Since HLA-DQB1*0602 is associated with narcolepsy type1, involvement of autoimmune mechanisms in orexin neuron cell death is suggested. However, no strong evidence of inflammatory processes or immune abnormalities associated with narcolepsy exists, and studies have not found classical autoantibodies or an increase in oligoclonal CSF bands in narcoleptic patients. On the other hand, it remains possible that a transient autoimmune reaction restricted to the CNS occurs around disease onset but disappears later.
Orexin deficiency also is found in symptomatic narcolepsy and EDS cases in various neurologic conditions, including immune-mediated neurologic disorders. Although only a small number of multiple sclerosis (MS) patients develop narcolepsy, a subset predominantly shows EDS and REM abnormalities. Specific immune-mediated mechanisms likely are involved in these cases. Recent case reports of MS and related disorders associated with bilateral symmetric hypothalamic lesions, orexin deficiency, and EDS often share clinical neuromyelitis optica (NMO) symptoms. Some of these patients are seropositive for anti-AQP4 antibody, suggesting a functional link to the antibody; bilateral symmetric hypothalamic lesions and anti-AQP4 antibody may be caused by immuno-attack on AQP4 and thus secondarily affect orexin neurons.
Previously 6 cases that the paraneoplastic syndrome of limbic encephalitis associated with the anti-Ma2 antibody had been reported, we recently experienced 51 years old male case. In this case, the onset of narcolepsy symptom was much older than usual, so we suspected of symptomatic narcolepsy and measured anti-AQP-4 and anti-Ma2 antibodies. The result was anti-Ma2 positive. Since anti-Ma2 antibody would be associated with testis tumor at high prevalence, we consulted urologist. The left testis tumor was found and high orchiectomy was performed. The pathology of tumor was seminoma. After the operation, his appetite got better and he gained weight slowly. His agitation was remained, but he can control it by himself. His narcoleptic symptoms were not changed. We use 100mg modafinil for hypersomnia and 10mg clomiplamine for cataplexy. In contrast to NMO due to AQP4 antibody, distinct CNS lesions were not observed in anti-Ma2 encephalitis. Nevertheless, orexin deficiency was observed in this condition. This suggests that the orexin deficiency in this condition may occur at the neuron or ligand levels. Considering that the autoimmune hypothesis is the most popular theory for orexin cell death in narcolepsy, but no clear inflammation was observed in the hypothalamus, a subset of Ma2 antibody positive paraneoplastic syndrome that is associated with orexin deficiency, may be important models for studying.
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