Some humans develop the axonal form of Guillain-Barré syndrome after receiving bovine brain ganglioside. On sensitization with the ganglioside mixture, all of a group of rabbits injected developed high anti-GM1 IgG antibody titers, flaccid limb weakness of acute onset, and a monophasic illness course. Pathological findings for the peripheral nerves showed predominant Wallerian-like degeneration, with neither lymphocytic infiltration nor demyelination. IgG was deposited on the axons of the anterior roots, and GM1 was proved to be present on the axons of peripheral nerves. Sensitization with purified GM1 also induced axonal neuropathy, indicating that GM1 was the immunogen in the mixture. A model of human axonal Guillain-Barré syndrome has been established that uses inoculation with a bovine brain ganglioside mixture or isolated GM1. This model may help to clarify the molecular pathogenesis of the syndrome and to develop new treatments for it.

Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

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To extend earlier observations on Schwann cell remyelination in multiple sclerosis (MS) lesions (Itoyama et al. 1983) we immunostained spinal cord sections from eight Japanese MS patients with antiserum to Po glycoprotein, a major constituent of peripheral nervous system (PNS) myelin, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP). Spinal cord sections from six of the eight Japanese MS patients contained large clusters of peripheral myelin sheaths with anti-Po immunoreactivity. In lesions found in four of the six patients, thousands of Po-stained PNS myelin sheaths were present. Necrosis was prominent in these lesions which included more than half of the spinal cord's transverse area. The number and density of regenerating myelin sheaths of peripheral origin were much greater than we observed in MS spinal cord lesions of white people (Itoyama et al. 1983). Anti-GFAP immunoreactivity was present in most brain and spinal cord lesions. However, the areas in lesions that contained large groups of PNS myelin sheaths lacked anti-GFAP immunoreactivity. Our data suggest that spinal MS lesions that are large, severely demyelinated, and partially necrotic may contain factors that inhibit fibrous astrogliosis. These factors, other substances in the large lesions and/or the lack of astrocytic scarring could then promote Schwann cell invasion, multiplication, and remyelination of surviving axons.

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