NMDA receptor antibody encephalitis presenting as Transient Epileptic Amnesia

Transient Epileptic Amnesia (TEA) is a subtype of temporal lobe epilepsy, typically presenting in a person's early 60s, and of unknown aetiology. Encephalitis caused by antibodies to NMDA receptors (NMDARE) has not previously been documented in TEA. We describe a 47-year-old male who satisfied criteria for TEA, but given his atypical symptoms, was also screened for autoimmune epilepsy. High levels of serum NMDAR antibodies were found, suggesting NMDARE. Immunosuppressive treatment gradually eliminated the NMDA receptor antibodies. Our case extends the clinical spectrum associated with neuronal cell-surface autoantibodies to include atypical cases of TEA.This article is freely available via Open Access. Click on the Publisher URL to access the full text

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field

Pathogenic potential of antibodies to the GABABreceptor

GABABreceptor (GABABR) autoantibodies have been detected in the serum of immunotherapy-responsive patients with autoimmune encephalitis. This study aimed to investigate the effect of immunoglobulin G (IgG) from a patient with GABABR antibodies on primary neuronal cultures and acute slices of entorhinal cortex. Primary hippocampal neuronal cultures were incubated with serum immunoglobulin from patients with GABABR or AMPA receptor (AMPAR) antibodies for up to 72 h to investigate their effect on receptor surface expression. Whole-cell patch-clamp recordings from layer III pyramidal cells of the medial entorhinal cortex were used to examine the effect on neuronal activity. GABABR surface expression was unaltered by incubation with GABABR antibodies. By contrast, after 24 h application of AMPAR antibodies, AMPARs were undetectable. However, acute application of GABABR IgG decreased both the duration of network UP states and the spike rate of pyramidal cells in the entorhinal cortex. GABABR antibodies do not appear to affect GABABRs by internalization but rather reduce excitability on the medial temporal lobe networks. This unusual mechanism of action may be exploited in rational drug development strategies

Human hippocampal CA3 damage disrupts both recent and remote episodic memories

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis

Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-D-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level

Use of intravenous immunoglobulin for the treatment of autoimmune encephalitis: audit of the NHS experience

OBJECTIVES: The treatments of limbic and other autoimmune encephalitis include immunosuppression, symptomatic treatment, and in the case of paraneoplastic syndromes, appropriate therapy for underlying neoplasms. When immunotherapy is considered, intravenous immunoglobulin is one option for treatment, either alone or in combination with corticosteroids. To date, however, evidence for the use of intravenous immunoglobulin in this context comes from case series/expert reviews as no controlled trials have been performed. We aimed to analyse the NHS England Database of intravenous immunoglobulin usage, which was designed to log use and guide procurement, to explore usage and therapeutic effect of intravenous immunoglobulin in autoimmune encephalitis in England. DESIGN: We conducted a retrospective audit and review of the NHS England Database on intravenous immunoglobulin use. Setting: NHS England Database of intravenous immunoglobulin use which covers secondary and tertiary care prescribing and use of intravenous immunoglobulin for all patients in hospitals in England. PARTICIPANTS: Hospital in-patients with confirmed or suspected autoimmune/limbic encephalitis between September 2010 and January 2017. RESULTS: A total of 625 patients who were 18 years of age or older were treated with intravenous immunoglobulin for autoimmune encephalitis, of whom 398 were determined as having 'highly likely' or 'definite' autoimmune/limbic encephalitis. Ninety-six percent were treated with a single course of intravenous immunoglobulin. The availability and accuracy of reporting of outcomes was very poor, with complete data only available in 27% of all cases. CONCLUSIONS: This is the first review of data from this unique national database. Whilst there was evidence for clinical improvement in many cases of patients treated with intravenous immunoglobulin, the quality of outcome data was generally inadequate. Methods to improve quality, accuracy and completeness of reporting are crucial to maximise the potential value of this resource as an auditing tool

Pathologic tearfulness after limbic encephalitis: A novel disorder and its neural basis

Objective We investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE). Methods We recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity. Results Pathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons. Conclusions Pathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease

Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective.

BACKGROUND AND OBJECTIVES Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. METHODS Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. RESULTS The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. DISCUSSION OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available

Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030

Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort