A significant drop in systolic blood pressure when moving from sitting or lying to the standing position is undoubtedly one of the most important symptoms of autonomic failure seen in PD. Orthostatism can be either symptomatic, in which patients complain of lightheadedness, dizziness or actual syncope, or asymptomatic in spite of significant drops in systolic blood pressure. When symptomatic, orthostatic hypotension can lead to significant disability including wheelchair or even bed confinement.
Estimates of the frequency of orthostatic hypotension vary. A community-based study conducted in U.K. found that 47% of a group of 89 patients enrolled had orthostatic hypotension, as defined by a drop of 20 mmHg when standing from a supine position or to a systolic pressure of less than 90 mmHg (19). They did not find an association between PD severity and the presence of orthostatic hypotension. In a study of early, untreated PD 14% of 51 patients met similar criteria for orthostatic hypotension (20). The strength of this study is that all patients were followed for at least seven years, and 9 of 60 patients were excluded from the analysis due to the development of other symptoms making the diagnosis of idiopathic PD insecure. Additionally, because all patients were evaluated before they began antiparkinson-ian medications, the confounding effect of drugs was not a factor in this study. This is an important consideration, as dopaminergic therapy is believed to aggravate orthostatism in patients with parkinsonism and autonomic failure. On the other hand, a comparative study of orthostatic blood pressure measurements in PD patients in both "off" and "on" states did not show a significant difference, indicating that blood pressure dysregulation is due mostly to neuropathologic changes rather than to the effect of dopaminergic drugs (21).
The underlying mechanism of orthostatic hypotension in PD and MSA has been studied. Goldstein et al. (22) noted that since patients with PD and orthostatic hypotension have cardiac sympathetic denervation (as shown consistently in studies of MIBG uptake) while MSA patients do not, the mechanism producing ortho-static hypotension must be different. They measured venous catecholamines and metanephrines, finding low levels of normetanephrine and dihydroxyphenylglycol in patients with PD and orthostatic hypotension, whereas in patients with MSA and orthostatic hypotension, normal levels were found. They concluded that in MSA, there is dysregulation but not loss of catecholamine secreting cells in the adrenal medulla and sympathetic nervous system, whereas in PD, there is loss of sympathetic nervous system cells with relative sparing of the adrenal medullary system.
Pathologically, studies have shown cell loss in the intermediolateral nucleus of the spinal cord in PD with Lewy bodies being found in the hypothalamus, sympathetic ganglia, sacral parasympathetic nuclei, and the GI tract. This widespread distribution of cell loss in structures important for autonomic function indicated that the dysau-tonomia seen in PD is due to both central and peripheral autonomic nervous system involvement (23,24).
In addition to the hypotension seen in PD patients when in the upright position, the autonomic dysfunction in PD leads often to supine hypertension at night. Plaschke et al. (25) performed 24-hour ambulatory blood pressure monitoring in PD patients with and without dysautonomia. They found that nocturnal mean arterial pressure was significantly higher in PD patients with dysautonomia (and in MSA patients) than in PD patients without autonomic symptoms. They suggested that supine hypertension may increase the risk of stroke in such patients.
Management of orthostatism begins with simple physical measures and progresses to drug therapy when severe. All patients with symptomatic orthostatic hypotension should be advised to raise the head of their bed by about 30 degrees. This maneuver activates the renin-angiotensin system and reduces salt excretion by the kidneys, thus increasing blood pressure. Patients should also consider liberalizing dietary salt, preferably by salting their food rather than by taking salt tablets, which may pass unabsorbed through the GI tract. Support hose are often recommended as well, but compliance with this measure is often poor, especially in men. When orthostatic hypotension is mild, these physical measures may be sufficient. For more severe orthostatic hypotension, fludrocortisone acetate is typically recommended at a dose of 0.1 to 0.2 mg daily. This drug promotes salt retention by the kidney, which in turn increases plasma volume and systemic blood pressure. Patients frequently develop mild ankle edema, which is evidence that this therapy is actually working. All patients taking fludrocortisone should receive periodic testing for serum potassium, as this ion is excreted from the kidney as sodium is retained. Potassium replacement therapy should be initiated if the levels fall outside the normal range.
For those in whom physical measures and fludrocortisone are insufficient to eliminate symptomatic orthostatic hypotension, pressor agents should be considered. Examples of drugs in this class with efficacy in orthostatic hypotension include ergotamine/caffeine (26), ephedrine (27), and indomethacin (28). Midodrine hydrochloride, approved for orthostatic hypotension in 1996, has been specifically studied as a treatment for symptomatic neurogenic orthostatic hypotension in PD (29). This drug has been shown to exhibit a dose-related increase in mean systolic blood pressure with the effect peaking at 1 hour (30). Due to its short half-life, the drug may need to be given three times daily during the waking day at doses ranging from 2.5 to 10 mg per administration. Care should be given not to give the drug late in the day, since supine hypertension may result after the patient retires for the night. Some PD patients with milder degrees of autonomic failure may develop orthostatic hypotension only after meals, so-called postprandial hypotension. This is believed to be related to a shunting of blood flow to the myenteric region with resulting diminished blood flow to the brain. In this case, midodrine could be administered right before a large meal to counteract this effect. Some patients find that several cups of coffee (containing caffeine) taken before or with meals may also help with postprandial orthostatic hypotension.
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