Norepinephrine precursor therapy in neurogenic orthostatic hypotension.

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.

Brain magnetic resonance imaging in multiple-system atrophy and Parkinson disease: a diagnostic algorithm.

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.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with multiple sclerosis.

OBJECTIVE: To describe temporal profile of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with definite, relapsing multiple sclerosis (MS). BACKGROUND: Peripheral demyelinating neuropathy has been rarely reported in association with central nervous system demyelinating disorder indistinguishable from MS. METHODS: In addition to usual diagnostic studies for CIDP and MS in all 5 patients, we studied proximal segments of nerves using deep tendon reflex latency measurements of biceps reflex, patellar reflex, and ankle reflex. RESULTS: All patients with MS subsequently (4-22 years) developed definite CIDP. Two of these patients developed multiple cranial nerve and spinal root enhancement on subsequent imaging without new intraparenchymal enhancement after a diagnosis of CIDP. The deep tendon reflex latencies were prolonged at more than 2 sites in all patients. Cerebral spinal fluid protein increased (70 +/- 19 to 144.8 +/- 17.4 mg/dL, P = 0.0001) at time of diagnosis of CIDP. Clinical improvement was observed in all patients after intravenous immunoglobulin therapy. CONCLUSIONS: When patients with MS develop CIDP, manifestations of central and peripheral disease involvement seem to respond to intravenous immunoglobulin. These cases suggest that there may be common antigenic targets in central and peripheral nervous system in this subset of patients.

Diagnostic role of deep tendon reflex latency measurement in small-fiber neuropathy.

Small-fiber neuropathy (SFN) is diagnosed on the basis of clinical features and specialized tests of small-fiber function because standard nerve conduction studies are normal. Thus, the objective of this study was to determine the value of deep tendon reflex (DTR) latency measurement in the diagnosis of SFN in patients with preserved DTR on clinical examination. We prospectively examined electromyographic reflexes from the biceps brachii [biceps brachii reflex (BR)], patellar [patellar reflex (PR)], and ankle [ankle reflex (AR)] using a manually operated electronic reflex hammer attached to electromyography machine and recorded by means of surface electrodes in 18 patients with SFN and 38 controls. Intra- and inter-evaluator reliability was good (intraclass correlation coefficient: 0.80-0.91, p < 0.01). In controls, the latencies at all sites were correlated to the height (R= 0.6, p < 0.01). Compared with controls, in patients with SFN, the mean latency in milliseconds was prolonged at all sites (BR: 12.8 +/- 1.6 vs. 8.9 +/- 1.9, p < 0.01; PR: 23.0 +/- 5.8 vs. 17.4 +/- 2.4, p < 0.01; and AR: 34.5 +/- 4.8 vs. 30.0 +/- 2.4, p < 0.01). The sensitivity [61.1% (95% CI: 51-94.9)] and specificity [92% (95% CI: 73-97.3)] of BR latency were roughly equal to those of PR and AR. We conclude that DTR latencies were significantly abnormal in the majority of the patients with SFN, suggestive of subclinical involvement of large myelinated fibers. DTR latency measurement is a reproducible, valuable, sensitive tool in the evaluation of mild subclinical involvement of large fibers.

Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study.

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.

Primary hyperhidrosis--evidence for autosomal dominant inheritance.

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.