Faculty Bibliography

Primary hyperhidrosis is a neurogenic disorder of unknown cause characterized by excessive sweating in the palmar surface of the hands, armpits, groin and feet. In the course of a therapeutic trial for primary hyperhidrosis, 62 % of patients reported a positive family history. Examination of these pedigrees demonstrated a sibling recurrence risk of lambdas = 29-48 and an offspring recurrence risk of lambdao = 41-68 indicating that hyperhidrosis can be an inherited condition. The pattern of inheritance suggests an autosomal dominant mode of transmission with incomplete disease penetrance

BACKGROUND: In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. METHODS AND RESULTS: We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients CONCLUSIONS: Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system

Autonomic failure with orthostatic and postprandial hypotension, bowel and bladder disturbances, and sexual dysfunction are frequent, disabling features in patients with the three most prevalent neurodegenerative movement disorders: Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA), and the related neurodegenerative Lewy-body disorder characterized by isolated severe autonomic failure (pure autonomic failure, PAF). All of these disorders have in common the presence of alpha-synuclein in the cytoplasmic precipitates found in neurons in Lewy body disorders or glia in MSA. Autonomic failure with disabling orthostatic hypotension is the clinical hallmark of PAF. It may also be the initial presentation of MSA, making diagnosis difficult. Within a few years, however, MSA patients develop movement disorders, which are differentiated from PD by the paucity of unilateral resting tremor, the lack of response to levodopa, and their rapidly progressive nature, resulting in disability and death in 7 to 8 years. Moderately effective treatment is available for autonomic symptoms, but management of movement disorders remains unsuccessful. Discoveries relevant to physiology and common pathological conditions were initially made in patients with autonomic failure. Meals induce profound hypotension in these patients. Conversely, commonly used nasal decongestants can produce substantial pressor effects. Even 500 mL of water can increase blood pressure by a previously unrecognized sympathetic reflex. Residual sympathetic tone is able to induce sustained supine hypertension in MSA, because it is resolved after ganglionic blockade. These phenomena were not previously recognized because of the buffering capacity of the baroreflex, but were unmasked in autonomic failure patients

BACKGROUND: Brain magnetic resonance (MR) imaging offers the potential for objective criteria in the differential diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson disease (PD), since it frequently shows characteristic abnormalities in patients with MSA-P and is believed to be normal in patients with PD. OBJECTIVE: To determine concordance between clinical and MR imaging-based diagnoses of MSA-P and PD. DESIGN: Two neuroradiologists identified and rated striatal and infratentorial abnormalities in 39 brain MR images and assigned a diagnosis of PD, MSA-P, or MSA with additional marked cerebellar ataxia (MSA-C). SETTING: Academic medical center. PATIENTS: Thirty-nine patients with parkinsonism, including 21 with a clinical diagnosis of PD, 14 with MSA-P, and 4 with MSA-C. RESULTS: All patients with MSA and 14 (67%) of 21 patients with PD had some abnormality on brain MR imaging. Brainstem atrophy was seen in patients with MSA-P and MSA-C. Putaminal atrophy was seen only in MSA-P. Putaminal hypointensity and lateral slitlike hyperintensity were seen in both PD and MSA-P but were always mild in PD. Cerebellar abnormalities, seen in all patients with MSA-C and 11 patients with MSA-P, were also identified in 6 patients with PD, albeit always rated as mild. Nonconcordance between clinical and radiological diagnosis occurred in 2 patients with PD, 5 with MSA-P, and 1 with MSA-C. CONCLUSION: Since several features on brain MR imaging are seen only in MSA-P, a simple diagnostic algorithm may improve the MR imaging diagnosis of MSA-P and PD

Neurally mediated syncope is the most frequent cause of syncope in patients without structural heart disease. Its most common trigger is a reduction in venous return to the heart due to excessive venous pooling in the legs. We conducted a double-blind, randomized, crossover trial to investigate the efficacy of midodrine, a selective alpha-1 adrenergic agonist that decreases venous capacitance, in preventing neurally mediated syncope triggered by passive head-up tilt. Twelve patients with history of recurrent neurally mediated syncope, which was reproduced during head-up tilt, were randomized to receive a nonpressor dose of midodrine (5mg) or placebo on day 1 and the opposite on day 3. One hour after drug or placebo administration, patients underwent 60-degree head-up tilt lasting 40 minutes (unless hypotension or bradycardia developed first). In the supine position, midodrine produced no significant change in blood pressure or heart rate. The responses to head-up tilt were significantly different on the midodrine and the placebo day: on the placebo day, 67% (8/12) of the subjects suffered neurally mediated syncope, whereas only 17% (2/12) of the subjects developed neurally mediated syncope on the midodrine day (p < 0.02). These results indicate that midodrine significantly improves orthostatic tolerance during head-up tilt in patients with recurrent neurally mediated syncope

We studied autonomic cardiovascular function in fourteen patients with Wilson's disease. Four had abnormalities on autonomic testing and, of these, three had evidence of severe central nervous system abnormalities. In contrast, of the remaining ten patients with normal cardiovascular reflexes, only two had severe deficits of the central nervous system. We suggest that autonomic impairment in Wilson's disease is due to involvement of central autonomic neurons

BACKGROUND: Syncope is caused by a severe but reversible reduction in blood flow to the brain stem neurons responsible for supporting consciousness (reticular activating system). Neurally mediated syncope, also referred to as vasovagal or reflex syncope, is the most frequent cause of loss of consciousness in apparently normal subjects. REVIEW SUMMARY: Neurally mediated syncope is believed to be a reflex response with afferent, central, and efferent pathways. Characteristic autonomic changes in neurally mediated syncope are an increase in parasympathetic efferent activity causing bradycardia and a reduction in sympathetic vasoconstrictor outflow causing vasodilatation. Premonitory symptoms, such as nausea, diaphoresis, abdominal discomfort, and blurred vision, are caused by autonomic activation and are distinguishing features of neurally mediated syncope. Neurally mediated syncope frequently has a characteristic trigger, although this may not be apparent. Testing orthostatic tolerance during passive head-up tilt is the best available diagnostic procedure to evaluate patients with syncope in whom a cardiac cause has been excluded. In many cases, once the diagnosis of neurally mediated syncope is confirmed, it may suffice to reassure the patient and teach him to avoid known triggers and to recognize and act upon early warning symptoms. Because subjects with neurally mediated syncope may potentially be sodium depleted, increasing salt intake can be beneficial in improving their orthostatic intolerance. CONCLUSIONS: Neurally mediated syncope is the most common form of syncope in healthy adults. The best diagnostic tools are the clinical history and passive head-up tilt. The best treatment strategies are the avoidance of triggering factors as well as intravascular volume expansion

OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient's overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.