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Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

ABSTRACT: Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.

SUBMITTER: Shojima Y

PROVIDER: S-EPMC6928500 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Shojima Yuri Y Nishioka Kenya K Watanabe Masao M Jo Takayuki T Tanaka Keiko K Takashima Hiroshi H Noda Kazuyuki K Okuma Yasuyuki Y Urabe Takao T Yokoyama Kazumasa K Hattori Nobutaka N

Internal medicine (Tokyo, Japan) 20190821 23

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 ca ...[more]

PMID: 31434821

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Project description:RationaleNeurosyphilis presenting as limbic encephalitis (LE) is an important differential diagnosis of autoimmune LE (ALE) defined by Graus in 2016. However, data on the clinical differences and similarities between neurosyphilis presenting as LE and ALE are limited. Herein, we report neurosyphilis presenting as ALE that fulfilled the main items of the Graus ALE criteria. Moreover, a literature review of neurosyphilis presenting as LE was performed.Patient concernsA 66-year-old Japanese man developed nonconvulsive status epilepticus. He presented with progressive personality change and working memory deficits within 3 months prior to admission. A hyperintense lesion localized in the bilateral medial temporal area was observed on T2-weighted fluid-attenuated inversion recovery brain magnetic resonance imaging. Cerebrospinal fluid analysis showed mild pleocytosis and the presence of oligoclonal band. However, in-house assays did not detect antineuronal antibodies. Electroencephalogram showed lateralized rhythmic delta activity in the right temporal area. The serum and cerebrospinal fluid serological and antigen tests for syphilis had positive results.DiagnosisALE was initially suspected based on the patient's symptoms and ancillary test findings that fulfilled the Graus ALE criteria. However, based on the positive confirmatory test results for syphilis, a diagnosis of neurosyphilis was eventually made.InterventionThe patient received intravenous midazolam, oral levetiracetam, and lacosamide to control nonconvulsive status epilepticus. In addition, he was treated with intravenous benzylpenicillin at a dose of 24 million units/day for 14 days.OutcomesThe patient's cognitive function relatively improved after antibiotic treatment. However, he presented with persistent mild working memory deficit, which was evaluated with the Wechsler Adult Intelligence Scale, 3rd edition. Therefore, on day 103 of hospitalization, he was transferred to another hospital for rehabilitation and long-term care due to limitations in performing activities of daily living.LessonsThe present case was diagnosed with neurosyphilis presenting as ALE, but meanwhile, in most case, neurosyphilis presenting as LE developed at a slower progressive rate, and it had a broader or restricted involvement on brain MRI than ALE based on the literature review. Therefore, an appropriate differential diagnosis of LE can be obtained by identifying clinical differences between the 2 conditions.

Project description:BackgroundVoltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis.MethodsWe analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice.FindingsImmunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia.InterpretationLGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy.FundingNational Institutes of Health, National Cancer Institute, and Euroimmun.

Project description:BackgroundSome encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved.Methods15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls.FindingsAll patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001).InterpretationGABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies.FundingNational Institutes of Health.

Dataset Information

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Publications

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

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