Clinical Aspects of Anti-NMDA Receptor Encephalitis

Abstract

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.