Post-acute anti-NMDAR encephalitis mirrors schizophrenia.

The post-acute evolution of the cognitive and psychiatric features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been poorly investigated so far. In recent work published in Lancet Neurology, Guasp et al. report that the neuropsychiatric symptoms of the post-acute phase mirror those observed in schizophrenia, although only patients with anti-NMDAR encephalitis showed improvements of their symptoms.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with small cell lung cancer and cytotoxic T-cell-mediated pathology: Case report.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is caused by a reversible inhibition of ion channel actions by autoantibodies and is associated with a relatively good prognosis. Pathological findings of NMDAR encephalitis usually do not show neurophagorous nodules, but rare or mild inflammatory infiltration. We report a patient of small cell lung cancer (SCLC)-related paraneoplastic encephalitis with NMDAR antibodies, a cytotoxic T-cell-mediated pathology of the brain, and a rapid clinical course. This case highlights that the neuropathological diversity of NMDAR encephalitis may be even broader than previously thought and that NMDAR antibodies may also be found in various pathological conditions with a vigorous immune response.

Anti-NMDA Receptor Encephalitis: Retrospective Analysis of 15 Cases, Literature Review, and Implications for Gynecologists.

Background: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare form of autoimmune encephalitis caused by anti-NMDA receptor antibodies. This disease mainly affects women of childbearing age and is commonly associated with ovarian teratoma. However, the relationship between anti-NMDA receptor encephalitis and ovarian teratoma and the role of anti-NMDA receptor antibody in the relationship remain unclear. Objectives: This study aimed to describe 15 cases of anti-NMDA receptor encephalitis (5 with ovarian teratoma), review literature, and reinforce the gynecologist's knowledge of this disorder. Methods: Clinical data of 15 patients from January 2015 to December 2020 admitted to The Second Hospital of Hebei Medical University were collected and analyzed. The diagnosis of anti-NMDA receptor encephalitis was based on the presence of anti-NMDA receptor antibodies in cerebrospinal fluid (CSF) and/or serum. Laparoscopic teratoma removal was performed in patients with ovarian teratoma. All patients had received immunotherapy. In addition, a review of the literature was performed to reinforce the gynecologist's knowledge of this disorder. Results: A total of 15 patients with anti-NMDA receptor encephalitis were screened, of whom 5 patients were confirmed with ovarian teratoma by pathology. The most common symptoms of anti-NMDAR encephalitis with teratoma are fever (5/5, 100%), seizure (5/5, 100%), mental and behavioral disorders (4/5, 80%), and decreased consciousness (4/5, 80%). Conversely, the most common symptoms of patients without teratoma were neuropsychiatric symptoms, including headache (6/10, 60%) and mental and behavioral disorders (7/10, 70%). All patients underwent immunotherapy, including steroids, intravenous immunoglobulin (IVIG), plasma exchange, and cyclophosphamide, and 4 out of 5 patients with ovarian teratomas underwent surgical treatment. All patients had a good outcome after systemic, surgical, and immunotherapy treatment. No patient who underwent surgical treatment developed a recurrence. Conversely, 2 of 10 patients without teratoma developed an anti-NMDA receptor encephalitis recurrence. Conclusions: Patients with anti-NMDA encephalitis show severe mental and neurological symptoms. Resection of teratoma is beneficial to the relief or disappearance of symptoms and has a good prognosis. This disorder should be fully recognized by gynecologists, who play an important role in diagnosis and treatment.

Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis.

Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( -) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABABR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( -) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis Associated with Mature Ovarian Teratoma in a Young Adolescent: A Case Report.

BACKGROUND: Ovarian teratoma has an uncommon association with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. This is a life-threatening condition, and here, we describe a case of an adolescent girl with anti-NMDAR encephalitis caused by an ovarian teratoma. CASE: A 14-year-old girl presented with acute features of fever, severe headache, altered behavioral changes, delirium, autonomic instability, episodes of seizure, and involuntary movement over a period of 1 month. Upon investigation, electroencephalogram (EEG), computed tomography (CT), and magnetic resonance imaging (MRI) of her brain showed normal findings. Her serum and cerebrospinal fluid were positive for anti-NMDARs, and a diagnosis of anti-NMDAR encephalitis was made, so she received a course of intravenous methyl prednisolone and immunoglobulin and was discharged after her neurological status improved. Upon further workup, she was suspected to have a left ovarian dermoid cyst on transabdominal ultrasonogram, which was an incidental finding. Her tumor marker panel showed normal serum lactate dehydrogenase, beta human chorionic gonadotropin, inhibin, alpha-fetoprotein, and carcinoembryonic antigen and a cancer antigen 125 level of 71.5 U/L. She eventually underwent laparoscopic left ovarian cystectomy and received immunotherapy in the postoperative period. She was discharged in stable condition on postoperative day 4. On histopathological examination, the specimen revealed a mature cystic teratoma with glial component. One year after surgery, the patient has recovered completely and has no residual psychiatric or neurological symptoms. CONCLUSION: Complete recovery after surgery in cases of anti-NMDAR encephalitis with ovarian teratoma emphasizes the need for early recognition of the entity, search for underlying tumor, and tumor removal to improve the prognosis.

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.

The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review.

Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

Limbic encephalitis in a child with ovarian teratoma and influenza B. Case report and critical review of the history of autoimmune anti-N-methyl-d-aspartate receptor encephalitis.

We report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

Virus reactivation after immunotherapy of anti-NMDAR encephalitis secondary to herpes simplex encephalitis: A case report.

Herpes simplex encephalitis is the most common cause of sporadic fatal encephalitis. More than half of patients with herpes simplex encephalitis will die and the vast majority of survivors have severe neurologic sequelae without effective antiviral therapy. Some people experience relapses such as secondary anti-N-methyl-d-aspartate receptor encephalitis despite appropriate antiviral treatment. It is rare that virus reactivation after immunotherapy of anti-N-methyl-d-aspartate receptor encephalitis after herpes simplex encephalitis. In the present study, we retrospectively review one patient who showed this rare situation.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis Associated with Ovarian Teratoma in South China-Clinical Features, Treatment, Immunopathology, and Surgical Outcomes of 21 Cases.

OBJECTIVE: To study the clinical characteristics and surgical outcomes of anti-NMDAR encephalitis and the immunopathology of associated teratomas. METHODS: Twenty-one patients were enrolled in this retrospective study, who were diagnosed with anti-NMDAR encephalitis with ovarian teratoma and admitted to two tertiary hospitals in South China from July 2014 to December 2019. The clinical data of patients were reviewed. Comparisons were made between the patients with different outcomes after surgery. Immunohistochemical analyses of associated ovarian teratomas were performed. RESULTS: The mean age of the patients was 24.33 ± 5.12 years. The peak seasons of disease onset were autumn and winter (30.61% and 32.65%). The symptoms could be divided into 8 categories, including psychiatric abnormalities, seizures, movement dysfunction, consciousness disorders, autonomic dysregulation, speech disturbance, central hypoventilation, and memory deficits. All patients developed four or more categories of symptoms within the first four weeks. Twelve patients (57.1%) had a maximum mRS of 5, and 11 patients (52.4%) were admitted to ICU. Twenty patients received surgery, and only 3 patients were diagnosed pathologically with immature ovarian teratomas, while the other 17 patients had mature ovarian teratomas. After surgery, 17 patients (85.0%) got clinical improvement. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. Immunohistochemical analysis revealed that there were NMDAR-positive neural tissues in all 8 teratomas and in which 3 cases also contained large numbers of NMDAR-positive sebaceous glands and squamous epithelial tissues. CONCLUSION: The disease is of high prevalence in autumn and winter. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. NMDAR-positive neural tissue is not the only etiological factor of encephalitis. We speculate that encephalitis development in some patients may result from NMDAR expression in sebaceous glands and squamous epithelial tissues.

Pediatric N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis, With and Without Herpes Encephalitis.

OBJECTIVE: To compare clinical, diagnostic, management, and outcome factors in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and a history of herpes simplex encephalitis (HSE) to children with NMDAR encephalitis without a history of HSE. METHODS: All patients with anti-NMDAR antibodies in cerebrospinal fluid treated at our institution between 2012 and 2019 were identified and divided into those with a history of HSE (HSE+NMDAR group) and those without a history of HSE (NMDAR-only group). Demographic data, clinical characteristics, immunotherapy, and outcome data were collected on all patients and compared between the 2 groups. RESULTS: Seventeen patients were identified with anti-NMDAR antibodies in cerebrospinal fluid, 6 of whom had a history of HSE. Mean age in the HSE+NMDAR cohort was significantly younger in the HSE+NMDAR cohort, as 5 of the 6 patients were infants. Of HSE+NMDAR patients, 50% had behavioral symptoms, 67% had movement disorders, and 100% had seizures at disease nadir. In the NMDAR-only group, 100% had behavioral symptoms, 73% had movement disorders, and 73% had seizures at nadir. HSE+NMDAR patients received a median of 1 immunotherapy, compared to a median of 4.5 immunotherapies in the NMDAR-only group. CONCLUSION: Behavioral symptoms were more common in NMDAR-only patients, whereas seizures were more common in HSE+NMDAR patients. Both groups had significant disability at disease nadir, with more improvement in disability over time in the NMDAR-only group. HSE+NMDAR patients received fewer immunotherapies than NMDAR-only patients. Outcomes of infants with HSE appear to primarily reflect sequelae from HSE.

CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study.

Background and Objectives: The two most common autoimmune encephalitides (AE), N-methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE. Methods: Patients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease). Results: A total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE. Discussion: CSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.

VNS Stopping Anti-NMDA Receptor Encephalitis-Triggered Nonconvulsive Status Epilepticus.

BACKGROUND: Anti-NMDA receptor encephalitis (ANRE) is a rare autoimmune neurologic disorder characterized by encephalitis and a constellational of symptoms, including seizures, psychiatric disturbances, autonomic instability, and respiratory insufficiency. It is caused by the anti-NMDA receptor antibody. The most common etiologies for ANRE include malignancy and infection. Ovarian teratoma is the most commonly associated malignancy. CASE DESCRIPTION: We describe the first reported case to our knowledge of ovarian teratoma causing ANRE resulting in nonconvulsive status epilepticus (NCSE), which was terminated with vagus nerve stimulation (VNS). CONCLUSIONS: This case report provides a temporal correlation suggesting that VNS significantly altered the natural history of this patient's NCSE-ANRE. As more data are collected, and the VNS treatment modality more liberally used to treat NCSE, especially in the situation of ANRE, stronger layers of evidence will emerge to fill the gaps of understanding beyond this case report.

IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation.

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.

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.