Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal

Abstract

Objective: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection.

Methods: We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present.

Results: All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically).

Conclusion: 1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.

Figure 1

Static video clip images and of Patient 3 This patient gradually developed orolingual dyskinesia and athetoid dystonic postures (A), followed by bizarre involuntary movements including, clenching of the teeth (B), disconjugate ocular deviation (B, covered by black bar), rhythmic contractions of upper extremities synchronized with orofacial dyskinesias (B), unsynchronized arrhythmic wiggling of the hands (C), and forceful jaw opening (D). Panel D shows four sequential static video images taken every 0.5 seconds revealing continuous jaw opening movements mimicking jaw-opening dystonia. Video clips were recorded on the 3rd day of the hospital stay (A), the 23rd day (B), the 35th day (C), and the 32nd day (D). Serial fluid-attenuated inversion recovery MRI shows progressive brain atrophy in the mesiotemporal and frontal lobes (E, F, G). Brain MRIs were obtained on the 4th day (E), 48th day (F), and 11th month after admission (G).

Figure 2

Antibodies to NR1/NR2 heteromers of NMDA receptor Panels A and C show nonpermeabilized cultures of hippocampal neurons incubated with sera of Patients 1 (A) and 3 (C) obtained at the time of symptom presentation. Panels B and D are similar cultures incubated with sera from the same patients obtained at follow-up 7 years 3 months and 6 years later. Note that sera obtained at the time of symptom presentation show intense immunolabeling of the cell surface of neurons and neuronal processes, whereas sera obtained at follow-up are not reactive. Insets correspond to sera from the same patients incubated with HEK293 cells expressing NR1/NR2B heteromers of the NMDA receptor. Sera from the time of symptom presentation (insets in A and C), but not from follow-up (insets in B and D), react with cells expressing NR1/NR2B heteromers (green cell membrane and cytoplasmic staining). The expression of NR1/NR2B heteromers was confirmed with double labeling with commercially available antibodies to NR1 and NR2B (not shown). Sera from controls (blood donors, lupus, and ovarian teratoma patients without encephalitis) did not show any reactivity with neurons or NR1/NR2B expressing cells (not shown). The methods used for these assays are identical to those previously reported. In all studies, sera were used at a dilution of 1:250. Immunofluorescence technique (A through D ×800, oil lens); all insets ×400. Nuclei of neurons and HEK293 cells visualized in blue with 4′,6-diamidino-2-phenylindole (DAPI).

Figure 3

Pelvic MRI of the patient obtained 4 to 7 years after symptom An ovarian tumor is demonstrated in three patients (Patients 1, 2, and 4) on T1-weighted fat suppression images (FSIs, A), T1-weighted MRI (out-of-phase image, B), and T2-weighted MRI (C, arrows). Note that the T1-weighted hyperintensity in the tumors was suppressed on FSI, indicating the presence of fat, compatible with ovarian teratoma. In Patient 3, the T1-weighted hyperintensity in the left ovary was not suppressed on FSI (arrowhead), suggesting a follicular or corpus luteum hemorrhage; however, the possibility of bleeding from a cystic teratoma cannot be completely ruled out. No calcification was found on pelvic CT (not shown).