We report four Japanese women who were initially diagnosed with juvenile acute nonherpetic encephalitis,13
a disorder for which an etiology has remained unknown until now. Their clinical pictures had such similarity with the recently reported anti-NMDAR encephalitis in patients with ovarian teratoma11
that it led us to investigate this possible association. Hence, using sera and CSF archived since the time of symptom presentation, up to 7 years ago, we have now confirmed the presence of NMDAR antibodies in all patients. Analysis of the target antigens was performed as previously reported, demonstrating high expression in the hippocampus, detectable with immunohistochemical but not immunoblot techniques, expressed on the cell surface of neuronal cultures, and the identity unambiguously established with immunocytochemistry of HEK293 cells transfected to express functional NR1/NR2B heteromers of the NMDAR.11
In addition, the antibody binding required the presence of NR1 (NR1 dependent), differentiating these antibodies (NR1/NR2B) from the less-specific antibodies reported against linear epitopes of NR2B.11
These findings provide strong evidence of an immune mediated etiology for juvenile acute nonherpetic encephalitis.1–5
The detection of antibodies to NR1/NR2B also led to the subsequent demonstration of pelvic tumors in three patients, all with pathologically confirmed mature ovarian teratoma containing neural tissue. The experience gained from the close clinical monitoring and long-term follow-up of these cases has important implications.
The clinical features of these patients emphasize the concept that antibodies to NR1/NR2 heteromers of the NMDAR associate with a characteristic syndrome that develops in several predictable stages. The disorder usually presents with a prodromic episode of fever, headache, or malaise, followed a few days later by mood and behavioral changes (sometimes severe short-term memory loss), psychiatric symptoms suggesting schizophrenia or catatonia, decline of level of consciousness, hypoventilation, hyperkinesias, and eventual recovery or death. Compared with previously reported patients,11,12
whose tumors were removed at early stages of the disease, none of our patients had early tumor removal.
Recently, the “NMDAR hypofunction hypothesis” of schizophrenia has emerged primarily based on observations that NMDAR antagonists exacerbate psychiatric symptoms in schizophrenia and induce schizophrenic symptoms in healthy individuals whereas agents that enhance NMDAR function ameliorate schizophrenic symptoms.17–22
The psychomimetic effects of NMDAR antagonists have been attributed to the functional blocking of NMDAR in presynaptic γ
-aminobutyric acid–mediated (GABAergic) interneurons of the thalamus and frontal cortex, causing a decrease of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal cortex, and glutamate and dopamine dysregulation.22
Although NR1/NR2 heteromers are expressed in the entire nervous system, the main epitope targets of patients with NMDAR autoimmunity are contained in NR1/NR2B heteromers.11
These are preferentially expressed in the adult forebrain, including the prefrontal cortex, hippocampus, amygdala, and hypothalamus, all structures involved in our patients (figure e-3). Therefore, we postulate that NMDAR antibodies may cause inhibition, rather than stimulation, of the NMDAR, contributing to the development of schizophrenia-like symptoms.
Central hypoventilation is an important feature of anti-NMDAR encephalitis, having been reported in 14 of 17 cases (82%), including our 4 patients.11,12
When we temporarily turned off ventilatory support, spontaneous breathing did not return, but the orofacial-limb dyskinesias persisted, suggesting that the hypoventilation was independent of the dyskinesias. Of interest, NR1 knockout animals die of hypoventilation.23
Because reactivity of patients’ antibodies depends on the presence of NR1 subunits,11
the frequent hypoventilation of patients with this disorder can be explained by the immune response. In fact, recent studies demonstrate that patients’ antibodies react not only with NR2B, but also with NR1, and that the reactivity with NR2B largely depends of coexpression of functional NR1/NR2B heteromers (Dalmau et al., unpublished data).
The long-lasting dyskinesias of our patients posed a major clinical problem. They presented gradually as orolingual dyskinesias with athetoid postures, and evolved to intractable bizarre involuntary movements, some of which resembled complex partial seizure status epilepticus or a psychogenic disorder. Extensive monitoring with EEG showed absence of paroxysmal discharges, suggesting that the movements were not epileptic. After unsuccessful trials with multiple antiepileptics and sedatives, the dyskinesias responded to propofol and midazolam. The mechanism of these dyskinesias remains unclear. Although one may consider the possibility of a side effect of the antipsychotic medication, many patients with anti-NMDAR encephalitis (even those who do not receive antipsychotics as our patients) develop dyskinesias, suggesting that they are part of the immune disorder.11
We do not have neuropathologic studies in the present patients, but other Japanese patients with similar encephalitis2,3
had pathologic findings closely resembling those of patients with anti-NMDAR encephalitis.11
These studies emphasized the paucity of inflammatory infiltrates relative to the severity of the neurologic deficits.1,3
These findings, the normal or mild changes in the initial MRI of our patients, and preservation of drug-induced fast EEG activity (implying that cortical oscillations mediated by GABAergic inhibitory interneurons are preserved)24,25
all concur with the potential reversibility of anti-NMDAR encephalitis.
Our study indicates that anti-NMDAR encephalitis and juvenile acute nonherpetic encephalitis or a subgroup of this disorder are the same. The reasons why this disorder is more frequent (or has received more attention) in Japan are unclear. The 4 patients reported here were seen in the past 8 years at a single institution. Another 11 patients with a similar syndrome were reported from another institution (antibodies to NR1/NR2 heteromers were not studied).1
These experiences, as well as the fact that some patients survive without recognizing the tumor and others may die without a diagnosis (i.e., some cases11
were diagnosed postmortem), suggest that the frequency of anti-NMDAR encephalitis is underestimated.
Our findings raise two questions. First, how often is anti-NMDAR encephalitis paraneoplastic? After a rapid increase of the number of identified cases, we have found that 26 of 33 patients (79%), including 3 reported here, had tumors or cysts usually in the pelvic region (20 pathologically confirmed teratomas of the ovary, 1 in the mediastinum, and 5 ovarian cysts under study). No tumor has been identified in the other 7 cases (3 of them men), who are being closely followed up for a possible occult neoplasm (Dalmau et al., unpublished data).
Second, is it necessary to remove the tumor or use immunotherapy to treat this disorder? A previously reported patient (Case 8 of reference 11
) and the current four patients demonstrate that the disorder may resolve without tumor removal. However, the duration of intensive care and ventilatory support in two of these patients (6 to 9 months) was significantly longer than that of all known cases that had tumor resection and immunotherapy (median 12 weeks, longest time of ventilation 4 months). Furthermore, the severity of this disorder, which may result in death or severe complications, and the reported responses to tumor resection and immunotherapy strongly support the use of these treatments.
Anti-NMDAR encephalitis is different from other types of paraneoplastic encephalitis in several ways: it results in a highly characteristic syndrome, usually affects young women, is treatment responsive, and associates with tumors that can be benign. Another difference shown here is that despite the presence of the tumor, the immune response is not maintained. This brings into consideration a contributory role of the prodromal “viral-like” disorder, which by itself or in combination with a teratoma sets off or enhances the autoimmune response. The answers to these questions will come from more experience and work in progress to model the disorder.