Corneal immune cells as a biomarker of inflammation in multiple sclerosis: a longitudinal study.

Background: Corneal immune cells (ICs) are antigen-presenting cells that are known to increase ocular and systemic inflammatory conditions. Objective: We aimed to assess longitudinal changes in corneal IC in patients with multiple sclerosis (MS) and relation to disability and ongoing treatment. Design: Prospective observational study conducted between September 2016 and February 2020. Methods: Patients with relapsing-remitting MS (RRMS) (n = 45) or secondary progressive MS (SPMS) (n = 15) underwent corneal confocal microscopy (CCM) at baseline and 2-year follow-up for estimation of corneal IC density [dendritic cells with (DCF) (cells/mm2) or without nerve fiber contact (DCP); and non-dendritic cells with (NCF) or without nerve fiber contact (NCP)]. Optical coherence tomography, neuroimaging, and disability assessments were additionally performed. Healthy controls (n = 20) were assessed at baseline. Results: In both RRMS and SPMS compared to controls, DCP (p < 0.001 and p < 0.001, respectively) and DCF (p < 0.001 and p = 0.005) were higher and NCF (p = 0.007 and p = 0.02) was lower at baseline. DCP showed excellent performance in identifying patients with MS (sensitivity/specificity = 0.88/0.90) followed by DCF (0.80/0.75) and NCF (0.80/0.85). At follow-up compared to baseline, DCP (p = 0.01) was significantly reduced, and NCP (p = 0.004) and NCF (p = 0.04) were increased. Subgroup analysis showed that baseline NCP and NCF were significantly higher (p = 0.04-0.05) in patients who switched disease-modifying treatment, and baseline NCP (p = 0.05) was higher in patients on interferon. Conclusion: Baseline and change in corneal IC were related to axonal degeneration and treatment status. Evaluation of corneal IC using CCM may allow an assessment of ongoing inflammation, disease progression, and the effect of treatment in MS.

Corneal axonal loss as an imaging biomarker of neurodegeneration in multiple sclerosis: a longitudinal study.

Background: Resourceful endpoints of axonal loss are needed to predict the course of multiple sclerosis (MS). Corneal confocal microscopy (CCM) can detect axonal loss in patients with clinically isolated syndrome and established MS, which relates to neurological disability. Objective: To assess corneal axonal loss over time in relation to retinal atrophy, and neurological and radiological abnormalities in MS. Methods: Patients with relapsing-remitting (RRMS) (n = 68) or secondary progressive MS (SPMS) (n = 15) underwent CCM and optical coherence tomography. Corneal nerve fibre density (CNFD-fibres/mm2), corneal nerve branch density (CNBD-branches/mm2), corneal nerve fibre length (CNFL-mm/mm2) and retinal nerve fibre layer (RNFL-µm) thickness were quantified along with neurological and radiological assessments at baseline and after 2 years of follow-up. Age-matched, healthy controls (n = 20) were also assessed. Results: In patients with RRMS compared with controls at baseline, CNFD (p = 0.004) and RNFL thickness (p < 0.001) were lower, and CNBD (p = 0.003) was higher. In patients with SPMS compared with controls, CNFD (p < 0.001), CNFL (p = 0.04) and RNFL thickness (p < 0.001) were lower. For identifying RRMS, CNBD had the highest area under the receiver operating characteristic (AUROC) curve (0.99); and for SPMS, CNFD had the highest AUROC (0.95). At follow-up, there was a further significant decrease in CNFD (p = 0.04), CNBD (p = 0.001), CNFL (p = 0.008) and RNFL (p = 0.002) in RRMS; in CNFD (p = 0.04) and CNBD (p = 0.002) in SPMS; and in CNBD (p = 0.01) in SPMS compared with RRMS. Follow-up corneal nerve loss was greater in patients with new enhancing lesions and optic neuritis history. Conclusion: Progressive corneal and retinal axonal loss was identified in patients with MS, especially those with more active disease. CCM may serve as an imaging biomarker of axonal loss in MS.

Real-world experience of ocrelizumab in multiple sclerosis in an Arab population.

OBJECTIVE: Pivotal clinical trials revealed good clinical efficiency of ocrelizumab while having a good safety profile in the management of multiple sclerosis (MS). However, real-world data of ocrelizumab in daily clinical practice remain scarce. The aim of this study was to evaluate the preliminary safety profile and effectiveness of ocrelizumab treatment for MS in an Arab population in a real-world clinical setting. METHODS: In this retrospective single-center observational study in Qatar, we reviewed the medical records and analyzed the clinical and MRI data of all patients with relapsing-remitting MS (RRMS) and active secondary progressive MS (aSPMS)-between October 2017 through December 2020-who had received at least one infusion of ocrelizumab (Q-OCRE). RESULTS: A total of 60 MS patients were included (57 with RRMS, three SPMS). The Median follow-up period was 19 months (range, 1-32). The most common reason for switching to ocrelizumab was increased disease activity and three-quarters of the patients were on a previous disease-modifying drug (DMD). No evidence of disease activity (NEDA) status at year 1 was achieved in 73% of the cohort. Mild infusion-related reactions (IRR) and infections were reported (mainly upper respiratory tract infections followed by urinary tract infection) with a declining percentage over the follow-up applications. No severe side effects were observed. CONCLUSION: Our real-world experience confirms good efficacy, tolerability, and safety of ocrelizumab in our Arab population.

Corneal Immune Cells Are Increased in Patients With Multiple Sclerosis.

Purpose: Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that has been used to identify increased corneal immune cells in patients with immune-mediated peripheral neuropathy. Given that multiple sclerosis has an immune-mediated etiology, we have compared corneal immune cell (IC) density and near-nerve distance in different subtypes of patients with multiple sclerosis (MS) to controls. Methods: This is a blinded, cross-sectional study conducted at a tertiary hospital. Patients with clinically isolated syndrome (CIS) (n = 9), relapsing-remitting multiple sclerosis (RRMS) (n = 43), secondary progressive multiple sclerosis (SPMS) (n = 22), and control subjects (n = 20) underwent CCM. The total, mature, and immature corneal IC density and their nearest nerve distance were quantified. Results: The total IC density was higher in patients with MS (P = 0.02), RRMS (P = 0.01), and SPMS (P = 0.04) but not CIS (P = 0.99) compared to controls. Immature IC density was higher in patients with MS (P = 0.03) and RRMS (P = 0.02) but not SPMS (P = 0.10) or CIS (P = 0.99) compared to controls. Mature IC density (P = 0.15) did not differ between patients with MS and controls. The immature IC near-nerve distance was significantly greater in patients with MS (P = 0.001), RRMS (P = 0.007), and SPMS (P = 0.002) compared to controls. Immature IC density correlated with the Symbol Digit Modalities Test (r = -0.281, P = 0.02) and near-nerve distance correlated with the Expanded Disability Status Scale (r = 0.289, P = 0.005). Conclusions: In vivo CCM demonstrates an increase in immature IC density and the near-nerve distance in patients with MS. These observations merit further studies to assess the utility of CCM in assessing neuroimmune alterations in MS. Translational Relevance: Multiple sclerosis is an immune-mediated neurodegenerative disease. Dendritic cells mediate communication between the innate and adaptive immune systems. We have used in vivo CCM to show increased corneal ICs and suggest it may act as an imaging biomarker for disease status in patients with MS.

Pregnancy-related issues in women with multiple sclerosis: an evidence-based review with practical recommendations.

Objective: To review the current evidence regarding pregnancy-related issues in multiple sclerosis (MS) and to provide recommendations specific for each of them. Research design and methods: A systematic review was performed based on a comprehensive literature search. Results: MS has no effect on fertility, pregnancy or fetal outcomes, and pregnancies do not affect the long-term disease course and accumulation of disability. There is a potential risk for relapse after use of gonadotropin-releasing hormone agonists during assisted reproduction techniques. At short-term, pregnancy leads to a reduction of relapses during the third trimester, followed by an increased risk of relapses during the first three months postpartum. Pregnancies in MS are not per se high risk pregnancies, and MS does not influence the mode of delivery or anesthesia unless in the presence of significant disability. MRI is not contraindicated during pregnancy; however, gadolinium contrast media should be avoided whenever possible. It is safe to use pulse dose methylprednisolone infusions to manage acute disabling relapses during pregnancy and breastfeeding. However, its use during the first trimester of pregnancy is still controversial. Women with MS should be encouraged to breastfeed with a possible favorable effect of exclusive breastfeeding. Disease-modifying drugs can be classified according to their potential for pregnancy-associated risk and impact on fetal outcome. Interferon beta (IFNß) and glatiramer acetate (GA) may be continued until pregnancy is confirmed and, after consideration of the individual risk-benefit if continued, during pregnancy. The benefit of continuing natalizumab during the entire pregnancy may outweigh the risk of recurring disease activity, particularly in women with highly active MS. GA and IFNß are considered safe during breastfeeding. The use of natalizumab during pregnancy or lactation requires monitoring of the newborn. Conclusions: This review provides current evidence and recommendations for counseling and management of women with MS preconception, during pregnancy and postpartum.

Severe rebound disease activity after fingolimod withdrawal in a pregnant woman with multiple sclerosis managed with rituximab: A case study.

Although pregnancy is potentially protective against relapses of multiple sclerosis, severe rebound of disease activity after withdrawal of fingolimod may occur. We report a woman with multiple sclerosis who discontinued fingolimod in the first month of her pregnancy. She developed severe disease rebound which responded poorly to steroids. She was started on rituximab, which was continued during the rest of her pregnancy and beyond. Rituximab appeared safe and well tolerated by both mother and infant, and could be considered in pregnancy for those patients with multiple sclerosis who are at high risk of gestational and postpartum relapse.

Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview.

BACKGROUND: The introduction of new disease-modifying therapies (DMTs) for remitting-relapsing multiple sclerosis (RRMS) has considerably transformed the landscape of therapeutic opportunities for this chronic disabling disease. Unlike injectable drugs, oral DMTs promote patient satisfaction and increase therapeutic adherence. REVIEW: This article reviews the salient features about the mode of action, efficacy, safety, and tolerability profile of approved oral DMTs in RRMS, and reviews their place in clinical algorithms in the Middle East and North Africa (MENA) region. A systematic review was conducted using a comprehensive search of MEDLINE, PubMed, Cochrane Database of Systematic Reviews (period January 1, 1995-January 31, 2018). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012-2017 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites, to obtain relevant safety information on these DMTs. CONCLUSIONS: Four oral DMTs: fingolimod, teriflunomide, dimethyl fumarate, and cladribine have been approved by the regulatory agencies. Based on the number needed to treat (NNT), the potential role of these DMTs in the management of active and highly active or rapidly evolving RRMS is assessed. Finally, the place of the oral DMTs in clinical algorithms in the MENA region is reviewed.

Peripheral neuropathy in patients with multiple sclerosis.

OBJECTIVES: To determine the prevalence and severity of neuropathic pain, sudomotor dysfunction and abnormal vibration perception in patients with MS. METHODS: 73 patients with MS and 32 age-matched healthy controls underwent assessment of expanded disability severity score (EDSS), DN4 to assess neuropathic pain, electrochemical skin conductance (ESC) to assess sudomotor function and vibration perception threshold (VPT). RESULTS: Patients with MS had a higher DN4 score (p < 0.001) with 14% fulfilling the criteria for neuropathic pain elevated VPT (p < 0.001) and lower ESC on the feet (p < 0.001) and hands (p < 0.001) compared to control participants. ESC on the feet (32% of MS patients) and hands (30% of MS patients) were lower, and DN4 (77% of MS patients) and VPT (64% of MS patients) were greater than 2SD of the healthy control values, respectively. EDSS correlated with the number of relapses (r = 0.564, p < 0.001), VPT (r = -0.457, < 0.001) and ESC on the feet (r = -0.268, p = 0.023). CONCLUSIONS: Patients with multiple sclerosis have evidence of sudomotor dysfunction and elevated vibration perception, which were associated with neurological disability from MS.

Optimization and stratification of multiple sclerosis treatment in fast developing economic countries: a perspective from Qatar.

OBJECTIVE: The introduction of disease-modifying therapies (DMTs) - with varying degrees of efficacy for reducing annual relapse rate and disability progression - has considerably transformed the therapeutic landscape of relapsing-remitting multiple sclerosis (RRMS). We aim to develop rational evidence-based treatment recommendations and algorithms for the management of clinically isolated syndrome (CIS) and RRMS that conform to the healthcare system in a fast-developing economic country such as Qatar. RESEARCH DESIGN AND METHODS: We conducted a systematic review using a comprehensive search of MEDLINE, PubMed, and Cochrane Database of Systematic Reviews (1 January 1990 through 30 September 2016). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012 through 2016 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites to obtain relevant safety information on these DMTs. RESULTS: For each of the DMTs, the mode of action, efficacy, safety and tolerability are briefly discussed. To facilitate the interpretation, the efficacy data of the pivotal phase III trials are expressed by their most clinically useful measure of therapeutic efficacy, the number needed to treat (NNT). In addition, an overview of head-to-head trials in RRMS is provided as well as a summary of the several different RRMS management strategies (lateral switching, escalation, induction, maintenance and combination therapy) and the potential role of each DMT. Finally, algorithms were developed for CIS, active and highly active or rapidly evolving RRMS and subsequent breakthrough disease or suboptimal treatment response while on DMTs. The benefit-to-risk profiles of the DMTs, taking into account patient preference, allowed the provision of rational and safe patient-tailored treatment algorithms. CONCLUSIONS: Recommendations and algorithms for the management of CIS and RRMS have been developed relevant to the healthcare system of this fast-developing economic country.

Prevalence, demographics and clinical characteristics of multiple sclerosis in Qatar.

No published epidemiologic data on multiple sclerosis (MS) in Qatar exist. Our objectives were to determine the prevalence, demographics and clinical characteristics of MS in the Middle Eastern country of Qatar. We analyzed data for Qatari MS patients fulfilling the McDonald diagnostic criteria. A total of 154 patients fulfilled the inclusion criteria. On 31 April 2010, the crude prevalence of MS in Qatar was 64.57 per 100,000 inhabitants (95% CI: 58.31-70.37). The female-to-male ratio was 1.33:1. A positive family history was found in 10.4% of included MS patients. We conclude that Qatar is now a medium-to-high risk area for MS, with some important differences in clinical characteristics as compared to other countries in the region.