Autoantibodies Targeting Unknown Epitope Autoimmune Encephalitis and the Effect of Modified Electroconvulsive Therapy: Report of Three Cases.

Objective: Generally autoimmune encephalitis (AE) cases present with central nervous system symptoms. Many types of autoantibodies are associated with autoimmune encephalitis, with anti-N-methyl-D-aspartate receptor being the most commonly reported. However, autoimmune encephalitis cases with autoantibodies targeting unknown epitopes are increasingly recognized. This article aims to summarize the clinical experience and assess the feasibility of modified electroconvulsive therapy (MECT) as an adjunctive treatment method for autoimmune encephalitis patients with poor response to first-line immunotherapy and mainly displaying psychiatric symptoms. Methods: This work reports three cases of which two have been diagnosed as autoantibodies targeting unknown epitope autoimmune encephalitis while one has been diagnosed as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and all were effectively treated with MECT. Results: All three cases that otherwise failed to respond to standard immunotherapy for controlling psychiatric symptoms exhibited excellent clinical outcomes following MECT. The underlying mechanism of action of MECT is unclear and whether such an effect involves a neurotransmitter rebalance in the brain remains uncertain. At present, we have observed only a small number of clinical cases, warranting further research among a larger number of clinical cases and more systematic multicenter retrospective analysis. Conclusions: It should be noted that, while our experience supports the utility of MECT in the treatment of certain cases of AE, this option should be regarded as an adjuvant therapy after standard immunosuppressive therapy. Clinicians must be aware that patients should be provided with psychiatric or neurological services for timely diagnosis along with timely and appropriate treatment.

[The Exorcist, The 8-Year Engagement, and Brain on Fire: Three Films about Anti-N-methyl-D-aspartate Receptor Encephalitis].

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is one of the most common forms of autoimmune encephalitis. It is more prevalent in young adult women than it is in men. The disease is characterized by a rapid progression of psychiatric symptoms and/or cognitive impairment. Common symptoms include changes in behavior (i.e. hallucination, paranoia, and aggression etc.), seizures, memory deficit, abnormal movements, and coma. Based on these symptoms, it was historically thought that this 'behavior' was the work of the devil, and exorcism by a shaman was sometimes required. In line with this, it has been suggested that the patient who the original Exorcist movie was based on had this disease. Although immunotherapy is an effective treatment for anti-NMDA encephalitis, recovery is slow with the majority of patients requiring more than a year after disease onset to make a full recovery. In light of this, the stories and experiences of patients with this disease have been depicted in films. Examples of the films include: The 8-year engagement (2017), a Japanese film directed by Takahisa Zeze, and Brain on fire (2016), directed by Irish filmmaker Gerrard Barrett. These films help to raise awareness and make this disease more recognized by the general public.

A case of GFAP-IgG positivity followed by anti-NMDAR encephalitis.

BACKGROUND: In recent years, there have been an increasing number of reports on overlapping antibodies in autoimmune encephalitis (AE). There are various types of overlapping antibodies, but the clinical significance of each type is not yet clear. Glial antibodies, such as MOG, AQP4, and especially NMDAR, can be detected in patients with AE. However, little is known about the overlapping antibodies of anti-glial fibrillary acidic protein (GFAP), and only a few case reports have described this overlap. Case presentation The patient was a 7-year-old girl with recurrent intermittent fever and seizures, and viral encephalitis was diagnosed at the beginning of the disease. She was discharged after treatment with acyclovir, high-dose immunoglobulins, and valproic acid as an antiseizure medication. Subsequently, the patient still had occasional seizures and abnormal behavior, and the anti-NMDAR antibody test was positive (1:3.2). She was treated with high-dose methylprednisolone and antiseizure therapy. Approximately half a year later, the patient experienced fever and seizures again, serum GFAP IgG was 1:100, and a head MRI indicated new lesions. Improvement was achieved after repeated high-dose methylprednisolone and continuous prednisone anti-inflammatory therapy. CONCLUSIONS: Anti-NMDAR encephalitis combined with GFAP-IgG is uncommon, and repeated tests for AE-associated antibodies may be required in patients with recurrent encephalitis. Compared with cerebrospinal fluid antibody-positive children, serum GFAP IgG-positive children should be comprehensively diagnosed according to their clinical manifestations. It is worth considering whether overlapping antibody syndrome can still be an issue for patients with AE who recover and have negative antibodies after a few months if disease recurrence and new antibodies are detected.

Late relapse of anti-N-methyl-d-aspartate receptor encephalitis with amusia and transiently reduced uptake in 123I-iomazenil single-photon emission computed tomography.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis has a high relapse rate at approximately 10-20%. Most relapses occur within 2 years from onset, and 5 years after onset is rare. We report a case of anti-NMDAR encephalitis relapse with amusia 10 years after the initial encephalitis and discuss the usefulness of 123I-iomazenil single-photon emission computerized tomography (IMZ-SPECT) for its diagnosis. CASE: A 13-year-old left-handed girl presented with a depressed level of consciousness and focal to bilateral tonic-clonic seizures. Cerebrospinal fluid (CSF) analysis showed a mildly increased white blood cell count, elevated neopterin levels, and positive oligoclonal bands. Brain MRI was normal. IMZ-SPECT revealed reduced uptake in the right frontoparietal region. She received intravenous pulse methylprednisolone (IVMP) and high-dose intravenous immunoglobulin for autoimmune encephalitis; her symptoms resolved without neurological deficits. At 23 years old, she had mild right-sided numbness, dysarthria, amusia, and tonic-clonic seizures. Although the CSF analysis and brain MRI were normal, IMZ-SPECT revealed reduced uptake, indicating a relapse of encephalitis. IVMP administration resolved the symptoms. After discharge, the initial and relapse CSF analysis revealed anti-NMDAR antibodies. CONCLUSION: An anti-NMDAR encephalitis relapse 10 years after onset has never been reported. IMZ-SPECT may help in the diagnosis of anti-NMDAR encephalitis.

Bilateral thalamic changes in anti-NMDAR encephalitis presenting with hemichorea and dystonia and acute transient psychotic disorder.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis. Both movement disorders and neuropsychiatric manifestations are considered core features of anti-NMDAR encephalitis. Strong clinical suspicion, along with NMDAR antibody positivity in paired sample of serum and cerebrospinal fluid, with supportive MRI changes clinch diagnosis in majority. We herein report a case of a middle-aged woman with subacute behavioral abnormalities, which were so severe that forced her to attempt suicide. Hemichorea and dystonia, which appeared later in course, are not previously reported movement disorders in combination in anti-NMDAR encephalitis. Further, magnetic resonance imaging showed bilateral thalamic hyperintensities with diffusion restriction, which are in turn not described in this entity. After amalgamation of history, especially the presence of neuropsychiatric symptoms, clinical features, physical examination, and investigations, the diagnosis of anti-NMDAR encephalitis could be established. Our case not only highlights that the combination of hemichorea and dystonia can be features of anti-NMDAR encephalitis, but adds novelty by bilateral symmetric thalamic changes.

Characterisation and outcome of neuropsychiatric symptoms in patients with anti-NMDAR encephalitis.

BACKGROUND: Encephalitis due to anti-N-methyl-D-aspartate receptor antibodies (ANMDARE) is the most frequent immune-mediated encephalitis. It is distinguished by the subacute onset of neuropsychiatric symptoms. OBJECTIVE: To evaluate the characteristic neuropsychiatric symptoms and their outcome in patients diagnosed with ANMDARE. METHODS: This was a prospective, longitudinal study in patients with a diagnostic suspicion of ANMDARE that presented to the National Institute of Neurology from March 2018 to February 2019. A comparative analysis of two groups (positive N-methyl-D-aspartate receptor [NMDAR] vs. negative NMDAR antibodies in cerebrospinal fluid [CSF]) was done on admission and at discharge. Neuropsychiatric systematic assessments included the Neuropsychiatric Inventory Questionnaire, the Bush Francis Catatonia Rating Scale, the Confusion Assessment Method Severity, the Montreal Cognitive Assessment, and the Overt Agitation Severity Scale. RESULTS: 24 individuals were analysed: 14 had positive NMDAR antibodies, and 10 had negative NMDAR antibodies in CSF. On admission, agitation/aggression, euphoria/exaltation, and disinhibition were more common in patients with positive antibodies. Excited catatonia and delirium were diagnosed more frequently in patients with positive antibodies. At discharge, there was an important decrease in neuropsychiatric symptoms, but substantial cognitive impairment remained. The mean hospitalisation length was 41.71 (SD 39.33) days for patients with definitive ANMDARE (p 0.259). CONCLUSIONS: Neuropsychiatric symptoms profile in ANMDARE was associated with the early onset of euphoria/exaltation and disinhibition, accompanied by marked psychomotor agitation. When ANMDARE was suspected, the presence of excited-type catatonia and delirium showed a tendency to predict definitive ANMDARE. At discharged, most patients recovered from catatonia, delirium, and psychosis, but marked cognitive symptoms, anxiety, and depression persisted at discharge.

Long-term cognitive and neuropsychiatric outcomes in patients with anti-NMDAR encephalitis.

OBJECTIVES: To evaluate the long-term cognitive or neuropsychiatric outcomes and potential risk factors associated with prolonged cognitive deficits or neuropsychiatric symptoms in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. METHODS: In this cohort follow-up study, patients with a definitive diagnosis of anti-NMDAR encephalitis from the inpatient of West China Hospital between June 2012 and December 2017 were included and underwent a prospective cognitive and neuropsychiatric assessment every 3 months by cognitive impairment rating scale, Neuropsychiatric Inventory (NPI) and/or Montreal Cognitive Assessment. RESULTS: Up to 97.5% patients had severe cognitive deficits and neuropsychiatric symptoms in acute phase. Decreasing proportion of patients with prolonged cognitive deficits was observed and time dependent. At 2 years' follow-up, 7.8% of patients with cognitive deficits were unable to complete some previous activities or return to work. The risk factors associated with persistent cognitive deficits included age of disease onset over 40 years old (HR, 1.77; 95% CI, 1.11-2.82; P = .01) and with clinical relapses (HR, 2.22; 95% CI, 1.21-4.09; P = .02). The predictors of prolonged neuropsychiatric symptoms included clinical relapses (HR, 2.79; 95% CI, 1.21-6.43; P = .02). Among the 12 neuropsychiatric symptoms of NPI, irritability was shown as the most prevalent and persistent. CONCLUSIONS: Combined cognitive and neuropsychiatric assessment and intervention are essential elements of comprehensive care of anti-NMDAR encephalitis.

The Challenge of Integrating Care in Dual Diagnosis; Anti-NMDA-Receptor Encephalitis; Presentation And Outcome In 3 Cases Referred For Complex Specialist Rehabilitation Services.

The successful implementation of an integrated care pathway (ICP) for any given condition is a challenge. Even more challenging is successful ICP implementation for individuals who have multiple co-morbidities. This is further compounded when there are dual mental health and physical disabilities that require integrated working across multiple disciplines, specialties, institutions and organisations. Anti-NMDA-Receptor encephalitis (aNMDARe) is a relatively new diagnostic entity with patients typically presenting with significant psychiatric symptoms followed by progressive neurological deterioration. In this case series, we describe 3 cases of females with aNMDARe who were referred for complex specialist rehabilitation (CSR) to The National Rehabilitation Hospital. CSR is the total active care of patients with a disabling condition, and their families, by a multi-professional team who have undergone recognised specialist training in rehabilitation, led /supported by a consultant trained and accredited in rehabilitation medicine (RM). These services provide for patients with highly complex rehabilitation needs that are beyond the scope of local services. In these cases, referral to CSR resulted in the construction of a bespoke integrated care pathway (ICP) that transcended the barriers between primary, secondary and tertiary care and across the boundaries of physical and mental health. A care pathway is a complex intervention for the mutual decision-making and organisation of care processes Rehabilitation services acted as the coordinator of services in these cases to ensure implementation of the care plan and to ensure successful transitions of care and supported local specialist and general teams in the management of these complex cases.

[Workup and treatment of autoimmune encephalitis]. / Udredning og behandling afautoimmun encephalitis.

Autoimmune encephalitis with antibodies against neuronal surface antigens is diagnosed with increasing frequency in recent years. If treated early and aggressively, these conditions often respond favourably to immunotherapy. We describe the clinical features, diagnosis and treatment of the two most common types of autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor or the leucine-rich glioma-inactivated 1 protein. Together, these two conditions comprise 80% of the autoimmune encephalitis cases diagnosed in Denmark. Autoimmune encephalitides with rare antibodies are also summarized.

Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis: case reports.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto immune-disorder. It is a life threatening condition that typically presents with viral illness, headaches, severe psychiatric symptoms, seizures, behavioural changes, decreasing levels of unconsciousness and progressive unresponsiveness, cognitive impairment, abnormal movements (e.g., dyskinesia), ataxia and hypoventilation. OBJECTIVE: This paper describes the long term outcome and rehabilitation management of patients with NMDAR encephalitis and highlights the diverse outcome of this condition and the unique and individual long term management needs associated with this disorder. METHODS: This is a case report study of three different patients with NMDAR encephalitis. All three cases are young women, two of whom presented with ovarian teratoma. Patient KH is the most impaired and was resident in a slow stream rehabilitation care home and presented with challenging behaviour. Patients RM and OA both lived in the community and presented with similar anxieties but diverse levels of cognition and motivation. A review of the literature is provided summarizing the disorder, interventions, management and challenges of this varied and complex condition. Standard neuropsychological tests and questionnaires to assess community integration (BICRO-39), quality of life (QOLIBRI-OS) and mood (HADS) were administered. RESULTS: Positive outcomes were achieved for all three patients using a variety of interventions which included behavioural management, family psycho-education and an integrated holistic multi-disciplinary team community approach. Memory and executive deficits were persistent in the long term and severity of impairments showed wide variability between patients. Emotional distress and behavioural difficulties were prominent and persistent and had a pronounced impact on rehabilitation. Continence issues were also a major factor impacting on the rehabilitation. CONCLUSIONS: Long term integrated and multi-disciplinary input by a variety of therapies and health disciplines is required in order to improve the long term outcome and quality of life for NMDAR patients and their families, and ultimately leads to improved positive outcomes. Each of these cases had markedly differing cognitive profiles suggesting that in the context of long term rehabilitation outcome, cognition may have less valence than emotional and behavioural factors. Guidelines and standardised procedures for ethical issues and counselling for iatrogenic infertility should be developed and integrated into long term programmes of rehabilitation care.

Anti-NMDA receptor encephalitis: psychiatric presentation and diagnostic challenges from psychosomatic medicine perspective.

We describe two cases of confirmed anti-NMDA receptor encephalitis; one patient initially presented with a clinical picture that resembled delirium and later appeared to present with a conversion reaction and the second patient presented with a first psychotic break followed by the clinical picture of neuroleptic malignant syndrome with catatonia. Neither patient had a previous history of psychiatric illness or recreational drug use. These cases illustrate the diagnostic and treatment challenges associated with this neuropsychiatric condition and underscore the role of psychosomatic medicine psychiatrists in diagnosing anti-NMDA receptor encephalitis.