Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis

When patients present with clinical features of encephalitis, viral etiologies are among the primary considerations in establishing a diagnosis, with HSV-1 and EV being among the most common offending agents [3, 8, 9]. Viral testing can be time consuming and, if it is unable to reveal the cause for the patient’s condition, can leave clinicians confounded as to how to proceed with further testing or treatment. Autoimmune etiologies should be considered in the differential diagnosis, even at initial presentation.

Despite the small sample of anti-NMDAR+ patients, there are clinical features that appear to be common in patients with anti-NMDAR+ encephalitis, and which correlate with those reported in other case series describing similar encephalitic patients. While prodromal symptoms were not highly patterned in the patients in this study, others have noted a consistent ‘flu-like’ viral illness prior to or with initial presentation, though most patients herein did report fever and headache [2, 10‐18]. The progression of illness noted in this series did, however, resemble that described in other studies.

Anti-NMDAR+ encephalitic patients appear to develop a somewhat predictable course of illness, during which a number of symptoms are frequently observed. Psychiatric symptoms manifest early in the course of illness, and patients are likely to display schizophrenia-like behaviors, such as psychosis and hallucinations. This is consistent with the observation that NMDAR antagonists can cause healthy individuals to develop schizophrenia-like symptoms [19‐21]. A newly published study also revealed that antibodies from patients with anti-NMDAR receptor encephalitis cause a dramatic decrease in the number of NMDAR postsynaptic clusters in neuronal cultures, suggesting a decrease in NMDAR function [22]. Behavior and personality changes, sometimes with notable aggression, appear to be additionally remarkable in patients with this form of encephalitis [2, 10‐18, 22]. Continued decompensation is the norm in these patients, with most requiring intensive care monitoring and possibly ventilatory support. Hypoventilation, in particular, has been described as a significant feature of this illness, affecting 66% of those in a 100-patient series [22]. Other neurologic symptoms also develop in nearly every patient, including dystonias, orofacial movements, particularly oral dyskinesias, and choreoathetosis; none of these have epileptic origins. However, seizures themselves, often of a tonic-clonic nature, are common, with no correlative epileptiform discharges that permitted localization on EEG [2, 16‐18, 22]. Mental status changes, though seen in some patients at presentation, consistently developed later in the course of illness, with many patients becoming non-responsive and non-verbal, and displaying low GCS scores. Autonomic instability is almost always observed.

Specific demographic characteristics were notable among our cases and, at times, possibly as a result of the small anti-NMDAR+ sample size, at odds with previous reports. There were a larger number of males in our series, which is likely a result of the selection process. However, it may also be that males have been less readily recognized with this diagnosis, as there have been inconsistent associations with concurrent neoplasms, making clinicians hesitant to attribute symptoms to this specific cause. It is not clear whether or not these individuals would ultimately be found to have tumors, or whether, as with other autoimmune encephalitides (e.g., that are associated with voltage-gated potassium channels), a substantial percentage of patients simply did not harbor neoplasms [23, 24]. This is often difficult to ascertain, as many paraneoplastic syndromes can precede the discovery of associated tumor by years [2].

Patients were also more likely to be of Asian or Pacific Islander descent, a finding suggested by a recent publication from Japan [15]. This was surprising, given that teratomas, which are the most common tumors associated with anti-NMDAR encephalitis, demonstrate no racial bias, though malignant ones are more common among Asians [25].

In the present series, the median age was younger than that in prior studies, in which a higher percentage of patients with teratomas were identified [2, 7, 10‐18, 22]. Given the small number of subjects, it is difficult to ascertain whether the true median age for this entity is as low as 18.5 years, but it is notable that a number of subjects in the current series were children. Those as young as 5 years of age have been described elsewhere, and the median age appears to be distinctly younger than that seen among those with classic paraneoplastic syndromes [2, 14, 16]. Only 20% of those examined herein had ovarian teratomas, and, interestingly, of those without tumors, 50% had positive Mycoplasma IgM serologies. As previously reported, the significance of an isolated positive M. pneumoniae serum IgM, especially without signs of Mycoplasma IgG change or polymerase chain reaction (PCR) positivity is unknown [26]. On average, only about 10% of CEP patients have positive serology for M. pneumoniae, making this percentage higher than generally expected. This observation lends itself to the speculation that anti-NMDAR+ patients may develop encephalitis as a result of a post-infectious, antibody-mediated process such as that observed in Sydenham’s chorea or other pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAs) in which antistreptococcal-antineuronal antibodies are thought to destroy healthy nervous system cells which serve as molecular mimics [27‐29]. Because the association with M. pneumoniae is not fully understood, clinicians should be cautioned against accepting M. pneumoniae as the sole explanation for an encephalitic illness, especially if this diagnosis is based on a single IgM test.

The differentiation of anti-NMDAR+ associated encephalitis from encephalitis of viral origin on clinical grounds alone is difficult, although our study reveals that there may be some useful clues. HSV-1 patients will typically be older than anti-NMDAR+ patients, and are less likely to display severe psychiatric disturbances and schizophrenia-like symptoms. HSV-1 encephalitis patients are also not as likely to display combinations of movement disorders, such as choreoathetosis and orofacial dyskinesias, as those with anti-NMDAR encephalitis [28, 29]. Autonomic instability is not a predominant feature of HSV. Focal EEG abnormalities of the temporal lobe may also point to a viral etiology and, of course, a positive HSV PCR in the CSF is a defining feature of herpes simplex encephalitis [3, 9, 30, 31].

EV encephalitis, like HSV-1 encephalitis, is generally associated with a higher WBC count and protein concentration in the CSF when compared to patients with anti-NMDAR+ encephalitis. Neuroimaging is nonspecific in these patients, but symptomatology can play a substantial role in differentiating these two etiologies because psychiatric and focal neurologic findings will be much less likely. Patients with EV-associated encephalitis are less apt to decompensate and become non-responsive and unable to verbally communicate. Autonomic instability with subsequent ventilatory support plays a much more subtle role in EV-affected individuals and, as with HSV-1 encephalitis, EV can be detected in the CSF [31, 32].

Rabies virus cases pose a particular diagnostic challenge because behavioral symptoms can be as prominent as they are with anti-NMDAR encephalitis. Exposure history, along with diagnostic testing for rabies, is of great value. Typically, more than one diagnostic test will be required to diagnose rabies encephalitis in antemortem patients, while a brainstem biopsy alone is required in post-mortem individuals [33].

The study results do merit a few additional considerations. Reports of cranial nerve abnormalities, ataxic gait, and aphasic findings, obtained from CEP questionnaires, can be subjective in their interpretation. For example, it may be that facial nerve dysfunction and ocular deviations were, in reality, of central origin, as oculogyric crises and facial dystonias have been reported to occur in anti-NMDAR+ patients [16, 22]. Yet, despite their variable interpretation, gait, facial, and verbal abnormalities, whether of central origin or not, are noted in many cases and can assist in suggesting a diagnosis. Furthermore, though many of our positive confirmed viral cases were not tested for the presence of NMDAR antibodies, samples from 16 patients within the CEP cohort with confirmed viral etiologies were negative for NMDAR antibodies, and based on previous work by Dalmau et al. [22], the antibody is both highly sensitive and specific. It binds to a distinct region of the NMDAR. Although viral encephalitis, stroke, chronic epilepsy, and lupus have been associated with NMDAR antibodies, the region of the NR1 portion of the receptor to which the NMDAR antibodies bind appears to be uniquely associated with anti-NMDAR encephalitis, as opposed to other conditions.

The management of anti-NMDAR+ encephalitis can prove to be very effective and involves the identification and treatment of the tumor, along with immunotherapy. In a series of 100 cases, 91 were women, and 63% had a tumor, primarily an ovarian teratoma. Only 2 of the 9 men had a tumor (one teratoma of the testis and one small-cell lung cancer). Patients with prompt tumor removal and immunotherapy (e.g., steroids) had better outcomes and fewer neurological relapses than those whose tumor was not treated or who had no tumor. Nevertheless, patients of the latter groups also responded to immunotherapy. Overall, 75% recovered or had mild deficits, while 18% had severe deficits, with 7% dying as a result of the encephalitis [22].

Larger studies are needed to estimate the true incidence of anti-NMDAR encephalitis among cases that, after extensive viral screenings, have previously been considered as ‘idiopathic encephalitis,’ ‘encephalitis of unclear etiology,’ or ‘encephalitis lethargica.’ Among these, our study shows that certain clinical profiles such as “encephalitis with dyskinesias or abnormal movements” are likely to be frequently related to anti-NMDAR encephalitis. Of the approximately 20 samples tested, ten (50%) were positive, suggesting that this syndrome is a relatively common cause of encephalitis and should be routinely considered in patients with characteristic clinical features. Moreover, although the set of symptoms associated with anti-NMDAR encephalitis is highly predictable and the frequency of dyskinesias very high [34], our study likely underestimates the true incidence of this disorder by focusing on a profile based on ‘dyskinesias or abnormal movements,’ and excluding milder forms or ‘formes frustes,’ such as those associated with ‘psychiatric symptoms and seizures’ with minimal or absent abnormal movements [35].

Anti-NMDAR+ encephalitis is a recognizable, diagnosable, and treatable illness. Patients, in general, will have good outcomes, particularly with aggressive and prompt therapy. Clinicians must be aware of this condition, especially when evaluating patients with encephalitis.