Blood-based biomarkers of neuronal and glial injury in active major neuropsychiatric systemic lupus erythematosus.

BACKGROUND: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. METHODS: This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6 months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. RESULTS: Thirteen patients with active major NPSLE, 13 age/sex/kidney function matched SLE controls without active major NPSLE, and 13 age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6 years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3 pg/ml (p = .42) and 1.2 pg/ml higher (p = .53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p < .001) and blood GFAP was on average 3.2 pg/ml higher (95% CI: 1.9, 5.5; p < .001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. CONCLUSIONS: Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting.

Longitudinal study of immunity to SARS-CoV2 in ocrelizumab-treated MS patients up to 2 years after COVID-19 vaccination.

OBJECTIVES: (1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity. METHODS: Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. RESULTS: The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity. INTERPRETATION: Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.

Anti-NMDA Receptor Encephalitis Related to Renal Cell Carcinoma: A Case Report.

Anti-NMDA receptor (NMDAR) encephalitis is characterized by a well-defined neuropsychiatric syndrome and CSF antibodies against the GluN1 subunit of the NMDAR. 40% of cases are related to underlying tumors, the vast majority ovarian teratomas (94%). We report a case of anti-NMDAR encephalitis associated with renal cell carcinoma (RCC). A 20-year-old female presented to the ED with behavioral changes, involuntary movements, tachycardia, and alternating obtundation with agitation which progressed over 3 weeks. Involuntary movements were severe, requiring intubation and sedation for control, and were accompanied by rhabdomyolysis. Brain MRI showed bilateral mesiotemporal T2/FLAIR hyperintensities. Anti-NMDAR antibodies were present in the serum (1:640) and CSF (1:320). Malignancy screening revealed a renal mass concerning for RCC, which was confirmed upon resection. She was started on high dose IV methylprednisolone and plasmapheresis, followed by rituximab. Lack of response led to escalating immunotherapy with cyclophosphamide. Clinical course was complicated by prolonged ICU admission, prolonged sedation, severe dysautonomia and bacteremia. Improvement began 2 months after immunotherapy, and she was discharged to rehabilitation 100 days after admission with mild neuropsychiatric symptoms. Repeat malignancy screenings, including whole-body imaging and transvaginal ultrasound were consistently negative. Herein, we describe a case of definite anti-NMDAR encephalitis in the setting of newly diagnosed RCC. This case illustrates how tumors other than ovarian teratomas may act as immunological triggers, as well as the complex and prolonged symptomatic and immunosuppressive therapies required in severe presentations of anti-NMDAR encephalitis.

SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis.

The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.

Diversity, equity, and inclusion (DEI) in medical education: DEI at the bedside.

BACKGROUND: The ability to recognize and address bias is an important communication skill not typically addressed during training. We describe the design of an educational curriculum that aims to identify and change behavior related to diversity, equity, and inclusion (DEI). "DEI at the Bedside" uses the existing infrastructure of bedside teaching and provides a tool to normalize DEI discussions and develop skills to address bias during a neurology inpatient rotation. METHODS: As part of traditional clinical rounds, team members on an inpatient service shared experiences with DEI topics, including bias. The team developed potential responses should they encounter a similar situation in the future. We report the results of our needs assessment and curriculum development to evaluate the feasibility of incorporating a DEI educational curriculum in the neurology inpatient setting. RESULTS: Forty-two DEI experiences were recorded. Medical students were the most frequent discussants (44%). Direction of bias occurred between healthcare team members (33%), against patients (31%), and patients against healthcare team members (28%). Experiences ranged from microaggressions to explicit comments of racism, sexism, and homophobia. CONCLUSIONS: Based on needs assessment data, we developed a DEI educational curriculum for the inpatient neurology setting aimed to improve knowledge and skills related to DEI topics as well as to normalize conversation of DEI in the clinical setting. Additional study will demonstrate whether this initiative translates into measurable and sustained improvement in knowledge of how bias and disparity show up in the clinical setting and behavioral intent to discuss and address them.

PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Successful Autologous Hematopoietic Stem Cell Transplant in Glycine Receptor Antibody-Positive Stiff Person Syndrome: A Case Report

BACKGROUND AND OBJECTIVES: To describe a case of glycine receptor (GlyR) antibody-positive stiff person syndrome (SPS) treated with autologous hematopoietic stem cell transplant (aHSCT). METHODS: This was a multicenter collaboration for the treatment of a single patient who underwent aHSCT as part of a clinical trial (NCT00716066). To objectively assess the response to transplantation, several clinical outcome measures were evaluated pretransplant and up to 18 months post-transplant, including modified Rankin Score (mRS), stiffness index, Hauser Ambulation Score (HAS), hypersensitivity index, timed 25-foot walk, and Montreal Cognitive Assessment. RESULTS: After transplant, the patient achieved sustained clinical improvement evidenced across various clinical scales, including mRS, stiffness index, HAS, and 25-foot walk time. DISCUSSION: aHSCT represents a promising treatment option for SPS, including for GlyR-positive patients. In addition, this case represents the need to validate and standardize best clinical outcome measures for patients with SPS. CLASSIFICATION OF EVIDENCE: Class IV; this is a single observational study without controls.

case of autoimmune GFAP astrocytopathy with eosinophils in the cerebrospinal fluid.

Cerebrospinal fluid (CSF) eosinophilia is associated with a narrow differential, primarily including parasitic and fungal infections, neoplasm, and chemical meningitis. It has rarely been reported in neuroinflammatory conditions including as a finding of CSF cytology in two autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy cases. Here we describe a case of autoimmune GFAP astrocytopathy with classic clinical and radiographic features as well as presence of eosinophils in the CSF. This case highlights a potential association of eosinophils in the CSF with autoimmune GFAP astrocytopathy, which may suggest its inclusion in the differential diagnosis of eosinophilic meningitis, encephalitis, or myelitis.

Autoimmune and paraneoplastic neurological disorders: A review of relevant neuroimaging findings.

INTRODUCTION: Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AIE) are immune-mediated disorders. PNS is linked to cancer, while AIE may not Their clinical manifestations and imaging patterns need further elucidation. OBJECTIVE/AIMS: To investigate the clinical profiles, antibody associations, neuroimaging patterns, treatments, and outcomes of PNS and AIE. METHODS: A systematic review of 379 articles published between 2014 and 2023 was conducted. Of the 55 studies screened, 333 patients were diagnosed with either PNS or AIE and tested positive for novel antibodies. Data on demographics, symptoms, imaging, antibodies, cancer associations, treatment, and outcomes were extracted. RESULTS: The study included 333 patients (mean age 54 years, 67% males) with PNS and AIE positive for various novel antibodies. 84% had central nervous system issues like cognitive impairment (53%), rhombencephalitis (17%), and cerebellar disorders (24%). Neuroimaging revealed distinct patterns with high-risk antibodies associated with brainstem lesions in 98%, cerebellar in 91%, hippocampal in 98%, basal ganglia in 75%, and spinal cord in 91%, while low/intermediate-risk antibodies were associated with medial temporal lobe lesions in 71% and other cortical/subcortical lesions in 55%. High-risk antibodies were associated with younger males, deep brain lesions, and increased mortality of 61%, while low/intermediate-risk antibodies were associated with females, cortical/subcortical lesions, and better outcomes with 39% mortality. Associated cancers included seminomas (23%), lung (19%), ovarian (2%), and breast (2%). Treatments included IVIG, chemotherapy, and plasmapheresis. Overall mortality was 25% in this cohort. CONCLUSION: PNS and AIE have distinct clinical and radiological patterns based on antibody profiles. High-risk antibodies are associated with increased mortality while low/intermediate-risk antibodies are associated with improved outcomes. Appropriate imaging and antibody testing are critical for accurate diagnosis.

Cognitive dysfunction in pediatric systemic lupus erythematosus: current knowledge and future directions.

Cognitive dysfunction (CD) is a neurologic complication of pediatric systemic lupus erythematosus (SLE) that remains poorly understood and understudied, despite the potential negative effects of CD on long-term socioeconomic status and quality of life. Data regarding the prevalence and risk factors for CD in pediatric SLE as well as the optimal screening, treatment, and long-term outcomes for CD are lacking. In this review, we present current knowledge on CD in pediatric SLE with a focus on the application to clinical practice. We discuss the challenges in diagnosis, clinical screening methods, potential impacts, and interventions for this complication. Finally, we discuss the remaining gaps in our knowledge of CD in pediatric SLE, and avenues for future research efforts.

SARS-CoV-2 mRNA vaccination induces an antigen-specific T cell response correlating with plasma interferon-gamma in B cell depleted patients.

Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective.

Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

Mycobacterium abscessus Meningitis Associated with Stem Cell Treatment During Medical Tourism.

Mycobacterium abscessus infections have been reported as adverse events related to medical tourism. We report M. abscessus meningitis in a patient who traveled from Colorado, USA, to Mexico to receive intrathecal stem cell injections as treatment for multiple sclerosis. We also review the management of this challenging central nervous system infection.

Safety and patient experience with at-home infusion of ocrelizumab for multiple sclerosis.

OBJECTIVE: This study aimed to evaluate safety (infusion-related reactions [IRRs]) and patient satisfaction (patient-reported outcomes [PROs]) for at-home ocrelizumab administration for patients with multiple sclerosis (MS). METHODS: This open-label study included adult patients with an MS diagnosis who had completed a ≥ 600-mg ocrelizumab dose, had a patient-determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600-mg ocrelizumab home-based infusion over 2 h, followed by 24-h and 2-week post-infusion follow-up calls. IRRs and adverse events (AEs) were documented during infusions and follow-up calls. PROs were completed before and 2 weeks post infusion. RESULTS: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)-similar to other shorter ocrelizumab infusion studies-and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at-home infusion process and confidence in the care provided. Patients also reported a significant preference for at-home infusion compared with prior infusion center experiences. INTERPRETATION: IRRs and AEs occurred at acceptable rates during in-home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home-based ocrelizumab infusion over a shorter infusion period.

PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) genes are associated with cancer-induced paraneoplastic syndromes that present with neurological symptoms and autoantibody production. How PNMA proteins trigger a severe autoimmune disease is unclear. PNMA genes are predominately expressed in the central nervous system with little known functions but are ectopically expressed in some tumors. Here, we show that PNMA2 is derived from a Ty3 retrotransposon that encodes a protein which forms virus-like capsids released from cells as non-enveloped particles. Recombinant PNMA2 capsids injected into mice induce a robust autoimmune reaction with significant generation of autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, while capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies present in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic neurologic disease show similar preferential binding to PNMA2 "spike" capsid epitopes. These observations suggest that PNMA2 capsids released from tumors trigger an autoimmune response that underlies Ma2 paraneoplastic neurological syndrome.

Herpesvirus-Associated Encephalitis: an Update.

Purpose of Review: Herpesviruses are a leading cause of encephalitis worldwide. The article reviews the eight human herpesviruses with a focus on recent advances as they pertain to encephalitis. Recent Findings: Notable recent updates include the development of multiplex polymerase chain reaction (PCR)-based panels, which have improved access to PCR tests, especially in rural and resource-limited areas. Despite unchanged treatment recommendations, research is ongoing into novel therapies. There have been recent advances in vaccines, particularly for varicella zoster virus (VZV) which may impact neurologic complications. Finally, the recent discovery of an association between herpes encephalitis and post-infectious autoimmune encephalitis has had a critical impact on the fields of infectious and autoimmune neurology, though there remains much to learn. Summary: Most herpesviruses are neurotropic and must be considered on the differential diagnosis for infectious encephalitis. This article describes recent advances in the diagnosis, treatment, complications, and management of these infections.

Evaluation of multiple consensus criteria for autoimmune encephalitis and temporal analysis of symptoms in a pediatric encephalitis cohort.

Objective: To evaluate the sensitivity and specificity of current criteria for the diagnosis of autoimmune encephalitis (AE) and the temporal onset of neuropsychiatric symptoms (NP) in a pediatric encephalitis cohort. Background: Multiple criteria for AE have been developed, including the Graus and pediatric-focused Cellucci consensus criteria, and the Determining Etiology in Encephalitis (DEE) score for patients with encephalitis. Early identification and treatment of AE is crucial to improve outcomes, but this can be difficult given the frequent overlap of clinical presentation between AE and infectious encephalitis (IE). Design/methods: A retrospective review was conducted of patients seen at our institution from 2000 to 2021 with a final diagnosis of AE or IE. These were narrowed through multiple exclusions to etiology-confirmed IE or antibody-positive/negative AE. Time of onset or results of all symptoms and diagnostics were recorded. Sensitivity and specificity of each criterion under various clinical scenarios were calculated over the first month after initial NP symptom onset. Results: A total of 23 antibody-positive AE, 9 antibody-negative AE and 23 IE patients were included in final analysis. Under an idealized scenario with rapid initial diagnostic evaluations, the sensitivity for pediatric AE by day 28 after onset of NP symptoms approached 90% for both Cellucci and Graus criteria. Specificity within these 28 days was low without infectious testing results, increasing the greatest with rapid PCR testing and second with infectious antibody testing-reaching ~90% with both. A DEE score of 3 provided a specificity of 100% in identifying IE, but low sensitivity (29%). Symptoms were noted to cluster within several days of onset in IE, but in AE were spread out. Personality/behavioral change, speech change, affective disorder, and sleep disturbance were noted more often in AE, while fever, elevated C-reactive protein or CSF protein, and abnormal MRI-Brain occurred more often in IE. Conclusion: In this study, we provide the first evaluation of the Cellucci criteria and the first validation of the DEE score in the differentiation of pediatric AE and IE. Further refinement of AE criteria is needed to improve early detection and treatment of pediatric AE.

Neurology of Acute Viral Infections.

As specialists in acute neurology, neurohospitalists are often called upon to diagnose and manage acute viral infections affecting the nervous system. In this broad review covering the neurology of several acute viral infections, our aim is to provide key diagnostic and therapeutic pearls of practical use to the busy neurohospitalist. We will review acute presentations, diagnosis, and treatment of human herpesviruses, arboviruses, enteroviruses, and some vaccine-preventable viruses. The neurological effects of coronaviruses, including COVID-19, are not covered in this review.