Pediatric Annals

Special Issue Article 

Pediatric Anti-NMDA-R Encephalitis: Presentation, Diagnosis, and Management

Karyn Gerstle, MD, MPH; Moon Hee Hur, MD; Taha Moussa, MD

Abstract

Immune-mediated encephalitis is the most common cause of encephalitis after infection in children and adults. Although this disease process was identified nearly 20 years ago, the variety of clinical presentations and the lack of specific diagnostic criteria can make the identification of anti-N-methyl-D-aspartate receptors (NMDA-R) encephalitis challenging. Moreover, identifying NMDA-R antibodies in blood or cerebrospinal fluid can take days to weeks, and thus clinicians need to have a high index of suspicion to investigate for this disease in patients who may appear to have an overlap of neurologic and psychiatric symptomatology. In this article, the authors describe three illustrative cases of anti-NMDA-R encephalitis in children age 3 to 16 years. The discussion reviews our current understanding of the clinical presentation, diagnostic criteria, and inpatient therapeutic management of anti-NMDA-R encephalitis, as well as illuminates the unique and often perplexing presentations of this disease process versus other organic and psychiatric causes of altered mental status. [Pediatr Ann. 2019;48(10):e387–e390.]

Abstract

Immune-mediated encephalitis is the most common cause of encephalitis after infection in children and adults. Although this disease process was identified nearly 20 years ago, the variety of clinical presentations and the lack of specific diagnostic criteria can make the identification of anti-N-methyl-D-aspartate receptors (NMDA-R) encephalitis challenging. Moreover, identifying NMDA-R antibodies in blood or cerebrospinal fluid can take days to weeks, and thus clinicians need to have a high index of suspicion to investigate for this disease in patients who may appear to have an overlap of neurologic and psychiatric symptomatology. In this article, the authors describe three illustrative cases of anti-NMDA-R encephalitis in children age 3 to 16 years. The discussion reviews our current understanding of the clinical presentation, diagnostic criteria, and inpatient therapeutic management of anti-NMDA-R encephalitis, as well as illuminates the unique and often perplexing presentations of this disease process versus other organic and psychiatric causes of altered mental status. [Pediatr Ann. 2019;48(10):e387–e390.]

In 2007, antibodies against functional N-methyl-D-aspartate receptors (NMDA-R) located in the hippocampus and forebrain were identified in 12 cases of paraneoplastic encephalitis in women.1 The people who presented with a constellation of symptoms, including behavior changes, speech disorders, seizures, and memory deficits, were among the first recognized cases of the newly named anti-NMDA-R encephalitis. Subsequent studies also documented this disease in children, and some research studies suggest that anti-NMDA-R encephalitis may be more common in children than adults.2 It usually presents with acute/subacute symptoms of seizure, behavior, cognition, movement, speech, and memory disorders. Seizure and movement disorders are more frequently the initial presentation in young patients (Table 1).2,3 However, behavior, memory, and cognitive deficits are more common in older patients (age 18 years and older).2,4 Although children often present with unique symptoms as compared to adults, a recent review showed the safety and benefit of electroconvulsive therapy (ECT) in both pediatric and adult population.5,6 The illustrative cases in this article describe three patients who did not respond to first- and second-line aggressive immunotherapy, but who eventually had varying degrees of improvement of severe symptoms when clinicians used a combination of ECT and immunotherapy.

Key Differences Between Pediatric and Adolescent/Adult Presentation of Anti-NMDA-R Encephalitis

Table 1:

Key Differences Between Pediatric and Adolescent/Adult Presentation of Anti-NMDA-R Encephalitis

Illustrative Case 1

A 16-year-old girl with no significant past medical history presented with episodes of crying, laughing, and perseveration in speech. She was initially treated with antipsychotics and developed acute onset of rigidity, autonomic changes, and elevated creatine kinase (CK). She was then suspected to have neuroleptic malignant syndrome, but her autonomic instability, rigidity, mutism, and cognitive dysfunction persisted despite normalization of her CK and temperature. During this time, the patient was undergoing extensive laboratory testing of the etiology of her symptoms, which included evaluation for underlying neurologic condition, inflammatory/infectious causes of encephalitis, and primary psychiatric disorder. Positive results for NMDA-R antibodies in her cerebrospinal fluid (CSF) were received 2 weeks after her initial evaluation. In the meantime, she was treated empirically for suspected autoimmune encephalitis. Her treatment included 5 days of high-dose methylprednisolone (30 mg/kg/day, maximum dose 1 g/day) followed by a steroid taper, as well as plasma exchange (one cycle every other day for five total cycles), then by intravenous immunoglobulin (IVIG) (2 g/kg). She continued to have altered sensorium, so rituximab treatment was also given. Despite this aggressive treatment with immune modulators and anti-epileptics (lorazepam and leviteracetam were started on day 5 of hospitalization after seizures were observed), she continued to show signs of malignant catatonia. She then received eight ECT treatments (Monday, Wednesday, and Friday for 2 weeks and then Monday and Wednesday during week 3) and her Bush-Francis Catatonia Rating Scale (BFCRS) decreased from 27 to 21. After an additional week of physical therapy, she was discharged from the hospital on melatonin, levetiracetam, tapering doses of prednisone, and lorazepam. Her verbal abilities and communication skills appeared normal at her 6-week follow-up appointment.

Illustrative Case 2

A 6-year-old boy with no significant past medical history presented with intractable seizures requiring pediatric intensive care unit admission. He then developed muscle weakness, altered gait, mutism, and lethargy. Infection and underlying connective tissue diseases were ruled out, and his blood and CSF samples eventually confirmed positive anti-NMDA-R antibodies. He received intense first-line immunotherapy, which included two rounds of pulse methylprednisolone for 5 days each, seven cycles of plasma exchange, and IVIG (2 g/kg) every 2 weeks. He also received second-line immunotherapy, which included two doses of rituximab plus one dose of cyclophosphamide, because of the severity of his presentation. He then received 11 ECT treatments for persistent catatonia, and his BFCRS decreased from 15 to 10. He was transferred to an inpatient rehabilitation facility for intensive physical, occupational, and speech therapy. Despite intensive immunotherapy, ECT, and rehabilitation, the patient continued to have severe altered mentation and significantly depressed motor ability, so he was started on another second-line immunotherapy agent, mycophenolate mofetil, in addition to his monthly IVIG treatments. Although he had improvement in motor skills, he continued to have significant decline in cognitive ability and remains mute.

Illustrative Case 3

A 3-year-old, previously healthy boy, presented with emotional lability, frequent episodes of leg extension and stiffening, and nonrhythmic movements 10 days after a new seizure diagnosis that was being managed with levetiracetam. He was found to be positive for anti-NMDA-R antibodies in both serum and CSF. He was then started on first-line immunotherapy with pulse steroids, IVIG, and plasma exchange. Although he had significant improvement in motor function and mentation, he still had mood lability, agitation, and posturing, so he was started on second-line immunotherapy with rituximab. Posturing with stereotypic facial grimacing persisted, and he was diagnosed with agitated catatonia and given eight ECT treatments over the course of 3 weeks. His BFCRS decreased from 17 to 3.

Differential Diagnosis

The differential diagnosis for anti-NMDA-R encephalitis is broad and includes central nervous system infections (eg, herpes simplex or West Nile virus encephalitis), vasculitis, acute demyelinating encephalomyelitis, malignancy, toxic or drug ingestion (eg, phencyclidine, ketamine, bath salts), nonconvulsive status epilepticus, neuroleptic malignant syndrome, inborn error of metabolism, or primary psychiatric disorders.7

The presence of anti-NMDA-R antibodies in serum or CSF confirms the diagnosis. CSF studies are more sensitive than serum studies, and about 15% of patients who have positive CSF antibodies have negative serum studies. Cell count may show lymphocytic pleocytosis with mild elevation in protein.7,8

Electroencephalogram (EEG) may show focal or diffuse slowing with periodic lateralizing epileptiform discharges and extreme delta brush, which is an EEG pattern unique to this condition that shows rhythmic delta wave activity at 1 to 3 Hz with superimposed bursts of rhythmic beats of 20 to 30 Hz beta frequency.9 A magnetic resonance imaging (MRI) of the brain can show cortical or subcortical T2 hyperintensities with or without meningeal enhancement, but is most commonly normal.7 Females are at risk for tumors related to anti-NMDA-R encephalitis. Ovarian teratoma is the most common, but extra ovarian teratoma and other tumors (lung, breast, testis and thymus carcinoma) have also been reported.2 Pelvic imaging (MRI or transvaginal/testicular ultrasound) is recommended given the association of anti-NMDA-R encephalitis presenting as a paraneoplastic syndrome in patients with ovarian teratomas and testicular tumors.10

Treatment Modalities

Treatment for anti-NMDA-R encephalitis always involves immunotherapy, but the intensity of treatment is dependent on the severity of symptoms at presentation and initial clinical response. Symptoms requiring intensive care unit admission are classified as severe. Possible underlying infectious etiology must be ruled out before starting immunotherapy. First-line immunotherapy includes high-dose corticosteroids, IVIG, and plasma exchange, as it has been shown that a decline in the autoantibody titers correlates with improvement in symptoms (Table 2). It is important to start treatment early if there is a high suspicion for anti-NMDA-R encephalitis as earlier immunotherapy has been associated with better outcomes and antibody testing can take several days to confirm.11 Second-line immunotherapy includes rituximab, with duration determined by clinical response.12,13 Other second-line immunotherapy agents (cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and methotrexate) were tried but with uncertain benefit. Patients who received second-line immunotherapy had a lower relapse rate, as did patients with an encephalitis-related tumor (after surgical removal).2 ECT, especially for catatonia, was effective in both pediatric and adult patients regardless of their immunotherapy,14 and clinical response can be measured using the BFCRS.14,15 A multidisciplinary approach, including hospitalist, neurologist, psychiatrist, rheumatologist, physical/occupational/speech therapist, social workers, and nurses, is imperative to treatment.8

Current Treatment Modalities for Anti-NMDA-R Encephalitis

Table 2:

Current Treatment Modalities for Anti-NMDA-R Encephalitis

Care after Discharge

Although patients often have improvement of symptoms within 4 weeks of initiation of intensive immunotherapy, most studies have found that a majority of patients continue to have some degree of motor, neurologic, or memory deficit at the 18-month and 24-month follow-up appointment.9 In addition, Barbagallo et al.6 found that about 15% of patients can have relapse of neurologic symptoms including behavior changes and seizures, and these symptoms may be milder than at initial presentation. Given the risk of relapse, some have recommended annual tumor surveillance for female patients.11,16–18

Conclusion

Patients with anti-NMDA-R encephalitis have a good prognosis if they are diagnosed early and started on appropriate immunotherapy treatment.2 There is limited evidence to demonstrate long-term effectiveness of current treatment modalities. In the acute phase, first-line immunotherapy with high-dose steroid, IVIG and plasma exchange alone, or combined, has shown symptom improvement after as little as 4 weeks of treatment. Conventional clinical neurological assessment and standard diagnostic tests (MRI, EEG, and CSF studies) are reasonable approaches to diagnose probable anti-NMDA-R encephalitis and begin empiric treatment. Antibody testing or response to immunotherapy are late diagnostic criteria, and early treatment is thought to improve outcomes. For patients with anti-NMDA-R encephalitis who present with catatonia refractory to benzodiazepines, ECT can be an effective additional treatment modality, even in younger patients.14 To prevent a delay in treatment and optimize prognosis, anti-NMDA-R antibody-associated encephalitis should be considered in all patients who present with unexplained altered mental status.

References

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Key Differences Between Pediatric and Adolescent/Adult Presentation of Anti-NMDA-R Encephalitis

Younger Than Age 12 Years Older Than Age 12 Years

Seizures Behavioral changes
Movement disorder Memory problems
Speech disorder Cognitive deficits

Current Treatment Modalities for Anti-NMDA-R Encephalitis

First-Line Immunotherapy Second-Line Immunotherapy Additional Treatment Option
Pulse steroids, 30 mg/kg (maximum 1 g) once daily for 3–7 days followed by 2 mg/kg (maximum 60 mg) with biweekly tapering (consider gastric protection accordingly), calcium (1,000 mg/day orally), vitamin D (1,000 IU/day orally) IVIG 2 g/kg (maximum 70 g) biweekly for 5 doses, then monthly for three doses Tissue plasma exchange 5–7 cycles every other day Rituximab 500 mg/m2 for two doses, 2 weeks apart (check for complete B cell/CD20 depletion) Bilateral ECT for 6–12 treatments 3 times per week (eg, Monday, Wednesday, Friday); exact course of treatment will depend on response
Authors

Karyn Gerstle, MD, MPH, is a Postgraduate Year 3 Pediatric Resident. Moon Hee Hur, MD, is a Postgraduate Year 4 Pediatric Neurology Fellow. Taha Moussa, MD, is a Postgraduate Year 7 Pediatric Rheumatology Fellow. All authors are affiliated with The University of Chicago.

Address correspondence to Moon Hee Hur, MD, The University of Chicago Medicine, 5841 S. Maryland Avenue, Room J-141, MC1052, Chicago, IL 60637; email: MoonHee.Hur@uchospitals.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20190917-01

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