Raed Behbehani

Real-World Use of Fingolimod in Patients with Relapsing Remitting Multiple Sclerosis: A Retrospective Study Using the National Multiple Sclerosis Registry in Kuwait

BackgroundFingolimod is an oral sphingosine-1-phosphate–receptor modulator, which has demonstrated efficacy in clinical trials and has recently been approved for multiple sclerosis (MS) treatment in Kuwait. Post-marketing studies are important to demonstrate real-life efficacy and safety.ObjectiveThe objective of this study was to examine the efficacy and safety of fingolimod treatment in a clinical setting.MethodsUsing the national Kuwait MS registry, relapsing remitting MS patients who had been prescribed fingolimod forxa0≥6xa0months were retrospectively identified. Three-monthly clinical evaluations and 6-monthly magnetic resonance imagings (MRIs) were performed. Patient status pre- and post-treatment was compared using chi-square and Student t-tests.ResultsA total of 175 patients were included: 75.4xa0% female (nxa0=xa0132); mean age 33.3xa0±xa09.2xa0years; mean disease duration 7.2xa0±xa05.2xa0years; mean fingolimod use 21.7xa0±xa09.1xa0months. Most had used previous disease-modifying therapy (78.9xa0%; nxa0=xa0138), mainly interferons (66.9xa0%; nxa0=xa0117). Twenty-three patients (11.4xa0%) discontinued/withdrew fingolimod; of whom eight had relapses. The proportion of relapse-free patients improved significantly (86.3xa0% vs. 32.6xa0%; pxa0<xa00.001), while the proportion of patients with MRI activity decreased (18.3.6xa0% vs. 77.7xa0%; pxa0<xa00.001). Mean expanded disability status scale (EDSS) score at the last visit improved when compared with pre-treatment (2.26xa0±xa01.49 vs. 2.60xa0±xa01.44; pxa0=xa00.03). Forty-three (24.6xa0%) patients experienced adverse events; headaches and lymphopenia were the most commonly reported adverse events.ConclusionFingolimod treatment was associated with reduced relapse and MRI activity, and an improved EDSS score. Discontinuation/withdrawal rates and adverse events were low. Fingolimod presents a promising treatment for MS in Kuwait.

Optical coherence tomography segmentation analysis in relapsing remitting versus progressive multiple sclerosis

Introduction Optical coherence tomography (OCT) with retinal segmentation analysis is a valuable tool in assessing axonal loss and neuro-degeneration in multiple sclerosis (MS) by in-vivo imaging, delineation and quantification of retinal layers. There is evidence of deep retinal involvement in MS beyond the inner retinal layers. The ultra-structural retinal changes in MS in different MS phenotypes can reflect differences in the pathophysiologic mechanisms. There is limited data on the pattern of deeper retinal layer involvement in progressive MS (PMS) versus relapsing remitting MS (RRMS). We have compared the OCT segmentation analysis in patients with relapsing-remitting MS and progressive MS. Methods Cross-sectional study of 113 MS patients (226 eyes) (29 PMS, 84 RRMS) and 38 healthy controls (72 eyes). Spectral domain OCT (SDOCT) using the macular cube acquisition protocol (Cirrus HDOCT 5000; Carl Zeiss Meditec) and segmentation of the retinal layers for quantifying the thicknesses of the retinal layers. Segmentation of the retinal layers was carried out utilizing Orion software (Voxeleron, USA) for quantifying the thicknesses of individual retinal layers. Results The retinal nerve finer layer (RNFL) (p = 0.023), the ganglion-cell/inner plexiform layer (GCIPL) (p = 0.006) and the outer plexiform layer (OPL) (p = 0.033) were significantly thinner in PMS compared to RRMS. There was significant negative correlation between the outer nuclear layer (ONL) and EDSS (r = -0.554, p = 0.02) in PMS patients. In RRMS patients with prior optic neuritis, the GCIPL correlated negatively (r = -0.317; p = 0.046), while the photoreceptor layer (PR) correlated positively with EDSS (r = 0.478; p = 0.003). Conclusions Patients with PMS exhibit more atrophy of both the inner and outer retinal layers than RRMS. The ONL in PMS and the GCIPL and PR in RRMS can serve as potential surrogate of disease burden and progression (EDSS). The specific retinal layer predilection and its correlation with disability may reflect different pathophysiologic mechanisms and various stages of progression in MS.

Retinal nerve fiber layer thickness and neurologic disability in relapsing–remitting multiple sclerosis

OBJECTIVEnTo assess the correlation between disability progression assessed by expanded disability status scale (EDSS) and peripapillary retinal nerve fiber layer thickness (RNFLT), macular thickness and macular volume obtained by spectral domain OCT (SDOCT) in patient with relapsing-remitting multiple sclerosis.nnnMETHODSnWe conducted a cross sectional study by recruiting 104 with relapsing-remitting MS patients and 51 healthy controls. Patients clinical characteristics and neurologic disability was recorded from the subject clinical records. All patients had complete neuro-ophthalmic and neurological assessments. SDOCT performed to obtain peripapillary RNFLT, macular thickness and volume.nnnRESULTSnThere was a statistically significant correlation between the mean EDSS scores and the average RNFLT (p = 0 .006; r = − 0.268) along with superior (p = 0.020; r = − 0.228), inferior (p = 0.007; r = − 0.262) and temporal (p = 0.031; r = − 0.212) quadrants. However, macular thickness (p = 0.205; r = − 0.125) and volume (p = 0.178; r = − 0.133) were not significantly correlated with EDSS scores.nnnCONCLUSIONnOur study showed a significant correlation between RNFLT and disability progression assessed by mean of EDSS in patients with relapsing-remitting MS. RNFLT can be a useful tool to estimate neurological disability in newly diagnosed patients or patients with early RRMS.

Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013.

OBJECTIVESnThis study aimed to assess the incidence and prevalence of pediatric-onset multiple sclerosis (POMS) along with temporal and gender differentials in these estimates in Kuwait.nnnMETHODSnWe identified MS patients with pediatric (age <18 years) onset between 1994 and 2013 from national MS registry. Year and gender-specific incidence rate and prevalence estimates were computed. Multivariable Poisson regression analyses of time-series cross-sectional panel data were conducted to evaluate temporal and gender related variations in yearly POMS incidence rate and prevalence.nnnRESULTSn122 POMS patients were identified; of which 90 (73.8%) were females. During 2013, POMS incidence rate and prevalence (per 100,000) were 2.1 and 6.0 respectively. Multivariable Poisson regression model revealed statistically significant 5% increase in POMS incidence rate (p=0.002) and 6% increase in prevalence (p<0.001) from 1994 to 2013. Furthermore, during the study period, female children were more likely to have higher POMS incidence rate (relative rate=2.9; p<0.001) and prevalence (prevalence ratio=2.8; p<0.001).nnnCONCLUSIONSnThe temporal increase and gender disparity in POMS incidence and prevalence corroborate the findings of earlier studies conducted elsewhere. Knowledge of increasing POMS burden may help in optimal planning for better management of patients in the region.

Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era

Objective To determine the rate of relapse occurrence during pregnancy and postpartum. Methods In a cross-sectional study using the national multiple sclerosis (MS) registry, pregnant women with relapsing MS were identified. Data on demographics, clinical characteristics, and disease-modifying therapies (DMTs), including washout periods, were collected. Timings and durations of relapses were extracted. A multivariate logistic regression was used to assess the relationship between relapses and prior use of different DMTs. Results Completed data were available for 99 pregnancies (87 patients). Mean age and mean age at onset were 31.8 ± 5 and 24.4 ± 5.6 years, respectively, while the mean disease duration was 7.4 ± 4.6 years. Most pregnancies (89.9%) occurred in patients who were on DMTs in the year preceding pregnancy with a mean treatment duration of 63.4 ± 29 months. The rates of occurrence of relapses during pregnancy and postpartum were 17.2% and 13.7%, respectively. Most of the relapses occurred during the first (n = 6) and third (n = 7) trimesters. Rate of relapse was highest among patients receiving natalizumab and fingolimod before pregnancy. A longer washout period was significantly associated with relapse occurrence. Conclusion The relapse occurrence during pregnancy is higher than the previously published rates. The use of high-efficacy therapies with long washout periods before conception was associated with an increased risk of relapses during pregnancy. Postpartum relapse occurrence was similar to that in previous reports.

Effectiveness and Safety of Dimethyl Fumarate Treatment in Relapsing Multiple Sclerosis Patients: Real-World Evidence

IntroductionDimethyl fumarate (DMF) has been recently approved as a disease-modifying therapy for the treatment of multiple sclerosis (MS). Post-marketing studies are important to confirm what was established in clinical trials.ObjectiveTo evaluate effectiveness and safety of DMF and to measure the occurrence of lymphopenia in a cohort of MS patients in a clinical setting.MethodsUsing the national MS registry, we prospectively assessed relapsing MS patients who had been prescribed DMF for at least 6xa0months. Primary outcome measure was the proportion of relapse-free patients at last follow-up visit. Secondary outcome measures were the mean change in expanded disability status scale (EDSS) and the proportion of patients with radiological activity (gadolinium-enhancing or new T2 lesions) at the last follow-up visit. Absolute lymphocyte count (ALC) was assessed at baseline (within 6xa0months prior to DMF initiation) and at one or more times during DMF treatment 3xa0months post-initiation.ResultsOf 134 patients identified, 119 were eligible and included in the analysis. Women represented 59.7% of the studied cohort. Mean age and mean disease duration were 33.5xa0±xa011.1 and 8.3xa0±xa07xa0years, respectively. A total of 75.6% of the patients received prior disease-modifying therapies. Mean duration of DMF exposure was 20.5xa0±xa09.5xa0months. The proportion of relapse-free patients increased significantly from 51.2% to 89.9% (pxa0<xa00.0001), while the mean EDSS score decreased from 2.8xa0±xa01.8 at baseline to 2.3xa0±xa01.7 (pxa0<xa00.058) at last follow-up visit. The proportion of patients with MRI activity decreased significantly from 61.1% to 15.1% (pxa0<xa00.0001). The mean ALCs decreased from 2170 to 1430 cells/μl (34% decrease). Lymphopenia was seen in 13 (10.9%) patients, of whom 3 (2.5%) patients had grade 3 lymphopenia necessitating discontinuation of DMF. Although no serious adverse events were reported, 19.3% of patients discontinued DMF.ConclusionIn clinical practice, DMF appeared to be effective in reducing disease activity and progression of disability throughout the observational period. DMF was well tolerated with no serious adverse events. ALC profiles in DMF-treated patients were generally stable throughout the observational period. The proportion of patients who developed severe lymphopenia was similar to figures in clinical trials.

Ganglion cell analysis in acute optic neuritis.

BACKGROUNDnOptic neuritis has a diagnostic and prognostic significance in predicting the development of multiple sclerosis. Optical coherence tomography is being increasingly used to detect and monitor axonal damage in MS by measuring the retinal nerve fiber layer (RNFL). However, RNFL can be affected by edema and inflammation and obscure early axonal damage.nnnOBJECTIVEnTo study the pattern of change in the ganglion cell and inner plexiform layer compared to retinal nerve fibber layer in acute optic neuritis using spectral domain OCT.nnnMETHODSnTen patients with acute optic neuritis were followed prospectively for 6 months with spectral domain optical coherence tomography. A group of 40 of eyes of 20 healthy controls was used for baseline comparison.nnnRESULTSnThe ganglion cell and inner plexiform layer (GCIPL) was significantly lower (thinner) at onset in patients affected (p=0.009) eyes. Both RNFL and GCIPL were significantly lower in affected eyes at 6 months (p=0.012 and p=0.007) respectively compared to baseline.nnnCONCLUSIONnThe GCIPL is probably more sensitive index of axonal loss than the RNFL in acute optic neuritis and could be a better index to detect neurodegeneration in multiple sclerosis. This can helpful in estimating early axonal loss and can potentially be used in therapeutic trials of neuroprotective drugs.

Is Time to Reach EDSS 6.0 Faster in Patients with Late-Onset versus Young-Onset Multiple Sclerosis?

Background & Objectives Published natural history data on late-onset of multiple sclerosis are limited. We aimed to assess the risk of attaining EDSS 6.0 among patients with late-onset (> 40 years) MS (LOMS) and young-onset (18–40 years) MS (YOMS). Methods This cross-sectional cohort study was conducted to identify LOMS and YOMS patients’ with relapsing remitting course at MS diagnosis. Time (years) to reach sustained EDSS 6.0 was compared between LOMS and AOMS patients. Cox proportional hazards model was used to evaluate the demographic and clinical predictors of time to EDSS 6.0 in these cohorts. Results LOMS and YOMS cohorts comprised 99 (10.7%) and 804 (89.3%) patients respectively. Spinal cord presentation at MS onset was more common among LOMS patients (46.5% vs. 32.3%). The proportions of LOMS and YOMS patients reaching EDSS 6.0 during the follow-up period were 19.2% and 15.7% respectively. In multivariable Cox proportional hazards model, older age at MS onset (adjusted hazard ratio (aHR) = 3.96; 95% CI: 2.14–7.32; p < 0.001), male gender (aHR = 1.85; 95% CI: 1.22–2.81; p = 0.004) and spinal cord presentation at onset (aHR = 1.47; 95% CI: 0.98–2.21; p = 0.062) were significantly associated with shorter time to EDSS 6.0. Conclusions LOMS patients attained EDSS 6.0 in a significantly shorter period that was influenced by male gender and spinal cord presentation at MS onset.

The Use of Natalizumab in Pediatric Patients With Active Relapsing Multiple Sclerosis: A Prospective Study

BACKGROUNDnPediatric multiple sclerosis (MS) has been increasingly recognized. In the absence of approved disease-modifying therapies (DMTs) for pediatric patients, clinicians resort to data extrapolated from clinical trials conducted in adults with MS. The objective of this article was to study the effectiveness and safety of natalizumab in with pediatric MS.nnnMETHODSnPatients with pediatric MS (agedxa0less thanxa018xa0years) who had been treated with natalizumab were followed up prospectively as part of the national MS registry. Data of relapsing patients who had at least a one-year follow-up were analyzed. The primary outcome measure was the annual relapse rate after natalizumab treatment. Secondary outcomes measures included the mean change in disease progression measured by the expanded disability status scale and the proportion of patients with radiologicxa0activity (gadolinium-enhancing or new T2 lesions) at the last follow-up visit.nnnRESULTSnThirty-two patients with pediatric MS had been treated with natalizumab for at least 12xa0months, of whom 72% were females. The mean age at onset and disease duration were 14.9xa0±xa02.6 and 5.1xa0±xa03.1xa0years, respectively. Most patients (nxa0=xa021, 66%) had breakthrough disease on first-line disease-modifying therapies. The mean number of natalizumab infusions was 34.5xa0±xa018. The annual relapse rate was significantly reduced (1.66xa0±xa00.5 vsxa00.06xa0±xa00.25; Pxa0<xa00.001), whereas the mean expanded disability status score improved (3.3xa0±xa01.3 vsxa02.2xa0±xa01.0; Pxa0<xa00.001) at the last follow-up visits. The proportion of patients with magnetic resonance imaging activity was significantly reduced (93.8% versusxa012.5%; Pxa0<xa00.001). No major adverse events were observed.nnnCONCLUSIONnIn our pediatric MS cohort with aggressive or breakthrough disease, treatment with natalizumab was effective in reducing clinical and radiologicxa0disease activity. Natalizumab has a similar clinical efficacy and safety profile as in adult MS.

Sensitivity of visual evoked potentials and spectral domain optical coherence tomography in early relapsing remitting multiple sclerosis

BACKGROUNDnVisual evoked potentials and spectral-domain optical coherence tomography are common ancillary studies that assess the visual pathways from a functional and structural aspect, respectively.nnnOBJECTIVEnTo compare prevalence of abnormalities of Visual evoked potentials (VEP) and spectral-domain optical coherence tomography (SDOCT) in patients with relapsing remitting multiple sclerosis (RRMS).nnnMETHODSnA cross-sectional study of 100 eyes with disease duration of less than 5 years since the diagnosis. Correlation between retinal nerve fiber layer and ganglion-cell/inner plexiform layer with pattern-reversal visual evoked potentials amplitude and latency and contrast sensitivity was performed.nnnRESULTSnThe prevalence of abnormalities in pattern-reversal visual VEP was 56% while that of SOCT was 48% in all eyes. There was significant negative correlations between the average RNFL (r=-0.34, p=0.001) and GCIPL (r=-0.39, p<0.001) with VEP latency. In eyes with prior optic neuritis, a significant negative correlation was seen between average RNFL (r=-0.33, p=0.037) and GCIPL (r=-0.40, p=0.010) with VEP latency.nnnCONCLUSIONSnWe have found higher prevalence of VEP abnormalities than SCOCT in early relapsing-remitting multiple sclerosis. This suggests that VEP has a higher sensitivity for detecting lesions of the visual pathway in patients with early RRMS.