C. Michel Harper

Rapsyn Mutations in Humans Cause Endplate Acetylcholine-Receptor Deficiency and Myasthenic Syndrome

Congenital myasthenic syndromes (CMSs) stem from genetic defects in endplate (EP)-specific presynaptic, synaptic, and postsynaptic proteins. The postsynaptic CMSs identified to date stem from a deficiency or kinetic abnormality of the acetylcholine receptor (AChR). All CMSs with a kinetic abnormality of AChR, as well as many CMSs with a deficiency of AChR, have been traced to mutations in AChR-subunit genes. However, in a subset of patients with EP AChR deficiency, the genetic defect has remained elusive. Rapsyn, a 43-kDa postsynaptic protein, plays an essential role in the clustering of AChR at the EP. Seven tetratricopeptide repeats (TPRs) of rapsyn subserve self-association, a coiled-coil domain binds to AChR, and a RING-H2 domain associates with beta-dystroglycan and links rapsyn to the subsynaptic cytoskeleton. Rapsyn self-association precedes recruitment of AChR to rapsyn clusters. In four patients with EP AChR deficiency but with no mutations in AChR subunits, we identify three recessive rapsyn mutations: one patient carries L14P in TPR1 and N88K in TPR3; two are homozygous for N88K; and one carries N88K and 553ins5, which frameshifts in TPR5. EP studies in each case show decreased staining for rapsyn and AChR, as well as impaired postsynaptic morphological development. Expression studies in HEK cells indicate that none of the mutations hinders rapsyn self-association but that all three diminish coclustering of AChR with rapsyn.

Lower extremity neuropathies associated with lithotomy positions

BackgroundThe goal of this project was to study the frequency and natural history of perioperative lower extremity neuropathies. MethodsA prospective evaluation of lower extremity neuropathies in 991 adult patients undergoing general anesthetics and surgical procedures while positioned in lithotomy was performed. Patients were assessed with use of a standard questionnaire and neurologic examination before surgery, daily during hospital stay in the first week after surgery, and by phone if discharged before 1 postoperative week. Patients in whom lower extremity neuropathies developed were observed for 6 months. ResultsLower extremity neuropathies developed in 15 patients (1.5%; 95% confidence interval, 0.8–2.5%). Unilateral or bilateral nerves were affected in patients as follows: obturator (five patients), lateral femoral cutaneous (four patients), sciatic (three patients), and peroneal (three patients). Paresthesia occurred in 14 of 15 patients, and 4 patients had burning or aching pain. No patient had weakness. Symptoms were noted within 4 h of completion of the anesthetic in all 15 patients. These symptoms resolved within 6 months in 14 of 15 patients. Prolonged positioning in a lithotomy position, especially for more than 2 h, was a major risk factor for this complication (P = 0.006). ConclusionsIn this surgical population, lower extremity neuropathies were infrequent complications that were noted very soon after surgery and anesthesia. None resulted in prolonged disability. The longer patients were positioned in lithotomy positions, the greater the chance of development of a neuropathy. These findings suggest that a reduction of duration of time in lithotomy positions may reduce the risk of lower extremity neuropathies.

Treatment of slow-channel congenital myasthenic syndrome with fluoxetine.

The authors found that fluoxetine significantly shortens at 5 μM/L and nearly normalizes at 10 μM/L the prolonged opening bursts of slow-channel congenital myasthenic syndrome (SCCMS) acetylcholine receptors (AChR) expressed in fibroblasts. Prompted by this observation, they treated two SCCMS patients allergic to quinidine with up to 80 to 120 mg of fluoxetine per day over 3 years (serum fluoxetine + norfluoxetine levels 8 to 11 μM/L). Both patients showed marked subjective and objective improvement by quantitative muscle strength testing and electromyography.

Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.

Detailed analysis of phenotypic and molecular genetic aspects of Dok‐7 myasthenia in 16 patients.

The natural history of long thoracic and spinal accessory neuropathies.

A cohort of 106 patients with electrodiagnostically confirmed long thoracic neuropathy (50 patients) or spinal accessory neuropathy (56 patients) seen at the Mayo Clinic over a 22‐year period were retrospectively studied to better understand the natural history of these disorders and to determine the role of electrodiagnostic testing in predicting prognosis. Mean follow‐up was 48 and 50 months, respectively. Good functional recovery was generally observed regardless of the results of electrodiagnostic studies, but improvement in the amplitude of the spinal accessory compound muscle action potential on serial nerve conduction studies tended to predict a good outcome. No electrodiagnostic findings correlated with poor outcome. Traumatic neuropathies generally did worse than neuropathies of other causes. In spinal accessory neuropathies, involvement of the dominant limb, scapular winging, and impaired arm elevation were associated with a poor outcome. Our data suggest that, contrary to other focal neuropathies, the electrodiagnostic findings do not predict functional outcome in these neuropathies.

Urgent Surgical Decompression Compared to Methylprednisolone for the Treatment of Acute Spinal Cord Injury: A Randomized Prospective Study in Beagle Dogs

Study Design. Experimental dog model of acute spinal cord injury. Objective. To compare the relative value of methylprednisolone, surgical decompression, or both for the treatment of traumatic spinal cord injury. Summary of Background Data. Acute spinal cord injury results from both primary damage to the spinal cord at the time of the initial injury as well as a deleterious secondary cascade of events, which leads to further damage. Surgical decompression is known to improve clinical outcomes, but the timing of surgical decompression remains controversial. Methods. A nylon tie was used to constrict the spinal cord in 18 adult male beagle dogs. The animals were then prospectively randomized to 3 groups: 1) surgical decompression at 6 hours and intravenous methylprednisolone; 2) surgical decompression at 6 hours and intravenous saline; and 3) intravenous methylprednisolone without surgical decompression. Each animal was evaluated by somatosensory-evoked potentials, daily neurologic assessment, and histologic examination at 2 weeks following injury. Results. Immediately following spinal cord constriction, all animals were paraplegic, incontinent, and the somatosensory-evoked potentials were abolished. Surgical decompression 6 hours after injury, with or without methylprednisolone, led to significantly better neurologic function at 2 weeks than methylprednisolone alone. Conclusion. In the setting of acute and persistent spinal cord compression in beagle dogs, surgical decompression 6 hours after injury, with or without methylprednisolone, is more effective for improving neurologic recovery than methylprednisolone alone.

Individual attributes versus composite scores of nerve conduction abnormality: Sensitivity, reproducibility, and concordance with impairment

Composite scores may be more sensitive and reproducible than single attributes of nerve conduction for detection of peripheral neuropathy, but this requires validation in large patient cohorts. Also, the concordance of individual attributes versus composite scores with clinical measures of severity has not been tested. Here, we study these issues in prospectively studied cohorts: diabetic patients from Rochester, Minnesota (RDNS; n = 396); chronic inflammatory demyelinating polyneuropathy (CIDP) patients (n = 55); and multifocal motor neuropathy (MMN) patients (n = 18). With specificity fixed at the 97.5 percentile, we found that, in generalized polyneuropathies (diabetic and CIDP), composite scores (especially ones including conduction velocity, distal latencies, and F‐waves) of individual or multiple nerves tended to be more sensitive than individual attributes. By contrast, for multiple mononeuropathies, some individual attributes or composite scores of individual nerves were more sensitive than composite scores. In diabetic polyneuropathy, composite scores tended to be more reproducible than individual attributes of nerve conduction. Highly significant correlations were found between individual attributes or composite scores and neurologic impairment in diabetic polyneuropathy and in CIDP; in general, correlation coefficients were higher for composite scores. These correlations were higher for amplitudes than for conduction velocities or distal latencies. We conclude that, with the availability of microprocessors and normative databases, electromyographers may increasingly seek to express nerve conduction abnormality also as composite scores of individual or several nerves. Muscle Nerve 27: 202–210, 2003

Frequency of seronegativity in adult-acquired generalized myasthenia gravis

We determined the prevalence of muscle acetylcholine receptor (AChR) antibodies in patients with adult‐acquired generalized myasthenia gravis (MG), the seroconversion rate at 12 months, and the prevalence of muscle‐specific tyrosine kinase (MuSK) antibody among persistently seronegative patients. We identified 562 consecutive Mayo Clinic patients with MG based on clinical and electrophysiological criteria. At presentation, 508 patients (90.4%) tested positive for AChR binding or AChR modulating antibodies. After 12 months, 15.2% of initially seronegative patients had become seropositive, yielding a seronegativity rate of 8.2% (95% confidence interval: 6.2–9.6%). Among seronegative patients not receiving immunosuppressants, 38% were MuSK antibody‐positive and 43% were seropositive for nonmuscle autoantibodies. Classification as seronegative MG should be reserved for nonimmunosuppressed patients with generalized MG who lack muscle AChR binding, AChR modulating, or MuSK antibodies at presentation and at follow‐up of at least 12 months. Muscle Nerve, 2007

Myasthenia, thymoma, presynaptic antibodies, and a continuum of neuromuscular hyperexcitability

To the Editor: We read with interest the case report by R. Staudinger and K. Henry1 describing the clinical improvement in a patient with AIDS-associated myelopathy after the use of highly active antiretroviral combination therapy. This is the first reported case of improvement of myelopathy with antiretroviral agents, and it may have important implications in the understanding of the pathogenesis and treatment of this rare but disabling complication of HIV infection. However, a number of considerations must be made before accepting the conclusions that the improvement resulted from antiretroviral treatment. First, we think that the authors should have quantified the evaluation of spinal cord function in order to strengthen their conclusions. Objective measurement of spinal cord function, such as central conduction time (CCT) of the somatosensory evoked potentials (SEPs), can be used to monitor the clinical progression of the disease.2 Neurophysiologic tests would have supported the clinical diagnosis at baseline and repeat SEPs could have helped determine whether the observed clinical improvement was accompanied by improved conduction of electrical impulses through the spinal cord. We have recently encountered a similar patient with AIDS-associated myelopathy whose symptoms improved greatly after the introduction of highly active antiretroviral combination therapy. However, despite a subjective improvement of strength a few weeks after starting therapy, he had slight worsening of CCT when SEPs were repeated. It is therefore possible that the clinical improvement observed after starting antiretroviral medications was related to the overall improvement of the patient’s general health that accompanied the dramatic increase in CD4 cell count and suppression of plasma viral load. The authors also argue that the dramatic reduction of the viral load may explain the clinical improvement, yet they do not report CSF viral load before and after starting combination antiretroviral therapy. Although the relationship between plasma and CSF viral load is not completely understood, there is a known relationship between AIDS-dementia and elevated CSF viral burden, and in individual patients there may be no association between plasma and CSF viral loads.3 Finally, although the antiretroviral regimens most effective in treating HIV-related CNS disorders have not yet been established, the regimen used in this patient included only one drug (stavudine) with favorable CSF penetration.4-6 We believe that objective measures of spinal cord function and measurement of CSF viral load should have been used to support the hypothesis that the clinical improvement was related to viral load suppression rather than the consequence of general health improvement.

Ultrasound‐guided needle EMG of the diaphragm: Technique description and case report

We describe an ultrasound (US)‐guided technique for needle examination of the diaphragm and report a case in which the adjuvant use of diagnostic US in conjunction with electrophysiologic studies provided additional information regarding the motion of the diaphragm in a patient who was a potential candidate for phrenic nerve pacing. US imaging provides excellent direct and real‐time visualization of soft tissue, anatomic landmarks, fascial planes, and neurovascular structures. It thereby enhances safety by avoiding accidental needle puncture of vital organs, and it also increases the diagnostic utility of the needle examination. Muscle Nerve 38: 1623–1626, 2008