Each antibody positive case is described, while the negative cases are summarized in Table 1. Psychiatric disorders, behavioral disorders, movement disorders, or sleep disorders are mainly presented. The DSM-IV diagnostic codes are included. The details of the clinical characteristics of the representative 3 cases of each group are presented in the text. Ten cases were anti-NMDAR antibody positive; 3 of 5 cases of typical encephalitis (group A), 3 of 5 cases with a broader range of psychiatric disorders including narcolepsy (group B) and 4 of 51 cases with schizophrenia or schizo-affective disorders (group C).

(Group A) Typical clinical pictures of anti-NMDAR encephalitis

We reviewed a case of acute limbic encephalitis (NMDAR antibody was detected retrospectively) diagnosed after improvement of psychotic symptoms by mECT. This case was first diagnosed as schizophrenia based on catatonia-like symptoms, auditory hallucinations, and delusions. Two other positive cases presented with psychosis, convulsions and were treated with steroid pulse therapy.

Case report

The patient (case 3) was a 27-year-old female and had no previous psychiatric, neurological, or family history of the disease. After a common cold, the patient had hypobulia, insomnia, and seizure-like episodes. In addition, the patient exhibited strange and incoherent behaviors. During her first visit to our department, she was substuporous. After hospitalization, the existence of auditory hallucination and persecutory delusions were also strongly suggested. Blood examinations, brain MRI, and EEG showed no abnormality. Therefore at first we diagnosed the patient as having acute schizophrenia. Since her psychotic symptoms were refractory to antipsychotic medication and adverse effects were severe, we applied mECT. The psychotic symptoms improved remarkably by this treatment. Accessibility was also improved, and we were able to identify various neurological and psychiatric symptoms including aphasia, agraphia, constructional apraxia, retrograde amnesia, personality change, and disinhibition. Laboratory examinations involving CSF and brain SPECT were performed. Brain SPECT showed decreased blood flux in her left limbic system and in the inside of the left temporal lobe. From the symptoms, clinical course, rareness of abnormality in various examinations, and the findings of brain SPECT, we diagnosed her as having limbic encephalitis. Thereafter her symptoms naturally improved without antipsychotics, and her mental condition has been kept stable and healthy.

Because her clinical picture resembled that of the recently reported anti-NMDAR encephalitis, we examined the possible association. An archived plasma sample from her initial presentation was submitted to Kanazawa Medical University, where the antibody against NMDAR was detected in the sample; the final diagnosis was anti-NMDAR encephalitis. Examinations for tumors were not performed at initial hospitalization.

The discrimination between functional (endogenous) psychosis and NMDAR encephalitis is sometimes very difficult. Therefore, we have to consider the possibility of anti-NMDAR encephalitis, especially when relatively young women are suffering acutely from psychotic symptoms.

We provided immunotherapy in case 1 and 2 but not in case 3 because non-herpes limbic encephalitis was initially suspected for the former two cases.

Another two subjects presented typical clinical pictures of anti-NMDAR encephalitis, beginning with psychotic symptoms, followed by seizures and subsequent disturbances of consciousness. However, these two subjects with similar clinical pictures to case 3 were negative for the anti-NMDAR antibody (Table 1, group NA).

(Group B) Narcolepsy cases with severe psychosis

We had previously reported a case with Parkinson’s disease (PD) comorbid with hypocretin (orexin) deficient narcolepsy [16, 17]. In this patient, severe psychosis presented subsequently to the diseases above, and has been treated by mECT in addition to anti-psychotics with a successful outcome. NMDAR antibody was detected retrospectively. The two other positive cases had narcolepsy with severe psychosis without neurodegenerative disease.

Case report

A 58-year-old male (case 4) with mild PD for 15 years was admitted to a hospital due to a sleep attack in 2004. He suffered from excessive daytime sleepiness (EDS) at high school, however, the patient had not been diagnosed or treated at that time. The patient had never had cataplexy (sudden loss of muscle tonus due to emotional trigger). At age 43, the patient had tremors in his left fingers and at age 45 was diagnosed with PD. The patient was hit by a motor vehicle due to EDS at age 55 and started experiencing frequent hypnagogic hallucinations with abnormal limb movements. The patient had Hoehn-Yahr stage 2 Parkinsonism and scored 14 in the unified PD rating scale part III. His epworth sleepiness scale result was 19/24 (normal range < 11/24). In the multiple sleep latency test (MSLT), mean sleep latency was shortened to 2 min (normal range >8 min) and sleep onset REM periods were present in all four naps. HLA was positive for DR15 (2) as typical for idiopathic narcolepsy. CSF hypocretin (orexin) concentration was very low (86 pg/ml, normal range >200 pg/ml). The patient was treated with methylphenidate (MPH) for EDS in addition to medications for PD. During the next two years, his condition was good. Thereafter, the patient became delusional and suffered from auditory hallucinations. MPH and medications for PD were stopped, and anti-psychotics were used. However, the serious psychotic symptoms persisted. Finally the patient was treated by mECT in addition to anti-psychotics with a successful outcome. The patient is now continuously treated with anti-psychotics and maintenance mECT every month. Later, at 63 years old, the NMDAR antibody was detected in both the serum and the CSF of this patient. The hypocretin level in the CSF sample (92 pg/ml) was unchanged from the time of his diagnosis.

We found that 2 other narcolepsy patients (among 5 examined), who had severe psychotic symptoms occurring 3 to 30 years after the onset of narcolepsy, were positive for the antibody (Table, group B). These cases were hypocretin deficient, but no significant encephalitis signs except predominant psychotic symptoms, were noted. They were under stimulant medications, and their hallucinations and delusions were unchanged when the stimulants were withdrawn. Antipsychotics (3 out of 3 cases) and mECT (one case) were required to manage the psychotic symptoms.

We also tested anti-NMDAR antibody in 10 hypocretin deficient narcolepsy patients without psychotic symptoms, and found 2 antibody positive patients (15/f, 22/f). Although antibody positive cases were found both in narcolepsy with and without psychotic symptoms, an increase in antibody positivity in the patients with psychotic symptoms was suggested (p = 0.025, Chi-square test).

(Group C) Psychiatry cases

In addition to these cases, we also found 4 antibody positive patients out of 51 patients with schizophrenia or schizo-affective disorders (group C). The neurological symptoms were mild in these cases, and mECT was effective in 3 cases. These 4 cases were female, two cases had convulsions (cases 7, 8), and two cases had ovarian tumors (cases 8, 10).

Case report

A 26-year-old female patient (case 10) had normal development during childhood [19]. She had no problems with friendships in elementary school and junior high school. She was aware of depressive symptoms when she was 16 years old, although she had no emotional stress. She was diagnosed with depression and received antidepressants from a clinic. Her diagnosis was changed to bipolar disorder because the patient presented a hypomanic episode at age 17. After that, her mood was stable and treatment was discontinued.

The patient had insomnia and hypobulia at age 22. The patient tried to jump out of a window (of the upper floor), and thus she was transferred to a closed ward. In this hospital, the patient exhibited a variety of symptoms including delusions of persecution and observation, self-injury (head banging) and substupor. There were no specific findings on brain MRI. The patient subsequently was treated with various anti-psychotics based on a schizophrenia diagnosis, however she was only in partial remission.

The patient had been treated with mECT (a total of ten times) since she was 23 years old, and her symptoms almost disappeared. Therefore her therapy focused on mECT, and she was transferred to our hospital. mECT was needed every other week continuously. The patient complained of atypical genital bleeding at age 24 years old, and an ovarian tumor was detected by abdominal ultrasonography. Pelvic MRI showed a cystic tumor in the right ovary with low T1 and high T2. The diameter and length were 4.7 × 3.4 cm and 4.3 cm, respectively.

She was positive for anti-NMDAR antibody. The patient underwent oophorectomy at age 26 years. The pathological diagnosis was ovarian cyst without teratoma. After the operation, she has been treated only with oral medication (antipsychotics) and follow-ups.

This patient showed atypical clinical history as a schizophrenic and resistance to pharmacological treatments, but responded relatively well to mECT. The percentage of NMDAR positive cases of this group C (4 out of 51 cases) is similar to that of Zandi’s report (3 out of 46 cases).