Neurology® Journal

Objective: To document neurologic, oncologic, and serologic associations of patients in whom voltage-gated potassium channel (VGKC) autoantibodies were detected in the course of serologic evaluation for neuronal, glial, and muscle autoantibodies.Methods: Indirect immunofluorescence screening of sera from 130,000 patients performed on a service basis for markers of paraneoplastic neurologic autoimmunity identified 80 patients whose IgG bound to the synapse-rich molecular layer of mouse cerebellar cortex in a pattern consistent with VGKC immunoreactivity. Antibody specificity was confirmed in all cases by immunoprecipitation of detergent-solubilized brain synaptic proteins complexed with 125I-alpha-dendrotoxin.Results: Clinical information was available for 72 patients: 51% women, median age at symptom onset 65 years, and median follow-up period 14 months. Neurologic manifestations were acute to subacute in onset in 71% and multifocal in 46%; 71% had cognitive impairment, 58% seizures, 33% dysautonomia, 29% myoclonus, 26% dyssomnia, 25% peripheral nerve dysfunction, 21% extrapyramidal dysfunction, and 19% brainstem/cranial nerve dysfunction. Creutzfeldt-Jakob disease was a common misdiagnosis (14%). Neoplasms encountered (confirmed histologically in 33%) included 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies. Hyponatremia was documented in 36%, other organ-specific autoantibodies in 49%, and a co-existing autoimmune disorder in 33% (including thyroiditis 21%, type 1 diabetes mellitus 11%). Benefit was reported for 34 of 38 patients (89%) receiving immunotherapy and was marked in 50%.Conclusions: The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized. Evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders.(C)2008AAN Enterprises, Inc.

Objective: This study was undertaken to examine differential functional MRI patterns in those at genetic risk for Alzheimer disease (AD), specifically investigating parietal lobe activation, a brain region with changes noted in the early stages of AD.Methods: This study uses functional MRI to investigate blood oxygenation level dependent changes in the parietal lobe in a high-risk sample of 18 asymptomatic offspring of autopsy-confirmed AD cases, compared to 15 matched controls. The cognitive activation paradigm was a mental rotation task, which requires individuals to rotate three-dimensional cube stimuli to judge their similarity.Results: We found no differences in either reaction time or performance accuracy between groups. However, the at-risk individuals showed increases in activation in the right superior parietal lobule (BA 7), the right insula (BA 13), the right middle frontal gyrus (BA 10), and the right inferior frontal gyrus (BA 47).Conclusions: We present evidence for a compensatory mechanism for those at increased risk for Alzheimer disease (AD). This study examines and confirms parietal changes with increased risk for late-onset AD, despite normal cognitive performance. Added to the previous findings from this group, these results demonstrate the sensitivity of functional imaging measures to brain changes that are not yet reflected in cognitive performance, which may ultimately serve as an important indicator of disease.(C)2008AAN Enterprises, Inc.

The training of clinical neurologists is undergoing profound change. Increasing subspecialization within neurology, the widening separation of clinical neurology from other branches of internal medicine, limitations of exposure to training in internal medicine, mandated restrictions in working hours, and attempts to shorten the training period are likely to have adverse effects on the next generation of clinical neurologists. Despite the need for a broad base in general medicine, discussed here, the exposure of neurology trainees to general medical disorders is diminishing. An emphasis on an algorithmic approach to patient management rather than on educating residents to use their reasoning faculties when applying new techniques and knowledge to clinical practice may adversely affect patient care. Neurologists require broad-based training in neurology, internal medicine, and psychiatry, to ensure excellence in clinical practice. It is time to question again whether they are receiving the training that they need.(C)2008AAN Enterprises, Inc.

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic ([alpha]3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacologic enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function. Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurologic disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. The patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents. Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10-15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.(C)2008AAN Enterprises, Inc.

Background: Physicians often do not have good understanding of research methodology. Unfortunately, the mechanism to achieve this important competency in a busy neurology residency program remains unclear. We tested the value and degree of acceptance by neurology residents of a multimodal educational intervention that consisted of biweekly teaching sessions in place of an existing journal club, as a way to provide formal training in research and statistical techniques.Methods: We used a pre- and post-test design with an educational intervention in between using neurology residents at the University of Iowa as subjects. Each test had 40 questions of research methodology. The educational intervention consisted of a biweekly, structured, topic-centered, research methodology-oriented elective seminar following a year-long predefined curriculum. An exit survey was offered to gather resident's perceptions about the course.Results: While a majority of residents agreed that the intervention enhanced their knowledge of research methodology, only 23% attended more than 40% of the sessions. There was no difference between pretest and post-test scores (p = 0.40).Conclusions: Our experience suggests that, in order to accomplish the Accreditation Council for Graduate Medical Education goals regarding increasing competency of residents in knowledge about research methodology, a major restructuring in the neurology residency curriculum with more intense formal training would be necessary.(C)2008AAN Enterprises, Inc.