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Background and objectivesAn unmet need exists for validated quantitative tools to measure multiple sclerosis (MS) disease activity and progression. We developed a custom immunoassay-based MS disease activity (MSDA) Test incorporating 18 protein concentrations into an algorithm to calculate four Disease Pathway scores (Immunomodulation, Neuroinflammation, Myelin Biology, and Neuroaxonal Integrity) and an overall Disease Activity score. The objective was to clinically validate the MSDA Test based on associations between scores and clinical/radiographic assessments.MethodsSerum samples (N=614) from patients with MS at multiple sites were split into Train (n=426; algorithm development) and Test (n=188; evaluation) subsets. Subsets were stratified by demographics, sample counts per site, and gadolinium-positive (Gd+) lesion counts; age and sex were used to demographically adjust protein concentrations. MSDA Test results were evaluated for potential association with Gd+ lesion presence/absence, new and enlarging (N/E) T2 lesion presence, and active versus stable disease status (composite endpoint combining radiographic and clinical evidence of disease activity).ResultsA multi-protein model was developed (trained and cross-validated) using the Train subset. When applied to the Test subset, the model classified the Gd+ lesion presence/absence, N/E T2 lesion presence, and active versus stable disease status assessments with an area under the receiver operating characteristic (AUROC) of 0.781, 0.750, and 0.768, respectively. In each case, the multi-protein model had significantly (bootstrapped, one-sidedpDiscussionThe MSDA Test was clinically validated; the multi-protein model had greater performance compared with the top-performing single-protein model. The MSDA Test may serve as a quantitative and objective tool to enhance care for MS.

Background and ObjectivesThe diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed because of the lack of objective clinical tools, which increases the diagnostic uncertainty and hampers the therapeutic development in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) has been proposed as a promising biomarker of progressive neurodegeneration. To explore longitudinal changes in the thicknesses of retinal layers on OCT in individuals with relapsing-remitting MS (RRMS) who converted to SPMS vs matched patients with RRMS who did not convert to SPMS. Our hypothesis is that the 2 cohorts exhibit different rates of retinal thinning.MethodsFrom our prospective observational cohort of patients with MS at the American University of Beirut, we selected patients with RRMS who converted to SPMS during the observation period and patients with RRMS, matched by age, disease duration, and Expanded Disability Status Scale (EDSS) at the first visit. Baseline retinal measurements were obtained using spectral domain OCT, and all patients underwent clinical and OCT evaluation every 6–12 months on average throughout the study period (mean = 4 years). Mixed-effect regression models were used to assess the annualized rates of retinal changes and the differences between the 2 groups and between converters to SPMS before and after their conversion.ResultsA total of 61 participants were selected (21 SPMS and 40 RRMS). There were no differences in baseline characteristics and retinal measurements between the 2 groups. The annualized rates of thinning of all retinal layers, except for macular volume, were greater in converters before conversion compared with nonconverters by 112% for peripapillary retinal nerve fiber layer (p= 0.008), 344% for tRNFL (p< 0.0001), and 82% for cell-inner plexiform layer (GCIPL) (p= 0.002). When comparing the annualized rate of thinning for the same patients with SPMS before and after conversion, no significant differences were found except for tRNFL and GCIPL with slower thinning rates postconversion (46% and 68%, respectively).DiscussionPatients who converted to SPMS exhibited faster retinal thinning as reflected on OCT. Longitudinal assessment of retinal thinning could confirm the transition to SPMS and help with the therapeutic decision making for patients with MS with clinical suspicion of disease progression.

Retinal optical coherence tomography (OCT) can differentiate definite NMOSD (dNMOSD) from multiple sclerosis (MS), but has not been evaluated in patients with a high clinical suspicion of NMOSD and not fulfilling the current consensus diagnostic criteria, referred in this paper as "potential" NMOSD (pNMOSD).To compare the retinal OCT measurements between patients with pNMOSD, dNMOSD, MS, and reference healthy controls (HC).In this cross-sectional study, clinical and demographic characteristics, as well as OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), inner nuclear layer (INL), macular retinal nerve fiber layer (mRNFL), outer nuclear layer (ONL) ganglion cell/inner plexiform layer (GCIPL), and macular volume (MV) were compared between groups. Mixed-effects regression models adjusting for within-patient inter-eye correlations, controlling for age, gender, disease duration and history of optic neuritis per eye were explored. Subgroup analyses were performed on eyes with previous optic neuritis.234 eyes (20 pNMOSD, 33 dNMOSD, 138 MS, and 43 HC) were included. Controlling for age, gender, disease duration, and history of optic neuritis per eye, pNMOSD eyes showed decreased GCIPL, pRNFL, mRNFL and MV thicknesses, similar to eyes with dNMOSD, but significantly thinner than MS and HC subjects' eyes. Similar results were obtained for the pRNFL, mRNFL, GCIPL, INL and MV thickness in the subgroup analysis exploring only eyes with history of optic neuritis (12 pNMOSD, 15 dNMOSD, and 27 MS).Retinal OCT measurements in patients with pNMOSD were similar to dNMOSD, but significantly lower than patients with MS and healthy controls. This suggests that retinal OCT measures could be helpful markers supportive of NMOSD diagnosis and should be explored in larger studies as a valuable addition to the current consensus diagnostic criteria.

Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients.Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy.DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = -0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = -0.049, p = 0.499).Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters.

Objective To explore prospectively through OCT the rate of retinal layer changes in relapsing-remitting multiple sclerosis patients followed up on fingolimod or interferon, as well as the treatments’ differential effects on cognitive tests scores. Methods This prospective observational study enrolled 128 stable RRMS patients treated either with fingolimod (n = 71) or interferon (n = 56). Symbol-Digit Modality Test and retinal OCT scans were obtained at baseline and every 6 to 12 months. A subgroup of patients underwent expanded cognitive tests annually (Brief visual-spatial memory-total recall, BVMT-delayed recall, and Montreal Cognitive Assessment). Retinal-OCT scans were also obtained from 22 age- and sex-matched healthy controls. Mixed effects regression was used to study annualized changes in retinal layers and cognitive function, including differences between treatment groups. Correlations between annualized changes in retinal measurements and cognitive scores were also explored. Results Fingolimod treated patients showed no significant difference in the rate of thinning of all retinal layers when compared to healthy controls and had significantly less GCIPL thinning when compared to interferons. SDMT scores improved similarly among both RRMS treatment groups. However, interferon but not fingolimod treated patients had significant decline in MOCA and total recall scores. We also found correlations between the annualized change in GCIPL thickness and annualized change in MOCA scores, and similar correlations with annualized change in total recall scores. Conclusion Fingolimod has a potential role in reducing retinal neurodegeneration in RRMS. Longitudinal OCT measures appear to be sensitive to changes in cognitive function and may be useful for monitoring neuroprotective therapies.

PURPOSE The object of the study is to relate the pattern reversal visual evoked potential (PRVEP) and flash VEP (f-VEP) latencies with retinal neurons and their fibers. METHODS We studied 104 eyes. Forty-two eyes from patients with optic neuritis (ON), 28 eyes from patients with multiple sclerosis without involvement of the optic nerves (MS-non-ON), and 34 eyes of normal controls. RESULTS Pattern reversal visual evoked potential latency is more delayed in patients with ON than in patients with multiple sclerosis nonON. Flash visual evoked potential (f-VEP) latency was delayed in both categories. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell/inner plexiform layer (GCIPL) thickness was lower in patients with ON and multiple sclerosis non-ON. In patients with ON, f-VEP latencies correlated negatively with pRNFL thickness but not GCIPL thickness. In patients with ON, PRVEP latencies did not correlate with pRNFL thickness but correlate negatively with GCIPL thickness. CONCLUSIONS Patients with ON have delayed VEPs and thinner optical coherence tomography values. Flash visual evoked potentials correlate with pRNFL, indicating axonal pathology. PRVEP correlate with GCIPL, indicating ganglion cell pathology. Abnormal PRVEP with preserved normal f-VEP indicate isolated myelin damage. Abnormalities in both PRVEP and f-VEP indicate myelin and axonal damage in the optic nerve. Combining the results of PRVEP, f-VEP, pRNFL, and GCIPL, one can define the location, type, and extent of the lesion in the macula and optic nerve.

Background The epidemiology of multiple sclerosis (MS) has been studied in many countries of the Middle East but the prevalence and incidence of MS in Lebanon is still unknown. Objectives To determine the incidence and prevalence of MS in Lebanon. Methods Lebanese patients diagnosed with MS between January 2018 and December 2018 were identified using the database of governmental third-party payers. The crude, age- and sex-specific 2018 prevalence and incidence among Lebanese patients were calculated. Results 2248 MS patients were identified of whom 67.1% were women (female: male ratio 2:1) with a mean age of 41.8 ± 12.96 years. The 2018 prevalence of MS was 62.91 cases per 100,000 persons (95% CI: 60.41 - 65.41). The overall incidence of MS in Lebanon was 8.36 cases per 100,000 (95% CI: 7.45 – 9.27) with a mean age at onset of 34.5 ± 12.5 years. Conclusion This is the first study to assess prevalence and incidence of MS in Lebanon, confirming that Lebanon is a moderate to high-risk area for MS. Those high rates are commensurate with recently published studies from the Middle East, pointing to a significant rise in incidence and prevalence of this disease in our region.

Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS.One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9-Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured.BREMSO score correlated negatively with SDMT at visit1 (β = -0.33, p = 0.019), visit2 (β = -0.34, p = 0.017) and visit3 (β = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p 0.03). No correlations were found with ICV and subcortical gray matter.BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS.

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. 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. Significant differences (FSL-Anat 1.474% p

Objective It is postulated that extending the dosing interval of natalizumab (NTZ) from 4 to 5–8 weeks might decrease the risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess the effect of extended interval dosing (EID) on the therapeutic efficacy of natalizumab. Methods We reviewed 85 patients treated at two MS centers in the Middle East with natalizumab for at least 6 months using EID. Patients were shifted after an initial treatment period at standard interval dosing (SID) to an EID ranging from 5–8 weeks. Results The mean treatment duration on SID and EID was 15.4 ± 11.9 and 11.8 ± 7.0 months, respectively. By the end of SID and EID treatment 95.3% and 93.9% of patients were free of relapses (P = 0.41) with an annualized relapse rate (ARR) of 0.0006 and 0.001 respectively (P = 0.42). The mean EDSS at the end of SID and EID periods was 2.56 ± 1.62 and 2.59 ± 1.61 respectively (P = 0.84). A total of 97.6% and 94.7% of patients had no enhancing lesions on MRI during the SID and EID periods respectively (P = 0.18). There were no cases of PML and the rate of infections was lower during the EID period. Conclusion In patients treated with natalizumab, shifting from SID to EID has no negative effect on efficacy as evidenced by relapse rate, disability progression and MRI activity.

We aimed to investigate the immunologic effects of vitamin D replacement in RRMS patients. In a controlled single center study, patients deficient in 25-hydroxyvitamin D (serum level 35 ng/ml) were followed for the same period. Assessments were performed at baseline and at 3 months. 25-hydroxyvitamin D levels increased significantly from baseline to month-3 in the deficient group after treatment and remained stable in the sufficient group. We observed a decreased interferon-γ (IFNγ) secretion by CD4+ T cells in vitamin D deficient group but not in the sufficient group, and a negative correlation between baseline serum vitamin D and IFNγ production. There was no change in the frequency of T helper or regulatory T cell subsets in either group. Increasing serum levels of 25-hydroxyvitamin D are associated with decreased production of IFNγ by CD4+ T cells.

Background Relapse rate in women with Multiple Sclerosis (MS) is reduced during pregnancy especially in the third trimester according to the previous studies. Objectives To measure the annual relapse rate (ARR) in women with MS during pregnancy. Methods A retrospective study was conducted using prospectively collected data from two MS registries in Kuwait and Lebanon. Demographics, clinical characteristics including relapses, disease modifying therapies (DMTs) and their washout periods were extracted. The annual relapse rates pre and post pregnancies were compared and the relationship between relapses and prior use of different DMTs was assessed. Results Data of 164 pregnancies (132 MS patients) was reviewed. Mean age and disease duration at the time of pregnancy confirmation were 32.4 ± 5.3 and 7.8 ± 4.7 years respectively. Most patients (91.7%; n = 121) were on DMTs in the year prior to pregnancy. The pre-pregnancy ARR was 0.10 (95% CI: 0.04 – 0.13), which increased to 0.20 (95% CI: 0.13– 0.29) during pregnancy. Most relapses occurred either during the 1st (ARR = 0.24; 95% CI: 0.12 – 0.44) or 3rd (ARR = 0.32; 95%CI: 0.17 – 0.53) trimesters. Fingolimod (31.8%) and natalizumab (22.7%) were the most commonly prescribed DMTs in patients who sustained relapses during pregnancy. The mean washout period was significantly longer among subjects with relapses (9.3 ± 6.6 vs. 2.5 ± 3.9; p Conclusions Relapse rate during pregnancy was higher than previous studies conducted in patients on platform therapies or untreated. Longer washout period prior to conception was associated with increased relapses especially in fingolimod and natalizumab treated patients.

A critical step in the diagnosis of multiple sclerosis is to rule out a heterogeneous variety of multiple sclerosis mimickers, which is crucial in the era of powerful immune-modulator treatments. In this review, we discuss the background of toxocariasis in general, present central nervous system Toxocara infection as one of the multiple sclerosis mimickers in the Middle East, and share our experience about the diagnosis and management of this condition. This entity seems very relevant in a region such as the Middle East, where displacement of populations and conflict can result in non-hygienic food and water management bundles. The diagnosis should be entertained, especially when assessing patients with myelopathy. The presence of a single lesion in the spinal cord with inflammatory features should prompt serological testing for Toxocara IgG and IgM in serum and the cerebrospinal fluid. This infection is treatable, with the regimen of high-dose albendazole being one of the most accepted treatments. Although most cases exhibit a good prognosis, some have residual deficits localized to the affected spinal cord level.

Objective. To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting. Methods. Clinical data for all adult patients with multiple sclerosis (MS) treated with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts. The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity. Results. A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6–12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p<0.0001) and from 0.25 to 0.16 in PMS patients (p=0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected. Conclusion. In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.

Background The burden of invasive meningococcal disease is substantial in older adults in whom the case fatality rate is high. Travelers to regions with high rates of meningococcal disease, such as Hajj pilgrims, are at increased risk of meningococcal infection, and disease transmission from travelers to their close contacts has been documented. In younger individuals, meningococcal conjugate vaccines offer advantages over polysaccharide vaccines in terms of duration of protection and boostability, and induction of herd immune effects through reductions in nasopharyngeal carriage of meningococci. To date, few data are available evaluating meningococcal conjugate vaccine use in adults >55 years of age. Objective To evaluate the immunogenicity and safety of quadrivalent meningococcal serogroups A, C, W-135 and Y vaccine with all serogroups conjugated to tetanus toxoid (MenACWY-TT, Nimenrix™, GlaxoSmithKline, Belgium) and a licensed quadrivalent polysaccharide vaccine (MenPS, Mencevax™ GlaxoSmithKline, Belgium) in adults >55 years of age. Methods This was a phase IIIb, open-label, randomized (3:1), controlled study conducted at one study center in Lebanon. A total of 400 healthy adults between 56 and 103 years of age without previous MenPS or tetanus toxoid vaccination within the previous 5 years or meningococcal conjugate vaccination at any time previously were included. They received a single-dose vaccination with MenACWY-TT or MenPS with blood sampling before and 1 month after vaccination. The main outcome measures were serum bactericidal activity (rabbit complement source: rSBA) vaccine response (VR) rate [rSBA titer of ≥1:32 in initially seronegative subjects (rSBA titer

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti-aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers.

Further studies are needed to determine the role of retinal optical coherence tomography (OCT) in non-optic neuritis (ON) eyes of patients with early MS. The objective of this study is to explore the relationship between retinal layers’ thickness and cognitive as well as physical disability in patients with the early RRMS. Participants in this cross-sectional study were adults with early RRMS, stable on interferon beta-1a, or fingolimod therapy, and without a history of ON in one or both eyes. Patients were evaluated clinically, underwent a battery of cognitive tests, and a retinal OCT scan which was also performed on a group of healthy age- and gender-matched controls. We studied 47 patients with RRMS, on interferon beta-1a (N = 32) or fingolimod (N = 15), and 18 healthy controls. Multivariate analyses controlling for age, disease duration, treatment, and education when exploring cognitive function, showed that pRNFL thickness correlated negatively with 9HPT (standardized Beta −0.4, p < 0.0001), and positively with SDMT (standardized Beta 0.72, p = 0.007). In patients with early RRMS without optic neuropathy, retinal thickness measures correlated with physical disability and cognitive disability, supporting their potential as biomarkers of axonal loss.

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