Successful treatment of neuropathies in patients with diabetes mellitus.

OBJECTIVES: To report and characterize two forms of disabling progressive peripheral neuropathy in patients with diabetes mellitus, which respond to anti-inflammatory and/or anti-immune treatment. DESIGN: Review of clinical, electrophysiologic, and pathologic findings and results of treatment. SETTING: University medical center. PATIENTS: Twenty-one patients with diabetes mellitus to whom we gave anti-inflammatory and/or anti-immune treatment for progressive peripheral neuropathy during the past 6 years. MAIN OUTCOME MEASURES: Patients were interviewed and examined at intervals before and after beginning treatment with intravenous immunoglobulin (n = 15), prednisone (n = 13), cyclophosphamide (n = 5), plasma exchange (n = 3), and azathioprine (n = 1) (alone or in combination). RESULTS: Fifteen patients had evidence of axonal neuropathy by electrophysiologic studies (group A). All 15 patients had non-insulin-dependent diabetes mellitus, 10 patients had weight loss, and 13 patients had prominent involvement of thighs and/or thoracic bands consistent with diabetic amyotrophy or mononeuropathy multiplex. Small vessel disease was seen in all 10 patients who underwent biopsy, with perivascular or vascular inflammation seen in seven patients. Six patients had demyelinating neuropathy by electrophysiologic criteria (group B). All these patients had insulin-dependent diabetes mellitus, and no one had weight loss. The process was asymmetric in three patients and involved thoracic or abdominal regions in two patients. Onion bulbs were seen in all four patients who underwent biopsy, but no vascular inflammation or occlusion was seen. In all patients in both groups, worsening of their conditions stopped and improvement started after beginning treatment. CONCLUSION: Neuropathies responsive to anti-inflammatory and/or anti-immune therapy in patients with diabetes mellitus include (1) multifocal axonal neuropathy caused by inflammatory vasculopathy, predominantly in patients with non-insulin-dependent diabetes mellitus, indistinguishable from diabetic proximal neuropathy or mononeuropathy multiplex, and (2) demyelinating neuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy, predominantly in patients with insulin-dependent diabetes mellitus.

Myoclonus and mitochondrial myopathy.

The CNS diseases that are associated with mitochondrial myopathy have been reviewed in this chapter. The disorders causing myoclonus have been compared to those in which myoclonus has been reported. Both groups have been associated with lactate and pyruvate accumulation, and both have a wide spectrum of clinical and pathologic findings. Deficiency of components of the respiratory chain has been offered as an explanation for the mitochondrial accumulation in the muscles of these patients. Skeletal muscle respiratory-chain components may be deficient, and there is experimental evidence that indicates that mitochondria will proliferate in muscle and other tissues when vital nutrients are withheld. There are two features of these patients that separate them from other patients with myoclonus. The first is the elevation of serum lactate and pyruvate due to deficient oxidative phosphorylation. The second is a pedigree that indicates maternal inheritance.

Clinical features of myasthenia gravis.

Myasthenia gravis (MG) is an antibody-mediated muscle disease in which any skeletal muscle can be affected. MG may produce numerous symptoms and signs. To doctors and patients, it may seem like lung disease, stroke, heart disease, or the effects of emotional stress. This article explores the "territory" between MG and diseases of the heart and lungs as well as the other neuromuscular diseases.

Sensitivity and specificity of vibrometry for detection of carpal tunnel syndrome.

A cross-sectional study was performed to assess the utility of vibrotactile thresholds (VTs) obtained before and after a 10-minute period of wrist flexion as a method for detection of carpal tunnel syndrome (CTS) among adult subjects. Subjects with hand discomfort were recruited from patients referred to a university-based electromyography laboratory. Asymptomatic subjects were recruited from among office and technical staff at a professional school. In addition to electrophysiologic evaluation (EP), all subjects were offered VT measurement of the index and small fingers, bilaterally, before and after a 10-minute period of wrist flexion. A total of 144 subjects were recruited, and three hand-condition groups were established: 57 hands had symptoms and EP results compatible with CTS (Group 1), 58 hands had symptoms compatible with CTS and normal EP results (Group 2), and 123 hands had no symptoms and normal EP results (Group 3). Group 1 was considered the "disease-positive" group, and Groups 2 and 3 were both considered "disease-negative" groups. Analyses were performed separately for dominant and nondominant hands, and results were pooled when appropriate. Outcomes of interest were the VTs obtained from the index and small fingers before and after 10 minutes of maximal voluntary wrist flexion as well as variables calculated from them. Significant differences in mean VT were observed between the three hand-condition groups for most of the outcomes evaluated. At any given level of specificity, the sensitivity of vibrometry performed after 10 minutes of wrist flexion was approximately two times that obtained before wrist flexion for detection of electrophysiologically confirmed CTS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effect of verapamil in a patient with the Lambert-Eaton syndrome.

A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer developed respiratory failure several hours after verapamil was given. Improvement in respiratory function did not occur when guanidine was given, but was delayed until verapamil was discontinued 3 days later. Although other factors may have contributed to the clinical deterioration of our patient, the temporal relationship to verapamil and the theoretical danger of calcium channel blockade lead us to believe that the drug should be used cautiously in LES.

Teaching in the field: the model of a one-day trip to an outreach clinic.

A trip to an outreach clinic in a 15-passenger van is presented as part of the answer to the forces negatively affecting the practice of academic medicine today. Any subspecialist in a medical center can use the model if a community can be identified that has a hospital or clinic building able to host the university group. County- or state-funded facilities are well suited to a periodic clinic, and public health nurses are well trained in their management. The Muscular Dystrophy Association is a private supporter of clinics like this, allowing specialty doctor visits close to home for patients with disabling weakness who might otherwise be excluded from our increasingly restricted health care system.

Progressive sensory neuropathy in patients without carcinoma: a disorder with distinctive clinical and electrophysiological findings.

Seven patients with severe progressive impairment of kinesthetic sense, mild dysfunction of cutaneous sense, and sparing of motor function were examined during a 3-year period. The clinical and electrophysiological findings are described in detail. None of these seven has had evidence of cancer despite a thorough investigation and a 3- to 16-year (average, 7 years) period of symptoms. These patients' symptoms were indistinguishable from those of patients with sensory neuropathy and coexistent carcinoma, suggesting that progressive sensory neuropathy is not invariably associated with carcinoma.

Emery-dreifuss humeroperoneal muscular dystrophy: an x-linked myopathy with unusual contractures and bradycardia.

Clinical, electromyographic, and muscle biopsy findings in the two largest known families with Emery-Dreifuss humeroperoneal muscular dystrophy indicate that this is an X-linked recessive muscle disease with stereotyped clinical manifestations but with variable pathological and electromyographic characteristics. Elbow contractures, involvement of humeral muscles, hyporeflexia, and abnormal electrocardiograms are present in our patients. The disorder is associated with a potentially lethal cardiac arrhythmia that should be managed by pacemaker insertion. The skeletal muscle disease is slowly progressive and is usually not life threatening. Muscle biopsy commonly shows type I fiber atrophy. Electromyography usually indicates myopathy, though the classic findings of myopathy may not be present in every muscle.

High serum levels of creatine kinase: asymptomatic prelude to distal myopathy.

Two brothers and an unrelated man had serum creatine kinase values of 3000-8000 units when they were asymptomatic, and there was no weakness on examination. EMG and muscle biopsy showed changes indicative of myopathy. Years later, all three developed weakness that was limited to the gastrocnemius. Because siblings were affected, the disorder can be regarded as a form of muscular dystrophy. The distribution of weakness, serum enzyme changes, and histologic changes resembled an autosomal recessive distal myopathy first described by Miyoshi and differed from many other reported cases of distal myopathy. Our cases also indicate that myopathy may be asymptomatic.

Neurogenic skeletal myopathy in patients with primary cardiomyopathy.

Eleven patients with hypertrophic obstructive cardiomyopathy and eight patients with idiopathic congestive cardiomyopathy underwent extensive neuromuscular studies to determine if a skeletal myopathy is associated with uncomplicated primary cardiomyopathy. The clinical examination revealed peripheral neuropathies in six patients, but no evidence of muscle weakness or atrophy. Nerve conduction studies demonstrated a neuropathy in five of these six and in one other patient: three were in the hypertrophic group and three in the congestive group. Seven patients had abnormal electromyography, but none had characteristic myopathic changes. Of these seven patients, muscle biopsies showed denervation in two patients in the congestive group and type II atrophy in two patients in the hypertrophic group. We found no evidence of primary skeletal muscle involvement; however, neuropathic features and biopsy changes of denervation were present in both groups.

Maternally inherited mitochondrial myopathy and myoclonic epilepsy.

A family is described with familial myoclonic epilepsy associated with mitochondrial myopathy. The disorder follows a maternal inheritance pattern consistent with a mitochondrial DNA (mtDNA) mutation. The large kindred permitted exclusion of autosomal dominant, recessive, and X-linked patterns of transmission. Several characteristics of the inheritance and variability of expression within the pedigree are consistent with recently acquired knowledge about the genetics of human mtDNA. The clinical spectrum of disease is compatible with a proportionality model of mutant and wild-type mtDNAs. Muscle biopsies of affected patients showed an increased number of abnormal muscle mitochondria. Serum levels of pyruvate or pyruvate and lactate were elevated. The most severely affected patient had constant myoclonic jerking, dementia, ataxia, spasticity, hearing loss, and hypoventilation. Cerebral dysfunction in patients with mild involvement was marked by prominent photic driving seen on electroencephalograms and high-amplitude visual and somatosensory evoked responses but no myoclonus, ataxia, or dementia. The individual clinical features of the disease worsen over time for all patients; however, mildly affected patients have not become moderately affected and moderately affected patients have not become severely affected.

Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is the third most common X-linked muscular dystrophy. This disorder is characterized by childhood onset of early contractures, humeroperoneal muscle atrophy, and cardiac conduction abnormalities. Weakness is slowly progressive, but there is a broad spectrum of clinical severity. Patients and carriers are at risk of sudden death. Regular cardiac evaluation is mandatory to assess the risk of cardiac arrhythmias. Unique atrial pathology is seen at autopsy. The mutated gene in EDMD is localized to the long arm of the X chromosome. Mutations in the gene lead to abolished synthesis of the gene product, emerin. Emerin is localized to the nuclear membrane of skeletal, cardiac, and smooth muscle. The term Emery-Dreifuss syndrome describes patients who have the EDMD phenotype without X-linked inheritance. There is no treatment for the underlying disease, but early placement of pacemakers may be lifesaving.

Sudden death of a carrier of X-linked Emery-Dreifuss muscular dystrophy.

OBJECTIVE: To report a sudden death in a female carrier of Emery-Dreifuss muscular dystrophy and to describe the cardiac abnormalities associated with this disease. STUDY DESIGN: Case series. SETTING: University hospital. PATIENTS: A 45-year-old carrier who died suddenly and two affected men who also died of cardiac manifestations of Emery-Dreifuss muscular dystrophy. MEASUREMENTS: Post-mortem gross pathologic and histopathologic study of the heart. RESULTS: All three hearts showed a unique pattern of pathologic findings. Marked loss of atrial myocardium had occurred. Myocardium had been replaced by adipose and fibrous tissue. The conduction system showed no significant abnormalities. Varying degrees of interstitial and replacement fibrosis were present in the ventricular myocardium. CONCLUSIONS: Emery-Dreifuss muscular dystrophy is associated with characteristic pathologic changes in the heart that can cause death in female carriers and affected men. Female carriers should be identified and evaluated because of the risk for sudden cardiac death.

Cardiac features of an unusual X-linked humeroperoneal neuromuscular disease.

To characterize an unusual, sex-linked recessive neuromuscular disease, we studied two families with 37 males who had involvement of distal leg and proximal arm muscle groups. Electromyography and muscle biopsy in five subjects showed features of both neuropathy and myopathy. Bradycardia and syncope in 15 involved subjects were associated with early death (before the age of 50 years). Electrocardiograms in 15 others showed a spectrum of atrial abnormalities that ranged from abnormal P waves to permanent atrial paralysis and from first-degree atrioventricular block to complete heart block. No patient exhibited clinical muscle disease without electrocardiographic atrial disease. Dilated, hypertrophied left ventricles with normal indexes of function were found in three cases with permanent atrial paralysis and chronic junctional bradycardia. Cardiomegaly and cardiac failure were not present in the other cases. We conclude that permanent ventricular pacing (instituted four patients) is indicated in many of these patients to prevent serious sequelae.

Localisation of the gene for Emery-Dreifuss muscular dystrophy to the distal long arm of the X chromosome.

The linkage relationships of the gene for Emery-Dreifuss muscular dystrophy have been analysed in a large American kindred using DNA probes from different regions of the X chromosome. Close linkage was found with the locus for factor VIII, with no recombinants in 12 opportunities (maximum lod score 4.3), and with locus DXS15 (two recombinants in 17 opportunities, maximum lod score 2.9 at 0 = 10 cM). No linkage was found with probes pERT87 and 754, which are closely linked to Duchenne and Becker muscular dystrophies at Xp21. These results confirm a separate localisation on the distal part of the long arm at q27-28 for Emery-Dreifuss muscular dystrophy and should provide the basis for prenatal diagnosis and improved carrier detection in this disorder if the linkage is confirmed to be close.

Mitral valve prolapse and ophthalmoplegia: a progressive, cardioneurologic syndrome.

Disorders characterized by both neurologic (ataxia, ophthalmoplegia, ptosis, neuromyopathy) and cardiologic (heart block, cardiomyopathy) abnormalities have been previously called the "ophthalmoplegia plus" syndromes. Most are not due to a specific enzyme defect or metabolic abnormality and thus may be similar phenotypic expressions of diverse causes. We studied seven patients with progressive external ophthalmoplegia and variable ataxia, with mitral valve prolapse and mitral regurgitation that progressed in severity as did the neuromuscular manifestations. Abnormal skeletal muscle biopsies showed "ragged-red" fibers or congenital fiber type disproportion; serum alanine levels were elevated; in-vivo and in-vitro tests of pyruvate metabolism gave abnormal results; C4 complement was decreased; and the patients' fibroblasts bound immunoglobulin when incubated with autologous serum. These data suggest a distinct neuromuscular disorder with metabolic and immunologic features associated with mitral valve prolapse and progressive mitral regurgitation.

Chronic lead absorption. Result of poor ventilation in an indoor pistol range.

Three cases of mild lead poisoning were discovered among instructors at an indoor pistol range. These cases were characterized by blood lead levels greater than 100 mug/100 ml, free erythrocyte protoporphyrin levels greater than 450 mug/100 ml of red blood cells, abdominal pain, and, in one instance, by slowing of motor and sensory nerve conduction velocity. Exposure to airborne lead produced during revolver-firing and bullet-molding accounted for the lead absorption. Ventilation in the range was inadequate.

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.

A large MERRF pedigree permitted the direct testing of the predictions for a mitochondrial DNA (mtDNA) mutation. A mtDNA mutation was demonstrated by proving maternal inheritance and by identifying specific deficiencies in muscle energetics and mitochondrial respiratory complexes I and IV. mtDNA heteroplasmy (a mixture of mutant and wild-type mtDNAs) was demonstrated by showing variation in the mitochondrial energetic capacity between family members. The phenotypic consequences of differential tissue-specific reliance on mitochondrial ATP was shown by correlating individual respiratory deficiency with the nature and severity of patients' clinical manifestations. The observed spectrum of clinical manifestations resulting from this heteroplasmic mtDNA mutation implies that mtDNA disease may be much more prevalent than previously anticipated.