Clinical manifestations of Parkinson disease

Tremor, bradykinesia, and rigidity.Postural instability does not generally occur until
much later in the course of the disease. The severity of motor symptoms appears to be
an independent predictor of mortality.

Tremor typically described as "pill-rolling," is a rest tremor, . Tremors in other

conditions, such as essential tremor or multiple sclerosis, are typically action tremors, in
which the tremor occurs when the affected limb is being used. It is not unusual for a
parkinsonian tremor to be present with postural maneuvers or with action, but in such
cases, the tremor is typically much more severe at rest. Because parkinsonian tremor
decreases with purposeful action, it is usually the least disabling of the cardinal
manifestations. However, when the tremor is severe, it can be difficult to distinguish a
primary resting tremor from a primary action tremor. Some patients with PD may have
a re-emergent tremor: a postural tremor that manifests after a latency of several seconds
and has a frequency typical of the rest tremor in PD This distinction is important, as a
re-emergent postural tremor may be misdiagnosed as having essential tremor The
tremor of early PD is most often intermittent, and may not be noticeable to others. In
fact, about half of patients with PD report a sensation of internal tremulousness in the
limbs or body that is unrelated to the presence of observable tremor .Tremor in the
limbs can be seen when the patient is relaxed with the hands resting quietly on the lap.
Distracting the patient often accentuates a mild tremor and may uncover a latent one.
Tremor is the presenting symptom in approximately 70 to 80 %. Tremor usually starts
unilaterally in the hand, and then spreads contralaterally several years after the onset of
symptoms .The tremor of PD can also involve the legs, lips, jaw, and tongue, but rarely
the head Anxiety, emotional excitement, or stressful situations can exacerbate it.

Bradykinesia is a generalized slowness of movement, , present at onset of PD in 80%,

is a major cause of disability in PD and is eventually seen in almost all patients.
"Weakness," "incoordination," and "tiredness" are often used to describe the decreased
ability to initiate voluntary movement. In the arms, bradykinesia typically starts distally
with decreased manual dexterity of the fingers. Patients often complain of difficulty
performing simple tasks, such as buttoning clothes, tying shoelaces, double clicking a
computer mouse, typing, or lifting coins from a pocket or purse.In the legs, common
complaints related to bradykinesia when walking include dragging the legs, shorter
(shuffling) steps, or a feeling of unsteadiness. Patients may also have difficulty standing
up from a chair or getting out of a car. As the disease progresses, gait freezing and
festination may develop. festination as "an irresistible impulse to take much quicker and
shorter steps, and thereby to adopt unwillingly a running pace" Clinical examination of
bradykinesia includes evaluation of limb movements on each side of the body. The
speed, amplitude, and rhythm of finger tapping, hand gripping, pronation-supination
hand movements, and heel or toe tapping . In mild PD, these tasks usually show some
slowing and decreased amplitude. As the disease progresses movements become less
coordinated, with frequent hesitations or arrests.

Rigidity Rigidity is an increased resistance to passive movement about a joint , often

begins unilaterally, and typically on the same side as the tremor if one is present.
Rigidity eventually progresses to the contralateral side, and remains asymmetric
throughout the disease Cogwheel rigidity can be seen in PD, ratchety pattern of
resistance and relaxation as the examiner moves the limb through its full range of
motion However, not all patients with PD have cogwheel rigidity; many instead will
have lead-pipe rigidity, a tonic resistance that is smooth throughout the entire range of
passive movement. Rigidity can affect any part of the body, and may contribute to
complaints of stiffness and pain. Features, such as the striatal hand (extension of the
proximal and distal interphalangeal joints with flexion at the metacarpophalangeal
joints), decreased arm swing with walking, and the typical stooped posture

Postural instability is an impairment of centrally-mediated postural reflexes that cause a

feeling of imbalance and a tendency to fall. Postural instability usually does not appear
until later in the course of PD, if pt fall early in the course of the illness most likely
have another parkinsonian syndrome, such as progressive supranuclear palsy or multiple
system atrophy. Postural instability is tested clinically with the "pull" test, where the
examiner stands behind the patient and firmly pulls the patient by the shoulders.
Patients with normal postural reflexes should be able to maintain balance and retropulse
(step backward) no more than one step. Patients with PD and postural instability, on the
other hand, are likely to fall or take multiple steps backwards.Initially, a positive pull
test may be the only sign of balance impairment. However, as postural instability
progresses, the gait may show signs of festination. Once postural reflexes are lost,
patients are generally wheelchair-bound. Among the primary motor features of PD,
postural instability is the least responsive to dopaminergic therapies

Other motor features seen in PD Craniofacial Hypomimia (masked facial expression)

Decreased spontaneous eye blink rate Speech impairment, including hypokinetic
dysarthria, hypophonia, and palilalia (repetition of a phrase or word with increasing
rapidity) Dysphagia Sialorrhea Visual Blurred vision Impaired contrast sensitivity
Musculoskeletal Micrographia Dystonia Myoclonus Stooped posture
Camptocormia (severe anterior flexion of the thoracolumbar spine) Pisa syndrome
(subacute axial dystonia with lateral flexion of the trunk, head, and neck) Difficulty
turning in bed Gait Shuffling, short-stepped gait Freezing Festination

Nonmotor manifestations Cognitive dysfunction and dementiaPsychosis and

hallucinationsMood disorders including depression, anxiety, and apathy/abuliaSleep
disturbancesFatigueAutonomic dysfunctionOlfactory dysfunctionGastrointestinal
dysfunctionPain and sensory disturbances Nonmotor symptoms in the psychiatric
domain occurred most frequently In some patients, certain nonmotor features of PD (eg,
olfactory dysfunction, constipation, depression, and REM sleep behavior disorder) may
present before the motor ones

Cognitive dysfunction and dementia are common and are an independent predictor of
mortality Older age and severity of PD motor symptoms,later age of onset of PD,
longer duration of PD symptoms, the presence of hallucinations, depressive symptoms,
and a family history of dementia may also be risk factors .It is a subcortical dementia,
with psychomotor retardation, memory difficulty, and altered personality. problems
with executive function (decision making or multi-tasking), memory retrieval, and
visuospatial misperception. Deficits in executive functioning are often the earliest
indicators of disturbed cognition. Dementia usually occurs late in the course of PD.
Dementia with Lewy bodies (DLB) patients have dementia, but also parkinsonian
features, visual hallucinations, and fluctuating cognition. Some experts believe to be
the same disorder. (Clinically, patients are diagnosed with PD dementia if their illness
begins with PD and they develop dementia at least a year after the onset of parkinsonian
motor symptoms. When dementia begins before or concurrently with parkinsonian
motor symptoms, DLB is the more likely diagnosis.

Psychosis occurs in 20 to 40 percent of drug-treated PD, and visual hallucinations are

the most common psychotic symptom. Auditory, olfactory, and tactile hallucinations
also occur in PD, although less frequently, and generally in conjunction with visual
hallucinations. The prevalence and severity of hallucinations increase over time .When
psychosis occurs, it is attributable to the underlying Lewy body disease, to
antiparkinson drug therapy, or a combination of the two. All antiparkinsonian
medications have been reported to induce psychosis but more often with dopamine
agonists than levodopa. Psychotic symptoms may persist but generally resolve when
PD medications are discontinued . Delusions can also be a prominent feature of
psychosis in PD, and are usually paranoid in nature. Common delusions include spousal
infidelity, people stealing money, intruders living in the house, or nurses planning
harmful plots. Many patients with PD who have psychotic symptoms nevertheless retain
the insight that their hallucinations are not real. However, patients with PD can also be
delirious or demented and manifest psychosis as a result. The patients in this latter
category tend to be less responsive to treatment. Commonly reported risk factors for
psychosis in PD include the use of high doses of antiparkinson drugs, the presence of
dementia, advancing age, impaired vision, depression, presence of sleep disorders, high
comorbid disease burden, and longer disease duration

Depression, anxiety, and abulia or apathy are mood disorders that occur most often in
PD. Depression is the most common, 50 % PD . Recognizing depressive features in PD
is a challenge. The psychomotor slowing and blunted affect commonly seen with
depression often resemble the bradykinesia and masked facial expression seen in PD.
Furthermore, somatic features of depression, such as decreased appetite, difficulty with
concentration, and sleep disturbances, are commonly seen in patients with PD who do
not have depression. PD who develop depression usually present with sadness,
anhedonia, and decreased interest in activities. Guilt and feelings of worthlessness may
occur less frequently in PD-related depression

Anxiety 30 %, generalized anxiety disorder and social phobia . Apathy defined as a

primary loss of motivation, diminished speech, motor activity, and emotional expression
abulia, loss of the impulse, will, or motivation to think, speak, and act. Diminished
motivation is the key concept . While apathy frequently accompanies depression, it can
occur in patients with PD who do not have depression .Mood is neutral in apathy
Apathy was less prevalent in patients with higher levodopa equivalent dosage (mainly
dopamine agonists), suggesting that dopamine agonists are a possible therapy

Sleep disorders including insomnia, daytime sleepiness with sleep attacks, restless legs
syndrome, and rapid eye movement sleep behavior disorder (RBD) affect between 55
and 80 %. The most common sleep disturbances in PD are sleep fragmentation
(frequent awakening throughout the night) and early morning awakening. Isomnia often
associates with depressin . Potential causes of frequent awakenings in PD are nocturia,
difficulty turning over in bed, cramps, vivid dreams or nightmares, and pain (especially
in the neck or back) . The rest tremor in PD disappears with rapid eye movement (REM)
sleep, but recurs during light sleep and may awaken the patient as a result . Some
patients may have painful dystonia, especially of the legs, that typically occurs in the
early morning and disrupts sleep. Depression is also commonly associated with poor
sleep efficiency, decreased sleep time, and early morning awakening

Symptoms of restless legs syndrome (RLS) are often reported in PD. an urge to move
the limbs, associated with an unpleasant sensation that occurs mainly or exclusively at
night, emerges or worsens with rest, and improves with movement, especially walking.
Periodic limb movements of sleep (PLMS) are frequently but not always associated
with RLS. The symptoms of PLMS are typically slow rhythmic movements of the legs,
consisting of dorsal flexion of the foot and great toe [

REM sleep behavior disorder (RBD) : vigorous movements that are related to increased
muscle tone during REM sleep. Patients with RBD often act out their dreams and
exhibit vocalizations as well as flailing, kicking, and punching motions of the limbs.
Over three-quarters of spontaneous RBD cases eventually develop PD

Excessive daytime somnolence Some patients may just be sleepy, while others have
additional unintended sleep episodes or sudden sleep "attacks"

Fatigue, common and significantly related to PD progression, depression, and EDS

Autonomic dysfunction : orthostasis, constipation, dysphagia, diaphoresis, urinary

difficulties, and sexual dysfunction . Also present in multiple system atrophy (MSA),
MSA tends to be less responsive to levodopa as the disease progresses, and MSA is
often associated with cerebellar and pyramidal findings. Orthostatic hypotension 58 %
PD, can be aggravated or caused by antiparkinsonian agents including levodopa,
dopamine agonists, and MAO-B inhibitors. Common urinary symptoms include
frequency, urgency, and urge incontinence Sexual dysfunction can range from
underactivity to hypersexuality, decreased interest and drive, inability to achieve or
maintain an erection, female often report vaginal tightness, dryness, an inability to
achieve orgasm, or involuntary micturition during sex

Olfactory dysfunction is common in PD; deficits in odor identification, discrimination,

and detection ,may precede motor symptoms or occur relatively early

Pain lancinating, burning, or tingling, and can be generalized or localized to

different areas of the body, including the face, abdomen, genitals, and joints .Painful
sensations in PD tend to correlate with motor fluctuations. Dystonia, which is often
painful, is a common symptom in PD. It can occur spontaneously in early PD, or it can
occur when levodopa wears off. Morning dystonia affecting the foot is a common "off"
response to abstinence from levodopa during sleep.

progression in PD is variable, and there currently are no symptoms or signs in

idiopathic PD that allow a practitioner to accurately predict the future course of PD for
any given individual. However 25 % severely disabled or dead within five years 67 %
at 5 to 9 years,.Transition from disease impairment to disability occurred generally
between three and seven years after the onset of PD
Pharmacologic treatment of Parkinson disease

In practice, nearly all of the available treatments are symptomatic in nature and do not
appear to slow or reverse the natural course of the disease. The decision to initiate
symptomatic medical therapy in patients with PD is determined by the degree to which
the patient is functionally impaired

Levodopa is the most effective drug for the symptomatic treatment of PD and is the
drug of first choice if symptoms, particularly those related to bradykinesia, become
intrusive or troublesome.Levodopa should be introduced when akinetic symptoms
become disabling for patients receiving other antiparkinsonian drugs.

The dopamine agonists may be employed either as monotherapy in early PD or in

combination with other antiparkinsonian drugs. They are ineffective in patients who
show no response to levodopa. While dopamine agonists possibly delay the need to
initiate levodopa therapy, their use is associated with an increased risk of impulse
control disorders.

Either levodopa or a dopamine agonist can be used initially for patients who require
symptomatic therapy for PD .Given the potential that dopamine agonists may be
associated with fewer motor fluctuations than levodopa, and the evidence that there is a
higher incidence of levodopa-related dyskinesia in young-onset PD, it is reasonable to
start therapy with a dopamine agonist in younger patients (age <65 years), and with
levodopa in older patients (age 65 years). In practice, while symptoms can be
controlled initially with dopamine agonists, few patients with progressive disease can be
satisfactorily maintained on dopamine agonist monotherapy for more than a few years
before levodopa is needed.

The MAO B inhibitors selegiline and rasagiline may be useful in patients with early
PD but have only modest symptomatic benefit as monotherapy.

Anticholinergic drugs are most useful as monotherapy in patients under 70 years of

age with disturbing tremor who do not have significant bradykinesia or gait disturbance.
They also may be useful in patients with more advanced disease who have persistent
tremor despite treatment with levodopa or dopamine agonists. Their use in older or
demented individuals and those without tremor is strongly discouraged.

Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most
useful in treating younger patients with early or mild PD and perhaps later when
dyskinesia becomes problematic.

Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women

Most patients with PD can go without antiparkinson medications for a brief period (ie,
<24 hours) when oral intake is temporarily restricted (eg, when perioperative or
periprocedural), or when seriously ill. In patients who are critically ill and bedbound,
the parkinsonian symptoms are typically overshadowed by the burden of other medical
problems, and antiparkinson medications may not provide any clear benefit. However,
sudden withdrawal or dose reduction of antiparkinson medications can rarely precipitate
the parkinsonism-hyperpyrexia syndrome. When treatment is still desired for patients
who are restricted to take nothing by mouth, options include transdermal rotigotine and
apomorphine by injection or continuous infusion. The use of apomorphine requires a
test dose prior to ongoing treatment. For patients with a nasogastric feeding tube,
levodopa tablets can be crushed and given through the tube. For patients with
dysphagia, orally disintegrating carbidopa-levodopa (Parcopa) is a potential treatment

Parkinsonism-hyperpyrexia syndrome neuroleptic malignant syndrome in the

context of sudden withdrawal or dose reductions of levodopa or dopamine agonists, and
rarely amantadine, as well as with switching from one agent to another. In this context,
the condition has been termed the parkinsonism-hyperpyrexia syndrome .Management
involves replacing antiparkinson medications at the dose that was used prior to the onset
of the syndrome .Levodopa and dopamine agonists can be given orally or via
nasogastric tube. Levodopa can also be given intravenously (50 to 100 mg infused over
three hours, repeated four times daily) , options for dopamine agonists include
transdermal rotigotine and apomorphine by injection or continuous infusion. In addition
to replacing antiparkinson medications, patients with significant hyperthermia and
rigidity should be admitted to an intensive care unit setting and undergo aggressive
supportive care as well as monitoring for potential dysautonomia. For patients with
severe symptoms who do not respond to restarting antiparkinson medications and
supportive care within the first day or two, additional though unproven measures to
consider include the use of dantrolene, bromocriptine, and/or amantadine.

Levodopa (L-dopa) is the most effective drug for the symptomatic treatment of
idiopathic or Lewy body PD , particularly effective for the management of bradykinetic
symptoms. Tremor and rigidity can also respond to levodopa therapy, but postural
instability is less likely to do so. Levodopa is combined with a peripheral
decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation
and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting,
and orthostatic hypotension.. The combination drug carbidopa-levodopa (immediate-
release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, An
immediate-release formulation of carbidopa-levodopa (Parcopa) is available that
dissolves on the tongue and can be taken without water ]; its time of onset of action is
not different from Sinemet. In some countries, benserazide is the peripheral
decarboxylase inhibitor. The combination drug benserazide-levodopa (Madopar or
Prolopa) is available in 25/100 and 50/200 mg tablets. Controlled-release formulations
of carbidopa-levodopa ,the absorption of the controlled-release formulations is
approximately 70 percent. An extended-release capsule formulation (Rytary in the US;
Numient in Europe) contains microbeads of carbidopa and levodopa in a 1:4 ratio that,
after dissolving, are absorbed in the gastrointestinal tract at different rates

Treatment should begin with small doses, such as carbidopa-levodopa (Sinemet) 25/100
mg, one-half tablet two to three times daily with meals. . Once initiated without side
effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over
several weeks to a full tablet of 25/100 mg three times daily as tolerated. Older adults or
those with dementia should begin with smaller doses and slower titration The usual
practice is to titrate to the lowest levodopa dose that produces a useful clinical response.
This varies from patient to patient, but at the start it is typically in the vicinity of 300 to
600 mg of levodopa daily. Complete absence of response to a levodopa dose of 1000 to
1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of
the other parkinsonian syndromes, such as multiple system atrophy, progressive
supranuclear palsy, or vascular parkinsonism should be considered. Levodopa should
not be stopped abruptly because sudden withdrawal has been associated (rarely) with a
syndrome resembling neuroleptic malignant syndrome or akinetic crisis

Controlled or sustained release levodopa preparations are less completely absorbed and
require a dose up to 30 percent higher to achieve an equivalent clinical effect. As a
result, it is recommended that therapy be started with an immediate release preparation
with a subsequent switch to controlled release if desired for convenience purposes.
Patients taking levodopa for the first time should take each dose with a meal or snack to
avoid nausea, a common early side effect. Patients with more advanced disease,
especially those with motor fluctuations, often notice that a dose of levodopa is more
effective if taken on an empty stomach 30 minutes before or one hour after meals due to
reduced competition with other amino acids for gastrointestinal absorption.

Small starting doses of levodopa of less than 25/100 mg three times daily combined
with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to
cause nausea because of inadequate amounts of carbidopa; this can be managed by
administering supplemental doses of carbidopa or by use of antiemetics such as
trimethobenzamide or domperidone taken prior to Sinemet. Phenothiazine antiemetics
such as prochlorperazine and metoclopramide should be avoided because they are
dopamine receptor blockers that can aggravate parkinsonian symptoms.

Adverse effects Nausea, somnolence, dizziness, and headache are among the more
common early side effects. More serious adverse reactions to levodopa (mainly in older
patients) may include confusion, hallucinations, delusions, agitation, psychosis, and
orthostatic hypotension.

Motor fluctuations levodopa-related complications within several years of starting

levodopa. These include motor fluctuations (the wearing-off phenomenon), involuntary
movements known as dyskinesia, abnormal cramps and postures of the extremities and
trunk known as dystonia, and a variety of complex fluctuations in motor function .The
risk of motor complications increases with a younger age at PD onset and with higher
levodopa doses. The increase in motor fluctuations over time is most likely due to
progressive degeneration of nigrostriatal dopamine terminals, Controlled release
preparations can be useful for management of these fluctuations,

Acute akinesia is a sudden exacerbation of PD characterized by an akinetic state that

lasts for several days and does not respond to treatment with antiparkinson medication.
This phenomenon is very different from the more common wearing "off" effects

DOPAMINE AGONISTS directly stimulate dopamine receptors and include

bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine.
Apomorphine and lisuride are additional DAs that can be administered parenterally for
"rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is available
in Europe.)

Unlike carbidopa-levodopa (Sinemet), these drugs are direct agonists that do not require
metabolic conversion, do not compete with amino acids for transport across the gut or
into the brain, and do not depend upon neuronal uptake and release. An additional
advantage over immediate-release forms of levodopa is the longer duration of action of
most of these agents.

Monotherapy Given the potential that DAs are associated with fewer motor
fluctuations and the evidence that there is a higher incidence of levodopa-related
dyskinesia in young-onset PD, some experts suggest using DAs as initial treatment for
PD in patients younger than age 60, and using the more effective agent levodopa in
patients 60 and older - the choice of initial therapy whether levodopa, dopamine
agonist, or monoamine oxidase (MAO) B inhibitor has little impact on the long-term
outcome of PD in terms of motor fluctuations and dyskinesia.

dopamine agonist (DA) drugs, including bromocriptine, pramipexole, and ropinirole,

are effective in patients with advanced PD complicated by motor fluctuations and
dyskinesia In addition, other studies have found that pramipexole, ropinirole, and
transdermal rotigotine are effective as monotherapy in patients with early disease . DAs
are ineffective in patients who have shown no therapeutic response to levodopa.

There is evidence from several clinical trials and a meta-analysis that early DA
monotherapy postpones the future onset of motor complications. This may simply be
because DAs are less potent than levodopa in their effects on motor function , the
benefit occurs at the expense of reduced efficacy when compared with levodopa. In
practice, while symptoms can be controlled initially with DAs, few patients with
progressive disease can be satisfactorily maintained on DA monotherapy for more than
a few years before levodopa is needed.

The DAs generally require administration at least three times a day Bromocriptine is
usually started at 1.25 mg twice a day; the dose is increased at two to four week
intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three
to four divided doses, although total daily doses as high as 90 mg can be used.
Pramipexole is usually started at 0.125 mg three times a day. The dose should be
increased gradually by 0.125 mg per dose every five to seven days. Most patients can be
managed on total daily doses of 1.5 to 4.5 mg. Ropinirole is usually started at 0.25
mg three times a day. The dose should be increased gradually by 0.25 mg per dose each
week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this
dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up
to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage
range of 12 to 16 mg per day. Pramipexole and ropinirole are available in sustained
release formulations, which are given once daily Transdermal rotigotine is a once-
daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the
patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours.

Apomorphine may be administered either as intermittent rescue injections or as

continuous infusions to treat "off" episodes or levodopa-related motor fluctuations. A
challenge test dose must precede routine use. This is usually done with a 2 mg
subcutaneous injection under medical supervision and monitoring of standing and
supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.
Antiemetic therapy (eg, with trimethobenzamide 300 mg three times a day) is initiated
three days prior to starting apomorphine and is usually continued for no longer than two
months before reassessing need, since trimethobenzamide may increase the risk of
somnolence, dizziness, and falls in patients treated with apomorphine
The use of apomorphine is contraindicated with ondansetron and other serotonin
receptor antagonists commonly used to treat nausea and vomiting, as the combination
may cause severe hypotension and loss of consciousness. In addition, dopamine
antagonists used to treat nausea and vomiting such as prochlorperazine and
metoclopramide should be avoided, as they may reduce the effectiveness of
apomorphine.

The usual starting dose for intermittent apomorphine use, if the patient tolerates and
responds to the test dose, is 2 mg. The dose may be increased by 1 mg per dose every
two to four days to a maximum of 6 mg per dose. The average dosing frequency is three
times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.

Dopamine agonists should not be stopped abruptly because sudden withdrawal of DAs
has been associated (rarely) with a syndrome resembling neuroleptic malignant
syndrome or akinetic crisis and with a stereotyped withdrawal syndrome

Adverse effects of dopamine agonists are similar to those of levodopa, including

nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations.
Peripheral edema is common with the chronic use of DAs .These adverse effects of DAs
can usually be avoided by initiating treatment with very small doses and titrating to
therapeutic levels slowly over several weeks. Patients intolerant of one DA may tolerate
another. As with all of the antiparkinsonian drugs, older adult and demented patients are
much more susceptible to psychiatric side effects. The use of DAs may lead to
compulsive use of dopaminergic drugs and/or impulse control disorders in up to 15 %
Transdermal rotigotine is associated with skin site reactions, typically transient and mild
to moderate in severity,

Adverse events with apomorphine are usually mild , predominantly of cutaneous

reactions and neuropsychiatric problems . Chest pain, angina, and orthostatic
hypotension are more serious problems; orthostasis peaks 20 minutes after dosing and
lasts at least 90 minutes. A test dose of apomorphine to establish tolerance and
responsiveness is essential prior to routine administration.

Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and

retroperitoneal or pulmonary fibrosis are uncommon with bromocriptine and pergolide,
and they do not occur at all with the nonergot agonists ropinirole, pramipexole, and
rotigotine.

Dopamine receptor agonists decrease prolactin concentration , decreased milk

production in postpartum women taking these agents, which are contraindicated in
women who are breast feeding.

Pramipexole has a warning regarding somnolence that can occur abruptly and without
premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at
particular risk , avoid concomitant sedating medications, sleep disorders, and
medications that increase pramipexole levels

Compulsive use of dopaminergic drugs develops in a small number of patients with

PD and has been termed the dopaminergic dysregulation syndrome (DDS) .
DDS typically involves male patients with early onset PD who take increasing
quantities of dopaminergic drugs despite increasingly severe drug-related dyskinesia.
DDS can be associated with a cyclical mood disorder characterized by hypomania or
manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of
dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or
withdrawal. Impulse control disorders including hypersexuality and pathologic
gambling may accompany DDS .A form of complex, prolonged, purposeless, and
stereotyped behavior called punding also may be associated with DDS . DDS appears to
be uncommon but not rare. DDS may occur more frequently with dopaminergic
agonists than with levodopa .Susceptibility factors for DDS included younger age at
disease onset, higher novelty seeking personality traits, depressive symptoms, and
alcohol intake .Management of DDS should includes limit dopaminergic dose increases
when possible . Continuous subcutaneous apomorphine infusions may be useful to
suppress off-period dysphoria, and low doses of clozapine or quetiapine may be helpful
for some patients

Dopamine (DA) agonist therapy is associated with an increased risk of impulse control
disorders including pathologic gambling, compulsive sexual behavior, or compulsive
buying .It usually resolves with tapering or discontinuation of DA therapy

Dopamine agonist withdrawal syndrome is seen in some patients with PD who abruptly
stop taking a DA . Symptoms resemble those of cocaine withdrawal and include
anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug
craving. These symptoms were refractory to other antiparkinson medications, including
levodopa, and only responded to resuming the DA.

MAO B INHIBITORS Monoamine oxidase MAO type B (MAO B) inhibitors

include selegiline, rasagiline, and safinamide.

Selegiline, is modestly effective as symptomatic treatment for PD and may have

neuroprotective properties. In many individuals, selegiline monotherapy does not
produce a functionally significant benefit. However, the use of selegiline in early PD is
a reasonable option as long as the patient understands its limitations.

Selegiline has mild symptomatic benefit, and it may be used in patients with early PD.
Its use should be limited to patients with early disease since the symptomatic benefits
are unlikely to be significant in those with more advanced PD. Nevertheless, patients
should understand that there may not be much symptomatic improvement if selegiline is
the initial treatment for early PD, and early follow-up and consideration of additional
symptomatic therapy should be arranged. The value of selegiline for neuroprotection is
unclear. Rasagiline is a monoamine oxidase (MAO) B inhibitor that has been
demonstrated in randomized trials to produce a statistically significant benefit as
monotherapy in PD. However, it is uncertain whether it also produces a clinically
meaningful benefit that is evident to the patient. (S

rasagiline has neuroprotective properties in animal models and appears modestly

effective as symptomatic treatment for PD in human clinical trials

Effectiveness treatment with MAO B inhibitors was associated with significantly better
total scores, motor scores, and activities of daily living scores on the Unified Parkinson
disease rating scale (UPDRS) at three months compared with controls., treatment with
MAO B inhibitors was associated with a delay in the need for additional levodopa
compared with controls and a modest reduction in the development of motor
fluctuations compared with controls. However, MAO B treatment was not associated
with a significant difference in the incidence of dyskinesia.

Safinamide was evaluated as adjunctive treatment for patients with PD taking levodopa
in randomized controlled trials . Compared with placebo in these trials, safinamide was
effective for increasing mean daily on time without troublesome dyskinesia and for
improving motor function.

Dosing The dose of selegiline used in DATATOP was 5 mg twice daily, with the
second dose given at noon to avoid insomnia. However, lower doses are sufficient to
induce MAO B inhibition, and 5 mg once daily in the morning is currently
recommended. Doses higher than 10 mg daily are of no additional benefit and may
result in nonselective MAO inhibition, thereby placing the patient at risk of
hypertensive crisis due to dietary interactions with tyramine-containing foods.

Rasagiline as monotherapy for PD is usually started at 1 mg daily. When used as

adjunctive therapy with levodopa, rasagiline is started at 0.5 mg once daily and can be
increased to 1 mg daily based upon response and tolerability.

Safinamide is usually given as adjunctive therapy with levodopa; safinamide is started

at 50 mg once daily and can be increased to 100 mg daily after 14 days based upon
tolerability and benefit.

Adverse effects Nausea and headache,. Other possible adverse effects include
confusion and hallucinations. Falls, insomnia, and dyskinesia also may occur, but these
may be manifestations of advanced PD rather than adverse effects of MAO B inhibitors.
Selegiline often causes confusion in older adults, thereby limiting its use in patients
with late-onset disease.Selegiline enhances the effect of levodopa by slowing its
oxidative metabolism. Thus, it may increase levodopa-related side effects such as
dyskinesia and psychiatric toxicity . However, the need for continued selegiline is
questionable once patients have reached the point of requiring levodopa.

Serious adverse reactions have rarely occurred following the concomitant use of
selegiline with tricyclic antidepressants or selective serotonin reuptake inhibitors
(SSRIs). In practice, the vast majority of patients on these combinations are able to
tolerate them for years without problems.

Unlike nonselective MAO inhibitors, selegiline does not precipitate a hypertensive

crisis in patients who concomitantly ingest tyramine-containing foods.

ANTICHOLINERGICS Dopamine and acetylcholine are normally in a state of

electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a
state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic
drugs improve parkinsonian symptoms
Anticholinergic drugs should be reserved for younger patients in whom tremor is the
predominant problem. Their use in older or demented individuals and those without
tremor is strongly discouraged

Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have

been used for many years in PD and continue to have a useful role . Other
anticholinergic agents such as biperiden, orphenadrine, and procyclidine produce
similar effects and are more commonly used in Europe than the United States.
Benztropine also may increase the effect of dopamine by inhibiting its presynaptic
reuptake,

Anticholinergic drugs are most useful as monotherapy for patients with PD who are <70
years of age and have disturbing tremor but do not have significant bradykinesia or gait
disturbance. They also may be useful in patients with more advanced disease who have
persistent tremor despite treatment with levodopa or dopamine agonists.

Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is

little evidence to suggest that one drug in this class is superior to another. The starting
dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three
times daily. Benztropine traditionally is more commonly used by psychiatrists for the
management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg
twice daily.

Adverse effects of anticholinergic drugs are common. Older adults and cognitively
impaired patients are particularly susceptible to memory impairment, confusion, and
hallucinations and should not receive these drugs. When an anticholinergic drug is used
to treat sialorrhea or urinary frequency, peripherally acting agents such as propantheline
should be used, although confusion and hallucinations are not infrequent adverse effects
with these drugs as well. Younger patients usually tolerate these agents better than older
adults, although some experience dysphoric symptoms, sedation, or memory impair

Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation,
nausea, urinary retention, impaired sweating, and tachycardia. Caution in prostatic
hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should
be performed gradually to avoid withdrawal symptoms that may manifest as an acute
exacerbation of parkinsonism,

AMANTADINE Amantadine is an antiviral agent that has mild antiparkinsonian

activity; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate
dopamine receptors, and it may possibly exert central anticholinergic effects .
amantadine monotherapy causes an improvement in bradykinesia, rigidity, and tremor
and it is more effective than anticholinergic drugs for bradykinesia and rigidity. The
benefit induced by amantadine appears to be transient in some patients; it is best used as
short-term monotherapy in those with mild disease. Amantadine is of little benefit when
added to levodopa, although the addition of levodopa to amantadine causes significant
additive improvement . Amantadine in divided doses of 200 to 400 mg a day may
reduce the intensity of levodopa-related dyskinesia and motor fluctuations in patients
with PD., experience has shown that individual patients with advanced PD who have
motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the
addition of amantadine to a regimen of levodopa
The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that
larger doses are of additional benefit. The main advantage of this agent is a low
incidence of side effects. It is excreted unchanged in the urine and should be used with
caution in the presence of renal failure.

Peripheral side effects include livedo reticularis and ankle edema, . Confusion,
hallucinations, and nightmares occur infrequently, but unpredictably, even after long
periods of use without side effects. These effects are more likely when amantadine is
used together with other antiparkinsonian drugs in older patients.

COMT INHIBITORS The catechol-O-methyl transferase (COMT) inhibitors

tolcapone and entacapone are ineffective when given alone, but they may prolong and
potentiate the levodopa effect when given with a dose of levodopa, and thus are useful
as levodopa extenders. Inhibition of COMT reduces the peripheral (entacapone) and
central (tolcapone) methylation of levodopa and dopamine, which in turn increases the
plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and
prolongs the therapeutic effect of each dose. These medications are mainly used to treat
patients with motor fluctuations with end-of-dose wearing "off" periods. There appears
to be no advantage for using levodopa combined with a COMT inhibitor, compared
with levodopa alone, as initial therapy for PD, or as add-on therapy for levodopa-treated
patients without motor complications. The starting dose of tolcapone is 100 mg three
times daily; the clinical effect is evident immediately. The dose of entacapone is one
200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.

The most common side effects of tolcapone are due to increased dopaminergic
stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic
hypotension. The adverse effects are managed by lowering the dose of levodopa either
before or after the addition of tolcapone. Diarrhea that is poorly responsive to
antidiarrheal medications appears in approximately 5 percent of patients.

Tolcapone has a very low risk of hepatotoxicity when appropriately monitored with
liver function tests for a period of six months after starting the drug.

ESTROGEN Low-dose estrogen may be helpful as adjunctive therapy in

postmenopausal women with motor fluctuations on antiparkinsonian medication /oral
conjugated estrogen 0.625 mg daily for eight weeks significantly improved "on" time
and motor control in such women, It is not clear if these results would be similar in
women taking combined estrogen/progestin therapy (necessary in women with an intact
uterus). Furthermore, concerns about adverse effects associated with long-term
estrogen/progestin therapy may limit its use in PD.

Management of nonmotor symptoms in Parkinson disease

(PD) is a chronic, progressive neurodegenerative disease with any combination of four

cardinal signs: rest tremor, rigidity, akinesia, and a shuffling gait. The clinical features
most suggestive of idiopathic PD rather than an atypical or secondary parkinsonian
syndrome include asymmetric or unilateral onset, the presence of resting tremor, and a
clear-cut response to treatment with L-dopa.
 Psychosis is a frequent complication of PD, and it is characterized mainly by visual
hallucinations and delusions, which are often paranoid in flavor .Psychosis may be
triggered by infection, delirium, dementia, or medications. The adverse effects of
antiparkinson medications, the dopamine agonists in particular, are probably the most
important cause of psychosis in patients with PD.

Psychoactive medications, including sedatives, anxiolytics, and antidepressants, are

potential culprits and should be reduced or stopped if possible.

Stopping all potentially offending antiparkinsonian drugs is usually not an option,

although dose reduction can frequently be accomplished with amelioration of
hallucinations and little loss of drug-related benefit. Antiparkinsonian drugs may be
reduced or stopped in reverse order of their potency and effectiveness if hallucinations
are causing disability. The suggested sequence begins with anticholinergic drugs,
followed by amantadine, monoamine oxidase type B (MAO B) inhibitors, catechol-O-
methyl transferase (COMT) inhibitors, and dopamine agonists. Levodopa, usually
combined with a peripheral decarboxylase inhibitor (eg, carbidopa-levodopa) should be
the last of a drug combination to be reduced, since it is the most effective antiparkinson
agent and least likely to cause psychosis). However, if given in unusually high doses, it
too might need to be reduced.

For patients with troublesome hallucinations or delusions despite antiparkinson

medication adjustments, options include quetiapine, clozapine, or pimavanserin.
starting with low doses and incrementing slowly according to clinical response (eg,
clozapine 12.5 to 50 mg at night or quetiapine 12.5 to 100 mg at night) . quetiapine is
easier to use than clozapine (no monitoring required) and is often effective, it should be
the treatment of first choice.

Clozapine is underutilized because of the burdensome requirement of hematologic

monitoring, but it is probably the most effective of the atypical neuroleptics in this
setting. Clozapine can cause granulocytopenia in 1 to 2 percent of patients, and weekly
to biweekly blood counts are required by law in order for patients to use it. The risk of
clozapine-induced leukopenia or agranulocytosis decreases exponentially over time, and
the likelihood of developing fatal granulocytopenia beyond six months of clozapine
treatment is almost nil . Clozapine and quetiapine do not appear to worsen
parkinsonism. In contrast, parkinsonism may be exacerbated by other atypical
neuroleptics such as risperidone and olanzapine, and by typical neuroleptics such as
haloperidol.

The antipsychotic agent pimavanserin, a selective serotonin 5-HT2A receptor inverse

agonist, was effective for reducing PD-related psychosis , well-tolerated , not associated
with worsening of motor symptoms or other adverse effectsand useful in hallucinations
and delusions associated with PD.

All antipsychotic drugs appear to be associated with a small increased risk of mortality
when used to treat behavioral disorders in older adult patients with dementia and adults
with PD

Cholinesterase inhibitors ( donazepil, mematadine) do not appear to improve

neuropsychiatric symptoms to a clinically significant extent.

DAYTIME SLEEPINESS , improve nocturnal sleep hygiene and to treat causes of

poor nocturnal sleep, such as nocturia and pain. Pharmacologic treatment with ,
methylphenidate, or judicious use of coffee during the day may offer some benefit.
Modafinil is not approved by the US Food and Drug Administration for the treatment of
sleepiness in PD.In the author's clinical experience, modafinil has not been effective for
treating drowsiness in patients with PD.

FATIGUE Fatigue is a common problem in patients with PD, and it appears to be an

independent symptom of PD . Excessive daytime sleepiness and depression are both the
most common and the most treatable identifiable causes . True fatigue unassociated
with sleepiness or depression is more difficult to treat. Suboptimally treated
bradykinesia sometimes presents as subjective fatigue . Medications used for empiric
treatment of fatigue, including amantadine and stimulants such as methylphenidate and
pemoline, are options. However, the response to these is often disappointing
methylphenidate is "possibly useful" for treating fatigue in patients with PD ,however, it
is unclear whether the benefit of methylphenidate for fatigue in PD is clinically
meaningful.
modafinil was not effective for improving excessive daytime sleepiness or fatigue

DEPRESSION

Desipramine and citalopram were equally effective .Paroxetine and venlafaxine

improved depression and did not worsen motor function . Dopaminergic agonists
ropinirole and pramipexole may improve depressive symptoms in patients with PD

It is reasonable to start with a selective serotonin reuptake inhibitor (SSRI) in most

patients, as the likelihood of adverse events is lower with SSRIs than with tricyclics
such as amitriptyline (and nortriptyline to a lesser extent). The anticholinergic side
effects of tricyclic medications, which can include cognitive impairment and orthostatic
hypotension with an increased risk of falls, may be particularly troublesome in the
setting of PD . However, for patients who do not improve with SSRI treatment, a
tricyclic antidepressant is a reasonable option when tremor is a dominant symptom and
the potential benefit is thought to outweigh the risk of anticholinergic side effects.

Patients with PD who have apathy as a feature of depression can be treated with
antidepressant medications, as there is no specific treatment for apathy or abulia in the
absence of depression. Importantly, suicidal ideation and thoughts of death are not
uncommon in PD, present in 20 to 33 percent of patients

There are two potential concerns regarding the use of SSRIs for treatment of depression
in patients with PD. These are the possibility of aggravating motor symptoms and the
possibility of an adverse interaction with selegiline, . Although the use of SSRIs in PD
with or without selegiline or rasagiline appears to be safe, caution is advised when
introducing these drugs.

Extrapyramidal symptoms such as dystonia, akathisia, tremor, and parkinsonism are

associated with SSRIs . SSRIs may also exacerbate the motor symptoms of PD
Fluoxetine and paroxetine have been the SSRIs most commonly associated with
increased parkinsonism, while sertraline has been associated with relatively few cases
However, the risk of exacerbation of PD is actually very low:

Serotonin syndrome is a potentially severe condition associated with increased

serotonergic activity in the central nervous system and severely disturbed mental,
motor, and autonomic function. The MAO B inhibitors selegiline and rasagiline should
be used only at recommended doses and with caution when combined with other
antidepressants, including tricyclics and SSRIs, because of the risk of causing the
serotonin syndrome .Despite this theoretical risk, specialists often use an MAO B
inhibitor and an antidepressant without causing serotonin syndrome. The risk of the
serotonin syndrome is uncertain but very low 0.24 %

At higher than recommended doses (10 mg daily for selegiline; 1 mg daily for
rasagiline) the MAO B inhibitors may also inhibit MAO A and, when given with an
antidepressant, carry the risk of the tyramine "cheese" reaction, characterized by a
severe hypertensive crisis.

CONSTIPATION autonomic dysfunction and slowed colonic transit time

lubiprostone, polyethylene glycol, and fermented milk containing probiotic strains and
prebiotic fiber may be useful

SIALORRHEA Sialorrhea or drooling related to reduced oromotor control and

autonomic dysfunction . For patients with mild symptoms, the use of chewing gum or
hard candy to encourage swallowing may reduce drooling in social situations For
patients with more severe symptoms, treatment with botulinum toxin injections into the
salivary glands is effective. Glycopyrrolate (1 mg three times daily) is also effective ,
has only a limited ability to cross the blood-brain barrier, which may reduce the risk of
central anticholinergic side effects. Other anticholinergic medications (eg, oral
hyoscyamine and amitriptyline; sublingual ipratropium bromide and sublingual atropine
[1 percent ophthalmic solution, one to two drops applied sublingually once or twice
daily]) have also been used to control sialorrhea and drooling

RHINORRHEA profuse runny nose that is unrelated to allergy, upper respiratory

infection, or sinus disease .there is no proven treatment for this symptom in PD, but
clinical experience suggests that ipratropium nasal spray is effective.

SEXUAL DYSFUNCTION . In some patients, improving motor function with

dopaminergic treatment may lead to improved sexual function. Men with erectile
dysfunction may benefit from treatment with sildenafil (25, 50, or 100 mg) taken one
hour prior to sex., tadalafil and vardenafil are also effective . Intrapenile injections of
vasoactive drugs are effective in treatment-refractory cases. Women may benefit from
vaginal lubricants and urinating prior to sexual activity.

ORTHOSTATIC HYPOTENSION common and disabling feature of the disease

itself or the medications used to treated PD, including levodopa, dopamine agonists, and
MAO-B inhibitors .Non-pharmacological should be tried first, including salt
supplementation, physical counter-maneuvers, abdominal bands, stockings, and
elevating the head of the bed. Pharmacological treatments are reserved for symptomatic
patients if no response . Options include droxidopa, fludrocortisone, pyridostigmine,
and midodrine, though this may lead to supine hypertension.

Motor fluctuations and dyskinesia in Parkinson disease

Motor fluctuations and dyskinesia are important complications of levodopa therapy that
affect many patients with advancing Parkinson disease (PD). Deep brain stimulation of
the subthalamic nucleus or globus pallidus is another therapeutic option that improves
motor function in selected patients with advanced typical PD and motor fluctuations,
whose condition cannot be further improved by medical therapy.

50 % on levodopa for several years will experience motor fluctuations and dyskinesia.
Motor fluctuations are alterations between periods of being "on," during which the
patient experiences a positive response to medication, and being "off," during which the
patient experiences a reemergence of the Parkinson symptoms suppressed during the
"on" state. Dyskinesia consists of levodopa-related abnormal, involuntary movements.
While caused by a relative excess amount of levodopa, dyskinesia can occur at a dose
that is otherwise therapeutic and does not necessarily represent an overdose. Dyskinesia
are especially common in patients with young-onset (eg, before age of 50 years) PD;
they are mostly associated with the use of levodopa but can occur with dopamine
agonists, especially when added to enhance the effect of levodopa.

Patients with PD typically experience a smooth and even response to the early stages of
levodopa treatment. As the disease advances, however, the effect of levodopa begins to
wear off several hours after some or even all doses, motor fluctuations evolve as PD
progresses because progressive degeneration of the nigro-striatal dopaminergic pathway
reduces the ability of nerve terminals to store and release dopamine physiologically. As
a result of this loss of storage capacity, the response to exogenous levodopa defaults to a
more pulsatile or bolus impact on postsynaptic dopamine receptors (the short duration
response) in keeping with levodopa's short (90 minute) half-life and its rapid cycling
pharmacokinetics. Plasma levels of levodopa may fluctuate because of the additional
problem of erratic intestinal absorption related to slowed intestinal motility

There are several types of motor fluctuations, including the following: "Wearing off"
phenomenon, characterized by the re-emergence of parkinsonian motor problems as the
effect of levodopa diminishes near the end of the dose interval Unpredictable "off"
periods, with no obvious relationship between the time of levodopa administration and
the appearance of "off" episodes Freezing of gait Failure of the "on" response, with
lack of an "on" response following a dose of levodopa Acute akinesia, which
manifests as a sudden severe exacerbation of PD including an akinetic state that lasts for
several days and does not respond to treatment with antiparkinson medication

Levodopa-related dyskinesia encompass a variety of involuntary movements, including

chorea, dystonia, ballism, and myoclonus. Dyskinesia tend to appear when the patient is
"on" and are usually choreiform. Dyskinesia in the "off" state is more commonly
dystonic but can be any of those listed above. Early morning dystonic inversion of a
foot (usually on the side of greater parkinsonian involvement) occurs as a withdrawal
reaction because of the long interval without medication overnight. Dyskinesia are
sometimes mistaken for manifestations of progressive PD or confused with tremor by
patients and their families, rather than recognized as reversible consequences of
levodopa treatment.

Peak-dose choreiform dyskinesia usually starts 30 to 90 minutes after a dose of

levodopa Diphasic dyskinesia has two peaks after each levodopa dose: the first when
patients turn "on" and the second when they begin to turn "off" "Wearing off"
dystonia; dyskinesia can take the form of dystonic posturing, which more commonly
occurs during an "off" period

Other antiparkinson drugs are much less likely to produce these motor abnormalities,
but some, such as the dopamine agonists, may exacerbate them once they have already
occurred following treatment with levodopa. Dyskinesia occurs in 30 to 40 percent of
patients treated with levodopa during the first five years of use and nearly 60 percent or
more by ten years .Dyskinesia is more likely to occur in patients with young-onset PD
(<50 years of age) than in older patients.

Evaluation = Ask if they sense jerky movements during a dosing cycle or a waning of
benefit of some or all of their doses before the next dose is due. Some patients may
confuse dyskinesia and tremor; direct observation or home video may be necessary
Inquire if the patient takes a dose of levodopa on a fixed schedule (by the clock) or
when he or she feels the current dose is wearing off. Since protein intake in the diet can
be a factor in causing an erratic response to levodopa, the clinician should pay close
attention to when and what the patient eats in relation to the response to levodopa
dosing Direct observation of the patient during a prolonged outpatient visit as he or she
passes through one or more dosing cycles can be useful to determine the relationship of
levodopa doses to "off" and "on" episodes and to observe directly for dyskinesia that
either are or are not perceptible to the patient.

MANAGEMENT Adjusting the levodopa doses and dosing scheduleAdding an

additional antiparkinson medication Manipulating dietary protein intake if there is
suspicion that it is contributing to motor fluctuation.For patients who fail medical
interventions, deep brain stimulation is an option.

"Wearing off" phenomenon Patients with PD often begin to be aware of a "wearing

off" or end-of-dose effect less than four hours following a dose of levodopa. This
problem may develop early but the majority will notice wearing off within three to five
years after starting levodopa. Examine the effect of diet, and advise those patients who
find that a high protein meal blocks the effect of a dose of levodopa taken at the time of
eating to take levodopa on an empty stomach, at least one-half hour or more before or
one hour after a meal In some cases, "wearing off" can initially be managed by
increasing the dose of levodopa if the patient is taking a relatively low dose and is not
having side effects. However, in most cases, individual levodopa doses should be left
unchanged. For patients with more advanced PD, reducing the interval between doses
by 30 to 60 minutes is often a more effective strategy. This may require the addition of
an extra levodopa dose at the end of the day, especially if the patient is planning to be
out of the house in the evening. Some patients may benefit from alternative levodopa
formulations, such as coated extended-release carbidopa-levodopa tablets . Adding an
oral dopamine agonist such as pramipexole or ropinirole (available as short- and long-
acting formulations), or the dopamine agonist in a skin patch formulation (rotigotine)
are other options, but watch for excessive dopaminergic effects (eg, visual
hallucinations, confusion, somnolence, hypotension, impulse control disorders, or an
increase in dyskinesia) and be prepared to lower the levodopa dose accordingly.
Subcutaneous apomorphine may be helpful for patients with sudden and severe
episodes of "wearing off." This rescue therapy is effective, but must be premedicated
with a prophylactic antiemetic such as trimethobenzamide because of apomorphine's
tendency to cause nausea and vomiting in the induction phase of its use; this can
generally be discontinued shortly after initiation of apomorphine. In addition, the
effective dose of subcutaneous apomorphine must be established for each patient by test
administration, starting with the lowest dose, Adding the catechol-O-methyl
transferase (COMT) inhibitors entacapone or tolcapone, which prolong and potentiate
the levodopa effect. Entacapone should be given first . Be prepared to lower the
levodopa dose by up to 30 percent because of the increased risk of peak-dose dyskinesia
if tolcapone is used. Adding the MAO B inhibitors rasagiline, safinamide, or
selegiline, which prolong the half-life of dopamine in the brain . Some experts believe
that the MAO B inhibitors are not as effective as entacapone, though some consider that
the effect of rasagiline is comparable to that of entacapone.

Alteration of levodopa dosing "Wearing off" can be managed initially by increasing

the dose of levodopa , if the patient is not having dyskinesia and is taking a relatively
low dose. However, increasing the dose of levodopa often exacerbates dyskinesia
without increasing the dose-related duration of benefit. Shortening the interdose interval
while administering lower doses (ie, smaller but more frequent doses, sometimes called
levodopa dose fractionation is usually a more effective approach. It is often difficult to
titrate the levodopa dose precisely, and some patients begin to exhibit an "all or none"
response, whereby individual lower doses produce no evident clinical response and
slightly higher doses trigger an over-response with dyskinesia. Liquifying carbidopa-
levodopa is used only occasionally for patients when titration of the dose and dose
interval using tablets is difficult. However, this approach is not typically practical since
carbidopa-levodopa is insoluble in water and no commercial preparation of liquid
carbidopa-levodopa is available. Carbidopa-levodopa gel infusion, delivered as a
continuous infusion (up to 16 hours a day) through a percutaneous gastrojejunostomy
tube by battery powered pump, may be used in place of oral carbidopa-levodopa to
decrease off time. Sudden cessation of levodopa effect may also occur if the duodenal
tube backs up into the stomach where some of the levodopa gel becomes inactivated by
gastric acidity.

A novel capsule formulation of extended-release carbidopa-levodopa may be more

effective than standard carbidopa-levodopa for reducing motor fluctuations. The
extended-release capsule contains beads of carbidopa and levodopa in a 1:4 ratio that,
after dissolving, are absorbed in the gastrointestinal tract at different rates. Extended-
release carbidopa-levodopa capsules can be opened and the beads sprinkled on a small
amount of apple sauce to ease administration for patients who have difficulty
swallowing pills. The older tablet formulation of controlled-release carbidopa-levodopa
did not reliably decrease "off" time compared with immediate-release formulations In
addition, the tablet formulation of controlled-release carbidopa-levodopa is less well
absorbed than immediate-release carbidopa-levodopa; thus, an individual dose increase
of approximately 30 percent may be required to achieve the same clinical response.

Adjunctive pharmacotherapy The addition of one or more drugs to the levodopa

regimen is a good practical option for reducing "off" time as long as the additions are
one at a time at the lowest possible doses.

Dopamine agonists When the combination works well, the dose of levodopa can be
reduced. The dopamine agonists include pramipexole, ropinirole, apomorphine, and
rotigotine. The dopamine agonist apomorphine administered subcutaneously can be
used for rapid onset (usually within 10 minutes) rescue therapy when patients suddenly
turn "off" Apomorphine is a much more potent and effective dopamine agonist than the
oral agonists. a 4 mg dose achieved a clinically significant improvement in 75 % pt.
However, an individual approach is key to finding the right dose for each patient.

COMT inhibitors COMT inhibitors such as entacapone and tolcapone can prolong
and potentiate the levodopa effect and reduce the "off" time when used as adjunctive
therapy with levodopa. The net result is an increased levodopa effect in fluctuating
patients. These medications may allow a reduction in the total daily levodopa dose by as
much as 30 percent. .The dose of entacapone is one 200 mg tablet with each dose of
levodopa, up to a maximum of eight doses per day. The starting dose of tolcapone is
100 mg three times daily; the clinical effect may be evident immediately, but trial and
error titration is required.
The most common side effects of COMT inhibitors are due to increased dopaminergic
stimulation and include dyskinesia, psychiatric effects (mainly visual hallucinations),
nausea, diarrhea, and orthostatic hypotension managed by lowering the dose of
levodopa either before or after the addition of tolcapone or entacapone. Both drugs may
also cause diarrhea and a brown-orange urine discoloration.

tolcapone was associated with transient, asymptomatic elevations of transaminases

(AST and ALT) in 1 to 3 % so the recommendation that it be used for treatment of
motor fluctuations only after other methods have been exhausted and with monitoring
of ALT and AST levels at baseline and then every two to four weeks for the first six
months of therapy. Entacapone has thus far not been associated with hepatotoxicity.

MAO B inhibitors Rasagiline, safinamide, and selegiline are selective monoamine

oxidase (MAO) B inhibitors. They have potential long-term enhancing effects on
dopamine transmission because of complete and irreversible inactivation of MAO B,
one of the main enzymes involved in the catabolic metabolism of levodopa. Rasagiline
appears to be effective for motor complications in PD . The beneficial effect of
rasagiline was independent of age (<70 versus 70 years) and of adjunct use of
dopamine agonists. Safinamide is useful as adjunctive treatment with levodopa , no
troublesome dyskinesia seen in trials .Selegiline may extend the levodopa effec tbut the
clinical benefit this produces appears to be relatively mild

Except occasionally for management of tremor, anticholinergic drugs and amantadine

are usually ineffective in managing the "wearing off" effect and are rarely indicated.
However, amantadine can be effective as an adjunctive medication in reducing
dyskinesia.

eradication of Helicobacter colonization may be a useful method for improving

levodopa absorption and reducing motor fluctuations in patients with PD [

Unpredictable "off" periods Transitions from being "on" to being "off" can be
sudden and unpredictable in some patients, and usually bear no obvious relationship
with the timing of levodopa dosing, These periods typically occur in patients with
advanced PD who are also experiencing other motor fluctuations and severe dyskinesia
The mechanism for these "off" episodes is not clear, but erratic absorption of levodopa
from the gut and pharmacodynamic changes in the brain at the level of the synapse or
dopamine receptors are likely culprits. .Document that "off" periods are in fact
unpredictable and long lasting as it often turns out that the "off" periods actually are
occurring as an end-of-dose phenomenon . True "off" periods usually affect the whole
body and should be differentiated from episodes of sudden transient freezing of gait,
which can be random and not related to levodopa fluctuations. Avoid taking levodopa
with high protein meals. Consider adjusting the levodopa dosing schedule. Plasma
levodopa levels may be falling below the therapeutic threshold, especially if erratic
absorption from the gut is suspected. However, controlled-release carbidopa-levodopa
preparations are usually not helpful and occasionally exacerbate the situation.
Alternatively, consider lowering the levodopa dose or adding and titrating a dopamine
agonist or COMT inhibitor. In rare cases, sudden "off" episodes may be due to
excessive levodopa effects.
Management of apparently unpredictable "off" periods is often enlightened by the use of
careful home diaries or by direct observation through several dose cycles in a prolonged
outpatient visit to determine the relationship of levodopa doses to "off" episodes. As
noted above, some patients may have the misperception that their "offs" are random and
unpredictable but learn from direct observation can prove that the "offs" are actually
episodes of predictable, dose related "wearing off." Avoiding levodopa within 30 to 60
minutes of a protein meal may be helpful. A protein redistribution diet in which most
dietary protein intake is reserved for the evening was useful in the majority of such
patients in small studies

Freezing of gait Freezing of gait (FOG) can occur as a transient "off" phenomenon,
treatable by the above strategies, or randomly at variable frequency in patients with
advanced PD. Random freezing is poorly responsive to any of the available treatment
modalities, including antiparkinson medications and deep brain stimulation. During an
episode of FOG, patients suddenly become immobilized for seconds to minutes at a
time, usually when initiating walking, in a confined space such as a doorway or a closet,
or when getting on or off an elevator. An episode of FOG can lead to falling, which is
usually forward as the individual tries to move forward and his feet remain behind.

]. First, whether freezing is troublesome needs to be determined. Attempts to treat it

with medication adjustments may not be necessary if it is brief and occurs only
occasionally. Physical and occupational therapy to determine if there are specific
precipitants such as turning, pivoting, or getting on an elevator may lead to suggestions
on how to avoid FOG. Movement strategies or cues to that may help the patient "get
into gear" include shifting weight, making wider turns, concentrating on taking larger
steps forward, or using visual imagery as if to step over an obstacle. A cane or special
laser cane may also be helpful for FOG . Management of more severe and prolonged
FOG includes medication adjustments, non-medication strategies, and assessing
comorbidities .In such cases, it is crucial to determine when and how FOG relates to the
timing of levodopa doses. Dopa-responsive FOG occurs during end of dose "wearing
off" periods and usually responds to shortening levodopa dose intervals or increasing
the levodopa dose to so as to avoid "wearing off" episodes. Adding or increasing
dopamine agonists is usually not as effective and may even aggravate FOG..
Subthalamic nucleus deep brain stimulation (DBS) is another option for levodopa-
responsive FOG.

Levodopa-related FOG is less common FOG, but much more difficult to treat.
Fortunately, it is usually far briefer in duration than dopa-responsive FOG. It occurs at
peak levodopa effect and may respond to reducing the dopamine agonist first followed
by reducing the levodopa dose (if necessary) although this step may compromise the
levodopa response of other motor symptoms. The value of pedunculopontine nucleus
DBS is unproven in the management of levodopa-related FOG

Failure of "on" response Patients with motor fluctuations sometimes fail to turn "on"
following a dose of levodopa. This has been called the "no-on" response In some cases,
this is due to poor absorption of a dose of levodopa due to delayed gastric motility. A
common reason for the "no-on" phenomenon is an excessively prolonged or severe
"off" period occurring before the "no-on." This is best managed by avoiding "offs."
Avoid taking levodopa with high protein meals.Examine gastrointestinal absorption
using isotope testing of gastrointestinal transit time.Prevent "wearing off" episodes;
failure or delay of the "on" responses often occurs after prolonged "wearing off"
periods.Failure of "on" response commonly occurs in mid-afternoon. Therefore, it may
be possible to adjust the dosing schedule to preempt such episodes, such as by adding a
dose of levodopa one hour before the usual failure of "on" time, if it is predictable.

The prokinetic drug metoclopramide is a dopamine receptor blocker that should be

avoided because it crosses the blood brain barrier and can worsen parkinsonian
symptoms. Domperidone is also a dopamine receptor blocker with selective peripheral
activity in the upper gastrointestinal tract, but it does not cross the blood-brain barrier
and therefore does not aggravate parkinsonian symptoms. It is not available in the
United States but is available in Canada and other countries. domperidone (starting at
10 mg four times daily) may be useful as a prokinetic agent to treat delayed gastric
emptying in patients with PD

Acute akinesia sudden exacerbation of PD characterized by an akinetic state that

lasts for several days and responds poorly to treatment with antiparkinson medication.
May sometimes occur in patients not previously treated with levodopa Acute akinesia
should prompt a search for systemic infection or other intercurrent medical problems
that are capable of causing a sudden worsening of parkinsonism, though it can also be
caused by medication error (eg, substituting carbidopalevodopa 25/100 instead of
25/250, or inadvertently using a dopamine receptor blocking agent such as
metoclopramide or an antipsychotic drug with dopamine blocking properties).

Dyskinesia Not all dyskinesia requires treatment .Approaches to managing

troublesome dyskinesia often begin with adjusting the levodopa regimen or the use of
adjunctive medications including dopamine agonists. There are also some data
suggesting that amantadine and clozapine can help to suppress dyskinesia.

Peak-dose dyskinesia Peak dose or "on" dyskinesia is usually choreiform in type It is

manifested by the appearance of restlessness and continuous jerky, involuntary
movements of the extremities, head, face, trunk, or respiratory muscles, typically
starting 30 to 90 minutes after a dose of levodopa. These dyskinetic movements tend to
be tolerated by most patients (more so than by family members or caregivers) since they
prefer being "on" with dyskinesia to being "off." However, severe dyskinesia may take
the form of large amplitude, ballistic movements that interfere with function and
become very disturbing to patients and their families.

Early in the course of PD, peak-dose dyskinesia can be managed by lowering the
levodopa dose, closer spacing if associated with "wearing off," switching to a
controlled-release preparation of levodopa, or reducing adjunctive drugs such as
dopamine agonists, selegiline, or anticholinergic drugs. However, in more advanced
patients with brittle responses, at some point, reducing the dose of levodopa below
therapeutic threshold may result in complete failure to generate an "on" response. In this
situation, the dose of dopamine agonist should be increased to compensate for the
lowering of levodopa dose and the levodopa dose reduced because dopamine agonists
are much less likely to induce dyskinesia than levodopa.

Diphasic dyskinesia Diphasic dyskinesia is an uncommon form of dyskinesia in

which dyskinesia peaks twice after each dose first when patients turn "on" and again
when they begin to turn "off" [2]. In the second phase, dyskinesia (often involving the
legs) in one body part may coexist with the emergence elsewhere in the body of
parkinsonian signs such as tremor and dyskinesia. This pattern is often unrecognized
and may only be appreciated if the patient is observed during a prolonged outpatient
visit. The diphasic pattern is notoriously difficult to manage and usually requires more
frequent levodopa dosing to prevent "wearing off" and the re-emergence of "off"
dyskinesia prior to each dose. However, this strategy may lead to progressively
increasing peak-dose dyskinesia as the day goes on. Addition of a dopamine agonist and
a marked reduction in the levodopa dose should be tried in such patients, or, in some
cases, if tolerated, frequent doses of levodopa can be kept high, above the dystonia
threshold. The main problem with this unusual form of motor fluctuation is
management of occasionally prolonged dyskinesia at the end of the day when the
patient goes to bed. Adjusted enteric levodopa infusion or deep brain stimulation should
be considered if other strategies for management are unsuccessful.

Controlled-release levodopa is best avoided in patients with severe or complex patterns

of dyskinesia since absorption may be delayed and dyskinesia tends to progressively
increase into the afternoon and evening.

Amantadine may be useful for treating dyskinesia in advanced PD and was not
associated with worsening of parkinsonism symptoms . The starting dose of amantadine
for dyskinesia is one tablet (100 mg) a day, titrating to as much as four times a day, as
needed. Side effects may include peripheral edema, psychosis, livedo reticularis
(mottled skin), and hallucinations, all reversible when the drug is stopped.

Clozapine Low doses of the antipsychotic drug clozapine (30 to 50 mg/day) reduced
dyskinesia in several studies and low dose clozapine (12.5 to 75 mg/day) was
significantly more effective than placebo. The usefulness of clozapine is limited by its
potential for inducing granulocytopenia, but this risk may be acceptably low with
monitoring. white blood cell count and absolute neutrophil count at baseline and weekly
for the first six months of continuous treatment, followed by biweekly after

Dystonia Dystonia is characterized by sustained or intermittent muscle contractions

causing abnormal, often repetitive, movements, postures, or both. Dystonic movements
are typically patterned and twisting, and may be tremulous. Dystonic postures usually
involve the limbs but can affect the face, neck, or trunk. Dystonia can be a manifestation
of early untreated PD (especially foot dystonia) or may appear as a complication of
levodopa treatment. A careful history is required since dystonia due to levodopa can
occur either as a peak levodopa effect or during "off" periods due to levodopa
withdrawal. Withdrawal dystonia most commonly occurs in the early morning when it
produces painful flexion and inversion postures of the feet and toes; this usually
resolves shortly after taking the first dose of levodopa.

"Off" period dystonia that occurs early in the morning is managed either by taking
controlled-release levodopa before retiring or by taking levodopa or a dopamine agonist
during the night or first thing in the morning before arising. "Off" period dystonia
during the day is managed similarly to other forms of the "wearing off" effect (eg,
shortening the levodopa dose intervals or adding a dopamine agonist). Peak-dose
dystonia is managed similarly to peak dyskinesia. (
Akathisia Another form of levodopa withdrawal is akathisia or motor restlessness,
which may resemble restless legs syndrome and usually occurs at night, several hours
after the last dose of levodopa. This is managed by providing slow release levodopa or a
dopamine agonist before retiring.Of note, some patients with PD have what seems to be
clear restless leg syndrome and not akathisia, even though they are very similar.

FAILURE OF MEDICAL MANAGEMENT deep brain stimulation of either the

subthalamic nucleus or the internal globus pallidus alleviates the motor fluctuations and
dyskinesia associated with advanced PD.