Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is an autoimmune disease first described in 2007 (Dalmau et al. 2011; Peery et al. 2012; Titulaer et al. 2013). It has since been increasingly recognized as one of the more common identifiable causes of encephalitis. These patients typically present with neuropsychiatric syndromes, including cognitive impairment, seizures, loss of consciousness, central hypoventilation, and autonomic nerve dysfunction. Its development is driven by an autoimmune reaction primarily against the NMDA-R. Anti-NMDA-R encephalitis is frequently a paraneoplastic syndrome; a recent multi-institutional observational study has shown that 38 % of patients have presence of a tumor, of which 94 % were ovarian teratomas (Dalmau et al. 2011). Initial therapy includes high-dose steroids, immunoglobulin, and plasma exchange, as well as removal of any causative neoplasm if present. Therefore, during the acute phase, most patients may undergo a surgical procedure and intensive care support, thus requiring general anesthesia and sedation. However, the optimal anesthetics/sedation methods for patients with anti-NMDA-R encephalitis remain to be established (Pryzbylkowski et al. 2011; Kawano et al. 2011; Lapébie et al. 2014; Broderick et al. 2014; Simon 2014).

The NMDA-Rs play a crucial role in controlling synaptic plasticity and memory function (Paoletti et al. 2013). The functional NMDA-R is composed of both the NR1 and NR2 subunits. The development of anti-NMDA-R encephalitis is associated with antibodies against NR1/NR2 heteromers, which reduce NMDA-R density by an increase in receptor movement into the plasma membrane, i.e., internalization (Hughes et al. 2010; van Coevorden-Hameete et al. 2014). The NMDA-Rs are also considered to be an important target of the most frequently used inhaled and non-inhaled anesthetics that inhibit its functions (Franks 2008). Therefore, sedative/anesthetic agents that act via antagonism of the NMDA-R may potentially aggravate the disease symptoms (Pryzbylkowski et al. 2011; Simon 2014).

Dexmedetomidine is now widely used to provide sedation, analgesia, and anti-sympathetic effects without respiratory depression during the perioperative period (Carollo et al. 2008). Additionally, recent studies suggest that dexmedetomidine exerts neuroprotective effects against brain injury in the central nervous system (Ma et al. 2004; Degos et al. 2013). The major sedative and antinociceptive effects of dexmedetomidine are due to its stimulation of α 2 -adrenoceptors located in the locus coeruleus (Hunter et al. 1997). Therefore, dexmedetomidine may be suitable for postoperative sedation of patients with anti-NMDA-R encephalitis. However, the interaction between dexmedetomidine and NMDA-R activity remains under investigation, and there have been no reports on the clinical use of dexmedetomidine in the patients with anti-NMDA-R encephalitis.

In this report, we present experimental data regarding the use of dexmedetomidine under simulated NMDA-R hypo-functions in rats and a clinical case of anti-NMDA-R encephalitis successfully sedated with dexmedetomidine postoperatively.

Animal experiments

It is well reported that antagonists of the NMDA-R, such as phencyclidine, produce symptoms similar to those observed in patients with anti-NMDA-R encephalitis (Dalmau et al. 2011). Furthermore, an NMDA-R antagonist, MK-801, induces schizophrenia-like symptoms and is widely used as a rodent model of schizophrenia (Andiné et al. 1999). Using this animal model, we investigated whether dexmedetomidine can be safely used under NMDA-R-deficient conditions, a mimic of anti-NMDA-R encephalitis.

All procedures were approved by the Kochi University Animal Experiment Committee. For the rat model of psychosis, male Sprague–Dawley rats (6 weeks old, body weight: 145–180 g) were intraperitoneally (i.p.) injected with MK-801 (Sigma-Aldrich, St. Louis, MO). Injections of 0.01, 0.02, or 0.05 mg/kg dexmedetomidine (n = 8 for each dose) were tested in this study. The NMDA-R antagonist anesthetic, ketamine, was used as a positive control at doses of 10, 50, and 100 mg/kg (n = 2–8, as indicated in Results).

On the day of the experiment, animals were placed inside a transparent Plexiglas chamber (45 × 45 × 40 cm). All animals were individually habituated in the test environment for at least 2 h prior to the test. MK-801 (0.1 mg/kg dissolved in 0.9 % saline) or an equal volume of saline was administered i.p., followed by a behavioral observation and rating procedure that started 15 min after the injection and continued for 60 min. Two types of behavior, locomotor activity and stereotyped behavior, which are well-characterized components associated with NMDA-R antagonism (Andiné et al. 1999), were assessed by an observer blind to drug treatment. Locomotor activity was measured using pairs of 16 photo beams positioned 10 cm apart and 5 cm from the floor of the cage (Fig. 1). The total count of horizontal beam crosses was recorded every 5 min. For stereotyped sniffing rating, animals received a score of 0 (absence), 1 (some rare), 2 (discontinuous, free interval of more than 5 s), or 3 (continuous), according to the method described previously (Sukhanov et al. 2014). The rating procedure consisted of observation for 30 s every 5 min. The results are presented as the mean ± standard error of the mean (SEM). Data were analyzed by two-way ANOVA repeated measures, followed by Bonferroni’s post hoc test. A p value of 0.05 was considered statistically significant.

Fig. 1 Picture of a rat during open-field test Full size image

As with previous reports (Andiné et al. 1999), acute administration of MK-801 induced hyperlocomotion (Fig. 2a) and stereotypic sniffing (Fig. 2b), compared with control rats (p < 0.05, main effect of group for each variable). Sub-anesthetic doses of ketamine (10 and 50 mg/kg) dose-dependently exaggerated MK-801-induced hyperlocomotion (Fig. 3a) and stereotypic sniffing (Fig. 3b; both p < 0.05). For the anesthetic dose of ketamine (100 mg/kg), the first two rats tested transiently developed seizure-like movement, preventing appropriate behavioral assessment, and subsequent investigation at this dose was discontinued. These results offer preclinical proof-of-concept that NMDA-R antagonist anesthetics, such as ketamine and N 2 O, should be avoided in patients with anti-NMDA-R encephalitis, due to possible further deterioration of NMDA-R hypofunction. On the other hand, sub-sedative doses of dexmedetomidine (0.01 and 0.02 mg/kg) had no influence on MK-801-induced hyperlocomotion (Fig. 4a) and stereotypic sniffing (Fig. 4b). Furthermore, the sedative dose of dexmedetomidine (0.05 mg/kg) significantly attenuated both behaviors; this may have been associated with its sedative effect.

Fig. 2 Time course of MK-801- or vehicle-induced locomotor activity (a) and stereotyped behavior (b). Each parameter was scored at baseline and at 5-min intervals starting 15 min after drug injection, and continued for 60 min. Each vertical bar represents the mean ± SEM (n = 8 in each experimental group) Full size image

Fig. 3 Effects of ketamine on MK-801-induced locomotor activity (a) stereotyped behavior (b). Each parameter was scored at baseline and at 10-min intervals starting 15 min after drug injection, and continued for 60 min after injection of either MK-801 alone or combined with ketamine (10 or 50 mg/kg). Each vertical bar represents the mean ± SEM (n = 8 in each experimental group) Full size image