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ObjectiveTo report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody–associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters.MethodsClinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques.ResultsFrom January 2005 to May 2017, 11 patients (median age 29 years, range 6–75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95.ConclusionsAnti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.

Objective:We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti–NMDA receptor (anti-NMDAR) encephalitis.Methods:Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1–6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored.Results:Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile.Conclusions:Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis.Classification of evidence:This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis.

Myelin basic protein (MBP) is one of the most abundant proteins in the human brain. Active immunization with MBP induces experimental autoimmune encephalomyelitis, and anti-MBP antibodies have been repeatedly described in MS.1 However, its role in MS pathogenesis or prediction of disease progression is still unclear.2,3 Previous studies utilized enzyme-linked immunosorbent assay or immunoblot assays with linear epitopes of MBP, thus potentially overlooking autoantibodies that bind to MBP's natural conformation. These initial studies also included antibodies against another myelin protein, myelin oligodendrocyte glycoprotein (MOG). As happened for MBP, conflicting results stimulated the discussion of whether MOG antibodies contribute to MS pathogenesis.2,3 More recent work demonstrated that there are presumably pathogenic MOG antibodies defining the new entity of MOG antibody-associated disease;4 however, they bind to conformational MOG only. The authors are grateful to Professor Brian Popko, Department of Neurology, University of Chicago, for providing MBP knockout mouse brains.

Background: Anti-NMDA-receptor (NMDAR) encephalitis is a severe disorder that occurs in association with antibodies to the NR1 subunit of the NMDAR and results in a characteristic syndrome. Objective: To determine in a single institution setting whether patients previously diagnosed with encephalitis of unknown origin had anti-NMDAR encephalitis. Methods: Charts of 505 patients aged 18 to 35 years admitted to the intensive care unit (ICU) during a 5-year period were retrospectively reviewed for criteria of encephalitis of unknown etiology. These included encephalitic signs with psychiatric symptoms (agitation, paranoid thoughts, irritability, or hallucinations); seizures; CSF inflammation; and exclusion of viral or bacterial infection. Archived serum and CSF samples of patients fulfilling these criteria were examined for NMDAR antibodies. Follow-up visits allowed the analysis of the natural disease course and estimation of prognosis. Results: Seven patients (all women) fulfilled the indicated criteria; 6 of them had NMDAR antibodies. Ovarian teratomas were detected in 2 patients, in one 3 years after the onset of encephalitis. Outcome was favorable in all patients. One patient without teratoma improved spontaneously along with disappearance of NMDAR antibodies. Conclusions: Anti-NMDAR encephalitis represented 1% of all young patients9 admissions to the ICU. Six of 7 cases with the indicated clinical criteria had anti-NMDAR encephalitis. NMDAR antibodies should be tested in all patients with encephalitis who fulfill these criteria.

AIM: KCNJ6 coding for potassium inwardly rectifying channels (Kir3.2, GIRK2) is important for opioid receptor transmission. The KCNJ6 rs2070995 AA genotype has been associated with increased opioid analgesic requirements in Japanese. We analyzed its consequences for other opioid effects. METHODS: Genotyping was done in 85 methadone-substituted former heroin addicts, 352 opioid-treated chronic pain patients, and in 51 healthy volunteers where miotic effects of levomethadone had been measured. Expression of Kir3.2 in the Edinger-Westphal nucleus of rat brains was analyzed by means of immunohistochemistry. RESULTS: Average daily methadone substitution doses during the first therapy year were larger in the AA genotype (n=4, 119.7+/-49.6 mg/day) than in other rs2070995 genotypes (77.5+/-26.2 mg/day, P=0.003) whereas AA carriers lacked opioid withdrawal symptoms. A similar tendency toward less opioid effectiveness was observed toward higher opioid dosing demands for analgesia in the AA genotype (n=17, opioid dose 2.03+/-0.45 log mg oral morphine equivalents per day, controls: 1.81+/-0.52 log mg oral morphine equivalents/day, P=0.093). In contrast, no pharmacogenetic effects were observed on miotic opioid effects. This could be traced back to the absence of Kir3.2 from the Edinger-Westphal nucleus in rat brains, a key cerebral structure governing pupil constriction. CONCLUSION: The association of the KCNJ6 rs2070995 AA genotype with increased opioid requirements extends from analgesia to opiate substitution therapy. Opioid induced miosis is exempted for molecular histological reasons.

Anti–NMDA receptor (NMDAR) encephalitis is an autoimmune-mediated disease with a wide range of neurologic and psychiatric symptoms including psychosis, cognitive deficits, movement disorders, and epileptic seizures.1,2

Editors' Note: In WriteClick this week, Drs. Finke and Pruss comment on influenza-associated encephalitis (IAE) as discussed in “Clinical Reasoning: A 57-year-old woman who developed acute amnesia following fever and upper respiratory symptoms,” and suggest patients with suspected IAE be tested for neuronal antibodies. In reference to “Spatial cluster analysis of population amyotrophic lateral sclerosis risk in Ireland,” …

Anti-NMDA receptor (NMDAR) encephalitis is a well-recognized immunotherapy-responsive condition, often diagnosed in younger individuals with characteristic clinical symptoms. In women, ovarian teratomas are frequently found and thought to trigger the antibody response against the NMDAR by ectopically expressing neuronal antigens. The present study describes the case of a patient with HSV encephalitis (HSVE) who develops a second episode of neurologic abnormalities, which is in fact NMDAR encephalitis.(1.)

A 50-year-old woman presented with a 10-year-history of paroxysmal attacks of severe rotational vertigo lasting seconds without hearing loss or tinnitus, occurring approximately once monthly. MRI revealed megadolichobasilar artery and white-matter lesions (figure, A). Figure. (A) T2-weighted axial MRI shows asymmetric, widespread, hyperintense white-matter lesions. (B, C) Three-dimensional-CISS …