Amyotrophic lateral sclerosis and occupational history. A pilot case-control study.

OBJECTIVE: To assess the association of a number of occupational and industrial exposures with amyotrophic lateral sclerosis (ALS). DESIGN: A case-control study of ALS cases matched by age and sex to 2 controls each: 1 from a neurologic clinic and 1 from a local community. Exposures were ascertained by questionnaire, and patients were requested before the interview to be to prepared to supply occupational histories. SETTING: Patients with ALS were enrolled at the University of Minnesota ALS Clinic in Minneapolis. PATIENTS: Patients with ALS (n = 25) were from the University of Minnesota ALS clinic, and clinic controls (n = 25) were patients with other neuromuscular diseases from the university's Muscle Disease Clinic, selected on the basis of clinic enrollment date nearest to that of the matched case. Clinic controls were principally patients with myopathies. Community controls (n = 25) were selected from the community using a random-digit-dialing protocol matching on the first 5 digits of the case patient's telephone number. RESULTS: The strongest association with disease was exposure to welding or soldering materials (odds ratio, 5.0) and the welding industry (odds ratio, 5.3). Electric plating showed a high odds ratio of 8 (95% confidence interval, 0.9-72.0), but low statistical significance (P < .07) Several exposures or industries, while not statistically different, showed enough difference that to ignore them might lead to a Type II error, a result of the pilot nature and small sample size. These included paint or pigment manufacturing, the petroleum industry, the printing industry, and shipbuilding. CONCLUSIONS: The association with welding, soldering, and the welding industry is strong and suggests a need for further work. This is despite the small numbers studied, thus making most industrial or occupational exposures too limited to draw conclusions or detect associations. Perhaps the most obvious candidate from the welding, soldering exposure for a common toxin would be lead. Other suggestions of risk were seen for paint or pigment manufacture, shipbuilding, electric plating, and the dairy industry. The degree of association for these, while high, is not statistically significant, and suggests that there may be 1 or more environmental toxins common to those industries that need more precise measurement.

Physical activity, trauma, and ALS: a case-control study.

AIMS: The association of trauma and physical activity with ALS is controversial. We explored the relation in a pilot case-control study. MATERIAL AND METHODS: ALS patients were selected from a university muscle disease clinic and paired with two matched controls: one from the clinic, but having different diseases, and one from the community. RESULTS: We found several strong and statistically significant differences between ALS cases and the matched controls. These included severe head, neck and back injury (OR = 5.3), the frequency of sweating in work (OR = 1.6) or leisure activity (also OR = 1.6), and earning a school letter (OR = 3.1). Other measures of trauma and activity, while not achieving statistical significance (p < 0.05), were in accord with these findings. DISCUSSION: Possible explanations include trauma and vigorous exercise precipitating ALS; trauma as an early sign of disease; or a third factor associated with ALS predisposing to injury. CONCLUSIONS: Severe head, neck, and back injury and frequency of sweating both in work and leisure activity showed a strong association with ALS. Further study could test narrower and less common exposures with greater statistical power.

The natural history of amyotrophic lateral sclerosis.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

Inclusion body myositis and renal cell carcinoma. Report of two cases and review of the literature.

OBJECTIVE: To describe the clinical course of 2 patients with concurrent inclusion body myositis and renal cell carcinoma and review published reports of inclusion body myositis associated with malignancy. METHODS: Prospective followup of 2 patients. Review of published case reports and series of patients with inclusion body myositis. RESULTS: Our 2 patients with inclusion body myositis and renal cell carcinoma had no improvement of strength following nephrectomy. Seven previously reported cases of inclusion body myositis and malignancy were identified and are discussed. CONCLUSION: Findings in our 2 patients suggest that there is no etiopathologic relationship between inclusion body myositis and malignancy.

Eosinophilia-myalgia syndrome associated with L-tryptophan use.

The eosinophilia-myalgia syndrome associated with the use of oral preparations of the amino acid L-tryptophan was recognized in late 1989. We describe the clinical and laboratory manifestations, pathological findings and early clinical course of 20 patients with the eosinophilia-myalgia syndrome. Prominent clinical findings included severe myalgias limiting function, fatigue, rashes, edema and weight gain, weight loss, muscle weakness and shortness of breath. Laboratory findings included eosinophilia (often marked), normal erythrocyte sedimentation rate, and elevated aldolase with normal or low creatine kinase values. On biopsy fascial inflammation was always seen consisting of lymphocytes, histiocytes and eosinophils in a perivascular distribution. Invasion of the vascular wall by lymphocytes was seen in 20%. Capillary and arteriolar endothelial cell thickening was found in most cases on electron microscopy and endothelial cell necrosis or mural invasion by lymphocytes was seen in 25% of cases. Two patients improved with no therapy. Ten patients responded to therapy with prednisone alone. Three patients have had progressive disease and one of these died. The relationship of this syndrome to previously described disease entities associated with eosinophilia is discussed.

Microangiopathy in the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome associated with the ingestion of L-tryptophan was recognized in late 1989. We describe our pathologic study of skin, fascial, and muscle biopsies from 21 patients evaluated by light microscopy, histochemistry, and electron microscopy. A perivascular, lymphocytic infiltrate with eosinophils was present in the dermis, fascia, and skeletal muscle. Lymphocytic infiltration of arteries and arterioles was seen. Ultrastructurally, capillary and arteriolar endothelial cell thickening and necrosis was present. This microangiopathy suggests that ischemia may be a contributing factor to the findings in this syndrome.

Human monoclonal IgM anti-Gal(beta 1-3)GalNAc autoantibodies bind to the surface of bovine spinal motoneurons.

An IgM monoclonal autoantibody (M-protein) with anti-Gal(beta 1-3)GalNAc activity from a patient with lower motor neuron disease bound to the surface of motoneurons isolated from bovine spinal cord. The Gal(beta 1-3)GalNAc epitope is shared by the gangliosides GM1 and GD1b and by several glycoproteins in the nervous system, and binding was abolished by preabsorbing the patient's serum with GM1. Antibodies specific for GM1, however, which do not bind to GaL(beta 1-3)GalNAc, did not bind to the motoneurons. This suggests that Gal(beta 1-3)GalNAc bearing glycoproteins or glycolipids other than GM1 are expressed on the surface of motoneurons, while GM1 may be absent or shielded, and that antibody binding to the cell surface might contribute to the development of the motor neuron disease.

Profound muscle weakness as the presenting feature of disseminated cryptococcal infection.

A patient with chronic lymphocytic leukemia who was treated with immunosuppressive therapy for a prolonged period presented with profound muscle weakness secondary to disseminated cryptococcosis. The infection developed despite 3 months of continuous ketoconazole therapy and was not responsive to amphotericin B or flucytosine. At autopsy, Cryptococcus neoformans was present in all sampled skeletal muscles, myocardium, and muscularis propria of the gastrointestinal tract but was not identified in either the central nervous system or the lungs. A review of the English-language literature failed to identify a similar case with such profound myotropism due to Cryptococcus. This case demonstrates that cryptococcosis should be considered in the differential diagnosis of an immunocompromised host presenting with muscle weakness.

Plasma exchange and prednisone in Guillain-Barré syndrome: a controlled randomized trial.

A controlled randomized trial of plasma exchange combined with prednisone was compared with supportive care alone in patients with Guillain-Barré syndrome (GBS). There was no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of 2 British Medical Research Council grades of strength between the groups. The difference in our results and others that indicated a beneficial effect of plasma exchange may reflect an adverse effect of prednisone on recovery in GBS. Failure to find a benefit of plasma exchange in our patients also raises the possibility that GBS may be a heterogeneous disorder with humoral factors playing a role in some but not all patients.

Plasma exchange and prednisone in acute inflammatory polyradiculoneuropathy: a controlled randomized trial.

A controlled-randomized trial of plasma exchange combined with prednisone was compared to supportive care alone in patients with acute inflammatory polyradiculoneuropathy (AIP). The design of this study differs from other reported trials of plasma exchange in AIP because prednisone was used in the treatment group to prevent the possibility of antibody rebound. Furthermore, in this study, detailed muscle strength testing formed the principal basis for assessment of therapeutic efficacy while in the British, North American, and French studies, a functional assessment scale was used. Analysis of our data revealed no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of two British Medical Research Council grades of strength between the groups. The difference in our results versus others (North American and French studies) probably reflects the adverse effects of prednisone on recovery in AIP. An additional consideration is that plasma exchange may have an overall modest effect on the course of AIP, less appreciated when individual muscles are tested compared to assessment by large functional categories.

Peripheral sensory neuropathy and cisplatin chemotherapy.

Patients with advanced cancer, previously untreated, were given 60 mg/m2 cisplatin plus 60 mg/m2 adriamycin by monthly intravenous injections. Signs and symptoms of a predominantly sensory peripheral neuropathy developed in 92% of the patients. Patients complained of dysesthesias and paresthesias in hands and feet. Clinically, there was progressive decrease or loss of tendon reflexes, decreased vibratory sense, and mild decrease in light touch and pin sensation. Distal sensory latencies became prolonged or dropped out completely, but there was little change in motor nerve conduction velocities or motor unit action potentials. Sural nerve biopsies showed loss of large-diameter nerve fibers, with axonal and myelin degeneration.

Intellectual function in Duchenne muscular dystrophy: the influence of penicillamine.

No effect of penicillamine upon intelligence was found in boys with Duchenne muscular dystrophy when compared to placebo administered in a double-blind fashion. All children, however, showed a significant progressive decline in intelligence quotient. An analysis of mental age showed no change over a 24-month period, suggesting that a static intellectual deficit exists. These data support other findings of a central nervous system dysfunction in patients with Duchenne muscular dystrophy.

Treatment of Duchenne's muscular dystrophy with penicillamine. Results of a double-blind trial.

Eleven boys with Duchenne's muscular dystrophy, randomly assigned to placebo (group A, n = 6) or penicillamine treatment (group B, n = 5), received three capsules per day containing lactose or 250 mg of penicillamine. All patients received pyridoxine, 50 mg daily. Mean age at entrance into study was similar for both groups (group A , 86.7 +/- 31.6 months; group B, 95.4 +/- 43.4 months). Clinical status was assessed with timed functional activities, manometric measurements of muscle force, and manual muscle testing. After 14 to 16 months of treatment, statistical analysis (analysis of variance) of data disclosed no significant differences in the overall performance of the two groups. A longer-duration trial, involving younger patients, is needed to determine whether there are palliative effects of penicillamine or other potentially therapeutic agents.

Friedreich's ataxia.

The clinical and pathologic findings in Friedreich's ataxia were discussed and recent literature was reviewed with respect to associated heart disease, diabetes mellitus, peripheral nerve involvement, and EEG changes. Recent research aimed toward discovering an enzyme defect or defects was reviewed and, when available, our conclusions were stated. Friedreich's ataxia remains an unexplained spinocerebellar degeneration occurring in early life, inherited in a predominantly autosomal recessive fashion, and associated with cardiac dysfunction, diabetes mellitus, and peripheral sensory nerve involvement.

Histochemical phosphorylase activity in regenerating muscle fibers from myophosphorylase-deficient patients.

Fresh frozen sections of mature skeletal muscle fibers from patients with genetically determined "absence" of skeletal muscle phosphorylase (McArdle's disease) have no histochemical phosphorylase activity. That regenerating muscle fibers, in vitro and in vivo, from such patients do have histochemical phosphorylase activity present suggests a loss of enzyme activity with fiber maturity.