Objective Neuromyelitis optica (NMO) is an inflammatory disease that affects the optic nerve and spinal cord. Optic neuritis and longitudinally extensive myelitis associated with systemic autoimmune disease have been recently defined as NMO spectrum disorder (NMOSD). In this study, we report the efficacy of intravenous cyclophosphamide (IVCY) therapy for NMOSD. Methods Four patients diagnosed with NMOSD were enrolled in this study. The expanded disability status scale (EDSS) score was used to evaluate the degree of severity. All of the patients received intravenous methylprednisolone (IVMP; 1 g/day for three days), and two patients also received plasmapheresis (PP). All of the patients were administered IVCY treatment. Results Anti-AQP4 antibodies were present in the sera of all patients. All patients exhibited longitudinally extensive transverse myelitis (LETM). Only one patient who fulfilled the criteria for a diagnosis of NMO exhibited optic neuritis. Two patients developed relapse under treatment with low-dose prednisolone (PSL) before the administration of IVCY. The patients in this study exhibited a median improvement in the EDSS score following IVCY treatment from 8.0 to 5.75. Adverse effects were observed in only one patient. Conclusion This study, despite its retrospective design, demonstrated the therapeutic efficacy of IVCY for NMOSD in both the acute and chronic phases of the disease and determined the IVCY dosage for Japanese women with NMOSD. Additionally, this study provided evidence that for NMOSD patients with severe disabilities, IVCY added to IVMP and PP may be a useful therapeutic modality.
Spinocerebellar ataxia (SCA) is a group of dominantly inherited heterogeneous disorders in which 43 subtypes have been identified to date. Recently, Japanese and French families with SCA type 42 (SCA42) were found to have a missense mutation (c.5144G>A; R1715H) in CACNA1G. We performed genetic analysis of 84 unrelated families to find the prevalence of SCA42 in Japan. Two families were found to have the previously reported missense mutation. Clinical presentations of the affected members of these families were similar to those of the previously reported French and Japanese families. Our study demonstrates that SCA42 exists in small numbers in Japan, and further supports the idea that SCA42 is a slowly progressive, pure cerebellar ataxia.
Cardiotrophin-1 (CT-1) has potent survival-promoting effects on motor neurons in vitro and in vivo and may be effective in treating motor neuron diseases (MND). We investigated the effects of CT-1 treatment in wobbler mouse MND. Wobbler mice were randomly assigned to receive subcutaneously injected CT-1 (1 mg/kg, n = 18, in two experiments) or vehicle (n = 18, in two experiments) daily, 6 times/week for 4 weeks after clinical diagnosis at age 3 to 4 weeks. Cardiotrophin-1 treatment prevented deterioration in paw position and walking pattern abnormalities. Grip strength declined steadily in the vehicle group, whereas in the CT-1 group it declined at week 1 but increased thereafter to exceed baseline strength by 5% (P = 0.0002) at week 4. Running speed was faster with CT-1 (P = 0.007). Biceps muscle twitch tension, muscle weight, mean muscle fiber diameter, and intramuscular axonal sprouting were significantly greater with CT-1 treatment than with vehicle treatment. Histometry revealed a trend that indicated CT-1 modestly increased the number of immunoreactive motor neurons, as determined by both choline acetyltransferase and c-Ret antibodies, and reduced the number of phosphorylated neurofilament immunoreactive perikarya (P = 0.05). The number of large myelinated motor axons significantly increased with treatment (206 versus 113, P = 0.01). We conclude that CT-1 exerts myotrophic effects as well as neurotrophic effects in a mouse model of spontaneous MND, a finding that has potential therapeutic implications for human MND.
Brain-derived neurotrophic factor (BDNF) is neuroprotective for motoneurons undergoing degeneration, including those in natural motor neuron disease (MND) in wobbler mice. To assess the role of BDNF in this model of MND, endogenous BDNF immunoreactivity was analyzed by semiquantitative video-image analysis. Affected cervical spinal cord motoneurons had significantly greater BDNF immunoreactivity compared to motoneurons of healthy littermates (P = 0.01) and affected lumbar spinal cord motoneurons (P = 0.008 at age 4 weeks; P = 0.005 at age 8 weeks). Neuronal nitric oxide synthase (n-NOS) immunocytochemistry revealed increased immunoreactivity in the affected cervical spinal cord motoneurons. Exogenous BDNF treatment partially inhibited the increased NOS activity, as quantitatively measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry. The mean number of NADPH-d(+) motoneurons in the cervical anterior horn decreased from 3.5 +/- 1.2 to 1.5 +/- 1.2 (P = 0.002). The increase in endogenous BDNF immunoreactivity in the affected spinal cord may be compensatory in diseased motoneurons, yet it appears to still be inadequate because exogenous BDNF treatment is required to suppress increased NOS activity in degenerating motoneurons. Our study indicates that BDNF is important in halting nitric oxide (NO)-mediated motor neuron degeneration, which has potential implications for the treatment of neurodegenerative disorders.
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