Intramedullary spinal cord tumors in pediatric patients presenting later with brain lesions: case series and systematic review of the literature.

PURPOSE: Intramedullary spinal cord tumors are an uncommon pathology in adults and children. Most descriptive studies of intramedullary spinal cord tumors have not focused on a possible association with future brain lesions. To the best of our knowledge, few reports describe this potential relationship. This is one of the most extensive case series of secondary brain lesions of intramedullary spinal cord tumors in the pediatric population. METHODS: Retrospective chart review was performed on pediatric patients (21 years old and younger) who underwent resection of an intramedullary spinal cord tumor at two tertiary care hospitals from 2001 to 2020. Patients previously treated or diagnosed with spinal cord tumor, and subsequent development of intracranial manifestation of the same or different tumor, were included. Data regarding epidemiology, surgical intervention, and clinical and follow-up course were gathered. Data analysis was performed according to a standardized clinical protocol with a literature review. RESULT: More than 500 patients underwent intradural spinal tumor resection surgeries at participating hospitals from 2001 to 2020. After excluding adult patients (older than 21 years old) and those with extramedullary lesions, 103 pediatric patients were identified who underwent resection of an intramedullary spinal cord tumor. Four underwent resection of an intermedullary tumor and later in their follow-up course developed a secondary intracranial neoplasm. In every case, the secondary neoplasm had the same pathology as the intramedullary tumor. Three of the patients had tumors at the cervico-thoracic junction, and one patient had a high cervical tumor. These patients had a negative primary workup for any metastatic disease at the time of the presentation or diagnosis. Complete and near complete resection was performed in three patients and subtotal in one patient. CONCLUSION: Secondary brain tumors disseminated after initial spinal cord tumor are extremely rare. This study aims to allow specialists to better understand these pathologies and treat these rare tumors with more certainty and better expectations of unusual associated lesions and conditions.

C1-C2 intraarticular distraction with anterior cervical cages for basilar invagination realignment: Operative technique nuances and review of literature.

Neurosurgical management of basilar invagination (BI) has traditionally been aimed at direct cervicomedullary decompression through transoral dens resection or suboccipital decompression with supplemental instrumented fixation. Dr. Goel introduced chronic atlantoaxial dislocation (AAD) as the etiology in most cases of BI and described a technique for distracting the C1-C2 joint with interfacet spacers to achieve reduction and anatomic realignment. We present our modification to Goel's surgical technique, in which we utilize anterior cervical discectomy (ACD) cages as C1-C2 interfacet implants. A young adult male presented to our institution with BI, cervicomedullary compression, occipitalization of C1, and Chiari 1 malformation. There was AAD of C1 over the C2 lateral masses. This reduced some with preoperative traction. He underwent successful C1-C2 interfacet joint reduction and arthrodesis with anterior cervical discectomy (ACD) cages and concomittant occiput to C2 instrumented fusion. BI can be effectively treated through reduction of AAD and by utilizing ACD cages as interfacet spacers.

Humoral immune response to COVID-19 mRNA vaccines in patients with relapsing multiple sclerosis treated with ofatumumab.

BACKGROUND: There are limited data available regarding the impact of ofatumumab, an anti-CD20 B-cell-depleting monoclonal antibody for relapsing multiple sclerosis (RMS), on vaccination response. The study objective was to assess humoral immune response (HIR) to non-live coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination in patients with RMS treated with ofatumumab. METHODS: This was an open-label, single-arm, multicenter, prospective pilot study of patients with RMS aged 18-55 years who received 2 or 3 doses of a COVID-19 mRNA vaccine after ≥1 month of subcutaneous ofatumumab (20 mg/month) treatment. The primary endpoint was the proportion of patients achieving HIR, as defined by local laboratory severe acute respiratory syndrome coronavirus-2 qualitative immunoglobulin G assays. Assay No. 1 was ≥14 days after the second or third vaccine dose. Assay No. 2 was 90 days thereafter. RESULTS: Of the 26 patients enrolled (median [range] age: 42 [27-54] years; median [range] ofatumumab treatment duration: 237 [50-364] days), HIR was achieved by 53.9% (14/26; 95% CI: 33.4 - 73.4%) at Assay No. 1 and 50.0% (13/26; 95% CI: 29.9 - 70.1%) at Assay No. 2. Patients who received 3 vaccine doses had higher HIR rates (Assay No. 1: 70.0% [7/10]; Assay No. 2: 77.8% [7/9]) than those who received 2 doses (Assay No. 1: 46.7% [7/15]; Assay No. 2: 42.9% [6/14]). Of patients aged <40 years without previous anti-CD20 therapy, HIR was achieved by 90.0% (9/10) at Assay No. 1 and 75.0% (6/8) at Assay No. 2. No serious adverse events were reported. CONCLUSION: Patients with RMS treated with ofatumumab can mount HIRs following COVID-19 vaccination. A plain language summary, infographic and a short video summarizing the key results are provided in supplementary material. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04847596 (https://clinicaltrials.gov/ct2/show/NCT04847596).

Real-World Safety and Effectiveness After 5 Years of Dimethyl Fumarate Treatment in Black and Hispanic Patients with Multiple Sclerosis in ESTEEM.

INTRODUCTION: Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. RESULTS: Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12 months before study entry (all p < 0.0001). CONCLUSION: The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02047097.

Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

Epidemiologic trends of multiple sclerosis in Puerto Rico (2013-2020).

BACKGROUND: Previous studies have demonstrated higher multiple sclerosis (MS) incidence and prevalence in Puerto Rico (PR) than in other Caribbean and Latin American countries. Our objectives are to update the epidemiologic trends in MS incidence and prevalence rates for PR from 2017 through 2020 and compare them to prior rate data from 2013 to 2016. METHODS: We used the Puerto Rico MS Foundation's registry (PRMS Registry) data to identify all newly diagnosed MS cases between January 2017 and December 2020. The study population included 568 MS patients, 406 women and 162 men living in PR. All individuals were 18 years and older and met the 2017 revised McDonald criteria for MS diagnosis. In addition, age- and sex-standardized incidence rates were estimated. RESULTS: A total of 568 new MS cases were diagnosed in Puerto Rico between 2017 and 2020. The 2020 MS cumulative prevalence for Puerto Rico was 95.3/100,000 (95% CI: 91.6, 99.1), higher than previously reported. The age- and sex-standardized MS incidence rate for Puerto Rico decreased from 6.5/100,000 (2017) to 6.3/100,000 (2020). The annual age-standardized MS incidence rates declined for females: from 9.5/100,000 (2017) to 8.2/100,000 (2020) but increased for males from 3.6/100,000 to 4.6/100,000 during the same period. CONCLUSION: These incidence and prevalence rates are among the highest reported among Caribbean and Latin American countries. A peak in the age- and sex-standardized MS incidence rate was observed after hurricane María (2018) and a decline during the first year of the COVID-19 pandemic (2020). Further investigation is needed to determine whether there was a causal relationship between the fluctuations observed and those natural events.

A Case of Neuromyelitis Optica: Puerto Rican Woman with an Increased Time Lag to Diagnosis and a High Response to Eculizumab Therapy.

A link between intractable hiccups, as the initial symptom, and a possible neuromyelitis optica spectrum disorder (NMOSD) diagnosis is confusing but vital and may not be made by health care providers (HCPs) if they are not aware of the 2015 NMOSD criteria. Early diagnosis and adequate treatment are essential to prevent disease progression. We report the case of a 46-year-old Puerto Rican female who presented intractable hiccups when she was 31 (in 2004). Almost 15 years passed since the initial symptom, and after two severe relapses, she received a formal NMOSD diagnosis in March 2019. Treatment started with rituximab 1000 mg IV in April 2019. However, a lack of response to treatment led to a switch to eculizumab therapy in August 2019. The patient had cervical and brain magnetic resonance imaging (MRI) conducted in June 2020, which depicted a remarkable decrease in swelling and hyperintensity within the cervical spinal cord with no enhancing lesions when compared with the first MRI from February 2019. In addition, the patient suffered no new relapses, an improvement regarding disability, and a reduction of the cervical spinal cord lesion size. Nonetheless, this substantial decrease does not occur on all NMOSD patients, but more awareness of the disease is needed, especially in Puerto Rico. This case illustrates the efficacy of eculizumab therapy and the importance of differentiating the clinical, histopathological, and neuroimaging characteristics that separate demyelinating autoimmune inflammatory disorders, such as NMOSD and multiple sclerosis (MS).

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.

Effectiveness of film as a health communication tool to improve perceptions and attitudes in multiple sclerosis.

BACKGROUND: Health communication tools like film are capable of reducing health disparities and could be effective in addressing negative illness perceptions of MS in Hispanics/Latinx. OBJECTIVE: To test the feasibility of using a culturally appropriate short narrative film to examine illness perceptions overtime and attitudes in Hispanics/Latinx affected with MS. METHODS: Participants were assigned to view a short narrative film (n = 130) or not (n = 106). The Brief Illness Perception Questionnaire (BIPQ) was used to examine illness perceptions at baseline, one and three months. Focus groups were conducted at 6 months. Measures of sociocultural integration were obtained. Individual group BIPQ domains were evaluated over time using paired sample t-test. Multivariate linear regression was used to examine predictors of BIPQ change. RESULTS: A more positive perception of treatment (p < 0.0001) and understanding (p = 0.0003) were seen at 3 months for those exposed to film. Focus groups were effective in highlighting that the perceived disease prognosis, family support and awareness of MS contributes to attitudes. Exposure to film was found to be the strongest predictor (Beta:6.31, p = 0.01) of BIPQ change at three months. CONCLUSION: Our results provide support that a short narrative film of MS in Hispanics/Latinx is a feasible intervention to change perceptions of MS to a more positive view.

Effect of Alemtuzumab Infusions on Vital Signs: A Prospective Observational Study in Patients with Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We characterize vital signs during and after the first alemtuzumab infusion course. METHODS: Patients with relapsing-remitting multiple sclerosis commercially prescribed alemtuzumab 12 mg/day on 5 consecutive days (initial course) were enrolled in this prospective, observational study. Preinfusion medications included methylprednisolone, antihistamine, and antipyretics. Primary end point: change from precourse baseline in vital signs during and 2 hours after each alemtuzumab infusion. Secondary end points: infusion duration and serious adverse events (AEs) starting within 24 hours and within 7 days after infusion (AEs collected up to 15 days after treatment). Potentially clinically significant vital sign abnormalities were based on predefined thresholds from literature review. RESULTS: In the 304 patients treated, minimal increases in mean systolic (≤8 mm Hg) and diastolic (≤3 mm Hg) blood pressures from precourse baseline were observed on infusion days 3 to 5. An increase in mean heart rate (20 beats per minute) during the first infusion day normalized by day 2, and smaller increases (5 beats per minute) occurred during subsequent infusions. Serious AEs occurred in two patients (0.7%) during or within 24 hours after infusion and in three patients (1.0%) within 7 days. Mean/median infusion duration was 4 hours. Vital sign abnormalities with potential clinical significance occurred in 62.5% of patients. CONCLUSIONS: Although most patients had potentially clinically significant vital sign abnormalities, mean changes from baseline during and after infusion of the first alemtuzumab course were clinically insignificant. No new safety signals were detected.