Clinical Aspects of Anti-NMDA Receptor Encephalitis

Paraneoplastic limbic encephalitis (PLE) is a rare neurological syndrome characterized by short-term memory impairment, seizures and various psychiatric disturbances. It is often associated with small-cell lung cancer, germ-cell tumors of the testis and breast cancer, but rarely with ovarian teratomas (Gultekin et al., 2000). Several cases of PLE with ovarian teratomas had been reported in Japan (Okamura, Oomori, and Uchitomi, 1997; Nokura et al., 1997), but the autoantigens in this disease remained unknown. In 2005, Dalmau et al. reported an antibody to the membranes of neurons of the hippocampus (antigens colocalized with exchange factor for ADP-ribosylation factor 6 A (EFA6A)) in association with PLE and ovarian teratomas (Ances et al., 2005; Vitaliani et al., 2005). We sent samples from a patient suffering from limbic encephalitis with an ovarian teratoma to Prof. Dalmau’s Laboratory in November 2005. They identified antibodies to the antigens colocalized with EFA6A in our patient’s samples (Figure 1) (Shimazaki et al., 2007), and in another Japanese one (Koide et al., 2007). Their further analysis of the antibodies disclosed that were ones against NR1/NR2 heteromers of N-methyl-D-aspartate (NMDA) receptors. They diagnosed and reported twelve women (including our case) as having ‘paraneoplastic anti-NMDA receptor encephalitis associated with an ovarian teratoma’, the cases developing prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and a decreased level of consciousness often requiring ventilatory support (Dalmau et al., 2007). After this publication, several reports about anti-NMDA receptor encephalitis have appeared in Japan (Iizuka et al., 2008; Seki et al., 2008; Kataoka, Dalmau, and Ueno, 2008; Ishiura et al., 2008; Shindo et al., 2009). Analysis of a worldwide one hundred anti-NMDA receptor encephalitis case series revealed that about 60% of them had associated tumors such as ovarian teratomas (Dalmau et al., 2008). Meanwhile, Kamei et al. proposed ‘acute juvenile female non-herpetic encephalitis (AJFNHE)’ (Kamei et al., 2009). The clinical symptoms and course of AJFNHE are similar to those of anti-NMDA receptor encephalitis. These two diseases are considered to be the same clinical entity, anti-NMDA receptor antibodies being detected in samples from some AJFNHE cases. We herein describe five young Japanese cases who had fever, psychiatric symptoms and orofacial dyskinesias, and whose sera and cerebrospinal fluids (CSF) contained antibodies against NMDA receptors.


Introduction
Paraneoplastic limbic encephalitis (PLE) is a rare neurological syndrome characterized by short-term memory impairment, seizures and various psychiatric disturbances.It is often associated with small-cell lung cancer, germ-cell tumors of the testis and breast cancer, but rarely with ovarian teratomas (Gultekin et al., 2000).Several cases of PLE with ovarian teratomas had been reported in Japan (Okamura, Oomori, and Uchitomi, 1997;Nokura et al., 1997), but the autoantigens in this disease remained unknown.In 2005, Dalmau et al. reported an antibody to the membranes of neurons of the hippocampus (antigens colocalized with exchange factor for ADP-ribosylation factor 6 A (EFA6A)) in association with PLE and ovarian teratomas (Ances et al., 2005;Vitaliani et al., 2005).We sent samples from a patient suffering from limbic encephalitis with an ovarian teratoma to Prof. Dalmau's Laboratory in November 2005.They identified antibodies to the antigens colocalized with EFA6A in our patient's samples (Figure 1) (Shimazaki et al., 2007), and in another Japanese one (Koide et al., 2007).Their further analysis of the antibodies disclosed that were ones against NR1/NR2 heteromers of N-methyl-D-aspartate (NMDA) receptors.They diagnosed and reported twelve women (including our case) as having 'paraneoplastic anti-NMDA receptor encephalitis associated with an ovarian teratoma', the cases developing prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and a decreased level of consciousness often requiring ventilatory support (Dalmau et al., 2007).After this publication, several reports about anti-NMDA receptor encephalitis have appeared in Japan (Iizuka et al., 2008;Seki et al., 2008;Kataoka, Dalmau, and Ueno, 2008;Ishiura et al., 2008;Shindo et al., 2009).Analysis of a worldwide one hundred anti-NMDA receptor encephalitis case series revealed that about 60% of them had associated tumors such as ovarian teratomas (Dalmau et al., 2008).Meanwhile, Kamei et al. proposed 'acute juvenile female non-herpetic encephalitis (AJFNHE)' (Kamei et al., 2009).The clinical symptoms and course of AJFNHE are similar to those of anti-NMDA receptor encephalitis.These two diseases are considered to be the same clinical entity, anti-NMDA receptor antibodies being detected in samples from some AJFNHE cases.We herein describe five young Japanese cases who had fever, psychiatric symptoms and orofacial dyskinesias, and whose sera and cerebrospinal fluids (CSF) contained antibodies against NMDA receptors.

Characteristic clinical features of anti-NMDA receptor encephalitis
The clinical symptoms of 100 cases of anti-NMDA receptor encephalitis have been reported in detail (Dalmau et al., 2008).According to this report, the median age of patients was 23 years (range, 5-76 years), and 91 out of the 100 cases were women.In our cases (Table 1), the time of disease onset ranged from 17 to 30 of age.Four cases were female and one was male.Headache, fever and flu-like symptoms preceded other encephalitis features in our cases and about 90% of the above 100 cases (Dalmau et al., 2008).To our knowledge, antecedent infection has not been described for this disease, but case 5 had suffered from influenza B infection before his psychiatric symptoms emerged.

Autonomic symptoms
Anti-NMDA receptor encephalitis is complicated by autonomic instability, which is indicated by an unstable blood pressure level or pulse rate, hypersalivation, central hypoventilation, etc.We found excess salivary excretion of up to 1400ml/day in all cases except for patients 4 and 5. Case 3 suffered from sudden hypotension and bradycardia.Three of the five cases were intubated and required mechanical ventilatory support due to the central hypoventilation, the other two cases not needing assisted ventilation.

Ovarian teratomas
Fifty-eight of 98 anti-NMDA receptor encephalitis patients had a neoplasm, the most frequent one being an ovarian teratoma (Dalmau et al., 2008).Analysis of 400 patients confirmed that the younger the patient, the less likely that a tumor will be detected (Dalmau et al., 2011), and that in female patients older than 18 years, the frequency of an underlying teratoma is much the same as they previously reported (Dalmau et al., 2008).Of our cases, two (22 and 30 years old) had ovarian teratomas, the other three (16, 18 and 19 years old) had no associated tumor.The mature teratoma of an ovary in case 1 was not discovered in hospital with encephalitis symptoms, but was diagnosed four years after onset (Figure 3A-a, b).The immature teratoma of an ovary in case 3 was detected at two weeks after onset (Figure 3B-a).Pelvic MRI showed her enlarged teratoma, double in diameter, at two months after onset (Figure 3B-b) (Shimazaki et al., 2007).Both teratomas were resected, but the tumors in the other three cases were not identified until now.

Brain MRI findings
Brain MRI showed abnormal findings in 55 of 100 cases with anti-NMDA receptor encephalitis (Dalmau et al., 2008).Of our cases, cases 1, 2 and 5 exhibited no remarkable findings on the brain MRI.FLAIR images of case 3 disclosed areas of high intensity in the bilateral medial temporal and hippocampal areas (Figure 4A-a), which disappeared after two months (Figure 4Ab) (Shimazaki et al., 2007).FLAIR images of case 4 showed areas of high intensity in the right ventral pons (Figure 4B

Electroencephalography (EEG)
Generalized or frontotemporal slow waves were observed in 71 of 100 cases with anti-NMDA receptor encephalitis.Epileptic discharges were only recorded in 22 of the 100 cases (Dalmau et al., 2008).The EEG records for all our cases except for case 5 mainly showed slow waves in the theta to delta ranges.

Cerebrospinal fluid findings
Cerebrospinal fluid (CSF) examination disclosed abnormal findings in 95 of 100 cases (Dalmau et al., 2008).Lymphocytic pleocytosis was found in 91 cases, and increased protein concentrations in 32 of the 100 cases.
In our cases, mild to moderate pleocytosis was found in all patients except for patient 5. CSF protein elevation was only observed in two cases (patients 2 and 3).

Treatment and prognosis
Several effective treatments have been reported for anti-NMDA receptor encephalitis other than the administration of steroids, immunoglobulin, and plasmapheresis.Ovarian tumor removal in the acute phase (Sansing et al., 2007;Seki et al., 2008), chemotherapy for the tumors (Eker et al., 2008), cyclophosphamide (Sansing et al., 2007;Wilder-Smith and Ng, 2008), and rituximab (Ishiura et al., 2008) were also effective treatments for a small number of cases.
In our cases (Table 1), corticosteroids were administered to four cases, and high-dose intravenous gammaglobulin to three cases.We performed plasmapheresis for two cases.Two women underwent resection of ovarian teratomas.Modified electroconvulsive therapy was found to be dramatically effective for the psychiatric symptoms in case 5.The severity of anti-NMDA receptor encephalitis is incompletely correlated with the titer of anti-NMDA receptor antibodies in the acute phase.(Prof.Dalmau, written communication Jul 2008).
In our cases, we did know the titers in three (Table 1).Case 3 exhibited the lowest titer with a full recovery, whereas case 2 exhibited the highest titer with severe involuntary movements and poor prognosis.The prognosis of anti-NMDA receptor encephalitis had relatively good compared to that of herpes simplex encephalitis.Of 100 cases, 47 exhibited full recovery, 28 mild stable deficits, 18 severe deficits, and seven died as a result of the neurological disorder (Dalmau et al., 2008).Our three cases exhibited a complete recovery, one had mild sequelae with epilepsy, and one died.

Conclusions
We have discussed five cases of anti-NMDA receptor encephalitis compared to the other numerous reported cases.From the clinical aspect, our cases and the reported ones had some symptoms in common, for example, preceding psychiatric symptoms, and characteristic orofacial dyskinesia.Meanwhile, the clinical manifestations in our cases included a peculiar ocular symptom (ocular dipping) in case 3 and an atypical clinical presentation (predominant schizophrenic www.intechopen.compsychiatric symptoms) in case 5.In particular, case 5 was initially misdiagnosed as having schizophrenia by a psychiatrist because of no findings of encephalitis (no CSF pleocytosis, normal brain MRI and EEG).Ovarian teratomas were found in two patients, one became rapidly enlarged in hospital, and the other was found at four years after onset.Therefore, we should carefully follow up patients even if the tumors are not identified during hospitalization.In our experience, anti-NMDA receptor encephalitis exhibits severe symptoms such as convulsions and hypoventilation in the acute phase, but this disease could be curable.Characteristic symptoms and antibody measurement can be useful for prompt diagnosis of this disease, and early immunosuppressive treatment and tumor resection are important as well as general care of critically ill patients.

Fig. 1 .
Fig. 1.Detection of anti-NMDA receptor antibodies in cerebrospinal fluid of case 3. Antibodies for the NR1/NR2 heteromers of NMDA receptors caused intense immunolabelling of cultured rat neuronal cell membranes and processes.

Fig. 2 .
Fig. 2. The position of the eyes in case 3 showed skew deviation when the inverse ocular bobbing resolved.
-a) and the right cerebellum (Figure 4B-b).A. Pelvic T2-weighted MRI (a: axial, b: sagittal image) in case 1 at four years after onset.It revealed a right ovarian teratoma with a diameter of 5 cm.It was resected and the pathological diagnosis was a mature teratoma (dermoid cyst).B. Pelvic enhanced CT in case 3. CT at two weeks after onset (a) revealed a 5 cm tumor in the right ovary, which was considered to be a benign cyst unrelated to the neurological disorder.At two months after onset, the patient developed progressive constipation and a bulging appearance of the lower abdomen.Follow-up abdominal computed tomography (b) and MRI showed an enlarged ovarian tumor, with a transverse diameter of 10 cm.Resection of the tumor revealed an immature teratoma that contained hair follicles, cartilage tissue, glandular structures and cerebral cortex-like tissue with normal appearing neurons.No inflammatory infiltrates were evident in the tumor.

Table 1 .
Clinical and laboratory findings in five cases of anti-NMDA receptor encephalitis.