The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment. METHODS: T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted. RESULTS: Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51). CONCLUSIONS: The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.

Exploring the neuroprotective role of artesunate in mouse models of anti-NMDAR encephalitis: insights from molecular mechanisms and transmission electron microscopy.

BACKGROUND: The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection. METHODS: Adult female mice aged 8-10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM. RESULTS: In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART's therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway. CONCLUSIONS: At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.

Reduced resilience of brain state transitions in anti-N-methyl-D-aspartate receptor encephalitis.

Patients with anti-N-methyl-aspartate receptor (NMDA) receptor encephalitis suffer from a severe neuropsychiatric syndrome, yet most patients show no abnormalities in routine magnetic resonance imaging. In contrast, advanced neuroimaging studies have consistently identified disrupted functional connectivity in these patients, with recent work suggesting increased volatility of functional state dynamics. Here, we investigate these network dynamics through the spatiotemporal trajectory of meta-state transitions, yielding a time-resolved account of brain state exploration in anti-NMDA receptor encephalitis. To this end, resting-state functional magnetic resonance imaging data were acquired in 73 patients with anti-NMDA receptor encephalitis and 73 age- and sex-matched healthy controls. Time-resolved functional connectivity was clustered into brain meta-states, giving rise to a time-resolved transition network graph with states as nodes and transitions between brain meta-states as weighted, directed edges. Network topology, robustness and transition cost of these transition networks were compared between groups. Transition networks of patients showed significantly lower local efficiency (t = -2.41, pFDR  = .029), lower robustness (t = -2.01, pFDR  = .048) and higher leap size (t = 2.18, pFDR  = .037) compared with controls. Furthermore, the ratio of within-to-between module transitions and state similarity was significantly lower in patients. Importantly, alterations of brain state transitions correlated with disease severity. Together, these findings reveal systematic alterations of transition networks in patients, suggesting that anti-NMDA receptor encephalitis is characterized by reduced stability of brain state transitions and that this reduced resilience of transition networks plays a clinically relevant role in the manifestation of the disease.

Lymphomatosis cerebri with coexistent anti-N-methyl-D-aspartate receptor antibody: A case report.

Diagnosis of lymphomatosis cerebri (LC) is usually delayed because of its rarity and the need for pathological confirmation. The association of LC with humoral immunity has scarcely been reported. Herein, we present a woman with a 2-week history of dizziness and gait ataxia, followed by diplopia, altered mental status, and spasticity of all limbs. Magnetic resonance imaging (MRI) of the brain showed multifocal lesions involving bilateral subcortical white matter, deep gray structures, and brainstem. Oligoclonal bands and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were present in cerebrospinal fluid (CSF) twice. She was initially treated with methylprednisolone but still worsening. A stereotactic brain biopsy confirmed the diagnosis of LC. This is a report on the distinctive coexistence of the rare CNS lymphoma variant and the anti-NMDAR antibody.

Anti-N-methyl-D-aspartate receptor encephalitis with concurrent human herpes virus-6A deoxyribonucleic acid detection: An autopsy case.

We report an autopsy case of anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis with concurrent human herpes virus-6 (HHV-6) A deoxyribonucleic acid (DNA) detection in cerebrospinal fluid (CSF). A 38-year-old previously healthy Japanese man presented with a generalized seizure. Brain magnetic resonance imaging (MRI) findings were unremarkable, but CSF revealed pleocytosis. On Day 11, HHV-6 DNA was detected in CSF, and IgG antibodies against the NR1 subunit of the NMDAR (GluN1) were subsequently detected. Since HHV-6 encephalitis was initially suspected, the patient was treated with foscarnet and ganciclovir, but the HHV-6A copy number increased from 200 (Day 22) to 2000 copies/mL (Day 47), and the therapy was ineffective. As typical symptoms of anti-NMDAR encephalitis developed, we changed the patient's treatment to combat anti-NMDAR encephalitis. He was repeatedly treated with first-line immunotherapy, and GluN1 antibody titer decreased. He was not treated with second-line immunotherapy because of recurrent infections; he died on Day 310. Postmortem examinations did not show systemic tumors. Microscopic examination of the brain revealed only severe neuronal rarefaction in the hippocampal cornu ammonis (CA) 3-4 areas with gliosis. Early initiation of aggressive immunotherapy may be required in a refractory case of anti-NMDAR encephalitis, even with HHV-6A DNA detection, because the significance of this concurrent detection in autoimmune encephalitis remains unclear.

Brain MRI features of anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis secondary to central nervous system infection in adult patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis secondary to central nervous system (CNS) infection is a unique subtype of the autoimmune-mediated disease, of which the imaging features are unclear. PURPOSE: To compare the brain magnetic resonance imaging (MRI) features between the anti-NMDAR encephalitis secondary to CNS infection and that without initial infection. MATERIAL AND METHODS: A total of 70 adult patients with anti-NMDAR encephalitis were retrospectively enrolled (24 in the post-infection group, 46 in the non-infection-related group). Their clinical and imaging features (lesion distribution, lesion shape, enhancement pattern, brain atrophy) were reviewed and summarized. Lesion distributions were compared between the two groups on lesion probability maps. RESULTS: The patients with normal brain MRI scans in the post-infection group were less than those in the non-infection related group (29% vs. 63%; P = 0.0113). Among the 24 patients in the post-infection group, visible lesions were shown at the anti-NMDAR encephalitis onset in 17 patients; lesion distribution was more diffuse than the non-infection-related group, showing higher lesion peak probabilities in the bilateral hippocampus, frontal lobe, temporal lobe, insula, and cingulate. The lesions with contrast enhancement were also more common in the post-infection group than the non-infection-related group (7/13 vs. 2/10). Brain atrophy was observed in eight patients in the post-infection group and three in the non-infection-related group. CONCLUSION: Anti-NMDAR encephalitis secondary to CNS infection has its imaging features-extensive lesion distribution, leptomeningeal enhancement, early atrophy, and necrosis-that could deepen the understanding of the pathophysiology and manifestation of the autoimmune encephalitis besides the classic type.

Neuropathological Variability within a Spectrum of NMDAR-Encephalitis.

OBJECTIVE: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. METHODS: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. RESULTS: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. INTERPRETATION: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.

Ovarian teratoma-associated anti-NMDAR encephalitis: a single-institute series of six patients from China.

PURPOSE: Ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis is a rare disease with uncertain etiology and pathogenesis. The disorder is severe and rare with a great impact on young adults. This study aimed to improve the awareness of the disease from experience in our single center. METHODS: Between July 2012 and December 2019, six patients with ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis were enrolled in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. All patients' data like manifestations, laboratory and radiological data, treatment, and follow-up were reviewed. RESULTS: Typical psychotic symptoms, memory, and consciousness disorders accompanied by seizures were observed in all patients from this study. All six patients showed positive signals in serum and cerebrospinal fluid samples for N-methyl-D-aspartate receptor and received immunotherapy. Three patients underwent unilateral oophorocystectomy and the other three underwent unilateral oophorectomy through minimally invasive surgeries, including laparoscopic and single-port laparoscopic surgeries. The median follow-up time 24.5 months (range from 6 to 93 months). No death occurred. Two patients had recurrent psychotic symptoms while the left four patients had no mental symptoms or tumor recurrence during postoperative follow-up. CONCLUSIONS: For patients with clinical manifestations of unexplained acute psychiatric symptoms accompanied by seizures, memory, and consciousness disorders, the possibility of anti-N-methyl-D-aspartate receptor encephalitis should be considered. To confirm the diagnosis, examinations of anti-N-methyl-D-aspartate receptor antibodies need to be completed as early as possible. Immunotherapy and tumor location should be given in time once the diagnosis is defined. We recommended removing the tumor as soon as possible without concerning whether the patient is in the acute phase or not. The surgical procedure should be decided based on pathology, age, fertility desire, and patients' requirements and it should be ensured that tumors are completely removed during operation. Postoperative follow-up is particularly important.

N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776.

Solitary juxtacortical lesion associated with anti-N-methyl-D-aspartate receptor encephalitis: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a severe autoimmune encephalitis mediated by anti-NMDA receptor antibodies. Brain MRI manifestations vary and are non-specific. If there are any lesions, they tend to be diffusely or multifocally distributed. Solitary lesion is relatively rare. CASE PRESENTATION: We report a 16-year-old girl who initially presented with focal seizures but developed severe psychiatric and extrapyramidal symptoms later on. Brain MRI revealed a solitary juxtacortical demyelinating lesion in the left frontal lobe. No enhancement was noted. Electroencephalogram captured epileptiform discharges in the same region. NMDAR IgGs were tested positive in the serum and cerebrospinal fluid. Corticosteroid and intravenous IgG were administered and the patient completely recovered. Brain MRI revealed a fainter lesion in the left frontal lobe. CONCLUSION: In very rare instances, anti-NMDA receptor encephalitis can present with a solitary brain lesion. A full panel of antibodies for autoimmune encephalitis is the key leading to the diagnosis.

Associations between seizures and MRI in patients with anti-NMDAR encephalitis.

OBJECTIVES: Seizures are a prominent feature of anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Nearly half of brain magnetic resonance image (MRI) results are abnormal. The aim of our study was to evaluate the associations between seizures and brain MRI results in patients with anti-NMDAR encephalitis. METHODS: Patients with anti-NMDAR encephalitis were enrolled between January 2015 and December 2018. The patients included were divided into normal and abnormal MRI groups. Seizure outcomes and modified Rankin Scale scores at the 1-year follow-up were assessed. Seizure characteristics and outcomes were compared between groups. RESULTS: Of 35 patients with anti-NMDAR encephalitis, 28 patients (80%) had reported seizures in the acute phase. Patients with abnormal MRI findings more frequently had focal seizures than patients with normal MRI findings (72.7% vs 17.6%, P < .01). The incidence of patients treated with 2 or more antiepileptic drugs was higher in the normal MRI group than in the abnormal MRI group (100% vs 45.4%, P < .01). The onset-immunotherapy time was shorter in the abnormal MRI group than in the normal MRI group (P < .05). There were no statistically significant differences in seizure outcomes between the normal and abnormal MRI groups (P > .05). CONCLUSIONS: Focal seizures were most common in patients with abnormal MRI lesions. In the acute stage of the disease, the abnormal MRI group was more likely than the normal MRI group to achieve seizure control. Abnormal MRI findings did not affect the overall good prognosis of patients with anti-NMDAR encephalitis with seizures.

Voxel-based analysis and multivariate pattern analysis of diffusion tensor imaging study in anti-NMDA receptor encephalitis.

PURPOSE: This study aimed to investigate brain white matter (WM) changes and their relationship to cognition in patients with anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis. Multivariate pattern analysis (MVPA) was used to explore brain regions that play an important role in classification. METHODS: Fifteen patients and fifteen controls underwent Montreal Cognitive Assessment (MoCA) and diffusion tensor imaging. Based on fractional anisotropy (FA) and mean diffusivity (MD) for MVPA classification, the weights of each brain region were calculated. RESULTS: Compared with the controls, the patients showed an FA reduction in right middle temporal gyrus, left middle cerebellar peduncle, right praecuneus, and an MD increase in left medial temporal gyrus and left frontal lobe. The MoCA score for patients was lower than controls, especially in executive function, fluency, delayed recall and visual perception items. The FA value of right praecuneus was positively correlated with total MoCA score and fluency score. The MD of left frontal lobe was negatively correlated with total MoCA score, and MD of the left medial temporal gyrus was positively correlated with delayed recall. The accuracy, sensitivity and specificity of classification based on FA were 70%, 60% and 80%, respectively. Based on MD, they were each 80%. The brain regions with large weights from FA and MD overlap in temporal lobe, cerebellum and hippocampus. CONCLUSIONS: These results suggest that WM changes are associated with cognitive deficits. MVPA based on FA and MD has good classification ability. Our study may provide new insights into the pathophysiological mechanisms of residual cognitive deficits.

Optic Nerve Atrophy in N-methyl-D-aspartate (NMDA) Encephalitis.

N-methyl-D-aspartate receptor (NMDA) encephalitis is a recently described autoimmune disease that typically presents with prodromal symptoms including upper respiratory tract infection, headache, fever, nausea, vomiting and diarrhea. Psychiatric symptoms follow within weeks, including anxiety, insomnia, mania, paranoia and grandiose delusions. The diagnosis is confirmed by the detection of NMDA antibodies in the serum or cerebrospinal fluid (CSF).1 Tumours, especially teratomas, are frequently associated with NMDA encephalitis; however, only 5% of male patients older than 18 years have been found to have an underlying tumour. Optic neuropathy associated with NMDA encephalitis is being increasingly recognised in the literature2-6 and was reviewed most recently by Mugavin et al.2 in 2017. In this report, we present a case of bilateral optic neuropathy in a young man diagnosed with NMDA receptor encephalitis.

Anti-N-methyl-D-aspartate Receptor Encephalitis: a Rare Complication of Ovarian Teratoma.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a potentially life-threatening but reversible autoimmune disorder characterized by psychiatric symptoms, cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation. It occurs predominantly in young women and approximately half of them have underlying tumors, mainly ovarian teratoma. A 24-year old woman was admitted because of fever, headache, abnormal movement and decreased mental status. Five cycles of plasmapheresis improved her neurological and mental status. Anti-NMDAR antibodies in her CSF and serum were positive, and computed tomography revealed a 1-cm sized mass suggestive of mature cystic teratoma arising from the right ovary. We promptly performed laparoscopic right ovarian cystectomy. She was discharged after 2 weeks with mild memory deficit. Prompt removal of ovarian teratoma and multidisciplinary care are particularly important for good outcome.

A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: Seizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. METHODS: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. RESULTS: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. SIGNIFICANCE: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

The diffuse involvement of anti-N-methyl-D-aspartate receptor encephalitis in brain: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe and most common autoimmune encephalitis in patients under 40 years old. Anti-NMDAR encephalitis has various clinical and neuroimaging findings. Here we report a special case of an anti-NMDAR encephalitis who had diffuse lesions in bilateral hemispheres with mild mass effects in left basal ganglia area. CASE PRESENTATIONS: A 28-year-old female anti-NMDAR encephalitis patient mainly presented with headache and fever. Brain magnetic resonance image (MRI) showed slightly contrasted diffuse lesions, involving the left temporal and frontal lobes, left basal ganglia area and splenium of corpus callosum, as well as the right frontal lobe, with mild edema surrounded in the left basal ganglia area. Cerebrospinal fluid (CSF) revealed a moderate pleocytosis with normal protein and glucose levels. Anti-NMDAR antibodies were identified in CSF. Transvaginal ovarian ultrasound did not reveal an ovarian teratoma. The patient was treated with immunoglobulin and steroid, and had a good recovery. CONCLUSIONS: Anti-NMDAR encephalitis has no special clinical manifestations and brain MRI is highly variable, which could be unremarkable or abnormal involving white and grey matters. The extensive lesions in frontal and temporal lobes, and basal ganglia area, with mild mass effects, have not been described previously. Recognition of various changes in brain MRI will enable the early detection of anti-NMDAR antibody and then effective treatments.

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

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.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.

Anti NMDA receptor antibody encephalitis in Pakistan: Clinicopathological features and treatment outcomes.

Anti-NMDA receptor antibody encephalitis (anti-NMDAR Encephalitis) is the most common subtype of autoimmune encephalitis in which IgG antibodies directed against NR1 subunit of NMDA receptors are present. It is a potentially lethal encephalitis which responds favourably to timely immunosuppressive therapy. If untreated, its progression leads from delusions, paranoia, movement disorder, memory deficit and seizures into a state of unresponsiveness with autonomic instability and even death. We present clinicopathological features, treatment and outcomes of eight autoantibodyproven cases of anti-NMDAR Encephalitis. There were 7 females and 1 male with a mean age of 15 years (age range: 1 to 28 years). Clinical features included seizures, altered consciousness, memory deficit, delusions, paranoia and hallucinations. Hyperactivity and irritability were prominent features among the children. Patients treated with immunosuppressive therapy including steroids, IVIg, plasmapheresis and Rituximab, recovered completely within a month of therapy. Whereas patients who received only steroids as immunosuppressive therapy suffered from residual brain damage.

Superficial white matter damage in anti-NMDA receptor encephalitis.

BACKGROUND: Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter. METHODS: Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity. RESULTS: Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients. CONCLUSIONS: Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

[Analysis of clinical characteristics and outcomes of mechanically ventilated patients with anti-N-methyl-D-aspartate receptor encephalitis].

Objective: To explore the clinical characteristics and long-term outcomes of mechanically ventilated patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Methods: In this observational study, patients with anti-NMDAR encephalitis were enrolled, who were admitted into Xuanwu Hospital of Capital Medical University from Jan 2012 to Jun 2015.All patients accepted tumor screening, symptomatic therapy, and immunotherapy.Outcomes were assessed by modified Rankin Scale (mRS) after immunotherapy every 6 months, and mRS 0-2 was defined as favorable outcome.The differences of clinical manifestations, auxiliary examinations, and outcomes between mechanical ventilation (MV) group and no MV group were analyzed. Results: Fifty-six patients (mean age 28±12 years, range 12 to 58 years) were enrolled, and 28 were male.MV group included 16 (28.6%) patients.Five female patients were diagnosed with ovarian teratoma.After 6 months, 50 patients (89.3%) had favorable outcomes, mortality was 0.The proportions of patients being female, with ovarian teratoma, conscious disturbance, dysautonomia, accepting plasmapheresis, immunodepressant treatment, admitted into neuro-critical care unit in MV group were significant higher than those in no MV group.The duration of illness prior to MV was 10-73 days (mean 33±19 days). The period of MV was 3-154 days (mean 46±41 days). There was no significant difference in the period of using MV among different outcome groups.After 6-48 months' follow-up, 6 patients (10.7%) relapsed, with 1 patient in MV group (1/16, 6.3%), 5 patients in no MV group (5/40, 12.5%). The relapses and long-term outcomes were not significant different between MV group and no MV group. Conclusions: The condition of mechanically ventilated patients with Anti-NMDAR encephalitis is severe, and the treatment is difficult. However, after active combined immunotherapy and life support, majority of these patients could get good long-term outcomes.