PARKINSONS DISEASE BASICS DESCRIPTION An adult-onset neurodegenerative disorder of the extrapyramidal system characterized by a combination of tremor at rest, rigidity

and bradykinesia. The diagnosis requires therapeutic response to levodopa which implies normal striatal neurons. This is the only neurodegenerative disease which is treatable long-term. System(s) affected: Nervous, Musculoskeletal Genetics: May be a genetic role with risk 2.95-fold in patients with positive family history in late onset disease; 7.76-fold increase in early onset disease (<50) Incidence/Prevalence in USA: 50,000 per year; 0.3% 55-64, 1% 65-74, 3.1% 75-84; 4.3% 85-94 Predominant age: Age 60 with 5% between the ages of 21 and 39 Predominant sex: Male > Female (1.4:1) SIGNS & SYMPTOMS Cardinal signs Tremor (4-8 Hz) in repose: Diagnostic, but not required; relieved with activity, concentration, and sleep; increases with stress; 10% of patients present with only tremor, 30% present without; most begin with unilateral tremor. Bradykinesia: required for diagnosis; most disabling symptom; movement initiation difficult, can be overcome with will; causes the gait and postural abnormalities Rigidity: lead pipe type; cog-wheeling with tremor Other associated signs and symptoms Speech is poorly enunciated, low volume, clipped Ocular abnormalities: Decreased blinking, blepharospasm, impaired upward gaze Seborrhea Dysautonomia with constipation, incontinence, sexual dysfunction Depression in 2/3 of patients Dementia in 20% of patients; more common in patients whose disease onset was bilateral - mild to moderate, 90% with Folstein MMSE >15 Gait disturbances including no arm swing, en mass turning, problems getting up from chair, festination, freezing Leaning posture Propulsion or retropulsion Micrographia Mask faces Neglect of swallowing with drooling Excessive daytime sleepiness increases with severity of disease and medication use Hoehn and Yahr scale of disability in Parkinson disease Stage 1 unilateral, minimal functional impairment Stage 2 bilateral without impairment of balance Stage 3 bilateral, positive instability, physically independent Stage 4 severe disability, can walk or stand without assist, but markedly incapacitated Stage 5 wheelchair bound or bedridden unless aided CAUSES Unknown Loss of dopaminergic neurons in the substantia nigra with rate of loss 1% per year in patients with Parkinson versus 0.5% in normal aging. Probably not genetic rather toxic or infectious Known toxins: MPTP, pesticides. Other non-dopaminergic neurons can be affected. RISK FACTORS Unknown in the idiopathic disease Association between smoking and increased caffeine intake and reduced risk for Parkinson disease has been reported

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DIAGNOSIS DIFFERENTIAL DIAGNOSIS Parkinsonism: bradykinesia and occasionally tremor with little or no response to levodopa indicating that the striatal neurons are also degenerated Progressive supranuclear palsy Multisystem atrophy Alzheimer with extrapyramidal features Side effects of neuroleptic medications Infectious - postencephalitic Vascular - lacunar state Toxins Metabolic - Wilson disease: onset <40 Benign essential tremor: positive family history and relief with alcohol LABORATORY N/A Drugs that may alter lab results: N/A Disorders that may alter lab results: N/A PATHOLOGICAL FINDINGS Typical changes that allow precise pathological diagnosis. Lewy bodies. IMAGING CT or MRI help rule out other disorders PET scanning DIAGNOSTIC PROCEDURES Diagnostic criteria: Clinically possible - any one of: Rest tremor Rigidity Bradykinesia Clinically probable - any 2 of: Rest tremor Rigidity Bradykinesia Impaired postural reflexes, or One of first three displaying asymmetry Clinically definite - any 3 of: Rest tremor Rigidity Bradykinesia Impaired postural reflexes, or Any 2 of above with one of first 3 displaying asymmetry TREATMENT APPROPRIATE HEALTH CARE Outpatient GENERAL MEASURES Drugs have therapeutic and toxic effects Acute worsening may indicate depression, non-compliance or supervening illness Course is progressive with or without drugs. Life-long therapy directed toward symptom control - treat disability Investigate for drug-induced cause; if found, discontinue drug. Symptom resolution may take weeks to months. Physical, occupational and speech therapy Physical limitations require adjustments in the home, e.g., special chairs, elevated toilet seat, eating utensils, dressing oneself

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SURGICAL MEASURES Adrenal medullary transplants, fetal midbrain with substantia nigra neurons - unproven Thalamotomy - akinesia Stereotactic pallidotomy - akinesia Deep brain stimulation subthalamic nucleus - dyskinesia, tremor response 88%; may worsen pre-existing psychiatric disorders; less off problems, less on dyskinesias, and 50% reduction of medications ACTIVITY Maintain activity to whatever degree possible; use cane for walking DIET Small frequent meals if difficulty in eating High liquid intake important; high bulk foods Reduced protein diet is unnecessary PATIENT EDUCATION Local support groups United Parkinson Foundation, 360 W. Superior St., Chicago, IL 60610, 312-664-2344 American Parkinson Disease Foundation, 1250 Hyland Blvd., Staten Island, NY 10305, 800-223-2732 MEDICATIONS DRUG(S) OF CHOICE Levodopa-carbidopa (Sinemet): may be initial drug of choice in older patients with more severe symptoms; although neuro-vegetative symptoms such as speech disorders and falls are resistant to levodopa Sinemet SR 50-200 (start with 1/2 tab) qid after food. Increase by 100 mg levodopa per day until desired effect or side effects occur. If early morning symptoms, add Sinemet 25-100 immediate release one half hour before arising. If switching to the SR, increase daily dose by 25% Add agonist if wear off or dyskinesia appears or when 800-1000 mg levodopa SR per day being taken Dopamine agonists. Low potency; long half-life; reduces wearing-off effects of levodopa. Add when levodopa > 500 mg/day. early monotherapy may reduce levodopa use and long-term effects. May be initial drug of choice in younger patients with milder symptoms. May slow progression of the disease vs. L-Dopa. Bromocriptine - start with 1.25 mg qd or bid Pergolide - 0.05 mg/d for 2 days and increase by 0.1 mg/d q 3 days x 12 days. If higher doses needed, then increase by 0.25 mg q 3 days. Mean dose is 3 mg. Pramipexole non-ergoline 0.125 mg tid, max 4.5 mg/day; useful for drug-resistant tremor Ropinirole non-ergoline. 0.25 mg tid, max 24 mg/day Titrate the levodopa-carbidopa combination downward as these agents are added such that 1 mg of bromocriptine equals 10 mg of levodopa and 1 mg of pergolide equals 10 mg of bromocriptine MAO inhibitors. Blocks metabolism of dopamine. May be neuro-protective. Added to levodopa to diminish motor fluctuations. Selegiline 5 mg - start with 1/2 tab qAM and 1/2 q noon; increase to 5 mg bid. If add to levodopa-carbidopa, lower dosage 20%. Anticholinergics. For tremor and rigidity in early stages or as an adjunct (30% improvement in 50% of patients). Not recommended for patients > age 65. Trihexyphenidyl (Artane): 1 mg/day, increase by 2 mg every 3 days until 6-10 mg/day Benztropine (Cogentin): 1-2 mg/day. Start with 0.5 mg/day and increase slowly by 0.5 mg every 6 days. Maximum 6 mg/day. Amantadine, mode of action unknown Similar to anticholinergics; improves bradykinesia and rigidity; rapid onset 48-72h Synergistic with L-dopa; reduces dyskinesia 100-200 mg/day COMT inhibitor

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 Reduces peripheral metabolism of levodopa permitting increase brain concentration Use as adjunct to L-dopa as in dopamine agonists May decrease motor fluctuation in late stage disease and reduce early wearing off of levodopa, requires fewer daily doses of levodopa Tolcapone - 100 mg tid, max 1200 mg/day Entacapone - 100 mg tid, max 1200 mg/day Contraindications: Refer to manufacturers literature Precautions: L-dopa/carbidopa - late effects Time related dosage problems occur in 50% of patients in 4-5 years Dyskinesias probably secondary to receptor hypersensitivity. - Inter dose dyskinesia: occurs at peak level of drug 2 hours after immediate release form, limb choreoathetosis and grimacing; change to sustained release, reduce levodopa dose plus add agonist or clozapine 100-200 mg. - Diphasic dyskinesia: mobile dystonia of limbs occurs as the dose is rising and falling; increase individual dose or subcutaneous apomorphine pulses. - Off period dyskinesia: may begin as early morning dystonia (foot); reduce inter-dose interval or switch to sustained release or agonist Wear-off phenomena: usually occurs 3-4 hours after last dose. Usually first sign of drug-response problems caused by increased severity of nigral degeneration. Use sustained release form with an agonist or selegiline. On/off phenomena: 15-20% of patients develop severe fluctuation of response. Longterm high dose levodopa may be cause. Try low protein diet, slow release preparations, continuous subcutaneous infusions, or enteral infusion into duodenum. Also can decrease dose until on-off phenomena disappears and then restart drug. COMT inhibitors increase on time and reduce off time Hourly liquid preparation - 10 tablets 25-100 plus 2g ascorbic acid crystals in 1L of tap water; 75 mL in AM, then 35-50 mL/hr Freezing: find a visual clue to step over or counting numbers in head Psychiatric side effects: confusion, hallucinations (well-formed visual or auditory) paranoia, nightmares. If mainly at night, reduce last evening dose or try clozapine. Agonists Somnolence (27%), nausea, nightmares, agitation, orthostatic hypertension, hallucinations (17%), edema (14%) Raynaud phenomena in doses > 30 mg/day, edema, hypertension, worsening CHF If stopped abruptly, can result in a syndrome resembling neuroleptic malignant syndrome MAO inhibitor: Anxiety/sleep disturbance Anticholinergics: Confusion, constipation, urinary retention, dry mouth and glaucoma Dopamine release stimulator: Confusion, hallucinations, edema, livedo reticularis, and worsening CHF Significant possible interactions: Most have additive therapeutic and side effects ALTERNATIVE DRUGS Tricyclic antidepressants for night time sedation and associated depression (50% of patients with Parkinson) Antioxidants or vitamin E have shown no definite benefit Selective COMT inhibitors Apomorphine as agonist or for freezing (use limited by adverse effects [vomiting] and need for parenteral administration) Clozapine: 70-200 mg/day can suppress frequency of dyskinesia and increase on time; also useful for hallucinations. Side effects include sedation and sialorrhea, and most serious, agranulocytosis. Use 50 mg or less per day for drug-induced psychosis. Donepezil 5-10 mg/day well tolerated, improved cognitive impairment Modafinil 100-200 mg q AM may improve excessive daytime sleepiness

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FOLLOWUP PATIENT MONITORING Life-long for medication adjustment and physical therapy PREVENTION/AVOIDANCE Avoid drugs known to cause tardive dyskinesia, such as: Fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, promazine, thioridazine, haloperidol, droperidol, benperidol, fl uspirilene, pimozide, trifluperidol, chlorprothixene, clopenthixol, thiothixene POSSIBLE COMPLICATIONS Dementia, depression, aspiration pneumonia, falls, freezing, dyskinesias; also associated with a twofold increase risk of death EXPECTED COURSE/PROGNOSIS More rapid progression: Older at disease onset; dementia Milder disease, the predominant feature is tremor MISCELLANEOUS ASSOCIATED CONDITIONS Psychosis; depression AGE-RELATED FACTORS Pediatric: May occur as secondary parkinsonism in this age group Geriatric: Common among elderly Others: N/A PREGNANCY N/A SYNONYMS Paralysis agitans Shaking palsy OTHER NOTES New approaches in treatment undergoing study ABBREVIATIONS COMT = catechol-O-methyltransferase REFERENCES Poewe WH, Wenning GK. The natural history of Parkinsons disease. Neurology 1996;47(3):s146-s51 Krauss JK, Jankovic J. Surgical treatment of Parkinsons disease. Am Fam Phys 1996;54(5):1621-8 Stacy M. Pharmacotherapy for advanced Parkinsons. Pharmacotherapy 2000;20(1):85-165 Stern M. Parkinsons Disease: Early Diagnosis and Management. J Fam Pract 1993;36:439-46 Koller WC, Calne DB, editors. Strategies for treating complications of levodopa therapy. Neurology 1994;44(Suppl 16) Siderowf A, Stern M. Update on Parkinson disease. Ann Intern Med 2003;138(8):651-8

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