Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

Goals: To describe and gain basic familiarity with major classes of abnormal movement symptoms seen in clinical practice: hypokinesias and hyperkinesias To understand the basic pathophysiology, differential diagnosis and key clinical features of some of the major movement disorder syndromes: 1. To describe parkinsonism and its differential diagnosis. To recognize features suggesting Parkinsons Disease. 2. To recognize clinical features of essential tremor versus parkinsonian tremor. 3. To describe clinical features and inheritance of Huntingtons Disease. 4. To recognize risk factors and clinical presentation of tardive dyskinesia. 5. To discuss site of abnormality producing hemiballism. 6. To recognize features which distinguish focal and generalized dystonia syndromes. 7. To describe the biochemical abnormality and clinical presentation of Wilsons Disease. 8. To recognize and describe the clinical presentation of Tourettes syndrome. 9. To describe some common myoclonus syndromes. 10. To describe medical and surgical treatments currently available for Parkinsons disease at early and late stages of disease Hypokinesias
(paucity of movement) Loss or absence of movem ent Slownes s of movem ent Stiffnes s muscle tone with passive movem ent

Hyperkinesias or Dyskinesias1
(excess of movement)

Akine sia Brady kinesi a

Tre mo r Ch ore a2

Oscillatory, rhythmical and regular, movement affecting one or more body parts. Involuntary, irregular, purposeless, nonrhythmic, rapid unsustained movements that flow from one body part to another

Rigidi ty

Dys toni a

Sustained muscle contractions, frequently causing appearance of twisting and repetitive, patterned movements or postures

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Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

Abnormal repetitive, intermittent, stereotypic movements (motor) or sounds (phonic) occurring abruptly and briefly from a background of normal activity. Tics are characteristically preceded by an urge and followed by temporarily relief of urge after the tic. Tics tend to be temporarily suppressible, often followed by a rebound in tic production. Sudden, brief, shock-like, involuntary movements usually caused by muscular contractions, but occasionally by inhibitions

Tic s

My ocl onu s
1

Dyskinesia:

Any type of abnormal or unnatural movement. Although may refer to either hypokinesias or hyperkinesias, it is usually used synonymously with hyperkinesias.

Athetosis and Ballism are often considered variations of chorea: Athetosis: Slow, writhing, continuous, involuntary movements. May resemble slow chorea Ballism: Large amplitude involuntary flinging limb movements. May resemble large amplitude chorea

1.

Akinetic-Rigid Syndromes (Parkinsonism) Akinesia and bradykinesia refer to lack or slowness of movement respectively. Patients with these features demonstrate a generalized paucity of movements which are normally made such as swinging of the arms while walking, use of the hands while talking, normal facial expression, placing the legs under the chair before rising, etc. There is also a reduction in the speed and amplitude of voluntary movements with gradual fatiguing as a task is continued. This complaint can interfere with many activities of daily living (brushing the teeth, writing, doing buttons etc). Rigidity often accompanies akinesia and describes an increase in muscle tone to passive stretch. The resistance is felt in both extensors and flexors equally (unlike spasticity).
Classic Parkinsonism Idiopathic Parkinsons Disease (80%) Drug-Induced Parkinsonism Postencephalitic Parkinsonism Parkinsonism-Plus Neurodegenerative syndromes: Progressive Supranuclear Palsy (PSP) Multiple System Atrophies (MSA): Striato-Nigral Degeneration (SND) Shy-Drager Syndrome (SDS) Olivopontocerebellar Degen (OPCD) Normal Pressure Hydrocephalus Multiple Cerebral Infarcts Wilsons Disease Creutzfelt-Jakob Disease other secondary causes exist

1.1. Idiopathic Parkinsons Disease (PD) The major features of this condition are due primarily to an idiopathic degeneration of the dopamine containing neurons in the substantia nigra in the midbrain which sends projections primarily to the striatum (caudate/putamen). The main clinical manifestations of this condition are: Tremor, Rigidity, Akinesia and Postural Disturbances (giving the mnemonic TRAP).

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Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

In Parkinsons disease, the tremor is primarily a rest tremor (see section 2.1). Rigidity and akinesia (bradykinesia) are discussed above. The postural disturbances are comprised of a flexed posture of trunk and limbs as well as poor postural stability. This latter disturbance accounts for the retropulsion seen when the patient is displaced backwards and propulsion forwards as if the patient is attempting to catch up with his center of gravity during gait (festination). Parkinsons disease is extremely common, occurring in approximately 1 in 1,000 in the general population but up to 1 in 100 or more in the over 65 age group. It is usually slowly progressive over the course of several years, but substantial individual variability can be present. 1.2. Other causes for Parkinsonism Dopamine receptor blocking agents such as the neuroleptics may result in all of the features of idiopathic Parkinsons disease. At the turn of the century, encephalitis lethargica lead to features of parkinsonism as a postencephalitic complication, but no new cases have been reported since the early 1920s. Other important secondary causes of parkinsonism are vascular parkinsonism and pressure hydrocephalus. Several other neurodegenerative diseases also have features of parkinsonism. Most are associated with degeneration of both the striato-nigral dopamine system (causing parkinsonism) and other neural systems which provide the clue that one is not dealing with idiopathic Parkinsons disease. However, in early stages, it may be impossible to distinguish true Parkinsons disease from these other conditions. Progressive supranuclear palsy is associated with abnormalities of eye movement (particularly downgaze). These patients also demonstrate features of pseudobulbar palsy, axial rigidity and early onset postural instability (often with backward falls). The multiple system atrophies demonstrate parkinsonism in addition to a combination of cerebellar features, autonomic disturbances, eye movement abnormalities, other movement disorders and mental state abnormalities. 2. Tremor syndromes Tremor is a rhythmical sinusoidal movement of body parts. The predominant distinction that must be made is between rest and action tremor. Any part of the body may be involved (e.g. limbs, neck (head), chin (jaw), vocal cords, tongue). Since tremor terminology can be confusing, I encourage the use of the following descriptive terms based on these definitions: Tremor types Rest tremor Postural tremor Action tremor
Tremor during any voluntary contraction of muscle

Definitions
Tremor in body part not activated and supported against gravity Tremor in body part being supported against gravity Simple kinetic tremor: Tremor in body part during non-goal-directed movement Intention (goal-directed) kinetic tremor: Tremor in body part increasing during pursuit of a goal

Kinetic tremor
Tremor in body part during any voluntary movement

Simple kinetic tremor (non-goal-directed) Intention tremor (goal-directed)

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Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

2.1. Parkinsonian tremor The most common cause for rest tremor is Parkinsons Disease or any of the parkinsonian syndromes. The parkinsonian rest tremor is typically 4-6 Hz. When occurring in the hand and wrist, it is described as pill-rolling. The tremor is prominent with the body part in complete repose and diminishes substantially or subsides with voluntary movement. It may occur in the jaw and limbs; less commonly, it may also occur in the head and trunk. 2.2. Essential tremor (ET) Essential tremor is a common syndrome and cause of action tremor with prominent postural and kinetic components. Tremor typically affects both upper extremities with a frequency about 6-10 Hz. Other body parts (head, voice, lower extremities) may be affected, but almost always in association with some upper extremity tremor. In many cases, ET is inherited as an autosomal dominant trait. It may begin or come to clinical attention at any time during life, but is more common in the elderly. The tremor may interfere with speaking, writing, holding objects, bringing a cup to the mouth, eating with utensils or simply cause social embarrassment. The tremor may be very mild and never come to medical attention. Many patients find that a small amount of alcohol dampens the tremor considerably. Mild ET may not require treatment. Approximately 40% of patients are helped by propanolol (nonselective beta-blocker). Side effects include depression, bronchospasm, loss of libido, and orthostatic hypotension. Primidone is a barbiturate anticonvulsant which may be equally effective in treating ET. Although primidone is associated with a variety of acute side effects (dizziness, sedation, nausea, headache), it may be better tolerated in the long run. For medically refractory and disabling essential tremor, deep brain stimulation (DBS) or thalamotomy (lesions) targeting the VIM nucleus in the thalamus can dramatically relieve contralateral tremor. 2.3. Other tremor syndromes Physiologic tremor is a subclinical fine tremor which present in all persons. It represents the natural oscillation of body parts at their resonant mechanical frequencies. Enhanced physiologic tremor (EPT) represents a clinically relevant exaggeration of physiologic tremor. It is typically a postural predominant tremor. Hyperadrenergic states such as anxiety, sympathomimetics, caffeine, cocaine, alcohol withdrawal are common causes of EPT. Other important causes are hyperthyroidism, fatigue, and stress. Intention tremor is associated with brainstem and cerebellar lesions. 3. Chorea syndromes Chorea is nonspecific and a symptom of many diseases. A partial list follows:
Cate gori es of Cho rea Dru gRela ted Cho rea Categ ories of Chor ea Inher ited Chor ea Example Etiologies Huntingtons Disease Wilsons Disease Neuroacanthocy tosis

Example Etiologies

Peak-dose: levodopa (esp in PD), acute neuroleptic withdrawal, sympathomimetics, anticonvulsants, lithium, ethanol Tardive chorea:

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Clinical Movement Disorders Updated 11/22/09

neuroleptics Systemic lupus erythematosus Antiphospholipid antibody syndrome Sydenhams chorea Chorea gravidarum Traumatic brain injury Hypoxic/anoxic encephalopathy Stroke (ischemic/hemorrhagic) Multiple sclerosis

Allan Wu, MD allanwu@mednet.ucla.edu

Imm unol ogic Cho rea Stru ctur al Cho rea

Meta bolic Chor ea Misce llane ous Chor ea

Hyperglycemia Hypoglycemia Hypocalcemia Hyperthyroidis m Encephalitis (many) Kernicterus Athetoid cerebral palsy

Chorea is defined as continuous flowing, irregular, brief, jerky and explosive movements. These flit from one portion of the body to another in random sequence. They are unpredictable in timing and site and completely involuntary. 3.1. Huntingtons Disease (HD) HD is inherited as an autosomal dominant trait with complete penetrance. Symptoms usually begin between the ages of 30 and 50, but occasionally it presents in childhood or in old age. The major features are psychiatric disturbances, progressive dementia and a movement disorder. Personality changes are a frequent early manifestation. Psychiatric features span much of psychiatric disease including depression and schizophrenia. The movement disorder is typically chorea involving all body parts. The eyebrows frequently lift, lips pucker, tongue protrudes into the cheek, head tilts, fingers flick, arms and legs jerk unpredictably, and trunk may lurch, particularly while walking giving the gait a stuttering, dancing appearance. Motor impersistence is another feature. This is classically demonstrated by lack of the ability to maintain a constant squeeze on the examiners fingers (milk-maid grip) or ability to maintain the tongue in protrusion. Other movement types may be present such as dystonia, tremor, myoclonus and even elements of bradykinesiarigidity. This condition is slowly progressive and death occurs approximately 15 years after the onset of symptoms. Pathology demonstrates marked neuronal loss and astrogliosis in the caudate nucleus and putamen. Treatment is only symptomatic at present. Psychiatric features are treated in a similar fashion to primary psychiatric illness. The chorea may be markedly improved by dopamine receptor blocking agents (neuroleptics), but significant side effects limit their use unless patients are disabled by the involuntary movements. The abnormal gene (huntingtin) was identified in 1993 as an unstable, expanded CAG trinucleotide repeat on chromosome 4. There is an inverse correlation between CAG repeat length and age of onset and severity. Genetic testing is available commercially, but careful informed consent and genetic counseling is strongly recommended before requesting such a test because of potential implications for family members. 3.2. Tardive dyskinesia A late (tardive) complication of chronic neuroleptic exposure is a choreiform movement disorder known as tardive dyskinesia. Chewing, smacking, tongue protrusion and other lower facial movements are the most common feature of this condition, but a wide range of both chorea and even dystonia can be seen. Pathogenesis is unclear, but increasing neuroleptics may treat the hyperkinesia at the expense of prolonging its manifestation. If the neuroleptic can be discontinued the disorder may remit in 50% or more of patients.

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Allan Wu, MD allanwu@mednet.ucla.edu

Otherwise, treatment is often very difficult and unsatisfactory. The best treatment is prevention by avoiding the use of antipsychotic drugs unless absolutely necessary. 3.3. Hemiballism (hemichorea) Infarcts or hemorrhages in the region of the subthalamic nucleus (less commonly elsewhere) often result in ballism of the opposite side of the body (hemiballism). Ballistic movements are wild, flinging, are irregular and unpredictable. If caused by an infarct or hemorrhage, the movement disorder gradually resolves over several months in most patients. At its peak the movements can be significantly disabling and are often improved by antidopaminergic drugs (neuroleptics or presynaptic dopamine depleters). 3.4. Sydenhams Chorea Sydenhams Chorea is a feature of acute rheumatic fever (ARF). ARF is a postinfectious immunologic reaction following Streptoccocus type A infection. The choreic manifestation is a late ARF often occurring several months after the index infection. The majority of patients are between 7 and 12 years old and females are more commonly affected than males. As the incidence of rheumatic fever has decreased this has become a rarer cause for chorea. Supportive evidence for Sydenhams chorea includes a positive antistreptoysin-O (ASO) titer (evidence for past exposure with Strep A) and cardiac valvular lesions compatible with ARF. 4. Dystonia Dystonia is characterized by prolonged co-contraction of agonist and antagonist muscles producing sustained torsion spasms or characteristic twisted postures in the limbs, trunk or face. In the neck there may be torticollis: rotation, anterocollis (flexion), or retrocollis (extension). The trunk may demonstrate excessive lordosis or scoliosis. The arms may be hyperpronated and the feet may be plantar flexed and inverted. In mild or early dystonia, the abnormal posture may be present only during certain voluntary actions and not on others (task-specific dystonia). Two classic examples are: the child with toe-walking forward but not backwards; dystonia only on writing but not on other manual tasks such as using eating utensils (simple writers cramp). More severe dystonia loses task-specificity and any motion may induce the action dystonia. Eventually, a fixed posture may result from constant dystonia. Sensory tricks (geste antagoniste), when present, are characteristic for dystonia and are particularly frequent in torticollis (cervical dystonia). A brief or light touch to the body part affected by dystonia can often temporarily help alleviate symptoms. A useful initial approach is to classify dystonia into either generalized dystonia or focal dystonia. Generalized dystonia tends to be childhood onset with progression. Adult-onset dystonia tends to be focal and nonprogressive. 4.1. Idiopathic torsion dystonia (ITD or generalized dystonia) Idiopathic torsion dystonia refers to a syndrome of progressive generalized dystonia with no identifiable cause. The older term for this syndrome is dystonia musculorum deformans, describing the appearance of these patients. The best-described generalized dystonia is DYT1 dystonia (Oppenheims Dystonia), an autosomal dominant disorder with incomplete penetrance. DYT1 dystonia begins in childhood in the lower extremities and gradually over months to years spreads to involve most parts of the body. Limbs, neck, head, and trunk frequently twist into particular postures resulting in bizarre postures and gaits. Usual walking and goaldirected movements may be impossible. Problems arise from the abnormal postures and impaired mobility (progressive scoliosis, joint contractures). Mentation tends to be spared. Genetic studies have identified the DYT1 gene on human chromosome 9q34 coding for a novel ATP-binding protein, termed torsin A. 11/28/11 page 6 of 12

Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

Anticholinergics, benzodiazepines and antispasticity agents are the mainstays of medication treatment. Because of a rare (but easily treatable) generalized dystonia of childhood called levodopa-responsive dystonia (DRD) (not discussed here), a trial of levodopa (L-dopa) is essential in all childhood onset dystonia. In medically refractory cases, various thalamic or basal ganglia neurosurgical procedures have reported improvement of limb and/or axial dystonia, but in small series of selected patients. 4.2. Focal dystonias In contrast to childhood onset progressive generalized dystonia, dystonia beginning in adult life is often restricted and nonprogressive, limited to one or two body areas (focal or segmental dystonia). The most common varieties of adult onset focal dystonia are cranial dystonia, blepharospasm (forced eyelid closure), Meige syndrome (cranio-cervical dystonia), spasmodic torticollis (cervical dystonia), upper limb dystonia (e.g., writers cramp). Treatment of focal dystonias with medications has been difficult, but the recent use of botulinum toxin injections, which chemically denervate selected overactive muscles, has afforded enormous relief to many of these patients. 4.3. Wilsons Disease (progressive hepatolenticular degeneration) In all children and young adults presenting with dystonia, tremor and akinetic rigid syndromes, Wilsons disease must be excluded. Its importance lays in that (1) it may present with virtually any combination of abnormal movement types (dystonia, tremor, myoclonus, chorea, ataxia, etc) and (2) it represents a treatable disorder. Wilsons Disease is inherited as an autosomal recessive trait. The clinical features are due to copper deposition in variety of tissues including brain, liver, kidney and cornea. The copper binding protein ceruloplasmin is deficient. This results in the laboratory abnormalities of decreased serum ceruloplasmin, raised urinary copper excretion, and raised liver copper on liver biopsy. Copper deposition and damage to the putamen and globus pallidus results in the movement disorders. Deposition of copper in the cornea causes the Kayser-Fleischer ring which much be searched for on slit lamp examination. Treatment includes restricting copper in the diet and the use of penicillamine which chelates excessive copper from the affected tissues. 4.4. Other secondary dystonias Similar to chorea, dystonia is a symptom with a variety of secondary causes. Symptomatic generalized torsion dystonia may occur secondary to other degenerative brain diseases or cerebral insults (hypoxia, kernicterus or dystonic extrapyramidal cerebral palsy). Neuroleptics may cause a tardive dystonia along with chorea. Acute dystonic drug reactions may occur within the first 48 hours of exposure to a neuroleptic. These may include involuntary spasms of gaze, (oculogyric crises) along with opisthotonic posturing and a variety of other abnormal movements. Such reactions usually resolve rapidly with parenteral injection of an anticholinergic drug or benzodiazepine. 5. Tic syndromes Tics are repetitive and stereotyped rapid movements. They can be held in check, at will, by the patient with resulting increased inner tension. The most common form is a simple transient tic of children which usually begins before age 12 and lasts for one to two years. Similar tics may be the first manifestation of Gilles de la Tourette syndrome and family members of patients with this latter condition may demonstrate simple tics alone. 5.1. Gilles de la Tourette syndrome Gilles de la Tourette syndrome usually begins between 2 and 15 with multiple involuntary motor and phonic (vocal) tics. These tics may be simple (motor and vocal) e.g. eye blinking, facial grimacing,

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Allan Wu, MD allanwu@mednet.ucla.edu

shoulder jerking, grunting, sniffing, throat clearing; or complex" such as complicated motor acts or verbalization. Tics range enormously in complexity, phenotype and disability. Behavioral disorders (typically obsessiveness, compulsiveness or attention deficit disorders) are also frequent. The severity of the symptoms waxes and wanes and some patients have short lived periods of complete remission. The cause is unknown. The syndrome is chronic but some patients have a complete and permanent resolution of symptoms in adolescence. Dopamine antagonists such as haloperidol or pimozide dramatically improve the symptoms. Clonidine, a central noradrenergic agonist and clonazepam, a benzodiazepine, have also had some success. 6. Myoclonus syndromes Myoclonus is defined as rapid, shock-like muscle jerks which are often repetitive and sometimes rhythmic. A simple clinical approach is to view myoclonus as focal or generalized. Generalized myoclonus includes progressive myoclonic epilepsies (primary seizure disorders), post-anoxic myoclonus (Lance-Adams syndrome) and benign essential (occasionally hereditary) myoclonus. Examples of focal myoclonic disorders include segmental myoclonus (e.g., spinal cord tumor) or palatal myoclonus (brainstem disease).
Categories of Myoclonus Physiologic Epileptic Hereditary Metabolic Sympto matic Example Etiologies Hypnic jerks Hypnogogic jerks Hiccups Progressive myoclonic epilepsies Epilepsia partialis continua Essential (idiopathic) myoclonus Anoxic encephalopathy (Lance-Adams syndrome) Uremia Hepatic failure Alzheimers Disease parkinsonism plus syndromes Huntingtons Disease Subacute sclerosing panencephalitis HIV

Degenerat ive Infectious

7. Medical treatment of Parkinsons disease The pharmacologic armamentarium for the medical treatment of Parkinsons disease has become much more complex and diverse in the last few years. It is important to remember that early disease that does not impact function does not require treatment. Symptomatic treatment focuses on maintaining independent function as long as is possible. As PD symptoms are related to the deficiency of dopamine, symptomatic therapy revolves around repletion of this neurotransmitter. Each patient is evaluated independently and presents with a unique spectrum of signs, symptoms, and response to medication with a host of social, occupational and emotional factors that need to be addressed. Table A (end of handout) provides basic information about symptomatic medications discussed below. Levodopa therapy still remains the gold standard of treatment in PD. It is administered with a peripheral decarboxylase inhibitor (carbidopa), which inhibits the peripheral conversion of levodopa to dopamine. Carbidopa allows for an approximately four-fold reduction in dose of levodopa and a significant reduction in nausea and vomiting.

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Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

Carbidopa/levodopa (Sinemet) is available in standard/immediate release and sustained/controlled release (CR) formulation. Sinemet CR provides a longer plasma half-life and lower peak plasma levels of levodopa. Unfortunately, CR has not been shown to prevent the development of response fluctuations. In addition, CR lacks a rapid response to each dose and delayed absorption can result in high levodopa levels and dyskinesia. The response to Sinemet CR is also less predictable than standard levodopa. Both immediate release and Sinemet CR can be used simultaneously to help smooth motor fluctuations. Dopamine is metabolized by catechol-o-methyl-transferase (COMT) in addition to dopa decarboxylase. Two COMT inhibitors, entacapone (Comtan) and tolcapone (Tasmar) are available in the USA. This class of medications increases the plasma half-life of levodopa without increasing the peak plasma concentration or time to peak concentration. Tolcapone is a tid medication and requires frequent liver function testing due to the potential for fulminant liver failure. While entacapone has no reported risk of liver dysfunction, it has a short half-life and must be dosed with each levodopa intake for effect. A combination product combines levodopa with both carbidopa and entacapone (Stalevo). After levodopa, dopamine agonists are the next most effective class of medications to treat PD. Agonists can be used in monotherapy or as adjunctive treatment to levodopa. Long-term clinical trials for many dopamine agonists have shown that initiating therapy with these agents notably delays the onset of dyskinesia compared to those initially treated with levodopa. The availability of multiple agonists allows the clinician to find one that is most effective and best tolerated for each patient. Each agonist stimulates the post-synaptic dopamine receptors a bit differently. All dopamine agonists can potentially cause confusion, sedation, psychosis, orthostatic hypotension and pedal edema. Dosing for all agonists must therefore be initiated very slowly and conservatively to avoid otherwise limiting nausea, dizziness and sedation. The most commonly used dopamine agonists are pramipexole (Mirapex) and ropinirole (Requip). A recently approved dopamine agonist (rotigotine, Neupro) was available in a daily patch formulation, but was recalled in 2008 due to a manufacturing defect but may eventually return to market. The older agonists, bromocriptine (Parlodel) and pergolide (Permax no longer available in USA) are ergot derivatives and can on rare occasion cause retroperitoneal, pleuropulmonary and pericardial fibrosis. Amantadine (Symmetrel) is a milder medication used to treat PD. It is thought to promote release of dopamine from nerve terminals and blocks reuptake. It additionally has both antimuscarinic and glutamate blocking properties. It is given as 100 mg bid-tid. It is effective in early PD as a mild symptomatic agent to delay the use of levodopa. It can also be used as adjunctive therapy in later stage disease with motor fluctuations to diminish wearing off and on-effect dyskinesia. Less than 10% of users experience pedal edema and livedo reticularis. Confusion and psychosis can occur in the more elderly patient. Selegiline (Eldepryl) and rasagiline (Azilect) are MAO-B (monoamine oxidase type B) inhibitors which have been hypothesized to be neuroprotective. However, careful follow-up suggests that the benefits of selegiline were due to mild symptomatic effects. Recent data suggests that early use of rasagiline may delay later disease severity and it has become an option for early monotherapy of PD. Other non-dopaminergic medications include anticholinergics such as trihexyphenidyl (Artane) and benztropine (Cogentin). These medicines diminish rest tremor but can cause peripheral anticholinergic side effects including dry mouth, blurred vision and urinary retention. Central side effects include short-term memory impairment, and psychosis, which may be prominent in the elderly.

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Clinical Movement Disorders Updated 11/22/09

Allan Wu, MD allanwu@mednet.ucla.edu

7.1. Early treatment of PD Pharmacologic treatment is reserved for patients with symptoms which begin to interfere with normal function. Such initial treatment often begins either with levodopa or dopamine agonists, but would not be uncommon to begin with rasagiline, an anticholinergic or amantadine. In general, levodopa is the most effective and potent antiparkinsonian agent. Its effects ameliorate many symptoms of PD, especially bradykinesia and rigidity. Since its introduction in the 1960s, levodopa has been shown to improve quality of life and decrease mortality in PD patients. Dopamine agonists may be less potent than levodopa, have a greater risk for side effects in the elderly, and take longer to achieve adequate dosing, but in clinical trials, they have been shown to be effective in delaying the onset of motor complications. The decision to start one or the other remains an individualized one. 7.2. Late considerations in PD treatment Long-term dopaminergic treatment and progression of PD over years can lead to motor complications (wearing-off, dose-related dyskinesias or on-off fluctuations) and behavioral problems (psychosis). These side effects can be dose limiting and become worse than the parkinsonian symptoms themselves. Wearing-off is when the patient loses a sustained effect of medication and needs to take the next dose earlier. Dose-related dyskinesias are abnormal involuntary movements in any body location (often choreiform, but may also be ballism, dystonia or myoclonus), which occur following each medication dose at peak bioavailability. Offperiods refer to a parkinsonian state with bradykinesia, rigidity and impaired gait and on-periods refer to benefit from dopaminergic medication with less akinetic-rigidity, improved mobility but sometimes with dyskinesia. On-off fluctuations describe a knife-edge phenomenon where medication provides an abrupt onperiod and wearing off causes an abrupt off-period, sometimes with very little optimal motor in-between state. Hallucinations, agitation, paranoia, insomnia, and nightmares also occur with levodopa. Treatment is with reduction of dopaminergic medication or addition of atypical neuroleptics such as quetiapine, clozapine, or olanzapine. Typical or classical neuroleptics block dopamine (D1, D2) receptors and can cause parkinsonism as a side effect. Atypical neuroleptics have much less D1 and D2 blocking properties and are thought to block psychosis by effects of D3 receptors in the mesolimbic and frontal cortex. Management of these late complications requires frequent medication adjustment and use of adjunctive medications. For instance, COMT-inhibitors are often used for wearing-off. For selected later-stage PD patients, surgical options may be available. 8. Surgical options in Parkinsons disease Stereotactic surgery for PD has been carried out since 1947. Stereotactic thalomotomy was popularized in the late 50s and 60s because of its effect in minimizing tremor. With the advent of levodopa in the late 60s, surgery for PD became infrequent. With improved understanding of the functional anatomy of the basal ganglia and modern neurosurgical stereotactic techniques, there is a renewed interest in PD neurosurgery. The standard basal ganglia model proposes that the output stage (globus pallidum - GPi) is overactive in PD. Since basal ganglia output is inhibitory, this produces an excess of inhibition on motor output explaining features of hypokinesia (paucity of movement) characterizing PD. The subthalamic nucleus (STN) is a component within the basal ganglia that directly drives the GPi and therefore tends to be similarly overactive in this scheme. As such, frequent targets for surgical intervention in PD are GPi and STN. Stereotactic lesions in the pallidum (pallidotomy) and thalamus (thalamotomy) were popular procedures in the early 90s. Since the development of implantable deep brain stimulation (DBS) techniques, lesion procedures 11/28/11 page 10 of 12

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Allan Wu, MD allanwu@mednet.ucla.edu

have become less common. DBS works by implanting electrodes into targets in the thalamus, globus pallidus (GPi) or STN. A pacermaker-like device, similarly placed under the skin near the collarbone, provides power to the electrodes and can be programmed in an office setting similar to cardiac pacemaker interrogation and adjustment. Continuous high-frequency stimulation produces a localized and adjustable function lesion while avoiding consequences of permanent brain lesions. DBS of GPi and STN has recently been approved by the FDA as a treatment modality for PD. DBS has a lower rate of complication than ablative surgery related to lack of a permanent lesion. There remains, however, a small risk of significant neurosurgical morbidity/mortality (1-3%) depending upon the center. Bilateral DBS is also safer than bilateral lesion procedures because the latter carry a substantially higher risk of dysarthria and dysphagia. STN and GPi DBS (as well as the pallidotomy procedure) are effective procedures for treating contralateral tremor, rigidity, dyskinesia, bradykinesia and in some cases, gait imbalance. Thalamic DBS is effective for tremor suppression. Disadvantages of DBS are high cost, complications of surgical implantation, adjustments for programming the DBS unit, hardware failures, and behavioral side-effects. DBS likely provides substantial benefit to selected PD patients. However, methods for selecting patients who are optimal for DBS procedures remain an area of active research. As a general guidelines, patients referred for these surgical procedures should undergo standardized testing, have been treated with best medical therapy, and be evaluated in a multidisciplinary center where neurologists work closely with neurosurgeons. Further, DBS does not represent cure and the surgical procedures probably do not make any patients better than their best response to medications. Therefore, DBS may be particularly helpful for those patients where medications work, but are associated with significant side-effects. Of relevance for all medical caregivers is that all warnings that apply to pacemakers also apply to DBS procedures. Further, because the leads are subcutaneous from the anterior chest wall to the upper scalp, significant neck injuries or movements may run the risk of damaging leads. The other major warning is that diathermy (a technique of using ultrasound to heat tissue used in rehabilitation and chronic pain) has been described to heat the electrodes used in DBS with stroke and death as a consequence. Therefore, any consideration of rehabilitation therapies or nonpharamacologic treatments that may use diathermy are strictly contraindicated.

Table A: Summary of PD medications, uses and side-effects

Category Agent

Mechanism of action
Converted to dopamine in CNS carbidopa inhibits peripheral levodopa metabolism (allowing more dopamine to cross into CNS) carbidopa as above, entacopone (COMT inhibitor)

Use and Effectiveness

Most potent agent: ameliorates many Parkinsons disease symptoms levodopa in combination with drugs that enhance its availability

Side Effects

levodopa

Dopamine precursors

levodopa + carbidopa levodopa + carbidopa + entacopone

Acute: nausea, vomiting, orthostatic hypotension Late: motor complications, behavioral alterations

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pramipexole Dopamine agonists ropinirole rotigotine (patch) apomorphine selegiline, rasagiline tolcapone entacapone anticholinergic agents (trihexyphenidyl, benztropine, etc) amantadine MAO-B inhibitors Postsynaptic dopamine receptor agonists

Allan Wu, MD allanwu@mednet.ucla.edu

Similar to levodopa. Used as monotherapy or adjunctive therapy adjunctive, acute, injectable therapy Adjunctive therapy or as early therapy (? possible neuroprotection) Adjunctive therapy with levodopa Adjunctive therapy. Usually used for tremor mild antiparkinsonian agent; may help dyskinesias Similar to levodopa but delays onset of motor complications; sleep attacks; nausea (esp apomorphine)

Dopamine breakdown inhibitors

Similar to levodopa. Similar to levodopa tolcapone: liver toxicity entacapone: diarrhea Confusion, sedation, orthostatic hypotension, urinary retention, dry mouth. Dermatological reactions, peripheral edema, mental disturbances

COMT inhibitors Block muscarinic acetylcholine receptors mechanism not certain (dopamine release or glutamate effects have been suggested)

Nondopaminergic modulating drugs

11/28/11

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