Movement DisordersMovement Disorders

Mary Quiceno, M.D.Mary Quiceno, M.D.

NeurologyNeurology

Hypokinetic & HyperkineticHypokinetic & HyperkineticMovement DisordersMovement Disorders

Parkinson’s diseaseParkinson’s disease Parkinson’s Plus Parkinson’s Plus

SyndromesSyndromes– PSPPSP– MSAMSA– SNDSND– OPCAOPCA– CBDCBD– AD w/Lewy bodiesAD w/Lewy bodies– LBDLBD

TremorTremor DystoniaDystonia MyoclonusMyoclonus ChoreaChorea TicsTics AkathisiaAkathisia StereotypyStereotypy RLSRLS

Basal GangliaBasal Ganglia

What is Parkinson's Disease? What is Parkinson's Disease?

Parkinsonism is the name given Parkinsonism is the name given to a collection of symptoms and to a collection of symptoms and signs consisting of:signs consisting of:– TremorTremor– RigidityRigidity– BradykinesiaBradykinesia– Unsteady gaitUnsteady gait

ParkinsonismParkinsonism

Many neurological disorders have Many neurological disorders have features of parkinsonism. features of parkinsonism.

When parkinsonism occurs without When parkinsonism occurs without any other neurological abnormalities, any other neurological abnormalities, and there is no recognizable cause of and there is no recognizable cause of it, the disorder is termed Parkinson's it, the disorder is termed Parkinson's diseasedisease – after the English physician who first after the English physician who first

described it fully in 1817. described it fully in 1817.

Evaluation by a neurologist is Evaluation by a neurologist is important for several reasons:important for several reasons:

All tremors are not Parkinson’s All tremors are not Parkinson’s disease.disease.– There are many causes of tremor. It should not be assumed that There are many causes of tremor. It should not be assumed that

someone has PD unless the tremor has all the features of the tremor someone has PD unless the tremor has all the features of the tremor that is known to occur in PD and other causes of tremor have been that is known to occur in PD and other causes of tremor have been excluded.excluded.

Parkinsonism is a symptom of Parkinsonism is a symptom of many disorders.many disorders.– There are a variety of disorders in which parkinsonism occurs without There are a variety of disorders in which parkinsonism occurs without

obvious cause, but these disorders usually have additional features obvious cause, but these disorders usually have additional features that distinguish them from classic PD. Such a distinction is important that distinguish them from classic PD. Such a distinction is important because the long-term outlook may differ and the treatment options because the long-term outlook may differ and the treatment options may be different.may be different.

ParkinsonismParkinsonism

Exclusion criteria for PDExclusion criteria for PD– NeurolepticsNeuroleptics– Toxin exposure Toxin exposure (MPTP, CO, Mn, Methanol)(MPTP, CO, Mn, Methanol)

– EncephalitisEncephalitis– StrokeStroke– Head injuriesHead injuries– Early and severe dementia or autonomic Early and severe dementia or autonomic

dysfunctiondysfunction– Levodopa non-responderLevodopa non-responder

Drug-induced ParkinsonismDrug-induced Parkinsonism More common in More common in

elderly and womenelderly and women

Symmetric onset of Symmetric onset of bradykinesia, tremor, bradykinesia, tremor, and/or rigidityand/or rigidity

Onset within a few Onset within a few days to 3 months in days to 3 months in 90% of affected 90% of affected patientspatients

Stop drug, try Stop drug, try anticholingeric anticholingeric therapytherapy

New and Old New and Old AntipsychoticsAntipsychotics– RisperdalRisperdal– HaldolHaldol

BenzamidesBenzamides– ReglanReglan

PhenothiazinesPhenothiazines– CompazineCompazine– PhenerganPhenergan

Others causing mainly Others causing mainly postural tremors:postural tremors:– LithiumLithium– DepakoteDepakote– AmiodaroneAmiodarone

How is Parkinson's Disease How is Parkinson's Disease Treated?Treated?

A number of treatment approaches help A number of treatment approaches help patients with Parkinson's disease. patients with Parkinson's disease. – General lifestyle modifications (rest and General lifestyle modifications (rest and

exercise)exercise)– Dietary considerationsDietary considerations– Physical therapy and speech therapyPhysical therapy and speech therapy– Medications and surgery Medications and surgery

Replace the dopamine, increase the lifetime of the Replace the dopamine, increase the lifetime of the dopamine at the synapse, or stimulate the dopamine dopamine at the synapse, or stimulate the dopamine receptors. receptors.

Medications for Parkinson's Medications for Parkinson's diseasedisease

Levodopa Levodopa (carbidopa/levodopa; Sinemet)(carbidopa/levodopa; Sinemet)

– Reduces the symptoms.Reduces the symptoms.– Carbidopa prevents peripheral break down of Carbidopa prevents peripheral break down of

levodopa. levodopa. Minimum of 75 mg/d to avoid nausea.Minimum of 75 mg/d to avoid nausea.

– Treatment over a number of years may lead to Treatment over a number of years may lead to variability in an individual's response to variability in an individual's response to treatment, called "motor fluctuations." treatment, called "motor fluctuations."

– Another form of motor fluctuation is Another form of motor fluctuation is uncontrolled writhing movement of the body or uncontrolled writhing movement of the body or a limb, which is called "dyskinesia." a limb, which is called "dyskinesia."

40% will develop motor fluctuations within six years 40% will develop motor fluctuations within six years of treatment. of treatment.

Drug TargetsDrug Targets

DA is made from DA is made from the amino acid L-the amino acid L-tyrosine.tyrosine.

DA is inactivated DA is inactivated after release by after release by reuptake.reuptake.

It can be It can be repackaged or repackaged or degraded by MAO-degraded by MAO-A & B and COMT.A & B and COMT.

LevodopaLevodopa Levodopa is rapidly absorbed from the small intestine. Most patients Levodopa is rapidly absorbed from the small intestine. Most patients

experience improvement in symptoms about 30 minutes after a dose, and experience improvement in symptoms about 30 minutes after a dose, and the benefit lasts about 3-5 hours. the benefit lasts about 3-5 hours.

Food (in particular, protein-rich food) delays absorption of levodopa. Food (in particular, protein-rich food) delays absorption of levodopa. Instruct patients to take levodopa 1 hour before meals.Instruct patients to take levodopa 1 hour before meals.

Levodopa is also available in a "controlled-release" (CR or SR) formulation. Levodopa is also available in a "controlled-release" (CR or SR) formulation. Controlled release levodopa provides a longer duration of action by Controlled release levodopa provides a longer duration of action by increasing the time it takes for the gastrointestinal tract to absorb increasing the time it takes for the gastrointestinal tract to absorb levodopa. However, CR only allows 70% of the levodopa to be absorbed by levodopa. However, CR only allows 70% of the levodopa to be absorbed by the gastrointestinal tractthe gastrointestinal tract

Levodopa preparationsLevodopa preparations– Standard release preparationsStandard release preparations

carbidopa/levodopa (Sinemet®): 10/100, 25/100, or 25/250 tabletscarbidopa/levodopa (Sinemet®): 10/100, 25/100, or 25/250 tablets– Extended release preparationsExtended release preparations

levodopa/carbiopa (Sinemet CR®): 25/100 or 50/200 tabletslevodopa/carbiopa (Sinemet CR®): 25/100 or 50/200 tablets

Side effects include nausea, vomiting, dry mouth, dyskinesias, and Side effects include nausea, vomiting, dry mouth, dyskinesias, and dizziness. In some individuals, levodopa may cause confusion, dizziness. In some individuals, levodopa may cause confusion, hallucinations, or psychosis. hallucinations, or psychosis.

Catechol-O-methyl transferase Catechol-O-methyl transferase (COMT) inhibitors(COMT) inhibitors

Like carbidopa, COMT inhibitors prevent the breakdown of Like carbidopa, COMT inhibitors prevent the breakdown of levodopa which prolongs the duration of action of a dose of levodopa which prolongs the duration of action of a dose of levodopa. levodopa.

COMT inhibitors may be prescribed when an individual COMT inhibitors may be prescribed when an individual experiences "wearing off," particularly when dopamine agonists experiences "wearing off," particularly when dopamine agonists (see below) are not tolerated. (see below) are not tolerated.

Entacapone (Comtan®)--available in the United States and many Entacapone (Comtan®)--available in the United States and many other countries.other countries.200 mg tablets usually given with each dose of levodopa.200 mg tablets usually given with each dose of levodopa.

Side effects include diarrhea, vivid dreams, visual hallucinations, Side effects include diarrhea, vivid dreams, visual hallucinations, drowsiness, urine discoloration, and dyskinesias. Fulminant drowsiness, urine discoloration, and dyskinesias. Fulminant hepatic failure has been reported in are patients receiving hepatic failure has been reported in are patients receiving tolcapone (Tasmar®).tolcapone (Tasmar®).

Combined carbidopa, levodopa Combined carbidopa, levodopa and entacaponeand entacapone

This preparation combines all 3 medications in one pill, This preparation combines all 3 medications in one pill, which may be more convenient but may not be as flexible which may be more convenient but may not be as flexible as taking the medications individually.as taking the medications individually.

Doses: Doses: – Stalevo® 50: 50 mg levodopa, 12.5 mg carbidopa, and 200 mg Stalevo® 50: 50 mg levodopa, 12.5 mg carbidopa, and 200 mg

entacaponeentacapone– Stalevo® 100: 100 mg levodopa, 25 mg caridopa and 200 mg Stalevo® 100: 100 mg levodopa, 25 mg caridopa and 200 mg

entacaponeentacapone– Stalevo® 150: 150 mg levodopa, 37.5 mg carbidopa, and 200 Stalevo® 150: 150 mg levodopa, 37.5 mg carbidopa, and 200

mg entacaponemg entacapone

Side effects of this combined preparation are the same as Side effects of this combined preparation are the same as for levodopa and entacapone and include: diarrhea, vivid for levodopa and entacapone and include: diarrhea, vivid dreams, visual hallucinations, drowsiness, urine dreams, visual hallucinations, drowsiness, urine discoloration and dyskinesias.discoloration and dyskinesias.

Dopamine agonistsDopamine agonists

They may be used in place of levodopa or They may be used in place of levodopa or in combination with it. in combination with it.

Cause less motor fluctuations.Cause less motor fluctuations.

More likely to cause a number of side More likely to cause a number of side effects (such as nausea, somnolence, effects (such as nausea, somnolence, sleep attackssleep attacks, postural hypotension, , postural hypotension, hallucinations, neuropsychiatric disorders, hallucinations, neuropsychiatric disorders, and lower extremity edema), and lower extremity edema), particularly particularly in patients over 70 and those with baseline in patients over 70 and those with baseline cognitive deficits. cognitive deficits.

Dopamine agonistsDopamine agonists Bromocriptine and pergolide (Permax ®) are ergot Bromocriptine and pergolide (Permax ®) are ergot

derivatives. derivatives. – May rarely cause retroperitoneal, pulmonary and May rarely cause retroperitoneal, pulmonary and

pericardial fibrosis. pericardial fibrosis. – Many reports of significant cardiac valve dysfunction Many reports of significant cardiac valve dysfunction

requiring replacement due to pergolide. requiring replacement due to pergolide.

Pramipexole (Mirapex ®) and ropinirole (Requip ®) are not Pramipexole (Mirapex ®) and ropinirole (Requip ®) are not ergot compounds. ergot compounds. – Can be used in early Parkinson's disease and reduce the Can be used in early Parkinson's disease and reduce the

severity of symptoms. severity of symptoms. – One side effect is daytime sleepiness and "sleep One side effect is daytime sleepiness and "sleep

attacks." Although this may occur with all of the attacks." Although this may occur with all of the dopamine agonists (and levodopa), it was first dopamine agonists (and levodopa), it was first appreciated in people treated with pramipexole. appreciated in people treated with pramipexole.

Dopamine agonistsDopamine agonists The response to a particular dopamine The response to a particular dopamine

agonist is idiosyncratic. agonist is idiosyncratic.

If one dopamine agonists does not offer If one dopamine agonists does not offer benefit or causes bothersome side effects, benefit or causes bothersome side effects, another agonist may be tried. another agonist may be tried.

Treatment with dopamine agonists often Treatment with dopamine agonists often begins at a very low dose. The dose is begins at a very low dose. The dose is increased at intervals (depending on the increased at intervals (depending on the agent) until benefit occurs. agent) until benefit occurs.

The case for starting treatment with The case for starting treatment with a dopamine agonista dopamine agonist

Less dyskinesias Less dyskinesias – 10%-20% versus 31%-45% during the first 2 to 5 years of 10%-20% versus 31%-45% during the first 2 to 5 years of

treatment.treatment. Less wearing off Less wearing off

– 24% versus 38%. 24% versus 38%.

Dopamine agonists may slow the progression of Parkinson's Dopamine agonists may slow the progression of Parkinson's disease. disease. – During a 4 year study of patients with early PD treated During a 4 year study of patients with early PD treated

with levodopa or pramipexole, those patients treated with with levodopa or pramipexole, those patients treated with pramipexole may experience neuroprotection of pramipexole may experience neuroprotection of dopamine-releasing neurons as demonstrated by SPECT. dopamine-releasing neurons as demonstrated by SPECT.

– Those treated with ropinirole lost less fluorodopa signal than Those treated with ropinirole lost less fluorodopa signal than those treated with levodopa over the course of the study as those treated with levodopa over the course of the study as documented by PET scanning. documented by PET scanning.

Trade off: More frequent side effects (drowsiness, Trade off: More frequent side effects (drowsiness, hallucinations, generalized swelling and leg swelling).hallucinations, generalized swelling and leg swelling).

Other medicationsOther medications

AmantadineAmantadine– Reduces fatigue and tremor and dyskinesias.Reduces fatigue and tremor and dyskinesias.– Amantadine (Symmetrel®) as 100 mg capsules or in liquid form.Amantadine (Symmetrel®) as 100 mg capsules or in liquid form.– Side effects may include difficulty concentrating, confusion, insomnia, Side effects may include difficulty concentrating, confusion, insomnia,

nightmares, agitation, headache, hallucinations, edema and livedo reticularis.nightmares, agitation, headache, hallucinations, edema and livedo reticularis.

Anticholinergic medications Anticholinergic medications – Reduce tremor and/or rigidity.Reduce tremor and/or rigidity.– Benztropine mesylate (Cogentin®): 0.5 mg, 1 mg, 2 mg tablets or Benztropine mesylate (Cogentin®): 0.5 mg, 1 mg, 2 mg tablets or

Trihexyphenidyl (Artane®): 2 mg and 5 mg tablets as well as liquid form.Trihexyphenidyl (Artane®): 2 mg and 5 mg tablets as well as liquid form.– Side effects may include dry mouth, blurred vision, sedation, delirium, Side effects may include dry mouth, blurred vision, sedation, delirium,

hallucination, constipation, and difficulty urinating.hallucination, constipation, and difficulty urinating.

SelegilineSelegiline– MAO-B (monoamine oxidase B) inhibitor prolonging the action of dopamine in the MAO-B (monoamine oxidase B) inhibitor prolonging the action of dopamine in the

brain. It also has a mild antidepressant effect. brain. It also has a mild antidepressant effect. – Eldepryl®: 5 mg capsule. Eldepryl®: 5 mg capsule. – Side effects may include heartburn, nausea, dry mouth, insomnia and dizziness. Side effects may include heartburn, nausea, dry mouth, insomnia and dizziness.

Confusion, nightmares, hallucinations, and headache occur less frequently and Confusion, nightmares, hallucinations, and headache occur less frequently and should be reported to your doctor.should be reported to your doctor.

Rasagiline (Agilect Rasagiline (Agilect ®®))– Soon to be released DA (MAO-B inhibitor) taken once daily in doses of 0.5 or 1 Soon to be released DA (MAO-B inhibitor) taken once daily in doses of 0.5 or 1

mg.mg.

Deep Brain Stimulation Deep Brain Stimulation Unlike lesion procedures, DBS leaves electrodes in place in the Unlike lesion procedures, DBS leaves electrodes in place in the

brain to deliver continuous stimulation. brain to deliver continuous stimulation.

Adjusting the stimulator and medications after electrode Adjusting the stimulator and medications after electrode implantation is a major time commitment on the part of the implantation is a major time commitment on the part of the neurological team and patient. neurological team and patient.

Risks for DBS procedures include surgical risks (hemorrhage, Risks for DBS procedures include surgical risks (hemorrhage, infection) as well as hardware complications. These include leads infection) as well as hardware complications. These include leads breaking, electrode malfunction, stimulator failure and battery breaking, electrode malfunction, stimulator failure and battery failure.failure.

Subthalamic Deep Brain Stimulation (DBS) improves dyskinesias Subthalamic Deep Brain Stimulation (DBS) improves dyskinesias and off time. It allows for a reduction in medication.and off time. It allows for a reduction in medication.

Neuropsychiatric adverse events have been increasingly reported. Neuropsychiatric adverse events have been increasingly reported. – Depression Depression – SuicideSuicide

Deep Brain StimulationDeep Brain Stimulation

Essential TremorEssential Tremor

Typically a postural tremor, but it may be Typically a postural tremor, but it may be accentuated by goal-directed movements accentuated by goal-directed movements and may be present at rest.and may be present at rest.

Flexion-extension movements at the wrist Flexion-extension movements at the wrist or adduction-abduction movements of the or adduction-abduction movements of the fingers or pronation-supination seen.fingers or pronation-supination seen.

Alcohol ameliorates tremor.Alcohol ameliorates tremor. Often there is a family history.Often there is a family history. No features of PD present.No features of PD present. Check thyroid.Check thyroid.

VideosVideos

– ParkinsonismParkinsonism– Tardive dyskinesiaTardive dyskinesia– UPDRSUPDRS

Progressive Supranuclear PalsyProgressive Supranuclear Palsy

ALL OF THESE FEATURESALL OF THESE FEATURES– Onset at age 40 or laterOnset at age 40 or later– Progressive courseProgressive course– BradykinesiaBradykinesia– Impaired vertical gaze (voluntary downgaze <15Impaired vertical gaze (voluntary downgaze <15oo))

PLUS THREE OF THESE FEATURESPLUS THREE OF THESE FEATURES– Frequent falls as an early manifestationFrequent falls as an early manifestation– Prominent axial rigidity Prominent axial rigidity

(neck rigidity > limb rigidity)(neck rigidity > limb rigidity) Neck hyperextendedNeck hyperextended

– Early dysarthriaEarly dysarthria– DysphagiaDysphagia– Lack of tremorLack of tremor

May see frontal lobe dementiaMay see frontal lobe dementia

Multiple Systems AtrophyMultiple Systems Atrophy

Three presentations:Three presentations:– Shy-Drager SyndromeShy-Drager Syndrome

Akinetic, rigid parkinsonism with early and Akinetic, rigid parkinsonism with early and prominent autonomic dysfunction (urinary prominent autonomic dysfunction (urinary incontinence, postural hypotension, upper incontinence, postural hypotension, upper airway obstruction, arrhythmias).airway obstruction, arrhythmias).

– Striatonigral DegenerationStriatonigral DegenerationAkinetic, rigid parkinsonism unresponsive to Akinetic, rigid parkinsonism unresponsive to

L-dopa.L-dopa.

– Olivopontocerebellar AtrophyOlivopontocerebellar AtrophyParkinsonism and cerebellar ataxia.Parkinsonism and cerebellar ataxia.

Corticobasal Ganglionic DegenerationCorticobasal Ganglionic Degeneration

Rigid-bradykinetic parkinsonism with Rigid-bradykinetic parkinsonism with cortical signs:cortical signs:– ApraxiaApraxia– Cortical sensory lossCortical sensory loss– Alien hand phenomenonAlien hand phenomenon

Asymmetric onset, dystonic limb Asymmetric onset, dystonic limb postures, myoclonus, and L-dopa postures, myoclonus, and L-dopa unresponsiveness are featuresunresponsiveness are features

Lewy Body Dementia & Lewy Body Dementia & Alzheimer’s disease with Lewy BodiesAlzheimer’s disease with Lewy Bodies

Pathologically Lewy bodies can be seen Pathologically Lewy bodies can be seen with AD pathology or they can cause a with AD pathology or they can cause a dementia by themselves.dementia by themselves.

LBD = dementia, fluctuating level of LBD = dementia, fluctuating level of awareness, visual hallucinations, awareness, visual hallucinations, parkinsonism, and sensitivity to parkinsonism, and sensitivity to neurolepticsneuroleptics

It is common to see parkinsonism develop It is common to see parkinsonism develop in patients with AD.in patients with AD.

MyoclonusMyoclonus

Sudden, shock-like muscle contractionsSudden, shock-like muscle contractions Random and irregularRandom and irregular Common manifestations:Common manifestations:

– Action myoclonusAction myoclonus Induced by voluntary movementInduced by voluntary movement Seen with metabolic abnormalities, metabolic Seen with metabolic abnormalities, metabolic

encephalopathy, lithium toxicity, CJD…encephalopathy, lithium toxicity, CJD…

– Lance-Adams syndromeLance-Adams syndrome Action myoclonus seen after cerebral anoxiaAction myoclonus seen after cerebral anoxia

– Asterixis Asterixis negative myoclonus (brief lapses of posture) seen in negative myoclonus (brief lapses of posture) seen in

metabolic encephalopathymetabolic encephalopathy