Hans E. Neville

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.

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.

Phase II/III randomized trial of TCH346 in patients with ALS

Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patients rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Reducing body myopathy

Case 1. This girl was born following a normal pregnancy. Delivery was one month prior to the expected date. Birth weight was 4 lb. 12 oz. She had no immediate problems during the neonatal period and was not noted to have any difficulty feeding. She was a floppy baby. Her parents are not certain when this was f i s t noted but it was definitely before 8 weeks of age. At 6 months she could just lift her head from the pillow when lying on her stomach but could do nothing else. At 8 months she would sit u p right when placed in that position but would not pull herself to a sitting position. At 9 months of age it was noted that she had bilateral contractures of the calf muscles. Mentally she appeared very bright and was speaking complete sentences by the age of 14 months. Shortly before her death, at 30 months of age, she was able to sit in a chair, feed herself, and, with some help, pedal a small tricycle. She could not, however, roll over, support her own weight when standing, or pull herself to a sitting position. At the age of 21 months she developed pneumonia for the first time. Because of difficulty with her respiratory muscles a tracheostomy was performed and she was placed in an intensive care unit. She recovered from this bout of pneumonia but at the age of 23 months had a second attack and was seen for the first time at the University of Colorado Medical Center. A t this time she was found to be atonic with wasting of both the proximal and the distal musculature. She had mild ptosis of both eyes and slight facial weakness bilaterally. Contractures of both gastrocnemii were present, and there were some contractures of the muscles of the forearm and upper arm bilaterally (Fig. 1). N o dysphagia or dysarthria was noted either at this admission or subsequently. The deep tendon reflexes were uniformly depressed. Plantar responses were flexor. There were no sensory abnormalities. No family history of muscle disease was obtained. A serum creatine phosphokinase (CPK) was within normal limits, as were other serum enzymes. The electromyographic findings of slightly short polyphasic potentials and a normal nerve conduction velocity were felt to indicate a myopathic picture. At 26 months she was again seen because of pneumonia, this time accompanied by bilateral pitting edema of the legs. No evidence of cardiac or renal disease was found and the edema disappeared spontaneously as the pneumonia improved. From this time on she had a constant difficulty with breathing. Her vital capacity vaned between 50 and 80 cc. She was discharged from the hospital requiring a respirator and died suddenly from respiratory failure at the age of 2% years. The muscle biopsy at the time of the f i s t admission was identical to a sample obtained postmortem and is discussed below. Only a limited autopsy was carried out but no abnormalities of heart, liver, or skin were found. No other laboratory studies relevant to the muscle disease were done. Case 2. This girl died at the age of 9 months following a progressive myopathy. She weighed 7 lb. 11 oz. at birth, and the pregnancy was described as entirely normal. I t was noted within a few days after birth that she was abnormally floppy. There was no problem with feeding nor was any specific muscle weakness noted during the f i s t few months. However, at 4 months her pediatrician observed that the child was unable to hold her head up. No family history of muscle disease was obtained. Examination at this time revealed an alert, happy child with no evidence of mental retardation. She was quite markedly hypotonic and had some proximal weakness. No abnormality was noted in the cranial nerves and sufficient strength was

Clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy

OBJECTIVE To describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM. METHODS Clinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis. RESULTS The clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002). CONCLUSION These findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM.

Familial inclusion body myositis : evidence for autosomal dominant inheritance

We report a kindred manifesting clinical features and muscle biopsy findings of inclusion body myositis (IBM). In this family, multiple members were affected in two generations with direct male-to-male and female-to-male transmission. This is the first reported instance of autosomal dominant inheritance in IBM, which usually occurs sporadically or, rarely, may be transmitted as an autosomal recessive disorder.

Ultrastructural and histochemical abnormalities of skeletal muscle in patients with chronic vitamin E deficiency

We report muscle biopsy abnormalities in four patients with a chronic cholestatic syndrome, low serum vitamin E levels, absent reflexes, mild limb weakness, ataxia, and sensory loss in arms and legs. Skeletal muscle fibers contained multiple autofluorescent inclusions that show strong acid phosphatase and esterase reactivity. By electronmicroscopy, the inclusions lying between myofibrils were membrane-bound dense bodies having characteristics of both lysosomes and lipopigment material. The material was similar to that observed in vitamin E-deficient animals and probably formed in response to disordered intracellular lipid peroxidation.

Friedreich's disease V. Variant form with vitamin E deficiency and normal fat absorption

A 30-year-old woman was thought to have Friedreichs disease because of progressive ataxia, dysarthria, and titubation from age 3 years. Her diet was normal, and there were neither symptoms nor laboratory evidence of liver disease or fat malabsorption. Serum vitamin E content and the ratio of serum vitamin E to total serum lipid were very low, but serum vitamin A, cholylglycine, and lipid levels were normal, as was an oral vitamin E tolerance test. Muscle biopsy showed the lysosomal inclusions of vitamin E deficiency. Mitochondria had normal oxidative phosphorylation using polarographic assays. The cause of her vitamin E deficiency was unknown.

Using the Frontal Assessment Battery to identify executive function impairments in amyotrophic lateral sclerosis: A preliminary experience.

Up to 50% of persons with amyotrophic lateral sclerosis (ALS) develop cognitive impairments, particularly of executive function (EF). The Frontal Assessment Battery (FAB) provides a method for rapid assessment of EF. We investigated the FAB as an assessment of cognitive impairment among 16 subjects with ALS, and evaluated their performance on the FAB and the Mini-Mental State Examination (MMSE). Raw FAB and MMSE scores were Z-transformed using published age- and education-based norms. FAB Z-scores were significantly lower than MMSE Z-scores (p<0.03). Eight subjects (50%) were impaired (Z ≤ −2) on the FAB while no subjects were impaired on the MMSE. MMSE and FAB scores did not vary as function of disease duration, laterality of onset, or Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Further study of the suitability of the FAB as a domain-specific screening measure of executive dysfunction for ALS is warranted.

Western ALS study group

As a prelude to carrying out ALS clinical trials, our Western ALS (WALS) study group carried out a natural history study of 167 ALS patients using 42 strength and functional efficacy assessments at monthly intervals at 5 centers. The results demonstrated that declining pulmonary function correlated closely with death. The study also highlighted the variability in measurements and the importance of vigorous training and monitoring.