**4.1 Anti-NMDA-receptor encephalitis**

The role of autoantibodies to the ionotropic NMDA (N-methyl-D-aspartate) glutamate receptor (NMDA-R; Figure 6) is well established in limbic encephalitis (Graus et al., 2010; Vincent et al., 2010; Dalmau et al., 2011).

Fig. 6. NMDA-receptor expression on the postsynaptic terminal of neurons.

These novel autoantibodies were first described by Dalmau et al. in serum samples of young women presenting with a subacute-onset encephalopathy often associated with movement disorders and an underlying ovarian teratoma (Dalmau et al., 2007; Dalmau et al., 2008). The presence of neuronal tissue expressing NMDA-R within the tumour was thought to trigger the production of paraneoplastic autoantibodies. However, the origin of the autoantibodies remains unresolved, as recent publications reported numerous of non-teratoma associated cases. Among some adults, most of these non-paraneoplastic NMDA-R encephalitis cases occurred in children (Dale et al., 2009; Florance et al., 2009; Irani et al., 2010). Anti-NMDA-R encephalitis is associated with a strong female predominance (female:male ratio is 8:1) occurring primarily at a median age of 23 years (Dalmau et al., 2008).

antibodies through the area postrema (Popescu et al., 2011). This was supported by findings of patients suffering from intractable vomiting and nausea as initial symptoms of NMO

The role of autoantibodies to the ionotropic NMDA (N-methyl-D-aspartate) glutamate receptor (NMDA-R; Figure 6) is well established in limbic encephalitis (Graus et al., 2010;

Fig. 6. NMDA-receptor expression on the postsynaptic terminal of neurons.

occurring primarily at a median age of 23 years (Dalmau et al., 2008).

These novel autoantibodies were first described by Dalmau et al. in serum samples of young women presenting with a subacute-onset encephalopathy often associated with movement disorders and an underlying ovarian teratoma (Dalmau et al., 2007; Dalmau et al., 2008). The presence of neuronal tissue expressing NMDA-R within the tumour was thought to trigger the production of paraneoplastic autoantibodies. However, the origin of the autoantibodies remains unresolved, as recent publications reported numerous of non-teratoma associated cases. Among some adults, most of these non-paraneoplastic NMDA-R encephalitis cases occurred in children (Dale et al., 2009; Florance et al., 2009; Irani et al., 2010). Anti-NMDA-R encephalitis is associated with a strong female predominance (female:male ratio is 8:1)

(Popescu et al., 2011).

**4. NMDA-receptor encephalomyelitis** 

**4.1 Anti-NMDA-receptor encephalitis** 

Vincent et al., 2010; Dalmau et al., 2011).

The characteristic symptoms of anti-NMDA-R positive patients are of prominent psychiatric and behavioral nature, including rapid memory loss, seizures, abnormal movements (dyskinesias), hypoventilation and autonomic instability. This disease usually progresses from initial neuropsychiatric symptoms into a state of unresponsiveness with catatonic features, commonly associated with abnormal movements, and autonomic- and breathing instability. Additionally, most patients show prodomal symptoms such as headache, fever, nausea, vomiting, diarrhea or upper respiratory-tract symptoms. Brain MRI data show no or only minor changes which usually occur transiently despite severity of symptoms. Concerning CSF parameters, 60% of patients show OCB and mild lymphocyte pleocytosis (Dalmau et al., 2011). Interestingly, intrathecal NMDA-R antibody synthesis was observed in a majority of patients and CSF titer levels were more likely to correlate with clinical severity, compared to serum titers (Dalmau et al., 2008; Dale et al., 2009; Florance et al., 2009; Irani et al., 2010).

Although the disease can be lethal in some rare cases and despite the severity of the symptoms, more than 70% of patients recover after treatment and less than 30% of patients show incomplete recovery with memory, cognitive and motor deficits. Treatment options include immunotherapy (corticosteroids, intravenous immunoglobulin or plasma exchange) and/or tumor removal with the aim to reduce anti-NMDA-R autoantibody levels. Recent studies showed that antibodies to the NMDA-R were predominantly of the IgG1 subclass and are able to activate complement on NMDA-R expressing human embryonic kidney cells (Irani et al., 2010). However, the role of complement activation remains controversial as other findings indicated a complement-independent mode of action. Several studies have addressed the issue regarding the binding site of the autoantibodies and possible functional consequences on the targeted NMDA-R. Dalmau et al. described the NR1 isoform or NR1/NR2 heterodimers of the NMDA-R as recognition site of anti-NMDA-R antibodies (Dalmau et al., 2011). Providing further insight into the mode of action, *in vitro* and *in vivo* studies nicely demonstrated that antibodies from patients with anti-NMDA-R encephalitis caused a rapid and reversible loss of surface NMDA-R by antibody-mediated capping and internalization, resulting in abrogation of NMDA-R-mediated synaptic function (Dalmau et al., 2008; Hughes et al., 2010).

Thus, similar to the role of anti-AQP4 IgG antibodies in NMO, anti-NMDA-R antibodies helped to define a new clinical syndrome, anti-NMDA receptor encephalitis (Dalmau et al., 2011).

#### **4.2 Anti-NMDA receptor antibodies in neuropsychiatric SLE**

Several reports confirmed the presence of autoantibodies to NMDA-R, particularly the NR2 isoform, in the majority of patients with neuropsychiatric SLE (DeGiorgio et al., 2001; Emmer et al., 2006; Hanly et al., 2006; Kowal et al., 2006; Lapteva et al., 2006; Arinuma et al., 2008; Fragoso-Loyo et al., 2008). These autoantibodies were not only detected in serum, but also in the CSF and brain parenchyma of some SLE patients. Furthermore, CSF titers correlate with neuropsychiatric symptoms. In SLE, anti-NMDA-R antibodies were demonstrated to bind to a small peptide (DWEYS) present in the extracellular, aminoterminal domain of NR2A and NR2B subunits (DeGiorgio et al., 2001; Gielen et al., 2009). Injection of murine or human monoclonal antibodies against this peptide into the hippocampus and cerebral cortex of mice resulted in local loss of neurons and induced activation of caspase-3 in cultured human and murine neurons (DeGiorgio et al., 2001; Kowal et al., 2006; Gielen et al., 2009). Furthermore, several experimental studies in mice

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**7. References** 

demonstrated a causal relationship between anti-NMDA-R autoantibodies with impairment in cognition and behavior (Diamond et al., 2009). A recent study provided evidence of a positive modulating effect on receptor function by low concentrations of anti-NMDA-R antibodies, resulting in an increase of NMDA-R mediated excitatory postsynaptic potentials. However, at high concentrations, these antibodies promote excitotoxicity through enhanced mitochondrial permeability transition. These findings might be an explanation for the either transient or permanent neuropsychiatric clinical course observed in SLE patients. In conclusion, antibodies to the NR2 isoform of NMDA-R could play an important role in the pathogenesis of neuropsychiatric lupus.

Many studies focusing on the detection of antibodies to the NMDA-R NR2A and NR2B subunits in SLE have used the ELISA technique. It is now essential that studies regarding antibody specificity in patient serum/CSF are confirmed using live cell-based assays expressing native NMDA-R or single subunits.

#### **4.3 Anti-NMDA receptor antibodies in inflammatory demyelinating diseases**

Interestingly, antibodies against NMDA-type glutamate receptors were also detected in both serum and CSF of patients with NMOSD (Ishikawa et al., 2007; Kruer et al., 2010). As previously described, the discovery of anti-AQP4 IgG antibodies in the serum of patients with NMOSD enables an early diagnosis and specific treatment of the disease. Despite the high percentage of AQP4-IgG seropositive NMO patients, several studies report on AQP4- IgG seronegative NMO patients who, however, show no differences in their clinical presentation. It might well be that AQP4-IgG seronegative patients represent a distinct subgroup of NMO patients, in whom the disease is triggered by other autoantibodies, such as antibodies to NMDA-R or yet unknown targets. So far, in literature there is a lack of information regarding the presence of anti-NMDA-R antibodies in other CNS demyelinating diseases, such as MS. Up to now, one case report speculates on a possible association of the rarely occurring epileptic seizures in MS (Catenoix et al., 2010) with anti-NMDA-R antibody seropositivity (Johnston et al., 2010).
