NMDAR Encephalitis Research Articles

Confusional state in a pregnant woman: A case of NMDA receptor encephalitis during pregnancy

We report the case of a pregnant female presenting with behavioral change and hallucinations followed by focal seizures with impaired awareness. EEG revealed generalized slowing interspersed with extreme delta-brush pattern and MRI brain was normal. Both Serum and CSF anti-N-methyl-d-aspartate receptor (NMDAR) antibodies were positive. Patient had a prolonged hospital stay with full recovery and delivered a healthy baby, highlighting the significance of early diagnosis and management in this disorder.

Anti–NMDAR encephalitis complicating pregnancy

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first reported in 2005 in four patients with ovarian teratomas; there have been many further cases reported since the antigen for the NMDAR antibody was...

WED 148 Imaging findings in autoimmune encephalitis: a retrospective review

BackgroundNeuroimaging findings in autoimmune encephalitis may include normal MRI as well as limbic and extra-limbic involvement. Prompt recognition allows early immunosuppression and improved outcomes.MethodsRetrospective review of patients with Autoimmune encephalitis over the last 5 years.ResultsWe identified N-methyl-d-aspartate receptor (NMDAR) n=8, voltage gated potassium channel (VGKC) n=11, and leucine-rich glioma inactivated 1 (LGI1) n=11 encephalitis patients. 1/8 NMDAR encephalitis patients had abnormal MRI findings of T2 hyper intense signal in right anterior temporal and bilateral frontal and left insular lobe. DWI sequence showed restricted diffusion. 4/11 with VGKC encephalitis had positive MRI findings. Two patients had limbic involvement while one also had involvement of basal ganglia. Two patients had modest cerebral atrophy. Four patients had normal MRI findings. MRI scan was not available for three patients. 5/11 LGI1 encephalitis patients had bilateral mesial temporal lobe changes. In one patient, MRI could not be done due to permanent pacemaker. Five patients had normal MRI findings.ConclusionsIn our series, 33% patients had abnormal MRI findings consistent with a diagnosis of autoimmune encephalitis, which is lower than reported in literature. High clinical suspicion should lead to prompt diagnosis even in the absence of typical encephalitic changes on MRI.

Affinities of human NMDA receptor autoantibodies: implications for disease mechanisms and clinical diagnostics

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis presenting with psychosis, dyskinesias, autonomic dysfunction and seizures. The underlying autoantibodies against the NR1 subunit are directly pathogenic by disrupting synaptic NMDAR currents. However, antibody titers correlate only partially with the clinical outcome, suggesting the relevance of other factors such as antibody affinity. We thus determined the binding curves of human monoclonal autoantibodies and patients’ cerebrospinal fluid (CSF) against NR1-expressing HEK293 cells using flow cytometry. Antibody affinity was highly variable with binding constants (half-maximal concentration, c50) ranging from 1 to 74 µg/ml for monoclonal antibodies. Comparing values of individual monoclonal antibodies with human CSF samples suggested that the CSF signal is predominantly represented by higher-affinity antibodies, potentially in a concentration range of NR1 antibodies between 0.1 and 5 µg/ml, roughly reflecting 1–10% of total CSF IgG in NMDAR encephalitis. Binding curves further depended on the CSF composition which must be considered when interpreting established clinical routine assays. Normalization of measurements using reference samples allowed high reproducibility. Accurate and reproducible measurement of NR1 antibody binding suggested that biophysical properties of the antibody might contribute to disease severity. Normalization of the data can be an elegant way to allow comparable inter-laboratory quantification of CSF NR1 antibody titers in autoimmune encephalitis patients, a prerequisite for use as surrogate markers in clinical trials. Based on our calculations, low-affinity antibodies can easily remain undetected in routine cell-based assays, indicating that their relation to clinical symptoms should be analyzed in future studies.

Thyroid Function and Autoimmune Indications in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Objective: Previous studies have shown that functional abnormalities of the thyroid are associated with the pathogenesis of several neurological diseases. However, their relationship in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis remains to be defined. Methods: Forty-three patients with anti-NMDAR encephalitis were examined for thyroid function and autoimmune indications, in comparison with 225 healthy controls (CTL). Patients were further classified into 2 subgroups based on their free tri-iodothyronine (fT3) levels. Moreover, fT3 levels were also investigated after at least three months of follow-up. The clinical characteristics of the patients and CTL were described in detail. Results: Serum levels of fT3 and thyroid-stimulating hormone (TSH) were found to be relatively lower in patients with anti-NMDAR encephalitis than in CTL (both p < 0.001). Low T3 syndrome also occurred more frequently in anti- NMDAR encephalitis (25.6 vs. 0.4%, p < 0.001). However, no statistical differences were detected between patients and CTL in terms of the positive rate of thyroid antibodies and other types of thyroid dysfunction. Patients with low T3 levels tended to have a longer hospital stay (p = 0.006), a higher rate of abnormal brain magnetic resonance imaging (MRI) findings (p = 0.033), a higher frequency of consciousness declination (p = 0.029), and a higher modified Rankin scale (mRS) score during hospitalization. Low fT3 levels were also associated with abnormal MRI findings, a decline in consciousness, and the mRS score on admission. In addition, fT3 seemed to gradually return to normal levels upon improvement of the mRS score (r = –0.649, p = 0.002). Conclusions: Low T3 syndrome often copresents in anti-NMDAR encephalitis and indicates a longer hospitalization, abnormal MRI findings, consciousness declination, and a higher clinical severity. However, fT3 levels do not seem to influence the prognosis of anti-NMDAR encephalitis.

Anti-NMDAR encephalitis in a patient with Crohn disease receiving adalimumab.

Anti–tumor necrosis factor alpha (TNF-α) therapies have been a significant advance in the treatment of autoimmune and rheumatologic diseases. Early preclinical and clinical studies of anti–TNF-α therapies emphasized infection and malignancy as serious adverse events associated with these agents.1 However, subsequent clinical experience has increasingly recognized a rare and seemingly paradoxical risk of autoimmunity with agents targeting the TNF-α pathway, most notably psoriatic eruptions,2 but also autoimmune processes associated with autoantibody production, including systemic vasculitis and lupus erythematosus.3,4 The development of neurologic diseases in association with anti–TNF-α therapy has been documented in case series and small prospective studies,5 with the most commonly reported associations being demyelinating diseases of the CNS and peripheral nervous systems. Here, we report a patient who developed anti–NMDA receptor (NMDAR) encephalitis while being treated with adalimumab for Crohn disease.

Clinical Characterization of mGluR5-Antibody Associated Encephalitis

Glutamate receptor antibodies have been implicated in NMDAR encephalitis, AMPAR encephalitis, and mGluR1 cerebellar dysfunction. Now, investigators

Reader response: Anti-cytosolic 5'-nucleotidase 1A (cN1A) autoantibodies in motor neuron diseases.

I read with interest the Clinical/Scientific Note by Dr. Liewluck1 that described 2 patients with motor neuron disease who tested positive for anti-cN1A antibodies by ELISA, a recently identified autoantibody reported to be highly specific for inclusion body myositis (IBM).2 Although an interesting observation, detail regarding the anti-cN1A antibody isotypes identified in both patients was lacking. Some ELISA tests are restricted to the detection of immunoglobulin (Ig) G anti-cN1A antibodies while others may identify the presence of IgG, IgA, or IgM anti-cN1A antibodies, and are potentially somewhat less specific for IBM.3,4 Important differences in the clinical relevance of antibody isotypes was previously noted in other neurologic diseases such as anti–NMDA receptor encephalitis. In this syndrome, IgG antibodies to the NR1 subunit of the NMDA receptor have high specificity, while IgA and IgM antibodies are nonspecific and may be found in patients with mild cognitive impairment or schizophrenia.5 Anti-cN1A antibody isotype data should routinely be included in publications reporting its presence in different patient populations, since this information may provide insight into isotype specificity (or lack thereof) for the diagnosis of IBM.

A diagnostic pearl in new-onset confusion: Answer

D The EEG reveals diffuse slowing and a characteristic pattern of fast (beta) activity overriding slow (delta) waves, giving a distinctive “brush” appearance termed extreme delta brush (EDB). This finding is considered highly specific for NMDAR antibody encephalitis and its electrographic recognition should prompt appropriate serological testing [[1]Wang J. Wang K. Wu D. Liang H. Zheng X. Luo B. Extreme delta brush guides to the diagnosis of anti-NMDAR encephalitis.J Neurol Sci. 2015; 353: 81-83Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. In our patient, NMDAR antibodies were strongly positive in both CSF and serum thus confirming the diagnosis. EDBs were first described in 2012 as a finding unique to NMDAR encephalitis [[2]Schmitt S.E. Pargeon K. Frechette E.S. Hirsch L.J. Dalmau J. Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis.Neurology. 2012; 79: 1094-1100Crossref PubMed Scopus (495) Google Scholar]. Various EEG alterations, commonly slowing but also epileptic activity, are identified in the vast majority of NMDAR encephalitis cases but these are non-specific; however up to 30% of cases will also have EDBs on EEG [2Schmitt S.E. Pargeon K. Frechette E.S. Hirsch L.J. Dalmau J. Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis.Neurology. 2012; 79: 1094-1100Crossref PubMed Scopus (495) Google Scholar, 3Veciana M. Becerra J.L. Fossas P. Muriana D. Sansa G. Santamarina E. et al.EEG extreme delta brush: an ictal pattern in patients with anti-NMDA receptor encephalitis.Epilepsy Behav. 2015; 49: 280-285Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. In addition to raising diagnostic suspicion, their presence suggests a more prolonged disease course and an association with seizures and status epilepticus [2Schmitt S.E. Pargeon K. Frechette E.S. Hirsch L.J. Dalmau J. Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis.Neurology. 2012; 79: 1094-1100Crossref PubMed Scopus (495) Google Scholar, 3Veciana M. Becerra J.L. Fossas P. Muriana D. Sansa G. Santamarina E. et al.EEG extreme delta brush: an ictal pattern in patients with anti-NMDA receptor encephalitis.Epilepsy Behav. 2015; 49: 280-285Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. NMDAR encephalitis is an autoimmune disorder mainly affecting younger patients with a female preponderance and varying reported rates of underlying malignancy; in particular ovarian teratoma [[4]Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1949) Google Scholar]. Insomnia, disturbed cognition, abnormal behaviour, psychosis, seizures and dsykinesias have all been described. Definite diagnosis requires positive identification of the pathogenic IgG antibodies against GluN1 subunit of the NMDA receptor [[4]Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1949) Google Scholar]. Our patients’ investigations for malignancy including whole-body PET/CT were all negative. Her CSF had otherwise shown a predominantly lymphocytic pleocytosis, marginally raised protein, normal glucose and negative viral PCR. During her prolonged hospital stay she developed frequent seizures and deteriorating consciousness refractory to immunomodulatory therapy in the form of high-dose corticosteroids, plasma exchange and cyclophosphamide. However she is responding well to rituximab and her serum NMDAR antibodies are now undetectable on this latest treatment. None (all authors). No funding was provided in relation to this manuscript. A diagnostic pearl in new-onset confusionJournal of Clinical NeuroscienceVol. 53PreviewA previously healthy 75-year-old lady presented with 2 weeks of subacute onset confusion and behavioural disturbance. On initial assessment she was afebrile with a Glasgow Coma Scale of 13/15 (E4M5V4), and apart from confusion her neurological examination was normal. Serum full blood count, inflammatory markers, electrolytes, renal and liver function tests were all within normal limits. Urinalysis, chest X-ray and computed tomography of the brain were unremarkable. An EEG was requested (Fig. 1A and B). Full-Text PDF

S62. Computational diagnosis of ion channel dysfunction in NMDA receptor antibody encephalitis

Introduction NMDA receptor (NMDAR) antibody encephalitis is an autoimmune disorder causing acute psychosis, confusion and seizures. Electroencephalography (EEG) findings are usually non-specific, with diagnosis confirmed by demonstration of serum/CSF autoantibodies. Improved clinical outcomes depend on early institution of immunotherapies. A non-invasive measure of NMDAR function could facilitate early treatment, and enable tracking of disease activity. Recent biophysical modeling advances allow inference of ion channel dynamics from macroscopic measures of brain activity. Here, we show that clinically relevant diagnoses of NMDAR ion channel dysfunction can be obtained using a microcircuit model fitted to individual human EEG data. Methods We compared resting state EEG cross-spectra from patients with NMDAR encephalitis, encephalopathy unrelated to NMDAR dysfunction, and non-encephalopathic controls. We fit biophysical models (dynamic causal models – DCMs) of connected neuronal ensembles, simulating post-synaptic membrane potentials and EEG spectra through lead field projection. We used canonical variate analysis (CVA) and an empirical Bayesian approach searching candidate models across the groups to reveal specific synaptic deficits. Results Clinical severity was matched between encephalopathic groups. However, there were clear differences in EEG cross-spectra at low (2–4 Hz) and high (28–40 Hz) frequencies, with increased beta-gamma power present in NMDAR antibody encephalitis patients. Subject-specific DCMs mapped model parameters representing dynamics at NMDA, AMPA and GABA receptors to spectral data features. Four inter-connected sources described delta-theta and beta-gamma cross-spectra observed at scalp sensors. Each source comprised a neural mass model with four neuronal subpopulations, with dynamics determined by intrinsic connections mediated via ionotropic receptors. Dynamics along intrinsic and extrinsic connections could reproduce scalp-based EEG recordings. Parameter estimate CVA showed significant differences between patients with and without NMDAR encephalitis in NMDAR parameters. A parametric empirical Bayes (PEB) analysis demonstrated that the group effects of NMDAR encephalitis were specific to NMDA model parameters, in contrast to other encephalopathies where differences were seen across receptor subtypes. Conclusion Neurological and psychiatric practice lack diagnostic probes to assess disease mechanisms at the neuronal level non-invasively in humans. We show that biophysical models of EEG applied to clinical EEG data identify abnormal NMDAR signaling in patients with NMDAR encephalitis but not in patients with other encephalopathies or neurological controls. By comparing model parameter estimates from these patient groups, we selectively identify NMDAR dysfunction in a multi ion-channel model. Given that EEG is ubiquitously available, our findings suggest the feasibility of EEG neuromodeling as a unique assay of brain dysfunction at the molecular-level.

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody (S52.006)

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody (S52.006)

T69. PERFORMANCE OF PATIENTS WITH NMDAR-AB ENCEPHALITIS COMPARED TO PATIENTS WITH SCHIZOPHRENIA AND HEALTHY CONTROLS USING FUNCTIONAL MAGNETIC RESONANCE IMAGING (F-MRI) AND A WORKING MEMORY PARADIGM

BackgroundN-methyl-D-aspartate receptor (NMDAR) encephalitis has prominent early psychotic features. It has been rarely misdiagnosed as schizophrenia. NMDAR encephalitis causes deficiencies in working memory in the short & long term. Early immunotherapy/tumour removal improves outcomes. Schizophrenia can cause significant cognitive performance deficits with working memory often severely affected.Clinical MRI in NMDAR encephalitis is usually normal, despite severe clinical course. Resting state fMRI studies have shown reduced functional connectivity of the left & right hippocampus. To date, to the best of our knowledge, functional neuroimaging utilising a working memory task such as the 1-back task (participant has to identify the number onscreen immediately before the number currently on screen) has not been utilised in NMDAR encephalitis. Potentially this may highlight alterations in brain regions through altered neuronal activity underlying working memory.We hypothesised that patients with NMDAR encephalitis would demonstrate a difference in BOLD response (a proxy for neuronal activity) compared to healthy controls during fMRI while performing the 1-back task. Additionally, we wished to compare task evoked BOLD response in patients with NMDAR-Ab encephalitis compared to patients with schizophrenia.MethodsUsing G*Power 3.1 software with effect size f (0.8), total sample size was calculated from data obtained from a previous study on working memory performance in NMDAR encephalitis for the 3 groups (NMDAR encephalitis, healthy controls & schizophrenia) (N=30). Following ethical approval, 12 individuals diagnosed with NMDAR encephalitis were recruited from neurological centres. Participants were trained in the 1-back task prior to scanning. Results were compared to previously collected data from cohorts of healthy controls (N=14) and schizophrenia (N=14). Cohorts were matched insofar as possible. Data was analysed using SPSS and ART toolbox.ResultsIn the NMDAR encephalitis (N=12) cohort, gender ratio F:M was (11:1), mean(s.d.) age 37.5(12.2) years. 50% identified ongoing memory problems. Schizophrenia cohort (N=14) gender ratio (7:7), mean (s.d.) age 39 (12.3) years. Healthy controls gender ratio (10.4) mean (s.d.) age 29.8 (6.5) years. There was no difference for gender, age or educational level between cohorts. FSIQ was higher (p<0.01) in controls & NMDAR encephalitis compared to schizophrenia cohorts. NMDAR encephalitis cohort had acute symptoms [mean (s.d.)] for 7.09 (2.43) weeks until treatment. 9 individuals were still on immunotherapy at time of entry.Duration since diagnosis to entry into this study was 55.18(23.13) months for NMDAR encephalitis and 12.6 (10.91) years for schizophrenia. There were no significant differences in number of ART motion outliers (p >0.05) between cohorts. Age & gender were added to second level analyses as covariates.One-way ANOVA was used to compare N-back accuracy & reaction time. There was a significant difference (p<0.01) between groups on accuracy but not reaction time, with only the schizophrenia group showing lower accuracy.1-back working memory condition was associated with significantly increased BOLD response across several brain regions that play a role in working memory, including the dorsolateral prefrontal cortex. However, there were no significant main effects on BOLD response for the 1-back task for any cohort.DiscussionPatients with NMDAR encephalitis report ongoing memory difficulties. However, in this study, there were no identifiable deficits compared to healthy controls using fMRI. This may relate to regeneration of NMDA receptors, the relatively long time until from diagnosis to follow up and early treatment with immunotherapy.

Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders.

Anti-N-Methyl-d-aspartate-receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in pediatric age. This retrospective observational study was aimed at describing the clinical characteristics of the disease in a cohort of children and teenagers. Eighteen patients (10 females and 8 males), with a median age of 12.4years at symptom onset were enrolled. The clinical presentation of the disease was marked by neurological manifestations in 13 patients and by severe psychiatric and behavioral symptoms in 5. The symptoms at onset varied according to the age: all the children presented with prominent neurological symptoms, whereas psychiatric symptoms were prominent in teenagers. Regardless the age, movement disorders (MDs) were distinctive symptoms during the acute stage of the disease. Several MDs might coexist in a given patient, and persist during sleep. The complexity, and the oddness of MDs often challenged their definition and the differential diagnosis with psychiatric manifestations and epileptic seizures. Stereotyped motor phenomena were the most typical MDs, and were recorded in all patients. Among them, perseveration, reproduction of acquired complex motor activities, and orofacial dyskinesia were the most distinctive features. In children, hyperkinetic MDs dominate; in teenagers, by contrast, a constellation of symptoms consistent with catatonia was the most frequent syndrome observed. The management of the several symptoms requires their accurate recognition, definition and assessment, and the knowledge of the potential side effects of antiepileptic and psychotropic drugs which could either mimic or worsen symptoms of encephalitis.

Comparison of myelin oligodendrocyte glycoprotein (MOG)-antibody disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis

BackgroundMyelin oligodendrocyte glycoprotein (MOG)-antibody (ab) disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) can co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis (NMDARe). ObjectivesTo characterize MOG-ab disease and AQP4-IgG-positive NMOSD during NMDARe. MethodsWe analyzed all the patients with overlapping MOG-ab disease and NMDARe (MNOS) and patients with AQP4-IgG-positive NMOSD and NMDARe (ANOS) in our hospital and compared those data with data from systematically review of previously published reports. ResultsIn our cohorts, 11.9% patients with MOG-ab disease and 0.6% patients with NMOSD had overlapping NMDARe (P < 0.01). After treatment with steroids and/or intravenous immunoglobulin (IVIg), the median modified Rankin Scale (mRS) of the MNOS group decreased significantly during attacks associated with or without NMDARe (P < 0.01 for both), while that of the ANOS group did not (attack: P < 0.05; attack associated with NMDARe: P > 0.05). Analyzed together with previously reported cases, 6% patients with MNOS and 40% patients with ANOS also used rituximab or cyclophosphamide after steroids and/or IVIg (P < 0.05) during attacks associated with NMDARe. ConclusionCompared with NMOSD, MOG-ab disease may more commonly co-exist with NMDARe. MNOS patients respond better to steroids and IVIg than do ANOS patients during attacks associated with NMDARe.

Cerebrospinal fluid from Dementia with Lewy body patients suppresses neuronal network activity

Cerebrospinal fluid from Dementia with Lewy body patients suppresses neuronal network activity

B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.

Increasing recognition of the role of B cells in the adaptive immune response makes B cells an important therapeutic target in autoimmunity. Numerous current and developmental immunotherapies target B cells for elimination through recognition of cell-surface proteins expressed specifically on B cells, in particular CD19 and CD20. Similarities and differences in the function and expression of these two molecules predict some shared, and some distinct, pharmacological effects of agents targeting CD19 versus CD20, potentially leading to differences in the clinical safety and efficacy of such agents. Here, we review current knowledge of CD19 and CD20 function and biology, survey current and developmental therapies that target these molecules, and discuss potential differences in elimination of B cells by drugs that target CD19 versus CD20, with particular focus on the central nervous system autoimmune diseases multiple sclerosis and neuromyelitis optica. The principles and mechanisms herein discussed might also be relevant to a variety of other nervous system autoimmune disorders, including NMDA (N-methyl-D-aspartate) receptor encephalitis, transverse myelitis and myasthenia gravis.

A case of anti‐NMDA receptor encephalitis revealed by insular epilepsy

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system that typically manifests predominantly as a psychiatric disorder. However, other manifestations such as epileptic seizures, abnormal movements, and memory or language complications are not unusual. Here, we report the case of a young man who presented with a new-onset epilepsy, with ictal semiology suggestive of insular involvement; this hypothesis was supported by a PET-CT study. Anti-NMDAR antibodies were found in the CSF, confirming the diagnosis of anti-NMDAR encephalitis. A review of the literature reveals that epilepsy can be the first manifestation of NMDAR encephalitis, with a clear male predominance. Despite its rarity, neurologists should consider this diagnosis for any young patient developing a new-onset epilepsy with temporal or insular features, particularly if the patient is male. Other cognitive or behavioural signs, even very subtle, should also prompt diagnosis.

Pediatric Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Review with Pooled Analysis and Critical Care Emphasis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is being recognized with increasing frequency among children. Given the paucity of evidence to guide the critical care management of these complex patients, we provide a comprehensive review of the literature with pooled analysis of published case reports and case series. We performed a comprehensive literature search using PubMed, Scopus, EMBASE, and Web of Science for relevant published studies. The literature search was conducted using the terms NMDA, anti-NMDA, Anti-N-methyl-d-aspartate, pediatric encephalitis, and anti-NMDAR and included articles published between 2005 and May 1, 2016. Forty-eight references met inclusion criteria accounting for 373 cases. For first-line treatments, 335 (89.8%) received high-dose corticosteroids, 296 received intravenous immunoglobulin (79.3%), and 116 (31%) received therapeutic plasma exchange. In these, 187 children (50.1%) had a full recovery with only minor deficits, 174 patients (46.7%) had partial recovery with major deficits, and 12 children died. In addition, 14 patients were reported to require mechanical ventilation. Anti-NMDA encephalitis is a formidable disease with great variation in clinical presentation and response to treatment. With early recognition of this second most common cause of pediatric encephalitis, a multidisciplinary approach by physicians may provide earlier access to first- and second-line therapies. Future studies are needed to examine the efficacy of these current therapeutic strategies on long-term morbidity.

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker.

Objective:To compare brain metabolism patterns on fluorodeoxyglucose (FDG)-PET/CT in anti–NMDA receptor and other definite autoimmune encephalitis (AE) and to assess how these patterns differ between anti–NMDA receptor neurologic disability groups.Methods:Retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with definite AE, per published consensus criteria, treated at a single academic medical center over a 10-year period. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections in comparison to age group–matched controls. Brain region mean Z scores with magnitudes ≥2.00 were interpreted as significant. Comparisons were made between anti–NMDA receptor and other definite AE patients as well as among patients with anti–NMDA receptor based on modified Rankin Scale (mRS) scores at the time of FDG-PET/CT.Results:The medial occipital lobes were markedly hypometabolic in 6 of 8 patients with anti–NMDA receptor encephalitis and as a group (Z = −4.02, interquartile range [IQR] 2.14) relative to those with definite AE (Z = −2.32, 1.46; p = 0.004). Among patients with anti–NMDA receptor encephalitis, the lateral and medial occipital lobes were markedly hypometabolic for patients with mRS 4–5 (lateral occipital lobe Z = −3.69, IQR 1; medial occipital lobe Z = −4.08, 1) compared with those with mRS 0–3 (lateral occipital lobe Z = −0.83, 2; p < 0.0005; medial occipital lobe Z = −1.07, 2; p = 0.001).Conclusions:Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti–NMDA receptor encephalitis from other AE. Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti–NMDA receptor encephalitis.

Anti-NMDA-Receptor Encephalitis: From Bench to Clinic.

NMDAR encephalitis is a common cause of autoimmune encephalitis, predominantly affecting young adults. Current data supports the idea that autoantibodies targeting NMDARs are responsible for disease pathogenesis. While these autoantibodies occur in the setting of underlying malignancy in approximately half of all patients, initiating factors for the autoimmune response in the remainder of patients are unclear. While there is increasing evidence supporting viral triggers such as herpes simplex encephalitis, this association and the mechanism of action have not yet been fully described. Although the majority of patients achieve good outcomes, those without an underlying tumor consistently show worse outcomes, prolonged recovery, and more frequent relapses. The cloning of patient-specific autoantibodies from affected individuals has raised important questions as to disease pathophysiology and clinical heterogeneity. Further advances in our understanding of this disease and underlying triggers are necessary to develop treatments which improve outcomes in patients presenting in the absence of tumors.