Rinsho Shinkeigaku (Clinical Neurology)


Rasmussen encephalitis and non-herpetic acute limbic encephalitis

Yukitoshi Takahashi, M.D., Yuko Kubota, M.D., Etsuko Yamasaki, M.D. and Kazumi Matsuda, M.D.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders

Rasmussen syndrome (RS) and non-herpetic acute limbic encephalitis (NHALE) have pathophysiological background related with autoimmunity to glutamate receptors (GluRs) after infections. RS and NHALE were reviewed, depending mainly on our recent studies.
RS is the prototype of autoimmune-mediated epilepsy. In patients with RS, several kinds of autoantibodies against neuronal molecules, for example, GluR3, GluRε2 (NMDA-R2B), etc., are reported. These autoantibodies are not specific for RS. About autoantibodies against GluR3, significance and stimulating effects to GluR3 are controversial. Autoantibodies against GluRε2 were detected in all patients within six months from epilepsy onset, and in some patients at chronic stage. These data suggest that autoantibodies against GluRε2 may be involved in the pathological mechanisms in the early stage, but we could not confirm the effect of the autoantibodies from RS patients on excitatory postsynaptic NMDA current using patch clump methods. However, anti-double-stranded DNA antibodies in patients with SLE are reported to cross-react with n-terminal of GluRε2, and cause neuronal apoptosis in rat hippocampus, ensuing memory impairment, and emotional behavior impairment in mice. Therefore, autoantibodies against GluRε2 may contribute to the cognitive and behavioral changes in RS.
Concerning about cellular immunity in RS, lymphocytes stimulating tests revealed peripheral lymphocytes sensitized by antigens containing GluRε2. Cytotoxic T cells (CTLs) excreting Granzyme B were reported in resected brain tissue, and we confirmed the elevated levels of Granzyme B, not in sera, but in CSF. These data suggest that CTLs activated by infection invade into CNS, and recognize neural antigens, and excrete Granzyme B.
The incidence of NHALE is 4.1/1 million/year in Japanese adults. Our study in 91 adult patients with NHALE revealed the following characteristics. Mean onset age was 35.2±16.9 years old, and preceding infections existed in 68.7% of patients, and predominant symptoms at the onset were psychiatric symptoms (33.3%) and convulsions (25.0%). CSF showed slightly elevated cell counts (55.5±139.9), protein levels (48.1±36.0 mg/dl), and IgG levels (4.5±3.9 mg/dl). MRI lesions with high intensity were found in 40.8% (DWI) and 54.2% (FLAIR) of patients in various stages after onsets.
Autoantibodies against GluRε2 in sera were detected in approximately 60% of NHALE patients from acute to chronic stages, and the autoantibodies in CSF were detected in 51.8% (acute stage), 41.4% (recovery stage), 28.6% (chronic stage) of patients and included epitopes to n-terminal of GluRε2 (NT1). These data suggest that autoantibodies against GluRε2 produced in sera after infection infiltrate into CNS through damaged BBB in acute stages, and affect n-terminal of GluRε2. In chronic stage, recovery of function of BBB reduces levels of the autoantibodies in CSF. Because BBB in hippocampi and amygdala are vulnerable, autoantibodies against GluRε2 including epitopes to n-terminal may contribute to the limbic symptoms around onset. Among several autoantibodies related with NHALE, autoantibodies against GluRε2 were found in patients around 15-34 years old, autoantibodies against VGKC were around 50.4 years old, autoantibodies against NAE were around 59 years old, autoantibodies against Hu were around 61.5 years old. These data suggest that autoantibodies related with NHALE have age-dependent heterogeneity.
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(CLINICA NEUROL, 48: 163|172, 2008)
key words: Rasmussen's syndrome, cytotoxic T cells, autoantibodies, glutamate receptor, acute limbic encephalitis

(Received: 8-Jan-08)