Autonomic Dysfunction

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Most studies of autonomic dysfunction in atypical parkinsonian disorders focus on MSA, where this feature is far more common than in CBD, PSP, or DLB. Neuropathological studies reveal neuronal loss in central adrenergic pathways, especially catecholaminergic neuron depletion in the rostral ventrolateral medulla, but not in the sympathetic ganglia (67,68). Asymptomatic orthostatic hypotension generally does not require treatment in MSA, since autoregulation seems preserved down to a systolic blood pressure of 60 mmHg, a value well below the 80 mmHg at which autoregulation fails in normal subjects (69).

For symptomatic orthostatic hypotension, fludrocortisone, acting through expanding plasma volume and reducing natriuresis, and midodrine, an a-1 adrenoreceptor agonist, generally appear to be the treatments of choice. A large, randomized, controlled trial showed that midodrine reduced ortho-static hypotension by increasing peripheral resistance (70). Midodrine can be initiated at 2.5 mg three times a day, increased up to 10 mg three times a day, if needed, whereas fludrocortisone, which has never been studied formally, is usually started at .1 mg daily, and increased to a maximum of four tablets per day in two or three divided doses (62). A placebo-controlled trial in 35 patients comparing the pressor effects of phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg) on seated systolic blood pressure showed a significant pressor response with phenylpropanolamine, yohimbine, and indomethacin; comparison of phenylpropanolamine (12.5 mg) and midodrine (5mg) in a subgroup of patients elicited similar effects (71).

In an uncontrolled, dose-ranging study of L-threo-dihydroxyphenylserine, 100, 200, and 300 mg twice daily were well tolerated, and the 300-mg dose seemed to offer the most effective control of symptomatic orthostatic hypotension (72). Similar results were observed when 60° head-up-tilt was performed after the daily oral administration of 300 mg L-threo-dihydroxyphenylserine for 2 wk (73). A small, open evaluation of chronic subcutaneous octreotide at 100 |g three times a day also suggested functional improvement (74). Furthermore, isolated cases include treatment with vasopressin in refractory hypotension (75) and erythropoietin in those with anemia (76).

Urinary problems also commonly afflict those with atypical parkinsonian syndromes. a1-adrener-gic receptors are present in the proximal urethra where impaired relaxation may be responsible for difficulty voiding and increased residual urine. An uncontrolled study showed that a1-adrenergic antagonists, prazosin (nonselective) and moxisylyte (selective), reduced residual urine volume, although side effects related to orthostatic hypotension were common in those with postural hypotension of more than -30 mmHg (77). An open study suggested that desmopressin at night may reverse nocturia (78). For incontinence, peripherally acting anticholinergics, such as tolterodine, oxybutynin, and propiverene, are used, albeit at the expense of causing retention (79). Although no formal studies have been done on these drugs, recommended doses are tolterodine 2-4 mg at bedtime or twice daily, oxybutinin 5-10 mg at bedtime, or propantheline 15-30 mg at bedtime if the pathophysiology involves detrusor hypereflexia (62).

Other common autonomic disturbances include erectile dysfunction and constipation. A randomized controlled study showed that sildenafil citrate (50 mg) is efficacious in the treatment of impotence, but may unmask or exacerbate preexisting hypotension (80); measurement of orthostastic blood pressure is thus recommended prior to the administration of this drug. General recommendations for constipation are a high-fiber diet, and over-the-counter laxatives or lactulose. In an open evaluation, macrogol 3350 was found to diminish constipation (81). Open-label studies have also suggested that subcutaneous bethanechol chloride, a muscarinic receptor agonist, improves tearing, salivation, sweating, gastrointestinal, and bladder functions (82), whereas sublingual atropine benefits sialorrhea, although with such side effects as delirium and hallucinations (83). Anticholinergics also risk exacerbating confusion and constipation as well as preexisting prostatism and glaucoma.

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