Steven P. Ringel

Chronic changes in skeletal muscle histology and function in peripheral arterial disease.

BackgroundPeripheral arterial disease (PAD) is associated with an impairment in exercise performance and muscle function that is not fully explained by the reduced leg blood flow during exercise. This study characterized the effects of PAD on muscle function, histology, and metabolism. Methods and ResultsTwenty-six patients with PAD and six age-matched control subjects were studied. Ten of the PAD patients had unilateral disease, which permitted paired comparisons between their diseased and nonsymptomatic legs. All PAD patients had a lower peak treadmill walking time and peak oxygen consumption than controls. Vascular disease (diseased leg in unilateral patients and the most severely diseased leg in bilateral patients) was associated with decreased calf muscle strength compared with control values. In patients with unilateral disease, the diseased legs had a greater percentage of angular fibers (indicating chronic denervation) and a decreased type H fiber cross-sectional area (expressed as percent of total fiber area) compared with the nonsymptomatic, or control, legs. In diseased legs, gastrocnemius muscle strength was correlated with the total calf cross-sectional area (r=0.78, p<0.05) and type II fiber cross-sectional area (r=0.63, p<0.05). Activities of citrate synthase, phosphofructokinase, and lactate dehydrogenase in all 26 PAD patients (most diseased leg) did not differ from control values. Despite a wide range in citrate synthase activity in PAD patients, activity of this enzyme was not correlated with muscle strength or treadmill exercise performance. ConclusionIn patients with PAD, gastrocnemius muscle weakness is associated with muscle fiber denervation and a decreased type II fiber cross-sectional area. In contrast, the PAD patients displayed substantial heterogeneity in muscle enzyme activities that was not associated with exercise performance. Denervation and type H fiber atrophy may contribute to the muscle dysfunction in patients with PAD and further confirm that the pathophysiology of chronic PAD extends beyond arterial obstruction.

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.

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.

Suprascapular neuropathy in pitchers

The clinical features and preoperative and postopera tive electrodiagnostic studies were reviewed in two professional pitchers with a suprascapular neuropathy. These studies demonstrate that denervation of the infraspinatus and/or supraspinatus muscle is not al ways due to entrapment of the nerve at the suprascap ular or spinoglenoid notches, as is often proposed. Similar studies in healthy pitchers during spring training and again at midseason demonstrate that slowing of suprascapular nerve conduction is detectable in some cases as the season progresses. Sagittal sections of a cadaver with the arm fixed in the acceleration phase of the pitching motion demon strate five possible sites of trauma to the suprascapular nerve. Mechanisms proposed to explain these progres sive, but potentially reversible, changes include consid eration of biomechanical factors as well as anatomical features. An alternative hypothesis to nerve trauma that explains this symptom complex is intimal damage to the axillary or suprascapular artery and subsequent production of microemboli which become trapped in the suprascapular nerve vasa nervorum.

Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency: Diagnosis and treatment with alpha tocopherol

We have studied four children (ages 6 to 17 years) with chronic cholestasis who developed a slowly progressive neuromuscular disease characterized by ataxia, dysmetria, areflexia, loss of vibratory sensation, and a variable ophthalmoplegia. Serum vitamin E concentration were low in all patients prior to treatment. Muscle histochemical studies in all four patients showed autofluorescent basophilic esterase and acid phosphatase-positive cytoplasmic inclusions and occasional necrotic fibers. These distinctive muscle changes are similar to those described in vitamin E-deficient animals. Intramuscular injections of alpha tocopherol were required in three patients to achieve normal serum vitamin E values. High-dose oral supplementation was effective in one patient. After normalization of serum vitamin E concentrations for six to 14 months, the neurologic disease has improved in all four patients.

Lack of Tocopherol in Peripheral Nerves of Vitamin E-Deficient Patients with Peripheral Neuropathy

Vitamin E deficiency is often associated with symptoms of a peripheral neuropathy. To evaluate whether vitamin E deficiency affects the vitamin E content of the peripheral nervous system, we measured the alpha-tocopherol content in biopsy specimens of sural nerve and adipose tissue from 5 patients with symptomatic vitamin E deficiency (2 with homozygous hypobetalipoproteinemia and 3 with familial isolated vitamin E deficiency) and 34 control patients with neurologic diseases without vitamin E deficiency. A significant reduction in tissue tocopherol content was present in the vitamin E-deficient patients, as compared with the controls, both in sural nerves (1.8 +/- 1.2 vs. 20 +/- 16 ng per microgram of cholesterol [P less than 0.001], or 7.7 +/- 5.4 vs. 64 +/- 44 ng per milligram of wet weight [P less than 0.01]) and in adipose tissue (46 +/- 43 vs. 222 +/- 111 ng per milligram of triglyceride [P less than 0.001]). Levels of tocopherol in adipose tissue were significantly correlated (P less than 0.001) with levels in peripheral nerves. The low tocopherol content of the nerves preceded histologic degeneration in three vitamin E-deficient patients, suggesting that the nerve injury resulted from the low nerve tocopherol content.

End-of-life care: A survey of US neurologists’ attitudes, behavior, and knowledge

Objective: The American Academy of Neurology (AAN) surveyed the attitudes, behavior, and knowledge of its members regarding care at the end of life. Three groups of AAN members were surveyed: neuro-oncologists, ALS specialists, and a representative sample of US neurologists. Methods: The survey presented two clinical scenarios involving end-of-life care. Neurologists were asked a series of questions to assess their knowledge of existing medical, ethical, and legal guidelines; their willingness to participate in physician-assisted suicide (PAS) or carry out voluntary euthanasia (VE); and their general attitudes regarding end-of-life care. Results: Neurologists support a patient’s right to refuse life-sustaining treatment, but many believe that they are killing their patients in supporting such refusals. Thirty-seven percent think it is illegal to administer analgesics in doses that risk respiratory depression to the point of death. Forty percent believe they should obtain legal counsel when considering stopping life-sustaining treatment. One half believe that PAS should be made explicitly legal by statute for terminally ill patients. Under current law, 13% would participate in PAS and 4% would carry out VE; if those procedures were legalized, 44% would participate in PAS and 28% in VE. Approximately one third believe that physicians have the same ethical duty to honor a terminally ill patient’s request for PAS as they do to honor a such a patient’s refusal of life-sustaining therapy. Conclusions: There is a gap between established medical, legal, and ethical guidelines for the care of dying patients and the beliefs and practices of many neurologists, suggesting a need for graduate and postgraduate education programs in the principles and practices of palliative care medicine. Many neurologists would participate in PAS and carry out VE if legalized.

The relationship of age to outcome in myasthenia gravis

This study, a retrospective review of 165 patients with myasthenia gravis, compares the course of the disease for patients with onset before 50 and at or after 50. There were no significant differences between age groups for presenting symptoms, but more of the older patients had progressed to severe disease. More of the younger than the older patients were in remission or were asymptomatic on medication at the last visit. Sixty-two percent of those treated with steroids developed complications, with a larger portion of these being in the older group. Cataracts, infection, and bone changes were particularly significant for the older population. Complications of azathioprine treatment and plasmapheresis were less common. Thymoma was more common in the older population; these patients did no worse than the population as a whole. Sixty-five percent of our patients have undergone thymectomy, most by a modified transsternal approach. A much larger portion of those who underwent thymectomy were in remission at the last visit than those who did not.

Diabetic muscle infarction: A new perspective on pathogenesis and management

Two patients with insulin dependent diabetes mellitus developed recurrent episodes of focal muscle pain and swelling. Clinical evaluation, magnetic resonance imaging (MRI) and muscle biopsy confirmed the diagnosis of recurrent hemorrhagic muscle infarctions. Our studies suggest that muscle infarction occurred because of hypercoagulability and associated vascular endothelial damage. Based on these findings we recommend long-term anticoagulation to prevent recurrent infarction.

The ALS Patient Care Database Goals, design, and early results

Objective: The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials. Background: Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now. Methods: This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists. Results: Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years ± 12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2 ± 1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died. Conclusions: The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.