HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia.

The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves. Rarely, polymyositis and myoglobinuria are seen. Two other neuromuscular syndromes in people with HIV antibodies are nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron disease. The associations between these diseases and the possibility that HIV infection could be a risk factor for either amyotrophic lateral sclerosis (ALS) itself or other motor neuron diseases are investigated.

Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot?

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.

Urinary excretion of carnitine in Duchenne muscular dystrophy.

The urinary excretion of carnitine by boys with Duchenne dystrophy did not differ significantly from age-matched controls. Since serum and muscle concentrations of carnitine are also normal in Duchenne dystrophy, it cannot be proved that this small molecule leaks from muscle in Duchenne dystrophy. If the muscle surface membrane is abnormally leaky in Duchenne dystrophy, different molecules seem to be affected in different ways.

Granulomatous angiitis of the brain. An inflammatory reaction of diverse etiology.

Granulomatous angiitis of the brain (GAB) is defined histologically by granulomatous inflammation of intracranial blood vessels. We have studied four patients with autopsy-proved GAB who had, respectively, Hodgkin's lymphoma, herpes zoster, neurosarcoidosis, and no associated illness. Headache, fever, or mental change was followed by hemiparesis or quadriparesis, coma, and death in all four patients. There were no diagnostic findings from cerebral computed tomograms, cerebrospinal fluid, or cerebral angiograms; the diagnosis was established only by postmortem examination. Vasculitis was limited to the brain in all four patients, and involved large arteries, small arteries and veins, or both large and small vessels. Differences in etiology and different particulars of the pathologic conditions imply that GAB is a nonspecific reaction, not a unique disease. The diagnosis, moreover, cannot be proved without histologic confirmation. A biopsy specimen is the only way to ascertain the diagnosis in living patients.

Amyotrophy in prion diseases.

Amyotrophic lateral sclerosis was once thought to be caused by persistent viral infection, partly because some patients with transmissible Creutzfeldt-Jakob disease showed prominent amyotrophy. However, in the past 15 years there has been little interest in the amyotrophy in prion diseases, and the possible link to amyotrophic lateral sclerosis has been eschewed. We analyzed case reports of prion disease published after 1968 for evidence of amyotrophy. We defined amyotrophy as clinically evident fasciculation buttressed by electromyographic results in some cases. We sought evidence of motor neuron degeneration at autopsy. Prion disease was proved by transmissibility, immunohistochemistry demonstration of protease-resistant prion protein, or finding a mutation in the prion protein gene. Amyotrophy was noted in 27 patients: 13 with sporadic Creutzfeldt-Jakob disease, 2 with familial Creutzfeldt-Jakob disease, and 12 with Gerstmann-Sträussler-Scheinker disease. Of the 27, 23 showed clinical fasciculation and 10 had electromyographic evidence of denervation. The spinal cord was examined in 8 patients: 6 showed loss of motor neurons, 1 showed vacuolation of motor neurons, and 1 reported no abnormalities. Another 23 patients had typical histopathological characteristics but lacked molecular or biochemical proof of prion disease. The total number of patients with amyotrophy and proven prion disease that we identified was 50. This case review supports the belief that amyotrophy is occasionally a prominent feature of Creutzfeldt-Jakob disease and underscores the importance of documenting lower motor neuron function and the crucial role of examining the spinal cord at autopsy in cases of prion disease.

Clinical varieties of neuromuscular disease in debrancher deficiency.

Two men and one woman with debrancher deficiency had symptoms and signs of neuromuscular disease. The two men had adult-onset and slowly progressive weakness, distal muscle wasting, "mixed" electromyographic patterns, and slow nerve conduction velocities; the initial diagnosis was Charcot-Marie-Tooth disease in one patient and motor neuron disease in the other. The woman had stunted growth, delayed motor milestones, and lifelong nonprogressive weakness. A muscle biopsy specimen showed severe vacuolar myopathy in all three cases. The glycogen concentration was increased threefold to sixfold and had an abnormal iodine spectrum. Anaerobic glycolysis in vitro showed impaired use of endogenous and exogenous glycogen but normal use of hexose-phosphate glycolytic intermediates. These three cases illustrated the clinical variety of neuromuscular disease in debrancher deficiency. In patients with weakness of adult onset, the diagnosis is impossible to make without performing a muscle biopsy.

Mother with amyotrophic lateral sclerosis and daughter with Creutzfeldt-Jakob disease.

OBJECTIVE: To describe a mother who had autopsy-proved amyotrophic lateral sclerosis and her daughter who had clinically diagnosed Creutzfeldt-Jakob disease. DESIGN: Case reports with molecular genetic analyses. SETTING: A tertiary care center. PATIENTS: The mother had progressive upper and lower motor neuron symptoms and signs starting at the age of 54 years. Electrophysiological testing supported the diagnosis of amyotrophic lateral sclerosis. Autopsy results confirmed the diagnosis. Her daughter had received injections of human growth hormone prepared from pooled human pituitary glands as a child. At the age of 31 years, she experienced the onset of gait ataxia and dysarthria. Cerebrospinal fluid showed the 14-3-3 protein. Cognitive difficulties ensued. She progressed to a nearly akinetic and mute state. She had overt visible fasciculations and muscle atrophy in the legs. MAIN OUTCOME MEASURES AND RESULTS: Neither patient carried a mutation in the prion protein gene. Both were homozygous for methionine at the polymorphic codon 129. Neither patient carried a deletion of the 5 exons of the superoxide dismutase 1 gene. CONCLUSIONS: It is uncertain whether the 2 cases occurred in the same family by chance or whether the patients shared genetic risk factors for the 2 diseases. The possibility that homozygosity at codon 129 is a risk factor for amyotrophic lateral sclerosis is being tested in a case-control study.

X-linked spinal muscular atrophy (Kennedy's syndrome). A kindred with hypobetalipoproteinemia.

Kennedy's syndrome, X-linked adult-onset bulbospinal muscular atrophy, has been described in over 30 families. The characteristic distribution of weakness creates a recognizable syndrome, augmented by frequent findings of testicular atrophy and gynecomastia. Type IV or type II hyperlipoproteinemia has been found in some families. We have studied another family with Kennedy's syndrome, this one with hypobetalipoproteinemia. The diversity of serum patterns suggests that lipoprotein abnormalities are not causally related to either the endocrinopathy or the spinal muscular atrophy. However, gene linkage studies indicate proximity of the gene for Kennedy's syndrome and the gene encoding the androgen receptor, which could explain the combination of a motor neuron disorder and the endocrine abnormalities.

Primary lateral sclerosis. A clinical diagnosis reemerges.

Adults with slowly progressive noninherited gait disorders may show no abnormalities on examination other than signs implicating the corticospinal tracts. That is the syndrome of "primary lateral sclerosis" (PLS), a clinical diagnosis that has been avoided because it is a diagnosis of exclusion, proven only at autopsy. Now, modern technology can exclude other disorders that can cause the syndrome with an accuracy of about 95%. That serves to eliminate the following: compressive lesions at the foramen magnum or cervical spinal cord, multiple sclerosis, amyotrophic lateral sclerosis, Chiari malformation, syringomyelia, biochemical abnormality, and persistent infection with human immunodeficiency virus or human T-lymphotrophic virus type I. We studied three autopsy-proved cases of PLS; six living patients in whom PLS was diagnosed clinically after comprehensive evaluations that excluded the alternative diagnoses; and two patients with this syndrome of PLS and antibodies to human immunodeficiency virus seropositivity that clinically resembled PLS. Primary lateral sclerosis is now a respectable and permissible diagnosis.

Inclusion body myositis mimicking motor neuron disease.

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Erroneous diagnosis corrected after 28 years. Not spinal muscular atrophy with ophthalmoplegia but minicore myopathy.

OBJECTIVE: To correct, after 28 years, the previously reported diagnosis of ophthalmoplegia in a patient with presumed childhood spinal muscular atrophy. DESIGN: Clinical follow-up, laboratory, electrophysiologic, and muscle biopsy data are provided. RESULTS: The findings of clinical follow-up examination, electrophysiologic tests, and histologic examination of muscle specimens led to a revised diagnosis of minicore myopathy. CONCLUSIONS: Spinal muscular atrophy was diagnosed in 1967, before histochemical techniques for examining muscle tissue and quantitative electromyography became widely available. Modern laboratory techniques later made the diagnosis of minicore myopathy possible. Progressive external ophthalmoplegia has been described in 24% of patients with minicore myopathy, but there have been only 7 reports of ophthalmoplegia with spinal muscular atrophy since 1954, and some of these diagnoses have been questioned.

Surgical treatment of cervical spondylotic myelopathy: time for a controlled trial.

Surgical procedures on the cervical spine are accepted therapies for the myelopathy of cervical spondylosis. However, reported improvement rates vary widely, and many reports indicate improvement in about one-half of the cases. It has not been proven that outcome after surgery is better than the natural history or conservative therapy. Radiographic or imaging evidence of cord impingement or compression may be seen in asymptomatic people. There are no clear guides to the selection of patients who may benefit from the operation and there has been no standardization of preoperative evaluation, trials of conservative therapy, ascertainment of progressive disability, or assessment of outcome. A multicenter controlled trial might answer these questions.

Adenyl cyclase abnormality in Duchenne muscular dystrophy: muscle cells in culture.

Cultured muscle cells from patients with Duchenne muscular dystrophy differed from cells of normal individuals and of patients with other muscle diseases. In Duchenne cells, basal activity of adenyl cyclase of myotubes was higher and was not stimulated significantly by epinephrine or isoproterenol, as it was in fused control cells, and the response to fluoride was less. The genetic defect in this disease may be an abnormality of the sruface membrane of muscle.

Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility.

Clinicians have long suspected an association of classic amyotrophic lateral sclerosis (ALS) with Parkinson's disease (PD), dementia, or both. If proven, this would raise the possibility of a shared genetic susceptibility to the three disorders. To investigate this hypothesis, we compared 151 newly diagnosed ALS patients (seven familial) with 140 controls in terms of cumulative incidence of ALS, PD, and dementia in parents, siblings, and grandparents. We used Cox proportional hazards analysis to compute rate ratios (RRs) for ALS, dementia, and PD in relatives of ALS patients versus relatives of controls. The risk for dementia was significantly higher in relatives of ALS patients than in those of controls (RR = 1.9; 95% CI 1.1-3.1) and was similar for relatives of patients with sporadic and familial ALS. The risk of PD was higher in relatives of patients with familial ALS (RR = 5.6; 95% CI 0.6-50.3) than in relatives of patients with sporadic ALS (RR = 1.8; 95% CI 0.5-6.0), but these differences were not statistically significant, probably due to insufficient statistical power with the available sample size. These findings indicate that ALS and dementia, and perhaps also PD, co-occur within families more often than expected by chance, suggesting that there may be a shared genetic susceptibility to these disorders.

Premorbid weight, body mass, and varsity athletics in ALS.

Several famous athletes have been affected by ALS, and some epidemiologic studies have indicated that vigorous physical activity (heavy labor or athletics) is a risk factor for the disease. In a case-control study of 279 patients with motor neuron diseases and 152 with other neurologic diseases, the authors found that subjects with motor neuron diseases were more likely than controls to report they had always been slim or they had been varsity athletes. For slimness, the odds ratio (OR) was 2.21; 95% CI, 1.40 to 3.47. For varsity athletics, the OR was 1.70; CI, 1.04 to 2.76.

Dystrophinopathy in isolated cases of myopathy in females.

X-linked dystrophinopathy is the most common cause of isolated cases of myopathy in males. To investigate dystrophin abnormalities as a cause of myopathy in girls and women, we used dystrophin immunocytochemistry to study muscle biopsies from 505 girls and women with neuromuscular disease. Forty-six muscle biopsies showed a combination of fibers containing or lacking dystrophin; this mosaic immunostaining pattern denoted a carrier status. Twenty-one of 46 (45.6%) had a family history of Duchenne muscular dystrophy in males. Twenty-five of 46 (54.3%) were isolated cases, with no previous family history of neuromuscular disorder. The laboratory findings of the isolated cases were consistent with the familial cases; all showed myopathic histopathology and abnormal elevations of serum CK. The clinical presentations of the isolated cases varied but were consistent with the familial cases: 40% (10/25) of isolated cases showed proximal limb weakness before age 10, 24% (6/25) presented with myalgias or cramps, 24% (6/25) presented with incidental findings of grossly elevated CK levels, 8% (2/25) noted easy fatigue, and 4% (1/25) had slowly progressive proximal limb weakness beginning at age 45. From our data, the clinical criteria for consideration of an underlying dystrophinopathy in isolated female cases of myopathy are CK levels greater than 1,000 IU/l and myopathic histopathology. About 10% of the isolated cases of hyperCKemic myopathy (25/210) were proven by dystrophin analysis to have a dystrophinopathy as the cause of their disease (manifesting carriers of Duchenne dystrophy). However, we feel that this may be an underestimate. The correct diagnosis in these patients is imperative for appropriate genetic counseling to the patients and their families.

Complications of intravenous immune globulin treatment in neurologic disease.

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritus 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state.

Impact of spirituality and religiousness on outcomes in patients with ALS.

The Project of Death in America Study at Columbia Presbyterian Medical Center enrolled 121 patients with ALS from 1996 through 1997, 46 of whom participated in a study assessing the effects of religiousness and spirituality (attachment to life, mental health, support group, health care proxy, and attitudes toward death) on outcomes (technology and death). Spirituality or religion influenced use of percutaneous endoscopic gastrostomy, noninvasive assisted ventilation, tracheotomy, and attitudes toward the dying process.

A prospective study of preferences and actual treatment choices in ALS.

OBJECTIVE: To determine whether ALS patients' preferences for ameliorative or life-extending technologies elicited early in the disease were related to later treatment choices. METHODS: In this prospective cohort study, 121 patients were seen at a tertiary ALS care center and followed for a median of 12 months. At baseline, patient preferences for use of tracheostomy and percutaneous endoscopic gastrostomy (PEG) placement were elicited. All patients received the same educational information before being interviewed about treatment preferences. Patients were then followed to determine if patients who viewed the interventions favorably at baseline were significantly more likely to use the interventions over follow-up. RESULTS: Six to twelve percent of patients were certain they wanted tracheostomy and 28.2% wanted PEG. Preferences were related to later treatment choices: 20% of patients who found tracheostomy acceptable had one in the follow-up period, compared with 3.4% of those not in favor (p < 0.001). For PEG, similar findings were obtained: 48.5% who initially found it acceptable had PEG, versus 8.1% of those not in favor of this treatment (p < 0.001). Patients who found the interventions acceptable were more likely to be recently diagnosed, expressed greater attachment to life, and showed greater declines in pulmonary function over follow-up. CONCLUSIONS: Patients with ALS were able to express their preferences for life-extending or ameliorative technologies and made choices consistent with these preferences. However, patient preferences may change over time, and clinical education efforts are required throughout the course of disease.

Motor neuron diseases and amyotrophic lateral sclerosis: GM1 antibodies and paraproteinemia.

Six of 110 patients (5.5%) with forms of motor neuron disease had abnormal titers of GM1 antibodies of 1:1,600 or higher. Four others came with previously known high titers. Three patients with upper motor neuron (UMN) signs had titers of 1,600; those with probable or no UMN signs had higher titers. Nine patients had conduction block; six of them had abnormal antibody titers, four with 6,400 or higher. Therefore, patients with motor neuron disease and abnormal anti-GM1 titers may have UMN signs or conduction block.