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AIAN REVIEW
Year : 2023 | Volume
: 26
| Issue : 1 | Page : 17-32
Anti-N-methyl D-aspartate receptor encephalitis in India: A literature review
Debashish Chowdhury1, Ashwin K Panda1, Ashutosh Gupta1, Samiran Chowdhury2, Ashish Duggal1, Arun Koul1
1 Department of Neurology, G. B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
2 Department of Internal Medicine, Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Correspondence Address:
Debashish Chowdhury
Department of Neurology, G. B. Pant Institute of Postgraduate Medical Education and Research, New Delhi
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_519_22
Abstract
Anti N-methyl D-aspartate receptor encephalitis (NMDAR-E) though rare, is currently considered as the commonest antibody mediated encephalitis in the world. No review on perspectives of NMDAR-E from India is available. The aim of the study was to review all the cases of NMDAR-E reported from India until June 2021 in terms of clinical features, diagnosis, and treatment, and perform a comparison of adult and paediatric cases. A literature review of NMDAR-E case reports/case series published from India till June 2021 was done. Demography, clinical profile, triggers, electroencephalography (EEG), neuroimaging, treatment details and outcomes were analysed. Sixteen case series and 35 case reports with a total of 249 cases were analysed. 82% of cases were from paediatric age group. The female to male ratio was 3:1. Psychiatric deficits, movement disorders, seizures, and language abnormalities were the most common clinical features. MRI brain abnormalities were seen in 45% patients. Electroencephalographic abnormalities were seen in 85% of patients. Infective triggers (herpes simplex virus and various other agents) were reported in 11% of the cases. Pediatric patients as compared with adults had more encephalopathy, autonomic dysfunctions, and normal imaging whereas the latter had more cognitive dysfunctions and delta brush pattern in electroencephalography (p<0.005). Therefore, to conclude, this literature review suggests that overall, the clinical spectrum of Indian cases is like cases described from other parts of the world. However, most reported cases from India belonged to paediatric age group who had more encephalopathy, autonomic dysfunctions, and normal brain imaging compared to adults. A few novel infectious agents as triggers were described from India.
Keywords: Adult, anti-N-methyl D-aspartate receptor encephalitis, delta brush pattern, pediatric, triggers
Introduction 
After its first description in 2007,[1] “Anti N-methyl D-aspartate receptor encephalitis” (NMDAR-E) has become the most common cause of antibody-mediated encephalitis in the world and is characterized by the presence of cerebrospinal fluid (CSF) antibodies against the Glutamate N1 subunit of the NMDAR.[2],[3] However, the overall incidence of the disease is rare, and it has been estimated that about 1.5 per million per year suffer from this disease.[4] Over the last decade, many cases and series have been published in different regions of the world updating the clinical spectrum with regard to the demography, symptoms, imaging, and triggers of NMDAR-E. The striking presence of psychiatric and behavioral symptoms at onset and multiple combinations of neurological manifestations such as movement disorders (MD), seizures, speech disorders, altered consciousness, insomnia, and autonomic dysfunctions characterizes the disease and hence may be challenging to diagnose clinically. However, early diagnosis of NMDAR-E is important as the disease is treatable with immunomodulation. Another important feature of NMDAR-E is its association with various tumors (especially ovarian teratoma) and infectious agents such as Herpes Simplex encephalitis.[2],[3],[4] Lately, non-HSV and other CNS/systemic infections are increasingly being implicated as triggers for NMDAR-E.[5],[6] It would be interesting to analyze Indian cases from this perspective as infectious diseases are common in India. Further, a comprehensive review of the available literature on NMDAR-E from India shall be useful by highlighting the differences in clinical and management details of this disease, if any. Also, over the years, relatively large case series and reviews have highlighted some differences between adult and pediatric NMDAR-E at the onset.[4],[7] Therefore, we aimed to present an analysis of the literature review of all the NMDAR-E cases reported from India till June 2021 focusing on the clinical spectrum, investigations, triggers, and outcomes. We also compared the differences between the clinical profile and the outcome of pediatric and adult NMDAR-E cases.
Methods We did a literature search on PUBMED for case reports (less than three cases) and case series (three or more cases) published from India up till June 2021 using the following MeSH: (anti-N-methyl-d-aspartate receptor encephalitis) OR (N-methyl-d-aspartate antibody encephalitis) OR (anti-NMDAR encephalitis) OR (anti-NMDA receptor encephalitis) OR (NMDA receptor encephalitis) OR (anti-N-methyl-d-aspartate receptor antibody encephalitis) and India in the English language. The demographic details, clinical symptoms, imaging, electroencephalography (EEG), and treatment details available in the reports were recorded and analyzed [Figure 1].
Figure 1: The PRISMA diagram detail the search and selection process applied during our systematic literature searchPatients of all age groups were included, and age was represented as “years.” Patients who were 18 years or above were classified as adults and those below 18 years of age were classified as pediatric patients. Various clinical symptoms were recorded and grouped as MD (tremor, dystonia, chorea, oro-mandibular movements, dyskinesia), seizures (focal, generalized tonic–clonic seizures, nonconvulsive status epilepticus, refractory seizures, infantile spasms, and status epilepticus), cognitive deficits (memory disturbances, attention disturbances, anterograde amnesia, calculation impairment, visuospatial impairment), psychiatric abnormalities (personality changes, psychomotor disturbance, irritability, anxiety, hallucinations, psychosis delusions, catatonia, agitation, and aggression), encephalopathy (confusion, altered sensorium, deterioration of consciousness, altered mental state), sleep disturbances (insomnia, excessive sleeping, disturbed sleep, decreased sleep), autonomic dysfunction (dysautonomia, sweating, tachycardia, blood pressure fluctuation), and language abnormalities (aphasia, dysphasia, mutism). MRI brain was categorized as normal or abnormal. When details were available, specific parts of the brain that were involved were noted such as the midbrain (MB), basal ganglia (BG), thalamus (TH), temporal lobe (T), frontal (F), occipital lobe (O), parietal (P), insula (ins), meninges (MEN), and white matter (WM). Treatment details were grouped as first-line and second-line treatment. Steroids [methylprednisolone (MPS)], intravenous human immunoglobulin (IVIG), and plasma exchange (PLEX) were grouped as first-line treatment, whereas rituximab (RTX), cyclophosphamide, and other agents were grouped as second-line treatment.[7] Outcome was noted as complete improvement (at discharge or during follow-up, whenever available) and partial improvement (with any neurological deficit at discharge or in subsequent follow-up).
Statistical analysis
Age was described as median years with an IQR. The diagnostic method used for NMDAR-E, clinical symptoms, treatment, imaging, and outcome were described as frequency or percentage. The proportion of various clinical variables between the adult and the pediatric cases were compared using Chi-square with Fischer's exact wherever applicable and odd's ratio and 95% confidence intervals were calculated.
Results Sixteen case series and 35 case reports totaling 249 cases were reported from India till June 2021.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57] The salient features of these studies are tabulated in [Table 1] and [Table 2].
Table 1: Clinical profile, treatment, and outcome details of Indian NMDAR-E patients as reported in the case series
Table 2: Clinical profile, treatment and outcome details of NMDAR-E patients in the case reportsAnalysis of the literature review of NMDAR-E cases from India
Demographic, clinical, imaging, treatment, and outcome details of 249 cases are tabulated in [Table 3]. These are described as follows:
Table 3: Demographic, clinical, imaging, treatment, and outcome details of all casesDemography: The median age of presentation was 12 years (mean 6, IQR 17.5). The female-to-male ratio was 2.8:1 (n = 183/66). One hundred and sixty-eight (81.55%) cases were from the pediatric age group and 38 (18.44%) were from the adult age group (the age details of 43 patients were not known).
Clinical profile: The reports mentioned a constellation of symptoms and signs at presentation and during illness. Overall, MD and psychiatric abnormalities (70%) were the most common manifestations. This was followed by seizures (62%), language abnormalities (55%), cognitive deficits (40%), sleep disturbances (34%), encephalopathy (27%), and autonomic dysfunction (16%).
Adult versus pediatric: When compared to adults, encephalopathy and autonomic dysfunction were reported more commonly in pediatric patients, that is, 13% versus 32% (P = 0.019) and 3% versus 23% (P = 0.003), respectively. Cognitive deficits were more common in adult patients as compared with pediatric patients [74% vs. 27% (P = 0.00001)]. MD and seizures were reported more in the pediatric population, whereas psychiatric abnormalities, language abnormalities, and sleep disturbances were marginally higher in the adult population although no statistical significance could be derived [Table 4].
Table 4: Comparison of clinical profile and outcome between adult and pediatric NMDAR-E patientsDiagnosis of NMDAR-E: Antibodies against NMDAR were tested in CSF, serum, and both CSF+ serum in the cases analyzed. Of the 160 cases whose data were available, 43% of cases were diagnosed by both CSF+ serum antibodies, while 31% of the cases were diagnosed by antibodies in serum and 26% of cases by antibodies in CSF.
Triggers: Triggers of NMDAR-E were reported in 27 cases (11%). Out of these, 18 were due to various infectious agents (HSV 9, Japanese encephalitis virus [JEV] 4, dengue virus 1, Salmonella 1, Mycobacterium tuberculosis 1, Treponema pallidum 1, Leptospira 1). Of these Leptospira, Mycobacterium tuberculosis, Salmonella, and dengue as triggers of NMDAR-E were reported for the first time from India.[9],[15],[25],[33] Nine cases had ovarian tumors.
Other investigations: Of the 232 patients whose imaging details were available, 108 (46%) patients had abnormal imaging. The abnormalities were described in 108 patients and temporal lobe of the brain (38%) was the most commonly affected area. It was found that the pediatric patients had a predilection toward having a normal MRI despite florid clinical symptoms when compared to adults, that is, 65% versus 38% (P = 0.005). Details of EEG were available for 183 patients. The number of patients with abnormal EEG records was 5.6 times more than those with normal records, that is, 85% of the patients had an abnormal record. Details were described in 146 patients where diffuse slowing was the most common abnormality (68%). Thirty-one percent patients showed epileptiform discharges and delta brush pattern was only reported in 11% of the patients. Delta brush was more likely to be found in adults than in pediatric patients (P = 0.00005).
Treatment and outcome: Of the 221 patients whose treatment detail was available, 139 (62%) received only first-line treatment, that is, MPS, and/or IVIG, and/or PLEX and 92 (32%) received second-line treatment. RTX, azathioprine, MMF, cyclophosphamide, and oophorectomy were the second-line treatment used. Details of outcome were available for 213 patients. The patients were followed up for the period of 4–24 months in different studies.[19],[20] Of these, 61% had improved completely, 35% had residual neurological deficits, while 4% of the patients died. Wherever details were available, the major cause of death was ICU-related complications, mainly VAP, tracheostomy related, and autonomic dysfunction.[18],[28],[35],[41] Similarly, relapses were seen in 24 patients.[16],[17],[39],[44] The main presenting symptoms in those patients were seizures and psychiatric abnormalities.
Discussion We conducted a thorough literature search and analyzed the NMDAR-E cases from India which provided an overview of the clinical spectrum, treatment, and outcome of this disease. Further, we found some important differences between the pediatric and adult cases of NMDAR-E.
Demography: We found a lower median age at presentation among the Indian patients, that is, 12 years. In a study of 577 patients, Titulaer et al.[7] mention the median age to be 21 years where only 36% of the patients in that series were below 18 years of age. Similarly in a review, Dalmau et al.[4] also report the median age at presentation to be 21 years. Therefore, the lower median age was probably due to a higher percentage of pediatric patients (82%) in our review. Higher proportion of pediatrics patients reported in India can be attributed to some key factors: (1) increased awareness, hence more frequent diagnosis—Dalmau et al.[2] in their review opine that as awareness and understanding of the disease has increased, NMDAR-E was found more frequently in younger individuals and in those without teratomas,[2] that is, men and children. This was further substantiated by Gable et al.[58] in their seminal paper where they mentioned that more than 65% of total NMDAR-E occurs in individuals aged less than 18 years of age. Further, NMDAR-E as a cause for encephalitis upstaged viral etiologies and became the second common cause of encephalitis in children after ADEM. From India too, Chandra et al.[14] in their series of 29 patients mention 80% of their patients to be below 18 years of age. (2) Florance et al.[59] opine that infections can cause an overdrive of the immune system leading to NMDAR-E as corroborated by post-HSV NMDAR-E; these infections are an important factor for NMDAR-E in children and adolescents. (3) Reporting bias—As NMDAR-E in young adults and women were being reported frequently in literature, it is a plausibility that further reporting was biased toward atypical or rare cases leading to more publications in the pediatric age group. Therefore, a prospective study with large number of patients can solve this conundrum of higher proportion of pediatric patients reported in the Indian population.
Females constituted 74% of the total cases as compared to 26% males (3:1) reported from India. In both the adult and pediatric patients, females were affected more than males (67% and 75%, respectively). Dalmau et al.[4] and other studies[5],[60],[61],[62] also mention this as an important demographic finding. However, few case series from China reported male predominance; for example, Liu et al.[63] reported a series of 11 patients in which adults made up 99% and males constituted 55% of the total cases and Zhang et al.[64] in a series of 53 cases reported males to constitute 47% of the total cases. The authors attribute it to sample size and racial differences between Chinese and western population. In this regard, it can be inferred that in the Indian population, the sex distribution of NMDAR-E is similar to that reported from the Western world.
Clinical spectrum: Overall, psychiatric abnormalities, MD, seizures, and language abnormalities were the most common clinical features in the Indian cases of NMDAR-E. These findings are consistent with previously published series.[1],[5],[60],[61],[62],[63],[64] It can be inferred that the clinical spectrum also does not vary across different geographical areas.
Adults versus pediatric: Majority (82%) of the patients were from the pediatric age group. MD, seizures, encephalopathy, and autonomic dysfunctions were seen in a higher percentage of pediatric patients than in adults. Ho et al.[65] in their series of NMDAR-E in children from Hong Kong also reported that seizures, MD, and psychiatric abnormalities were the common clinical features. Similarly, a case series if 111 pediatric patients from southern China and a series of 32 patients from the USA reported these symptoms to be the common.[59],[66] Contrarily in adults, cognitive deficits, psychiatric abnormalities, sleep disturbances, and language abnormalities were seen in a higher percentage of patients in our review. Titular et al.[7] had reported that in adults, psychiatric abnormalities are present more commonly than in pediatric patients. We also found that in Indian patients, autonomic dysfunctions were predominantly reported in pediatric patients as compared to adults (22% vs. 5%). Eighty percent of the children (median age 14) were reported to have autonomic dysfunctions in a study by Florance et al.,[59] whereas other studies report 69% of the patients (median age 23)[1] and 40% of the patients (median age 26)[64] having autonomic dysfunctions. As the median age of the studies increased, the percentage of autonomic dysfunctions reported in them also seems to decrease. Whether this can imply that pediatric patients suffer from more autonomic dysfunctions than adults as reflected by our analysis is a question of further evaluation as autonomic dysfunctions have received little attention in prior studies and are both elusive and difficult to assess. Hence, drawing a conclusion can be an over-reach and further large studies are needed.
Neuroimaging: Forty-five percent of NMDAR-E patients from India had abnormal imaging with temporal lobe being the most involved structure of the brain (40%). Previous studies from the world reported 33–55% patients with an abnormal MRI.[1],[5] Dalmau et al.[4] had also reported that the temporal lobe was the most implicated anatomical structure in NMDAR-E. They also reported that the cortex, cerebellum, brainstem, and BG may be afflicted in NMDAR-E patients. We also found these structures to be involved in the reported Indian cases.
Further, we found that pediatric patients had normal MR imaging more frequently when compared to adults (65% vs. 40%, P = 0.015). Bacchi et al.[67] in a systematic review reported similar findings, that is, 65% of the pediatric patients (158/242) and 53% of adults (106/198) had a normal MR imaging. Contrary to this, Zhang et al.[64] report pediatric and adult patients to have similar percentages of normal MRI scans (53%, P = 0.991). Bacchi et al.[67] acknowledge the importance of the stage of the disease at which the MRI is done, as the abnormalities tend to decrease as the disease progresses. Zhang et al.[64] mention that the mean time of acquiring MR images in their study was 36 ± 15 days. Hence, although our review indicates the pediatric population to have fewer abnormalities on MRI, detailed studies focusing on MR imaging should be done to corroborate these findings as most studies in our review mentioned MRI as part of their routine patient workup without mentioning the time of acquisition of these scans. These findings also suggest that despite the presence of various florid clinical symptoms in NMDAR-E, MRI may be normal often. In this scenario, functional imaging like FDG-PET showing metabolic changes in various parts of the brain may aid in explaining the clinical findings.[68],[69]
EEG: EEG abnormalities were seen in 85% of the patients with diffuse slowing being the most common abnormality (68%) followed by epileptiform discharges (31%) and delta brush pattern (12%). Indian studies report that 78–100% of the patients have abnormal EEG patterns.[7],[12],[20] This is in concordance with studies from other parts of the world where 90–100% of patients had abnormal EEG patterns.[70],[71],[72] It is worth noting that more patients of NMDAR-E have an abnormal EEG than an abnormal MRI. In primary psychiatric illnesses, screening EEG abnormalities are seen only in 17–19% patients.[73],[74] Thus, an EEG becomes important in cases where the first manifestations are psychiatric or behavioral abnormalities, aiding the differentiation between a psychiatric illness and NMDAR-E. A systematic review by Gillinder et al.[75] reports epileptiform discharges in 18% of the patients and delta brush in 8% of the patients. They mention timing of EEG (whether in acute stage), duration of recording (initially 30% of the patients have normal records), and deep or widespread foci/functional abnormalities as probable reasons for reporting lesser focal findings vis-à-vis diffuse slowing.[75] Usually, studies report 18–30% of patients with the delta brush pattern[70],[71] but Meyer et al.[72] reported delta brush pattern in 53% of their patients. They conducted a median of 8 h of monitoring per patient and all of them were put on continuous EEG monitoring.[72] Hence, the yield of delta brush pattern increased in patients who were on continuous EEG monitoring.[4],[72] We also report adults to have a significantly higher percentage of delta brush pattern as compared to pediatric patients but as age-wise details were not specifically reported in the Indian literature, further studies would be needed to substantiate this EEG finding.
Triggers: Overall, 11% of patients in the review had a trigger for NMDAR-E. Infective causes as triggers were seen in 66% (18/27) of the cases with HSV being the commonest cause (44%). The other infections reported in the Indian cases were JEV, dengue virus, T. pallidum (syphilis), Salmonella typhi, Leptospira, and MTB. HSV as an important preceding infection triggering NMDAR-E has been highlighted by many case reports/series and in a review by Nosadini et al.[5] JEV and MTB as possible triggers have been reported in a review on non-HSV NMDAR-E cases by Cavaliere et al.[6] Our review of Indian studies appends S. typhi, dengue virus, M. tuberculosis, and Leptospira as non-HSV infections which can trigger NMDAR-E. Also, ovarian teratoma and adenomas were responsible for triggering NMDAR-E in nine Indian cases (seven adults, two pediatrics) in our review. Ovarian teratomas are the most common tumors responsible for NMDAR-E, although other tumors are also implicated in triggering NMDAR-E.[1],[4] Ovarian teratomas are postulated to express neuronal tissues and antigens against which antibodies are produced causing NMDAR-E.[76] The majority of cases with infective triggers were from the pediatric age group (90%). Previously published case series also reported that 32–80% of pediatric cases had evidence of infections before or concurrent to NMDAR-E.[1],[77],[78],[79],[80]
Treatment: Although no consensus guidelines exist for NMDAR-E treatment, the treatment protocol reported in Indian studies reflects the preference of clinicians toward MPS, IVIG, and RTX as published earlier by Titulaer et al.[7] Treatment details were available for 221 patients. Sixty-two percent (137) of the patients received first-line treatment (MPS and/or IVIG) and the rest (84) received additional second-line treatment. MPS was administered to 201 patients (only first line—137, first + second line—64) while IVIG was given to 123 patients (only first line—63, first + second line—60). RTX (48/84) was the most preferred drug for second-line treatment. Of the nine cases with ovarian tumors, five underwent oophorectomy. Two improved completely, in-fact there was rapid improvement leading to weaning off from ventilators within a week.[48],[51] Two patients had partial deficits and one patient died due to ICU complications. All patients had received immunotherapy. Dalmau et al.[1] mention that patients with early surgery along with immunotherapy benefit more than those who are not operated or operated late. Hence, patients with ovarian tumors should be operated after immunotherapy despite improvement as those who were not operated or operated late had higher chances of relapse.
Outcome: Of the 213 patients whose outcome details were available for analysis, nearly two-thirds of the patients improved completely, whereas one-third of them had partial deficits despite treatment (61% vs. 35%). The previous reports of deficits after NMDAR-E ranged between 27% and 85% of the patients.[1],[3],[5] The predictors for a better outcome in NMDAR_E patients have been noted to be an early institution of therapy, younger age, and better GCS (Glasgow coma scale >8) at admission.[5],[81] We could not analyze predictors for all the cases reported from India as majority of the papers were lacking the requisite details.
Strengths and limitations
The review analyzes the available data of all cases on NMDAR-E published from India to characterize that it is the clinical spectrum, treatment, and outcome. The limitations include, publication bias which may have led to a higher number of pediatric cases and their atypical presentation. Further, there was significant heterogeneity among the studies including definition of symptoms, treatment/management protocol, and missing data which precluded analysis of many aspects such as clinical symptoms, triggers, and predictors of outcome or hampered a robust assessment of the burden of certain aspects like symptoms, EEG, MRI, and treatment protocols. Also, the details about treatment, follow-up care, and disability were not mentioned in many reports, making it difficult to infer the standard clinical practice in the country with respect to NMDAR-E. Despite these limitations, our review provides for the first time a consolidated overview of various aspects of NMDAR-E from India. This overview of all cases from the country brings forth the Indian scenario of NMDAR-E while highlighting unique infective triggers. It also highlights the importance of a large prospective study of patients with NMDAR-E with uniform clinical definitions, treatment/management protocols, and follow-up of discharged patients to elucidate the clinical spectrum of NMDAR-E from India.
Conclusions Based on our review of 249 previously published cases from India, we conclude that NMDAR-E is reported more commonly in the pediatric population (82%) and in females (74%). A large prospective study/registry is needed to resolve the demographic profile of NMDAR-E in India. In the pediatric age group, seizures, MD, encephalopathy, and autonomic dysfunctions were more common while in adults had more cognitive deficits, psychiatric abnormalities, sleep disturbances, and language abnormalities. MRI abnormalities were seen in 45% of the patients. Pediatric patients had lesser MRI abnormalities as compared to adults. EEG abnormalities were seen in 85% of the patients, diffuse slowing being the commonest abnormality (68%). Delta brush was seen in 11% of the patients and significantly more in adults. Infections were important trigger factors for NMDAR-E. Though HSV infections were the commonest triggers, non-HSV infections can also trigger NMDAR-E. Indian neurologists have used MP, IVIG, and RTX and reported complete recovery in two-thirds of the patients.
Acknowledgments
The authors acknowledge the family members of the patients for their involvement in providing the clinical history of the patients. They also acknowledge the role of neurology residents of the institute in the care of the NMDAR-E patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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