We studied 74 patients with progressive, asymmetrical lower motor neuron syndromes. Clinical features of these patients, including age, sex, disease duration, patterns of weakness, and reflex changes, were evaluated by review of records. In each patient the clinical features were compared to the type of nerve conduction abnormalities and to the specificities of high-titer serum antiglycolipid antibodies. Antibody specificities were determined by an enzyme-linked immunosorbent assay using purified glycolipids and carbohydrates as substrates. Our results show that high titers of antibodies to glycolipids are common in sera of patients with lower motor neuron syndromes. Selective patterns of reactivity indicate that specific carbohydrate epitopes on the glycolipids are the targets of the high-titer antibodies in individual patients with lower motor neuron syndromes. Several distinct lower motor neuron syndromes can be identified based on clinical, physiological, and antiglycolipid antibody characteristics. These syndromes include multifocal motor neuropathy with evidence of multifocal conduction block on motor, but not sensory, axons and frequent (84%) high titers of anti-GM1 ganglioside antibodies; a lower motor neuron syndrome with predominantly distal weakness early in the disease course, no conduction block, and a high incidence (64%) of anti-GM1 antibodies; and a lower motor neuron syndrome with predominant early weakness in proximal muscles and serum antibodies to asialo-GM1 that do not cross-react with GM1 ganglioside.

Hindlimb hypokinesia was induced in rats by the Morey method to characterize the response of the soleus muscle. Rats suspended for 1-4 wk exhibited continuous and significant declines in soleus mass, function, and contractile duration. Soleus speeding was in part explained by an alteration in fiber type. The normal incidence of 70-90% type I fibers in the soleus muscle was reduced after 4 wk of suspension to 50% or less in 9 of 11 rats. A significant decline in type I myosin isozyme content occurred without a change in that of type II. Other observed histochemical changes were characteristic of denervation. Consistent with soleus atrophy, there was a significant increase in lysosomal (acid) protease activity. One week of recovery after a 2-wk suspension was characterized by a return to values not significantly different from control for muscle wet weights, peak contraction force, one-half relaxation time, and type I myosin. Persistent differences from control were observed in maximal rate of tension development, contraction time, and denervation-like changes.

We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

Three months after gastric partitioning for morbid obesity, two patients developed an unusual and severe form of polyneuropathy that affected their sense of position maximally. This disorder produced severe ataxia of the upper extremities and trunk, and pseudochorea. One patient died and the autopsy showed an extensive demyelinating polyneuropathy. Neuronal cell bodies in the anterior horns and dorsal root ganglia showed extensive accumulations of lipofuscin and Schwann cells showed extensive accumulations of lipid. This neuronal and Schwann cell lipidosis appears to result from starvation of the obese and has never been reported in other forms of human starvation or nutritional deficiency.

Examination of oxidative metabolism in mitochondria isolated from quadriceps skeletal muscle biopsy specimens of 4 patients with Kearns-Sayre syndrome has shown that the mitochondria were tightly coupled, with maximal respiratory rates depending on the presence of adenosine diphosphate (ADP), Ca2+, or uncoupler. The state 3 respiratory rates with nicotinamide adenine dinucleotide (NAD)-linked substrates and succinate were much lower than those of control subjects. The cytochrome oxidase activities (measured with ascorbate + phenazine methosulfate as substrates) were also decreased, but this segment of the respiratory chain was not rate-limiting for succinate or NAD-linked substrate oxidation. Analyses of the steady-state reduction kinetics of the respiratory chain carriers revealed that the rate-limiting step of the impaired respiration with succinate or NAD-linked substrates lies between the c cytochromes and cytochrome oxidase. Measurement of the total substrate-reducible (at anaerobiosis) and chemically reducible levels of the cytochromes in mitochondria from 3 patients showed a severe deficiency of cytochrome a + a3 and an excess of the c cytochromes. To our knowledge, this is the first instance in which a mitochondrial electron transfer defect and cytochrome oxidase deficiency has been shown to be associated with an excess of the c cytochromes.