Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

BACKGROUND: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. OBJECTIVE: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. METHODS: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores. RESULTS: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p < 0.001) and EDSS (ß = 0.16, p < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p = 0.01) and EDSS (ß = -0.06, p < 0.001). Neither presentation was associated with changes in relapse risk. CONCLUSION: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Impact of Low Ankle-Brachial Index on the Risk of Recurrent Vascular Events.

Background and Purpose- Low ankle-brachial index (ABI) identifies a stroke subgroup with high risk of recurrent stroke, cardiovascular events, and death. However, limited data exist on the relationship between low ABI and stroke in low and middle-income countries. Therefore, we evaluated the prevalence of ABI ≤0.90 (which is diagnostic of peripheral artery disease) in nonembolic stroke patients or transient ischemic attack and assessed the correlation of low ABI with stroke risk, factors, and recurrent vascular events and death. Methods- Patients ≥45 years with acute transient ischemic attack or minor ischemic strokes were recruited consecutively from over 17 low-income and middle-income countries (Latin America [1543 patients], Middle East [1041 patients], North Africa [834 patients], and South Africa [217 patients]). The ABI measurement was performed at a single visit. Stroke recurrence and risk of new vascular events were assessed after 24 months of follow-up. Results- Among 3487 enrolled patients, abnormal ABI (<0.9) was present in 22.3 %. Patients with an ABI of ≤0.9 were more likely ( P<0.05) to be male, older, and have a history of peripheral artery disease, hypertension, and diabetes mellitus. During 2-year follow-up, the rate of major cardiovascular event was higher in patients with ABI <0.9 than those with ABI ≥0.9 (Kaplan-Meier estimates, 22.5%; 95% CI, 19.6-25.8 versus 13.7%; 21.4-15.1; P<0.001), and when ABI was categorized into 4 groups (≤0.6; 95% CI, 0.6-0.9; 0.9-1; 1-1.4), the rate of major cardiovascular event was higher in those with ABI ≤0.6 than the other groups (Kaplan-Meier estimates, 32.6%; 95% CI, 21.0-48.3 for ABI≤0.6 versus 21.7%; 95% CI, 18.8-25.0 for ABI 0.6-0.9 versus 14.3%; 95% CI, 12.4-16.6 for ABI 0.9-1 versus 13.3%; 95% CI, 11.6-15.2 for ABI 1-1.4; P<0.001). Conclusions- Among patients with nonembolic ischemic stroke or transient ischemic attack, those with low ABI had a higher rate of vascular events and death in this population. Screening for ABI in stroke patients may help identify patients at high risk of future events.

Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease of autoimmune etiology, mediated by activated T cells with evolving evidence of a significant contribution from B cells and cells of the innate immune system. The disease is thought to be due to a complex interaction between different genetic and environmental factors. The prevalence of MS is rising all over the world, due on one hand to earlier diagnosis and prolonged survival, and on the other to a true increase in incidence of the disease. The diagnosis of MS remains clinical despite recent advances in diagnostics and relies on demonstrating dissemination in space and time while excluding alternative diagnoses. The Mc Donald diagnostic criteria, with their recent 2017 revision, are currently widely accepted in the MS community. Although no cure is yet available, many disease-modifying therapies (DMTs) have shown different levels of efficacy in preventing relapses, accumulation of lesions on magnetic resonance imaging (MRI), and disability progression. Current treatment strategies include gradual escalation based on clinical and radiological criteria that determine treatment response, or initial induction with high efficacy DMTs especially in patients with an early aggressive course.

Gadolinium effect on thalamus and whole brain tissue segmentation.

PURPOSE: Gadolinium-based contrast agent (GBCA) effect on automated segmentation algorithms of subcortical gray matter (GM) is not fully known. The aim of this study is to determine gadolinium effect on the segmentation of the thalamus and whole brain tissue using different automated segmentation techniques. METHODS: Eighty-four multiple sclerosis (MS) patients underwent an MRI acquisition of two 3DT1-weighted sequences with and without gadolinium injection among which 10 were excluded after image quality check. Manual thalamic segmentation considered as gold standard was performed on unenhanced T1 images. volBrain and FSL-Anat were used to automatically segment the thalamus on both enhanced and unenhanced T1 and the degree of similitude (DICE) values were compared between manual and automatic segmentations. Whole brain tissue segmentation (GM, white matter (WM), and lateral ventricles (LV)) was also performed using SIENAX. A paired samples t test was applied to test the significance of DICE value differences between the thalamic manual and automatic segmentations of both enhanced and unenhanced T1 images. RESULTS: Significant differences (FSL-Anat 1.474% p < 0.001 and volBrain 1.990% p < 0.001) in DICE between thalamic manual and automatic segmentations on both enhanced and unenhanced images were observed. Automatic tissue segmentation showed a mean DICE of 81.5%, with LV having the lowest DICE value (74.2%). When compared to tissue segmentations, automatic thalamic segmentations by FSL-Anat or volBrain demonstrated a higher degree of similitude (FSL-Anat = 91.7% and volBrain = 90.7%). CONCLUSION: Gadolinium has a significant effect on subcortical GM segmentation. Although significant, the observed subtle changes could be considered acceptable when used for region-based analysis in perfusion or diffusion imaging.

Catastrophic relapses following initiation of dimethyl fumarate in two patients with neuromyelitis optica spectrum disorder.

We report two cases of neuromyelitis optica spectrum disorder (NMOSD) who were misdiagnosed as multiple sclerosis (MS) and developed catastrophic relapses following initiation of dimethyl fumarate. Both patients developed a severe myelitis extending from the cervical cord to the medulla with significant cord swelling, resulting in complete quadriplegia and respiratory difficulties, in addition to severe bilateral visual loss in one patient. It is of note that both catastrophic relapses occurred 2 and 3 months following initiation of dimethyl fumarate.

Natalizumab treatment for multiple sclerosis: Middle East and North Africa regional recommendations for patient selection and monitoring.

BACKGROUND: Natalizumab, a highly specific α4-integrin antagonist, , has recently been registered across the Middle East and North Africa region. It improves clinical and magnetic resonance imaging (MRI) outcomes and reduces the rate of relapse and disability progression in relapsing-remitting multiple sclerosis (MS). Natalizumab is recommended for patients who fail first-line disease-modifying therapy or who have very active disease. Progressive multifocal leukoencephalopathy is a rare, serious adverse event associated with natalizumab. We aim to develop regional recommendations for the selection and monitoring of MS patients to be treated with natalizumab in order to guide local neurological societies. METHODS: After a review of available literature, a group of neurologists with expertise in the management of MS met to discuss the evidence and develop regional recommendations to guide appropriate use of natalizumab in the region. RESULTS: Disease breakthrough is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. Natalizumab is recommended as an escalation therapy in patients with breakthrough disease based on its established efficacy in Phase III studies. Several factors including prior immunosuppressant therapy, anti-John Cunningham virus (JCV) antibody status and patient choice will affect the selection of natalizumab. In highly active MS, natalizumab is considered as a first-line therapy for naive patients with disabling relapses in association with MRI activity. The anti-JCV antibody test is used to assess anti-JCV antibody status and identify the risk of PML. While seronegative patients should continue treatment with natalizumab, anti-JCV antibody testing every 6 months and annual MRI scans are recommended as part of patient monitoring. In seropositive patients, the expected benefits of natalizumab treatment have to be weighed against the risks of PML. Clinical vigilance and follow-up MRI scans remain the cornerstone of monitoring. After 2 years of natalizumab therapy, monitoring should include more frequent MRI scans (every 3-4 months) for seropositive patients, and the risk-benefit ratio should be reassessed and discussed with patients. CONCLUSIONS: Recommendations have been developed to guide neurologists in the Middle East and North Africa on patient selection for natalizumab treatment and monitoring.

Characteristics of multiple sclerosis in the Middle East with special reference to the applicability of international guidelines to the region.

We have reviewed the clinical literature with reference to the local applicability of guidelines for the diagnosis and management of multiple sclerosis (MS) in the Middle East. There is a substantial burden of MS in the region: the prevalence of the disease appears to have increased markedly in recent decades, with a faster rate of increase in female vs. male patients. The aetiology and presentation of MS appears to be broadly similar in the Middle East to that in other regions. Interferon-ß is the most commonly used treatment for MS in the Middle East, as elsewhere, although it is unclear to what extent economic constraints act as a barrier to accessing this treatment. Similarly, limited available data suggest that the availability of MRI scanners appears to be lower in the Middle East than in more developed nations. Little is known concerning other potential barriers to treatment. There is a need for further research on aspects of management of MS beyond the pharmacological aspects of treatment to assess fully the potential barriers to the adoption of international guidelines for the diagnosis and management of the disease in the Middle East.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). CLASSIFICATION OF EVIDENCE: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.

Will new injection devices for interferon ß-1a s.c. affect treatment adherence in patients with multiple sclerosis? An expert opinion in the Middle East.

Treatment adherence to disease modifying drugs (DMDs) in multiple sclerosis is sub-optimal. This, in turn, can affect patients' long-term responses to therapy. A key factor that influences treatment adherence is the need for self-injection of DMDs, which can be demanding and disruptive for patients, and difficult for those with cognitive difficulties or reduced manual dexterity. In addition, pain resulting from poor injection technique, and needle anxiety, may both compromise adherence. Changes to the formulation of interferon (IFN) beta-1a for subcutaneous injection that were designed to improve injection local tolerability, and changes in drug-delivery technology, designed to make injections simpler and more convenient for patients, were reviewed by a group of experts on MS in the Middle East. The group also considered the possible effects of these changes in drug delivery technology on patient adherence to IFN beta-1a s.c.

The importance of quality-of-life assessment in the management of patients with multiple sclerosis. Recommendations from the Middle East MS Advisory Group.

Multiple sclerosis (MS) has a major negative impact on patients` health-related quality of life (QoL). A group of MS experts in the Middle East met to develop recommendations for the routine assessment of QoL in patients with MS. The group recommended that patients need to be assessed once a year using the multiple sclerosis international QoL questionnaire (MusiQoL), which is available in Arabic. Assessments should be made when patients are relapse-free to avoid confounding factors. At other clinic visits, patients` QoL should also be monitored, alongside their physical assessment, using open and structured questions on disease features that are likely to affect their QoL. This approach should allow long-term monitoring of key features of MS that are important to patients` well being, and aid decision-making regarding their management, including the use of disease-modifying drugs.

MENACTRIMS practice guideline for COVID-19 vaccination in patients with multiple sclerosis.

Patients with multiple sclerosis (MS) should be vaccinated against COVID-19. All COVID-19 vaccines are effective and do not appear to carry any additional risk for patients with MS. Patients with MS should get a COVID-19 vaccine as soon as it becomes available. The risks of COVID-19 disease outweigh any potential risks from the vaccine. Even if vaccinated, patients with MS should continue to practice standard and recommended precautions against COVID-19, such as wearing a face mask, social distancing and washing hands. There is no evidence that patients with MS are at higher risk of complications from the mRNA, non-replicating viral vector, inactivated virus or protein COVID-19 vaccines, compared to the general population. COVID-19 Vaccines are safe to use in patients with MS treated with disease-modifying therapies (DMTs). The effectiveness of vaccination may be affected by few of the DMTs but yet some protection is still provided. For certain DMTs we may consider coordinating the timing of the vaccine with the timing of the DMT dose to increase vaccine efficacy.

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis.

OBJECTIVE: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. METHODS: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. RESULTS: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. CONCLUSION: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.

Adherence to disease-modifying drugs in patients with multiple sclerosis: a consensus statement from the Middle East MS Advisory Group.

Adherence to therapy is a key issue in chronic illnesses. In addition, several features of multiple sclerosis (MS) and its treatment may increase the likelihood of patient nonadherence and discontinuation of treatment. Nonadherence will obviously compromise the efficacy of disease-modifying drugs in patients with MS. This subject was discussed by a group of local MS specialists from the Middle East. The group debated several key questions about the features and causes of patient nonadherence and its management. Further, they made recommendations for optimizing treatment adherence in this area.

Treatment of multiple sclerosis in special populations: The case of refugees.

Multiple sclerosis was long considered a relatively rare entity in the Middle East, but research over the past 10 years and the publication of the Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis guidelines for multiple sclerosis have allowed diagnosis and treatment to occur more efficiently. Most of the first and second-line disease-modifying therapies approved by the Food and Drug Administration and the European Medicine Agency are available in the Middle East. However, the availability of disease-modifying therapies is quite variable, with some countries having access to all multiple sclerosis disease-modifying therapies, while in others there is only one therapeutic option. Economic limitations remain a challenge for the management of multiple sclerosis, especially in countries of war. Moreover, the burden of multiple sclerosis treatment in Syrian and Palestinian refugees is likely high due to the non-availability of funds to cover the high cost of disease-modifying therapies.

Epidemiology and phenotypes of multiple sclerosis in the Middle East North Africa (MENA) region.

The Middle East North Africa (MENA) region falls in the low-to-moderate multiple sclerosis (MS) prevalence zone, with prevalence rates slightly lower than Southern Europe but much higher than sub-Saharan Africa. However, there is clearly a trend toward increased MS prevalence over the last few decades, consistent with the globally rising prevalence of the disease. We analyzed all data collected from the MENACTRIMS (Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis) registry by the end of December 2018. A total of 6885 patients were eligible for the study. Overall, the clinical phenotype of MS in the MENA region was not different from the Western phenotype except for earlier age at onset and a more aggressive clinical course leading to earlier disability.

Skin warts during fingolimod treatment in patients with multiple sclerosis.

BACKGROUND: Fingolimod is associated with different infections including lower respiratory tract, herpes virus, cryptococcal meningitis, histoplasmosis, progressive multifocal leukoencephalopathy, atypical mycobacterial infections, kaposi sarcoma and reactivation of hepatitis c. OBJECTIVES: To describe five cases of skin warts in MS patients treated with fingolimod at the American University of Beirut Medical Center (AUBMC) MS center (MSC). METHODS: We reviewed all MS patients treated with fingolimod at our MSC and identified patients who developed skin warts during treatment. We also reviewed a control group of patients treated with different interferons matched for age and sex. RESULTS: Of 220 patients treated with fingolimod at our MSC, 5 (2.2%) developed skin warts. In 220 patients treated with different interferons and matched for age and sex, no cases of skin warts could be detected. CONCLUSIONS: In conclusion, we report five patients who developed skin warts during fingolimod therapy, especially HPV-related, for an overall incidence of 2.2%. Larger cohorts are needed to confirm this proposed higher susceptibility of fingolimod-treated patients to HPV infections.