Background
Limbic encephalitis (LE) frequently associates with antibodies to cell surface antigens. Characterization of these antigens is important because it facilitates the diagnosis of those disorders that are treatment-responsive. We report a novel antigen of LE and the effect of patients' antibodies on neuronal cultures.
Methods
Clinical analysis of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. HEK293 cells expressing the antigens were used in immunocytochemistry and ELISA. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy.
Results
Median age was 60 years (38-87); 9 were women. Seven had tumors of the lung, breast or thymus. Nine patients responded to immunotherapy or oncological therapy but neurologic relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the GluR1 and GluR2 subunits of the AMPA receptor (AMPAR). HEK293 cells expressing GluR1/2 reacted with all patients' sera or CSF, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal.
Conclusions
Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment-responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPAR.
Neuromyelitis optica spectrum disorder (NMOsd) is a group of demyelinating disorders recently redefined and associated with NMO-IgG/anti-aquaporin 4 antibodies. Because NMOsd is of unknown prevalence worldwide, we conducted a retrospective, cross-sectional study of 850 patients with demyelinating disorders hospitalized in North East Tuscany from 1998 to 2006 to examine the prevalence of NMO and related disorders among unselected consecutive neurological patients with inflammatory CNS diseases and to evaluate the clinical phenotype spectrum of identified cases. Clinical data were updated after at least 2 years of follow-up. An immunofluorescence technique was used to detect NMO-IgG on rat brain tissue. Sera from other 828 neurological patients, 65 non-neurological patients and 50 healthy donors served as controls. The prevalence of NMOsd was 1.5%, with a MS:NMOsd ratio of 42.7. Among 13 NMOsd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up. The final EDSS score ranged from 1 to 10, mainly depending on brainstem involvement occurrence. Our findings confirm a low prevalence of NMO and related disorders among demyelinating inflammatory diseases in a Caucasian population. Moreover, this study demonstrates an unexpectedly high prevalence of limited and atypical variants of this disease, not previously documented.
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