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Anti-NMDAR Encephalitis in Children
Introduction
Following the first report of pediatric anti-NMDAR encephalitis in China in 2010, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is now recognized more frequently and commonly in the pediatric population. It is the second most common etiology for acute demyelinating encephalitis after mixed disturbance encephalitis surpassing all viral etiologies for encephalitis.[1][2]
Etiology
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Etiology
Anti-NMDAR encephalitis is an immune-mediated neuroinflammatory disease characterized by autoantibodies against the GluN1 subunit 2B (NR2B)/NMDA subunit 2A (NR2A) subunits of the NDMA receptor in the hippocampus causing the symptoms. Initially, it was diagnosed as a paraneoplastic disease most commonly associated with ovarian teratoma.[3][4][5] However, published case reports show evidence of this association in only 31% of children <18 years and 9% of children under the age of 14 years.[5][6]
Another confirmed association has been seen with herpes simplex encephalitis.[7] In a case series comprising of 99 patients, it was found out that 27% (64% NMDAR antibody positive) of the patients developed autoimmune encephalitis 2-16 weeks after herpes simplex encephalitis.[8] Two studies suggest an association with HLA-I allele B*07:02 and HLA-II allele DRB1*16:02, however more evidential proof needs to be researched.[9][10]
In the California encephalitis project, it was found out that anti-NMDAR antibodies were produced in children post-infection with mycoplasma.[11] It was attributed to the body expressing a nonspecific immune response to the pathogens leading to antibodies directed against NMDAR. Therefore, it becomes necessary to screen for concomitant autoimmune encephalitis in an unusual presentation of viral encephalitis.[12][13]
Epidemiology
Despite being recognized only 13 years ago and having an incidence of only 1.5 per million population per year, more than 1000 cases have been reported until now. It affects most age groups and both genders, with more incidence seen in females (75% cases).[4][5][14][15][16][17] Literature shows that non-White race individuals have a higher risk of ovarian teratoma, hence the lifetime risk of getting anti-NMDAR encephalitis increases in these people.[14] This association has been documented in the literature in individuals as young as three months of age.[18][19][20]
Pathophysiology
NMDAR is an excitatory glutamate receptor that, when activated, allows the passage of sodium and calcium ions through the channel. Activation occurs by the removal of magnesium plug, leading to glutamate and glycine binding to their respective sites.[21]
Evidence suggests that these antibodies are produced in the CNS by antibody-producing cells that cross the blood-brain barrier.[22] When antibodies bind to NMDAR, it causes internalization of these receptors from the cell surface leading to receptor hypofunction. The hypoactive receptors failed to cause tonic inhibition on the dopaminergic mesolimbic pathway resulting in psychosis.[21]
Iizuka et al. postulated that NMDAR is present in high density in the frontotemporal area, which atrophies in anti-NMDAR encephalitis leading to changes in behavior, learning, and memory.[23] Research utilizing a super-resolution microscopy model and Monte Carlo simulation found the importance of the interaction between NMDAR with other proteins (e.g., with EphB2R [ephrin-type B receptor 2] and other unknown interacting proteins).[24] Disruption of these interactions reproduced the observed clinical symptoms seen in patients. Drugs such as phencyclidine can mimic the symptoms of anti-NMDAR encephalitis as they are an antagonist at the receptor.
History and Physical
Anti-NMDAR encephalitis has four clinical stages.[25]
- Prodromal phase (phase 1): this stage is characterized by fever, headache, nausea, vomiting, and upper respiratory tract infection-like symptoms.[3][26][27]
- Illness phase (phase 2): During this stage, MRI abnormalities or pleocytosis can be seen, which decreases over several weeks without any visible changes in the symptoms.[6] These findings are strikingly different from the cytotoxic CD8 + T cell-mediated encephalitis, where there is an extensive neuronal loss.[28]
- Psychiatric phase- This phase lasts for 1 to 2 weeks. Children present with behavioral changes, irritability, tantrums, coma, manic symptoms, behavioral outbursts, sleep dysfunction, and hyperactivity.
- Neurological phase- This phase lasts for weeks to months. Children present with seizures (focal, motor, complex partial), dystonia, or status epilepticus.[29] Within weeks, changes in speech and language (mutism and decreased responsiveness) can be seen. Catatonia, cardiac arrhythmia, autonomic instability, hypoventilation, and uncoordinated respiration occur, which requires ICU admission. Speech dysfunction is much more commonly seen in children than autonomic dysfunction and hyperventilation.[26][30] Motor dysfunction, in addition to the typical seizures, can develop as dyskinetic movements such as orofacial dyskinesia. Young children can have ataxia or difficulty walking and even lose the ability to walk.
- Recovery phase (phase 3): Recovery has been described in the reverse order of the presentation of symptoms.[6] The slowest to improve are the cognitive and psychiatric functions.[25] With appropriate immunotherapy and multidisciplinary care, the patients can enter the recovery phase after a few months of treatment. The presence of inflammation on MRI and CSF is minimal. Antibodies can persist even after complete recovery.[31]
- Late phase (phase 4): The majority of the patients make a full recovery of cognition and behavioral abnormality at the time of hospital discharge.
Evaluation
Every child should be tested for herpes simplex virus (HSV) and other viral etiology testing can be based on time of year and geographical location. Diagnostic clues for diagnosing anti- NMDAR encephalitis are shown in figure 1. Confirmation of the clinical diagnosis requires demonstration of IgG antibodies against the GluN1 subunit of NMDAR in the serum or CSF sample.[15][32] CSF sample also demonstrates lymphocytic pleocytosis, the elevation of proteins, and CSF-specific oligoclonal bands.[33][3]
Brain MRI demonstrates bilateral T2 or FLAIR signal hyperintensities in hippocampi, frontal cortex, medial temporal lobe, cerebellar cortex, spinal cord, and medulla oblongata.[34] However, these findings were evident in only 30% of the patients in the study conducted by Titulaer et al.[35] Most commonly, the lesions present in the hippocampus, and therefore it is the main predictor of poor prognosis in patients.
Electroencephalography shows a slow continuous rhythmic and disorganized activity in delta and theta range superimposed seizures, as 90% of patients have a slowing of EEG at some point during the illness.[5][35]
Treatment / Management
Autonomic dysfunction, hyperventilation, cardiac arrhythmia, or hyperkinetic crisis can occur in children presenting with neurological symptoms. These children should be managed in the ICU. First-line treatment involves teratoma resection (if present), immunotherapy comprising of corticosteroids, intravenous immunoglobulins or plasma exchange, and supportive care.[25][32] Second-line treatment (table 1) using rituximab or cyclophosphamide is most often necessary when the patient does not have an underlying tumor.[4][3][5][36] Relapse is more common in patients without a tumor; therefore, continued immunosuppression is recommended for at least one year using drugs such as mycophenolate mofetil or azathioprine.[5][14][32] (B2)
Clonidine, trazodone, and benzodiazepines help to reverse sleep disturbances. Phenobarbital, trihexyphenidyl, and opioids can treat extreme agitation.[37][38][39][40] Methotrimeprazine or dexmedetomidine infusion prove beneficial for children with refractory agitation. Benzodiazepines manage the catatonic symptoms. A daily dose of up to 20-30 milligrams of lorazepam can be given to patients. In the absence of a response to benzodiazepines, electroconvulsive therapy can be a treatment option.[41][42] In animal models, electroconvulsive therapy has been shown to upregulate the NMDR.[43](B3)
Psychotic and behavioral symptoms are managed using typical or atypical antipsychotics. Severe dopamine blockage can exacerbate dyskinetic movements. The development of neuroleptic malignant syndrome may occur, which can complicate and misdiagnose anti NMDAR encephalitis. Quetiapine is the drug of choice for treating psychosis. Valproate works as an excellent mood stabilizer and also offers seizure prophylaxis. Gabapentin and lithium can also be used for mood dysregulation.[38][39][44](B3)
If children show no improvement with any of the above treatment modalities, mechanical ventilation, and ketamine or propofol infusion can be considered. Children under the age of 5 years are at a higher risk of precipitating propofol infusion syndrome. Vigilant laboratory surveillance is needed in children receiving propofol for longer than 24 hours.[45][46][47] Noise reduction can help to avoid agitation. Muscle relaxants concomitant to corticosteroid therapy should be avoided in children in order to prevent myopathies.[48](B3)
Resting tachycardia is one of the most common autonomic and hemodynamic instability seen in the pediatric population suffering from anti-NMDAR encephalitis.[3][5][29] Bradycardia is associated with seizures in the pediatric age group; hence round the clock, EEG is essential. Medications such as glycopyrrolate or theophylline have been shown to prevent severe bradycardia.[49] Autonomic dysfunction can manifest as fluctuating temperature and blood pressure dysregulation. Movement disorders exacerbate during a febrile state; it is essential to maintain and aggressive temperature control using antipyretics and cooling blankets.(B2)
In the third week, placement of tracheostomy and gastrostomy tubes have shown to improve patient safety and also allows to switch to lesser sedation. Once feasible, it becomes of the utmost importance, that a comprehensive rehabilitation program is begun.[50][51][52] Rehabilitation should include physical therapy, occupational therapy, and speech therapy.(B3)
Differential Diagnosis
The condition can be presented to either a neurologist or a psychiatrist. The following should be considered as differentials: Drug abuse, post-infectious syndromes (viral, Mycoplasma, pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections). Acquired reversible autistic syndrome in acute encephalopathic illness in children, immune-mediated chorea encephalopathy syndrome in childhood, acute diffuse lymphocytic meningoencephalitis, acute reversible limbic encephalitis, acute juvenile non-herpetic encephalitis, acute disseminated encephalomyelitis (ADEM), inborn errors of metabolism (including urea cycle disorders), environmental toxins and medication overdose, rheumatological conditions such as neuropsychiatric lupus and primary psychiatric conditions such as schizophrenia. Due to the extensive differential diagnosis, the patient’s diagnostic workup should be individualized.
Prognosis
In the research, Dalmau showed that 75% of the patients with NMDAR encephalitis recover entirely or with mild sequelae while the other 25% have severe CNS deficits or eventually die.[3] Some other studies have identified a similar history and symptoms in the preceding months of diagnosis, indicating that there is a lifetime risk of 12% to 24% for relapse.[53][54]
In a study using the data obtained from 382 patients aged between 1 to 85 years, Balu et al. devised a five-point predictions score, Anti-NMDAR encephalitis 1-year functioning status (NEOS) score.[22] This score uses five variables, which account for one point each. The variables are ICU admission, treatment delay of greater than four weeks, lack of clinical improvement within four weeks, abnormal MRI, and CSF WBC count higher than 20 microlitres. A score of zero or one was associated with a 3% chance of having poor functional status at one year.[22] A score of 4 or 5 was associated with 69% chances of having a poor functional condition at the end of 1 year.[22] 1-year functional status is of great importance to physicians and healthcare providers when they are discussing the prognosis with family members.
Complications
Early identification and treatment have been shown to cause less damage to the hippocampus, yet the optimal time window between symptom onset and treatment initiation is still not identified.[55] Dalmau has reported in his research that recovery develops as a multistage process that occurs in the reverse order of the appearance of symptoms.[32]
Deterrence and Patient Education
A careful look at the symptoms and identification of IgG antibodies in CSF is vital to prevent misdiagnosis in patients presenting with anti-NMDAR encephalitis. No specific biomarker exists to predict the outcomes for this encephalitis. Therefore, the dissemination of knowledge about this disorder is required for better patient outcomes.
Enhancing Healthcare Team Outcomes
Child neurologists must work in a timely manner to facilitate early screening and diagnosis. Management of patients in ICU requires a multidisciplinary approach from a team comprising of neurologists, psychiatrists, nutritionists, and physical therapists. Arrangements should be made for social workers, pastoral care, and child life experts to be actively involved in care as children and families find that helpful.
Anti NMDAR encephalitis can be easily diagnosed using serum or CSF sample testing. An index of suspicion should be raised in children, presenting with personality changes, abnormal movements or postures, seizures, autonomic instability, or hypoventilation. It poses considerable difficulty in early diagnosis and treatment. Management may also prove to be clinically challenging as it involves treating both the cause and the symptoms.
The recovery is slow; hence, long-term monitoring is required by an interprofessional team consisting of doctors, and social workers would help decreasing morbidity tremendously. A continuous follow-up by the rehabilitation and neurology team is essential. A psychiatry consultation might be needed for both patients and family members in order to cope during the recovery. Interdisciplinary communication and collaboration are quintessential to good patient outcomes with this condition.
Media
(Click Image to Enlarge)
Clues to diagnose anti NMDAR encephalitis in patients presenting with new acute onset of psychosis. Contributed by Ritika Agarwal, Adapted from Dalmua et al 2019
(Click Image to Enlarge)
Table describing the proposed therapy for treatment of Anti NMDAR encephalitis along with dosage. Contributed by Ritika Agarwal, Adapted from Remy et al (2017)
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