Case Report: HSV-2 Encephalitis Presenting With Chorea; Effects of Infection Alone or Combination of Infection and Autoimmunity?

Background: Chorea as a symptom of late-onset post-infectious autoimmune encephalitis has been reported with HSV-1 but not HSV-2 encephalitis. Extrapyramidal symptoms are typically associated with the presence of anti-NMDA receptor antibodies but may also exist in antibody-negative individuals.Case: This case highlights a patient who presented with mental status changes and chorea as the initial manifestation of HSV-2 encephalitis. The choreiform movements failed to respond to antiviral medications but were rapidly responsive to plasmapheresis, which, together with abnormal intrathecal immunoglobulin synthesis, suggests a potential contribution of parainfectious immune-mediated process. The patient made a full recovery and a complete resolution of the chorea.Discussion: This is the first case associating HSV-2 encephalitis presentation with chorea. The neurological complications, including chorea, are largely related to active CNS HSV-2 infection, possibly together with triggered CNS autoimmunity despite undetectable CSF neuronal autoantibodies and normal neuroimaging. Early diagnosis and treatment with antiviral agent and immune therapies might be pivotal to optimize the clinical outcome.

Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis

Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-d-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these—and other—limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher’s test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.

Paraneoplastic encephalomyeloradiculits with multiple autoantibodies against ITPR-1, GFAP and MOG: case report and literature review

Background Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies. Case presentation and literature review A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed. Conclusion Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.

Case Report: Longitudinal Extensive Transverse Myelitis With Novel Autoantibodies Following Two Rounds of Pembrolizumab

A 63-year-old male with metastatic non-small cell lung cancer developed longitudinal extensive transverse myelitis (LETM) following two cycles of Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting the programmed cell death receptor 1 (PD-1). Magnetic resonance imaging (MRI) showed centromedullary contrast enhancement at several levels, cerebrospinal fluid (CSF) cytology showed lymphocytic pleocytosis, and indirect immunofluorescence assay (IFA) on the primate cerebellum, pancreas, and intestine revealed strong binding of neuronal autoantibodies to unknown antigens. CSF C–X–C motif ligand 13 (CXCL13) was elevated. The patient was treated with plasma exchange (PEX) and intravenous (i.v.) methylprednisolone (MP) 1 g/day for 5 days followed by oral (p.o.) MP 100 mg/day for 10 days with clinical and radiological response. However, after discontinuation of MP, LETM relapsed and the patient developed paralytic ileus presumably due to autoimmune enteropathy and suffered a fatal gastrointestinal sepsis. Findings of novel neuronal autoantibodies and highly elevated CXCL13 in CSF suggest that the severe neurological immune-related adverse event (nirAE) was B-cell mediated contrary to the commonly assumed ICI-induced T-cell toxicity. An individual evaluation of the underlying pathophysiology behind rare nirAEs is essential for choosing treatment regimens and securing optimal outcome.

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.

Critical Analysis of a Challenging Case of Post-Infectious N-Methyl-D-Aspartate Receptor Encephalitis

Infections are increasingly recognized as a common trigger of autoimmune disease, including autoimmune encephalitis. A significant association is particularly shown between HSV-1 encephalitis (HSVE) and a post-infectious autoimmune encephalitis mediated by neuronal autoantibodies, most notably anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. The clinical significance of these and other novel post-infectious autoantibodies has led to new diagnostic and treatment challenges for clinicians. Here we present a case of a 19-year-old female with premorbid psychiatric disease and neuropsychiatric sequelae from HSVE who presented over a year after her initial HSVE with behavioral changes and positive anti-NMDAR antibodies. The clinical challenges encountered during this case are explored in detail based on a review of the literature. Research is needed to help guide management in these complex clinical situations.