Glenn Lopate

Myopathy with antibodies to the signal recognition particle: clinical and pathological features

Objectives: To study myopathies with serum antibodies to the signal recognition particle (SRP), an unusual, myositis specific antibody associated syndrome that has not been well characterised pathologically. Methods: Clinical, laboratory, and myopathological features were evaluated in seven consecutive patients with a myopathy and serum anti-SRP antibodies, identified over three years. The anti-SRP myopathy was compared with myopathology in other types of inflammatory and immune myopathies. Results: The patients with anti-SRP antibodies developed weakness at ages ranging from 32 to 70 years. Onset was seasonal (August to January). Weakness became severe and disability developed rapidly over a period of months. Muscle pain and fatigue were present in some patients. No patient had a dermatomyositis-like rash. Serum creatine kinase was very high (3000 to 25 000 IU/l). Muscle biopsies showed an active myopathy, including muscle fibre necrosis and regeneration. There was prominent endomysial fibrosis, but little or no inflammation. Endomysial capillaries were enlarged, reduced in number, and associated with deposits of the terminal components of complement (C5b-9, membrane attack complex). Strength improved in several patients after corticosteroid treatment. Conclusions: Myopathies associated with anti-SRP antibodies may produce severe and rapidly progressive weakness and disability. Muscle biopsies show active myopathy with pathological changes in endomysial capillaries but little inflammation. Corticosteroid treatment early in the course of the illness is often followed by improvement in strength. In patients with rapidly progressive myopathies and a high serum creatine kinase but little inflammation on muscle biopsy, measurement of anti-SRP antibodies and pathological examination of muscle, including evaluation of endomysial capillaries, may provide useful information on diagnosis and treatment.

A RANDOMIZED CONTROLLED TRIAL OF RESISTANCE EXERCISE IN INDIVIDUALS WITH ALS

Objective: To determine the effects of resistance exercise on function, fatigue, and quality of life in individuals with ALS. Methods: Subjects with a diagnosis of clinically definite, probable, or laboratory-supported ALS, forced vital capacity (FVC) of 90% predicted or greater, and an ALS Functional Rating Scale (ALSFRS) score of 30 or greater were randomly assigned to a resistance exercise group that received a home exercise program consisting of daily stretching and resistance exercises three times weekly or to a usual care group, who performed only the daily stretching exercises. ALSFRS, the Fatigue Severity Scale (FSS), and Short Form-36 (SF-36) were completed at baseline and monthly for 6 months. FVC and maximum voluntary isometric contraction (MVIC) were monitored monthly throughout the study. Results: Of 33 subjects screened, 27 were randomly assigned (resistance = 13; usual care = 14). Eight resistance exercise subjects and 10 usual care subjects completed the trial. At 6 months, the resistance exercise group had significantly higher ALSFRS and SF-36 physical function subscale scores. No adverse events related to the intervention occurred, MVIC and FVC indicated no negative effects, and less decline in leg strength measured by MVIC was found in the resistance exercise group. Conclusion: Our study, although small, showed that the resistance exercise group had significantly better function, as measured by total ALS Functional Rating Scale and upper and lower extremity subscale scores, and quality of life without adverse effects as compared with subjects receiving usual care.

Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy

To identify the causative gene in an autosomal dominant limb‐girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles.

Sensory exam with a quantitative tuning fork Rapid, sensitive and predictive of SNAP amplitude

Background: In the standard neurologic examination, outcome measures of sensation testing are typically qualitative and subjective. The authors compared the outcome of vibratory sense evaluation using a quantitative Rydel-Seiffer 64 Hz tuning fork with qualitative vibration testing, and two other features of the neurologic evaluation, deep tendon reflexes and sensory nerve conduction studies. Methods: The authors studied 184 subjects, including 126 with Waldenström’s macroglobulinemia and 58 controls, over the course of a weekend. Standard neurologic examinations and quantitative vibratory testing were performed. Sensory nerve action potentials (SNAP) were tested as a measure of sensory nerve function. Tests were carried out by different examiners who were blinded to the results of other testing and to clinical information other than the diagnosis of Waldenström’s macroglobulinemia. Results: Quantitative vibration measurements in all body regions correlated with sural SNAP amplitudes. Quantitative vibration outcomes were more strongly related to sural SNAP results than qualitative evaluations of vibration. Quantitative vibration testing also detected a loss of sensation with increased age in all body regions tested. Conclusions: Quantitative vibratory evaluation with Rydel-Seiffer tuning fork is rapid, has high inter- and intrarater reliability, and provides measures for evaluating changes in sensory function over time. Examinations with the quantitative tuning fork are also more sensitive and specific than qualitative vibration testing for detecting changes in sensory nerve function. Use of the quantitative tuning fork takes no more time, provides more objective information, and should replace the qualitative vibratory testing method that is now commonly used in the standard neurologic examination.

Distal lower motor neuron syndrome with high‐titer serum IgM anti‐GM1 antibodies Improvement following immunotherapy with monthly plasma exchange and intravenous cyclophosphamide

Motor neuropathies associated with electrodiagnostic evidence of motor conduction block often improve after treatment with immunotherapy, but there is less evidence about the responsiveness of lower motor neuron (LMN) syndromes without conduction block. In this study we treated four patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 ganglioside antibodies but without conduction block on electrodiagnostic testing. Treatment courses consisted of five to seven repeated monthly regimens of plasma exchange on 2 consecutive days followed, on day 3, by intravenous cyclophosphamide (1 g/m2). The results of treatment were quantitatively measured using hand-held dynamometry. We found that all four patients showed progressive improvement in strength over the 6 to 24 months following treatment. Improvement was documented by both objective muscle testing and patient reports of increased strength and less fatigability. We conclude that immunotherapy may be followed by useful functional benefit in selected patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 antibodies. Gradual improvement often begins as late as 6 to 9 months after the onset of treatment and may persist for 1 to 2 years, or longer, after immunosuppressive treatment is stopped.

Selective staining of the cerebellar molecular layer by serum IgG in Miller-Fisher and related syndromes

During 1 year, we used immunocytochemical staining of human cerebellum to screen 1,488 serums for IgG autoantibodies to Hu and Yo antigens.Three serums had none of the classically described patterns of IgG binding but, instead, selectively stained the cerebellar molecular layer. Evaluation of clinical data showed that the patients had either typical Miller Fisher syndrome (MFS) or Guillain-Barre syndrome with ophthalmoplegia. Further analysis by ELISA assay showed that all three serums had high titers of IgG anti-GQ1b autoantibodies. IgG autoantibody staining of human cerebellum, which is used for the diagnosis of paraneoplastic disorders, may have additional specificity for other, presumably autoimmune, syndromes such as MFS. The specificity of the serum IgG autoantibody binding to the cerebellar molecular layer may be related to the ataxia that often occurs in these patients. NEUROLOGY 1996;47: 1317-1320

Motor neuron disease associated with copper deficiency.

Copper deficiency in humans is a rare cause of myeloneuropathy that usually presents with a spastic ataxic gait, hyperreflexia, and distal sensory loss similar to that seen in patients with subacute combined degeneration. We describe three copper‐deficient patients, two of whom were referred with a presumptive diagnosis of amyotrophic lateral sclerosis, who had progressive asymmetric weakness or electrodiagnostic findings of proximal and distal denervation suggestive of lower motor neuron disease. Copper replacement resulted in stabilization or mild improvement in weakness. The clinical spectrum of human copper deficiency should include lower motor neuron disease in addition to a syndrome of spastic ataxia. Muscle Nerve, 2006

Peripheral neuropathies in Waldenström’s macroglobulinaemia

Objective: We sought to determine the prevalence, clinical features, and laboratory characteristics of polyneuropathies in Waldenström’s macroglobulinaemia (WM), a malignant bone marrow disorder with lymphocytes that produce monoclonal IgM. Methods: We prospectively studied 119 patients with WM and 58 controls. Medical history was taken, and neurological examinations, electrodiagnostic tests, and serum studies were performed by different examiners who were blinded to results except the diagnosis of WM. Results: Polyneuropathy symptoms, including discomfort and sensory loss in the legs, occurred more frequently (p<0.001) in patients with WM (47%) than in controls (9%). Patients with WM had 35% lower quantitative vibration scores, and more frequent pin loss (3.4 times) and gait disorders (5.5 times) than controls (all p<0.001). Patients with IgM binding to sulphatide (5% of WM) had sensory axon loss; those with IgM binding to myelin associated glycoprotein (MAG) (4% of WM) had sensorimotor axon loss and demyelination. Patients with WM with IgM binding to sulphatide (p<0.005) or MAG (p<0.001) had more severe sensory axon loss than other patients with WM. Demyelination occurred in 4% of patients with WM with no IgM binding to MAG. Age related reductions in vibration sense and sural SNAP amplitudes were similar (∼30%) in WM and controls. Conclusions: Peripheral nerve symptoms and signs occur more frequently in patients with WM than controls, involve sensory modalities, and are often associated with gait disorders. IgM binding to MAG or sulphatide is associated with a further increase in the frequency and severity of peripheral nerve involvement. Age related changes, similar to those in controls, add to the degree of reduced nerve function in patients with WM.

Cavernous hemangioma of the spinal cord : report of 2 unusual cases

We present 2 cases of spinal cord intramedullary cavernous hemangioma; 1 patient is the 1st reported case of multiple spinal cord lesions. Diagnosis is greatly enhanced by the use of MRI.

Peripheral neuropathy in an outpatient cohort of patients with Sjögren's syndrome

Peripheral neuropathy is common in patients with Sjögrens syndrome (SS), but its precise prevalence is unknown. Most prior studies were conducted at neurology or rheumatology specialty clinics and likely selected for a more severely affected population. We evaluated 22 SS patients and 10 controls for evidence of neuropathy in an outpatient setting at a regional meeting of the Sjögrens Syndrome Foundation. We performed neurological examinations and nerve conduction studies (NCSs) and measured serum antinuclear antibody (ANA) and SS‐A and SS‐B antibody levels. Participants filled out a questionnaire pertaining to symptoms, diagnosis, and treatment. We found that signs and symptoms related to small axons were more common in patients with SS than in controls. Complaints of painful distal paresthesias in the feet were noted in 59% of patients but in only 10% of controls, and of abnormal sweating in 41% and 0%, respectively. Examination revealed decreased pinprick sensation in 64% of patients with SS, but in only 30% of controls. Overall, 45% of the patients but none of the controls were thought to have an isolated small‐fiber neuropathy. Large‐fiber dysfunction (as measured by testing vibration, deep tendon reflexes, and NCSs) was similar between the two groups. We conclude that small‐fiber neuropathy is common in patients with SS. Muscle Nerve 2006