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Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis.

ABSTRACT: To evaluate the therapeutic potential of bortezomib, a proteasome inhibitor that target plasma cells, in order to revive stalled recovery in patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis who remain bedridden even after aggressive immunotherapy.We consecutively enrolled patients with anti-NMDA receptor encephalitis who remained bedridden after first-line immunotherapy (steroids and intravenous immunoglobulin), second-line immunotherapy (rituximab), and tocilizumab treatment, and treated them with subcutaneous bortezomib. Clinical response, functional recovery, and changes in antibody titer in the serum and cerebrospinal fluid were measured.Before the bortezomib treatment, the five patients with severe refractory anti-NMDA receptor encephalitis were in a vegetative state. During the 8 months of follow-up period, three patients improved to minimally conscious states within 2 months of bortezomib treatment, one failed to improve from a vegetative state. However, no patient achieved functional recovery as measured by the modified Rankin Scale score (mRS). Three patients advanced to a cyclophosphamide with bortezomib and dexamethasone regimen, which only resulted in additional adverse events, without mRS improvement. Among the four patients whose antibody titer was followed, two demonstrated a twofold decrease in the antibody titer in serum and/or cerebrospinal fluid after 2 cycles of bortezomib.Although there were some improvements in severe refractory patients, clinical response to bortezomib was limited and not clearly distinguishable from the natural course of the disease. The clinical benefit of bortezomib in recent studies requires further validation in different clinical settings.

SUBMITTER: Shin YW

PROVIDER: S-EPMC5945964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Efficacy of Therapeutic Plasma Exchange in Patients with Severe Refractory Anti-NMDA Receptor Encephalitis.

Project description:The objective of the present study was to assess the efficacy of therapeutic plasma exchange (TPE) in patients with severe refractory anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis. Patients with severe anti-NMDA receptor encephalitis who showed no improvement after steroids and/or intravenous immunoglobulin treatment for at least 10 days were enrolled. All patients received immunotherapy and were divided into a TPE group and a non-TPE group according to treatment received. Each patient in the TPE group received at least 1 TPE course. NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and plasma were evaluated within 1 week after the last TPE procedure. The clinical efficacy of treatment was evaluated after 1 month, 2 months, 3 months, 6 months, and 12 months. Forty patients were enrolled: 19 in the TPE group and 21 in the non-TPE group. Nineteen patients received TPE for a total of 118 procedures. NMDA receptor antibody titers in the CSF and/or plasma decreased or were negative after the last TPE procedure in 18 patients (94.7%). Compared with the non-TPE group, the TPE group exhibited greater clinical improvement after 1 month and 2 months following treatment (P < 0.05). After 3 months, 6 months, and 12 months, there were no significant differences in the outcomes between the TPE group and non-TPE group. The results suggest that TPE might rapidly improve the clinical manifestations in patients with severe refractory anti-NMDA receptor encephalitis, and we believe that TPE should be considered as a first-line treatment.

| S-EPMC6694354 | biostudies-literature

Anti-NMDA Receptor Encephalitis and Vaccination.

Project description:Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune neurological disorder. The cause of this disease is often unknown, and previous studies revealed that it might be caused by a virus, vaccine or tumor. It occurs more often in females than in males. Several cases were reported to be related to vaccination such as the H1N1 vaccine and tetanus/diphtheria/pertussis and polio vaccines. In this study, we reported an anti-NMDA receptor encephalitis case that may be caused by Japanese encephalitis vaccination. To investigate the association between anti-NMDA receptor encephalitis and vaccination, we analyzed the phylogenetic relationship of the microRNAs, which significantly regulate these vaccine viruses or bacteria, and the phylogenetic relationship of these viruses and bacteria. This reveals that anti-NMDA receptor encephalitis may be caused by Japanese encephalitis vaccination, as well as H1N1 vaccination or tetanus/diphtheria/pertussis and polio vaccinations, from the phylogenetic viewpoint.

| S-EPMC5297824 | biostudies-literature

Late-onset anti-NMDA receptor encephalitis.

Project description:ObjectiveTo describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients ≥45 years old.MethodObservational cohort study.ResultsIn a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs. 12%, p < 0.0001), had lower frequency of tumors (23% vs. 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs. 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs. 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04-0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up.ConclusionsAnti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

| S-EPMC3795591 | biostudies-literature

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Project description: Not available

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| S-EPMC7327341 | biostudies-literature

Anti-NMDA Receptor Autoimmune Encephalitis: Diagnosis and Management Strategies.

Project description:Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most recognized form of autoimmune encephalitis. It is characterized by a constellation of neurologic and psychiatric features along with positive NMDAR antibody, which is more sensitive and specific in CSF than serum. All patients should be screened at least once for neoplasm, with ovarian teratoma being found in most tumor-related cases. In the acute phase, first-line immunotherapy, often a combination of high-dose steroids, immunoglobulins, and/or plasma exchange, is strongly recommended. When first-line therapy fails, escalation to second-line immunotherapy, particularly rituximab, can further improve outcomes and prevent relapses. In refractory cases, additional complementary immunotherapies, such as cyclophosphamide, bortezomib and/or tocilizumab may be considered. Relapses occur in 10-30% of cases, mostly within the first two years from onset. Individuals should be followed up to determine if chronic maintenance therapy is required.

| S-EPMC9826635 | biostudies-literature

Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus.

Project description: Not available

| S-EPMC3039209 | biostudies-literature

Superficial white matter damage in anti-NMDA receptor encephalitis.

Project description:BACKGROUND:Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter. METHODS:Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity. RESULTS:Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients. CONCLUSIONS:Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

| S-EPMC5899027 | biostudies-literature

Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.

Project description:We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.

| S-EPMC2868315 | biostudies-other

Case report: Rapid recovery after intrathecal rituximab administration in refractory anti-NMDA receptor encephalitis: report of two cases.

Project description:BackgroundAnti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the most prevalent etiologies of autoimmune encephalitis. Approximately 25% of anti-NMDAR encephalitis cases prove refractory to both first- and second-line treatments, posing a therapeutic dilemma due to the scarcity of evidence-based data for informed decision-making. Intravenous rituximab is commonly administered as a second-line agent; however, the efficacy of its intrathecal administration has rarely been reported.Case summaryWe report two cases of severe anti-NMDAR encephalitis refractory to conventional therapies. These patients presented with acute-onset psychosis progressing to a fulminant picture of encephalitis manifesting with seizures, dyskinesia, and dysautonomia refractory to early initiation of first- and second-line therapeutic agents. Both patients received 25 mg of rituximab administered intrathecally, repeated weekly for a total of four doses, with no reported adverse effects. Improvement began 2-3 days after the first intrathecal administration, leading to a dramatic recovery in clinical status and functional performance. At the last follow-up of 6 months, both patients remain in remission without the need for maintenance immunosuppression.ConclusionOur cases provide evidence supporting the intrathecal administration of rituximab as a therapeutic option for patients with refractory anti-NMDAR encephalitis. Considering the limited penetration of intravenous rituximab into the central nervous system, a plausible argument can be made favoring intrathecal administration as the preferred route or the simultaneous administration of intravenous and intrathecal rituximab. This proposition warrants thorough investigation in subsequent clinical trials.

| S-EPMC10950913 | biostudies-literature

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