[Limbic encephalitis up to date].

Limbic encephalitis (LE) refers to an inflammatory disorder involving the hippocampus, amygdala and insular cortex. LE is now regarded as a more frequent disorder than it was previously thought, and the concept of LE has been expanded because of the development of neuroimaging and the increasing recognition of the associated antibodies. We categorized LE into 5 groups. LE caused by virus infection, autoantibody-mediated LE, LE with autoimmune disease, LE associated with drugs and LE during pregnancy. LE having the antibodies against intracellular antigens frequently related to cancer and are resistant to treatment. While, LE with antibodies against cell-membrane antigens, including NMDAR, AMPAR, GABA(B)R, VGKC, tend to respond better to antitumor therapy and immunotherapy.

[Limbic encephalitis--history,symptoms,and the latest classification].

The concept of limbic encephalitis has changed over time. Since the introduction of "limbic encephalitis" (LE) in 1968, LE was thought to almost always be associated with carcinoma; this belief led to the coining of the term "paraneoplastic limbic encephalitis" (PLE). In the 1990s, antineuronal antibodies, including anti-Hu and anti-Ta/Ma2, were detected; this supported the hypothesis of an autoimmune mechanism for PLE. The prognosis of patients with PLE was, however, poor. Since 2001, there have been reports of patients with LE exhibiting antibodies to the voltage-gated potassium channel; this observation is intriguing because in such cases the encephalitis was usually independent of carcinoma, and its clinical course was often reversible. Since the 1990s, cases of non-herpetic acute limbic encephalitis have been reported in Japan. In some of these cases, an autoantibody to GluRepsilon2 (NR2B) has been detected; GluRepsilon2 is a subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor found in the limbic forebrain. A postulated pathophysiologic role of this antibody led to the concept of autoantibody-mediated acute reversible LE (AMED-ARLE). In 2007, some patients with ovarian teratoma developed encephalitis and exhibited antibodies to the NMDA receptor; this antibody is thought to recognize NR1/NR2 heteromers. Later, anti-NMDA receptor antibodies were also detected in some Japanese patients who had been previously diagnosed with juvenile acute non-herpetic encephalitis. Currently, limbic encephalitis is categorized into 3 groups: limbic encephalitis caused by virus infection, autoantibody-mediated limbic encephalitis (AMLE), and limbic encephalitis with autoimmune disease. In AMLE, antibodies to cytoplasmic antigens cause classical PLE (type I). In contrast, antibodies to cell membrane antigens often cause reversible limbic encephalitis in patients with (PLE type II) or without tumors (AMED-ARLE).

[Limbic encephalitis: the new cell membrane antigens and a proposal of clinical-immunological classification with therapeutic implications]. / Encefalitis límbica: los nuevos antígenos y propuesta de una clasificación clinicoinmunológica con implicaciones terapéuticas.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Limbic encephalitis and variants: classification, diagnosis and treatment.

BACKGROUND AND OBJECTIVE: Recent studies suggest that a substantial number of patients with autoimmune limbic encephalitis may improve if properly diagnosed and treated. This is due, in part, to the increasing recognition of disorders that associate with antibodies to neuronal cell membrane antigens. This review focuses in these disorders, framed in a clinically useful immunologic classification of limbic encephalitis. REVIEW SUMMARY: Patients with limbic encephalitis usually present with rapidly progressive short-term memory deficits, psychiatric symptoms, and seizures. After excluding viral and systemic autoimmune disorders, many patients with limbic encephalitis (paraneoplastic or not) have cerebrospinal fluid inflammatory findings, EEG or MRI abnormalities in the temporal lobes, and antineuronal antibodies. These antibodies are directed against 2 broad categories of antigens: (1) intracellular or classic paraneoplastic antigens, including Hu, Ma2, CV2/CRMP5, and amphiphysin among others, and (2) cell membrane antigens, including voltage-gated potassium channels, N-methyl-D-aspartate receptor, and others expressed in the neuropil of hippocampus and cerebellum (pending characterization). Whereas the disorders related to the first category of antibodies associate with cancer (lung, testis and other), prominent brain infiltrates of cytotoxic T-cells, and limited response to treatment, the disorders related to the second category of antibodies associate less frequently with cancer (thymoma, teratoma), seem to be antibody-mediated, and respond significantly better to immunotherapy. CONCLUSIONS: Once considered an extremely rare disorder, almost always related to cancer, and refractory to treatment, limbic encephalitis is now regarded as a relatively frequent disorder, often unrelated to cancer, and with clinical-immunologic variants that respond to treatment.