Anti–N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis (NMDARE) is an autoimmune disorder characterized by antibodies targeting the NR1 subunit of NMDARs in the central nervous system [1]. The condition predominantly affects children and young adults, with a greater prevalence among females. Common clinical features include psychiatric symptoms, seizures, movement disorders, and autonomic dysfunction, and the condition is frequently associated with ovarian teratomas [2,3]. Early diagnosis and treatment are critical for improving outcomes. Serum and cerebrospinal fluid samples should be collected promptly for antibody testing to confirm the diagnosis. First-line treatment typically involves corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis alongside tumor removal if applicable. Supportive care, including anti-seizure and antipsychotic medications, is essential for optimal recovery [4]. While mortality rates are relatively low (approximately 20%), some patients may develop focal neurological deficits. Relapses occur in about 10% of cases, usually within 2 years of the initial presentation, and tend to be less severe [5]. This case series describes the clinical features, treatments, complications, and outcomes of six patients with NMDARE, alongside a review of Indian literature on the condition.

The present study included consecutive patients diagnosed with definite NMDARE over a 2-year period, based on the criteria of Graus et al. [6]. Clinical features, hospital course, and outcomes were analyzed. Laboratory diagnosis was determined in cerebrospinal fluid (with paired serum) using a cell-based assay for NMDARE using transfected HEK cells in a quaternary institution from India, with antibody titers above 1:10 considered to be positive [7]. The Institutional Review Board of King George’s Medical University waived the requirement for approval, and written informed consent was obtained from all participants. A comprehensive literature review was also conducted using PubMed, Scopus, Embase, and Google Scholar, selecting studies published up to January 2025.

The case series included six patients (four females, two males) aged 10–19 years (mean age, 14.5 ± 3.02 years) (Table 1). Seizures were the most common presenting symptom, occurring in five patients, with two having super-refractory status epilepticus (SRSE). Psychiatric symptoms, such as agitation, hallucinations, and personality changes, were universal. Movement disorders, including dystonia and tremors, were observed in three patients, along with the presence of rubral tremors in one patient. Symptom duration ranged from 1 to 4 months (mean, 2.67 ± 1.25 months). Tumor screening was negative in all cases. Magnetic resonance imaging (MRI) of the brain revealed T2/FLAIR hyperintensities in the medial temporal lobe, periventricular white matter, basal ganglia, and midbrain in five patients, while one patient had a normal scan. Electroencephalographic (EEG) abnormalities included diffuse slowing in three patients and extreme delta brush and epileptiform discharges in two patients, while two patients had normal EEG studies. Treatment involved high-dose intravenous methylprednisolone and IVIg for all patients, with rituximab administered in three cases and cyclophosphamide given in one (with SRSE). Five patients received anti-seizure medications, and four required antipsychotic medications. Most patients achieved good functional recovery (modified Rankin Scale [mRS] score, 1–2 points), with one patient’s mRS score improving from 3 points to 2 points at 6 months of follow-up and one patient experiencing two relapses during 18 months of follow-up.

A search of the Indian literature on NMDARE revealed 60 studies, among which case reports were excluded and 12 clinical studies and case series were included for final review [8-19] (Table 2). A total of 115 patients were enrolled across these 12 studies, with individual sample sizes ranging from two to 29 patients. There was a female predominance in the total literature patient population, with many studies reporting a higher number of female cases (e.g., 26/29 in Chandra et al. [10]; 16/21 in Basheer et al. [17]). This observation is in line with global trends, where NMDARE is more common in females, particularly among younger individuals [4]. Most included patients were children or young adults, reinforcing the notion that NMDARE primarily affects children and adolescents. Psychiatric symptoms were the most common presenting feature, observed in nearly all patients, with the most common symptoms being agitation, aggression, hallucinations, and personality changes. Seizures were another major presenting symptom, with generalized seizures being more frequent than focal seizures and with three studies reporting cases of status epilepticus. Movement disorders, such as dystonia, myoclonus, ataxia, and rubral tremor, were more frequently reported among the included Indian studies when compared to some Western cohorts. Other, less common neurological features included hemiplegia, aphasia, and dysarthria, which were seen in a few cases. Only the study by Kumari et al. [16] reported an association with ovarian teratomas; this contrasts with Western literature, where up to 50% of female cases have been linked to teratomas [3]. MRI findings varied significantly—while several patients had normal MRI findings, others exhibited T2 hyperintensities in the medial temporal region, basal ganglia, cerebellum, or caudate nucleus, consistent with autoimmune encephalitis. EEG abnormalities were common, with diffuse background slowing being the most frequent finding. Extreme delta brush, a hallmark EEG finding of NMDARE, was also identified in some studies. Most patients tested positive for anti-NMDAR antibodies, but, in some cases, testing was not performed. In most patients, treatment consisted of first-line immunotherapy, in the form of high-dose intravenous methylprednisolone (30 mg/kg/day for 5 days) and IVIg. However, the use of second-line immunotherapy (rituximab, cyclophosphamide) was limited, and plasmapheresis (therapeutic plasma exchange) was performed selectively. Anti-seizure medications were widely prescribed for seizure control, and antipsychotic medications were administered to manage psychiatric symptoms. Most patients showed good functional recovery, with many returning to their premorbid state. However, a small proportion experienced relapses, requiring further immunotherapy. Some studies reported residual neurological deficits, primarily affecting cognitive and mood functions, even after initial improvement. Mortality was low but present, emphasizing the importance of early recognition and aggressive treatment.

The present case series and literature review provide valuable insights into the clinical profile, diagnostic challenges, and treatment outcomes of NMDARE in the Indian population. The predominance of female and pediatric or adolescent patients observed in this study aligns with global reports, further emphasizing the vulnerability of young females to this disorder [20]. The high frequency of psychiatric symptoms as the initial presentation highlights the complexity of early diagnosis, often leading to misdiagnosis or delayed initiation of treatment [21]. Seizures were a prominent feature in both the case series and the literature review, with generalized seizures being more common. The occurrence of SRSE in two patients in our case series highlighted the potential severity of the disease, which necessitates prompt recognition and aggressive management. Movement disorders, particularly dystonia and tremors, were more frequently reported in Indian cohorts compared to Western studies [22]. This observation suggests that ethnic or genetic differences might lead to variations in the clinial manifestations reported in NMDARE. The higher occurence of rubral tremors in our case series was a distinctive finding relative to rates in the reviewed literature. The rarity of ovarian teratomas in Indian patients is another striking observation; while Western literature frequently links NMDARE in females to ovarian teratomas at presentation, Indian studies report a much lower prevalence [23]. A similar finding was observed in our case series as well. This discrepancy may stem from differences in genetic predisposition, infectious and environmental factors, long-term imaging follow-up, and reporting for tumor screening as a late occurrence in the disease timeline. Further studies are needed to explore the underlying reasons for this disparity and to assess the role of systematic tumor screening protocols in the Indian population. Neuroimaging findings were heterogeneous but comparable between our cohort and reviewed studies, with a majority of patients exhibiting T2 hyperintensities in the medial temporal lobes, basal ganglia, and brainstem (in some patients), aligning with previously reported findings, suggesting that these regions may be particularly vulnerable in autoimmune encephalitis [24]. A subset of patients also exhibited normal MRI findings in our cohort as well as in the reviewed literature. This highlights the importance of clinical suspicion and antibody testing in the diagnosis of NMDARE. Interestingly, there is a concept of overlapping syndrome in NMDARE, wherein there is coexistence of other demyelinating antibodies like myelin oligodendrocyte glycoprotein antibodies or aquaporin-4 antibodies in disorders of similar presentation in combination with NMDAR antibodies. However, none of the cases in our series showed such coexistence. EEG abnormalities were frequently observed, with diffuse delta slowing being the most common finding. The identification of extreme delta brush in a subset of patients reinforces its diagnostic significance [25]. A combination of psychiatric symptoms, seizures, movement disorders, and EEG abnormalities should prompt clinicians to consider NMDARE, even in the absence of definitive neuroimaging findings.

The therapeutic approach in both the case series and the literature review largely encompassed first-line immunotherapy, with limited use of second-line agents. This may reflect a lack of standardized treatment protocols and practices, limited access to advanced immunotherapy options in some centers, diagnostic dilemmas leading to treatment delays, affordability concerns in a resource-limited region, early treatment-related fluctuations, and the discontinuation of undetermined social and family beliefs. The overall favorable outcomes in most patients consolidated the role of early immunotherapy, although the occurrence of relapses and residual cognitive deficits in some cases highlights the need for long-term follow-up and rehabilitation with second-line immunotherapy [26].

The low mortality rate we observed among Indian studies is encouraging, but it also emphasizes the importance of early diagnosis and prompt initiation of immunotherapy. The findings of this review call for greater awareness among clinicians, particularly psychiatrists, neurologists, and intensivists, to improve the recognition of NMDARE and optimize patient outcomes. Future studies should focus on establishing a standardized predictive model for treatment nonresponse and relapse of this potentially life-threatening disorder. A limitation of this case series and literature review was the inability to perform tissue-based analysis of NMDAR antibodies, owing to the nonavailability of such testing in governmental institutions in India to date. The provision of such data could have further consolidated the findings of this series and the literature analysis.

In conclusion, NMDARE presents with diverse clinical manifestations, posing diagnostic and therapeutic challenges, along with a variable prognosis. Early recognition and aggressive immunotherapy are crucial for favorable outcomes. While mortality is low, relapses and residual deficits render management difficult and necessitate long-term follow-up in these patients. Large-scale, multicenter studies are essential to better understand the condition’s epidemiology, treatment responses, and long-term outcomes in the Indian population. Use of second-line immunotherapy agents needs to be explored for refractory cases. Enhancing clinician awareness and improving access to diagnostic tools will further aid in the timely management of this treatable yet potentially severe condition.