidized by society. Further, the license to practice is not a right
but a privilege extended to physicians and healthcare professionals, which
entail obligations. The years spent in school and in training do not convey any
entitlement.
P reface xi
The Second Plea

The second plea is best conveyed by the lines of Alexander Pope (An Essay on
Criticism,1711):
A little learning is a dangrous thing;
Drink deep, or taste not the Pierian spring:
There shallow draughts intoxicate the brain,
And drinking largely sobers us again.
Fird at first sight with what the Muse imparts,
In fearless youth we tempt the heights of arts,
While from the bounded level of our mind,
Short views we take, nor see the lengths behind,
But more advancd, behold with strange surprise
New, distant scenes of endless science rise!
So pleasd at first, the towring Alps we try,
Mount oer the vales, and seem to tread the sky;
Th eternal snows appear already past,
And the first clouds and mountains seem the last;
But those attaind, we tremble to survey
The growing labours of the lengthend way,
Th increasing prospect tires our wandring eyes,
Hills peep oer hills, and Alps on Alps arise!
DBS is remarkable, and its promises for the future are great, as it is a new era in
the treatment of neurological and psychiatric disorders. But all too often, the potential of DBS is cut short by all too facile explanations presupposed by treatments of
the past that cannot begin to capture the complexity of DBS. Perhaps it would be far
better for everyone just to say we have no idea how DBS works and then to begin
with a clean slate. However desirable that might be, it is contrary to human nature.
The only prevention is to continual admonish ourselves to drink deeper, which only
happens when we are not easily satisfied.
This book is intended to drink deeper, and it will demonstrate that the thirst to
understand is far from being satisfied. What is thought to be known actually are
obstacles to truly knowing. Such statements will not make me popular particularly
with those whose careers have been devoted to claiming sure knowledge.
Difficult Questions
DBS is revolutionary and unlike any previous therapy. It represents a paradigm
shift, and as Thomas Kuhn (1963) beautifully described in his book, The Structure
of Scientific Revolutions, such paradigm shifts do not come easily. In Kuhns historical analysis, paradigm shifts come when the current paradigm fails increasingly
xii P reface
to explain accumulating observations. However, a tipping point is required before

current paradigms are overthrown, and often immediate successors must be waiting in the wings. Such a formula proves problematic for DBS as challenges to current paradigms are denied access to the marketplace of ideas and the questions
are continually framed in the old paradigm, making it difficult to demonstrate
their failings. Further, someone who says most of those about him are going in the
wrong direction are seldom sought out and given a voice. In the fable The Emperors
New Clothes (Hans Christian Anderson), the boy who noted the emperors nakedness was called a fool, grabbed, and taken away. Interestingly, the emperor kept
walking, not wanting to compound his foolishness by admitting it. Science does
not bury dead theories as no one wants to admit they once held them.
As befits its revolutionary nature, DBS raises a myriad of questions that are scientific, statistical, clinical, political, social, ethical, and moral. The enormity of
the issues calls for an analysis at a meta-level. It is not sufficient to know what the
observations or facts are but whether they really are facts and how is it that they
have come to be known. However, meta-cognition has never been popular or the
strong suit of scientists, even back to the days of the origin of the Royal Society, as
amply argued by Thomas Hobbs (Shapin and Schaffer 1985). Paraphrasing Claude
Bernard, called the father of modern physiology, we are more often fooled by things
we think we know than things we do not. What one often thinks they know are presumptions that find there ways into habits of thinking. As a caution, the words of
John Stuart Mill (2009) are recalled:I had learnt from experience that many false
opinions may be exchanged for true ones, without in the least altering the habits of
mind of which false opinions are made. One might think, then, that the place to
start is an analysis of what we think we know. This textbook addresses a subset of
important topics related to DBS. Experts in DBS may find the discussion provocative at times, but Ihope that they might also find it helpful.
Misunderstandings, confusion, and counterproductive recommendations
result from failing to recognize various demands and their particular contexts.
Discussions of DBS prove no exception in this respect. Virtually every set of guidelines written by experts, for example, includes criteria for the ideal or best DBS candidate, that is, the patient most likely to benefit from the therapy. Ideal candidates,
however, are not the population of most concern. Indeed, faithful application of
ideal-candidate criteria would end up eliminating from candidacy many patients
who stand to benefit from DBS and who otherwise face suboptimal alternatives.
Rather than identifying the ideal candidate, criteria ought to identify the patient
whose probability of improvement is the lowest acceptable. Some centers, for example, require that before being offered DBS a patient with Parkinsons disease show
at least a 30% improvement in the Unified Parkinson Disease Rating Scales following a levodopa challenge test. Yet application of this criterion would exclude many
patients whose postoperative improvement was shown to match, and in many cases
exceed, patients whose preoperative Unified Parkinson Disease Rating Scales demonstrated greater than 30% improvement (Charles etal. 2002).
This book seeks to challenge notions often taken for granted in order to encourage
the narrative with greater critical analysis. Such a challenge is not meant to call into
question the judgment of the many thoughtful and intelligent experts whose analyses and recommendations are critiqued herein. Indeed, considered in their historical context, those analyses and recommendations appear eminently reasonable. But
P reface xiii
though historical context may have changed, physicians, who tend not to be terribly
introspective, have not. For example, that which passes for meta-analysis in medicine
is typically summation of randomized controlled trials (RCTs) or other empirical
studies. At no point does one find evidence of higher order abstraction, which the
very term meta-analysis suggests. Neither a contrarian nor iconoclastic impulse
informs this writing. It is, rather, a plea for more meta-analytical thinking to inform
the empirical.
EPI ST EM O LO GY O F C L I N I CA L D EC I S I O N - M A K I N G
Epistemology is a domain of philosophical inquiry concerned with knowledgeits nature, validity, and methods of acquisition, particularly. The current vogue for Evidence-Based Medicine has served to increase epistemologys
importance. Evidence-Based medicine appears to judge the veracity of claims
treatment Aeffectively treats disease B, for exampleaccording to how they are
made. Claims inferred from RCTs tend to be deemed more credible than those
inferred from the results of uncontrolled trials. They are also esteemed over
observations drawn from clinical experience. A judgment made in the context
of Evidence-Based Medicine presumes the epistemological. The reason it is not
fully appreciated as such owes to the fact that current versions of Evidence-Based
Medicine simply affirm a synonymy with RCTs. Alternatives are neither entertained nor even recognized. Treating RCTs as the sole means of establishing
claims credibility thus moots any epistemic question that would arise by contrast
or challenge.
To claim that RCTs represent the only epistemologically valid source of knowledge risks an error of reasoning known as the fallacy of limited alternatives. One
may construct a number of approaches to justify a medical claim. These alternatives may include open-label studies and other clinical trials run without controls,
case series, case reports, and expert consensus. These alternatives may be found to
contain faults and for this reason be eliminated as justification for a claim, while
the faults or inherent limitations of RCTs go uncommented. Credibility thus falls to
the last option standing, which tends to be Evidence-Based Medicine. Yet the credibility of the sole remaining option ought not to depend on the faults that toppled
the others.
Evidence-Based Medicine, in its current invocation, depends primarily on RCTs.
Although RCTs may make statements as to a claims statistical significance (the
basis for confidence in a claim), they cannot establish its clinical meaningfulness.
For instance, an RCT may claim that the effect of treatment Aresults in a statistically significant greater change in some measure of disease B compared to placebos.
One ought not infer from this finding, however, that medicine A is an effective
treatment of disease B.To say that treatment Ais effective requires considerations
of risks, benefits, and issues of healthcare resource allocation, which RCTs are not
designed to answer (Montgomery and Turkstra 2003). Rather, RCTs require the
importation of knowledge, facts, and value judgments external to RCTs in order
to convert statistical significance to clinical meaningfulness. A novel analysis of
RCTs from the perspective of information-theoretic entropy and the Second Law of
Thermodynamics is presented in chapter15.
xiv P reface
The Unique Nature of Medical Decisions

Medical decisions require action. The decision whether to treat, for example, partly
depends on deciding whether a disease is in fact present. It is impossible for a disease to be slightly present, and it is therefore unreasonable to think that a slight
amount of treatment may be given. The decision is dichotomous, depending as it
does on a yes or no answer to its central question, and thus admits of a limited
set of alternatives (two in the present instance).
The dichotomous nature of the necessary decision belies the typically continuous data on which the decision relies. The magnitude of symptoms, for example,
may fall anywhere on a spectrum ranging from absent to maximum possible. Yet
deciding whether symptoms are severe enough to warrant DBS surgery requires
that one situate symptoms on one side or the other of a line dividing symptoms
which sufficiently warrant surgery from those that do not. Exceedingly few medical decisions admit of a simple and explicit calculus enabling one to define a cutoff
that effectively transforms a continuous variable to a dichotomous variable. For
example, one ought not to administer pure arsenic in any amount. Yet the same
does not hold true for arsenic compounds (Salvarsan), which before the advent of
antibiotics were used to treat syphilis (Lockhart and Atkinson 1919).
There are a number of approaches to establishing a cutoff for a dichotomous
medical decision. One approach involves basing the cutoff on a normal populations statistical properties, the abnormal side of the dichotomy based on difference from the mean (median) of an appropriately determined normal population
in terms of the variance of the normal population results (standard deviation).
For example, test result A may be considered abnormal if the value is greater
than two standard deviations from the mean of the normal population. Applying
this criterion is roughly analogous to using p < .05 as a cutoff for statistical significance in many, if not most, clinical studies. Yet doing so creates a situation
in which 4.55% of normal subjects taking test Aproduce results interpreted as
abnormal. Normal subjects producing abnormal results would be categorized as
false positives, while truly abnormal subjects who tested as normal would be categorized as false negatives. Such false results can have enormous consequences.
A large majority of medical decisions require a tradeoff between the rate of true
positive decisions and false positive decisions. The rate of true positive decisionsa
particular patients having disease B, for instancerelates to the sensitivity of the
diagnostic test. The rate of true negativespatients who test negative for a disease
they do not haverelates to the specificity. One may increase the sensitivity and
reduce the risk of false negatives, but so doing usually results in a loss of specificity
and greater rates of false positives. One may plot the effects of different cutoff on
the sensitivity and specificity by using logistic regression and plotting the Receiver
Operator Curve. One may then select the inflection point or another point on the
ReceiverOperator Curve and use as the cutoff the value of test Aassociated with
that point. Again, this cutoff is based on the statistical properties of the populations.
Determining the consequences of the false positive rate and false negative rate
is the most appropriate means of establishing a cutoff for the purpose of translating a continuous variable into a dichotomous variable, which allows one to make
a decision. In other words, there remains to be determined the cost, considered
in its widest connotation, associated with missing a diagnosis and thus failing to
P reface xv
provide the appropriate treatment as opposed to making an incorrect diagnosis

and thus providing unnecessary treatment (Montgomery and Turkstra 2003). This
cost is at once medical, sociological, psychological, political, economic, ethical, and
moral. It is unsurprising, then, to see that RCTs in themselves do not address the
consequences, which are critical for determining the clinical meaningfulness of the
inferences drawn from any RCT.
The n-of-One Problem

Population studiesstudies that report the mean and standard deviation of an
effect, such as a specific treatment on a sample of some number of subjectsface
the critical problem of implementing and applying the inferences drawn from the
sample to the individual patient (Montgomery and Turkstra 2003; Montgomery
2013). The task requires estimating the probability of the effect for the individual
patient. For example, a RCT involves patients who are given either experimental
medication Aor placebo. The effect on some measure of health, B, was determined.
In order to establish the probability of an individual patients responding to medication Ain some way distinct from a response to placebo, one must examine the
distribution of responses in both groups. There may be considerable separation in
the distributions of the measure of health B between those subjects who received
the placebo and those who received medication A. Thus it is clear that any subject receiving medication Awill show improvement in the measure of health B.Yet
there may be considerable overlap in the two measures. It remains unclear, therefore, whether a subject who may or may not be receiving medication Awill see an
improvement in the measure of health B.Often the situation is that there appears
some overlap, and the situation is consequently less clear.
Bayes Theorem
Virtually every medical decision is a form of diagnosis. A physician may have to
decide, for example, whether a particular patient has Parkinsons disease or Essential
tremor. The reverse also holds true:a therapeutic decision may be rephrased as a
diagnostic issue. For example, there are two groups of patients with disease B.The
first consists of patients who would benefit from treatment A, and the second of
patients who would not. Anew patient appears to have disease B, and the diagnosing clinician must decide whether she belongs with the first or second group. As
this example demonstrates, rephrasing treatment decisions as diagnostic questions
allows one to apply to questions of treatment diagnostic tools and modes of thinking.
Most diagnoses are based on a set of criteria that typically consists of the symptoms and signs associated with a single diagnostic category or some number of categories. A patients meeting these criteria is considered tantamount to her having
the disease. Criteria for DBS surgery candidates are held in much the same regard.
Patients whose diseases meet selection criteria fall under the diagnostic category of
patients who enjoy a reasonable chance of benefiting from DBS. One may evaluate
DBS selection criteria in much the same way as one evaluates diagnostic criteria
according to specificity and sensitivity. Sensitivity, for example, would depend on
xvi P reface
the probability that a patient who meets the selection criteria would respond well
to DBS and specificity on the probability that a patient would respond poorly. Yet
consideration of specificity and sensitivity remains insufficient.
To consideration of specificity and sensitivity must be added consideration of
prior probabilities. In typical diagnostic tests, prior probability rests on the prevalence of the disease in the population of concern. For example, a test for Parkinsons
disease diagnosis, which is 97% specific and 97% sensitive, is applied to a population of persons over the age of 65, because it is understood that Parkinsons disease
is more likely in older subjects. If one assumes that the prevalence of Parkinsons
disease in this population is 3%, then the diagnostic test would result in as many
false positive diagnoses as true positive diagnoses and as many false negatives
and true negatives. If the prior probability (or prevalence) of Parkinsons disease
were higher, however, then the number of true positives diagnoses would exceed
the number of false positives and, similarly, the numbers of true negatives would
exceed the number of the false negatives (Montgomery 2013).
Application of Bayes theorem allows one to appreciate the role played by prior
probabilities in diagnosis. The diagnosis that a patient who meets the selection criteria (SC+) enjoys a reasonable chance of DBS benefit (P(DBS+)) corresponds to the
following formula, which is expressed in terms of Bayes theorem,
P(DBS+|SC+)=(P(SC+|DBS+)*P(DBS+))/P(SC+)
where P(SC+|DBS+) is the probability that someone responding well to DBS meets
the criteria, P(DBS+) the probability that any appropriately diagnosed patient will
respond well to DBS, and P(SC+) the probability that any appropriately diagnosed
patient will meet the selection criteria.
P(DBS+|SC+) represents the positive predictive value of the selection criteria.
Again, this prediction value is incomplete, because one must also consider the
negative predictive value, which is given by P(DBS|SC) and indicates the probability of a poor DBS outcome for the subject who fails to meet the selection criteria.
Like the positive predictive value, the negative predictive value may be determined
according to the following formula:
P(DBS|SC)=(P(SC|DBS) P(DBS))/P(SC)
where P(SC|DBS) is the probability that those subjects whose DBS outcome was
poor would not have met the selection criteria, P(DBS) is probability of a poor DBS
outcome irrespective of selection criteria, and P(SC) the probability of a possible
DBS candidate population selection criterias going unmet by a particular patient.
The goal behind any selection criterion is to determine P(DBS+|SC+), which
indicates the probability of a beneficial DBS response. In certain circumstances
the important issue becomes the negative prediction P(DBS|SC). If, for example,
DBS carried no risks but refusing a patient DBS did carry substantial ones, then the
negative prediction may be more important.
A concern arises when P(DBS+|SC+) does not equal P(DBS+), in which case
there would be patients who would benefit from DBS who do not meet the selection criteria. From use of the selection criteria would thus follow the consequence
of some patients being inappropriately denied DBS benefit. Whether P(DBS+|SC+)
P reface xvii
does not equal P(DBS+) depends on P(SC+), which is the measure of how frequently patients in the population of concern meet the selection criteria, and on
P(SC+|DBS+), which indicates the probability that patients who underwent DBS
without being submitted to selection criteria would retrospectively have been
shown to have met them. Because no study has been made to discover the value permitting the determination of P(SC+|DBS+), it remains unknown. Merely assuming
that P(DBS+|SC+) equals P(DBS+) is a mistake, if not an injustice and patients who
would benefit may be denied. Assuming that P(DBS|SC) does not equal P(DBS)
represents much the same issue, namely, whether falling short of the selection criteria amounts to guaranteed failure to realized benefit from DBS.
Though one may lack all the probabilities necessary for a complete determination of Bayes theorem, the theorem itself remains critical. Indeed, exercise of
sound clinical wisdom requires that clinicians offer some expert estimate, through
application of the appropriate RCTs or other means, of those probabilities which
are not explicitly known. Though Imay not always explicitly apply Bayes theorem,
Iwill employ Bayesian reasoning throughout the discussion to follow.
S O U N D E T H I C S, SO U N D M ED I C I N E
The discussion here makes clear that a specific selection criteria may fail to identify
all those patients who may benefit from DBS, as well as and all those who may not.
The actual selection criteria, moreover, consist of continuous variables, whereas
a decision represents the imposition of dichotomous categories. There is thus no
objective way to determine where may lie the cutoff that divides and sorts continuous variables into dichotomous categories. Rather than emerging from RCTs, the
appropriate cutoff value results from the application of information, knowledge,
wisdom, and value judgments external to RCTs.
The problem of constructing the cutoff admits of at least two solutions. The first
solution is that of an arbitrary decision explicitly or implicitly made. Merely transferring the enrollment criteria for patients with Parkinsons disease used in RCTs
to general practice is an example of an implicit arbitrary cutoff. Though the current
vogue for Evidence-Based Medicine certainly makes it appear reasonable, such a
transfer contains an element of solipsism, because it rests on an assumption that
RCTs represent the sole route to clinical knowledge and therefore the sole basis for
legitimate medical action. To act on this assumption would be to ignore serious
inherent limitations that render RCTs, in themselves incapable of informing medical decisions. In other words, RCTs, considered in isolation, offer no information
about clinical meaningfulness. Indeed, the enrollment criteria for RCTs may prove
counterproductive. They often delay or deny DBS treatment. This holds especially
true in cases of Parkinsons disease (see chapter4).
Defining as contractual the cutoff suggested by a specific selection criterion represents a second approach. By contractual one is to understand a patients acceptance of the extent and limits of the care responsible organizations (physicians,
healthcare providers, insurers, governmental agencies) are willing to provide. No
justification beyond commercial or political interest exists for this approach. In
order for patients to secure their interests they must be able to negotiate on the
basis of sufficient knowledge, and sufficient knowledge requires that a high degree
xviii P reface
of transparency characterize the proceedings. Rarely, however, do patients have

knowledge sufficient for negotiating their interests. Indeed, expecting them to have
it is unreasonable; patients presume that the loyalty of their physicians and healthcare professionals lies first and foremost with them.
The requisite transparency cuts two ways. In order to practice wisely, physicians
and healthcare professionals must understand the epistemic basis for the decisions
they must make.
Patients negotiate their interests from a disadvantageous position if their counterparties lack sufficient knowledge. Negotiations made under such conditions may
be said to have been made in bad faith.
Recognizing that most current medical decisions are ethical decisions represents
yet another approach. Admittedly, many conditions are untreatable but manageable. Little is at stake in negotiations turning on care of these. Remarkable advances
in medicine, however, have led to the development of many treatments whose
implementation lies beyond the capability of current healthcare delivery systems
to provide. Whether this situation was intended is debatable. Suffice it to say that
in cases in which a treatment exceeds a systems capabilities, responsible physicians
and healthcare professionals face an ethical decision, which they must acknowledge
as such. For example, say a physician fails to keep abreast of the state of the art in
treatment yet refuses to refer a patient to another physician who has kept abreast.
Has this first physician engaged in unethical behavior? These issues are addressed
more fully in chapter19.
Ethics involves the search for practical solutions to moral problems. Whereas
morality addresses issues of right or wrong, ethics addresses the navigation of the
particulars of right and wrong action. Whether healthcare is a privilege or a right is
a moral question in medicine. If it is a privilege then it is negotiable, but it is not if
it is a right, natural or legal. In a sense, laws define some ethical norms. Yet not all
laws reveal themselves as compatible with every moral system. What, then, is to be
done? Reconciling ethics to morality proves difficult in a pluralistic society. In order
to overcome this difficulty, an attempt may be made to define the common morality,
that is, the system of principles that every moral person ought to uphold (Beauchamp
and Childress 2013). These principles are beneficence, nonmalfeasance, autonomy,
and justice. Various discussions of DBS presume that these principles are in force.
In c hapter19 and elsewhere these ethical issues will surface. They factor in the
decision as to whether a patients symptoms have become severe enough to warrant
DBS, whether this assessment rests with the patient suffering the symptoms or the
physician treating her, whether the impact of these symptoms on quality of life is
better determined by a patient or her treating physician, whether leaving this determination to the patient (or her legal surrogate) effectively forces the physician to
do harm, and whether denying a patient DBS is justified by the healthcare systems
inability to provide it.
I M P O R TA N C E O F M E TA- R EFL ECT I O N
Epistemology of medical decisions involves meta-reflection, that is, the mental act by which one assimilates facts or knowledge to an understanding of their
origin and their proximal and antecedent causes. For example, the knowledge
P reface xix
that Parkinsons disease, at least its motoric symptoms, is a dopamine deficiency

is derived from three proximate facts:(1)patient with Parkinsons disease have a
deficiency of dopamine in certain regions of the brain, and this is consequent to
degeneration of dopamine neurons of the substantia nigra pars compacta; (2)the
findings in humans with Parkinsons disease can be replicated in laboratory animals by lesioning (destroying) the animals dopamine neurons; and (3)dopamine
replacement in humans with Parkinsons disease and parkinsonian laboratory animals improves the motoric symptoms. The knowledge following from these three
proximate facts, however, is false. One need simply adopt a broader perspective to
see that this is so.
It is not that the aforementioned facts, which support the knowledge that
Parkinsons disease is a dopamine deficiency, are incorrect. The problem lies with
ignoring facts that argue against the inference in favor of facts that support the
inference that Parkinsons disease is dopamine deficiency (Confirmation Bias). For
example, replacing dopamine by medications or fetal cell transplantation does little
or nothing to improve the symptoms of patients with advanced Parkinsons disease. Technological limitations and other factors may explain the failure of fetal cell
transplantation. Yet the failure may be a failure to recognize that simply replacing
dopamine is insufficient, which is tantamount to attempting to repair a computer
by opening it and tossing in a handful of transistors. A computers proper function
does of course depend on transistors, but it would be mistaken to suggest that a
computer malfunction owes to deficiency of them.
The question as to why the notion that Parkinsons disease is a dopamine deficiency achieved preeminence over other theories of equal explanatory power finds
an answer in historical antecedents that created a context in which the former
notion would flourish and alternatives ignored.
T H E ST R U CT U R E O F T H E B O O K
The majority of this book deals with specific clinical indications for DBS. Ihope
readers will find it a valuable tool in the management of their patients. Most of the
chapters are designed to stand alone. Common elements obtain among movement
and psychiatric disorders. Thus there may be considerable redundancy across
chapters discussing selection criteria for other DBS indications. This redundancy
was made necessary by the expectation that readers may return to specific chapters as their needs demand. Idid not want the reader to have to read other chapters that contained discussions relevant to the chapter on the specific issue. For
that reason, the redundancy was retained, with due apologies to the reader.
AC K N OW L ED G M EN TS
I want to thank the professors at the Department of Philosophy at Washington

University in Saint Louis between 1980 and 1990 who put up with the presence
of a young assistant professor of neurology in their graduate seminars. The experience was grueling and demanding (in some ways more difficult than medical
school) but exhilarating. While fanning the flames of intellectual curiosity, the
xx P reface
professors also imparted discipline and an obligation and loyalty to truth, however defined. Ialso had the privilege and pleasure of many conversations with
Dr.Joseph Fins, a renowned bioethicist at Weil College of Medicine in NewYork.
I also want to acknowledge Erwin B. Montgomery III, Ph.D., without whose
editorial assistance this writing would be largely incomprehensible, and FHC, Inc.
which provided unrestricted funds to support the editing.
R EFER EN C ES
American Board of Psychiatry and Neurology. Certification Examination in Neurology
2013 Content Blueprint. Buffalo Grove, IL: American Board of Psychiatry and
Neurology, 2012.
Beauchamp TL, Childress JR. Principles of Biomedical Ethics. New York: Oxford
University Press; 2013.
Charles PD, Van Blercom N, Krack P, etal. Predictors of effective bilateral subthalamic
nucleus stimulation for PD. Neurology 2002;59(6):932934.
Cooper IS, Upton AR, Amin I. Reversibility of chronic neurologic deficits: some
effects of electrical stimulation of the thalamus and internal capsule in man. Appl
Neurophysiol. 1980;43(35):244258.
Dieckmann G. Chronic mediothalamic stimulation for control of phobias. In:Hitchcock
ER Jr., Ballantine HT, Meyerson MBA, eds. Modern Concepts in Psychiatric Surgery.
Amsterdam:Elsevier; 1979:8593.
Kuhn TS. The Structure of Scientific Revolutions. Chicago:University of Chicago Press;
1963.
Lockhart WT, Atkinson JR. Administration of arsenic in syphilis. Can Med Assoc J.
1919;9(2):129135.
Mill JS. Autobiography. Miami:Seven Treasures Publications; 2009.
Montgomery EB Jr., Turkstra LS. Evidenced based medicine:lets be reasonable. J Med
Speech Lang Pathol. 2003;11:ixxii.
Montgomery EB Jr. Predictors of Parkinsons diseasenot quite sound. Mov Disord.
2013;28(4):413415.
Pope, Alexander. An Essay on Criticism. London:n.p.; 1711.
American Board of Psychiatry & Neurology, Neurology Core Competencies Outline
http://www.abpn.com/downloads/core_comp_outlines/2011_core_N_MREE.
pdf Shapin S, Schaffer S. Leviathan and the Air-Pump: Hobbes, Boyle, and the
Experimental Life. Princeton, NJ:Princeton University Press; 1985.
What Is Deep Brain Stimulation?
The most revolutionary treatment for neurological and psychiatric disorders to

come along in centuries, Deep Brain Stimulation (DBS) is to date the most important research tool for understanding the physiology and pathophysiology of the
human brain, at least as far as motor control is concerned. In light of the pace of
neurotechnological (in contradistinction to neuroscientific) development, this
seems a bold statement. Remarkable examples of neurotechnology include functional Magnetic Resonance Imaging (fMRI) and genetic manipulation. Yet many
false or counterproductive presumptions and assumptions currently constraining neuroscience have prevented the deployment of these latter neurotechnologies
(Montgomery 2012).
Clinically speaking, DBS is the most powerful tool for controlling the symptoms
and disabilities associated with neurological and psychiatric disease. Indeed, it is
more powerful than pharmacological agents or ablative neurosurgery. In the few
head-to-head comparisons of Parkinsons disease and other movement disorders
that make use of Evidence-Based Medicine randomized control trials, DBS is the
best in terms of greatest long-term efficacy and fewest long-term adverse effects
(see c hapter3). Besides randomized control trials, however, there are other sources
of medical knowledge and understanding that most reasonable individuals would
consider compelling (Montgomery and Turkstra 2003). Early clinical trials of DBS,
which for reasons of technical and ethical difficulties were not controlled in the
sense of being blinded, included subjects whose selection was determined by failure,
despite treatment by capable physicians, of aggressive pharmacological alternative
therapies primarily. In these subjects DBS successfully controlled their movement.
In fact, DBS succeeds where brain transplant (fetal cell transplants in treatment
of Parkinsons disease, for example) fails (Olanow etal. 2003). The improvement
provided by DBS to date is greater than that provided by gene therapies aimed at
reversing the neurotransmitter mechanisms of subthalamic nucleus neurons.
The United States Food and Drug Administration (FDA) has approved
DBS for treatment of Essential tremor and Parkinsons disease and granted it a
Humanitarian Device Exemption for treatment of Obsessive Compulsive Disorder
and Primary Dystonia. The exemption rests on the notion that, because fewer
than 4,000 patients with each of these disorders were expected to be treated in
a years time, prospective randomized control trials would prove problematic to
conduct. The absence of the normal vetting requiring demonstration of safety and
efficacy by sufficiently powered randomized control trials led the FDA to require
2
2 0 T hings to K now A bout D eep B rain S timulation
Institutional Review Board (IRB) supervision for obtaining informed consent. For
DBS in treatment of Obsessive-Compulsive Disorder, the IRB must approve the
purchase of devices from manufacturers, because the lead used is unique. The same
FDA-approved, commercially available device for treating Parkinsons disease and
Essential tremor may be used for dystonia. Surgeons may elect to use the device
as an off-label indication, or they may seek IRB approval for its use as labeled for
dystonia. The second course makes it easier for manufacturers to document and
number the cases of DBS surgery for indications approved under the Humanitarian
Device Exemption.
I consider DBS a standard and accepted (off-label) therapy for cerebellar outflow
tremor, Tourettes syndrome, dystonia of any cause, and hyperkinetic disorders of
any etiology. In multiple sclerosis and a wide variety of other disorders, cerebellar
outflow tremor has been shown to respond to DBS in the vicinity of the thalamus
(Montgomery 2008). Similarly responsive are hyperkinetic disorders, such as those
that arise from Huntingtons disease, chorea-acanthocytosis, and tardive dyskinesia (Montgomery 2004). These observations support the notion that DBS therapy
is symptom-based rather than disease-based. As such, they carry important
implications. A diseased-based treatment has the expectation that the safety and
efficacy for every possible disease indication be established. Doing so would prove
extremely problematic in treatment of rare disorders. If DBS is considered a symptom-based therapy, however, then one simply needs to demonstrate its safety and
efficacy relative to the symptoms (see more extensive discussion in chapter 15).
Pain medication trials offer a useful analogy: every possible cause of pain does not
require its own prospective clinical trial.
Clinical trials are underway for a wide range of neurological and psychiatric
disorders, including epilepsy, depression, and Alzheimers disease. Indeed, which
neurological and psychiatric disorders one may deem beforehand as inappropriate
for DBS is unclear. It is a greatly underappreciated fact that the brain is basically a
device that processes and transmits information electrically. Neurotransmitters are
simply messengers between neurons; they are not the message itself. The information transmitted does involve precise and pulsatile release of a neurotransmitter
from the presynaptic neuron and the pulsatile change in membrane potential in the
postsynaptic neuron, but the pattern of neurotransmitter release is determined in
large part by the pattern of action potentials descending to the synaptic terminals.
The processing of information in the postsynaptic neuron is based on the integration of membrane electrical potential changes induced by neurotransmitters. Yet
the information, again, is integrated and processed electronically. Saying that a
neurotransmitter has a specific behavioral function amounts to saying that an electron moving in a computer determines the function of the computer; for example
the electron is responsible for googling. Precise control of the dynamics of electron flows, rather, accounts for the power of the computer. Additionally, the notion
that behavioral functions may be attributed to a neurotransmitter falls victim to an
error in reasoning known as the Mereological fallacy, in which the function of the
whole is ascribed to a part.
DBS research is demonstrating that many, if not most, neurological disorders
(and likely psychiatric disorders) result from misinformation (Montgomery and
Gale 2008)rather than from a structures relative overactivity or underactivity, or
from the relative overabundance or paucity of a neurotransmitter or a particular
1. What Is Deep Brain Stimulation?3
oscillation in local field potentials. These latter approaches reflect a one-dimensional

pushpull approach to physiology and pathophysiology that is incorrect, its intuitive appeal notwithstanding (Montgomery 2012).
Despite DBSs remarkable effectiveness, little is known about its mechanism
of action. Though there has been an increase in information concerning the way
in which the brain and its elements at varying levels of organization respond to
the DBS electrical pulse, a cogent unifying understanding has yet to coalesce.
DBS-related research clearly challenges long-held notions of physiology and pathophysiology (discussed in c hapter18). As will be discussed later, current pathophysiological theories and, more fundamentally, physiology contribute significantly to
the failure in understanding of DBS mechanisms of action. It is insufficient merely
to state that most current theories are incorrect in their implications for the DBS
mechanisms, because the same assumptions and presumptions underlying the current theories are likely to hamper any new theory or, at least, any serious entertainment of competing alternatives.
T H E M EC H A N I C S O F D EEP B R A I N ST I M U L AT I O N
DBS involves the implantation of electrical stimulating electrodes in various regions

of the brain. Electrical stimulation of the spinal cord and peripheral and cranial
nerves is also performed for neurological and psychiatric disorders. DBS specifically relates to stimulation of the brain and brainstem. DBS is often considered a
specific example of neuromodulation, which includes the other forms of simulation
previously mentioned. The designation deep in Deep Brain Stimulation reflects
the fact that the therapys original targets were subcortical. Though such cortical
structures as the subgenu cingulum and motor cortex subsequently became potential targets, their stimulation is nonetheless subsumed under DBS.
Current DBS involves inserting a long lead through an incision in a patients
scalp and burr hole in the skull to reach a target in the brain. One example of a
DBS lead is a long insulated bundle of wires sporting four metal electrical contacts
placed in a row along the long axis of the lead (Figure 1.1). Separated from its fellows by 1.5mm, each contact measures approximately 1.27mm in diameter and
1.5mm in length. (Note that other DBS leads may have closer spacing, but these
are not recommended; Montgomery 2010.) The other end of the DBS lead exits the
burr hole and is connected to an extension wire behind the ear. The extension wire
travels beneath the skin to connect to the subcutaneously implanted pulse generator situated over the chest. The system is capable of a wide variety of stimulation
patterns and strengths that are programmed by a telemetric-like device.
Targeting the brain structure to be stimulated is complex (Montgomery 2014). It
is a process that usually begins with an MRI or computerized tomography scan of
the patients head. Because exact targets tend not to be visually discernible, surrogates are detected, such as the anterior and posterior commissures and the line that
connects them (ACPC line; Figure 1.2). One approach to subsequently identifying
the potential DBS target is to measure specific distances from the anterior-posterior,
medial-lateral, and dorsal-ventral from the midpoint of the AC-PC line.
Though there is some disagreement, most experts believe that image-guided
(MRI or computerized tomography) surgical navigation is insufficient for two
4
Electrical contacts
Figure1.1 The DBS lead demonstrating the four electrical contacts. Also, a sagittal
section of an MRI scan showing a DBS lead placed in the vicinity of the subthalamic
nucleus.
reasons: (1) normal biological variability in the optimal targets exact anatomical locations and (2)increased variability (error or brain shift) introduced by the
surgery itself. In frequent use, microelectrode recording of neuronal extracellular action potentials locates the optimal target prior to implantation of the DBS
lead. This is particularly important because the targets are physiological rather
than anatomical. For example, the sensimotor region within the ventral intermediate nucleus of the thalamus, subthalamic nucleus, and globus pallidus interna
is believed to be the optimal target. Though the ability of anatomy-based visual
targeting systems to identify the sensorimotor region is uncertain, the ability of
microelectrode recordings is not.
In the United States, the FDA regulates the interstate commerce of such devices as
the DBS system. It has yet to regulate, however, the manner in which DBS surgery is
performed and prerequisite training of those performing it. The administrations of
institutions where DBS surgery takes place grant privileges and credentials at their
discretion to surgeons. Because not many people within these institutions are able
to conduct a critical review without requesting such a privilege from physicians,

A
AC
PC
Figure1.2 Panel Ademonstrates an axial MRI scan. The white indicates one of the
white dots, which are fiducials in the external frame (shown schematically in B). As
indicated, the frame is held in place by four pins that insert into the outer table of the
skull. Also seen are the anterior commissure (AC) and the posterior commissure (PC).
Often the targets for DBS are mapped by their distance from the midpoint of a line that
connects the AC and PC. There are frameless alternatives (see Montgomery 2014).
administrations often find themselves granting privileges and credentials to surgeons on the basis of the surgeons good word alone; however, these surgeons often
have an inherent conflict of interest. Not a few institutions have become embroiled
in this conflict.
An interesting ethical issue is the nature, limit, and extent of the responsibility borne by a physician referring a patient to a neurosurgeon. In the absence of
an effective vetting process for surgeons, does the responsibility fall on a referring
physician to ensure a surgeons competence? It certainly squares with a neurologists expertise to form some professional opinion of a surgeon receiving a referral.
Balkanization of health care providers further complicates this issue. They resolve
into veritable fiefdoms. Questioning the ability of any fiefdoms surgeon may thus
be greeted with annoyance, if not an act of defiance. These issues are addressed in
chapter19.
Some general parameters enable one to judge a DBS program. The incidence of
any infection around the implanted DBS system should be 4% or less; the risk of
an infection necessitating removal of the DBS lead, 2% or less; the risk of serious or
permanent complications, 2% or less; the frequency of DBS lead revision in response
to poor outcome, 2% or less; and the risk of death, 0.2% to 0.5%. The average degree
of improvement depends on the condition being treated and the measures taken to
treat it. Treatment of Parkinsons disease should result in a 50% or greater improvement in the Unified Parkinson Disease Rating Scales and a 50% or greater reduction in medication use in the case of DBS in the vicinity of the subthalamic nucleus.
Note that the terminology DBS in the vicinity of the subthalamic nucleus is used
6
instead of STN DBS or DBS of the subthalamic nucleus. The term in the vicinity
is used to note that DBS in the vicinity of the subthalamic nucleus does not imply
that the therapeutic effects as well as adverse effects arise from activations of neurons in the subthalamic nucleus. Indeed, there is considerable evidence that it does
not (Montgomery and Gale 2008). Unfortunately, there is the widespread notion
that the efficacy of DBS in the vicinity of subthalamic nucleus is synonymous with
change in subthalamic nucleus neuronal activities, which may well be incorrect.
The mistake is perpetuated by using the synecdoche, subthalamic nucleus DBS.
D EEP B R A I N ST I M U L AT I O N I S N OT A
N EU R O S U R G I CA LT R E AT M EN T
No matter the condition, DBSs efficiency rarely begins with the implantation of
the DBS system. Rather, it beginsand indeed depends oneffective postoperative management of DBS devices, medications, and behavioral therapies. Accurate
placement by expert neurosurgeons, however, does facilitate desirable outcomes.
Appropriate patient selection also facilitates desirable outcomes. Most current
indications, as well as those expected in the near future, require as a major selection criterion exhaustion of all reasonable pharmacological and behavioral therapies (if appropriate). In the case of movement disorders, most neurosurgeons lack
the training or experience necessary for determining whether this criterion has
been met. Itherefore believe that movement disorders neurologists and psychiatrists experienced in DBS should have the primary responsibility for vetting DBS
candidates. Other criteria do exist, such as an ability to tolerate the surgery and the
presence of preexisting psychological issues. These criteria necessitate the participation of neurosurgeons, healthcare professionals, and, depending on the circumstances, psychiatrists.
The most effective outcomes depend on balancing pharmacological and behavioral therapies, which often patients may have begun prior to surgery, with their
DBS. Most patients continue their preoperative medications, which have a synergistic effect with the DBS. In most cases, then, optimal care is typically achieved
by managing both DBS and medications or managing behavioral therapies. This
is particularly true in Parkinsons disease. Optimal postoperative outcomes will
require not only accurate placement of the DBS lead and knowledge of programming but also expertise in pharmacological and behavioral therapies (Montgomery
2010).
Effective DBS is a team effort; each physician, surgeon, and healthcare professional plays a role. The outcome is less assured should team discipline experience
any lapses. Indeed, one may argue that a fully functioning team, which includes
those members assigned postoperative management, is a necessary prerequisite.
Without such a team assembled, therefore, proceeding with DBS surgery may well
be unethical. Yet assembling such a team may prove problematic in the face of a
paucity of neurologists and psychiatrists trained in postoperative DBS management and particularly in areas remote from the major medical centers that typically
implant DBS systems. Many misunderstandings have prevented more physicians
from involving themselves in postoperative care, particularly those previously
uninvolved in the surgery itself or preoperative patient selection (Montgomery
2010). Efforts are underway to develop Internet-based postoperative care methods

that use approaches characteristic of automated expert systems and telemedicine.
Lack of federal jurisdiction over Internet-based and telemedicine services, however, hinders these efforts, and the current patchwork of state jurisdictions, many
of which are insufficiently developed, is the result.
T H E I N V ER S E PA N D O R AS B OX O F
D EEP B R A I N ST I M U L AT I O N
The goddess of Greek mythology Pandora received a beautiful box that she was
instructed to leave unopened. She violated this command and in so doing released
all sorts of evil into the world. In the box also was hope, and it was the last thing
to escape. DBS represents something of the inverse of Pandoras box:Hope was
first to issue from it, and various evils followed. The evils in this case are the
current healthcare systems various limitations, which challenge the capacity to
provide DBS therapy. Identifying the limitations proves awkward. It used to be
said in medicine, If you do not want to treat the disease, dont do the test. At
least in some cases, making the diagnosis carries with it an obligation to treat the
disease. One wonders whether the professional community truly wants to know
the nature of the problems plaguing healthcare delivery systems when it comes
to providing DBS.
Though the exact numbers are unknown, some 15% of patients with Parkinsons
disease are suitable for DBS, and a mere 1% of DBS-suitable patients receive it.
Patients and their family members and caregivers commonly complain of the
long delay that often precedes DBS recommendations from physicians. Few would
disagree with the claim that DBS is underused in treating even those indications
approved by the FDA and other countries equivalent agencies. In human terms,
this underuse means patient suffering, much of it perhaps unnecessary. As such,
it raises the question whether of healthcare provider systems are obliged to change
this situation.
A particularly vexing issue is that of using FDA-approved devices for indications
on which the FDA has not ventured an opinion. As Carl Sagan was said to observed,
The absence of data is not evidence of absence. Similarly, the absence of an opinion by the FDA is not a negative opinion on its use, and it therefore has no bearing
on issues of safety and efficacy of an approved devices use. Nor does it stand as evidence that safety and efficacy does not exist either. On its website, the FDA defines its
policies governing off-label use under the title Off-Label and Investigational Use
of Marketed Drugs, Biologics, and Medical DevicesInformation Sheet:Guidance
for Institutional Review Boards and Clinical Investigators:
Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best
knowledge and judgment. If physicians use a product for an indication not in
the approved labeling, they have the responsibility to be well informed about
the product, to base its use on firm scientific rationale and on sound medical
evidence, and to maintain records of the products use and effects. Use of a
marketed product in this manner when the intent is the practice of medicine
8
does not require the submission of an Investigational New Drug Application

(IND), Investigational Device Exemption (IDE) or review by an Institutional
Review Board (IRB) [italics added]. However, the institution at which the product will be used may, under its own authority, require IRB review or other
institutional oversight.
The FDA does grant Investigational Device Exemptions to physicians who intend
to offer such off-label use to a number of patients. The fact that these exemptions
impose a cap, however, creates difficulty in providing continued care once the cap
is reached. Insurers, moreover, may refuse to reimburse healthcare providers on
the basis of the experimental nature of the proposed use, citing the Investigational
Device Exemption as justification. Acursory review of the literature reveals that,
though DBS is safe and effective for a wide variety of disorders, it has yet to receive
FDA approval for treating them. Chances are it never will. Asituation involving
an extremely rare disorder presents a useful illustration. In the treatment of this
disorder, prospective randomized control trials, as demanded by Evidence-Based
Medicine, are unfeasible. Yet most would consider lack of feasibility an inappropriate justification for denying the patient the treatment. Such is the case with DBS.
This issue is discussed at length in the context of DBS for hyperkinetic disorders
(chapter15).
Patients and their family members and caregivers may be willing to travel to a
distant major medical center to have a DBS system implanted, but traveling that
same distance repeatedly to obtain appropriate postoperative management is inordinately burdensome. Yet postoperative management brings the benefits that justify the surgical risk. Imagine this same patient is admitted to a local emergency
room, whose staff are unfamiliar with DBS and its management. What will become
of him? Interestingly, no mention of Deep Brain Stimulation or DBS is made in
the Content Blueprint 2013 published by the American Board of Neurology and
Psychiatry (2012) for the education of future neurologists.
S O M E E T H I CA L I S S U ES
As demonstrated, most of the issues related to DBS have little to do with the technology or knowledge base. The indications for DBS discussed in this textbook
are either FDA approved or are considered appropriate off-label indications for
FDA-approved devices, with the latter supported by substantial scientific and clinical data. Rather, the most vexing questions are how to judge the knowledge thus
far gained in order to make decisions relative to the provision of DBS. Whether
or not the data supports the use of DBS for a specific indication is a judgment call.
Whether a particular patient has symptoms sufficient to warrant consideration of
DBS is a judgment call. Invariably, these questions are decided based on value judgments and value judgments invariably depend on ethical and moral stances. Thus
to render a considered judgment requires addressing the ethical issues.
Clinicians must note the difference between those treatments that are most powerful and those that are simply sufficient. Considerable evidence supports the finding that DBS is more powerful than levodopa and other dopaminergic agonists
in treating greatly advanced cases of Parkinsons disease. In many patients with
Parkinsons disease, pharmacological therapies had proven insufficient but DBS

helped. Levodopa and other pharmacological agents may be sufficient in providing satisfactory relief from the symptoms and disabilities of Parkinsons disease.
In these cases, associated costs (in its widest connotation) rather than power to
reverse symptoms and disabilities governed the choice of therapy. Though serious
or persistent (irreversible) adverse effects are rare in DBSestimated to be 3% to
5%their consequences can be severe. If two alternative treatments are equally
sufficient, the option with the least risk and cost, understood in their widest sense,
thus becomes the first choice. In the diseases early stages at least, risk and cost
analyses favor pharmacological and behavioral therapies.
The notion of sufficiency as a guide for therapeutic options is problematic if for
no other reason than its epistemological basis. The explicit or implicit means to
determine sufficiency form this basis. The issue becomes, then, that of identifying the individual who has the authority and right to judge. Many, if not most,
clinicians would be shocked merely by having this issue raised. As gatekeepers to
treatment options, physicians and healthcare professionals may base their medical
opinions on certain assumptions and presuppositions that may be incompatible or
at least inconsistent with those of patients or their legal representatives. At the very
least, this situation would require that physicians and healthcare professionals recognize the range of options and have knowledge sufficient for presenting it. These
issues are addressed in detail in chapter19. Indeed, this purpose of this book is to
enable meaningful discussion of the DBS option between physicians and healthcare professionals and patients and their family members and caregivers.
Meeting this obligation is challenging because of the question: who owns the
right to decide whether patients receive DBS? Does the right belong to patients and
patients family members or caregivers, or does it belong to physicians or healthcare
professionals? The relationship between physicians and healthcare professionals on
one side and patients and patients family members and caregivers on the other
naturally admits of asymmetry. Members of the lay group likely do not have the
education and experience necessary for adjudicating options. To expect them to
have this education and experience is unfair. Yet the bedrock of informed consent is
respect for the decision of patients or their legal representatives. Informed consent
also requires that patients or their legal representatives be provided with sufficient
information on all available options. One may argue that failing to discuss alternatives with a patient invalidates her informed consent. A physician or healthcare
professional treating a patient whose informed consent has thus been invalidated
may be guilty of battery.
The wide discretion historically afforded to a patient and legal representative
is contextual; it depends on the risksthose faced by a patient, as well as those
faced by a physician or healthcare professional (the latter arguably represent the
most important practical reasons for signed informed consent). However, in todays
healthcare delivery climate, such discretion often produces economic effects or creates risks. Physicians and healthcare professionals often assume these economic
risks. Their doing so may appear ethically suspect, inasmuch as it represents a conflict of interest.
For practical purposes, one may cast the risk-to-benefit ratio as an analysis of cost
effectiveness, the acceptance of risks representing the cost function. Representing
benefit is effectiveness, that is, the degree of improvement from the therapy typically
10
in terms of relief from symptoms and disabilities, while cost is that which is paid
in order to realize the benefit. The cost acceptable for gaining a potential of benefit is a value judgment. Properly posed, the question is whether physicians and
healthcare professionals are in a better position to determine the amount a patient
or his family member or caregiver will pay in order to gain relief. Physicians and
healthcare professionals have no way of determining a sufficient degree of relief and
the amount patients or their family members and caregivers will pay to realize it.
D EEP B R A I N ST I M U L AT I O N I S R E VO LU T I O N A RY
DBS is revolutionary primarily because of those things it does not do. DBS does
not directly or primarily target neurotransmitter functions that underlie most
pharmacological therapies. Consequently, it is not primarily a means of affecting
neurotransmitter function. Indeed, it is quite probable that the main, or at least
proximal, effect of DBS is that of generating antidromic action potentials, which
affect the excitability of the neuron that gave rise to the axon conducting the antidromic action potential. In so doing, it bypasses neurotransmitters altogether
(Montgomery 2013). Yet, as described previously, neurotransmitters are the messengers; they are not the message. The message is contained in the pulsatile pattern
of neurotransmitter release, which is determined by the pattern or electronic neuronal action potentials arriving at the synaptic terminal.
Where the effects of DBS on neurotransmitter function have been directly studied, as in the case of Parkinsons disease, therapeutic DBS is not associated with
changes in dopamine function (Hilker etal. 2003). If one presumes that the loss
of information attendant on the degeneration of neurons in the substantia nigra
pars compacta is mediated by the sensorimotor-related components of the basal
ganglia-thalamic-cortical system, then it stands to reason that the proximate effects
are mediated by the putamen. In advanced Parkinsons disease, however, dopamine
levels are depleted by more than 99%.
Qualitative differences in behavior associated with DBS and behavior associated
with levodopa therapy offer indirect evidence that, at least as inferred from the
pharmacology, DBS therapeutic effect is not synonymous with neurotransmitter
function. Levodopa therapy may cause involuntary movements (dyskinesias). DBS
in the vicinity of the globus pallidus interna alleviates them.
DBS is not synonymous with surgical ablation, that is, the removal of such troublemakers in the brain as putative overactive globus pallidus interna neurons,
overactive subthalamic nucleus neurons, or excessive high beta oscillations (oscillations in neuronal activities, typically in local field potentials in the range of 15 Hz to
30 Hz). Strenuously argued early theories insisted that the similarity of DBS in the
vicinity of the globus pallidus interna to pallidotomy was evidence for mechanisms
common to both therapies, namely, reduced activity of the globus pallidus interna.
Such reasoning, however, falls victim to the fallacy of pseudotransitivity, which
may be formally expressed as if a implies c and b implies c, then a implies b (where
a is DBS in the vicinity of the globus pallidus interna, b is pallidotomy, and c
is improved Parkinsonism). Stroke and curare poisoning both cause paralysis.
Yet no one would suggest that stroke and curare share the same mechanisms. The
DBSsurgical ablation nonequivalence rests on the qualitative difference between
the effects of the lesions on the globus pallidus externa that are associated with producing Parkinsonism and the effects of DBS in the vicinity of the globus pallidus
externa that improve the symptoms of Parkinsons disease (Vitek etal. 2012).
DBS is revolutionary because it has no conceptual antecedents. Past concepts of
therapies based on pharmacological replacement of depleted neurotransmitters or
blocking neurotransmitter receptors do not apply to DBS. Indeed, DBS succeeds
where pharmacological therapies fail. This success thus argues for the existence of
some novel mechanism of disease affected by DBS that, in the case of Parkinsons
disease, is not inherently neurochemical.
Some 160years after Luigi Galvani established the importance of electricity and
electronics in animal behaviors by eliciting them with external electrical stimulation, the discovery of chemical neurotransmission served to diminish this importance. Interestingly, initial evidence of chemical neurotransmission arose from an
equating of the effects of the chemical acetylcholine on the heart to the effects of
electrically stimulating the vagus nerve (Valenstein 2005). It bears mentioning that
the reasoning behind this equivalence falls victim to the fallacy of pseudotransitivity as described previously. DBS thus represents a new era for neurological and
psychiatric therapeutics.
Past concepts imputed responsibility for disease manifestation (pathophysiology)
on specific structures within systems, the cause (pathoetiology) notwithstanding.
Yet these concepts did not precede DBS conceptually. Current theories, for example, posit a causal relationship between overactivity of the globus pallidus interna
and dopamine depletion associated with Parkinsons disease, the second a consequence of the first. It is intuitively appealing therefore to argue that pallidotomy
and DBS in the vicinity of the globus pallidus interna suppresses this troublesome
structure. Parkinsonism, however, may be produced by lesions at multiple loci in
the basal ganglia-thalamic-cortical system (Montgomery 2007; Montgomery and
Gale 2008). DBS at many of these same loci, meanwhile, improve Parkinsonism.
Of the many dimensions commonly occupied by DBS, pharmacological treatments, and surgical ablative treatments, perhaps the most fundamental is that of
dynamics, or changes in states over time (Montgomery 2007). Patterns of neuronal
activities are an example. In pharmacology-based treatments, the time of action
likely parallels the duration of action of the medication on brain activities, which is
typically hours. Surgical ablation, on the other hand, is static. The time scale of DBS
actions is milliseconds. One recalls that the primary difference in a therapeutic
DBS frequency of 150 pulses per second versus a nontherapeutic DBS frequency of
100 pulses per second is 3 ms or 3/1000th of a second between pulses.
A person prevents a cup from tipping by grasping it and returning it to its
proper position. This volitional behavior, which requires prior recognition of
the situation, is executed over many different muscles, whose various respective
functions require orchestration (Montgomery 2013). From the instant information is generated to the instant it is implemented by the muscles, execution of
this behavior requires fewer than 200 ms. The relevant time scales are such as to
prohibit information encoding in the actions of pharmacological agents or surgical ablations. Pharmacological agents and surgical ablations must be viewed,
rather, as creating states conducive to generation of more normal information.
Yet the level of information is that at which DBS likely operates (Montgomery
and Gale 2008; Montgomery 2013).
12
Before the advent of DBS for psychiatric disorders in 1979 and movement disorders in 1980, a few researchers had noted the importance of dynamics (Dieckmann
1979; Cooper etal. 1980). If the basal ganglias role, as inferred from abnormalities
of movement, is to generate normal movements, then the fact that so little work has
been done on its necessary dynamics is puzzling. Many reasons exist for this inattention, but full discussion of them lies beyond the scope of this chapter. It must
suffice at present to note that widespread failure to appreciate the importance of
dynamics owes to a lack of a need to do soa lack with a history that reaches back
to Aristotle and includes such noted neuroscientists as John Hughlings Jackson
and Sir Charles Sherrington. These leaders posited the dynamics in nature generally and the brain specifically as one-dimensional pushpull systems (Montgomery
2004).
A remarkable and revolutionary therapy, DBS promises to change the lives of
patients living with movement disorders. Indeed, its promise extends to Obsessive
Compulsive Disorder and other psychiatric indications. Realization of this promise depends on knowledgeable physicians and healthcare professionals who remain
committed to helping their patients.
S U M M A RY
DBS is a therapy like no other. Its mechanisms of action cannot be subsumed by any
antecedent conceptual approach such as from anatomy or pharmacology. Being
thus novel, it provides unparalleled opportunities for insight into brain function
and dysfunction. Similarly, its revolutionary nature provides challenges to clinical
use. Indeed, DBS may require a change in the mode of thinking of which nonsurgeons are unaccustomed. The remarkable benefits yet their uneven application
raises serious concerns about distributed justice and the responsibilities and obligations of individual physicians and healthcare professionals.
R EFER EN C ES
American Board of Psychiatry and Neurology. Certification Examination in Neurology
2013 Content Blueprint. Buffalo Grove, IL: American Board of Psychiatry and
Neurology, 2012.
Neurophysiol.;43(35):244258.
ER Jr, Ballantine HT, Meyerson BA, eds. Modern Concepts in Psychiatric Surgery.
Hilker R, Voges J, Ghaemi M, etal. Deep brain stimulation of the subthalamic nucleus
does not increase the striatal dopamine concentration in Parkinsonian humans. Mov
Disord. 2003;18(1):4148.
Montgomery EB Jr. Deep brain stimulation for hyperkinetic disorders. Neurosurg
Focus. 2004;17(1):E1.
Montgomery EB Jr. Dynamically coupled, high-frequency reentrant, non-linear

oscillators embedded in scale-free basal ganglia-thalamic-cortical networks
mediating function and deep brain stimulation effects. Nonlinear Studies.
2004;11:385421.
Montgomery EB Jr. Basal ganglia physiology and pathophysiology: a reappraisal.
Parkinsonism Relat Disord. 2007;13(8):455465.
Montgomery EB Jr. Thalamic deep brain stimulation for other tremors. In: Tarsy
D, Vitek JL, Starr PA, Okun MS, eds. Deep Brain Stimulation in Neurological
and Psychiatric Disorders and Psychiatric Disorders. New York: Humana Press;
2008:215228.
Montgomery EB Jr. Deep Brain Stimulation Programming: Principles and Practice,
Oxford:Oxford University Press; 2010.
Montgomery EB Jr. The epistemology of deep brain stimulation and neuronal pathophysiology. Front Integr Neurosci. 2012;6:78.
Montgomery EB Jr. Deep brain stimulation:mechanisms of action. In:Ejamel S, Slavin
KV, eds. Neurostimulation:Principles and Practice. Chichester:John Wiley & Sons;
2013:319.
Montgomery EB Jr. Neurophysiology. In Pahwa R, Lyons KE, eds. The Handbook of
Parkinsons Disease. Boca Raton:CRC Press; 2013:258280.
Montgomery EB Jr. Intraoperative Neurophysiological Monitoring for Deep Brain
Stimulation: Principles, Practice and Cases. New York: Oxford University Press;
2014.
Montgomery EB Jr, Gale JT. Mechanisms of action of deep brain stimulation (DBS).
Neurosci Biobehav Rev. 2008;32(3):388407.
Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial
of bilateral fetal nigral transplantation in Parkinsons disease. Ann Neurol.
2003;54(3):403414.
US Food and Drug Administration. Off-Label and Investigational Use of Marketed
Drugs, Biologics, and Medical DevicesInformation Sheet. http://www.fda.gov/
regulatoryinformation/guidances/ucm126486.htm
Valenstein ES. The War of the Soups and Sparks:The Discovery of Neurotransmitters and
the Dispute over How Nerves Communicate. NewYork:Columbia University Press;
2005.
Vitek JL, Zhang J, Hashimoto T, et al. External pallidal stimulation improves
Parkinsonian motor signs and modulates neuronal activity throughout the basal
ganglia thalamic network. Exp Neurol. 2012;233(1):58158.
Why Deep Brain Stimulation?
T H E F R A M I N G PR O B L EM
Why Deep Brain Stimulation (DBS)? The answer is opportunitythe opportunity

to help patients when all else fails. One might argue that the opportunities are obvious at least for conditions recognized as safe and effective by the US Food and Drug
Administration or by scientific data in the case of off-label uses. However, the
importance of emphasizing opportunity can be seen from what is called the framing problem. Consider the statement DBS can be used when all reasonable alternatives fail compared to DBS is the most effective therapy and is only held in reserve
because of surgical risks. While perhaps subtle, the differences in connotation are
significant. The differences may be seen in thresholds for each decision. When
framed as something to be considered in the setting of failed pharmacological
therapy, it fails to emphasize the value of DBS in its own right and may result in an
inappropriate reticence to recommend DBS. Framing DBS as something that one
defaults to, particularly if DBS is viewed as just another way to affect neurotransmitters, overactivity of the globus pallidus interna, or excessive neural oscillations
in the low beta frequencies, fails to distinguish DBS from pharmacological treatments. Framing DBS as the most effective therapy reserved only because of surgical
risks makes DBS an active consideration from the start. Ideally, there should not
be any difference in the decisions each framing produces, but historically this has
not been the case.
The situation of DBS, as an underutilized safe and effective therapy, has parallels
in epilepsy surgery. Despite the long history of successful epilepsy surgery, indeed
in some cases curative, there is a worldwide underreferral for epilepsy surgery (Uijl
etal. 2012). The underreferral is despite well-established guidelines, such as medically intractable seizures for two years despite use of three first-line anticonvulsants. Among the reason for not referring patientsparticularly patients thought
appropriate by expertsphysicians argued that the patients seizure burden was
insufficient and thus did not discuss the potential for surgery, a form of paternalism called soft paternalism (Beauchamp and Childress 2013). In an Italian study,
physicians who did not refer expressed less positive expectations for outcomes and
viewed surgery as the last resort, resulting in prolonged, unsuccessful pharmacological management (Erba etal. 2012). This reasoning could just as well describe the
attitudes of many neurologists to DBS.
2. Why Deep Brain Stimulation?15
DBS provides an opportunity to decrease healthcare costs by demonstrating less

cost than medical therapy in patients with Parkinsons disease (Meissner etal. 2005;
Valldeoriola etal. 2007; Dams etal. 2013). Further, DBS provides better symptom
relief than pharmacological treatments for many disorders.
DBS provides an opportunity to reexamine many of the assumptions and presumptions affecting the presumptions and assumptions operative in acceptance of
therapies by physicians and healthcare professionals. As is discussed later in this
chapter, notions of pathophysiology plays a significant role in acceptance of new
therapies. These issues play out most clearly in Parkinsons disease, but the same
issues are relevant for brain disorders in general. The presumption that Parkinsons
disease is a dopamine deficiency state may prejudice physicians and healthcare professionals against DBS, as the evidence suggests that DBS is not mediated by its
effects on dopamine (Hilker et al. 2003). For example, it is interesting that stem
cell dopamine replacement therapies should find such favor over DBS. At least with
respect to risk, these are greater than DBS, for example in the number of penetrations of the brain in order to deliver therapy. Also, many patients with fetal dopamine cell transplants for Parkinsons disease develop runaway dyskinesia (Olanow
etal. 2003)for which DBS has been called upon to control.
I M P O R TA N C E O F PAT H O PH YS I O LO GY
Notions of pathophysiology are critical to acceptance of therapies that are

thought to address the pathophysiology. For example, the notion that Parkinsons
disease is a dopamine deficiency, even if false, justifies confidence in dopamine
replacement therapy, such as by oral agents and stem cell transplants. Alternative
therapeutic approaches that do not clearly demonstrate an intuitive relationship
with the putative pathophysiological mechanisms do not appear to gain traction
with physicians and healthcare professionals. Even randomized controlled trials appear to be unconvincing. Randomized controlled trials can demonstrate
that DBS produces greater changes in some measures but cannot explain why
or how the treatment relates to the pathophysiology. Nothing about EvidenceBased Medicine explains DBSs superiority. Certainly, Evidence-Based Medicine
can test claims as to why DBS is better, but it cannot generate the hypotheses that
constituted claims. If, for example, powderized kitchen sink porcelain was shown
better than placebo at relieving a certain diseases symptoms, then anyone who
endorses Evidence-Based Medicine must also endorse powderized kitchen sink
porcelain.
The influence of pathophysiology theories on acceptance of therapies is seen in
the resurgence of interest in DBS in the late 1980s, yet DBS, as currently practiced,
was used for psychiatric disorders in 1979 (Dieckmann 1979)and for movement
disorders in 1980 (Cooper etal. 1980). The delay did not await new technologies
or new realizations of the need for surgical therapies. Rather, it was the resurgence
of interest in pallidotomies that paved the way for DBS. The resurgence of interest
pallidotomies was because of the development of a theory that had explanatory
power, specifically the Globus Pallidus Interna Rate theory. This theory posited
overactivity of the globus pallidus interna as a consequence of dopamine depletion.
The overactivity was thought to cause suppression of neuronal activity with the
16
ventral oral posterior thalamus and subsequently in the motor cortex. This theory
has since been proven wrong, but it enabled the resurgence of interest in DBS.
The Globus Pallidus Interna Rate theory was derivative of the concept of
Parkinsons disease as a dopamine depletion state. Thus the falling out of favor
of the Globus Pallidus Interna Rate theory did little to dampen acceptance of the
notion of Parkinsons disease as a dopamine deficiency state.
Notions of pathophysiology and physiology (the latter often derived from inverse
reasoning from the former) will be important in the future development of DBS.
Most applications of DBS have replicated previous ablations preceded from the
assumption that DBS is equivalent to surgical ablations, a presumption that has
been proven incorrect. There is a move to evaluate DBS from a physiological rather
than anatomical perspective by seeing DBS as a positive intervention, for example
the development of DBS for minimally conscious states. These issues are addressed
in chapter20.
DY N A M I C S
DBS is not simply another means of affecting neurotransmitters. The onedimensional pushpull dynamics, the relative excess or deficiency of neurotransmitters that excite or inhibit, characteristic of pharmacology may hinder a greater
understanding of DBSs mechanisms of action, thus placing therapeutic advances
in jeopardy.
Parkinsons disease treatment makes readily apparent the difference between
DBS and pharmacological therapies. Radioisotope displacement studies using
Positron Emission Tomography imaging demonstrate that therapeutic DBS does
not increase dopamine release in the basal ganglia (Hilker etal. 2003). Also, DBS
provides significant incremental benefit in cases in which dopaminergic pharmacological agents are maximizedwith medications or fetal cell transplant, for
example. Such benefit would be unlikely if DBS produced a dopamine-like effect.
Rather, DBS produces in patients with Parkinsons disease some effects that are the
converse of levodopa.
The dynamics of DBS are different. Dynamics refers to changes in state (the
nature of the system under consideration) over time. The dynamics of levodopa
therapy presents a useful example. The blood levels of levodopa increase immediately after administration, peak approximately 30 minutes after administration,
and have a half-life of approximately 90 minutes (though the half-life of brain
response, as inferred from the clinical response, may be considerably longer early
in the disease). The dynamics of the levodopa effect, then, is at least on the order of
tens of minutes. Asecond example involves a case in which 130 pulse per second
(pps) stimulation proves effective, but 100 pps stimulation proves ineffective. The
difference in the interstimulus pulse interval is on the order of 3 ms, or 3/1,000th
of a second. Whatever mechanisms underlie DBSs therapeutic effect thus operate
on a time scale that is on the order of milliseconds. Such is not likely to be the case
with dopamineor, at least, dopamine pharmacologically administered through
its prodrug, levodopa (a prodrug is an agent other than the primary agent that is
transformed into the primary agent by metabolism). The dynamics of DBS are discussed more fully in c hapter18.
One may argue that in the cases of pharmacological or cell transplant repletion
of dopamine, fault lies with the manner in which the dopamine is replaced. This
is correct. Dopamine neurons are normally phasic: they precisely modulate the
release of dopamine over the course of a few hundred milliseconds (Figure 2.1),
rather than over the uncontrolled hours required by pharmacologically administered dopamine or the years required by cell transplantadministered dopamine.
What controls the precise modulation of dopamine by the substantia nigra pars
compacta? It is the integrated electrical activities that fall on individual substantia nigra pars compacta neurons. Pharmacologically administered dopamine and
cell transplantadministered dopamines respective time courses do not begin to
match the naturally occurring time course.
These same issues arise for Essential tremor, dystonia, and other movement disorders. The dynamics in the pathophysiology clearly operate on a time scale that
pharmacological agents cannot match. But DBS can match it. One may argue that
the continuous application of electrical pulses differs little from continuous application of dopamine by fetal cell transplantation or other means. More important
than constant application of electrical energy by DBS, however, are the aforementioned pulses occurring at millisecond intervals.
Reward predicted
Reward occurs
CS
Figure2.1 Peri-event raster and histogram of the neuronal activity (assessed by

recording extracellular action potentials [spikes]) of a dopamine in a nonhuman
primate trained to perform an arm movement in response to a cue. The raster shows
the relative time of occurrence of each neuronal spike as a dot, and each row of dots
shows the neuronal activity over the multiple trials. The histogram shows average
neuronal activities over multiple trials. At baseline, dopamine neurons are extremely
inactive, but they dramatically increase their firing in response to a cue to make a
movement. This increase lasts a few hundredths of a millisecond. It is thus highly
unlikely that pharmacological applications of dopamine will be able to replicate the
normal dynamics of dopamine neuron physiology (with permission (Schultz and
Romo 1990)).
18
C O N FL AT I O N O F PAT H O E T I O LO GY
A N DPAT H O PH YS I O LO GY
Using DBS for Parkinsons disease as the archetypical example to consider DBS in
a wider context, it is clear that there is a dissociation between the mechanisms that
cause idiopathic Parkinsons disease, the pathoetiology (the term pathogenesis
is not specific enough), is different than the mechanisms that cause the behavioral
(motor) abnormalities, pathophysiology, as therapeutic DBS must be affecting those
mechanisms. Loss of dopamine attendant on degeneration of neurons in the substantia nigra pars compacta relates to the pathoetiology. DBS, as described, is not
mediated by dopamine yet it reverses at least some pathophysiological mechanisms
which are unlikely to involve dopamine. Clearly, therapies addressing the pathoetiology have been successful but not completely and certainly not to the extent that
therapies addressing the pathophysiology have.
Conceptually what does it mean to say that pathoetiology and pathophysiology
are not synonymous? It implies that there is some mechanistic distance between
the proximate consequences of dopamine cell loss in the substantia nigra pars compacta and the eventual changes in orchestration of the activities of motor units
(the combination of muscle fibers and their innervating lower motor neuron in
the brainstem and spinal cord). The mechanisms proximate to abnormal motor
unit activity are distant from those proximate to dopamine cell degeneration. This
proves an opportunity to intervene at those sites proximate to abnormal motor unit
activity that are independent of mechanisms proximate to dopamine cell degeneration. This is evidenced the fact that virtually all the same abnormalities of motor
unit activity, producing the same symptoms and signs as those associated with
dopamine cell depletion, can be produced by lesions not involving dopamine neurons. Parkinsonism has been associated with lesions of the globus pallidus, particularly the external segment, ventral oral posterior thalamus (the relay nucleus
of the basal ganglia output to the cortex), and the supplementary motor area
(Montgomery etal. 2011).
Differentiating between pathophysiology and pathoetiology is important,
because conflating the two leads to the mistaken notion that correcting the
pathoetiology is the best way to affect the pathophysiology and thus improve the
functional disability. The bias in favor of treatments directed more at pathoetiology than pathophysiology rests on this mistaken notion, which may account for
the failure of DBSs wider adoption. Indeed, such conflation of pathoetiology and
pathophysiology may explain the greater favor for dopamine cell replacement therapeutic despite its much more problematic nature and doubts about whether such
therapies can attain the efficacy and safety of current DBS techniques. It is hard
to see how stem cells will fare any better than the failure of fetal dopamine cell
transplant and much enthusiasm must stem from preoccupation with pathoetiology rather than pathophysiology.
There is another level where conflation of pathoetiology and pathophysiology is
problematic. Pervading physicians thinking, at least as far as Parkinsons disease
is concerned, is a second factor, namely, the paradigm of pathoetiology as pathophysiology. Thinking according to this paradigm reduces science to more elemental
notions. Increasingly, these elemental notions are viewed as molecular. Because a
critique of reductionism is beyond the scope of this discussion, it must suffice to
suggest that studying Complex Systems theory offers insight into the pathoetiology
as pathophysiology paradigms shortcomings. According to Complex Systems theory, mathematical and other systems reducible to fundamental functions and axioms are capable of unpredictable behavior. Complex Systems theory thus shatters
the reductionists hope that an organism may be reconstructed from fundamental
molecular mechanisms, which is the real appeal of reductionism.
A bias favoring pharmacological, and now molecular, mechanistic accounts
over electrical preceded the present era of molecular neurobiology. It has its origin in the early 1940s, when it was shown that pharmacological agents applied to
the heart produced the same response as did stimulating the hearts vagus nerve
(Valenstein 2005). This observation engendered two influential notions:(1)synaptic transmission is chemical in nature, and (2)neurochemistry is synonymous with
neurophysiology. When applied to a consideration of DBSs remarkable effect in the
face of pharmacological treatments failure, however, these notions come into question, because one gains the sense that DBS and neurochemistry, as a more general
domain encompassing neuropharmacology, are not synonymous. Further confusion is sown by the notion that understanding a single synapsing neuron is sufficient to understand neurophysiology. This notion is known as the Neuron Doctrine.
Again, a discussion of this topic is beyond the scope of this writing. Suffice it to say
that blame for this way of thinking belongs to Santiago Ramn y Cajal. His ideas
should have ceded to those of Camillo Golgi, who argued that explaining behavior
requires a conception of networks.
None of the foregoing discussion is meant to disparage pharmacological
approaches to movement disorders treatment. Indeed, pharmacological treatments are potentially reversible and relatively safethough there does exist a risk
of levodopa dyskinesia in patients of Parkinsons disease. DBS surgery, on the other
hand, carries a risk of irreversible complications. Pharmacological treatments
therefore remain treatment mainstays. Also, a demonstrated failure to respond to
all reasonable pharmacological approaches is a main criterion for candidacy for
DBS surgery. (That which constitutes a reasonable approach is discussed later.) One
ought not consider simultaneously DBS and pharmacological therapies, in other
words, because due deliberation must always end in a preference for the latter, if for
no other reason than that of the risk attending DBS surgery.
S U M M A RY
Judgment requires balancing pharmacological and surgical approaches. Directly

comparing DBS, pharmacological, and other therapies is problematic. Each therapy has its advantages. But, by the same token, each has its disadvantages as well.
Consequently, it is not simply a matter of which is most efficacious and has the fewest side effects. Indeed, DBS in Parkinsons disease cases decisively recommends
itselfprovided no consideration is given to surgical risk. Rather, consideration
must be given to many other factors, such as a risk of side effects (permanent as
opposed to reversible), the functional demands on the patient, family members,
and caregivers and the patients general state of health. (Discussion of these issues
appears in subsequent chapters.)
20
This book seeks to establish that the field of DBS is fraught with misunderstanding. This owes to the fact that important questions concerning it are poorly
framed and thus met with poor answers. It also suffers a legacy that, though outmoded, outdated, and counterproductive, continues to influence thought about it.
Reversing this legacy will be difficult, if for no other reason than that given by
father of modern physiology Claude Bernard, who observed, It is what we think
we know already that often prevents us from learning. One hopes are that such
reversal does not come to pass according to the process described by Max Planck,
who wrote, A new scientific truth does not triumph by convincing its opponents
and making them see the light, but rather because its opponents eventually die,
and a new generation grows up that is familiar with it (quoted in T.S. Kuhn, The
Structure of Scientific Revolutions [Chicago:University of Chicago Press,1962]).
In the final analysis, judgmentthe application of reason and wisdomis
required. Yet the requisite wisdom presupposes active and genuine meta-reflection
on possible error, because knowing an idea or claims origin is often as important as
knowing an idea or claim itself.
R EFER ENCES
Neurophysiol. 1980;43(35):244258.
Dams J, Siebert U, Bornschein B, etal. Cost-effectiveness of deep brain stimulation in
patients with Parkinsons disease. Mov Disord. 2013;28(6):763771.
Dieckmann G. Chronic mediothalamic stimulation for control of phobias.
In:Hitchcock ER Jr., Ballantine MBA, eds. Modern Concepts in Psychiatric Surgery.
Erba G, Moja L, Beghi E, etal. Barriers toward epilepsy surgery:a survey among practicing neurologists. Epilepsia 2012;53(1):3543.
does not increase the striatal dopamine concentration in parkinsonian humans. Mov
Disord. 2003;18(1):4148.
Meissner W, Schreiter D, Volkmann J, et al. Deep brain stimulation in late
stage Parkinsons disease: a retrospective cost analysis in Germany. J Neurol.
2005;252(2):218223.
Montgomery EB Jr., Huang H, Walker HC, et al. High-frequency deep brain stimulation of the putamen improves bradykinesia in Parkinsons disease. Mov Disord.
2011;26(12):22322238.
Olanow CW, Goetz CG, Kordower JH, etal. A double-blind controlled trial of bilateral
fetal nigral transplantation in Parkinsons disease. Ann Neurol. 2003;54(3):403414.
Schultz W, Romo R. Dopamine neurons of the monkey midbrain: contingencies
of response to stimuli eliciting immediate behavioral reactions. J Neurophysiol.
1990;63:607624.
Uijl SG, Leijten FS, Moons KG, etal. Epilepsy surgery can help many more adult patients
with intractable seizures. Epilepsy Res. 2012;101(3):210216.
Valenstein ES. The War of the Soups and Sparks:The Discovery of Neurotransmitters and
the Dispute over How Nerves Communicate. NewYork:Columbia University Press;
2005.
Valldeoriola F, Morsi O, Tolosa E, et al. Prospective comparative study on
cost-effectiveness of subthalamic stimulation and best medical treatment in advanced
Parkinsons disease. Mov Disord. 2007;22(15):21832191.
Deep Brain Stimulation Is

Effective for Patients with
ParkinsonsDisease
J U D G I N G EFFECT I V EN ES S
Deep Brain Stimulation (DBS) is remarkably effective for the treatment of

Parkinsons disease. However, the effectiveness of DBS is a complex calculation.
Its complexity is reflected in the fact that different physicians may look at the
same data and come to different conclusions. Some physicians readily recommend
patients for consideration of DBS surgery; others seldom do. Indeed, it is estimated
that, although 15% to 20% of patients are candidates for DBS, less than 5% are being
referred. At any rate, the consensus of most experts is that DBS is underutilized.
It is difficult to explain the large variance and referral bias according to published
facts that attest to DBSs remarkable efficacy and safety. Something else is obviously
operating under the surface.
T H E FACTS
The Measures
The first consideration is that of determining a measure and its means of application
for improvement or worsening following DBS for Parkinsons disease. Examples
of the latter include a choice between open-labeled studies and blinded studies, a
choice between prospective studies and retrospective studies, and the composition
of any control or comparison group. Each has its particular advantages and disadvantages, which must be considered in the context of specific goals. Early in the
development of a new therapy, for example, it may be best to conduct an open-label
study in which a patient acts as her own control may be reasonable prior to more
controlled, prospective studies. In the case of an early study, the issue is simply that
of demonstrating an effect that justifies further evaluation. The primary concern in
the early study is a type II error in which an effect of a treatment (assuming here
beneficial) is missed and a prospective treatment abandoned.
3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease23
Evidence-Based Medicine has become an important standard for interpreting

facts in the interest of improving medical care and has become synonymous with
randomized controlled studies (RCTs), which typically involve prospective studies
whose subjects and evaluators are blinded to the experimental condition. Original
descriptions of Evidence-Based Medicine included a range of different types of evidence and did not necessarily include value judgments as to the priority of the different levels.
Evidence-Based Medicine based on RCTs has become the gold standard. Yet
RCTs numerous weaknesses make their application to clinical decisions highly
problematic (Montgomery and Turkstra 2003). The greatest disadvantage lies in
the fact that the means that render RCTs possible to begin withincreasing statistical power and controlling for confounding factors, for examplelimit the possible generalization to an individuals optimal treatment. The former include strict
inclusion criteria. Subjects actually enrolled in an RCT often have little in common with those individuals in the general population for whom the treatment was
intended. Indeed, this discrepancy between RCT results may vary greatly from
actual use in practice, as evidenced by many treatments that have been modified
or outright abandoned following RCTs consequent to postUS Food and Drug
Administration approval experience. A potential difference is that the subjects
studied were substantially different from those to whom the treatments were
applied in general use.
RCTs depend on randomization to counterbalance confounding issues that cannot be controlled by elimination according to strict enrollment criteria. The rationale is that the experimental and control groups will experience the same number
of enrolled subjects with confounding problem A. Confounding problem A thus
affects both groups to an equal or nearly equal degree, thereby cancelling each
other out. For example, hypertension may confound studies of stroke prevention.
Consequently, the hope is that randomization will result in as many patients with
hypertension in the experimental group as are in the control group. However, an
individual patient simultaneously has and does not have hypertension. The RCT
provides no means by which to determine the effect of the confound so that it may
aid the care of the individual patient (see discussion in chapter15 regarding population statistics and the Second Law of Thermodynamics).
Included among the measures are the following examples: (1) symptom-based
assessments as the motor examination of the Unified Parkinson Disease Rating
Scales (UPDRS); (2)a functional assessment as the ability to carry out activities of
daily living, which is determined by use of part2 of the UPRDS; (3)degree of gait
and balance involvement, as assessed according to such a measure as the Hohen and
Yahr scale; (4)quality of life measures; (5)a patients global perspective; (6)global
perspective of a patients caregiver; 6) a physician or healthcare professionals
global perspective; and (7)such a specific and perhaps ad hoc criterion as a patients
being off and maximally symptomatic, on insofar as many primary symptoms
have improved, and on with dyskinesia, which means that the primary symptoms
have improved but the patient is manifesting some limiting side effect. (In this last
example, the involuntary movement is dyskinesia.) Again, each measure is unique
in terms of advantages and disadvantages. Awise physician or healthcare professional integrates from the diverse measures to establish an approach best suited to
an individual patient.
24
The most typical are symptom-based measures due to (1)similarity to the types
of evaluations routinely performed by physicians and healthcare professionals;
(2) presumption of greater objectivity, that is, a minimal amount of rater interpretation; and (3) customary use of the degree of symptoms as that which most
concerns physicians and healthcare professionals. The presumption is that control
of the symptoms, directly or as a marker of benefit, is sufficient to meet a patients
needs, as well as the needs of her family member or caregiver. However, patients
needs have increasingly been interpreted in terms of quality of life. Attempts to
assess a patients needs is observed in the use of measures based on the degree of
dependence for performing activities of daily living. Even these measures, however,
may not predict quality of life. Measures therefore exist that attempt to define quality of life. Yet most appear to depend on the emotional or psychological response to
a disorder and its treatment on the part of a patient or her family member or caregiver. An example of the difficulties in choosing the proper measure is observed in
patients whose motoric symptoms have greatly improved but whose quality of life
has not. From a motoric perspective, DBS in the vicinity of the subthalamic nucleus
may be a success even if the patient and family are worse off (Schupbach etal. 2006).
These discussions indicate how physicians and healthcare providers are to view
and interpret the range of available facts, and they argue for a consideration of the
full range of facts, because sole reliance on RCTs may not be in patients best interests. Physicians and healthcare professionals must choose or weigh more heavily
those measures they think most germane to a patients situations.
T H E S A L I EN T ST U D I ES
The discussion to follow offers no extensive review of the literature on the efficacy of
DBS for Parkinsons disease. It reviews, rather, a number of studies that are particularly important in assessing current efficacy. Other studies reviewed are to illustrate
various principles that may guide future studies and their interpretation and implementation in the care of patients.
Published in 2001, one of the first major studies appeared in the New England
Journal of Medicine. It was written by the Deep Brain Stimulation Study Group,
a consortium of physicians, surgeons, and healthcare professionals (Deep-Brain
Stimulation for Parkinsons Disease Study Group 2001). Some of the major findings
were based on a symptomatic measurethe motor examination of the UPDRS,
specifically. These measures were taken under the following four conditions: (1) on
medications and on DBS, (2) off medications and on DBS, (3) on medications and
off DBS, (4) off medications and off DBS. Another measure was the duration of a
presumably good state, namely, on but without dyskinesia taken before and after
the incorporation of DBS. Patients underwent DBS in the vicinity of the globus
pallidus interna or subthalamic nucleus DBS but were not randomized. The specific
surgery was selected by a patients treating physician.
The study demonstrated a 51.3% improvement in the motor UPDRS at six months
between patients receiving DBS in the vicinity of the subthalamic nucleus being
off or on while the patient was off medications. Note that the term in the vicinity of a specific structure is used to emphasize that the therapeutic effects have
little to do with the target in which the DBS lead is implanted (Montgomery and
Gale 2008). In the condition of medications on, the improvement with the stimulator powered on was 25.8%. Both were statistically significant. Some have argued
that comparison with the stimulation on and off in the medication off condition
is not really relevant, because most patients are not off medications. These critics hold that the comparison between the stimulator powered on and powered off
during the on medication conditions that is most relevant. The unspoken criticism
is that the 25.8% difference did not appear to be significant clinically, despite the
factthat the difference was significant statistically or, at the very least, that it justified the expense and risks of the surgery. Similar findings were obtained with DBS
in the vicinity of the globus pallidus interna:off medications in such cases showed
a 44.3% and a 26.8% improvement while on medications.
The response to this criticism is that patients with advanced Parkinsons disease
are essentially off their medications a great percentage of the day, if by being off
it is meant that the symptoms returned despite the fact that medication was taken.
The percentage of waking hours in the off condition was 49% prior to DBS in those
patients whose subthalamic nucleus was targeted comparted to 19% with DBS on.
Thus it is reasonable to believe that the difference in the DBS effect off medications
is germane to the 49% of the waking day where patient would have been off without
DBS. There was similarly a reduction of off time from 37% to 27% with DBS in the
vicinity of the globus pallidus interna. Consequently, the degree of improvement
following DBS while off medications is relevant.
Greater weighting of the improvements while on medications and DBS is most
relevant to judgments of clinical efficacy in that this condition enjoys ecological
validity with respect to an individual patient. In some ways, this situation is analogous to the intention-to-treat analyses of clinical trials, in which all available data
is collected and analyzed according to the group to which patients were originally
assigned, even if some patients were noncompliant or, in the case of the control
group, given the study treatment. Originally designed to avoid possible biases
resulting from data censoring for incomplete data or protocol violations, intention
to treat may better reflect the population efficacy of the treatment in general use, a
context in which some (perhaps many) patients will be noncompliant.
Conversely, some experts consider the assessment of symptomatic improvement
with DBS while the patient is off medications. Although these findings are relatively irrelevant to clinical judgment on efficacy, because patients usually continue
to take medications, the attractiveness of this assessment may relate to the presumption that assessment off medications more clearly demonstrates the effects of
DBS. Perhaps these observations justify the use of DBS by demonstrating a direct
benefit immediately attributable to DBS rather than the medications. Their proving
to do so may be analogous to a philosophical position that any treatment must be
better than placebo, provided one recognizes that purely clinical benefit alone cannot differentiate a priori the mechanisms of any treatment from those of a placebo.
Though a purely utilitarian argument is occasionally made as to whether proven
placebos should be used clinically, most clinicians reject it.
Since the paper by the DBS for Parkinsons Disease Study Group, there have
a number of prospective controlled studies demonstrating similar findings
(Weaver etal. 2009). The exception was the Veterans Affairs cooperative study,
which demonstrated a lesser degree of benefits. The benefits of DBS in the vicinity of both the subthalamic nucleus and the globus pallidus interna, however,
26
were statistically significant. In addition, quality of life and other outcome measures have demonstrated statistically significant improvements. Substantial evidence exists to encourage confidence in the conclusion that DBS, in the vicinity
of both the subthalamic nucleus and the globus pallidus interna, improve motor
symptoms, functional disabilities, and quality of life in patients with Parkinsons
disease.
C O M PA R I S O N TO PH A R M AC O LO G I CA L T R E AT M EN TS
The decision to offer DBS surgery depends on alternatives. In this case, the question
becomes whether DBS is better than the best medical therapy. Several prospective randomized studies have compared DBS in the vicinity of the globus pallidus
interna and the subthalamic nucleus to best medical therapies (Weaver etal. 2009).
These studies consistently demonstrate greater symptomatic improvement than
those brought about by best medical therapies.
It may be argued that this question was already answered in the DBS for
Parkinsons Disease Study Group study and other initial studies (Deep-Brain
Stimulation for Parkinsons Disease Study Group 2001). In those early studies,
failure of medical therapy was an enrollment criterion. Most of these studies also
involved experts in the treatment of Parkinsons disease. One may reasonably
assume that these patients did receive best medical therapy. The argument may
be made that subsequent RCTs merely replicated at great expense that which was
already known (Weaver etal. 2009). Perhaps the funds devoted to those RCTs could
have been put to better use.
One asks whether the considerable expense of the subsequent RCTs was justified. Those who would answer Yes, clearly may claim that the previous studies,
which were not RCTs, do not constitute evidence. Idisagree with that claim. To
claim that were the non-RCTs accepted as evidence it would be somehow less valid
than evidence obtained by RCTs leaves unestablished the latters a priori superiority. Perhaps the most significant act would be to blind patient and raters, because
to do so would be to mitigate placebo effect and expectation bias. UPDRS and
other such measures, however, have demonstrated validity and reliability in other
blinded studies, which typically focused on medications. One would have to argue,
therefore, that this validity is sufficiently different from the validity established in
the case of DBS. One wonders whether there could be other, less expensive ways to
rule out the placebo effectsprolonged observation, for example.
The phrases sufficiently important and sufficiently different raise questions as
to that which is denoted by sufficiently and the way one measures it. Sufficiently
in this case means that an anticipated result justifies the efforts required to determine it. Presumably RCTs are conducted because they had not previously been conducted. This reason recalls the reason Sir Edmund Hillary gave for scaling Mount
Everest:Because it was there.
The very idea of comparing DBS to best medical therapy belies a mode of thinking. Is it important to ask whether a comparison between DBS and best medical therapy has been made. More important, should money be spent to make it,
in the event that it has not yet been made? What is the presumed or anticipated
consequence of making such a comparison? Is the situation such that if DBS was
demonstrated more effective than best medical therapy, patients would be routinely
be offered DBS as first choice?
Though rare, serious adverse effects from DBS are possible. It is therefore unlikely
that DBS would win priority over medical therapy. The issue is not whether DBS
results in greater improvement in the UPDRS. It is whether DBS produces sufficient
benefit for an individual patient in whom medical therapies have failed. The reasonable approach would be to determine the probability that DBS will be sufficient, or
at least more nearly sufficient, for the patient for whom the best medical therapy is
insufficient. Note that the Veterans AffairsNational Institutes of Health cooperative study (Weaver etal. 2009)cannot directly answer this question. Though the
overall rate of adverse effects after six months of DBS is less than those randomized
to best medical therapy (Weaver etal. 2009), the adverse effects of medications are
typically reversible. Some surgery-related adverse effects, on the other hand, may
be irreversible.
Some may argue that it may be more effective to take patients to DBS surgery
earlier rather than prolong the disabilities while pursuing best medical therapy. If
best medical therapy can be achieved in a reasonable period of time, then the issue
of delaying DBS is not a serious one. If the time required to determine whether best
medical therapy is insufficient would subject the patient to excessively prolonged
disability, then the problem lies with the clinician and not the therapy. Certainly,
methods of healthcare delivery system that limit every decision to adjust medications to the traditional three- to six-month follow-up is likely to excessively prolong
the process. However, subjecting the patient to DBS because of a healthcare systematic failure to optimize medical therapy efficiently and in a timely fashion appears
to run counter to medicines proper purpose.
If one assumes that the potential patient has exhausted all reasonable attempts at
medications and failed to achieve satisfactory control, the potential effectiveness of
DBS should be considered in the context of the available alternatives. Patients who
have exhausted all reasonable attempts at medications have no alternative except
that of continued disability. This latter circumstance illustrates that there are risks
to undergoing DBS and risks to not undergoing DBS. The risks of not undergoing
DBS are the adverse effects of suboptimally treated Parkinsons diseasefalls, for
example.
Some physicians and healthcare professionals feel that it would be worse were
they to recommend DBS surgery and an adverse effect to arise than were they not to
recommend DBS and the patient experience a serious complication for the poorly
treated Parkinsons disease. The former are considered errors of commission and
the latter errors of omission. The latter are commonly deemed less detrimental.
Ethically speaking, however, such thinking is outmoded (see chapter19).
A DV ER S E EFF ECTS
Improvements must be considered in the context of the possible price to be paid,

such as experiencing adverse effects. Again, caution is required in the interpretation of the reported facts as to adverse effects. First, the issue is how adverse effects
are defined. In many clinical trials the definition of adverse effects is the definition devised by the US Food and Drug Administration:An adverse event is any
28
undesirable experience associated with the use of a medical product in a patient.

(http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm). In the situation of DBS in the vicinity of the subthalamic nucleus, for example, production of
paresthesias owing to spread of stimulation current to the medial lemniscus that
courses behind the subthalamic nucleus is routinely produced during postoperative DBS programming. The question is whether spread of current should be considered an adverse effect.
This issue of what constitutes an adverse effect is seen in the Veterans Affairs
Cooperative study; the reported initial risk of adverse effects at six months were
resolved in 99% of cases. This reduction may be related to finally establishing an
optimal DBS electrode configuration and stimulation parameters. Unfortunately,
an unsophisticated clinician might be misled by reports of high complication rates
associated with DBS.
The judgment of effectiveness must also include assessments of risks. In the case
of DBS, risks may be conceptualized as those risks associated with the surgical
procedureinfection, bleeding, or seizures, for exampleand the risk of lead misplacement, which would require repeat surgery. The last risk includes a special risk
Irefer to as the tyranny of partial benefit. The benefit in DBS is directly proportional to the severity of the symptoms to be treated. Greater preoperative disability
means a chance at much greater benefit. For example, if a DBS surgery results in
poorly placed electrodes owing to failure to prevent intracranial air and subsequent
displacement of the brain (Montgomery 2010), the patient may experience only a
partial benefit. The subsequent decision whether to revise the poorly placed DBS
lead must weigh the risk, which is the same as the initial surgery, against the incremental benefit that might be gained. The incremental benefit is less because of the
partial benefit achieved by the first DBS system. If the incremental benefit is considered as insufficiently justifying the risks, a patient is confined to the partial benefit
obtained.
Risks are associated with the act of stimulation; however, interpreting the literature is problematic because of the nature of adverse events reporting in clinical
trials. For example, one cause of adverse effects, albeit typically slight, involves side
effects consequent to unintentional spread of stimulation current to adjacent structures, such as a spread to the corticospinal tract in the posterior limb of the internal
capsule. Such spread of electrical stimulation may produce tonic muscle contraction. These side effects may be relieved with adjustments to the stimulator. Indeed,
these side effects are frequently encountered, at times purposely, during the course
of routine postoperative DBS programming.
Given that these putative adverse effects are easily reversible and indeed, often
purposefully produced, it does not seem reasonable to call them adverse effects
with the consequence of causing undue concern. However, it does not appear that
the conduct of the clinical trials allowed for this distinction, and, consequently,
the risk of these effects were reported as undifferentiated adverse effects. This is
yet another example of how the structure of clinical trials limits the utility of their
results to the management of patients as part of routine care (Montgomery and
Turkstra 2003).
Some effects of stimulation may be quite adverse. In Parkinsons disease and
particularly with DBS in the vicinity of the subthalamic nucleus, sudden changes
in mood, either euphoria or depression, or changes in impulse control may have
serious consequences. These adverse effects may often be relieved by adjustment of

the electrode configuration or stimulation parameters (Montgomery 2010).
It is not clear how many physicians and healthcare professionals have gained
the wrong impression, but there are likely to be a few. Patients accordingly suffer.
If the side effects described from inadvertent spread of electrical stimulation to
adjacent structures prevented the titration of stimulation to produce therapeutic
benefit, the side effects are appropriately described as adverse effects and therefore
constituterisk.
Another source of risk is the sudden failure of the system to provide therapeutic
stimulation. This may owe to battery exhaustion or failure to recharge the implanted
pulse generator for those patients who have been implanted with a rechargeable
system. This risk should be low, however, if physicians and healthcare professionals
educate patients and patients family members/caregivers in how to check battery
status. The problem is that long battery life leads to complacency. I recommend
checking the battery on a weekly basis from the start in order to establish a habit.
Clearly, for the patients and their family members or caregivers to be able to check
the battery, it is important that they have the device used for checking the battery
with them. There can be a sudden stimulation failure due to hardware failure, such
as a broken electrical wire or sudden loss of power to the implanted pulse generator.
The risk of sudden stimulator failure is often directly proportional to the degree
of benefit, in the sense that greater benefit often is associated with greater reduction in concurrent medications. Thus should a DBS system fail, there is little or
no medication to compensate. Attempting to restore medications to compensate is
problematic because the time required to re-establish the medications prohibits it.
Prevention of failure is therefore the best medicine.
Clinical trials of DBS have shed light on the nonmotoric aspects of Parkinsons
disease following DBSissues of impulse control and suicide, for example. For
these issues, it is unclear whether DBS was actually associated with an increased
risk of these complications or whether these would be otherwise present by virtue
of the disease regardless of the DBS. For the duration of follow-up, these complications may have been more prevalent in the DBS clinical trials because study design
necessitated closer scrutiny, the frequency at which these potential problems were
clinically assessed. As many of these nonmotoric effects are not constant but episodic, the probability of detection is related to the frequency these problems appear,
the frequency at which they are assessed (sampling rate), and the duration of observation. Probability of detection may be assessed using Bernoulli-type statistical
studies, which to my knowledge have not been conducted.
The frequency and quality of risk assessments also has to be determined in light
of their prevention or reversibility. Adequate surveillance may mitigate the risks
of DBS. It must therefore figure in the overall assessment of the riskbenefit ratio.
Also, most studies can quantitate various outcome measures. Yet interpreting them
in light of clinical meaning is highly problematic. Not doing so risks misrepresentation. For example, one of the most consistent cognitive complications directly
relatable to DBS surgery is a reduction in verbal fluency. The degree of clinical
impairment, however, is mild to moderate.
As with any medical intervention, there are risks. DBS surgery carries risks of
irreversible or significant complications on the order of 1% to 3%, and deaths have
occurred with a risk of 0.2%.
30
R ED U CT I O N O F M ED I CAT I O N S
Many patients with Parkinsons disease do well from a motoric perspective with
medications but are unable to tolerate effective doses. One of the benefits of DBS
is reduction of medication-induced side effects following successful DBS surgery,
particularly DBS in the vicinity of the subthalamic nucleus. For example, a patient
may experience very good symptomatic control with medications but be unable
to tolerate the hallucinations and delusions that resolve when the medications are
reduced. The benefit of DBS may be increased by corresponding reduction in medications allowed by successful surgery. This also is the case for patients who do well
with symptomatic control but develop disabling dyskinesia. Again, DBS allows for
control of dyskinesias, and, at least in the case of DBS in the vicinity of the globus
pallidus interna, the stimulation may control the dyskinesia and allow the patient
to be treated medically with greater aggressiveness.
D U R AT I O N O F B EN EFI T
The duration of benefit is a critical question. The clinician clearly does not wish
to subject a patient to the risks of DBS surgery if the benefit will be short-lived.
In the case of DBS for Parkinsons disease, this is a relatively minor issue because
most long-term studies have demonstrated long term benefits (Rodriguez-Oroz
etal. 2012). This issue will become central in DBS for other conditions, such as DBS
in the vicinity of the thalamus DBS for cerebellar outflow tremor in patients with
multiple sclerosis.
PH A R M AC O EC O N O M I C C O N S I D ER AT I O N S
Medical decisions are increasingly being taken out of the hands of individual
patients and their physicians or healthcare professionals. How a patient may be
treated is increasingly determined by those entities that pay for the treatment
private and governmental agencies, for example. One approach is to assess the
respective economic consequences of doing and not doing DBS. Studies demonstrate the cost benefit of DBS surgery over the long term, but even this is complicated by the mechanisms by which the long-term savings are realized and by whom
(Tomaszewski and Holloway 2001; Meissner et al. 2005; Valldeoriola et al. 2007;
Shan etal. 2011; Dams etal. 2013; Valldeoriola etal. 2013). In a healthcare system
in which patients change insurers every few years, for example, long-term concerns
are more problematic. The initial insurer may not directly reap the benefit for the
investment of surgery while a subsequent insurer may.
Admittedly, if every insurer were to provide for DBS, then all parties would benefit in the long term. The insurer of the initial surgery may not realize the return
on that investment before the patient moves on to another insurer. However, that
initial insurer may realize the return when another patient becomes a client of the
insurer and had DBS done previously. It is not clear, however, whether such rationale is typically implemented by insurers.
C O M PE T EN C E O F T H O S E S EL ECT I N G PAT I EN TS,

I M PL A N T I N G D B S SYST EM S, A N D PR OV I D I N G
T H E P O STO PER AT I V E CA R E
DBS surgery is complicated by any measure. At the very least, the complexity is
evidenced by the controversies in the literature regarding who and when should be
selected, how the surgery should be done, and who should provide the postoperative care. Further, the complexities usually mean that there is likely to be significant
variance in the skills of the physicians and healthcare professionals involved. This
variance is worsened by the lack of well-substantiated, prospectively proven methodologies. Though such studies are highly problematic to conduct, it is not clear
how patients may simply be asked to wait. Admittedly, there are basic principles
that can and should provide guidance (Montgomery 2010). Yet it is unclear how
often they are used. At the least there appears to be consensus that it is important
to place the DBS lead in the sensorimotor region of the subthalamic nucleus, globus pallidus interna, and ventral intermediate nucleus of the thalamus. Yet there
appears to be little consensus of how to place the DBS lead. There is not even agreement as to how one might develop a consensus about how to place the DBS lead.
The epistemic (how facts come to be known) and ontological (what those facts are)
implications do not obviate the need to make decisions, and the clinician is left to
make a decision that is based on reason, however reason is defined. What is clear is
that making the decision is not a responsibility that can be avoided. One can delegate
authority or choose not to exercise it, but one cannot delegate responsibility.
For referring physicians, responsibility means that they must have a sound
understanding of that which may be optimally achieved by DBS and of whether
the surgical team and those providing postoperative care may reasonably achieve
the optimum. Referring physicians or healthcare professionals may delegate the
authority by virtue of referring strictly within their healthcare provider network in
the belief that they may avoid responsibility with respect to the competence of the
neurosurgeon and to the managers of the healthcare provider network. It would
seem that the implicit responsibility physicians have for their patients would obligate them to refer to a reasonably competent surgical team. The balkanization of
healthcare delivery and the restrictive constraints on patients certainly limits the
prerogatives of the latter to maximize their utility as far as healthcare expenditures
are concerned.
FACTS A N D A D D I T I O N A L FACTO R S
The following discussion is more from a conceptual perspective rather than an enumeration of the various outcome measures and incidences of adverse effects. It is
presented in this manner because enumerated statistics, such as those discussed
previously, have little value in themselves alone. This is evidenced by the relative
paucity of patients actually referred for DBS. In order to achieve any clinical meaning, the statistics must be placed in context. Therein lies the problem. There are
at least two necessary contexts. One is epistemological, and the other is ethical.
Epistemology deals with how one knows that which one purports to know. It is
32
therefore important to understand the source of some measures used to assess benefit and risk and to assess their validity in judging benefit and risk.
The second perspective is ethical because the questions of benefit and risk require
at least two pieces of knowledge, which the statistics of outcome measures and incidence of adverse effects cannot answer. The first is the necessary dichotomization of
data situated on a continuum (see c hapter13 for an extensive discussion). Outcome
measures are typically continuousthe speed of movements, for example. This
continuum must be divided into slow, normal, or fast, because the decision must be
made whether to operate or not to operate.
The second piece of knowledge is how to compare benefit to risk so as to know
what ratio can be dichotomized into either too little or sufficient benefit relative
to the risk. This is very much like comparing apples to oranges. This calculation
is made more problematic by the occasionally opposing ethical principles of a
patients (or a patients legal surrogates) autonomy and the principle of nonmalfeasance (refraining from causing harm), which particularly bear on physicians.
Patient or their surrogates cannot force a physician or healthcare professional to
do something that the latter would consider malfeasance. Alternatively, physicians
and healthcare professionals must recognize that they cannot possibility know the
extent to which a patients disease affects quality of life. Apatient alone knows how
much risk she is willing to face.
A physician or healthcare professionals notion of nonmalfeasance may be
affected by omission bias, in which an error of commission (referring a patient for
surgery) outweighs an error of omission (not referring a patient). This notion of
Omission bias is outmoded, because it does not bear on the patients ultimate quality of life (see chapter19).
D EEP B R A I N ST I M U L AT I O N TA R G E TS
There are a number and perhaps increasing targets for DBS in Parkinsons disease.
Currently, those include the subthalamic nucleus, globus pallidus interna, ventral
intermediate thalamus, pedunculopontine nucleus, and motor cortex (the latter
two considered off-label use of an FDA approved device). Also demonstrating
benefit in experimental or anecdotal studies are the globus pallidus externa (Vitek
etal. 2012), zona incerta (Khan etal. 2011), and putamen (Huang etal. 2014). The
different targets demonstrating clinical benefit in large-scale studies are discussed
first, because they may vary in the benefits and risks (direct surgical risks excepted).
Incidence of intracranial hemorrhage is consistent across disease indications and
targets. The risk of an intracerebral hemorrhage is on the order of 10% based on
postoperative neuroimaging. Incidence of symptomatic hemorrhage, however, is
on the order of 1% to 2%. The severity of the intracerebral hemorrhage is a function
of the volume or extent of the hemorrhage. The symptoms relate to the regional
anatomy although with respect to weakness related to involvement of the corticospinal tract is close to all of the targets with the possible exception of the putamen.
DBS in the vicinity of the subthalamic nucleus appears to have the consensus as
being the most effective. The primary evidence for this is fact that early clinical trials
demonstrated greater improvement in the motor UPDRS with DBS in the vicinity
of the subthalamic nucleus compared to the vicinity of the globus pallidus interna
(Deep Brain Stimulation for Parkinsons Disease Study Group 2001). However,
patients were not randomized to the subthalamic nucleus or globus pallidus
interna. Those patients who underwent DBS in the vicinity of the globus pallidus
interna tended to be done earlier in the study compared to those who had DBS in
the vicinity of the subthalamic nucleus. It is therefore not clear that the greater
improvement with DBS in the vicinity of the subthalamic nucleus reflected overall
increases in experience and skill that benefited those latter patients who predominantly had DBS in the vicinity of the subthalamic nucleus.
Subsequent studies in which patients were randomized to DBS either in the
vicinity of the subthalamic nucleus or the globus pallidus interna did not demonstrate any statistically significant differences. This may only mean that if there was a
difference it could not be found. Such a conclusion may reflect a type II error rather
than any truly existing difference. The more appropriate test is to determine what a
meaningful difference between DBS in the vicinity of the subthalamic nucleus and
globus pallidus interna would be and then estimate the power based on this difference and the variance determined in the study. If the sample size was sufficientan
80% probability of demonstrating a difference of p <.05, for examplethen it may
be concluded that DBS in the vicinity of the subthalamic nucleus and globus pallidus interna effects are equivalent relative to the motor UPDRS (Wellek 2010).
Early studies (Deep Brain Stimulation for Parkinsons Disease Study Group2001)
demonstrated statistically significant improvement in posture and gait scores
within the motor UPDRS with subthalamic nucleus stimulation and not statistically significant difference with stimulation of the globus pallidus interna. This is
problematic, however, because failure to demonstrate a statistically significant difference is not synonymous with the claim that there is no difference. Astudy may
fail to demonstrate a statistically significant difference as a consequence of variability in the outcome measures, despite the fact that the mean (or median) changes are
different between the experimental and control group. The proper question regards
demonstrating inferiority or noninferiority of one group vis--vis another. Such
demonstration requires a very different approach (Wellek 2010). The implication
was that DBS in the vicinity of the subthalamic nucleus addresses a wider range of
symptoms and is therefore clinically superior.
Comparison between the associated medication reductions between DBS in the
vicinity of the subthalamic nucleus and the globus pallidus interna may be taken as
an indication of the relative efficacy with the presumption that greater medication
reduction will occur with use of the more powerful treatment. This is problematic,
however, because the effects of DBS of the two structures on medication-related
dyskinesia render it so. DBS in the vicinity of the globus pallidus interna directly
reduces dyskinesia and thereby may reduce the inducement to reduce medications,
if dyskinesia is a major factor. Yet DBS in the vicinity of the subthalamic nucleus
initially may cause an increase in dyskinesia, thereby creating a greater inducement
to reduce medications.
There does appear to be a consensus that DBS in the vicinity of the globus pallidus interna is associated with fewer cognitive complications than DBS in the
vicinity of the subthalamic nucleus. Clinical studies have been inconsistent in demonstrating no difference in cognitive problems between DBS of the two structures,
or when there was a difference, the incidence of cognitive problems were less with
globus pallidus interna DBS. Apossible explanation is that the subthalamic nucleus
34
is a more compact structure. As such it makes avoiding nonmotor (limbic and cognitive) regions of the subthalamic nucleus more difficult than is the case with the
globus pallidus interna.
The relative differences in efficacy and adverse effects between DBS in the vicinity of the subthalamic nucleus and the globus pallidus internal must be taken in the
context of the technical requirements of placing the DBS lead. In my opinion, DBS
in the vicinity of the globus pallidus interna is technically more complicated than
DBS in the vicinity of the subthalamic nucleus, inasmuch as it concerns the context
of using microelectrode recordings for target localization. In one study, the number
of microelectrode penetrations to reach the physiologically defined optimal target
in the subthalamic nucleus was 1.44 (Montgomery 2012). The number of penetrations by the same group in globus pallidus were at least 3 penetrations in order to
define the posterior limb of the internal capsule (unpublished observation).
Conspicuously absent in the discussion is DBS in the vicinity of the thalamus
DBS. There is clear evidence that thalamic DBS improves the tremor of Parkinsons
disease. The presumption is that DBS in the vicinity of the thalamus is less effective
for other symptoms such as bradykinesia. Yet this may not be accurate, because
most patients subjected to DBS in the vicinity of the thalamus were selected predominantly on account of their tremor. Their other symptoms were minimal. The
effect of DBS in the vicinity of the thalamus on the symptoms other than tremor
cannot therefore be excluded. However, the potential effects of DBS in the vicinity
of the thalamus on speech, particularly in patients with bilateral disease who may
need bilateral DBS in the vicinity of the thalamus, militates against the use of DBS
in the vicinity of the thalamus.
Some have argued that unilateral DBS in the vicinity of the thalamus may be
very effective in patients with unilateral and sever tremor. The problem is that the
symptoms are unlikely to remain only tremor, assuming the patient has idiopathic
Parkinsons disease as opposed to other conditions such as Essential tremor or dystonic tremor.
Other structures are under consideration for the treatment of Parkinsons disease, although the experience thus far makes definitive recommendations problematic. Perhaps most discussed is the pedunculopontine nucleus, especially for
gait and postural problems. To date, DBS in the vicinity of the pedunculopontine
does not appear to be very effective for upper extremity function (Stefani etal. 2007;
Khan etal. 2011). In a patient with significant gait and postural disturbance, the
DBS in the vicinity of the subthalamic nucleus may be the initial choice, because
clinical evidence suggests that it may help with gait and upper extremity function.
If the DBS in the vicinity of the subthalamic nucleus fails to improve gait and posture, then DBS in the vicinity of the pedunulopontine nucleus may be considered.
It is interesting that, notwithstanding the fact that for some targets experience
is too meager to recommend clinical use, stimulating virtually anywhere within
the basal ganglia-thalamic-cortical system improves the symptoms of Parkinsons
disease. Nevertheless, the fact that DBS of virtually any structure within the basal
ganglia-thalamic-cortical system may improve Parkinsons disease argues that
Parkinsons disease is not the consequence of a disorder in any single component
the globus pallidus interna, for example. Current theories suggest the opposite.
Rather, Parkinsons disease is a systems disorder whose pathophysiology results
from altered physiology of the entire basal ganglia-thalamic-cortical system.
Because DBS anywhere within the system is efficacious, clinical decisions are
based on motor-adverse effects. Most adverse effects are related to unintended
stimulation of structures adjacent to the main target. It may well be that some targets have few adjacent structures that, when stimulated, give rise to adverse effects.
The putamen is a possible example.
S U M M A RY
DBS in the vicinity of the subthalamic nucleus or globus pallidus interna is effective
and relatively safe. DBS provides greater improvement and causes fewer long-term
side effects than best medical therapy. The surgical risks while significant are infrequent. In patients who have exhausted all reasonable attempts at medication therapy,
DBS is a reasonable option. Indeed, it appears unreasonable not to consider DBS.
R EFER ENCES
Dams J, Siebert U, Bornschein B, etal. Cost-effectiveness of deep brain stimulation in
patients with Parkinsons disease. Mov Disord. 2013;28(6):763771.
Deep-Brain Stimulation for Parkinsons Disease Study Group. Deep-brain stimulation
of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinsons
disease. N Engl J Med. 2001;345(13):956963.
Huang H, Watts RL, Montgomery EB Jr. Effects of deep brain stimulation frequency on
bradykinesia of Parkinsons disease. Mov Disord. 2014;29(2):203206.
Khan S, Mooney L, Plaha P, etal. Outcomes from stimulation of the caudal zona incerta
and pedunculopontine nucleus in patients with Parkinsons disease. Br J Neurosurg.
2011;25(2):273280.
Meissner W, Schreiter D, Volkmann J, et al. Deep brain stimulation in late
stage Parkinsons disease: a retrospective cost analysis in Germany. J Neurol.
2005;252(2):218223.
Montgomery EB Jr., Gale JT. Mechanisms of action of deep brain stimulation (DBS).
Neurosci Biobehav Rev. 2008;32(3):388407.
Montgomery EB Jr. Deep Brain Stimulation Programming: Principles and Practice.
Oxford:Oxford University Press; 2010.
Montgomery EB Jr. Microelectrode targeting of the subthalamic nucleus for deep brain
stimulation surgery. Mov Disord. 2012;27(11):13871391.
Rodriguez-Oroz MC, Moro E, Krack P. Long-term outcomes of surgical therapies for
Schupbach M, Gargiulo M, Welter ML, etal. Neurosurgery in Parkinson disease:a distressed mind in a repaired body? Neurology 2006;66(12):18111816.
Shan DE, Wu HC, Chan LY, et al. Cost-utility analysis of Parkinsons disease. Acta
Neurol Taiwan 2011;20(1):6572.
Stefani A, Lozano AM, Peppe A, etal. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinsons disease. Brain 2007;130(Pt
6):15961607.
36
Tomaszewski KJ, Holloway RG:Deep brain stimulation in the treatment of Parkinsons

disease:a cost-effectiveness analysis. Neurology 2001;57(4):663671.
Valldeoriola F, Morsi O, Tolosa E, et al. Prospective comparative study on
cost-effectiveness of subthalamic stimulation and best medical treatment in advanced
Valldeoriola F, Puig-Junoy J, Puig-Peiro R, et al. Cost analysis of the treatments
for patients with advanced Parkinsons disease: SCOPE study. J Med Econ
2013;16(2):191201.
Vitek JL, Zhang J, Hashimoto T, etal. External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia
thalamic network. Exp Neurol. 2012;233(1):581586.
Weaver FM, Follett K, Stern M, etal. Bilateral deep brain stimulation vs best medical
therapy for patients with advanced Parkinson disease:a randomized controlled trial.
JAMA 2009;301(1):6373.
Wellek S. Testing Statistical Hypotheses of Equivalence and Noninferiority. Boca Raton,
FL:CRC Press; 2010.
Identifying the Least Acceptable

Deep Brain Stimulation
Candidates Among Patients with
ParkinsonsDisease
T H E L E AST AC C EP TA B L E?
The title seems counterintuitive, but the real issue in patient selection is not identifying the best patient, unless the purpose is to cherry-pick so as to have the best
outcomes. However, this would be a violation of the obligation to beneficence and
justice to those who are on the edge of candidacy (see c hapter19). While generally
there is relatively little contention when the best patient presents, the challenge is
when the less than perfect patient who has failed all other hopes at relief presents for
consideration of DBS. When consideration reaches to discussion among surgeons,
physicians, and healthcare professionals, the discussion often exposes the means
of reasoning, presuppositions, and limits of supporting data. More important, the
discussion reveals the epistemic nature of the information or data on which decisions are based compared to the nature of the decision.
The decision to offer Deep Drain Stimulation (DBS) is a dichotomous variable with only two conditions, either recommend or not recommend. The data
on which the decision is made, typically, is continuous. Patients have a range
of responsiveness to levodopa, a range of disabilities, and a range of cognitive
involvement, for example. The question is where to draw the line in the continuous range so that the dichotomous decision can be made. One tendency is to
also dichotomize the otherwise continuous criteria. Thus the criteria often take
the appearance of a checklist, wherein each criterion is described as present or
absent. Appreciation that the decisions are not nearly so neat is lost. Yet there is
something appealing to dealing with dichotomized criteria rather than grappling
with data on a continuum.
In a continuum, only the extremes are easily recognized, and this has driven
conceptualizations since Aristotle and his notions of the contraries. The physicists [...] have two modes of explanation, Aristotle wrote. The first set make the
38
underlying body oneeither one of the three or something else which is denser
than fire and rarer than airthen generate everything else from this, and obtain in
multiplicity by condensation and rarefaction. Now these are contraries which may
be generalized into excess and defect. (Aristotle 2001). The second set, according
to Aristotle, consist of contrarieties [that] are contained in the one and emerge
from it by segregation and that also produce other things from their mixture
by segregation (Aristotle 2001). Aristotle dismissed the second set. The appeal of
dealing only with the best candidates or noncandidates by defining criteria applicable to only the best or unacceptable candidates is understandable. Not only is
this unfair to patients, as described previously, but it is a disservice to nonexpert
physicians and healthcare professionals who are expected to be the gatekeepers for
access to DBS.
Perhaps one source of cognitive discomfort is the realization (explicitly or implicitly) that, ultimately, the decision on where to draw the line is a value judgment that
immediately entails ethical concerns. These ethical concerns seem out of place in
medicine that has been invaded by scientism since the late 1800s. Indeed, some
of the most vociferous objections to the publication of the Code of Ethics by the
American Medical Association in 1847 were the academic physicians who believed
that scientific advances would make ethical concerns obsolete. Even within science there has been a discussion of whether science must be value free (Douglas
2009). It is an irony that it is precisely the advance of science, particularly medical science, that has generated even more ethical concerns and the relevance of
addressing them. It was the outrageous actions of medical scientists that culminated in the Belmont Report that established ethical supervision for the conduct
of human research (National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research 1979).
T H E PAT I EN T- S EL ECT I O N C O N T E X T
Patient selection should be considered within the context of healthcare care delivery systems. Movement disorders specialists usually do not initiate the selection
process, if for no other reason than their already few numbers are dwindling.
Indeed, the selection process often begins with the primary physician or healthcare
professional who fields the first mention of a complaint referable to Parkinsons
disease.
Admittedly, no DBS recommendation is likely to issue from a patients initial
visit. Yet understanding the primary care physicians and healthcare professionals
respective roles is nonetheless important. For example, a number of door-to-door
community surveys found that 24% to 42% of subjects with Parkinsons disease,
whom the survey sought to identify, had gone undiagnosed (cited in de Lau and
Breteler 2006). At least 5% of patients diagnosed with Parkinsons disease are likely
to be misdiagnosed (Newman et al. 2009). Extrapolation suggests considerable
numbers of patients are not being offered the potential benefits of DBS, while other
patients may be inappropriately subjected to the risks of DBS surgery because of
being misdiagnosed with Parkinsons disease. This reflects a failure of the healthcare delivery systems primary care services. It is not reasonable to heap upon the
4. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinsons Disease39
many demands already borne by primary care physicians and healthcare professionals the additional responsibility of being movement disorders experts as well.
Yet that is precisely the effect of most published selection criteria, as the actual
use of such criteria implies a high level of movement disorders sophistication, as
described in the following.
When constructing a system of DBS patient selection, physicians or healthcare
professionals must address the problems attending their initial fateful decision,
which is but the first of several. Suspicion of Parkinsons disease represents the first
selection criterion, and insufficient symptomatic benefit with a Parkinsons disease
diagnosis represents the second. Evidence suggestive of either criterion offers sufficient grounds for referring a patient to the next level of expertise. Aprimary care
physician may refer a patient to a general practice neurologist, who may in turn
refer her to a movement disorders neurologist.
EPI ST EM O LO GY O F S EL ECT I O N C R I T ER I A
Several publications treat the matter of selection criteria. The following discussion
distills various considerations of some of the more problematic criteria. Some considerations focus on the epistemology behind the reigning criteria, that is, the basis
on which rest the claim or inference informing a criterion rather than a criterions
particular content. Lang and colleagues (2006), for example, offer an extensive
and evenhanded analysis of possible selection criteria. Yet they drew much of the
data informing their analysis and subsequent recommendations from publications
reviewing benefits, complications, and other aspects of experience with DBS. In
truth, the recommendations are circular because the patients whose response to
DBS provided the basis for the recommendation had been previously subjected
to prior selection criteria. The subsequent recommendations are for clinical care,
while the criteria that formed the basis of the sequent recommendations were for
research. There is thus no way to know how the previous selection criteria might
skew the current recommendations. At the very least, the two criteria are fundamentally different given their intent.
A typical example is the issue of preexisting cognitive problems. Current clinical
recommendations exclude patients with any cognitive problems, as did the clinical research trials. The question becomes:on what basis was the clinical criterion
prohibition based on cognitive problems made? It certainly is not based on reasonable experience with DBS in patients with cognitive problems, as the experience
excluded those patients. However, as Carl Sagan was said to say, The absence of
evidence is not evidence of absence. This is a form of argumentum ignorantium, or
arguing from ignorance. There is no data on the effects of DBS on patients with preexisting cognitive problems; therefore, it is taken that preexisting cognitive problems represent unacceptable risk.
It is clear that selection criteria may exert a significant influence. Morgante and
colleagues (2007), for example, applied the Core Assessment Program for Surgical
Interventional Therapies in Parkinsons disease and found that 1.6% met the DBS
in the vicinity of the subthalamic nucleus consideration criteria. Application of criteria of greater flexibilitya higher age limit of 75years, for exampleincreased
40
that number to 4.5%. If the relaxed criteria were more appropriate, then adhering
to the previous strict criteria would result in a significant number of patients being
denied DBS inappropriately.
Greatest proximity to actual provision of surgery determines the ultimate selection criterion, which may be any one of the following criteria:(1)diagnosis of idiopathic Parkinsons disease, (2) exhaustion of all reasonable medication options,
(3)lack of any cognitive deficits that limit subsequent benefit despite improvement
in motor symptoms, (4)surgery tolerance, or (5)adequate postoperative management. Each criterion is discussed in the following.
Diagnosis of Idiopathic Parkinsons Disease

The first criterion, diagnosis of idiopathic Parkinsons disease, or differential
diagnosis of Parkinsons disease according to its clinical manifestations, involves
but is not limited to the following syndromes:(1)idiopathic Parkinsons disease,
(2)multisystems atrophy (MSA), (3)progressive supranuclear palsy (PSP), (4)vascular Parkinsons disease, (5) normal pressure hydrocephalus, (6) drug-induced
parkinsonism; (7)Wilsons disease, and (8)Kuffs disease or another rare neurodegenerative disorder. Currently indicated for idiopathic Parkinsons disease, DBS in
patients with other-than-idiopathic Parkinsons disease, as experience has shown
in most cases, failed to improve or worsened their symptoms (Tarsy et al. 2003;
Chou etal. 2004; Talmant etal. 2006; Lambrecq etal. 2008; Zhu etal. 2014). Most
selection criteria are therefore directed at minimizing the risk of performing DBS
on patients with other-than-idiopathic Parkinsons disease.
An understanding of any diagnostic procedures epistemic basis is important.
Measures of the effectiveness of diagnostic tests are understood as positive predictive value (the probability that a positive test actually indicates the presence of
the disease) and the negative predictive value (the probability that a negative test
actually indicates the absence of the disease). Positive predictive value and negative
predictive value depend on the sensitivity and specificity of the test. Test sensitivity is determined by the percent of patients with the disease who test positive,
and specificity is the percent of persons without the disease who test normal. In
addition to the specificities and sensitivities, prior probabilitiesthe prevalence of
the disorderare combined to produce the positive predictive value and negative
predictive value (both are based on Bayes theorem, which is discussed extensively
in the Preface).
No perfect test for diagnosing idiopathic Parkinsons disease exists. The existing
imperfect test faces significant risk of producing false positives and false negatives.
Whether tests are derived from patient history, physical examination, or neuroimaging, diagnostic measures demonstrate overlap between idiopathic Parkinsons
disease and such conditions as MSA and PSP. One may thus adjust the number of
false positives relative to the number of false negatives by adjusting the cutoff of the
diagnostic measures. Reducing the number of false positives, however, typically
increases the risk of false negatives and vice versa. Reason demands that the cutoff
in use be adjusted to provide the best balance between the consequences, in the
widest sense, of a false positive or a false negative diagnosis.
One must bear in mind the practical consideration that a number of different
diagnoses of Parkinsons disease vary according to the consequences of either misdiagnosis (that of Parkinsons disease in patients who in fact have a different disease) or missed diagnosis. As the consequences vary under different circumstances,
particularly as they touch upon the choice of therapeutic intervention, so too do the
diagnostic criteria vary. For example, if the consequence of making a diagnosis is
to begin a patient on levodopa, a generally well-tolerated medication, the criteria
are far less stringent than does proposing DBS as a treatment, whose consequences
are serious but rare. Levodopa seldom harms patients who are believed to have
Parkinsons disease but who in truth have MSA or PSA. Indeed, they may gain
some benefit. If the consequence is levodopa prescription, mistakenly diagnosing idiopathic Parkinsons disease in patients with MSA or PSP admits of a small
downside beyond that of an inability to provide patients and their family members
or caregivers with the appropriate prognosis. If the consequence is DBS surgery,
however, mistakenly diagnosing idiopathic Parkinsons disease in patients with
MSA or PSP admits of a large downside in the form of major risks with little or no
accompanying benefit. The criteria in the latter case will clearly be more stringent.
The critical task becomes that of determining the set of criteria for the diagnosis
of idiopathic Parkinsons disease that is just barely sufficient to justify DBS. The
criteria have to be such that not too many patients with MSA or PSP are mistakenly sent to surgery and not too many patients with idiopathic Parkinsons disease
are denied surgery and its subsequent benefit. This raises the ethical issue of the
number of patients with idiopathic Parkinsons disease who go without a potentially life-changing treatment relative to the number of patients without idiopathic
Parkinsons disease who receive it. Regardless of the criteria, the risk of denying a
patient with idiopathic Parkinsons disease is high, because the prevalence (prior
probability) of idiopathic Parkinsons disease to other forms of parkinsonism is
quite high.
A test for distinguishing patients with idiopathic Parkinsons disease from those
with MSA or PSA offers a useful example. Consider a hypothetical test whose specificity is assumed to be 80% and its sensitivity 80%, levels that many would consider
suitable for diagnosis. Yet in a situation in which the population is 80% patients
with idiopathic Parkinsons disease and 20% patients with MSA or PSA, the test
will identify 20% of patients with MSA and PSP as having idiopathic Parkinsons
disease. If the total population consists of 100 patients, then 16 of the 20 patients
with MSA and PSA would receive a correct diagnosis and thus avoid ultimately
ineffective surgery. The remaining four patients, however, would receive an incorrect diagnosis of idiopathic Parkinsons disease and consequently undergo ineffective surgery. Furthermore, 64 of 80 patients with idiopathic Parkinsons disease
would be diagnosed correctly and offered DBS, and 16 would not. For every one
patient with MSA or PSA who is protected from ineffective DBS, four patients with
idiopathic Parkinsons disease will be denied effective DBS. Is this ratio acceptable,
ethically speaking? If it is not, what ratio would be?
No calculus or set of facts promises to answer to this question. Because it is situated on a continuous rather than a dichotomized scale, moreover, the degree of
confidence associated with any set of diagnostic criteria cannot rest on any absolute judgment. How slowly must a patient perform a hand openingclosing task
for the rate of speed to be deemed symptomatic of bradykinesia in support of a
42
diagnosis of idiopathic Parkinsons disease? What degree of action tremor remains

within the diagnostic bounds of idiopathic Parkinsons disease rather than entering the diagnostic bounds of MSA or Essential tremor? Answers to questions of
this sort ultimately depend on the physicians degree of confidence, as well as the
willingness of patients and their family members or caregivers to accept some
uncertainty.
Current Typical Criteria Related to the

Diagnosis of Idiopathic Parkinsons Disease
The following requirements determine the typical criteria for DBS candidacy:(1)unilateral onset of symptoms or, at the very least, asymmetric severity;
(2)disease duration of five years or greater; (3)history of levodopa responsiveness
(either by patient history or formal evaluation); (4) absence of early dementia;
(5)absence of early and advanced autonomic dysfunction; (6)absence of symptoms suggestive of cerebellar dysfunction; and (7)absence of evidence of upper
motor neuron syndrome. These criteria were designed to reduce the number of
false positives arising during selection of patients with idiopathic Parkinsons
diseasefalse positives, that may result in diagnosis of Parkinsons disease in
patients who actually have MSA or PSP, in an excessive numbers of patients. One
might add to the list the following three requirements:(1)absence of significant
cognitive dysfunction, (2) absence of significant depression, and (3) absence of
significant impulse control issues. The second and third additional criteria are
based on experience following DBS surgery. The more problematic first criterion
is discussed in the following.
The criteria for weeding out patients with MSA and PSP are based on the
United Kingdom Brain Bank study of postmortem clinicalpathological correlations (Hughes, Ben-Shlomo, etal. 1992). Autopsy-controlled studies suggest that as
many as 25% of patients thought to have idiopathic Parkinsons disease instead had
MSA, PSP, or some other form of parkinsonism for which DBS is likely not indicated (Hughes, Daniel, etal. 1992). The criteria enumerated previously are thought
to be effective at reducing inclusion of patients with such atypical parkinsonism
such as MSA or PSP.
It appears these criteria for DBS candidacy for clinical purposes are essentially
the same as for clinical trials research. The problem is that these research criteria
appear to have been translated, whole-cloth and rather uncritically, into clinical
criteria. Clinical criteria should reflect patients best interest. It is not at all clear
that the best interests of a clinical trial necessarily are the same as patients best
interests. These criteria are very appropriate for research as they are thought to
exclude patients with atypical parkinsonism who would expect to be less responsive
to treatments. The consequence would be a reduction of statistical effect size and an
increase in statistical variance, which would necessitate a large sample size, thereby
increasing the costs to the clinical trial. For the trial, the issue of inappropriately
excluding a patient with idiopathic Parkinsons disease is not an issueanother
patient with idiopathic Parkinsons disease can be found. At the very least, these
criteria in clinical applications need to be reexamined in the context of patients
best interests.
As a criterion, primarily unilateral or asymmetric presentation rests heavily on
the issue of tremor and the question of whether the patient has tremor-predominant
idiopathic Parkinsons disease or Essential tremor. The presumption is that patients

with Essential tremor are more likely than are patients with idiopathic Parkinsons
disease to present with bilateral and symmetric tremor. Evidence exists, however,
that shows tremor is often asymmetric in both Parkinsons disease and Essential
tremor. Careful tremor analysis in 48 patients with Parkinsons disease and 47
patients with Essential tremor found no group-side interactions on an analysis of
variance and that patients with Essential tremor were asymmetric (Farkas et al.
2006). ASydney multicenter study on the use of bromocriptine found that patients
who had a sustained response to bromocriptine had a higher rate of asymmetry of
77% compared to those who failed bromocriptine (asymmetry rate = 36%; Hely
etal. 1994). If one assumes that the patients meet reasonable criteria for idiopathic
Parkinsons disease, then 23% in the first group and 67% in the second group had
symmetric disease. Thus asymmetric symptoms may not be appropriate criterion,
as this would exclude many who have idiopathic Parkinsons disease.
The requirement that a patient have parkinsonism for at least five years is
based on the observation that early in the course of a patients disease it is difficult to distinguish MSA or PSP from idiopathic Parkinsons disease. MSA and
PSP advance more rapidly than does idiopathic Parkinsons disease; time must
pass before a patients symptoms reveal themselves as belonging to any one of
those diseases. Again, this point of differentiation has not been subjected to the
type of analyses necessary to establish diagnostic tests. According to this criterion, a patient with idiopathic Parkinsons disease who meets all other criteria
after the first year must wait an additional four years before she is offered the
potential benefit of DBS. Most physicians and healthcare professionals would
agree that requiring a patient to wait an additional four years is unreasonable.
The criterion therefore cannot be taken literally. Yet doing so has the advantage
of simplifying the decision, which may benefit physicians and healthcare professionals but does little for patients.
The issue of time of consideration for DBS has spawned an interest in studying
DBS in subjects with less than or equal to three years of disease (Deuschl et al.
2013). The assumption is that more effective DBS would lead to an overall greater
degree of function. However, if one is willing to give up the criteria that a patient
has to wait five years, as argued for, then a study of early intervention is moot.
The requirement for demonstration of levodopa responsiveness derives from clinicalpathological correlations. These correlations established that 97% of patients
with autopsy-proven idiopathic Parkinsons disease had a history of responsiveness to levodopa (Hughes, Daniel, et al. 1992). Failure to respond to levodopa
indicates a mere 3% probability that a patient has idiopathic Parkinsons disease.
Approximately 25% of patients with MSA or PSP realize a benefit from levodopa
that ranges from slight to moderate. In terms of an idiopathic Parkinsons disease
diagnosis, a 3% chance of a false negative appears to attend lack of levodopa responsiveness, whereas a 25% chance of a false positive appears to attend demonstrated
levodopa response.
These false positive and false negative rates relate to the specificity and sensitivity
of levodopa responsiveness. Consideration of prior probabilities, however, must be
based on the prevalence of idiopathic Parkinsons disease relative to MSA and PSP,
which is 75% to 25%, respectively. Of 100 subjects presenting for consideration of
DBS for idiopathic Parkinsons disease, 75 subjects will actually have the disease.
44
Of those approximately two (or 3%) will go undiagnosed because they will fail to
respond to levodopa. The false positive rate will be 6, or 25% of the remaining 25
subjects with MSA or PSA. Application of the levodopa-responsiveness criterion to
all 100 subjects leads to the denial of DBS to 2 patients with idiopathic Parkinsons
disease and unnecessary DBS surgery on 6 patients with other-than-idiopathic
Parkinsons disease. One must decide whether the fact that more patients will
undergo unnecessary DBS surgery than will be denied it represents a reasonable
tradeoff.
Some centers formalize the assessment of levodopa responsiveness by evaluating patients before they take some dose of levodopa and again after they take it.
Some centers have established a criterion of a 30% improvement according to the
motor scales of the Unified Parkinsons Disease Rating Scales. One study compared
the preoperative levodopa response to the postoperative improvement in the motor
Unified Parkinsons Disease Rating Scales (Charles etal. 2002). That study demonstrated a correlation between the degree of levodopa improvement shown during
the challenge test and the degree of improvement shown after it. The adjusted R 2
was 0.32, however, which means that the levodopa response explained only 33%
of the outcome. Also, all of patients who would had levodopa improvement of less
than 30% did as well as some patients who had over a 39% improvement. As other
studies have demonstrated, patients with severe tremor or dyskinesia induced by
levodopa, which improved symptoms by less than 30%, nonetheless experienced
significant benefit from DBS (Morishita etal. 2011).
Though the study by Charles etal. (2002) was not intended to distinguish idiopathic Parkinsons disease from other-than-idiopathic Parkinsons disease, it does
have value in the consideration of selection criteria. In this case, the correlation
coefficient is not a proper measure of diagnostic utility. More appropriate would
have been a ReceiverOperator Characteristic curve analysis, because the area
under the ReceiverOperator Characteristic curve provides a reliable estimate of
diagnostic utility by showing the tradeoff between specificity and sensitivity evident at different cutoffs (degrees of improvement with levodopa). I require some
evidence of levodopa responsiveness and have found that patient history offers sufficient evidence.
The presence of early dementia is thought to be more consistent with atypical
Parkinsons disease; the presence of cerebellar signs and corticospinal tract involvement were thought to be more indicative of atypical parkinsonism. Insufficient epidemiological evidence exists to permit precise accounting of the diagnostic value
of these individual criteria.
A diagnostic utility derived from the United Kingdom Brain Bank criteria has
been shown to have an 82% accuracy rate, which is the combined rate of true
positives and true negatives (Hughes, Daniel, et al. 1992). Sixteen of 24 subjects
with atypical Parkinsons disease met the criteria for idiopathic Parkinsons disease, whereas of 76 total, a mere 3 subjects with pathologically demonstrated idiopathic Parkinsons disease received an incorrect diagnosis of atypical Parkinsons
diseasea diagnosis that would have led to their being improperly denied DBS.
Sixteen patients with atypical Parkinsons disease would have been misdiagnosed
as having idiopathic Parkinsons disease and subjected to ineffective DBS surgery.
Given this possibility, one must doubt the accuracy of selection according to United
Kingdom Brain Bank criteria.
Exhaustion of All Reasonable Attempts at

Nonsurgical Management
By reasonable attempts at nonsurgical management is primarily meant
medications. A plethora of medications might be used. At least two forms of
levodopa-containing medications (regular and sustained-release), five dopamine
agonists (regular, sustained, and transdermal, among others), two monoamine
oxidase type B (MAO-B) inhibitors, and two catecholamine-o-methyltransferase
(COMT) inhibitors are available in the United States, for instance. These 11 forms
of medication therapy admit of 2,047 possible combinations. Only slightly fewer are
the possible combinations of MAO-B and COMT inhibitors, which are rarely used
in monotherapy for purpose of controlling symptoms. If one assumes that a trial
of each combination, which consists of a titration period and evaluation period,
requires at least two months time to complete, trying every possible combination
would require over 300years. This is clearly unacceptable. The task becomes, then,
that of reducing combinations to some reasonable number.
To the extent that it is synonymous with randomized control trials (RCTs),
Evidence-Based Medicine is unfortunately of no help. If one faithfully follows the
stipulations of Evidence-Based Medicine, then one must perform an independent
clinical trial of each of the nearly 2,000 combinations. Instead, we must therefore
develop a plan according to Reason-Based Medicine (Montgomery 2012).
In view of the large number of possible combinations of medications, one has
to adopt some strategy based on the most relevant question. The first question
is whether any agent used was used in sufficient quantity. Sufficient quantity is
defined as that dose that (1)achieves a sufficient level of relief (not relevant in the
consideration of DBS candidacy), (2)is limited by some adverse effect that cannot
be circumvented, or (3)attains a dose where any further increase is futile. The latter
requires a doseresponse analysis that plots the number of patients who achieve
a satisfactory level of control at a particular dose. The point on such a plot that
becomes asymptotic would indicate the dose at which no further increase has a
significant probability of achieving additional benefit. A similar analysis can be
performed relative to adverse effects.
Clinical trials that include an initial dose titration period could provide some
insight into the doseresponse curve unless there was a maximum dose and a significant number of subjects reached the maximum dose. Anumber of studies limited the dose of ropinirole to 12 mg per day and the average doses were very near
that limit. Consequently, the data most likely reached a ceiling effect that would
prevent determination of a dose beyond which there is futile hope of increased efficacy or tolerance. Similarly, a number of studies limited pramipexole to 4.5 mg
per day as the average daily dose, and the standard deviation suggested that most
reached the maximum dose allowed. Unfortunately, these studies do not answer the
question:at what dose is further increase futile either because of lack of increased
efficacy or adverse effects.
A dose-ranging study of pramipexole had a maximal dose of 6 mg per day.
In that study 67% completed the study, suggesting that a significant number of
patients can tolerate doses of pramipexole of 6 mg per day (Safety and Efficacy
of Pramipexole 1997). Extrapolating to candidacy for DBS, if a patient took less
than 6 mg per day and were not experiencing any dose-limiting side effect, then
46
one might consider further upward titration. With respect to transdermal rotigotine, one study demonstrated that 8 mg/day was the minimum dose necessary to
achieve a significant effect (Nicholas etal. 2014). Unfortunately, no mention was
made as to the maximum dose, and it may well be that 8 mg per day was the maximal dose allowed in the study. The doses of the MAO-B inhibitors, selegiline, and
rasagiline are limited to 10 mg and 1 mg, respectively, as significantly higher doses
greatly increase the risks associated with systemic inhibition of MAO. Doses of
entacapone are limited by their plasma half-life and typically are taken as adjunct
to levodopa.
Unfortunately, after extensive search in PubMed, Icould not find sufficient data
to determine a dose beyond which further efficacy would be futile or would have a
high risk of adverse effects. Nevertheless, Ihave adopted a maximal dose of ropinirole as 24 mg/day; pramipexole as 6 mg per day; rotigotine as 12 mg per day, and
levodopa as 2,000 mg per day assuming no dose-limiting adverse effects. One must
bear in mind that some doses may exceed those described in FDA-authorized package inserts and FDAcompliant online medical texts.
The question arises as to the status of anticholingeric, including amantadine
(as used for Parkinsonian symptoms rather than dyskinesia). The consensus
appears to minimize their role despite evidence of effectiveness and relative safety
(Katzenschlager et al. 2003). Concerns have been raised about their use in older
patients. However, one study prospectively treated 90 patients ages 35 to 92years
(mean 55.9, standard deviation 13.4) of which only 8 developed cognitive problems,
and these patients were not disproportionately older (Nishiyama etal. 1998). There
has been the assumption that anticholinergics are better for tremor and dystonic
features; however, this has not been borne out by a meta-analysis (Katzenschlager
etal. 2003).
An interesting and potentially helpful approach is to look at the total daily dose
of medications as levodopa equivalents. However, Ihave no experience with this
approach nor do Iknow of any data published that bear directly on it. Rather, it
is offered as a suggestion for consideration. In the Deep-Brain Stimulation for
Parkinsons Disease Study, the total levodopa equivalence in the patients undergoing DBS in the vicinity of the subthalamic nucleus was 1,218 mg per day with a standard deviation of 575 mg. The dose at the 95% of the one-tailed normal distribution
would put the dose at 2,164 mg per day in levodopa equivalence if one assumes
there was no upper limit on the agents that could be used in combination, particularly levodopa (Deep Brain Stimulation for Parkinsons Disease Study Group2001).
Similar findings were found in a separate clinical trial (Deuschl et al. 2006). In
calculating the levodopa equivalents one adds to the total daily immediate-release
levodopa dose 0.75 times the total daily dose of controlled-release levodopa; 1.11
times the duodopa dose; 20 times the ropinirole dose; 30 times the rotigotine; and
100 times the pramipexole dose. When immediate-release levodopa is taken with
medications that affect the bioavailability of levodopa such as entacapone, tolcapone, rasagiline, and selegiline, the total daily levodopa dose is multiplied by 0.33
times the entacapone and then added to the total daily levodopa dose; 0.5 the tolcapone and then added to the total daily levodopa dose; 10 times the oral seleiline
dose and then added to the total daily levodopa dose; 80 times sublingual selegiline
dose and then added to the total daily levodopa dose, and 100 times rasagiline dose
and then added to the total daily levodopa dose (www.birmingham.ac.uk).
The next issue is the sequential use of different agents. The question is whether,
for a patient who failed maximal use of drug A, it is necessary to attempt
drug B either because of efficacy or adverse effects. It is important to note that
population-collapsed data (in other words, when data is compared across subjects)
rather within-subject data is not helpful. Just because drug A may be much more
effective than drug B in a population does not mean that an individual patient
who fails drug A will not respond to drug B. To precisely answer the question, a
study would have to identify subjects who failed drug A and then test whether they
improved with drug B. Given the paucity of data that directly bears on this subject,
one could just take the position that drug A, shown to be more effective than drug
B in population studies, will obviate the need to try drug B should drug A fail. This
approach certainly would make the problem of excluding all reasonable attempts
at medication therapy more tractable. Similarly, if drug A has a higher incidence
of the same spectrum of adverse effects compared to drug B, then failure of drug
B could be taken to obviate the need to try drug A. Such an approach would be
arbitrary, but in the absence of data that directly bears on the question, it may be
practical and hence constitutes an accepted approach to reducing the number of
medication combinations to a feasible number.
Issues of Efficacy
A significant problem is the lack of any structured data that bears on the issue and
the complexity of the pharmacokinetics and pharmacodynamics relative to efficacy. There is considerable evidence that maintaining a constant level of levodopa
in the blood, and hence in the brain, provides the continuous optimal control. It is
important to note that plasma and brain levels are not synonymous necessarily. For
example, early in Parkinsons disease, the functional response to levodopa can far
outlast or have a longer functional half-life (related to the duration of the clinical effect) than the plasma half-life. The pharmacokinetics makes this problematic
for medications that have a short effective plasma presence or functional half-life.
In situations with short plasma presence, efficacy can be considered as peak-dose
effect and duration of effect. For example, the plasma presence of levodopa and
immediate-release carbidopa/levodopa approximates its plasma half-life of approximately 90 minutes. Early in the disease patients may do well with dosing three
times per day, indicating the functional half-life is considerably longer than the
plasma half-life. However, with more advanced disease the functional half-life
begins to approximate the plasma half-life. Similar considerations are true of controlled or extended-release agents.
The issue of efficacy can be divided into peak-dose effect and duration of effect.
Peak-dose effect is the clinical response when the medication is at its highest brain
level, often approximated by the peak plasma level. The duration of effect relates to
the duration of sufficient symptomatic relief. Thus an agent can have an acceptable
peak-dose effect but an insufficient duration of effect. Consequently, assessment of
exhaustion of reasonable medications based on efficacy must separately address
peak-dose effect and duration of effect. For example, agonists and controlled-release
preparation of levodopa may be more efficacious for problems with duration of
effect but perhaps not with peak-dose effect.
First addressed is the peak-dose efficacy. There is considerable but indirect
evidence that levodopa is more efficacious than dopamine agonists alone. In
48
prospective trials involving randomization to either dopamine agonists, ropinirole

and pramipexole, versus levodopa, substantial numbers of subjects required adjunctive levodopa to their dose of dopamine agonists (Parkinson Study Group 2000;
Rascol et al. 2000). Thus patients who have not had sufficient peak-dose benefit
with dopamine agonists still may benefit from the addition of levodopa. However,
it is not clear that a patient who has not received a sufficient peak-dose effect from
levodopa would obtain a sufficient peak-dose effect from dopamine agonists alone.
There are a number of studies demonstrating increased efficacy with the use of
dopamine agonists adjunctive to levodopa (Mizuno etal. 2007). This might suggest
that patients who have not had sufficient efficacy with levodopa should be tried on
dopamine agonists as adjunct. However, the clinical trials do not appear to differentiate the added value of dopamine agonists on peak dose versus duration of
effect. Clearly, the dopamine agonists have an advantage of a longer plasma half-life
and therefore may be adjunctive to levodopa regimens associated with wearing-off
effect. However, it is not clear that adjunctive use of dopamine agonists ameliorate insufficient peak-dose effects from levodopa. Consequently, if levodopa proves
insufficient in terms of peak-dose effect, it is reasonable to conclude that adjunctive
use of dopamine agonists, including ropinirole, pramipexole, and rotigotine, are
unlikely to increase the peak-dose efficacy. However, problems with duration of
effect are a different issue with dopamine agonist effective for wearing-off effect.
It is unclear whether immediate-release carbidopa/levodopa has the greater
peak-dose efficacy than controlled- or extended-release carbidopa/levodopa; however, controlled- or extended-release carbidopa/levodopa has greater duration of
action. A similar consideration applies to intraduodenal infusions of levodopa
preparation. In some countries governmental approval is pending for the use of
constant intraduodenal infusions of levodopa-containing medications, which is
expected to be effective in improving insufficient duration of peak-dose effects
(Palhagen et al. 2012). Three patients (8%) had tube stoma infections, and one
patient (3%) had peritonitis. This method carries surgical risks, because a catheter
must be inserted in the duodenum. Uncertain at present is whether the riskbenefit
ratio is such that intraduodenal levodopa infusions should be considered prior to
considering DBS. If the issue is peak-dose efficacy, in my judgment it is unlikely
that a patient failing immediate-release carbidopa/levodopa will have any greater
peak-dose efficacy with controlled- or extended-release carbidopa/levodopa, and
the same may be true for intraduodenal infusions of levodopa. The primary reason
is that, in the absence of adverse effects and without consideration of wearing-off
effects, there is no reason to believe that higher peak-dose effects can be achieved
with controlled- or extended-release carbidopa/levodopa, immediate-release carbidopa/levodopa, or intraduodenal levodopa preparations than with any other.
However, controlled- or extended-release carbidopa/levodopa may provide greater
duration of effect and thus be of benefit in situations of wearing-off effect compared
to immediate-release carbidopa/levodopa.
In my experience, the use of controlled- or extended-release carbidopa/levodopa
appears to have fallen out of favor despite clinical trials that demonstrate significant peak-dose effects and an advantageous duration of effect. It appears that
the between-individual variability in absorption makes the use of controlled- or
extended-release carbidopa/levodopa problematic. Levodopa can only be absorbed
in the distal jejunum. Thus if the tablet of controlled or extended release is only
partially dissolved by the time the medication reaches the distal jejunum, less
levodopa will be absorbed and less clinical effect will be achieved.
Absorption of levodopa from controlled- or extended-release carbidopa/
levodopa is dependent on gastrointestinal motility, which can be quite variable
between subjects and within a subject. Thus controlled- or extended-release carbidopa/levodopa may be unpredictable, making achieving a consistent response
problematic. However, one cannot know a priori whether an individual patient will
have a consistent and effective response. Thus it is reasonable that the patient should
be given the benefit of the doubt and treated with controlled- or extended-release
carbidopa/levodopa if wearing off is a problem.
Similar rationales extend to the adjunctive use of MAO-B and COMT inhibitors,
as there is nothing in principle to suggest that high plasma levels of levodopa cannot be achieved with immediate-release carbidopa/levodopa alone as compared to
levodopa with adjunctive MAO-B or COMT inhibition. However, adjunctive use
of MAO-B and COMT-inhibitors may provide greater relief of wearing-off effect
compared to immediate-release carbidopa/levodopa alone.
If one MAO-B inhibitor also failed to provide the patient adequate symptomatic
control, there is insufficient evidence to suggest anything is to be gained by switching to a different MAO-B inhibitor. The same situation may be different among the
COMT inhibitors where tolcapone may be more effective, as the former inhibits
COMT in the peripheral while the latter inhibits COMT in the periphery and in the
central nervous system. However, there are concerns about hepatotoxicity with the
use of tolcapone. With respect to efficacy within the dopamine agonists there is evidence to suggest that rotigotine is greater than pramipexole, which is greater than
ropinirole (Chitnis etal. 2012). However, there are few head-to-head comparisons,
particularly where a patient fails at one agent then improves on another.
Adverse Effects
Two types of adverse effects are considered. First are peak-dose dyskinesias where
the risk for dyskinesia follows the same considerations as peak-dose effects. In
other words, agents or combinations of agents with the greatest peak-dose effect are
more likely to produce dyskinesia. Consequently, if peak-dose dyskinesia is the factor limiting medication use, then switching to medications with lower risks of dyskinesia may be effective if they have not been attempted previously. Alternatively,
one can try adjunct of amantadine up to 300 mg per day.
There are many and diverse adverse effects from the treatment of Parkinsons disease in addition to dyskinesia. Many are treatable by the choice of anti-Parkinson
medications used or by adjunctive use of other medications. For example,
anti-Parkinson medications vary in their risk for confusion or disorientation with
immediate-release carbidopa/levodopa having the least risk (Etminan etal. 2003).
Dopamine agonists also vary in their risk for cognitive side effects, with ropinirole
and rotigotine having less risk than pramipexole.
The same relative ranking in risks for cognitive problems appears to be similar to
those producing paranoia and hallucinations. The latter can be treated with atypical neuroleptics such as quetiapine and clozapine with the latter the most effective.
Nausea often can be treated with adjunctive use of plain carbidopa or domperidone.
Similarly, orthostatic hypotension can be treated by migrating away from agents
with the greatest risk, such as dopamine agonists, to those with the least risk, such
50
as immediate-release carbidopa/levodopa. Also, orthostatic hypotension can be

treated with thigh-high antiorthostatic hypotension stockings giving 30 to 40mm
Hg compression with caution to avoid letting the stockings bunch, gather, or roll as
this may cause a tight ligature and interfere with circulation in the lower extremities. In addition, mineralocorticoids and sympathomimetic drugs can be used such
as droxidopa and midodrine.
As has been the case, there are few if any direct studies comparing all the options
within a category such as agents for hallucinations, and so on. While population
studies may suggest one agent may be more efficacious or have lower risk of adverse
effects, these data are difficult to extrapolate to individuals.
The Issue of Preexisting Cognitive Impairment

A lack of directly relevant data makes the issue of preexisting cognitive impairment difficult to address. In many ways, RCTs performed under the auspices of
Evidence-Based Medicine is partly responsible for this difficulty. Patients with significant preoperative cognitive impairments were excluded despite a lack of any
clear evidence of significant incremental risks. Their exclusion was based, rather,
on the supposition that they would experience greater complications from the DBS
surgery. Evidence-Based Medicine also provides no means of mitigating the impact
of the exact conditions under which the associated RCTs were conducted. In other
words, the DBS RCTs provide no data or knowledge for fair resolution of the issue
of preoperative cognitive impairment. No studies have demonstrated any predicative value of cognitive measures for patient outcomes. This may owe in part to a
need for a certain degree of variability in subjects cognitive functions in the correlation study in order to parse the effects of cognitive function on the outcome
measure. As patients with cognitive problems were excluded, there is insufficient
variance by which to establish any correlations.
An approach anchored in Reason-Based Medicine is to invent a heuristic to deal
with this issue. If the issue is risk of cognitive decline following DBS surgery, one
must determine whether the risk is high. If it is, then it may be reasonable to presume that patients with preexisting cognitive impairment face higher risk of further cognitive decline, one which may be deemed unacceptable.
It does not appear to be the case that DBS surgery carries a high risk of significantly worsened cognitive function. Admittedly, a decrease in verbal fluency has
been described regularly, but the effect is mild to moderate. These observations are
only of partial help, however, because it is unknown whether the risk for surgically
induced significant decline is different for patients with significant preoperative
cognitive impairments as these patients generally have not been allowed DBS. One
quite reasonable heuristic is thus to assess the degree to which preexisting cognitive
decline impairs the patients quality of life. If the cognitive impairment is such that
anticipated improvements in motoric function would not significantly improve the
patients quality of life, then proceeding to DBS is of little value.
The task becomes that of determining the best way to proceed in the absence of
definitive evidence. One option is to maintain possibly quite restrictive requirements while awaiting the results of Evidence-Based Medicine RCTs that may never
be conducted. Doing so would be to potentially deny patients the DBS benefit.
Asecond option is to proceed with careful observation in some type of open-label

study that is conducted in much the manner as is a quality-control program.
Operating on patients with limited but significant cognitive impairment, on the
other hand, is undesirable if no follow-up on the issue is expected.
Drug-induced cognitive or psychological impairments represent a special case.
Selection for DBS is appropriate in cases in which the diagnosing physician is confident that these problems are the result of medications rather than the underlying
disease. Many patients are able to substantially reduce their medications. It is therefore reasonable to expect improvement in drug-induced cognitive and psychological problems.
The Issue of Depression

Following DBS surgery, there is concern that patients with Parkinsons disease face
a risk of suicide that, though small, is significant. RCTs suggest that this is not the
case (Weintraub et al. 2013). Nevertheless, potential risk of increased depression
following DBS surgery must not be discounted. This does not mean that significant depression represents an exclusionary criterion unless there is concern that
this depression adversely affects a patients ability to make decisions. It may simply
mean, rather, that a physician or healthcare professional needs to establish a prior
plan for psychiatric surveillance and intervention.
Impulse Control Problems
Impulse control problems are common in patients with Parkinsons disease irrespective of treatment. There is some concern that DBS may increase impulsivity.
Patients must therefore be screened preoperatively. This does not mean, however,
that impulsivity is an exclusionary criterion. Rather, increased surveillance and
methods for intervention, such as those devised to mitigate suicide risk, must be in
place prior to DBS surgery.
Ability to Tolerate Surgery

The patient must not have any psychological or physical health problems that
increase the risk of complications or reduce the potential for benefit. Implanted cardiac defibrillators and other conditions may contraindicate DBS surgery. Patients
whose psychiatric disorders may warrant electroshock or electroconvulsive therapy
must consider forgoing DBS surgery, the few successes in this area notwithstanding. Patients who are likely to be exposed to strong environmental electromagnetic
fields may be advised to forgo DBS surgery. Patients for whom DBS surgery is contraindicated may wish to consider pallidotomy or thalamotomy.
Age
Early in the history of DBS therapies, some institutions enforced a rigid age restriction they had been uncritically imported from DBS clinical trials. Considerable
evidence suggests that, depending on biological (overall condition and comorbidities) as opposed to chronological age, patients of advanced age face no undue risk
and may therefore benefit from DBS (Ory-Magne etal. 2007).
52
Degree of Severity
Potential benefits, which are clearly related to the severity of the disease, serve,
when measured against risks and alternatives, as the basis for a decision to proceed with DBS surgery. The severity of the disease is not measured by the motor
examination of the Unified Parkinsons Disease Rating Scales or any quality-of-life
measure. Only patients or their surrogates may determine the degree to which the
disease compromises their life and what they are willing to risk.
A physician or healthcare professionals role is to ensure that patients or their
surrogates have sufficient understanding for making an informed decision. Any
physician or healthcare professional who decides for a patient, or who acts in a
manner contrary to a patients decision, violates that patients autonomy and thus
commits an ethical breach. Ethical standards have long stipulated that physicians
and healthcare professionals respect wide discretion on the part of patients or their
surrogates. Yet physicians and healthcare professionals cannot be forced to provide
treatments they deem malfeasant. In such circumstances, consultation with a bioethicist may help (see c hapter19).
Plans for Postoperative Care

No DBS benefit is realized until such time as an implanted pulse generator is activated and programmed. Consequently, it could be considered unethical to proceed
with DBS surgery without prior assurance of timely and appropriate postoperative DBS management. This is not an inconsequential concern. Traveling a great
distance to undergo DBS surgery may pose no problem, but traveling that same
distance repeatedly for postoperative DBS management does. Despite what one
might expect, the majority of neurologists appear unwilling to offer postoperative
DBS management. Most neurologists are very busy. Persuading them to take on the
additional responsibility of DBS management is problematic. In most cases nurse
practitioners and physician assistants may attend to the DBS systems day-to-day
management. Yet a physician must nonetheless play a supervisory role.
Patients postoperative DBS management requires more than an implanted pulse
generator adjustment; a patients medications must be adjusted as well. Unless a
neurosurgeon has extensive knowledge and experience in medication adjustments,
she may not be in the best position to provide postoperative care. Further, industry
representatives likely do not have sufficient breadth and depth of knowledge, particularly as it relates to medications and other nonsurgical therapies adjunctive to
the treatment of Parkinsons disease. Certainly, industry representatives are helpful in consulting as to the electronics, but asking them to do more is unfair to the
representatives as well as the patient.
Exercise of Judgment and Sharing the Decisional Burden

It is quite clear from this chapter that once one looks beneath the general descriptions of selection criteria, they become highly problematic. There is very little
evidence that would directly bear on the choices one has to make in considering referring a patient for surgery. Using available data requires highly inexact
extrapolations from highly imperfect data; yet physicians and healthcare professionals cannot just avoid the question of whether to refer for DBS surgery.
Achoice to defer is a choice to withhold DBS. It is highly unlikely that the data
necessary for unambiguous resolution of who is the least appropriate patient for
DBS will be available.
Judgment is difficult, as physicians, healthcare professionals, patients, patient
surrogates, and society are asked to make comparisons that do not have the same
basis or reference, often having to compare apples to oranges. A place to start
is first critically examining what one thinks one knows. For example, one might
ask: where did current recommendations originate? Are those circumstances, if
from clinical trials, appropriate for clinical practice? At the least, such analysis
establishes the epistemic context that then creates the bounds of confidence within
which a decision must be made.
At this time it is not possible for a physician or healthcare professional to answer
exactly the question of whether a particular individual patient meets the least
acceptable criteria for candidacy for DBS surgery, nor is it necessary. Rather, the
physician and healthcare professional can educate the patient or surrogate as to the
current state-of-knowledge, however imperfect, and enlist the patient or surrogate
into a joint decision. Ultimately, the patient or surrogate makes the final decision, if
only to refuse DBS. The lack of perfect knowledge does not mean that the patient or
surrogate cannot make an informed decision that has ethical status.
S U M M A RY
DBS provides remarkable relief of the suffering and disability of patients with
Parkinsons disease. Like any diagnostic test, patient selection produces occasional
false positives (patients who face high risk but enjoy no prospect of benefit) and
false negatives (patients who enjoy a decent prospect of benefit but who are denied
DBS). Both eventualities must be carefully considered, and appropriate selection
criteria must strike a balance between them. Criteria developed for DBS RCTs are
inappropriate when adopted whole-cloth without prior critical review.
As can be seen, there is a paucity of data that address the direct concerns in
patient selection for DBS. However, this should not occasion nihilism or adventurism. Rather, the physicians and healthcare professionals are expected to use
their best judgment based on what evidence is available. If anything, the current
situation should engender equipoise, particularly if patients or patients surrogate is
included in the decision making (as they should be). The physician and healthcare
professional can not only discuss the state of knowledge but also the epistemic limits or uncertainty of that knowledge. The uncertainly should not engender cognitive paralysis.
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Postoperative Management of
Patients with Parkinsons Disease
EN S U R I N G T H E B EN EFI TS A N D M I N I M IZI N G T H E R I S KS
The benefits of Deep Brain Stimulation (DBS) accrue solely upon activation and
programming of the implanted pulse generator (IPG). Merely one part of postoperative DBS management, management of the IPG requires that one program electrode configurations (the combinations of active negative and positive electrical
contacts of an implanted lead) and electrical stimulation parameters, which include
the per-pulse amount of electrical current or voltage applied to the electrical contacts, pulse duration, and pulse frequency.
Despite DBSs remarkable benefits, patients with implanted DBS systems encounter difficulty receiving adequate, ongoing postoperative management, because they
cannot find physicians and healthcare professionals reasonably close to home to
provide it. Of the various reasons that exist for why postoperative DBS care provisions have not been more widely adopted by healthcare professionals, one should
not be postoperative DBS programmings inherent difficulty. Programming is
admittedly complex; many variables intervene. Yet the clinical task is made tractable by an understanding of the basic and fundamental principles of neuroanatomy
and physiology. Also, methodological descriptions and algorithms are published to
aid programmers (Montgomery 2010). In most cases, reimbursement for efforts in
postoperative care is reasonable, particularly if one considers that healthcare professionalsnurse practitioners and physician assistants, for examplemay provide
most postoperative management. Many would no doubt deem it unjust to deny
patients DBS on the basis of their place of residence. Few experiences gratify a physician or healthcare professional like that of observing the immediate, often dramatic response to DBS by patients who, moments before activation, were extremely
disabled.
IPG management serves the purpose of stimulating sufficiently intended brain
targets while at the same time avoiding stimulating unintended targets which
would produce adverse effects. In the brain the stimulation pulses generate a localized electrical field that primarily excites neuronal axons. One may control the size,
shape, intensity, and distribution of the electrical field by adjusting the electrode
configurations and stimulation parameters. These adjustments maximize benefit
5. Postoperative Management of Patients with Parkinsons Disease57
and minimize adverse effects. DBS enjoys the great advantage of providing individualized therapy by virtue of its many combinations of electrode configurations
and stimulation parameters. At the same time, a physician or healthcare professional assuming responsibility for a patients postoperative DBS management may
find the large array of combinations daunting.
Efficient, cost-effective DBS programming follows from employment of basic
principles of electronics, neuronal electrophysiology, and regional anatomy.
Though the principles and practice of IPG programming are beyond the scope of
this chapter, readers may find them treated in my other text, Deep Brain Stimulation
Programming: Principles and Practice (Montgomery 2010). The present text discusses issues of postoperative DBS care that go beyond IPG programming. Further,
postoperative management must address other forms of therapies, particularly
medication that act synergistically with DBS. Indeed, postoperative management
of medication therapies are integral to stimulator adjustments. For that reason, it is
inappropriate to defer stimulator management to an industrial representative who
lacks the knowledge, education, and skills necessary to adjust both the stimulator
and the medications. Because pharmacological management of Parkinsons disease
also lies beyond the scope of this text; readers are referred to Movement Disorders
(Watts etal. 2012).
R O L E O F PH YS I C I A N S A N D H E A LT H CA R E
PR O F ES S I O N A L S N OT D I R ECT LY I N VO LV ED I N
D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G
Though they may not provide programming, treating physicians or healthcare

professionals nonetheless continue to be involved, by election or default, in
a patients postoperative management, particularly if they referred the patient
for DBS surgery. They see patients frequently and may therefore be the first to
notice suboptimal control of the patients symptoms. Patient care stands to be
improved by an increased ability to recognize suboptimal DBS therapy:treating
physicians and healthcare professional are able to send their patients back to DBS
programmers.
Treating physicians and healthcare professionals are the first to observe a potential DBS adverse effect. The way in which they act in response to their observation depends on their understanding of the adverse effect. They must determine
whether it is related to DBS, changes in medications, or other factors.
In some circumstances, surgeons who implant patients electrode assume DBS
programming responsibility, but they may delegate the task of managing patients
medications to referring or treating physicians, associated healthcare professionals,
or industry representatives, who may lack sufficient knowledge and experience to
complete this task. Surgeons may change electrode configurations and stimulation
parameters, in other words, but leave subsequent medication changes to treating
physicians or healthcare professionals. This is not optimal.
Such division of labor is to be discouraged. DBS and the medications work synergistically. Changes to patients DBS programming tend to affect their medication requirements, and vice versa. Optimal programming therefore requires that
58
one adjust the DBS and medications together. A case illustrative of this point is
that of DBS in the vicinity of the subthalamic nucleus, an increase in whose intensity produces dyskinesia. On observing dyskinesia a DBS programmer unfamiliar
with appropriate medication adjustments is likely to reduce stimulation intensity,
which tends to reduce DBS benefit in the bargain. Leaving the stimulation intensity
unchanged and instead reducing medications, particularly those most likely to be
associated with the dyskinesia, is the better approach.
The goal of DBS is to provide optimal relief of symptoms and disabilities. It is
not necessarily to reduce medications arbitrarily. My experience, however, suggests that the degree of medication reduction, particularly in the case of DBS in
the vicinity of the subthalamic nucleus, is an indicator of DBS programmings
success. A Veterans Affairs and National Institutes of Health cooperative clinical
trial of DBS in the vicinity of the subthalamic nucleus has served to substantiate
this experience (Weaver et al. 2012). The degree of improvement as measured by
changes in the Unified Parkinson Disease Rating Scales in that study was significantly less than it was in other comparable studies, and the degree of medication
reduction was lower as well. I have seen DBS programmers who quickly and prematurely became frustrated, often because they did not fully understand DBS programming, reverting to that which they did know, namely, the use of medications.
Situation of this sort are unfortunate, because had medications been effective in
the first place, the patient taking them would have not needed DBS. Resorting to
medications essentially amounts to refusing to provide the patient with optimal
benefit.
I N D I CAT I O N S T H AT F U RT H ER I M PL A N T ED PU L S E
G EN ER ATO R PR O G R A M M I N G O R M ED I CAT I O N
A D J U ST M EN TS A R E N EC ES S A RY
Because the majority of patients with Parkinsons disease continue to require medications, the effectiveness of the medications and possible adverse effects from the
medications must be distinguished from those of the IPG. Though DBS is also
remarkably effective in reversing motoric symptoms, it typically does not improve
nonmotoric symptoms of Parkinsons disease, which significantly reduce quality
of life of patients and those who care for them. Indeed, DBS may worsen impulse
control disorder, depression, and other nonmotoric symptoms. Physicians and
healthcare professionals must therefore distinguish DBS effects from those of the
medications and the disease.
The importance of distinguishing the efficacy of DBS from that of medications rests on its ability to aid physicians and healthcare professionals subsequent
efforts at adjusting DBS or medications. One approach to drawing such a distinction is to determine whether the patient depends primarily on medications or DBS.
Apatients continued dependence on medications suggests that her DBS programming may be suboptimal.
Physicians and healthcare professionals must make a point of inquiring into a
patients ability to control his movements prior to taking his first morning dose of
anti- Parkinsons disease medications. Because DBS systems typically remain activated around the clock, movement control prior to the first anti-Parkinsons disease
medication dose reflects the degree to which DBS is responsible for that control.
Apatients showing significant symptoms indicates that DBS does not play a sufficient role in controlling them, and further efforts at programming the IPG are
therefore necessary. If however, the patient appears to be doing well in the morning,
then it is likely that the IPG is providing sufficient benefit.
A caveat concerning interpretation of symptoms status upon a patients waking:some patients with Parkinsons disease may enjoy a remarkable sleep benefit,
experiencing symptom relief independent of any specific treatment. In such cases,
it may be the sleep benefit rather than any optimal DBS that explains a patients
state. One must look to other helpful information, especially if the patients symptomatic control should fluctuate during the course of the day.
A wearing off effect, in which symptoms worsen about the time a patient is
to take his next dose, suggests that the patient continues to depend on medications, because the DBS effect is insufficient to prevent a patients symptoms from
worsening as the brain levels of medications fall. One may also ask the following
additional questions:(1)Do your symptoms get better or worse through the course
of the day? (2)Can you (or your caregiver) tell when its nearly time to take your
anti-Parkinsons disease medications? (3)Do your symptoms worsen if you forget
to take, or delay taking, your anti-Parkinsons disease medications? An affirmative
answer to any of these questions indicates that the patient continues to depend on
medications. His DBS is therefore failing to provide sufficient benefit. In such cases
efforts ought to be directed toward IPG programming.
It is possible that a patient may experience sustained insufficient symptomatic
control rather than fluctuations in the symptoms. Sustained insufficient symptomatic control suggests insufficiency of both DBS and medications. In this case, the
first effort should be directed at the IPG programming, because DBS is more likely
to provide sustained benefit, and because the medications have proven themselves
insufficient (the patient would not have otherwise undergone DBS surgery).
My practice is to make a conscientious effort at minimizing patients medications, which is done in an iterative fashion. Through the immediate postoperative
period, Imaintain a patient on the same dose of anti-Parkinsons disease medications. Some centers make an immediate and arbitrary reduction in medications
postoperatively. In my opinion, this practice carries significant risks that owe to
the fact that it is impossible to determine a priori the exact degree of medication
reduction.
The patients IPG is programmed to provide the maximum benefit possible without adverse effects. The patient is observed for a period of time to ensure that the
benefits are sustainedone week in the case of Parkinsons disease, for example.
If the benefit is sustained, the medications are reduced. The patient and her family
members and caregivers are warned that a loss of symptomatic control is expected
and, indeed, desired, because it permits symptoms to manifest sufficiently to provide a target for subsequent IPG programming. The patient returns for reprogramming and is observed to determine whether her symptoms have improved. If they
have, her medications are again reduced. This process is continued until the patient
receives maximally effective DBS at a minimal dose of anti-Parkinsons disease
medications.
Which medications to reduce first is a problematic issue. Ifocus on those medications that would be most responsible for any adverse effects the patient experiences.
60
In patients taking both a dopamine agonist and levodopa-containing compounds

who experience hallucinations and delusions, for example, the dopamine agonist would be the first to be reduced on account of its greater propensity to cause
hallucinations and delusions. If dyskinesias are a significant problem, however,
levodopa-containing compounds would be the first to be targeted on account of
their propensity to produce dyskinesia, which is greater than that of the dopamine
agonist. If a patient with dyskinesia takes an MAO-B or a COMT inhibitor along
with levodopa and dopamine agonists, the MAO-B or COMT inhibitor would be
the first to be targeted for reduction.
If the patient experiences no adverse effects, then her least effective medications
are reduced first. Patients taking both a dopamine agonist and levodopa-containing
compounds, for example, would first have the dopamine agonist reduced.
The number of electrode configuration combinations and stimulation parameters is extremely large. As such, it may cause a physician and healthcare professional to lose heart when confronted with a patient whose DBS appears ineffective.
They may give up too early. Experience at major DBS centers has shown that many
patients referred to them as DBS failures gain remarkable benefit from expert
reprogramming (Okun etal. 2005).
A DV ER S E EF F ECTS
An understanding of the regional anatomy around the DBS lead makes determining
whether any adverse effects are related to DBS, medications, or the patients underlying disease easier. Propagation of electrical current to unintended structures is the
basis for most of DBSs adverse effects. These adverse effects are DBS target-specific.
In the case of DBS in the vicinity of the subthalamic nucleus, adverse effects
result from inadvertent stimulation of the following structures:(1)the medial lemniscus (paresthesias); (2)the corticospinal tract (muscle contraction); (3)the fascicles of the oculomotor nerve (dysconjugate gaze, diplopia, eyelid apraxia); (4)the
brachium conjunctivum (ataxia); and (5)corticobulbar fibers. These symptoms are
unlikely to be caused by anti-Parkinsons disease medications. Their presence suggests, rather, that IPG reprogramming is necessary.
The electrical field from the DBS may extend medially or ventrally to the limbic and associative regions of the subthalamic nucleus. Unintended stimulation of
these regions may cause such mood abnormalities as depression and euphoria, or it
may cause increased impulse control disorder. IPG reprogramming often improves
these problems.
Speech involvement by DBS in the vicinity of the subthalamic nucleus can be
problematic. It may be due to involvement of upper motor neurons in the corticobulbar tract. If so, further increasing the stimulation voltage or current should
elicit facial muscle contraction. Alternatively, the effects on speech may be intrinsic
to the subthalamic nucleus and not related to unintended spread of stimulation
electrical current (or voltage) to the corticobulbar fibers. In this case, continued
increase in the stimulation electrical current may not produce facial muscle contraction. It is important to increase the stimulation current (or voltage) in order to
clarify which situation prevails.
In the vicinity of the globus pallidus interna, inadvertent stimulation may produce adverse effects in the following anatomical structures: (1) the corticospinal
pathway (muscle contraction), (2) the corticobulbar system (speech difficulties),
and (3)the optic tract producing (phosphenes, i.e., bright lights and other visual
hallucinations). Patients experiencing these problems may benefit from IPG
reprogramming.
Although rarely performed in patients with Parkinsons disease, DBS in the
vicinity of the ventral intermediate nucleus of the thalamus may affect, if inadvertently stimulated, the following structures:(1)the ventral caudal nucleus of the
thalamus (paresthesias), (2)the corticobulbar fibers (speech), and (3)the corticospinal tract (muscle contraction). As with DBS in the vicinity of the subthalamic
nucleus, speech involvement with DBS in the vicinity of the ventral intermediate
nucleus may be due to stimulation of the thalamus and not to corticobulbar fibers.
This situation should be assessed with increased stimulation as described previously. During the immediate postoperative period, patients with DBS in the vicinity of the ventral intermediate nucleus of the thalamus may experience occasional
gait problems, which are presumed to owe to stimulation of the ventral intermediate nucleus of the thalamus, which is the relay nucleus for cerebellar output to the
cortex. In the first few weeks following the beginning of DBS, patients may experience depression. Though this depression typically improves spontaneously, one
must stand ready and prepared to intervene.
Other adverse effects less likely to owe to DBS suggest referral to the patients
pharmacological management or the status of her underlying disease. Aphysician
or healthcare professional may discontinue DBS temporarily to observe whether
the adverse effects resolve. Care must be taken in this, however, because severe
worsening of a patients symptoms and disabilities may result. Case reports exist
that describe neuroleptic malignant-like syndromes manifesting with abrupt DBS
discontinuation (Urasaki etal. 2013).
PSYC H O SO C I A L D I S LO CAT I O N
Despite an immediately prior remarkable improvement in their motoric symptoms, some patients appear to experience an emotional and psychosocial breakdown (Schupbach etal. 2006)unlike the kind typical of depression or psychosis.
Many patients whose symptoms were considerably improved by medications experience similar emotional and psychological difficulties, the mechanisms of which
are unknown. One conjecture is that the remarkable improvement on the part of
the patient disrupts the psychosocial situation that had evolved during the patients
period of great disability; family members or caregivers seem to lose a sense of
self-worth that depended on giving care to an extent rendered unnecessary by DBS,
while the patient receiving their care comes to demand greater autonomy.
One must eliminate other possible causes, such as depression or euphoria related
to DBS. Again one can discontinue DBS temporarily to observe the effects and
at the same time watch for any exacerbation of the patients parkinsonism or the
development of a neuroleptic malignant-like syndrome. Impulse control problems
can be similarly addressed. However, problems such as gambling can be devastating
62
before they are recognized. Postoperative care must therefore include monitoring,
as well as individual and family counseling.
D E A L I N G W I T H EM ER G EN CY S I T UAT I O N S I N VO LV I N G
A PAT I EN T W I T H D EEP B R A I N ST I M U L AT I O N
As patients with implanted DBS systems increase, their presenting in emergency

situations will also increase. Unfortunately, most emergency-room personnel are
unfamiliar with the management of patients with DBS, and many, if not most,
neurologists called in to aid are likewise unfamiliar. In events in which expert
physicians and healthcare professionals in DBS management are unavailable,
emergency-room personnel may be tempted to consult industry representatives.
Yet industry representatives rarely have the necessary expertise or skills to deal
with emergencies. There are some basic steps, however, that emergency-room personnel may take to resolve an emergency.
As in any emergency situation, any immediate threats to life or limb must first
be addressed. Differential diagnosis in patients with an implanted DBS system is
no different than it is patients without DBS who present in the same manner. To
the usual differential diagnosis, rather, are added the potential DBS-related complications. Some emergency personnel leap to the inappropriate conclusion that the
condition is related to the DBS, and the presence of the DBS system itself may affect
the way in which they manage a patient in an emergency situation.
A number of acute and urgent problems attend the use of an implanted DBS
system. As foreign objects, they are at increased risk of infection. Risk of infection increases from skin erosion caused by the hardware. Because it is close to the
brain, the site at which the DBS lead exits the skull presents a particular cause for
concern in the event that it becomes infected. Intracranial hematomas, which tend
to occur during the immediate postoperative period but may occur any time postoperatively, may also result. The implanted DBS system itself may cause subdural
hematomas.
Patients with DBS may have seizures. Patients who have a seizure within a week
following DBS surgery appear to run no greater risk of subsequent seizures than
those who do not (Pouratian etal. 2011). Apatients circumstances may be such as
to necessitate short-term treatment with anticonvulsants. Seizures occurring later
in the postoperative period are associated with increased risk of recurrent seizures.
Seizure prophylaxis is therefore indicated.
Though unusual, urgent problems may be caused by brain stimulation. For
example, electrical current may spread to the corticospinal tract, causing tonic
muscle contraction that may continue until such time as the DBS is turned off or
reprogrammed. Similarly, patients may have persistent paresthesias owing to the
currents spreading to the medial lemniscuses posterior to the subthalamic nucleus.
Sudden failure of DBS may cause significant exacerbation of the very symptoms
for which the DBS was implanted. For example, a patient who underwent fetal cell
transplantation for Parkinsons disease developed severe runaway dyskinesia. DBS
controlled the dyskinesia. Once the DBS systems batteries were exhausted, however, the dyskinesia again became severe. The patient was managed by use of neuroleptics (dopamine antagonists) until the IPG was replaced. Because one is able
to determine whether a battery is low, sudden DBS failure may be prevented. As a

matter of standard and accepted care, all physicians and healthcare professionals
involved in postoperative DBS management must routinely check the IPG for its
remaining battery life.
Patients and their family members or caregivers must be given a device that
checks the IPGs battery status and instruction in its use. For their part, patients
and their family members or caregivers must make a habit of checking. Irecommend that patients and their family members or caregivers begin checking immediately after DBS implantation surgery so they may fall into the habit.
It is urgent that an IPG whose battery indicates eminent failure be replaced, even
if doing so inconveniences the implanting surgeon. Because the implanting surgeon may be unable to be available on a continuous basis, appropriate backup support must be arranged in advance.
Unless something about the situation forbids itinability to take medications
orally or the presence of an ileus, for instancea patient is given medications to
manage acute and severe symptom exacerbation attending DBS failure. In situations in which oral medication is impossible, transdermal rotigotine is an option
for worsening symptoms referable to Parkinsons disease. Irecommend that emergency facilities maintain a supply of transdermal rotigotine for emergency situations. Difficult at best, attempts to compensate sudden DBS failure with medications
often encounter substantial delays in reaching efficacy. One thus avoids the need for
medication compensation by never allowing an IPG battery to fail.
Patients and their family members and caregivers must be advised to keep the
IPG status-checking device with them at all times, because even during a short
errand an accident necessitating emergency care may happen. Also, it is likely that
the emergency-room personnel may need to rely on the patients device, because
they do not have at hand medical equipment necessary to control the DBS. The IPG
status-checking device must never be stowed in luggage that cannot be accessed
during a long trip. Physicians and healthcare professionals bear the responsibility
of ensuring that patients and their family members and caregivers understand these
instructions, because they are neither commonly known nor intuitively obvious.
In addition to battery exhaustion, sudden DBS failure may owe to, among others,
the following common causes:(1)lead or extension fracture, (2)poor or loose connection between the DBS lead and the extension or between the extension and the
IPG, (3)DBS lead migration that shifts the electrodes electrical contacts from their
proper positions, and (4)various other types of hardware failure. Irecommend that
routine AP and lateral skull, cervical spine, and chest X-rays be taken immediately
after DBS system implantation. These X-rays then serve as an important reference
and may be easily compared to similar X-rays obtained in the emergency situation,
especially if MRI or CT scan personnel are unavailable.
Patients with implanted DBS systems are more likely to present emergently
for reasons other than those related to their DBS. In those circumstances, the
presence of the implanted DBS system may affect a patients subsequent diagnostic workup and management. Exposing patients with implanted DBS systems
to high-strength electromagnetic energy, for example, may result in injury and
DBS malfunction. Some physicians, unaware of these risks, order MRIs for a
patient with an implanted DBS system. Certain head MRIs may be performed
under specific circumstances and by use of specific techniques, provided that the
64
DBS system is powered down beforehand. MRI of the chest, spine, or abdomen,
on the other hand, are contraindicated with current technology. In order to prepare for the event of treating a patient with DBS, emergency personnel are urged
to consult with the device manufacturers and establish evaluation and management plans. Physicians and healthcare professionals must also vie against a tendency toward being overly cautious, which may cause them to withhold certain
evaluations or managements and, in so doing, place a patient with DBS at even
greater risk.
The presence of the DBS hardware on X-rays or other imaging studies may obscure
underlying tissue and thus possibly confuse the radiology staff. The presence of the
DBS pulse artifacts on an EKG or EEG may also cause confusion. The presence of
an implanted DBS system may complicate surgical care:a surgeon working near
the implanted DBS hardware may damage it. In the situation of emergency cardioversion, care must be taken to minimize electrical current flow through the IPG.
Certain procedures, including but not limited to ultrasound or radiofrequency diathermy, are contraindicated with the current technology. Physicians and healthcare
professionals are strongly encourage to study educational materials and manuals
provided by the device manufacturers.
S U M M A RY
Physicians and healthcare professionals are likely to find providing DBS for patients
with Parkinsons disease a remarkably gratifying experience. Understandably, novice physicians and healthcare professionals may be somewhat reluctant to provide
this therapy, given the complexity of its postoperative management and the unfamiliar electrophysiology involved. Yet there are some fundamental principles that,
once mastered, render postoperative DBS management effective and efficient. Those
physicians and healthcare professionals who refrain from offering most operative
DBS programming may nonetheless become involved in postoperative management of patients with DBS, whether as a consequence of medical management of
the patients Parkinsons disease or some urgent situation. All parties involved
patients, physicians, healthcare professionalsmust prepare themselves for any
such eventuality.
R EFER ENCES
NewYork:Oxford University Press; 2010.
Okun MS, Tagliati M, Pourfar M, etal. Management of referred deep brain stimulation
failures:a retrospective analysis from 2 movement disorders centers. Arch Neurol.
2005;62(8):12501255.
Pouratian N, Reames DL, Frysinger R, et al. Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery: clinical article. J Neurosurg.
2011;115(2):310315.
Urasaki E, Fukudome T, Hirose M, et al. Neuroleptic malignant syndrome

(parkinsonism-hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus. J Clin Neurosci. 2013;20(5):740741.
Watts RL, Standaert DG, Obeso J. Movement Disorders. New York: McGraw Hill;
2012.
Weaver FM, Follett KA, Stern M, etal. Randomized trial of deep brain stimulation for
Parkinson disease:thirty-six-month outcomes. Neurology 2012;79(1):5565.
Deep Brain Stimulation Is Safe and

Effective for Essential Tremor
D EEP B R A I N ST I M U L AT I O N:AS A FE A N D EF F ECT I V E

T R E AT M EN T FO R ES S EN T I A L T R EM O R
Of unknown etiology, Essential tremor is a disorder that causes tremor as one of

the more prominent symptoms. The significant prevalence of tremor in relatives
of patients with Essential tremor argues for a genetic cause: incomplete or complex inheritance or additional contributing factors. Though tremor may occur at
any age, it typically occurs in adults. Because symptomatic tremor may be present
when a patient is at rest, Essential tremor is often mistaken for Parkinsons disease.
Though tremor frequency is thought to be generally higher in Essential tremor
(6 Hz to 15 Hz) than it is in Parkinsons disease (approximately 4 Hz), it has been
shown that rest tremors frequency of Essential tremor may slow with age. Rest
tremor in an elderly patient with Essential tremor may therefore have the same frequency as does rest tremor of someone with Parkinsons disease. Along with tremor
at rest, patients with Essential tremor may also exhibit tremor while holding their
arms outstretched or maintaining other sustained postures. Tremor of this kind
may also be present in patients with Parkinsons disease. Though rarely present in
Parkinsons disease, patients with Essential tremor also experience tremor when
they bring their fingertip to the tip of their nose or engage in similar actions.
It may be difficult at times to distinguish Essential tremor from tremorpredominant Parkinsons disease. Aclinician typically looks for other symptoms
that distinguish Essential tremor from Parkinsons disease. Bradykinesia is an
example. Adding to the difficulty of a differential diagnosis is the fact that bradykinesia may be seen in patients with Essential tremor to the same degree as it
does in patients with early Parkinsons disease (Montgomery etal. 1999). And, like
patients with early Parkinsons disease, patients with Essential tremor may manifest
cogwheel- or ratchet-like resistance to passive joint rotations. Unlike most patients
with Parkinsons disease, however, patients with Essential tremor often preserve
a normal sense of smell when corrected for age and sex. Recent imaging of the
dopamine transporter, which compare scans of patients with Essential tremor with
those of patients with Parkinsons disease, have reportedly revealed a preserved
sense of smell in the former. Positive and negative predictive values, however, have
not been determined for the most relevant clinical scenario, specifically in early or
6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor67
mild Parkinsons disease in which differential diagnosis between Essential tremor

and tremor-predominant Parkinsons disease is most acute. It is usually easy to
distinguish Essential tremor from Parkinsons disease in cases in which the disease
is advanced.
Though Essential tremor is more common than Parkinsons disease, fewer
patients with Essential tremor than patients with Parkinsons disease undergo
Deep Brain Stimulation (DBS). This tendency may owe to a number of causal factors. First, many patients or their physicians may think that patients tremor does
not warrant DBS (physicians deeming patients tremor insufficiently debilitating
to warrant DBS raises certain ethical issues; see c hapter19 for a discussion of these
issues). Also, patients may be unaware that DBS is an option for them, because their
treating physicians, who in most instances are not neurologists, may be unaware of
the fact that DBS is safe and effective. Many patients see a neurologist initially and
are prescribed medications. When these medications prove ineffective, as they do
in many cases, the patients taking them, despairing of any other treatment options,
give up their search for benefit (Lyons etal. 2003).
T H E N AT U R E O F D EEP B R A I N ST I M U L AT I O N
FO R ES S EN T I A L T R EM O R
The primary target for DBS is the ventral intermediate nucleus of the thalamus;
however, there are case reports of other targets being effective as well. The ventral intermediate nucleus of the thalamus is the relay nucleus for information
that originates in the cerebellum and travels to the motor cortex. I recommend
that microelectrode recordings be used to localize the target. First, no imagining technique differentiates the ventral intermediate nucleus of the thalamus
compared to the posterior ventral caudal thalamus, which must be avoided to
prevent limiting paresthesias with stimulation. One could argue that the posterior ventral caudal thalamus is sufficiently distant from the ventral intermediate thalamus. While this may be true in an anatomical distance between the
nuclei within an individual, it cannot be assumed true when biological variance
between individuals and increased variance due to technical issues are considered. Consequently, one cannot be confident that the image-based targeting,
particularly relative to the anterior and posterior commissure, can identify the
ventral intermediate thalamus.
Further, it is important to identify the specific homuncular representation
within the ventral intermediate thalamus. Also to be avoided is the head homuncular representation of the ventral intermediate nucleus of thalamus. Propagation
of electrical current from DBS to the head representation is thought to increase
the risk of speech, language, and swallowing problems. It is important to identify
the appropriate homuncular representation associated with the most bothersome
symptoms. Because tremor in Essential tremor, for example, is most often distal in
the upper extremity, the representation of the distal extremity must be targeted.
Conversely, in some forms of cerebellar outflow tremor, such as tremor related to
multiple sclerosis, the tremor is more proximal. The proximal representation is
therefore targeted. For cerebellar outflow tremor, DBS is considered an appropriate
off-label use of a device approved by the US Food and Drug Administration. The
68
rare patient may have lower extremity or orthostatic tremor, which indicates that
the lower extremity representation should be targeted.
The ventral intermediate nucleus of the thalamus is large (particularly in the
medial-lateral direction). It is therefore impossible to cover the entire structure by
indiscriminant placement of the DBS lead within the ventral intermediate thalamus. This is particularly true because the ventral intermediate thalamus, which is
narrow in the anterior-posterior direction, limits the volume of tissue activation.
As a consequence, it also limits the stimulation intensity in order to avoid posterior
extension of the field to the tactile region of the ventral caudal thalamus.
To date, no imaging studies differentiate the ventral intermediate, ventral caudal
nuclei of the thalamus, or various homuncular representations within the ventral
intermediate nucleus of the thalamus. One who foregoes microelectrode recordings
must use distances for the midpoint on the line that connects the anterior and posterior commissure. As a matter of practice, however, the position of the neurophysiologically defined optimal target and the target relative to the midpoint of the line
connecting the anterior and posterior commissure vary considerably. The source of
the variability is debatable. To some extent it may be related to biological variability
or to other factors related to variability in the DBS surgical methods. The latter is
particularly true for surgeons who are not assiduous in avoiding intracranial air,
which may expand as it warms to body temperature, thus causing significant brain
shifts. Forgoing microelectrode recordings and relying instead on imaging are thus
suboptimal practices.
One may argue that a surgeons choice rest mostly on habits developed in apprenticeship training. Unfortunately, habit is commonly confused for knowledge.
Surgeons may also become wedded to their methods for psychological reasons
(Fins 2008). Neurosurgeons are certainly not absolved of the responsibility of being
reasonable (and neither are physicians and healthcare professionals of any disciple),
but they seldom receive instruction in how to become so. For whatever reason, surgeons and physicians alike rarely stand to account for their practices unless they are
sued. For the threat of lawsuits to motivate reasonable practice, however, it must be
credible, and for the threat to be credible, injured patients must be able to recognize
that poor practice has done them the injury. Yet a patient is usually the party least
aware of whether a practice was good.
The situation appears to lead to the conclusion that a referring physician is perhaps in the best position to enforce effective surgical practice and may do so merely
by selecting the surgeon to whom to refer (see chapter19). The current balkanization of healthcare delivery into feudal fiefdoms, however, makes such enforcement
problematic. Of aid would be a movement to total accountability and reimbursement based on outcomes. These would provide incentive for all to practice reasonably as a way of ensuring optimal outcomes.
Significant concerns relate to whether bilateral ventral intermediate nucleus
DBS increases risks, particularly for speech, language, and swallowing difficulties. In many respects, this concern owes to the legacy of thalamotomy. Early in
its history, bilateral thalamotomy was found to carry unacceptable risk for speech,
language, and swallowing. However, immediate and unconditional transference
of concerns about bilateral thalamotomy to bilateral thalamic DBS probably is
likely unreasonable because thalamic DBS is reversible. In a five-year follow-up
studywhich consisted of 26 patients with Essential tremor and 19 patients with
Parkinsons disease, among the former of whom 18 had unilateral and 8 had bilateral thalamic DBSthe incidence of speech problems was 17% for unilateral and
63% for bilateral thalamic DBS (Pahwa et al. 2006). No unilaterally implanted
patients and 25% of bilaterally implanted patients exhibited gait disorders. Irecommend that if bilateral thalamic DBS is considered, it be staged in such a way
that the patient is observed following a unilateral procedure to ensure that the
thalamus suffered irreversible damage, which would increase the risks associated
with a second surgery on the contralateral side. In any event, a second thalamic
DBS on the contralateral side would constitute an off-label use of a Food and Drug
Administrationapproved device.
Some case series suggest that DBS in the vicinity of the subthalamic nucleus
may be effective for tremor owing to Essential tremor, an indication considered
off-label (Blomstedt et al. 2010). As it stands presently, it is hard to argue for
selecting the subthalamic nucleus over the ventral intermediate nucleus as the target. One possible advantage of DBS in the vicinity of the subthalamic nucleus, if its
efficacy is assumed to be equivalent to the efficacy of ventral intermediate nucleus
DBS, is lower risk of speech, language, and swallowing complications. This risk may
be reduced further in the event that an actual diagnosis is tremor-predominant
Parkinsons disease, the other symptoms of which are essentially treated in advance
of their subsequently becoming manifest.
EF FI CACY
Numerous studies demonstrate safety and efficacy. In a five-year follow-up of 26

patients, those patients with unilateral DBS in the vicinity of the ventral intermediate nucleus of the thalamus DBS experienced a 75% improvement in tremor, and
those with bilateral implants experienced a 65% improvement (Pahwa etal. 2006).
Iam aware of no randomized control trials (RCTs) that directly compare DBS to
best medical therapy in treatment of Essential tremor. Provided they are relatively
inexpensive, such RCTs would be welcome. Yet, because the cost promises to be
quite high, these studies will likely never be conducted. Clinicians must therefore
employ their best reasoning in light of available evidence. Those who suggest that
RCTs alone are capable of providing reasonable evidence are at best incapable of
understanding the nature of RCTs and their fundamental limitations. At worst,
they are solipsists.
Early studies demonstrating the effectiveness of DBS in the vicinity of the ventral intermediate thalamus required that patients exhaust all reasonable attempts at
medication therapies prior to undergoing DBS surgery. Even in those subjects, DBS
was remarkably effective. It is reasonable to conclude, therefore, that DBS exceeds
best medical therapies in effectiveness. Sufficiently many other studies have demonstrated that the placebo effect is an unlikely explanation for the sustained benefit
of DBS in the vicinity of the ventral intermediate nucleus of the thalamus DBS.
Whether DBS is more effective than best medical therapy, however, is an issue of
little clinical relevance. Surgical risks of permanent harm argue for continuing to
exhaust all reasonable medical therapies before considering DBS.
From a clinical standpoint, the task is that of determining a therapy that adequately controls a patients symptoms and relieves her disability. Medications
70
that provide sufficient benefit and carry less risk of irreversible significant adverse
effects are preferred to DBS surgery. Failing availability of such medications, DBS
surgery or continued suffering become a patients sole remaining options. The issue
becomes whether success or failure of medications is predictive of success or failure
of DBS. As demonstrated clearly in early non-RCT trials, one expects in this case
that medications failure is not predictive of DBS failure. If it were, there would be
no reason to offer DBS surgery, because those patients would not need it, having
succeeded with medications.
A RCT involving patients who have been randomized to best medical therapy or
DBS and compared is incapable of determining whether medication failure is predictive of DBS failure. Also, a RCT that rests on a population approach is incapable,
because even if one could demonstrate that 50% of patients fail medication therapy
and 50% succeeded with DBS, one cannot know whether these represent the same
population, namely, those that will fail with medications but benefit from DBS. In
order to know this, one would have to design the study in such a way that the subjects are randomized to one treatment and discontinued on it before proceeding to
a second treatment. Design of this kind is unethical, at least for those subjects who
did well on the medication therapy to which they were randomized. To remove subjects from an effective medical therapy and expose them to the significant risks of
DBS surgery is unjustifiable, because, in terms of sufficiency of response, DBS will
not surpass the medication therapy in effectiveness.
Those who insist on a RCT that directly randomizes subjects to DBS or best
medical therapy may cherish a scientific bias. Such RCTs may offer important
insights into the nature of DBS versus the nature of medication therapy, for example, which shows that the former provides better or different benefits than does
the latter and which suggests that the latter involves a different set of physiological mechanisms than does the former. This finding, however, is not likely to aid
clinical decision-making, which is relative to referring patients for DBS surgery.
The mindset is most likely one in which scientific questions are believed to be synonymous with clinical questions. As such, it would lead those who hold it never to
entertain the issue. Though it is doubtful whether scientific questions and clinical
questions are synonymous, the notion that they are so is likely an inheritance from
the Flexnerian revolution in medicine championing scientific medicine but whose
success was largely political and reflected more the dominance of allopathic medicine than it did any inherent superiority of scientific medicine of the day. (The 1847
Code of Ethics of the American Medical Association contains language evocative
of the Flexnerian revolution.)
R I S KS
At a conceptual level, risks may be classified as those associated with surgery and
those associated with stimulation. One usually thinks of surgical risks as attending
the perioperative period. This belief is generally true. Certain longer term risks,
however, are primarily associated with the DBS system hardware. As such, they are
subsumed under surgical risks. Among the acute perioperative risks are the following complications:(1)intracerebral hemorrhage; (2)seizure; (3)infection; (4)symptoms related to withholding medications; (5) acute but self-limiting depression;
(6) ataxia; (7) speech, language, and swallowing problems; and (8) general risks
associated with surgical procedures.
Risk of symptomatic intracerebral hemorrhage is on the order of 1%, although
immediate postoperative imaging suggests that a rate of all hemorrhages is
approximately 10%. Most of the intracerebral hemorrhages are therefore small and
asymptomatic. Asurgeon planning the electrode trajectories may reduce the risk
of intracerebral hemorrhages by use of contrasted Magnetic Resonance Imaging
scans as a way to visualize vasculature. Planned trajectories must avoid any visible
blood vessels, the lateral ventricles, the thalamostriate veins, the choroid plexus,
and the sulci (Piacentino et al. 2013; Montgomery 2014). Also, patient histories
must be reviewed for medication that may increase the risk of bleeding. The number and types of medications are large, and the number of generic formulations
and combination medications argues for a formal review by a pharmacist prior to
surgery. Whether implemented by a surgeon or a referring physician, these recommendations should be a part of quality control supervision.
The symptomatology of intracerebral hemorrhage depends on the hemorrhages
location and extent, as well as any accompanying mass effect or cerebrospinal fluid
flow obstruction. The mortality risk of intracerebral hemorrhage is approximately
0.2%. The risk rates reported herein, however, are typically those observed at large
centers whose personnel is of high expertise. Again, evaluation of the incidence of
intracerebral hemorrhage should be part of any quality control program. Though
subdural hematoma may occur at any time following DBS surgery, Ihave found
risk of it to be extremely small. Its possibility must therefore be kept in mind for
any patient experiencing neurological compromise following DBS lead implantation surgery.
Infections are divided into two types:(1)infections that present a high risk of
necessary DBS lead removal and (2)infections that present a lower risk of necessary
DBS lead removal. The risk of necessary DBS lead removal relates to the proximity of the infection to the DBS lead. Most infections occur at the implanted pulse
generator (IPG). They may be treated with antibiotics and with removal of the IPG.
Occasionally, the extension wire must also be removed. If the infection occurs near
a DBS lead, the lead must be removed, the infection treated, and the DBS replaced
after an appropriate interval. DBS lead replacement unfortunately requires a second full implantation surgery. Though intracerebral infection following DBS lead
implantation is exceedingly rare, it should be considered in a setting of neurological
complaints arising at any point following DBS lead implantation.
Though infection may occur at any time following DBS surgery, it typically
occurs during the initial few postoperative weeks. Later infections often occur at
sites where DBS hardware has eroded the skin. Patients and caregivers must therefore be advised to inspect the areas beneath which runs the DBS hardware for signs
of skin erosion such as soreness, redness, swelling, or leaking fluid. Infections and
skin erosions require urgent care.
Published evidence suggests that the infection rate is higher with subsequent IPG
replacements (Pepper etal. 2013). This observation argues for the use of rechargeable IPGs, particularly in those patients for whom rapid battery exhaustion is either
an actuality or a likely possibilitypatients who require high stimulus voltage or
current, large pulse widths, high frequencies of stimulation, or multiple negative
contacts. Though in the short term rechargeable IPGs are much more expensive,
72
they may be less expensive in the long term. The nature of healthcare reimbursement, which may make long-term cost saving appear less attractive, raises serious
ethical issues.
There arises the question of antibiotic coverage for medical or surgical procedures performed subsequent to DBS system placement. Atransient bacteremia may
seed hardware sites and thus breed infection. There is little published data on the
issue. Generalization from experience with ventriculoperitoneal shunts might offer
some reasonable indication. Yet literature on this subject is meager as well. In this
case, more general surgical experience may serve as a guideline, and Idefer to the
surgeon.
Seizures occurs in some 1% of cases and fall into one of two categories:(1)those
that are likely to increase the risk of subsequent seizures and (2) those that are
unlikely to do so. The two categories require different approaches to treatment. The
general consensus is that seizures occurring a few days after DBS lead implantation
are less likely to increase the risk of subsequent and ongoing seizures, whereas seizures starting latter may give rise to increased risk of subsequent seizures. Aphysician may elect to treat acute onset of seizures with seizure prophylaxis, the value
of which is reinforced by the unsettling sight of a patient seizing (Pouratian etal.
2011). Subacute seizures are quite reasonably treated with prophylactic medication.
Patients may experience self-limiting depression following thalamic DBS
lead implantation surgery. Their DBS systems need not even be activated. The
self-limiting depression mechanism is unknown. Patients with histories of significant depression require anticipatory close postoperative supervision. In some cases,
a psychiatrist may need to intervene.
For two weeks following DBS surgery patients may experience difficulty with
walking. Patients must use caution during this time. The precise mechanisms
responsible for the difficulty are unknown. It is known that the thalamic target is
usually the cerebellar relay nucleus. Disruption of this system may produce ataxia
and may owe to local edema that resolves with time.
Adverse effects of thalamic DBS on speech, language, and swallowing may be
particularly disconcerting. Should these adverse effects arise while active stimulation is being set, they may prevent DBS from reaching stimulation parameters that
are sufficient to control a patients tremor. Avoiding DBS lead placement in the head
representation may reduce but will not eliminate the risk. Yet in order to avoid the
head representation, one must know its location. Microelectrode recordings are the
sole existing means of doing so. For some patients it is necessary to allow selection
of two (or more) stimulation settings. In situations in which tremor control is more
important than are clear speech or swallowing, stimulation at higher intensities or
frequencies may be used. In situations in which clear speech or safe swallowing is
paramount, stimulation intensity or frequency may be reduced. Some IPGs permit
one to program different sets of stimulation parameters and allow a patient or caregiver to alternate between them.
Adverse effects related to stimulation likely owe to stimulation currents
unintended propagation to nearby structures. Current propagation to the tactile
region of the ventral caudal thalamus may cause paraesthesias at stimulation
intensities lower than are necessary to control tremor. Stimulation of the adjacent
corticospinal tract in the posterior limb of the internal capsule may cause tonic
muscle contraction. Additional adverse effects may be related to stimulation of
the ventral intermediate nucleus of the thalamus, particularly speech, language,

and swallowing problems. The majority of time DBS may be adjusted to avoid
these effects. Indeed, they often occur during the course of programming, and
their appearance may be useful in understanding the regional physiological
anatomy around the DBS electrical contacts (Montgomery 2010). It is therefore
unclear whether the appearance of such reversal stimulation induced effects as
paresthesias or muscle contraction should be regarded as adverse effects, as they
often are in publications of RCTs.
S U M M A RY
Though there are significant surgical risks associated with DBS in the vicinity of
the ventral intermediate thalamus for essential tremor, adverse effects are relatively
rare. For patients for whom all reasonable attempts at medication therapy have
failed, DBS remains an effective option.
R EFER ENCES
Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic
area in the treatment of essential tremor. Mov Disord. 2010;25(10):13501356.
Fins JJ. Surgical innovation and ethical dilemmas:precautions and proximity. Cleveland
Clinic Journal of Medicine 2008;75(Suppl.6):S7S12.
Lyons KE, Pahwa R, Comella CL, et al. Benefits and risks of pharmacological treatments for essential tremor. Drug Saf. 2003;26(7):461481.
Montgomery EB Jr. Deep Brain Stimulation Programming: Principles and Practice,
Stimulation: Principles, Practice and Cases. New York: Oxford University Press,
2014.
Montgomery EB Jr., Baker KB, Lyons K, etal. Abnormal performance on the PD test
battery by asymptomatic first-degree relatives. Neurology 1999;52:757762
Pahwa R, Lyons KE, Wilkinson SB, etal. Long-term evaluation of deep brain stimulation of the thalamus. J Neurosurg. 2006;104(4):506512.
Pepper J, Zrinzo L, Mirza B, etal. The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure. Stereotact Funct Neurosurg. 2013;91(1):5665.
Piacentino M, Zambon G, Pilleri M, etal. Comparison of the incidence of intracranial
hemorrhage in two different planning techniques for stereotactic electrode placement in the deep brain stimulation. J Neurosurg Sci. 2013;57(1):6367.
Pouratian N, Reames DL, Frysinger R, et al. Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery: clinical article. J Neurosurg.
2011;115(2):310315.

Candidates Among Patients
withEssentialTremor
D EFI N I N G T H E R ES P O N S I B I L I T I ES FO R
CA N D I DAT ES EL ECT I O N
There is a logical error that is rampant in medicine regarding the selection of patients
for any particular treatment. Even a causal review will demonstrate that, in nearly
every case, the criteria are described as for the best candidate, that is, the candidate
with the best chance of the best outcome. But seldom is that the real issue. The more
vexing question is:what are the criteria that identify a patient with the least acceptable chance of improvement relative to the risks? Focusing on the best criteria risks
cherry-picking, which, while improving surgical and hospital outcomes, violates
the ethical obligation to beneficence to those patients who entrust their care to physicians and healthcare professionals. Consideration of the least acceptable patient
may challenge the ethical presumptions of physicians and healthcare professionals,
which typically do not arise when considering patients who meet the criteria for the
best candidate. The obligation to treat the least candidate may be deontologicala
moral duty to treator it may be contractual (even informally or implicitly) where
a physician has a fiduciary responsibility. Any treatment by a physician and healthcare professional necessitates informed consent, which necessitates explanation of
all potential treatments according to what is reasonable to a patient, not necessarily
reasonable to a physician or healthcare professional. Those with the least acceptable
criteria are no less deserving of the therapy.
The criteria for the best candidate are easy because they are uncontroversial
and liable to be readily accepted by all involved, including a patient or a patients
surrogate. The borderline cases may invite differences of opinion. A patient or her
surrogate ultimately holds the trump card: refuse therapy. The more problematic
situations arise when a patient or her surrogate wants the treatment and physicians
or healthcare professionals are uncertain. The reason for the problematic situation
7. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor75
is that ultimately it is a value judgment. The question thus arises as to whose values,
a patient or surrogate or the physician and healthcare professional, ought to prevail. Because only a patient or surrogate knows acceptable risk in light of potential
benefit, greatest credence should be given to her. Though physicians and healthcare
professionals are not obligated to provide therapies they feel would violate the ethical principle of nonmalfeasance, respecting a patient or her surrogate is consistent
with the principle of autonomy and with statements of ethics from professional
organizations.
S EL ECT I O N C R I T ER I A
The selection criteria for patients with Essential tremor considering Deep Brain
Stimulation (DBS) resemble those of other indications. There are two levels: a relatively low threshold held by physicians and healthcare professionals who are not
expert or experienced with DBS and an appropriately higher threshold by those
with expertise. This concept may be understood in terms of the specificity and
sensitivity of a diagnostic test, in this case the diagnosis is one of DBS candidacy.
The percent sensitivity means the percentage of patients identified as candidates
who actually are candidates for DBS. Percent specificity means the percentage of
patients identified as not candidates who are actually not candidates.
The appropriate balance between sensitivity and specificity is determined by
the consequences, as there are no a priori standards. More stringent criteria will
result in a great specificity but typically at the cost of patients being inappropriately
excluded from DBS. On the other hand, less stringent criteria will result in fewer
candidates being inappropriately discouraged from DBS but more patients undergoing DBS that perhaps should not have.
The appropriate specificity and sensitivity are based on the consequences, which
in turn depend on a judgment of the risks, potential benefits, efforts to realize
continued benefits, and, importantly, alternatives. I recommend a set of criteria
for nonexperts that has a high sensitivity even at the expense of a low specificity.
Conversely, an expert should have a high specificity. Because the final assessment
of an individuals unique risk, potential benefit, efforts for continued benefit, and
alternatives is often complicated, this judgment ought to be made in the context of
an experienced expert in DBS. The expert then has sufficient experience to exert
high specificity in recommending DBS. However, the expert is usually dependent
on a referring physician for patients. If the referring physician has a high specificity, then there is a risk of low sensitivity. Appropriate patients may therefore not
be referred. A high sensitivity may mean that the referring physician may refer
patients who are not necessarily appropriate for DBS. Yet the costs for such referral are far lower than the costs associated with a patients continued disability as a
consequence of ineffectively treated disease.
Because the complex decision to offer a patient DBS often involves a multidisciplinary team, it is not reasonable to expect a nonexpert physician without such
a team to make a decision as to a patients candidacy, despite calls that she do so
(Martinez-Ramirez and Okun 2014). This is clearly the case when a major criterion
is failure of all reasonable alternatives. It is not clear the every nonexpert physician knows or has the experience to know when that criterion has been satisfied.
76
In a study comparing the pharmacological treatments of patients with Essential

tremor, there were significant differences between movement disorders specialists
and general neurologists. The latter tended to undertreat. For example, only 37.8%
of general neurologists patients had taken primidone or propranolol, which are the
mainstays of treatment (Diaz and Louis 2010).
Every physician ought to recognize when his efforts fail to provide complete
relief of a patients symptoms. It is at that point he should refer to the DBS expert.
The cost is a consultation fee. Yet this is little compared to the cost of failed therapies. In addition, the most frequent cause of patients being inappropriate candidates is a failure to exhaust all reasonable medications. ADBS consulting physician
thus often provides recommendations for further treatment, which offsets the cost
of a consultation that does not lead to DBS surgery. The considerations described
here are particularly acute, because most neurologists do not see many patients
with Essential tremor in their practice. Indeed, many are followed by an internist,
because often a patient and internists are discouraged by the previous referrals that
often do not lead to effective treatments, the nature of Essential tremor influencing
this outcome (Louis etal. 2010).
The admonition to refer all patients who have not received an acceptable response
to medication therapies is not to suggest that every patient ought to expect a complete response to medications or DBS. The problem, however, is that there is no a
priori method of predicting which patients will benefit from DBS. It would seem
appropriate to assume that every patient may potentially benefit. Should they meet
the criteria established by DBS experts, then they ought to be given the opportunity
to benefit.
The difficult decision is the definition of acceptable response to medication therapies and, more important, who decides the definition. Is it a physician, a patient, a
family member or caregiver? The failure to provide beneficence does not constitute
violation of the ethical principle of nonmalfeasance (do no harm). Apatients right
to expect beneficence is unclear. In the British system, a physician is the one who
decides what therapies are offered. In the United States it is more likely the standards of practice (Note Iam not an attorney and am not offering a legal opinion
here.) Often the standards of practice are what reasonably similarly situated physicians would do. The extent to which such physicians consider patients desires when
they may not resonate with the opinion of the physician is not clear (see chapter19).
An excellent study examined the factors the influence acceptance of DBS surgery in patients with Essential tremor (Louis and Gillman 2011). The severity of the
tremor was only a modest factor but perhaps one that might motivate a physician
and healthcare professional. The most important factor from a patients perspective
was the degree of her embarrassment. Unless a physician clearly assesses the degree
a patient finds the tremor embarrassing and socially disabling, a physician is likely
to base his recommendation on the severity of the tremor, which may have less
relevance to a patients needs.
The degree of embarrassment is clearly contextual. Though it appears obvious,
it may not be appreciated that it is a patients perspective that determines when the
embarrassment is intolerable. Further, only a patient knows how much he is willing
to risk for relief of the embarrassment.
The selection criteria follow the same general approach as other disorders, such as
Parkinsons disease. Among the elements of the approach are the following:(1)an
appropriate diagnosis of a condition that will respond to DBS, (2)exhaustion of all

reasonable lower-risk treatments, (3)ability to tolerate the procedure, and (4)assurance of postoperative follow-up.
Diagnosis
The diagnosis of Essential tremor is based on the symptoms and signs. There is as
yet no imaging or laboratory test that has been validated to differentiate Essential
tremor from those conditions that are in the differential diagnosis of tremor. The
diagnosis is strictly phenomenological, resting on the appearance of the tremor and
the conditions under which the tremor is present. Tremor is described as being at
rest, with sustained posture, (holding the hand and arm outstretched, for example),
and with action (bringing the tip of ones finger to her nose, for example). In addition, the frequency of the tremor is noted. In the upper extremity, the distribution
of the tremor (in the proximal or distal musculature, for example) is also noted.
Unfortunately, nothing unique to these criteria is pathognomonic for Essential
tremor. As with Parkinsons disease, for example, Essential tremor may occur at
rest. In contrast to Parkinsons disease, the tremor of Essential tremor is high frequency (6 Hz to 10 Hz), whereas the tremor of Parkinsons disease is approximately
4 Hz to 6 Hz. The frequency of tremor in Essential tremor slows with aging, such
that the tremor in an older patient with Essential tremor may be the same as a
patient with Parkinsons disease.
Among the other features that support a diagnosis of Essential tremor are (1)a
chronic condition; (2) reduction of tremor with alcohol ingestion (although the
absence of an effect is not evidence against Essential tremor); (3)a family history
of tremor (although studies demonstrate a considerable prevalence of significant
tremor in first-degree relatives of patients without tremor [Louis etal.2001]; a family history may therefore not have sufficient positive or negative predictive value);
(4)absence of evidence of neurological symptoms beyond tremor, such as evidence
of sensory, pyramidal, or hyperkinetic extrapyramidal (e.g., dystonia) system
involvement.
The differential diagnosis for the type of tremor relevant to Essential tremor is
fairly long and includes a variety of neurodegenerative, toxic, and metabolic disorders (Buijink etal. 2012). Every patient has a degree of tremor. Yet it is not to the
severity typically associated with Essential tremor. However, a number of conditions
and medications, including those obtained without a prescription, may exacerbate
physiologic tremor. These include, but are not limited to, the following:(1)hyperthyroidism, (2) hyperadrenalism, (3) phenochromocytomas, and (4) sympatheticomemitic medications. Anumber of other medications can produce tremor, such
as valproic acid, neuroleptics, lithium, selective serotonin reuptake inhibitors,
-agonist (albuterol), central nervous system stimulants (methylphenidate), central
nervous system depressants, and rebound phenomena (ethanol, benzodiazepines;
Elias and Shah 2014). Also to be considered are tremor-predominant Parkinsons
disease, drug-induced parkinsonism, dystonic tremor, and psychogenic factors.
Some investigators have advocated the use of electrophysiological measures
using electromyographic and accelerometer data. In one study, use of such measures demonstrated a sensitivity of 97.7% and a specificity of 82.3% for Essential
78
tremor (Gironell etal. 2004). Specificity and sensitivity, however, are inappropriate
measures of diagnostic utility. More appropriate are positive and negative predictive values based on prior probabilities (the prevalence of patients with essential
tremor and other tremor conditions). Given the population of patients seen in the
clinic of the investigators, the positive predictive value was 95.1% and the negative
predictive value was 91.1%. The question becomes:what are the prior probabilities
in the specific context of the referring physician and healthcare professional?
Before applying such criteria to DBS for patients with tremor, one must first consider the prior probabilities for patients seeking DBS. In this case, it is the percentage of those who actually have Essential tremor from others that have another
tremor syndrome, the most frequent being tremor-predominant Parkinsons disease (as distinct from other presentations of Parkinsons disease). Iknow of no data
by which to assess the prior probabilities. There is no way, therefore, to assess the
diagnostic value of the electrophysiological studies.
Because there is nothing pathognomonic about the nature of the tremor of
Essential tremor, the diagnosis of Essential tremor in many ways remains one of
exclusion, relying on determining whether there are symptoms, signs, and histories
that would be inconsistent with Essential tremor and indicative of other conditions.
The presence of abnormalities of sensory, pyramidal, and hyperkinetic extrapyramidal systems, for example, is inconsistent with Essential tremor. Also, a history
of certain drug usage correlated with the history of the tremor would favor a toxic
tremor. Symptoms and signs of hyperthyroidism may suggest a metabolic tremor.
The issues of differential diagnoses is problematic, thanks to the Gamblers fallacy and the premium often placed on jumping to the diagnosis without consideration of a differential diagnosis. For example, a patient with tremor and a family
history of tremor is almost immediately diagnosed as having Essential tremor
without further consideration of possible contemporaneous presence of another
cause of tremor, such as hyperthyroidism. What are the odds of a patient having both Essential tremor and hyperthyroidism? Such a presumption implies that
somehow the probability of having Essential tremor lowers the probability of having hyperthyroidism, much like the gambler who believes that past losses means
that he is due for a win.
A coin toss presents a useful example. What is the probability of two heads in a
row? The answer is 25%. After the first flip resulting in heads, what is the probability
of the second flip also being heads? From the prior probability (before any flips) that
there would be two head in a row being 25%, one might say that the probability of
the second flip being heads following the first flip of heads is 25%. But the correct
answer is that the probability of the second flip being heads after the first flip being
heads is 50%.
In the case of the differential diagnosis of tremor, the probability of hyperthyroidism is sufficiently high to warrant the appropriate history, physical examination, and laboratory tests. After the diagnosis of Essential tremor, the probability
of hyperthyroidism remains undiminished. If the probability of hyperthyroidism
was sufficient to pursue the possible diagnosis of hyperthyroidism, the probability
is no lower following the diagnosis of Essential tremor. Thus the mere diagnosis of
Essential tremor is insufficient to warrant exclusion of other simultaneous causes of
tremor. It may be infeasible to exclude every other possible cause of tremor. Where
to draw the line is a matter of judgment rather than habit or default.
Perhaps the most frequent diagnosis to exclude is tremor-predominant

Parkinsons disease. Distinguishing between Essential tremor and tremor-predominant Parkinsons disease may be problematic for a number of reasons. Patients with
Essential tremor may have bradykinesia to the same extent as patients with early
Parkinsons disease (Montgomery et al. 2000) as well as micrographia (MartinezHernandez and Louis 2014). As discussed previously, the tremor frequency of older
patients with Essential tremor may be the same as that of patients with Parkinsons
disease, and the latter can have postural and action tremor as well. Also, a significant number of patients presumed to have Parkinsons disease have tremor that is
unresponsive or only partially responsive to levodopa. In a study of nine patients
with Parkinsons disease, five experienced less than or equal to 50% reduction in
tremor, and one patient, who failed to respond to levodopa, nonetheless experienced nearly complete reduction in tremor with trihexyphenidyl (Koller 1986). The
response to the trihexyphenidyl in a patient who did not respond to levodopa may
mitigate to some degree the fact that she did not have Parkinsons disease. Hence,
levodopa unresponsiveness is problematic as a criteria to differentiate Essential
tremor from tremor-predominant Parkinsons disease.
Some experts have advocated use of dopamine transporter ligand imagingsingle photon emission computerized tomography (SPECT), for example. In order to
do so, one would have to demonstrate sufficient positive and negative predictive
value. Yet this demonstration must be based on prevalence of the relevant populations. In this case, it would not be patients with obvious Parkinsons disease;
it would be patients with tremor-predominant Parkinsons disease rather than
Essential tremor. One study focusing on tremor-predominant Parkinsons disease versus non-parkinsonian tremor found that 10% of patients diagnosed with
non-parkinsonian tremor experienced reduced ligand uptake. Yet this uptake
occurred only symmetrically (Sixel-Doring etal. 2011). Fourteen percent of patients
diagnosed with Parkinsonism had a normal SPECT scan.
If one assumes that future studies substantiate those described here, the real
question is:what would be the consequence? Apatient with Essential tremor may
be falsely identified as having Parkinsons disease and undergo DBS in the vicinity of the subthalamic nucleus or the globus pallidus interna. At least if a patient
is referred for DBS in the vicinity of the posterior subthalamic area, there is some
evidence that a patients Essential tremor may be helped (Blomstedt et al. 2010).
Unfortunately, there is no data for DBS in the vicinity of the globus pallidus interna
for Essential tremor.
If a patient with Parkinsons disease is misidentified as having Essential tremor,
she may undergo DBS in the vicinity of the ventral intermediate thalamic nucleus.
Though a patients tremor would probably improve (Stover etal. 2005; Lind etal.
2008), conventional wisdom holds that other symptoms, which may appear years
later, will not be controlled by DBS in the vicinity of the thalamus. There is little
evidence to support the conventional wisdom. Patients selected for DBS in the
vicinity of the ventral intermediate thalamus are selected on the basis of the predominant symptom of tremor. Other symptoms undergo little evaluation. Should
it be the case that symptoms other than tremor in patients with Parkinsons disease
improve with DBS in the vicinity of the ventral intermediate nucleus of the thalamus, there is little to be gained by undergoing expensive and invasive tests such
as SPECT scans. The important point is to avoid DBS in the vicinity of the globus
80
pallidus interna for patients for whom the diagnosis is between Essential tremor
and tremor-predominant Parkinsons disease, because there is no evidence that
DBS in the vicinity of the globus pallidus interna improves Essential tremor. The
final decision is ultimately based on the judgment of experienced experts, which
rests on the best available information.
Exhaustion of All Reasonable Less Invasive Alternative Therapies

According to historical data, a strong argument may be made that DBS in the
vicinity of the ventral intermediate nucleus of the thalamus, and probably in the
vicinity of the subthalamic nucleus, is more effective than medications and intramuscular injections of botulinum toxin. DBS in the vicinity of the ventral intermediate nucleus of the thalamus produces an approximate mean 75% improvement,
whereas medications produce less than 50%. Botulinum toxin produces even less.
The exception may be patients whose head tremor is the only symptom warranted
consideration of DBS in the vicinity of the ventral intermediate nucleus of the
thalamus. Targeting the head representation, which would be necessary for the
treatment of the head tremor, probably significantly increases the risk for speech,
language, and swallowing complications.
To report these mean improvements is to convey a misrepresentation. Contrary
to the practice in the vast majority of publications, publishing mean improvement
in response to any therapy is meaningless. What often goes unreported is the statistical distribution of the response of each subject. The mean value is only meaningful if one knows the distribution. One finds an example of this in the situation
in which one subject realizes 100% improvement and a second 0% improvement.
The mean improvement is 50%. Yet should both subjects realize a 50% improvement, the mean is likewise 50%. In the first situation, it is essentially a flip of the
coin whether a particular patient would experience benefit. In the second situation,
there is little question that a patient would benefit.
One might object by claiming that no one would base a judgment on a mere two
subjects. If a version of the first example involves a case in which 1million subjects
realized 100% improvement and 1million subjects realized 0% improvement, the
mean remains the same:To wit, 50% improvement and the probability that any one
patient would benefit would be a flip of the coin. One must know the distribution of
results from which the mean was obtained.
In some studies, standard deviations (or the derivative confidence intervals)
are provided in addition to the mean. Yet the standard deviation is uninformative if the distribution is heavily skewed or platykurtic (of more uniform distribution), because the calculation of the standard deviation is heavily influenced by
outliers and therefore overestimates the actual variance. The practical result may
be an overestimation or an underestimation of the potential benefits that may be
expected (perhaps related to the degree the physician and healthcare professionals
are optimists or pessimists). Thus, without knowing the underlying distribution,
one finds it difficult to have confidence in such descriptive statistics as mean, standard deviation, and confidence intervals. Better estimates when the distribution is
unknown or not reported are the medians and quartiles.
Unlike science, in which a conclusion may be postponed until additional subjects

or laboratory animals can be utilized, a physician or healthcare professional is confronted with the immediacy of a patients needs. The lack of statistically complete
data, such as would be expected in randomized controlled trials in Evidence-Based
Medicine, is license neither to act indiscriminately nor to refrain from acting.
Rather, a physician or healthcare professional must use judgment guided in many
cases by the principles or spirit of statistical inference (Montgomery and Turkstra
2003)while respecting the necessity of values.
The adequacy of prior nonsurgical treatments may be posed as two questions:Were
enough different treatments considered? Was each treatment maximized to the
point where any further increase in the intensity of the treatment would be futile?
With respect to the range of treatments and combinations attempted, one may
confront the assessment of whether a patient has exhausted all reasonable attempts
at medication and botulinum toxin injection. Immediately one is confronted by
the fact there are more combinations of different agents than could be tried in any
patient. For example, a review listed 14 beta blockers, 11 anticonvulsants, and 3
neuroleptics for a total of 28 agents (Zappia et al. 2013), for a total of 268,435,455
combinations. If each combination was tried for three months before rendering a
verdict, then it would take 67,108,864 years. The combinations are even greater if
intramuscular botulinum toxin injections are included.
One may argue that only one agent in each category need be attempted (an
assumption not tested by randomized control trials), in which case the combinations would be 15. With a trial of each combination requiring three months, it
would take three years and nine months to try them all. Anewly diagnosed patient
with Essential tremor suffers diminished quality of life. If one assumes that he will
need DBS, he would have to endure diminished quality of life for nearly four years
before receiving definitive treatment. The necessary presumption is that each agent
within each group has exactly the same efficacy and safety. If one assumes that it is
only necessary to test two agents from each group, the number of combinations is
162, which would require 40years and 6months to test.
One may take a sequential approach, in which the initial agent with the highest
probability of efficacy with a corresponding low risk of adverse effects is titrated to
the maximal dose, according to efficacy or tolerance. If the initial agent provides no
benefit, it is discontinued. If the initial agent provides some benefit and is tolerated,
it is retained. Asecond agent is introduced and managed in the same way as was the
initial agent. If one assumes that each of these steps takes 3months, one would need
7years to exhaust the entire 28 agents or 9months if only one agent is attempted
from each category.
The review by members of the Italian Movement Disorders Association (Zappia
et al. 2013) provided some data for stratification of agents with categories. Yet it
is important to note that only crossover studies in which the same patient was
exposed to all the medications being compared can provide useful data for consideration of stratification. For example, a study was cited in which patients were
treated with arotinolol 30 mg per day and propranolol 160 mg per day (lesser doses
were studied but those results are not relevant to the present considerations), which
were comparable in efficacy and tolerance. These conclusions were based on group
data (Lee etal. 2003). Left unasked was the most important question:How many
82
patients did not benefit on one agent but did benefit on the other? In this case, the
crossover design allowed for a higher powered study but failed to address the most
pressing issue that would allow one to stratify the regimen.
Another study cited studied five different beta blockers in each of nine patients
(Jefferson etal. 1979). The agents included placebo, propranolol, sotalol, and atenolol. Their analysis appears to have pooled data across subjects rather than examine
the differences between the responses to each agent within an individual subject. The
subjective reports on efficacy for tremor were reported for each patient. Reanalysis
using a Friedmans Analysis of Variance on ranks with repeated measures demonstrated no statistically significant differences. The p value, which was.067, suggested
a trend. One must not conclude, however, that the five different beta blockers were
all the same. Rather, the study probably was underpowered as a consequence of the
small sample size and variability among the subjects. To conclude that the medications are equivalent is therefore to commit a type II statistical error of inferring that
there is no difference when one truly exists. However, the evidence is insufficient
to rule out the use of one agent if another agent failed, provided one requires a 95%
confidence in the evidence.
An analogous situation exists in the treatment of epilepsy with concern to overtreatment. One aspect of overtreatment is the number of medications simultaneously used (polypharmacy). In one study of patients with newly diagnosed and
chronic epilepsy seizure-free for at least a year, 86% were on two, 13% were on three,
and 1% were on four drugs (Stephen and Brodie 2002). Thus it would seem futile
to go beyond three agents and, for select patients, surgery for epilepsy may be indicated. Unfortunately, comparable data does not exist for patients with Essential
tremor (or most other indications for DBS).
The issue of what constitutes an adequate trial of primidone, propranolol, clonazepam, and topiramate is addressed next. Generally, an adequate trial is defined
by three results:(1)a dose that produces adequate relief and is tolerated, (2)a dose
at which there is a limiting adverse effect that cannot be circumvented, and (3)a
dose beyond which there is little likelihood of benefit owing either to lack of efficacy
or the risk of adverse effects. The first criteria is not relevant to patients considering DBS. The second criteria is rather unproblematic. The complicated criteria is at
what dose would any further increase be not likely to produce benefit. This depends
on establishing a doseresponse curve for each agent.
In one study employing propranolol up to 800 mg per day, the maximum effect
of propranolol on tremor for all subjects was at 320 mg per day in total daily dose;
higher doses did not help (Koller 1986). Based on this study, the dose of propranolol should logically be increased to 320 mg per day, although such higher doses are
likely associated with a much higher risk of adverse effects. However, this higher
risk is not germane because of criteria 2, which holds that a dose associated with an
adverse effect that cannot be circumvented constitutes a reasonable trial.
A dose-ranging study for primidone based on 22 subjects was reported, although
the results are not described to the level of detail for the purposes here (Koller and
Royse 1986). Doses of primidone were increased until a patients tremor was under
sufficient control or experienced limiting adverse effects. In that study, nine patients
went to 250 mg per day. Eight patients went to 750 mg per day, and all of those went
on to 1,000 mg per day. At the least it states that some patients tolerate but do not
appear to have any greater benefit with doses higher than 250 mg per day. Apatient
that took up to 250 mg per day could be considered to have maximized the dose of
primidone.
A study of topiramate utilized a dose-escalation procedure to the maximum tolerated or reaching a sufficient therapeutic effect. Unfortunately, a doseresponse
curve was not provided to see at which dose the response became asymptotic suggesting a limit to any further increases (Ondo etal. 2006). The final attained dose
for topiramate was 292 (assuming mean) with a standard deviation of 129 mg/day
topiramate. A median, 375 mg/day, was reported, suggesting a skewed distribution toward higher doses. The maximum dose for that study was 400 mg per day
at 50 mg increments. This suggests that a very large percentage of patients reached
maximal doses. This means it is unknown whether higher doses would have produced greater benefit. This study thus suggests that at least 400 mg per day would
be expected, but even if a patient reached that dose, one could not assume that no
further doses would provide sufficient benefit.
No doseresponse data for clonazapine in Essential tremor could be found on
PubMed search.
Intramuscular injections of botulinum toxin injections into the sets of antagonist muscles whose reciprocal activations are causing tremor can be considered,
particularly for no-no tremor. Injections for yes-yes tremor likely will increase
the risk for dysphagia. Distal hand tremor could be treated; however, there is the
risk of weakness adversely affecting hand function. The same questions attend the
adequacy of intramuscular injections of botulinum toxin as for other disorders,
and this issue is discussed in more detail in chapter10.
In the final analysis, there is insufficient knowledge to effectively determine when
all reasonable medical treatments have been exhausted for patients with Essential
tremor considering DBS. Clearly, a shotgun approach where every possible medication is attempted is not feasible, yet there is no a priori knowledge that automatically reduces the range of medications that might be effective. Irecommend a
history of adequate trial of primidone, propranolol, clonazepam, and topiramate.
Botulinum toxin injections are suggested for patients with predominately head
tremor (particularly no-no tremor) and are mentioned for distal upper extremity
tremor for consideration by a patient.
The lack of knowledge as to what constitutes exhaustion of all reasonable
medications should not instill therapeutic nihilism or panic but rather equipoise. Further, equipoise can be achieved by including a patient or a patients
surrogate in the decision-making process. When carefully explained to a patient
or the surrogate and when the patient and/or surrogate has an understanding of
the epistemic status of the issue, all can take comfort by believing that the most
reasonable decision has been made based on the proper balance of uncertainty
that might continue attempts at non-DBS treatment versus how pressing is the
need to relieve the tremor.
Ability to Tolerate Deep Brain Stimulation Surgery

Unlike patients with Parkinsons disease, cognitive issues appear to be less pressing in patients with Essential tremor. Certainly, if there is a significant dementia,
it is necessary to clearly judge whether any reduction in tremor would have any
84
meaningful impact on a patients quality of life considered in its widest connotation. As per previous discussions in other chapters, significant deference should be
given to a patients or the patients surrogate as to the quality of life a patient has and
how much a patient or a patients surrogate would be willing to risk.
Depression or an exacerbation of depression may occur postoperatively, but this
typically resolves. However, it is important to be cognizant of the risk and where
necessary assure the capability of urgent psychiatric intervention postoperatively
should that be needed. Transient worsening of gait also may be seen.
Patients with significant speech, language, and swallowing problems are of concern, although the presence of these symptoms are unusual in Essential tremor preoperatively. Consequently, their presence should alert the physician and healthcare
professional as to an alternative diagnosis.
Optimal placement of the DBS lead necessitates its being placed in the appropriate homuncular representation, typically the distal upper extremity although the
lower extremity may be indicated for orthostatic tremor. It is also important to
avoid the head representation in order to minimize the risk of worsened speech,
language, and swallowing problems. Currently, the only method for such localization is intraoperative neurophysiological monitoring. Though it is optimal to have a
patient awake during the intraoperative microelectrode recording and test stimulation through the DBS lead, surgery may be accomplished successfully with the use
of dexmedetomidine anesthesia.
Assurance of Appropriate Postoperative Care

Benefit does not accrue with the surgical implantation of the DBS lead but rather
when electrical stimulation is begun and adjusted. DBS adjustment requires simultaneous adjustments of medications and, consequently, DBS programmers must
have sufficient knowledge, experience, skills, and credentials in managing the medications as well as the DBS system. DBS adjustment may require relatively frequent
visits for adjustments. Ethical considerations are discussed in chapter19.
S U M M A RY
Patient selection for DBS in the vicinity of the ventral intermediate nucleus of the
thalamus depends on demonstrating the appropriate diagnosis, exhaustion of all
reasonable medications, ability to tolerate the surgery, and assurance of adequate
postoperative care. Deciding when a patient has exhausted all reasonable nonsurgical alternatives is highly problematic given the paucity of knowledge directly bearing on the relevant questions. Nonetheless, patients, family members and caregivers
expect that the physician and healthcare professionals provide advice based on a
rational analysis of the best data available. Declining to address the issue by avoiding discussion of DBS as an option is not tenable or ethical. The postoperative care
requires physicians and healthcare professionals with sufficient knowledge, experience, skills, and credentials to manage medications as well as the DBS systems.
R EFER ENCES
Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic
area in the treatment of essential tremor. Mov Disord. 2010;25(10):13501356.
Buijink AW, Contarino MF, Koelman JH, et al. How to tackle tremorsystematic
review of the literature and diagnostic work-up. Front Neurol. 2012;3:146.
Diaz NL, Louis ED: Survey of medication usage patterns among essential tremor
patients:movement disorder specialists vs. general neurologists. Parkinsonism Relat
Disord. 2010;16(9):604607.
Elias WJ, Shah BB:Tremor. JAMA 2014;311(9):948954.
Gironell A, Kulisevsky J, Pascual-Sedano B, etal. Routine neurophysiologic tremor analysis as a diagnostic tool for essential tremor:a prospective study. J Clin Neurophysiol.
2004;21(6):446450.
Jefferson D, Jenner P, Marsden CD. beta-Adrenoreceptor antagonists in essential
tremor. J Neurol Neurosurg Psychiatry 1979;42(10):904909.
Koller WC. Doseresponse relationship of propranolol in the treatment of essential
tremor. Arch Neurol. 1986;43(1):4243.
Koller WC. Pharmacologic treatment of parkinsonian tremor. Arch Neurol.
1986;43(2):126127.
Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology
1986;36(1):121124.
Lee KS, Kim JS, Kim JW, etal. A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor. Parkinsonism Relat
Disord. 2003;9(6):341347.
Lind G, Schechtmann G, Lind C, etal. Subthalamic stimulation for essential tremor.
short- and long-term results and critical target area. Stereotact Funct Neurosurg.
2008;86(4):253258.
Louis ED, Ford B, Frucht S, et al. Mild tremor in relatives of patients with essential
tremor: what does this tell us about the penetrance of the disease? Arch Neurol.
2001;58(10):15841589.
Louis ED, Gillman A:Factors associated with receptivity to deep brain stimulation surgery among essential tremor cases. Parkinsonism Relat Disord. 2011;17(6):482485.
Louis ED, Rios E, Henchcliffe C: How are we doing with the treatment of essential
tremor (ET)? Persistence of patients with ET on medication:data from 528 patients
in three settings. Eur J Neurol. 2010;17(6):882884.
Martinez-Hernandez HR, Louis ED: Macrographia in essential tremor: a study of
patients with and without rest tremor. Mov Disord. 2014;29(7):960961.
Martinez-Ramirez D, Okun MS:Rationale and clinical pearls for primary care doctors
referring patients for deep brain stimulation. Gerontology 2014;60(1):3848.
Montgomery EB Jr., Baker KB, Lyons K, etal. Motor initiation and execution in essential tremor and Parkinsons disease. Mov Disord. 2000;15(3):511515.
Speech Lang Pathol 2003;11:ixxii.
Ondo WG, Jankovic J, Connor GS, etal. Topiramate in essential tremor:a double-blind,
placebo-controlled trial. Neurology 2006;66(5):672677.
Sixel-Doring F, Liepe K, Mollenhauer B, etal. The role of 123I-FP-CIT-SPECT in the
differential diagnosis of Parkinson and tremor syndromes:a critical assessment of
125 cases. J Neurol. 2011;258(12):21472154.
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Stephen LJ, Brodie MJ:Seizure freedom with more than one antiepileptic drug. Seizure
2002;11(6):349351.
Stover NP, Okun MS, Evatt ML, et al. Stimulation of the subthalamic nucleus
in a patient with Parkinson disease and essential tremor. Arch Neurol.
2005;62(1):141143.
Zappia M, Albanese A, Bruno E, et al. Treatment of essential tremor: a systematic
review of evidence and recommendations from the Italian Movement Disorders
Association. J Neurol. 2013;260(3):714740.
Postoperative Care for

EssentialTremor
C H A L L EN G ES
Postoperative care centers mostly around Deep Brain Stimulation (DBS) programming, though not exclusively, and addresses several issues:(1)efficacy, (2)adverse
effects related to the stimulation, (3) adjustments of other treatments such as
medications, and (4)the impact of the postoperative status on psychosocial issues.
For example, patients with Parkinsons disease can experience severe psychosocial
stress even as their symptoms improve (Schupbach etal. 2006). The adverse effects
related to stimulation may be specific, meaning explainable by spread of electrical current to unintended targets, such as the tactile region of the ventral caudal
thalamus producing intolerable paresthesias. Alternatively, stimulation can produce adverse effects that are not clearly related to the structures in the immediate
anatomical regions but may be related to stimulation of the ventral intermediate
nucleus of the thalamus. The same considerations apply to DBS programming of
DBS in the vicinity of the subthalamic nucleus, which is discussed in c hapter5.
This chapter addresses primarily DBS vicinity of the ventral intermediate nucleus
of the thalamus rather than other targets that have been proposed for Essential
tremor.
EF FI CACY
Detailed discussions of programming of DBS in the vicinity of the ventral intermediate nucleus of the thalamus is beyond the scope of this chapter, and readers
are referred to Montgomery (2010). Discussed here are some of the basic considerations of issues that might involve the nonprogramming physician and healthcare
professional. There are literally thousands of combinations of electrode configurations (the set of active electrical contacts on the DBS lead) and stimulation parameters (voltage or electrical current, pulse width, and stimulation frequency or rate).
Thus the approach to DBS programming is important for efficient and effective
programming. The large number of potentially relevant combinations of electrode
88
configurations and stimulation parameters could bewilder some programmers,

potentially leading to ineffective and inefficient programming and, consequently,
continued requirements of medical regimens that were proven ineffective for the
patient in the first place. Such patients may be falsely labeled as DBS failures and
fall back to the referring physician and healthcare professional no better off for the
risks, discomforts, and inconveniences related to DBS surgery.
Quite often, the programmer will start from those electrode configurations and
stimulation parameters described in the literature as the mean or most typical. The
critical issue is how far from the mean stimulation parameters and typical electrode
configurations the programmer is willing to venture. In my experience, most programmers do not venture far. For example, in one study the mean voltage was 2.17
with a standard deviation of 0.81 volts (V). Unfortunately, the voltages provided by
the typical implanted pulse generators are ordinal, noninterval values rendering
application of typical parametric summary statistics problematic. However, setting
those concerns aside, the mean and standard deviation suggests that the range of
voltages used was from 1.36 to 2.98 V in 68% of patients. With respect to frequency,
the mean was 156.36 pulses per second (pps) with a standard deviation of 24.72
pps. This would mean that the range of frequencies for 68% of the patients would
be from 131.6 to 181.1 pps (Limousin etal. 1999). When the fact is recognized that
the standard deviations described, based on the nature of the data, overestimates
the actual variance, the number of programs not venturing far from the mean or
median is much greater.
It may be that these stimulation parameters are just what 68% of patients need.
Alternatively, it may be that these parameters are just what were tried in 68% of the
patients. It should be noted that studies of patients thought to be DBS failures demonstrated that 50 of them had good outcomes with reprogramming (Okun etal.
2005). At the least, these observations point to the critical importance of careful
postoperative programming and of surveying a sufficiently large number of electrode combinations and stimulation parameters. While considering a wider range
of possible electrode configurations and stimulation parameters increases the
demands on programmers to be efficient, there are a number of techniques that can
be used to facilitate efficient programming (Montgomery 2010).
With the awareness of the importance of postoperative programming to the
benefit of DBS, there is a significant problem. One of the major problems facing
patients with DBS is finding appropriate postoperative care. Patients may be willing to travel hundreds of miles for DBS implantation surgery yet not willing to
make the same trip on a biweekly or monthly basis for programming. One could
argue that it is unethical to implant a DBS system without prior arrangements for
postoperative care (see chapter19). The benefit does not come from the DBS lead
being implanted but with the stimulator turned on and programmed. Web-based
programs are being developed to assist those without sufficient or ongoing experience to provide expert postoperative programming.
The critical factor underlying efficacy is delivery of negative electrical charges
onto the surface of the neural elements, such as the axons (Montgomery 2010).
The total number of negative electrical charges is determined by the electrical current and the duration of the electrical pulse. Programming with a constant voltage implanted pulse generator does not directly control the electrical current and
thus does not directly control the amount of electrical charges onto the neuronal
8. Postoperative Care for Essential Tremor89
elements. Rather, the effects of the stimulation voltage are mediated by the impedance, which can vary substantially.
Any abrupt change in the impedance at the DBS electrodebrain interface can change the effective current being delivered to the brain when using a
constant-voltage implanted pulse generator. The consequence can be a marked
change in efficacy. This can be avoided by the use of constant current implanted
pulse generators. Despite the significant technical and neurophysiological advantages of constant current DBS, it does not seem popular. If this is correct, then one
has to wonder what drives the approach to postoperative programming:principles
or habit. The danger is that habit can be confused with knowledge.
Sudden changes in efficacy can be due to failure of the DBS system, with sudden
and potentially severe exacerbation of the underlying disease for which the DBS was
indicated. There can be a number of reasons for failure, including battery failure;
failure to recharge the battery in rechargeable units; electrical discontinuity, such
as lead fracture; and lead migration. Irecommend obtaining an anterior-posterior
and lateral skull and chest X-rays to demonstrate the physical status of the system
and position of the DBS lead in the brain relative to skull structures. In the event of
a change in efficacy, an easily obtained repeat skull and chest X-rays may demonstrate a break in the electrical connections or DBS lead migration.
Habituation may develop limiting continued tremor control (Barbe etal. 2011).
Many patients can regain tremor control by changing electrode configurations or
stimulation parameters. Often it is not necessary to increase the strength of the
stimulation. Generally, and particularly for those experiencing some tolerance,
patients are advised to turn the stimulator off at night. For some patients with significant tolerance, a weeklong holiday from stimulation may be recommended. In
both cases, it is important to be prepared for a significant worsening of the tremor.
Interesting, some patients develop an adaptive plasticity such that the tremor continues after the DBS has stopped, such as the battery running out.
A DV ER S E EFF ECTS
Adverse effects can be related to the surgical procedure and from stimulation. The
former typically involve the risks of intracranial hemorrhage and infection. The
postoperative consequences of intracranial hemorrhage depend on the location and
extent of the hemorrhage. Management of this complication is no different from
intracranial hemorrhage or infarction from any other cause. It is important to note
that intracranial hemorrhages may be delayed and, hence, continued suspicion of
the possibility of an intracranial hemorrhage in the event of a late adverse neurological change is needed (Chung etal. 2014). Also related to surgery is the risk
of infection discussed in the following. Occasionally, ataxia may be seen postoperatively even before active DBS. Typically this is self-limiting. Also, some patients
can be acutely more depressed in the immediate postoperative period, but typically
this is self-limiting. For patients with preexisting depression, increased surveillance postoperatively would be indicated. For patients with significant histories of
depression, arrangements for urgent psychiatric intervention postoperatively might
be made.
90
Adverse effects may be related to the DBS stimulation. In these cases, the adverse
effects can be related to spread of stimulation current to unintended structures. For
example, spread to the tactile region of the ventral caudal thalamus can produce
paresthesias. Spread to the posterior limb of the internal capsule can result in tonic
muscle contraction. In most cases, these adverse effects can be circumvented by
programming (Montgomery 2010). Stimulation of the head homuncular representation can be associated with increased risks of problems with speech, language,
or swallowing. Sometimes disorders of speech, language, or swallowing can be
relieved by programming by selecting negative contacts (cathodes) that avoid the
head representation, which typically is in the center in the dorsal ventral axis and
medial. Thus confining the volume of tissue activation by using narrow bipolar
configurations to confine the volume of tissue activation above or below the head
representation may help. However, prevention of this complication is important
and can only be accomplished by identifying the homuncular representation during DBS lead implantation surgery. To date, this requires the use of intraoperative
microelectrode recordings (Montgomery 2014).
There is a mistaken notion that macrostimulation, such as through the DBS
lead, can identify the homuncular representation, and some surgeons believe that
transient paresthesias in the contralateral hand is evidence sufficient for DBS lead
implantation. This is not the case, as one study of microstimulation demonstrated
that the regions of paresthesias do not correspond to the homuncular representation identified by microelectrode recordings (Grill etal. 2005). The choice of surgeon to whom the patient is referred is a choice for the methods used. The question
is whether the referring physician has a responsibility to choose surgeons employing what reason would argue as the most appropriate methods (see chapter19).
It is not infrequent that no combination of electrode configurations and stimulation parameters effectively relieve tremor without also affecting speech, language,
and swallowing. For these patients, it may be possible to program a set of alternative
stimulation configurations and parameters. For example, one program may stimulate at a higher current or voltage in order to control the tremor but temporarily
sacrificing speech, language, and swallowing for when tremor control is at a premium. When speech, language, and swallowing are a premium, the program can
be switched to one with a lower voltage or current.
To date and contrary to DBS for Parkinsons disease, there has been little published related to the psychosocial complications associated with the patients
change in psychosocial status with family, friends, and coworkers (Schupbach
etal. 2006). The remarkable and somewhat abrupt improvement in patients with
Parkinsons disease can disrupt the relationships that evolved when the patient was
more limited. While this does not appear to be a major problem for most patients
with Essential tremor, some degree of surveillance might be appropriate.
M ED I CAT I O N A D J U ST M EN TS
Many patients can substantially reduce medications following successful DBS

(Resnick etal. 2012). Reduction of medications should be strategic, starting with
those medications causing the most significant adverse effects. For example, beta
blockers can be associated with fixed cardiac output syndrome, bradycardia, and
heart failure. Primidone often causes confusion and lethargy. It is important to

recognize that programming and medication adjustments are done in an iterative
fashion. For example, the DBS is programming is done to optimize tremor control.
Then the medications are reduced, and, if the tremor worsens, the DBS is adjusted
rather than the medications increased. The process continues until the medications
are minimized and the tremor control maximized.
The primary goal is to obtain sufficient control of tremor and minimize adverse
effects whether by stimulation in combination with medications or by stimulation
alone. However, a secondary goal should be minimizing the medications while
optimizing DBS with an effort to reduce any adverse effects from the medications
and to gain economic benefit for medication reduction. This latter goal often is
not appreciated by DBS programmers, particularly when the programmer lacks
the knowledge, experience, skill, and credentials to adjust medications, such as an
industry representative.
D EEP B R A I N ST I M U L AT I O N R EL AT ED EM ER G EN C I ES
The number of patients with implanted DBS systems continues to expand. Many
will be in areas where there are no expert physicians and healthcare professionals. As these patients age, it will become increasingly likely that they will present
with urgent medical conditions, either related to their DBS, the underlying disease
for which the DBS system was implanted to treat, or other conditions that may be
complicated by the presence of the DBS system. Often, physicians and healthcare
professionals unfamiliar with DBS will be overly concerned and avoid diagnostic
or treatment procedures that otherwise should be done. Alternatively, these physicians and healthcare professionals will perform procedures that place the patient
and the DBS systems at risk. In many situations where DBS may interfere with a
diagnostic test, the DBS system can be turned off temporarily, such as for electrocardiograms, electromyography, and electroencephalography, with adequate
preparation for worsening of the underlying disorder for which the DBS system is
being used. Indeed, failure to do so may be a departure from the standards of care.
Imaging of patients with implanted DBS systems can be dangerous to the patient
and to the DBS system. For example, Magnetic Resonance Imaging scans using
a body coil typically are contraindicated (Oluigbo and Rezai 2013). However,
when performed carefully using only a head coil, the information obtained may
be entirely justified given clinical concerns (Chhabra et al. 2010). There have been
some concerns about Computed Tomography scans. Diathermy is contraindicated.
The fundamental principle that should be kept in mind by all physicians and healthcare professionals working with patients with implanted DBS systems is that any
procedure that involves the application of energy, typically but not exclusively electrical, magnetic, or ultrasound, must be done with caution. (These energies cause
rapid atomic motion that generates heat by friction.) All physicians and healthcare
professionals are advised to consult with the device manufacturer before exposing
patients to any form of external energy.
A full discussion of emergencies in patients with implanted DBS systems is
beyond the scope of this book. Readers are referred to Morishita et al. (2010).
Suggestions include consult with the manufacturer of the implanted DBS
92
systems, and, when in doubt as to what is going on, turn the DBS system off.
Patients or caregivers often are given devices that allow the DBS system to be
turned off and typically are advised to keep such devices with the patient. When
the physician and healthcare professional do not have access to the professional
DBS programming devices, they may need to use the device provided by the
patient or the patients caregiver. If the physician and healthcare professional
elect to turn the DBS system off, they need to be prepared for a marked exacerbation of the underlying disease the DBS was intended to treat. This problem often
is exacerbated by the fact that many patients have reduced their medications
significantly, thereby having little synergistic treatments to rely on if the DBS
system is turned off.
Infections can arise at any time. After the immediate postoperative period, possible skin erosions over the implanted hardware are a source of infection. Although
rare, there have been intracranial infections. Most infections occur at the site of the
implanted pulse generator and on occasion may be successfully treated with antibiotics and sometimes with explantation of the implanted pulse generator. However,
any infection that is tracking up the DBS extension or is over the head necessitates
immediate attention and probable explantation of the DBS system. The issue of
prophylactic antibiotics for medical procedures is problematic. The issue probably
should be referred to the surgeon who implanted the DBS system.
Intracranial hemorrhages most often occur in the immediate postoperative
period. However, delayed hemorrhages are possible, for example subdural hematomas. The question is whether patients with implanted DBS systems can be on anticoagulation for infarction prevention or in the setting of atrial fibrillation. No studies
bearing on this issue could be found in PubMed. However, Ihave been involved
in a number of cases of DBS for patients in atrial fibrillation. Anticoagulants are
discontinued prior to surgery and then restarted postoperatively. No intracranial
hemorrhages were experienced.
S U M M A RY
DBS is highly effective but depends on appropriate postoperative programming.

Most patients tolerate DBS well, and, in the worst-case scenario, DBS can be stopped
if it produces intolerable adverse effects. Most surgical-type complications occur in
the perioperative time period but can also present late after surgery.
R EFER ENCES
Barbe MT, Liebhart L, Runge M, etal. Deep brain stimulation in the nucleus ventralis intermedius in patients with essential tremor:habituation of tremor suppression.
Jeurol. 2011;258(3):434439.
Chhabra V, Sung E, Mewes K, etal. Safety of magnetic resonance imaging of deep brain
stimulator systems: a serial imaging and clinical retrospective study. J Neurosurg.
2010;112(3):497502.
Chung EJ, Kim MS and Kim SJ: Delayed intracranial hemorrhage after deep brain
stimulation in two Parkinsons disease patients. J Neurol Sci. 2014;342(12):202203.
Grill WM, Simmons AM, Cooper SE, et al. Temporal excitation properties
of paresthesias evoked by thalamic microstimulation. Clin Neurophysiol.
2005;116(5):12271234.
Limousin P, Speelman JD, Gielen F, et al. Multicentre European study of thalamic
stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry
1999;66(3):289296.
2014.
Morishita T, Foote KD, Burdick AP, etal. Identification and management of deep brain
stimulation intra- and postoperative urgencies and emergencies. Parkinsonism Relat
Disord. 2010;16(3):153162.
Okun MS, Tagliati M, Pourfar M, etal. Management of referred deep brain stimulation
failures:a retrospective analysis from 2 movement disorders centers. Arch Neurol.
2005;62(8):12501255.
Oluigbo CO, Rezai AR:Magnetic resonance imaging safety of deep brain stimulator
devices. Handb Clin Neurol. 2013;116:7376.
Resnick AS, Okun MS, Malapira T, et al. Sustained medication reduction following
unilateral VIM thalamic stimulation for essential tremor. Tremor Other Hyperkinet
Mov. 2012;1(1):2.

Effective for Patients with Dystonia
PR I M A RY DYSTO N I A , S EC O N DA RY DYSTO N I A
Primary dystonia originally applied to patients without a discernible historical

cause related to some such event as perinatal hypoxic/ischemic injury or a demonstrable pathology. Included in this category are the genetic generalized dystonias.
Many of these dystonias have known causesspecific genetic abnormalities and
the like. Yet these diagnoses remain under the category of primary dystonias.
Secondary dystonias are associated with known such causes as tardive dystonia
secondary to neuroleptic use and postanoxic dystonia typically associated with
lesions in the globus pallidus.
Such a distinction is not merely semantic. There are significant clinical implications. For example, physicians make comparisons in the respective outcomes for
Deep Brain Stimulation (DBS) for primary and secondary dystonia. The latter does
not do as well. The inference is that patients with secondary dystonia are somehow less eligible for DBS. There is a tendency not to judge DBS for patients with
secondary dystonia according to the merits specific to secondary dystonia. What
difference does it make if a patient with secondary dystonia obtains a clinically
meaningful benefit without adverse effects, even if the degree of benefit is less than
what might be seen in primary dystonia? Further, the presupposition that primary
dystonias respond better than secondary dystonias is suspect.
There is an immediate practical difference in that the US Food and Drug
Administration (FDA) has approved DBS for primary dystonia under a
Humanitarian Device Exemption. This technically leaves DBS for secondary dystonia as investigational (under Medicare definitions; Rossi etal. 2014)or off-label.
In either circumstance, reimbursement for physicians providing DBS to patients
with secondary dystonia is problematic. According to the FDA at least, DBS for
secondary dystonia is well within a physicians purview in the practice of medicine.
Chapter15 contains an extensive discussion of the off-label use of FDA-approved
drugs and devices for hyperkinetic disorders
The historical evolution of the notion or primary versus secondary diagnoses
provides interesting insight into the evolution of medical thinking. Primary in
this case originally indicated that the syndrome was idiopathic (of unknown cause).
9. Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia95
This leaves the syndrome of secondary dystonia to cover those diseases whose cause
is known. Primary dystonia traditionally included such disorders as generalized
torsion dystonia (dystonia musculorum deformans), as well as such focal dystonias as cervical dystonia and the condition commonly known as writers cramp.
The secondary dystonia include dystonia consequent to perinatal hypoxic-anoxic
injury, Kernicterus, trauma, and other conditions that left telltale signs of physical injury to the brain. Clinical correlations with specific events, such as ingestion
of neuroleptic agents block dopamine receptors, generate a new secondary dystonia:tardive dystonia.
I M P O R TA N C E O F (SC I EN T I FI C) CAU S A L M EC H A N I S M S
With the advent of molecular neurobiology, maintaining a distinction between

primary and secondary dystonia becomes increasingly problematic. For example,
at least 25 genetic mutations are associated with generalized torsion dystonia.
Though only a minority of patients with generalized torsion dystonia have an identifiable genetic abnormality, it would appear inconsistent to describe these patients
as primary generalized torsion dystonia. And though only a few patients with cervical dystonia have a known genetic abnormality, the probability of a family member also having dystonia is approximately 24% (Groen etal. 2012). This suggests
that it is only a matter of time before other putative genetic causes are discovered.
It seems reasonable to claim that nearly every disease was primary at some point,
and, with advances in molecular neurobiology and imaging, that every disease will
someday be secondary.
It is interesting to note that the distinction of allopathic medicine (forerunner of
modern medical doctors) rested on its purported scientific basis. This distinction
received its greatest boost with the expansion of the field of microscopic pathology
by Rudolf Virchow (18211902) and with the Germ Theory of the mid-nineteenth
century. One of the reasons for the remarkable fame of William Osler (18491919),
the most prominent physician of his time, was his ability to merge physical diagnosis with pathological studies (Bliss 1999). The first Code of Ethics published by
the American Medical Association in 1847 claimed the high ground of science by
stipulating that no one can be considered as a regular practitioner, or a fit associate
in consultation, whose practice is based on an exclusive dogma, to the rejection of
the accumulated experience of the profession, and of the aids actually furnished by
anatomy, physiology, pathology, and organic chemistry (italics added). The Code
of Ethics also sought to enlist the publics help in protecting the profession: The
public ought likewise to entertain a just appreciation of medical qualifications;to
make a proper discrimination between true science and the assumptions of ignorance
and empiricism,to afford every encouragement and facility for the acquisition of
medical education. It is likely that the reference to exclusive dogma refers to the
ancient Greek dogmatic school of medicine, which posited that reason alone is sufficient to practice medicine (Marcum n.d.) and to empiricists who argued observation alone without reference to underlying and unseen mechanisms were sufficient
for medical practice (Marcum n.d.). The distinction of a scientific basis claimed by
allopathic physicians claiming is interesting, because the actual treatments they
96
offered was little different than those earlier physician who held to the ideas of
Galen (130200 ad). Indeed, many of the practices engaged in by William Osler
were much the same as those of Galens followers (Bliss 1999).
The emergence and present dominance of Evidence-Based Medicine, which
has become synonymous with randomized control trials (RCTs), have been striking. RCTs represent the supreme standard of medical knowledge and the most (if
not sole) legitimate director of patient care. Yet, there is nothing scientific about
Evidence-Based Medicine and RCTs. There is nothing in either that requires any
kind of causal mechanism in the diagnostic selection criteria or in the choice of
treatments to study. Conceptually speaking, there is nothing within either that
would prohibit a study of pulverized porcelain. It would be hard to believe that any
medical scientist would suggest choosing a treatment to test willy-nilly, as might
be suggested by the choice of pulverized porcelain (reminiscent of the empiricists
rejected by the allopathic physicians in the 1847 Code of Ethics of the American
Medical Association). Yet the only reason this would not happen is some other
knowledge, presumably scientific, is brought to bear on the RCT. The question is
the origin and nature of the outside knowledge.
T H E I M P O R TA N C E O F D I AG N O S I S
One may say that the combination of clinical symptoms and signs consistent with
dystonia, occurring early in life in a patient who has a family history of similar
conditions and without any known neurological insult, would likely benefit from
DBS. This does not require the presence of a known cause, such as the DTY1 genetic
abnormality (or others). This is based on the accumulated clinical experience that
such patients experience significant improvement in their dystonia following DBS.
The question becomes:what is it about the cluster of features described here that
prognosticates the potential for improvement with DBS? More important, what is
the cluster of features in patients for whom DBS does not bring sufficient relief, presumably those with secondary dystonia? One may argue that the common features
suggest a good prognosis to DBS, whereas disparate features present in those who
do not do as well may imply a poor prognosis. The features that are conjunctive and
those that are disjunctive may be used as selection criteria for candidacy for DBS.
If, for example, symptom or sign X is always associated with a poorer prognosis,
then it is likely (though not proven) that dystonia without symptom of sign X is
associated with a good prognosis regardless of etiology. One may say therefore that
DBS is a treatment for the symptom of dystonia and not for any particular cause of
dystonia.
EFFI CACY
Vidailhet and colleagues (2005) published an extensive review of the literature

relative the clinical efficacy of DBS for many forms of dystonia. These authors paid
close attention to those features that were unimproved with DBS, as well as other
features that may account for the variability in clinical efficacy. Their analysis was
hampered by the relative dearth of randomized controlled prospective studies and
lack of consistent outcomes measures. Based on case reports and small series, however, their review suggested a degree of improvement in symptom or physical sign
based assessments, such as the Burke-Marsden-Fahn Rating Scales, on the order
of 50% to 60% for primary generalized torsion dystonia in more than 200 patients.
Eight of 26 patients with DYT1 generalized torsion dystonia experienced worsening that required placement of a second DBS lead (Cif etal. 2010), of whom half
improved and none worsened.
Patients with cervical dystonia improved to a similar degree as did patients with
primary generalized torsion dystonia and patients with such myoclonus-dystonia
disorders and cranial dystonias, such as Meige syndrome and blepharospasm.
Interestingly, in these patients with cranial dystonias, no improvement was observed
in speech or swallowing. This resembles failure for these symptoms to improve with
DBS for Parkinsons disease and other conditions. Interestingly, Vidailhet and colleagues (2005) included tardive dystonia as a primary dystonia and noted improvements not inferior to those described earlier in this chapter.
The similar degree of improvement in dystonia over these different dystonic syndromes suggests that pathogenesis does not affect therapeutic efficacy. This lends
support to the notion that, for dystonia, DBS is a symptomatic treatment rather
than disease-specific treatment.
Vidailhet and colleagues (2005) included among the secondary dystonias
dystonia-choreoathetotic cerebral palsy and a group of neurodegenerative or metabolic abnormalities. In the latter, only the group with NAIB (a neurological disorder
associated with abnormal iron accumulation in the brain), of which Pantothenate
kinaseassociated neurodegeneration is an example, demonstrated a wide range
of improvements, with many reaching the degree of improvement observed in primary generalized torsion dystonia.
The study of patients with dystonia-choreoathetotic cerebral palsy demonstrated
a wide range of improvement24% on average but as much as 55% in some cases
(Vidailhet etal. 2009). Unfortunately, the relevance of this study for dystonia secondary to perinatal hypoxic-ischemic injury is problematic, because it is unlikely
that any patients had significant dystonia. This probably owed to the selection criteria, which required an Ashworth scale of less than 2.The presumption is that the
Ashworth scale is specific for spasticity. It is not. Yet it also is affected by dystonia
(Gordon etal. 2006). In the attempt to exclude spasticity as a confound, therefore,
the study probably also excluded patients with significant dystonia, leaving a population with predominantly chorea.
A DV ER S E E V EN TS
Adverse events may be distinguished conceptually as events associated with DBS

surgery, events associated with hardware failures, events related to stimulation, and
events related to the psychosocial impact of the treatment. Adverse effects related to
stimulation include those related to the spread of electrical current to unintended
structures in the regional anatomy around the DBS lead, effects related to stimulating the intended target, and nonspecific effects. With respect to perioperative
complications, the most frequent concerns related to intracranial hemorrhage and
infection. With respect to both, studies across a number of disease indications and
98
DBS targets suggest that the risks are generally the same. The incidence of intracranial hemorrhage is on the order of 10% when actively sought with postoperative imaging. Amere 10% or so of these, however, are significantly symptomatic.
Overall risk is thus approximately 1%. The nature and severity of complications
relate to the location and extent of the hemorrhage. Though most intracranial hemorrhages occur acutely, there have been instances of hemorrhages remote in time
to DBS lead implantation surgery. Often these hemorrhages are subdural in origin.
Infections are conceptually distinguished as those that necessitate removal of the
DBS lead and those that do not. Removal of the DBS lead clearly results in a second
surgery to replace it. In some cases it may be necessary to remove the implanted
pulse generator (IPG), the area in which it is placed being the most frequent site of
infection. In either case, the removal of the DBS lead or the IPG results in an interruption in the patients treatment and a return of symptoms and disabilities. In a
review, the overall risk of infections associated with DBS surgery was 5.6%. The
incidence of infections solely with IPG replacement was 17.6%, a finding consistent
with the general impression that infections at the IPG site are more common that
they are at the DBS lead implantation site. Sillay and colleagues (2008) reviewed
their vast experience and found that their infection rate was approximately 4.6%.
The large majority of infections occurs in the area of the chest associated with the
IPG (Sillay etal. 2008). Of 14 patients with infection, partial removal of the hardwarethe IPG, presumablywas attempted and met with success in 9 patients.
If the other 5 patients from whom the DBS hardware was removed entirely also
involved failures to salvage the DBS lead, then the risk of having to replace the
DBS lead is approximately 47%. The overall risk of infection necessitating DBS lead
removal is thus approximately 2.6%.
In reviews of the literature, the posterior lateral globus pallidus interna has been
the most common target (Vidailhet etal. 2013). There have been reports of DBS in
the vicinity of the thalamus and the subthalamic nucleus, all of which have been
associated with improvements in dystonia. The question becomes which target to
recommend.
There are several aspects to the choice of target. One rests on the confidence that
stimulation of a specific target will provide sufficient efficacy and minimize the risk
of adverse events. Alternatively, the choice may be made according to theories of
pathophysiology. In the case of Parkinsons disease, for example, the globus pallidus
interna was favored initially, because the choice was supported by the theory of globus pallidus interna hyperactivity as causal to Parkinsons disease and the notion
that high-frequency DBS was analogous to pallidotomy. Both of these notions are
incorrect (Montgomery 2012). The notion of hyperactivity of the globus pallidus
interna as central to Parkinsons disease was extrapolated to its role in other movement disorders of the basal ganglia. In Parkinsons disease, however, DBS of nearly
every structure within the basal ganglia-thalamic-cortical system may improve the
symptoms and signs of Parkinsons disease. This fact suggests that Parkinsons disease is not a disorder of the globus pallidus interna but rather of the entire basal
ganglia-thalamic-cortical system. DBS in Parkinsons disease is likewise a result of
an effect on the entire basal ganglia-thalamic-cortical system. DBS in the vicinity of

the globus pallidus interna is simply incidental and represents merely one route to
introduce neuronal activations to the basal ganglia-thalamic-cortical system.
Whether the concept of a systems disorder applies to the pathophysiology of
dystonia is unclear. In large part this is due to relatively little knowledge of pathophysiology of human dystonia. However, it is important to keep the notion of
pathophysiology separate from notions of pathoetiology. For example, there may
be many causes of dystonia, in other words many ways to damage to neurons, but
the consequence that alters the physiology to produce the symptoms and signs of
dystonia may not be specific to the mechanisms that cause neuronal injury. This is
a lesson learned from pathophysiological studies of Parkinsonism (Montgomery
2007), and there is little reason, a priori, to argue that it would not be the case for
dystonia.
Confidence relative to the efficacy related to DBS of specific targets is problematic, given the relative lack of data. The globus pallidus interna represents a possible
exception. To be sure, there have not been controlled studies where patients are randomized to the globus pallidus interna, thalamus, or subthalamic nucleus. It would
not be unreasonable to suggest that the greatest confidence related to efficacy is
with DBS in the vicinity of the globus pallidus interna. Risk of adverse effects must
be weighed against possible benefit. If there is relatively little confidence that DBS
in the vicinity of the thalamus or subthalamic nucleus is efficacious, the issue of
risk becomes practically moot. This is not to suggest that future clinical trials of the
thalamus and subthalamic nucleus are unwarranted. They are entirely warranted.
T H E D EC I S I O N TO PR O C EED W I T H S U R G ERY
Though is it common knowledge that one must weigh risks against benefit, many
alternatives are often overlooked. By definition, however, there are no other reasonable alternatives for patients with dystonia who are under consideration for
DBS. Were reasonable alternatives to exist, the patient would not be a candidate.
There is another alternative: not offering surgery to patients who have no other
alternative. The no-surgery alternative is certainly considered in the context of benefit, because benefit is directly consequential to performing the surgery. However,
the no-surgery alternative may be given more ethical weight as a consequence of
Omission bias. This bias, which is endemic, is embodied in the physicians motto,
Do no harm (Primum non nocere). This motto suggests that errors of commission
are worse than errors of omission (see chapter19). Patients with dystonia who have
exhausted all other reasonable therapies face continued suffering and danger from
the risks associated their dystonia if no DBS surgery is offered to them.
S U M M A RY
DBS is safe and effective. The average improvement in dystonic symptoms is

approximately 50% to 60% in primary dystonia. Many secondary dystonias achieve
the same level of benefit. One must therefore ask whether maintaining a distinction between primary and secondary dystonia for the purpose of considering DBS
100
makes sense. The risk are relatively small. The risk of serious intracranial hemorrhage is approximately 2%, and the risk of infections that necessitate the removal
of the DBS lead is approximately 2%. Other complications related to DBS surgery
seizure, deathare exceptionally rare.
Adverse effects attributable to the spread of electrical current to unintended
structures usually resolve with careful DBS programming. Other adverse effects
associated with DBS, which are difficult to attribute to surgical trauma or stimulation of unintended structures, depend on the DBS target. DBS of the globus pallidus interna has generally a low risk of these complications. Vigilance is nonetheless
required.
R EFER ENCES
Bliss M. William Osler:ALife in Medicine. NewYork:Oxford University Press; 1999.
Cif L, Vasques X, Gonzalez V, et al. Long-term follow-up of DYT1 dystonia
patients treated by deep brain stimulation: an open-label study. Mov Disord.
2010;25(3):289299.
Gordon LM, Keller JL, Stashinko EE, et al. Can spasticity and dystonia be independently measured in cerebral palsy? Pediatr Neurol. 2006;35(6):375381.
Groen JL, Kallen MC, van de Warrenburg BP, et al. Phenotypes and genetic
architecture of focal primary torsion dystonia. J Neurol Neurosurg Psychiatry
2012;83(10):10061011.
Marcum JA. Philosophy of medicine. In Internet Encyclopedia of Philosophy, n.d. http://
www.iep.utm.edu/medicine/
Rossi PJ, Machado A, Okun MS. Medicare coverage of investigational devices: the
troubled path forward for deep brain stimulation. JAMA Neurol. 2014;71(5):535536.
Sillay KA, Larson PS, Starr PA. Deep brain stimulator hardware-related infections:incidence and management in a large series. Neurosurgery 2008;62(2):360366; discussion 366367.
Vidailhet M, Jutras MF, Grabli D, etal. Deep brain stimulation for dystonia. J Neurol
Neurosurg Psychiatry 2013;84(9):10291042.
Vidailhet M, Vercueil L, Houeto JL, etal. Bilateral deep-brain stimulation of the globus
pallidus in primary generalized dystonia. N Engl J Med. 2005;352(5):459467.
Vidailhet M, Yelnik J, Lagrange C, etal.:Bilateral pallidal deep brain stimulation for
the treatment of patients with dystonia-choreoathetosis cerebral palsy:a prospective
pilot study. Lancet Neurol. 2009;8(8):709717.
10

Deep Brain Stimulation Candidates
Among Patients with Dystonia
The chapter title sounds counterintuitive. In nearly every other publication, the
present selection criteria indicate who the best candidates are. But that is not where
the difficulty lies. The much harder question is which patient has the minimum
acceptable criteria for an outcome whose benefit outweighs the risks. The conceptual basis of this topic is discussed in detail in chapter4.
Deep Brain Stimulation (DBS) is remarkably effective in treating dystonia,
provided patients are selected carefully. Though careful selection would seem to
apply to patients undergoing any treatment, one must pause to consider exactly
the factors involved. Considerations of the ratio of risk to potential benefit are
certainly germane to any treatment. Among the risks is possible irreversibility.
With DBS the incidence of irreversible risks relates primarily to surgical risks,
which are quite smallon the order of 2% to 4% for serious or permanent disability. These risks have been consistent over multiple indications and in multiple
DBS targets. One must bear in mind that many other risks associated with DBS
are usually reversible. To reverse them one either adjusts the stimulation or ceases
it altogether.
A presumption prevails that severe adverse effects associated with medications
are reversible, whereas those associated with surgery are irreversible. Physicians,
patients, and patients family members and caregivers may hold a bias that unduly
colors their impression of DBS surgery. In many instances medications carry
greater risk of irreversible consequences. Neuroleptics, for example used in treating
dystonia and other hyperkinetic disorders, may produce Tardive Dyskinesia and
Tardive Dystonia.
PR I M A RY DYSTO N I A V ER S U S S EC O N DA RY DYSTO N I A
In medical literature and by the US Food and Drug Administration (FDA), a distinction is drawn between primary dystonia and secondary dystonia. The FDA,
in fact, has approved DBS for primary dystonia under a Humanitarian Device
102
Exemption. It has not, however, approved DBS for secondary dystonia. Where no
approval has been given, lack of approval may be perceived as pejorative and may
prevent patients with secondary dystonia from receiving a therapy that would otherwise benefit them. Physicians may refuse to offer it, and insurers may refuse to
cover it, because they consider it experimental or investigational, which it is not.
A detailed discussion of the issue of off-label use of FDA approved devices is
discussed in c hapter15 with respect to hyperkinetic disorders, and the ethics are
addressed in c hapter19. As discussed in chapter9, however, DBS proves effective
in treating some cases of secondary dystonia as it is in treating primary dystonia. Because DBS should be considered standard and accepted off-label use of an
FDA-approved device, the selection criteria discussed here observe no distinction
between primary dystonia and secondary dystonia.
I believe that comorbidities associated with some forms of secondary dystonia
reduce DBS efficacy. Patients with dystonic cerebral palsy, for example, often present with considerable spasticity, a phenomenon that is often difficult to distinguish
from dystonia. The Ashworth scale and other clinical rating scales do a poor job
of distinguishing dystonia from spasticity. The Burke-Marsden-Fahn scale, meanwhile, is not specific to dystonia (Gordon etal. 2006). There is no reason to believe
a priori that DBS would prove an effective treatment for spasticity and consequently; it is likely that the relative poorer outcomes with DBS in the vicinity of the
globus pallidus interna is due to the effects of residual spasticity.
Evidence (Gordon etal. 2006)and clinical experience exist to suggest that muscle
tone (resistance to passive joint rotation) that depends on velocity is likely spasticity, particularly if one notes a catch and release associated with the joint rotation. Muscle tone that is constant despite the velocity of joint rotation, on the other
hand, likely owes to dystonia. This distinction may guide consideration of patients
with secondary dystonia for DBS.
The distinction between spasticity and dystonia according to velocity of joint
rotation relates to the mechanisms underlying the increased muscle tone. Spasticity
is thought to be related to increased excitability of the alpha lower motor neurons.
Muscle spindle feedback results in an exaggerated output of the alpha lower motor
neurons that increases resistance to muscles stretching in response to joint rotation. Because many muscle spindles are sensitive to velocity, greater rapidity of
joint rotation elicits greater muscle spindle output to the alpha lower motor neuron
resulting in increased resistance. Though the precise mechanism of dystonia-related
increased muscle tone are unknown, excessive excitability of the reflex arch involving the muscle spindles and the alpha lower motor neuron is ruled out as a cause. If
one assumes this to be true, one would not expect dystonia to depend on velocity.
This is supported by the observation that the deep tendon reflex involves muscle
spindles and the alpha lower motor neuron in an exaggerated manner in spasticity
and does not do so in dystonia.
Methods available or under development may be able to distinguish spasticity
from dystonia and provide a quantitative estimate of each. This would enable clinical trials to determine whether the lower degree of DBS benefit in patients with
dystonic cerebral palsy correlates to the degree of spasticity.
Another example of a comorbidity that confounds assessment of DBS efficacy
may be found in those cases of cranial dystonia in which speech and swallowing
do not improve and may indeed worsen. Speech and swallowing, however, pose
10. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia103
problems to DBS for Parkinsons disease and other conditions. If DBS is directed to
some other aim than improving speech and swallowing, then lack of their improvement should not deter physicians from offering DBS surgery.
For the aforementioned reasons, Iexclude from selection criteria the diagnosis
of primary or secondary dystonia. Rather, Irecommend that the comorbidities be
carefully considered, because they are more common in secondary dystonias and
thus unlikely to be helped by DBS. If these comorbidities are the limiting factor to
improvement, then DBS is not likely to make a meaningful difference. If a patient
has spasticity severe enough to limit her quality of life, for example, then DBS is not
likely to result in a satisfactory or acceptable improvement.
P OT EN T I A L FO R S P O N TA N EO U S R EM I S S I O N
Attending cases of Tourettes syndrome is an expectation that the symptoms will

decrease in severity over time (see chapter13 for a detailed analysis). The question is
whether this is relevant for dystonia. It remains uncertain whether this expectation
is realistic, because it is impossible to foretell whether any particular young patient
with the condition will experience an improvement in his symptoms. Nonetheless,
one may feel reluctant to subject a patient to DBS risks if that patient enjoys even
a small chance of spontaneous remission, failure of alternative therapies notwithstanding. The task thus becomes that of determining the probability of a spontaneous remission in a particular form of dystonia.
Tardive Dystonia
The task of determining the probability of spontaneous remission is an appreciable
concern when treating Tardive Dystonia. This disorder is typically consequent to
exposure to agents that block dopamine receptors. Traditional neuroleptics, such as
haloperidol or chlorpromazine, are widely recognized as carrying a risk of producing Tardive Dystonia. Many atypical neuroleptics carry this risk as well. Over half of
patients with Tardive Dyskinesia experience spontaneous remission of their symptoms, but in one study none of the nine participating patients improved or remitted
(Gimenez-Roldan etal. 1985). Alarger retrospective study of 107 patients, however,
demonstrated a spontaneous remission rate of approximately 14% (Kiriakakis etal.
1998). The mean number of years for remission was 5.2 following diagnosis and 2.6
following discontinuation of the neuroleptic. The authors noted a fivefold greater
chance of remission in patients with fewer than 10years of symptoms over those
with more than 10years.
Unfortunately, I was unable to find any published survival curves of the
Kaplan-Meier type that would provide a threshold in terms of disease duration.
Adisease-duration threshold in turn predicts the threshold at which probability of
spontaneous recovery is sufficiently low to justify a DBS referral. One could argue
that a mean of 2.6years following discontinuation of the offending agent suggests
that, if one assumes the data conforms to a Gaussian distribution, fewer than half
of patients experienced spontaneous remission after 2.6 years. Data distribution
highly skewed to the left results in a mean that is likely to be heavily influenced by
104
outliers in those whose remission required a greater amount of time. If such were
the case, fewer than half of patients living with symptoms for more than 2.6years
would experience spontaneous remission.
A patient with Tardive Dystonia who is assumed to have exhausted all reasonable alternative needs to weigh, when in discussion with her treating physician, the
possibility of spontaneous remission against the dystonias severity and impact on
her quality of life. The more persistent the dystonia, the less likely becomes spontaneous remission.
Cervical Dystonia
Similar considerations pertain to patients with cervical dystonia. Again, a Kaplan-Meier
type survival curve would be helpful in predicting the potential for spontaneous
remissions based on the duration of symptoms. Anumber of studies present findings
that suggest a spontaneous remission rate of 20% (Jahanshahi etal. 1990). There followed, however, a significant number of relapses. In one study, a median remission
duration of three years was observed in nine of the participating patients. The studys
authors reported that 87% of the spontaneous remissions occurred in the first five
years. For approximately 70% of participating patients, age at onset, form of torticollis,
gender, and direction of head deviation predicted the chance of a sustained remission.
Depending on severity of symptoms and impact on the quality of life, patients who
have lived with cervical dystonia for fewer than five years may wish to consider delaying
DBS surgery if they deem a 20% chance of spontaneous remission acceptable.
Blepharospasm and Meiges Syndrome

In one study, 27% of participating patients experienced remission, the median span
from onset to remission being three years (Castelbuono and Miller 1998). In other
words, half of patients who experienced remissions did so in the first three years of
symptoms. The range was from 3months to 22years. Amean duration of 4.85years
indicated that the distribution was heavily weighted toward shorter durations.
Again, patients must discuss with their physicians the feasibility of DBS, given the
probability of spontaneous remission. Of course, the longer a patient lives with
symptoms, the lower the probability that he will experience spontaneous remission.
Generalized Torsion Dystonia

In one study, 6 of 226 participating patients (2.7%) were shown, upon retrospective chart review, to have had a history of spontaneous remission (Cooper et al.
1976). One may argue that it cannot be known whether these six patients actually had generalized torsion dystonia instead of psychogenic dystonia or some
other reversible form. Though the statement may be made, it lacks force, because
it lapses into an error in reasoning known as argumentum ad ignorantiam (argument from ignorance), which rests on the notion that an assertions validity derives
from an inability to assert the contrary. The most appropriate criticism is whether
the patients studied in the retrospective chart reviewthe sampletruly represented the population of concern, namely, all patients with dystonia. Indeed, it is
the most appropriate criticism because it is perennially pertinent:One may gain
exhaustive knowledge only of an investigators sampling of the population, never of
the population itself. To claim otherwise courts error in the form of the Fallacy of
Induction, in which an observed common quality among entities that are regarded
as belonging the same kind is presumed to enjoy universal validity. Its fallaciousness owes to the fact that the possibility remains open that an unexamined entity
otherwise belonging to that kind may lack that quality. For instance, the statement
all ravens are black, which rests on the observation of the uniform blackness of all
ravens heretofore encountered, becomes immediately falsified upon encounter with
a single raven whose coloring is something other than black. The dilemma is that
one can never be sure that there exists an unobserved non-black raven.
If one assumes that a physician diagnosing generalized torsion dystonia is as
competent as those physicians who made the diagnosis obtained for the retrospective study, then any sampling issues remain the same. The sample of the review that
found a 2.6% spontaneous remission therefore continues to be relevant to physicians. Tests exists today, however, that enable one to test for known genetic disorders as part of the diagnostic procedure. These tests were unavailable at the time the
study was conducted. Yet cases of dystonia involving known genetic abnormalities
represent only 20% to 30% of the cases (Dressler 2011). Reduced penetrance evident
even in individuals with identified genetic abnormalities indicates that the presence
of the gene does not guarantee the development of dystonia. The issue is whether a
2.6% chance of spontaneous remission is sufficiently clinically meaningful to dissuade a patient with generalized torsion dystonia from undergoing DBS surgery.
Physiological Dystonic Postures Versus Anatomical Dystonic Postures

The distinction between physiological and anatomical dystonic postures is predicated on the notion that anatomical changes in bones, joints, muscles, and tendons
contribute to or create dystonic postures. Dystonia produced by such changes is
known as fixed dystonia. Cervical spondylitis, for example, may create abnormal
postures indistinguishable from cervical dystonia. Postures limited by anatomical
changes are not likely to respond to DBS. Physiological dystonia suggests that the
abnormalities owe to abnormal brain activitys driving muscles to form the abnormal postures. Evidence for this notion, at least in the case of cervical dystonia, is
found in the effectiveness of partial denervation surgery.
Anatomical changes that prevent DBS or other therapies from fully relieving dystonia may result from physiological driving of abnormal postures and thus confound the
distinction between physiological and anatomical dystonic postures. Kyphoscoliosis,
for example, is a common complication of generalized torsion dystonia. In fact, the
risk for secondary anatomical changes argues for early aggressive treatment.
One may distinguish anatomical dystonic postures from physiological by observing the degree to which a dystonic posture is corrected actively by the patient
the geste antagoniste maneuver as performed by patients with cervical dystonia,
for exampleor passively by the examiner. On occasion, a physiological dystonic
posture proves sufficiently strong to thwart any active and passive attempts at
106
correcting it. In such cases, observing patients while they are sleeping or sedated
enables determination of whether theirs is physiological dystonia, which will relax
when they are in such a state, or anatomical (fixed) dystonia, which will not.
Dystonia in Children
Children are prone to both physiological and anatomical dystonia (Herman 2006).
Interestingly, of most genetic generalized torsion dystonias affecting young children, dystonia secondary to perinatal hypoxic-ischemic injury may present earlier.
Avariety of congenital bony abnormalities present in children as anatomical dystonias. Later in childhood (adolescence particularly), trauma may result in bony,
muscular, and tendonous abnormalities that present as anatomical dystonia. Also,
in children, differential diagnosis (of cervical dystonia particularly) is skewed eye
deviation, a condition that children intuitively learn to correct by assuming an
unusual head tilt. Also, children with posterior fossa tumors, such as cerebellar
astrocytomas, may present with unusual head postures (Caress etal. 1996).
Neurodegenerative Disorders and Metabolic Disease

Neurodegenerative disorders and metabolic disease that present with dystonia
include mitochondrial disorders, organic acidemia, guanidinoacetate methyltransferase deficiency, Nieman Pick C, homocystinuria, abnormal dopamine
metabolism (Segawa disease or late-onset tyrosine hydroxylase deficiency, glucose
transporter type 1)deficiency, glutaric aciduria type 1 (Pierre 2013), pantothenate
kinase-associated neurodegeneration, Fahrs disease, and Wilsons disease. Many
diseases are rare and are associated with other neurological features. These facts,
which suggest atypical dystonia, should invite further investigation. Though many
diseases present in infancy, many do not. Some, moreover, may be precipitated by
specific conditions. Some may be treated with special diets. Segawa disease and
late-onset tyrosine hydroxylase deficiency may improve with levodopa therapy.
It is traditional to discuss the differential diagnosis, but the question is whether it matters and, if it does, to what degree and in what aspect. If one assumes that DBS would
be reasonably effective, in its widest connotation, in any of the conditions listed previously, then the only material effect of a specific diagnosis is whether there is some unique
medical treatment. For example, Wilsons disease is treated by D-penicilamine, trientine, zinc, and ammonium tetrathiomolybate. However, some patients are refractory to
these treatments, and DBS may be effective (Sidiropoulos etal. 2013; Hedera 2014).
FA I LU R E O F A LT ER N AT I V E T H ER A PI ES
Because most treatments other than DBS have a very low incidence of life-threatening
or irreversible complications (intrathecal baclofen and intraventricular baclofen
being exceptions), they must be exhausted before a patient is exposed to the risks
of DBS. However, it is important to identify those actions that constitute a reasonable attempt at these other therapies. Medications must be attempted at dosages
sufficient to render negligible the probability of improvement with further increases

or doses that produce intolerable yet unavoidable side effects.
Medications
The various classes of agents used include the anticholinergics, dopamine
agonists (levodopa particularly), dopamine antagonists, dopamine-depleting
agents, and such gamma-aminobutyric acidrelated agents as baclofen and the
benzodiazepines. Within each class are multiple agents. The possible number of
combinations is thus 31 among the five classes and 1,023 if two agents from each
class are considered. Exhausting every possible combination is clearly problematic. One must construct, rather, a strategy based on relative efficacy and adverse
effects.
Unfortunately, there exist no pharmacological studies that provide dose
response curves for efficacy or adverse effects. In the case of doseresponse curves
for efficacy, one may take the point of the graph (provided it displays saturation
kinetics) and select the dose at which the curve becomes asymptotic. This dose suggests that further dosage increases will accomplish little. The same approach with
respect to adverse effects is not likely to prove fruitful, because the degree of tolerability is highly specific to the patient. Every patient may have different threshold
for tolerance based on his particular medical, social, psychological, and economic
contexts.
Adding to the difficulty is a lack of rigorously controlled trials and any direct
comparisons, within and between classes, of various options (Albanese etal. 2006).
Using a hierarchical approach, Greene and colleagues (1988) performed a retrospective chart analysis of 600 charts. Patients were started on anticholinergics that
were titrated up to either the maximum tolerated dosage, 50 mg per day, or the level
of sufficient benefit. Those patients who failed anticholinergics were then started
on another agent. If the anticholinergic medication provided some benefit (presumably without intolerable side effects), another agent was added. Otherwise, the
anticholinergics were reduced and discontinued.
Approximately 20% of patients who failed to achieve satisfactory benefit from
anticholinergics improved with baclofen. Thus, if a patient fails anticholinergics,
baclofen should be tried. Failure of anticholinergics, in other words, does not predict failure with baclofen. Greene etal. (1988) stated that patients did not respond
as well to clonazepam as they did to baclofen. One thus draws the reasonable,
albeit tentative, inference that those who fail baclofen are unlikely to benefit from
clonazepam.
The benefit realized by use of levodopa in patients with Segawa disease and
late-onset tyrosine hydroxylase deficiency argues for a therapeutic trial, the rarity of these conditions notwithstanding. The use of dopamine antagonists has
been reported as useful. Haloperidol has been found to be effective in cases in
which such atypical neuroleptics as risperidone have been found to be ineffective
(Albanese etal. 2006). Tetrabenazine and similar dopamine-depleting agents have
been reported effective in treating dystonia (Chen etal. 2012). Worsening depression and increased risk of suicide are important considerations in any review of
these findings.
108
Many of the agents described here are the same as those used in the treatment
of other hyperkinetic disorders. The issues of whether a dose can be found such at
any dose higher would be futile in terms of efficacy or have an unacceptable risk of
adverse effects are discussed in c hapter15.
Botulinum Toxin
Because it has proven remarkably effective, intramuscular injection of botulinum
toxin, when feasible, is the treatment of choice for dystonia. Eligible patients are
typically those whose distribution of quality-of-lifelimiting dystonias are amenable to intramuscular injections at safe doses. Even patients with generalized
dystonia may experience sufficient improvement in their quality of life if the most
offending muscles are few and accessible. In patients with Tardive dystonia, for
example, the offending muscles may be widespread. Yet of the various symptoms,
oral-mandibular dystonia may be the most limiting, for example, and amendable
to intramuscular botulinum toxin. With its control, therefore, a patient may regain
satisfactory quality of life. Botulinum toxin may bring similar, if perhaps temporary, relief to the distal lower extremities of some patients with generalized torsion
dystonia.
The difficult question is whether a patient who presents for consideration of
DBS and whose previous attempts at intramuscular injections of botulinum toxin
appear to have failed is truly refractory or unlikely to benefit from further attempts.
At least two important issues bear on this question:(1)secondary nonresponders,
that is, patients in whom develop neutralizing antibodies subsequent to an initial
response that cause botulinum toxin injections to fail, and (2)failure owing to technique. Among all patients with cervical dystonia, some 5% are secondary nonresponders, and of all nonresponders, the nonresponse of 2% owes to neutralizing
antibodies (Kessler etal. 1999). Nonresponse in secondary nonresponders may also
owe to such technical issues as changes in the pattern of muscles involved in the
dystonia, which, as a consequence of the sampling thereof, leads to failure to adjust
technique. This is particularly true when the intramuscular injections of botulinum toxin were delivered without electromyographic guidance (Dressler 2000).
Secondary nonresponders nonresponse to intramuscular injections of botulinum toxin may be related to neutralizing antibodies. Because testing serum of
neutralizing antibodies presents difficulties, consideration should turn to therapeutic trials of botulinum injections in the frontalis muscle or another muscle that,
from a technical standpoint, presents few difficulties to injecting it and observing
its response. For those patients who are discovered to be resistant to one serotype
of botulinum toxin, trials of alternative serotypes should be considered. In cases in
which there occurs some cross-reactivity between serotypes Aand B, therapeutic
trial with alternative serotypes is indicated.
In one retrospective study, 4 of 24 patients were found to be primary nonresponders (17%; Berman etal. 2005). It is important that an adequate trial of intramuscular injections be conducted. In a doseresponse study based on improvement
with consecutive doses in the severity of dystonia, the curve became asymptotic
at six injections, a result that suggests that this number represents the minimum
number of injections necessary to determine the degree of relief a patient might

expect.
As it relates to targeting and injecting the muscle that contributes to the dystonia, technical complexity creates a situation in which experience and skill makes a
significant difference. Because experience and skill may vary among physicians, it
my opinion that a patient with a documented failure to respond to intramuscular
injections be evaluated by a physician with extensive training, experience, and skill
in using electromyographic targeting.
Selective Peripheral Denervation

In all cervical dystonia except that of severe anterocollis, selective peripheral denervation may be considered. In a comparison within a single institution where 20
patients underwent selective peripheral nerve denervation and 15 underwent globus
palldius interna DBS, the outcomes were considerably better in patients undergoing DBS (Contarino etal. 2014). Of participating patients who reported experiencing marked improvement, 60% were patients with DBS and 5% were patients who
had undergone selective peripheral nerve denervation. Fair to good responses
represented 26.7% and 30% of participants, respectively, and bad outcomes 13.3%
and 65%, respectively. Eleven of 20 (55%) of patients who had initially undergone
selective peripheral nerve denervation required a second surgery, compared to only
1 of 15 patients who were undergoing DBS.
Adverse effects were reported in 75% of patients who underwent selective peripheral nerve denervation, compared to 60% of those underwent DBS. Changes in sensation experienced by patients with selective peripheral nerve denervation were
most commonly whereas problems with hardware and altered speech, which these
patients experienced while occupying the DBS group. One patient who underwent
DBS experienced severe intracranial hemorrhage. It is important to realize that
adverse effects from selective peripheral denervation are likely permanent, whereas
those associated with DBS are usually resolved by programming adjustment or, at
worst, discontinuation of stimulation.
Of the 8 patients who from a group of 24 were selected to undergo DBS in the
vicinity of the globus palldius interna, most improved in such a way as there was no
statistically significant differences in the outcome measures compared to those with
peripheral denervation (Huh et al. 2010). However, those results are uninterpretable.
One cannot claim that because a difference was not found by use of typical hypothesis testing statistical measures, there truly is no difference. Poor power may have
engendered a type II error, in which no difference is found where one truly exists.
The appropriate method, rather, is to determine a clinically meaningful degree
of change in the outcome measure and then conduct a sample-size calculation to
determine whether a sufficient number of subjects were enrolled (Wellek 2010).
In a retrospective study that focused solely on selective peripheral denervation,
follow-up after three months demonstrated that 77% of the 162 available subjects
experienced moderate to excellent improvement in their head position, and 81%
experienced moderate to marked improvement in their pain. These figures are
comparable to those reported for DBS in the vicinity of the globus palldius interna.
110
Ofthose who experienced moderate to excellent improvement, 71% retained the benefit for a mean postsurgical duration of 3.4years (Cohen-Gadol etal. 2003)meaning
that 55% of patients continued to experience moderate to excellent relief.
A 155-patient retrospective study whose mean follow-up was 32.8months gathered follow-up results on 140 patients who underwent selective peripheral denervation. Of those 140 patients, 18 (13%) reported complete relief of their symptoms,
50 significant relief (36%), and 34 moderate relief (24%). Nineteen (14%) noted
only minor relief, and the remaining 19 (14%) no improvement (Braun and Richter
2002). Arecurrence rate of 11% was noted.
By comparison, the long-term follow-up (typically on the order of 30months)
of patients with cervical dystonia undergoing DBS found that, of 20 patients combined in two studies, only 1 patient failed to experience sustained benefit (Hung
etal. 2007; Cacciola etal. 2010). In summary, though selective peripheral denervation and DBS produce comparable improvement, the improvement is less sustained
in patients with selective peripheral nerve denervation.
Intrathecal and Intraventricular Baclofen

Intrathecal baclofen is administered through a catheter that is inserted in the lumber spine interspace and, depending on the distribution of the dystonia or spasticity,
threaded as high as the cervical region. Intrathecal baclofen is particularly effective
in treating spasticity of the lower extremities. In patients with combined dystonia
and spasticity, which is commonly seen in patients with perinatal hypoxic-ischemic
disease, intrathecal baclofen is highly effective.
Concern has been expressed over the fact that in intrathecal baclofen for treatment of upper extremity dystonia (and spasticity), the placement of the tip of the
intrathecal catheter is such that the upper extremity would fail to see improvement.
In one study, however, 8 of 11 patients demonstrated improvement in upper extremity function great enough to be deemed meaningful (Motta etal. 2009). Anumber
of reports demonstrate general improvements but do not specify the distribution of
those improvements. For example, they do not indicate whether improvement was
seen in upper extremities or lower.
Complications occur more frequently with intrathecal baclofen than they do
with DBS. Motta and Antonello (2014) reported that of the 430 patients who
participated in their study, 25% experienced at least one complication, 9.3%
developed infections, 4.9% experienced leakage of their cerebrospinal fluid,
15.1% developed catheter problems, and 1% experienced pump problems.
Intraventricular baclofen has been reported to have fewer complications than
intrathecal baclofen; however, the experience is insufficient for generalization
(Albright and Ferson 2009).
Intrathecal baclofen and intraventricular baclofen in patients may help patients
for whom spasticity is a major contributor to impaired quality of life. This is supported by the effectiveness of intrathecal baclofen for spasticity resulting from
disorders that develop independently of dystonia. For such patients, DBS in the
vicinity of the globus pallidus interna is unlikely to offer sufficient benefit. Of
patients with significant spasticity who undergo intrathecal baclofen, however,
experience is limited. The relatively high rate of complications associated with this
treatment serves, moreover, to recommend DBS if spasticity is not a limiting factor.
DYSTO N I A O F A S E V ER I T Y S U FFI C I EN T TO
WA R R A N T D EEP B R A I N ST I M U L AT I O N
Determining whether a patients dystonia is of sufficient severity to warrant

DBS poses a challenge. Adding to the challenge is the tendency of physicians
to reserve to themselves jurisdiction over the determination, notwithstanding
the fact that they can know neither the suffering of the patient in question nor
the amount of risk he, his family members, or his caregivers will agree to face
in order to gain relief. Any physician who preempts a patient by making the
determination stands guilty of paternalistism; she violates the ethical principle
of autonomy, or respect for the patient. Beauchamp and Childress (2013) draw a
distinction between hard paternalism and soft paternalism. One finds examples of soft paternalism in those occasions in which a patient or his family member is unable to render a decision. This inability is understandable; most patients
or patients family members are not physicians or surgeons and are therefore
in no position to dictate the technicalities of care. Patients and their family
members do implicitly consent to defer to physicians, surgeons, and healthcare
professionals judgment in technical matters. Yet physicians and surgeons may
exceed the scope and limit of this consent should they interpret it as license to
render general decisions as to the extent of a patients suffering. In instances of
hard paternalismwhich, though rare, do continue to occurphysicians override the expressed wishes of the patient or his surrogate.
Hard paternalism may take a subtler form. This subtler form is instantiated when physicians and surgeons fail to provide patients with information
or include them in a decision. This form of hard paternalism violates informed
consent, which requires that patients or surrogates be informed of all reasonable alternatives. Areasonable alternative is any that contains information that
might affect the decision of the patient or her surrogate. An alternative that contains information that might affect the physicians decision does not qualify as
reasonable. Any physician who treats a patient without receiving her informed
consent beforehand risks committing assault and battery. These ethical issues
are discussed in c hapter19.
A B I L I T Y TO TO L ER AT E D EEP B R A I N
ST I M U L AT I O NS U R G ERY
The patients overall health, comorbidities, and ability to cooperate with DBS surgery are important considerations. Ibelieve that optimal DBS benefit depends on a
DBS leads accurate placement, to which microelectrode recordings and microstimulation are critically important. Optimal microelectrode recordings and microstimulation require a patients ability to participate. Thus DBS surgically is ideally
performed on patients who have received local anesthetic rather than undergone
112
sedation (Montgomery 2014). In less ideal circumstances, microelectrode recordings may be made and, to an extent, microstimulation performed on patients
sedated with dexmedetomidine.
PR OV I S I O N O F P O STO PER AT I V E D EEP B R A I N

ST I M U L AT I O N PR O G R A M M I N G
The misconception prevails that DBS is a neurosurgical treatment. It is not. DBS

benefit comes not when the DBS lead is placed surgically but when the stimulation
begins and it, along with any medication, is adjusted. Responsibility for adjusting
stimulation and medication typically falls to a neurologist. Any risk assumed by a
patient before and during surgery is recompensed by the benefit realized in an outpatient clinic. DBS surgery must therefore await the arrangement of postoperative
DBS management. Doing otherwise is unethical, because the risk faced by a patient
would lack any compensatory future benefit.
S U M M A RY
Safe and effective for dystonia, DBS presents a sound option to patients who have
exhausted all reasonable alternatives. When feasible, intramuscular injections of
botulinum toxin should be exhaustively pursued. Failing this, oral medications
may prove effective. One must bear in mind, however, that adults taking tolerable
doses often realize inadequate results. Though a relative minority of patients may
experience satisfactory improvement with medications, DBS should remain a consideration from the outset. Selective peripheral denervation presents an alternative
in certain circumstances. Provided the situation is not that of anterocolis, it may
produce comparable benefit to that produced by DBS. It is attended, however, by
a higher reoperation rate and a greater chance of significant, possibly irreversible
complication. Quality-of-lifelimiting spasticity in patients with a mix of dystonia
and spasticity may benefit from intrathecal baclofen.
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11
Postoperative Management of
Patients with Dystonia
There is the misconception that Deep Brain Stimulation (DBS) is a surgical therapy.
It is not. The benefit from DBS accrues not with placement of the DBS hardware but
with the initiation and adjustment of actual brain stimulation. As DBS programming cannot happen in isolationthat is, without consideration and adjustments
of concomitant medicationsthe person responsible for postoperative DBS management must know thoroughly the disease treated in its fullest medical, ethical,
psychological, social, economic, and political context (necessitated by the complexities in healthcare insurance and provision of care).
The complex cognitive skills required similarly necessitate ongoing experience
to maintain. Though there are neurosurgeons who have these skills, and though
any neurosurgeon may obtain these skills, typical neurosurgical training does not
lend itself to gaining and maintaining them. There is, moreover, nothing inherent
in postoperative care that prevents any physician or healthcare professional from
obtaining and maintaining these skills. Neurologists, however, are expected to
have the prerequisite skills and experience to provide postoperative DBS care,
as are also healthcare professionals under the supervision of neurologists. The
ethical issue is whether the possession of those skills implies an obligation on
the part of neurologists to assume responsibility for providing postoperative DBS
care (see chapter19).
Another interesting issue is whether it is ethical for a neurosurgeon to implant a
DBS system without first assuring feasible and reasonable postoperative care. If she
fails to do so, she harms a patient during the course of surgery, even if the harm is
no more than the risks of serious complications and the pain and self-limiting disability associated with the postoperative recovery. Doing harm violates the ethical
principle of nonmalfeasance (Beauchamp and Childress 2013). Potential for benefit justifies the malfeasance. The Principle of Double Effect attempts to reconcile
the infliction of malfeasance with the provision of benefit. To justify the infliction of malfeasance in order to provide benefit, the malfeasance, or harm, must
not be an end or intent but a necessary means to the end of providing benefit. One
may reasonably argue that a surgeon who performs DBS surgery without assuring
appropriate postoperative care makes the surgery and its accompanying malfeasance ends, because no provision is in place to assure that the surgery is a means to
a benefit. Unfortunately, the balkanization of healthcare provision tends to obscure
116
responsibilities that transcend the boundaries of a physician or healthcare professionals specialty.

T H E U N I Q U E PR O B L EM O F D EEP B R A I N ST I M U L AT I O N
PR O G R A M M I N G I N DYSTO N I A
This section discusses general approaches. A detailed discussion is beyond the

scope of this project and is addressed elsewhere (Montgomery 2010). It is hoped
that many physicians and healthcare professionals would help patients by providing DBS programming. Yet this hope may go unrealized. Though patients principle
care providers may not be the ones who perform DBS programming, it is important
that they understand a patients experience.
DBS programming for dystonia presents principle care providers with challenges
they usually do not face with DBS programming for Parkinsons disease, tremor, or
hyperkinetic disorders. The symptoms of these latter disorders respond fairly rapidly, allowing fast titration of electrode configurations and stimulation parameters.
The electrode configuration is a combination of active negative (cathode) and positive (anode) electrical contacts. Stimulation parameters include voltage or electrical
current for each pulse (the first phase of the biphasic pulse), initial polarity (negative or positive) at a specific electrical contact, width of the stimulation pulse, and
frequency at which the pulse is delivered (Montgomery 2010).
Tremor responds to effective DBS in seconds. Bradykinesia associated with
Parkinsons disease and hyperkinesia responds in a few tens of a second. Similarly,
adverse effects related to inadvertent stimulation of adjacent structurestonic
muscle contraction, diplopia, changes in speechappear in a few tens of a second.
Such other changes as mood and affect may require a few tens of a second to appear.
In the clinic it is thus possible to attempt an assessment of the effects of many different combinations of electrode configurations and stimulation parameters within
a reasonable period of time.
In Parkinsons disease, the effects of DBS on gait and balance may take tens
of minutes to manifest. It is therefore impractical to use assessments of gait and
balance for titrating the DBS in the clinic visit. The effects of DBS on more rapidly responding symptoms of tremor, muscle tone, and bradykinesia, however,
are generally a reasonable predictor of improvement in gait and balance. Yet,
because this is not always the case, patients must be observed for 30 minutes following their final DBS adjustment in order to ensure that their gait and balance
are optimal.
Many of the symptoms of dystonia may require hours weeks or months to
respond. In one study of DBS parameters in dystonia selected patients, subjects
showed improvement of at least 30% in the Burke-Marsden-Fahn Dystonia Scale
within an hour of the stimulation adjustment (Kupsch et al. 2003). Even with a
response that comes after one hour, titration in a single clinic visit may yet prove
impractical.
Dystonic symptoms may be categorized as tonic and phasic. Tonic symptoms
refer to the abnormal sustained postures. Phasic symptoms refer to symptoms that
often accompanies the tonic symptoms, such as tremor. Conventional wisdom
holds that tonic and phasic symptoms may respond differently to such medications
11. Postoperative Management of Patients with Dystonia117
as anticholinergics or the dopaminergics. This appears to be the case for DBS as

well:Phasic symptoms often respond rapidly to DBS changes and may be used for
titration within the clinic visit. It is unlikely, however, that the tonic symptoms will
respond rapidly to severe titration in the clinic. This means that titration must take
place over an extended period of time, with DBS adjustment performed every few
weeks rather than every few minutes (see review by Kupsch, etal. 2011).
Whether phasic symptoms of dystonia are predictive of tonic symptoms
response is unknown. Experience suggests that phasic responses may be predictive. If they prove to be predictive, then one might titrate to the desired effect of the
phasic symptoms, the presumption being that the tonic symptoms will respond in
due course. This issue deserves further study. At any rate, phasic symptoms merit
treatment in their own right.
EPI ST EM O LO G I CA L C O N S I D ER AT I O N S
Epistemology refers to critical analysis of the acquisition and validation of

knowledge. A number of publications have reviewed the published literature
in an attempt to codify general approaches (see review in Kupsch, et al. 2011).
With the exception of this textbook, virtually all of them adopt a descriptive as
opposed to a normative approach. By descriptive Imean basing recommendations on experience rather than principle. Experience may certainly be quantified
and subjected to population statistical analysis. From summary statistics may be
drawn from recommendations for appropriate means. Yet there is no reason to
presume that such descriptive analyses are inherently superior to those that are
based on principle.
A tension between descriptive and normative approaches in science has long
characterized science. The inductive approach first articulated by Francis Bacon
(15611626) typifies the descriptive approach. It emphasized observation and
hypothesis generation and testing. Rene Descartes (15961650) advanced a competing notion that emphasized reasoning from scientifically established principles,
primarily by use of mathematics. One might argue that empirical Baconian science
is less prone to bias and systematic errors than is Cartesian rationalism, but to do
so would be nave.
The recommendation made by Kupsch and colleagues (2011) to begin DBS programming at 130 pulses per second (pps) presents a useful example. Their rationale
appears to be that 130 pps is used in the majority of published studies. Yet, Kupsch
and colleagues (2003) reported that patients responded better at 180 pps and 250
pps. Another study cited only DBS performed at 130 pps (Kupsch etal. 2006). In
another study, which involved 130 pps at 3months and at 12months, all but 5 participating patients continued their DBS at that rate (Vidailhet etal. 2005).
Kupsch and colleagues (2006) recommendation to begin DBS programming at
130 pps may only be called descriptive, because 130 pps was the sole frequency used
in nearly all cases. Though none of the primary sources justified their selection,
the experience with DBS for Parkinsons disease likely informed their selection.
Application of such statistical measures as mean or median with respect to DBS frequencies is nonsensical. Though one may claim that the sole motivation was habit
118
generated by extrapolation from experience with Parkinsons disease, selection of

frequencies used in Parkinsons disease likely owe more to force of habit.
The recommendation by Kupsch and colleagues (2006) to begin DBS programming at 90 microseconds (s) merits similar analysis. The recommendation appears
to rest on the only study that involved systematically varied pulse widths of 60s,
150s, and 450s and found no difference. It is not clear why 90s was preferred
to 60s.
Determination of electrode configurations (the set of active cathodes [negative contacts] and anodes [positive contacts]) is largely determined by the adverse
effects. Guiding the choice of electrode configurations is a goal of maximizing the
volume of tissue stimulated for efficacy. Excessive extension of the electrical field at
the site of stimulation produces adverse events.
The purpose of the forgoing discussion is not to recommend different starting
points for dystonia DBS programming. Rather it is to point out the fact that the lack
of substantial evidence for the recommended stimulation parameters and electrode
configurations simply indicates the importance of considering alternatives. Ihave
observed that there is a tendency to begin with reported average or typical settings in the literature and to avoid venturing terribly far from them.
Kupsch and colleagues (2011) are to be commended for the wide-ranging scope
of the recommendations. They recommended a practical initial follow-up at 4 to 12
weeks and, if the patient is stable, every 6months thereafter. It is unclear whether
these recommendations are influenced by those cases in which the DBS stimulation
was initiated within the immediate postoperative period. Kupsch and colleagues
themselves admit that in developing their recommendations they included visit
schedules of clinical trials. The suggested schedule probably reflects the typical
follow-up interval in most clinics. Their recommendations are therefore descriptive rather than normative. Such importation may represent a logical error of the
categorical type (Ryle 2002), because the conditions constructed for a clinical trial
may be irrelevant to a patient managed in actual practice (see c hapter4).
These recommendations prima facie lack validity; one finds immediately two reasons for suspicion. First, symptoms of the type that require weeks to improve will
likely also require more than a single programming session. Second, unless there is
some a priori method for it, reducing medication should be avoided, because doing
so while also programming DBS proves difficult.
A PPR OAC H ES TO D EEP B R A I N
ST I M U L AT I O N PR O G R A M M I N G
A rational approach begins by defining DBS programming goals. The ultimate goal
is that of maximizing reduction in disabilities while minimizing adverse effects.
The second goal is to achieve the first goal as rapidly as possible. The third goal is to
reduce any relevant medications, particularly those that produce adverse effects, to
the greatest possible degree that remains consistent with the first goal.
In order to achieve the second goal of rapidly reducing disability, one must
determine the time required to observe any evidence of effectiveness with stimulation parameters where electrode configurations are largely related to the regional
anatomy around the DBS lead and, thus, adverse effects. Though this cannot be
determined beforehand, one might get a sense of it from the monopolar survey, in
which stimulation is applied to each contact to a maximal voltage or current. The
voltage or electrical current is increased until the symptoms associated with the
disability change, the patient experiences an adverse effect, or a maximal voltage
(up to 10 volts) or current (4 milliamps) is reached. Depending on the electrode
impedance, such voltages or electrical currents may exceed the maximum safety
limit (programmers must consult the manufactures operation manuals for the
devices).
One approach to programming is to start with initial stimulator parameters at
those associated with the reported maximum for benefit. Studies have shown relatively little benefit in pulse widths that exceed 120s. Chronaxie is the pulse width
that produces a response that is one-half of the response of a theoretical infinitely
long pulse width. In computational modeling and in experiments, chronaxie values ranged between 100s and 200s and became asymptotic with slightly higher
pulse widths (see Miocinovic and Grill 2004). The recommended stimulation frequency is 185 pps.
The time required for a change in the appropriate symptom offers an estimate
of the length of time a patient would have to be observed at each set of stimulation parameters in order for a change to become evident. If the change becomes
evident in a reasonable period of time, titration within a DBS programming clinic
session may be possible. There may not be any response observed during a reasonable period following a change in stimulation parameters. Lack of response suggests that titration during a single DBS programming clinic visit may be infeasible.
An alternative approach is to start minimal setting and then increase as needed
and then titrate upwards as needed. This minimizes current drain from the
implantable pulse generator. It is important to recognize that an improvement
observed during a single DBS programming clinic session does not mean that it
is maximal for the specific set of stimulation parameters. It is therefore important
to program the DBS stimulation parameters to the minimal pulse width first and
frequency second. Doing so ensures a response and minimizes the drain on the
battery. Apatient is discharged and asked to report back to her DBS programmer
immediately upon a plateau in her response, no matter whether if it happens in
hours or days. One may schedule programming at comparable intervals according
to the time to plateau.
In the event that no improvement becomes evident during an initial monopolar
survey, one may assume that any improvement in symptoms may require a longer
duration of stimulation and that titration within a single DBS programming clinic
session is therefore infeasible. Adifferent approach becomes necessary.
Those patients whose symptoms associated with disability show no response
within the time of the DBS programming clinic session may have their stimulation parameters set at a pulse width of 120s and frequency of 185 pps (for reasons
discussed earlier), and they may have their voltage or current increased until they
experience an adverse event. On instance of an adverse event, stimulation voltage
or current is reduced by 10% to 15% in accordance with Kupsch and colleagues
(2006) recommendation. Apatient is asked to report the amount of time required
to experience a change in the appropriate symptoms and the specific moment at
which that change plateau. These times offer a means of establishing a reasonable
schedule for DBS programming sessions.
120
Because many DBS devices enable patients and their family members and caregivers to adjust stimulation parameters outside the physician or healthcare professional office, some physicians enlist these parties in the titration process. Caution
is necessary. Physicians must establish the limits within which a patient or a family
member or caregiver may adjust the stimulation in order to avoid exceeding safe
levels. Patients and family members and caregivers must observe the limits established by physicians.
It may be difficult for a patient or a family member or caregiver to observe a change
in symptoms that occurs over a long period. Absent some objective assessment, an
implicit shift in the reference or scale may occur. Expectations of patients or their
family members or caregivers may similarly influence subjective observations.
D EEP B R A I N ST I M U L AT I O N I N D U C ED PL AST I C I T Y
Long duration of stimulation prior to improvement in some symptoms of dystonia suggests the existence of changes beyond those that are immediately produced
by the DBS stimulation pulses. There is, in other words, some plasticity, the time
course of which is variable. Some studies suggest that it may require hours or days
for symptoms to return or worsen following discontinuation of DBS. Indeed, some
patients with Essential tremor continue to experience reduced tremor long after
their implantable pulse generator battery has been drained. Such patients exemplify
positive adaptation. Conversely, there have been instances in which initial improvement disappeared after a few hours or days. In such cases it is often unnecessary to
increase stimulation strength. Because it appears that a brain may adaptor, more
accurately, maladaptto specific stimulation parameters, it is frequently necessary
simply to stimulate with different parameters (Montgomery etal. 1999).
Among the mechanisms one may exploit to improve DBS response are long-term
potentiation (LTP) and long-term depression (LTD), the latter of which is also
known as spike timing-dependent plasticity or Hebbian learning. LTP and LTD are
long-term changes that follow a high-frequency volley of input to a neuron, such as
that which occurs with stimulation. LTP induces an increase in excitability; LTD
reduces excitability. Both LTP and LTD carry important implications for computation in neural systems.
It is unclear whether high-frequency DBS is able to produce LTP or LTD. Though
pulses are delivered at high frequency, a mere 10% of them result in axonal excitation, as evidenced by recordings of antidromic action potentials (Walker et al.
2011). Aneuron may experience an effective stimulation rate of only 13 pps, despite
the fact that the DBS system delivers 130 pps.
Another form of Hebbian learning happens when a synaptic input, typically a
depolarization, occurs at site of prior postsynaptic depolarizationa previous synaptic input, for example (see Caporale and Dan 2008). When two synaptic inputs
share a source, LTP results. Yet two inputs need not share a source; they need simply to occur near the same time. Indeed, a potent way of inducing LTP or Hebbian
learning is to induce back-propagation of the action potential to the soma (cell
body) and the entire dendritic tree. This increases the odds that some inputs will
follow depolarization from the antidromic potential, the result of which is Hebbian
learning.
A possible source of back-propagation of action potentials, DBS prompts antidromic activation. As such, it recommends itself as a source of LTP and LTD, which
in turn produce plasticity. It remains to be seen whether an effect on plasticity
explains the time course of some symptomatic responses or a prolonged response
following discontinuation of DBS. However, it is possible that, when coupled with
rehabilitative therapies and training, DBS plasticity may produce a marked synergistic effect. Research support should be allocated to the study of this possibility.
S U M M A RY
DBS is safe and effective for the treatment of dystonia. The time course of response
of symptoms and disabilities to initiation and changes in DBS presents problems
for postoperative DBS programming. The rapid response of some symptoms make
titration during a single DBS programming clinic session feasible. Slower response
of other symptoms makes titration difficult. Strategies must be developed to accommodate lag times. Some arbitrary time frame, selected because it accommodates a
physician or healthcare professionals schedule, is suboptimal, because it may simply prolong the time needed to achieve a satisfactory response. It therefore also prolongs a patients discomfort and disability, as well her exposure to risks associated
with her condition.
R EFER ENCES
Caporale N, Dan Y. Spike timing-dependent plasticity:a Hebbian learning rule. Annu
Rev Neurosci. 2008;31:2546.
Kupsch A, Benecke R, Muller J, etal. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med. 2006;355(19):19781990.
Kupsch A, Klaffke S, Kuhn AA, etal. The effects of frequency in pallidal deep brain
stimulation for primary dystonia. J Neurol. 2003;250(10):12011205.
Kupsch A, Tagliati M, Vidailhet M, et al. Early postoperative management of DBS
in dystonia: programming, response to stimulation, adverse events, medication
changes, evaluations, and troubleshooting. Mov Disord. 2011;26(Suppl.1):S37S53.
Miocinovic S, Grill WM. Sensitivity of temporal excitation properties to the neuronal
element activated by extracellular stimulation. J Neurosci Methods 2004;132(1):9199.
Montgomery EB, Jr., Baker KB, Kinkel RP, etal. Chronic thalamic stimulation for the
tremor of multiple sclerosis. Neurology 1999;53(3):625628.
Ryle G. The Concept of Mind. Chicago:University of Chicago Press; 2002.
Vidailhet M, Vercueil L, Houeto JL, etal. Bilateral deep-brain stimulation of the globus
pallidus in primary generalized dystonia. N Engl J Med. 2005;352(5):459467.
Walker HC, Watts RL, Schrandt CJ, etal. Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease. J Neurophysiol.
2011;105(3):11121121.
12

Effective for Tourettes Syndrome
U N I T ED STAT ED FO O D A N D D R U G
A D M I N I ST R AT I O NSTAT U S
Deep Brain Stimulation (DBS) for Tourettes syndrome represents an off-label

use of an US Food and Drug Administration (FDA)-approved device. In other
words, the FDA has approved the DBS systems, yet it has done so for Parkinsons
disease and other indications. The FDA has not offered any position on the
use of DBS for Tourettes syndrome. It is important to recognize that the use
of FDA-approved devices and drugs for indications on which the FDA has no
stated position is often considered standard and accepted. Indeed, in many cases
it would be considered malfeasance not to use certain FDA-approved drugs in an
off-label manner. The FDA recognizes the prerogative of physicians to treat in the
best interests of their patients. It does not stipulate how medicine is to be practiced. The FDA does require that if drugs, biologics, and devices are used in an
off-label manner it is done in a responsible manner. There must be established scientific evidence of safety and efficacy, even if the level of evidence does not reach
the level typically accepted by the FDA in its approval process (see chapter15 for
an extensive discussion).
The use of off-label indications does present some challenges. First, insurance
companies often deem experimental or investigational any use of an FDA-approved
device or drug for any indication not expressly approved by the FDA. This is inappropriate. Yet nothing prevents an insurer from making the claim, which presents a
sufficient enough hurtle that most physicians will simply defer to the insurers position. According to most canons of medical ethics, such action could be considered
unethical, because the principle of beneficence requires that physicians provide the
best treatment. Second, programmatic denial of off-label uses violates the ethical
principle of justice, because whether a patient receives the benefit of an appropriate off-label use depends solely on her insurer. The benefit of off-label use, in other
words, becomes a lottery (Beauchamp and Childress 2013).
One may argue that patients may choose the insurer they contract for insurance
coverage. Most individuals, however, cannot predict the future illnesses or injuries that will befall them. This places insurance companies at a significant advantage in contract negotiations. Indeed, as a consequence of the Patient Protection
12. Deep Brain Stimulation Is Safe and Effective for Tourettes Syndrome123
and Affordable Care Act of 2010 (otherwise known as Obamacare), thousands of

policy holders in the United States had their insurance cancelled. Amajor reason
is that the insurance policies did not meet the minimum protections required by
the Patient Protection and Affordable Care Act. This strongly suggests that a great
many policy holders were unable to recognize or afford a reasonable health insurance program.
Lack of FDA approval may be considered by some physicians and healthcare professionals as evidence of a lack of safety and efficacy. In this they commit an error
in reasoning known as argumentum ad ignorantiam (arguing from ignorance). An
example of argumentum ad ignorantiam is found in the statement, Because Ido
not know that you are an honorable person, you must be dishonorable.
Considerable valid evidence indicates that DBS is safe and effective for the treatment of Tourettes syndrome, and consistent with FDA guidelines, DBS is appropriate for patients with Tourettes syndrome.
D EEP B R A I N ST I M U L AT I O N TA R G E TS A N D
T H EC O N D I T I O N S T R E AT ED
There are a number of targets for DBS. These include the intralaminar nuclei
of the thalamus, specifically the centromedian-parafascicular nucleus, the
posterior-lateral region of the globus pallidus interna, the anterior-medial region
of the globus pallidus interna, the globus pallidus externa, the nucleus accumbens, and the posterior limb of the internal capsule. All of these targets have
been reported to produce varying degrees of benefit. The plethora of targets may
be unsettling, owing to the suspicion that all these targets are unlikely to affect
the basic underlying mechanisms. Any benefit is thus unrelated to the underlying
causal mechanism.
Thinking in neurology has long been dominated by the notion that various
brain functions are parsed out among specific structures and that most functions are a consequence of an assembly linelike process. In the basal ganglia,
for example, the caudate nucleus and putamen are considered the input stage,
whereas the globus pallidus interna and substantia nigra pars reticulata are considered the output stage. This clearly suggests a one-dimensional sequential process. A specific brain function is attributed to the putamen, for example, and
a different function attributed to the globus pallidus interna. This notion of a
modular approach, in which interactions are sequential and hierarchical, is also
observed in the attribution of the symptoms, signs, and disabilities of Parkinsons
disease to hyperactivity of the globus pallidus interna. This a notion has since
been refuted (Montgomery 2004).
This mode of thinking may rest on a mereological fallacy, which attributes
the function of the whole to its parts. The role of generating movement falls to
the control exerted by the globus pallidus interna. Lesions of nearly every structure within the basal ganglia-thalamic-cortical system, however, have been
described as causing parkinsonism, and DBS of nearly every structure in the basal
ganglia-thalamic-cortical system has been described as improving parkinsonism.
Either there are as many different mechanisms that produce and alleviate parkinsonism as there are lesions and DBS targets, or there is one that involves all the
124
structures of the basal ganglia-thalamic-cortical system. Parkinsonism is the result

of a disordered system and not simply a disordered globus pallidus interna.
The notion of a modular sequential and hierarchical organization has been facilitated by two prevalent but incorrect notions. The first is the Neuron Doctrine, which
is derivative of the Cell Theory. The consequence has been to identify the neuron
as the basic unit of brain function. Nuclei, by virtue of the collection of neurons,
then become a higher expression of the basic brain function. The second notion
is that of inferring physiology from anatomy and neurochemistry (Montgomery
2004). Indeed, the anatomical structure is viewed as one large neuron (macroneuron). The basal ganglia-thalamic-cortical system is thus considered a small group
of macroneurons. The interactions between macroneurons is inferred from their
neurotransmitter. The function of the basal ganglia-thalamic-cortical system is
inferred from the arrangements of macroneurons. This mode of reasoning suggests
that, given understanding of a single ants properties, one may come to understand
the function of an anthill.
In the case of Tourettes syndrome, another consideration is that the symptomology is complex and multifaceted. In addition to involuntary movements, described
as tics, patients with Tourettes syndrome also experience psychological problems,
including depression, obsessive-compulsive symptoms, and attention deficit hyperactivity disorder. It is possible that DBS of different regions within the targets have
different effects on the varied symptoms. For example, DBS in the vicinity of the
sensorimotor region of the posterior-lateral globus pallidus interna may have significant benefit for tics but relatively little effect on the psychological problems.
Conversely, DBS in the vicinity of the anterior-medial globus pallidus, segments
that interact with the limbic and cognitive systems, may have relatively little effect
on tics but significant benefit on psychological problems. As reviewed by Hariz and
Robertson (2010), reports of DBS effect frequently have not distinguished among
motor, psychological, and cognitive effects.
EF FI CACY A N D A DV ER S E E V EN TS
The choice of target then depends on the symptoms and disabilities considered to
have the highest priority. If, for example, the tics are the major factor limiting the
quality of life, then targets most related to the motor functions should be targeted.
These include the posterior-lateral globus pallidus interna and possibly the centromedian-parafascicular nuclei. There appears to be more evidence in the literature
related to DBS in the vicinity of the globus pallidus interna. Generally the results
have demonstrated significant improvements in tics. Most studies have been individual or small case series. Yet there have been two prospective studies with blinded
assessments that have demonstrated benefit of DBS in the vicinity of the thalamus
or globus pallidus interna (Servello et al. 2010; Porta et al. 2012). One outcomes
measure is the Yale Global Tic Severity Scale. Reports demonstrate improvements
on the order of 20% to 80% for DBS in the vicinity of the centromedian-parafascicular and globus pallidus interna (reviewed by Kim and Pouratian 2014).
Some efficacy measures for psychological impairments include the Yale Brown
Obsessive Compulsive Scale, which has demonstrated reductions from 23% to 75%
over a range of targets. Anumber of patients failed to improve or remain improved
over time, and rarely the obsessive-compulsive disorder symptoms worsened

(reviewed by Kim and Pouratian 2014).
A considerable majority of authors of papers describing benefits have indicated
the importance of prospective randomized controlled trials (RCTs). Unfortunately,
such studies are expensive and difficult to design. It is difficult to control by blinding a patient to the presence or absence of DBS, particularly because adverse effects
associated with active stimulation make it so. Given the number of centers already
performing DBS for Tourettes syndrome and the generally positive results, one
finds it problematic to randomize patients to undergoing DBS surgery but not being
stimulated for any period of time, especially if the length of observation necessary
to have confidence in the results is quite long.
The problem is one of clinical equipoise as a necessary condition of ethical clinical trials. Equipoise is achieved when a researcher believes that two or more options
are equal relative to the risks and potential benefits of each option. The equality can
exist as a consequence of the fact that no one has any idea about the risks and potential benefits of each option. This approach to equipoise, however, would generally
be unethical. The risk of doing harm (the avoidance of doing harm is the ethical
principle of nonmalfeasance) that would be difficult to offset if there were no prior
evidence of possible benefit. It is important to consider risk and potential benefit in
the widest connotation. One may randomize patients to DBS versus best medical
therapy, for example, even when the risks associated with DBS are thought to be
higher, provided there is also a compensating belief that DBS will be more effective.
The subject may also obtain benefit of another kind for participating, which might
compensate for the risk of randomization to an option that has a poorer riskbenefit ratio. Those benefits may be social, assuming the form of increased knowledge
that may benefit future patients, despite no direct benefit to a patient.
When attempting to establish equipoise, there is no simple calculus. One often
finds oneself in the situation of comparing incommensurables. No calculus exists
with which to equate incommensurables without the same units of measure. Such
comparisons are nonetheless required nearly every day in medicine. The general
approach is to respect the patients preference (the ethical principle of autonomy)
and adhere as closely to the ethical principles of beneficence, nonmalfeasance, and
justice.
One approach would be to declare by fiat that only RCTs, which have become synonymous with Evidence Based Medicine, constitute evidence. All the case reports
only serve to indicate the potential of benefit and risk so as to motivate the appropriate RCT. The case reports themselves provide no evidentiary support to offering
DBS for care outside a RCT. This is an inordinately narrow view of Evidence Based
Medicine (Montgomery and Turkstra 2003)and would be solipsistic.
R I S KS
Risks may be apportioned to those related to the surgery, those related to the DBS
target, and those related to the disease. Surgical risks predominantly involve bleeding and infection. Risks with respect to intracranial hemorrhage and infection have
been consistent across different DBS targets and different conditions. Kim and
Pouratian (2014) raised concerns about increased risks in patients with Tourettes
126
syndrome, citing a study by Servello and colleagues (2010). Servello and colleagues
report that the rate of intracranial complications, which occurred primarily as
hemorrhages, was 3.9%. The problems with the study by these authors are the small
sample size (36 patients), and the relative low rate of complications risks a type
I statistical error (finding a difference when none truly exists). Similar concerns
are raised with respect to infections and hardware failure. Areasonable estimation
would thus be a 1% to 2% risk of intracranial hemorrhage with significant or permanent disabilities and a rate of 2% to 5% for infections that necessitated removal
of the DBS lead.
There are complications related to the stimulation. These are generally caused by
spread of electrical current to unintended structures. The target for motor symptoms in the globus pallidus interna, for example, lies extremely close to the optic
tract. Excessive electrical current may spread to the optic track and produce phosphenes or other visual disturbances. The posterior limb of the internal capsule lies
immediately posterior to the target in the globus pallidus interna. Unintended stimulation spreading to the internal capsule may produce tonic muscle contraction.
The centromedian-parafascicular nucleus lies medially and ventrally in the
thalamus. It is extremely close to the interstitial nucleus of the medial longitudinal fasciculus, which is involved in vertical eye movements. Spread of electrical
current from the centromedian-parafascicular nucleus to the interstitial nucleus of
the medial longitudinal fasciculus may cause vertical eye deviations and perhaps
other deviations that may impair vision. The centromedian-parafascicular nucleus
is also immediately ventral to the medial dorsal nucleus of the thalamus, which
is involved in cognition, memory, motivation, and emotions. Unintended spread
of electrical current from the centromedian-parafascicular nucleus to the medical
dorsal nucleus may account for the reported cognitive adverse effects, apathy, and
lethargy (Muller-Vahl etal. 2011).
The adverse effects related to the spread of electrical current to unintended structures may be resolved with proper adjustment of DBS electrode configurationsa
combination of active cathodes (negative contacts) and anodes (positive contacts)
and stimulation parameters (pulse with, rate or frequency, and voltage or current). In a prospective study of DBS in the vicinity of the globus pallidus interna
and subhthalamic nucleus for Parkinsons disease, for example, 83% experienced
adverse effects, primarily as a consequence of stimulation, of which nearly all were
resolved within six months. This is suggestive of resolution with appropriate DBS
programming (Weaver etal. 2009).
There may be adverse effects from stimulating the target. Yet these are not due
to stimulation of an adjacent structure. DBS in the vicinity of the globus pallidus interna, for example, may interfere with speech, which may not be attributable to electrical current spreading to neighboring structures. In addition, the
centromedian-parafascicular nucleus appears to be involved in sexual function and
attentional mechanisms, which may explain changes in sexual function and other
adverse effects.
The effects of DBS, whether successful or unsuccessful, on the larger context of
the disease must be considered. Even when DBS for Parkinsons disease is successful at controlling the motoric symptoms, for example, the improvements may cause
severe stress to patients and caregivers alike. Much of the stress may be related
to the relatively sudden changes in psychosocial relationships between the patient
and family members/caregivers. Patients and their family members or caregivers

have evolved to a certain psychological and social equilibrium dictated by patients
motor disabilities. Suddenly changing a patients functional abilities disrupts that
equilibrium. Patients may be more demanding of their independence and the familys role, because a beneficent manager may change and thus occasion concern and
mistrust.
There is insufficient experience to understand psychiatric, psychological, and
sociological dynamics in patients with Tourettes syndrome. The high prevalence
of psychiatric, psychological, and sociological comorbidities greatly complicates
the decisions to proceed with DBS. I attempt to determine the overall controlling problems that most significantly affect the patients quality of life. If they are
motoric, then one may proceed to DBS with greater confidence of a good outcome.
Unfortunately, the same cannot be said when the psychiatric, psychological, and
sociological comorbidities are dominant limiting factors.
A D EQ UAT I O N O F PAT I EN T TO TA R G E T
The lack of RCTs renders recommendations as to the appropriate target somewhat

problematic. However, the lack does not relieve the physician from making a decision other than not to offer DBS. Before a physician defaults to not offering DBS,
she must realize that she is committing the patient to continued suffering and
disability.
One of the issues that the physician must decide is his relative confidence in
the data that does exist. Ibelieve that there is sufficient clinical experience to warrant consideration of DBS in the vicinity of the globus pallidus interna and the
centromedian-parafascicular nucleus. Admittedly, patients should be made aware
that the recommendation for DBS is based on limited experience. Apatient may
then weigh the relative risks against possible benefits in light of the degree of confidence that current medical knowledge provides and with the recognition that the
only real alternative is to do nothing. At least from a fiduciary perspective, a patient
has a right to be made aware of the possibility of DBS, and failure to inform the
patient of that alternative may obviate the informed consent implicit (or explicit)
in every patientphysician relationship. Informed consent requires the patient to
be made aware of alternatives. The alternatives presented to the patient cannot be
determined by a physicians opinion. It must rest on that which a reasonable patient
would want to know.
An important concept in support of DBS in the vicinity of the globus pallidus
interna for tics is the effectiveness of DBS for a variety of hyperkinetic disorders.
DBS in the vicinity of the globus pallidus interna is effective for drug-induced
dyskinesia, Huntingtons disease, primary and secondary dystonia, chorea
secondary to acanthocytosis, tardive dyskinesia, hemiballismus secondary to
stroke, and chorea secondary to pantothenate kinase-associated neurodegeneration, among others. This argues strongly for the view that DBS in the vicinity of the globus pallidus interna is a symptom-specific treatment rather than
a disease-specific treatment (Montgomery 2004). This logic would support the
notion that, as a symptomatic treatment, DBS in the vicinity of the globus pallidus interna DBS should be effective for the tics of Tourettes syndrome. Yet it is
128
not clear that the standard DBS directed at the sensorimotor region of the globus
pallidus interna would be effective for the nonmotoric symptoms of Tourettes
syndrome.
Interestingly, a Canadian consensus group did not recommend DBS for Tourettes
syndrome, finding it investigational (Steeves etal. 2012). These recommendations
were based on the findings in only three RCTs. They ignored case series, as well as
the concept of DBS as a symptom-specific rather than disease-specific treatment.
This position is contrary to the actions of the FDAs approval of DBS for primary
dystonia, which was based on the weight of accumulated case reports and in the
absence of prospective RCTs. The Canadian recommendations are a disservice to
patients, because the likelihood of conducting the type of prospective RCTs is poor.
DBS would therefore never be recommended by any group that deems RCTs the
only permissible evidence.
Confidence in DBS of the centromedian-parafascicular nucleus is more
problematic, thanks to the relative paucity of controlled studies and publication bias against negative or poor results. Insofar as motoric symptoms and
related disabilities are concerned, Ifavor DBS in the vicinity of the globus pallidus interna. Though there is a relative paucity of controlled studies regarding DBS in the vicinity of the globus pallidus interna specifically for Tourettes
syndrome, the benefit of DBS in the vicinity of the globus pallidus interna for
other hyperkinetic disorders lends the aforementioned support. The proximity of the centromedian-parafascicular nucleus to structures whose unintended
stimulation may result in significant adverse effects is more of a problem for the
centromedian-parafascicular nucleus than it is for the globus pallidus interna.
One of the advantages of the globus pallidus interna being relatively large is the
cognitive and emotional components are spread out over a larger volume and are
thus more easily avoided.
The issue of DBS for the nonmotoric symptoms and disabilities of Tourettes syndrome are more problematic. According to anatomically connections, however, it
would appear that DBS of the centromedian-parafascicular nucleus would be more
effective than the sensorimotor region of the globus pallidus interna.
S U M M A RY
While the number of patients receiving DBS for Tourettes syndrome is relatively small, most studies demonstrate improvement and relative safety. The
issue is whether this is sufficient to consider DBS in the vicinity of the globus
pallidus interna for the motoric symptoms of Tourettes is reasonable. Ibelieve
it is, especially when the experience of DBS in the vicinity of the globus pallidus interna for other hyperkinetic disorders (see chapter 15) is considered
based on the notion that DBS is a symptom- rather than a disease-specific treatment. Unfortunately, the same cannot be said for DBS in the vicinity of the
centromedian-parafascicular nuclei of the thalamus. Well-conceived clinical
trials of DBS in the vicinity of the centromedian-parafascicular nuclei of the
thalamus should be conducted.
R EFER ENCES
Hariz MI, Robertson MM. Gilles de la Tourette syndrome and deep brain stimulation.
Eur J Neurosci. 2010;32(7):11281134.
Kim W, Pouratian N. Deep brain stimulation for Tourette syndrome. Neurosurg Clin N
Am. 2014;25(1):117135.
Montgomery EB Jr. Deep brain stimulation for hyperkinetic disorders. Neurosurg
Focus. 2004;17(1):E1.
Montgomery EB Jr. Dynamically coupled, high-frequency reentrant, non-linear oscillators embedded in scale-free basal ganglia-thalamic-cortical networks mediating
function and deep brain stimulation effects. Nonlinear Studies 2004;11:385421.
Muller-Vahl KR, Cath DC, Cavanna AE, etal. European clinical guidelines for Tourette
syndrome and other tic disorders. Part IV:deep brain stimulation. Eur Child Adolesc
Psychiatry 2011;20(4):209217.
Porta M, Servello D, Zanaboni C, et al. Deep brain stimulation for treatment of
refractory Tourette syndrome: long-term follow-up. Acta Neurochir (Wien).
2012;154(11):20292041.
Servello D, Sassi M, Brambilla A, etal. Long-term, post-deep brain stimulation management of a series of 36 patients affected with refractory Gilles de la Tourette syndrome. Neuromodulation 2010;13(3):187194.
Steeves T, McKinlay BD, Gorman D, etal. Canadian guidelines for the evidence-based
treatment of tic disorders: behavioural therapy, deep brain stimulation, and transcranial magnetic stimulation. Can J Psychiatry 2012;57(3):144151.
JAMA 2009;301(1):6373.
13

Candidates Among Patients
withTourettesSyndrome
T H E L E AST AC C EP TA B L E CA N D I DAT E
As discussed in other chapters, the notion of establishing selection criteria for the
least acceptable candidate for Deep Brain Stimulation (DBS) appears counterintuitive. Nearly every published criteria identifies those criteria that identify the best
candidate. However, this is least relevant to actual clinical practice. While there seldom is disagreement when the best candidate is considered, and perhaps that is the
reason the published criteria focus on the best candidate, the real challenge is doing
due diligence to those that are not ideal. Further, the majority of criteria published
are based on dichotomous criteria, which is the presence or absence of some feature. Yet rarely does clinical experience admit of a dichotomous variable. Far more
often the degree of a feature must be considered, and the presence or absence truly
reflects whether some threshold is exceeded. These epistemic issues are discussed
more fully in chapter4.
The complexity of the clinical phenomenology of Tourettes syndrome presents
an opportunity to review critically selection criteria for DBS. The review models
the method by which selection criteria for other indications are created. Chapter4
contains criticism of commonly accepted DBS selection criteria for patients with
Parkinsons disease. The basis of that criticism was the fact that those criteria were
imported whole-cloth from clinical trials criteria. In order to increase the effect size
and decrease the variance, the criteria, which were a convenience to the clinical trials, were created to exclude patients with atypical parkinsonism who were unlikely
to benefit and who were more likely to suffer other complications. Yet in doing
so the clinical trials distanced themselves from those patients who were likeliest
in need of DBS. The clinical trials organized around these exclusionary selection
criteria rendered less generalizable results. In light of real-world need, then, the
13. Identifying the Least Acceptable DBS Candidates Among Patients with Tourettes Syndrome 131
criteria appear arbitrary as they may unfairly exclude patients who would benefit
from DBS.
Because large-scale clinical trials have not been conducted, one cannot make the
same criticism about suggested clinical criteria for DBS candidacy for patients with
Tourettes syndrome. Also, there is too little experience to justify retrospectively
defining and prospectively testing variables predictive of success. Shaped by expert
opinion, criteria rest on a kind of consensus created by wide distribution of print
and electronic scientific publications. This consensus appears as something of a
meme. The proposed criteria thus offer insights into experts thoughts and present
an opportunity for an epistemological analysis that may improve them.
Though Tourettes syndrome is predominantly associated with simple and complex motor and vocal tics, it is attended by number of significant psychiatric comorbidities, such as attention deficit hyperactivity disorder (ADHD) and Obsessive
Compulsive Disorder (OCD). The fifth edition of the Diagnostic and Statistical
Manual of Mental Disorders (American Psychiatric Association 2012)offers the following four-part definition of Tourettes syndrome: (1) both multiple motor and
one or more vocal tics have been present at some time during the illness, although
not necessarily concurrently; (2)tics may wax and wane in frequency but have persisted for more than 1year since their onset; (3)onset occurs before age 18years;
(4) the disturbance is not attributable to the physiological effects of a substance
(e.g., cocaine) or another medical condition (e.g., Huntingtons disease, postviral
encephalitis).
D I AG N O S I S O F TO U R E T T ES SY N D R O M E
A key criteria is the onset of symptoms prior to age 18years. Indeed, many epidemiological studies demonstrate onset in early childhood. Yet the question
remains whether these epidemiological studies confirming the age of onset prior
to age 18years employed circular reasoning, because most of them involved children drawn from primary schools. The choice reflects a potential bias of convenience sample and a presumption that Tourettes syndrome is a childhood disease.
A PubMed survey reveals virtually no age-specific incidence of Tourettes syndrome beyond childhood.
The notion that Tourettes syndrome is exclusive to childhood does not square
the experience of many movement disorders specialists who treat adults. In a
retrospective study, Jankovic and colleagues (2010) found 46 adult patients
(19years of age or older) with Tourettes syndrome, of whom 8, or 18.6%, experienced no tics prior to age 18years. It is important to note that, with the exception
of age on onset, these adults met the same Diagnostic and Statistical Manual of
Mental Disorders (fourth edition, text revision; American Psychiatric Association
2000)criteria as did a comparison group of 100 patients with Tourettes syndrome
under age 18years.
In any retrospective study, ascertainment is a critical issue. Perhaps every adult
did show symptoms prior to age 18years, but for some reason they went unnoticed
in the eight adult patients who had no history of tics prior to age 18years. The issue
of ascertainment cuts both ways with respect to selection criteria of DBS surgery.
132
Even if it were absolutely true that all patients with Tourettes syndrome experience
onset of symptoms prior to age 18years and that the outliers were those in whom
a history of tics prior to age 18 years went undiscovered, to insist on symptoms
onset prior to age 18years is to discriminate against those who, for whatever reason,
experienced symptoms that went unnoticed before they reached age 19years.
The argument in support of maintaining as a criterion the onset of symptoms
prior to 18 years of age likely rests on the negligibly small probability of having
Tourettes syndrome but having no history of it prior to age 18years. This argument
fails for two reasons. The first reason rests on an application of Bayes theorem. By
use of Bayes theorem, the probability that one has Tourettes syndrome may be
expressed as T+, the probability of having Tourettes syndrome if symptoms appear
after age 18years would be P(T+|18), and if symptoms appear before age 18years
the probability would be P(T+|18+), which is just 1 P(T+|18). Thus results the
following formula:
P(T+|18)=(P(18|T+)*P(T+))/P(18)
where P(18|T+) is the probability of the first 18years without symptoms if one has
Tourettes syndrome, P(T+) is the probability of having Tourettes syndrome, and
P(18) is the probability of being free of symptoms for the first 18years of life. These
probabilities are known as prior probabilities. In the general population, P(T+) is
very low and P(18) is very high. P(T+|18) is consequently very low.
The problem is that the prior probabilities discussed here are not relevant to the
situation of deciding candidacy for DBS. First, the probability of Tourettes syndrome in the population of concernthe population being considered for DBSis
not very low. Indeed, it is 1, because all the patients presenting for DBS display
symptoms that are consistent with Tourettes syndrome, if one assumes for the
moment that age of onset of symptoms prior to 18years has been discounted. The
probability of experiencing no symptoms for the first 18years of life is not low in
this population. According to data presented by Jankovic etal. (2010), it is 0.08. The
probability of experiencing no symptoms for the first 18years of life, (P[18]) is 0.08
in the population of concern. In other words 8 of every 100 individuals who present
for DBS and who meetall the diagnostic criteria except that of onset of symptoms
prior to age 18 would be denied the potential benefits of DBS were diagnosing physicians to insist on that criterion because they are wish to remain consistent with
the Diagnostic and Statistical Manual of Mental Disorders.
The forgoing discussion is not merely academic. Areview by Piedad and colleageus (2012) cited a five-case series in which four cases included a diagnosis according to Diagnostic and Statistical Manual of Mental Disorders criteria. Interestingly,
the European Society for the Study of Tourette Syndrome, perhaps wishing to avoid
the aforementioned issues, suggested a diagnosis of Tourettes syndrome or chronic
tics (Muller-Vahl etal. 2011).
M I N I M U M AG E FO R S U R G ERY
According to some expert reviews, 18years is the minimum age for DBS candidacy.
According to others, the minimum age is 25years. These age requirements are not
based on issues of safety in children. For children as young as seven years, the US
Food and Drug Administration (FDA) has approved DBS for treatment of primary
dystonia under a Humanitarian Device Exemption. It is believed that by age seven
years, a childs head has reached 95% of its eventual adult circumference. DBS lead
displacement consequent to later skull growth thus does not present a significant
issue, particularly if allowances are madeslightly deeper DBS lead placement or
extra length in the extension that connects the DBS lead to the implanted pulse
generator, for example.
The minimum age requirement rests on the rationale that symptoms of
Tourettes syndrome are often self-limiting. It is presumed that any patient under
age 18 enjoys a significant chance of a spontaneous remission, which would obviate the need for DBS surgery. Leckman and colleagues (1998) demonstrated
that by age 18 approximately one-half of the patients who participated in their
study were free of symptoms. The real determination, however, is the number of
patients under consideration for DBS who will spontaneously remit in a period
that is sufficiently reasonable to render DBS unwarranted. Even a minimum age
of 25 years leaves unknown the number of patients whose symptoms will fail to
remit. Those who seek to make this determination often invoke Leckman and
colleagues article. Yet application of Leckman and colleagues data to the issue
of a minimum age for candidacy requires extrapolation rather than interpolation
(see Figure 13.1).
A retrospective study conducted by Pappert and colleagues (2003) involved the use
videos of patients that were assessed by a blinded rater. Fifty-six adults with Tourettes
syndrome, who had video taken of themselves as children, were asked to participate
in another video-recording. Among the study participants, the mean age of symptom
onset during childhood was 7.2 years ( 2.4 standard deviation). The mean age at
the time of the initial video-recording was 12.2 years (2.2 standard deviation). This
age roughly correlates with age of maximum tic severity noted by Leckman and colleagues (1998; see Figure 13.1). Of the 36 subjects contacted as adults, 31 agreed to be
reevaluated (mean age 24.2, 3.5 standard deviation years). At the time of the later
video-recording, 90% of the participants continued to experience tics, though most
were observed to have diminished since childhood. However, 10 of the 31 subjects
experienced objectively worse tic symptoms at the time of the later video-recording.
Interestingly, all participants considered themselves free of tics.
A correlation was found in tic severity between childhood and adulthood, but
no correlation was found in the duration of time that elapsed between the earlier
and later video-recordings. Though one must bear in mind that failure to find a
correlation may represent a type II statistical error (failure to find a truly existing correlation), the time course of tic severity in any one patient does appear to
be unpredictable. One notes that in the study by Leckman and colleagues (1998)
the time course of worsening tic symptoms is a composite score consisting of data
pooled across individuals. Extrapolation from a population statistic to that of an
individual is highly problematic. Yet when considering DBS candidacy, physicians
do not deal with a population; they deal with individuals.
A strict DBScandidacy age threshold fails to resolve the issue of maximum severity of the tics, which Leckman and colleagues (1998) found to be approximately
10years of age. Of study participants, 22% experienced tics so disabling that they
interfered with schooling. A minimum age of at least 18 years is unlikely to help
134
Plot of mean tic severity, ages 2 to 18 years.
Relative tic severity (ARRTS)
2
B
1
Actual Means
Estimates from Model
0
10
15
C
20
25
Age (y)
Figure13.1 Plot of tic severity over time for data compiled for the first 18years of life.
One observes that the data does not extend to age 25years, which some experts would
establish as minimum age for DBS consideration. If one extrapolates linearly from
the final phase of the model (line A), it appears that no patient age 23 or older would
experience symptoms. Because this clearly is not the case, the extrapolation must
deviate from linearity. Yet the appropriate nonlinearity of the extrapolation cannot be
known beforehand. Shown here are two hypothetical extrapolations that illustrate the
implications. The extrapolation represented by line B suggests a curve asymptotic to a
horizontal line, which in turn suggests that beyond some age tic severity improves no
further. In such case DBS is warranted, because the prospect of a patients spontaneously
improving is unlikely. The extrapolation represented by line C, however, suggests
continued probability of improvement beyond age 25years (modified with permission
from Leckman etal. 1998).
children who might benefit from DBS. One group has suggested that the psychosocial
consequences of tics are greatest at age 18. This conclusion is highly suspect, because
no evidence appears to support it. Studies have demonstrated marked increase in susceptibility to peer influence at ages 13 to 16years (Turkstra 2000). Again, considerable
injury to the child is likely if definitive treatment is delayed until age 18years.
D U R AT I O N O F SY M P TO M S
The European Society for the Study of Tourette Syndrome (Muller-Vahl et al.
2011)recommends that a patient experience symptoms for at least five years and severe
symptoms for at least one year. Unlike many other recommendations, these recommendations were not referenced and may represent a consensus based on anecdotal
experience. This is not to suggest that such consensus is uninformative. Indeed, the
originators of Evidence-Based Medicine recognized the validity and value of expert
consensus. Yet the recommendation does pose problems. For example, a patient with
severe Tourettes syndrome who began to experience symptoms at age 20years and
who presents with DBS meets the duration criterion but fails to meet the age criterion. Also, a patient with Tourettes syndrome who began to experience symptoms at
age 17years and whose severe symptoms have persisted for four yearsmust she be
required to suffer another year before she undergoes DBS?
PR ED I CT I N G C H A N G E I N SY M P TO M S E V ER I T Y OV ER T I M E
Motivating the search for a proper minimum age for DBS and sufficient duration of
symptomssevere symptoms, particularlyis a concern about exposing a patient
who might yet spontaneously remit to DBS surgery risks. These criteria appear ad
hoc and are at best extrapolations from anecdotal experience. Harm may therefore
result by commission (operating too early) or omission (operating too late or not at
all). The recommendations anecdotal nature raises the real possibility of Omission
bias, that is, bias toward inaction because it is preferable to acting in a harmful way.
The long history of this bias is encapsulated in the proverbial directive, First, do no
harm (Primum non nocere). This directive rests on an outmoded ethical concept
and tends to make physicians rather than patients feel better (see chapter19).
If it could be established that the prognosis of spontaneous remission is essentially zero within one year, is it fair to expect a patient to suffer for an additional
four years in order to meet the criteria? What if the prognosis cannot be established
in a five-year observation period? Does not proceeding after five years expose the
patient to the possibility of unnecessary surgery?
The key is to detect a change in the frequency of severe tic exacerbation. Detecting
any worsening of tics would certainly help, and it may make likelier a patients DBS
candidacy. However, detecting an unlikelihood for positive change is helpful as
well. Such detection depends heavily on the statistical nature of the time series
of severe tic exacerbation. For example, a time series with a relatively long period
between events is highly variable. As such it renders detecting a change quite difficult. Atime series with an extremely short inter-event interval and very low variability, on the other hand, becomes relatively easy to detect. Both the inter-event
time interval as well as its variability are critical to the determination of prognosis
for spontaneous change. These factors affect the period of observation needed for
prognostication. There is no reason to assume that a five-year history of symptoms
or a one-year history of severe symptoms is sufficient for any individual patient. As
Claude Bernard observed, individuals are more often fooled by things they think
they know than there are by things they do not know. Process control, in which an
attempt is made to minimize the time to detect a fault, creates this type of situation.
ABayesian approach and other statistical approaches have been developed (Barry
and Hartigan 1993), but to my knowledge, no studies have taken these approaches.
E X H AU ST I O N O F A L L R E ASO N A B L E A LT ER N AT I V E T H ER A PI ES
Medications
Medications are grouped in three general classes:(1)alpha agonists (of which there
are two); (2)antipsychotics (four generally recommended but more are possible);
136
(3) a dopamine depletory (Kurlan 2014; see Table 13.1). In order to exhaust all
possibilities for medical therapy, a treating physician or healthcare professional
must compare all 127 drug combinations. If each possible combination required
six monthsthe usual amount of time that elapses between clinic visitsthen
63.5years would be required to test all of them. Even if changes in medication regimens were possible every three months, 31years would be required to exhaust all
the combinations thereof. If only one agent from each group required testing, then
the possible combinations are seven. Exhausting all reasonable medical options
would take 3.5years if the latter were changed every six months, and it would take
1.75years if the latter were changed every three months.
The task becomes that of deciding whether multiple agents in a group must be
attempted prior to considering DBS. As with similar considerations in the case of
Parkinsons disease, the question may be divided into questions of efficacy and
questions of adverse effects. Anumber of studies have compared pimozide to haloperidol. In a Cochrane Database of Systematic Review, one study demonstrated
pimozide to be inferior to haloperidol, and two others showed no statistically significant differences in efficacy against tics (Pringsheim and Marras 2009). One
must bear in mind, however, the following caveat:failure to demonstrate a statistically significant difference is no demonstration of a lack of difference. Agreat deal
depends on the power of the statistical analysis and sample size. Also, the more
similar the agents are in the outcome measure the harder it is to demonstrate sufficient statistical power. The appropriate approach is therefore to define a clinically
meaningful difference in outcome measures and calculate the sample size for reasonable probability (power) in order to find a statistically significant difference at
the appropriate cutoff (p value). Most studies demonstrated fewer side effects with
pimozide, particularly lethargy (Ross and Moldofsky 1978). The few studies comparing pimozide to risperidone have demonstrated no statistically significant differences (the aforementioned caveat applies in this case). One study, which directly
compared either pimozide or haloperidol to fluphenazine in patients with Tourettes
syndrome, suggested equal efficacy but fewer adverse effects with pimozide (Singer
etal. 19851986).
Table13-1.Tic-Suppressing
Medication
Alpha agonists
Clonidine
Guanfacine
Antipsychotics
Haloperidol*
Fluphenazine
Pimozide*
Risperidone
Dopamine depletory
Tetrabenazine
Note: This list is not comprehensive.
*FDA-approved for this indication.
Daily dose (mg)

0.050.5
0.54
0.520
0.520
0.510
0.516
12.5100
Pringsheim and colleagues (2012) issued clinical guidelines that made the recommendations shown in Table 13.2. These recommendations greatly increased the
number of antipsychotic agents for consideration. As a result, they also increased
the possibility for proliferation of the number of combinations that one may need
to consider before recommending DBS. Strict adherence to the directive that all
medication options be exhausted prior to considering DBS risks preventing certain
patients from ever receiving DBS.
The review associated with the Canadian recommendations provided the same
data as previously discussed. Yet the review presented no comparisons for the additional six agents. It is likely that no such comparisons were made. It is therefore
impossible to recommend ways of streamlining the choice among these options.
Table13-2.GRADE Recommendations for Antipsychotics
for the Treatmentof Tics
Suggestions for medication dosing
(mgper day)
Medication
GRADE
Pimozide
Weak recommendation Children:1 to 4
Adults:1 to 6
High-quality evidence
Haloperidol
Weak recommendation Children:0.5 to 3
Adults:0.5 to 3
Fluphenazine
Adults:2.5 to 10
Low-quality evidence
Metoclopramide
Weak
recommendation
Children:0.5 mg/kg Adults:no data

on
per day, up to 40 mg adult treatment

(children age
6years and older)
Risperidone
Adults:0.25 to 6
Aripiprazole
Adults:2 to 20
Olanzapine
Adults:2.5 to 20
Quetiapine
Adults:25 to 400
Very low-quality
evidence
Ziprasidone
Adults:no data
on
adult treatment
Source: Pringsheim etal. (2012).
138
A reasonable conclusion is that no great difference exists between pimozide and

haloperidol; if one fails, it may not be necessary to try the other. If, however, haloperidol produces intolerable adverse effects in a patient who has not tried pimozide,
a trial of pimozide may be reasonable. If pimozide fails, it is unlikely that risperidone
will succeed. Integration of metoclopramide, aripiprazole, olanzapine, quetiapine,
and ziprasidone into a single approach for antipsychotic use is simply impossible.
Caution is advised. Meta-analyses of the use of antipyschotics has demonstrated
an increased risk of sudden unexplained death in the elderly. Literature on the
risks associated with typical and atypical antipsychotics has been inconsistent
(Murray-Thomas etal. 2013). With use of atypical antipsychotics especially, prolongation of the QT interval in electrocardiograms has been observed. Yet at least
one study suggested that prolongation of the QT interval was not associated with
increased risk of sudden cardiac death (Leonard etal. 2013).
Alpha Agonists
A search of PubMed revealed no studies that directly compared guanfacine and
clonidine in patients with Tourettes syndrome. No judgment regarding the advantage of one over the other is therefore possible. Of importance in this case is the
judgment whether the failure of one medication justifies attempting the other.
A search on PubMed reveals no comparison studies of guanfacine and clonidine in terms of relative frequency and severity of adverse effects in Tourettes
syndrome. Studies on the use of these agents in hypertension, however, have been
conducted, and they have revealed that there is little difference between them in
terms of adverse effects (Wilson etal. 1986).
Behavioral Intervention
A recent consensus report examined six types of behavioral intervention: (1) habit-reversal therapy, (2) massed negative practice, (3) self-monitoring,
(4)contingency management, (5)exposure and response prevention, and (6)generic
cognitive-behavioral treatment (Steeves etal. 2012). Of those six types of behavioral
intervention, only habit-reversal therapy and exposure and response prevention
underwent clinical trials in sufficient number for the consensus committee to recommend the former as effective treatments.
S E V ER I T Y S U F FI C I EN T TO R EC O M M EN D
D EEP B R A I N ST I M U L AT I O N
Most experts agree that in order to warrant DBS surgical and postoperative stimulation risk a patients tics must be sufficient severity. Anumber of groups have written that the score on Yale Global Tic Severity Scale (YGTSS) should reach 35 points
or more (Leckman etal. 1989). Yet what is to become of a patient who scores 34?
If she is considered for DBS, ought not a patient who scores 33 also win the same
consideration?
The YGTSS consists of three components: (1) motor tics, (2) phonic tics, and
(3) overall impairment. Interestingly, those who advocate the use of the YGTSS
appear to rely on combined motor and phonic tic scores instead of the impairment
score. The overall impairment score correlates the phonic score with a Pearson
r=0.42, the square of which is 0.18. The phonic tic scores thus explain approximately 18% of the overall improvement score (Storch etal. 2007). The correlation
between overall improvement and motor tic score is 0.81, the square of which is
0.66. This means that the motor tic score only accounts for two-thirds of the overall
impairment score. If the endpoint is improvement in a patients quality of life, then
it is not certain that the YGTSS represents the most appropriate measure.
Use of the total tic score from the YGTSS raises additional concerns. These
are suggested by the failure of the total tic score to correlate with the TNO-AZL
Childrens Quality of Life scale in children (Bernard etal. 2009). Measures of ADHD
and OCD correlated better. Cavanna and colleagues (2013) recently reviewed issues
surrounding development of quality of life measures. Psychiatric and psychological comorbidities greatly affected most quality of life measures, especially in children. Yet even patients whose pure Tourettes syndrome bespoke of no significant
comorbidities experienced diminished quality of life as a consequence of their
severe tics.
Because the structure of most tic severity and quality of life measures is effectively continuous, it occupies a range of values. Decisions require a dichotomous
variable: a surgeon must either operate or not operate. Some means of converting continuous or multivalued continuous data to a dichotomous value is therefore
needed. Such transitions often employ a thresholding process. Nothing in the data
itself suggests an appropriate threshold or cutoff. The appropriate approach requires
that one determine the cutoff by examining the consequences (Montgomery
and Turkstra 2003), which must be considered in their particular medical, ethical, moral, social, political, and economic contexts. Because the consequences are
highly contextual and specific to the individual, it is difficult to accept how severity,
age, duration of symptoms, or any other possible cutoff may be unilaterally established by physicians.
C O M O R B I D I T I ES
ADHD and OCD occur in patients with Tourettes syndrome so frequently as to be

thought part of the syndrome. Further, ADHD and OCD play a prominent role in
the quality of life, particularly during childhood. Other significant psychiatric and
psychological comorbiditiesdepression, impulse control problems, self-injury
are common enough to be of concern. The presence of an implanted DBS system
increases concern for patients who engage in self-injurious behavior.
Though evidence suggests that DBS may alleviate some OCD symptoms, DBS in
the vicinity of the sensorimotor region in the posterior lateral aspect of the globus
pallidus interna is unlikely to benefit OCD or ADHD. And though these symptoms
may benefit from DBS in the vicinity of the centromedian-parafascicular nucleus,
Icannot recommend it, because Ihave not seen sufficient evidence. For the present, improvements in OCD or ADHD must not be the intent behind recommending DBS for Tourettes syndrome. Growing evidence of the effectiveness of DBS in
140
the vicinity of the anterior limb of the internal capsule for OCD (approved by the
FDA under a Humanitarian Device Exemption), however, suggests that DBS in the
vicinity of the anterior limb of the internal capsule may be an option for patients
with severe OCD, provided there is no expectation of also improving their tics.
Apatient with Tourettes syndrome for whom ADHD and OCD are the main limiting factors for quality of life are unlikely to benefit from DBS in the vicinity of the
posterior lateral globus pallidus interna. I ask patients or their family members/
caregivers to estimate the degree to which quality of life would improve with relief
from tics. If they estimate only a slight improvement, then Iadvise them that DBS
will offer no significant benefit.
Presence of significant depression is a concern. Experience with DBS for
Parkinsons disease and Essential tremor has shown an increased risk for depression or exacerbation of depression following DBS. Sometimes the depression or
exacerbation is transient. This is not to say that the presence of depression is a contraindication to DBS surgery. It is to say, rather, that physicians and healthcare
professionals must be proactive in anticipating worsened depression and have contingency plans in place.
The effect of self-injurious behavior is more problematic. Of course, patients
with active self-injurious behavior may need to be excluded. Whether the history
of self-injurious behavior is sufficient to exclude a patient is difficult to determine.
The determination depends on how readily any increase in risk for self-injurious
behavior may be detected and treated.
R E A L I ST I C AS S ES S M EN T O F R I S K A N D A LT ER N AT I V ES
The decision to proceed to DBS surgery must rest on dispassionate analysis and
rational; all the options must be weighed in terms of their advantages and disadvantages, which in turn must be considered in light of the consequences of every
alternative decision. The consequences must be considered in their widest extent.
Medications enjoy no inherent advantage over surgery. Many physicians, for example, have few reservations about prescribing chemotherapy. Yet one study demonstrated a 7.5% mortality rate within 30days of chemotherapy commencement, and
the chemotherapy agent was the cause of death (OBrien etal. 2006). This mortality
rate is much higher than the mortality rate of DBS surgery.
Admittedly, chemotherapy and DBS surgery are somewhat incommensurate. Yet the fact remains that medications can be more dangerous than surgeries.
Programmatically preferring medications to surgeries is therefore unreasonable. As
discussed in c hapter3, the risk of serious morbidity with DBS surgery is on the order of
2% for serious or permanent complications, which are typically related to intracerebral
hemorrhages, and 2% for infections that necessitate removal of a DBS lead. Mortality
is quite rare. The concern is that physicians will object reflexively to offering surgeries.
Admittedly, physicians are prone to the same biases and failures of logic as anyone
else (Johnson-Laird 2006). Relevant here is the issue of Confirmation bias, in which
an individual admits only those data or experiences that resonate with his particular experiences and expectations. Entry to DBS surgery traditionally lies through a
neurologist, whose tools of the trade are medications. It is therefore unsurprising, if
ultimately irrational, that physicians default to medications. Such bias is avoided if
one recognizes it as a possibility and consciously attempts to counteract it.
D EC I S I O N S I N T H E FAC E O F U N C ERTA I N T Y
The foregoing critique of proposed selection criteria does not extend to the various
motivations that prompt physicians and healthcare professionals to help patients
and avoid preventable harm. The criticism focuses, rather, on the means by which
this help is given. When examined critically from an epistemological standpoint,
the current criteria appear to fail to accomplish the desired end. This holds especially true for any criterion associated with a fixed threshold. Though the forgoing
criticism may appear deflating, one must not consider it so. It reflects, rather, the
current state of knowledge and the obligation it places on physicians. The criticism certainly does call for nuanced, complex decision-making. Uncertainty will
remain, no matter how many subsequent randomized controlled trials are conducted (Montgomery and Turkstra 2003; Montgomery 2011).
Uncertainty is the lot of physicians and healthcare professionals. Scientists faced
with uncertainty may run more subjects or conduct more experiments. Uncertainty
for scientists is reduced by the presumption that the median or mean, which represents
the central tendency, is synonymous with the entity sought. Any uncertainty in the
data is thus considered noise. These devices are insufficient for a physician, who must
think scientifically but must also adopt other frames of mind. Patients needs trump
the demands placed on physicians and healthcare professionals, which compel them
to act assuredly. Scientists and computers compare incommensurables, such as apples
and oranges only with great difficulty. Physicians and healthcare professionals, on the
other hand, must regularly compare the incommensurables of risk and benefit.
Physicians and healthcare professionals are not alone in this task. Patients or
their surrogates may aid them by helping to manage otherwise ineradicable uncertainty. Patients or their surrogates may determine an acceptable degree of uncertainty attending both risk and benefit. They alone may determine the amount of
willingness that attends any riskbenefit assessment. Yet there has been published
no selection criteria that offers any formal means of soliciting and incorporating
patients individual value systems. Indeed, many criteria that impose hard and
fixed cutoff thresholds militate against enlisting patients in the DBS decision.
Hard and fixed cutoffs violate a patients autonomy (Beauchamp and Childress
2013). Honest reflection clearly demonstrates, for example, that any assessment of
degree of severity is really an attempt to measure a patients quality of life. Yet quality of life is highly contextual. The exact same degree of symptom severity in one
patient may result in less diminished quality of life in one context and more diminished quality of life in another. As yet, no published criteria offer any modifier or
measure that captures the specific context in which a patient is bound.
H OW Q U EST I O N S A R E FR A M ED A N D W H AT T H E Y R E V E A L
A B O U T T H O S E W H O FR A M E T H EM
The way one sets about identifying the best DBS candidates among patients with
Tourettes syndrome speaks volumes about physicians and healthcare professionals. The aforementioned Omission bias represents the fear associated with taking
action that has immense consequences for others. Limiting patients participation
in the DBS decision to that of accepting or rejecting offers constructed by physicians
and healthcare professionals represents a form of paternalism that is unacceptable
142
in the modern medical community. Yet it represents an honest attempt by physicians and healthcare professionals who may themselves be cowed by the complex
nature of the decision and therefore doubt a patients ability to decide.
The use of symptom- and sign-based assessment instead of quality-of-life
measures (assuming that valid ones are available) may lack ecological validity,
because the former may not translate to any relevant patient concern. Physicians
and healthcare professionals perform symptom- and sign-based assessments
all the time. They therefore know that symptoms and signs are part of disease
pathophysiology. The symptoms and signs are thus closer to the real disease than
they that are too vague and perhaps indiscriminate quality-of-life measures.
Studies have shown relatively consistent agreement among patients, their family
members, and their physicians on symptoms and signs. Yet agreement by these
same parties on subjective measuresquality of life, happinessis poor (Janse
et al. 2004).
S U M M A RY
Sufficient evidence exists to support the use of DBS directed at the sensorimotor
region of the globus pallidus interna for the treatment of disabling tics or tics that
significantly reduce the quality of life of patients with Tourettes syndrome. DBS in
the vicinity of the globus pallidus interna DBS should be considered an accepted
and standard use of an FDA-approved device. The limited direct clinical experience
associated with this use, however, must be supplemented by the experience that has
shown DBS in the vicinity of the globus pallidus interna to be effective for a wide
range of hyperkinetic disorders. In this sense, DBS in the vicinity of the globus
pallidus interna is an effective symptomatic treatment for Tourettes syndrome and
other hyperkinetic disorders.
Unfortunately, what may be said regarding DBS in the vicinity of the
globus pallidus interna may not be said of DBS in the vicinity of the
centromedian-parafascicular nucleus. The latter may be effective for such a comorbidity as OCD, but there is insufficient evidence to warrant its use as a standard
and accepted off-label use of an FDA-approved device. In the case of DBS in the
vicinity of the centromedian-parafascicular nucleus, the therapy must be considered investigational.
Criticisms of selection criteria require considerable nuance, which hard, fixed
cutoff criteria render impossible. Rather, these criteria must be understood, rather,
as a basis for conversation with the patient in order to assure ecological validity,
that is, relevance to an individuals unique context.
Indecision carries consequences as surely as does any decision. Offering a patient
DBS produces one outcome, and not offering it produces another. Adecision must
ultimately rest on its consequences and not some set of rules imposed on it.
R EFER ENCES
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American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC:American Psychiatric Association; 2000.
Barry D, Hartigan JA. A Bayesian analysis for change point problems. Journal of the
American Statistical Association 1993;88:309319.
Bernard BA, Stebbins GT, Siegel S, etal. Determinants of quality of life in children with
Gilles de la Tourette syndrome. Mov Disord. 2009;24(7):10701073.
Cavanna AE, David K, Bandera V, etal. Health-related quality of life in Gilles de la
Tourette syndrome:a decade of research. Behav Neurol. 2013;27(1):8393.
Jankovic J, Gelineau-Kattner R, Davidson A. Tourettes syndrome in adults. Mov
Disord. 2010;25(13):21712175.
Janse AJ, Gemke RJ, Uiterwaal CS, et al. Quality of life: patients and doctors dont
always agree:a meta-analysis. J Clin Epidemiol. 2004;57(7):653661.
Johnson-Laird PN. How We Reason. NewYork:Oxford University Press; 2006.
Kurlan RM. Treatment of Tourette syndrome. Neurotherapeutics 2014;11(1):161165.
Leckman JF, Riddle MA, Hardin MT, etal. The Yale Global Tic Severity Scale:initial
testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry
1989;28(4):566573.
Leckman JF, Zhang H, Vitale A, etal. Course of tic severity in Tourette syndrome:the
first two decades. Pediatrics 1998;102(1 Pt 1):1419.
Leonard CE, Freeman CP, Newcomb CW, etal. Antipsychotics and the risks of sudden cardiac death and all-cause death: cohort studies in Medicaid and dually
eligible Medicaid-Medicare beneficiaries of five states. J Clin Exp Cardiolog.
2013;10(Suppl.6):19.
Montgomery EB Jr. Ask the expert: what is your interpretation of the ADAGIO
study and has it influenced your clinical practice? Neurodegen Dis Manage. 2011;
1:2123.
Psychiatry 2011;20(4):209217.
Murray-Thomas T, Jones ME, Patel D, etal. Risk of mortality (including sudden cardiac
death) and major cardiovascular events in atypical and typical antipsychotic users:a
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2013;12:115.
OBrien ME, Borthwick A, Rigg A, et al. Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients. Br J Cancer
2006;95(12):16321636.
Pappert EJ, Goetz CG, Louis ED, etal. Objective assessments of longitudinal outcome
in Gilles de la Tourettes syndrome. Neurology 2003;61(7):936940.
Piedad JC, Rickards HE, Cavanna AE. What patients with Gilles de la Tourette syndrome should be treated with deep brain stimulation and what is the best target?
Neurosurgery 2012;71(1):173192.
Pringsheim T, Doja A, Gorman D, etal. Canadian guidelines for the evidence-based
treatment of tic disorders:pharmacotherapy. Can J Psychiatry 2012;57(3):133143.
Pringsheim T, Marras C. Pimozide for tics in Tourettes syndrome. Cochrane Database
Syst Rev. 2009;(2):CD006996.
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Ross MS, Moldofsky H. A comparison of pimozide and haloperidol in the treatment of

Gilles de la Tourettes syndrome. Am J Psychiatry 1978;135(5):585587.
Singer HS, Gammon K, Quaske S. Haloperidol, fluphenazine and clonidine in Tourette
syndrome:controversies in treatment. Pediatr Neurosci. 19851986;12:7174.
Storch EA, Murphy TK, Fernandez M, etal. Factor-analytic study of the Yale Global Tic
Severity Scale. Psychiatry Res. 2007;149(13):231237.
Turkstra L. Should my shirt be tucked in or left out? The communication context of
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14
Deep Brain Stimulation for

Cerebellar Outflow Tremor
FO O D A N D D R U G A D M I N I ST R AT I O N STAT U S
The US Food and Drug Administration (FDA) has approved Deep Brain Stimulation
(DBS) in the vicinity of the thalamuss ventral intermediate nucleus for treatment of
Essential tremor and Parkinsons disease-related tremor. The FDA has yet to comment on DBS as treatment for postanoxic tremor, posttraumatic tremor, and tremor
related to Multiple Sclerosis. DBS for these indications thus constitutes off-label
use of an FDAapproved device.
Physicians must weigh several factors when considering DBS in the vicinity of
the thalamus as treatment for cerebellar outflow tremors. They must discover, for
instance, whether any specific prohibition exists against the use of FDA-approved
drugs, biologics, and devices in treating conditions on which the FDA has not
established a position. In its regulatory guidelines, the FDA states that [g]ood
medical practice and the best interests of the patient require that physicians use
legally available drugs, biologics, and devices according to their best knowledge
and judgment. Physicians who use a product for an indication other than those
listed in the approved labeling must become well informed about the product,
base its use on firm scientific rationale and sound medical evidence, and maintain
records of the products use and effects. Use of a marketed product in this manner
when the intent is the practice of medicine does not require the submission of an
Investigational New Drug Application (IND), Investigational Device Exemption
(IDE) or review by an Institutional Review Board (IRB), the FDA guidelines continue. However, the institution at which the product will be used may, under its
own authority, require IRB review or other institutional oversight. Indeed, state
laws and legal court decisions exist to protect the privilege of physicians prescribing
drugs or devices for off-label use.
The issue is whether lack of approval prohibits use of DBS to treat tremor due to
other conditions than Essential tremor and Parkinsons disease. One may simply
decree that no treatment be offered without FDA approval. To do so, however,
would be to violate the law and FDA policy, as well the ethical principle of benevolence, because some off-label uses are considered standard, accepted first-line
therapies.
146
To claim that lack of FDA approval indicates the ineffectiveness or inferiority of

off-label uses is to commit an error in reasoning known as arguing from ignorance
(argumentum ad ignorantiam). As Carl Sagan famously observed, the absence
of evidence is not evidence of absence. Lack of an FDA position on a particular
off-label use is therefore no evidence at all of the FDAs disapproval of that use. Yet
lack of an FDA position is not license to do as one pleases. Aphysician must base
her choice to pursue an off-label use on reasonable scientific evidence.
Any medical decision rests on an assessment of risks, potential benefits, and
alternatives. It is often the case that the value one assigns to the facts matters
as much as the facts themselves. Thus, of two studiesa randomized two-limb
(separate control and experimental groups) and blinded study and a single-limb
study with blinded assessments with the patient serving as her own control
the first study is deemed more credible. Indeed, the first study may appear
superior from a strictly academic perspective, or at least from a perspective
that privileges purity of method over any conclusions. Yet from its superiority
it derives no necessary justification for regarding its results as more meaningful
than the second studys results. The two studies must be compared according to
the strength of their evidence rather than the meaningfulness of their respective outcomes.
An expensive study sponsored by the National Institutes of Health and the
Veterans Affairs administration offers a useful example. In it patients with
Parkinsons disease were randomized to two groups:(1)best medical therapy and
(2)DBS (Weaver etal. 2009). The second group was randomized to either DBS in
the vicinity of the subthalamic nucleus or globus pallidus. It was found that patients
treated with DBS enjoyed better control of their symptoms and experienced fewer
long-term side effects than did patients who received best medical therapy. A2001
study conducted by experts in the management of Parkinsons disease (Deep-Brain
Stimulation for Parkinsons Disease Study 2001) found that patients who had
exhausted all reasonable attempts at medical therapy and arguably failed best medical therapy experienced, after undergoing DBS, degrees of improvement theretofore unseen with medications. However, the second study did not randomize to
a control group of patients having best medical therapy. In a sense, the patients
entered into the study had already received best medical care. Indeed, if one accepts
this position, the results of the 2001 study would be superior to the latter randomized study because the former would be a within-subject design because it more
directly addresses the question of whether a patient who failed medications would
benefit from DBS.
A purist may argue that the study that randomized to a second limb (Weaver etal.
2009)was better than the initially nonrandomized study (Deep-Brain Stimulation
for Parkinsons Disease Study 2001). This claim leaves one wondering about the way
in which the second study is better. The study randomized to a second limb arrived
at essentially the same conclusions as the first nonrandomized study (Deep-Brain
Stimulation for Parkinsons Disease Study 2001). Any superiority, therefore, does
not rest on the results. Indeed, it could be argued that the randomized study was
unlikely to result in any difference. Rather, any presumed superiority rests on the
confidence one has in the results. Whether an incremental improvement was worth
the millions of tax dollars spent to realize it remains debatable. Ipersonally hold
the opinion that it was not.
14. Deep Brain Stimulation for Cerebellar Outflow Tremor147
Voltaire famously observed that the best is the enemy of the good. The physician and healthcare professional must constantly decide whether the good is good
enough, the best being unrealizable. The fact that patients lives and health are at
stake makes this anything but an academic discussion. Scientists may simply take
their time reaching a conclusion and run more experiments. Physicians and healthcare professionals, however, enjoy no such luxury. They must make care decisions
as patients stand before them.
The decision to treat or not to treat, which every physician and healthcare professional confronts, is dichotomous in nature, admitting of no middle way or compromise. To refrain from deciding is to decide not to treat. The imperative, Do no
harm (Primum no nocere), which enjoys long historical standing but is in truth
faulty, allows physicians or healthcare professionals beset by uncertainty to beat a
retreat. Yet doing so is to fall victim to Omission bias, which holds that sins of commission are worse than sins of omission. The so-called trolley car dilemma offers
an example of Omission bias at work (Foot 1978; Thomson 1985). A trolley car
experiences brake failure and goes hurtling down the tracks, jeopardizing the lives
of five individuals standing downfield. Asixth individual observes this situation.
She notices also that she stands near a switch that, if thrown, would send the trolley down a siding rather than into the five endangered individuals. Along the siding downfield, however, stand two individuals who would be struck by the trolley
should the switch be thrown. The question becomes, then, whether the individual
near the switch should throw it.
A subsequent variation on the trolley car dilemma further complicates the issue.
The sixth individual no longer stands near a switch but on a bridge near a large man
who holds a heavy bag. The sixth individual realizes that were she to shove the man
from the bridge and onto the tracks, she could stop the runaway trolley and save
the other five individuals downfield. Should she give that large man the fatal shove?
Asked to put themselves in the place of the sixth individual, respondents tend to
show greater willingness to throw the switch than shove the man, despite the fact
that throwing the switch results in double the deaths. Proximity of the actor to
the consequence perhaps explains this tendency. Throwing the switch seems a less
personal act than does shoving the man. Asimilar tendency pervades medicine as
currently practiced.
A PPR O PR I AT E M E AS U R ES
Medical decision-making requires that decision-makers balance risks, potential benefits, and alternatives. Because it is dichotomous, consisting solely of two
options (to treat or to refrain from treating), the decision rests on estimations of
risks and potential benefits, as well as the confidence felt in those estimates by the
decision-maker, who subsequently judges the balance between risks and potential
benefits in light of alternatives. In most cases in which DBS is being considered, no
alternatives exist, and their risks include those associated with the decision not to
provide DBS. Sin of omission in such cases is that of not providing DBS, which is
every bit as bad, ethically speaking, as any sin of commission.
DBS carries a number of different types of risks. Surgical risks relate primarily
to the risk of intracranial bleeding and infection. Review of the literature suggests
148
that these DBS risks differ little from one disorder to another and from one target
to another. The consequences may vary according to target and the functional
anatomical systems affected, but risk for hemorrhagic or infection complication
appears the same. It is therefore reasonable to extrapolate the risks of these surgical
complications to such other indications as Parkinsons disease and Essential tremor
and to extrapolate risks associated with DBS to cerebellar outflow tremor. The risks
are estimated to be 1% to 2% for intracranial hemorrhage and for infection serious
enough to necessitate the removal of the DBS lead (risk of infection around the
implanted pulse generator is significantly higher).
Risks associated with actual brain stimulation are specific to the DBS target and
the surrounding functional anatomy. DBS in the vicinity of the ventral intermediate nucleus of the thalamus, for example, may be different than stimulation in
the vicinity of the subthalamic nucleus. Experience to date, however, suggests that
the adverse effects of stimulation of the thalamus are no different between patients
with Essential tremor and those with Parkinsons disease. The adverse effects with
stimulation in the vicinity of the ventral intermediate nucleus of the thalamus are
therefore unlikely to be significantly different in patients whose cerebellar outflow
tremor owes to other causes.
The caveat that other comorbidities may influence the effects of DBS must be
borne in mind. The presumption is that patients with significant dysphagia, dysarthria, or language problems, for example, face greater risk of exacerbation should
they undergo DBS in the vicinity of the thalamus. This presumption has yet to find
any evidence to support, because patients with significant dysphagia, dysarthria, or
language problems are generally excluded from DBS consideration. One therefore
cannot know whether these patients are at risk. Neither can one have any confidence in any position, pro or contra, on DBS for patients with significant dysphagia, dysarthria, or language problems. For example, a systematic review by Troche
and colleagues (2013) found no significant overall change in swallowing functions.
The review did note that a majority of patients experienced only mild swallowing
problems prior to DBS surgery (Troche etal. 2013). The range of severities would
be insufficient to establish a correlation, in terms of predictive value, between the
preoperative status and the postoperative response. Whereas it seems prudent to
exclude patients with significant preexisting dysphagia, dysarthria, or language
problems, any assumption of prudence presupposes Omission bias, because there
is no evidence to justify it.
A second caveat is this:Patients with different disorders may be susceptible to
nonspecific risks. Patients with Multiple Sclerosis, for example, may experience an
exacerbation of the sort that occurs with infection or any other source of stress. It
is unknown whether a patients preoperative stability (exacerbation frequency and
recentness) is predictive of nonspecific exacerbation. Despite the fact that its actual
consequences remain unknown, recent exacerbation may be a reasonable criterion
for excluding patients, especially if a decision must be made.
The decision for excluding patients with Multiple Sclerosis and significant dysphagia and dysarthria presents a difficult ethical problem. In force is the principle
of beneficencean obligation to improve a patients symptoms and disabilities
which admits of an obverse in nonmaleficence, that is, an ethical obligation to do
no harm. In the patient, harm takes the form of adverse effects. In society, it takes
the form of medical costs. At issue is autonomy, that is, respect for a patient. As
it bears on making a decision, autonomy is difficult to invoke, because maintaining that patients and their legal representatives have a right to pursue ineffective
treatments violates the principle of nonmalfeasance. Yet the exercise of autonomy
depends on having proper knowledge. If patients and their legal representatives
lack proper knowledge, they cannot exercise autonomy. Called for in this situation,
perhaps, is a fourth ethical principle:justice (Beauchamp and Childress 2013).
Justice redresses a libertarian position that otherwise resolves around the situation. The libertarian perspective holds that the amount and quality of care available
to patients is determined by social contract and that society has the right to dictate
the contracts terms. An egalitarian position, meanwhile, rests on a notion of fair
and just application of criteria for the amount and quality of care patients may
expect, however these criteria come to be determined. They may come to be determined by way of utilitarian calculus, which seeks to weigh the good realized by
offering DBS against the good realized by refraining from offering it. This of course
presupposes that one may calculate and compare good. And, like the exercise of
autonomy, it requires having proper knowledge. The criteria for the amount and
quality of care patients may expect may also come to be determined by deontological argument, which insists on the duty attending the healthcare professions. Yet to
whom or what they owe this duty is unclear. This duty clearly is not that of upholding autonomy. If it is dedicated either to benefice or nonmalfeasance, however, it
may bring consequences few would value or deem appropriate.
The decision of whether to offer patients DBS in the case of cerebellar outflow
tremor admits of a third alternative, which is fairly straightforward, particularly if
one recalls that few other medical or physical therapy options exist (Samkoff and
Goodman 2011). The few possibly effective options may be assessed in short order.
The tasks become that of determining and measuring benefit. Historically,
common outcome measures were symptoms, which were voiced by patients, and
signs, which were physically assessed by physicians and healthcare professionals.
In the case of cerebellar outflow tremor, the physically assessed measure is the
tremors character, which is typically its amplitude. It is not at all clear, however,
that symptom- or sign-based outcome measures reflect any true value to a patient
or society. It does not reflect, for example, improvement in a patients life, however that improvement is defined. Symptom- and sign-based assessments relate
to a disorders pathophysiology and pathoetiology, which is another reason some
physicians prefer them. Any changes in symptoms or signs may consequently
be attributed to a specific causal mechanism and thus appear to validate the
treatment.
The degree to which a disorder impairs such ordinary activities as eating and
dressing (assessed according to the amount of independence evident) presents an
alternative outcome measure. This alternative, however, admits of some uncertainty. Degree-of-difficulty ratings tend to vary according to the rater. Scales were
therefore developed to measure the quality of life enjoyed by patients, as well as
patients family members and caregivers. Highly subjective, these measures are
sensitive to influences not directly affected by the treatment. Atreatment evaluated
according to quality-of-life scales may be judged a failure, the fact that it effectively
treats the proper symptoms notwithstanding.
The differences in the outcome measures affect the conclusions drawn. In
patients with Multiple Sclerosis, studies utilizing the Expanded Disability Status
150
Scale frequently demonstrated no significant change following DBS in the vicinity

of the ventral intermediate nucleus of the thalamus. Yet these same studies demonstrate marked and continued improvement in tremor. The explanation for this
improvement lies in the fact that Multiple Sclerosis is a progressive disorder. Even
if the tremor remains under satisfactory control, impaired gait and other problems
appear to worsen. The Expanded Disability Status Scale is heavily weighted toward
effects on ambulation. If the patient already had significant gait involvement, any
benefit attributed to reduction of tremor in a single upper extremity would not
affect the Expanded Disability Status Scale. Improvement restricted to the single
upper extremity, on the other hand, may indicate relative independence when performing such tasks as eating finger food, dialing a telephone, or driving a motorized wheelchair.
G EN ER A L S EL ECT I O N C R I T ER I A
While remaining cognizant of the lack of prospective controlled studies, Iemploy

the following selection criteria:
1. Tremoraction tremor, typicallysevere enough to interfere with the
patients quality of life directly as well as indirectly, in that others must
contribute care. Other symptoms or disabilities not responsive to DBS
should lack the degree of severity sufficient to hinder quality of life even if
the expected tremor relief follows.
2. Distal rather than proximal tremor (this criterion rests on my experience,
which has shown that proximal tremor is more difficult to relieve than is
distal tremor).
3. Absence of significant dysarthria, dysphagia, or speech problems.
4. At least a six-month absence of symptom exacerbation in patients with
Multiple Sclerosis (though insufficient evidence exists to suggest that
DBS may increase exacerbation risks, this criterion seems prudent for the
reason that it delays DBS treatment only slightly).
5. An absence of significant weakness or sensory loss in the extremity
targeted for DBS (contributing to tremor are weakness and sensory loss,
the amenability to DBS of whose mechanisms, while unknown, has been
suggested by a series of cases of tremor associated with neuropathies,
which were shown to improve).
6. Increased risks associated with medications that may interfere with
wound healing or result in infection (of particular concern are patients
with Multiple Sclerosis and their medical regime).
7. Failure of all reasonable attempts at medication therapies (though many
physicians try amantadine, and some try primidone, medication therapies
for tremor are few).
8. An absence of significant problems with depression or impulse
control problems (arrangements must be made prior to the surgery for
postoperative intervention should these problems begin to affect patients).
9. Degree of preexisting cognitive problems (though this is a problematic
criterion because there is no method with which to predict risk for
subsequent worsening, particularly in patients with Multiple Sclerosis, a

patients preexisting cognitive status must not be such as to severely limit
his quality of life, significant improvement in tremor notwithstanding).
TA R G E T I N G C O N S I D ER AT I O N S
In my experience, tremor generated at more proximal muscles is more common

in patients with cerebellar outflow tremor than it is in patients with other kinds of
tremor. The motor homunculus within the ventral intermediate nucleus of the thalamus is also larger than the effective volume of tissue affected by the typical DBS
stimulation parameters. This requires that the DBS lead be placed in the appropriate homuncular representation, which often means the more proximal representation than is typical for Essential tremor. It is unlikely that a DBS lead placed in
the leg representation will help to relieve tremor in the upper extremity. A DBS
lead placed in the distal hand representation is similarly less likely to help a patient
whose tremor is more proximal.
P O STO PER AT I V E PR O G R A M M I N G
DBS programming for patients with Multiple Sclerosis is similar to that provided
for patients with Essential tremor (see chapter8 and Montgomery 2010). Asomewhat unique feature in patients with cerebellar outflow tremorcerebellar outflow
tremor owing to Multiple Sclerosis, particularlyis a tolerance that develops with
continuous use. Patients may gain significant improvement in the clinic and then
worsen days or weeks later. Itherefore generally recommend that patients power off
stimulators when they are least neededduring sleep hours, for example. Patients
who rapidly develop tolerance may benefit from a stimulation holiday of a weeks
duration. It is extremely important, however, to advise patients who take such a
holiday that tremor will recur once they resume DBS and that they may experience
adverse effects.
DBS tolerance does not appear to require ever increasing stimulation strength to
overcome it. Sometimes reducing stimulation strength may help patients to regain
control.
M U LT I PL E SC L ER O S I S
DBS is effective in treating patients whose severe tremor owes to Multiple Sclerosis,
particularly in such cases where the goal is control of a single upper extremitys use.
Areview of 12 studies found that all of the 75 participating patients were documented as experiencing improvement in tremor (Montgomery 2008), the quantity
for which was determined to be approximately 60% to 70%. Those using ordinal
noninterval scales, improvement ranged from preoperative scores of 4 (a score indicating inability to perform such a task as bring a cup to the lips) to postoperative
scores ranging from 0 to 2 (the latter a score indicating an amplitude between 1cm
to 3cm).
152
Of the few long-term studies conducted in this area, all have shown continued
tremor control. As discussed previously, continued tremor improvement occurs as
other disabilities related to the Multiple Sclerosis accumulate, and this phenomenon serves to limit the benefit of tremor control in a single upper extremity. One
study found that a large majority of patients DBS was helpful for about two years
(Montgomery 2008). Whether a two-year benefit justifies DBS-associated risks and
expenses becomes the pertinent ethical considerationone that is better addressed
by society than by physicians or insurers, the latter of whom face a highly problematic conflict of interests (see c hapter19).
P O STA N OX I C A N D P O ST T R AU M AT I C T R EM O R
Common forms of disabling tremor, postanoxic and posttraumatic tremor may be

reduced by DBS (Umemura etal. 2004; Foote etal. 2006; Park etal. 2011; Reese
etal. 2011). Unlike Multiple Sclerosis, these conditions are typically not degenerative. DBS in their treatment, therefore, likely leads to sustained improvement.
OT H ER T Y PES O F T R EM O R
Case reports indicate improvement in tremor owing to a variety of unusual causes.

One must recognize that behind these reports may lie negative-report bias:some
patients experience ineffective DBS and therefore go unreported. Among these
unusual causes are the following: (1) Klinefelter syndrome (Koegl-Wallner
et al. 2014); (2) dystonic tremor (Fasano 2014); (3) Fragile X-Associated Tremor
(Mehanna and Itin 2014); (4)posttraumatic tremor (Follett etal. 2014); (5)abetalipoproteinemia (Mammis etal. 2012); (6)Holmes tremor from structural lesions
(Nikkhah etal. 2004; Sanborn etal. 2009; Aydin etal. 2013); (7)fragile X-associated
tremor (Senova et al. 2012); (8) neuropathies (Bayreuther et al. 2009; Breit et al.
2009; Shields etal. 2011); (9)spinocerebellar degeneration (Shimojima etal. 2005;
Freund et al. 2007); (10) mitochondrial encephalopathy (Kovacs et al. 2006);
(11) phenylketonuria-associated tremor (Payne et al. 2005); (12) Behr syndrome
(Schramm etal. 2005); and (13) poststroke tremor (Yamamoto etal. 2004).
SY M P TO M - S PEC I FI C, N OT D I S E AS E- S PEC I FI C
Case reports and small-cases series conjure the impression that DBS in the vicinity
of the ventral intermediate nucleus of the thalamus is effective for a wide variety of
disorders. There could arise the temptation to require full-blown prospective randomized control trials before general acceptance of DBS in the vicinity of the ventral intermediate nucleus of the thalamus for these disorders. Too few prospective
patients for the trials, however, would likely be found in order to muster statistical
power enough for drawing any inferences. The choice becomes, then, whether to
recommend DBS in the vicinity of the ventral intermediate thalamic as standard
and accepted treatment for these patients, provided they meet the criteria listed
earlier, or allow them otherwise to continue suffering their tremor.
An alternative is to consider DBS in the vicinity of the ventral intermediate

thalamus as a symptom-specific treatment rather than disease-specific treatment.
Randomized controlled trials of pain medications are not conducted for every conceivable cause of pain. Rather, it is sufficient to demonstrate that a medication be
shown effective for pain, irrespective of its cause. DBS in the vicinity of the ventral
intermediate thalamus should similarly be considered specific to relief of the symptom of tremor rather than any particular disease.
S U M M A RY
Though thalamic DBS is effective for the relief of tremor in a wide variety of disorders,
it must win acceptance as an off-label use of an FDA-approved device. Complicating
the issue is the possibility that some insurers will specifically exclude off-label use on
the mistaken belief that such use is experimental or investigational. Were it to happen,
this exclusion would prove unfair to many patients. The rarity of some disorders, moreover, prevents conducting randomized control trials to demonstrate disease-specific
efficacy. The FDA has approved DBS for primary dystonia and some other indications
and has based its approval on extensive case reports and case studies rather than traditional randomized control trials. Yet many disorders, which may be helped by DBS,
are so rare as to render infeasible the collection of a sufficient number of cases.
R EFER ENCES
Aydin S, Abuzayed B, Kiziltan G, etal. Unilateral thalamic VIM and GPi stimulation
for the treatment of Holmes tremor caused by midbrain cavernoma:case report and
review of the literature. J Neurol Surg ACent Eur Neurosurg. 2013;74(4):271276.
Bayreuther C, Delmont E, Borg M, etal. Deep brain stimulation of the ventral intermediate thalamic nucleus for severe tremor in anti-MAG neuropathy. Mov Disord.
2009;24(14):21572158.
University Press, 2013.
Breit S, Wachter T, Schols L, etal. Effective thalamic deep brain stimulation for neuropathic tremor in a patient with severe demyelinating neuropathy. J Neurol Neurosurg
Psychiatry 2009;80(2):235236.
Fasano A, Bove F, Lang AE. The treatment of dystonic tremor: a systematic review.
JNeurol Neurosurg Psychiatry 2014;85(7):759769.
Follett MA, Torres-Russotto D, Follett KA. Bilateral deep brain stimulation of the
ventral intermediate nucleus of the thalamus for posttraumatic midbrain tremor.
Neuromodulation 2014;17(3):289291.
Foot P. The Problem of Abortion and the Doctrine of the Double Effect in Virtues and
Vices. Oxford:Basil Blackwell, 1978.
Foote KD, Seignourel P, Fernandez HH, etal. Dual electrode thalamic deep brain stimulation for the treatment of posttraumatic and multiple sclerosis tremor. Neurosurgery
2006;58(4 Suppl 2):ONS-280-285; discussion ONS-285-286.
154
Freund HJ, Barnikol UB, Nolte D, etal. Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor-A unusual clinical benefit. Mov Disord.
2007;22(5):732735.
Koegl-Wallner M, Katschnig-Winter P, Pendl T, etal. Tremor associated with Klinefelter
syndromea case series and review of the literature. Parkinsonism Relat Disord.
2014;20(3):323327.
Kovacs N, Pal E, Balas I, et al. Neurosurgical treatment of tremor in mitochondrial
encephalopathy. Mov Disord. 2006;21(12):22272230.
Mammis A, Pourfar M, Feigin A, et al. Deep brain stimulation for the treatment of
tremor and ataxia associated with abetalipoproteinemia. Tremor Other Hyperkinet
Mov. 2012;1(1):2.
Mehanna R, Itin I. Which approach is better? Bilateral versus unilateral thalamic deep
brain stimulation in patients with fragile X-associated tremor ataxia syndrome.
Cerebellum 2014;13(2):222225.
Montgomery EB Jr. Thalamic deep brain stimulation for other tremors. In Tarsy D,
Vitek JL, Starr PA, Okun MS, eds. Deep Brain Stimulation in Neurological and
Psychiatric Disorders. Totowa, NJ:Humana Press; 2008:215228.
Nikkhah G, Prokop T, Hellwig B, etal. Deep brain stimulation of the nucleus ventralis
intermedius for Holmes (rubral) tremor and associated dystonia caused by upper
brainstem lesions:report of two cases. J Neurosurg. 2004;100(6):10791083.
Park YS, Kim J, Chang WS, et al. Management of a DBS system in patients with
traumatic brain injury:case report. Neuromodulation 2011;14(3):214218; discussion 218.
Payne MS, Brown BL, Rao J, et al. Treatment of phenylketonuria-associated tremor
with deep brain stimulation:case report. Neurosurgery 2005;56(4):E868; discussion
E868.
Reese R, Herzog J, Falk D, etal. Successful deep brain stimulation in a case of posttraumatic tremor and hemiparkinsonism. Mov Disord. 2011;26(10):19541955.
Samkoff LM, Goodman AD. Symptomatic management in multiple sclerosis. Neurol
Clin. 2011;29(2):449463.
Sanborn MR, Danish SF, Ranalli NJ, etal. Thalamic deep brain stimulation for midbrain tremor secondary to cystic degeneration of the brainstem. Stereotact Funct
Neurosurg. 2009;87(2):128133.
Schramm P, Scheihing M, Rasche D, etal. Behr syndrome variant with tremor treated
by VIM stimulation. Acta Neurochir (Wien); 2005;147(6):679683; discussion 683.
Senova S, Jarraya B, Iwamuro H, etal. Unilateral thalamic stimulation safely improved
fragile X-associated tremor ataxia:a case report. Mov Disord. 2012;27(6):797799.
Shields DC, Flaherty AW, Eskandar EN, et al. Ventral intermediate thalamic stimulation for monoclonal gammopathy-associated tremor: case report. Neurosurgery
2011;68(5):E14641467.
Shimojima Y, Hashimoto T, Kaneko K, et al. Thalamic stimulation for disabling
tremor in a patient with spinocerebellar degeneration. Stereotact Funct Neurosurg.
2005;83(4):131134.
Thomson JJ. The trolley problem. Yale Law Journal;1985;94:13951415.
Troche MS, Brandimore AE, Foote KD, et al. Swallowing and deep brain stimulation in Parkinsons disease: a systematic review. Parkinsonism Relat Disord.
2013;19(9):783788.
Umemura A, Samadani U, Jaggi JL, etal. Thalamic deep brain stimulation for posttraumatic action tremor. Clin Neurol Neurosurg. 2004;106(4):280283.
JAMA 2009;301(1):6373.
Yamamoto T, Katayama Y, Kano T, etal. Deep brain stimulation for the treatment of
parkinsonian, essential, and poststroke tremor:a suitable stimulation method and
changes in effective stimulation intensity. J Neurosurg. 2004;101(2):201209.
15
Deep Brain Stimulation for

Hyperkinetic Disorders
Deep Brain Stimulation (DBS), discussed here specifically in the vicinity of the
sensorimotor region of the globus pallidus interna, is remarkably effective and
safe for variety of hyperkinetic disorders, even in cases in which all other alternatives have failed. Included among the latter are the following five indications: (1)
tardive dyskinesia (Martinez et al. 2013, n = 8; Mentzel et al. 2012, n = 50); (2)
Huntingtons disease (Hebb et al. 2006, n = 1; Velez-Lago et al. 2013, n = 2; Kang
et al. 2011, n = 2; Fasano et al. 2008, n = 1; Moro et al. 2004, n = 1); (3) hemiballismus (Vitek et al. 1999, n = 1); (4) pantothenate kinease deficiency (Ge et al.
2011, n = 1; Umemura et al. 2004, n = 1; Hurtado et al. 2009, n = 1); (5) choreaacanthocytosis (Miquel et al. 2013, n = 12; Lim et al. 2013, n = 1; Shin et al. 2012,
n = 1, although one case report suggested no improvement in one patient; Wihl
et al. 2001, n = 1). These disorders have the potential to devastate a patients quality of life, thereby placing a large burden on families and societies. Many face
no alternative besides DBS. The question for a clinician is whether sufficient evidence exists to justify offering DBS to a patient. The question is an epistemic one,
although the epistemic presuppositions are presumed rather than explicitly recognized. There is the ontological question, which is: what is the evidence or data?
However, there is the question, and perhaps the most important question: what is
the nature of the evidence? This extends to the question that must be asked first:
what is the nature of acceptable evidence?
The nature of acceptable evidence, at least in academia, appears to be dictated by
Evidence-Based Medicine, which increasingly has become synonymous with randomized control trials (RCTs) even though the original version of Evidence-Based
Medicine recognized other legitimate forms of evidence, including case series, case
reports, and expert opinion. Interestingly, the US Food and Drug Administration
(FDA) recognizes the privilege of physicians to use their professional judgment that
does not exclusively rely on RCTs in the form of off-label uses of FDA-approved
drugs and devices. Interestingly, a PubMed review of physician acceptance and
Evidence-Based Medicine readily demonstrates that significant numbers of physicians do not follow Evidence-Based Medicinederived guidelines (Grol 2001), yet
the issues discussed most frequently are how to enforce compliance rather than
asking whether such guidelines are valid or appropriate or the degree to which they
are valid and appropriate (Montgomery and Turkstra 2003).
15. Deep Brain Stimulation for Hyperkinetic Disorders157
The truly Evidence-Based MedicineRCT committed would have to act as

though there is no evidence in support of the use of DBS for the conditions
described previously. The problem is that it is unlikely there ever would be such
evidence, and the Evidence-Based Medicine RCT committed would have to
let patient with those conditions continue to suffer. The small number of cases
described for each aforementioned condition could be taken as prima fascie
evidence of insufficient evidence, an issue discussed later. However, it also can
be taken as evidence of the rarity of DBS candidates among patients with the
conditions listed here and thus as evidence for the impossibility of satisfying
Evidence-Based Medicine demand for RCTs. Even more critical is the mathematical fact that there likely would never be sufficient Evidence-Based Medicine
that is synonymous with RCTs that are exclusively and directly relevant to the
individual patient (Montgomery and Turkstra 2003).
It is not difficult to understand the reticence of many physicians, particularly those in private practice, given the limitations of Evidence-Based Medicine
described here. Perhaps it is because they recognize, at least implicitly, that RCTs
can only demonstrate findings that are statistically significant, which in themselves
do not translate into clinical meaningfulness (Montgomery and Turkstra 2003).
The interesting question is why would academic physicians, who presumably have
the same ethical obligation of beneficence to their individual patients, so readily promulgate Evidence-Based Medicine RCTderived guidelines? Is the ethical
obligation to beneficence somehow different for a private practice compared to an
academic physician? Perhaps it is scientism, which has pervaded academic medical
institutions since the mid-1800s, that has led to an overestimation of the power of
RCTs. Nevertheless, this disparity can only mean that some group of patients may
not be receiving the most reasonable and rational care.
For DBS the question regarding the nature of acceptable evidence turns on the
surgical nature of DBS and, consequently, is heir to prejudicial presuppositions. In
the past, physicians and healthcare professionals would perhaps reflexively adhere
to the directive, First, do no harm (Primum non nocere). Because doing so suggested possible bias against DBS, it quickly presented an ethical issue. Indeed, the
most fundamental aspects of the issue of DBS for hyperkinetic disorders are neither scientific nor technical. The data is as it appears. No amount of wishing it
to be something more obviates decisions confronted by patients and their surrogates, physicians, and healthcare professionals. The issues are not technical. The
methods employed by DBS for hyperkinetic disorders are exactly the same as those
employed for other such accepted DBS therapies such as Parkinsons disease and
primary dystonia.
The directive First, do no harm rests on an outmoded ethical notion that
sins of commission are worse than sins of omission. This notion results in
Omission bias (Powell et al. 2012; Mamede and Schmidt 2014), which in turn
leads to significant harm. Child vaccination is an example. Refusing to vaccinate
a child places her at significant risk of harm to herself, as well as the children
around her. Astudy of biases in moral judgments in children and adults found
that participants at all ages judged that it was worse to produce harm when
harm occurred (a)through action rather than inaction (omission bias), (b)when
physical contact with the victim was involved (physical contact principle), and
(c)when the harm was produced as a direct means to an end rather than as an
158
unintended but foreseeable side effect of the action (intention principle) (Powell
etal. 2012, p.186). These factors are highly relevant to physicians and healthcare
professionals who must decide whether to offer DBS to patients with hyperkinetic disorders. Understanding (and perhaps overestimating) risks, physicians
and healthcare professionals who make referrals engage in a direct act. Indeed,
DBS surgery would be impossible without the direct action of referring physicians and healthcare professionals. The effect of referral is moreover tantamount to a physical act. Finally, the risk of harm is little different from actual
harm done a patientundergoing evaluations and surgery except in degree, for
example. The latter types of unavoidable harm are clearly intentional; performing DBS surgery would be impossible without them.
A number of psychological and emotional factors that underlie Omission bias
underlie biases toward procrastination, cognitive inertia, and maintaining the
status quo as well. Any of these possibly results in denying patients benefit of
DBS (Anderson 2003). Though these factors are certainly present in patients and
their surrogates, the ethical principle of autonomy demands that they receive
deference. What remains unclear, however, is whether it is appropriate or ethical for these psychological and emotional factors to play a role in the action (or
inaction) of physicians and healthcare professionals. Indeed, is physicians and
healthcare professionals deferral to their own psychology or emotions ethical?
The paucity of DBS referrals for hyperkinetic disorders and most other accepted
indications suggests that psychologically or emotionally motivated reticence is
common.
The complex and extensive ethical issues surrounding DBS are addressed more
fully in c hapter19. At any rate, physicians and healthcare professionals who have
established relationships with patients are obliged to treat them according to
standards of care. Yet the standards of care are evolving. Early standards of care
amounted to standards observed among peer physicians. Courts recognized that
risk criteria based on early standards of care may serve more physicians and healthcare professionals interests than those of patients. They thus evolved to standards
that a reasonable peer-physician might observe (Peters 2000). The notion of reasonable is clearly problematic, but the vast expansion of clinical guidelines, recommendations of professional organizations, and increased sophistication on the
part of legal professionals and juries appear to have strengthened the requirement
for reasonableness. The task becomes, then, determining reasonableness of DBS for
hyperkinetic disorders.
Physicians and healthcare professionals need not be experts in DBS. They
need not actually decide whether patients with hyperkinetic disorders should
undergo DBS. Lack of expertise, however, does not absolve physicians and
healthcare professionals of their obligation to patients with respect to DBS.
There are [...] no concessions for a lack of relevant experience, according to
Bryden and Storey (2011), and a doctor in the first day of a new post is expected
to work to the same standard of public safety as one who is on the last day of the
post. The difference in performance of the two relates to the degree by which
the new doctor may be expected to consult and seek assistance to compensate
for their relative lack of knowledge or skill. Indeed, the Code of Ethics published in 1847 by the American Medical Association called on physicians to
seek consultations.
EPI ST EM I C STAT U S O F D EEP B R A I N ST I M U L AT I O N FO R

H Y PER K I N E T I C D I SO R D ER S
Epistemology refers to analyses and understanding of the nature of knowledge; it

concerns not the contents of knowledge but the method and nature of their acquisition. Virtually every medical decision involves uncertainty, which owe to biological variability and idiosyncratic vulnerabilities if nothing else. Uncertainty cannot
be eliminated; it may only be converted from one form to another. Indeed, RCTs
absorb uncertainty owing to individual variation by translating individual variations to population description or information. Yet information concerning the
individual is lost. It cannot be recovered from the population information. What
is gained by reducing uncertainty, usually by restraining the information content
by the central tendency (statistic means and medians) and the variance (standard
deviations or quartiles, parametric or nonparametric data, respectively), comes at
the cost of being able to retroactively apply population data to an individual patient
(Montgomery 2011).
One may discuss uncertainty according to two directly related elements:amount
of information and quality of information. In a real sense, information exists in a
physical state, as suggested by the parallels between Claude E.Shannons Information
theory and the Second Law of Thermodynamics (Mahesh Karnani et al. 2009).
Entropyrandomness in a physical systemaffects information as well. In such
cases it is known as InformationTheoretic entropy. Any increase in entropy is a
loss of information. Physically isolated systems tend to maximum entropy (maximum information loss). The Second Law of Thermodynamics is reversible: The
original state of a physical system, which has undergone some change, may be
restored. Its restoration requires the addition of energy. In most natural systems,
however, the energy dissipates, leaving the physical system unable to return to its
original state. Information contained in the original state is lost. Similar dynamics
applied to logical systems demonstrate an irrevocable loss of information if systems
undergo logically irreversible operations (Landauer 2000). By logically irreversible
operations is meant operations whose output does not uniquely define its inputs.
The process of calculating the mean is an example of a logically irreversible operation. Offering a useful example is the situation in which the inputs are the values,
10, 20, 15, 5, 25, and 15. The mean of these values is 15. When presented with the
mean alone, one cannot recreate the initial values, because a large number of different sets of values also has a mean of 15, such as 1, 14, 2, 13, 3, and 12. When
presented with the mean alone, as is common in the reports of large RCTs, it is
impossible to know the values of the individual subjects, which in turn renders it
impossible to know the generalizability of population statistical inferences to an
individual patient. Admittedly, some measure of the variance may help. Yet this
help remains incomplete, particularly with respect to unusual data distributions.
Calculating a mean results in a loss of information.
Counterbalancing potential confounds in RCTs by matching for confounds or by
randomization implies a loss of information. Evaluating the effects of a medication
for stroke, for example, will be confounded by the presence or absence of such factors as hypertension and diabetes. In order to manage confounds, subjects are randomized in the hope that the experimentally and placebo treated groups show the
same prevalence of confounds, which suggests that the effects are counterbalanced
160
and presumably negated. This practice may only manage confounds. It cannot
eliminate them. Calculating the population statistical descriptors is a logically irreversible operation, because the output does not uniquely identify such inputs as
exactly which subjects have hypertension or diabetes. Stratifying the results negates
the value of the computations for the population descriptors and reduces the statistical power, the analyses on subpopulations with increased uncertainly resting on
type I and type II statistical errors.
RCTs, which have become synonymous with Evidence-Based Medicine, necessarily lose information, if for no other reason than they are subject to the Second
Law of Thermodynamics. The information lost is precisely that which is necessary
to apply the RCTs results to treatment of individual patients. One may argue that it
is unnecessary to reverse precisely the logical operations and that the approximations enabled by descriptors of the central tendency (the mean, for example) and the
variance (standard deviation, for example) are sufficient descriptors of the inputs to
the logical operations. This would not be true, however, in the situation of counterbalancing confounds, because information is irrevocably lost therein.
Such information as knowledge and values external to the RCT must invariably
be brought into the RCT in order to obtain meaningful results (Montgomery and
Turkstra 2003). The foregoing discussion should not be construed as denigrating
the importance of RCTs and Evidence-Based Medicine. RCTs and Evidence-Based
Medicine are tools. Like any tool, they must be used in accordance with their design
limitations. Indeed, one notes with some bemusement case series reports on rare
conditions that conclude clinical trials are warranted. Such recommendations raise
two serious concerns. First, any clinical trial will use some measurement of statistical effect size that will be affected by patient variability and that necessitates
a certain sample size. It is highly likely that there will be an insufficient number
of subjects to power a clinical trial for rare conditions. It is not the rarity of the
condition per setype-2 pantothenate kinase deficiency, for example. It is, rather,
the extremely small subset of those patients that would be considered candidates
for DBS. The second concern is that to call for clinical trials is to presuppose some
defect in the case series, which diminishes the importance of their use in clinical
decisions. If this is the case, then there always will be a prejudice against offering
patients with rare conditions the possibility of improved quality of life.
A possible solution to the question of clinical trials for rare causes of hyperkinetic disorders is to consider DBS a symptomatic treatment. The plethora of
hyperkinetic disorders that respond to DBS suggests the DBS is a symptom-specific rather than a disease-specific treatment. If it is the former, then there occurs
a change in conceptions about the scientific support of efficacy: The effectiveness
and safety for one hyperkinetic syndrome is supportive evidence for the use of
DBS in treating another hyperkinetic syndrome. In the references cited earlier,
approximately 92 patients with hyperkinetic disorders have demonstrated the
effectiveness and safety of DBS. If one adds to this the multitude of patients with
Parkinsons disease whose levodopa-induced dyskinesia improved with DBS, then
the number of cases supporting the symptomatic use of DBS becomes overwhelming. After all, one does not have to conduct a RCT of a pain medication for every
conceivable cause of pain.
The forgoing discussion does not suggest that it is feasible or even desirable that clinicians in some sense be physicists, mathematicians, or statisticians.
Unfortunately, the same may not be said about those who provide advice, particularly when such advice is reduced to simple bullet points or cookbook recipes.
Because it is never so simple, clinicians must at least treat with skepticism advice
that appears simple. The decision to refer patients with hyperkinetic disorders is
certainly not simple. Where are these clinicians to look to for guidance? The FDA
is not the place to look, at least inasmuch as off-label indications are concerned. The
use of DBS for these indications, which would be off-label, lack FDA approval. The
issue of off-label use thus creates considerable confusion on the part of patients,
patients family members and caregivers, physicians, healthcare professionals,
and insurers. Because the stakes are high for all parties involved, it is important to
review the issues of off-label use.
O F F- L A B EL U S ES O F U S FO O D A N D D R U G
A D M I N I ST R AT I O N A PPR OV ED D E V I C ES
It seems counterintuitive to suggest that the FDA is not a good source for information regarding off-label use of FDA-approved drugs and devices. Off-label means
that the FDA has not rendered an opinion on the intended use. In other words, on
those indications under consideration for off-label use, the FDA is effectively silent.
To some physicians, healthcare professionals, and insurers, the silence speaks volumes. For these parties the lack of position by the FDA is considered negative. Yet
as Carl Sagan observed, the absence of evidence is not evidence of absence.
As levodopa-induced dyskinesia and dystonia is typically not subsumed in the category of a hyperkinetic disorder such as chorea occupies, there is no hyperkinetic
disorder for which the FDA has approved DBS. Awealth of peer-reviewed publications demonstrating the efficacy and safety of DBS for hyperkinetic disorders,
however, comports to FDA regulations related to off-label use of FDA-approved
drugs and devices. Good medical practice and the best interests of the patient
require that physicians use legally available drugs, biologics and devices according
to their best knowledge and judgment, reads the FDAs policy, which appears on
its website:
If physicians use a product for an indication not in the approved labeling, they
have the responsibility to be well informed about the product, to base its use
on firm scientific rationale and on sound medical evidence, and to maintain
records of the products use and effects. Use of a marketed product in this
manner when the intent is the practice of medicine does not require the submission of an Investigational New Drug Application (IND), Investigational
Device Exemption (IDE) or review by an Institutional Review Board (IRB).
However, the institution at which the product will be used may, under its own
authority, require IRB review or other institutional oversight. (FDA 2014)
Most physicians encounter little difficulty in using FDA-approved drugs and
devices in an off-label way. This is particularly true in pediatrics and oncology.
Indeed, there are many situations in which such use is standard practice, and forgoing it constitutes malfeasance (Noah 1994; Radley etal. 2006). Indeed, the original
approval for DBS in the vicinity of the ventral intermediate nucleus of the thalamus
162
was restricted to unilateral DBS in patients with Parkinsons disease and Essential
tremor. The use of bilateral DBS in the vicinity of the ventral intermediate nucleus
of the thalamus is therefore off-label although most physicians do not make a qualitative distinction between unilateral and bilateral DBS in the vicinity of the ventral
intermediate thalamus. Some states have mandated that insurers cover off-label
use, provided that there are at least two scientific studies attesting to the safety and
efficacy of the intended use have been published.
Such physician prerogatives to use FDA-approved drugs and devices consistent
with FDA policy may not be extended by insurance companies that equate experimental or investigational with any FDA-approved drug or device approved for
indications other than the indication approved by the FDA. Legal scholars have
argued that the definitions of experimental and investigational are statutory
and found in the Code of Federal Regulations (section 312.3[b]for experimental
and section 50.3[c] for investigational). The definition of these terms rests entirely
on research rather than medical practice. For insurers to label as experimental
or investigational the intended use because an otherwise approved device lacks
approval for that use requires novel definitions that may be indefensible.
Whether the terms of experimental and investigational necessarily apply to
the off-label use of FDA-approved drugs or devices may be seen in various court
cases in which plaintiffs have argued that failure of a physician to inform the patient
that the intended use represented an off-label use amounts to a failure to obtain
informed consent. Courts have ruled that physicians need not inform patients
regarding the off-label use of an FDA-approved drug or device and that off-label
connotes no medical information, which would not be the case if the off-label use
truly was experimental or investigational. For example, in Klein v.Biscup. (109
Ohio App.3d 855 [Ohio Ct. App.,1996]), the court held that [t]he decision whether
or not to use a drug for an off-label purpose is a matter of medical judgment, not of
regulatory approval. By analogy, the off-label use of a medical device is also a matter of medical judgment, and as such, subjects a physician to professional liability
for exercising professional medical judgment. Off-label use of a medical device is
not a material risk inherently involved in a proposed therapy which a physician
should have disclosed to a patient prior to the therapy (cited in Riley and Basilius
2007). Admittedly, physicians may be held accountable for their off-label use should
it fail to conform to the standards of care. Riley and Basilius go on to suggest that
whenever a physician prescribes a drug [device] for off-label use, it should be based
on:(1)the doctors own expert medical judgment; (2)peer-reviewed articles reflecting sound scientific evidence; (3)documented medical practice; (4)if possible, the
opinions of the physicians local colleagues; and (5)a desire to directly benefit the
patient for whom it is prescribed (p.37).
It would seem that off-label uses of FDA-approved drugs and devices (when
used in conformity with FDA policy) have the same status as do uses specifically
approved by the FDA, at least from the physicians and healthcare professionals
perspective. The question thus becomes: what is a physicians or healthcare professionals responsibility in terms of advising patients about the potential use of
off-label drugs and devices? The answer is complicated, and readers must bear
in mind that Iam not an attorney and that my remarks are not legal opinions or
advice. One possible standard is that which similarly situated reasonable physicians
and healthcare professionals would do. If the standard of practice is to inform the
patient, then a physicians failure to inform a patient may be considered in breach

of the standard of practice. Alternatively, when a physician and healthcare professional obtain informed consent, generally they are obliged to inform a patient of all
reasonable alternatives, which could well include off-label treatments. The definition of reasonable alternatives has been described as those that would be of concern
to, or would have affected the decision of, a reasonable patient rather than a physician or healthcare provider.
The FDA policy cited previously refers to a potential role of the Institutional
Review Board (IRB) that may prove problematic. IRBs mandate is to regulate
human research. According to the FDAs own policies, off-label use excludes
research. The question thus arises as to the appropriateness of IRBs to regulate the
off-label uses. Indeed, the Belmont Report, which set the field of biomedical ethics
and was responsible for the genesis of IRBs, specifically differentiated innovative
therapies from research, advocated IRB jurisdiction only over research, and did not
require IRB approval for innovative therapies. Distinctions were made between the
goals of a provider of innovative therapies and those of research. The formers goals
are unique and specific to a patient; a patient is therefore the end to which effort
is directed. The latter seeks to increase generalizable knowledge. In that regard, a
patient becomes a means to an end rather than an end in herself. This presumes,
however, that there is no other conflict of interest, pecuniary or otherwise (Taylor
2010). Some institutions establish committees separate from the IRB to rule on
appropriate use of innovative treatments.
Selection criteria of DBS candidates resemble the selection criteria for other conditions. Among the latter are included the following:(1)a diagnosis of a condition
that is likely to benefit and improve the patients quality of life, (2)exhaustion of
all reasonable alternative treatments, (3)a patients ability to tolerate the DBS procedures, and (4)assurance of appropriate follow-up management, including DBS
programming.
Diagnosis
The criterion of a condition that may benefit appears to clash with the aforementioned notion of DBS as a symptomatic treatment. As applied in the case of hyperkinetic disorders, however, the criterion is to address causes of hyperkinesia that
require other than symptomatic treatments. Among those are disorders related
to medication use or underlying metabolic abnormalitieschorea gravidarum
related to the use of oral contraceptives or other hormones, for example. Among
other causes are the following: (1) vitamin B12 deficiency (Souza and Moloi 2014);
(2) anti-NMDA receptor encephalitis (Sharma et al. 2014); (3) pseudoathetosis
secondary to sensory loss; (4) such medications as dopamine agonists, sympathomimetic, amphetamines, and cocaine (crack dancing) and such anticonvulsants
as phenytoin (Nausieda et al. 1979), tricyclic antidepressants (Fann et al. 1976),
and calcium channel blockers; (5) such autoimmune disorders as systemic lupus
164
erythematosus, Sydenhams, and lupus anticoagulant syndrome; (6) polycythemia

vera; (7) psychogenic disorders; and (8) beta-ketothiolase deficiency (Buhas et al.
2013).
Tardive dyskinesia may spontaneous remit and therefore represents a special
case. The data on this issue is mixed, however, with some studies demonstrating
no remission. In one study, 33 of 53 patients followed over a long term experienced
complete resolution of the tardive dyskinesia. The time to remission, however,
was not described (Fernandez and Friedman 2003). Some 25% to 50% of patients
improved within one year. According to one case review of patients who experienced late spontaneous remissions, three patients improved after two and a half
years, two patients improved after three years, and two patients improved after
four and a half years (Klawans etal. 1984). (This situation is analogous to that of
Tourettes syndrome; see chapter13).
The task becomes that of determining the amount of time a patient must wait
before the prospect of spontaneous remission appears unlikely. Such a determination may be modeled as a negative binomial (or Pascal) distribution in statistics.
Unfortunately, insufficient data exists to enable such modeling. There is no point
in time at which probability of spontaneous remission may be said to be zero. One
must determine, rather, the point at which probability of spontaneous remission is
low enough to urge consideration of DBS on a patient. This requires one to determine a patients willingness to face surgical risk. Patients alone must determine
their level of willingness.
Exhaustion of All Reasonable Alternatives

The criterion of a condition exhaustion of all reasonable and less risky alternative
therapies are specific to symptomatic relief of hyperkinesia. Treatments specific to
the underlying diagnosis were addressed previously. Alternative treatments include
medications and intramuscular injections of botulinum toxin. Medications typically act to deplete dopamine or block its action at the dopamine receptor (dopamine antagonists).
There are several issues related to the question of exhaustion of all reasonable
alternatives. The first issue relates to the adequacy in the trial of an individual treatment. The second issue concerns whether a sufficient range of treatments have been
attempted. With respect to the first question, that which is needed is a dose-response
curve that displays the number of patients at each dose who achieved sufficient control and also the dose at which each patient experienced a limiting adverse effect.
The task thus becomes that of determining the dose at which a dose-response curve
becomes asymptomatic, because this suggests that any further increases would be
futile or would introduce a high risk of limiting adverse effects.
Efficacy and safety present somewhat different issues in deciding whether a
patient has exhausted all reasonable alternatives. The issue is not comparative effectiveness in samples of patients treated with different agents. One is not tasked with
determining, for example, whether traditional neuroleptics are any more effective
than atypical neuroleptics. Rather, the task becomes that of determining whether
a patient who has failed on one specific agent will find another agent efficacious.
Similarly, one must determine the probability that a patient unable to tolerate a
traditional neuroleptic will be able to tolerate an atypical neuroleptic. Such determinations require a controlled cross-over study conducted on single subjects rather
than populational studies over many.
Absent any of the suitably designed studies described here, one must consider population-based studies while acknowledging such studies limitations.
Acknowledgment of these limitations need not occasion therapeutic nihilism.
Indeed, physicians and healthcare professionals are accustomed to making decisions involving imperfect and categorically different data. Given the large number
of potential agents, one cannot simply attempt every combination, because doing
so would result in a number of combinations impossible in a single lifetime. Some
reasonable strategy is therefore required.
The dopamine antagonists typically are organized into traditional and atypical neuroleptics. In terms of efficacy, the only completed study that may bear on
the question was a meta-analysis of risperidone versus traditional neuroleptics in
Tourettes syndrome, which can be considered a type of hyperkinetic disorders
(Cheng et al. 2012). In that study, the atypical neuroleptic risperidone appeared
to match the efficacy of traditional agents and was better tolerated. It is unknown,
however, whether a patient who failed one agent would respond to the other. Iwas
unable to find data published in the literature to establish a dose-response curve
in order to demonstrate the maximal dose beyond which treatment would be
ineffective.
Tetrabenazine is a dopamine-depleting agent that has been approved by the FDA
for the treatment of the chorea associated with Huntingtons disease (Poon et al.
2010). Evidence-based guidelines recommend tetrabenazine for the treatment of
Tardive dyskinesia, but this would be considered an off-label use. Tetrabenazine has
been effective in treating hemiballismus (Grandas 2011). Also, case reports demonstrated that tetrabenazine improved post-pump chorea in a 77-year-old (Saft et
al. 2011) and hyperglycemic-induced hemi-chorea (Sitburana and Ondo 2006). The
multitude of etiologies responsive to tetrabenazine argue for the conclusion that
tetrabenazine should be considered a symptomatic treatment for hyperkinetic disorders irrespective of etiology.
As to adequate dosing, some insight may be gained in the RCT for the treatment
of Huntingtons disease (Huntington Study 2006). Tetrabenazine was titrated up to
a maximal dose of 100 mg per day. Forty-five percent of subjects reached this dose.
Unfortunately, it is not clear from the study whether those who did not reach the
maximum dose did so because limiting adverse effects prevented them or because
the subject had obtained a satisfactory control. The sole conclusion therefore is that
some patients may require and tolerate more than 100 mg per day.
In another study of patients with Huntingtons disease who took stable doses
of tetrabenazine, the mean and standard deviation of the dose in the group with
the highest mean was 62.5 mg with a standard deviation of 38.1 mg (Frank etal.
2008). The enabling assumption being that the standard deviation was representative of the true variance, 68% of subjects took total daily doses of tetrabenazine that
ranged from 24.4 mg to 100.6 mg in total daily dose. If the typical maximal daily
dose assumed by the physicians is 100 mg per day, this means that a significant
percentage reached the maximum. Thus it cannot be known whether higher doses
would be effective for other subjects (the subjects of this study were all stable and
adequate responders). For patients whose genotype of CYP2D6 suggests extensive
166
metabolizers of tetrabenazine, the FDA recommends a maximum of 100 mg per

day (Mehanna etal. 2013). Genotyping should be considered when evaluating the
adequacy of dosing in the event that the patient is a poor or extensive metabolizer
of tetrabenazine.
In a third study in which doses were permitted to range to 200 mg, the mean
dose was 74.2 mg per day with a standard deviation of 40.9 mg (Frank et al.
2008). The distribution of doses reached was fairly normal. This suggests that
the mean and standard deviations are representative of the sample. This being
the case, more than 95% of patients were treated with 150 mg or less (based on
dose increments of 12.5 mg per day). Achieving 95% confidence that a patient
being considered for DBS for hyperkinetic disorders (which assumes the data for
Huntingtons disease is relevant to other causes of hyperkinetic disorders) would
not respond to a higher dose of tetrabenazine requires that the dose be at least
150 mg per day. This dose exceeds the maximum recommended by the FDA.
Intramuscular injections of botulinum toxin may be effective in the treatment
of hyperkinetic disorders, particularly if the muscles associated with movements
most affecting the quality of life are fairly restricted. In those patients for whom
otherwise reasonable intramuscular injections of botulinum toxin have failed, it
is important to substantiate the reason for failure. Specifically, it is important to
ensure that no technical issues related to injections caused the failure. In refractory patients, for example, one must learn whether electromyographic guidance
was used and whether the injections were given by an experienced physician. There
is also the possible effect of neutralizing antibodies. Subcutaneous injections into
the frontalis muscle (forehead test) may be an assay for botulinum toxin sensitivity
(Hanna and Jankovic 1998). If the forehead test suggests resistance to one serotype
of botulinum toxin, one must learn whether an alternative serotype was attempted.
As in the dose-response issue for medications, the question arises as to how many
trials of intramuscular botulinum toxin injections should be attempted before it is
considered futile. In one retrospective study, 4 of 24 participating patients were
found to be primary nonresponders (17%; Berman etal. 2005). An adequate trial
of intramuscular injections must be conducted. In a dose-response study based on
improvement with consecutive doses in the severity of dystonia, the curve became
asymptotic at six injections, a result that suggests that this number represents the
minimum number of injections necessary to determine the degree of relief a patient
might expect.
As noted, there is a paucity of data that informs the questions most relevant
to establishing the candidacy for DBS according to exhaustion of all reasonable
alternativesmedication and intramuscular injections of botulinum specifically. Physicians and healthcare professionals must therefore use their judgment.
Refusing to address the issue is no answer, because it obviates a patients opportunity to benefit from DBS.
Ability to Tolerate Deep Brain Stimulation Surgery

Patients must be cleared for DBS surgery just as they would be for any other major
surgery. It is extremely important that one utilize intraoperative neurophysiological monitoring, particularly microelectrode recordings, in order to accurately and
precisely identify the optimal target. In the globus pallidus interna, the somatotopic
or homuncular representation is larger than the volume of tissue activation possible with most DBS leads (Montgomery 2014). Thus it is important to identify the
homuncular representation associated with the part of the body whose involuntary
movements are the greatest contributor to a patients diminished quality of life. For
example, if head movements are the most clinically limiting, the head representation must be targeted. If the DBS lead is placed in the lower limb representation,
the patient may not receive the expected benefit. Dexmedetomidine enables one to
anesthetize patients unable to remain awake during the intraoperative neurophysiological monitoring while continuing to use microelectrode recording.
Arrangements for Postoperative Deep Brain

StimulationManagement
Arrangements for postoperative DBS management must be assured before the
patient undergoes DBS surgery. My experience has shown that such assurances
have not always been in place. Often postoperative DBS programming is left to an
industry representative. This is inappropriate. Though most industry representatives are well versed in the technology of the devices, they are not trained to perform appropriate neurological evaluations or adjust medications. The latter is very
important, particularly if the medications produce adverse effects.
S U M M A RY
DBS is effective for a wide range of hyperkinetic disorders. The rarity of many of
these disorders makes RCTs and hence level-1 Evidence-Based Medicine criteria
unattainable. Most information is derived from case series. The fact that such a
wide variety of disorders are responsive to DBS suggests that DBS of the globus pallidus interna must be considered a symptom-specific rather than a disease-specific
treatment. When case experiences are summed over the range of etiologies, the evidence is strong for efficacy and safety. The lack of FDA position on these indications
is not evidence against efficacy and safety. These indications are neither experimental nor investigational. It may befall physicians and healthcare professionals
to advocate on their patients behalf for access to these therapies.
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16

Is Safe and Effective for
Obsessive-CompulsiveDisorder
Though Iam not a psychiatrist, Ihave participated in early clinical trials of Deep
Brain Stimulation (DBS) in treatment of Obsessive-Compulsive Disorder (OCD).
My involvement owed to a belief, then prevailing and since substantiated, that
many similarities obtain between the assessment and management of patients
with such psychiatric disorders as OCD and those with such movement disorders
as Parkinsons disease. Patients with Parkinsons disease experience depression,
obsessive and compulsive symptoms, and other significant psychiatric comorbidities. Similarly, patients with Parkinsons disease, as movement disorders neurologists may attest, experience DBS-induced hypomania, compulsive behaviors, and
changes in mood.
As a movement disorders neurologist, I hope this chapter represents a unique
contribution to discussions of the treatment of OCD and other psychiatric disorders. Admittedly, certain social and political realities, which pose real challenges to
the practice of psychiatry, may have escaped my awareness. Yet Ideem this partial
ignorance a possible advantage, because it may help me to avoid the temptation of
regarding psychiatric disorders as cases distinct from other medical disorders in
terms of DBS treatment. Ido not suggest that psychiatrists believe OCD and other
psychiatric disorders to be something other than medical disorders. Isimply wish
to acknowledge that psychiatrists must contend as much with matters of perception
as they do with medical fact. Indeed, Iseek to establish the idea that any distinction
between psychiatric and neurologic disorders, which becomes readily evident in
the approach to such a therapy as DBS, is more perceived than real and rests more
on physicians and healthcare professionals presuppositions than it does on actual
psychiatric diseases.
DBS for OCD has been approved by the US Food and Drug Administration
(FDA) under a Humanitarian Device Exemption (HDE). This approval marks
DBSs first psychiatric indication although the first description of DBS (in its current form) as a treatment for DBS appeared in 1979. As a treatment for OCD, DBS
is not without precedent. It follows a tradition established by ablative surgery. It
departs from this tradition, however, in terms of the considerations that attend it.
172
Patient selection and informed consent typically endure greater scrutiny in cases of
psychiatric disorder than they do in cases of movement disorders. DBS for psychiatric disorders thus raises questions as to how psychiatric disorders stand distinct
from other disorders.
The answer perhaps lies in an examination that blends epistemology and the
history of science. If one regards the question from the perspective of genesis
and validity, one discovers a source in seventeenth-century French philosopher
Rene Descartess metaphysical dualism, which divided mind from body. Prior to
Descartes, the notions of the ancient Roman physician Galen prevailed. Drawing
on Aristotles mechanistic hypotheses, Galen viewed all human physiological
and psychological activity as governed by four bodily humorsblood, phlegm,
black bile, and yellow bile (Arikha 2007). An absence of disorders signaled a
balance among the humors. The presence of a disorder signaled an imbalance.
The rise of Cartesian dualism had positive and negative effects:The identification of the mind as an entity distinct from the brain encouraged the advent of
neurophysiology, because scientists no longer found it necessary to couch their
explanations of human behavior in metaphysical, particularly religious, speculation. Rather, they became able to anchor their inquiries in the physical realm.
In fact, Sir Charles Sherrington, the reputed father of neurophysiology and a
religious man, explicitly credits Descartes for enabling him to pursue neurophysiology free of any metaphysical or theological constraints. As it turned out,
Sherringtons theory, which posited all animal behavior as an effect of simple
physical reflex arcs conducted through the spinal cord, left the soul free of any
mechanistic taint.
The rise of Cartesian dualism also had a negative effect:Because the human
mind came to be regarded as consisting of substance distinct from the substance
constitutive of the human body (the substance of thought Descartes designated
res cogitans and the substance of matter, res extensa), treatment of disorders
affecting the mind demanded a wholly different approach. The development
of Freudian psychology and psychoanalysis presented the pathophysiological
mechanisms of psychiatric disease in terms of id, ego, and superego and the
dynamics of personality development. It was on the basis of these abstractions
that Freudian psychologists and psychoanalysts opposed electroconvulsive therapy (ECT), a treatment attuned more to a physical than to a mental conception
of psychiatry.
The advent of ECT and, later, neuroleptic medications clearly reveals the importance of physical abnormalities to psychopathology. The idea nonetheless persists
that one may control a mental disorder by controlling the mind it disorders. Various
historical attempts at physical treatments of major psychotic illnessesice baths,
ECT, lobotomyappear barbaric in light of the gentler, more comfortable psychiatric treatments currently practiced. If one recalls, however, that the sole alternative
to these harsh therapies was institutionalization, it is easier to understand the difficulty faced by psychiatrists of yesteryear.
Neuroleptics, lithium, and antidepressants emptied institutions of their mentally ill inmates. The effect was profound. Images of the days before neuroleptics
should be remembered, however, when a psychiatric patient is under consideration
for DBS; because, like his institutionalized forebears, all other treatments have
failed him.
16. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder173
T H E STAT U S O F D EEP B R A I N ST I M U L AT I O N FO R
O B S ES S I V E- C O M PU L S I V E D I SO R D ER
The status of DBS for OCD has occasioned debate. Some experts maintain that DBS
for treatment of psychiatric disorders is experimental, the FDAs HDE approval
notwithstanding (Blomstedt etal. 2013; Morishita etal. 2013). In a certain sense,
the respective positions of the FDA and experts claiming DBSs experimental status are irreconcilable, the former basing its approval on sufficient evidence of safety
and efficacy and the low number of patients treated (few than 4,000 annually;
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm110194.htm). The low number of participating patients reflects the
fact that it is difficult to conduct randomized control trials of treatments for relatively rare diseases. The issue turns on the outcome measure, the magnitude of
the effect as measured, and the variability of the measurements. Agreat deal of
noise in the form of variability in a measure, for example, requires that the effect
be much greater than the noise in order to generate data sufficient to average out
the latter. Variability in the measurements may owe to biological or instrumental
influences.
An HDE approval is based on safety and probable benefit, the FDA literature
states. The literature goes on to elaborate a distinction between use of a HDE
and investigational use/clinical investigation of a HDE. The term use in this
document, when unmodified, refers to the use of a HDE according to its approved
labeling and indication(s). The significance of the FDAs findings becomes quite
apparent in light of the fact that, because insurers may claim that the use of DBS for
OCD is experimental or investigational, patients may be deprived of possible benefit. The FDA maintains the position that a device under a HDE is not experimental
if it is used for approved indications. Statements made by experts that DBS for OCD
is experimental serve merely to complicate an otherwise a rather clear issue and
thus increase the chance of insurers rejection.
The FDA does require that an institution interested in offering DBS for OCD
obtain approval from an Institutional Review Board (IRB). Though the exact procedures for obtaining IRB approval may vary according to the institution in question,
the FDA does not require that the IRB obtain protocols from the surgeon or decide
on individual patients. One emphasizes that the FDA already has determined that
DBS for OCD is safe and reasonably likely to benefit patients. Thus the IRB is not
expected to make such determinations. The unstated purpose of IRB involvement
is to ensure an appropriate informed-consent process in order to compensate for
the fact that the FDA approval process did not follow the typical process for most
drugs and devices.
DBS remains an experimental treatment for medication refractory OCD
because of the mixed outcomes and the lack of standardized patient selection methods, according to Morishita and colleagues (2013). Though there are several trials
available, they are all small research trials, and more information will be needed
to move this therapy beyond an FDA Humanitarian Device. Morishita and colleagues position is difficult to justify, at least as it applies to the ventral and anterior
limb of the internal capsule. For DBS in the vicinity of the anterior limbventral
striatum DBS, the weighted average improvement in the Yale Brown Obsessive
Compulsive Score was 41%. This result is particularly remarkable in light of the
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fact that these patients were refractory to every reasonable pharmacological and
behavioral therapy.
Whatever the limitations of the lack of standardized patient selection methods,
they do not appear to have adversely affected the potential for benefit. Even if one
were to argue that such standardization may improve benefit, the already established potential for benefit represents minimum benefit and is therefore sufficient
for the purpose of gathering informed consent. Describing DBS for OCD as experimental presents a classic instance of making the perfect the enemy of the good, to
paraphrase Voltaire, because it risks reducing the availability of DBS benefits to
many patients.
The standardization advocated by Morishita and colleagues (2013) may even
prove counterproductive. The standardization under discussion typically exists
for the convenience of investigators who conduct the clinical trials. Participating
patients may be cherry-picked, because the selection criteria may be biased in favor
of those patients who stand the likeliest chance of benefiting. Selection criteria may
also limit variability and so increases statistical power and thus decreases sample
size and trial costs. Such selection criteria increase the risk that the results from the
study of a select group may not be generalizable to the actual population in need
of treatment and for whom DBS for OCD would be reasonable (Montgomery and
Turkstra 2003). Selection criteria that are less standardized resemble those that govern the intent to treat clinical trials that are more relevant to the poststudy phase.
The results of such standardized randomized control trials are more likely to overestimate benefit and minimize risk, effects that may engender misrepresentations
in the informed-consent process. The risk of misrepresentation highlights the need
for surveillance of treatments once they have reached market. Though the need is
critical, meeting it presents problems.
Additional support for DBS of the ventral capsule/ventral striatum comes from
the demonstrated effectiveness and safety (relative to the risks of untreated severe
OCD) of capsulotomy for OCD (DAstous etal. 2013; Zhan etal. 2014). The issue
is whether it is reasonable to extrapolate from the capsulotomy experience to support DBS for OCD. There are many examples in which the benefits of DBS equal
or exceed the benefits of ablative surgical procedures. These include pallidotomy
and DBS in the vicinity of the globus pallidus interna, thalamatomy and DBS in
the vicinity of the ventral intermediate thalamus, and subthalamotomy and DBS in
the vicinity of the subthalamic. Aproblem arises, however, when the task becomes
that of defining reasonable. If one defines it as a quality of anything that proceeds from understanding or judgments formed of logic, one discovers that inductive reasoning is in operation specifically. From examples of the benefits of ablative
therapies, it was concluded that DBS produces similar benefits. Rampant radical
skepticism and solipsism partly engendered by a misreading of Evidence-Based
Medicine (Montgomery and Turkstra 2003)do not appear to leave much room for
logic.
One may argue that deference to such standardized (aka scientific) experiences
represents a form of scientism, that is, faith in the methods of science to remove
uncertainty, find correct answers, and guide correct actions. Present-day scientism perhaps has its roots in the original code of ethics published by the American
Medical Association in 1847, which was intended to distinguish allopathic medicine from other forms then current. Interestingly, some of the strongest opposition
to the code was mounted by the new breed of scientific physicians. They were convinced that scientific advances would render the need for any such code obsolete.
The presumption that randomized control trials, the sine qua non of
Evidence-Based Medicine, will remove uncertainty is scientific faith indeed. Rather
than remove uncertainty, randomized control trials merely recast it in a new guise.
Uncertainty that results from individual variation is mitigated by an appeal to
descriptive statistics of population. The reverse actionapplying descriptive statistics of population to an individual in order to eliminate the original individual
variabilityis impossible. The very means by which one attempts to contend with
individual variation thus serve to distance randomized control trials results from
an individual patients management (Montgomery and Turkstra 2003; Montgomery
2011). One thus finds to be an expression of solipsism the belief in randomized control trials as the sole route to secure knowledge. Uncertainty may be said to obey
a law similar to the law obeyed by energy:it is neither created nor destroyed but
simply transformed. It is a delusion to think one can eliminate it. The standardized experiences encouraged in a regime of Evidence-Based Medicine demonstrate
merely that which is statistically significant, whereas that which is clinically meaningful remains beyond its reach. Rendering randomized control trials meaningful requires importation of value judgments that rest on its ethical, moral, social,
political, economic, and medical consequences (Montgomery and Turkstra 2003).
Finally, Morishita and colleagues (2013) insist on the necessity of mov[ing] this
therapy beyond an FDA Humanitarian Device. Their reason for calling for this
remains unclear, especially when one considers the expense attending the widespread randomized control trials that would be needed to secure FDA premarket
approval. However, this argument misrepresents the nature of the Humanitarian
Device Exemption which is not based on the nature of the evidence but by the number of patients potentially benefiting. There should not be anything pejorative about
labeling a device and indication as approved under an HDE, unless the subsequent
need for obtaining IRB approval proves unreasonably onerous.
Consider the Veteran AffairsNational Institutes of Health (VANIH) randomized clinical trial of DBS in the vicinity of the globus pallidus interna and subthalamic nucleus for Parkinsons disease (Weaver etal. 2009). Given the fact that
there had been conducted a number of prior nonrandomized clinical trials that
demonstrated DBS to be safe and effective, one had little reason to believe thatthe
VANIH trial would produce a different result. Notwithstanding the fact that
theparticipating patients were randomized between DBS and best medical therapy, the VANIH trial differed little from previous trials, which, like the former,
involved experts and included patients for whom medication therapy had failed.
These experts were comparable toif not the sameexperts who were involved in
the best medical therapy limb of the VANIH trial.
At issue may not be whether the VANIH study essentially recapitulated previous findings as to the safety and effectiveness of DBS for Parkinsons disease, but
whether there were sufficient grounds to believe that the findings would be different
when the time arrives for deciding to proceed with the VANIH study. Absence of
any previously conducted randomized control trial is insufficient reason to perform one. This holds particularly true in an era of finite resources. The decision to
fund the VANIH study was made at the same time as a decision not to fund other
research. The VANIH grant presupposed that alternative methods of knowledge
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are inferior to randomized control trials. Such is not the case, however, because
peculiar drawbacks limit the utility of randomized control trials in guiding treatment (Montgomery and Turkstra 2003).
T H E B U R D EN O F O B S ES S I V E- C O M PU L S I V E D I S O R D ER
A common disorder, OCD has a prevalence rate of approximately 2% among psychiatric patients. Of this 2% of patients, nearly 10% are refractory to pharmacological and behavioral therapies. Two of 1,000 individuals, in other words, find
no relief from their suffering (de Koning etal. 2011). Obsessions and compulsions
may cause severe functional, occupational, and social disability. Obsessions are
persistent thoughts, impulses, or mental images that impair normal, everyday life.
Compulsions are repetitive behaviors or mental acts often performed in order to
avoid anxiety. Themes involved in obsessions and compulsions are often linked,
such as they are in an individuals repeatedly checking locked doors to ensure that
they are indeed locked, a behavior indicative of a desire to avoid harm. Added to the
debilities associated with obsessions and compulsions are significant depression
and, among women especially, eating disorders. Patients with OCD and depressive
features also face higher risk of suicide (Diaconu and Turecki 2009).
The fact that a mere 15% of the general public, when presented descriptive clinical vignettes, most of which lacked any label, failed to identify psychiatric disorder symptoms suggests that many patients suffer in obscurity. Many lay people
make normalizing attributions; that is, they attribute the unusual and undiagnosed symptoms of OCD to situational disturbances rather than psychiatric disorders (Furnham and Winceslaus 2012). Interestingly, this phenomenon on the part
of physicians is also observed in the context of patients presenting to primary care
physiciansthe usual entry to medical care.
Indeed, many of characteristics of OCD are observed in highly successful individuals. The difference between a highly successful individual and an individual
with OCD is thus one of degree rather than kind. Its measure is the amount of
disruption it introduces into the activities of an individuals life. Such a measure
renders difficult, however, the task of avoiding the tendency of attributing the illness to something a patient should be able to overcomea tendency that moreover
imposes a sense of illegitimacy on that patients wish to seek medical help.
The history of psychiatric disorders, their treatment, and their reception by the
general public has been a troubled one. ECT offers a telling example. Popular representations of it have been predominantly negative. They bear little resemblance
to current practice and, what is worse, impute to caregivers a sinister intent of
controlling the patient (McDonald and Walter 2009). Negative attitudes toward
ECT among medical students who participated in one study increased following a
viewing of popular films in which the treatment was portrayed. Also, following the
viewing the number of medical students who stated that they would advise against
ECT increased from 10% to 25% (Walter etal. 2002). In the 1980s, a short-lived
ban on ECT performed within the city limits of Berkeley, California, ended only
by court order.
The general public tends to look more favorably on psychotherapy and lifestyle
treatments than it does on medical treatments for schizophrenia and depression
(Jorm et al. 1997). When considering whether psychotherapy and lifestyle treatments are alternatives to medical treatments, one must recognize that the development of medications brought about the emptying and closing of most institutions
for the mentally ill. In a meta-analysis of cognitive-behavioral therapies (CBTs) in
schizophrenia, CBTs did not reduce the relapse rate but did improve mental states
and increased medication compliance (Pilling etal. 2002). One should not gather
from this that CBT is ineffective in treatment of OCD but rather the opposite:CBT
improves OCD by 40% to 60% in about 50% of patients. CBT must therefore be
exhausted prior to any consideration for DBS surgery. However, the public may
hold unrealistic notions about the importance of medical and surgical treatments
for psychiatric disorders. Thus the danger is that the unrealistic and unsympathetic
attitudes on the part of the public may unduly influence patients, patients family
members, physicians, and healthcare professionals.
Because it was thought to impair a patients decision-making capability, OCD
may invite the hard paternalism of which Beauchamp and Childress warn (2013).
Hard paternalism may take active forms and passive forms. One example of a passive form is that of failing to raise the possibility of such an alternative treatment
option as DBS. Studies have demonstrated that patients with OCD are no more
willing to take risks (based on the Iowa Gambling Test) than are normal subjects
(Boisseau etal. 2013). Also, nondelusional patients with OCD showed themselves
no more likely to draw hasty conclusions than were nonclinical control subjects
(Jacobsen etal. 2012). These observations belie the notion that patients with OCD
are more vulnerable and thus need paternalistic protections.
One presumes that the superior ability of psychiatrists and mental health professionals to diagnose mental illness renders them less likely to make normalizing
attributions. At issue are not psychiatrists and mental health professionals perceptions but patients perceptions and the effects these perceptions have on their
pursuit of treatment.
L AC K O F PER S PECT I V E A N D C O N T E X T
Numerous statements have been made about patients with psychiatric disorders
and DBS surgery. For example, many authors describe DBS as highly invasive.
Yet one doubts that it is any more invasive than is an endarterectomy. From the
perspective of a patients quality of life, a stroke caused by operating on the internal
carotid artery is no more or less invasive than is a stroke (or hemorrhage) related
to DBS surgery. Yet DBS is safer than carotid endarterectomy (Goldstein et al.
1997). The perceived difference in the invasiveness of DBS and endarterectomy to
prevent stroke is in the perception of the physician and represents an inappropriate
countertransference. Chapter 19 contains a discussion of countertransference in
the context of the ethical problem known as the trolley car dilemma. It is likely that
it is the proximity of the physician to the harm that might be done that is the significant factor. Operating on the carotid artery resulting in a stroke seems removed
from placing an electrode, by ones hand, into the brain. However, the difference is
only perceived by the physician, not the patient.
Much has been made of the fact that as many as 40% of patients undergoing
DBS for OCD expressed unhappiness, with the inference that patients with OCD
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somehow face greater risk of disappointment. On the other hand, patients with
OCD do experience increased difficulty in understanding the nature, risks, potential
benefits, and alternatives to DBS. These latter are elements critical to the informed
consent. There follows, then, the unsophisticated extrapolation that patients with
OCD are vulnerable and in need of special protection. However, extending such
protection may well constitute an act that violates two ethical principlesthe principle of autonomy and the principle of beneficencethat for patients sakes must be
observed, because failing to do so carries the consequence of unduly reducing the
potential for DBS relief.
In a study of DBS in patients with Parkinsons disease, 8 of 30 patients (27%)
experienced a subjectively negative result from DBS (Maier etal. 2013). One may
ask whether this result is different than it is for patients with OCD. If it is not,
one must ask whether treating patients with OCD differently than patients with
Parkinsons disease is ethical, notwithstanding the fact that doing so violates virtually all moral theories. An egalitarian moral theory, for example, posits that a
persons fate should not be determined by forces beyond his control. Because it is
doubtful that individuals develop OCD as a consequence of their own actions, it is
unfair to hold them to a different standard than standards applied to patients with
Parkinsons disease or other conditions. Autilitarian moral theory, on the other
hand, holds that the greater good is served by relieving patients of the pain and suffering caused by OCD. Adeontological theory, meanwhile, holds that helping them
is a matter of ethical duty. Alibertarian theory, finally, holds that freeing patients
from bondage to OCD maximizes their individual liberty and is therefore good. If
DBS for OCD is justified, no matter the ethical or moral theory applied, any reticence in offering it to patients with this condition is puzzling. Such reticence may
owe less to patients attitudes than they do to those of physicians and healthcare
professionals.
The stigma associated with neurosurgical therapies for psychiatric disorders perhaps owes its existence to the almost theatrical lobotomies performed by Walter
Freeman in the 1940s. One must bear in mind, however, that other reputable physicians performed lobotomies on patients with severe schizophrenia because the progressive nature of the disease and absence of alternatives compelled them (Hegarty
etal. 1994). That Egas Moniz received the Nobel Prize in 1949 for frontal lobotomies
offers some indication of the desperate state of mid-twentieth-century schizophrenia treatment. In one retrospective study of schizophrenia, 27% of patients admitted to a psychiatric hospital improved, 52% failed to improve, and 5% committed
suicide (Stephens etal. 2000). Of the 13 patients who improved, 11 never gained
employment following their discharge. Of the 31 patients who failed to improve, 20
were continuously hospitalized. Lobotomies eventually diminished with the introduction of neuroleptics in the 1950s.
It may well be that DBS of the anterior limb of the internal capsulethe ventral capsule/ventral striatum target, for exampleowes its existence to transorbital or prefrontal lobotomies. In 1949, Jean Talairach sought a safer alternative
to lobotomies by targeting the anterior limb of the internal capsule (Leveque etal.
2013). Known as a capsulotomy, the treatment developed by Talairach subsequently
became an accepted option for patients with intractable OCD. Because the extrapolation from capsulotomies to DBS was extremely short, one wonders whether surgeons performing lobotomies, though crude in their approach, were on the right
track; however, one must bear in mind that crude achieves sense solely in light of
contrasting contemporaneous alternatives.
Early following the introduction of ECT for severe depression, the treatment was
well received. In the 1950s there began a backlash. However, it is important to view
the use of ECT in the context of severe major depressive illness at the time ECT was
introduced, not by more modern times following the introduction of powerful antidepressants. In a retrospective study of patients hospitalized for major depressive
illness between 1913 and 1940, only 11% of patients with bipolar and 22% with unipolar did not experience further episodes. Seventy-seven percent of patients with
bipolar disease had to be hospitalized, as did 56% of patients with unipolar disease
(Stephens etal. 2000).
For extreme diseases, Hippocrates wrote, extreme methods of cure [...] are
most suitable. Though there now exists a wealth of effective pharmacological
therapies for major psychiatric disorders that mitigate the need for extreme cures,
it is hubristic to judge physicians of the past according to present relative comforts. Patients in the 1940s confronted quite a different situation than that faced by
present-day patients. The former could often expect little besides suffering. Yet, like
patients of the 1940s, those present-day patients for whom every reasonable alternative treatment has failed have little hope beyond that held out by DBS.
Every ethical deliberation requires an awareness of context. Ethical principles
beneficence, nonmalfeasance, autonomy, justicecannot be adjudicated in the
abstract. Often, in any given situation, these principles are in conflict. Often it is
solely assigning some weight to any particular principle or subset of principles that
a satisfactory resolution possible. The weight falling on any particular ethical principle derives uniquely from the specific situation. This process of determining and
applying weights by appealing to context is known as specification (Beauchamp
and Childress 2013). One thus commits a categorical error should one apply the
ethics characterizing one situation to another (Ryle 2002).
AU TO N O M Y
The ethical principle of autonomy most commonly connotes respect for a patients
right to determine her fate. This connotation particularly applies to human clinical trials that have followed such scandals as the Tuskegee Syphilis Study and the
Willow Brook School. Law, and policy specifies a patients right to autonomous
decision in human research.
Outside of human clinical trials the right to autonomy becomes more complicated. No one enjoys a legal right to autonomy per se. Autonomy derives, rather,
from the right to bodily integrity, which everyone does enjoy. To violate another
persons right to bodily integrity is to commit battery. Though one enjoys the right
to refuse treatment, whether he also enjoys the right to receive treatment is unclear.
For instance, a patient enjoys an uncontested right to refuse DBS. Yet it is not clear
that a patient enjoys the right to demand DBS (chapter19 contains a discussion of
this issue of the right to receive DBS.) Indeed, only pertinent laws and contracts
that specify minimum coverage make any assertions to this effect.
Physicians and healthcare professionals are committed to beneficence, that
is, the principle of serving a patients good. Likewise, physicians and healthcare
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professionals are committed to nonmalfeasancethe principle of doing no harm.

Admittedly, physicians and healthcare professionals are well able to estimate the
potential benefits and harms in terms of physical and psychiatric symptoms and
signs. Symptoms and signs are not, however, the same as impairments, disabilities,
and handicaps.
Though symptoms and signs may be the purview of physicians and healthcare
professionals, disabilities and handicaps are functions of patients and their particular ecologies. No calculus exists that allows physicians to weight the symptoms and
signs associated with risks against risks associated with potential benefit and with
leaving a disease untreated. The language of risk is different from the language of
benefit. The value placed on the consequences of risks and benefits on disabilities
and handicaps is therefore critical. Only a patient or her surrogate may assign this
value, which she does in the context of the patients unique ecology.
Autonomy involves more than respect for a patients right to make medical decisions. It also involves respect for the patient in his own right. Of relevance is the
ethical theory of nineteenth-century German philosopher Immanuel Kant, who
argued that individuals are to be treated as ends in themselves and never merely
as means to some further end. The patient, then, is an end herself. Service to that
end becomes evident in her enhanced health, well-being, or quality of life. If it
becomes evident, however, that another end is being serveda physicians sense
of self-satisfaction, for examplethen it is fairly certain that the patient has been
made a means. Physicians who act in this manner may cherish the notion that
they have acted with beneficence, but they in fact stand guilty of paternalism. Such
paternalism, which violates the principle of autonomy, is often instanced when a
physician or healthcare professional imposes his value system on the patient.
A dose of humility remedies paternalism. Obtaining informed consent by way
educating and understanding choices made by patients or their surrogates necessarily involves an invocation of meaning, which words alone communicates only
imperfectly. Risk and invasive, for example, are fraught terms in medicine. Yet
they admit of a range of variance, which one may reduce somewhat by appeal to
context. Nonetheless, even this practice is limited because it is ultimately indeterminate. The philosopher W.V.O. Quine (2013) demonstrated this indeterminacy in
his seminal text, in which he points to inscrutability of reference and indeterminacy of translation. He argues that no common reference ever grounds meaning,
notwithstanding the most painstaking deconstruction. According to Quine, such
irremediable indeterminacy owes to the inscrutability of reference. Lack of common reference renders every communication between individuals tentative.
One should not conclude from the foregoing discussion that communication
is futile. Human beings do a remarkably good job of it most of the time, despite
its imperfections. Rather, Quines concepts of inscrutability of reference and
indeterminacy of translation discourage one from cherishing any notion as to
the exactitude of language, whether one uses it to convey information or to give
consent. Some allowance is thus necessary to avoid overly restrictive expectations
on informed consent, both on patients or their surrogates as well as physicians or
healthcare professionals. Overly restrictive conditions may prevent patients from
receiving treatment. Such a bind is usually escaped by way of appeal to a normative
understanding, such as may be had by a reasonable person, of consent or an idea
communicated to her. If patients with OCD are presumed to be unreasonable, it is
the case that the very presumption violates the principle of beneficence as well as
autonomy. Physicians and healthcare professional must examine their presumptions and be prepared to abandon them if necessary.
A number of DBS targets have been studied. As Morishita and colleagues (2013)
note in their review of the literature, the study involving the largest number of
patients (68) focused on the ventral capsule/ventral striatum. The ventral capsule/
ventral striatum is typically accessed via the anterior limb of the internal capsule, which lies at a depth at which the internal capsule becomes fenestrated with
islands of interposed striatal tissue. This method of access is consistent with the
FDA-approved method of accessing the internal capsules anterior limb. The study
involving the next largest number of patients (23) focused on the subthalamic
nucleus. Other targets include the nucleus accumbens and the inferior thalamic
peduncle.
Such targets as the anterior limb of the internal capsule and the ventral capsule/
ventral striatum have been implanted with a special DBS lead whose contacts are
long and widely spaced. Commercial use of these DBS leads currently requires IRB
approval. DBS leads commercially available for certain targets have been implanted
in targets other than those specified. It is conceivable that these leads could find
off-label use as FDA-approved devices for other indications, but the current paucity
of experience appears insufficient to justify such use.
D EEP B R A I N ST I M U L AT I O N I S EFFECT I V E
Consideration now turns to efficacy of DBS of the ventral capsule/ventral striatum, for which exists a reasonable amount of experience. Morishita and colleagues
(2013) reviewed the efficacy. Their information is problematic, however, because
the average composite scoresscores generated by more than one patient in any
studywere reported without any description of the variance. The average is virtually meaningless unless it is attended by some understanding of the distribution
of the raw data. Illustrative of this point is a situation that involves 10 patients,
each of whom produced different scores that ranging from 1 to 10 in increments of
1.Though the average is 5, only one individual would produce that score. In this
case the average is virtually meaningless, particularly in comparison to a situation
in which half of the 10 participating patients produced a score of 4 and the other
half a score of 6 with the average remaining5.
Nonetheless, in the studies listed by Morishita and colleagues (2013), the average
change, weighted by the number of subjects, was 41%. Also, Morishita and colleagues describe a study that reported improvement in the Yale Brown Obsessive
Compulsive Score by 16 of 26 participating patients. Greater than 35%, this
improvement was deemed clinically significant.
This improvement needs to be put in context. First, the noted improvements occurred in patients whose condition was refractory to all reasonable
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pharmacological and CBTs. This in itself is remarkable. The other context is the
degree of benefit with DBS, even in the difficult population studied, in light of other
accepted therapies. CBTs, for example, are reported to produce improvements on
the order of 40% to 60% in a mere 50% of patients treated. Thus it appears that the
results obtained with DBS are comparable to those obtained with CBT. If CBT is
considered efficacious solely from the perspective of benefit, then DBS should be
considered equally efficacious.
D EEP B R A I N ST I M U L AT I O N I S S A FE
In terms of conceptual arrangement, adverse effects may be categorized as those

that are related to a surgical procedure, those related to stimulation, and those
related to the disease. Surgical procedure adverse effects relate primarily to risks of
intracranial hemorrhage and infection. In one of the largest studies of DBS of the
ventral capsule/ventral striatum, 2 of 26 participating subjects (7.6%) experienced
intracranial hemorrhage from which they made full recovery (Greenberg et al.
2010). One patient (3.8% of the group) developed a superficial infection, which antibiotics remedied. One patient (3.8% of the group) experienced a single seizure in
the immediate postoperative setting. One patient (3.8% of the group) experienced
a lead break. These surgery-related complications are on par with many studies of
DBS of other targets for other indications.
Three patients each experienced four incidents of increased depression or suicidal ideation as a side effect of stimulation. Afew patients experienced worsened
OCD when their stimulators were powered off, and one patient experienced OCD
when his stimulator was powered on. There was one report of hypomania and one
of increased domestic problems. There were readily reversible adverse effects, such
as changes in sensation and muscle contractions, associated with trials of different
electrode configurations and stimulation parameters.
Similar to those for other indications, selection criteria for OCD DBS include (1)
refractoriness to all reasonable medication and behavioral therapies; (2) the degree
to which a possibly treatable handicap represents a rate-limiting factor in a patients
quality of life; (3) whether the benefits a patient may reasonably expect outweigh
the risks, including those associated with such comorbidities such as depression
and suicide; (4) feasible access to postoperative DBS programming. Consensus
guidelines for alternative medication and behavioral therapies indicate treatment
with CBT, particularly exposure and response prevention. The National Institute
for Health and Clinical Excellence (2005; United Kingdom) recommends at least
10 hours of CBT.
Pharmacological treatments consist primarily of serotonin reuptake inhibitors
and selective serotonin reuptake inhibitors (SSRIs). Though the different SSRIs may
be similar in their efficacy, tolerance to them appears to admit of some idiosyncrasy (Work Group on Obsessive-Compulsive Disorder et al. 2007). Thus, if one
SSRI proves ineffective and no adverse effects limit it, then one is free to consider
whether a different SSRI may prove effective. However, if adverse effects prevent a
patient from reaching a maximal dose of one SSRI, then a different SSRI may bring
benefit. The situation with SSRIs is similar to the situation in which dopamine agonists are used to treat Parkinsons disease.
It is important to note that a DBS surgery sites IRB may impose other requirements. For example, it is not unusual for IRBs to require an independent committee to oversee the selection process, to ensure the patient meets the criteria, and to
assure appropriate informed consent process.
D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G
Most studies of DBS for OCD report a long latency to improvement. A similar phenomenon characterizes DBS for dystonia. In one study, all 26 participating subjects who underwent ventral capsule/ventral striatum DBS experienced
a plateau in their response at three months. In some patients the most immediate response is a changeoften for the betterin anxiety and mood. It remains
unclear whether such a change is predictive of subsequent improvements in OCD.
If subsequently demonstrated to be predictive, changes in anxiety and depression
may act as biomarkers in early adjustments. Rapid changes in anxiety and mood
allow for a titration upward in electrode configurations and stimulation parameters. Patients whose dystonia symptoms are phasic or active symptoms respond
quickly to changes in DBS. One may also attempt to maximize the stimulation
effects, by selecting appropriate electrode configurations and stimulation parameters (Montgomery 2010) that produce no adverse effects. Such an approach has
been suggested by Nuttin and colleagues (2003).
Rather than be discouraged by the lack of definitive, effective, and efficient programming algorithms, one should feel emboldened to engage in systematic exploration of the parameter space from which it may be possible to deduce general
principles. It is also possible that by relating efficacy to specific anatomical locations or developing such rapidly responding predictive biomarkers as DBS-evoked
EEG potentials one may aid the development of those algorithms. Educated trial
and error, meanwhile, must continue to guide exploration. Of great help would be
a registry, which would help to expand experience rapidly.
S U M M A RY
Though DBSof the ventral capsule/ventral striatum, specificallyis safe and

effective for treating OCD that is refractory to pharmacological and behavioral
therapy, its acceptance is complicated by many presuppositions on the part of
patients and patients families, as well as physicians, healthcare professionals, and
the public. These presuppositions are perhaps unfounded: There is little reason
to believe that a nondelusional patient with OCD is any less capable of providing
informed consent than is a patient with Parkinsons disease or some other movement disorder. To insist otherwise is to violate the ethical principles of beneficence
and autonomy.
184
Admittedly, the fraught legacy of mid-twentieth-century lobotomy and ECT

exerts perhaps undue influence. The actions of a few unethical surgeons and physicians of yesteryear should not impugn those of the majority of their colleagues, who
no doubt are honest and motivated by compassion. Like many present-day patients
with OCD, past patients with psychiatric disorders faced no alternative other than
continued suffering. This being the case, any reasonable attempt at treatment,
whether with medication, DBS, or indeed even lobotomy and ECT, must appear as
a ray of hope.
R EFER ENCES
Arikha N. Passions and Tempers:AHistory of the Humours. NewYork:HarperCollins;
2007.
Blomstedt P, Sjoberg RL, Hansson M, etal. Deep brain stimulation in the treatment of
obsessive-compulsive disorder. World Neurosurg. 2013;80(6):e245e253.
Boisseau CL, Thompson-Brenner H, Pratt EM, et al. The relationship between
decision-making and perfectionism in obsessive-compulsive disorder and eating
disorders. J Behav Ther Exp Psychiatry 2013;44(3):316321.
DAstous M, Cottin S, Roy M, et al. Bilateral stereotactic anterior capsulotomy for
obsessive-compulsive disorder:long-term follow-up. J Neurol Neurosurg Psychiatry
2013;84(11):12081213.
de Koning PP, Figee M, van den Munckhof P, etal. Current status of deep brain stimulation for obsessive-compulsive disorder:a clinical review of different targets. Curr
Psychiatry Rep. 2011;13(4):274282.
Diaconu G, Turecki G. Obsessive-compulsive personality disorder and suicidal behavior: evidence for a positive association in a sample of depressed patients. J Clin
Psychiatry 2009;70(11):15511556.
Furnham A, Winceslaus J. Psychiatric literacy and the personality disorders.
Psychopathology 2012;45(1):2941.
Goldstein LB, Moore WS, Robertson JT, etal. Complication rates for carotid endarterectomy. Stroke 1997;28:889890.
Greenberg BD, Gabriels LA, Malone DA Jr., etal. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder:worldwide
experience. Mol Psychiatry 2010;15(1):6479.
Hegarty JD, Baldessarini RJ, Tohen M, et al. One hundred years of schizophrenia: a
meta-analysis of the outcome literature. Am J Psychiatry 1994;151(10):14091416.
Jacobsen P, Freeman D, Salkovskis P. Reasoning bias and belief conviction in
obsessive-compulsive disorder and delusions:jumping to conclusions across disorders? Br J Clin Psychol. 2012;51(1):8499.
Jorm AF, Korten AE, Rodgers B, etal. Belief systems of the general public concerning
the appropriate treatments for mental disorders. Soc Psychiatry Psychiatr Epidemiol.
1997;32(8):468473.
Leveque M, Carron R, Regis J. Radiosurgery for the treatment of psychiatric disorders:a review. World Neurosurg. 2013;80(34):e31e39.
Maier F, Lewis CJ, Horstkoetter N, et al. Patients expectations of deep brain
stimulation, and subjective perceived outcome related to clinical measures in
Parkinsons disease: a mixed-method approach. J Neurol Neurosurg Psychiatry

2013;84(11):12731281.
McDonald A, Walter G:Hollywood and ECT. Int Rev Psychiatry 2009;21(3):200206.
Montgomery EB Jr., Turkstra LS:Evidenced based medicine:lets be reasonable. J Med
NewYork:Oxford University Press, 2010.
Montgomery EB Jr. Ask the expert:what is your interpretation of the ADAGIO study
and has it influenced your clinical practice? Neurodegen Dis Manage. 2011;1:2123.
Morishita T, Fayad SM, Goodman WK, et al. Surgical neuroanatomy and programming in deep brain stimulation for obsessive compulsive disorder. Neuromodulation
2013;17(4)312319.
National Institute for Health and Care Excellence. Obsessive-Compulsive
Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder
and Body Dysmorphic Disorder. NICE Clinical Guideline 312005. London:National
Institute for Health and Care Excellence; 2005.
Nuttin BJ, Gabriels LA, Cosyns PR, et al. Long-term electrical capsular stimulation
in patients with obsessive-compulsive disorder. Neurosurgery 2003;52(6):12631272;
discussion 12721264.
Pilling S, Bebbington P, Kuipers E, et al. Psychological treatments in schizophrenia:I.meta-analysis of family intervention and cognitive behaviour therapy. Psychol
Med. 2002;32(5):763782.
Quine WVO. Word and Object. Cambridge, MA:MIT Press; 2013.
Stephens JH, Richard P, McHugh PR. Long-term follow-up of patients with
a diagnosis of paranoid state and hospitalized, 1913 to 1940. J Nerv Ment Dis.
2000;188(4):202208.
Walter G, McDonald A, Rey JM, et al. Medical student knowledge and attitudes
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2014;119:9195.
17
Could Deep Brain Stimulation

Be Effective in the Treatment of
Posttraumatic Stress Disorder?
This chapter concerns future Deep Brain Stimulation (DBS) therapies such as
Posttraumatic Stress Disorder (PTSD). The purpose here is not to argue DBSs effectiveness in treating PTSD or to call for clinical trials to begin. It is, rather, to discuss the challenges faced in conducting a clinical trial. This chapter considers the
reception of the idea of DBS as a PTSD therapy and the implications this reception
carries for future innovative clinical trials of DBS. Of no concern here are issues
of honest differences of opinion. Many decisions concerning approval of innovative clinical research rest on value judgments with respect to risk and benefits. In
the case of innovative clinical research, particular value judgments are necessary,
because risk and benefits may only be estimated. Often it is difficult to know, for
example, when there exists preclinical data sufficient to justify a transition to clinical trials.
The intent behind this chapter is not to criticize individual reviewers, who are no
doubt highly intelligent, accomplished, and respected. Many criticisms and their
consequent recommendations would appear entirely reasonable by approaches and
concepts implicitly held. Therein lies the paradox. Resistance comes in response not
to the facts themselveswhich, in the case of research, are necessarily incomplete
or indirectbut rather to certain presuppositions and prejudices. Indeed, uninformed predispositions betray habits of thought that actually oppose innovative
research, because they frame questions and determine beforehand criteria for evidence that supports the proposed clinical trial.
The research proposal reproduced in detail here models the construction of a
preliminary or pilot clinical research protocol. In order to preserve a sense of fairness, it also provides thorough context for reviewers responses, which are the focus
of the discussion that follows the text of the proposal. Readers may wish to skip
the latter, however, and resume their reading with the discussion of the reviewers
responses.
17. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?187
R ES E A R C H PR O P O S A L
PTSD may be severely disabling, even life-threatening. Patients avoid public places,
a tendency that limits their interactions with family and community. They also
relive the terrifying experience that led to their PTSD. They face high risks of
depression, suicide, and substance abuse. Although many patients benefit from
medications and psychological therapies, some experience no benefit from any
standard therapy. It is the possibility of offering these patients an effective alternative therapy that drove the proposed research.
DBS has helped other types of psychiatric or psychological disorders. DBS has
been approved to relieve the suffering of patients with severe Obsessive-Compulsive
Disorder (OCD) following failure of medications and psychological therapy.
Current clinical research also demonstrates that DBS can help patients with severe
depression following failure of alternative medications and psychological therapies. This outcome inspired confidence in the idea that DBS may help patients with
PTSD. In DBS, electrodes are implanted in various parts of the brain and are connected to a stimulator placed under the skin of the chest.
Considerable scientific evidence suggests that a part of the brain called the anterior cingulum may be involved in PTSD. The anterior cingulum is part of the limbic
system that controls fear responses and psychological distress. The anterior cingulum has been shown to be abnormal in humans with PTSD. Electric stimulation of the limbic system has improved symptoms in an animal model of PTSD.
Humans with PTSD have experienced benefit from a form of electrical stimulation
that is introduced to the brain through the scalp and skull rather than by implanted
electrodes (Transcranial Magnetic Stimulation). This, however, is an impractical
approach.
Deciding the exact time to begin human clinical trials of a new treatment is
always difficult, particularly when they involve surgery. Physicians and healthcare
professionals wish to avoid harming patients. The question becomes whether the
refusal to offer a therapy results in greater harm. Though it may seem frightening, DBS surgery carries risks comparable to those attending surgery to unblock
an artery in the neck or heart. Risks must nonetheless be considered. As measured
against potential benefit, three or four of 100 patients who undergo DBS surgery
experience paralysis or another serious, possibly permanent complication. Because
one cannot know the likelihood of DBS benefit for PTSD, a proposed clinical trial
is necessary. Patients with PTSD invited to join the study face a stark choice:either
participate or continue to suffer a debilitating condition.
The design of research clinical trials of DBS is complicated. One wishes to assure
participating patients that following their participation they and the rest of society
will know whether patients stand to benefit from DBS. Further, given the psychological and possible physical placebo effects, some patients may respond positivity even if the DBS was inherently ineffective. Alternatively, DBS may be helpful.
Further complicating the situation is that the placebo or an actual benefit may vary
among patients. Acoin that is slightly biased in favor of heads may take many flips
before one can be sure that the coin is biased. Similarly, it may take a considerable
number of patients to benefit from DBS for PTSD to know whether there is a real
188
possibility that DBS may help. Yet one finds it difficult to know how many patients
would need to undergo DBS before one may claim with confidence that DBS helps.
When designing a clinical trial to demonstrate whether or not a treatment is
effective, one first has to determine the number of subjects to be entered, analogous
to the number of coin flips to be performed as described previously. Yet often it is
not possible to determine ahead of time how many subjects should be planned for.
In that case, one can conduct a pilot study, not to demonstrate whether or not DBS
is clinically effective but rather to determine the effect size of the treatment and
the variance in the primary outcome measure in order to determine sample size.
Further, a pilot project can demonstrate the feasibility of a subsequent full-scale
clinical trial.
The proposed research sought to improve estimates of that sufficient number,
which, as turns out, is about half the number needed to prove that DBS works. The
proposed research thus represents a necessary intermediate step toward full-fledged
studies that seek to establish DBS as an effective treatment of PTSD. Involved in the
proposed research was implantation of DBS systems in patients with severe refractory PTSD for the purpose of developing methods for optimal brain stimulation.
B AC KG R O U N D A N D S I G N I FI CA N C E
A significant cause of morbidity and mortality, PTSD incorporates three well-known

symptom clusters:avoidance, reexperiencing, and hyperarousal. Quite serious when
taken individually, these symptoms may lead to total incapacitation and even suicide when taken in combination. The rate of attempted suicide in PTSD is estimated
to be 20%, whereas rates of panic disorder, substance abuse, and major depression
in PTSD patients are significantly higher than they are in the general population
(Davidson 2001). The cognitive effects of these symptoms interfere with patients
ability to socialize normally, remain employed, maintain family relationships, or
muster the wherewithal to visit the doctor or the supermarket. Unemployment costs
taxpayers some $3million (Davidson 2001). Symptoms often overlap with depressed
mood and exacerbate feelings of hopelessness and helplessness.
PTSD is often refractory to the best pharmacological and behavioral therapies.
Though numerous treatment modalities have produced a partial response in many
patients and complete recovery in some others, there exist treatment-resistant cases
that defy even the most vigorous regimen. Though effective nonsurgical therapies
do exist, a significant number of patients are refractory to or ineligible for these
therapies. Another option is clearly needed.
J U ST I FI CAT I O N FO R PR O P O S ED R ES E A R C H ST R U CT U R E
The proposed research sought to demonstrate that DBS of the anterior cingulum is a
safe and effective therapy for patients with PTSD. The issue is how to proceed in this
demonstration. Indeed, on this issue there are probably as many different opinions
as there are individuals holding them. Some advocate beginning with a large-scale
study powered to demonstrate efficacy and safety, the former typically requiring
much larger sample sizes. For example, demonstrating an adequately clinically
meaningful 10% improvement in the Clinician Administered PTSD Scale (CAPS)

would require a sample size of 30 subjects. These estimates are based on published
data for subjects with a wide range of severity. Extending the effect size and variance to estimates of the population of patients refractory to medical and behavioral therapy is highly problematic. Better estimates are needed to plan appropriate
large-scale studies. The population of concern would possibly have a greater effect
size and lower variance, which requires exposing fewer subjects to risk.
Most would agree that it is unreasonable to place so many patients at risk in
a full-scale clinical trial without some prior assurance that DBS will be safe and
effective. Yet any study with a smaller sample size risks both type I and type II
statistical errors, the former finding a difference when one does not exist and the
latter not finding a difference when one exists (see Sample Size Justification section). Asample size of 15 subjects, however, would have an acceptable probability
of providing a reasonable estimate of the mean and variance on the outcome measure. A sample size of 15 provides a 53% probability of detecting an adequately
meaningful effect. The proposed research could thus elicit some appreciation for
the potential benefit of DBS.
E T H I CA L I S S U ES I N PR O P O S I N G
T H E R ES E A R C H PR O J ECT
Every medical decision involves assessing risk and potential benefit in the context
of alternatives and finding a balance between the two. Risk involves at least two
aspects:frequency and severity. Benefit likewise includes the frequency and magnitude of benefit. There is unfortunately no calculus to relate risk to benefit. Rather,
balancing risk and potential benefit remains a matter of judgment. Admittedly, such
ethical principles as beneficence, autonomy, nonmalfeasance, and justice may constrain the limits of clinical research. Operating within those limits, however, requires
the judgment of reasonable women and men. The exercise of this judgment is often
more problematic in surgical trials. As DBS-related research ethics expert Joseph Fins
(2008) has noted, surgical clinical trials in which the actions of the surgeon are more
proximate to the surgical outcomes are much more personal (Fins 2008).
Judgments are affected by the psychological impact of the medical decision on
the clinician, scientist, grant reviewer, or Institutional Review Board (IRB) member
making it. There is the precautionary principle in ethics, which, according to Fins
(2008),
urges caution and prudence when facing unknowns and is an antecedent
sort of utilitarianism. One makes judgments about the advisability of actions
based on a prior assessment of foreseeable risks and benefits. [...] When the
precautionary principle is implicitly invoked in making judgments about
research, the objective is to pursue a degree of safety that is comparable to that
of established therapy. [...] The challenge posed by innovation or novelty creates the possibility of untoward events. It leads to invocation of the precautionary principle, which, echoing the admonitions of the philosopher Hans Jonas,
urges us to give greater weight to the prognosis of doom than to that of bliss.
[...] [W]hat is knownthe status quoand what is unknown is invariably
190
more risky than the familiar. Needless to say, this is antithetical to innovation because discovery invariably requires scenarios that involve novelty and
unknown risks. When faced with the certain security of stasis or the potential
dangers of innovation, the precautionary principle will invariably choose stasis, leading us, as the legal scholar Cass Sunstein notes, in no direction at all.
As concerns patients with PTSD in general, DBS in no way compares with the
safety of established therapies that include pharmacological and behavioral treatments. To apply this aspect of the precautionary principle to subjects to be enrolled
in the DBS clinical trial, however, would be inappropriate, because, in order for
them to be considered, every reasonable pharmacological and behavioral treatment
must fail. There are thus no established treatments for these patients and no level of
safety to which the proposed research may be compared.
One may argue that animal studies should be conducted prior to any human
ones. Indeed, there are at least two aspects in which animal studies facilitate discussion of clinical trials. These relate to potential for benefit and for risk. With respect
to the latter there is sufficient experience regarding the safety of DBS in humans
(see later discussion). The incidence and nature of adverse events directly related to
surgery have been consistent across many different disorders and targets. It is therefore reasonable to extrapolate from that experience to the potential for surgical risk
in the proposed study. From a standpoint of assessing surgical risk, then, further
animal studies are unnecessary.
Concerning risks directly related to stimulation of the anterior cingulum, Lozano
and colleagues (2008) report no adverse effects in 20 subjects having undergone
DBS in the vicinity of the anterior cingulum for depression. Should there be any
stimulation-induced adverse effects, the subject or safety monitoring committee
could order the stimulation stopped. To date, there has not been any evidence of
persistent stimulation-induced adverse effects that have continued once DBS was
ceased. Concerning benefit, a study in the rodent model of PTSD demonstrated significant improvement with DBS-like stimulation of the amygdala (Langevin etal.
2010).
The decision of when to make the translational jump from animal to human
studies is always problematic. Indeed, it is a topic that admits of a wide range of
honest opinions. Requiring additional animal studies will necessarily delay the
translation to human studies. As a consequence, many patients will suffer in the
interim. Conversely, one does not want to subject a patient to risk of harm. The
injunction do no harm has been a cornerstone of medicine since Hippocrates.
Yet even this must be kept in balance, lest it lead to Omission bias in which psychological reaction to the threat of harm through an action outweighs larger risks
associated with not acting. Alapse into Omission bias may engender therapeutic
nihilism (Tversky and Kahneman 1991; Ritov and Baron 1990; Spranca etal. 1991;
Asch etal. 1994). In the case of the proposed clinical trial, the harm of not offering DBS for this particular set of patients is that of a high probability of continued
disability and suffering. How to balance this potential harm of omission with the
potential harm of commission is difficult. The grant reviewer, IRB member, and
physician are fortunately not alone in dealing with this question; subjects will also
weigh the risks of omission versus those of commission, provided they are given
the opportunity.
E V I D EN C E FO R A R O L E O F T H E A N T ER I O R C I N G U L AT E
C O R T E X I N P O ST T R AU M AT I C ST R ES S D I S O R D ER
Though whole or regional magnetic resonance imaging (MRI) brain volumes of

PTSD-positive subjects who were involved in a coal-mining disaster in China were
not significantly different from PTSD-negative subjects, there did occur significantly reduced fractional anisotropy values in the right posterior cingulum and
bilateral hippocampal body (Wang etal. 2010). Similar findings were reported in
Japanese Sarin gas attack survivors suffering from PTSD (Abe etal. 2006). Children
and young adults with PTSD following traumatic brain injury (TBI) were more
likely to experience recurring symptoms when the anterior cingulate was relatively
intact (Herskovits etal. 2002).
T H E B AS I C SC I EN C E O F T H E A N T ER I O R C I N G U L AT E
A N D T H E P OT EN T I A L R EL E VA N C E TO P O ST T R AU M AT I C
ST R ES S D I SO R D ER
Richard Davidson and colleagues (Shackman et al. 2011) reviewed the extensive
literature on ways the anterior cingulate provides support to the integration of the
expression of affect, motivation, response to pain, and cognitive function, the last
of which heretofore having been believed to act independently. Davidson and colleagues hypothesized a rich integration of these functions within the cingulum,
and thus it plays a significant role integrating affect, motivation, response to pain,
and cognitive function. The parallel to domains affected by PTSD in humans is
striking.
Changes are noted in the anterior cingulate in response to pain and other adverse
experiences (Vogt 2005), and neuronal recording in the cingulate of humans demonstrate correlations in neuronal activity changes with painful stimuli (Hutchison
et al. 1999). The anterior cingulate demonstrated significant neurometabolic
changes in response to the experience of intense negative affect, particularly anticipation (Sehlmeyer etal. 2009; Mobbs etal. 2010; Drabant etal. 2011). The anterior
cingulate interconnects with the ventral striatum, which in addition to its role in
reward mechanisms is also involved in the anticipation and avoidance of pain and
other aversive stimuli (Jensen etal. 2003; Delgado etal. 2008; Levita etal. 2009;
Robinson etal. 2010). Via projections from the substantia nigra pars compacta to
the anterior cingulum, activities in the substantia nigra pars compacta related to
prediction of aversive stimuli, particularly reinforcers, may parallel similar functions in the anterior cingulum (Williams and Goldman-Rakic 1998). Increased
unpredictability of a physical threat also activates the anterior cingulum (Alvarez
etal. 2011). It is conjectured that there may be some analogy to the anticipation of
intense negative affective conditions and the hypervigilance symptoms of PTSD.
Indeed, the anterior cingulate is activated in nonhuman primates in response to an
imminent threat (Kalin etal. 2005).
Davidson and colleagues reviewed considerable evidence demonstrating that
the cingulum overlaps in its involvement with negative affect, pain prediction
and avoidance, and motivation (Shackman etal. 2011). They hypothesize that the
primary role of the cingulum is to integrate and thus to exert cognitive control
192
over all these domains. Again, it is interesting to speculate that PTSD may reflect
an impaired cognitive control mechanism involving the anterior cingulum. This
hypothesis and its supporting observations described previously provide a cogent
rationale for the proposed study.
I N D I R ECT E V I D EN C E I N S U PP O RT O F A P O S S I B L E D EEP
B R A I N ST I M U L AT I O N B EN EFI T
The anatomical target for DBS demonstrates abnormal neurometabolic activity

in patients with PTSD (Felmingham etal. 2003). Using changes in skin conductance as a marker of emotional responsiveness, investigators recorded in subjects
with PTSD a reduction in the blood oxygen level dependent response in functional
MRI (fMRI) of the ventral anterior cingulum region compared to normal for non
trauma-related stimuli that elicited skin conductance changes. This region is analogous to the proposed target of DBS.
Boggio etal. (2005) demonstrated that 20 Hz repetitive Transcranial Magnetic
Stimulation over the dorsal lateral prefrontal cortex improved PTSD symptoms,
as measured by the PTSD Checklist and Treatment Outcome PTSD Scales, which
still were significant at 3months following treatment. In addition, depression was
improved. Importantly, there was no evidence of cognitive worsening. Cohen etal.
(2004) reported similar results. Interestingly, DBS-like stimulation of the basolateral nucleus of the amygdala unilaterally improved behavior in the rodent model of
PTSD (Langevin etal. 2010).
I M PR OV EM EN T O F OT H ER
N EU R O PSYC H I AT R I CD I SO R D ER S
Though it is highly problematic to generalize from other disorders, such as OCD

and depression, DBS has demonstrated benefit in the face of failed pharmacological and behavioral therapies. DBS of the anterior limb of the internal capsule and
the subthalamic nucleus (Mallet etal. 2008)improves OCD. DBS of the subgenu
cingulum (area 25)(Kennedy etal. 2011)improves depression.
All of these treatments share certain ethical issues. In all cases a decision had to
be made between the unknown but possible benefit compared to the known risks
and, more important, of the risks of not intervening. In the latter case, subjects
quite literally had no other alternative than to continue to suffer. Such would also
be the case of potential subjects of the proposed research.
AS S ES S M EN T O F R I S K
As in any medical decision, potential benefits must be weighed against risks.

Though the potential benefits of DBS in PTSD are unknown, some observations
have been made that suggest the potential benefit described previously. Many
aspects of the risk assessment, however, are relatively well known. In this case, risks
may be categorized as those related to the surgical implantation of the DBS device;
those related to the effects of stimulation such as psychiatric, psychological, as well

as neurological; and those related to the psychosocial consequences of changes
either in the direction of improvement or of further deteriorationin the PTSD.
Risks related to surgical implantation of the DBS system are well known, thanks
to extensive published experience. For example, the Veterans AffairsNational
Institutes of Health cooperative study in which 299 subjects with Parkinsons disease underwent DBS had a surgical complication rate of nearly 50%. This rate is
most likely related to the definitions used for adverse events, which include transient side effects routinely experienced during DBS programming. These are not
generally considered adverse events. Evidence for this is the fact that 99% of events
considered adverse were resolved in 24months (Weave etal. 2009). The validity of
extrapolating these complications to possible surgical risks in PTSD is reasonable,
because the same rates of surgical complications have been seen in such other types
of DBS surgery as OCD, Essential tremor, and dystonia. The surgical complication
rates thus appear to generalize well across different diagnoses. They should be relevant to surgical risk assessments for subjects with PTSD.
There may be risks associated with stimulation that are unique to the stimulated structure. Stimulation of the globus pallidus interna, for example, risks
temporary tonic contraction as a consequence of the proximity of the DBS electrodes to the corticospinal tract, and it risks temporary phosphenes (visual hallucinations of bright lights) as a consequence of the proximity of the stimulation
site to the optic tract. Similarly, DBS in the vicinity of the subthalamic nucleus
has been associated with depression or euphoria when stimulation is excessively
ventral and medial in the subthalamic nucleus. These problems typically resolve
with adjustments of the stimulation configurations and parameters. Published
literature of DBS in patients with depression, which involves the same targets as
those in the proposed research, demonstrates few adverse effects that would be
specifically referable to DBS of subgenu cingulum. In 20 patients with DBS of the
anterior cingulum, over the initial 12 months the following adverse effects were
observed: wound infection and hardware removal (three patients); reinsertion of
DBS hardware (one patient); wound infection (in one patient; managed with antibiotics alone); perioperative seizure (one patient); worsening mood or irritability
(two patients); perioperative headache (four patients); and pain at pulse generator site (one patient). Seven patients experienced no adverse effects (Lozano
et al. 2008). Follow-up after 3 to 6 years demonstrated continued efficacy without
additional adverse effects except that of completed suicide in 2 of the 20 subjects
(Kennedy et al. 2011).
There may appear adverse effects related to the psychosocial consequences of
changeseither in the direction of improvement or of further deteriorationin the
PTSD. This possibility has been demonstrated in patients with Parkinsons disease
following DBS (Schupbach et al. 2006). Disturbances, psychosocial dislocations,
and dissatisfaction with family may occur despite clear symptomatic improvement.
The types of adverse effects unique to PTSD unfortunately cannot be anticipated,
because no experience with DBS in PTSD yet exists. These types of adverse effects
may indeed be significant. The study will therefore include close surveillance. The
experience of thousands of patients undergoing DBS for other indications; however, demonstrates that these effects are reversible with the discontinuation of DBS,
which will be an option in the proposed study.
194
T R AU M AT I C B R A I N I NJ U RY AS A P OT EN T I A L C O N FO U N D
The tension that drives the TBI-related selection criteria is an interest in minimizing
structural changes in the brain undetectable with MRI that would reduce, perhaps
years after a traumatic event, the effectiveness of DBS (effect size) or increase the
variance of the outcome measures. Given that MRI done at enrollment may miss
significant brain injury, such as diffuse axonal shearing, a behavioral-historical
assessment is needed. The goal is to minimize the potential confounding effect
while maintaining a sufficient sample, particularly one that remains relevant to the
ultimately intended population. Consequently, any subject with mild or greater TBI
would have been excluded, at least initially. Four criteria for mild TBI are (1)any
period of loss of consciousness; (2) any loss of memory for events immediately
before or after the accident; (3) any alteration in mental state at the time of the
accident (e.g., feeling dazed, disoriented, or confused); and (4)focal neurological
deficit(s) that may be transient but where the severity of the injury does not result
in loss of consciousness of approximately 30 minutes or less, loss of consciousness
after 30 minutes, and initial Glasgow Coma Scale of 13 to 15, or posttraumatic
amnesia of less than 24 hours in duration (Kay 1993). It is recognized that these criteria suffer from recall problems particularly with remote TBI. Nonetheless, these
historical criteria, where obtainable, will be used.
Though most patients who sustain mild TBI recover within several months, a
subset of patients will experience lingering symptoms, known collectively as postconcussive syndrome, which can mimic those of PTSD. Such symptoms include
irritability, emotional liability, difficulty concentrating, and slowed mental processing. Though these lingering TBI symptoms typically do not include such PTSD
symptoms as avoidance, reexperiencing, and hyperarousal, they may present difficulties when attempting to differentiate PTSD and postconcussive syndrome in a
clinical population (Stein and McAllister 2009). Additionally, both TBI and PTSD
can result in changes in such psychosocial functioning as difficulty socializing,
problems maintaining employment and relationships with family and friends, and
difficulty in effectively engaging in activities of daily living. It is important to consider the cause of these psychosocial functioning deficits when assessing patients
and their family members perceptions of the effectiveness of the DBS procedure. If
a the patient continues to experience deficits in psychosocial functioning following
the DBS procedure, it is important to know whether a prior history of TBI rather
than the PTSD contributes most to the current deficits. Studies of patients and their
family members perceptions and experiences are critically important to any future
large-scale clinical trial.
Though subjects with significant TBIas demonstrated by a positive history of a
concussion or worse traumawould not have been enrolled, it is widely recognized
that there may be significant brain injury with less severe trauma. The selection criteria would minimize the potential confound of concomitant TBI, but it would not
eliminate it. Some effort was therefore necessary to establish a measure that reflects
the psychosocial sequelae of mild to moderate TBI as opposed to those of PTSD.
It is important to account for the potential of enrolling subjects with TBI of lower
severity than that which constitutes the cutoff. Though TBI may not produce the
symptoms of avoidance, reexperiencing, and hyperarousal typical of PTSD, overlaps do exist (Stein and McAllister 2009). Following the recommendations of the
PTSD Work Group appointed by the intergovernmental Common Data Elements

Interagency Steering Committee, investigators would pay careful attention to TBI.
Investigators would also follow the committees recommendations for various
instruments (Kaloupek etal. 2010).
Attempts to differentiate subjects with PTSD alone (without TBI history) from
those with combined PTSD and TBI have, unfortunately, not been successful
(Bahraini etal. 2009). This likely owes to the fact that there have been relatively
few studies, perhaps because current therapies do not require such differentiation.
The situation may be different, given the surgical risks associated with DBS. It is
important to note that the proposed research was not a study of PTSD versus TBI.
If these measure correlated with DBS outcomes in the proposed study, however,
they would have been even more important in follow-up large-scale clinical trials
in which enrollment would be extended to include those patients who suffer more
significant TBI.
Some studies of long-term (>10year) cognitive sequelae from TBI have been conducted. Persistent deficits have been demonstrated in mental processing speed (e.g.,
the Symbol Digit Modalities Test, memory (Rey Auditory Verbal Learning Test),
and executive function. Interestingly, no differences were observed between subjects with PTSD and normal controls in the Rey Auditory Verbal Learning Test
(Brenner et al. 2009). Visual memory is similarly affected in mild to moderate
TBI (Miotto etal. 2010)and does not appear to be affected in PTSD (Vasterling
etal. 1998; Neylan etal. 2004). Digit span is also normal in PTSD (Neylan etal.
2004). The California Verbal Learning Test score is normal in PTSD but abnormal in TBI subjects tested 3 to 5years after injury (Dikmen etal. 2003). The Digit
Span, Spatial Span, Family Pictures, and Iand II subtests of the Wechsler Memory
ScaleIII would therefore have been investigated. In addition, the Benton Visual
Form Discrimination would have been administered. These measures would have
been correlated with DBS outcome for the purpose of future selection criteria for
the large-scale follow-up study. For example, does an abnormal California Verbal
Learning Test score predict a poorer DBS outcome?
Deficits that are consistently shown in post-mild TBI patients include slowed
mental processing speed, diminished memory, and impaired executive functioning (Mathias etal. 2004; Lundin etal. 2006). Neuropsychological testing in those
with PTSD typically shows deficits in attention and memory (Vasterling et al.
1998; Horner and Hamner 2002). Processing speed and executive functioning do
appear to be potential areas in which the two groups diverge (Neylan etal. 2004).
The following neuropsychological measures would have been administered preand post-DBS to assess any changes in cognitive functioning following surgery.
Additionally, the measures may be beneficial in assessing for any effects that TBI
may have on outcome.
1. Trail Making Test Parts Aand B
2. Stroop Color-Word Test
3. Wechsler Adult Intelligence ScaleIV Digit Symbol Coding
4. Wechsler Adult Intelligence ScaleIV Symbol Search
5. California Verbal Learning Test, Second Edition
6. Rey Osterrieth Complex Figure Test
7. Controlled Oral Word AssociationTest
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8. Wisconsin Card Sorting Test

9. Weschler Test of Adult Reading
PR EL I M I N A RY ST U D I ES
This would have been the first foray into a clinical trial of DBS for PTSD. No preliminary studies exist. However, related studies, such as the effects of repetitive
Transcranial Magnetic Stimulation on PTSD and the effects of area 25 DBS for
depression, offer the investigators assurance that the proposed studies are worthwhile (see Background and Significance section).
D ES I G N A N D M E T H O D S
Overview
The general design of this clinical trial would have involved placement of DBS
leads in the subgenu cingulum (area 25g) bilaterally. Subjects would then have
been randomized initially to two limbs of Part A:A-start and A-delayed. Part
A would have consisted of a double-blinded (subject blinded) dose-ranging
adjustments of the DBS systems, which would have begin approximately two
weeks following lead implantation (Part A-start) or following sham DBS adjustments for six months (Part A-delayed) analogous to a delayed start protocol.
Once programming has been optimized according a plateau in efficacy over a
time of observation of at least three months and an absence of bothersome side
effects, subjects would have entered a double-blinded study (Part B) in which the
DBS systems are randomized, according to a blinding protocol described later,
to being left powered on or powered off for six months. Acrossover would have
followed this having the stimulation powered off (if previously on) or powered
on (if previously off), again according to a blinding protocol. Note:The safety
monitoring committee could override the protocol should any significant concerns arise from the crossover between on or off DBS. Should this occur, the
observations up to the point of intervention by the safety monitoring committee
would have been carried forward.
The CAPS (primary clinical outcomes measures) would have been obtained at
the preoperative baseline and then upon the completion of the on stimulation
and off stimulation phases of Part B.Note:The same outcomes measure would
have been obtained at monthly intervals throughout but would have been treated
as secondary measures to be carried forward in the event of subject dropout. For
example, measures would have been obtained at the end of Part A-start and at the
start of active DBS in Part A-delayed in order to assess effects related to enrollment
in a closely supervised clinical trial and to nonspecific effects of the surgical procedure rather than to active DBS. Acompassionate use open-label extension study
would have been offered to subjects who complete Parts Athrough B.Healthcare
professionals providing postoperative care would have been able to adjust medications as indicated by routine care principles.
Rationale
Parts Aand B, in which the subject but not the DBS programmer would have been
blinded to the stimulation adjustments, are necessary. Note: Raters would have
been be blinded throughout the study. Although the initial DBS programming settings and subsequent adjustments would have been modeled after those used in
DBS of the subgenu cingulum for depression, whether these settings would have
proved optimal for PTSD cannot would have been established in advance. The programmer thus needed to enjoy flexibility in DBS programming. Sham DBS programming (Part A-delayed) would have been necessary to control for the effects
of the close postoperative care and testing. These experiences could either have
been be stressful or reassuring, and thus they affect the PTSD symptoms. The sham
DBS programming phase would have allowed determination and control for these
potential unintended effects.
CAPS obtained monthly would have been secondary and not used to determine
the possible therapeutic effect size unless the last secondary observation has to be
carried forward in the event of a dropout. Rather, the purpose of the interim CAPS
assessments was to determine the possible presence and duration of wash-in and
wash-out periods that would have been important for any follow-on large-scale
clinical trial. In addition, the monthly results, after detrending, will allow some
estimation of within- and between-subject variance in the outcomes measures that
would have been important for future studies.
For several reasons, healthcare professionals would have been at liberty to adjust
medications, as they would under routine medical care. First, the duration of
wash-in and wash-out effects are not known in advance. Consequently, if being
off medications is a selection criterion, there is no way to establish how long a subject would have to be off medications to rule out medication effects. Also, it is not
clear that subjects would be able to tolerate being off medications, and this could
pose considerable risk. One could require stable (unchanging) doses of medications prior to enrollment. Yet there exists no prior information to guide this decision. Potential synergistic effects between DBS and medications, particularly those
considered adverse, cannot be excluded. There are two potential consequences.
First, inability of reduce medications may exert a ceiling effect on DBS titration,
which could thereby prevent optimization of DBS. Second, the potential for DBS
to reduce medication needs and potentially medication-related side effects would
be lost. Indeed, changes in medication use would have been one of the secondary
outcomes measures.
Allowing the healthcare professional to improvise adjustments to medications
reflects future intended clinical use. Requiring abstention from medications or an
unchanging medication regimen would have risked loss of the ability to generalize
from the clinical trial to real-world use.
D ESC R I P T I O N S O F PR O C ED U R ES A N D M E AS U R ES
Instruments to be applied follow from the PTSD Work Group appointed by the
intergovernmental Common Data Elements Interagency Steering Committee
(Kaloupek etal. 2010), which also reference various measures from the Common
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Data Elements for TBI (Maas etal. 2010; Thurmond etal. 2010). To be obtained at
enrollment were the following six measures, which were taken from the Common
Data Elements for TBI (http://www.tbi-impact.org/cde/): (1) demographics
advanced; (2)socioeconomic status:education and social roleadvanced; (3)significant medical historyadvanced; (4) history of exposure to TBI (the Ohio
State University TBI Identification Method, Short Form); (5)behavioral history
advanced; and (6) screening for mild/moderate TBI. The study will also include
the following additional four measures:(1)Combat Exposure Scale; (2)Structured
Clinical Interview for DSM-IV Diagnosis; (3) Traumatic History Screen; and
(4)Life Stressor Checklist.
The following additional measures would have been applied at various times
during the study:(1)CAPS (primary outcome measure); (2)Hamilton Depression
Inventory (Ham-D); (3) Hamilton Anxiety Scale (Ham-A); (4) Columbia Suicide
Risk screen, SF-12 Quality of Life measure (Ware etal. 1996).
D E V ELO PM EN T O F S EL ECT I O N C R I T ER I A
Because there are no known selection criteria, the proposed research would have
used criteria based on best medical practices. Included are the following selection
criteria:
1. Confirmed diagnosis of PTSD that
a. Meets the Structured Clinical Interview for DSMIV DisordersPTSD
module criteria for PTSD.
b. Meets CAPS criteria for PTSD, which includes a history of traumatic
event(s) and a score of at least 3 on criteria A1 and A2; on > 1 cluster B,
> 3 cluster C and > 2 cluster D symptoms (Bahraini etal. 2009).
c. Has been made on a subject who is 19years or older.
2. Absence of suicidal risk, as measured by the Columbia Suicide Severity
Rating Scale.
3. Absence of significant TBI (see Traumatic Brain Injury as a Potential
Confound section). The stringent criteria regarding TBI may have made
it difficult to enroll sufficient number of subjects. If that appeared to be
the case, patients with nothing greater than mild TBI would have been
enrolled.
4. Absence of significant dementia as determined by the Dementia Rating
Scale.
5. Absence of structural brain damage as evidenced on MRI scan. The
rationale is that structural changes may interfere with surgical navigation
and intraoperative neurophysiological mapping.
6. Exhaustion of all reasonable attempts at pharmacological and behavioral
therapies. Patient should be resistant to at least four medications from at
least three different classesselective serotonin re-uptake inhibitors (Stein
et al. 2006), serotoninnorepinephrine reuptake inhibitors, bupropion,
antipsychotics, and tricyclic mirtazapineas well as resistant to an
evidence-based psychotherapy intervention such as prolonged exposure
therapy or cognitive behavioral therapy, stress management, and eye
movement desensitization and reprocessing according to the Cochrane

Database (Bisson and Andrew 2007). Because the study involves surgical
risks, the patient must have demonstrated a resistance to any other
intervention. An independent committee to assure candidacy, consisting
of at least one psychiatrist, one neurosurgeon, and one neurologist not
involved in the project, would have reviewed case information for each
subject in order to determine that the subject has indeed exhausted all
reasonable medical and behavioral therapies.
7. No current treatment involving valproic acid, aspirin, or other platelet
inhibitors.
8. The ability to provide informed consent.
9. An MRI scan consistent with the recommendations of the working group
on the Common Data Elements in Radiologic Imaging of Traumatic Brain
Injury (Haacke etal. 2010)in the context of chronic TBI will include
the following five elements:(1)T1-weighted imaging; (2)T2-weighted
imaging; (3)T2-weighted fluid attenuated inversion recovery;
(4)T2*-weighted gradient-echo imaging; and (5)diffusion-weighted
imaging.
Specific measures that would have been obtained for consideration in future selection criteria include the following:
1. History of exposure to TBI (the Ohio State University TBI Identification
Method, Short Form)
2. Behavioral historyadvanced
3. Screening for mild to moderate TBI
4. Combat Exposure Scale
5. Traumatic History Screen
6. Life Stressor Checklist
7. CAPS (primary outcome measure)
8. Ham-D
9. Ham-A
10. Columbia Suicide Risk screen
11. SF-12 Quality of Life measure
12. Trail Making Test Parts Aand B
13. Stroop Color-Word Test
14. Wechsler Adult Intelligence Scale-IV Digit Symbol Coding
15. Wechsler Adult Intelligence ScaleIV Symbol Search
16. California Verbal Learning TestSecond Edition
17. Rey Osterrieth Complex Figure Test
18. Controlled Oral Word Association Test
19. Wisconsin Card Sorting Test
20. Weschler Test of Adult Reading
An initial univariate regression analysis for each measure described here against
the change in the CAPS would have been performed. Any measure that fails to
demonstrate an adjusted R 2 of at least 0.3 would have been excluded from subsequent analysis. The remaining measures would have been subjected to data
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reduction by use of principle components analysis. This will be followed by a hierarchical series of logistic regression analyses that has proven effective in developing
predictions using diverse data will be used as described in peer-reviewed publications (Montgomery etal. 2000).
Specific Hypothesis
Values from these quantitative measures would have been normalized by z-score
transformation according to means and variances taken from normal controls in
the published literature. Multivariate and logistic regression analyses, including
Receiver-Operator-Characteristics-Curve analyses, would have been performed.
Aregression model, based on these measures, would have both anticipate and correlate with outcomes.
P O STO PER AT I V E D EEP B R A I N ST I M U L AT I O N
PR O G R A M M I N G A N D M A N AG EM EN T
Postoperative DBS programming follows from well-established neurophysiological and anatomical principles (Montgomery 2010). Safety limits with respect to
the effects of electrical current on brain tissue are well established, that being less
than 30C/cm2/phase. The number of microcoulombs is determined from (voltage/impedance) (pulse-width). The cm2 is the surface area of the active electrical contacts. Phase is the time of passing current in either the negative or positive
direction. These parameters are known to and controlled by the programmer. In
addition, the handheld device for programming (NVision programmer, Medtronic
Neuromodulation, Inc., Minneapolis, MN) has built-in warning systems that activate when unsafe stimulation currents are approached.
The exploration of electrode configurations and stimulation parameters would
have been conducted according to previously published and well-established algorithms (Montgomery 2010). The principles instantiated in the algorithms differentiate between problems of efficacy and problems of side effects. Problems of efficacy
are approached by increasing the volume of tissue activation and electrical current
density in the volume of tissue activation. For example, monopolar stimulation
(cathodes in the DBS lead and the Implanted Pulse Generator case as the anode)
provides a larger though less intense volume of electrical charge than does a bipolar
stimulation (in which the cathodes and anodes use the most dorsal and most ventral electrical contacts). Bipolar configurations, however, provide a more intense
volume of electrical charge. Use of multiple cathodes can increase the volume of
tissue activation. Increased stimulation voltage can also increase the volume of tissue activation.
Problems with side effects would have been approached by constraining the volume of tissue activation. One approach is to reduce the voltage (this risks reduction
in efficacy). Alternatively, progressively narrower bipolar configurations can reduce
the volume of tissue activation. Tripolar configurations can further constrain the
volume of tissue activation.
Specific Hypothesis
At least some programming assessment measures will demonstrate a dose
response effect as demonstrated in subject correlation between the outcomes
measure and the stimulation parameters that are based on multivariate regression analyses.
VA L I DAT I O N O F S I N G L E- B L I N D I N G PR O C ED U R E
Past experience indicates that while patients may know when the DBS is turned
on, they do not know when it is turned off. This has been documented in patients
with DBS of the subgenu cingulum for depression (Lozano et al. 2008). In an
unpublished study, 10 subjects with thalamic and subthalamic nucleus DBS for
Parkinsons disease or tremor were all turned to their on DBS condition. Every
five minutes, the DBS was pseudorandomly turned off or continued in the on
condition. The pseudorandom schedule was a fixed schedule, though the order
within the schedule was randomized to ensure five conditions in which there
was a transition between on to off and on to remaining on. Subjects were asked
to guess whether the stimulator was on or off. Nine of the 10 subjects were at
chance levels when deciding whether the stimulator was turned off or left on.
One of the 10 subjects who guessed above chance levels later reported persistent
paresthesias when in the on DBS condition.
The same procedure would have been used in the proposed research. The unblinded
programmer would have turned the DBS on to assess the clinical response. The programmer would have then randomly turned the DBS off or leave it on and would
have asked the blinded subject to guess whether the stimulation is on or off.
Specific Hypothesis
It was anticipated that subjects will be operating at chance in guessing whether the
DBS stimulation is off or on, according to a Fisher exact test with a p < .05. This
would have demonstrated that single-blinded procedure can be of use in follow-on
large-scale clinical trials, as it will allow for controlling subject bias in reporting
subjective symptoms used for titration of DBS.
O U TC O M ES M E AS U R E
The primary outcome measure is the CAPS.
Specific Hypothesis
The mean difference scoreseffect size, preoperative scores (minus postoperative
scores)and the variance of these measures would have been determined. Itwas
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anticipated that the mean effect size and variance would have permitted sufficient power for a follow-on large-scale study of efficacy in a feasible sample size.
Note:The analyses would not have tested whether DBS produces a statistically significant improvement in the CAPS score (this would require a much larger scale
study). The primary outcomes would have been, rather, reasonable estimations of
effect size and variance in the primary outcomes measure and estimates to PTSD
DBS specific adverse effects.
Adverse Event and Product Problem Monitoring

The US Food and Drug Administration (FDA) definitions of adverse events would
have beenused:
Adverse event:Any incident where the use of a medication (drug or biologic,
including human cell, tissue, or cellular or tissue-based product (HCT/P), at
any dose, or a medical device (including in vitro diagnostics) is suspected
to have resulted in an adverse outcome in a patient. Product problem (e.g.,
defects/malfunctions): Any report regarding the quality, performance, or
safety of any medical product. This category is selected when reporting device
malfunctions that could lead to a death or serious injury if the malfunction
were to recur.
In addition, the IRB definitions and policies would have been followed. The Adverse
Event and Serious Adverse Events reporting forms from the NINDS Common Data
Elements program would have been used (US FDA).
All incidents of adverse effects and product problems would have been reported
to the independent safety monitoring committee, the IRB, and the morbidity and
mortality conference in the Department of Surgery. At each quarterly meeting the
committee will determine whether the incidence of events or problems exceeds
those reported in the literature by the Fisher exact test using a p < .05.
T EST I N G SC H ED U L E
Preoperative:(1)demographicsadvanced; (2)socioeconomic status:education

and social roleadvanced; (3)significant medical historyadvanced;
(4)history of exposure to TBI (the Ohio State University TBI Identification
Method, Short Form); (5)behavioral historyadvanced; (6)screening for
mild/moderate TBI; (7)Combat Exposure Scale; (8)Structured Clinical
Interview for DSMIV Diagnosis; (9)Traumatic History Screen; (10) Life
Stressor Checklist; (11) CAPS; (12) Ham-D; (13) Ham-A; (14) Columbia
Suicide Risk screen; (15) SF-12 Quality of Life measure (Ware etal. 1996);
and (16) diagnostic MRI.
End of Part A(at such time as a stable response is achieved or after three
months, whichever comes first):(1)CAPS; (2)Ham-D; (3)Ham-A; and
(4)Columbia Suicide Risk screen.
End of Part B (following onset of active when stable response achieved or after
three months, whichever comes first):(1)CAPS; (2)Ham-D; (3)Ham-A; and
(4)Columbia Suicide Severity Rating Scale.
End of Part C prior to crossover and at end of crossover:(1)CAPS; (2)Ham-D;
(3)Ham-A; and (4)Columbia Suicide Risk screen.
Interim visits: (1) CAPS; (2) Ham-D; (3) Ham-A; and (4) Columbia Suicide Risk
screen.
D EEP B R A I N ST I M U L AT I O N SYST EM I M PL A N TAT I O N
Bilateral DBS systems would have been implanted because studies of DBS for depression and OCD have utilized bilateral stimulation (Burdick et al. 2009; Kennedy
et al. 2011). In the future, unilateral DBS may demonstrate sufficient efficacy, as
has been increasingly the case with DBS in the treatment of Parkinsons disease
(Walker etal. 2009). The risk attending doing only unilateral DBS initially is that
any effect may be too small to detect, however, and as a consequence a potentially
important therapy may be abandoned prematurely. Future follow-on studies may
examine the efficacy of unilateral DBS.
Implantation of the DBS system would have been performed according to standard surgical procedure for Brodmann Area 25WM (Cg25) DBS
implantation. The Activa DBS system for Parkinsons disease (Medtronic
Neuromodulation, Inc., Minneapolis, MN) would have been used including the
Model 3387 DBS lead and the Activa PC Implanted Pulse Generator. This system has FDA approval, and, like its predecessors, it has been implanted in many
tens of thousands of patients worldwide since its first description of use in 1979
(Dieckmann 1979). Medtronic Neuromodulation has the only FDA-approved
commercially available system in the United States. The investigators have
extensive experience in the use of this system, having conducted many hundreds of DBS surgeries.
Microelectrode Recordings for Target Localization

Microelectrode recordings would have been conducted as previously described
(Baker et al. 2004). The methods are well established and will therefore not be
reviewed here.
Postoperative Lead Localization

The lead would have been imaged postimplantation to confirm lead location
according to current neurosurgical procedures (this may include postoperative
MRI scans or preoperative MRI fused with CT images). Patient may have needed
to undergo an additional surgery if the lead or leads is or are found not to be in the
recommended location.
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S A M PL E S IZE EST I M AT I O N A N D J U ST I FI CAT I O N
Subjects would have had a prior diagnosis of PTSD independent of their enrollment in the proposed research. All subjects would have exhausted all reasonable
attempts at pharmacological and behavioral therapies as determined by their treating healthcare professionals. The latter would not have been involved in the proposed research.
Sample-size calculations performed on a mean of 70 on the CAPS having a
variance of 13 (as extracted from published trials) and an effect size of 10 points
demonstrated that 30 subjects would have been needed in order to have an 80%
probability of detecting the difference of 10 points to a p < .05. Numeric (computational) simulations were performed to estimate the effects of sample size on
reasonable estimates of means and standard deviations. This was based on the
mean and standard deviation of the CAPS reported in the literature. A population
of 200 CAPS was created by random number generator according to a mean of 83
and a standard deviation of 17. One hundred samples at each of increasing sample
size (2 to 100 in two subject increments) were randomly selected from the population. The mean and standard deviations for each sample were then plotted versus
sample size (Figure 17.1). A sample size of 15 provides a reasonable estimate of the
mean and variance of the population and should consequently allow a reasonable
estimate of sample size for follow-on large scale studies. At any rate, such was the
primary purpose of the proposed study.
Mean CAPS
Mean
150
100
50
0
20
40
60
Sample Size
80
100
80
100
Standard deviation
60
Std
40
20
0
20
40
60
Sample Size
Figure17.1 Results of computer simulations calculating mean and standard deviations

as a function of sample size. As can be seen, the distribution stabilizes at approximately
15 subjects (indicated by the arrow).
H U M A N S U B J ECTS
Recruitment and Informed Consent

After having obtained IRB approval and an Investigational Device Exemption from
the FDA, investigators would have recruited subjects to participate in the study.
The independent safety monitoring committee consisting of neurologists, neurosurgeons, and psychiatrists not directly involved in the proposed research would
have reviewed all subjects.
Human Subjects Involvement and Characteristics

Included would have been the following criteria:
1. Adiagnosis of PTSD according to the CAPS and the Structured Interview
for DSMIV Diagnosis.
2. Low suicide risk as defined by the Columbia Suicide Severity Rating Scale.
3. Absence of any structural abnormalities on brain MRI that could interfere
with the performance of the surgery.
4. Absences of TBI at the level of concussion or more severe trauma.
5. Ability to cooperate with the microelectrode recordings.
6. Ability to provide informed consent to participate in the research project.
7. Exhaustion of all reasonable attempts at pharmacological and behavioral
therapy as determined by the Safety and Monitoring Committee. (See
Development of Selection Criteria, criteria 7.)
8. Absence of concomitant medical or psychiatric disorders that significantly
alter the benefit to risk ratio (e.g., the presence of dementia).
9. Absence of cardiac pacemakers or defibrillators.
10. Absence of a history of depression that could reasonably require
electroconvulsive therapy.
11. Nonuse of aspirin or other agents that may inhibit platelet function for at
least two weeks.
12. Nonuse of valproate for at least four weeks.
Adequacy of Protection from Risks

This includes recruitment and informed consent and protections against risks,
including data security and sharing. The principal investigator answers directly to
the IRB regarding the safe conduct of the proposed research. With respect to the
intraoperative studies, the Departments of Neurology and Neurosurgery hold morbidity and mortality conferences to review any untoward events in the context of
surgery. Subject recruitment, data acquisition, and analysis and storage would have
been under the direct supervision of the principal investigator. The research neurologists and psychiatrist would have been seen subjects at frequent intervals. These
206
assessments would have included specific indicators of significant psychosocial

stress and suicidal ideation or intent. The Columbia Scale for Suicide Risk would
have been applied at each visit. Telephone numbers to contact staff on a 24-hour
basis would have been provided to the subjects.
Data and Safety Monitoring Plan

The independent safety and monitoring committee would have reviewed and
approved each prospective surgical candidate and the progress of research not less
than three times annually as described previously.
Potential Benefits of Research to Subjects and Others

The subjects may not have received any direct benefit from participation in the proposed research, or they may have experienced improvement of their symptoms as
a result of DBS. The knowledge potentially gained may lead to future clinical trials
that may prove the safety and efficacy of DBS for PTSD so that future patients and
society, in general, may benefit.
Importance of Knowledge To Be Gained

PTSD may be severely disabling and may even threaten life. There are many patients
who do not benefit from medications or behavioral therapies. These patients find
little hope or few alternatives to suffering and disability. DBS has been proven effective in patients with obsessive-compulsive disorder, depression, and other similarly
refractory psychiatric disorders. This experience, combined with considerable scientific evidence, provided confidence that DBS of the anterior cingulum may help
in PTSD. Proof of that benefit was the purpose of the proposed research.
R ES P O N S E TO T H E PR O P O S A L
Evidence to support reasonable expectations of clinical utility. One scientific

reviewer wrote that even a few pilot human subject cases would have been useful to assess the likely clinical impact. As it stands, the pilot data in the preliminary study section (DBS in other conditions) address research capabilities but not
clinical applicability of DBS to PTSD. As such, clinical utility is less certain in
comparison to DBSs application to other disorders where clinical utility is better
documented. Though the caution and keenly felt sense of responsibility evidenced
by the reviewers comments are commendable, the comments themselves recommend a false and, indeed, impossible course of action, because the very nature of
innovative clinical research militates against any demonstration of the same clinical utility as that enjoyed by established DBS applications. Requiring that the former ensure the same level of certainty as the latter would thus make the former
impossible, a danger discussed by Fins (2008), a leading ethicist in the field of DBS
research. Also, the pejorative connotation regarding the lack of demonstrated clinical utility of DBS for PTSD in the comment by the reviewer demonstrates a common misconception in which the absence of data is taken as negative data; hence
the pejorative connotation.
One reads between the lines of these comments to gather the impression that the
reviewer who made them understands their inherently paradoxical character. As a
means of perhaps overcoming this paradox, the reviewer suggests that a small case
series of some unstated number be obtained first. However, any reassurance the
reviewer may feel in making this suggestion is false, because the suggested actions
would be uninformative and thus not provide any basis to evaluate the proposal.
Statistical power and sample size are at issue here; the salient matter concerns the
determination of the number of subjects sufficient for ensuring a reasonable probability (however this is defined) of demonstrating a meaningful effect (however this
is defined). Underpowered studies, in terms of statistical power and sample size,
risk committing a type II error, which one may define as the failure to find a difference where one actually exists, as well as a type Ierror, which one may define as the
discovery of a difference where no difference exists.
Consider the situation in which a treatment is 70% effective and no reasonable
alternatives exist. Assume three cases would have been sufficient to reassure the
reviewer described previously. According to the Bernoulli distribution, there is a
3% chance that all three cases would not show a benefit. There is a 19% chance
that only one of the three would demonstrate a benefit, and this result could lead
one to the erroneous conclusion that DBS is only 33% effective. Were the reviewer
to extrapolate from these cases that the treatment was ineffective, he would only
compound the error.
Now consider the situation in which the risk of a serious complication is 3%
but it happens that one of the three cases has a serious complication that produces
the false impression that the complication rate is 33%. Must the research be abandoned? Calculating the Bernoulli probability, one finds that the chance of one of
the three cases having a serious complication is 8%.
The converse is even more striking:What if the actual risk of a serious complication is 10% and is therefore deemed unacceptable? The Bernoulli probability of the
first three cases avoiding serious complication is 73%. Does this mean that those
who sit in judgment should conclude that it is appropriate to continue?
Requiring that one perform an initial small case series raises certain ethical concerns. The case series likely will be underpowered, which means that no reasonable
statistical and scientific inferences can be drawn and that any data produced would
prove useless in terms of assessing the value of a clinical trial. This being so, one
would think an IRB would no doubt have a difficult time sanctioning a small case
series that has a high probability of being underpowered, because it will prove statistically and scientifically uninformative and consequently unethical. Yet experience with the IRB has been to the contrary.
Several experts in PTSD research have argued that pilot studies (and, by implication, small case series) should not be done (Leon and Davis 2009)if, rather than
efficacy or safety, the purpose is to determine the appropriate sample size for the
design of subsequent clinical trials. If the issue of feasibility is not in doubt, apparently investigators are encouraged to forge ahead with a full-fledged clinical trial
to demonstrate efficacy and safety. The argument is that it is impossible to make an
208
accurate estimate of the probability of benefit and risk, based on effect size and variance, from anything less than a full-fledged clinical trial. As a full-fledged clinical
trial places subjects at risk, most investigators or reviewers (such as the one quoted
earlier) would want some assurance as to the positive outcomes. This situation thus
represents a paradox.
A second paradox follows on the heels of the first, and it involves the question,
faced by proponents of full-fledged clinical trials, as to how they may calculate
beforehand the sample size for the full-fledged studies. The implications of underpowering for both a type Iand a type II statistical error attend this second paradox
every bit as much as they do the first. Aseries of interim analyses based on repetitive assessments of sample size and variance in the primary outcome measures,
which go on until such time as statistically sufficient sample size is reached, recommends itself as an expedient. Yet such an expedient faces the risk of alpha inflation
owing to multiple repeated analyses. Alpha inflation increases the risk of a spurious statistical significance. Prevention is attempted by increasingly conservative
p values. However, this risks such a conservative p value that there is little chance
of demonstrating a statistically significant result. Thus there is the risk of a type II
error.
One cannot escape these paradoxes; one may only reach reasonable compromise regarding them. It was in the spirit of attempting to forge such a compromise
that the grant proposal submitted included numerical simulations of the effects of
sample size on estimates of effect size and variance. These numerical simulations
were achieved by creating a population of subjects using effect sizes and variance
in conformity with published studies of nonsurgical treatments. The simulations
were performed with the recognition that the population they constituted was
not exactly the same as the population to be studied in the proposed research.
Repetitive sampling without replacement of this population was conducted with
increasing sample size. The histogram of the variability of the effects sizes and variances with different sample sizes becomes asymptotic at 15 subjects (Figure 17.1).
Asample size of 20 (with 5 subjects added in case of some subjects not completing the study) would thus arguably represent the minimum from which could be
made a reasonable estimate of the effect size and variance for the exact population
under consideration. The results from the initial 20 subjects could subsequently be
used to calculate a reasonable sample size for future studies to demonstrate clinical efficacy.
Assessment of Risk
Assessment of risk complements concerns and expectations of clinical utility.
Several reviewers referred to DBS as highly invasive brain surgery, though they
failed to specify what they meant by use of such fraught terms, thus leaving one
with an unqualified impression of inappropriate risk. Yet such a statement and its
connotation belie clinical experience. Extensive reviews offered in the proposal
demonstrate relatively consistent surgical risks regardless of disease or DBS target. There exists no anatomical, physiological, or biochemical reason to suspect the
target proposed would be any different in terms of the surgical risk of directing
DBS for PTSD. Ablative surgery of the proposed target was not associated with
any greater risks than were other targets. One would thus consider it reasonable to
generalize from DBS surgery in other targets and conditions to the DBS target for
PTSD in assessing surgical risk.
Similarly, one can draw from DBS-induced risks associated with the treatment of
other disorders inferences as to the risk attending stimulation of the PTSD target.
In view of the close observations the research subjects would be under in this case,
the risks are small. Though issues were thoroughly discussed in the grant proposals, they perhaps were not discussed with sufficient clarity. One cannot exclude the
possibility, however, that reviewer bias blunted any effect of reasoned argument.
If it were to be deemed inappropriate to generalize from DBS for other surgeries to DBS for PTSD, whether for the same or a different target, paralysis would
result, because any reasonable estimate of risk for PTSD DBS would be impossible
to establish beforehand. If one considers it reasonable to generalize from DBS for
other conditions and other targets, however, then one must conclude that DBS for
PTSD is no more invasive than is DBS with respect to such accepted indications as
Parkinsons disease and Essential tremor.
Maintaining that DBS is somehow more invasive in PTSD than it is in Parkinsons
disease or Essential tremor leaves unanswered the question as to how exactly one
determines that it is so. It can only be that the invasiveness of DBS is conditional on
the expectations of benefit. DBS in Parkinsons disease and Essential tremor is thus
less invasive by virtue of expectations for benefit, while DBS for PTSD is more
invasive by virtue of the uncertainty of benefit. Yet such uncertainty always attends
innovative (nonincremental) clinical trials. The reviewers apparently encountered
difficulty in disentangling potential benefits from potential risksdifficulty that
caused them to overestimate the latter.
The Unique Nature of Surgical Clinical Trials

The characterization of DBS for PTSD as highly invasive rests on Omission bias
(Ritov and Baron 1990; Asch etal. 1994)and carries a negative connotation consequent to the unique nature of surgical trials (Fins 2008). DBS for PTSD or any
other condition is no more invasive than is chemotherapy in the treatment of certain cancers. Indeed, the risk of mortality for inpatient administration of chemotherapy is much higher than the risk of DBS (OBrien etal. 2006). Even in the case
of Parkinsons disease, DBS produced fewer side effects than did best medical management (Weaver et al. 2009). From the patients perspective, then, medications
may be more invasive than DBS.
Surgical interventions are held in quite a different regard than are medical
interventions, even in such instances in which the latter are more dangerous. The
apparent proximity of cause to effect, particularly if that effect should happen to
be adverse, perhaps contributes to this bias; more degrees of separation obtain
between physicians prescribing a medication and the complications that arise from
it than between a surgeon and her actions (Fins 2008). Yet no matter how many
degrees of separation there may be, they are illusory from the patients standpoint.
The proximity of actor to effect influencing ethical positions is seen in the trolley
car dilemma in which a person is standing at the switch of a railway where a trolley
car is approaching out of control. Atrolley car experiences brake failure and goes
210
hurtling down the tracks, jeopardizing the lives of five individuals standing downfield. A sixth individual observes this situation. She notices also that she stands
near a switch that, if thrown, would send the trolley down a siding rather than into
the five endangered individuals. Along the siding downfield, however, stand two
individuals who would be struck by the trolley should the switch be thrown. The
question becomes, then, whether the individual near the switch should throw it.
A subsequent variation on the trolley car dilemma further complicates the issue.
The sixth individual no longer stands near a switch but on a bridge near a large man
who holds a heavy bag. The sixth individual realizes that were she to shove the man
from the bridge and onto the tracks, she could stop the runaway trolley and save
the other five individuals downfield. Should she give that large man the fatal shove?
Asked to put themselves in the place of the sixth individual, respondents tend to
show greater willingness to throw the switch than shove the man, despite the fact
that throwing the switch results in double the deaths. Proximity of the actor to the
consequence perhaps explains this tendency. Throwing the switch seems a less personal act than does shoving the man.
The example of endarterectomy illustrates this problem of characterizing procedures as highly invasive. In selected patients endarterectomy is considered reasonable, despite the fact that its complication rate is greater than that of DBS (Goldstein
etal. 1997). Certainly, most would not consider endarterectomy as highly invasive
and a risk for serious brain injury (anonymous scientific reviewer), but the patient
undergoing this procedure might disagree. Patients undergoing endarterectomy,
an invasive procedure typically of the neck rather than the brain, risk certain neurological complications (not the least of which being stroke, a serious brain injury).
To someone who does not know how the surgery is performed, the endarterectomy procedure and any possible complications appear qualitatively equivalent
to that of DBS. The reviewers would have found no similar equivalence between
endarterectomies and DBS. The difference may lie in the fact that, unlike an endarterectomy, DBS requires that the surgeon operate directly on the brain. Greater
proximity between surgical actions and adverse events thus attends DBS. What
remains unclear, however, is whether there exists any ethical distinction between
adverse effects accompanying DBS and those accompanying endarterectomy.
Proximity of Pathophysiological Cause and Therapeutic Effect

Although not specifically raised in the formal reviews, the proximity of pathophysiological cause and therapeutic effect is operating in the subtexta mechanistic
rationale that links in lockstep a transition from cause to effect, in other words.
Such a rationale would be hard to construct for DBS and PTSD. Perhaps this rationale informs the reasoning of one reviewer, who wrote: My own review of the
literature suggests that the psychiatric clinical trial are small and methodologically
challenged. The importance of a scientific rationale is amply demonstrated in the
resurgent interest in DBS for Parkinsons disease, in which there did appear to be a
direct mechanisms link between DBS mechanisms and Parkinsons disease pathophysiology (Montgomery 2011). However, the posited theories of pathophysiology
and DBS mechanisms were wrong (Montgomery 2011). This suggests that merely
having some intuitive sense overcomes the sense of uncertainty (Johnson-Laird

2006).
Expectations as to prior demonstrations of cost effectiveness and social utility also inform the recommendations made by the reviewers. They object that,
because the study would require several years to complete, the cost of providing
DBS for patients with PTSD would ultimately prove too high. If the estimate of
the applicable population is very small relative to the heterogeneous population
of PTSD, one reviewer wrote, the costly and invasive application of DBS may
not be as attractive or cost efficient as other means of treatment; e.g., improving
compliance, treatment of comorbid conditions. The reviewer failed to appreciate the unique circumstances of the patient population for which the study was
proposed. Refractory to alternatives, these subjects look forward to few if any
other means of treatment geared toward improving compliance or relieving
comorbid conditions.
Though resolution of these issues would be welcome, it is not germane to the
clinical trial. Clinical investigators and researchers should not worry about questions like:what is a reasonable price to pay for relieving a patient from incapacitating PTSD? There is no way, a priori, to render any reasonable judgment. One can
hold out hope for a less invasive and expensive treatment, but there is no telling
when such a thing may come along. In the interim, suffering and debilitation will
continue unrelieved.
Even clinical situations with extensive level-1 Evidence-Based Medicine support require investigators to exercise judgment (Montgomery and Turkstra
2003). Judgment is needed even more in innovative clinical trials and other situations in which level-1 Evidence-Based Medicine does not exist. In my opinion,
reasoned judgment is often altogether lacking. This may owe to the fact that
those who should be exercising it have received little education or training in
how to do it effectively. One is left to common intellectual heritage and experience and perhaps the common sense of the scientific community, which, to
paraphrase a quote attributed to Albert Einstein (Bell 1951), is nothing more
than the common prejudice.
What are the means by which to effect such an education so as to improve evaluate proposals for innovative DBS clinical trials? Can this improvement be realized
in a single grant application limited to 15 or 20 pages that is permitted but a single
resubmission? One doubts that such an undertaking is possible. At the very least,
some rethinking may be in order.
S U M M A RY
Whether DBS could be effective for PTSD or whether such a clinical trial should
be undertaken is not the main point of this chapter. Rather the question is how
clinical scientists and administrators deal with difficult surgical clinical trials,
particularly those for psychiatric disorders. The risk is that Omission bias and
unsophistication regarding the statistical necessities of such trials may make it
difficult to conduct such studies, potentially denying patients relief from severe
suffering disability.
212
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18
Deep Brain Stimulation and

Insights to Pathophysiology
andPhysiology
W H Y D EEP B R A I N ST I M U L AT I O N I S
R EM A R K A B LY EFFECT I V E
Deep Brain Stimulation (DBS) is perhaps the most remarkable treatment for
movement disorders specifically, and neurology generally, since the development of levodopa for the treatment of Parkinsons disease. Indeed, a paradigm
shift followed the rational development of levodopa therapy upon demonstration
that levodopa reverses catatonia in rodents treated with dopamine antagonists
and that Parkinsons disease is associated with a loss of dopamine, which was
correlated with neuronal degeneration of the substantia nigra pars compacta.
It solidified the paradigm of pharmacology as physiology: that physiology and
pathophysiology could be inferred from the neurochemistry reflected in the
pharmacology (Montgomery 2004). Unfortunately, the paradigm is wrong. An
explanation is beyond the scope of the present. Suffice it to say at present its
long history dates to Galen (130200 ce) which derived from Aristotles physics
(Aristotle 2001).
In a similar manner, DBS has ushered in another narrative quite distinct from
the notion of Parkinsons disease as a dopamine deficiency, the rational treatment
of which involves replacing the dopamine effect. Whatever the effects of DBS on
Parkinsons disease, they are not mediated by dopamine (Hilker etal. 2003). It is
remarkable that DBS has provided considerable evidence against theories of pathophysiology prevalent at the time DBS was discovered by Benebid and colleagues
(1987). (Actually, Benebid and colleagues were credited with the discovery in the
same sense that Christopher Columbus was said to have discovered America.
Rather, Christopher Columbus was the last man to discover North America [the
Viking having preceded him], as has been said, as there was no subsequent need to
discover North America.)
The prevailing theory of Parkinsons disease pathophysiology was that degeneration of the dopamine neurons in the substantia nigra pars compacta set in
motion a sequence of eventsdescribable as a series of one-dimensional pushpull
18. Deep Brain Stimulation and Insights to Pathophysiology and Physiology217
mechanicsthat resulted in overactivity of the globus pallidus interna (globus

pallidus interna) and subsequent suppression of the thalamus and motor cortexs power to inhibit movement. The therapeutic effects of DBS were interpreted
in light of the prevailing theory. The therapeutic effects were thus attributed to
high-frequency stimulation, which caused inhibition of globus pallidus interna
neurons and release of the thalamus and motor cortex, freeing those centers to
initiate movement (Montgomery 2012).
Research conducted in the context of DBS clearly demonstrates that DBS
in the vicinity of the globus pallidus interna activates the output of the globus pallidus interna neurons to produce initial inhibition of the thalamic neurons. For many neurons, however, initial inhibition was followed by rebound
excitation. Contrary to prevailing theories dependent on the notion of globus
pallidus interna regulation of the thalamus by inhibition, then, globus pallidus
interna influences may be more appropriately considered delayed excitation
(Montgomery 2006). According to the prevailing theory, DBS in the vicinity
of the globus pallidus interna should worsen rather than improve Parkinsons
disease symptoms.
DBS in the vicinity of the subthalamic nucleus was similarly presumed to inhibit
the subthalamic nucleus. The basis for this presumption was that the subthalamic
nucleus neurons are overactive and drive the overactivity of the globus pallidus interna. Considerable evidence suggests that overactivity of the subthalamic
nucleus neurons is neither a necessary nor a sufficient condition for Parkinsons
disease (Montgomery 2008).
T H E I M P O R TA N C E O F T H E PR E VA I L I N G
PR ED I S P O S I N G T H EO R I ES
The key point from this discussion is that the preexisting theories of pathophysiology essentially determined the interpretation of the observations regarding
mechanisms of action. The interpretation of the therapeutic mechanism of DBS
in the vicinity of the globus pallidus interna actually followed on theories of the
therapeutic mechanisms of pallidotomy, which similarly improved the symptoms
of Parkinsons disease. The similarity of clinical benefit was taken as evidence of
similar mechanisms.
This extrapolation rests on a number of logical fallacies. The first is the Fallacy
of Psueudotransitivity, which may be expressed in the following form:If a implies
c and b implies c then a implies b. In this case a is pallidotomy reduces globus
pallidus interna output, c is improves Parkinsons disease, and b is the mechanism of DBS in the vicinity of the globus pallidus interna; then the false conclusion is that reduced globus pallidus interna out is the same as the mechanism
of DBS in the vicinity of the globus pallidus interna. The second logical error is
the Fallacy of Confirming the Consequence, which is of the form if a implies b is
true and b is true then a is true. In this case, a is DBS in the vicinity of the globus
pallidus interna reduces globus pallidus interna output, which similar to pallidotomy, should improve Parkinsons disease symptoms and b is Parkinsons disease
symptoms are improved. As DBS in the vicinity of the globus pallidus interna
does improve Parkinsons disease symptoms, then b is true, from which it is falsely
218
concluded that DBS in the vicinity of the globus pallidus interna reduces globus
pallidus interna output.
The theory of the mechanisms of action of pallidotomy, which directly lead to the
early theories regarding the mechanisms of action of DBS in the vicinity of the globus pallidus interna, were contradicted by numerous observations made virtually
since the theory of globus pallidus interna overactivity was described (Montgomery
2007). Yet the theory of globus pallidus interna overactivity in Parkinsons disease
has survived for more than 20 years, having proponents to this day. There must
have been something about the theory that allowed it to persist despite the contrary
evidence. It may well be that the theory of globus pallidus interna overactivity was
intuitively appealing. Its underlying one-dimensional pushpull dynamics have
been popular since Aristotles notion of contraries (Aristotle 2001). Humans prefer
an intuitively appealing story to no story at allindeed to the point that they easily
overlook contrary evidence (Johnson-Laird 2006).
AVO I D I N G T H E I N T U I T I V E A PPE A L BY I N S I ST I N G
O N A C O M PL E T E E X PL A N AT I O N
The problem with intuitively appealing theories is that they seem reasonable in
that their understandability offers some comfort and thus possibly occasions complacency. Critical and forceful confrontation with all the facts and insistence on a
complete understanding offer an antidote.
In the case of the pathophysiology of Parkinsons disease, the explanation
offered by the theory must extend from the pathoetiological events, such as
degeneration of the dopamine neurons in the substantia nigra pars compacta,
to the end effector organs, specifically the lower motor neuron in the brainstem
and spinal cord that drive the muscles (comprising the motor unit) to produce
the abnormal behavior.
Any theory whose explanations stop short invites extrapolation from the point at
which the considered evidence leaves off before reaching the lower motor neurons.
Extrapolation is different from interpolation. The latter defines a trend anchored
by reference points at the beginning and the end. In this case, the range of possible interpolations are constrained by the anchors at each end. With extrapolation,
there is only a single end that is fixed by evidence. The projection from the evidence is thus unconstrained and admits of a potentially infinite number of possible
projections.
The problem of extrapolation for an incomplete theoretical explanation is also
reflected in the so-called Inverse Problem. In the case of motor control, any movement trajectory effected by sequences of joint rotations may be effected by a variety
of different muscular synergies. It is impossible to infer the exact muscular synergy from observation. One may infer only the movement trajectory. It is likewise
impossible to predict the exact pattern of muscle synergies underlying abnormal
movement, activity in the motor cortex, and the basal ganglia.
Admittedly, it is unsurprising that prior theorists felt no compunction to extend
explanations of pathophysiology to the level of the motor unit. The Henneman Size
Principle argued that the orchestration of motor unit behavior owes to the biophysical properties of the lower motor neurons, thereby relieving the basal ganglia,
as well as the motor cortex, of the responsibility to account for motor unit control. There now is evidence that the motor unit recruitment order is affected in
Parkinsons disease and normalized by high-frequency DBS (Montgomery 2013).
There are multiple levels of motor unit orchestration over numerous time scales,
which implies the presence of underlying dynamics over different bandwidths. At
the lowest level is the order of motor unit recruitment. At the next level is the time
course of motor unit activations. At the next level are synergies between agonists
and antagonists, and at the final level is control of sets of agonistantagonists over
multiple joints. It is now clear that all these levels of motor unit control are affected
by Parkinsons disease (Montgomery 2013). Any theory of basal ganglia pathophysiology must therefore account for changes at all levels of motor unit control. Any
theories that do not must be recognized as incomplete.
EN T ER TA I N I N G T H E W I D EST T H EO RY- D I F F ER EN T I A L
D I AG N O S I S P O S S I B L E
The notion of theory-differential diagnosis is analogous to the differential diagnosis

physicians and healthcare professionals construct in light of a patients constellation of symptoms and signs. A good clinician will entertain the widest range of
diagnostic possibilities reasonable and give each its due consideration. An unwise
clinician jumps to a conclusion of a single diagnosis and therefore risks misdiagnosis. As Tolstoy noted, The totality of causes of phenomena is inaccessible to the
human mind. But the need to seek causes has been put into the soul of man. And
the human mind, without grasping in their countlessness and complexity the conditions of phenomena, of which each separately may appear as a cause, takes hold
of the first, most comprehensible approximation and says:here is the cause (Pevear
and Volokhonsky 2007).
It is not simply a matter of neglecting an actual diagnosis; leaping to a single
diagnosis risks commission the Fallacy of Limited Alternatives, which may be
expressed in the following form:If a, b, and c implies d and b and c are found false
and d is true, then a must be true. The falsity of b and c has no impact on the truth
or falsity of a. Indeed, this can be seen when b and c are removed and one is left with
if a implies d is true and d is true then a is true, which is the Fallacy of Confirming
the Consequence. The question arises as to how many scientific reports contain a
theory-differential diagnosis, that is, a reasonable, consistent array of alternative
theories.
W H AT I S K N OW N A B O U T D B S M EC H A N I S M S
O F T H ER A PEU T I C ACT I O N?
What is known about the therapeutic mechanisms of action? The honest answer
is:nothing. Until there is some complete better theory of the pathophysiology of
Parkinsons disease and similar disorders, it will be impossible to know the therapeutic mechanisms. Researchers may at most be able to demonstrate those mechanisms
that are not therapeuticby demonstrating a failure of any particular mechanism
to correlate with the presence of disease symptoms, for example. However, the
220
complexity and interconnectedness of the basal ganglia-thalamic-cortical system

(and others) commonly means that clear exclusion of any particular mechanism
is highly problematic. Even attempts to quantify degrees of correlation are highly
problematic and often require assumptions unmet in experimental conditions.
Another approach is captured by the philosophical notion of necessary and sufficient conditions. For example, a specific condition A may be necessary for an effect;
the effect is not possible without the presence of the condition A. The condition A
may be necessary but it may not be sufficient. In other words, some other condition is necessary in conjunction with condition A to produce the effect. Condition
B may not be necessary, meaning that the effect may be present in the absence of
condition B. However, condition B may be sufficient:The effect will occur if condition B is present.
The utility of this approach lies in its being able to disprove necessary or sufficient conditions. It is only necessary to demonstrate a single example of the effect in
the absence of condition A to demonstrate that condition A is not a necessary condition. It does not matter how many times the effect was paired with the presence of
condition A. Similarly, one need only demonstrate a single case in which the effect
was present without condition A to demonstrate that condition A is not a sufficient
condition. It does not matter how many other times the effect was associated with
the presence of condition A.
If there is one example out of a multitude where condition A was present without
the presence of the effect, numerically there will be a correlation. Yet despite the
high correlation, condition A may be excluded as a necessary condition. Similarly,
there may be a multitude of occasions where condition A was associated with the
effect but only one where there was not association. The incidence of condition A
with the presence of effect will produce a high correlation. One may nonetheless
assert that condition A is not a sufficient condition. Now one may demonstrate that
even in the face of high correlations, condition A is neither necessary nor sufficient.
Condition A is, in other words, epiphenomenal to the effect.
Application of the technique of necessary and sufficient conditions may be
implemented by defining some condition A and then identifying or creating circumstances in which condition A is present and others in which it is absent before
looking at the presence or absence of the effect. For example, testing whether
high-frequency neuronal activity of globus pallidus interna and subthalamic
nucleus neurons is causal to Parkinsons disease requires creation or identification of situations in which globus pallidus interna or subthalamic nucleus neurons
are increased and situations in which they are found not to be increased in the
presence of parkinsonism, if one assumes that one has reference data to determine
whether the activity is increased. In the case of subthalamic nucleus, recordings
in patients with Parkinsons disease and patients with epilepsy demonstrated no
significant differences in the distribution of discharge frequencies or in the coefficients of variation of the discharge frequencies (Montgomery 2008). Studies in nonhuman primates before and after induction of parkinsonism using the neurotoxin
n-methyl-4-phenyl-1, 2, 3, 4-tetrahydropyridine demonstrate unchanged globus
pallidus interna and subthalamic nucleus discharge frequencies in the presence of
parkinsonism (Montgomery etal. 1986; Wang etal. 2009). It is clear that increased
globus pallidus interna or subthalamic nucleus neuronal discharge frequencies are
not a necessary condition.
In order to determine whether increase neuronal activities in globus pallidus

interna or subthalamic nucleus is a sufficient condition, it is necessary to demonstrate the absence of parkinsonism in the presence of increased globus pallidus
interna and subthalamic nucleus neuronal activities. DBS may be used to drive
the globus pallidus interna and subthalamic nucleus neurons at a high rate, and
in those circumstances parkinsonism improved (Montgomery 2006). The presence
of increased globus pallidus interna and subthalamic nucleus neuronal activities
is clearly not a sufficient condition. The logical conclusion is that in those circumstances associated with increased globus pallidus interna and subthalamic nucleus
neuronal activities in the presence of parkinsonism, the increased activities were
epiphenomenal rather than causal to parkinsonism.
The same analysis may be applied to the notion of increased beta (10 Hz to 30
Hz) oscillations in parkinsonism. In some studies, a significant number of patients
experienced parkinsonian symptoms without an increase in beta oscillations.
Increased beta oscillations is therefore not a necessary condition. Demonstrating
that increased beta oscillations in the absence of parkinsonism is more problematic. If one assumes that beta oscillations may be increased by DBS at the beta
frequencies, then DBS at those frequencies may be tested for their effect on the
parkinsonian symptoms. Some studies have demonstrated that stimulation in the
beta frequencies do not worsen parkinsonism; it actually makes some symptoms
better. At least for those symptoms, then, increased beta oscillations is not a sufficient condition (Huang etal. 2014). The logical conclusion is that the increased beta
oscillations are epiphenomenal.
Because the pathophysiological mechanisms of disorders of the basal ganglia are
unknown in most cases, it is not possible to state which types of brain responses
are the therapeutic mechanisms. Much has been learned about brain responses,
however, even if they cannot be attributed a causal role. It has been learned that
DBS does not inhibit neurons, at least not directly. It has also been learned that DBS
activates neuronal elements, particularly in the form of generating action potentials, axon terminals having the lowest threshold. Finally, it has been learned that
the axons themselves (particularly the nodes of Ranvier), the neuronal cell body
(soma), and dendrites have higher threshold.
DBS activates neurons to produce orthodromically and antidromically conducted action potentials. The orthodromically conducted potentials may end
locally for local axons or project to downstream structures in terms of efferent
axons. Action potentials may be generated in axons that are in transit. One immediate effect of the orthodromic action potentials is the release of neurotransmistters
from the presynaptic terminals. Because gamma amino butyric acid (GABA) is the
most common neurotransmitter, particularly in the basal ganglia, DBS is associated with local release of GABA, which typically causes inhibition in the postsynaptic neuron, which accounts for the suppression of neuronal activities within such
DBS targets as globus pallidus interna and subthalamic neurons.
Interpretation of this suppression of local neurons due to increased release of
GABA in the target is problematic, because these same neurons that are inhibited
may nonetheless continue to generate action potentials in the axons of these same
neurons (McIntyre and Grill 1999). There may be reduced neuronal action potentials when recording within the DBS structure. Yet increased output from the neurons of that structure continues. To emphasize the notion of local inhibition as a
222
therapeutic mechanism is therefore inappropriate, because the output of the structure is the same as if the neuronal activities within the structure were increased.
The event that is causal is unknown.
Action potentials in axons exiting the DBS structure go on to cause changes in
neuronal activities in downstream structures. One might think that these effects
can be predicted by the neurotransmitter released by the presynaptic terminals of
the DBS structure efferent axons terminating in the downstream structure. Because
GABA is the most common neurotransmitter, particularly in the output of basal
ganglia nuclei, the predicted effect is inhibition of downstream structures. However,
this is not entirely true:Many neurons, such as the basal ganglia relay nucleus of the
thalamus, display postinhibitory rebound excitation. Recording in the ventral lateral pars oralis nucleus of the thalamus, for example, demonstrates a reduction in
thalamic action potentials approximately 3 ms after a globus pallidus interna DBS
pulse. This inhibition is followed by a remarkable rebound excitation, which for
many thalamic neurons results in a net increase in thalamic neuronal activities in
response to DBS in the vicinity of the globus pallidus interna (Montgomery 2006).
Antidromically generated action potentials may propagate backward up the
axon to the neurons of origin, whether locally or outside the DBS target. It is now
clear in a nonhuman primate model and humans that DBS in the vicinity of the
subthalamic produces antidromic activation of cortical neurons, presumably by
depolarizing axons passing to or by the subthalamic nucleus.
The antidromic action potentials may greatly change the excitability of the parent neuron by depolarizing the neuron soma and dendrites. Also, because there
is a relatively massive discharge in the dendrites by retrograde propagation of the
action potential, the possibility of coincident depolarizationsone from the antidromic action potential and others from the usual synaptic inputs to the parent
neuronmay represent a source of Hebbian learning and may underlie some of the
long-term or plastic changes observed clinically with DBS. Antidromically conducted action potentials can reach a branch point with subsequent orthodromic
conduction to other neurons.
These effects are referred to as first-order effects, that is, effects on the local neuronal elements, particularly axon terminals and axons in the vicinity of the DBS
pulse. These include the orthodromic and antidromic response described previously. Second-order effects include the effects of neurotransmitter release from the
axons excited by the first-order effect. These include the effects of neurotransmitters
from presynaptic terminals within the electrical field generated by the DBS pulse
and the presynaptic terminals of efferent axons from the vicinity of the electrical
fieldthe effects of the globus pallidus interna DBS pulse on the thalamic neurons
described previously, for example. Local effects may include the effects of the DBS
pulse on glial cells and the local microvasculature.
Second-order effects generate third-order effects. The release GABA onto thalamic neurons in response to globus pallidus interna DBS, for example, produces
postinhibitory rebound excitation, which generates postsynaptic effects on neurons
that receive inputs from such thalamic neurons as cortical neurons. Action potentials conducted orthodromically generated by antidromic action potentials that
reach the axon collateral may activate neurons innervated by the axon collaterals.
Axon collaterals are typically local. In the case of cortical neurons activated by
antidromic action potentials, the axon collaterals of these neurons excite neighboring cortical neurons.
One can anticipate fourth and higher orders of effects as the third-order effects
percolate and reverberate through the neural networks. This may account for the
changes seen once DBS is discontinuedthe reduction in globus pallidus interna
neuronal activity following excitation by a train of DBS pulses in the vicinity of the
subthalamic nucleus, for example. DBS-related activities percolate and reverberate
throughout the neural networks over time, engendering complicated interactions
between all of these effects and ongoing DBS pulses when delivered continuously
for therapy. Indeed, there is not solely a monotonic increase or decrease in neuronal activities that remain the same when DBS is started. There is a complex evolution in the neuronal responses, at least in the subthalamic nucleus on one side in
response to DBS in the vicinity of the other subthalamic nucleus. The component
in the complex evolution of response that proves therapeutic is unknown. These late
effects may not be trivial, however, because they may explain why some symptoms
take time to respond.
C L A I M S W I T H O U T STA N D I N G, C L A I M S W I T H O U T VA L I D I T Y
Any physiological or behavioral change associated with DBS of a particular structure cannot be attributed to the structure stimulated. One cannot state, for example, that the effects of DBS in the vicinity of the subthalamic nucleus on speech
reflects a specific role of the subthalamic nucleus in speech. This statement does
not exclude a role of the subthalamic nucleus in speech. It simply states that the
DBS effect cannot be taken as evidence for such a role. Rather, the effects of DBS
in the vicinity of the subthalamic nucleus on speech may owe to any number of
other effects discussed previously. Similarly, any physiological or behavioral change
associated with DBS of a particular structure cannot be attributed to its effects on
downstream structures for the same aforementioned reasons.
Reduction of a symptom or the appearance of a new deficit with DBS cannot
be attributed to inhibition or the inhibition of inhibition. Again, this is not to say
that neuronal inhibition, particularly through the release of GABA in response to
DBS, plays no role. It says only that such changes are not evidence of inhibition.
For example, reduction of tremor may be achieved by activation to the corticospinal tract, perhaps owing to disruption of synchronization of descending neuronal
activities. Yet this is not the same as saying that the tremor was inhibited.
One cannot infer DBS mechanisms from such neurometabolic imaging as
Positron Emission Tomography and functional Magnetic Resonance Imaging,
which depend on the temporal dynamics of the blood oxygen dependent response.
The temporal dynamics of the multiordered responses are far too rapid (on the
order of milliseconds) to be revealed in the blood oxygen dependent response,
which has a typical latency of several seconds. Many of the effects are also related
to antidromic action potentials. Evidence suggests that neurometabolic imaging is
relatively insensitive to antidromic effects (Logothetis and Wandell 2004).
The limitations as to inferences from DBS-related research, in addition to those
described here, include all the limitations associated neurophysiological research
224
in general. Addressing these issues is beyond the scope of this chapter and have
been discussed elsewhere (Montgomery 2012).
S U M M A RY
DBS has presented a remarkable opportunity to study the human brain in a

manner previously impossible. The ability to power the DBS on and off at will
provided remarkable experimental control. Its therapeutic benefit in Parkinsons
disease is independent of dopamine and thus provides a contrasting perspective
in which to study pathophysiology and physiology. The brain responses to DBS
are multiple and multifaceted. Interpretation of the mechanisms underlying
phenomena affected by DBS is thus highly problematic. Care in designing and
interpreting DBS-related experiments is critical, because the potential insights
are well worth it.
R EFER ENCES
Aristotle. The Basic Works of Aristotle. McKeon, R, ed. New York: Modern Library;
2001.
Benabid AL, Pollak P, Louveau A, etal. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl
Neurophysiol. 1987;50(16):344346.
does not increase the striatal dopamine concentration in parkinsonian humans. Mov
Disord. 2003;18(1):4148.
Logothetis NK, Wandell BA. Interpreting the BOLD signal. Annu Rev Physiol.
2004;66:735769.
McIntyre CC, Grill WM. Excitation of central nervous system neurons by nonuniform
electric fields. Biophys J. 1999;76(2):878888.
Montgomery EB Jr. Dynamically coupled, high-frequency reentrant, non-linear oscillators embedded in scale-free basal ganglia-thalamic-cortical networks mediating
function and deep brain stimulation effects. Nonlinear Studies 2004;11:385421.
Montgomery EB Jr. Effects of GPi stimulation on human thalamic neuronal activity.
Clin Neurophysiol. 2006;117(12):26912702.
Montgomery EB Jr. Subthalamic nucleus neuronal activity in Parkinsons disease and
epilepsy subjects. Parkinsonism Relat Disord. 2008;14(2):120125.
Montgomery EB Jr. Neurophysiology. In:Pahwa R, Lyons KE, eds. The Handbook of
Parkinsons Disease. Boca Raton, FL:CRC Press; 2013:258280.
Montgomery EB Jr., Buchholz SR, Delitto A, etal. Alterations in basal ganglia physiology following MPTP in monkeys. In:Markey SP, Castagnoli N, Trevor AJ, etal.,
eds. A Neurotoxin Producing a Parkinsonian Syndrome. London, Academic Press;

1986:679682.
Pevear R, Volokhonsky L. War and Peace. NewYork:Vintage Books; 2007.
Wang Z, Jensen A, Baker KB, etal. Neurophysiological changes in the basal ganglia
in mild parkinsonism:a study in the non-human primate model of Parkinsons disease. Program No. 828.9. 2009 Neuroscience Meeting Planner. Chicago:Society for
Neuroscience; 2009. Online.
19
Ethical Issues of
Though this chapter contains references to laws and legal decisions, it contains no
legal opinions or advice. Legal subjects are discussed for the sole purpose of illuminating ethical concerns. Because law regulates relations among citizens, it fulfills a
function similar to the function fulfilled by ethics, which refers to principles that
apply to how people should act.
I F D EEP B R A I N ST I M U L AT I O N I S SO EFFECT I V E, W H Y A R E
N OT M O R E PAT I EN TS U N D ER G O I N G T H E PR O C ED U R E?
As discussed at various points in other chapters, Deep Brain Stimulation (DBS) is

remarkably effective and safe for many patients with Parkinsons disease, Essential
tremor, dystonia, and other movement disorders, as well as Obsessive-Compulsive
Disorder. Agrowing number of clinical research studies have demonstrated effectiveness in depression, epilepsy, and Alzheimers disease, among others. Yet though
DBS is considered standard and accepted therapy for many disorders, a small percentage of eligible patients are actually referred for it. What is worse, their referrals
often come only after years of unnecessary suffering. Indeed, patients with DBS
commonly wonder, upon having undergone the surgery, why it took their physician
so long to refer them. Considered individually, such delays may seem small, albeit
regrettable, matters. Considered in the aggregate, however, they represent a failure
of the healthcare delivery system.
If one accepts the premise that the mission of those who practice medicine is
to relieve suffering, then failure to do so is an ethical failure. Perhaps it is a moral
failure as well, as morals relate to what is right or wrong, good or harm. No doubt
the vast majority of physicians and healthcare professionals would agree that they
are under an ethical, and perhaps even moral, obligation to relieve suffering. If one
does not accept that such is the case, she may have difficulty acknowledging that a
problem exists. If ethics concerns the manner in which one must conduct oneself
in order to accomplish a moral good, then failure to provide such a moral good as
the relief brought by DBS becomes an ethical issue.
Every physician and healthcare professional must navigate in their practice
the ethical and moral terrain of medicine. For this reason, all physicians and
19. Ethical Issues of Deep Brain Stimulation227
healthcare professionals are ethicists. The question is how well they fulfill their
ethical obligations.
E T H I CA L PR I N C I PL ES A N D M O R A L T H EO R I ES I N B R I EF
Nearly every individual leaves infancy with some ethical and moral notions. These
tend to develop implicitly, usually in response to consequences of some act committed by the individual in question. However, it is not at all clear how conducive implicit
ethics are to the ethical practice of medicine. As an individual gains language skills
and the capacity for conceptual understanding, the development of implicit ethical
and moral notions is attended by explanations, perhaps to the point of some body
of principles. It is unclear, however, whether explanations actually serve to supplant
the implicit developed. They may serve strictly as post hoc rationales rather than
deliberate and critical assessments and formulations. Critical approaches to ethics
has been a subject of scholarly analysis for millennia and are embodied in the formal
discipline of philosophy. The approaches developed in philosophy can guide or at
least illuminate the issues and questions involved in ethical practice. It simply is
insufficient to allow physicians and healthcare professionals to merely continue with
the ad hoc folk ethics gained during childhood. Children ages 2 and 3years express
distress with ethical or behavioral transgressions regardless of whether their setting is supervised or unsupervised (Kochanska and Aksan 2006). Also, they imitate
their mothers in scripted contexts of teaching some precept, and they express greater
distress when they see that a cookie jar has been broken in order to steal its contents
than they do when they see that it has been broken by accident.
By the time they reach the age at which they pursue studies in medical and
healthcare professions, individuals have certain ethical and moral notions established in their minds. In one medical ethics course offered to undergraduates at
a small liberal arts college, each of the 30 students in attendance responded to a
question put to them the first day of class. They were asked whether they believed
it was appropriate for a physician to lie to an insurance company if it meant getting
necessary care for the patient covered. All students gave the same response:As telling a lie is never good, the physician must not lie.
Likely informing the students initial response was a prima facie ethical truth
that it is bad to lie. Absent context, the case no doubt invites such a conclusion. The
same question was given a twist and posed again. Each student was asked to imagine that the patient in question was his or her mother. The answers some students
gave to the new version of the question changed. Whether a physician should lie to
an insurance company depends on whether the insurance company was a good or
bad one, they said.
The students responses stand in contrast to those offered by physicians in one
survey, of whom a mere 17% believed it was acceptable to overstate or falsify a
patients condition when submitting claim seeking prior authorization (http://
www.medscape.com/features/slideshow/public/ethical-dilemmas). Another survey, however, showed that
physicians were willing to use deception in the coronary bypass surgery
(57.7%), arterial revascularization (56.2%), intravenous pain medication and
228
nutrition (47.5%), screening mammography (34.8%), and emergent psychiatric referral (32.1%) vignettes. There was little willingness to use deception
for cosmetic rhinoplasty (2.5%). Rates were highest for physicians practicing
in predominantly managed care markets, for clinically severe vignettes, and
for physicians spending less time in clinical practice. Physician ratings of the
justifiability of deception varied by perspective and vignette. (Freeman etal.
1999, p.2263)
The difference between the question posed in the first survey and the question
posed in the second turns on context: the second provides it and the first offers
none. Both surveys nonetheless suggest a dichotomy between that which is practiced and that which is preached. That which is practiced presents an example of
an ethics proceeding from the gut rather than the brain. The dichotomy between
gut and brain ethics exists within individual physicians. That this is the case
renders the instruction of medical students tremendously difficult.
Evidence exists that challenges the notion that adequate contextualization
resolves an ethical dilemma by revealing the appropriate solution. More senior
medical studentsnamely, those who have arrived at the clinical years of medical
school and thus face ethical issues of greater contextualizationperformed worse
than beginning students in measures of ethical sensitivity (Akabayashi etal. 2004).
It is altogether unclear that postgraduate medical education emphasizes ethics
to an extent sufficient to compensate for the relative ineffectiveness of such education in medical school. If anything, the growing cynicism resulting from the rapid
changes in the delivery of health care following the introduction of the Health
Maintenance Organization Act of 1973 and the Employee Retirement Income
Security Act of 1974 in the United States has served to aggravate the situation.
The point is that a medical or healthcare professional student does not enter professional school as a blank slate (tabula rasa) upon whom may be inscribed ethical
precepts. Rather they bring with them many presumptions, predispositions, and
expectations. Their untutored native conceptions, though they may prove useful in
ordinary interactions, will fail to serve them in the increasing rarified air of current healthcare delivery. Indeed, early serious opposition to the development and
codification of specific biomedical ethical principles came from those who insisted
that, because sound ethics guide competent physicians actions by definition, there
was no need to codify them. Of course, the Tuskegee Syphilis Study, the Willow
Brook School scandal, and other similar incidents put to rest to any conviction that
a competent physicians actions are ethical on their face.
For the codification of ethics, neither the Hippocratic Oath nor the Declaration
of Geneva are any help. This is the case for two reasons. First, current medical ethics, as they pertain to the physicianpatient relationship, emerged with the formulation of the Hippocratic Oath and have remained unchanged in spirit through
1847, with the advent of the various Codes of Ethics of the American Medical
Association, and 1948, with the Declaration of Geneva adopted by the General
Assembly of the World Medical Association. What did change with subsequent
versions of the Codes of Ethics of the American Medical Association are rules for
governance of the profession. These include rules against fraternizing with nonallopathic physicians, restricting rights of pharmacists, regulating relationships to
government-sponsored health care, and regulating large corporations delivery of
health care. Consequently, the ethical guidelines regarding the ethical relationship
between patient and physician and healthcare professional essentially have not
changed despite the remarkable, even revolutionary, changes that have occurred in
the delivery of health care.
It is unclear whether these codes remain relevant in the current system of healthcare delivery, at least as they relate to the relationship between a patient and physician or healthcare professional. Indeed, these codes enshrine patient care as the
ultimate arbiter of professional conduct. The ascendency of Health Maintenance
Organizations and other systems that restrict access to care, along with the balkanization of a formerly collegial loose affiliation of physicians, may not have
changed the rules implicit in the aforementioned ethics, but they have certainly
changed the field in which these rules play out.
The second reason for the lack of aid offered by the Hippocratic Oath and the
Declaration of Geneva in codifying ethics derives from the first reason. This second reason is that ethical questions cannot be settled in the abstract. They require,
rather, specification or context (Beauchamp and Childress 2013). Few reasonable
individuals would argue that the principles of beneficence (do good), nonmalfeasance (do not harm), autonomy (respect the patient), and justice are inherently
unworthy. Yet in some contexts they may come into conflict. Productive discussion of these principles thus requires contextualization for the purpose of deconstructing the ethical question in order to understand their dynamics. For example,
performing surgery presents a harm, that is the pain, cost, and risks inherent in
surgery, clearly a violation of the principle of nonmalfeasance. The term malfeasance is taken in its ethical context (Beauchamp and Childress 2013) to mean any
case of harm regardless of the intent and is not meant in the legal sense of failure
to act in accordance of the standards of practice. The purpose is to simply the discussion so that one does not have a variety of types of malfeasance conditioned on
difficult notions of intent.
Counterbalancing the malfeasance (harm) of surgery is providing benefit. Thus
the two ethical principles are in conflict. It then follows that there must be some
procedure of ethics to strike the appropriate balance. One technique is the Principle
of Double Effect, initially developed by Thomas Aquinas (Summa Theologica, 1274).
One of the precepts of the Principle of Double Effect is that the harm must not
be the end in itself but rather a means to achieve the end of beneficence. In DBS,
providing or even referring for surgery without assuring adequate postoperative
DBS programming could be said to violate the Principle of Double Effect and consequently creating the harm (surgery) as an ends in itself rather than a means to
benefit (DBS programming).
Scholars in ethics have shown little interest in the responsibility physicians
and healthcare professionals have to patients, the issue having been deemed by
them a fait accompli dating back to Hippocrates. Interest in biomedical ethics
stemmed primarily from many human research scandals, as well as remarkable
advances in medical technology that challenged established notions of personhood. The context surrounding biomedical ethics is different from the context surrounding everyday medicine. Applying biomedical ethics to everyday
medicine is therefore difficult, because it involves the need for a specification
typically in the context not relevant or germane to research or direct issues of
personhood. Patient autonomy in the context of biomedical ethics, for example,
230
is enshrined as a specific and inalienable right in research ethics. In the context

of everyday medicine, however, laws reflect the fact that patient autonomy enjoys
no such status. Ethical principles may nonetheless guide ones decisions in the
DBS context as well.
This chapter applies four ethical principles borrowed from biomedical ethics:(1)autonomy, (2)beneficence, (3)nonmalfeasance, and (4)justice. Autonomy
indicates the respect physicians and healthcare professionals must show for
patients, one example of which is a patients right with respect to medical decisions. Beneficence indicates the obligation physicians and healthcare professionals
are under to act solely in ways that conduce to the patients good. Nonmalfeasance
indicates the obligation physicians and healthcare professionals have to act solely
in ways that avoid harming patients or at least mitigate the harm by beneficence as
described in the Principle of Double Effect. Four general moral theories are subsumed under the ethical principle of justice:(1)egalitarianism, (2)libertarianism,
(3)utilitarianism, (4)deontology. Egalitarianism holds that desirable or undesirable consequences of human action (individual or collective) must exclude factors
beyond the actors control, such his familys class status or the specific nature of the
condition affecting him. Whether a patient becomes a recipient of a physician or
healthcare professionals beneficence or nonmalfeasance should not depend on lottery, according to Beauchamp and Childress (2013), such as being poor with limited
insurance options.
Utilitarianism privileges those actions that promote the greatest good.
Particularly challenging to utilitarianism is any situation in which there arise
incommensurable, competing interestsdeployment of a state-of-the-art weapon
system whose financing impoverishes citizens it protects, for example.
Libertarianism privileges those actions that maximize personal liberty.
Should libertarianism become hegemonic, undesirable consequences may follow. Recent experience has shown that absent any legal or contractual constraints, libertarianism may lapse into anarchy. At any rate, whether current
laws or contracts manage or enforce a physician or healthcare professionals duty
to a patient rather than some other interest, such as shareholder, is unclear. US
Supreme Court decisions make questions of bringing a law suit against an health
maintenance organizations on the basis of denial of coverage for medical treatment a contractual issue, not an issue of medical malpractice, and consequently
not subject to jurisdiction in state courts, as would be the case if the result of
denial of coverage actually resulted in malpractice (Pegram v. Herdrich, 530 U.S.
211 [2000]).
Finally, deontology privileges moral duty over all other duties. Aphysician or
healthcare professional is simply obliged to act in beneficent and nonmalfeasant
ways. The best action is that which most fully discharges ones duty.
B EN EFI C EN C E V ER S U S N O N M A L FE AS A N C E
The balance of beneficence (benefit) versus the risk of harm (violating nonmalfeasance) is central to nearly every decision made in medicine. Even diagnostic tests threaten harm:False negatives may encourage complacency, and false
positives may lead to inappropriate treatment. Issues related to mammography

in relatively young women who face no increased genetic risk, for example, play
potential benefit of early detection against the consequence of a false positive.
Their doing so may lead to unnecessary biopsies or worse. Balancing beneficence and nonmalfeasance is made more difficult by the fact that the language
of risk is often different from the language of benefit. Any direct comparison
thus becomes a comparison of incommensurablesapples and oranges, as the
saying goes.
Nonetheless, patients or their surrogates in fact must compare incommensurables when consulting physicians and healthcare professionals. Even randomized
control trials, which have become synonymous with Evidence-Based Medicine, are
powerless in this situation (Montgomery and Turkstra, 2003). Adecision cannot
go unmade, and any indecision already casts a lot:indecision is a choice not to do
something.
First described by Thomas Aquinas (Summa Theologica, 1274), the Principle of
Double Effect offers guidelines for balancing beneficence with nonmalfeasance.
To accord with nonmalfeasance, an act must be means to a beneficent end. This
condition relates to intention; one must not intend to commit harm (malfeasance).
There are a number of corollaries that help to demonstrate an absence of harmful
or malfeasant intent. The mechanism to produce the beneficence is the same as the
mechanism that risks malfeasance. Were they separate, they could be separately
manipulable. One then may act with beneficence without acting with nonmalfeasance, and vice versa, by the choice of mechanism. Nonmalfeasance must occur
in temporal proximity to the beneficence. In other words, it is difficult to argue
a lack of harmful intent behind the commission of a present harmful act, despite
any distant future benefit the act might bring about, for example offering DBS lead
implantation surgery without assurance of postoperative programming. Finally,
a nonmalfeasant mechanism must not admit of a more beneficent alternative. To
choose a mechanism that has attending it risks of greater harm is to make the incremental greater harm an end.
Though proponents of algorithmic medicine may insist otherwise, patients are
not widgets. Neither are physicians and healthcare professionals. Clearly, a motivation other than financial must exist, because individuals in the medical and
healthcare professionals always have before them the option of pursuing other
equallyor, indeed, moreremunerative careers. All but the most jaded physicians and healthcare professional experience a sense of wanting to help and a sense
of pride in being able to doing so. Consequently, a physician or healthcare professionals self-esteem is also subject to the beneficence or malfeasance inherent in any
medical decision.
C O U N T ER T R A N S FER EN C E AS A G U I D E TO PH YS I C I A N
A N D H E A LT H CA R E PR O FES S I O N A L ACT I O N S
Physicians and healthcare professionals emotional investment, implicit or otherwise, engenders risk of countertransference. Countertransference occurs when
physicians and healthcare professionals impose their emotions on patients. As
such, it is the inverse of the Freudian notion of transference, in which a patient
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projects her feelings onto a physician or healthcare professional. When transference is recognized, it helps a patient. In a sense, blaming a physician or healthcare
professional is symptomatic of the patients own underlying fears that then can
be recognized and treated. Within limits, countertransference may likewise prove
helpful, because it may align a patient and a physician or healthcare professionals
respective interests. An individual motivated by the untimely death of a loved one
to become a physician or healthcare professional, for example, helps others, though
she was unable to help her loved one.
One finds additional examples of countertransference in a situation in which a
physician or healthcare professional tells a patient or his surrogate that the patients
symptoms do not warrant such a therapy as DBS, or in a situation in which a physician or healthcare professional refrainsor refusesto mention the potential use
of a treatment believed by him to fail to balance beneficence and nonmalfeasence
for a patients sake. If such a belief prompts a definite act, it may violate the autonomy of the patient in question, as well as its derivative, informed consent.
In these examples a physician or healthcare professional transfers to a patient his
notion of a sound balance of beneficence and nonmalfeasance. Doing so requires
translation of his notion of a balance between beneficence and nonmalfeasance to
notion that, according to him, a patient or her surrogate should hold. Yet just as
there is no ready calculus to compare, as in an equation, the beneficence and nonmalfeasance for the physician and healthcare professional, there is none to compare
the beneficence and nonmalfeasance that a patient or her surrogate would hold.
Whether implicit or explicit, countertransference of a desire to help may be tremendously powerful, as well double-edged, bridging the respective motivations of
patient and physician or healthcare provider on one hand, transferring the respective biases of the latter to the former on the other. Consequently, it is important to
recognize and manage any potential biases.
Perhaps the most pernicious and widespread bias on the physician side of the
medicalsurgical divide is expressed in the imperative, Do no harm (Primum non
nocere), which suggests the errors of omission are somehow less onerous than errors
of commission. Refraining from action thus becomes the preferable option in situations in which all things are equal or in which some things are indeterminate. One
is left wondering, however, whether it is preferable for the individual acting (the
physician and healthcare professional) or the individual acted on (the patient). The
bias of the physician and healthcare professional not to act becomes a burden on
the patient, as it is the patient who continues to suffer from lack of treatment by the
physician, and healthcare professionals are comforted by the knowledge that they
did no harm. In addition to accepting surgical risk, a patient must also confront
possible effects of Omission bias in the person of her physician or healthcare professional. Apatient placed in this predicament has arguably suffered an injustice.
Omission bias is particularly strong in considerations of surgical therapies. This
is the case for two reasons. First, there prevails the perception that surgical therapies carry greater risks than do nonsurgical treatments, notwithstanding the fact
that the magnitude of complications attending chemotherapy and other medical
therapies may be as great or greater. Second, surgical therapies differ according to
proximity of an actor to an action. In the case of medical treatments, the chain of
events typically extends over a longer time frame and follows an indirect route to
the effect, thus placing physicians or healthcare professionals at a distance from the
effects of a medication prescribed by them. Adverse events consequent of surgery,

on the other hand, are most often immediate, direct, and owe perceptibly to the
actor.
The runaway trolley car dilemma, which was introduced in print by philosopher
Philippa Foot (1978), illustrates this issue of proximity of actor to action. Arunaway trolley car barrels down a track. Downfield from it stand five unsuspecting individuals in danger of being struck and killed. Between the car and the five
unsuspecting bystanders is a siding. Timely throwing of a switch will divert the car
to a siding. On this siding, however, stand two unsuspecting bystanders who will
be struck and killed if the car is diverted. As Foot reveals, most readers imagining
themselves in the situation would throw the switch, believing that it would be better to sacrifice two persons to save five.
A variation on the runaway trolley car scenario, first elaborated by Judith Jarvis
Thomson (1985), involves the same trolley car bearing down on the same five people, but it also involves an extremely large man who wears a heavy backpack and
stands on a bridge over the tracks. Areader is invited to imagine that she is standing on the bridge next to the man wearing the backpack. She is invited to imagine
also that, though she is too small to stop the runaway trolley by leaping on the track
below, she does have the strength to push the man with the backpack, who is large
enough to stop the car. As Thomson reveals, most readers would not push the large
man off the bridge. In other words, they would sacrifice five lives to spare one. It has
been suggested that the dramatic change in response from the first scenario to the
second owes to the presence of the switch, which intervenes between the actor and
the action. Direct responsibility for one death most readers apparently find more
difficult to accept than indirect responsibility for five.
An experiment in which a group of surplus mice were to be euthanized presents
another example (Falk and Szech 2013). Experiment participants were given money
with which to purchase mice from euthanasia and allow them to live out their lives.
In one circumstance, the price was 10 euros. Nearly half the individuals paid it. In
another circumstance, one person was given 20 euros and another person custody
of the mice. The two individuals were required to negotiate an exchange of euros
for the lives of the mice. In the majority of instances, they were unable to reach an
agreement, and all the mice were euthanized.
Again a possible explanation for the inability to reach an agreement owes to the
proximity of the actor to the action. In the case of the single individual who must
purchase the lives of the mice, the action is direct. Whether the mice lived or died
depended on the decision of the individual. In the second case, two individuals
decide the fate of the mice. Responsibility is therefore diffused and the relationship
less direct between actor and the action.
The argument advanced here is that one possible reason for the reluctance of
medical physicians (as opposed to surgeons) to recommend DBS is related to
Omission bias. The adverse consequences of surgery, which follow directly from
a physicians recommendation, is more personal and therefore more salient than
are the consequences of untreated disease, which do not follow directly from any
actions on the part of the medical physician.
Omission bias also plagues DBS clinical research. As discussed in chapter17, the
Institutional Review Board (IRB) did not approve a 20-subject pilot clinical trial
of DBS in the vicinity of the anterior cingulum for the treatment of medically and
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behaviorally refractory Posttraumatic Stress Disorder, notwithstanding the fact

that patients with this disorder suffer greatly, face increased suicide risk, and have
no other options. The disapproval had nothing to do with the risks and potential
benefits themselves or with the appropriateness of the rationale. The reason for the
disapproval in the IRBs recommendation was the request that the surgery be performed on three to five patients and, if the results proved favorable, permission
would be requested to enroll up to 20 subjects. Though the IRB was told that a study
of three to five patients would be uninterpretable, it maintained its position. The
initial three to five patients would thus face risks of DBS surgery, but there would
be no hope of a result in which anyone may have confidence.
The IRB must have surmised that the risk of the research summed over the 20
patients with severe intractable Posttraumatic Stress Disorder exceeded the potential benefit. Yet, 3 patients or 20, each face the same individual risk. The risk to a
patient would be just the same as the risk of each of 1,000 patients. The whole point
of the research is, in part, to determine what the risk to the individual is, and there
is no way that operating on three to five patients would have answered that question. Further, if the IRB was to make a decision on the remaining 15 to 17 subjects
in the original estimate of 20 patients, based on the first three to five subjects, it
would be illogical and irrational.
I believe that Omission bias keeps effective treatment from patients who have
no other hope, and it keeps DBS therapies from advancing further in order to help
patients with severe neurological and psychiatric disorders who otherwise have no
hope. Ultimately the physicians and healthcare professionals problem, Omission
bias has been made the patients problem. This is unfair.
B EN EFI C EN C E V ER S U S N O N M A L FE AS A N C E
A N D AU TO N O M Y
As discussed previously, beneficence and nonmalfeasance are often opposed. In

the effort to provide relief from disease or some similar good, it often is necessary to expose the patient to the risk of adverse effects. Physicians and healthcare
professionals must therefore balance the two. Yet because the balance that must be
struck is between estimations of the value of the benefit and an estimation of the
value of the harm, the arbitrating value system becomes the issue. One may take
a deontological position and insist that a patient (or a physician) retains the right
to determine the values of the potential benefit and harm. However, an approach
informed by a deontological commitment to patient sovereignty is unfeasible,
because it allows patients to dictate their care without regard to any effect on others. Apatient may demand treatment that effectively denies benefit to others, for
example, because it draws inordinately on limited resources. By the same token, an
opposing approach informed by a deontological commitment to the special status
of the physician encourages defaulting to a physicians judgment, which is unwise
because it invites abuse, as the Tuskegee Syphilis Study and the Willow Brook
School scandal amply attest.
An approach informed by a utilitarian commitment, which deems an action
that maximizes benefit and minimizes risk a good, presupposes that good may be
quantified in such a way as to permit comparison. However, what good is to be
maximizedthat of the patient or those who have a competing interest such as

paying for the care? Such a utilitarian approach in providing Medicaid in Oregon
was attempted. In that case, diseases were ranked on a number of utilitarian criteria
such as age, prognosis, and cost. Afixed sum of funds were applied, and however
far down the priority list the money went, those funded received care. Ultimately,
the system failed to gain the necessary support from the US Federal government,
perhaps from fear that it was contrary to the American with Disabilities Act, and
was abandoned.
An approach informed by an egalitarian commitment, meanwhile, does not fit
the issue because it holds that a chosen formula must apply without discrimination
to everyone. In other words, the care afforded patients should not depend on luck,
such the class into which they are borne or the diseases that befall them. If one person is to be denied a treatment such as DBS, then all must be denied DBS. If one is
allowed DBS, then all must be.
An approach informed by a libertarian commitment treats maximization of
individual liberty as the paramount concern. DBS delivers relief, and in doing so
increases in one respect the liberty of the individual relieved. Yet in another respect
it demands that the individual surrender a degree of liberty, that is, having the
freedom to spend funds on something of desire rather than of necessity like treatment. DBS comes at a price, and meeting that price requires money that may have
been otherwise devoted to other purposes. In this case the benefit is the liberty that
comes with relief from a disability. The benefit clearly reaches a patient, but it also
reaches those who care for a patient, whether in a direct way as a caregiver or an
indirect way as an insurance underwriter or a provider of services to the disabled. If
a patient paid the total cost of the treatment as well as any later foreseen or unforeseen expenses directly or indirectly, then from a physician or healthcare professionals perspective, providing the treatment admits of little downside.
Because physicians or healthcare professionals pay neither the costs of the
treatment nor any later expenses, their personal liberty is not at risk. Of course,
preference for a libertarian commitment over a deontological brackets the sense
of morals on the part of physicians and healthcare professionals. The libertarian
approach necessitates a contractual obligation that does not necessarily turn on
the physicians or healthcare professionals moral stance. Admittedly, a physician
or healthcare professionals moral stance may be excluded only for purpose of academic discussion; in the real world it remains a significant factor in diagnoses and
decisions. Yet throughout medicines long history, considerable deference has been
paid to patients or their surrogates.
If physicians and healthcare professionals were to not only treat a patient but
also, as members of the same insurance plan, underwrite the patients insurance or,
as taxpayers, subsidize the patients treatment, they may object on the basis of malfeasancethat is unreasonable expenditure of resources. Even in this case, physicians and healthcare professionals are not afforded any privileged position. Their
opinion holds no more sway than the opinion of any insurance plan member or
taxpayer.
If physicians and healthcare professionals were made surrogates of the insurance
company, their opinions would hold more sway. Insurance companies could jeopardize the liberty of the physicians and healthcare professionals, in other words, by
imposing on them capitated care, which forces them to bear the cost of treatment.
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To do so would be to place physicians and healthcare professionals at a conflict

of interest with their patients that, were it to become known, would outrage any
patient or patient surrogate.
Physicians and healthcare professionals are in a position to know and communicate possible benefits and risks but are in no position to place a value on them.
The task of placing value on benefits and risks falls to a patient or her surrogate
and, contractually, on the evaluations of the patients insurance underwriters. The
practical point of this discussion is that physicians and healthcare professionals
cannot know a potential benefits value; only patients can know to the first approximation. Likewise, physicians and healthcare professionals cannot evaluate the
risks that patients or their surrogates are willing to face against the benefits value.
Any attempt to a physician or healthcare professionals valuation for a patients
instances the hard paternalism described by Beauchamp and Childress (2013)
and is unethical.
Autonomy does not solely concern the issue of whether patients or their surrogates should decide a medical issue; it also involves respect for patientsrespect
that extends beyond their right to choice. Respect is important even in situations in
which choice is not an issue. Autonomy for medical care means treating a patient
as the end (or goal) of efforts. It places the patient at the center of intentions.
Such respect protects both patient and physician or healthcare professional from
the possible ill effects of countertransference. Showing respect for a patient helps
to disentangle a patients interests from the interest of a physician or healthcare
professional.
AU TO N O M Y A N D I N FO R M ED C O N S EN T
Patients who successfully underwent DBS frequently ask, Why did my physician
wait so long to recommend DBS? Some patients resort to referring themselves in
order to gain access to DBS. These situations raise the question about the ethics
of failing to inform patients as to the potential for DBS. Is a physician obliged to
inform patients about the possibility of DBS? If such an obligation exists and a
physician fails to live up to it, is that physician acting unethically? These questions
admit of no clear answers.
Central to this question is the notion of autonomy. Autonomy does not necessarily mean that every patient who wants DBS has a right to receive it. Autonomy
is not simply about a patients right to decide acceptable treatments. Rather, it
implies a respect for patients, which in turn implies an obligation on the part
of physicians and healthcare professionals to address the issues valued by the
patient or surrogate.
Autonomy as it relates to a patients rights to refuse treatment are clear and
well established by case law. This right, however, would appear to be one of veto
power rather than legislative. For example, the President of the United States cannot pass laws; Congress alone may do so. The president may sign (enact) or veto
the laws passed by Congress. Similarly, a patient has the right to refuse a treatment recommended by a physician but may lack a right to treatments not recommended by a physician. Patients in Great Britain had a right to veto a physicians
recommendations but no right to request or expect that a physician recommend

specific treatments. Laws to this effect presume that a physician is the final arbiter
of medically indicated or warranted treatments (Coggon 2007). Aphysician and
healthcare professional thus have rights analogous to those enjoyed by Congress.
Patients, meanwhile, function as chief executives, reserving unto themselves veto
power. Just as the Congress is under no obligation to pass laws the president would
like to see enacted, physicians and healthcare professionals are under no obligation
to offer treatments they are not inclined to offer. It is not so clear in other countries.
One sees readily how a physician and healthcare professional may abuse such
discretionary power. In the Tuskegee Syphilis Study, physicians did not offer
patients antibiotic treatment. A physician and healthcare professional may have
moral objections to certain treatmentsbirth control or abortion, for example
and may therefore conceal them from patients by failing to mention them. In doing
so, she effectively denies patients their right to those treatments.
The situation is different in research, which requires that prospective subjects
are informed about all reasonable alternatives. Neither physicians nor healthcare
professionals are empowered to determine what is reasonable. Rather, information
that, if provided to a patient would lead him to refuse to participate in the research
establishes the standard for what is reasonable. In this case, one expects that a physician or healthcare professional tasked with enrolling subjects in a clinical trial of
a medication for a disorder that is treatable by DBS, such as Parkinsons disease,
would be required to inform the subject that DBS may be an alternative to participation. To fail to do so would be to invalidate a patients informed consent, and
to treat a subject in such a circumstance would be to commit battery, an act that
exposes the guilty physician or healthcare professional to legal action.
Assuming in a particular context, DBS is an option that, if presented to a reasonable patient, could be chosen by that patient. However, the situation is clinical
and not research. If it were research, the physician would have a legal obligation to
mention DBS. However, it is not clear that it is typical for physicians to have the
same obligation in the clinic. The question is whether there is any a different set of
ethics that apply in the research situation that does not apply in the clinic. It does
not appear that there is any material difference with respect to beneficence, nonmalfeasance, or autonomy. The presumption is that the physician and healthcare
professional have the obligation to do good, avoid harm, and respect the patient
regardless of whether the relationship involves research or clinical care.
The difference is the apparent obligation to informed consent that necessitated
disclosure of all alternatives that would be material to a reasonable patient in the
context of research rather than the clinic is historical. It is likely that the relationship of physician and healthcare professional was soft paternalism (Beauchamp
and Childress 2013) where physicians and healthcare professionals determined
themselves what were reasonable alternatives (see previous discussion of countertransference). This situation was true in research as well as in the clinic. It was
the scandals involving medical research, such as the Tuskegee Syphilis Study, that
resulted in the presidential commission that established the rules for informed consent. Informed consent in the clinic seems to have escaped.
The necessity to explicitly stipulate the nature of informed consent and taking that out of the hands of physicians and healthcare professionals in the context of research was necessary to prevent the potential for self-interest on the part
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of physicians and healthcare professionals to create a conflict of interest. Clearly,

whether an experimental treatment will help or not is not known at the time of
consent. The value comes from learning whether the treatment is a benefit or not.
However, it may well be that the research participant will never benefit other than
from the satisfaction that may come from contributing to the greater good of all
through the increase in knowledge. Indeed, such satisfaction is the only action
that can counterbalance the harm the patient is exposed to in order to fulfill the
Principle of Double Effect. For the researcher, there is the potential of research
funding and fame, powerful conflicts of interest.
In routine medical care it is presumed that a physician or healthcare professional has no conflict of interest and their recommendations are directed solely
to the patients benefit. The belief that physicians or healthcare professionals act
in patients best interest perhaps explains the British law that grants them wide
berth to determine which treatments to offer. In the modern system of healthcare
delivery in the United States, financial gain or loss based on the physicians and
healthcare professionals recommendations immediately places the physician and
healthcare professional at a conflict of interest, where financial gain may run counter to the patients best interests. In the case of Pegram v.Herdrich (530 U.S. 211
[2000]), a physician refused to perform an abdominal ultrasound on a patient with
abdominal pain that subsequently became a ruptured appendix. The physician was
in a group practice that was rewarded physicians for minimizing care. The patient
brought a lawsuit against the insurance plan claiming that the insurance plan created an inappropriate inducement for the physician to withhold the ultrasound.
The US Supreme Court held that the insurance company could not be held liable.
Thus it is clear that many (if not most) physicians and healthcare professionals have
conflicts of interest little different from those of the researcher. The reasonable conclusion would be that physicians and healthcare professionals in the clinic should
be held to the same standards of informed consent as the research.
One finds perhaps the most visible instantiation of patient autonomy in the legal
process of obtaining informed consent. Interestingly, autonomy was as murky a
right in 1985 as it is today. It appears that autonomy is not a right in itself but a
derivative of other rights (Shultz 1985). One route to autonomy lies through the
right to bodily security. Touching another person without her permission constitutes battery, which is illegal and unethical. However, as shown by Shultz (1985),
the fact that battery is an act of commissionsomeone must do somethingrenders the designation somewhat problematic. For example, a surgeon who operates
on a patient unable to give consent commits battery.
As a means of mitigating a charge of battery, informed consent presents clear and
extensive requirements. Among them is the requirement that a patient or his surrogate be informed of reasonable alternatives, namely, alternatives that, if a reasonable patient knew of them, he would elect not to proceed with a proposed treatment.
Whether a proposed treatment injures a patient does not matter.
The issue becomes whether not treating the patientby refraining from recommending DBS or some other waymay reasonably be considered an act of omission. Acharge of battery most likely does not apply because no bodily transgression
had occurred, notwithstanding the fact that the patient in question would have
been much better off with the treatment the physician or healthcare professional
failed to mention.
One may argue that an institution must require full disclosure of alternatives
prior to use of a medication or any other treatment recommendation, because failing to do so would represent bodily transgression. Constituting an exception is a
case in which a patient experiences failure of a medication she had long been taking. If her physician recommends no new or altered treatment, such as DBS, that
would necessitate a discussion of permission, then the issue of informed consent
may not arise. Such at least is my impression, who admittedly is not an attorney and
wishes to avoid being understood as rendering legal opinions.
A second, similar situation may illuminate the issue. The Presidential
Commission for the Study of Bioethical Issues (2013) reviewed the issues associated with incidental findings that resulted from various tests and proceduresa
benign meningioma appearing on a CT scan, for example. The commission stated
that no federal or state statute directly addresses the duty of a physician or healthcare professional to report an incidental finding to patients or their surrogates. The
commission went on to discuss whether failure to report the incidental finding
constitutes malpractice. It indicated that few cases address this issue, and it found
malfeasance in reports of incidental findings that would have prevented harm or
altered the course of future disease. However, the commission also mentioned the
2006 case, Riley v.Stone, (900 A.2d 1087 [R.I.2006]), in which a Rhode Island court
found a neurologist who deemed an incidental finding as posing no danger free of
any obligation to report it.
In the aforementioned case, a patient continues on a treatment that, because it
remains unchanged, does not prompt the necessity to recommend another treatment, which carries with it an obligation to inform the patient of DBS or another
alternative, thus raising the question of whether failure to improve eo ipso constitutes a type of finding similar to the incidental finding discussed earlier. If one
assumes that the analogy is appropriate, then the recognition that a patient has not
achieved the desired improvement obliges a physician to discuss DBS and other
alternatives.
The issue of failure to inform in the absence of battery (bodily transgression) falls
within the domain of medical malfeasance or malpractice which is different from
the notion of malfeasance in the ethical principle of nonmalfeasance. This subjects
a physician who fails to inform a patient of alternative treatments to the standards
of malpractice law, with malpractice defined as a departure from the standards of
practice expected of similar physicians and healthcare professionals under similar
circumstances. In assessing any alleged lapse in upholding standards, courts usually look to experts, findings and codes of conduct governing professional organizations and societies. If in a context in which there occurs no bodily transgression
most physicians and healthcare professionals fail to mention treatments, then failing to mention these treatments does not amount to malpractice.
D ESC R I P T I V E V ER S U S N O R M AT I V E E T H I C S
Ethics that reflect the behavior of a majority of individuals are said to be descriptive. Ethics that reflect an ideal for behavior other than any behavior exhibited by
a majority of individuals are said to be normative. Aphysicians discussing DBS
or other treatment options with a patient reflects descriptive ethics if it reflects a
240
typical tendency among physicians regardless of whether it happens in a context

of initiating a treatment change, which would otherwise raise issues of informed
consent and battery. Aphysicians discussing DBS or other treatment options with
a patient reflects normative ethics if it observes the prohibition against battery.
The issue of whether to discuss DBS appears to fall within the domain of standard of care, which rests on descriptive ethics. Indeed, a society may have a vice
that is so common as to be thought a virtue. Descriptive ethics would enshrine the
vice as the standard. In a context in which most physicians do not discuss DBS,
descriptive ethics would hold that failing to present DBS as a treatment option is
entirely ethical.
Descriptive ethics and codes of conduct that rest on them can produce perverse consequences. For example, Medicare significantly altered its reimbursement to hospitals from a fee-for-service arrangement to a prospective payment
based on diagnosis. According to their diagnosis, patients are typically assigned
to a Diagnosis-Related Group (DRG), and the amount of reimbursement paid to
a hospital is based on the average length of stay associated with a specific DRG.
Ahospital thus receives the same reimbursement regardless of its actual expenses.
Justification for doing so rests on the assumption that losses incurred as a result of
any patients hospitalization exceeding the DRG length of stay would be compensated by early discharges of other patients belonging to the same DRG group.
The DRG system appears reasonable from the perspective of the US government,
which is interested in limiting expenditures. Some studies have demonstrated that
prospective payment based on diagnosis have not altered the quality of health.
Certain methodological and statistical considerations, however, render this finding
highly suspect. Indeed, the large increase in hospital readmissions following the
introduction of prospective payments based on DRGs suggest that the participating
patients received suboptimal care.
This outcome leads one to wonder further whether length of stays associated
with specific DRGs depended on physicians and healthcare professionals perceptions of the methods of calculation. DRG length of stays were calculated according
to the average length of stay divided by the number of cases in the database studied
after removing the outliers (Office of Inspector General 2001). If one assumes a normal distribution of lengths of stays in the database, then the average length of stay
approximates the median:half of the patients required shorter than average length
of stays and half required longer than average length of stays.
According to a rational analysis of the length of stays for a specific DRG, a hospital should have as many patients whose stays are longer than a DRG length of stay
as it does patients whose stays are shorter. If the patients whose stays are shorter
are fewer than 50% of all patients involved, then a reasonable inference, statistically speaking, is that many patients have received inappropriate and unnecessary
care. The converse holds true as well. If fewer than 50% of all patients involved stay
longer than the DRG length of stay, then an inordinate number of them received
insufficient care.
Unfortunately, a DRG length of stay may appear quite different to a clinician than it does to a hospital administrator. Having become an administrative
target for the clinician, it pressures a physician to discharge a patient before the
length of stay is reached. By definition, as discussed previously, the physician
discharging all or most of her patients prior to the length of stay has a high risk
of discharging patients prematurely. This tendency is reinforced by insurance

companies who limit the number of days approved for hospitalization to the
DRG length of stay.
A median or mean is meaningless in itself; variance or distribution of data,
rather, is critical. For example, a DRG length of stay, whose basis lies in database
of 5days and whose range is 1 to 9days, comes to mean something quite different
if the range becomes 4 to 6days. In the former instance, a patient who requires a
9-day stay, which would not be outside the range, but stays 5days presumably faces
much more possible harm than does a patient who requires a 6-day stay but stays
5days.
If the standard of care represents the average practice of physician colleagues,
then it describes the central tendencythe mean or average, for example. If the
variability in practice was slight, the standard of care is easily construed. Most
evidence suggests, however, that physicians substantially vary their practice, and
likely due to differences other than differences in patients within each practice.
For example, a distribution of the nature and quality of practice ranges from the
exceptional to unexceptional. Physicians and healthcare professionals with adequate time and resources tend to be rated as exceptional, and their peers who lack
adequate time and resources tend to be rated as unexceptional. A consensus of
actual practice, then, indicates that expectations do not reflect exceptional care.
Rather they reflect the quality of care given by physicians and healthcare professionals whose time and resources are limited. Aphysician or healthcare professional who practices exceptional medicine therefore would not be practicing
according to the standards of care.
E XC EL L EN C E:AM AT T ER O F PER SO N A L C H O I C E
Every physician and healthcare professional wishes to provide excellent care.

Whether they are obliged to provide it is another matter. If they are, then the issue
becomes that of enforcing the obligation. Should there be any means of enforcement in place, or should faith be placed solely in physicians and healthcare professionals good will? As far as law, insurance, and healthcare provider systems are
concerned, physicians and healthcare professionals practice should be governed by
standards of care implicitly derived from reasonable consensus practices of peers.
Such standards reflect descriptive ethics and therefore fail to establish any obligation to provide excellent care.
Because standards of care are reflective of descriptive ethics, they cannot establish a standard for excellence. Standards are reflective of normative ethics that
must supersede descriptive ethics. Such standards do not simply reflect consensus
practices. Rather, they dictate best practices and compel physicians and healthcare
professionals to engage in them. Professional organizations have long upheld established therapeutic guidelines and algorithms for excellent care. Yet the fidelity with
which they are followed remains unclear. Many, if not most, professional and governmental guidelines for practice carry a disclaimer concerning any binding rules
and any guarantees of patient outcomes. The practical strength of the guidelines
also stems from their use by insurers in reimbursement. As discussed previously,
most restrictions relate to acts of commission rather than omission.
242
The issue thus becomes whether compliance with professional guidelines affect
medical liability. Increased use of professional guidelines have affected their use
in court cases. One of the fundamental aspects of medical malpractice is a departure from professional standards. In the past, these standards have been descriptive
rather than normative. The standard in some cases rests on actions of a prudent
and diligent medical practitioner. Courts and juries, meanwhile, treat professional guidelines as prima facie evidence of prudent and diligent medical practice
(Guillod 2010). Courts also may refuse to follow guidelines, particularly those that
appear lax in light of patient protections or that betray motivations inordinately
favorable to the profession.
The potential for Evidence-Based Medicine to establish standards of practice presents an interesting dilemma. Contrary to its original description,
Evidence-Based Medicine has become synonymous with prospective randomized
clinical trials. Thus, in an environment in which Evidence-Based Medicine is hegemonic, expert opinion and case studies are ignored or seriously devalued. Thus
even appeal to expert testimony in a malpractice case may prove problematic when
Evidence-Based Medicine is introduced.
Practice guidelines list DBS as an effective treatment for Essential tremor
(Zesiewicz et al. 2005), dystonia (Albanese et al. 2006), and Parkinsons disease
(Pahwa etal. 2006). One professional organization held DBS to be recommended
for the treatment of Tourettes syndrome, (Muller-Vahl etal. 2011), though it also
called for further clinical trials. Another professional organization held that DBS is
an experimental treatment for Tourettes syndrome (Steeves etal. 2012).
Though many clinical cases have shown DBS benefit for cerebellar outflow
tremor for anoxia, hypoxia, multiple sclerosis, and other conditions affecting the
cerebellum or its pathways, as well as for hyperkinetic disorders from a wide variety
of etiologies, the issue of actual recommendation remains unclear. The issue of DBS
for treating Obsessive-Compulsive disorder is a bit clearer. In addition to supportive clinical studies, the US Food and Drug Administration has approved DBS for
Obsessive-Compulsive Disorder under a Humanitarian Device Exemption.
EPI ST EM I C I S S U ES I N D EEP B R A I N
ST I M U L AT I O N AC C EP TA N C E
The clinical studies documented throughout this book attest to DBSs remarkable
effectiveness. Rigorous randomized control trials that directly compared best medical therapy to DBS for Parkinsons disease have demonstrated the superiority of
DBS (Weaver etal. 2009). Other studies, not of randomized controlled trial design,
have shown that DBS succeeded to provide benefit where all medication alternatives
had failed. Conducted by experts in pharmacological management thereby mitigating the lack of pharmacological optimized control groups, these studies have had
their findings challenged. Critics claimed that, because they were neither randomized nor blinded, the findings failed to substantiate DBSs superiority. Hubris alone
supported them. These same critics went on to suggest that the experts could better
used medication solely by engaging in a randomized clinical trial.
To wonder why a minority of patients who need and would benefit from
DBS are referred for it is to do more than engage in idle speculation. It may be
that, in addition to the reasons discussed here, DBS somehow fails to accord
with physicians notions of pathophysiology. The fact that Parkinsons disease
is often viewed as a dopamine deficiency, for example, may lead some physicians to think that the only sensible treatments are those that directly restore
the dopamine effect. DBS does not accomplish this. Stem cell transplantation
to restore dopamine neurons, on the other hand, appears to have captured physicians and healthcare professionals imaginations. Unfortunately, stem cells
become fetal dopamine cells. Fetal dopamine cells fail to provide meaningful
relief, demonstrated replacement of dopamine in the striatum notwithstanding.
Whether stem cell transplantation would share the same fate as fetal dopamine
cell transplantation is unclear.
The notion of Parkinsons disease as a dopamine deficiency derives in part
from the recognition that Parkinsons disease is associated with degeneration of the dopamine neurons of the substantia nigra pars compacta. Yet this
is true from the standpoint of pathoetiology (cause of the pathology). From
the standpoint of pathophysiology (altered physiological mechanisms consequent to a cause), it is not true. Loss of dopamine neurons results in a cascade
of effects that describes the pathophysiology. It is possible, then, to affect the
pathophysiology by intervening at subsequent steps in the pathophysiological
process. This conclusion admits of a corollary:Multiple etiologies may result in
the same pathophysiological mechanisms, which in turn result in a single clinical syndrome. Pathoetiologies are therefore not synonymous with pathophysiology. Symptomatic treatments, which must be directed at pathophysiology, may
or may not be directed at pathoetiologies. Failure to realize this principle may
engender undue bias in favor of dopamine-based therapies that may end up
harming patients.
PH YS I C I A N S R ES P O N S I B I L I T Y TO N EU R O S U R G EO N S
When referring a patient to a neurosurgeon for DBS, a referring physician must

adhere to the ethical principles of beneficence and nonmalfeasance. Yet were he to
refer a patient who is unlikely to gain reasonable expected benefit, he would act in
a way that is devoid of beneficence. He must also refrain from referring a patient
to a surgeon whom a court has deemed incompetent or impaired. In Beaumont
Spine Pain and Sports Medicine Clinic, Inc. v.Swan, Texass Ninth District Court
of Appeals affirmed expert testimony given in an earlier trial. The individual who
gave that testimony stated that the referring physician
should have known of [the surgeons] history through the TBME [Texan Board
of Medical Examiners] newsletter, information on the TBME website about
complaints concerning [the surgeon], the published court cases involving malpractice by [the surgeon], and [the surgeons] loss of privileges at two hospitals.
[The expert] opined that [the referring physician] breached the standard of
care by referring [the patient] to [the surgeon] because [the referring physician] failed to ascertain [the surgeons] qualifications, and that if [the referring physician] had not referred [the patient] to [the surgeon], [the patient...]
would not have died.
244
This cases circumstances were extreme. Yet the court recognized a principle of
joint responsibility, ruling that [t]he theory of joint enterprise imputes liability
to one who, although he did no wrong, is so closely connected to the wrongdoer
that it justifies the imposition of vicarious liability (David L. Smith & Assocs.,
L.L.P.v.Stealth Detection, Inc., 327 S.W.3d 873, 878 [Tex. App.Dallas 2010, no
pet.]; see also St. Joseph Hosp. v.Wolff, 94 S.W.3d 513, 517 [Tex.2002]; noting that
joint enterprise is a theory of vicarious liability). There was, in other words, shared
responsibility for violating the principle of nonmalfeasance. Because a referring
physician and a surgeon shared responsibility with respect to malfeasance, they
may also share a responsibility for beneficence.
Should the shared responsibility for beneficence become open-ended, the issue
of referral presents problems. If, for example, the obligation to beneficence involves
referring a patient to the greatest surgeon, referring to any lesser means the referring physician has failed to provide beneficence. The resulting situation would be
untenable, because many patients would go unseen and untreated. One must ask,
rather, whether considerations of beneficence admit of any idea of sufficiency rather
than exceptional.
No easy answer presents itself. One anchored in descriptivist ethics would suffer from the problems discussed previously. Normative ethics alone point a way to
an answer. They would establish the ways in which a neurosurgeon must perform
DBS. Yet the ways in which DBS surgeries are performed vary significantly, and
there exists no accrediting body to credential surgeons who perform surgical techniques in ways faithful to normative standards. Asurvey in the literature reveals a
tremendous variety of methodseverything from recording neuronal activity to
using temporarily implanted microelectrodes to identify the optimal target prior to
inserting a permanent DBS lead. The potential of inducting principles from observations of practices in the hope of generating subsequent normative guidelines is
thus highly problematic.
One may engage in a meta-analysis of issues concerning the accurate placement
of DBS leads. A meta-analysis of this sort requires that one identify the proper
target and then select navigation methods capable of revealing differences between
the target and adjacent untargeted regions (Montgomery 2014). Contrary to the
prevailing notion, the target is neither the subthalamic nucleus nor the globus pallidus interna; it is the sensorimotor region of those nuclei (Montgomery 2014). One
is unable to use MRI and CT to discover sensorimotor regions from other adjacent brain tissue, because scans fail to distinguish. Certain visible markersfor
example, the anterior and posterior commissures (reference points for MRI- and
CT-based targeting)do not provide sufficient accuracy (Nestor etal. 2014).
The paucity of randomized controlled clinical trials of surgical techniques owes
to surgeons unique situation (Fins 2008). Aproper trial would require that a single
physician randomize the patient to one of several different techniques. Most surgeons, however, favor one technique over another for specific reasons. It is therefore
quite difficult for surgeons to reach equipoise when participating in trials that may
require them to perform a surgery whose technique they believe inferior to their
own.
The same holds true for surgeons who provide routine surgical care. In a sense,
a surgeon is wedded to her usual technique. When a physician refers a patient to
a specific surgeon, she essentially selects the surgical technique. If, for example,
a surgeon does not perform microelectrode recordings, and if one assumes that
surgery without microelectrode recordings offers a lower probability of benefit and
higher risk of adverse effects with DBS, then a physician referring to that surgeon
fails to act in a spirit of beneficence and nonmalfeasance. The referring physician
in question may be free of legal culpability, but whether she remains free of her
conscience is another matter.
S U M M A RY
Relatively few good candidates are referred for DBS. This situation raises important ethical questions, particularly if one feels obligated to ensure access to all who
might benefit. Most physicians and healthcare professionals observe certain ethical
principles in their practice. Yet these principles may well be informed by nonprofessional past experiences. The unique circumstances surrounding DBS requires careful consideration of a physicians and healthcare professionals presumptive ethics.
This consideration is best accomplished by way of a systematic deconstruction of
the ethical and moral theories undergirding those principles.
A duty to behave ethically falls to all individuals charged with caring for patients,
both those who receive DBS and those who do not. Though referring physicians
and healthcare professionals may be unaccustomed to this duty, it remains a most
pressing one.
R EFER ENCES
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for evaluating moral sensitivity and reasoning in medical students. BMC Med Ethics
2004;5:E1.
Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diagnosis and
treatment of primary (idiopathic) dystonia and dystonia plus syndromes:report of
an EFNS/MDS-ES Task Force. Eur J Neurol. 2006;13(5):433444.
Coggon J. Varied and principled understanding of autonomy in English law. Health
Care Analysis;2007;15(3):235255.
Falk A, Szech N. Morals and markets. Science 2013;340(6133):707711.
Fins JJ. Surgical innovation and ethical dilemmas: precautions and proximity. Cleve
Clin J Med. 2008;75(Suppl.6):S7S12.
Foot P. The Problem of Abortion and the Doctrine of the Double Effect in Virtues and
Vices. Oxford:Basil Blackwell; 1978.
Freeman VG, Rathore SS, Weinfurt KP, etal. Lying for patients:physician deception of
third-party payers. Arch Intern Med. 1999;159(19):22632270.
Guillod O. Clinical guidelines and professional liability: a short comment from
the legal side. ORL J Otorhinolaryngol Relat Spec. 2010;72(3):133136; discussion
136137.
Kochanska G, Aksan N. Childrens conscience and self-regulation. J Pers.
2006;74(6):15871617.
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2014.
Montgomery EB Jr. Letter to the editor:deep brain stimulation without microelectrode
recording. J Neurosurg. 2014;120(6):14971498.
Montgomery Jr. EB, Turkstra LS. Evidenced based medicine:lets be reasonable. J Med
Speech Lang Pathol 2003;11:ixxii.
Psychiatry 2011;20(4):209217.
Nestor KA, Jones JD, Butson CR, etal. Coordinate-based lead location does not predict
Parkinsons disease deep brain stimulation outcome. PLoS One 2014;9(4):e93524.
Office of Inspector General. Medicare hospital prospective payment system:How DRG
rates are calculated and updated. Washington, DC:Centers for Medicare & Medicaid
Services; 2001.
Pahwa R, Factor SA, Lyons KE, etal. Practice Parameter:treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report
of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2006;66(7):983995.
Pegram v. Herdrich, 530 U.S. 211 (2000) No. 98-1949. United States Supreme Court.
Argued February 23, 2000. Decided June 12, 2000.
Presidental Commission for the Study of Bioethical Issues. Anticipate and communicate: ethical management of incidental and secondary findings in the clinical,
research, and direct-to-consumer contexts. Washington, DC: US Department of
Health & Human Services; 2013.
Shultz MM. From informed consent to patient choice:a new protected interest. Yale
Law J. 1985;95:219299.
Thomson JJ. The trolley problem. Yale Law J. 1985;94:13951415.
JAMA. 2009;301(1):6373.
Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential
tremor:report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology 2005;64(12):20082020.
20
The Future of
C U R R EN T C L I N I CA L T R I A L S
Although Deep Brain Stimulation (DBS) provides remarkable benefitgreater benefit than that provided by best medical therapy in many casesits future is uncertain because the neurological community appears uninterested in it. One finds
evidence for this lack of interest in the fact that the 2014 meeting of the American
Academy of Neurology featured no plenary sessions, panel talks, or posters on DBS.
Its presence was limited to a single educational course devoted to postoperative
programming. A recent articles authors surveyed patients who underwent DBS
and found that a large number had to fight aggressively to obtain it. This chapter
examines some conceptual prejudices that dampen appreciation of DBS as a therapy and hinder development of future DBS therapies. It will be shown that these
prejudicesscientific, medical, and ethical (see chapter19)are entrenched and
pervasive.
Currently underway are a variety of clinical trials for the treatment of neurological and psychiatric disorders. These include depression (Lozano etal. 2012), memory disorders in Alzheimers disease (Laxton etal. 2010), cluster headache (Seijo
etal. 2011), epilepsy (Lee etal. 2012), and anorexia nervosa (Lipsman etal. 2013).
Review of the clinical trials registry at the National Institutes of Health (http://
www.clinicaltrials.gov/) reveals that many more conditions are under consideration for DBS.
That anyone would be surprised by what appears to be a large list of potential DBS therapies offers some sense of the challenge confronting DBS. As an
electrical device, the brain processes and conveys information electronically.
Neurotransmitters and neuromodulators are simply the messenger; they are
neither message nor information. Neurotransmitters and neuromodulators are
analogous to electrons that traverse computer circuitry. While a computer cannot
function without electrons, there is nothing inherent in the electrons that would
predict a computer. Likewise, there is nothing inherent in dopamine that would
automatically determine the nature of Parkinsons disease, as flooding the brain
with dopamine, whether by drugs or fetal dopamine cell transplants, does not in
itself cure Parkinsons disease.
248
I hold that the vast majority of neurological and psychiatric disorders owe to
abnormalities of normal information processing, which results in misinformation.
Information and misinformation alike are encoded in the patterns of electrical
impulses received by neurons that are electronically processed and relayed to the
next neurons. Appropriate electrical stimulation of the brain thus ought to affect
and hopefully improvenearly every disorder of the central nervous system. DBS
has been said to be another means of affecting neurotransmitters. This nave notion
and others like it will only hamper future development of DBS. This statement is
analogous to saying that DBS is another means to affect electrons.
Neurological and psychiatric disorders owe no more to relative excess or deficiency of neurotransmitters and neuromodulators than computer failure owes to an
excess or deficiency of electrons. Admittedly, most modern computers do require
electrons. Depriving them of electrons by powering them off will cause them to fail.
Flooding their circuitry with static electricity will likewise cause them to fail. Yet a
computers function does not solely depend on electrons.
To argue that any given neurotransmitter or neuromodulator is the source of
the function or behavior is to commit the logical error of confusing the actor for
the action. An actor follows a script that prompts her to certain actions. It would
be illogical to say those actions originated with the actor rather than the script; one
may replace the actor in question with another yet observe the same actions. One
may also have the same actor perform many different actions. Nothing specific to
the actor determines the actions to any significant extent. Similarly, nothing specific to the dopamine molecule leads in one circumstance to schizophrenia (assuming the theory of excess dopamine), to excessive movement in another (such as
levodopa induced dyskinesia), and to relief of depression in yet another. Dopamine
in all these circumstances retains the exact same molecular structure.
One may argue that dopamines action and site of application combine to produce a specific effect. Such an argument simply translates the problem; it does not
solve it. If one were to accept the premise that dopamines action following from its
structure and site of application determine the effect, then one wonders as to what
is specific to a location such that the application of dopamine produces a specific
effect, given the fact that the specifier does not reside in the dopamine molecule.
The specifier cannot be in the individual neurons, because it is doubtful that the
neurons have sufficient uniqueness to specify certain behaviors.
The notion of idiopathic Parkinsons disease as a dopamine-deficient state
presents a useful example. Indeed, the absence of dopamine has become the sine
qua non for Parkinsons disease. So entrenched has it become, in fact, that when
world experts carefully diagnosed a set of patients as having idiopathic Parkinsons
disease who subsequently evidenced no dopamine depletion in neuroimaging, a
new disease was invented on the spot:Symptoms without Evidence of Dopamine
Depletion (SWEDDs).
Parkinsons disease is not a dopamine-deficient state. This conclusion rests on
the fact that repletion of dopamine in the basal ganglia by fetal dopamine cell
transplants or other techniques failed to reverse the symptoms of Parkinsons
disease. Indeed, dopamine imaging of patients who underwent fetal dopamine
cells showed repletion of dopamine. Yet their symptoms continued unabated.
These patients who show no evidence of dopamine depletion after transplant
are they to be denied the diagnosis of idiopathic Parkinsons disease and instead
20. The Future of Deep Brain Stimulation249
called SWEDDs? Again, something that escapes properties of dopamine alone

causes the symptoms and disabilities of idiopathic Parkinsons disease. To return
to the previous analogy:dopamine is the actor; the script for Parkinsons disease
is written elsewhere. Dopamine replacement does not recapitulate physiology.
The predisposition to think that it does or should instances the pharmacology-asphysiology paradigm.
Abraham Maslow wrote, When all one has is a hammer, the whole world looks
like a nail. The problem of the pharmacology-as-physiology paradigm may be appreciated in light of this observation. To someone beholden to the pharmacology-asphysiology paradigm, DBS appears unimpressive. The pharmacology-as-physiology
paradigm has a long history, which testifies to its power, for example in the pharmacology of the four Galenic humors (Galen 130200 ce) that determine behavior
(physiology; Arikha 2007). Within this dominant paradigm, the origin of which
dates to classical antiquity, DBS as an electrophysiological treatment will win
acceptance only with tremendous difficulty.
A PPR EC I AT I N G PAT H O PH YS I O LO GY
D E T ER M I N ES T R E AT M EN T
The practice of medicine has always been a curious mix of intuition and deduction.
Prior to the Germ theory, histological pathology, and radiology, diagnosis was primarily intuitive. The diagnostician considered not only a patients symptoms, but
his lifestyle, the season, and the environment as well. Summer months in swampy
areas suggested certain intuitions. The development of the Germ theory, histological pathology, and radiology dramatically changed diagnoses (or so it would
seem). Indeed, Sir William Osler perhaps owes his remarkable success as a physician and educator to his diagnostic acumen and the fact that throughout his career
he worked as a pathologist and frequently conducted postmortem examinations on
his own patients (Bliss 1999).
Remarkable diagnostic skills notwithstanding, Osler practiced many forms of
medicine developed early in the first millennium by the physician Galen. Galens
conception of pathophysiology of disease rested on metaphysical concepts advanced
by Aristotle metaphysics. According to Galen, four humorsblood, phlegm,
black bile, and yellow bilecontrol the body. These humors Galen patterned after
Aristotles four elementsair, earth, fire, and waterand the excess or deficiency
of each with respect to the others produces various diseases. The symptoms of an
excess were the opposite of the symptoms associated with deficiency. Understood
as excesses or deficiencies, dynamics of disease were thus oppositional (pushpull)
and one-dimensional. Apathophysiology that posits an excess of a humor dictated
therapeutic efforts to reduce that humor by such treatments as bloodletting and
cupping. Reasoning from Galenic pathophysiology to the individual patient, Osler
deduced his choices for treatment.
Pathophysiology continues to have an important place in selecting treatments.
One finds examples of this in attitudes related to approaches to medical treatment
that have no obvious connection to, or follow intuitively from, a pathophysiology.
Evidence-Based Medicine (EBM) based on randomized control trials (RCTs) has
been touted as critical to efficient and effective medical care. Yet there has been
250
considerable difficulty in persuading physicians to accept EBM. Their reluctance

appears to result not from any epistemic reservations about EBM. Rather, EBM
appears simply to fail to resonate with them.
That EBM fails to resonate with physicians perhaps owes to the fact that theories of pathophysiology are ultimately irrelevant to EBM, because EBM is based on
RCTs. Nothing in the structure of a RCT requires pathophysiological justification
or relevance. If an RCT demonstrated statistically significant benefit over placebo
to ingesting pulverized kitchen sink, then the logic of EBM demands that pulverized kitchen sink be offered as a therapy.
The recommendation that unless a genetic or other kind of risk is present, women
under 50years of age forgo mammograms (US Preventative Services Task Force
2009)and that elderly men should forgo having their prostate specific antigen levels
studied (US Preventative Services Task Force 2009)have found little purchase with
physicians. Disregard for these recommendations makes perfect sense: The earlier cancer is detected, the greater the probability of a happy outcome. That which
seems reasonable from a folk notion of pathophysiology clashes with a statistical
sense, specifically Bayes theorem. The recommendation for women under age 50
to forego mammograms is based on the fact that there may be many false positives
because of the relative low prior probabilities of women with breast cancer under
50 years of age, thereby exposing these women to unnecessary procedures with
their risks. Most physicians do not profess to be statisticians. Yet every physician
and healthcare professional is in truth a statistician. Whether they are good or bad
statisticians is the question.
The acceptance of DBS for Parkinsons disease is a case in point. Acceptance of
DBS was driven by a resurgence of interest in pallidotomy in the late 1980s. The
resurgence of pallidotomy did not owe to new surgical technologies. Indeed, many
of the leaders in the resurgence continued to use ventriculography for targeting.
Nor did it owe to a sudden recognition of the need for pallidotomy. It has been clear
since the early 1970s that long-term successful management with medications was
problematic for a great many patients.
Resurgent interest in pallidotomy likely owes to the advent of the Globus Pallidus
Interna Rate theory of pathophysiology, which holds that excessive neuronal activity in the globus pallidus interna consequent to the loss of dopamine in the basal
ganglia is causal to Parkinsonism. Despite considerable contrary evidence, the
Globus Pallidus Interna Rate theory positing over activity of the globus pallidus
interna endures and provided intuitive justification for pallidotomy. DBS was
seen as a form of pallidotomy and thus borrowed from the interest in pallidotomy. Equating the mechanisms of pallidotomy with high-frequency stimulation
of the globus pallidus interna rests on an error in reasoning known as the Fallacy
of Pseudotransitivity, which enables a transference of the justification from pallidotomy to pallidal DBS.
The Fallacy of Pseudotransitivity may be expressed in the following form:If a
implies c and b implies c then a implies b. The reasoning is false. In the case of pallidotomy and DBS, the fallacy takes the following form:Pallidal DBS (a) improves
Parkinsonism (c) and pallidotomy (b) improves Parkinsonism (c) therefore pallidal
DBS (a) implies pallidotomy (b). The fallacy becomes clearer in the following analogy:Stroke (a) causes weakness (c) and curare (b) causes weakness (c). The resulting
fallacy is that stroke (a) implies curare (b).
Other than fallacious reasoning, nothing justifies the notion, which inference
from a comparison to pallidotomy otherwise supports, that high-frequency DBS
inhibits excessive neuronal activity. The first direct studies clearly demonstrated
that DBS of the globus pallidus interna or the subthalamic nucleus activated action
potentials in the efferent neurons (Baker et al. 2002; Montgomery 2006; Walker
etal. 2011, 2012). Admittedly, the prior precedent of surgical ablations for neurological and psychiatric disorders was a boon to the early development of DBS, much of
which amounted to chasing lesions:Previously lesioned structures subsequently
underwent stimulation.
The pathophysiological notions that neurological and psychiatric disorders are
related to various structures excessive activity and that high-frequency DBS inhibits this activity figured prominently in the development of DBS of the subgenu
cingulum for the treatment of depression resistant to medication and behavioral
therapy. Helen Mayberg and colleagues compared Positron Emission Tomography
regional blood flow of patients responsive to medication therapy for depression
to those of patients who were refractory (Mayberg etal. 2005). In comparisons to
responding patients, some sites in the refractory patients showed increased blood
flow and some reduced blood flow. Based on the presupposition that high-frequency
DBS inhibits, the subgenu cingulum, which demonstrated increased blood flow,
was picked as the target and was successful. Whether DBS of those targets associated with decreased blood flow likewise would have improved is unknown.
One finds a useful example in the situation of Parkinsons disease. Targeting
the globus pallidus interna and subthalamic nucleus made sense in view of the
Globus Pallidus Interna Rate theory. However, it is clear that stimulation in any site
within the basal gangliathalamic-cortical system improves Parkinsonism (Huang
etal. 2014).
The critical question becomes whether current notions of pathophysiology constrain the range of possible future DBS therapies (Montgomery 2013).
DY N A M I C S
Dynamics refers to changes in a state over time. The dynamics involved in reaching for a cup offers a useful example. At the first level of analysis, there must occur
orderly recruitment of motor units of individual muscles. (A motor unit consists
of muscle fibers innervated by a single lower motor neuron in the brainstem and
spinal cord.) As the force required for rotating joints to produce the desired task is
reached, small motor units are recruited first and larger motor units follow. At the
next level, motor units are organized into bursts of activities between the muscles
agonistic and antagonistic to the joint rotation in order to accelerate, brake, and
carefully rotate the joint to the desired angle (Montgomery 2013). Most movements
may involve multiple rotations of a specific joint and rotations about multiple joints,
each requiring the first two levels of orchestration and also imposing higher levels
of organization.
The abovementioned dynamics of a normal multisegmented limb movement are
very complex. The effects of diseaseParkinsons disease, for examplemust likewise be complex, because abnormal multisegmented movements still are possible.
The complexity of the dynamics is far greater than that suggested by the simple role
252
posited for the globus pallidus interna, namely that of acting to permit or prevent
movements in a one-dimensional system. It is unrealistic to think that the Globus
Pallidus Interna theory or another simple theory of physiology or pathophysiology merits consideration as adequate. The fact that it has been considered adequate
merely serves to underscore how simplistic the requirements of any theory under
current perspectives are where anatomy and pharmacology serve as metaphors for
physiology. The one-dimensional pushpull dynamics posited by current theories
appears reasonable, because virtually all theories posit one-dimensional pushpull
systems (Montgomery 2012).
Prior to Globus Pallidus Interna Rate theory, which posited overactivity of the
globus pallidus interna as causal to Parkinsonism, there was the Acetylcholine/
Dopamine Imbalance theory. This theory held that abnormal overactivity of the
cholinergic system and underactivity of the dopaminergic system were causal to
Parkinsonism. Apopular current theory holds that overactivity of low beta oscillators (1020 Hz) are causal to Parkinsonism. This theory, like its predecessors, posits
a pushpull system whose single dimension is the amount of low beta oscillations.
Evidence of one-dimensional pushpull dynamics is not difficult to discover if
one knows where to look. One place to search is in the physics of Aristotle. Aristotle
posited contraries. The physical world consists of reciprocally related dichotomized
elements, which, Aristotle (2001) wrote, may be generalized into excess and
defect. The same holds true of other things also, he continued, even things
which are not simple but complex follow the same principle, but the opposite state
has not received a name, so we fail to notice the fact. What is in tune must come
from what is not in tune, and vice versa; the tuned passes into untunednessand
not into any untunedness, but into the corresponding opposite (Aristotle 2001).
The relation between the objects dichotomized thusly is reciprocal or, as Aristotle
termed it, one of contraries. The ontological status as reciprocal presupposes the
nature of the interactions among the ontological entitiesinteractions that are
clearly one-dimensional and antagonistic.
It is not difficult to understand the motivation behind Aristotles positing contraries. Most observations vary in a continuous manner rather than according to
a dichotomous presence or absence. In a continuum, the only readily discernible
condition are the extremes. Given this, the question is whether to ascribe a unique
physics or metaphysics to every possible condition along the continuum, which
could risk an infinite number of conditions, or to state that all conditions along a
continuum is some amalgam of the two conditions that constitute the extremes.
One notes that this differs little from the early notion of atomistic theories of the
ancient Greeks, in which all bodies were some admixture of a finite set of different
atoms. The ancient Greeks also held that all bodies were some admixture of the four
elements:earth, air, fire, and water. What characterizes a body is the position along
the single dimension of each element. As beautifully discussed by Noga Arikha
(2007), Galen extrapolated Aristotles four elements and the one-dimensional
dynamics within each element to his humoral theory of disease. Arikha argues
rather persuasively that many current medical therapies for neurological and psychiatric disorders continue to adhere to the one-dimensional pushpull paradigm
of Galen.
Closer to the present one finds a second instance of one-dimensional pushpull
dynamics paradigm in nineteenth-century German philosopher G.W.F. Hegels
dialectics. Hegel argued that all knowledge is a synthesis of thesis and antithesis.
Though the combinatorial mechanisms of Hegels dialectics are not as quantitative
as they were for the ancient Greeks, they are nonetheless organized according to a
one-dimensional pushpull scheme, even if it results in a number of systems.
The extrapolation of one-dimensional pushpull systems may be observed in
the work of John Hughlings Jackson, which has helped to shape current concepts
of neurological disorders. According to Hughlings Jackson, symptoms and signs
owe to excess or defect of function. Seizure and involuntary movement are examples of excessive function. Paralysis is an example of absence of function. Because
Hughlings Jacksons theory continues to influence current neurological thinking, it
continues also to sow confusion.
Demonstration of the power of neurologys notion of positive and negative
symptoms may be seen in the opinion of Francis Martin Rouse Walshe, a famous
British neurologist. Of beriberineuropathy now clearly known to be a deficiency
of thiamineWalshe wrote:
It is not too far-fetched, perhaps, to recall in this connection a famous axiom
of Hughlings Jackson with regard to cerebral disease. He said that negative
or destructive lesions could not cause positive symptoms, but might allow of
their developmentin other words two factors were concerned in the production of spastic paralysis, destruction of pyramidal fibers causing the negative symptom paralysis, and consequently unbalances activity of other centers
causing positive the symptom spasticity. [...] So with beriberi, absence of vitamine cannot be an adequate cause of polyneuritis, which is clearly a positive
reaction to a direct and positive cause. (quoted in Phillips 1974)
For the ancient Greeks, the contraries require an embodiment. This requirement
continues to hold true for the modern approach to neurological and psychiatric
disorders. If a patient becomes self-centered and heedless of social norms after part
of her brain suffers damage, then the behavior must represent excessive function
elsewhere, because the frontal lobe has lost its ability to influence social behavior. If
the frontal lobes lose their ability to function but the antisocial behavior is regarded
as a positive symptom, then excessive activity must occur in some other structure
previously suppressed by the frontal lobe. It is as though an individuals frontal
lobe, rather than the individual herself, makes an intentional value judgment to
repress antisocial activities.
D EEP B R A I N ST I M U L AT I O N:A N U N E X PECT ED
SE AOFCHANGE
Whatever their nature, DBSs mechanisms of action are complex. Illustrative of

this point is the fact that 100-pps DBS typically fails to improve the symptoms of
Parkinsons disease, whereas 130-pps DBS succeeds. The difference in the interstimulus pulse interval between the two is approximately 3 ms or 0.003 of a second.
DBS mechanisms of action operate on time scales that pharmacological therapies
cannot approach. This being the case, one has to wonder about inferences to physiological mechanisms based on pharmacological observations or any observation
254
based on dynamics that are far slower, such as functional Magnetic Resonance
Imaging, and how they relate to the physiology and pathophysiology.
One wonders how inferences about physiology and pathophysiology from
pharmacology, neurochemistry, and anatomy may inform actual physiology and
pathophysiology, which operate on extremely short dynamical time scalesthe
millisecond time scale at which therapeutic DBS appears to operate, for example.
None of the major theories proposed since the 1970sthe Acetylcholine/Dopamine
Imbalance theory, the Globus Pallidus Interna Rate theory, the Low-beta Oscillator
theory, or the Indirect/Direct/Hyperdirect Imbalance theory, for examplebegin
to approach the necessary dynamics. One may test this claim by attempting to
explain how these theories explain the complex time course of muscular actions
necessary to produce movement, even altered movement observed in movement
disorders. The dynamics of these theories may at best be described as related solely
to steady-state dynamics.
FA I LU R E O F I M AG I N AT I O N
Any novel DBS therapy must arise out of researchas proofs of concept initially
and then as proofs of clinical efficacy and safety. The success of surgical ablations
for neurological disorders, for example, became the proofs of concept for subsequent DBS. The range of surgical ablative treatments replaceable by DBS, however,
is limited. Alternative means to proofs -of-concepts are necessary.
Proofs of concept require a concept to be proven. The concept of DBS suppression
of pathologically overactive regions of the brain, for example, became the rationale
for a proof of concept for the pilot studies of DBS for depression. Positron Emission
Tomography imaging demonstrated that subgenu cingulum of patients who were
refractory to current treatment of depression had higher metabolic activity in the
subgenu cingulum. The plausibility of subgenu cingulum DBS followed from the presumption that high-frequency DBS inhibits activity. Fortunately, the proof of concept
worked even if for the wrong reason. Proofs of clinical efficacy and safety are currently underway, despite the fact that the concepts themselves were ill founded. One
may argue that the concept rested on the now untenable assumption that DBS inhibits
excessive activity. All that remained was to find an overactive region of the brain.
Future possible targets for DBS may follow from improved understanding of DBS
mechanisms and the mechanisms of physiology and pathophysiology. The remarkable development of the proof of concept that DBS of the intralaminar nuclei of the
thalamus for minimally conscious states, for example, followed on the research of
Dr.Nicholas Schiff and colleagues, who demonstrated that in nonhuman primates
the intralaminar nuclei of the thalamus were important to maintaining attention.
They also demonstrated that the thalamus of patients in minimally conscious
states was intact, whereas the thalamus in patients in persistent vegetative states
was not. Demonstrated spontaneous arousal of patients in minimally conscious
states argues for the relative preservation of mechanisms for arousal and attention
that might be supported by DBS. Such a hypothesis clearly would not follow from
the notion of DBSs inhibitory effect. Schiff and colleagues (2007) demonstrated a
proof of this concept. They actually demonstrated that the arousal of a patient in a
minimally conscious state is consistent with the hypothesis; it is not proof of it. The
success is nonetheless an important development, not only in terms of potential

clinical impact but also in terms of possible eventual testable hypotheses and an
extended range of DBS therapies.
Though Schiff and colleagues demonstrated that the arousal of a patient in a minimally conscious state is consistent with but not proof of their hypothesis, their finding does not rule out their hypothesis. This offers an important lesson. Ahypothesis
may only be disproven; it cannot be proven. To suggest that because an experiments
results are consistent with a hypothesis they prove that hypothesis is to commit an
error in reasoning known as the Fallacy of Confirming the Consequence. This fallacy
takes the following form:If a implies b is true and b is true, then a is true. The lapse in
logic lies in the fact that b may be true for any number of reasons. Confidence that a
is true rests solely on the fact that b is be true if and only if a is true. Any confidence
one may have about a hypothesis that is consistent with subsequent demonstration
of its predictions thus depends on the degree to which one may be certain that all
other reasonable explanations have been excluded.
The best ally of a researcher who attends to logic is another researcher who
attempts to prove an alternative hypothesis. Every researcher thus should encourage researchers with reasonable alternative hypotheses to pursue them. Whether
such encouragement is forthcoming becomes the question. Though many critics may dispute the philosophical underpinnings of Thomas Kuhns (1963) The
Structure of Scientific Revolutions, no one may dispute the accuracy of the historical observations contained in that text, which describe a particular progression:established hypotheses persist, by the power of incumbency with it hegemony
of resources, until some overwhelming intervening crisis forces a change. The
potential untoward effect due to dominance of one perspective was recognized as
early as the Middle Ages by members of many Italian universities. In an attempt
to prevent such hegemony, an advocate for a prevailing theory would be made
departmental chairman, while an advocate of popular alternative theory would
be made vice-chairman. Needless to say, this practice has since been abandoned.
Much to its authors dismay, The Structure of Scientific Revolutions (Kuhn
1963)was received as more of a political, psychological, or sociological than a scientific work. Many scientists have rejected outright Kuhns historical analyses.
Politics, psychology, and sociology do admittedly play roles in decisions as to which
theories are protected and advanced, but an explanation need not rest solely on
them. Kuhns concept of incommensurability suggests that proponents of one theory often cannot grasp another and, consequently, the difference between antagonistic perspectives cannot be adjudicated by science alone and naturally opens the
way for politics, sociology, and psychology. The idea behind Kuhns incommensurability echoes the idea behind Maslows observation that the whole world appears as
a nail to an individual equipped only with a hammer. Someone with only a hammer
would understandably be suspicious and perhaps unfairly critical of the hypothesis
advanced by someone to whom the world appears to be a screw.
T H E I N C O M PL E T EN ES S O F T H E SC I EN T I FI C M E T H O D
Introduced by the Englishman Francis Bacon (15611626), the Scientific Method

observes a particular sequence. Ahypothesis is generated, tested by demonstrating
256
its predictions, and revised should the predictions fail. The presumption of truth
is applied if the predictions succeeded. The Scientific Method was instrumental in
the establishment of the Royal Society in 1660 and the British Association for the
Advancement of Science in 1831. One who understands the Fallacy of Confirming
the Consequence, however, understands that the Scientific Method works only
when experiments fail. Yet no one designs experiments to fail. Designing experiments to succeed, on the other hand, opens the door to the Fallacy of Confirming
the Consequence. The Scientific Method reveals nothing about hypotheses origins.
If an unreasonable hypothesis is not proven wrong, the risk is that it will be taken
as right.
The Scientific Method is deductive in the sense that a hypothesis is used to derive
a set of particulars, that is, a set of expected observations based on a hypothesis and
an exact experimental context. Deduction does not result in any new knowledge.
It merely preserves knowledge already contained (or thought to be contained) in
the hypothesis. It seems logical to think that scientific advancement depends on an
adequate understanding of hypothesis generation. Yet these concerns are often dismissed as happenstance or a matter for psychologists, because they appear foreign
to most scientific discussions.
One may argue that hypothesis generation often proceeds by metaphor. Mary
Walker, for example, noted that patients with myasthenia gravis exhibit weakness similar to the weakness exhibited by patients with curare poisoning. She thus
established the following analogy:Curare is to myasthenia as anticholinesterases
for curare poisoning are to X for myasthenia gravis. The variable X in this case also
stands for anticholinesterases. As curare poisoning is alleviated with application
of anticholinesterases, so might also myasthenia gravis be alleviated with application of anticholinesterases. Subsequent research demonstrated the hypothesis to be
correct.
It is important to note that metaphors do not generate evidence; they generate only
hypotheses. When such metaphors are taken as evidence, science may be impeded.
For example, early in DBS, there appeared the following metaphor: Pallidotomy
improvement in Parkinsons disease is to pallidal DBS improvement in Parkinsons
disease as reduced globus pallidus output from pallidotomy is to X in pallidal DBS.
The variable X in this case also stands for reduced globus pallidus interna output,
the presumed mechanism of action, which continues to inform criticisms of alternative explanations.
Because analogies generate hypotheses, which are critical to new knowledge, the
task becomes that of determining those analogies that will generate hypotheses
amenable to advancing the field of DBS. Analogies derived from pharmacology,
neurochemistry, and anatomy will not advance the understanding of DBS, pathophysiological mechanisms addressed by DBS, or physiological mechanisms that
may be used by DBS. An analogy must be at least as complex as the phenomenon its
hypothesis attempts to explain.
Thanks to recent advances in physics and mathematics, Complex Systems theory
may provide a sufficiently complex analogy. Antithetical to the one-dimensional
pushpull dynamics characteristic of most current theories of basal ganglia physiology and pathophysiology, complex systems often involve highly nonlinear interactions. These complex systems may also give rise to metastable states and transitions
between metastable states. These offer a basis for understanding behaviorthe
transition, for example, from a state that produces Parkinsonian tremor at rest to a
state during action in which the behaviors do not self-organize to produce tremor,
and then back to a system that produces tremor when returning to rest.
A significant advantage to self-organizing dynamics in complex systems is the
ability to discard anthropomorphic notions of intentionality that characterize
current theories of brain function. The Globus Pallidus Interna Rate theory, for
example, holds that the globus pallidus interna intends to halt inappropriate movement and that the frontal lobe intends to suppress antisocial behaviors. The theory thus invites a ghost in the machine criticism (see Descartes Myth, in Ryle
2002). Of the basal ganglia-thalamic-cortical system, one may say that the system
self-organizes into a series of transitions (bifurcations) that produce normal movement and that, as a consequence of disease, the organization is such that symptoms
manifest. Eliminated from this theory is any notion of intention.
A LT ER N AT I V E C O N C EP T I O N
An alternative to one-dimensional pushpull systems mediated by relative excesses

and deficiencies of neurotransmitters or low-beta oscillations is consideration of
a disease as misinformation (Montgomery 2013). Offering a useful example is the
varying precise orchestration of motor unit recruitment over multiple muscles and
multiple joints. The orchestration relies on information from the central nervous
system. Patients with Parkinsons disease maintain an ability to move. Therefore,
though motor units receive information, it is abnormal, that is, misinformation.
To the degree that DBS normalizes movement, it also normalizes the information
transmitted to the motor units.
It becomes important, then, to consider the ways DBS may improve the information transmitted to motor units to normalize behavior. The DBS pulse train
contains no information. A hypothetical DBS pulse train, for example, contains
00000010000000010000001 (0 is the time between pulses and 1 is the pulse), yet
contains no information. Asecond pulse train, 01000101 01000011 01010011, contains variation in the order of zeroes and ones and may encode unique information. In this case, the information is the ASCII binary code for ECS. Simply by
changing the 8th, 16th, and 24th bit from a 1 to a 0, one changes the information to
misinformation01000100 01000010 01010010 or DBR. Adding the DBS pulse
train to the DBR pulse train restores the original ECS pulse train. This is not to
suggest that this is how DBS actually works. It is simply to demonstrate how misinformation may be created and corrected.
The abovementioned mechanism may be explained by way of analogy to an
amplitude modulated radio, whose antenna picks up of a multitude of radio signals.
The radio must select a desired signal from all signals received. It accomplishes
this by setting an oscillator within the radio to the same frequency as the desired
signal. The radios oscillators interacts (resonates) with a desired radio signal frequency to amplify it above other signals in order to render it audible. Originally
lost in the noise created by the other radio signals, a desired radio signal is amplified by the radios oscillator above the noise. The radios oscillator, in other words,
increases the signal-to-noise ratio. One may regard DBS as an oscillator (in the
radio) that interacts with oscillators in the basal ganglia-thalamic-cortical system
258
(in the transmission from the radio station). In interacting with them, the DBS
signal amplifies the neural signal above the noise created by disease to restore the
information contained in the neural signal (Montgomery 2013).
Alternatively, the DBS pulse train may overwrite the misinformation with information01000100 01000010 01010010 to 00000010000000010000001. It has
been demonstrated that the brain often fares better without information than it
does with misinformation. Indeed, the therapeutic mechanism of pallidotomy and
other surgical ablations reduces misinformation to no information.
S U M M A RY
DBSs remarkable therapeutic benefits have been demonstrated. There appears to

be no reason to believe that virtually any neurological and psychiatric disorder
will fail to improve with DBS. The future success of DBS, however, is anything but
assured. Further research is needed in order to confront presumptions inimical to
the fundamentals of DBS and, ultimately, the physiology and pathophysiology of
the nervous system.
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Publishers; 2007.
Aristotle. The Basic Works of Aristotle. McKeon, R, ed. New York: Modern Library;
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Baker KB, Montgomery EB Jr, Rezai AR, etal. Subthalamic nucleus deep brain stimulus evoked potentials: physiological and therapeutic implications. Mov Disord.
2002;17(5):969983.
Bliss M. William Osler:ALife in Medicine. NewYork:Oxford University Press; 1999.
Kuhn TS. The Structure of Scientific Revolutions. Chicago:University of Chicago Press;
1963.
Laxton AW, Tang-Wai DF, McAndrews MP, etal. A phase Itrial of deep brain stimulation of memory circuits in Alzheimers disease. Ann Neurol. 2010;68(4):521534.
Lee KJ, Shon YM, Cho CB. Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy. Stereotact Funct Neurosurg. 2012;90(6):379385.
Lipsman N, Woodside DB, Giacobbe P, et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet
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Lozano AM, Giacobbe P, Hamani C, etal. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg.
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Mayberg HS, Lozano AM, Voon V, etal. Deep brain stimulation for treatment-resistant
depression. Neuron 2005;45(5):651660.
Montgomery EB Jr. Effects of GPi stimulation on human thalamic neuronal activity.
Clin Neurophysiol. 2006;117(12):26912702.
Montgomery EB Jr. Neurophysiology. In:Pahwa R, Lyons KE, eds. The Handbook of
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Phillips CG. Francis Martin Rouse Walshe, 18851973. Biogr Mem Fellows R Soc.
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Schiff ND, Giacino JT, Kalmar K, etal. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 2007;448(7153):600603.
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Walker HC, Huang H, Gonzalez CL, et al. Short latency activation of cortex during
clinically effective subthalamic deep brain stimulation for Parkinsons disease. Mov
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INDEX
Abetalipoproteinemia, 152
Abnormal dopamine metabolism, 106
Acanthocytosis, chorea secondary to,
127
Acetylcholine/Dopamine Imbalance
theory, 252, 254
Action potentials, DBS production of,
221222
Activities of daily living (ADLs), 23
ADHD (attention deficit hyperactivity
disorder), in Tourettes syndrome
patients, 131, 139140
Adverse effects
in DBS for dystonia, 9798
in DBS for Parkinsons disease,
2729
peak-dose dyskinesias as, 49
in postoperative patients with
Essential tremor, 8990
Parkinsons disease, 6061
reporting protocols for, 202
of selective peripheral denervation
for dystonia, 109
tissue activation volume constraints
to reduce, 200
in Tourettes syndrome, 124125
Affordable Care Act of 2010, 123
Allopathic medicine, 70
Alpha agonist medications, for
Tourettes syndrome, 135138
Alzheimers disease, 247
American Academy of
Neurology, 247
American Board of Neurology and

Psychiatry, 8
American Medical Association, 38,
9596, 158, 228
American Psychiatric Association, 131
Americans with Disabilities Act, 235
Anorexia nervosa, 247
Anterior cingulate cortex role in PTSD,
187, 191192
Anterior limb of the internal capsule,
as DBS target, 140, 178, 181
Anterior-medial region of the globus
pallidus interna, as DBS target,
123124, 127128
Anticonvulsants, 163
Anti-NMDA receptor encephalitis, 163
Antipsychotic medications, for
Antonello, C.E., 110
Aquinas, Thomas, 229, 231
Arikha, Noga, 252
Aristotle, 12, 3738, 172, 216, 249, 252
Ashworth scale, 97, 102
Ataxia, 89
Atrial fibrillation, DBS and, 92
Attention deficit hyperactivity disorder
(ADHD) in Tourettes syndrome
patients, 131, 139140
Autoimmune disorders, 163
Autonomy
beneficence versus nonmalfeasance
and, 234236
description of, 230
ethical principle of, 179181
262
Autonomy(Cont.)
informed consent and, 236239
respect for patients in, 236
Bacon, Francis, 117, 255
Basal ganglia-thalamic-cortical system,
as DBS target in Parkinsons
disease, 3435, 98, 123
Beauchamp, T.L., 111, 230, 236
Beaumont Spine Pain and Sports
Medicine Clinic, Inc. v.Swan,
243244
Behavioral intervention, for Tourettes
syndrome,138
Belmont Report, 38
Benebid, A.L., 216
Beneficence
description of, 230
malfeasance versus, balance
of, 229
nonmalfeasance versus, 230231,
234236
Benton Visual Form Discrimination,
195
Bernard, Claude, 135
Beta-ketotheolase deficiency, 164
Bilateral DBS systems, for PTSD
research, 203
Biomedical ethics, 229230. See also
Ethical issues
Blepharospasm, 97, 104
Boggio, P.S., 192
Botulinum toxin
for dystonia, 108
for Essential tremor, 80, 83
for hyperkinetic disorders, 166
Bradykinesia, 66
British Association for the
Advancement of Science, 256
Bromocriptine, response to, 43
Bryden, D., 158
Burke-Marsden-Fahn Rating Scales, 97,
102, 116
California Verbal Learning Test,
195, 199
CAPS (Clinician Administered
PTSD Scale). See Clinician
Administered PTSD Scale (CAPS)
INDEX
Capsulotomy, 178
Catecholamine-o-methyltransferase
(COMT) inhibitors, 45, 49
Cavanna, A.E., 139
CBT (cognitive-behavioral therapy),
138, 199
Cell Theory, 124
Centromedian-parafascicular nucleus,
as DBS target, 123, 126, 128
Cerebellar outflow tremor, 145155
appropriate measures, 147150
DBS targets, 151
from multiple sclerosis, 151152
off-label DBS use for, 2, 67, 145147
from postanoxic and posttraumatic
tremor, 152
postoperative programming, 151
selection criteria, 150151
symptom-specific versus
disease-specific, 152153
Cerebral palsy, dystonia-choreoathetotic,
97, 102
Cervical dystonia, 95, 97, 104, 109110
Children
with dystonia, 106, 133
with Tourettes syndrome, 131132
Childress, J.R., 111, 230, 236
Chorea-acanthocytosis, 2, 156
Chorea gravidarum, 163
Chorea secondary to acanthocytosis,
127
Chorea secondary to pantothenate
kinase-associated neurodegeneration, 127
Chronic tics, 132
Clinical trials for DBS, 247249. See
also Posttraumatic stress disorder
(PTSD)
Clinician Administered PTSD Scale
(CAPS), 189, 196199, 201202, 204
Cluster headaches, 247
Cocaine use, hyperkinetic disorders
from, 163
Cochrane Database of Systematic
Review, 136, 199
Cognitive-behavioral therapy (CBT),
138, 182
Cognitive impairment
drug-induced, 51
INDEX263
as Parkinsons disease medication

side effect, 4950
in Parkinsons disease patients least
acceptable for DBS, 39, 5051
Columbia Suicide Risk screen,
198199
Combat Exposure Scale, 198199
Common Data Elements for TBI,
197198
Common Data Elements in Radiologic
Imaging of Traumatic Brain
Injury, 199
Common Data Elements Interagency
Steering Committee, 195, 197
Comorbidities in Tourettes syndrome
patients, 139140
Complex Systems theory, 256257
Computed Tomography scans, 91
COMT (catecholamine-o-methyltransferase) inhibitors, 45, 49
Confirmation bias, 140
Confirming the Consequence, fallacy
of, 217, 255256
Contingency management, for
Controlled Oral Word Association
Test, 195, 199
Core Assessment Program for Surgical
Intervention Therapies in
Cost-benefit of DBS surgery, for
Countertransference, 231234
Crack dancing, 163
Cranial dystonia, 97, 102103
Davidson, Richard, 191
Declaration of Geneva, General
Assembly of the World Medical
Association, 228229
Deep brain stimulation (DBS), future
of, 247259
alternative conception, 257258
clinical trials, 247249
complex mechanisms of action,
253254
dynamics, 251253
pathophysiology determining treatment, 249251

proofs of concept, 254255
scientific method incompleteness,
255257
Deep brain stimulation (DBS),
overview of, 113
ethical issues, 810
healthcare system limitations and,
78
mechanics of, 36
for neurological and psychiatric
disease symptom control, 13
neurosurgical treatment versus, 67
revolutionary nature of, 1012
Deep brain stimulation (DBS), purpose
of, 1421
dynamics, 1617
pathoetiology and pathophysiology
conflation, 1819
pathophysiology importance, 1516
when all else fails, 1415
Deep Brain Stimulation for Parkinsons
Disease Study Group, 24, 26, 46
Programming:Principles and
Practice (Montgomery), 57
Dementia, in atypical Parkinsons
disease, 44
Deontology, 230
Depression
DBS surgery and, 51, 140
electroconvulsive therapy (ECT)
for, 179
in postoperative Essential tremor
patients, 84, 89
in posttraumatic stress disorder, 188
regional blood flow in, 251
self-limiting, 72
Descartes, Rene, 117, 172
Descriptive ethics, normative
ethics versus, 239241
Diagnosis-Related Group (DRG),
patients assigned to, 240241
Diagnostic and Statistical Manual of
Mental Disorders (DSM, American
Psychiatric Association), 131132
Diathermy, 91
Disease-based treatments, 2
264
Dopamine agonists, 45, 49, 163, 165

Dopamine depleting agents, 135137,
165
Dopamine transporter ligand
imaging-single photon emission
computerized tomography
(SPECT), 79
Double Effect, Principle of (Aquinas),
229231, 238
DRG (Diagnosis-Related Group),
patients assigned to, 240241
Drug-induced dyskinesia, 127
Drug-induced parkinsonism, 40
DSM (Diagnostic and Statistical
Manual of Mental Disorders,
American Psychiatric
Association), 131132
Duration of effect, of DBS, 30, 4649
Dynamics
complexity of, 251253
overview, 1112
time dimension of, 1617
Dyskinesias. See also Hyperkinetic
disorders
DBS battery failure and, 6263
drug-induced, 127
peak-dose, 49
tardive, 103, 127, 156, 164
Dystonia, 94100
causal mechanisms, 9596
children with, 133
DBS adverse effects, 9798
DBS efficacy, 9697
DBS in globus pallidus interna for,
127
DBS in practice guidelines for, 242
DBS targets, 9899
decision for DBS, 99
diagnosis, 96
FDA Humanitarian Device
Exemption for, 12
levodopa-induced, 161
primary and secondary, 9495
Dystonia, postoperative care of patients
with, 115121
DBS-induced plasticity, 120121
epistemological considerations,
117118
overview, 115116
INDEX
programming approaches, 118120

programming problems, 116117
Dystonia-choreoathetotic cerebral
palsy, 97, 102
Dystonia patients least acceptable for
DBS, 101114
alternative therapy failure, 106111
overview, 101
postoperative programming
provision, 112
primary versus secondary, 101103
severity, 111
spontaneous remission potential,
103106
tolerability, 111112
Dystonic tremor, 152
ECT (electroconvulsive therapy), 172,
179
Efficacy. See also Parkinsons disease
in dystonia, 9697
in Essential tremor, 6970
in obsessive compulsive disorder
(OCD), 181182
peak-dose, 4647
in Tourettes syndrome, 124125
Egalitarianism, 230
Electroconvulsive therapy (ECT), 172, 179
Embarrassment, in Essential
tremor, 76
Emergency situations, 6264, 9192
Employee Retirement Income Security
Act of 1974, 228
Epilepsy, 220, 247
DBS adverse effects, 7073
DBS efficacy, 6970
DBS nature of, 6769
DBS risks, 7073
DBS safety and effectiveness, 6667
FDA approved DBS for, 1
tremor-predominant idiopathic
Parkinsons disease versus, 4243
Essential tremor, postoperative care
of patients with, 8793
adverse effects, 8990
INDEX265
availability of, 84
challenges of, 87
efficacy, 8789
emergencies, 9192
medication adjustments, 9091
Essential tremor patients least acceptable
for DBS, 7486
candidate selection responsibilities,
7475
diagnosis, 7780
exhaustion of less invasive therapies,
8083
overview, 7577
postoperative care availability, 84
tolerability, 8384
Ethical issues, 226246
American Medical Association Code
of Ethics, 38, 9596, 158, 174, 228
autonomy, 179181, 234239
beneficence versus nonmalfeasance,
230231, 234236
comorbidities as exclusion basis,
148149
context of, 179
countertransference, 231234
in DBS for Parkinsons disease, 3132
descriptive versus normative ethics,
239241
efficacy versus prevalence, 226227
epistemic issues in DBS acceptance,
242243
excellence, choosing, 241242
informed consent, 236239
in neurosurgery referrals, 5
Omission bias, 99
overview, 810
in patient selection, 38, 41
physicians' responsibility to
neurosurgeons, 243245
in postoperative care, 115
in posttraumatic stress disorder
research, 189190, 205206
principles and theories overview,
227230
European Society for the Study of
Tourettes Syndrome, 132, 134
Exposure and response prevention, for
Fahrs disease, 106

Failure to inform, 239
FDA (U.S. Food and Drug
Administration). See U.S. Food
and Drug Administration (FDA)
Fins, Joseph, 189
Fixed dystonia, 105
Flexnerian revolution in medicine, 70
fMRI (functional Magnetic Resonance
Imaging), 1, 192, 223
Foot, Philippa, 233
Fragile-X-Associated Tremor, 152
Freud, Sigmund, 172, 231
Friedmans Analysis of Variance, 82
Functional assessments, 23
Functional Magnetic Resonance
Imaging (fMRI), 1, 192, 223
Gait and balance involvement, in
Galen, 96, 172, 216, 249, 252
Galvani, Luigi, 11
Gamma amino butyric acid (GABA)
neurotransmitter, 221222
General Assembly of the World
Medical Association, 228
Generalized torsion dystonia, 97,
104106
Germ Theory, 95
Glasgow Coma Scale, 194
Global perspective measures of
patient, caregiver, and health care
provider
in Parkinsons disease, 23
Globus pallidus externa, as DBS target,
32, 123
Globus pallidus interna, as DBS target,
3234, 217
Globus Pallidus Interna Rate theory,
15, 250252, 254, 257
Glutaric aciduria type I, 106
Greene, P., 107
Guanidinoacetate methyl-transferase
deficiency, 106
Habit-reversal therapy, for Tourettes
syndrome, 138
Hamilton Anxiety Scale (Ham-A),
198199
266
Hamilton Depression Inventory

(Ham-D), 198199
Hariz, M.I., 124
Healthcare system limitations, 78
Health Maintenance Organization Act
of 1974, 228
Hebbian learning, 120
Hegel, G.W. F., 252253
Hemiballismus, 127, 156
Henneman Size Principle, 218
Hippocrates, 179, 190
Hippocratic Oath, 228229
Hohen and Yahr scale, 23
Holmes' tremor, 152
Homocystinuria, 106
Humanitarian Device Exemption
for children with dystonia, 133
from FDA, 1
for obsessive-compulsive disorder,
171, 173
for primary dystonia, 94
Human subjects, research on, 38. See
also Ethical issues
Huntingtons disease, 2, 127, 156, 165
Hyperkinetic disorders, 156170
DBS for, 2
epistemic status, 159161
off-label uses of FDA-approved
devices, 161163
overview, 156158
Hyperthyoidism, tremor and, 78
Idiopathic Parkinsons disease
diagnosis, 4044
Implanted pulse generator (IPG)
DBS benefits dependent on, 5657
impedance effects, 89
infection risk with replacement,
71, 98
Medtronic Neuromodulation, 203
programming adjustments to, 5860
status checking, 6263
Impulse control, DBS surgery and, 51
Indirect/Direct/Hyperdirect Imbalance
theory, 254
Infections, postoperative, 7172, 92, 98
Inferior thalamic peduncle, as DBS
target, 181
INDEX
Information Theoretic entropy

(Shannon), 158
Informed consent
autonomy and, 236239
Institutional Review Board (IRB)
supervision for, 2
for PTSD DBS research, 205
understanding choices for, 180
adverse event definition and
policies of, 202
for DBS for obsessive-compulsive
disorder, 173, 183
informed consent and, 2
on off-label use of devices, 145, 161,
163
psychological impact on judgments
of, 189
PTSD DBS study disapproved by,
233234
Insurance
off-label use deemed experimental
by, 122, 162
Pegram v.Herdrich (2000), 238
physician ethical dilemmas with,
227228
Internet, postoperative care methods on, 7
Intracerebral hemorrhage, 7071
Intracranial hemorrhage
in patients with dystonia, 98
in patients with Essential tremor,
89, 92
in patients with obsessive compulsive
disorder, 182
in patients with Tourettes syndrome,
125126
Intralaminar nuclei of thalamus, as
DBS target, 123
Intrathecal and intraventricular
baclofen, 110
Inverse Problem, 218
Investigational Device Exemption
(IDE), from FDA, 8, 145, 161
Investigational New Drug Application
(IND), to FDA, 145, 161
IPG (implanted pulse generator). See
Implanted pulse generator (IPG)
Italian Movement Disorders
Association, 81
INDEX267
Jackson, John Hughlings, 12, 253

Jankovic, K., 131
Justice, 149, 230
Kant, Immanuel, 180
Kaplan-Meier survival
curves,103104
Kim, W., 125
Klein v.Biscup (1996), 162
Klinefelter syndrome, 152
Kuffs disease, 40
Kuhn, Thomas, 255
Kupsch, A., 117118
Kyphoscoliosis, 105
Lead misplacement, repeat surgery
and, 28
Leckman, J.F., 133
Levodopa equivalents, 46
Levodopa treatment
dyskinesia from, 160161
dystonia from, 161
overview, 810
peak-dose efficacy of, 4749
response to, in idiopathic
for Segawa disease and tyrosine
hydroxylase deficiency, 107
unresponsiveness to, in Essential
tremor diagnosis, 79
Libertarianism, 230
Life Stressor Checklist, 198199
Long-term depression (LTD), to
improve DBS response in
dystonia, 120
Long-term potentiation (LTP), to
improve DBS response in
dystonia, 120
Low-beta Oscillator theory, 254
Lupus anticoagulant syndrome, 164
Magnetic Resonance Imaging (MRI),
91, 191
Malfeasance versus beneficence,
balance of, 229
Malpractice, HMO denial of coverage
as, 230
MAO-B (monoamine oxidase type B)
inhibitors, 45, 49
Maslow, Abraham, 249, 255

Massed negative practice, for Tourettes
syndrome, 138
Mayberg, Helen, 251
Medicare, reimbursement policies of,
240
Medication reduction with DBS,
Medtronic Neuromodulation, 203
Meige syndrome, 97, 104
Mereological fallacy, 2, 123
Metabolic disease, neurodegenerative
disorders with, 106
Misinformation, neurological
disorders resulting from,
23
Mitochondrial disorders, 106
Mitochondrial encephalopathy,
152
Monoamine oxidase type B (MAO-B)
inhibitors, 45, 49
Montgomery, E.B., Jr., 57
Morishita, T., 173, 181
Motor cortex, as DBS target in
Motta, F., 110
Movement Disorders (Watts etal.),
57
Multiple sclerosis
cerebellar outflow tremor in, 2, 67,
151152
DBS nonspecific risks and, 148
Expanded Disability Status Scale for,
150151
Multisystem atrophy (MSA), 40
Myoclonus-dystonia disorders, 97
National Institute for Health
and Clinical Excellence
(UK), 182
National Institutes of Health, 25, 28,
58, 146, 193, 247
Neurodegenerative disorders
with metabolic disease,
106
Neuroleptics, tardive dystonia from,
103
Neuron Doctrine, 124
Neuropathies, 152
268
Neurosurgeons, physicians
responsibility to, 243245
Neurosurgical treatment, DBS
versus, 67
Neurotransmitters, DBS mechanism
of action versus, 16
New England Journal of Medicine, 24
Nieman Pick C disease, 106
NINDS Common Data Elements
program, 202
Nonmalfeasance, beneficence versus,
230231, 234236
Nonsurgical management means,
4550
Normal pressure hydrocephalus, 40
Normative ethics, 239241, 244
Nucleus accumbens, as DBS target,
123, 181
Obsessive compulsive disorder
(OCD), 171185
autonomy, ethical principle of,
179181
burden of, 176177
DBS efficacy, 181182
DBS programming, 183
DBS safety, 182
DBS status for, 173176
DBS targets, 181
FDA Humanitarian Device
Exemption for, 12, 242
lack of perspective and context,
177179
overview, 171172
in Tourettes syndrome patients, 131,
139140
Off-label DBS use
for cerebellar outflow tremor, 2, 67,
145146
for hyperkinetic disorders,
161163
for secondary dystonia, 94, 102
for Tourettes syndrome, 122123
Omission bias
Do no harm imperative and, 147,
157, 232
non-surgery alternative preferred
because of, 99, 135, 141
INDEX
as patients' problem, 234

psychological and emotional factors
under, 158
in PTSD, 209
as therapeutic nihilism, 190
Tourettes syndrome selection
criteria affected by, 135, 141142,
147
One-dimensional push-pull dynamics
paradigm, 16, 216, 218, 252253
Organic acidemia, 106
Osler, Sir William, 9596, 249
Pallidotomy, 218, 250
Panic disorder, in PTSD, 188
Pantothenate kinase-associated
neurodegeneration, 106, 127
Pantothenate kinease deficiency, 156
Parkinsons disease, 2236. See also
Obsessive compulsive disorder
(OCD)
adverse effects of treatments,
2729
as basal-ganglia-thalamic-cortical
system disorder, 3435, 9899,
123
DBS effectiveness measures, 2224
DBS effect unrelated to dopamine,
216
DBS program evaluation based on
improvements in, 5
DBS studies, 2426
DBS targets, 3235
dopamine deficiency as focus, 243,
248250
duration of benefit with DBS, 30
epistemological and ethical DBS
factors, 3132
FDA approved DBS for, 1
Globus Pallidus Interna Rate theory
and, 252
healthcare-related DBS issues, 31
medication reduction with DBS,
30
pathophysiology of, 218219
patients suitable for DBS with, 7
pharmacoeconomic considerations,
30
INDEX269
pharmacological treatments versus

DBS, 2627
sufficient versus powerful
treatments for, 89
Parkinsons disease, postoperative
management of patients with,
5665
adverse effects, 6061
emergency situations, 6264
ensuring benefits and minimizing
risks, 5657
importance of, 5253
physician and healthcare professional
roles, 5758
programming or medication
adjustments, 5860
psychosocial dislocation, 6162
Parkinsons disease patients least
acceptable for DBS, 3755
epistemology of selection criteria
exhaustion of nonsurgical
management means, 4550
idiopathic Parkinsons disease
diagnosis, 4044
overview, 39
postoperative care plans, 5253
preexising cognitive impairment,
5051
toleration of surgery, 5152
overview, 3738
patient-selection context, 3839
Paternalism, 111. See also Omission
bias
Pathoetiology, 1819
Pathophysiology and physiology
insights, 216225
DBS effectiveness, 216217
DBS therapeutic action, 219223
importance of, 1516
intuitive appeal versus complex
explanations, 218219
invalid claims, 223224
pathoetiology and, 1819
prevailing predisposing theories,
217218
theory-differential diagnoses, 219
Patient Protection and Affordable Care
Act of 2010, 123
Patients. See various conditions
Peak-dose dyskinesias, 49
Peak-dose efficacy, 4647
Pedunculopontine nucleus, as DBS
target, 32, 34
Pegram v.Herdrich (2000), 238
PET (Positron Emission Tomography),
223, 251, 254
Pharmacology as physiology paradigm,
216, 249
Phasic dystonic symptoms, 116117
Phenylketonuria-associated tremor, 152
Physicians responsibility to neurosurgeons, 243245
Physiology insights. See
Pathophysiology and physiology
insights
Piedad, J.C., 132
Plasticity, DBS-induced, 120121
Polycythemia vera, 164
Positron Emission Tomography (PET),
223, 251, 254
Postanoxic tremor, 152
Posterior lateral globus pallidus
interna, as DBS target, 9899,
123124
Posterior limb of the internal capsule,
as DBS target, 123
Postoperative management. See various
conditions
Poststroke tremor, 152
Posttraumatic stress disorder (PTSD),
186215
anterior cingulate cortex role in,
191192
background and significance, 188
DBS implantation, 203
DBS possible benefit, 192
design and methods for research,
196197
ethical issues in research on, 189190
human subjects issues, 205206
disapproval of DBS study on,
233234
justification for research structure,
188189
neuropsychiatric disorder
improvement, 192
outcomes measure, 201202
270
Posttraumatic stress disorder

(PTSD)(Cont.)
overview, 186
postoperative programming and
management, 200201
procedures and measures for
research, 197198
research proposal, 187188
response to research proposal,
206211
risk assessment, 192193
sample size estimation and
justification, 204
selection criteria for research,
198200
single-blinding procedure
validation, 201
testing schedule, 202203
traumatic brain injury impact,
194196
Posttraumatic tremor, 152
Pouratian, N., 125
Presidential Commission for the Study
of Bioethical Issues, 239
Primary dystonia, 1, 9495, 101103
Principle of Double Effect (Aquinas),
229231, 238
Pringsheim, T., 137
Progressive supranuclear palsy
(PSP), 40
Pseudoathetosis secondary to sensory
loss, 163
Pseudotransitivity fallacy, 10,
217, 250
Psychogenic disorders, 164
Psychosocial dislocation, 6162
PTSD (posttraumatic stress disorder).
See Posttraumatic stress
disorder (PTSD)
PTSD Work Group, 197
Putamen, as DBS target, 32
Quality of life measures, 23, 139, 142,
198199
Quine, W.V. O., 180
Randomized controlled trials (RCTs),
23, 125. See also Posttraumatic
stress disorder (PTSD)
INDEX
Reason-Base Medicine, 45, 50

Receiver-Operator-CharacteristicsCurve analysis, 44, 200
Rechargeable implanted pulse
generator (IPG), 71
Remission, spontaneous, 103106
Rey Auditory Verbal Learning Test, 195
Rey Osterrieth Complex Figure Test,
195, 199
Riley v.Stone (2006), 239
Robertson, M.M., 124
Royal Society, 256
Sagan, Carl, 7, 39, 146, 161
Schiff, N.D., 254255
Scientific Method, incompleteness
of, 255257
Scientism, 38
Secondary dystonia, 9495, 101103
Second Law of Thermodynamics,
159160
Segawa disease, 106107
Seizures, 62, 72
Selective peripheral denervation, 109
Selective serotonin reuptake inhibitors
(SSRIs), 182183
Self-injurious behavior, DBS exclusion
based on, 140
Self-monitoring, for Tourettes
syndrome, 138
Sensorimotor region of the globus
pallidus interna, as DBS target,
156
Servello, D., 126
Severe runaway dyskinesia, 62
SF-12 Quality of Life measure, 198199
Shannon, Claude E., 158
Sherrington, Sir Charles, 12, 172
Sillay, K.A., 98
Single-blinding procedure validation,
201
Smell, sense of, in Essential tremor, 66
Spasticity, 97, 102, 110
Speech, adverse impacts on
in dystonia, 90, 102103
Spike timing-dependent plasticity, 120
Spinocerebellar degeneration, 152
INDEX271
Spontaneous remission
of dystonia, 103106
of tardive dyskinesia, 164
of Tourettes syndrome, 133
SSRIs (selective serotonin reuptake
inhibitors), 182183
Stimulation risks, in Tourettes
syndrome, 126
Storey, I., 158
Stroke, hemiballismus secondary to,
127
Stroop Color-Word Test, 195, 199
Structured Clinical Interview for
DSM-IV Diagnosis, 198
Structure of Scientific Revolutions, The
(Kuhn), 255
Substance abuse, in posttraumatic
stress disorder, 188
Subthalamic nucleus, as DBS target,
3234, 98, 181, 217
Sufficient treatments, powerful
treatments versus, 89
Suicide, in posttraumatic stress
disorder, 188
Sunstein, Cass, 190
Surgical ablation, 1011
Swallowing, adverse impacts on
in dystonia, 90, 102103
Sydenhams syndrome, 164
Symbol Digit Modalities Test, 195
Symptom-based therapies, 2, 2324,
127, 152153, 160
Symptoms without Evidence of
Dopamine Depletion (SWEDDs),
248
Systemic lupus erythematosus,
163164
TNO-AZL Childrens Quality of Life

scale, 139
Tolstoy, L., 219
Tonic dystonic symptoms, 116117
Tourettes syndrome, 2, 122129
adequation of patient to target,
127128
DBS efficacy and adverse effects,
124125
DBS risks, 125127
DBS targets and conditions treated,
123124
FDA off-label DBS use for, 122123
professional organization
recommendations of DBS for, 242
Tourettes syndrome patients least
acceptable for DBS, 130144
comorbidities, 139140
diagnosis, 131132
duration of symptoms, 134135
exhaustion of alternative therapies,
135138
minimum age for surgery, 132134
Omission bias impact on, 141142
risk assessment, 140
severity sufficient for DBS, 138139
symptom severity change, 135
uncertainty in decision making, 141
Trail Making Test, 195, 199
Transcranial Magnetic Stimulation,
187, 192
Traumatic brain injury (TBI), 191,
194196
Traumatic History Screen, 198199
Tremor-predominant Parkinsons
disease, 4243, 66, 7980
Tyrosine hydroxylase deficiency,
106107
Talairach, Jean, 178

Tardive dyskinesia, 2, 103, 127, 156, 164
Tardive dystonia, 97, 103104
TBI (traumatic brain injury), 191,
194196
Telemedicine services, 7
Thalamus, as DBS target, 34, 98
Theory-differential diagnoses, 219
Thomson, Judith Jarvis, 233
Tic-suppressing medications, 135137
Unified Parkinsons Disease Rating

Scales, 5, 2324, 33, 58
United Kingdom Brain Bank study,
42, 44
U.S. Food and Drug Administration
(FDA)
adverse effects definition of,
2728, 202
DBS approved for Essential tremor
and Parkinsons disease, 1
272
U.S. Food and Drug Administration

(FDA)(Cont.)
DBS approved for primary dystonia,
94, 101102
DBS for children with dystonia, 133
Humanitarian Device Exemption for
DBS use in OCD, 171, 173, 242
Investigational Device Exemption, 8
on off-label DBS use for cerebellar
outflow tremor, 67
on off-label DBS use for Tourettes
syndrome, 122123
off-label use policies, 7, 156,
161163
U.S. Supreme Court, 230, 238
Utilitarianism, 230, 234235
Vascular Parkinsons disease, 40
Ventral capsule and ventral striatum,
as DBS targets, 181
Ventral intermediate nucleus, as
DBS target, 67
Ventral intermediate thalamus, as
DBS target, 32, 153
Veterans Affairs and National
Institutes of Health Cooperative
Study, 25, 28, 58, 146, 193
INDEX
Vidailhet, M., 97
Virchow, Rudolf, 95
Vision impairment, in postoperative
patients with Tourettes syndrome,
126
Vitamin B12 deficiency, 163
Voltaire, 147
Walker, Mary, 256
Walking difficulties, in postoperative
patients with Essential tremor, 72
Walshe, Francis Martin Rouse, 253
Watts, R.L., 57
Wechsler Adult Intelligence Scale, 195,
199
Wechsler Memory Scale-III, 195
Wechsler Test of Adult Reading, 196, 199
Wilsons disease, 40, 106
Wisconsin Card Sorting Test, 196, 199
World Medical Association, 228
Yale Brown Obsessive Compulsive
Scale, 124, 181
Yale Global Tic Severity Scale (YGTSS),
124, 138139
Zona incerta, as DBS target, 32

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20 Things to Know about

20 Things to Know about Deep

Oxford University Press 2015

To Lyn Turkstra, whose unfailing support made every house a home,

The First Plea

In my experience, the enthusiasm at potentially helping patients with severe

The Second Plea

to explain accumulating observations. However, a tipping point is required before

The Unique Nature of Medical Decisions

provide the appropriate treatment as opposed to making an incorrect diagnosis

The n-of-One Problem

of transparency characterize the proceedings. Rarely, however, do patients have

that Parkinsons disease, at least its motoric symptoms, is a dopamine deficiency

I want to thank the professors at the Department of Philosophy at Washington

What Is Deep Brain Stimulation?

The most revolutionary treatment for neurological and psychiatric disorders to

2 0 T hings to K now A bout D eep B rain S timulation

1. What Is Deep Brain Stimulation?3

oscillation in local field potentials. These latter approaches reflect a one-dimensional

DBS involves the implantation of electrical stimulating electrodes in various regions

2 0 T hings to K now A bout D eep B rain S timulation

1. What Is Deep Brain Stimulation?5

2 0 T hings to K now A bout D eep B rain S timulation

1. What Is Deep Brain Stimulation?7

2010). Efforts are underway to develop Internet-based postoperative care methods

2 0 T hings to K now A bout D eep B rain S timulation

does not require the submission of an Investigational New Drug Application

1. What Is Deep Brain Stimulation?9

Parkinsons disease, pharmacological therapies had proven insufficient but DBS

2 0 T hings to K now A bout D eep B rain S timulation

1. What Is Deep Brain Stimulation?11

2 0 T hings to K now A bout D eep B rain S timulation

1. What Is Deep Brain Stimulation?13

Montgomery EB Jr. Dynamically coupled, high-frequency reentrant, non-linear

Why Deep Brain Stimulation?

Why Deep Brain Stimulation (DBS)? The answer is opportunitythe opportunity

2. Why Deep Brain Stimulation?15

DBS provides an opportunity to decrease healthcare costs by demonstrating less

Notions of pathophysiology are critical to acceptance of therapies that are

2 0 T hings to K now A bout D eep B rain S timulation

2. Why Deep Brain Stimulation?17

Figure2.1 Peri-event raster and histogram of the neuronal activity (assessed by

2 0 T hings to K now A bout D eep B rain S timulation

2. Why Deep Brain Stimulation?19

Judgment requires balancing pharmacological and surgical approaches. Directly

2 0 T hings to K now A bout D eep B rain S timulation

2. Why Deep Brain Stimulation?21

Deep Brain Stimulation Is

Deep Brain Stimulation (DBS) is remarkably effective for the treatment of

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease23

Evidence-Based Medicine has become an important standard for interpreting

2 0 T hings to K now A bout D eep B rain S timulation

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease25

2 0 T hings to K now A bout D eep B rain S timulation

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease27

Improvements must be considered in the context of the possible price to be paid,

2 0 T hings to K now A bout D eep B rain S timulation

undesirable experience associated with the use of a medical product in a patient.

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease29

serious consequences. These adverse effects may often be relieved by adjustment of

2 0 T hings to K now A bout D eep B rain S timulation

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease31

C O M PE T EN C E O F T H O S E S EL ECT I N G PAT I EN TS,

1. What Is Deep Brain Stimulation?3

1. What Is Deep Brain Stimulation?5

1. What Is Deep Brain Stimulation?7

1. What Is Deep Brain Stimulation?9

1. What Is Deep Brain Stimulation?11

1. What Is Deep Brain Stimulation?13

2. Why Deep Brain Stimulation?15

2. Why Deep Brain Stimulation?17

2. Why Deep Brain Stimulation?19

2. Why Deep Brain Stimulation?21

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease23

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease25

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease27

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease29

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease31

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease33

3. Deep Brain Stimulation Is Effective for Patients with Parkinsons Disease35

5. Postoperative Management of Patients with Parkinsons Disease57

5. Postoperative Management of Patients with Parkinsons Disease59

5. Postoperative Management of Patients with Parkinsons Disease61

5. Postoperative Management of Patients with Parkinsons Disease63

5. Postoperative Management of Patients with Parkinsons Disease65

6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor67

6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor69

6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor71

6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor73