[Limbic encephalitis: the new cell membrane antigens and a proposal of clinical-immunological classification with...

Most studies of patients with limbic encephalitis, paraneoplastic or not, use rigid clinical-radiological entry criteria or select patients previously known to have cancer or to harbor well characterized paraneoplastic antibodies. In practice this selection excludes a significant number of patients with autoimmune encephalitides, some of which may represent new disorders.

Review of the literature and our clinical experience with patients with limbic encephalitis. Description of the studies that led to the identification of new antibodies and antigens related to several types of autoimmune encephalitis.

82 % of prospectively identified patients with non-viral limbic encephalitis at our institution had 526 antibodies against proteins of the CNS. These antibodies were directed against two category of antigens: a) intracellular or classical paraneoplastic antigens (Hu, Ma2, among other), and b) cell membrane antigens including the voltage-gated potassium channels and the newly identified antigens of the neuropil of hippocampus. Each category of antigens included several subgroups with distinctive clinical-immunological associations. While the encephalitides related to intracellular antigens are predominantly mediated by cytotoxic T-cell mechanisms and are poorly responsive to treatment, those related to cell membrane antigens appear to be mediated by antibodies and often respond to treatment. Among the newly identified antigens, the NR1/NR2B heteromers of the NMDA receptor are of great interest due to their critical role in synaptic plasticity and memory. Patients with antibodies against these receptors are young women with benign-appearing cystic tumors of the ovary (mature or immature teratomas), who develop a severe and characteristic encephalitis that we report in detail. Despite the severity of the disorder, patients often recover after treatment of the tumor and immunotherapy.

Approximately 40 % of patients with classical or atypical limbic encephalitis develop relevant immune responses that are not identified by currently available commercial tests. Different from the previously known paraneoplastic antigens, which location is intracellular and associate with syndromes that are poorly responsive to treatment, the newly identified antigens of the neuropil of hippocampus are in the neuronal cell membrane and the related syndromes, although severe and potentially lethal, often respond to treatment.