Anti-NMDAR Encephalitis Presenting as Stroke-like Episodes in Children: A Case Series from a Tertiary Care Referral Centre from Southern India.

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the common causes of treatable encephalitis in children characterized by severe memory deficit, speech disturbances, seizures, autonomic dysfunction, and movement disorders. Hemiparesis/stroke-like episode is not a usual presenting complaint of NMDAR encephalitis. The objective of this study was to report confirmed cases of seropositive anti-NMDAR encephalitis in children who presented with hemiparesis/stroke-like episodes. Materials and
Methods: Retrospective review of charts of patients with a diagnosis of NMDAR encephalitis was performed at the pediatric neurology department attached to a tertiary care hospital for 6 years from March 2014 to February 2020. Only those case records with NMDAR seropositivity in the cerebrospinal fluid were collected and those who presented with stroke-like episode/hemiparesis were retrieved separately and the data were extracted in a predesigned proforma and analyzed.
Results: Six children of 24 seropositive anti-NMDAR encephalitis presented with hemiparesis/stroke-like episode. All the six patients presented with hemiparesis, behavioral changes, and regression of speech. Three children had seizures and one child had Epilepsia partialis continua. Two children had dystonia and choreoathetosis. Methylprednisolone followed by oral steroids were administered in all patients. Cases 1, 2, and 4 made a full recovery within 7 days, but cases 3, 5, and 6 showed improvement after 20 days following additional IVIG. Four children have cognitive decline and behavioral problems. Case 6 had relapse and recovered with rituximab.
Conclusion: Anti-NMDA receptor encephalitis which is a potentially treatable disease should be considered in the differential diagnosis when a child presents with hemiparesis/stroke-like episode. Copyright:

INTRODUCTION

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the common causes of treatable encephalitis in children.[1] It is caused by the autoimmune response primarily against NR1 subunit of NMDA receptor. Stroke-like episodes (SLEs) is a new focal neurological deficit, occurring with or without the context of seizures lasting longer than 24 h and the neurological deficit do not correspond to a specific vascular territory.

Anti-NMDAR encephalitis is usually present with cognitive/behavioral decline, extrapyramidal movements, seizures, speech disturbance, and autonomic dysfunction.[2] Hemiparesis/SLEs is not a usual presenting complaint of NMDAR encephalitis in children. Here we report confirmed seropositive anti-NMDAR encephalitis in children who presented with hemiparesis/SLEs.

MATERIALS AND METHODS

Retrospective review of charts of patients with a diagnosis of NMDAR encephalitis was performed at the pediatric neurology department attached to a tertiary care hospital for 6 years from March 2014 to February 2020. Only those case records with NMDAR seropositivity in the cerebrospinal fluid (CSF) were collected. Among these case records of definite anti-NMDAR encephalitis with seropositivity in the CSF, those who presented with hemiparesis/SLE were retrieved separately and analyzed. The clinical, laboratory, neuroimaging findings, treatment, and follow-up details were extracted in a predesigned proforma and the data was analyzed. The outcome was assessed from the follow-up notes in the chart and telephonic interview of the patients who did not come for follow-up visits. Ethical clearance was obtained from institutional ethical committee.

RESULTS

There were totally 24 children with definite NMDAR encephalitis in this study period and 6 (25%) presented with hemiparesis/SLE. All the six patients had initial normal development and presented with hemiparesis, behavioral changes, and regression of speech. Cases 1, 2, 5, and 6 in addition had seizures. Case 6 had Epilepsia partialis continua (EPC). All cases except cases 1 and 6 in addition had dystonia and choreoathetosis on examination. Anti-NMDAR antibodies were detected in the CSF of all patients. MRI brain including MR angiography was normal in all the six children. Electroencephalography (EEG) revealed diffuse slowing with absence of sleep markers in all the six children and focal epileptiform discharges in four children. Ultrasound abdomen and chest X-ray were normal in all the six patients. Methylprednisolone for 5 days followed by oral steroids over a period of 3 months were administered in all the six patients and anticonvulsants were administered for those with seizures. Cases 1, 2, and 4 made a full recovery within 7days, but cases 3, 5, and 6 showed improvement after 20 days following additional IVIG. All children except cases 5 and 6 have returned to school. Although cases 1 and 2 have made significant improvement, cases 3, 4, and 5 have made good improvement but with cognitive decline and behavioral problems persisting. Case 5 has significant behavioral problems and severe hyperactivity which has limited her from joining school. Case 6 had relapse of symptoms after 10 months of wellness and she responded well to intravenous rituximab weekly 4 doses for the relapse and she is on follow-up with significant behavioral problems and hyperactivity. The details of all these six patients with confirmed anti-NMDAR encephalitis presenting with hemiparesis/SLE are mentioned in Table 1. Tumor screening was negative in all the six patients in our study.

Table 1

Clinical and laboratory profile of study population

Parameter	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Age at onset	3 years 10 months	4 years 7 months	4 years	8 years	5 years	4 years
Gender	Male	Female	Female	Female	Female	Female
Weakness	Left	Left	Left	Right	Left	Left
Power	3/5	3/5	3/5	3/5	3/5	3/5
Seizures	Left focal	Left focal	NIL	NIL	Left focal	Left focal
Speech disturbances	Reduced speech	Reduced speech	Reduced speech	Mutism	Reduced speech	Reduced speech
Behavioral problems	Hyperactivity, abusive language	Agitated, emotional liability	Agitated, temper tantrums	Agitated, temper tantrums	Agitated	Agitated
Choreoathetosis	Absent	Present	Present	Present	Present	Absent
Dystonia	Absent	Present	Present	Present	Present	Absent
Orofacial dyskinesias	Absent	Present	Present	Absent	Present	Absent
Investigations
CSF anti-NMDAR antibodies	Positive	Positive	Positive	Positive	Positive	Positive
MRI brain	Normal	Normal	Normal	Normal	Normal	Normal
EEG––diffuse slowing	Yes	Yes	Yes	Yes	Yes	Yes
Focal epileptiform EEG changes	Right cerebral hemisphere	Right frontal region	None	None	Right frontal region	Right frontal region
Treatment given
Steroids	Yes	Yes	Yes	Yes	Yes	Yes
IVIG	Not given	Not given	Given	Not given	Given	Given
Response to treatment	For steroids within 1week	For steroids within 1week	For IVIG after 1 week	For steroids within 1week	For IVIG after 1 week	Relapse, responded rituximab
Outcome	Significant improvement	Significant improvement	Good but cognitive decline and behavioral issues	Good but cognitive and scholastic decline	Good but cognitive decline and hyperactivity	Relapse, good but behavioral problems and hyperactivity

IVIG = intravenous immunoglobulins

DISCUSSION

The causes of encephalitis in children are numerous and are often thought to be mediated by infections, commonly viral.[34] The recent emergence of potentially treatable disease entities like autoimmune encephalitis has led to a dramatic shift in the approach to the management of encephalitis.[5] The landmark California Encephalitis Project focusing on the epidemiology of encephalitis showed that the frequency of anti-NMDAR encephalitis surpassed that of any individual viral etiology, especially in young individuals.[6] Anti-NMDAR-mediated autoimmune encephalitis is the most common cause of pediatric autoimmune encephalitis. Pediatric NMDAR encephalitis presents as a subacute onset encephalopathy with extrapyramidal involvement, seizures with speech /sleep disturbances/autonomic involvement. Anti-NMDAR encephalitis should be suspected in any child or teenager, who develops a rapid change of behavior or psychosis, abnormal postures, or movements (mostly oro-lingual-facial and limb dyskinesia), seizures, and variable signs of autonomic instability.[7]

SLE is a new focal neurological deficit lasting longer than 24 h and the focal neurological deficit does not confine to a specific vascular territory. They may occur with or without the context of seizures. The onset is usually very gradual, and severity of weakness is mild in an SLE compared to abrupt onset and severe weakness in classical stroke. Magnetic resonance angiography is normal and shows no evidence of vascular obstruction in an SLE.

Neurologic presentations of NMDAR encephalitis are more frequent in patients younger than 12 years; those older than 12 years present more often with psychiatric dysfunction.[8] Seizures and movement disorders have been the most common initial presentations of pediatric anti-NMDAR encephalitis. Atypical presentations reported till date include insomnia, gait disturbances, and status epilepticus.[91011] SLEs as a presentation of anti-NMDAR as seen in this study is a novel observation and there is paucity of literature regarding the same. To the best of our knowledge, there is a single observation of hemiparesis reported in 1 of 29 patients (both pediatric and adults) with definite NMDAR encephalitis by Chandra et al.[12] and there is no other literature where hemiparesis/SLEs have been reported as a presenting feature of NMDAR encephalitis.

Anti-NMDAR antibodies are associated with a characteristic syndrome that develops in several stages of illness and recovery, as first reported by Iizuka et al.[13] and Sansing et al.[14] Slight female predominance is noted below the age of 12 years.[8] In our patient profile too, female preponderance was seen.

Regardless of the initial presentation, more than 90% of patients develop at least 3 of the following groups of symptoms within 1 month of disease onset new-onset: temper tantrums, agitation, aggression, and changes in mood or personality, changes in speech, including reduced speech, mutism, echolalia, or perseveration, memory disturbance, seizures, dyskinesias, or autonomic instability.[15] Similar was the sequence in our patients too, who developed behavioral changes within 2 weeks of stroke presentation in three children and subtle behavioral change was present even at the time of presentation on close examination in two children retrospectively.

Patients develop serum and CSF antibodies to a restricted epitope region of the NR1 subunit of the NMDAR.[2] NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, stroke, and dementia, whereas low activity produces symptoms of schizophrenia.[1617]

EEG showing delta brush is typically described, most often in patients who are comatose and seen more commonly in adults.[18] In this study, delta brush was not observed in any of the six children. EEG was suggestive of diffuse slowing with absence of sleep markers in all the six children with the presence of focal epileptiform discharges in only four children. As noted in the previous case series, most children with anti-NMDAR encephalitis and especially below 8 years do not have an underlying tumor.[1920] None of them had tumor in this study.

All the six children had normal MRI brain and normal neuroimaging is a common observation in pediatric NMDAR encephalitis. By contrast to the consistency of the clinical picture, MRI findings are less predictable in anti-NMDAR encephalitis as per literature; only 55% patients have an abnormal MRI and they may have nonspecific T2 or FLAIR signal hyperintensity seen in the hippocampi, cerebellar, or cerebral cortex, frontobasal and insular regions, basal ganglia, brainstem and infrequently, the spinal cord without significant correlation with patients symptoms.[21] The findings are usually mild or transient.[22]

Recovery from anti-NMDAR encephalitis occurs as a multistage process that happens in the reverse order of symptom presentation.[23] The median time from the start of immunotherapy until the first sign of improvement was reported to be 11.5 days in nearly 85% of the cases,[8] which was similarly observed in our cases too. Rest 15% remain severely disabled or die.[15] However, none of the children in this study expired and all are on neurodevelopmental follow-up. The last symptoms to improve are social interactions, language, and executive functions[1523], and similar pattern was observed in this study as well. Relapses occur in 24% of cases as per literature.[15] However only one of six children who presented with SLE had relapse so far during a median follow-up period of 28 months.

The exact pathophysiology behind the occurrence of stroke-like presentation in anti-NMDAR encephalitis is not known. One of the postulates proposed for underlying mechanism for epilepsy and stroke in anti-NMDAR encephalitis is overactivity of NMDA receptors causing excitotoxicity causing injury. However, it must be noted that both children with seizure as well as without seizure have developed hemiparesis/SLEs in this study which leads us to more questions and speculations but without answers with evidence at this stage. The reason behind could be focal epileptiform discharges and a subsequent Todd’s paresis or due to some probable small vessel vasculitis and all these are only our thoughts at this stage and future research is needed in this emerging area. One of the limitations of our study is that no formal functional, cognitive, and disability assessment was performed in these children due to local factors. Despite unanswered questions and limitations, this case series of children with seropositive anti-NMDAR encephalitis presenting with hemiparesis/SLEs is a novel observation of this emerging and treatable disorder leading us to the right path of understanding the pathophysiology of this disorder better in future and it throws light in the right direction for the medical and research community.

CONCLUSION

To conclude, anti-NMDAR encephalitis can present with SLE/hemiparesis in children. Anti-NMDAR encephalitis should be considered as one of the most important differential diagnoses in all patients with SLEs with preceding or subsequent unexplained behavioral changes/seizures/movement disorders. Early diagnosis and therapeutic intervention usually achieve a favorable outcome and hence it is important for the clinician to be aware of this novel presentation of this treatable disorder.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.