Anti-NMDAR Encephalitis in the Netherlands, Focusing on Late-Onset Patients and Antibody Test Accuracy.

BACKGROUND AND OBJECTIVES: To describe the clinical features of anti-NMDAR encephalitis, emphasizing on late-onset patients and antibody test characteristics in serum and CSF. METHODS: Nationwide observational Dutch cohort study, in patients diagnosed with anti-NMDAR encephalitis between 2007 and 2019. RESULTS: One hundred twenty-six patients with anti-NMDAR encephalitis were included with a median age of 24 years (range 1-86 years). The mean annual incidence was 1.00/million (95% CI 0.62-1.59). Patients ≥45 years of age at onset (19%) had fewer seizures (46% vs 71%, p = 0.021), fewer symptoms during disease course (3 vs 6 symptoms, p = 0.020), and more often undetectable serum antibodies compared with younger patients (p = 0.031). In the late-onset group, outcome was worse, and all tumors were carcinomas (both p < 0.0001). CSF was more accurate than serum to detect anti-NMDAR encephalitis (sensitivity 99% vs 68%, p < 0.0001). Using cell-based assay (CBA), CSF provided an unconfirmed positive test result in 11/2,600 patients (0.4%); 6/11 had a neuroinflammatory disease (other than anti-NMDAR encephalitis). Patients with anti-NMDAR encephalitis, who tested positive in CSF only, had lower CSF antibody titers (p = 0.003), but appeared to have an equally severe disease course. DISCUSSION: Anti-NMDAR encephalitis occurs at all ages and is less rare in the elderly patients than initially anticipated. In older patients, the clinical phenotype is less outspoken, has different tumor association, and a less favorable recovery. Detection of antibodies in CSF is the gold standard, and although the CBA has very good validity, it is not perfect. The clinical phenotype should be leading, and confirmation in a research laboratory is recommended, when in doubt.

Dysregulated CD40 and CD40 ligand expression in anti-N-methyl-d-aspartate receptor encephalitis.

Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a B cell- and antibody-mediated autoimmune disease which may be regulated by CD40/CD40L signaling pathway. we enrolled anti-NMDARE patients and measured the serum CD40 and CD40L concentrations. The serum concentration of CD40 was decreased, while CD40L was increased in anti-NMDARE patients compared with that of healthy controls. The concentrations of CD40 and CD40L were both elevated in the acute stage of anti-NMDARE and were reduced during remission. Serum CD40L levels were positively correlated with serum CD40 levels. These results revealed that the CD40/CD40L signaling pathway might contribute to the pathogenesis of anti-NMDARE.

Cytokine/chemokine levels in the CSF and serum of anti-NMDAR encephalitis: A systematic review and meta-analysis.

Objectives: To summarize the cytokine/chemokine levels of anti-N-methyl-Daspartate receptor encephalitis (NMDAR-E) and explore the potential role of these molecules and immune cells in the pathogenic mechanism. Methods: The PubMed, Cochrane Library, Embase, and Web of Science databases were searched for various articles that assessed the concentrations of cytokines/chemokines in the unstimulated cerebrospinal fluid (CSF) or serum of patients with NMDAR-E in this systematic review and meta-analysis. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated by Stata17.0. Results: A total of 19 articles were included in the systematic review from 260 candidate papers, and cytokine/chemokine levels reported in the CSF/serum were examined in each article. This meta-analysis included 17 eligible studies comprising 579 patients with NMDAR-E, 367 patients with noninflammatory neurological disorders, and 42 healthy controls from China, Spain, South Korea, Australia, Czechia, and Sweden. The results indicated that the levels of different cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, IL-13, IL-1ß, IL-12, and IL-17 and chemokine C-X-C motif ligand (CXCL)10 in the CSF were significantly higher in NMDAR-E patients with a large effect size. In addition, B cell activating factor (BAFF), CXCL13, and interferon (IFN)-γ levels in the CSF were higher in NMDAR-E patients with a middle effect size. In contrast, levels of IL-2 and IL-4 in the CSF and CXCL13 and BAFF in the serum did not show a significant difference between cases and controls. Conclusions: These analyses showed that the central immune response in NMDAR-E is a process that involves multiple immune cell interactions mediated by cytokines/chemokines, and T cells play an important role in the pathogenesis of immunity. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022342485).

The changing spectrum of antibody-mediated encephalitis in China.

In the past 5 years, the positivity rate of autoimmune encephalitis antibody panels has significantly decreased in patients with clinically suspected encephalitis in an encephalitis center in China. Furthermore, the spectrum of patients with autoantibodies related to autoimmune encephalitis has changed significantly, exhibiting a decreased percentage of patients with anti-N-methyl-d-aspartate receptor antibodies and an increased percentage of patients with infrequently observed autoantibodies. Meanwhile, a small but non-negligible proportion of patients with autoantibodies against cell surface and synaptic proteins exhibited positivity for more than one autoantibody.

Presence of Anti-Thyroid Antibodies Correlate to Worse Outcome of Anti-NMDAR Encephalitis.

Objective: To investigate the characteristics and prognosis of anti-NMDAR encephalitis with the prevalence of anti-thyroid antibodies (ATAbs). Methods: The clinical data of anti-NMDAR encephalitis patients admitted to Xuanwu Hospital from January 2012 to August 2018 was prospectively analyzed, and the patients were followed up for 24 months. Results: A total of 120 patients were enrolled, of which 34.2% (41/120) were positive for ATAbs. The antibodies were more frequent in patients with severe disease compared to the non-severe group (51.4% vs. 25.6%, P=0.008). In addition, prevalence of ATAbs correlated with a higher incidence of disturbed consciousness, autonomic dysfunction, central hypoventilation and mechanical ventilation. The ATAbs-positive patients were also more likely to receive intravenous gamma immunoglobulin and immunosuppressor compared to the ATAbs-negative cases (P=0.006; P=0.035). Although the presence of ATAbs was associated with longer hospital stays and worse prognosis at 6 months (P=0.006; P=0.038), it had no impact on long-term patient prognosis. Positive status of anti-thyroglobulin antibody was an independent risk factor for worse prognosis at 6 months [odds ratio (OR)= 3.907, 95% CI: 1.178-12.958, P=0.026]. Conclusion: ATAbs are prevalent in patients with anti-NMDAR encephalitis, especially in severe cases, and correlate with poor prognosis and impaired short-term neurological recovery.

Seasonal variation in autoimmune encephalitis: A multi-center retrospective study.

OBJECTIVE: The aim of this study was to examine the seasonal distribution in clinical onset of autoimmune encephalitis (AE) in a multi-center cohort in China. METHODS: This retrospective study consecutively recruited patients with new-onset definite neuronal surface antibody-associated AE between January 2015 and December 2020 from 3 tertiary hospitals. Demographic and clinical characteristics of the participants were comprehensively collected. Statistical analyses were performed using R. RESULTS: Of the 184 patients of AE in our database, 149 (81.0%) were included in the final analysis. The median age of onset was 40.0 years, and 66 (44.3%) patients were female. AE predominantly started in autumn (47, 31.5%) and summer (43, 28.9%) months. Summer-autumn predominance of the clinical onsets was also present in the anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis group (54, 60.0%) and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis group (20, 76.9%). No obvious seasonal variations were observed among gender, onset age, disease duration, prodromal symptoms, clinical type of initial symptoms, and disease severity by the time of admission. CONCLUSION: This study suggested summer-autumn predominance of the clinical onsets in patients with AE, especially anti-NMDAR and anti-LGI1 encephalitis. Therefore, clinicians should have a high index of suspicion for AE in encephalopathy patients in summer and autumn period.

Association of serum Gasdermin D with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti-NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti-NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow-up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti-NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti-NMDAR encephalitis than in healthy controls (p = 0.002, padjusted  = 0.009), especially in males (p = 0.001, padjusted  = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = -0.419 and -0.426, p = 0.011 and 0.012, respectively). Furthermore, 3-month follow-up evaluation revealed that after treatment, anti-NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = -0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti-NMDAR encephalitis and are associated with disease prognosis.

Autoimmune encephalitis in a South Asian population.

BACKGROUND: Autoimmune encephalitis (AE) is now considered a main, potentially curable cause of encephalitis, but remains conspicuously underreported from South Asia. We studied the clinical characteristics in relation to their antibody status and outcomes of patients presenting with AE in Sri Lanka. METHODS: Patients admitting to government hospitals who were clinically suspected of AE by an on-site neurologist were prospectively recruited over a period of 12 months. Sera and cerebrospinal fluid were tested for NMDAR, AMPAR1, AMPAR2, LGI1, CASPR2, GABARB1/B2 antibodies (Ab) using commercial cell-based assays. Demographic, clinical and laboratory data were compiled into an investigator-administered proforma. Patients were reviewed at 1 year follow up either in person or via telephone. RESULTS: One-hundred and forty-two patients from 21 of 25 districts in Sri Lanka (median age = 20.5 years; range 1-86 years; females = 61.3%) were recruited. Of them, 65 (45.8%; median age = 19 years; range 1-86 years; females = 64.6%) fulfilled diagnostic criteria for probable NMDAR-antibody encephalitis (NMDARE) and 6 (4.2%; median age = 44 years; range 28-71 years; females = 83.3%) limbic encephalitis (LE). Abnormal behaviour (95.3%), seizures (81.5%) and movement disorders (69.2%) were the most frequent clinical manifestations of probable NMDARE. NMDAR-antibodies were detectable in 29 (44.6%) and not detectable in 36 in CSF of probable-NMDARE patients. Abnormal EEG was more frequent (p = 0.003) while a worse outcome (OR = 2.78; 95% CI = 0.88-9.09) and deaths (OR = 2.38; 95% CI = 0.67-8.33) were more likely in antibody-negative than antibody-positive probable-NMDARE. Most patients with LE had amnesia (50%) and/or confusion (100%) with agitation (83.3%) and seizures (100%) but none had detectable antibodies to any of the antigens tested. CONCLUSIONS: NMDARE is the commonest type of AE among South Asians as is the case worldwide. Clinical presentations of NMDARAb-positive and NMDARAb-negative AE patients do not significantly differ but EEG may be a useful marker of an autoimmune basis for psychiatric symptoms.

Refractory NMDA-receptor encephalitis in a teenager: A novel use of Bortezomib.

We report the case of a 14-year-old girl who was diagnosed with N-methyl-d-aspartate (NMDA)-receptor encephalitis, with severe features and autonomic instability, requiring intensive care unit admission. She had poor clinical response to the first-line therapies, she was then started on Rituximab and 6 cycles of Cytoxan infusion. She responded to Bortezomib therapy within 2 weeks of initiation, and with long-term sustenance of improvement in the long-term, also demonstrated by an improvement in NMDA titers . As far as we know, this is the first report of use of Bortezomib therapy in a child with refractory NMDA-receptor encephalitis.

Emerging role of free triiodothyronine in patients with anti-N-methyl-D-aspartate receptor encephalitis.

We aimed to investigate the role of free triiodothyronine (FT3) in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. 137 consecutive inpatients (2016-2019) were registered prospectively and followed up for 12 months. 96 eligible patients were included in the study. The modified Rankin scale (mRS) score was collected, and the score of 3-6 was defined as a poor outcome. The patients were equally classified into 3 subgroups based on their FT3 levels obtained within 24 h of admission, and the subgroup differences were analyzed by parametric or nonparametric tests as appropriate. Logistic regression analysis was performed. We found that there was no difference in the mRS scores upon admission among 3 subgroups, however, patients in the low-FT3 subgroup tended to have higher disease severity during hospitalization and worse outcome in follow-up visits, represented by higher chances of intense care unit (ICU) admission (P < 0.001), longer hospital stay (P < 0.001), greater maximum mRS scores during hospitalization (P = 0.011), lower rates of getting clinical improvement within 4 weeks of starting treatment (P = 0.006), and higher percentages of poor 1-year outcome (P = 0.002). The level of FT3 was an independent factor correlated with ICU admission (P = 0.002) and might be a potential predictor for 1-year outcome. Our preliminary results suggest that the FT3 may be a risk factor involved in the evolution and progression of anti-NMDAR encephalitis, whereas the underline mechanisms remain to be explored. Attention should be paid to these patients with relatively low FT3 upon admission, which might possibly aid clinical prediction and guide clinical decision-making.

High serum creatinine is associated with reduction of psychiatric symptoms in female patients with anti-NMDAR encephalitis.

OBJECTIVE: Serum creatinine (SCR) has been shown to be associated with many neurodegenerative diseases. In this study, we investigated the relationship between SCR levels and the incidence of psychiatric symptoms in patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. METHODS: The SCR levels were tested in 69 patients with anti-NMDAR encephalitis at admission. Clinical characteristics and blood and CSF parameters were compared between the group of patients with psychiatric symptoms (P + group) and the group of those without psychiatric symptoms (P- group). The association between SCR and the incidence of psychiatric symptoms was determined by multivariate-adjusted linear regression analyses. RESULTS: The SCR levels in the P + group were significantly lower than those in the P- group (P < 0.001). In the female subgroup, the SCR levels in the P + group were significantly lower compared to the P- group (P < 0.001), whereas in the male subgroup, the SCR levels did not differ between the two groups (P = 0.084). Furthermore, the highest SCR tercile overall had a significantly lower incidence of psychiatric symptoms than the lowest tercile (P < 0.001), and a significant negative correlation between the SCR levels and the occurrence of psychiatric symptoms was observed (r = -0.392, P < 0.001). Multivariate logistic regression analysis showed that the association was independent after adjusting for age, cystatin C and the modified Rankin Scale (mRS) score (P = 0.001). A similar result was found in the female subgroup (P = 0.010), but not in the male subgroup (P = 0.225). CONCLUSION: Our study indicated that the SCR level was negatively correlated with incidence of psychiatric symptoms in female patients, and higher SCR level could be a protective factor for psychiatric symptoms in female patients with anti-NMDAR encephalitis.

Continuous EEG Findings in Autoimmune Encephalitis.

PURPOSE: Autoimmune encephalitis (AE) is a cause of new-onset seizures, including new-onset refractory status epilepticus, yet there have been few studies assessing the EEG signature of AE. METHODS: Multicenter retrospective review of patients diagnosed with AE who underwent continuous EEG monitoring. RESULTS: We identified 64 patients (male, 39%; white, 49%; median age, 44 years); of whom, 43 (67%) were antibody-proven AE patients. Of the patients with confirmed antibody AE, the following were identified: N-methyl-D-aspartate receptor (n = 17, 27%), voltage-gated potassium channel (n = 16, 25%), glutamic acid decarboxylase (n = 6, 9%), and other (n = 4, 6%). The remaining patients were classified as probable antibody-negative AE (n = 11, 17%), definite limbic encephalitis (antibody-negative) (n = 2, 3%), and Hashimoto encephalopathy (n = 8, 13%). Fifty-three percent exhibited electrographic seizures. New-onset refractory status epilepticus was identified in 19% of patients. Sixty-three percent had periodic or rhythmic patterns; of which, 38% had plus modifiers. Generalized rhythmic delta activity was identified in 33% of patients. Generalized rhythmic delta activity and generalized rhythmic delta activity plus fast activity were more common in anti-N-methyl-D-aspartate AE (P = 0.0001 and 0.0003, respectively). No other periodic or rhythmic patterns exhibited AE subtype association. Forty-two percent had good outcome on discharge. Periodic or rhythmic patterns, seizures, and new-onset refractory status epilepticus conferred an increased risk of poor outcome (OR, 6.4; P = 0.0012; OR, 3; P = 0.0372; OR, 12.3; P = 0.02, respectively). CONCLUSION: Our study confirms a signature EEG pattern in anti-N-methyl-D-aspartate AE, termed extreme delta brush, identified as generalized rhythmic delta activity plus fast activity in our study. We found no other pattern association with other AE subtypes. We also found a high incidence of seizures among patients with AE. Finally, periodic or rhythmic patterns, seizures, and new-onset refractory status epilepticus conferred an increased risk of poor outcome regardless of AE subtype.

The differential expression and potential roles of circular RNAs in children with anti-NMDA receptor encephalitis.

To explore the role of circular RNAs (circRNAs) in pediatric anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, we assessed the profiles of circRNAs and mRNAs in blood leukocytes from anti-NMDA receptor encephalitis patients and healthy controls using microarray analysis. 1196 circRNAs and 719 mRNAs (change ≥2, p < .05) were dysregulated in anti-NMDA receptor encephalitis patients, relative to healthy controls, based on microarray data. Further bioinformatic analysis demonstrated that the host genes of dysregulated circRNAs are primarily associated with receptor internalization. In conclusion, circRNAs may be implicated in the pathogenesis of pediatric anti-NMDA receptor encephalitis.

Anti-NMDA receptor encephalitis concomitant with myelin oligodendrocyte glycoprotein antibody diseases: A retrospective observational study.

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) can coexist with myelin oligodendrocyte glycoprotein antibody (MOG-ab) disease.To characterize MOG-ab disease during NMDARe, we analyzed all the patients with MOG-ab disease and NMDARe from our hospital from December 2018 to December 2019 and data from a systematical review of previously published reports. Details of the patients identified were summarized and literature was reviewed.Four of thirty (14.2%) patients with anti-NMDARe had overlapping MOG-ab disease in our department. Analyze together with previously reported cases. Thirty-two NMDARe patients had overlapping MOG-ab disease. The onset age ranged from 3 to 48 years. Twenty-four patients (74%) developed abnormal behavior or cognitive dysfunction during the episodes of anti-NMDARe. None of these patients had tumors. 84% (27/32) patients received high doses of steroids as first-line immunotherapy and 28% (9/32) received mycophenolate mofetil (MMF) to prevent relapse. Twenty-six of twenty-seven (96%) had a good outcome.Steroids are the most common first-line immunotherapies in NMDARe overlapping MOG-ab disease. Most of the NMDARe patients overlapping MOG-ab disease have a good prognosis.

Clinical analysis of anti-NMDAR encephalitis combined with MOG antibody in children.

OBJECTIVE: To analyze the clinical features in children with anti-NMDAR encephalitis combined with myelin oligodendrocyte glycoprotein antibody (MOG ab). METHODS: Clinical data of 7 children with anti-NMDAR encephalitis combined with MOG ab(+) were collected in Guangzhou Women and Children's Medical Center from January, 2016 to June, 2019. Children with NMDAR ab(+)/MOG ab(-) and MOG ab(+)/NMDAR ab(-) were randomly selected as controls. RESULTS: Onset age was 6.0 (IQR 5.0-7.0) years old, male to female was 2:5. Prominent symptoms include abnormal mental behavior (7/7), sleep disorder (6/7), speech disorder (6/7), involuntary movement (4/7) and paralysis (4/7). There were significant differences between NMDAR ab(+)/MOG ab(+) group versus MOG ab(+)/NMDAR ab(-) and NMDAR ab(+)/MOG ab(-) group versus MOG ab(+)/NMDAR ab(-) group (P< 0.0167, Fisher exact tests) in abnormal mental behavior, sleep disorder, speech disorder and involuntary movement. 1 case developed anti-NMDAR encephalitis 1 year after recovery from MOG ab related acute disseminated encephalomyelitis (ADEM). 4 cases developed anti-NMDAR encephalitis and MOG ab related ADEM simultaneously, with 2 cases relapsed. 2 cases were anti-NMDAR encephalitis with only MOG ab positive. In terms of MRI, there were differences in subcortical white matter, basal ganglia and brainstem (P < 0.0167, Fisher exact tests) between NMDAR ab(+)/MOG ab(+) group versus NMDAR ab(+)/MOG ab(-) (P < 0.0001) and NMDAR ab(+)/MOG ab(-) group versus MOG ab(+)/NMDAR ab(-) group(P<0.0001). There were significant differences in MOG antibody titer (Z = -=2.03, P = 0.042) and duration (Z = -1.97, P = 0.049) between relapsed and non-relapsed patients. 3 cases had neurological sequelae. The differences of NMDAR antibody titer (Z = -2.22, P = 0.026) and duration (Z = -2.18, P = 0.029) were significant between patients with and without neurological sequelae. CONCLUSION: NMDAR and MOG antibodies can coexist in children with autoimmune encephalitis. Double antibody positive subjects had more overlaps in clinical manifestations with NMDAR encephalitis, and more overlaps in MRI changes with MOG ab related disease. Higher persistent MOG antibody titer may indicate recurrence, while higher persistent NMDAR antibodies titer may cause neurological sequelae.

Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.

OBJECTIVE: To determine the frequency and significance of concurrent glial (glial-Ab) or neuronal-surface (NS-Ab) antibodies in patients with anti-NMDA receptor (NMDAR) encephalitis. METHODS: Patients were identified during initial routine screening of a cohort (C1) of 646 patients consecutively diagnosed with anti-NMDAR encephalitis and another cohort (C2) of 200 patients systematically rescreened. Antibodies were determined with rat brain immunostaining and cell-based assays. RESULTS: Concurrent antibodies were identified in 42 patients (4% from C1 and 7.5% from C2): 30 (71%) with glial-Ab and 12 (29%) with NS-Ab. Glial-Ab included myelin oligodendrocyte glycoprotein (MOG) (57%), glial fibrillary acidic protein (GFAP) (33%), and aquaporin 4 (AQP4) (10%). NS-Ab included AMPA receptor (AMPAR) (50%), GABAa receptor (GABAaR) (42%), and GABAb receptor (8%). In 39 (95%) of 41 patients, concurrent antibodies were detected in CSF, and in 17 (41%), concurrent antibodies were undetectable in serum. On routine clinical-immunologic studies, the presence of MOG-Ab and AQP4-Ab was suggested by previous episodes of encephalitis or demyelinating disorders (8, 27%), current clinical-radiologic features (e.g., optic neuritis, white matter changes), or standard rat brain immunohistochemistry (e.g., AQP4 reactivity). GFAP-Ab did not associate with distinct clinical-radiologic features. NS-Ab were suggested by MRI findings (e.g., medial temporal lobe changes [AMPAR-Ab], or multifocal cortico-subcortical abnormalities [GABAaR-Ab]), uncommon comorbid conditions (e.g., recent herpesvirus encephalitis), atypical tumors (e.g., breast cancer, neuroblastoma), or rat brain immunostaining. Patients with NS-Ab were less likely to have substantial recovery than those with glial-Ab (5 of 10 [50%] vs 17 of 19 [89%], p = 0.03). CONCLUSIONS: Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.

Understanding the tests that we order: screening for anti-NMDA receptor encephalitis in first episode psychosis.

OBJECTIVE: The current guidelines recommend screening all patients with first episode psychosis (FEP) for anti-NMDA receptor encephalitis. This paper explores the pitfalls of this strategy. CONCLUSION: Screening for anti-NMDA receptor encephalitis in patients with FEP when the pre-test probability based on the clinical presentation is low creates a risk of false positive results. Testing based on clinical suspicion would be preferable.

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series.

OBJECTIVE: To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies. METHODS: We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic. RESULTS: We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects. CONCLUSIONS: Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.

Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis.

OBJECTIVE: To determine the frequency of anti-NMDA receptor encephalitis without detectable serum NMDAR antibodies and to compare the clinical features of these patients with those with NMDAR antibodies in serum and CSF. METHODS: This is a retrospective assessment of serum antibody status and clinical features of 489 patients with anti-NMDAR encephalitis, defined by the presence of NMDAR antibodies in the CSF, and available paired serum/CSF samples examined at Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, between January 2007 and December 2017. NMDAR antibodies were determined with rat brain immunostaining, in-house cell-based assay (CBA), and a commercial CBA. Patients were considered seronegative if NMDAR antibodies were undetectable with the 3 indicated techniques. RESULTS: Serum NMDAR antibodies were not detected in 75 of 489 (15%) patients. Compared with the 414 seropositive patients, the seronegative were older (23.5 years [interquartile range (IQR): 17-43] vs 20.5 [IQR: 14-31]; p < 0.0001) and less frequently women (39 [52%] vs 313 [76%]; p < 0.001) and had less tumors (6 [9%] vs 128 [32%]; p < 0.001). In multivariate analysis, older age at diagnosis (odds ratio [OR]: 1.35 [per decade]; 95% confidence interval [CI]: 1.10-1.67), absence of tumor (OR: 0.14; 95% CI: 0.05-0.43), and less need for intensive care unit admission (OR: 0.35; 95% CI: 0.18-0.69) were independent variables associated with the absence of serum NMDAR antibodies. Time to diagnosis, treatment with immunotherapy, relapses, and outcome were similar in seronegative and seropositive patients. CONCLUSIONS: NMDAR antibodies are not detected in the serum of 15% of the patients with anti-NMDAR encephalitis. These patients appear to be older and have milder neurologic symptoms with less frequency of tumors.