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In 2005, a bizarre syndrome consisting of severe neuropsychiatric symptoms, seizures, loss of consciousness, and central hypoventilation was reported in 4 young women with ovarian teratoma (OT).
In 2005, a bizarre syndrome consisting of severe neuropsychiatric symptoms, seizures, loss of consciousness, and central hypoventilation was reported in 4 young women with ovarian teratoma (OT).1 Following the discovery of the pathologic autoantibody in 2007, anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis became a recognized autoimmune, inflammatory syndrome.2 Since then, more than 400 cases of anti-NMDAR encephalitis have been described in the pediatric age group, including children aged as young as 8 months (Table 13-11; Table 24,7,11-25). Beyond the neonatal period, this unique autoimmune encephalitis is more common than any specific form of infectious encephalitis, including the herpes simplex virus.5
Many different known autoantibodies play a pathogenic role in autoimmune encephalitides, including anti-NMDAR and voltage-gated potassium channel complex antibodies (leucine-rich glioma-inactivated protein 1 [LGI1] and contactin-associated protein-like 2 [Caspr2]).26,27 Given that the capability of definitively diagnosing anti-NMDAR encephalitis is relatively new, the exact incidence of this disorder is not well defined.
A multicenter, prospective study examining causes of encephalitis in the United Kingdom demonstrated that 4% of patients had an etiology secondary to anti-NMDAR encephalitis, rendering it the second-most-frequent cause of autoimmune-mediated encephalitis.26 Recent retrospective data from 164 Australian children determined the relative subtype frequencies of encephalitis etiologies.27 Autoimmunity was the leading cause of encephalitis, constituting 34% of all cases, followed by infectious etiologies (30%), unknown (28%), and infection-associated encephalopathies (8%). Second only to acute disseminated encephalomyelitis, anti-NMDAR encephalitis was a significant cause of autoimmune cases, constituting 6% of all patients. In addition, the State of California encephalitis registry found that anti-NMDAR encephalitis was a leading entity of all known causes of encephalitis.5
This disorder has become a well-recognized cause of autoimmune encephalitis in children and adolescents, with 40% of patients reported aged younger than 18 years. Young women are more likely to be affected and constitute 80% of all pediatric cases.4 Approximately 80% of patients with anti-NMDAR encephalitis have been reported to survive with minimal to no residual deficits.
Data from several retrospective outcome studies of patients who survived anti-NMDAR encephalitis revealed that 16% suffered serious disability within a 2-year period from onset of disease.21 Improved outcomes appear to be directly correlated with earlier diagnosis, early initiation of first-line immunomodulatory therapy (and, if needed, second-line therapy), surgical excision of OT, and absence of requirement for intensive care.
The N-methyl-D-aspartate (NMDA) receptors are neuronal extracellular membrane antigens that are found throughout the brain and play a role in synaptic transmission and plasticity that underlie memory, behavior, and learning.28 Some OTs, and rarely other tumor types, appear to stimulate and regulate production of anti-NMDAR antibodies in the tumor tissue and in the intrathecal regions of the brain.29,30 The immunoglobulin G (IgG), subclass G1, autoantibodies bind the NR1 subunit of the NMDA receptor and cause a profound (but reversible) neuronal loss of surface NMDA receptors.31,32
Anti-NMDAR encephalitis progresses through several distinct stages of illness, frequently followed by ultimate recovery.
The initial prodromal phase typically lasts from a few days to a few weeks. Prodromal symptoms typically include upper respiratory or gastrointestinal symptoms, low-grade fever, and headache. A prodromal phase may not be evident in up to half of children.4,12
Several weeks after the prodromal phase, children may present with more subtle behavioral changes, including temper tantrums and irritability, in addition to psychiatric symptoms.4,29 These symptoms may wax and wane and eventually escalate.4,33 The vast majority of patients, despite their initial presenting symptoms, develop 3 or more of the following groups of symptoms within 3 to 4 weeks of disease onset: psychiatric features, memory disturbance, speech disorder, seizures, dyskinesias, decreased level of consciousness, autonomic instability, or hypoventilation.21 Of all noted presenting symptoms, cognitive/behavioral changes, seizures, and movement disorders appear to be the most frequently noted symptoms in children.21
Often psychiatrists are urgently consulted to help manage a pediatric patient with difficult-to-manage aggression, agitation, sleep disturbances, hallucinations, psychosis, and catatonia.34,35 In the mid-to-late stages, the patient may experience auditory or visual hallucinations. Such neuropsychiatric symptoms during adolescence may prompt consideration of other mimicking entities, including drug reactions (eg, phencyclidine, ketamine, bath salts), serotonin syndrome, neuroleptic malignant syndrome, and neuropsychiatric systemic lupus erythematosus (Table 36,29,36).
Seizures are present in up to 80% of patients and are more likely to be the presenting feature of anti-NMDAR encephalitis in children as opposed to adults.4,21 In a review of 211 pediatric patients diagnosed with anti-NMDAR encephalitis, there was no ultimate difference in the general occurrence of seizures among preadolescents, adolescents, and adults.21 Seizures, either focal or generalized at onset, can be difficult to control and may prompt use of multiple antiseizure medications.12 Status epilepticus is infrequent but has been reported.37 Movement disorders such as stereotypies are often confused with seizures and continuous-video electroencephalogram (EEG) monitoring is highly recommended.38
Abnormal movements are frequently noted in anti-NMDAR encephalitis and include oral-lingual-facial dyskinesias. This is the most characteristic movement disorder and consists of semirepetitive grimacing, chewing, or biting movements.37 Additional abnormal movements include stereotypies, catatonic rigidity, chorea, dystonia of the face and limbs, and tremors.4,13,37
Autonomic nervous system (ANS) dysfunction, often manifesting with symptoms of hypersalivation, sweating, labile pulse, respiratory rate, blood pressure, and temperature instability, is less frequently noted in younger children.21 Central hypoventilation is also less prominent in pediatric cases when compared with adult-onset cases.21 Cardiac dysfunction, including episodic hypotension and dysrhythmia, occur more often in adult patients but may be present in children with this disorder.39 Dysfunction of the ANS occurs in about 40% of preadolescent children and 50% of adolescents.21 Speech dysfunction, including mutism and echolalia, occurs at the highest frequency in preadolescent children (>80% patients).
By the end of the first month, the patient alternates between periods of agitation and catatonia. During this period, decreased responsiveness typically begins and often progresses to a comatose state. In addition, seizures, abnormal movements including expressionless staring spells, extremity hypertonic rigidity, posturing, eye deviation, and autonomic instability may be prominent.4,21,29,37
CONVALESCENT AND RECUPERATION STAGES
The final stages of the disease include slow convalescence, recuperation, and, potentially, clinical relapses. Convalescence typically proceeds over the course of many weeks or months.4,21 In patients with delayed diagnosis, additional treatment with second-line immunotherapy is usually needed.4,10,29,40 Early diagnosis with undelayed initiation of appropriate immunomodulatory therapy and early excision of a teratoma appear to beneficially impact long-term prognosis, however, resulting in improved clinical outcomes and a lower likelihood of subsequent relapse.4,37
The comprehensive laboratory and imaging evaluation for a child with anti-NMDAR encephalitis requires input from pediatric neurology, infectious disease, and psychiatry. Table 429,36 lists some helpful laboratory and imaging tests when considering a differential that includes anti-NMDAR encephalitis.
Detection of NMDAR autoantibodies in serum and cerebrospinal fluid (CSF) is the diagnostic feature of anti-NMDAR encephalitis.37 The detection of anti-NMDAR antibodies in the serum or CSF is performed using a semiquantitative cell-based assay that detects specific IgG antibodies to NMDAR by indirect immunofluorescence.30
Approximately 15% of patients have positive CSF titers with concurrent negative anti-NMDAR serum antibody. Anti-NMDA receptor antibody titers appear to correlate strongly with the clinical disease course and remain elevated in those who experience a relapse or do not show primary clinical improvement.
Laboratories that routinely perform qualitative screening and subsequent reflex, quantitative levels of IgG antibodies to NMDA receptors (performed only if qualitative screen yields positive results for IgG antibodies) include the University of Pennsylvania, (Philadelphia), Mayo Clinic Laboratory (Rochester, Minnesota), and a few specialized commercial clinical laboratories including Associated Regional and University Pathologist Laboratories in Salt Lake City, Utah. Testing sample requirements often require 1 or 2 mL of CSF, uncontaminated by blood, collected in a preservative-free and anticoagulant-free standard transport screw-top tube. The tube can be kept under refrigeration for up to 2 weeks and should be transported to the laboratory under cold conditions.
No findings on magnetic resonance imaging (MRI) of the brain are pathognomonic for the diagnosis of anti-NMDAR encephalitis. However, brain MRI may demonstrate abnormalities in approximately 33% to 55% of patients.2,4,21,37 Typical MRI findings include cortical and/or subcortical T2- and fluid-attenuated inversion recovery hyperintensities seen in 1 or more of the following areas: medial temporal lobe, cerebral cortex, cerebellum, basal ganglia, or brain stem.2 The extent and location of these imaging abnormalities do not appear to have reliable correlation with clinical course. Magnetic resonance spectroscopy may show a reduced peak of N-acetylaspartate in the basal ganglia.41
The younger the patient is, the less likely that a tumor will be detected.2 Silent OTs are found in 30% of girls aged 18 years and younger and in only 9% of girls aged younger than 14 years.4 As such, pelvic and transvaginal ultrasonography is recommended for all female patients (if age appropriate) to assess for evidence of an OT. This test, if negative, is often followed by an MRI of the abdomen and pelvis, given the radiation risks of computed tomography in children.
In men, the presence of a teratoma of the testis is rare but can be evaluated with an ultrasound of the testes. This type of tumor, however, has not been reported in young boys with anti-NMDAR encephalitis.29,36 In adults, cases of nonovarian tumors have been reported with this disease.21,37
An EEG in anti-NMDAR encephalitis may demonstrate abnormalities in up to 90% of patients.21 The EEG often has nonspecific slowing or epileptiform abnormalities, such as spikes or sharp waves. In 30% of EEGs in adults (and some children) with anti-NMDAR encephalitis, a unique pattern known as “extreme delta brush” can be detected and may assist in diagnosis.12,42
The management of anti-NMDAR encephalitis should focus on providing appropriate first-line immunotherapy in addition to determining the presence of a teratoma (and if present, surgically excising it). Most patients receive empiric first-line treatment with corticosteroids and intravenous immunoglobulins (IVIGs) or plasma exchange.29 There are no comparative studies, however, assessing the relative effectiveness of these therapies.
Given that up to 40% of children do not respond adequately to first-line therapies, a treating physician should be proactive about instituting second-line therapies if there is little or no improvement within a few weeks of completing first-line treatment and surgical teratoma excision.4,10,36
Second-line immunosuppression recommendations currently include therapy with rituximab, a B-cell-depleting monoclonal antibody, and/or cyclophosphamide, an alkylating agent that interferes with DNA transcription. Several case reports and case series have illustrated the benefits of these second-line therapies in children who prove refractory to first-line therapies.4,10.25,39,43
It may take several weeks to months before the amelioration of neuropsychiatric, speech, cognition, sleep, or ANS disorders occurs.4,21,29,36
Aggressive behavior, depression, anxiety, and sleep disorders may require assistance from a child psychiatrist. Pharmacologic management of psychiatric problems can be frustrating because of poor responses to therapy in addition to a plethora of adverse effects from psychotropic medications. A combination of benzodiazepines, antipsychotics, alpha-adrenergic medications, and others may be recommended by psychiatry.34
Clinical relapse occurs in up to 25% of patients in all age groups.4,7,29 These patients may have undetected tumor, recurrent tumor, or no tumor. For this reason, older female children that have recovered from anti-NMDAR encephalitis should undergo regular tumor surveillance by ultrasound, even if there was no tumor found during the acute phase of the first episode.29 Trending serial analysis of CSF for elevated NMDAR antibody titers may be considered in cases of suspected relapse. Given that the relapse rate is high and unpredictable, there is strong argument for considering maintenance immunosuppression with a steroid-sparing agent (such as with mycophenolate mofetil or azathioprine) for up to 1 year in tumor-negative patients.29
As stated earlier, major aims of management of anti-NMDAR encephalitis include: identification and resection of any tumor (if present) at onset, early initiation of immunotherapy, and management of comorbidities (seizures, movement disorders, psychiatric symptoms). Prolonged duration of hospitalization for several months, often including management in an intensive care unit, is not unusual.21
Management of patients with anti-NMDAR encephalitis thus requires a multidisciplinary effort with close communication between team members and the patient and family. Team members include hospitalists, pediatric neurologists, psychiatrists, rheumatologists, intensivists, physical/occupational/speech therapists, social workers, and nursing staff, all working together to provide comprehensive care to the patient. After discharge from the acute setting, long-term follow-up with many of these subspecialists and the child’s primary care physician is required.44
The prognosis of patients with anti-NMDAR encephalitis is dependent on early recognition of the complex of neuropsychiatric signs and symptoms, tumor removal, and early treatment with combination immunotherapy.4,37 The recovery process typically occurs over months in a multistage fashion, occurring in reverse of the order in which the symptoms presented.29
Up to 80% of patients have substantial or full recovery, with reports of gradual, continuing improvement noted up to 2 years after initial presentation.21,29 Children with anti-NMDAR encephalitis appear more likely to have long-term dysfunction in terms of movement, speech, autonomic, and psychiatric abnormalities when compared with other causes of encephalitis.27 Many recovering patients will experience postillness amnesia with an inability to recall the majority of their acute disease course.37
Anti-NMDAR encephalitis, an autoimmune disease that may be associated with OT, is more common in females and should be suspected in any child, adolescent, or young adult who develops a rapid and persistent profound change in behavior or distortion of cognition, abnormal postures or movements, new-onset seizures, and/or signs of autonomic instability. The diagnostic test for this disorder is a 2-stage reflex titer for anti-NMDA receptor antibodies in concurrent samples of both serum and CSF. Imaging of the contents of the abdomen and pelvis by high-resolution ultrasound and/or contrast-enhanced MRI in all female patients is mandatory to exclude occult OT.
Earlier immunotherapy (and surgical excision of a teratoma) is associated with improved outcomes. Early institution of corticosteroid and IVIG therapy for anti-NMDAR encephalitis is important, but only after serum and CSF are obtained for antibody testing and infectious evaluation. Initiation of second-line medical therapy should be strongly considered if little to no improvement is noted after appropriate first-line therapy.
Death is rare (4% of all patients) in the context of anti-NMDAR encephalitis, but recovery is slow, frequently taking months. Comprehensive care of this disorder requires a multidisciplinary team approach to effectively treat all aspects of this disease.
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Dr Brenton is assistant professor of neurology and pediatrics, Department of Neurology, Division of Pediatric Neurology, University of Virginia, Charlottesville. Dr Schwartz is professor of pediatrics, Department of Pediatrics, University of Virginia School of Medicine, Inova Children’s Hospital Campus, Falls Church, Virginia. Dr Madoo is pediatric chief resident, Inova Children’s Hospital, Falls Church, Virginia. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.