A4V superoxide dismutase mutation in apparently sporadic ALS resembling neuralgic amyotrophy.

We report a case of apparently sporadic amyotrophic lateral sclerosis (ALS) in a young pregnant woman presenting subacutely with severe left shoulder pain followed by progressive weakness and wasting of the left arm, mimicking neuralgic amyotrophy. She was later found electrophysiologically to have widespread denervation involving more than just the arm and an alanine for valine substitution in codon 4 (A4V) in the gene for Cu/Zn superoxide dismutase 1 (SOD1). Her case illustrates that pain on initial presentation, though uncommon, does not exclude a diagnosis of ALS.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

Late-onset SCA2: 33 CAG repeats are sufficient to cause disease.

SCA-2 is an autosomal dominant inherited disorder characterized by ataxia, slow saccades, and hyporeflexia. The authors evaluated a patient with a mild balance problem with a SCA-2 allele sized at 33 CAG repeats. The authors then ascertained her 91 year-old mother, who showed disease onset at age 86 with an SCA-2 allele of identical size. Their study indicates that 33 CAG repeats can be pathogenic at the SCA-2 locus, though such an allele may produce an extremely late onset and gradual rate of disease progression.

AAEM minimonograph #48: autonomic nervous system testing.

The autonomic nervous system maintains internal homeostasis by regulating cardiovascular, thermoregulatory, gastrointestinal, genitourinary, exocrine, and pupillary function. Testing and quantifying autonomic nervous system function is an important but difficult area of clinical neurophysiology. Tests of parasympathetic cardiovagal regulation include heart rate analysis during standing (the 30:15 ratio), heart rate variation with deep breathing, and the Valsalva ratio. Tests of sympathetic adrenergic vascular regulation include blood pressure analysis while standing, the Valsalva maneuver, sustained handgrip, mental stress, and cold water immersion. Tests of sympathetic cholinergic sudomotor function include the sympathetic skin response, quantitative sudomotor axon reflex test, sweat box testing, and quantification of sweat imprints. Pupil function is tested pharmacologically and with pupiilographic techniques. Tests of gastrointestinal and genitourinary function do not satisfactorily isolate autonomic regulation from their other functions. The available tests have various sensitivities and ease of administration. They are typically administered in a battery of multiple tests, which improves sensitivity and reliability, and allows probing of various autonomic functions.

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes.

Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition.

Myasthenic (Eaton-Lambert) syndrome associated with pulmonary large-cell neuroendocrine carcinoma.

A 66-year-old woman presented clinical findings of Eaton-Lambert (myasthenic) syndrome (ELS). Fifteen months later, large-cell pulmonary carcinoma was detected. After systemic chemotherapy and radiotherapy, the tumor regressed and neurologic function improved. Although ELS is usually associated with pulmonary small-cell carcinoma, a minority of tumors are of squamous or glandular differentiation. We believe this is the first case report of ELS associated with large-cell neuroendocrine carcinoma in the English language literature, and it illustrates the importance of an aggressive approach to diagnosis and treatment.

A double-blind trial of isoniazid for essential tremor and other action tremors.

We conducted a double-blind trial of isoniazid in 11 patients with essential tremor and four patients with other types of postural action tremor. The tremor had not been helped by beta-blockers or primidone. Isoniazid was given in doses up to 1,200 mg daily, together with 100 mg pyridoxine, for four weeks. Results were assessed with subjective and objective scales. Only two patients with essential tremor appeared to benefit enough to continue the drug after the trial, and only one has benefited from its long-term use. Isoniazid may be useful in rare cases of essential tremor, but must be monitored carefully because of its toxicity.

Clinical and electromyographic studies of postpoliomyelitis muscular atrophy.

Eleven patients with progressive weakness following polio (postpoliomyelitis muscular atrophy syndrome) were compared electromyographically with nine patients who had stable strength following polio. Abnormalities included (1) abnormal motor unit characteristics in many muscles indicating widespread loss of motor neurons and reinnervation in muscles, including many not clinically affected by the polio; (2) prevalent spontaneous denervation potentials; and (3) abnormal single-fiber electromyographic jitter. These electromyographic abnormalities were similar in progressive and stable postpoliomyelitis patients even when muscles were separated by strength, stability, age and duration of the postpoliomyelitis state. Postpoliomyelitis muscular atrophy appears to be the clinically apparent end of the spectrum of abnormalities existing in all postpoliomyelitis patients.

Botulinum toxin therapy in hemifacial spasm: clinical and electrophysiologic studies.

Three patients with idiopathic hemifacial spasm were studied clinically and electrophysiologically before and after injections of botulinum toxin into the involved periocular and facial muscles. The spasms were improved for approximately 3 months, and the effect was repeatable on reinjection. The spasms diminished only as long as the muscles were clinically weak, and spasms were observed electromyographically even though therapy eliminated the clinical spasms. Uninjected muscles continued to have spasms. Transmission of excitation from the zygomatic branch to the marginal mandibular branch of the facial nerve and vice versa in all patients was unaltered after therapy, but the amplitude of the response was decreased. The efficacy of botulinum toxin in hemifacial spasm appears to be related to the production of muscle weakness; there is no demonstrable effect on phenomena believed to be ectopic excitation or ephaptic transmission in the facial nerve.

Stimulus artifact compensation using biphasic stimulation.

The feasibility of using biphasic stimulation as a method of reducing stimulus artifact was explored in several different circumstances. Sensory and muscle evoked potentials were compared using monophasic and biphasic constant-current stimuli. The monophasic stimulus was a negative rectangular pulse with a duration of 0.1-0.2 msec. The biphasic stimulus was a negative rectangular pulse of 0.1-0.2 msec duration followed, after a variable delay, by a positive rectangular pulse of the same duration and variable amplitude. When the conducting distances were long, stimulus artifact did not disturb either monophasically or biphasically evoked potentials. When the conducting distances were short, stimulus artifact occurred with monophasic stimulation but could be diminished readily using biphasic stimulation. The method can be accomplished easily using standard instruments with dual stimulators.

Myasthenia gravis. A well-understood neuromuscular disorder.

Myasthenia gravis is a disorder of neuromuscular function caused by autoimmunity to acetylcholine receptors and the postsynaptic region of the neuromuscular junction. Clinically, it is manifest by abnormal weakness and fatigability of skeletal muscle. Distribution and severity of weakness vary among patients. Most cases can be treated effectively with a combination of anticholinesterase inhibitors and glucocorticoids. Thymectomy is often recommended.

A long-term follow-up study of patients with post-poliomyelitis neuromuscular symptoms.

A "post-polio" syndrome characterized by new neuromuscular symptoms, including muscle weakness, may develop years after recovery from acute paralytic poliomyelitis. We studied 27 patients (mean age, 50.6 years) in whom new muscle weakness developed a mean of 28.8 years after recovery from acute polio. We reevaluated these patients during a mean follow-up period of 8.2 years (range, 4.5 to 20) after they were originally studied at the National Institutes of Health. The total mean follow-up period after the onset of new weakness was 12.2 years (range, 6 to 29). The patients were assessed with quantitative muscle testing, muscle biopsy, electromyography, and virologic and immunologic examination of the cerebrospinal fluid. Muscle strength had declined in all patients. The rate of decline averaged 1 percent per year. The decrease was irregular, with subjective plateau periods that ranged from 1 to 10 years. None of the patients had amyotrophic lateral sclerosis. Oligoclonal bands (IgG) were found in the cerebrospinal fluid of 7 of 13 patients studied, but no specific elevation of antibodies to poliovirus was observed in the cerebrospinal fluid. The newly affected muscles that were evaluated longitudinally with follow-up muscle biopsies and electromyography showed signs of chronic and new denervation. Groups of atrophic muscle fibers (group atrophy) and "neurogenic jitter" were not present. New post-polio muscle weakness is not a life-threatening form of motor-neuron deterioration. It appears that this weakness is not due to a loss of whole motor neurons, as in amyotrophic lateral sclerosis, but that it is due to a dysfunction of the surviving motor neurons that causes a slow disintegration of the terminals of individual nerve axons.

Primary writing tremor and myoclonic writer's cramp.

Four patients with primary writing tremor had a focal, task-specific tremor that responded to anticholinergic drugs. Physiologic features included EMG activity alternating in antagonist muscles, 5- to 20-microV cerebral potentials evoked by stretch of pronator teres, and no C-reflexes. Another patient had myoclonic jerks of the forearm on attempts to write ("myoclonic writer's cramp") that also responded to anticholinergic drugs; EMG activity appeared synchronously or alternating in antagonist muscles. These disorders have features of dystonia and enlarge the spectrum of writer's cramp.

Transient monocular visual loss from narrow-angle glaucoma.

Three patients had transient monocular visual loss from subacute attacks of narrow-angle glaucoma. In all three cases the visual loss had been previously diagnosed as being due to other neurologic causes.

No morphometric abnormality recurrent laryngeal nerve in spastic dysphonia.

Spastic dysphonia is a disorder of phonation that is usually markedly improved by surgical resection of one recurrent laryngeal nerve (RLN). In this study, biopsies of the RLN were obtained at surgery from nine patients with spastic dysphonia (disease group) and eight patients with laryngeal cancer (control group). The RLN was found to be composed of several nerve regions having characteristic fiber compositions. For the various nerve regions and for the whole nerve, we evaluated morphology, median fiber diameter, density, and size distribution of fibers. The morphologies of teased fibers were also evaluated. We found no significant differences between the nerves of the disease and control groups. Therefore, we were unable to verify previous reports of neuropathic abnormality of the RLN in spastic dysphonia.

Prostatic adenocarcinoma of ductal origin.

Adenocarcinomas that arise from primary or secondary prostatic ducts have distinctive histopathologic features. The age of patients, symptoms, findings on digital rectal examination and determinations of serum acid and alkaline phosphatase are similar to those of patients with acinic carcinomas. Carcinomas of secondary ducts may be less responsive to endocrine manipulation and of greater malignancy than carcinomas of primary ducts. The course and survival of patients with ductal carcinomas treated conservatively are poor.