Clinical and economic evaluations of natalizumab, rituximab, and ocrelizumab for the management of relapsing-remitting multiple sclerosis in Saudi Arabia.

INTRODUCTION: The advent of new disease-modifying therapies (DMTs), such as monoclonal antibodies (mAbs), resulted in significant changes in the treatment guidelines for Multiple sclerosis (MS) and improvement in the clinical outcomes. However, mAbs, such as rituximab, natalizumab, and ocrelizumab, are expensive with variable effectiveness rates. Thus, the present study aimed to compare the direct medical cost and consequences (e.g., clinical relapse, disability progression, and new MRI lesions) between rituximab and natalizumab in managing relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia. Also, the study aimed to explore the cost and consequence of ocrelizumab in managing RRMS as a second-choice treatment. METHODS: The electronic medical records (EMRs) of patients with RRMS were retrospectively reviewed to retrieve the patients' baseline characteristics and disease progression from two tertiary care centers in Riyadh, Saudi Arabia. Biologic-naïve patients treated with rituximab or natalizumab or those switched to ocrelizumab and treated for at least six months were included in the study. The effectiveness rate was defined as no evidence of disease activity (NEDA-3) (i.e., absence of new T2 or T1 gadolinium (Gd) lesions as demonstrated by the Magnetic Resonance Imaging (MRI), disability progression, and clinical relapses), while the direct medical costs were estimated based on the utilization of healthcare resources. In addition, bootstrapping with 10,000 replications and inverse probability weighting based on propensity score were conducted. RESULTS: Ninety-three patients met the inclusion criteria and were included in the analysis (natalizumab (n = 50), rituximab (n = 26), ocrelizumab (n = 17)). Most of the patients were otherwise healthy (81.72%), under 35 years of age (76.34%), females (61.29%), and on the same mAb for more than one year (83.87%). The mean effectiveness rates for natalizumab, rituximab, and ocrelizumab were 72.00%, 76.92%, and 58.83%, respectively. Natalizumab mean incremental cost compared to rituximab was $35,383 (95% CI: $25,401.09- $49,717.92), and its mean effectiveness rate was 4.92% lower than rituximab (95% CI: -30-27.5) with 59.41% confidence level that rituximab will be dominant. CONCLUSIONS: Rituximab seems to be more effective and is less costly than natalizumab in the management of RRMS. Ocrelizumab does not seem to slow the rates of disease progression among patients previously treated with natalizumab.

Waterpipe Tobacco Smoking and Other Multiple Sclerosis Environmental Risk Factors.

INTRODUCTION: There are a number of well-established risk factors for multiple sclerosis (MS). Other factors, however, showed conflicting or inconsistent results. Here, we examine some factors that are unique to or more practiced in Saudi Arabia (SA) and the Arab region such as waterpipe tobacco smoking (WTS), face veiling, raw milk (RM) and camel milk (CM) consumption, and tuberculosis (TB) infection in addition to other traditional factors. METHODS: This is a sex- and age-matched case-control study in which we used a structured questionnaire to examine the relation between a number of factors and exposures and the risk of MS. Three hundred MS patients and 601 controls were included. Data were analyzed across different statistical models using logistic regression adjusting for age, sex, marital status, duration of breastfeeding, age first joining school, coffee consumption, and face exposure. RESULTS: Cigarette smoking (OR = 1.79, [95% CI: 1.01-3.17], p = 0.047), WTS (OR = 2.25, [95% CI: 1.21-4.15], p = 0.010), and CM consumption (OR = 2.50, [95% CI: 1.20-5.21], p = 0.014) increased the risk of MS, while performing hajj (OR = 0.47, [95% CI: 0.34-0.67], p = 0.001), TB infection (OR = 0.29, [95% CI: 0.11-0.78], p = 0.015), face veiling (OR = 0.32, [95% CI: 0.23-0.47], p = 0.001), and coffee consumption (OR = 0.67, [95% CI: 0.49-0.89], p = 0.008) appeared to be associated with decreased risk. No association was found between fast food, processed meat, soft drinks, animal milk (other than camel), or RM consumption and the risk of MS. CONCLUSION: The results of this case-control study confirm that different means of tobacco smoking are associated with increased risk of MS. It also sheds more light on the complex association between infections and MS.

Assessment of factors associated with depression and anxiety among pwMS in Saudi Arabia.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory chronic disease that is characterized by an increased prevalence of adverse mental health outcomes in patients with MS (pwMS). The main aim of this study is to investigate the factors of depression and anxiety in pwMS in the Kingdom of Saudi Arabia (KSA). MATERIALS AND METHODS: This is a cross-sectional study conducted in KSA during the period from March to June 2020. Participants were recruited from the Neuroimmunology clinics in King Fahad Medical City (KFMC) and King Saud University medical city (KSUMC)in Riyadh City, KSA. The Hospital Anxiety and Depression Scale (HADS) was used to measure depression and anxiety. Fatigue Severity Scale (FSS) was used to measure fatigue in pwMS. A simple random sampling technique was utilized to select participants and the data were analyzed using SPSS v.24.0. RESULTS: A total of 529 participants participated in this study with a response rate of 53.1%. The prevalences of anxiety and depression were 35.3% and 19.7%, respectively. The findings also revealed that depression was more likely to be significantly affected by being male, low education, unemployment, physical inactivity, and fatigue but the anxiety was significantly affected by region, unemployment, short duration since last MS relapse, physical inactivity, and fatigue. CONCLUSION: Anxiety and depression are not uncommon in pwMS. Given their impact on the lives of affected patients, early detection and management of these symptoms and their associated factors are crucial.

Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature.

BACKGROUND: Among the rare neurological complications of substances of abuse is the selective cerebral white matter injury (leukoencephalopathy). Of which, the syndrome of delayed post hypoxic encephalopathy (DPHL) that follows an acute drug overdose, in addition to "chasing the dragon" toxicity which results from chronic heroin vapor inhalation remain the most commonly described syndromes of toxic leukoencephalopathy. These syndromes are reported in association with opioid use. There are very few cases in the literature that described leukoencephalopathy following benzodiazepines, especially with an acute and progressive course. In this paper, we present a patient who developed an acute severe fatal leukoencephalopathy following hypoxic coma and systemic shock induced by benzodiazepine overdose. CASE PRESENTATION: A 19-year-old male was found comatose at home and brought to hospital in a deep coma, shock, hypoxia, and acidosis. Brain magnetic resonant imaging (MRI) revealed a strikingly selective white matter injury early in the course of the disease. The patient remained in a comatose state with no signs of neurologic recovery until he died few weeks later following an increase in the brain edema and herniation. CONCLUSION: Toxic leukoencephalopathy can occur acutely following an overdose of benzodiazepine and respiratory failure. This is unlike the usual cases of toxic leukoencephalopathy where there is a period of lucidity between the overdose and the development of white matter disease. Unfortunately, this syndrome remains of an unclear pathophysiology and with no successful treatment.

Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders.

OBJECTIVE: To describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability. BACKGROUND: There is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD. DESIGN/METHODS: Observational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes. RESULTS: Cohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06-4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63-14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01-1.06), female sex (OR 1.99; CI 1.01-4.01), Black race (OR 4.14; CI 1.79-10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04-7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22-0.92) or use of assistive device (OR 0.79; CI 0.66-0.94). CONCLUSIONS: We present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

Cross-cultural adaptation and validation of the Arabic version of the Multiple Sclerosis Impact Scale-29.

PURPOSE: The Multiple Sclerosis Impact Scale-29 (MSIS-29) is a patient self-reported outcome (PRO) that measures patients' quality of life, and it is divided into two sub-scales for the physical (PHYS) and psychological (PSYCH) domains. This study aimed to translate the MSIS-29 into Arabic, cross-culturally adapt it, and examine its psychometric properties. MATERIALS AND METHODS: One hundred fifty patients with MS completed the MSIS-29-Ar, the Functional Assessment of Multiple Sclerosis (FAMS), and the Short-Form Health Survey (SF-36). After one week, 60 participants were asked to complete the MSIS-29-Ar again to examine test-retest reliability. RESULTS: The MSIS-29-Ar was clear and understandable among patients with MS in Saudi Arabia. The internal consistency for the MSIS-29-Ar-PHYS was excellent, with a Cronbach's alpha of 0.955, and was good for the MSIS-29-Ar-PSYCH, with a Cronbach's alpha of 0.891. The test-retest reliability for MSIS-29-Ar-PHYS was ICC2,1 = 0.97; 95% confidence interval (0.93, 0.99) and ICC2,1 = 0.95.; 95% confidence interval (0.897, 0.976) for MSIS-29-Ar-PSYCH domains. The minimal detectable change with 95% confidence (MDC95) was 10.28 and 13.37 for the MSIS-29-Ar-PHYS and MSIS-29-Ar-PSYCH, respectively. No floor and ceiling effects were observed. Convergent and divergent validity was supported by 75% of the predefined hypotheses and correlated with the other health-related quality-of-life measures, SF-36 and FAMS. CONCLUSION: The MSIS-29-Ar questionnaire is a valid and reliable outcome measure among Saudi patients with MS.IMPLICATION FOR REHABILITATIONRehabilitation specialists can confidently interpret patient scores in the MSIS-29-Ar to measure physical and psychological factors impacting patients' quality of life with Multiple Sclerosis (MS).Patients with unchanged clinical status will have similar scores in the MSIS-29-Ar with repeated scale administrations over time.The MSIS-29-Ar can be used in clinical practice and research studies to measure factors that impact the quality of life in Arabic-speaking patients with MS.

Occlusive Retinal Vasculitis in Patients with Multiple Sclerosis.

PURPOSE: To investigate the frequency, clinical findings and outcomes of occlusive retinal vasculitis in patients with multiple sclerosis (MS). METHODS: A retrospective case series. RESULTS: During the period between January 2000 and December 2021, we identified 24 patients who were diagnosed to have uveitis associated with MS. Among them, four (16.6%) patients presented with bilateral occlusive retinal vasculitis who were diagnosed to have MS prior to presentation. All patients were treated successfully with a combination of systemic corticosteroids combined with mycophenolate mofetil. In addition, scatter laser photocoagulation was applied to the ischemic retina in all eyes. CONCLUSIONS: Early recognition and prompt treatment with systemic immunosuppressive agents and scatter laser photocoagulation prevent complications and improve outcomes in MS patients with occlusive retinal vasculitis.

Restless leg syndrome in multiple sclerosis: a case-control study.

Objectives: This study assessed the prevalence of restless leg syndrome (RLS) among patients with multiple sclerosis (pwMS) and the association between RLS and MS disease duration, sleep disturbance, and daytime fatigue. Methods: In this cross-sectional study, we interviewed 123 patients via phone calls using preset questionnaires containing the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS) diagnostic criteria validated in both Arabic and English. The prevalence of RLS in MS was compared to a group of healthy controls. Results: The prevalence of RLS in pwMS, defined by meeting all four requirements included in the IRLSSG diagnostic criteria, was 30.3% compared to 8.3% in the control group. About 27.3% had mild RLS, 36.4% presented with moderate, and the remaining had severe or very severe symptoms. Patients with MS who experience RLS had a 2.8 times higher risk of fatigue compared to pwMS without RLS. pwMS with RLS had worse sleep quality, with a mean difference of 0.64 in the global PSQI score. Sleep disturbance and latency had the most significant impact on sleep quality. Conclusion: The prevalence of RLS among MS patients was significantly higher compared to the control group. We recommend educating neurologists and general physicians to increase their awareness of the increasing prevalence of RLS and its association with fatigue and sleep disturbance in patients with MS.

Performance of an Arabic translation of the patient determined disease steps (PDDS) scale in Saudi patients with multiple sclerosis.

The Expanded Disability Status Scale (EDSS) is commonly used to measure and quantify disabilities in patients with multiple sclerosis (MS). The patient-determined disease steps (PDDS) scale is a patient-reported measure of disability that is useful in MS. However, the Arabic version of the PDDS has only been tested in Jordanian patients. Although both populations share similar Arabic languages, it is plausible that differences in dialects and educational systems could alter the generalizability of the tool. In this prospective study, patients with MS were asked to complete a printed translated version of the (PDDS), and the results were compared to their EDSS scores, functional system scores, and walking speed measures. Patients with relapsing or progressive MS were included in the study. Spearman rho rank-order correlation coefficients (P) were used to measure the correlation between the PDDS and other variables. We considered previously reported P values > .1, .3, and .5 as small, moderate, and strong correlations, respectively. A total of 79 patients completed the study. The PDDS showed a strong correlation with the EDSS (P = .69, 95% confidence interval 0.55-0.79, P < .001). PDDS is associated with cerebellar, pyramidal, and bladder dysfunctions. It was also moderately correlated with the timed-25-foot walk test and timed-up-and-go test. The Arabic version of the PDDS performed similarly to English and other languages when tested on a cohort of patients with MS.

Fatigue, Depression, and Anxiety Among Ambulating Multiple Sclerosis Patients.

Background: Multiple sclerosis (MS) is an inflammatory disease associated with adverse effects: including depression, anxiety, fatigue, which may affect physical activity and the quality of life (QoL) among patients with MS (pwMS). Objective: This study aims to assess the prevalence of depression, anxiety, and fatigue among pwMS who have no physical disability in Saudi Arabia, and demonstrate any correlation between these factors and physical activity as well as the QoL. Methods: A cross-sectional study was conducted in the Neuroimmunology outpatient clinics in King Fahad Medical City (KFMC) and King Saud University Medical City (KSUMC) in Riyadh City, KSA. The Arabic version of the Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression levels. The HADS scores were then categorized into three levels according to the total points: normal (0-7 points), borderline (7-10 points), and anxiety/depression (11 - 21 points). The Arabic version of the Fatigue Severity Scale (FSS) was used to measure fatigue (cut-off point ≥5). The physical activity was measured by the Arabic version of the short form of the International Physical Activity Questionnaire (IPAQ), which measure time spent walking, moderate- and vigorous-intensity physical activity of at least 10 minutes duration. The QoL was also measured by the Arabic version of the EuroQOL five-dimensional (EQ-5D-3L) instrument (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Results: A total of 323 pwMS participated in this study, 83 had scores that indicated anxiety (25.7%) and 44 had depression (13.6%). The majority of patients had scores with the normal range of depression and anxiety (70% and 57% respectively). The mean of EuroQol Group visual analogue scale (EQ-VAS) score was 80.43 (SD=19.8). 156 (48.3%) out of 323 pwMS reported fatigue while the remainder had no fatigue (n=167, 51.7%). The results indicate that only 143 patients (44.3%) had participated in vigorous physical activity during the last 70 days, with a median of 3 days per week (IQR= 5-3) and a median of 60 minutes per day 0 (Interquartile range: IQR = 60-30). Only 149 patients (49.2%) had patricpated in moderate physical activities during the previous week with a median of 3 days per week (IQR = 5-3) and a median of 40 minutes per day (IQR = 60-30). 194 patients had participated in walking activities (60.0%) with a median of 5 days per week (IQR = 7-3) and a median of 45 minutes per day (IQR = 60-30). The results revealed that fatigue was positively correlated with depression (r = 0.407, p-value < 0.001) and anxiety (r = 0.289, p-value < 0.001). Conclusion: The current study shows depression, anxiety, and fatigue tend to be correlated and clustered together among pwMS in our cohort. However, fatigue is not associated with the intensity of physical activity undertaken. The results of this study are important for the improvement of the clinical management of MS patients.

Real-world effectiveness and safety profile of teriflunomide in the management of multiple sclerosis in the Gulf Cooperation Council countries: An expert consensus narrative review.

Background: The prevalence of multiple sclerosis (MS) is increasing in Gulf Cooperation Council (GCC) countries. Multiple sclerosis contributes to significant burden on patients and caregivers. The pharmacological treatment in MS involves treating acute exacerbations and preventing relapses and disability progression using disease-modifying therapies. Clinical evidence suggests that teriflunomide is one of the therapeutic choices for patients with relapsing-remitting MS (RRMS). However, genetic and cultural differences across different regions may contribute to variations in drug use. Therefore, it is necessary to consider real-world evidence for teriflunomide usage in GCC countries. Methods: An expert group for MS gathered from GCC countries in December 2020. The consensus highlighting role of teriflunomide in MS management has been developed using clinical experiences and evidence-based approach. Results: The expert-recommended patient profile for teriflunomide usage includes individuals aged 18 years and above, both men and women (on effective contraceptives) with clinically isolated syndrome or RRMS. The factors considered were cost-effectiveness of the drug, patient preference, adherence, monitoring, established safety profile, and coronavirus disease 2019 status. Conclusion: Expert recommendations based on their clinical experience will be more helpful to clinicians in clinical settings regarding the usage of teriflunomide and provide valuable insights applicable in day-to-day practice.

Unmet Needs and Treatment of Relapsing-Remitting Multiple Sclerosis in Saudi Arabia: Focus on the Role of Ofatumumab.

Treatment-pattern data suggest that some patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) may not be receiving optimal treatment. A virtual meeting of ten expert Saudi neurologists, held on October 23, 2020, discussed unmet needs in relapsing-remitting MS (RRMS), and the role of ofatumumab as a suitable treatment in the KSA. Multiple unmet needs were identified: poor quality of life, with high rates of depression and anxiety; a negative impact of MS on work ability; treatment choices that may compromise efficacy for safety or vice versa; inconvenient or complex dosage regimens; and limited access to patient education and support. Early use of highly effective disease-modifying treatments (DMTs) results in better patient outcomes than starting with less effective treatments and downstream escalation, but this strategy may be underutilized in the KSA. B cells are important in MS pathogenesis, and treatments targeting these may improve clinical outcomes. Ofatumumab differs from other B cell-depleting therapies, being a fully human monoclonal antibody that binds to CD20 at a completely separate site from the epitope bound by ocrelizumab, and being administered by subcutaneous injection. When compared with teriflunomide in two randomized, phase 3 clinical trials in patients with RRMS, ofatumumab was associated with significant reductions in annualized relapse rates, rates of confirmed disability worsening, and active lesions on magnetic resonance imaging. The incidence of adverse events, including serious infections, was similar with the two treatments. Ofatumumab is a valuable first- or second-line treatment option for RRMS in the KSA, particularly for patients who would benefit from highly effective DMTs early in the disease course, and for those who prefer the convenience of self-injection. Future research will clarify the position of ofatumumab in RRMS treatment, and comparative cost data may support the broad inclusion of ofatumumab in formularies across the KSA.

Saudi consensus recommendations on the management of Neuromyelitis Optica Spectrum Disorders (NMOSD).

This article focuses on the diagnosis and management of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is an autoimmune, demyelinating condition characterized by inflammation of the optic nerve and/or the spinal cord, with symptoms that can range from mild impairment of movement to paralysis. The newly approved diagnostic criteria have improved the accuracy of NMOSD diagnosis. The management of NMOSD is under major revolution due to the many new therapeutic options. The role of the antibodies directed at aquaporin-4 (AQP4) has materialized as a biomarker for NMOSD. Several new treatments that target variable aspects in immunopathology such as IL-6, complement, or depletion of B cells are emerging. The management of AQP4-negative patients remains challenging.

Use of subcutaneous immunoglobulin in stiff person syndrome: Case series.

INTRODUCTION: Intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of stiff person syndrome (SPS). However, some patients might not tolerate it. We report the tolerability profile of subcutaneous immunoglobulin (SCIg) in patients with SPS who did not tolerate IVIG. To our knowledge, the use of SCIg in SPS has not been reported before in a case series. PATIENT CONCERNS: The five patients included in this case series presented with various combinations of symptoms of spasms, axial and limb stiffness, and exaggerated responses to outside stimuli. These symptoms often lead to gait and functional impairment. DIAGNOSIS: Patients were diagnosed with classic SPS as they met the clinical criteria, which require the presence of spasms, axial rigidity, and hyperexcitability. INTERVENTIONS: Subcutaneous immunoglobulin infusion. OUTCOMES: Five patients were identified that were treated with SCIg. Three tested positive for serum anti-glutamic acid decarboxylase 65 antibodies prior to any treatment. The mean age at SCIg initiation was 33 years (range: 22-47). The mean duration of SPS prior to SCIg initiation was 5.9 years (range: 2.5-7). All patients used IVIG for at least two months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean, 19.2 months). Upon switching to SCIg, the SPS symptoms remained stable. SCIg was well-tolerated in most as only one patient discontinued SCIg due to side effects. CONCLUSION: This case series highlights that SCIg could be a treatment option for patients with SPS, especially when IVIG is not feasible. Injection site reactions might be a limiting factor in some patients treated with SCIg. Prospective controlled studies are needed to confirm SCIg treatment durability and efficacy.

Polyneuropathy and Korsakoff syndrome complicating sleeve gastrectomy.

We report a case of a 36 year old gentleman presenting with polyneuropathy and Korsakkoff Syndrome complicating Sleeve Gastrectomy.

Real-World Comparative Cost-Effectiveness Analysis of Different Classes of Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in Saudi Arabia.

The very fact that multiple sclerosis (MS) is incurable and necessitates life-long care makes it one of the most burdensome illnesses. The aim of this study was to compare the cost-effectiveness of orally administered medications (e.g., fingolimod, dimethyl fumarate, and teriflunomide), interferon (IFN)-based therapy, and monoclonal antibodies (MABs) (e.g., natalizumab and rituximab) in the management of relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia using real-world data. This was a retrospective cohort study in which patients with RRMS aged ≥18 years without any other chronic health conditions with non-missing data for at least 12 months were recruited from the electronic health records of a university-affiliated tertiary care center. Multiple logistic regressions controlling for age, sex, and duration of therapy were conducted to examine the odds of disability progression, clinical relapse, MRI lesions, and composite outcome (e.g., relapse, lesion development on MRI, disability progression). The number of patients who met the inclusion criteria and were included in the analysis was 146. Most of the patients were female (70.51%) and young (e.g., ≤35 years of age). There were 40 patients on the orally administered agents (e.g., dimethyl fumarate, teriflunomide, fingolimod), 66 patients were on IFN-based therapy (e.g., Rebif®), and 40 patients were on monoclonal antibodies (e.g., rituximab and natalizumab). Patients on MABs had lower odds of the composite outcome (OR = 0.17 (95% CI: 0.068-0.428)). The use of orally administered agents was dominant (e.g., more effective and less costly), with average annual cost savings of USD -4336.65 (95% CI: -5207.89--3903.32) and 8.11% higher rate of effectiveness (95% CI: -14.81-18.07) when compared with Rebif®. With regard to the use of MABs in comparison to Rebif®, MABs were associated with higher cost but a better rate of effectiveness, with an average additional annual cost of USD 1381.54 (95% CI: 421.31-3621.06) and 43.11% higher rate of effectiveness (95% CI: 30.38-61.15) when compared with Rebif®. In addition, the use of MABs was associated with higher cost but a better rate of effectiveness, with an average additional annual cost of USD 5717.88 (95% CI: 4970.75-8272.66) and 35% higher rate of effectiveness (95% CI: 10.0-42.50) when compared with orally administered agents. The use of MABs in the management of RRMS among the young patient population has shown to be the most effective therapy in comparison to both IFN-based therapy (e.g., Rebif®) and orally administered agents, but with higher cost. Orally administered agents resulted in better outcomes and lower costs in comparison to IFN-based therapy. Future studies should further examine the cost-effectiveness of different disease-modifying therapies for the management of RRMS using more robust study designs.

Shared breastfeeding & other early multiple sclerosis risk factors: A case-control study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease. Etiology is thought to be multifactorial with genetic and environmental factors interplay. Our objective in this study is to evaluate culture specific and other early life risk factors for MS. We examined the association between MS and breastfeeding including shared breastfeeding, parental consanguinity, being born abroad or living abroad during childhood, prematurity, vaccination, tonsillectomy, rank among siblings, number of siblings, number of household members (HHM) at birth, and age first time joining school. METHODS: This is an age and sex matched case-control study that was conducted in Riyadh, Kingdom of Saudi Arabia (KSA). We enrolled 300 cases and 601 controls. A structured questionnaire about demographics, consanguinity and potential environmental factors was answered by participants. Data was analyzed using logistic regression adjusting for covariates occurring later in life such as waterpipe smoking and performing Hajj. RESULTS: About two thirds of the cases and the controls were females. Mean age was 34.8 (9.2) for the cases and 33.6 (10.6) for the controls. We found that shared breastfeeding (OR=0.58; 95% CI, 0.35-0.96, p = 0.033), and older age first joining school (OR=0.83; 95% CI, 0.73-0.94, p = 0.005) were associated with decrease risk of MS. While longer duration of breastfeeding by biological mother (OR=1.03; 95% CI, 1.01-1.04, p = 0.001), rank among siblings of ≥6 (OR=1.69; 95% CI, 1.11-2.56, p = 0.014), and larger number of HHM at birth (OR=2.32; 95% CI, 1.64-3.28, p = 0.001) were associated with increased risk. Patients with MS were less likely to receive formula with breastfeeding than controls (OR=0.72; 95% CI, 0.51-0.99, p = 0.046). No association was found with breastfeeding by biological mother, number of siblings, prematurity, being born abroad or living abroad during childhood, vaccination, consanguinity, or tonsillectomy. CONCLUSION: The findings of this case-control study add to the accumulating evidence that early life factors could modify the risk of developing MS. Among these, novel associations with shared breastfeeding and number of HHM at birth are suggested. Future studies are needed to verify the observed results.

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.

BACKGROUND: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. METHODS: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. FINDINGS: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). INTERPRETATION: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. FUNDING: Patient-Centered Outcomes Research Institute.

Registry of patients with multiple sclerosis and COVID-19 infection in Saudi Arabia.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread and developed as a pandemic threatening global health. Patients with multiple sclerosis (MS)-an autoimmune demyelinating inflammatory disease of the central nervous system (CNS)-are predominantly treated with immunomodulatory/immunosuppressive disease-modifying therapies (DMTs), which can increase the risk of infection. Therefore, there is concern that these patients may have a higher risk of COVID-19. In response to growing concerns of neurologists and patients, this study aimed to determine the prevalence, severity, and possible complications of COVID-19 infection in patients with MS in Saudi Arabia (SA). METHODS: In this prospective cohort study, demographic and clinical data were obtained from patients residing in SA with MS who had a positive result for COVID-19 per reverse transcription-polymerase chain reaction test or viral gene sequencing, using respiratory or plasma samples. Comparison of COVID-19 severity groups was performed using one-way ANOVA or Kruskal-Wallis test for numerical variables and Chi-squared test for categorical variables. RESULTS: Seventy patients with MS and COVID-19 (71% female) were included in this analysis. Of the 53 (75.7%) patients receiving a DMT at the time of COVID-19 infection, the most frequently used DMTs were fingolimod (25%) and interferon-beta (25%). Nine (13%) patients had MS relapse and were treated with intravenous methylprednisolone in the four weeks before COVID-19 infection. The most common symptoms at the peak of COVID-19 infection were fever (46%), fatigue (37%), and headache (36%). Symptoms lasted for a mean duration of 8.7 days; all symptomatic patients recovered and no deaths were reported. COVID-19 severity was categorized in three groups: asymptomatic (n = 12), mild-not requiring hospitalization (n = 48), and requiring hospitalization (n = 10; two of whom were admitted to the intensive care unit [ICU]). Between the three groups, comparison of age, body mass index , Expanded Disability Severity Score , MS disease duration, and DMT use at the time of infection showed no significant differences. A higher percentage of patients who were admitted to hospital or the ICU (40%; p = 0.026) presented with an MS relapse within the prior four weeks compared with those who were asymptomatic or had a mild infection (both 8.3%). CONCLUSION: These findings present a reassuring picture regarding COVID-19 infection in patients with MS. However, patients with MS who have had a relapse in the preceding four weeks (requiring glucocorticoid treatment) may have an increased risk of severe COVID-19.

Primary progressive multiple sclerosis to be treated with ocrelizumab: a mistaken case of cobalamin deficiency.

Cobalamin (vitamin B12) deficiency often manifests with neurologic symptoms and may rarely mimic multiple sclerosis (MS) among other neurological disorders. However, MRI changes associated with cobalamin deficiency are typically spinal predominant and distinct from MS-related changes. We report a case of a patient with cobalamin deficiency who was recommended by her primary neurologist to commence treatment with ocrelizumab, a potent anti-CD20 B-cell depleting monoclonal antibody, after being diagnosed with primary progressive MS. However, cervical spine MRI demonstrated changes classical of cobalamin deficiency including 'inverted V sign' signal hyperintensity and following parenteral cobalamin supplementation her neurological symptoms quickly and dramatically improved.