In 1960, Shy and Drager first described the combination of progressive autonomic failure and multiple system atrophy that manifested as orthostatic hypotension, akinesia, and rigidity that led to incapacity in a few years (see Chapt.e.r,,.34.). In the ensuing years, conditions including striatonigral degeneration and forms of olivoponto-cerebellar atrophy have been combined with Shy-Drager syndrome under the larger category of degenerative processes called multiple system atrophy. This discussion focuses on the phenotype with prominent dysautonomia that was described by Shy and Drager.
Shy-Drager syndrome affects men more often than women, most often in middle age or later. A Japanese series calculated the prevalence to be 0.3 per 100,000. y There have been reports of families with autosomal dominant inheritance. A genetic basis was postulated in 1983 when an association was found between HLA antigen Aw32 and autonomic failure.y Thus far, no gene has been identified.
There is degeneration of both pigmented catecholamine-containing cells in the brain stem and cholinergic cells in the intermediolateral columns, along with distal ganglionic and postganglionic degeneration. The abnormality in sympathetic function leads to depressed circulating norepinephrine responses to standing and exertion. There is enhanced blood pressure response to norepinephrine administration, along with evidence of increased and beta receptor concentrations, which correlates to supersensitivity to norepinephrine. Basal norepinephrine levels are normal. Generally, catecholamine is depleted in sympathetic nerve endings around blood vessels. y
Often in the male, the first symptom is impotence and loss of libido, with disturbance in micturition being common in both sexes. The characteristic orthostatic hypotension may be seen either as so-called drop attacks or as a gradual loss of consciousness over about a minute that is often associated with a neckache that radiates to the occiput and shoulders. Generally, there is at least partial loss of thermoregulatory sweating. Respiratory disturbance occurs as involuntary gasping, cluster breathing, and laryngeal stridor that may lead to obstructive sleep apnea and even death, or to central sleep apnea.
On neurological examination, abnormalities of the pupil, including Horner's syndrome, alternating anisocoria, and abnormal responses to drugs may be seen. Mild parkinsonian features or cerebellar ataxia may accompany the condition, but dysautonomia is the predominant dysfunction. In the striatonigral degeneration variant, or multiple system atrophy, rigidity with little tremor, progressive loss of facial expression, limb akinesias, anterocollis, and gait instability predominate (see Chapter.,34 ). There is difficulty walking, standing, turning, and feeding oneself, and the speech is faint and slurred. With pyramidal lesions, there may be an increase in tone, along with impaired rapid hand and foot movements and exaggerated deep tendon reflexes and bilateral extensor responses. Primitive reflexes may be present, and amyotrophy is common. Dementia is not seen more often than would be expected by chance owing to the age of this population. When the olivopontocerebellar variant is present, ataxia and limb tremor develops. y
Differential Diagnosis. Pure autonomic failure (Bradbury-Eggleston syndrome) may present with the same autonomic disturbance as Shy-Drager syndrome, but it does not have any other neurological symptoms. Amyloidosis may also look similar but generally is associated with a greater degree of bowel involvement (see Cha.pter,21. ). Familial dysautonomia (Riley-Day syndrome, or HSAN III) presents in children and therefore is distinguishable from Shy-Drager syndrome.
Management. Several general actions may help the patient avoid aggravation of orthostatic hypotension: maintenance of adequate blood volume with fluid intake of 2 to 2.5 L/day, sleeping in a semirecumbent position, and rising slowly to standing. In addition, patients should avoid excessive warmth (in bathing and climate); do moderate rather than vigorous exercise; eat small, frequent meals; and avoid vasodilators, such as alcohol and nitroglycerin. Mechanical support may be provided by Jobst's stockings in combination with abdominal binding. Severe orthostatic hypotension has been successfully managed with an air force anti-gravity suite. y The most common pharmacological agent used is fludrocortisone, which increases blood volume and maintains venous return to the heart. Second-line drugs are the vasoconstrictors, such as phenylephrine and ephedrine, with the prostaglandin inhibitors being the next choice, followed by beta-1 agonists. Early tracheostomy for laryngeal stridor may prevent premature death.
A recent Japanese study concluded that 90 percent of patients are alive 3 years after their first symptoms and 54 percent are alive after 6 years. Earlier onset of more extensive autonomic disturbance was associated with a poorer prognosis. y
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