Acute onset behavioral change in Pediatric Age group: Understanding NMDA Encephalitis

Dr.Rithwik Sunil, Dr. Vinayan(Pediatric Neurology), Dr.Sajith Kesavan(Intensivist and Paed pulmonologist,, Dr.Greeshma Issac(Intensivist), Dr. C Jayakumar

Two year old boy, developmentally normal and immunised for age, presented with complaints of excessive lethargy , behavioral issues and hyperkinetic movements following a  febrile illness. Child initially had a URTI which was treated symptomatically. The following days, child showed excessive sleepiness and lethargy.
This later changed to increased aggression, abnormal perioral movements and not recognizing parents.
Examination
Child was disoriented, irritable, hyperactive & showed little response to pain.
Vitals stable
PICCLE normal 
Auxology:
Weight: 10.5kg, (0 & -2SD)
Height:100cm (>3SD)
HC: 47cm(btw 0 & -1 SD)
No neurocutaneous markers, dysmorphism, autonomic fluctuations, and no meaningful eye contact
CNS examination; child showed continuous dyskinetic movements mostly in the perioral region , trunk and limbs. Normal Cranial nerves and motor system examination 
Other systems; Normal

Differentials 
Viral encephalitis
Anti NMDA encephalitis
Inborn errors of Metabolsim
Drugs/Toxins exposure
Childhood disintegrative disorder/late- onset autism 

Investigations
Total count:17,00
N:75%, L:18.5%
SGOT: 57.2,  SGPT:21
Total protein: 7.2g/dl
S.Albumin:4g/dl
Creatinine:0.34mg/dl, 
Na+:146.4mEq/L, K+:4.1mEq/L
CRP:0.68mg/dl
Creatine kinase:4546U/L
VBG done at time of admission: Normal
EEG: Generalized non specific disturbances of electric function more on the left hemisphere. Excess of beta activity was noted.
MRI abdomen contrast no significant abnormality is detected
Ultrasound of abdomen :no abnormality detected
CT brain done: normal 
MRI spine: cytology, protein, sugar- normal
CSF analysis: normal
CSF meningoencephalitis panel: negative
Immune work up-Serum & CSF NMDA:strongly positive.
Management 
Child was admitted in the PICU and started on IVIG(2gm/kg) and IV methyl prednisolone(at 30mg/kg/dose)tapered to oral steroids(1gm/kg/day). Despite IVMP and IVIG, child continued to be encephalopathic with only mild improvement in functional status.Child was started on Rituximab 375mg/m2 weekly dose. Parents were counselled about the need for further rounds of immunomodulatory therapy. Child is not having behavioural issues or lethargy 



Discussion
In NMDA receptor antibody encephalitis immunoglobulin G antibodies target the GluN1 subunit of the NMDA receptor.
The disorder usually presents with prominent psychiatric manifestations that may include rapidly progressive anxiety, agitation, delusional thoughts, bizarre behavior, labile affect, mood disturbances (mania), catatonic features, memory deficit, language disintegration, aggression, and insomnia or other sleep disturbances. 
In many cases, these symptoms had been preceded a few days of prodromal headache, fever, or viral infection–like symptoms. 
Brain MRI studies are abnormal in approximately 35% of patients, usually showing nonspecific cortical and subcortical T2–fluid-attenuated inversion recovery (FLAIR) signal abnormalities, sometimes with transient cortical or meningeal enhancement; nonspecific white matter abnormalities can occur. 
The cerebrospinal fluid (CSF) is initially abnormal in approximately 80% of patients, showing moderate lymphocytic pleocytosis. The electroencephalogram (EEG) is abnormal in virtually all patients, and it usually shows focal or diffuse slow activity in the delta and theta ranges. 
The diagnosis of the disorder is established demonstrating NMDAR antibodies in CSF and serum. The sensitivity is higher in CSF compared with serum (100% vs 85%), and the levels of antibodies in CSF appear to correlate better with the outcome. 
Most children receive first-line immunotherapies, including corticosteroids, IVIG, or plasma exchange. However, because these treatments fail in almost 50% of patients, and with an increasing number of reports showing that rituximab can be effective, this treatment is increasingly being used in combination with IVIG and steroids or after first-line immunotherapies. Cyclophosphamide can be effective when there has been no response to these treatments. 

Take home message
Acute onset behavioral changes should be should be always taken seriously in the Paediatric age group. Diagnosis of possible autoimmune encephalitis should always be kept in mind as these symptoms are often misdiagnosed as temper tantrums.