Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis.

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development.

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AID). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4+ B cells and plasma cells. Therefore, we compared the B cell compartment of patients from four different IgG4-AID with two IgG1-3-AID and healthy donors, using flow cytometry. Relative subset abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5+ cells. IgG4+ B cell and plasma cell numbers were normal in IgG4-AID patients, however they had a (sub)class-independent 8-fold increase in circulating CD20-CD138+ cells. No autoreactivity was found in this subset. These results argue against aberrant B cell development and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between IgG4-AID suggest that, despite displaying variable clinical phenotypes, they share a similar underlying immune profile.

Viral, Bacterial, Metabolic, and Autoimmune Causes of Severe Acute Encephalopathy in Sub-Saharan Africa: A Multicenter Cohort Study.

OBJECTIVES: To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan Africa. STUDY DESIGN: One hundred thirty-four children (6 months to 18 years) presenting with nontraumatic coma or convulsive status epilepticus to 1 of 4 medical referral centers in Uganda, Malawi, and Rwanda were enrolled between 2015 and 2016. Locally available diagnostic tests could be supplemented in 117 patients by viral, bacterial, and 16s quantitative polymerase chain reaction testing, metagenomics, untargeted metabolomics, and autoimmune immunohistochemistry screening. RESULTS: Fourteen (12%) cases of viral encephalopathies, 8 (7%) cases of bacterial central nervous system (CNS) infections, and 4 (4%) cases of inherited metabolic disorders (IMDs) were newly identified by additional diagnostic testing as the most likely cause of encephalopathy. No confirmed cases of autoimmune encephalitis were found. Patients for whom additional diagnostic testing aided causal evaluation (aOR 3.59, 90% CI 1.57-8.36), patients with a viral CNS infection (aOR 7.91, 90% CI 2.49-30.07), and patients with an IMD (aOR 9.10, 90% CI 1.37-110.45) were at increased risk for poor outcome of disease. CONCLUSIONS: Viral and bacterial CNS infections and IMDs are prevalent causes of severe acute encephalopathy in children in Uganda, Malawi, and Rwanda that are missed by conventional diagnostics and are associated with poor outcome of disease. Improved diagnostic capacity may increase diagnostic yield and might improve outcome of disease.

Cerebrospinal fluid proteomics indicates immune dysregulation and neuronal dysfunction in antibody associated autoimmune encephalitis.

Autoimmune Encephalitis (AE) spans a group of non-infectious inflammatory conditions of the central nervous system due to an imbalanced immune response. Aiming to elucidate the pathophysiological mechanisms of AE, we applied an unsupervised proteomic approach to analyze the cerebrospinal fluid (CSF) protein profile of AE patients with autoantibodies against N-methyl-d-aspartate receptor (NMDAR) (n = 9), leucine-rich glioma-inactivated protein 1 (LGI1) (n = 9), or glutamate decarboxylase 65 (GAD65) (n = 8) compared to 9 patients with relapsing-remitting multiple sclerosis as inflammatory controls, and 10 patients with somatic symptom disorder as non-inflammatory controls. We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Furthermore, elevated levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Moreover, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls which may facilitate future identification of disease-specific biomarkers. Overall, CSF proteomics provides insights into the complex pathophysiological mechanisms of AE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function.

Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort.

BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

Comprehensive overview of autoantibody isotype and subclass distribution.

The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies.

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

OBJECTIVE: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects. METHODS: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells. RESULTS: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization. INTERPRETATION: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107-123.

The association between systemic autoimmune disorders and epilepsy and its clinical implications.

Systemic autoimmune disorders occur more frequently in patients with epilepsy than in the general population, suggesting shared disease mechanisms. The risk of epilepsy is elevated across the spectrum of systemic autoimmune disorders but is highest in systemic lupus erythematosus and type 1 diabetes mellitus. Vascular and metabolic factors are the most important mediators between systemic autoimmune disorders and epilepsy. Systemic immune dysfunction can also affect neuronal excitability, not only through innate immune activation and blood-brain barrier dysfunction in most epilepsies but also adaptive immunity in autoimmune encephalitis. The presence of systemic autoimmune disorders in subjects with acute seizures warrants evaluation for infectious, vascular, toxic and metabolic causes of acute symptomatic seizures, but clinical signs of autoimmune encephalitis should not be missed. Immunosuppressive medications may have antiseizure properties and trigger certain drug interactions with antiseizure treatments. A better understanding of mechanisms underlying the co-existence of epilepsy and systemic autoimmune disorders is needed to guide new antiseizure and anti-epileptogenic treatments. This review aims to summarize the epidemiological evidence for systemic autoimmune disorders as comorbidities of epilepsy, explore potential immune and non-immune mechanisms, and provide practical implications on diagnostic and therapeutic approach to epilepsy in those with comorbid systemic autoimmune disorders.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia-Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias.

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome.

BACKGROUND: Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition of this rare disease. METHODS: We determined the sensitivity and specificity of 60% and 100% cutoff values in all consecutive patients who underwent increment testing in our hospital from 1999 to 2016. RESULTS: We included 156 patients, 63 with LEMS and 93 without LEMS. Sensitivity of a 60% cutoff for increment testing was 77.8% (95% confidence interval 65.5%-87.3%) and 58.7% (45.6%-71.0%) for 100%. Specificity was 98.9% (94.2%-100%) and 100% (96.1%-100%) using a threshold of 60% and 100%, respectively. CONCLUSIONS: Lowering the cutoff value for abnormal increment to 60% greatly increases sensitivity to diagnose LEMS without an overt loss in specificity.

The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies.

In this study we report the clinical features of 32 patients with gamma aminobutyric acid B receptor (GABABR) antibodies, identify additional autoantibodies in patients with anti-GABABR encephalitis that mark the presence of an underlying small cell lung carcinoma and optimize laboratory methods for the detection of GABABR antibodies. Patients (n = 3225) were tested for the presence of GABABR antibodies using cell-based assay, immunohistochemistry and live hippocampal neurons. Clinical data were obtained retrospectively. Potassium channel tetramerization domain-containing (KCTD)16 antibodies were identified by immunoprecipitation, mass spectrometry analysis and cell-based assays. KCTD16 antibodies were identified in 23/32 patients with anti-GABABR encephalitis, and in 1/26 patients with small cell lung carcinoma and Hu antibodies, but not in 329 healthy subjects and disease controls. Of the anti-GABABR encephalitis patients that were screened sufficiently, 18/19 (95%) patients with KCTD16 antibodies had a tumour versus 3/9 (33%) anti-GABABR encephalitis patients without KCTD16 antibodies (P = 0.001). In most cases this was a small cell lung carcinoma. Patients had cognitive or behavioural changes (97%) and prominent seizures (90%). Thirteen patients developed a refractory status epilepticus with intensive care unit admittance (42%). Strikingly, 4/32 patients had a rapidly progressive dementia. The addition of KCTD16 to the GABABR cell-based assay improved sensitivity of the in-house fixed cell-based assay, without loss of specificity. Twenty-two of 26 patients improved (partially) to immunotherapy or chemotherapy. Anti-GABABR encephalitis is a limbic encephalitis with prominent, severe seizures, but patients can also present with rapidly progressive dementia. The co-occurrence of KCTD16 antibodies points towards a paraneoplastic origin. The addition of KCTD16 improves the sensitivity of the cell-based assay.

Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4.

Leucine-rich glioma-inactivated1 (LGI1) encephalitis is an antibody-associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte antigen (HLA) analysis in 25 nontumor anti-LGI1 patients and discovered a remarkably strong HLA association. HLA-DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 × 10-11 ). HLA-DRB4 was present in all patients and in 46.5% controls (p = 1.19 × 10-7 ). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor-LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA-DR7 or HLA-DRB4 could raise tumor suspicion in anti-LGI1 patients. Ann Neurol 2017;81:193-198.

Predictive value of electroencephalography in anti-NMDA receptor encephalitis.

OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatable disease. This study aims to give a detailed description of electroencephalogram (EEG) results in paediatric and adult patients to improve disease recognition, and analyses the predictive value of the first EEG for the final clinical outcome. METHODS: This nationwide cohort study includes patients with N-methyl-D-aspartate receptor antibodies confirmed with cell-based assay and immunohistochemistry in serum and cerebrospinal fluid. EEG recordings were re-evaluated by two experienced neurophysiologists, mixed with control EEGs for blinding. Initial EEG as well as follow-up registrations were analysed. RESULTS: 35 adults and 18 children were included. Only two patients (4%) had a normal EEG. During the first recording, the majority of the patients had normal posterior rhythm (71%), which was associated with better modified Rankin Scale at final outcome (OR 4.74; 95% CI 1.56 to 14.47; p=0.006). In addition, EEGs showed focal (73%) or diffuse (67%) slowing. The first EEG was severely abnormal in 26%. However, 8 of 14 patients with a severely abnormal first EEG still had a favourable outcome. During the course of the disease, extreme delta brushes (EDBs) were present in 6 of 53(11%)patients. CONCLUSIONS: The first EEG commonly shows normal posterior rhythm with focal or diffuse slowing. Although the sensitivity of an abnormal EEG is high (96%), normal EEG does not exclude anti-NMDARE. EDBs are only present in severely affected patients. The first EEG recording is predictive of the final clinical outcome.

Autoimmune encephalitis with anti-leucine-rich glioma-inactivated 1 or anti-contactin-associated protein-like 2 antibodies (formerly called voltage-gated potassium channel-complex antibodies).

PURPOSE OF REVIEW: Twenty years since the discovery of voltage-gated potassium channel (VGKC)-related autoimmunity; it is currently known that the antibodies are not directed at the VGKC itself but to two closely associated proteins, anti-leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2). Antibodies to LGI1 and Caspr2 give well-described clinical phenotypes. Anti-LGI1 encephalitis patients mostly have limbic symptoms, and anti-Caspr2 patients have variable syndromes with both central and peripheral symptoms. A large group of patients with heterogeneous symptoms are VGKC positive but do not have antibodies against LGI1 or Caspr2. The clinical relevance of VGKC positivity in these 'double-negative' patients is questionable. This review focusses on these three essentially different subgroups. RECENT FINDINGS: The clinical phenotypes of anti-LGI1 encephalitis and anti-Caspr2 encephalitis have been described in more detail including data on treatment and long-term follow-up. A specific human leukocyte antigen (HLA) association was found in nontumor anti-LGI1 encephalitis, but not clearly in those with tumors. There has been increasing interest in the VGKC patients without LGI1/Caspr2 antibodies questioning its relevance in clinical practice. SUMMARY: Anti-LGI1 encephalitis and anti-Caspr2 encephalitis are separate clinical entities. Early recognition and treatment is necessary and rewarding. The term VGKC-complex antibodies, lumping patients with anti-LGI1, anti-Caspr2 antibodies or lacking both, should be considered obsolete.

Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity.

OBJECTIVE: To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. METHODS: One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. RESULTS: Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity. INTERPRETATION: Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388-400.