Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates

Abstract

We report seven patients, six from a single institution, who developed subacute limbic encephalitis initially considered of uncertain aetiology. Four patients presented with symptoms of hippocampal dysfunction (i.e. severe short-term memory loss) and three with extensive limbic dysfunction (i.e. confusion, seizures and suspected psychosis). Brain MRI and [(18)F]fluorodeoxyglucose (FDG)-PET complemented each other but did not overlap in 50% of the patients. Combining both tests, all patients had temporal lobe abnormalities, five with additional areas involved. In one patient, FDG hyperactivity in the brainstem that was normal on MRI correlated with central hypoventilation; in another case, hyperactivity in the cerebellum anticipated ataxia. All patients had abnormal CSF: six pleocytosis, six had increased protein concentration, and three of five examined had oligoclonal bands. A tumour was identified and removed in four patients (mediastinal teratoma, thymoma, thymic carcinoma and thyroid cancer) and not treated in one (ovarian teratoma). An immunohistochemical technique that facilitates the detection of antibodies to cell surface or synaptic proteins demonstrated that six patients had antibodies to the neuropil of hippocampus or cerebellum, and one to intraneuronal antigens. Only one of the neuropil antibodies corresponded to voltage-gated potassium channel (VGKC) antibodies; the other five (two with identical specificity) reacted with antigens concentrated in areas of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum. Preliminary characterization of these antigens indicates that they are diverse and expressed on the neuronal cell membrane and dendrites; they do not co-localize with VGKCs, but partially co-localize with spinophilin. A target autoantigen in one of the patients co-localizes with a cell surface protein involved in hippocampal dendritic development. All patients except the one with antibodies to intracellular antigens had dramatic clinical and neuroimaging responses to immunotherapy or tumour resection; two patients had neurological relapse and improved with immunotherapy. Overall, the phenotype associated with the novel neuropil antibodies includes dominant behavioural and psychiatric symptoms and seizures that often interfere with the evaluation of cognition and memory, and brain MRI or FDG-PET abnormalities less frequently restricted to the medial temporal lobes than in patients with classical paraneoplastic or VGKC antibodies. When compared with patients with VGKC antibodies, patients with these novel antibodies are more likely to have CSF inflammatory abnormalities and systemic tumours (teratoma and thymoma), and they do not develop SIADH-like hyponatraemia. Although most autoantigens await characterization, all share intense expression by the neuropil of hippocampus, with patterns of immunolabelling characteristic enough to suggest the diagnosis of these disorders and predict response to treatment.

MRI Findings in Autoimmune Voltage-Gated Potassium Channel Complex Encephalitis with Seizures: One Potential Etiology for Mesial Temporal Sclerosis

“…These findings are nonspecific and are similar to those associated with infectious limbic encephalitis 15 and diverse paraneoplastic limbic encephalitides 2,16 and to those demonstrated in several smaller series of autoimmune VGKC encephalitis. 1,[8][9][10]17,18 Our study emphasizes the need to include autoimmune VGKC encephalitis in the differential diagnosis of patients presenting with these MR imaging findings.…”

“…Autoimmune limbic encephalitis may occur as a paraneoplastic phenomenon associated with certain tumors or may occur in the absence of a neoplasm. [1][2][3] Autoimmune voltage-gated potassium channel complex (VGKC) encephalitis is one of the most common forms of autoimmune encephalitis. It is frequently found in the absence of associated tumor.…”

Squamous Cell Lung Carcinoma Presenting With Refractory Status Epilepticus: A Case Report of Paraneoplastic Limbic Encephalitis

“…Treatment-responsive limbic encephalitis has been described in patients who do not possess the classical autoantibodies but are characterized by antibodies to the neuropil of the hippocampus or cerebellum using a novel experimental immunohistochemical technique. 8 However, overall neurological recovery in patients with PLE is rare in the reported literature, 6,9 and treatment with immunotherapy has yielded disappointing results. 10 Our patient made great improvements in his cognitive impairment after immunotherapy and surgery; however, his impairment it was still significant enough to be debilitating.…”

Limbic encephalitis associated with anti‐GAD antibody and common variable immune deficiency

“…3 The list of autoantibodies identified in patients with nonparaneoplastic limbic encephalitis has been expanding. These are the antibodies targeted against cell-membrane antigens such as VGKC, novel cell-membrane antigens, 8 and the NMDA receptor. 9 Recently, Mata et al described the association between non-paraneoplastic limbic encephalitis and anti-GAD antibodies.…”