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BACKGROUND: This study aimed to compare the impact of olanzapine, magnesium valproate, and lamotrigine as adjunctive treatments for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. And it is expected to add supporting points related to the rebalance of neurotransmitters in the brain through adjuvant therapy in the clinical management of anti-NMDAR encephalitis. METHODS: This retrospective study included patients diagnosed with anti-NMDAR encephalitis who received standardized immunotherapy at Hunan Brain Hospital between January 2018 and December 2020. RESULTS: Compared to the olanzapine group, both the magnesium valproate and lamotrigine groups showed lower scores on the positive and negative symptom scale (PANSS) total score after 3 weeks of treatment (all P < 0.05). The Montreal Cognitive Assessment Scale (MoCA) scores in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group after 3 weeks and 3 months of treatment (all P < 0.05). After 3 months of treatment, the proportions of patients with a modified Rankin scale score (mRS) of 0-1 in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group (all P < 0.05). The electroencephalogram (EEG) abnormality ranks at 3 months were significantly lower in the magnesium valproate and lamotrigine groups compared with the olanzapine group (all P < 0.05). Furthermore, the Glx/Cr ratio significantly decreased after 3 months of treatment (all P < 0.05) in the magnesium valproate and lamotrigine groups, while the Glx/Cr ratio in the olanzapine group showed no significant change (P > 0.05). CONCLUSION: Compared with olanzapine, the addition of magnesium valproate or lamotrigine to immunotherapy might be associated with a lower PANSS score, higher MoCA score, and lower mRS score. The improvement of neurological functions and cognitive function may be related to the decreased Glx/Cr ratio.

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The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.

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N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-ß (Aß) synaptotoxicity. Our previous studies have demonstrated an oppose (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 µM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 µM) of NMDA both exerts neuroprotective effect in Aß-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aß neurotoxicity remains unclear. Based on our previous related work, in this study, using a co-cultured cell model of primary hippocampal neurons and astrocytes, we further investigated the possible factors involved in 1 µM of NMDA activating astrocytic NMDARs to oppose Aß-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 µM NMDA rescued Aß-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aß-induced increase of GFAP, complement 3 (C3) and activation of NF-κB Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 µM NMDA to counteract the effects of Aß decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aß-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aß.

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Rituximab is recommended as the preferred second-line immunotherapy for autoimmune encephalitis (AE). However, Ofatumumab (OFA), a novel fully human anti-CD20 antibody, has been reported infrequently in patients with AE. Among the various forms of AE, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common and severe. This study presents three cases of severe anti-NMDAR encephalitis treated with OFA following the failure of first-line immunotherapy. The results indicated that the patients experienced no significant adverse reactions after receiving OFA, and their clinical symptoms improved markedly within one week of treatment. One month post-treatment with OFA, scores on the Glasgow Coma Scale (GCS) and the Barthel Index of Activities of Daily Living (Barthel-ADL) increased, while scores on the modified Rankin Scale (mRS), Clinical Assessment Scale in Autoimmune Encephalitis (CASE), and Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) decreased. During the three-month and six-month follow-up periods, patients exhibited further symptomatic improvement, suggesting that OFA is a safe and effective treatment option for anti-NMDAR encephalitis. These findings propose a novel therapeutic strategy for severe refractory anti-NMDAR encephalitis.

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ETHNOPHARMACOLOGICAL RELEVANCE: Anti-NMDAR encephalitis is one of the most common types of autoimmune encephalitis, primarily presenting with prodromal symptoms, such as fever and headache, followed by a range of neurological and psychiatric symptoms. Chaihu Guizhi Decoction (CGD), a traditional Chinese medicine formulated by Zhang Zhongjing in the Eastern Han Dynasty, has been effectively used in clinical practice to treat the symptoms of Taiyang and Shaoyang disorders, including fever, headache, and psychiatric disorders. AIM OF THE STUDY: To demonstrate the protective effects of CGD in an animal model of anti-NMDAR encephalitis and explore the potential mechanisms involved. MATERIALS AND METHODS: UHPLC-HRMS was used to identify CGD's chemical components and serum metabolomic profiles. Network pharmacology and molecular docking were performed to predict potential targets of CGD for the treatment of anti-NMDAR encephalitis. The effect of CGD on anti-NMDAR encephalitis was evaluated using a mouse model induced by patients' antibodies. Behavioral tests were performed to assess cognitive impairment and schizophrenia-like behaviors. The effect of CGD on the cell-surface NMDAR GluN1 subunit in cultured neurons treated with patient antibodies was detected by immunofluorescence. Golgi staining was used to observe morphological changes in hippocampal dendrites. The expression of NMDAR-interacting proteins and various neuroreceptors in the hippocampus were examined to validate the targets predicted using network pharmacology and molecular docking. RESULTS: CGD alleviated cognitive, memory, and sensorimotor gating deficits in mice treated with anti-NMDAR encephalitis patients' antibodies. Further experiments demonstrated the effect of CGD in preventing NMDAR reduction both in vitro and in vivo. Meanwhile, CGD regulated NMDAR-interacting proteins and dopamine receptors but did not affect hippocampal dendritic morphology and synaptic density. Additionally, CGD modifies metabolic pathways associated with anti-NMDAR encephalitis and other neurological and psychiatric disorders. CONCLUSIONS: CGD exhibited protective effects against anti-NMDAR encephalitis by mitigating the antibody-induced reduction in NMDAR and NMDAR-interacting proteins.

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BACKGROUND: Little is known about the association between serum neuron-specific enolase (NSE) concentration and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate if serum NSE concentration is related to the clinical features of anti-NMDAR encephalitis. METHODS: Serum NSE levels were detected in 58 anti-NMDAR encephalitis cases, 58 matched healthy controls and 58 matched disease controls. Demographic features, clinical symptoms, cerebrospinal fluid parameters and brain MRI indexes of the cases were evaluated. RESULTS: Serum NSE concentrations were significant higher in case group than those in healthy controls and disease controls (both p < 0.001). Serum NSE concentrations in patients with mRS≥3 one year after onset were obviously higher than in those with mRS<3 (p < 0.001). Patients with status epilepticus or central hypoventilation had higher serum NSE levels than those without (p = 0.003 and p = 0.006). Serum NSE concentrations in cases with brain lesions or brain atrophy were significant higher than in those without (p = 0.001 and p < 0.001, respectively). Serum NSE concentrations were found to be significant higher in cases with limited response to treatment compared to those with favourable therapy outcomes (p < 0.001). Spearman's correlation analysis showed a significant positive association between serum NSE concentration and mRS score at the most critical time (max mRS) (r = 0.575, p < 0.001) and one year after onset (r = 0.705, p < 0.001). Cox regression results reflected that high serum NSE level was an independent predictor of poor prognosis in anti-NMDAR encephalitis group (p = 0.001), and the ROC curve threshold value was 15.72 ng/ml. CONCLUSIONS: Serum NSE concentrations in anti-NMDAR encephalitis cases are higher than those in controls. It can be used to predict the brain damage degree and prognosis of anti-NMDAR encephalitis cases.

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A 46-year-old woman with Turner syndrome (TS) (45,X/46,X,idic (X) (p11.4) mosaic) presented with a fever, unresponsiveness, hyperhidrosis, and rigidity approximately one month after episodes of confusion and suicide attempts, prompting a diagnosis of schizophrenia. Cerebrospinal fluid (CSF) showed mild hypercellularity with oligoclonal bands. Brain and abdominal magnetic resonance imaging showed no abnormalities. Bizarre upper-extremity movements and spasms followed the trial administration of acyclovir, and autoimmune encephalitis was suspected. Intensive immunotherapy was initiated, and the symptoms improved. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis was diagnosed based on the presence of anti-NMDAR antibodies in her spinal fluid. This case represents a rare presentation of anti-NMDAR encephalitis in TS, which is susceptible to autoimmune disease complications.

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Background: Patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis often experience severe symptoms. Resting-state functional MRI (rs-fMRI) has revealed widespread impairment of functional networks in patients. However, the changes in information flow remain unclear. This study aims to investigate the intrinsic functional connectivity (FC) both within and between resting-state networks (RSNs), as well as the alterations in effective connectivity (EC) between these networks. Methods: Resting-state functional MRI (rs-fMRI) data were collected from 25 patients with anti-NMDAR encephalitis and 30 healthy controls (HCs) matched for age, sex, and educational level. Changes in the intrinsic functional connectivity (FC) within and between RSNs were analyzed using independent component analysis (ICA). The functional interaction between RSNs was identified by granger causality analysis (GCA). Results: Compared to HCs, patients with anti-NMDAR encephalitis exhibited lower performance on the Wisconsin Card Sorting Test (WCST), both in terms of correct numbers and correct categories. Additionally, these patients demonstrated decreased scores on the Montreal Cognitive Assessment (MoCA). Neuroimaging studies revealed abnormal intra-FC within the default mode network (DMN), increased intra-FC within the visual network (VN) and dorsal attention network (DAN), as well as increased inter-FC between VN and the frontoparietal network (FPN). Furthermore, aberrant effective connectivity (EC) was observed among the DMN, DAN, FPN, VN, and somatomotor network (SMN). Conclusion: Patients with anti-NMDAR encephalitis displayed noticeable deficits in both memory and executive function. Notably, these patients exhibited widespread impairments in intra-FC, inter-FC, and EC. These results may help to explain the pathophysiological mechanism of anti-NMDAR encephalitis.

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Background and aims: Psychiatrists are often the first to be consulted in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Thus, they need to be aware of clinical features, differential diagnoses, and treatment options for this condition. In this study, we aimed to investigate the familiarity of Romanian psychiatrists with anti-NMDAR encephalitis. Methods: We recruited psychiatrists from Romania and conducted a cross-sectional observational study by using a web-based survey. Results: The survey was completed by 111 psychiatrists, of whom 47 (42.34%) were specialists, while 64 (57.66%) were trainees. The median length of training for specialists was ten years (interquartile range - IQR 9.5), while for trainees it was 2.5 years (IQR 3). In total, 31 (27.93%) psychiatrists encountered a case of anti-NMDAR encephalitis, with no significant difference between specialists and trainees. 31 (27.93%) psychiatrists were either unaware of the disorder or only knew its name, while 77 (69.37%) had knowledge of an outline of it. Only 3 (2.7%) psychiatrists had comprehensive knowledge of the disorder. Respondents with a higher awareness level had undergone significantly longer training (p=0.014). Unsurprisingly, having encountered a case significantly influenced awareness levels (p<0.001). There were no significant differences between specialists and trainees regarding specific knowledge about anti-NMDAR encephalitis. However, higher awareness levels and having encountered a case significantly influenced answer accuracy for questions regarding psychiatric presentation and epidemiological features. Conclusions: Our study indicates that Romanian psychiatrists have suboptimal knowledge of anti-NMDAR encephalitis, highlighting the need for improved awareness of this disorder.

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OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. RESULTS: Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

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BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways. OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment. METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model. RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.

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Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

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Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

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OBJECTIVE: This investigation was to determine the relationship between changes in the expression levels of miR-134 and the E2F transcription factor 6 (E2F6) in mediating control of apoptosis in N-methyl-D-aspartate (NMDA)-induced glaucomatous mice. METHODS: Morphological and structural changes were quantitatively analyzed along with apoptosis in the retinal ganglion cell (RGC) layer, internal plexiform layer and RGCs. Glaucomatous RGCs were transfected, and cell viability and apoptosis were examined. The targeting relationship between miR-134 and E2F6 was analyzed, as well as their expression pattern. RESULTS: Intravitreal injection of NMDA induced a significant reduction in the number of RGCs and thinning of IPL thickness. miR-134 was highly expressed and E2F6 was lowly expressed in glaucoma mice. Suppression of miR-134 or E2F6 overexpression inhibited apoptosis in the glaucomatous RGCs and instead their proliferative activity. MiR-134 targeted inhibition of E2F6 expression. Suppressing rises in E2F6 expression reduced the interfering effect of miR-134 on glaucomatous RGC development. CONCLUSION: Depleting miR134 expression increases, in turn, E2F6 expression levels and in turn reduces glaucomatous RGC apoptosis expression.

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BACKGROUND: Recognizing the predictors of poor short-term prognosis after first-line immunotherapy in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is essential for individualized treatment strategy. The objective of this study was to ascertain the factors that forecast short-term prognosis in patients with anti-NMDAR encephalitis, develop a prognostic prediction model, and authenticate its efficacy in an external validation cohort. Further, all patients were followed-up long-term to assess the factors of long-term outcome and relapses. METHODS: A prospective enrollment of patients diagnosed with anti-NMDAR encephalitis was conducted across five clinical centers in China from June 2014 to Mar 2022. The enrolled patients were divided into the derivation and validation sets based on enrollment time. The short-term prognostic model was visualized using a nomogram. Further, all patients were followed-up long-term to assess the factors of long-term outcome. RESULTS: This study found that poor short-term prognosis was a risk factor for poor long-term outcome (6-month prognosis, OR 29.792, 95%CI 6.507-136.398, p < 0.001; 12-month prognosis, OR 15.756, 95%CI 3.384-73.075, p < 0.001; 24-month prognosis, OR 5.500, 95%CI 1.045-28.955, p = 0.044). Abnormal behavior or cognitive dysfunction (OR 8.57, 95%CI 1.48-49.79, p = 0.017), consciousness impairment (OR19.32, 95%CI 3.03-123.09, p = 0.002), autonomic dysfunction or central hypoventilation (OR 5.66, 95%CI 1.25-25.75, p = 0.025), CSF pleocytosis (OR 4.33, 95%CI 1.48-12.65, p = 0.007), abnormal EEG (OR 5.48, 95% CI 1.09-27.54, p = 0.039) were independent predictors for a poor short-term prognosis after first-line immunotherapy. A nomogram that incorporated those factors showed good discrimination and calibration abilities. The area under the curve (AUC) for the prognostic model were 0.866 (95%CI: 0.798-0.934) with a sensitivity of 0.761 and specificity of 0.869. CONCLUSION: We established and validated a prognostic model that can provide individual prediction of short-term prognosis after first-line immunotherapy for patients with anti-NMDAR encephalitis. This practical prognostic model may help neurologists to predict the short-term prognosis early and potentially assist in adjusting appropriate treatment timely.

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Anti-N-methyl-d-aspartate receptor encephalitis is an autoimmune disorder characterized by various neurological symptoms with a relatively favorable prognosis. We present a case of prolonged dysphagia successfully managed with outpatient rehabilitation, including interferential current stimulation and resistance exercises. Significant improvement was observed, highlighting the efficacy of combined treatment in overcoming chronic dysphagia.

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BACKGROUND: Herpes simplex virus encephalitis (HSE) frequently triggers secondary anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), but markers predicting the occurrence of this entity (HSE-NMDARE) are lacking. METHODS: We conducted a retrospective description of patients with HSE-NMDARE diagnosed between July 2014 and August 2022 and compared them to both patients with regular forms of HSE and NMDARE. RESULTS: Among the 375 patients with NMDARE, 13 HSE-NMDARE were included. The median age was 19 years (0.5-73), 4/13 (31%) were children < 4 years old, and 7/13 (54%) were male. The median time between HSE and NMDARE onset was 30 days (21-46). During NMDARE, symptoms differed from HSE, including increased behavioral changes (92% vs 23%, p = 0.008), movements disorders (62% vs 0%, p = 0.013), and dysautonomia (54% vs 0%, p = 0.041). Compared to 21 patients with regular HSE, patients with HSE-NMDARE more often achieved severity-associated criteria on initial MRIs, with extensive lesions (11/11, 100% vs 10/21, 48%, p = 0.005) and bilateral diffusion-weighted imaging sequence abnormalities (9/10, 90% vs 6/21, 29%, p = 0.002). Compared to 198 patients with regular NMDARE, patients with HSE-NMDARE were more frequently males (7/13, 54% vs 43/198, 22%; p = 0.015) and children < 4 (4/13, 31% vs 14/198, 7%; p = 0.016), with a worse 12-month mRS (2[1-6] vs 1[0-6], p = 0.023). CONCLUSIONS: Herein, patients with HSE-NMDARE have a poorer long-term prognosis than patients with regular NMDARE. We report a greater rate of severity-associated criteria on initial MRIs for HSE-NMDARE compared to regular HSE, which may help identify patients with higher risk of HSE-NMDARE.

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Glutamate activates the NMDARs, significantly affecting multiple processes such as learning, memory, synaptic integration, and excitatory transmission in the central nervous system. Uncontrolled activation of NMDARs is a significant contributor to synaptic dysfunction. Having a properly functioning NMDAR and synapse is crucial for maintaining neuronal communication. In addition, the dysfunction of NMDAR and synapse function could contribute to the development of neurological disorders at the neuronal level; hence, targeting NMDARs with antagonists in the fight against neurological disorders is a promising route. Recently published results from the animal study on different kinds of brain diseases like stroke, epilepsy, tinnitus, ataxia, Alzheimer's disease, Parkinson's disease, and spinal cord injury have demonstrated promising therapeutic scopes. Several NMDA receptor antagonists, such as memantine, MK801, ketamine, ifenprodil, gacyclidine, amantadine, agmatine, etc., showed encouraging results against different brain disease mouse models. Given the unique expression of different subunits of the well-organized NMDA receptor system by neurons. It could potentially lead to the development of medications specifically targeting certain receptor subtypes. For a future researcher, conducting more targeted research and trials is crucial to fully understand and develop highly specific medications with good clinical effects and potential neuroprotective properties.

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Here we described an 18-year-old woman who were initially misdiagnosed as psychiatric disorders in a psychiatric institution. She was transferred to our neurological ward because of impaired consciousness. Neuronal antibody testing confirmed the diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Cerebral magnetic resonance imaging (MRI) revealed a concomitant disorder named reversible splenial lesion syndrome (RESLES). After administration of combined immunotherapy, the patient recovered completely 3 months after discharge. To our knowledge, co-occurrence of RESLES and anti-NMDAR encephalitis was only described in two patients with teratoma and we provide another case without teratoma. We highlight that anti-NMDAR antibodies can be added to the multiple causes of RESLES. It is therefore imperative for clinicians to detect anti-neuronal antibodies in patients with RESLES to avoid missed diagnosis.

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The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.

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