Publications by authors named "Murat Terzi"

63 Publications

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
January 2021

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

Neurology 2021 02 28;96(5):e783-e797. Epub 2020 Dec 28.

From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.

Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, = 0.0016), worsening of disability (0.56, 0.38-0.82, = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, = 10) and worsening of disability (0.81, 0.67-0.99, = 0.043).

Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.

Classification Of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000011242DOI Listing
February 2021

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial.

Mult Scler Relat Disord 2021 Jan 26;47:102641. Epub 2020 Nov 26.

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address:

Background: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT.

Methods: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity.

Results: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder.

Conclusion: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate.

Trial Registration: NCT01892345 (ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.msard.2020.102641DOI Listing
January 2021

Treatment Response Score to Glatiramer Acetate or Interferon Beta-1a.

Neurology 2021 01 6;96(2):e214-e227. Epub 2020 Oct 6.

From the Department of Health Sciences (DISSAL) (F.B., M.P.S.), University of Genoa, Italy; CORe (T.K., C.M.), Department of Medicine, University of Melbourne, Australia; Department of Neurology (F.L.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Biostatistics (G.C.), University of Alabama at Birmingham; Department of Neurology and Center for Clinical Neuroscience (D.H., E.K.H.), First Medical Faculty, Charles University, Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Department of Neuroscience (A.P., M.G., P.D.), Faculty of Medicine, Université de Montréal, Quebec, Canada; Department of Neuroscience, Imaging, and Clinical Sciences (M.O.), University G. d'Annunzio, Chieti; IRCCS Istituto delle Scienze Neurologiche di Bologna (A.L.); Dipartimento di Scienze Biomediche e Neuromotorie (A.L.), Università di Bologna, Italy; Hospital Universitario Virgen Macarena (G. Izquierdo. S.E.), Sevilla, Spain; Department of Medical, Surgical Science and Advanced Technology "GF Ingrassia" (F.P.), University of Catania, Italy; Ondokuz Mayis University (M. Terzi), Department of Neurology, Samsun, Turkey; CISSS Chaudi're-Appalache (P.G.), Centre-Hospitalier, Levis, Quebec, Canada; IRCCS Mondino Foundation (R.B.), Pavia; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Department of Neurology (S.O.), Dokuz Eylul University, Izmir, Turkey; Ospedali Riuniti di Salerno (G. Iuliano), Salerno, Italy; Department of Neurology (C.B.), Karadeniz Technical University, Trabzon, Turkey; Department of Neurology (R.H.), Zuyderland Medical Center, Sittard, the Netherlands; Neuro Rive-Sud (F.G.), Hôpital Charles LeMoyne, Greenfield Park, Quebec, Canada; Clinico San Carlos (C.O.-G), Madrid, Spain; Cliniques Universitaires Saint-Luc (V.v.P.); Université Catholique de Louvain (V.v.P.), Brussels, Belgium; UOC Neurologia (E.C.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Kommunehospitalet (T.P.), Arhus C, Denmark; Koc University (A.A.), School of Medicine; Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases (A.S.), Istanbul, Turkey; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; University of Queensland (P.M.), Brisbane, Australia; Haydarpasa Numune Training and Research Hospital (R.T.), Istanbul, Turkey; Central Clinical School (H.B.), Monash University, Melbourne, Australia; The University of Texas Health Science Center at Houston (J.S.W.); Rehabilitation Unit (C.S.), "Mons. L. Novarese" Hospital, Moncrivello; and IRCCS Ospedale Policlinico San Martino (M.P.S.), Genoa, Italy.

Objective: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments.

Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

Results: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity < 0.0001).

Conclusions: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000010991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905777PMC
January 2021

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

Brain 2020 09;143(9):2742-2756

CORe, Department of Medicine, University of Melbourne, Melbourne, 3050, Australia.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
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http://dx.doi.org/10.1093/brain/awaa231DOI Listing
September 2020

Methylprednisolone Concentrations in Breast Milk and Serum of Patients with Multiple Sclerosis Treated with IV Pulse Methylprednisolone.

Clin Neurol Neurosurg 2020 Oct 29;197:106118. Epub 2020 Jul 29.

Ondokuz Mayıs University, Faculty of Medicine, Department of Neurology, Samsun, Turkey.

Background: It is commonly known that women with multiple sclerosis (MS) have an increased risk for relapses during the post-partum period. High-dose IV methylprednisolone is the first-line treatment for acute relapses. Methylprednisolone is administered to lactating women although there is insufficient data as to the levels of concentration in breast milk and serum, and the calculated steroid exposure to infants.

Objectives: The study aimed to measure the transfer of methylprednisolone into breast milk and the correlation of milk and serum methylprednisolone concentrations in breastfeeding MS patients during and after infusion therapy.

Methods: IV methylprednisolone pulse therapy was given to 12 lactating MS patients. Breast milk and maternal serum samples were obtained; before infusion, 30 minutes into the infusion, at the end of infusion and at the 1, 2, 4, 8, 12 and 24 hours subsequently.

Results: The highest level of methylprednisolone concentration in breast milk (2.09 μg/ml) and serum (6.09 μg/ml) was detected at the end of the infusion. According to the measurements recorded at the 1, 2, 4, 8, 12, and 24 hours after infusion, the concentrations showed a gradual decrease both breast milk and serum. The milk and serum methylprednisolone concentrations were below detection limits just before infusion and at the 24 hour after infusion. A highly significant correlation was found between breast milk and maternal serum levels. The absolute infant dose was calculated to be 69.50 μg/kg/day and the relative infant dose (RID) was 0.50%.

Conclusion: Results have shown that the transfer of methylprednisolone into breast milk seems to be low. Although, concentration levels may not seem to pose a threat to the infant, mothers can choose to wait 2 to 4 hours to further limit the level of exposure.
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http://dx.doi.org/10.1016/j.clineuro.2020.106118DOI Listing
October 2020

Association of Sustained Immunotherapy With Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis.

JAMA Neurol 2020 Jul 27. Epub 2020 Jul 27.

Clinical Outcomes Research Unit (CORe), Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS).

Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation.

Design, Setting, And Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020.

Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated.

Main Outcomes And Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models).

Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent.

Conclusions And Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
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http://dx.doi.org/10.1001/jamaneurol.2020.2453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385679PMC
July 2020

Screening of dysphagia by DYMUS (Dysphagia in multiple sclerosis) and SWALQoL (Swallowing quality of life) surveys in patients with multiple sclerosis.

Mult Scler Relat Disord 2020 Oct 14;45:102397. Epub 2020 Jul 14.

Ondokuz Mayıs University School of Medicine Dept. of Neurology, Samsun, Turkey.

Background: Dysphagia is a life-threating symptom in patients with multiple sclerosis (MS) because aspiration pneumonia develops as a consequence of swallowing disorders. Dysphagia can be detected by using patient-reported outcome measures in order to prevent complications.

Objective: To identify the dysphagia prevalence, severity, and swallowing related quality of life (QoL), by using two validated dysphagia questionnaires.

Method: Dysphagia in Multiple Sclerosis (DYMUS) and Swallowing Quality of Life (SWALQoL) questionnaires were collected from 64 patients with MS.

Results: The mean total SWALQoL score was 67.9 (±11.2) and the mean DYMUS score was 2.02 (±1.3). The highest mean SWALQoL subdomain score belonged to communication (76.7 ± 15.8), and the lowest score belonged to sleep (54.2 ± 12.2). There was a significant correlation between age and DYMUS and SWALQoL scores (r: 0.539 and r: -0.610 respectively, P < .001). Additionally, there was a significant moderate correlation between disease duration and DYMUS and SWALQoL scores (r: 0.693 and r: -0.697 respectively, P < .001). DYMUS and SWALQoL scores did not vary between males and females (P > .05). Patients with secondary progressive MS had higher DYMUS and lower SWALQoL scores (more dysphagia) than in primary progressive or relapsing-type MS. There was a strong, negative and statistically significant correlation between DYMUS and total SWALQoL scores (Spearman's rho: -0.862, p < .001).

Conclusion: MS causes dysphagia and reduces QoL. Age, disease duration, and MS type are major factors that influence SWALQoL. DYMUS and SWALQoL are well correlated. DYMUS is an easy to answer tool that may advised for screening dysphagia in patients with MS.
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http://dx.doi.org/10.1016/j.msard.2020.102397DOI Listing
October 2020

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Mult Scler 2020 Jun 15:1352458520926955. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
June 2020

'Is RLS a harbinger and consequence of MS?: Striking results of the 'RELOMS-T' study'.

Mult Scler Relat Disord 2020 Jul 16;42:102055. Epub 2020 Mar 16.

Dokuz Eylül University, Izmir, Turkey.

Background: Although studies report a high prevalence rate of restless legs syndrome (RLS) among patients with multiple sclerosis (PwMS) ranging from 13.3 to 65.1%, little is known about the causes of this relationship.

Methods: To ascertain the prevalence, features and impact of RLS among PwMS a nation-wide, multicenter, prospective and a cross-sectional survey, designed to reflect all of the PwMS throughout Turkey, was conducted in 13 centers. Exploring the relationship of the two conditions could possibly contribute to the understanding of the causes of the high and wide-ranging prevalence rates and the pathophysiology of both diseases.

Results: Of the 1068 participants 173 (16,2%) found to have RLS [RLS(+)] and 895 (83,8%) did not [RLS(-)]. Among the RLS(+) 173, all but 8 patients (4,6%) were underdiagnosed in terms of RLS. More than half of the patients with RLS had 'severe' or 'very severe' RLS. The onset of RLS was before or synchronous with the onset of MS in about a half of our patients.

Conclusion: We conclude that RLS should be meticulously investigated in PwMS and MS can be a direct cause of RLS at least in part of PwMS. Our data about the timing of the onset of MS and RLS, along with the high prevalence of RLS in PwMS suggest that the pathologic changes in the initial phases of MS can possibly trigger RLS symptoms.
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http://dx.doi.org/10.1016/j.msard.2020.102055DOI Listing
July 2020

The Effectiveness of New Adiposity Indices on Plasma Lipid Profile in Patients with Multiple Sclerosis: A Cross-Sectional Study with A Body Shape Index, Body Roundness Index, and Visceral Adiposity Index.

Mult Scler Relat Disord 2020 Aug 23;43:102214. Epub 2020 May 23.

Ondokuz Mayıs University, Faculty of Science, Department of Statistics.

Objective: This study aimed to determine the effectiveness of three different indices used to identify the effect of visceral adiposity on lipid profile markers in patients with multiple sclerosis.

Methods: The study consisted of a total of 152 patients with relapsing-remitting multiple sclerosis who were aged 18 years and older. High-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglyceride (TG) were accessed from the patient system. Patients' height, body weight, waist circumference, and hip circumference measurements were also obtained. The effects of three different adiposity indices, including A Body Shape Index (ABSI), the Body Roundness Index (BRI), and the Visceral Adiposity Index (VAI), on plasma lipid profile in multiple sclerosis patients were evaluated. The data were analyzed using the R software and SPSS 21 statistical software package.

Results: HDL-c was impacted by ABSI and VAI in males and only VAI in females (p < 0.05). An increase of 0.01 units of ABSI in males led to an increase of 5.88 mg/dL in plasma HDL-c level. In male patients with multiple sclerosis, LDL-c was positively affected by BRI and VAI changes (p < 0.05). One unit increase in BRI in males increased LDL-c level by 5.56 mg/dL, whereas 1 unit increase in VAI increased LDL-c level by 3.52 mg/dL (p < 0.05).

Conclusion: This study indicated that these three different indices employed to evaluate adiposity were associated with plasma lipid profile. The effect of VAI on plasma lipids is higher than that of the other indices. In patients with multiple sclerosis, the use of these practical and non-invasive indices will be useful in assessing plasma lipid profile.
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http://dx.doi.org/10.1016/j.msard.2020.102214DOI Listing
August 2020

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Feb 25;38:101868. Epub 2019 Nov 25.

CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. Electronic address:

Background: Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.

Method: This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model.

Results: 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024).

Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.
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http://dx.doi.org/10.1016/j.msard.2019.101868DOI Listing
February 2020

Comparative analysis of fingolimod versus teriflunomide in relapsing-remitting multiple sclerosis.

Mult Scler Relat Disord 2019 Nov 26;36:101376. Epub 2019 Aug 26.

Dokuz Eylul University, Department of Neurology, Izmir, Turkey.

Background: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed.

Objectives: The objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS.

Methods: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared.

Results: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001).

Conclusion: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. The two oral therapies exhibited similar effects on disability outcomes.
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http://dx.doi.org/10.1016/j.msard.2019.101376DOI Listing
November 2019

Risk of secondary progressive multiple sclerosis: A longitudinal study.

Mult Scler 2020 01 9;26(1):79-90. Epub 2019 Aug 9.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia/L4 Centre, Melbourne Brain Centre at Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested.

Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis.

Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed.

Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02,  < 0.001), longer disease duration (HR = 1.01,  = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30,  < 0.001), more rapid disability trajectory (HR = 2.82,  < 0.001) and greater number of relapses in the previous year (HR = 1.07,  = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62,  = 0.039) and disease-modifying therapy exposure (HR = 0.71,  = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion.

Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
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http://dx.doi.org/10.1177/1352458519868990DOI Listing
January 2020

Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

N Engl J Med 2019 08 3;381(7):614-625. Epub 2019 May 3.

From the Mayo Clinic, Rochester, MN (S.J.P.); Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany (A.B.); Tohoku University Graduate School of Medicine (K.F., I.N.) and Tohoku Medical and Pharmaceutical University (I.N.), Sendai, School of Medicine, Fukushima Medical University, Fukushima City (K.F.), and Southern Tohoku Research Institute for Neuroscience, Koriyama (K.F.) - all in Japan; Research Institute and Hospital, National Cancer Center, Goyang, South Korea (H.J.K.); Johns Hopkins University, Baltimore (M.L.); Massachusetts General Hospital and Harvard Medical School (M.L.) and Alexion Pharmaceuticals (A.P., K.P.F., R.A.) - all in Boston; John Radcliffe Hospital, Oxford, United Kingdom (J.P.); Ondokuz Mayis University, Samsun, Turkey (M.T.); First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia (N.T.); Kuala Lumpur Hospital, Kuala Lumpur, Malaysia (S.V.); Cheng-Hsin General Hospital and School of Medicine, National Yang Ming University, Taipei, Taiwan (K.-C.W.); and the Mayo Clinic, Scottsdale, AZ (D.M.W.).

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse.

Methods: In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death).

Results: The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group.

Conclusions: Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).
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http://dx.doi.org/10.1056/NEJMoa1900866DOI Listing
August 2019

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

JAMA 2019 01;321(2):175-187

Institute for Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales.

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

Design, Setting, And Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.

Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

Main Outcome And Measure: Conversion to objectively defined secondary progressive MS.

Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

Conclusions And Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
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http://dx.doi.org/10.1001/jama.2018.20588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439772PMC
January 2019

Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.

J Neurol Neurosurg Psychiatry 2019 04 13;90(4):458-468. Epub 2019 Jan 13.

Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objective: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.

Methods: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).

Results: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).

Conclusion: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
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http://dx.doi.org/10.1136/jnnp-2018-319831DOI Listing
April 2019

Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study.

Mult Scler Relat Disord 2019 Feb 3;28:235-243. Epub 2019 Jan 3.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Australia. Electronic address:

Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.

Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS.

Methods: We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed.

Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births.

Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.
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http://dx.doi.org/10.1016/j.msard.2019.01.003DOI Listing
February 2019

Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy.

J Neurol Sci 2018 08 2;391:72-76. Epub 2018 Jun 2.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, VIC, Australia; Box Hill Hospital, Melbourne, VIC, Australia.

Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs.

Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation.

Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP.

Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.
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http://dx.doi.org/10.1016/j.jns.2018.06.001DOI Listing
August 2018

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

JAMA Neurol 2018 11;75(11):1407-1415

CORe, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.

Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested.

Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes.

Design, Setting, And Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44 449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed.

Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse.

Main Outcomes And Measures: Cumulative hazard of disability progression.

Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P = .003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P = .01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P = .26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P = .16).

Conclusions And Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.
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http://dx.doi.org/10.1001/jamaneurol.2018.2109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248114PMC
November 2018

Effects of short and long term electromagnetic fields exposure on the human hippocampus.

J Microsc Ultrastruct 2017 Oct-Dec;5(4):191-197. Epub 2017 Jul 13.

Department of Medicine and Public Health, The Hebrew University, Jerusalem, Israel.

The increasing use of mobile phones may have a number of physiological and psychological effects on human health. Many animal and human studies have reported various effects on the central nervous system and cognitive performance from of exposure to electromagnetic fields (EMF) emitted by mobile phones. The aim of the present study was to evaluate the effects of mobile phones on the morphology of the human brain and on cognitive performance using stereological and spectroscopic methods and neurocognitive tests. Sixty healthy female medical school students aged 18-25 years were divided into a low exposure group (30 subjects, <30 min daily use by the head) and high exposure group (30 subjects, >90 min daily use by the head). Magnetic resonance images (MRI) of the brain analysed on OsiriX 3.2.1 workstation. Neuropsychological tests were performed for each subject. In addition, three dominant specific metabolites were analysed, choline at 3.21 ppm, creatine at 3.04 ppm and -acetyl aspartate at 2.02 ppm. Analysis of the spectroscopic results revealed no significant difference in specific metabolites between the groups (p > 0.05). There was also no significant difference in terms of hippocampal volume between the groups (p > 0.05). In contrast, the results of the stroop and digit span (backward) neurocognitive tests of high exposure group for evaluating attention were significantly poorer from low exposure group (p < 0.05). Based on these results, we conclude that a lack of attention and concentration may occur in subjects who talk on mobile phones for longer times, compared to those who use phones relatively less.
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http://dx.doi.org/10.1016/j.jmau.2017.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025790PMC
July 2017

Prevalence of and risk factors for cognitive impairment in patients with relapsing-remitting multiple sclerosis: Multi-center, controlled trial.

Mult Scler Relat Disord 2018 May 24;22:70-76. Epub 2018 Mar 24.

Uludag University, Bursa, Turkey.

Background: Cognitive impairment (CI) is a common problem in multiple sclerosis (MS), may occur either in early or late phase of the disease, and impairs quality of life.

Objectives: This study aimed to determine the prevalence of CI and related risk factors in relapsing-remitting MS (RRMS) patients in Turkey.

Methods: The present cross-sectional, multi-center, and nationally representative study included RRMS patients. Sociodemographic characteristics, cognitive functions and additional outcomes were compared between patients with and without CI.

Results: The analyses included 487 RRMS patients. According to the BRB-N battery results, CI prevalence was 53.7%. There was a negative significant correlation of BRB-N subtests with age, disease duration, and EDSS and MSNQ-patient rated scores. On the logistic regression analysis, increased age, living in village/rural area, high income level, and high EDSS score were significant increasing risk factors in the development of CI.

Conclusions: This is the first national cognitive data obtained from MS in Turkey, which is a country between Europe and Asia and thus has characteristics of both continents. The similarity of the results of the present study obtained from Turkey to the Western-based data indicates that CI is universal in MS and the main factors affecting CI have not changed.
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http://dx.doi.org/10.1016/j.msard.2018.03.009DOI Listing
May 2018

Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod.

Mult Scler Relat Disord 2018 Jan 22;19:105-108. Epub 2017 Nov 22.

Box Hill Hospital, Eastern Health, Melbourne, Australia.

Background: Fingolimod is an efficient and safe drug for treating relapsing-remitting multiple sclerosis (RRMS). In vivo, fingolimod is phosphorylated and binds to "sphingosine-1-phosphate"(S1P) receptors that are expressed in a wide range of cells, including lymphocytes. Under the effect of fingolimod, lymphocytes are retained in lymphoid tissues through the regulation of S1P receptors. The aim of the present study was to assess whether the degree of lymphopenia was correlated to the positive treatment response of RRMS patients with fingolimod.

Methods: Data was sourced from the MSBase Registry. Patients were divided into two groups, according to the lymphocyte count on peripheral blood examination. Annualized Relapse Rate (ARR), time to first relapse and time to six-month confirmed disability progression were compared between groups.

Results: Group one consisted of 202 patients who reached 750 lymphocytes/mm during treatment while the comparison group two included 101 patients who never reached less than 1000 lymphocytes/mm in peripheral blood during the observation period. There were no differences between groups in ARR, time to first relapse or time to six-month confirmed disability progression.

Conclusion: The degree of lymphopenia in peripheral blood was not associated to the positive treatment response of fingolimod in RRMS patients.
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http://dx.doi.org/10.1016/j.msard.2017.11.018DOI Listing
January 2018

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Brain 2017 Sep;140(9):2426-2443

Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
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http://dx.doi.org/10.1093/brain/awx185DOI Listing
September 2017

Testing patient-reported outcome measurement equivalence in multinational clinical trials: An exemplar using the 12-item Multiple Sclerosis Walking Scale.

Mult Scler J Exp Transl Clin 2017 Jul-Sep;3(3):2055217317728740. Epub 2017 Sep 1.

Department of Clinical Trials and Health Research: Translational & Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, UK.

Background: Although multinational clinical trials frequently use patient-reported outcomes to measure efficacy, measurement equivalence across cultures and languages, a scientific requirement, is rarely tested. Clinically accessible accounts are rare; exemplars are needed.

Objective: To develop and test a Turkish version of the Multiple Sclerosis Walking Scale (MSWS-12v2) as a clinical exemplar for examining measurement equivalence.

Methods: The MSWS-12v2 Turkish (MSWS-12v2T) was developed using recognised methods for linguistic equivalence. Rasch measurement theory was used to examine measurement performance (multiple tests of targeting, scale performance, and person measurement) and measurement equivalence (differential item functioning). UK data ( = 3310) were used for comparisons and differential item functioning testing.

Results: One hundred and twenty-four people from two Turkish centres completed the MSWS-12v2T. Rasch measurement theory evidence supported MSWS-12v2T as reliable (person separation = 0.96) and valid (thresholds ordered; no concerning item misfit, bias, or person misfit). However, four items demonstrated significantly different performance between UK and Turkish samples. These item differences significantly affected scores (person measurements) at the group-level ( < 0.001). Individual person differences were less pronounced.

Conclusions: Linguistic equivalence does not guarantee measurement equivalence; independent testing is required. Rasch measurement theory enables sophisticated and unique examinations of cross-cultural measurement equivalence and we recommend this be tested routinely in pivotal multiple sclerosis clinical trials.
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http://dx.doi.org/10.1177/2055217317728740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613845PMC
September 2017

Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis.

Mult Scler 2018 10 31;24(12):1617-1626. Epub 2017 Aug 31.

Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia/Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.
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http://dx.doi.org/10.1177/1352458517728812DOI Listing
October 2018

Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS.

Neurology 2017 Sep 9;89(10):1050-1059. Epub 2017 Aug 9.

Objective: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).

Methods: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.

Results: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, = 0.09). Secondary and sensitivity analyses confirmed the results.

Conclusions: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

Classification Of Evidence: This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
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http://dx.doi.org/10.1212/WNL.0000000000004330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589791PMC
September 2017

Safety of IV pulse methylprednisolone therapy during breastfeeding in patients with multiple sclerosis.

Mult Scler 2018 08 26;24(9):1205-1211. Epub 2017 Jun 26.

Jasem Laboratory System and Solutions, Istanbul, Turkey.

Background: Women with multiple sclerosis (MS) experience an increased risk of relapse in the postpartum period. High-dose methylprednisolone is the first-line treatment for acute relapses.

Objectives: To determine the transfer of methylprednisolone into human milk in breastfeeding MS patients.

Methods: Methylprednisolone therapy was given for postpartum relapse to nine patients for three consecutive days, and seven patients received a daily infusion once a month. Breast milk samples were obtained before infusion and 1, 2, 4, 8, and 12 hours after completion of infusion.

Results: Methylprednisolone concentrations in milk were below detection limits immediately before infusion. C was measured at 1, 2, 4, 8, and 12 hours after infusion and levels of 2.100, 1.659, 0.680, 0.174, and 0.102 µg/mL were determined, respectively. The absolute infant dose was 98.98 µg/kg/day, and the relative infant dose (RID) was 0.71% of the weight-adjusted maternal dose.

Conclusion: The level of methylprednisolone transfer into breast milk is very low. The RID for methylprednisolone was lower than the generally accepted value. As methylprednisolone therapy is of short duration, infant exposure would be very low should a mother choose to breastfeed 1 hour after infusion. Waiting 2-4 hours after infusion will limit infant exposure still further.
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http://dx.doi.org/10.1177/1352458517717806DOI Listing
August 2018