Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis.

An 18-protein multiple sclerosis (MS) disease activity (DA) test was validated based on associations between algorithm scores and clinical/radiographic assessments (N = 614 serum samples; Train [n = 426; algorithm development] and Test [n = 188; evaluation] subsets). The multi-protein model was trained based on presence/absence of gadolinium-positive (Gd+) lesions and was also strongly associated with new/enlarging T2 lesions, and active versus stable disease (composite of radiographic and clinical evidence of DA) with improved performance (p < 0.05) compared to the neurofilament light single protein model. The odds of having ≥1 Gd+ lesions with a moderate/high DA score were 4.49 times that of a low DA score, and the odds of having ≥2 Gd+ lesions with a high DA score were 20.99 times that of a low/moderate DA score. The MSDA Test was clinically validated with improved performance compared to the top-performing single-protein model and can serve as a quantitative tool to enhance the care of MS patients.

Current and future trends in multiple sclerosis management: Near East perspective.

BACKGROUND: Multiple sclerosis (MS) prevalence is rising in the Middle East. Most MS medications are available in the region, but not all, possibly affecting neurologists' prescribing habits. OBJECTIVES: To provide an overview of the current practices of Near East (NE) healthcare practitioners by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers. METHODS: A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling. RESULTS: The survey included 98 neurologists. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. Among patients with MS, the most challenging factor for the patients was thought to be related to family planning, followed by affordability and tolerability of side effects. In the treatment of mild to moderate relapsing remitting multiple sclerosis (RRMS) in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. Interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. When asked to position future disease-modifying therapies five years from today, more than 45% of physicians expressed a lack of information on Bruton's tyrosine kinase (BTK) inhibitors. CONCLUSIONS: Most neurologists in the NE region followed Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) recommendations for prescribing treatment. The treatment choice also depended on the availability of disease-modifying therapies (DMTs) in the region. Regarding the use of upcoming DMTs, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MS.

Rate of Retinal Layer Thinning as a Biomarker for Conversion to Progressive Disease in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The 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. METHODS: From 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. RESULTS: A 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). DISCUSSION: Patients 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.

Effect of fingolimod vs interferon treatment on OCT measurements and cognitive function in RRMS.

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.

Serum vitamin D level is associated with speed of processing in multiple sclerosis patients.

Multiple Sclerosis (MS) is often associated with low serum 25(OH)D levels, as well as cognitive dysfunctions. The relationship between 25(OH)D and the most commonly affected cognitive domain in MS; processing speed, is poorly explored. The purpose of this study is to: (1) assess the effect of serum 25(OH)D change on processing speed in MS, and (2) explore the relationship between serum 25(OH)D and brain volume changes in MS. A retrospective chart review was conducted, data from 299 patients were extracted (baseline), of whom 163 had follow-up measurements (after at least a 9-month interval). The Symbol Digits Modalities Test (SDMT) was used as a measure of processing speed. MRI data was available from 78 individuals at baseline, and 70 at follow-up. SDMT scores and brain volumes (Cerebellum (total, grey, and white), intracranial, Grey Matter (GM), and White Matter (WM)) were compared based on 25(OH)D levels and their changes towards follow-up. Results indicated that patients with deficient 25(OH)D levels had lower SDMT scores when compared to those with sufficient levels, and SDMT scores improved as a function of 25(OH)D. For MRI measures, only patients with sufficient 25(OH)D levels during both assessment periods had significant changes in intracranial and total cerebellum volumes. We conclude that 25(OH)D levels seem to have an effect on processing speed in MS, thus the importance of clinical monitoring and supplementation in this regard is reinforced.

Toxocara infection in the differential diagnosis of multiple sclerosis in the Middle East.

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.

Risk of relapses during pregnancy among multiple sclerosis patients.

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 ±â€¯5.3 and 7.8 ±â€¯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 ±â€¯6.6 vs. 2.5 ±â€¯3.9; p < 0.001) than those of without relapses. 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.

Gadoterate Meglumine Administration in Multiple Sclerosis has no Effect on the Dentate Nucleus and the Globus Pallidus Signal Intensities.

RATIONALE AND OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) 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). CONCLUSION: 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.

Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study.

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.

The Bayesian risk estimate at onset (BREMSO) correlates with cognitive and physical disability in patients with early multiple sclerosis.

BACKGROUND: 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. METHODS: 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. RESULTS: BREMSO score correlated negatively with SDMT at visit1 (ß = -0.33, p = 0.019), visit2 (ß = -0.34, p = 0.017) and visit3 (ß = -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. CONCLUSIONS: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS.

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.

Effect of vitamin D replacement on immunological biomarkers in patients with multiple sclerosis.

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<25ng/ml) received 10,000IU/week cholecalciferol for 3months. Sufficient vitamin D patients (serum level>35ng/ml) were followed for the same period. Assessments were performed at baseline and at 3months. 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.

Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases.

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.

Retinal measures correlate with cognitive and physical disability in early multiple sclerosis.

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.