1. Movement Disorders Mary Quiceno, M.D. Neurology

2. Hypokinetic & Hyperkinetic Movement Disorders  Parkinson’s disease  Parkinson’s Plus Syndromes –PSP –MSA –SND –OPCA –CBD –AD w/Lewy bodies –LBD  Tremor  Dystonia  Myoclonus  Chorea  Tics  Akathisia  Stereotypy  RLS

3. Basal Ganglia

4. What is Parkinson's Disease?  Parkinsonism is the name given to a collection of symptoms and signs consisting of: –Tremor –Rigidity –Bradykinesia –Unsteady gait

5. Parkinsonism  Many neurological disorders have features of parkinsonism.  When parkinsonism occurs without any other neurological abnormalities, and there is no recognizable cause of it, the disorder is termed Parkinson's disease –after the English physician who first described it fully in 1817.

6. Evaluation by a neurologist is important for several reasons: All tremors are not Parkinson’s disease. –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 that is known to occur in PD and other causes of tremor have been excluded. Parkinsonism is a symptom of many disorders. –There are a variety of disorders in which parkinsonism occurs without obvious cause, but these disorders usually have additional features that distinguish them from classic PD. Such a distinction is important because the long-term outlook may differ and the treatment options may be different.

7. Parkinsonism  Exclusion criteria for PD –Neuroleptics –Toxin exposure (MPTP, CO, Mn, Methanol) –Encephalitis –Stroke –Head injuries –Early and severe dementia or autonomic dysfunction –Levodopa non-responder

8. Drug-induced Parkinsonism  More common in elderly and women  Symmetric onset of bradykinesia, tremor, and/or rigidity  Onset within a few days to 3 months in 90% of affected patients  Stop drug, try anticholingeric therapy  New and Old Antipsychotics –Risperdal –Haldol  Benzamides –Reglan  Phenothiazines –Compazine –Phenergan  Others causing mainly postural tremors: –Lithium –Depakote –Amiodarone

9. How is Parkinson's Disease Treated?  A number of treatment approaches help patients with Parkinson's disease. –General lifestyle modifications (rest and exercise) –Dietary considerations –Physical therapy and speech therapy –Medications and surgery  Replace the dopamine, increase the lifetime of the dopamine at the synapse, or stimulate the dopamine receptors.

10. Medications for Parkinson's disease  Levodopa (carbidopa/levodopa; Sinemet) –Reduces the symptoms. –Carbidopa prevents peripheral break down of levodopa.  Minimum of 75 mg/d to avoid nausea. –Treatment over a number of years may lead to variability in an individual's response to treatment, called "motor fluctuations." –Another form of motor fluctuation is uncontrolled writhing movement of the body or a limb, which is called "dyskinesia."  40% will develop motor fluctuations within six years of treatment.

11. Drug Targets  DA is made from the amino acid L- tyrosine.  DA is inactivated after release by reuptake.  It can be repackaged or degraded by MAO- A & B and COMT.

12. Levodopa  Levodopa is rapidly absorbed from the small intestine. Most patients experience improvement in symptoms about 30 minutes after a dose, and the benefit lasts about 3-5 hours.  Food (in particular, protein-rich food) delays absorption of levodopa. Instruct patients to take levodopa 1 hour before meals.  Levodopa is also available in a "controlled-release" (CR or SR) formulation. Controlled release levodopa provides a longer duration of action by increasing the time it takes for the gastrointestinal tract to absorb levodopa. However, CR only allows 70% of the levodopa to be absorbed by the gastrointestinal tract  Levodopa preparations –Standard release preparations carbidopa/levodopa (Sinemet®): 10/100, 25/100, or 25/250 tablets –Extended release preparations levodopa/carbiopa (Sinemet CR®): 25/100 or 50/200 tablets  Side effects include nausea, vomiting, dry mouth, dyskinesias, and dizziness. In some individuals, levodopa may cause confusion, hallucinations, or psychosis.

13. Catechol-O-methyl transferase (COMT) inhibitors  Like carbidopa, COMT inhibitors prevent the breakdown of levodopa which prolongs the duration of action of a dose of levodopa.  COMT inhibitors may be prescribed when an individual experiences "wearing off," particularly when dopamine agonists (see below) are not tolerated.  Entacapone (Comtan®)--available in the United States and many other countries. 200 mg tablets usually given with each dose of levodopa.  Side effects include diarrhea, vivid dreams, visual hallucinations, drowsiness, urine discoloration, and dyskinesias. Fulminant hepatic failure has been reported in are patients receiving tolcapone (Tasmar®).

14. Combined carbidopa, levodopa and entacapone  This preparation combines all 3 medications in one pill, which may be more convenient but may not be as flexible as taking the medications individually.  Doses: –Stalevo® 50: 50 mg levodopa, 12.5 mg carbidopa, and 200 mg entacapone –Stalevo® 100: 100 mg levodopa, 25 mg caridopa and 200 mg entacapone –Stalevo® 150: 150 mg levodopa, 37.5 mg carbidopa, and 200 mg entacapone  Side effects of this combined preparation are the same as for levodopa and entacapone and include: diarrhea, vivid dreams, visual hallucinations, drowsiness, urine discoloration and dyskinesias.

15. Dopamine agonists  They may be used in place of levodopa or in combination with it.  Cause less motor fluctuations.  More likely to cause a number of side effects (such as nausea, somnolence, sleep attacks, postural hypotension, hallucinations, neuropsychiatric disorders, and lower extremity edema), particularly in patients over 70 and those with baseline cognitive deficits.

16. Dopamine agonists  Bromocriptine and pergolide (Permax ®) are ergot derivatives. –May rarely cause retroperitoneal, pulmonary and pericardial fibrosis. –Many reports of significant cardiac valve dysfunction requiring replacement due to pergolide.  Pramipexole (Mirapex ®) and ropinirole (Requip ®) are not ergot compounds. –Can be used in early Parkinson's disease and reduce the severity of symptoms. –One side effect is daytime sleepiness and "sleep attacks." Although this may occur with all of the dopamine agonists (and levodopa), it was first appreciated in people treated with pramipexole.

17. Dopamine agonists  The response to a particular dopamine agonist is idiosyncratic.  If one dopamine agonists does not offer benefit or causes bothersome side effects, another agonist may be tried.  Treatment with dopamine agonists often begins at a very low dose. The dose is increased at intervals (depending on the agent) until benefit occurs.

18. The case for starting treatment with a dopamine agonist  Less dyskinesias –10%-20% versus 31%-45% during the first 2 to 5 years of treatment.  Less wearing off –24% versus 38%.  Dopamine agonists may slow the progression of Parkinson's disease. –During a 4 year study of patients with early PD treated with levodopa or pramipexole, those patients treated with pramipexole may experience neuroprotection of dopamine-releasing neurons as demonstrated by SPECT. –Those treated with ropinirole lost less fluorodopa signal than those treated with levodopa over the course of the study as documented by PET scanning.  Trade off: More frequent side effects (drowsiness, hallucinations, generalized swelling and leg swelling).

19. Other medications  Amantadine –Reduces fatigue and tremor and dyskinesias. –Amantadine (Symmetrel®) as 100 mg capsules or in liquid form. –Side effects may include difficulty concentrating, confusion, insomnia, nightmares, agitation, headache, hallucinations, edema and livedo reticularis.  Anticholinergic medications –Reduce tremor and/or rigidity. –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. –Side effects may include dry mouth, blurred vision, sedation, delirium, hallucination, constipation, and difficulty urinating.  Selegiline –MAO-B (monoamine oxidase B) inhibitor prolonging the action of dopamine in the brain. It also has a mild antidepressant effect. –Eldepryl®: 5 mg capsule. –Side effects may include heartburn, nausea, dry mouth, insomnia and dizziness. Confusion, nightmares, hallucinations, and headache occur less frequently and should be reported to your doctor.  Rasagiline (Agilect ® ) –Soon to be released DA (MAO-B inhibitor) taken once daily in doses of 0.5 or 1 mg.

20. Deep Brain Stimulation  Unlike lesion procedures, DBS leaves electrodes in place in the brain to deliver continuous stimulation.  Adjusting the stimulator and medications after electrode implantation is a major time commitment on the part of the neurological team and patient.  Risks for DBS procedures include surgical risks (hemorrhage, infection) as well as hardware complications. These include leads breaking, electrode malfunction, stimulator failure and battery failure.  Subthalamic Deep Brain Stimulation (DBS) improves dyskinesias and off time. It allows for a reduction in medication.  Neuropsychiatric adverse events have been increasingly reported. –Depression –Suicide

21. Deep Brain Stimulation

22. Essential Tremor  Typically a postural tremor, but it may be accentuated by goal-directed movements and may be present at rest.  Flexion-extension movements at the wrist or adduction-abduction movements of the fingers or pronation-supination seen.  Alcohol ameliorates tremor.  Often there is a family history.  No features of PD present.  Check thyroid.

23. Videos –Parkinsonism –Tardive dyskinesia –UPDRS

24. Progressive Supranuclear Palsy  ALL OF THESE FEATURES –Onset at age 40 or later –Progressive course –Bradykinesia –Impaired vertical gaze (voluntary downgaze <15 o )  PLUS THREE OF THESE FEATURES –Frequent falls as an early manifestation –Prominent axial rigidity  (neck rigidity > limb rigidity)  Neck hyperextended –Early dysarthria –Dysphagia –Lack of tremor  May see frontal lobe dementia

25. Multiple Systems Atrophy  Three presentations: –Shy-Drager Syndrome  Akinetic, rigid parkinsonism with early and prominent autonomic dysfunction (urinary incontinence, postural hypotension, upper airway obstruction, arrhythmias). –Striatonigral Degeneration  Akinetic, rigid parkinsonism unresponsive to L-dopa. –Olivopontocerebellar Atrophy  Parkinsonism and cerebellar ataxia.

26. Corticobasal Ganglionic Degeneration  Rigid-bradykinetic parkinsonism with cortical signs: –Apraxia –Cortical sensory loss –Alien hand phenomenon  Asymmetric onset, dystonic limb postures, myoclonus, and L-dopa unresponsiveness are features

27. Lewy Body Dementia & Alzheimer’s disease with Lewy Bodies  Pathologically Lewy bodies can be seen with AD pathology or they can cause a dementia by themselves.  LBD = dementia, fluctuating level of awareness, visual hallucinations, parkinsonism, and sensitivity to neuroleptics  It is common to see parkinsonism develop in patients with AD.

28. Myoclonus  Sudden, shock-like muscle contractions  Random and irregular  Common manifestations: –Action myoclonus  Induced by voluntary movement  Seen with metabolic abnormalities, metabolic encephalopathy, lithium toxicity, CJD… –Lance-Adams syndrome  Action myoclonus seen after cerebral anoxia –Asterixis  negative myoclonus (brief lapses of posture) seen in metabolic encephalopathy