Inflammatory vaginitis in four B-cell suppressed women with Multiple Sclerosis.

B-cell depleting therapies are effective in multiple sclerosis (MS) and are widely used (Hauser et al., 2017). Inflammatory vaginitis (IV), characterized by unexplained vaginal symptoms including mucopurulent discharge, pain, irritation, and dyspareunia, has been reported in one MS patient on ocrelizumab (Filikci and Jensen, 2022), and to be present in 3.5 % of women on rituximab for autoimmune diseases (Yockey et al., 2021). We report here four cases of IV in B cell depleted women with MS. B-cell reconstitution was temporally associated with improvement of IV symptoms. Further investigation and vigilance for this potential treatment emergent adverse event affecting sexual and reproductive health of women with MS is needed.

Toward Precision Phenotyping of Multiple Sclerosis.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.

Contrast study after gastric repair: a review of incidence, outcomes and risk factors at an adult level 1 trauma center.

PURPOSE: The role of contrast study after traumatic gastric repair, continues to be controversial. To that end, we aim to review the incidence, outcomes, and risk factors of patients undergoing contrast study after traumatic gastric repair. METHODS: This was a retrospective review of all trauma patients admitted to a level 1 trauma center that sustained gastric injuries with subsequent repair between 2011 and 2018. Demographics, surgical interventions, complications, and clinical outcomes were evaluated. Statistical analysis included Chi-square/Fisher exact univariate analysis and multivariate logistic regression analysis with a 5% significance level. RESULTS: A total of 233 patients received a gastric repair, of whom 49 (21%) had a contrast study performed. Out of 49 patients with a contrast study, one was found to have a gastric leak. Mean time to contrast study was 6.3 ± 2.7 days. There was no statistically significant difference in post-operative complications between non-contrast and contrast study groups. Multivariate logistic regression analysis demonstrated a lack of statistical significance in clinical risk factors that would lead to obtaining a contrast study. CONCLUSION: Gastric leak after repair is rare and there is no statistically significant difference in clinical outcomes when comparing patients who underwent contrast study to those who did not. Routine contrast study after traumatic gastric repair may not be necessary and further evidence is warranted to determine the risk factors for a selective contrast study.

Axicabtagene Ciloleucel in Patients Ineligible for ZUMA-1 Because of CNS Involvement and/or HIV: A Multicenter Experience.

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

Vaccination Against SARS-CoV-2 in Neuroinflammatory Disease: Early Safety/Tolerability Data.

BACKGROUND: Patients with autoimmune disease and on immunotherapy were largely excluded from seminal anti-SARS-CoV-2 vaccine trials. This has led to significant vaccine hesitancy in patients with neuroinflammatory diseases (NID); including, but not limited to: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), neurosarcoidosis and myelin oligodendrocyte antibody-mediated disease (MOG-AD). Data is urgently needed to help guide clinical care in the NID population. METHODS: This was a cross-sectional observational study evaluating adults with a neurologist-confirmed diagnosis of a neuroinflammatory disease (NID) and a neurologically asymptomatic control population. Participants were recruited from multiple academic centers participating in the MS Resilience to COVID-19 Collaborative study. We analyzed participant responses from a vaccine-specific questionnaire collected between February and May 2021. RESULTS: 1164 participants with NID and 595 controls completed the vaccine survey. Hesitancy rates were similar between NID and control groups (n = 134, 32.7% NID vs. n = 56, 30.6% control; p = 0.82). The most common reasons for hesitancy in NID participants were lack of testing in the autoimmune population and fear of demyelinating/neurologic events. Unvaccinated patients who had discussed vaccination with their doctor were less likely to be hesitant (n=184, 73.6% vs. n=83, 59.7%; p = 0.007). 634 NID patients and 332 controls had received at least one dose of a vaccine against SARS-CoV-2 at the time of survey completion. After adjusting for age, BMI, and comorbidities, there was no difference in self-reported side effects (SE) between groups with the first dose (n = 256, 42.2% NID vs. 141, 45.3% control; p = 0.20) or second dose (n = 246, 67.0% NID vs. n = 114, 64.8% control, p = 0.85) of the mRNA vaccines nor with the viral-vector vaccines (n = 6, 46% NID vs. n = 8, 66% control; p = 0.39). All reported SEs fell into the expected SE profile. There was no difference in report of new/recurrent neurologic symptoms (n = 110, 16.2% vaccinated vs. 71, 18.2% unvaccinated; p = 0.44) nor radiologic disease activity (n = 40, 5.9% vaccinated vs. n = 30, 7.6% unvaccinated) between vaccinated and unvaccinated NID participants. CONCLUSIONS: We found no difference in patient-reported vaccine side effects and no evidence of NID worsening after vaccination. Large-scale real-world evidence is needed for further validation.

Intracranial Complications From Immune Checkpoint Therapy in a Patient With NSCLC and Multiple Sclerosis: Case Report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become an increasingly important tool in cancer treatment, revealing durable responses in several different types of tumors, including NSCLCs. Nevertheless, ICIs carry a risk of immune-mediated toxicities. There is a paucity of data for concurrent use of these agents in patients with autoimmune disorders, such as multiple sclerosis (MS). CASE PRESENTATION: We report a case of a man with a history of MS and metastatic NSCLC with brain metastases who had cancer progression after receiving chemotherapy, whole-brain radiation therapy, and stereotactic radiosurgery to brain lesions and was treated with the programmed death-ligand 1 inhibitor, atezolizumab. He had dramatic clinical and radiographic benefit but developed a severe MS flare and neurologic decline precluding further treatment. Considerable growth of a previously radiated brain lesion prompted resection, with pathologic findings consistent with radiation necrosis and demyelination without viable tumor cells. CONCLUSIONS: Although patients with preexisting autoimmune diseases, including MS, might be at an increased risk of developing immune-related adverse events with ICIs, they may also experience anticancer benefit. Intracranial disease can be challenging to accurately diagnose in a patient with MS who previously underwent radiation, as progressing lesions can be tumor growth, MS flare, or radiation necrosis.

Neuroinflammation Associated With Tumor Necrosis Factor-α Inhibitor Exposure.

OBJECTIVE: To identify the frequency and clinical spectrum of neuroinflammation associated with exposure to tumor necrosis factor-α inhibitors (TNFi). METHODS: We performed a single-system retrospective cohort study. Adults in the Yale New Haven Health System with documented use of any US Food and Drug Administration-approved TNFi between 2007 and 2017 were identified via automated review of the electronic medical record. Those who also had brain MRIs were identified and categorized as either TNFi exposed or unexposed. Individuals with MRI findings concerning for neuroinflammation were identified, and detailed chart reviews were performed. RESULTS: A total of 4,391 patients received TNFi, and 547 also had brain MRI. After exclusion criteria were applied, 375 MRIs occurred after TNFi exposure, and 132 MRIs occurred before TNFi. MRIs were normal for 20.8% of exposed patients. The most common abnormal finding was nonspecific, punctate T2 hyperintensities. Seventeen cases (4.5%) among the exposed cohort had findings consistent with neuroinflammation, of which 58.8% required TNFi discontinuation and additional immunotherapy, whereas an additional 23.5% discontinued TNFi alone. After 3 years, 70.6% had stable MRI findings, whereas 11.8% demonstrated progression. The 10-year period prevalence of neuroinflammation in all subjects exposed to TNFi was 0.4%. CONCLUSIONS: Neuroinflammatory phenomena following TNFi are a common concern for those treating patients with autoimmune disease. This is a large-scale study identifying the epidemiology surrounding this phenomenon. TNFi-associated inflammation was a rare outcome in our cohort. Most treated patients had either normal or nonspecific MRI findings. Further risk stratification parameters need to be identified.

Neurologic Safety Monitoring of COVID-19 Vaccines: Lessons From the Past to Inform the Present.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).

Neurological Immunotoxicity from Cancer Treatment.

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.

Evaluation of ocrelizumab in older progressive multiple sclerosis patients.

BACKGROUND: Seminal trials evaluating anti-CD20 therapy in progressive MS primarily found benefit in younger, less-disabled patients with more inflammatory disease activity. The risks and benefits of ocrelizumab use in older patients with progressive froms of MS are not known. METHODS: Retrospective chart review was performed for patients older than 55 with primary or secondary progressive MS at the time of ocrelizumab initiation. Clinical endpoints from 2 years prior to anti-CD20 therapy served as a within-subject control. RESULTS: Data was reviewed for 56 patients older than the age of 55 at the time of ocrelizumab initiation. Of 37 patients with 2-years of follow up on ocrelizumab, 40%(n=15) experienced confirmed disability progression (CDP) while 60% (n=22) remained stable or improved. 24 patients had data available for the within-subject control; for these patients, median age was 67, baseline EDSS 6.3, and disease duration 20.5 years. Prior to anti-CD20 therapy, 58% (n=14) of patients remained stable and 42% (n=10) experienced CDP. After ocrelizumab initiation, 71% (n=17) remained stable and 29% (n=7) experienced CDP. There was no difference between CDP (p=0.54) or change in EDSS (p=0.09) between time periods. Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control. CONCLUSIONS: We found no difference in clinical endpoints for patients on ocrelizumab compared to prior to anti-CD20 therapy; however, we could not exclude a modest effect given our sample size. Larger trials are needed to evaluate ocrelizumab use in this understudied MS subpopulation.

Worldwide survey of neurologists on approach to autoimmune encephalitis.

OBJECTIVE: To explore practice differences in the diagnosis and management of autoimmune encephalitis (AE), which is complicated by issues with sensitivity/specificity of antibody testing, nonspecific MRI/EEG/CSF findings, and competing differential diagnoses. METHODS: We used a worldwide electronic survey with practice-related demographic questions and clinical questions about 2 cases: (1) a 20-year-old woman with a neuropsychiatric presentation strongly suspicious of AE and (2) a 40-year-old man with new temporal lobe seizures and cognitive impairment. Responses among different groups were compared using multivariable logistic regression. RESULTS: We received 1,333 responses from 94 countries; 12.0% identified as neuroimmunologists. Case 1: those treating >5 AE cases per year were more likely to send antibodies in both serum and CSF (adjusted odds ratio [aOR] vs 0 per year: 3.29, 95% CI 1.31-8.28, p = 0.011), pursue empiric immunotherapy (aOR: 2.42, 95% CI 1.33-4.40, p = 0.004), and continue immunotherapy despite no response and negative antibodies at 2 weeks (aOR: 1.65, 95% CI 1.02-2.69, p = 0.043). Case 2: neuroimmunologists were more likely to send antibodies in both serum and CSF (aOR: 1.80, 95% CI 1.12-2.90, p = 0.015). Those seeing >5 AE cases per year (aOR: 1.86, 95% CI 1.22-2.86, p = 0.004) were more likely to start immunotherapy without waiting for antibody results. CONCLUSIONS: Our results highlight the heterogeneous management of AE. Neuroimmunologists and those treating more AE cases generally take a more proactive approach to testing and immunotherapy than peers. Results highlight the need for higher-quality cohorts and trials to guide empiric immunotherapy, and evidence-based guidelines aimed at both experts and nonexperts. Because the average AE patient is unlikely to be first seen by a neuroimmunologist, ensuring greater uniformity in our approach to suspected cases is essential to ensure that patients are appropriately managed.

Meningoradiculitis and transaminitis from neuroborreliosis: A case of variant Bannwarth syndrome.

BACKGROUND: Lyme disease is a common vector-borne illness in the U.S. caused by Borrelia species spirochetes. Neuroborreliosis has variable presentations, rarely manifesting as meningoradiculitis or "Bannwarth Syndrome", characterized by painful radiculopathy, neuropathy, varying degrees of motor weakness, peripheral facial nerve palsy and cerebrospinal fluid (CSF) lymphocytic pleocytosis. We present a case of Bannwarth Syndrome manifesting with transaminitis and significant weight loss. CASE PRESENTATION: A 60-year-old man with history of hypertension presented with 3 weeks of progressive back pain, bilateral arm and leg weakness, bilateral hand numbness and a right facial droop in absence of sphincter dysfunction. He reported an 11.3 kg unintentional weight loss and recent holiday to Egypt. Patient was afebrile with normal vital signs but with profound transaminitis on presentation. Exam revealed a lower motor neuron right facial nerve palsy, diffuse quadriparesis, areflexia but isolated brisk ankle reflexes. A left complete facial palsy developed shortly after admission. Concern for leptomeningeal plus peripheral nerve involvement led to consideration of oncologic, infectious and inflammatory etiologies, along with Guillain-Barre variants. Contrasted MRI of the brain and total spine was normal. CSF revealed lymphocytic pleocytosis (cell count 134), elevated protein (156) with normal glucose, cytology, AFB culture, viral PCRs and paraneoplastic antibodies. Serum and CSF Lyme IgG and IgM were positive. IV Ceftriaxone 2 g daily was started one day after admission. EMG/Nerve conduction studies showed diffuse polyradiculopathy without evidence of Guillain-Barre syndrome. Babesia co-infection was considered given unexplained transaminitis but PCR and quantitation were negative. CSF following 1 week of antibiotics showed improving cell and protein counts with resolving transaminitis. On follow-up at 2 months, facial paralysis, pain, motor and sensory deficits had resolved with return to baseline weight and liver function tests. CONCLUSIONS: Bannwarth syndrome, a subacute painful meningoradiculitis caused by Borrelia species infection, is an uncommon presentation of neuroborreliosis in the U.S. Our case demonstrates previously unreported features such as profound transaminitis and weight loss without evidence of co-infection. Clinical manifestations of neuroborreliosis are variable, thus it is important to consider Bannwarth syndrome in the differential of meningoradiculitis in areas where Lyme Disease is prevalent.

Autoimmune Encephalitides and Rapidly Progressive Dementias.

Rapidly progressive dementia (RPD) or cognitive decline is a common presenting complaint in neurology. While primary dementia is often a concern, other forms of reversible dementia must be thoroughly considered. This article focuses on the growing field of autoimmune encephalitis (AE) as it pertains to the differential diagnostic considerations in a work-up for RPD. Understanding clues in the history and examination is the first step in identifying patients with a potential autoimmune cause for RPD. While testing for infectious and toxic-metabolic etiologies is commonly preformed, it is necessary to consider early ancillary testing for AE in appropriate cases of RPD. Autoantibody testing in the spinal fluid and serum, brain imaging, and electroencephalography all form the first line of investigations for AE. Treatment options and strategies depend on the AE subtype and a number of individual patient considerations.

Practice Current: When do you suspect autoimmune encephalitis and what is the role of antibody testing?

Diagnosing autoimmune encephalitis (AE) is complicated by several factors, including issues with availability, sensitivity, and specificity of antibody testing, particularly with variability in assay techniques and new antibodies being rapidly identified; nonspecific findings on MRI, EEG, and lumbar puncture; and competing differential diagnoses. Through case-based discussions with 3 experts from 3 continents, this article discusses the challenges of AE diagnosis, important clinical characteristics of AE, preferences for methods of autoantibody testing and interpretation, and treatment-related questions. In particular, we explore the following question: If a patient's clinical presentation seems consistent with AE but antibody testing is negative, can one still diagnose the patient with AE? Furthermore, what factors does one consider when making this determination, and should treatment proceed independent of antibody testing in suspected cases? The same case-based questions were posed to the rest of our readership in an online survey, the results of which are also presented.

Incidence of meningeal enhancement on brain MRI secondary to lumbar puncture.

BACKGROUND: Concern for reactive meningeal enhancement after lumbar puncture (LP) is a common reason for performing brain MRI prior to LP. We sought to determine actual incidence of unexplained meningeal enhancement after LP. METHODS: We collected results from all contrasted brain MRIs in patients admitted to adult neurology at a New York City hospital over a 3-year period. We used electronic medical records to determine whether an LP had been done within 30 days prior to brain MRI. The control group comprised those brain MRIs not preceded by an LP within 30 days prior to imaging. Number of cases of unexplained meningeal enhancement was compared between groups using a Fisher exact test. We recorded variables such as number of LP attempts, needle size, amount of fluid removed, and days from LP to brain MRI. RESULTS: From 2011 to 2013, there were 77 cases of LP prior to brain MRI and 707 controls (n = 784). Of the cases, 3 had meningeal enhancement, 1 (1.2%) of which was unexplained. Of the 707 controls, 36 had enhancement, and none was unexplained. The p value comparing unexplained enhancement in the cases vs controls was 0.098. CONCLUSIONS: Iatrogenic meningeal enhancement from prior LP that is not attributable to traumatic LP or intracranial hypotension is rare and not more common than in cases without a prior LP. Results suggest that the practice of delaying LP until after brain MRI might not be supported in cases where LP is necessary.

The use of the right ventricular diameter and tricuspid annular tissue Doppler velocity parameter to predict the presence of pulmonary hypertension.

AIMS: Detecting the presence of pulmonary hypertension (PH) is important especially with unexplained dyspnoea and suspected thromboembolism. Although PH can be detected invasively by right ventricular (RV) catheterisation, accurate non-invasive assessment by echocardiography has many advantages. This however relies on the presence of tricuspid regurgitation (TR). We examined if the presence of PH can be predicted echocardiographically without relying on TR. METHODS AND RESULTS: Seventy-six consecutive patients with TR were recruited, and another 32 were used for prediction study. RV end-diastolic diameter (RVD) was measured in the apical view and tissue Doppler imaging (TDI) parameters were obtained from the lateral tricuspid annulus motion. Pulmonary artery systolic pressures (PASP) were estimated from TR. The RVD, and the TDI duration from start of isovolumic contraction to peak systole, T(peak), correlated with PASP. However, the RVD/T(peak) ratio offered the best correlation and, at a cutoff of 22 cm/s, predicted the presence of PH with 80% sensitivity and 83% specificity. The same results were obtained even if the study was confined to patients with or without RV dysfunction. The ratio displayed a good correlation with catheter-derived PASP in nine separate patients. CONCLUSION: While RVD and T(peak) can adequately detect the presence of PH, RVD/T(peak) acted as the best predictor for PH. The results apply regardless of the presence or absence of RV dysfunction.