Anti-N-methyl-d-aspartate receptor encephalitis affects both males and females, with a higher incidence among females (75% cases) (8, 32, 52, 59–62). Although it was originally described as a paraneoplastic disease with 58% patients showing evidence of an underlying tumor (most commonly ovarian teratoma), published literature reports only 31 and 9% of children younger than 18 years and younger than 14 years, respectively, had evidence of tumor (8, 16). As non-Caucasians have a higher incidence of ovarian teratomas, they also have higher incidence of anti-NMDAR encephalitis (32, 59). This association has been described in children as young as 3 months of age; however, most of the reported cases are adolescents (21, 61, 63, 64). In our pooled analysis, we have identified similar findings to those reported previously, with almost 70% of cases being female, an average age of 10 years, and 18% patients having a teratoma.

Despite these data, the diagnosis of anti-NMDAR encephalitis is still uncommon with many cases designated as idiopathic and possible or probable. Only 79 patients had identifiable diagnoses in the California Encephalitis Project of 761 cases, with 32 children having anti-NMDAR encephalitis (4.2%) and 30 children with enteroviral encephalitis (3.9%). Within this cohort, DuBray et al. described that 11% of children with encephalitis at her single center (compared to the entire centers in the project) occurred secondary to Mycoplasma infection, with a slightly lower incidence of 3.6% resulting from anti-NMDAR antibodies (65). Of interest, one-half of the cases with idiopathic psychiatric symptoms had antibodies against NMDAR (3, 22). This raises the question whether children with postinfectious encephalitis (i.e., HSV and Mycoplasma) and without tumor develop anti-NMDAR antibodies as parts of a larger, nonspecific immune response to these pathogens. The inciting infection may trigger antibodies directed against NMDAR, and thus, unusual presentations of viral encephalitis should be screened for concomitant autoimmune encephalitis (17, 42). Awareness of this disease and the availability of diagnostic molecular tests may improve our ability to diagnose the underlying etiologies of pediatric encephalitides.

Some authors have described anti-NMDAR encephalitis as having three clinical stages; a prodromal stage, an early (psychotic and/or seizure phase), and a late (hyperkinetic) phase (62, 66). Most interestingly, serum and CSF antibody titers seem to correlate with the disease course: a decline in titers coincides with improvement in symptoms (16). In the prodromal stage, symptoms include fever, nausea, vomiting, or upper respiratory tract infection-like symptoms (4, 22, 31, 67). This prodrome may last up to 2 weeks in 70% of patients (2, 31). During the early stage, patients may develop psychiatric symptoms such as fear, delusions, mania, and/or paranoia—manifesting in children as behavioral disturbances and tantrums rather than an underlying pathologic process. Children are more likely than adults to present with seizures, dystonia, or status epilepticus (11). Within 3–4 weeks, a more fulminant stage develops. Rapid disintegration of speech and language, hyperactivity, mutism, and irritability are often seen. Progression to decreased responsiveness, catatonia, autonomic instability, cardiac arrhythmias, hypoventilation, and uncoordinated respiration can lead to rapid deterioration and need for critical care interventions. Autonomic dysregulation and hypoventilation are less common in children than adults, while speech dysfunction appears more frequently (22, 68). During treatment, recovery has been described as reversal of symptoms in the reverse order of presentation (16).

Once clinical suspicion is raised, all patients presenting with encephalitis should be evaluated for anti-NMDAR antibodies and receive imaging studies to exclude the presence of a teratoma (62, 69). Definitive diagnosis is made by CSF evidence of anti-NMDAR antibodies. CSF studies usually demonstrate an elevated white blood cell count, lymphocytic pleocytosis in 87% of children, and oligoclonal bands in 60% of patients (16, 31, 69). In our analysis, most patients had positive serum and/or CSF antibodies to NMDAR. However, one must interpret our findings with caution as reporting bias may falsely elevate positive results. While examining for anti-NMDAR encephalitis, one should also consider other encephalitides including AMPA-R, metabotropic glutamate receptor, voltage-gated potassium channels (LGI1, CASPR2, or contactin-2), anti-Hu, anti-CV2, anti-CRM, anti-P5, anti-MA proteins, voltage-gated calcium channel defects, GABA^B-R, glycine-R, and GABA^A-R defects (53, 70, 71).

When there is high clinical suspicion for the disease, rapid treatment should occur in a stepwise fashion as confirmatory testing is not performed at some centers and may take days to weeks (62, 66). The known pathophysiology and current (low-grade) evidence suggests that starting therapy earlier may lead to better outcomes. With appropriate treatment, substantial improvement or complete recovery can occur in up to 75% of patients (4, 14). However, relapses may occur in approximately 25% of children even after resolution (8). Surgical removal of a teratoma or other tumor is necessary but should not delay initiation of definitive therapy. In our small cohort of reports that defined clinical symptom time course of presentation and resolution after treatment, there was great variation among different aged patients and response to therapies. This makes generalizations of presentation and treatment findings difficult to assess. However, from current evidence, first-line therapies have included plasma exchange, IVIG, or high-dose corticosteroids. Based on all available information, it seems that IVIG therapy with 0.4 g/kg daily for 5 days or 1 g/kg on day 1 followed by 0.5 g/kg/day for 2 additional days and methylprednisolone 1 g (adults) or 30 mg/kg (children up to 40 kg) daily for 3 days or daily plasma exchange for six cycles would likely have favorable clinical effects (Table 2). In refractory cases or critically ill patients, second-line immunomodulation with rituximab or cyclophosphamide may be attempted (2, 4, 8, 27, 31). In adults and children, combined second-line therapies of rituximab 375 mg/m² weekly for 4 weeks and cyclophosphamide 750 mg/m² monthly have been proposed (27, 51). After therapy is completed, some authors recommend yearly screening with pelvic magnetic resonance imaging to assess for ovarian tumors (8, 32, 69). Details of critical care management for individual patients were unavailable for us to define treatment benefit with individual treatment approaches. Future prospective studies should evaluate the need and indications for ICU admission, duration of ICU care, complications associated with the disease and/or treatments, and evaluation of all-cause mortality among patients with this disease.

Children with significant neurological symptoms should be initially managed in an ICU as autonomic dysfunction, airway protection, hypoventilation, cardiac arrhythmia, or hyperkinetic crisis may occur. Pediatric critical care requires an interdisciplinary team including neurologists, psychiatrists, cardiologists, nutritionists, physical therapists, social workers, physiatrists, pastoral care, and child life experts. Symptom-guided therapies are listed in Table 3.

There are two main variations of instability that require critical care management: a neurologic type with catatonic or hyperkinetic crises and one that manifests with autonomic and hemodynamic instability (10, 27, 50). Although 84% of children have hyperkinetic movements, the literature is lacking in effective therapies (8). Valproic acid, gabapentin, and lithium have been used for mood dysregulation (25, 28, 31, 72). Clonidine, trazodone, and benzodiazepines target sleep cycle dysregulation, and phenobarbital, trihexyphenidyl (Artane™), and opioids are used for extreme agitation (10, 25, 28, 30, 38, 50). For catatonia, benzodiazepines or rarely ECTs have been reported (8, 16, 51, 73, 74). Routine management of agitation may include low-dose opioids, other sedatives, anxiolytics, or anti-psychotic drugs. For refractory agitation, methotrimeprazine or dexmedetomidine infusion may be beneficial for both intubated and non-intubated patients. For continued refractory symptoms, mechanical ventilation and low-dose propofol or ketamine infusions may be beneficial, although used with extreme caution. Careful attention and laboratory surveillance are needed to avoid propofol infusion syndrome, especially for children younger than 5 years and those receiving propofol for longer than 24 hours (75–78). Barbiturates and dexmedetomidine should be used at the lowest possible dosing to avoid bradycardia. Non-pharmacological therapies (noise reduction, adjusting room ambiance) should be employed to avoid agitation. Finally, muscle relaxants should be avoided to avoid ICU myopathies, especially with concomitant corticosteroid therapy (79).

The autonomic and hemodynamic instability can be difficult to manage. Resting tachycardia is widely reported in multiple case studies of pediatric patients (4, 8, 11). However, severe bradycardia and asystole events may be exacerbated by vagal stimulation including endotracheal tube suctioning or bowel movements (36, 80). Foley catheter use, bowel regimens to prevent constipation, and careful suctioning of the endotracheal tube are essential to minimize parasympathetic stimulation. Bradycardia events were also associated with seizures in this patient population and continuous electroencephalogram should be considered to capture these events (81).

Chronic use of medications such as glycopyrrolate or theophylline may be considered for preventing severe bradycardia; these medications have been successful in other disease processes to prevent symptomatic bradycardia (82). If severe bradycardia is frequent and unresponsive to medical therapies, an implantable pacemaker may be considered (83). Brain imaging to diagnose hydrocephalus may be indicated with new onset of bradycardia events in some patients (69).

Autonomic dysfunction also manifests as impaired temperature or blood pressure regulation. While patients are maintained on immunosuppressant therapies, infectious etiologies for hypothermia/hyperthermia must be considered. We have observed that movement disorders are often exacerbated during the febrile state; aggressive temperature control should be implemented with antipyretics, environmental cooling, and cooling blankets as indicated.

Hypoventilation in ICU patients with anti-NMDAR encephalitis may make it difficult to wean from mechanical ventilation. Ventilator weaning in these patients is further complicated by delirium, agitation, and movement disorders that may require heavy sedation. Placement of a tracheostomy and gastrostomy tube in the third week after diagnosis may improve patient safety and allow for less sedation and earlier rehabilitation.

Once medically feasible, it is paramount to begin a comprehensive rehabilitation program including physical, occupational, speech, and dysphagia therapy to improve long-term outcomes (24, 84). Functional decline in motor skills and cognition is common among patients with anti-NMDAR encephalitis and physical therapists with physiatrists should be engaged early in their management.

The available heterogeneous data impose methodological limitations for pooled analysis. Thus, one weakness of this review is the lack of statistical analysis for successful treatment or prognostic indicators. Our recommendations are limited to available low-grade evidence. However, this study provides a first step toward conducting randomized controlled trials to evaluate the efficacy of potential therapies.