# IgG-NR2B--A Potentially Valuable Biomarker in the Management of Refractory Anti-NMDAR Encephalitis
## 3 Discussion
### Pathophysiological Insights  
As we have mentioned before, both of these disorders have a common pathogenesis with IgG antibodies against the NR1 and NR2 subunits of NMDARs [4]. NMDARs are one of the non-selective ionotropic glutamate channels with high calcium permeability and are located throughout the cerebral cortex, including in the hippocampus. They perform a crucial role in the regulation of synaptic plasticity and synaptic transmission [8]. These hetero-tetrameric proteins are composed of NR1, NR2 (NR2A-D), and NR3(NR3A-B) subunits, usually observed to be di-heteromers (NR1/NR2A, NR1/NR2B) and tri-heteromers (NR1/NR2/NR3B). All of these subunits contain a large extracellular amino-terminal domain (N-terminal); three transmembrane segments forming an ion channel, which determine the calcium permeability of the channel; and an intracellular C-terminal domain [9; 10]. The extracellular N-terminal domain of the NR1 subunit binds the glycine co-agonist, whereas the NR2 subunit has a binding place for the glutamate neurotransmitter. The maximum activation of NMDARs requires the presence of both neurotransmitters [9; 11]. This activation opens up the channel pore, which determines the influx of Na\({}^{+}\) and Ca\({}^{2+}\) ions and enables many physiological processes such as learning and memory [9; 11]. The dysfunction of NMDARs including both the NR1 and NR2 subunits leads to the dysregulation of synaptic communication between neurons, thus inducing many neurological diseases, including schizophrenia or schizophrenia-like syndromes [7; 11]. Negative symptoms (blunted affect, alogia) commonly seen in schizophrenia were also noticed in our case. NR1 subunits are situated all over the brain, while NR2 subunits are expressed in distinct places within the central nervous system due to their special functions. Both NR2A and NR2B subunits are placed in the mature cerebral cortex and hippocampus, usually as di-heteromers (NR1/NR2A, NR1/NR2B), but they can also be tri-heteromers (NR1/NR2A/NR2B) [10; 12]. The NR2 subunits control protein-protein interactions and the properties of receptor transmissions. The expression of NR2B subunits increases gradually during the early stage of development and decreases with advancing age, while the expression of NR2A subunits increases over the entire course of development [12]. However, there are some differences in the receptors' degradation process. The NR2A subunits work through endocytosis and degradation pathways that involve lysosomes. On the other hand, the NR2B subunits undergo recycling on the cell surface after endocytosis [12]. The NR2B subunits have a higher affinity for glutamate, thus leading to longer channel opening times than those for the NR2A subunits, which confer faster deactivation kinetics and considerable calcium-sensitive desensitization. An imbalance between the expression of these two subunits could be one of the key points in the pathogenesis of NMDAE [9]. The inadequate activation of NR2B subunits leads to excitotoxicity with neuron degradation, which can be observed upon MRI as frontotemporal atrophy due to the distribution of the NMDARs. Also, T2/FLAIR hyperintensities can be found in the hippocampus, brainstem, and cerebral cortex region [4]. FLAIR- and T2-weighted MRI showed a pontine hyperintense lesion in our patient. The expression of NMDARs is not enough to induce anti-NMDARE. [PERSON] and colleagues reported that NR1 subunits of NMDARs were detected in their group of patients with teratomas associated with anti-NMDARE (55%) and also in the control group (64%) who did not have a clinical presentation of encephalitis. Thus, the production of anti-NMDAR antibodies is crucial in the pathogenesis of anti-NMDARE. They proved that there was a presence of immune cell infiltration near the neuroglial tissue in all cases of teratomas associated with anti-NMDARE and only in two cases from the control group.