# IgG-NR2B--A Potentially Valuable Biomarker in the Management of Refractory Anti-NMDAR Encephalitis
###### Abstract  
The autoantibodies against the NR1 subunit are well known in the pathomechanism of NMDAR encephalitis. The dysfunction of the NR2 subunit could be a critical factor in this neurological disorder due to its important role in the postsynaptic pathways that direct synaptic plasticity. We report a case of paraneoplastic anti-NMDAR encephalitis presented alongside very severe illness. Computed tomography (CT) of the brain, as well as FLAIR and T2-weighted MRI, was performed to rule out any other acute brain processes. A semi-quantitative method was applied to detect the presence of anti-NMDAR antibodies in the serum and CSF. A CT chest-abdomen-pelvis scan was performed that detected an ovarian teratoma. A histopathological examination was performed after a laparoscopic right-ovary cystectomy. Subsequent immunofluorescence immunohistochemical staining showed the expression of NMDA receptors of type NR2B. Treatment included first-line immunotherapy, second-line immunotherapy, tumor removal, and intrathecal injections with methotrexate and dexamethasone. The histological finding for our patient after tumor removal was ovarian teratoma. Hematoxylin-eosin (HE) staining revealed a characteristic spectrum of elements, including stratified squamous epithelium and fat tissue accompanied by neuroglial cells. Subsequent immunohistochemical staining showed an expression of NMDA receptors of type NR2B in different structures of the teratoma, including the neuroglial cells. The first-line immunotherapy following the tumor removal was insufficient in our patient. The paraneoplastic anti-NMDAR encephalitis with a coexpressed NR2B subunit on the neural cells of the ovarian teratoma may suggest a different inflammation process and could be the key factor in the pathomechanism and treatment of the refractory anti-NMDAR encephalitis.  
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studies have reported cases without tumor findings, including sporadic teratomas without anti-NMDARE presentation [1]. Thus, available data suggest that the expression of NMDAR is not enough to induce anti-NMDARE [2]. The clinical presentation of NMDARE is characterized by a prodromal phase of a viral-like illness (fever, headache, respiratory and gastrointestinal symptoms) followed by psychiatric symptoms (memory loss, hyperreligiosity, agitation, psychosis, auditory and visual hallucinations), physical signs (dyskinetic movements, orofacial dyskinesias, epileptic seizures) and autonomic dysfunction [1,4]. The diagnosis of anti-NMDARE is established upon the detection of anti-NMDAR antibodies in serum and CSF. There are no established guidelines for its treatment, but first-line immunotherapy (corticosteroids, immunoglobulin (IVIG), plasma exchange (PLEX)), as in most other autoimmune inflammatory disorders, is recommended, including tumor removal [1,4]. Second-line immunotherapy (rituximab, cyclophosphamide, tocilizumab) may be needed in cases when the diagnosis of anti-NMDARE is delayed [4]. Intrathecal therapy with methotrexate may be a useful therapy in cases where there is an insufficient response to first- and second-line immunotherapy (Table 1) with poor functional outcomes [5]. Optimized treatment strategies have not yet been determined and randomized controlled trials are necessary to confirm the efficacy and safety of all forms of immunotherapy [6]. We report a case of paraneoplastic anti-NMDAR encephalitis that presented with very severe illness, where the patient did not respond to first- or second-line immunotherapy following tumor removal.