Kotaro Mizutani

Tumor necrosis factor-α in peripheral nerve lesions

Abstract Immunocytochemical expression of tumor necrosis factor-α (TNF-α) was examined in nerve biopsy samples of patients with various disorders, focusing on nerve injury. TNF-α was mainly associated with phagocytosing macrophages in acute axonal injury, but the staining was more frequently seen in sections from patients with vasculitis than with metabolic neuropathy. Ramified macrophages outside nerve fibers were also positive for TNF-α in the acute stage of vasculitis. In active demyelinating lesions from patients with chronic inflammatory demyelinating neuropathy (CIDP), macrophages outside nerve fibers showed weak staining with TNF-α, but the cells adhering to myelinated nerve fibers showed definite staining. This may be due, in part, to the smouldering course of CIDP, and expression may be up-regulated transiently during the demyelinating process. These results indicate that macrophages, as the effector cells for both axonal injury and active demyelination, express TNF-α, but their activation mechanisms may vary among vasculitis, metabolic axonopathy and inflammatory demyelination.

Chronic motor axonal neuropathy associated with antibodies monospecific for n‐acetylgalactosaminyl GD1a

We report on three patients with chronic motor neuropathy who had elevated titers of immunoglobulin (Ig)G antibodies against N‐acetylgalactosaminyl GD1a (GalNAc‐GD1a) and normal titers of antibodies against other gangliosides. Presenting with progressive muscular atrophy, fasciculations, and no sensory deficits, the patients had been diagnosed to have motor neuron disease. Electrodiagnostic features were predominantly axonal. Two patients clinically improved after intravenous Ig infusion and cyclophosphamide therapy. Increased titers of IgM antibodies to GalNAc‐GD1a were also found in two of 15 patients with multifocal motor neuropathy with conduction block but were associated with concomitant rise of anti‐GM1 antibodies. These three cases represent a chronic motor axonal neuropathy in which antibody testing for a minor ganglioside was helpful for instituting therapy.

Hypoxia-inducible factor 1α may be a marker for vasculitic neuropathy

Neuromuscular biopsy is still an essential method for diagnosing vasculitic neuropathy, although its diagnostic sensitivity is at most 60%. Our objective was to examine the expression of hypoxia‐inducible factor 1α (HIF‐1α) in peripheral nerves and to evaluate its usefulness in diagnosing vasculitic neuropathy, especially for discrimination from other axonal neuropathies. Forty‐one patients with vasculitic neuropathy consisting of 20 definite, 14 probable and seven possible diagnoses, 15 patients with metabolic neuropathy, five with motor neuron disease and six with chronic inflammatory demyelinating polyneuropathy were included. Nerve biopsy specimens were immunohistochemically examined for HIF‐1α and various cell markers. Distinct immunoreactivity (IR) was observed in nuclei of endoneurial cells in 54% (22/41) of vasculitic patients, while specimens from metabolic neuropathies showed less nuclear IR and the difference of mean density of HIF‐1α‐positive nuclei was significant. Two patients with possible vasculitis who showed HIF‐1α‐positive nuclei in endoneurium, were later confirmed to have vasculitis by skin biopsies. Most of the cells expressing HIF were demonstrated to be Schwann cells. There was a trend in the vasculitic patients with early phase nerve damage to display higher endoneurial HIF‐1α‐IR. HIF‐1α may be an immunohistochemical marker for vasculitic neuropathy, especially when the observed section contains no vasculitic lesions.

Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter.

Departments of a Neurology and b Nuclear Medicine and Diagnostic Imaging and c Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto , d Department of Neurology, Sakakibara Hakuho Hospital, Mie , Departments of e Neurology and f Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata , and g Department of Speech Physiology, Graduate School of Medicine, University of Tokyo, Tokyo , Japan

CD16+CD57– Natural Killer Cells in Multifocal Motor Neuropathy

We analyzed the CD16+CD57– lymphocyte subset, which is considered to have strong natural killer (NK) cell activity, in peripheral blood from patients with chronic immune-mediated neuropathies and patients with other neurological diseases. We found that the ratio of CD16+CD57– NK cells to total lymphocytes was increased in 4 of 6 patients with multifocal motor neuropathy (MMN) with persistent conduction block. Since the CD16 molecule is an Fc receptor for immunoglobulin G (IgG), high-dose intravenous immunoglobulin (IVIg) may interfere with CD16+CD57– NK cells via Fc receptor blockade. In addition, cyclophosphamide (Cy) is often used to suppress NK cells. Therefore, our findings may partly account for the effectiveness of IVIg or Cy, which is the current treatment of choice for MMN.

Sensorimotor demyelinating neuropathy with IgM antibody against gangliosides GD1a, GT1b and GM3

We report a patient with sensorimotor demyelinating neuropathy with high-titer IgM antibody against gangliosides GD1a, GT1b and GM3. The patient was a 65-year-old male who was hospitalized with chief complaints of muscular weakness of all limbs and numbness of the hands and feet. Nerve-conduction studies revealed reduced conduction velocities of the motor nerves with increased temporal dispersion and loss of sensory nerve action potentials. Treatment with steroids was ineffective. IgM antibody against GD1a, GT1b and GM3, which are known to be the ligands for myelin-associated glycoprotein (MAG), might have played a role in the demyelination in this patient by inhibiting adhesion between myelin and axonal membrane.

Enhancement of TNF-α production by ganglioside GM2 in human mononuclear cell culture

Some gangliosides have been regarded as autoantigens of immune-mediated neurological disorders such as Guillain-Barre syndrome (GBS), Miller Fisher syndrome and multifocal motor neuropathy. On the other hand, proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), may be important in the pathogenesis of some neuroimmunological disorders. To clarify the interactions between immune cells and gangliosides, we investigated the effects of gangliosides on the production of proinflammatory cytokines in peripheral blood mononuclear cell (PBMC) cultures. We found that ganglioside GM2 markedly enhances the production of TNF-alpha and that TNF-alpha induction by coated GM2 is still more marked. These findings suggest that immune cells, especially monocytes/macrophages, cause inflammation upon encountering GM2.

Adult-onset leukoencephalopathy with vanishing white matter

Abstract Leukoencephalopathy with vanishing white matter is a new disease entity with characteristic features of MRI. This disease usually occurs in children and is thought to be rare, particularly in the non-Caucasian population. We present an adult-onset Japanese case of leukoencephalopathy with vanishing white matter. MRI findings in this case included linear high signal intensity on T2-weighted and fluid-attenuated inversion recovery images in the pons in addition to typical abnormalities in the cerebral white matter.