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.

Efficacy and safety of different oral prednisone tapering courses in adult anti-NMDAR encephalitis: A multicenter prospective cohort study.

OBJECTIVE: In adult anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first-line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT courses in anti-NMDAR encephalitis. METHODS: The CHASE study, a multicenter prospective observational cohort study, enrolled patients with autoimmune encephalitis from October 2011 to March 2023. Patients were grouped based on oral prednisone tapering course: ≤3 months (Group ≤3 month), 3-6 months (Group 3-6 months, including 3 months), and >6 months (Group > 6 months). Kaplan-Meier plots were used to analyze time to relapse and time to total recovery within 2 years. RESULTS: Among 666 screened patients, 171 (median [IQR] age 27 [21.0-36.5] years, 55.0% female) met selection criteria. Responders at 3 months were prevalent in Group ≤3 months (OR 7.251 [95% CI 2.252 to 23.344] and Group 3-6 months (OR, 3.857 [95% CI 1.107 to 13.440] than in Group >6 months. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months were higher in Group >6 months than in Group ≤3 months and Group 3-6 months (ß, -2.329 [95% CI -3.784 to -.875]; ß, -2.871 [95% CI -4.490, -1.253]). CASE seizures subscore was higher in Group >6 months than in Group 3-6 months (ß, -.452 [95% CI -.788 to -.116]). No significant difference in seizure freedom rates among the groups. Adverse events were higher in Group 3-6 months and Group >6 months than in Group ≤3 months (OR 6.045 [95% CI 2.352 to 15.538]; OR 6.782 [95% CI 1.911 to 24.073]). SIGNIFICANCE: Longer oral prednisone courses for adult patients with anti-NMDAR encephalitis did not show superior effects compared to shorter courses in improving modified Rankin Scale (mRS) scores and CASE scores, reducing the risk of relapse within 2 years, or achieving seizure freedom. Instead, extended prednisone courses may lead to more side effects- particularly weight gain. This outcome recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.

Anti-NMDAR encephalitis with delayed ovarian teratoma in a young woman: a case report with 5 years of follow-up.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder with a variety of clinical manifestations. It has been established that anti-NMDAR encephalitis may be related to ovarian teratoma in female patients. However, a considerable number of patients have no obvious evidence of ovarian teratoma during the onset of the disease. CASE: A 25-year-old previously-healthy female experienced a series of acute symptoms within two days, including confusion, disorientation, short-term memory loss, auditory hallucinations, abnormal behavior, refractory status epilepticus, etc. Her brain MRI and abdominal imaging showed no definite abnormality while her electroencephalogram exhibited the presence of low to moderate amplitude sharp, spike, and multi-spike waves. Serum and cerebrospinal fluid tests yielded positive results for anti-NMDAR antibodies. However, an ultrasound scan failed to identify an ovarian teratoma. Consequently, the diagnosis of anti-NMDAR encephalitis without teratoma was made after 4 days onset. After the plasma exchange and immunoglobulin therapy, her neurological symptoms improved and obtained a clinical cure. In the next eight months of follow-up, the patient accidentally touched a lump in the lower abdomen without any symptoms, and abdominal ultrasound and CT scan revealed a left ovarian tumor. Then she underwent left ovarian teratoma resection surgery and histopathology showed a mature cystic teratoma with neural components. The patient continued to receive five years of follow-up, and her condition remained stable without any recurrence, except that there had been a low titer of anti-NMDAR antibody in her serum. CONCLUSION: Our case demonstrated the importance of long-term follow-up for female patients with anti-NMDAR encephalitis, since anti-NMDAR encephalitis-associated ovarian teratomas may develop in a delayed manner, even without any symptoms.

A case of NMDAR Encephalitis with muscular pain as the main presentation.

BACKGROUND: Persistent somatoform pain disorder (PSPD) is often the initial diagnosis in patients seeking treatment in psychiatric departments, making it challenging to consider organic nervous system diseases. However, autoimmune encephalitis can present with atypical initial symptoms, leading to misdiagnosis or missed diagnosis. Lumbar puncture, with antibody support, plays a crucial role in diagnosing autoimmune encephalitis. CASE PRESENTATION: This report describes a 40-year-old male adult patient who was initially diagnosed with persistent somatoform pain disorder in 2022. The patient reported a reduction in pain while resting on his back. There were no fever or relevant medical history. Despite 8 months of symptomatic treatment, the symptoms did not improve. Moreover, the patient developed confusion, gibberish speech, non-cooperation during questioning, and increased frequency and amplitude of upper limb convulsions. Lumbar puncture revealed elevated protein levels and protein-cell dissociation. The autoimmune encephalitis antibody NMDAR (+) was detected, leading to a diagnosis of autoimmune encephalitis (NMDAR). CONCLUSION: Autoimmune encephalitis (NMDAR), starting with persistent somatoform pain (PSPD), often presents with atypical symptoms and can be easily misdiagnosed. Therefore, it is important to consider the possibility of organic nervous system disease in time, and to test serum or cerebrospinal fluid antibodies to rule out organic nervous system disease after symptomatic treatment of mental disorders is ineffective. This approach facilitates the early diagnosis of autoimmune encephalitis and other underlying organic neurological disorders.

Clinical features of adult patients with positive NMDAR-IgG coexisting with MOG-IgG.

INTRODUCTION: This study was designed to analyze clinical and radiographic features of adult patients coexisting with NMDAR-IgG and MOG-IgG. METHODS: Eleven adult patients coexisting with NMDAR-IgG and MOG-IgG were collected from Xiangya Hospital, Central South University, between June 2017 and December 2021. Fifty-five patients with anti-NMDAR encephalitis and 49 with MOG-AD were served as controls. RESULTS: Onset age was 27 (IQR 20-34) years old. Seizures and psychotic symptoms were prominent symptoms. Ten of eleven patients presented abnormal T2/FLAIR hyperintensity, mainly involving the cortex, brainstem, and optic nerve. Compared with the NMDAR IgG ( +)/MOG IgG ( -) group, the NMDAR IgG ( +)/MOG IgG ( +) group showed more ataxia symptoms (27.3% vs. 3.6%, P = 0.037), while more T2/FLAIR hyperintensity lesions were found in the brainstem (54.5% vs. 7.3%, P < 0.001) and optic nerve (27.3% vs. 1.8%, P = 0.011) with more abnormal MRI patterns (90.9% vs. 41.8%, P = 0.003). In comparison with the NMDAR IgG ( -)/MOG IgG ( +) group, the NMDAR IgG ( +)/MOG IgG ( +) group had more seizures (72.7% vs. 24.5%, P = 0.007) and mental symptoms (45.5% vs. 0, P < 0.001). The NMDAR IgG ( +)/MOG IgG ( +) group tended to be treated with corticosteroids alone (63.6% vs. 20.0%, P = 0.009), more prone to recur (36.5% vs. 7.3%, P = 0.028) and lower mRS score (P = 0.036) at the last follow-up than pure anti-NMDAR encephalitis. CONCLUSION: The symptoms of the NMDAR IgG ( +)/MOG IgG ( +) group were more similar to anti-NMDAR encephalitis, while MRI patterns overlapped more with MOG-AD. Detecting both NMDAR-IgG and MOG-IgG maybe warranted in patients with atypical encephalitis symptoms and demyelinating lesions in infratentorial regions.

Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis.

INTRODUCTION: Neuroinfection is associated with the deposition of amyloid-beta (Aß) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aß peptides in the brain is unreported. METHODS: We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aß1-42 (cAß1-42), Aß1-40 (cAß1-40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis. RESULTS: NMDAR-E patients had lower cAß1-42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAß1-42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAß1-42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAß1-42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAß1-42 levels and high levels of several blood parameters. cAß1-42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAß1-42 and some inflammatory indicators. CONCLUSION: cAß1-42 was decreased in NMDAR-E patients. cAß1-42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAß1-42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E.

Aberrant Brain Networks and Relative Band Power in Patients with Acute Anti-NMDA Receptor Encephalitis: A Study of Resting-State EEG.

OBJECTIVE: The alterations of the functional network (FN) in anti-N-methyl-Daspartate receptor (NMDAR) encephalitis have been recognized by functional magnetic resonance imaging studies. However, few studies using the electroencephalogram (EEG) have been performed to explore the possible FN changes in anti-NMDAR encephalitis. In this study, the aim was to explore any FN changes in patients with anti-NMDAR encephalitis. METHODS: Twenty-nine anti-NMDAR encephalitis patients and 29 age- and gender-matched healthy controls (HC) were assessed using 19-channel EEG examination. For each participant, five 10-second epochs of resting state EEG with eyes closed were extracted. The cortical source signals of 84 Brodmann areas were calculated using the exact low resolution brain electromagnetic tomography (eLORETA) inverse solution by LORETA-KEY. Phase Lag Index (PLI) matrices were then obtained and graph and relative band power (RBP) analyses were performed. RESULTS: Compared with healthy controls, functional connectivity (FC) in the delta, theta, beta 1 and beta 2 bands significantly increased within the 84 cortical source signals of anti-NMDAR encephalitis patients (p < 0.05) and scalp FC in the alpha band decreased within the 19 electrodes. Additionally, the anti-NMDAR encephalitis group exhibited higher local efficiency and clustering coefficient compared to the healthy control group in the four bands. The slowing band RBP increased while the fast band RBP decreased in multiple-lobes and some of these changes in RBP were correlated with the modified Rankin Scale (mRS) and Mini-mental State Examination (MMSE) in anti-NMDAR encephalitis patients. CONCLUSIONS: This study further deepens the understanding of related changes in the abnormal brain network and power spectrum of anti-NMDA receptor encephalitis. The decreased scalp alpha FC may indicate brain dysfunction, while the increased source beta FC may indicate a compensatory mechanism for brain function in anti-NMDAR encephalitis patients. These findings extend understanding of how the brain FN changes from a cortical source perspective. Further studies are needed to detect correlations between altered FNs and clinical features and characterize their potential value for the management of anti-NMDAR encephalitis.

What we've learnt about autoimmune neurological diseases from neuropathology.

Antibody-associated autoimmune neurological diseases are a group of disorders with various immune effector mechanisms that result in significant differences in disease course and prognosis. Paraneoplastic or idiopathic autoimmune encephalitis associated with antibodies against intracellular antigens are mostly characterized by a T-cell-dominated inflammation with neuronal loss, astrogliosis, and microglial nodules. In anti-Yo paraneoplastic cerebellar degeneration CD8+/granzymeB+ T cells were demonstrated in close apposition to neurons along with a nuclear upregulation of the activator of transcription 1, suggesting an important role of interferon-gamma in disease pathogenesis. Early and late disease stages may show different lesion types. For example, tissue samples from patients with temporal lobe epilepsy associated with antiglutamic acid decarboxylase 65 antibodies in early disease stages show numerous infiltrating T cells targeting hippocampal neurons and high numbers of B cells and plasma cells, while in chronic stages inflammation gets less and is followed by hippocampal sclerosis. Similarly, antiglial fibrillary acidic protein meningoencephalomyelitis may show loss of astrocytes only in the very early lesions, whereas in subacute and chronic stages astrocytes can get replenished most likely due to their high regeneration potential. In contrast, neuropathology of autoimmune neurological diseases mediated by surface antibodies is mostly characterized by a dysfunction of neurons in the absence of immune-mediated neuronal damage. The interaction of surface antibodies with their target antigen and the resulting downstream mechanisms are variable and can range from an internalization of the receptor in well-preserved neurons in anti-N-methyl-D-aspartate receptor encephalitis to an irreversible internalization and blocking of the receptor that may be associated with an accumulation of phosphorylated tau in specific brain regions in anti-IgLON5 disease. Interestingly, anti-IgLON5 patients with short disease duration were shown to present prominent deposition of IgG4 in the neuropil and on neuronal membranes in the absence of neuronal tau deposits, suggesting that the immune mechanisms precede neurodegeneration. Knowledge about pathomechanisms and patterns of tissue damage in different disease stages of antibody-associated autoimmune diseases will help to identify novel biomarkers and can give important clues for possible therapeutic interventions.

Anti-NMDAR1 antibody impairs dendritic branching in immature cultured neurons.

Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by IgG antibodies targeting NMDAR. The prevalence is remarkably higher in women and some develop the condition during pregnancy. While immunotherapies have shown good outcomes for pregnant mothers and their infants, the impact on early neurodevelopment remains elusive. This study investigates the effects of anti-NMDAR antibody on the development of primary cortical cultures. Anti-NMDAR antibody was administered to the cultures at day in vitro 5 for the following 5 days to assess dendritic branching and arbor complexity, and at day in vitro 14 for measuring the expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. Immature cultured neurons treated with anti-NMDAR antibody exhibited impaired dendritic branching and arbor complexity. Interestingly, BDNF expression was unaffected in mature neurons. Additionally, GluN1 expression, a mandatory NMDAR subunit, was significantly reduced, while no significant alterations were observed in PSD-95, gephyrin and synaptophysin expression. These findings shed light on the structural and synaptic impacts of anti-NMDAR antibody on immature neurons, providing evidence for their consequences in early neuronal development.

Neuropsychiatric phenotypes of anti-NMDAR encephalitis: a prospective study.

BACKGROUND: Patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) show a wide range of behavioral abnormalities and are often mistaken for primary psychiatric presentations. We aimed to determine the behavioral hallmarks of ANMDARE with the use of systematic neuropsychiatric and cognitive assessments. METHODS: A prospective study was conducted, with 160 patients admitted to the National Institute of Neurology and Neurosurgery of Mexico, who fulfilled criteria for possible autoimmune encephalitis and/or red flags along a time window of seven years. Cerebrospinal fluid (CSF) antibodies against the NR1 subunit of the NMDAR were processed with rat brain immunohistochemistry and cell-based assays with NMDA expressing cells. Systematic cognitive, neuropsychiatric, and functional assessments were conducted before knowing NMDAR antibodies results. A multivariate analysis was used to compare patients with and without definite ANMDARE according to antibodies in CSF. RESULTS: After obtaining the CSF antibodies results in 160 consecutive cases, 100 patients were positive and classified as having definite ANMDARE. The most frequent neuropsychiatric patterns were psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%). Cognition was significantly impaired. A total of 34% of the patients had a predominantly neuropsychiatric presentation without seizures. After multivariate analysis, the clinical hallmarks of ANMDARE consisted of a catatonia-delirium comorbidity, tonic-clonic seizures, and orolingual dyskinesia. CONCLUSIONS: Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia-delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage.

The disruption of the blood-brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.

Suicidal Thoughts and Behaviors in Anti-NMDA Receptor Encephalitis: Psychopathological Features and Clinical Outcomes.

OBJECTIVE: A wide variety of neuropsychiatric symptoms are described during the acute phase of anti-N-methyl-d-aspartate receptor encephalitis (ANMDARE), including psychosis, mania, depression, and catatonia, but there are few reports on suicidal thought and behaviors in ANMDARE. To address this gap in the literature, the authors measured the presence of suicidal thoughts and behaviors among a large cohort of Mexican patients diagnosed with definite ANMDARE. METHODS: This observational and longitudinal study included patients with definite ANMDARE hospitalized at the National Institute of Neurology and Neurosurgery of Mexico between 2014 and 2021. Suicidal thoughts and behaviors were assessed before and after treatment by means of a clinical interview with relatives and a direct clinical assessment with each patient. Thoughts of engaging in suicide-related behavior and acts of suicidal and nonsuicidal self-directed violence before and during hospitalization were recorded. RESULTS: From a total sample of 120 patients who fulfilled the diagnostic criteria for definite ANMDARE, 15 patients (13%) had suicidal thoughts and behaviors during the acute phase of the disease. All 15 of these patients experienced psychosis and had suicidal ideation with intention. Three patients engaged in preparatory behaviors and seven carried out suicidal self-directed violence. Psychotic depression and impulsivity were more frequent among those patients with suicidal thoughts and behaviors than among those without any form of suicidality. Four patients engaged in self-directed violence during hospitalization. Remission was sustained in 14 of 15 patients, with suicidal ideation and self-directed violence persisting during follow-up in only one patient. CONCLUSIONS: Suicidal thoughts and behaviors are not uncommon during the acute phase of ANMDARE. On the basis of our sample, the persistence of these features after immunotherapy is rare but may be observed. A targeted assessment of suicidal risk should be strongly considered in this population.

Psychiatric features in NMDAR and LGI1 antibody-associated autoimmune encephalitis.

Patients with autoimmune encephalitis (AE) often developed psychiatric features during the disease course. Many studies focused on the psychiatric characteristic in anti-NMDAR encephalitis (NMDAR-E), but anti-LGI1 encephalitis (LGI1-E) had received less attention regarding the analysis of psychiatric features, and no study compared psychiatric characteristic between these two groups. The clinical data of AE patients (62 NMDAR-E and 20 LGI1-E) who developed psychiatric symptoms were analyzed in this study. In NMDAR-E, the most common higher-level feature was "behavior changes" (60/62, 96.8%) and the lower-level feature "incoherent speech" was observed in 33 patients (33/62, 53.2%), followed by "agitation" (29/62, 46.8%) and "incongruent laughter/crying" (20/62, 32.3%). Similar to NMDAR-E, "behavior changes" was most common in LGI1-E (17/20, 85.0%), but the features of suicidality, eating, and obsessive-compulsive were not reported. The top three lower-level features were visual hallucinations (9/20, 45.0%), incoherent speech (8/20, 40.0%), and mood instability (7/20, 35.0%). The comparative study found that "incongruent laughter/crying", in lower-level features, was more frequently observed in NMDAR-E (32.3% vs. 0%, p = 0.002). Moreover, the Bush Francis Catatonia Rating Scale (BFCRS) assessing the catatonic symptoms in NMDAR-E were higher than LGI1-E, but the 18 item-Brief Psychiatric Rating Scale (BPRS-18) showed no difference in the two groups. In summary, both NMDAR-E and LGI1-E often developed psychiatric symptoms. In contrast with LGI1-E, the psychiatric feature "incongruent laughter/crying" was more frequently associated with NMDAR-E, and catatonic symptoms were more severe in NMDAR-E.

Catatonia in adult anti-NMDAR encephalitis: an observational cohort study.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent autoimmune encephalitis and is closely related to catatonia. This study aimed to investigate the clinical features and disease outcomes of adult catatonic anti-NMDAR encephalitis patients. METHODS: Adult patients diagnosed with anti-NMDAR encephalitis between January 2013 and October 2021 were retrospectively enrolled in this study. According to the Bush Francis Catatonia screening instrument (BFCSI), patients were divided into two groups: those with catatonia and those without catatonia. The modified Rankin scale (mRS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), Neuropsychiatric Inventory (NPI), Patient Health Questionnaire-9 (PHQ-9) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7) scores were assessed at follow-up. The Mann-Whitney U test (nonparametric), Student's t test (parametric), and chi-squared test were used to analyse the differences between the two groups. RESULTS: Eighty-four patients were recruited, including twenty-five catatonic patients and fifty-nine noncatatonic patients. Among them, 28 had positive antibody only in cerebrospinal fluid (CSF), 4 had positive antibody only in serum and 52 had positive antibody both in CSF and serum. Catatonic patients experienced more disturbance of consciousness (p = 0.01), aggression (p = 0.046) and affective disorders (p = 0.043) than noncatatonic patients. The mRS scores of the catatonia group assessed at admission (p = 0.045) were worse than those of the non-catatonia group. Catatonic patients were more inclined to develop deep vein thrombosis (p = 0.003), decubitus (p = 0.046), pneumonia (p = 0.025), and to be admitted to the intensive care unit (ICU) (p = 0.011) than noncatatonic patients. All patients in the catatonia group received first-line immunotherapy. At the 24-month follow-up, 2 patients in the catatonia group did not achieve good outcomes. At the last follow-up, the catatonia group had more relapses (p = 0.014) and more neuropsychiatric problems (p = 0.035). CONCLUSIONS: Adult anti-NMDAR encephalitis patients with catatonia present distinct clinical features in disease course and are prone to experience more relapses and long-term neuropsychiatric problems than those without catatonia.

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.

Clinical outcome in an infant with anti-NMDA receptor encephalitis: case report and literature review.

Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that often presents with various neurological and neuropsychiatric symptoms. Although most reported cases occur in children, only a limited number of studies on children are available. The subject of this case report is an 8-month-old female who presented with fever, vomiting, and seizure. She was diagnosed with encephalitis and treated with acyclovir. After 21 days, she showed irritability, seizure, orolingual-facial dyskinesias, choreodystonic movements, hemiparesis, dysphagia, strabismus, lack of interest in light and objects. Clinical signs, neuroimaging findings, and serum analysis of anti-NMDAR antibodies confirmed the diagnosis of anti-NMDAR encephalitis. After the first line of treatment, she showed full recovery. We update the infants with anti-NMDAR encephalitis in the literature. Clinical outcomes suggest that patients with anti-NMDAR encephalitis are mostly poor in the infants, excluding our case. We propose that early and appropriate treatments are critical for timely diagnosis and rapid improvement.

Correlation analysis between regional homogeneity and executive dysfunction in anti-N-methyl-D-aspartate receptor encephalitis patients.

BACKGROUND AND PURPOSE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by a range of cognitive impairments, especially in executive function. Our study aims to identify the abnormal regional homogeneity (ReHo) in anti-NMDAR encephalitis patients and its relationship with the executive function. METHODS: Forty patients and 42 healthy volunteers undertook an Attention Network Test and a resting-state functional magnetic resonance imaging scan. ReHo analysis was performed to investigate the neuronal activity synchronization in all subjects. Based on ReHo analysis, a multivariate pattern analysis (MVPA) was carried out to identify the brain regions that differed the most between the two groups. RESULTS: Compared to controls, the patients had higher executive control scores (p < 0.05). The patients presented reduced ReHo values in the bilateral posterior cerebellar lobe, anterior cerebellar lobe, midbrain, bilateral caudate nucleus, right superior frontal gyrus, right middle temporal gyrus, bilateral inferior parietal lobule and the left middle frontal gyrus. The ReHo values of the bilateral inferior parietal lobule in patients were found to be negatively associated with executive control scores. The classification of patients and controls using MVPA had an accuracy of 76.83%, a sensitivity of 82.50%, a specificity of 71.43% and the area under the curve was 0.83. CONCLUSIONS: Our study provides evidence of abnormal cerebral function in anti-NMDAR encephalitis patients, which may contribute to unveiling the neuropathological mechanisms of anti-NMDAR encephalitis and their influences on executive dysfunction. The MVPA classifier, based on ReHo, is helpful in identifying anti-NMDAR encephalitis patients from healthy controls.

Anti-N-methyl-D-aspartate receptor encephalitis associated with chronic myelogenous leukemia, causality or coincidence? A case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune paraneoplastic encephalitis, and is primarily associated with ovarian teratomas. Here, we report the first case of a patient diagnosed with chronic myelogenous leukemia (CML) during the recovery phase of anti-NMDAR encephalitis. CASE PRESENTATION: The patient was admitted with fever, headache, and seizures. Brain MRI revealed a cerebrospinal fluid (CSF)-containing arachnoid cyst in the left temporal lobe with no other abnormal signals. EEG showed diffuse background slowing in the delta-theta range. The patient tested positive for anti-NMDAR antibodies in both the serum and CSF. One year after the onset of encephalitis, the patient was referred to the Department of Hematology for extreme leukocytosis. Karyotype analysis showed the presence of Philadelphia chromosome t(9;22)(q34;q11). Quantitative reverse transcriptase PCR analysis further identified BCR/ABL1 fusion transcripts; thus, CML was diagnosed. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-NMDAR encephalitis associated with CML. This report should alert clinicians to consider CML as a malignancy that is possibly associated with limbic encephalitis.

Aberrant resting-state interhemispheric functional connectivity in patients with anti-N-methyl-D-aspartate receptor encephalitis.

PURPOSE: Previous studies have discovered different neuroimaging features in anti-NMDAR encephalitis associated with cognitive dysfunction. However, it is unknown whether there is a correlation between abnormal homotopic connectivity and cognitive impairment in anti-NMDAR encephalitis. We aim to explore the homotopic connectivity patterns of patients with anti-NMDAR encephalitis and their associations with clinical characteristics. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was performed on 29 patients with anti-NMDAR encephalitis and 26 healthy controls (HCs). Voxel-mirrored homotopic connectivity (VMHC) and multivariate pattern analysis (MVPA) were applied to analyze the imaging data. A correlation was also performed between aberrant brain regions and clinical parameters. RESULTS: Compared to HCs, the performance of alertness in the patient group was typically worse (p < 0.05). A significant decrease in VMHC was observed in many regions of the patients in comparison to HCs, including the cerebellar 6, para-hippocampal gyrus, insula, precuneus, and middle frontal gyrus (p < 0.001). The insula and middle frontal gyrus were found to show positive correlations with alertness. The MVPA method achieved a classification accuracy of 74.55% with a sensitivity of 82.76% and a specificity of 65.38% in discriminating patients from HCs. CONCLUSION: Our findings indicate that interhemispheric functional imbalance may play a significant role in the pathophysiology of cognitive dysfunction in anti-NMDAR encephalitis. The MVPA results suggest that abnormal VMHC may play a crucial role in the identification of patients with anti-NMDAR encephalitis from HCs.

[18F]FDG brain PET and clinical symptoms in different autoantibodies of autoimmune encephalitis: a systematic review.

INTRODUCTION: Autoimmune encephalitis (AE) is caused by the antibodies that target receptors and intracellular or surface proteins. To achieve the appropriate therapeutic results, early and proper diagnosis is still the most important issue. In this review, we provide an overview of FDG-PET imaging findings in AE patients and possible relation to different subtypes and clinical features. METHODS: PubMed, Web of Science, and Scopus were searched in August 2021 using a predefined search strategy. RESULTS: After two-step reviewing, 22 studies with a total of 332 participants were entered into our qualitative synthesis. In anti-NMDAR encephalitis, decreased activity in the occipital lobe was present, in addition, to an increase in frontal, parietal, and specifically medial temporal activity. Anti-VGKC patients showed altered metabolism in cortical and subcortical regions such as striata and cerebellum. Abnormal metabolism in patients with anti-LGI1 has been reported in diverse areas of the brain including medial temporal, hippocampus, cerebellum, and basal ganglia all of which had hypermetabolism. Hypometabolism in parietal, frontal, occipital lobes, temporal, frontal, and hippocampus was observed in AE patients with anti-GAD antibodies. CONCLUSION: Our results indicate huge diversity in metabolic patterns among different AE subtypes and it is hard to draw a firm conclusion. Moreover, the timing of imaging, seizures, and acute treatments can alter the PET patterns strongly. Further prospective investigations with specific inclusion and exclusion criteria should be carried out to identify the metabolic defect in different AE subtypes.