Nejm 2005;353:1021

Cause:Idiopathic, vascular, or postencephalitis lethargica (1918 flu); some genetic component, rare autosomal dom (Jama 1999;281:341)

Pathophys:Relative dopamine deficiency in basal ganglia with concomitant increased inhibitory GABA activity w Lewy bodies of -synuclein throughout brain when demented; increased risk in patients with idiopathic REM sleep behavior disorder (RBD) (Neurol 2009;72:1296)

M/F = 1.5. Present in high % of US elderly: 15% by age 65-75 yr, 30% by 75-85 yr, 50% over 85 yr (Nejm 1996;334:71). Early onset type assoc w genetic mutations (Nejm 2000;342:1560) causing -synuclein deposition.

Increased incidence in Guam of a variant with more dementia, where is associated with ALS (O. Sacks, Island of the Color Blind, A. Knopf, 1996; Nejm 1970;282:947)

Decr incidence in coffee and other caffeine users (Jama 2000;283:2674), and smoking (1/2 risk)

Incr w pesticides and welding; sx of stiffness, tremor, and imbalance often precede clinical dx (Arch Neurol 2006;63:362); Vit D: 70% have insufficiency and 26% deficient at time of dx (Arch Neurol 2011;68:314)

Sx: (Jama 2003;289:347) Resting tremor, akinesia, drooling, characteristic stooping posture, rigidity

Si:

4 major sx; dx if at least 2 present:

• Tremor, 3-4/sec, "pill rolling" at rest; asymmetric onset
• Bradykinesia, with masked facies; a paucity of movement; slow finger tapping; however, can still respond to true danger easily
• Rigidity, cogwheeling muscle type
• Gait disturbance: forward falling, shuffling; diminished arm swing, prolonged turning

Also seborrhea; low-volume voice, micrographia, failure to extinguish blinking w glabellar tapping

Progressive; risk of death (Nejm 1996;334:71) 2× that of pts w/o, worse if gait disturbance

Anxiety/depression; inanition; upper airway obstruction due to tremor and stiffness of upper airway muscles (Nejm 1984;311:438); postural hypotension (Dysautonomias) from autonomic insufficiency (Ann IM 2000;133:338); drowsiness and “sleep attacks” (Jama 2002;287:455, 509); constipation; progressive hallucinations (Arch Neuro 2006;63:713)

Cognitive impairments: 40% prevalence stage 1, 65% stage 2, 75% stage 3, 85% stage 4 or by 8 yr, higher w incr age. Dementia incidence 4%/yr, usually many years into course, never in less than 1 yr of onset. If seen, then dx is primary Lewy body dementia

r/o (Bmj 1995;310:447) parkinsonism induced by phenothiazines, metoclopramide (Reglan) (Jama 1995;274:1780), Wilson's disease, reserpine (Nejm 1976;295:816), manganese toxicity (Nejm 1970;282:5), carbon monoxide toxicity, drug impurity in heroin addicts (Nejm 1985;312:1418)

r/o "parkinsonism plus" syndromes like: Lewy body dementia (Alzheimer's Dementia (Dementia, Alzheimer's Type) (DAT); normal pressure hydrocephalus (Normal Pressure Hydrocephalus); PROGRESSIVE SUPRANUCLEAR PALSY, a “tauopathy” w paresis of downward or upward gaze, bradykinesia, frontal lobe si’s, prominent falls in year 1, and L-dopa no help; and multisystem atrophy subtypes (OLIVOPONTINE CEREBELLAR ATROPHY, STRIATONIGRAL DEGENERATION, SHY-DRAGER SYNDROME, and CORTICAL BASAL GANGLIONIC DEGENERATION tauopathy) (Ann Neurol 2003;54S5:15; Nejm 1993;324:1560) w focal apraxia, alien limb, myoclonus, dystonia

Lab:

Path:Substantia nigra and locus coeruleus have lost melanin-containing neurons; remaining neurons have lacy bodies with eosinophilic inclusion bodies in cytoplasm

Rx:

(Ann IM 2003;138:651; Med Let 1993;35:31; Nejm 1993;329:1021)

Avoid metoclopramide (Reglan), a CNS dopa antagonist

to slow progression:

• Dopamine agonists (see below)
• Exercise programs?
• Coenzyme Q-10 600 mg po qd (Arch Neurol 2002;59:1541); cost >$2000/yr; multivitamins and vitamin E 400-800 U po qd

of major sx:

• 1st, esp if over age 70 yr or demented; 80% end up on:
• L-dopa (Nejm 2008;359:2468) with carbidopa, a decarboxylase inhibitor, = Sinemet 25/100 or 250 (not 10/100), or as Parcopa, a more expensive immediate-release formulation (Med Let 2005;47:12); w up to 100 mg carbidopa qd and as little L-dopa as can get away with (2-8 gm qd); Sinemet CR 50/200 mg sustained release may be preferable and save money, but it takes 30% more than other forms since less bioavailable, start 1/2 po bid fasting, may need plain Sinemet to jump-start in morning (Med Let 1991;33:92); adverse effects (drug holidays no help); $40/mo:
• Postural hypotension, due to diuretic effect, nausea, and vomiting
• Mental changes, esp hallucinations in older patients (Neurology 1983;33:1518)
• On–off phenomena, most commonly in patients age <60 yr; including wearing off too soon, and start hesitation, esp after 5 yr of use; rx w apomorphine (Apokyn) (Med Let 2005;47:7) 2-10 mg sc up to qid, a dopamine agonist esp good for "off"; $3/mg
• Dyskinesias, dystonias, and athetosis always within 5 yr (rx with lowering dose and adding bromocryptine, antihistamine, amantadine, or baclofen); the major reason for waiting to add L-dopa (Nejm 2000;342:1484); the therapeutic window gets narrower over time
• Peripheral adrenergic effects that lead to loss of weight and appetite (use the higher doses of carbidopa to prevent, and pretreat 2-3 d before start L-dopa)
• Overall, decreased effectiveness after 5 yr
• 2nd (1st if under 70 yr), dopamine agonists (Med Let 2001;43:59), which delay onset of motor sx and are neuroprotective. No effect of food in absorption; all can cause edema, sedation, hallucinations, nausea, dyskinesias, and all these worse w incr age; unclear if their fewer side effects but lesser motor improvements than L-dopa make them preferable (Jama 2000;284:1971):
• Ropinirole (Requip) 3-5 mg po tid, slowly incr dose; hepatic metabolism; adv effecs: nausea, syncope, drowsiness, headache; incr levels w cipro, decr w antipsychotics and metoclopramide
• Pramipexole (Mirapex) (Jama 2000;284:1931) 0.125-1.5 mg po tid; renal clearance; adv effects: sudden sleep attacks, hallucinations, nausea, incr levels w cimetidine; >$170/mo
• Bromocriptine (Parlodel) 5-10 mg po tid alone or with L-dopa, or if L-dopa fails; not as good as other dopamine agonists; adverse effects: orthostatic BP changes, sweating, mental status changes; >$240/mo
• Rotigotine (Neupro) pd, transdermal may eventually prove useful (Med Let 2007;49:69)

Ancillary meds:

• Amphetamines like dexedrine 5 mg po bid-tid help akinesia and psych depression
• Anticholinergics (inhibit the dopamine-uninhibited acetylcholine neurons) (ACP J Club 2004;140:15), like antihistamines, eg, diphenhydramine (Benadryl) 50 mg tid po, or benztropine (Cogentin), or trihexyphenidyl (Artane) (Nejm 1971;284:413), help tremors; lots of side effects
• Amantadine 100 mg po bid, effect diminishes in 6 mo, helps 64% (Jama 1972;222:792), helps rigidity and bradykinesia, used late in the disease for L-dopa dyskinesias too
• Apomorphine for "off" periods, injectable, expensive, slow onset, prolongs QT

MAO-B inhibitors (Med Let 2006;48:97): weak effect often not worth cost and side effects; adverse effects: may incr mortality (Bmj 1995;311:1602; ACP J Club 1996;124:57); interactions with meperidine (Demerol) (Can J Psych 1990;35:571), causing sedation and/or hallucinations, and w tricyclics and SSRI antidepressants, causing severe agitation; insomnia; depression

• Selegiline (Zelapar, Eldepryl) 1.25-5 mg po bid; $107/mo
• Rasagiline (Azilect) (Arch Neurol 2004;61:561) 0.5 mg po qd; $240/mo

COMT (catechol-O methyltransferase) INHIBITORS, block DOPA breakdown in brain

• Tolcapone (Tasmar) (Med Let 1998;40:60) 100-200 mg po tid; works as an L-dopa booster; helps w early "wearing-off" phenomenon; use when other drugs fail; adv effects: signif hepatotoxicity, pulled off Canadian mkt; $162/mo for 100 mg tid
• Entacapone (Comtan) (Med Let 2004;46:39) 200 mg po w each 50, 100, or 150 L-dopa dose, esp for "wearing off"; less hepatotoxicity; $180/mo

Of depression: TCA (nortriptyline) more effective than SSRI (paroxitine CR) (Neurol 2009;72:886)

Rehab: strength training and front-wheeled walker

Surgical (Nejm 2010;362:2077):

• Pallidotomy? (Nejm 2000;342:1708; 1997;337:1036, 1996;334:114) for bradykinesia and tremor, or
• Subthalamic nucleus electrical stimulation (Jama 2009;301:63; Nejm 2000;342:461) temporarily inhibits basal ganglion function; for severe tremor unresponsive to meds; adv effects: depression, hypomania; or
• Fetal dopa-producing brain cell implants to caudate nucleus or putamen perhaps (Nejm 2001;344:710; 1995;332:1118), but "on" dyskinesias made much worse

of dementia: rivastigmine (Exelon), esp patch to minimize N⁺V, and other cholinesterase inhibitors that effect a modest improvement but cause N, V, and tremor (Nejm 2004;351:2509)

of depression: SSRIs, nortriptyline, CBT