Publications by authors named "Rana Karabudak"

57 Publications

An immunological and transcriptomics approach on differential modulation of NK cells in multiple sclerosis patients under interferon-β1 and fingolimod therapy.

J Neuroimmunol 2020 10 30;347:577353. Epub 2020 Jul 30.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

This study aims to compare NK cells obtained from multiple sclerosis (MS) patients receiving interferon-β1 and fingolimod therapies. Fingolimod reduced the CD56 NK cell subset. The remaining CD56 NK cells displayed NKG2D, NKp46, CD107a, and IFN-γ levels similar to those from the patients under interferon-β1 therapy. Alternatively, comparative transcriptomics and pathway analyses revealed significant distinctions between two therapy modalities. Molecular signature of the CD56 NK cells from fingolimod-treated MS patients was closely associated to those from healthy subjects. The basic assets of NK cells were modestly influenced by interferon-β1 and fingolimod, however transcriptomics showed profound alterations in NK responses.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577353DOI Listing
October 2020

Myelin oligodendrocyte glycoprotein antibody associated central nervous system demyelinating disease: a tertiary center experience from Turkey.

Mult Scler Relat Disord 2020 Sep 4;44:102376. Epub 2020 Jul 4.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: To identify the clinical and radiological characteristics of adult patients with myelin oligodendrocyte glycoprotein antibody disease (MOG-AD) in a Turkish cohort.

Methods: Clinical and radiological data were obtained retrospectively. Serological testing was done with fixed and live cell-based assays.

Results: Optic neuritis was the most common presenting symptom, and neuromyelitis optica spectrum disorder (NMOSD) without aquaporin-4 antibody (AQP4-IgG) was the most common phenotype. Most patients had a relapsing course. Steroid dependency was common. Conus involvement was a frequent clinical and radiological feature. Radiological features such as long segment involvement and perineural optic nerve gadolinium enhancement were also typical in our cohort. One patient presented with encephalopathy and seizures, pointing out to the importance of testing of myelin oligodendrocyte antibody (MOG-IgG) in such patients as well.

Conclusion: Myelin oligodendrocyte glycoprotein antibody disease is a heterogeneous clinical entity with characteristic clinical and radiological features. Our single-center experience underlines prominent clinical and magnetic resonance imaging (MRI) features and provides our treatment experiences.
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http://dx.doi.org/10.1016/j.msard.2020.102376DOI Listing
September 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

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

Predictors of progression in primary progressive multiple sclerosis in a large Turkish cohort.

Mult Scler Relat Disord 2020 Feb 12;38:101520. Epub 2019 Nov 12.

Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey; Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: Studies on the predictors of progression for primary progressive multiple sclerosis (PPMS) are limited and there is no information in the literature for populations outside Europe and North America. In this study, we aimed to identify predictors of progression in a large Turkish PPMS cohort.

Methods: We analyzed a cohort of 157 PPMS patients to investigate the effect of age of onset, gender, onset symptoms, presence or absence of relapses, and baseline gadolinium-enhancing lesions on the rate of progression to EDSS6 by using Kaplan-Meier analysis and multivariate Cox regression.

Results: Older age of onset and presence of spinal motor symptoms at onset were associated with a shorter time to EDSS6 and presence of supratentorial signs at onset was associated with a longer time to EDSS6 according to Kaplan-Meier analysis. These factors remained significant after multivariate Cox-regression analysis. Clinical relapses were present in 22.3% and gadolinium-enhancing lesions on baseline MRI were present in 28% of patients, but these factors were not predictive of time to EDSS6.

Conclusion: We identified age of onset and symptom at onset as predictors of progression in Turkish PPMS patients. Presence of clinical relapses or baseline gadolinium-enhancing lesions did not affect PPMS progression rate.
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http://dx.doi.org/10.1016/j.msard.2019.101520DOI Listing
February 2020

Identification of circulating MOG-specific B cells in patients with MOG antibodies.

Neurol Neuroimmunol Neuroinflamm 2019 11 14;6(6):625. Epub 2019 Oct 14.

From the Institute of Clinical Neuroimmunology (S.W., M. Schlüter, M. Spadaro, F.S.T., A.V., R.G., C.M., S.M., R.H., T.K., E.M.), Biomedical Center and University Hospitals, Ludwig Maximilian University Munich, Germany; Research Center for Translational Medicine (A.V.), Koç University School of Medicine, Istanbul, Turkey; Department of Neurology, (A.K., B.I., R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey; Department of Basic Oncology (F.G.Ö., G.E.), Hacettepe University Cancer Institute, Ankara Turkey; and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Germany.

Objective: To identify circulating myelin oligodendrocyte glycoprotein (MOG)-specific B cells in the blood of patients with MOG antibodies (Abs) and to determine whether circulating MOG-specific B cells are linked to levels and epitope specificity of serum anti-MOG-Abs.

Methods: We compared peripheral blood from 21 patients with MOG-Abs and 26 controls for the presence of MOG-specific B cells. We differentiated blood-derived B cells in vitro in separate culture wells to Ab-producing cells via engagement of Toll-like receptors 7 and 8. We quantified the anti-MOG reactivity with a live cell-based assay by flow cytometry. We determined the recognition of MOG epitopes with a panel of mutated variants of MOG.

Results: MOG-Ab-positive patients had a higher frequency of MOG-specific B cells in blood than controls, but MOG-specific B cells were only detected in about 60% of these patients. MOG-specific B cells in blood showed no correlation with anti-MOG Ab levels in serum, neither in the whole group nor in the untreated patients. Epitope analysis of MOG-Abs secreted from MOG-specific B cells cultured in different wells revealed an intraindividual heterogeneity of the anti-MOG autoimmunity.

Conclusions: This study shows that patients with MOG-Abs greatly differ in the abundance of circulating MOG-specific B cells, which are not linked to levels of MOG-Abs in serum suggesting different sources of MOG-Abs. Identification of MOG-specific B cells in blood could be of future relevance for selecting patients with MOG-Abs for B cell-directed therapy.
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http://dx.doi.org/10.1212/NXI.0000000000000625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857907PMC
November 2019

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

Erratum: Evaluating Treatment Decision for Multiple Sclerosis: Real Life and Patient Experiences.

Noro Psikiyatr Ars 2019 03;56(1):82

Department of Neurology, Hacettepe University, School of Medicine, Ankara, Turkey.

[This corrects the article on p. S10 in vol. 55, PMID: 30692848.].
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http://dx.doi.org/10.29399/npa.23599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427070PMC
March 2019

Progressive Onset Multiple Sclerosis: Demographic, Clinical and Laboratory Characteristics of Patients With and Without Relapses in the Course.

Noro Psikiyatr Ars 2019 Mar 4;56(1):23-26. Epub 2018 Jul 4.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Amaç: Primer progresif multipl skleroz (PPMS) ve progresif relapsing multipl skleroz (PRMS) başlangıçtan beri olan progresyon ile karakterize MS tipleridir. Nadir görülmelerinden dolayı, literatürde diğer MS formlarına göre daha az bilgi bulunmaktadır. Bu çalışmanın amacı progresif başlangıçlı MS (PBMS) hastalarında klinik ve laboratuvar özelliklerini ortaya koymaktır.

Yöntem: PBMS hastaları 2010-2014 yılları arasında değerlendirilip demografik, klinik özellikleri ve beyin omurilik sıvısı (BOS) bulguları belirlendi.

Bulgular: Otuz iki PBMS hastası ile ilgili veriler değerlendirildi. Hastalık seyri 24 hastada relaps olmadan (PPMS), sekiz hastada ise relapslı progresifti (PRMS). Kadın/erkek oranı tüm grupta 1'di. Ortalama başlangıç yaşı tüm grup için 40 (23-55) yaştı. Gruplar arasında hastalık başlangıç yaşı ortancası anlamlı farklı bulunmadı (p=0,053). En sık prezantasyon belirtisi motor bozukluklardı. Relapslar tüm hastalarda hastalığın ilk 10 yılında görüldü. BOS analizinde oligoklonal bant pozitifliği ve artmış IgG indeksi açısından gruplar arasında fark saptanmadı (p=0,938, p=0,058). Hastalık süresi her iki grupta da benzer olduğu halde, PPMS grubunda değerlendirme sırasında ortanca EDSS skoru daha yüksek bulundu (p=0,020).

Sonuç: Çalışmamız Türk PBMS hastalarının klinik seyir ve laboratuvar bulgularına odaklanmış ilk çalışmadır. İki grubun klinik ve laboratuvar bulgularının karşılaştırılması benzer sonuçlar göstermiştir. Gruplar arasında hastalık başlangıç yaşı ve artmış IgG indeksi açısından farklılık olup olmadığını netleştirmek için gelecekte daha geniş örneklemli çalışmalar yapılması gerekmektedir.
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http://dx.doi.org/10.5152/npa.2017.19269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427076PMC
March 2019

Evaluating Treatment Decision for Multiple Sclerosis: Real Life and Patient Experiences.

Noro Psikiyatr Ars 2018 ;55(Suppl 1):S10-S14

Department of Neurology, Hacettepe University, School of Medicine, Ankara, Turkey.

There are different decision-making models in medicine for treatment decisions. Shared decision-making model is the most appropriate and widely used model for chronic diseases like Multiple Sclerosis (MS). In this model, the decision making process like treatment options is being discussed step by step between patients and physicians. However, increasing treatment options and medication side effects make the decision-making process more difficult for physicians and reveal the need to share wider knowledge with the patient. In this article we evaluate treatment decision making in patients with MS involving real life experiences.
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http://dx.doi.org/10.29399/npa.23164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278628PMC
January 2018

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

Sudden Sensoryneural Hearing Loss As a Rare Attack Type in Multiple Sclerosis.

Noro Psikiyatr Ars 2018 Dec 4;55(4):380-382. Epub 2018 Jul 4.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

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http://dx.doi.org/10.5152/npa.2017.19270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300834PMC
December 2018

Retinal degeneration is associated with brain volume reduction and prognosis in radiologically isolated syndrome.

Mult Scler 2020 01 11;26(1):38-47. Epub 2018 Dec 11.

Department of Neurology, Hacettepe University, Ankara, Turkey.

Background: The extent of neurodegeneration in the earliest stages of central nervous system (CNS) demyelination is not known. Optical coherence tomography (OCT) is a powerful tool to study neurodegeneration in demyelinating disorders.

Objectives: To study neuroaxonal loss in the retina of individuals with radiologically isolated syndrome (RIS) and investigate whether OCT measurements are associated with brain volumetrics and clinical conversion to multiple sclerosis (MS).

Methods: Subjects fulfilling the Okuda criteria for RIS ( = 15 patients, 30 eyes) and age- and sex-matched healthy controls (HC) underwent spectral-domain OCT and magnetic resonance imaging for volumetric measurement of brain structures.

Results: Macular ganglion cell-inner plexiform layer (mGCIPL), macular retinal nerve fiber layer (mRNFL), and temporal peripapillary RNFL (pRNFL) thickness; normalized total brain volume (nTBV); and normalized thalamic volume (nTV) were reduced in RIS compared to HC. mGCIPL, mRNFL, and pRNFL measurements were associated with nTBV, nTV, and normalized gray and white matter volumes in the RIS group. pRNFL was thinner in individuals with RIS who converted to MS in 5 years.

Conclusions: Retinal neurodegeneration can be detected in the papillomacular region in the earliest stages of CNS demyelination and reflects global disease processes in the brain. OCT can be potentially useful for predicting prognosis in RIS.
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http://dx.doi.org/10.1177/1352458518817987DOI Listing
January 2020

Are there any clinical and electrocardiographic predictors of heart rate reduction in relapsing- remitting multiple sclerosis patients treated with fingolimod?

Mult Scler Relat Disord 2019 Jan 10;27:276-280. Epub 2018 Nov 10.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod.

Methods: We retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed.

Results: A total of 114 RRMS patients (65.8% female, 33.58 ± 8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p < 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions.

Conclusion: Our findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod.
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http://dx.doi.org/10.1016/j.msard.2018.11.006DOI Listing
January 2019

Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia.

Mult Scler Relat Disord 2017 Nov 29;18:135-140. Epub 2017 Sep 29.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: Ataxia is an extremely common problem in multiple sclerosis (MS) patients. Thus, appropriate scales are required for detailed assessment of this issue. The aim of our study was to investigate the reliability and validity of the Turkish version of the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA), which are widely used in ataxia evaluation in the context of other cerebellar diseases.

Method: This cross-sectional study included 80 MS patients with Kurtzke cerebellar functional system score (C-FSS) greater than zero and slight pyramidal involvement. The Expanded Disability Status Scale (EDSS), C-FSS, and Berg Balance Scale (BBS) were administered. SARA and ICARS were assessed on first admission by two physical therapists. Seven days later, second assessments were repeated in same way for reliability.

Results: Intra-rater and inter-rater reliability were found to be high for both ICARS and SARA (p< 0.001) The Cronbach's α coefficients were 0.922 and 0.921 for SARA (reviewer 1 and reviewer 2 respectively) and 0.952 and 0.952 for ICARS (reviewer 1 and reviewer 2, respectively). There were no floor or ceiling effects determined for either scale except for item 17 of ICARS (p= 0.055). The EDSS total score had significant correlations with both SARA and ICARS (rho: 0.557 and 0.707, respectively). C-FSS had moderate correlation with SARA and high correlation with ICARS (rho: 0.469 and 0.653, respectively). BBS had no significant correlation with SARA and ICARS. (rho: -0.048 and -0.008 respectively). According to the area under the curve (AUC) value, ICARS is the best scale to discriminate mild and moderate ataxia. (AUC: 0.875). Factor analyses of ICARS showed that the rating results were determined by five different factors that did not coincide with the ICARS sub-scales.

Conclusion: Our study demonstrated that ICARS and SARA are both reliable in MS patients with ataxia. Although ICARS has some structural problems, it seems to be more valid given its high correlations with EDSS and C-FSS. SARA also can be preferred as a brief assessment.
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http://dx.doi.org/10.1016/j.msard.2017.09.032DOI Listing
November 2017

Differences Between General Neurologists and Multiple Sclerosis Specialists in the Management of Multiple Sclerosis Patients: A National Survey.

Noro Psikiyatr Ars 2019 Dec 20;56(4):269-272. Epub 2017 Jun 20.

Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpaşa, Istanbul, Turkey.

Introduction: The management of multiple sclerosis (MS) has become more complicated after the introduction of new diagnostic and treatment options. Despite the abundance of guidelines, the experience of physicians still plays a major role in the management of patients. This study aimed to define differences in behavior patterns between general neurologists (GNs) and MS specialists (MSSs).

Methods: We conducted a survey of 36 questions to 318 neurologists, including 33 MSSs. The survey covered topics including laboratory investigations, pregnancy, and treatment.

Results: Our study found many differences between GNs and MSSs in terms of management, the most important being treatment initiation and switching. GNs had a tendency to initiate treatment later than MSSs however, they tended to switch treatment faster. Our study also showed that GNs ordered magnetic resonance imaging (MRI) more frequently than MSSs, even if patients were clinically stable. Moreover, although GNs more frequently relied on MRI, they did not consider brain atrophy as an important measure in the follow-up of their patients. Furthermore, GNs considered replacement therapy less often than MSSs, even in patients with vitamin D deficiency.

Discussion: Our study revealed important discrepancies between the management patterns of GNs and MSSs in MS patients. These findings suggest the need for a national education program for GNs on MSSs.
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http://dx.doi.org/10.5152/npa.2017.19387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927082PMC
December 2019

Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks.

Mult Scler Int 2016 18;2016:1034912. Epub 2016 Dec 18.

Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

The burden of multiple sclerosis (MS) in women of childbearing potential is increasing, with peak incidence around the age of 30 years, increasing incidence and prevalence, and growing female : male ratio. Guidelines recommend early use of disease-modifying therapies (DMTs), which are contraindicated or recommended with considerable caution, during pregnancy/breastfeeding. Many physicians are reluctant to prescribe them for a woman who is/is planning to be pregnant. Interferons are not absolutely contraindicated during pregnancy, since interferon- appears to lack serious adverse effects in pregnancy, despite a warning in its labelling concerning risk of spontaneous abortion. Glatiramer acetate, natalizumab, and alemtuzumab also may not induce adverse pregnancy outcomes, although natalizumab may induce haematologic abnormalities in newborns. An accelerated elimination procedure is needed for teriflunomide if pregnancy occurs on treatment or if pregnancy is planned. Current evidence supports the contraindication for fingolimod during pregnancy; data on other DMTs remains limited. Increased relapse rates following withdrawal of some DMTs in pregnancy are concerning and require further research. The postpartum period brings increased risk of disease reactivation that needs to be carefully addressed through effective communication between treating physicians and mothers intending to breastfeed. We address the potential for use of the first- and second-line DMTs in pregnancy and lactation.
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http://dx.doi.org/10.1155/2016/1034912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203912PMC
December 2016

Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

Int J Neurosci 2017 Oct 12;127(10):944-951. Epub 2017 Jan 12.

o Neuropsychiatric Department, Faculty of Medicine , Ain Shams University , Egypt.

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.
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http://dx.doi.org/10.1080/00207454.2016.1277424DOI Listing
October 2017

The association of cognitive impairment with gray matter atrophy and cortical lesion load in clinically isolated syndrome.

Mult Scler Relat Disord 2016 Nov 16;10:14-21. Epub 2016 Aug 16.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. Electronic address:

Background: Multiple sclerosis can impair cognition from the early stages and has been shown to be associated with gray matter damage in addition to white matter pathology.

Objectives: To investigate the profile of cognitive impairment in clinically isolated syndrome (CIS), and the contribution of cortical inflammation, cortical and deep gray matter atrophy, and white matter lesions to cognitive decline.

Methods: Thirty patients with clinically isolated syndrome and twenty demographically- matched healthy controls underwent neuropsychologic assessment through the Rao Brief Repeatable Battery, and brain magnetic resonance imaging with double inversion recovery using a 3T scanner.

Results: Patients with clinically isolated syndrome performed significantly worse than healthy controls on tests that evaluated verbal memory, visuospatial learning and memory, and verbal fluency. Significant deep gray matter atrophy was found in the patients but cortical volume was not lower than the controls. Visual memory tests correlated with the volume of the hippocampus, cerebral white matter and deep gray matter structures and with cerebellar cortical atrophy. Cortical or white matter lesion load did not affect cognitive test results.

Conclusion: In our patients with CIS, it was shown that cognitive impairment was mainly related to cerebral white matter, cerebellar cortical and deep gray matter atrophy, but not with cortical inflammation, at least in the early stage of disease.
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http://dx.doi.org/10.1016/j.msard.2016.08.008DOI Listing
November 2016

Effects of different exercise modalities on ataxia in multiple sclerosis patients: a randomized controlled study.

Disabil Rehabil 2017 Dec 29;39(26):2626-2632. Epub 2016 Oct 29.

b Department of Neurology, Faculty of Medicine , Hacettepe University , Ankara , Turkey.

Purpose: To investigate the effects of different exercise protocols on ataxia in patients with multiple sclerosis (MS).

Method: A total of 42 MS patients, 17 male and 25 female (Expanded Disability Status Scale (EDSS): 3-5), were enrolled in this randomized controlled study. The patients were divided into three groups: a balance training (BT) group, a lumbar stabilization (LS) group and a task-oriented training (TT) group. All groups received balance training; additionally, the LS group received lumbar stabilization exercises, and the TT group received task-oriented training. The Berg Balance Scale (BBS), International Cooperative Ataxia Rating Scale (ICARS), Functional Reach Test (FRT), 2-Minute Walk Test (2MWT), Sensory Organization Test (SOT), and measurement of Somatosensory Evoked Potentials (SSEPs) were performed before and at the end of the 18 training sessions.

Results: The BBS, ICARS, FRT, 2MWT, and composite balance score of the SOT were improved in all groups. The ICARS kinetic function sub-score and the left limb cortical onset amplitudes of SSEPs were increased significantly in both the TT and the LS groups. The ICARS total score, composite balance score, and 2MWT were different between groups (p < 0.05). According to multiple comparison analyses of the ICARS total score and the composite balance score, the LS, and the TT group were different from the BT group (p < 0.005), while the LS and the TT groups improved similarly (p > 0.005). The 2MWT results were better for the LS group than the BT group, while the BT and the TT groups improved similarly.

Conclusion: Balance training alone is not sufficient for rehabilitation of ataxic MS patients. A combination of lumbar stabilization exercises or task-oriented training increases the success of balance rehabilitation. Implications for rehabilitation Multiple sclerosis is a chronic inflammatory and autoimmune disease of central nervous system and ataxia is one of the most challenging symptoms of this disease. Different exercise modalities are commonly employed to control ataxic symptoms in MS patients. Lumbar stabilization exercises or task-oriented training should be considered as complementary approach to improve balance and coordination in ataxic multiple sclerosis patients.
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http://dx.doi.org/10.1080/09638288.2016.1236411DOI Listing
December 2017

Unfavorable outcome of pediatric onset multiple sclerosis: Follow-up in the pediatric and adult neurology departments of one referral center, in Turkey.

Mult Scler Relat Disord 2016 Sep 8;9:1-4. Epub 2016 Jun 8.

Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Hacettepe Üniversitesi Tıp Fakültesi, 06100 Sıhhiye Ankara, Turkey.

Background: The prevalence of MS starting under 18 years of age ranges between 2-10% of the total MS population.

Objective: We aimed to examine the clinical and long term follow-up data of pediatric-onset cases in our institutional MS database.

Method: We evaluated the clinical data from the MS database of the Departments of Neurology and Pediatric Neurology of Hacettepe University Hospital.

Results: The clinical features of 74 patients who had experienced the first attack before age 18 years comprised 3.9% of our MS population. Median age at onset was 15 (3, 5-17, IQR=3.63) years, and female: male ratio was 2.4. The most frequent symptom at onset was brainstem/cerebellar dysfunction (32.4%). Seventy two patients (97.3%) initially had relapsing remitting course and in the follow-up, 17 (23%) of them developed secondary progressive (SP) course. The median interval to develop SPMS course was 10 (5-21, IQR=8) years. At the last visit, median disease duration was 6.67 (0.83-25, IQR=9.06) years, 41 (55.4%) of them had EDSS of ≥4.

Conclusion: These findings illustrate the profile of our pediatric MS patients: almost all are relapsing-remitting initially; about one fourth become secondarily progressive in 10 years, and about half acquire disability EDSS ≥4 in mean 8 years.
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http://dx.doi.org/10.1016/j.msard.2016.06.002DOI Listing
September 2016

Acute Disseminated Encephalomyelitis after Oral Therapy with Herbal Extracts: A Case Report.

Balkan Med J 2016 May 1;33(3):366-9. Epub 2016 May 1.

Department of Neurology, Hacettepe University School of Medicine, Ankara, Turkey.

Background: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system, commonly attributed to infections or vaccinations. Toxic or allergenic compounds can also trigger a response in the immune system and may cause demyelination. We present a case with ADEM after using oral herbal medications.

Case Report: A 25 year-old male developed bilateral central facial palsy and severe quadriparesis after taking herbal drugs (containing echinacea and many other herbal ingredients) for two weeks. He had used the extract to increase his potency and reproductivity. He had no past history of recent immunization or viral infection. The clinical findings, cerebrospinal fluid (CSF) analysis and brain magnetic resonance imaging (MRI) were compatible with ADEM. The neurological findings were improved after seven doses of pulse methylprednisolone treatment. To our knowledge, this is the third report in the literature that links herbal therapy and demyelinating disease.

Conclusion: Most of the ADEM cases related to herbal therapy in the literature similarly used echinacea. It is our opinion that other ingredients of the herbal extract used by our case, besides echinacea, could have the potential to cause a trigger in the immune system. Further studies are needed to clarify the immunological effects of different kinds of herbal compounds, as well as the effects of different parts of the plants and the results of various dosages. Moreover, ingredients should also be tested for toxicity, adverse effects and drug interactions.
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http://dx.doi.org/10.5152/balkanmedj.2016.140420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899001PMC
May 2016

Rituximab in Turkish neuromyelitis optica patients with limited response to other immunosuppressants.

J Neurol Sci 2015 Dec 23;359(1-2):106-7. Epub 2015 Oct 23.

Hacettepe University, Faculty of Medicine, Department of Neurology, Ankara, Turkey.

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http://dx.doi.org/10.1016/j.jns.2015.10.036DOI Listing
December 2015

Magnetic Resonance Imaging as a Major Milestone in Multiple Sclerosis Diagnosis and Treatment.

Authors:
Rana Karabudak

Noro Psikiyatr Ars 2015 Dec 1;52(Suppl 1):S16-S24. Epub 2015 Dec 1.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Magnetic resonance imaging (MRI) has played a unique role in the diagnosis and management of patients with MS. In recent years, there have been considerable changes in the diagnostic criteria for MS as MRI-based studies have demonstrated their power in the earlier and more accurate diagnosis of the disease. Moreover, MRI metrics have become key supportive outcome measures for evaluating the efficacy of experimental treatments in randomized controlled trials. MRI can also be used as a prognostic tool in patients with clinically isolated syndrome (CIS). Conventional MR techniques including proton density, T1/T2-weighted images, and FLAIR sequences are now accepted in standard protocols for diagnostic and treatment outcome measures in clinical trials for MS. Radiological features may show a similarity between radiologically isolated syndrome and MS. Approximately two-thirds of individuals with RIS exhibit radiological progression and one-third develop neurological symptoms during mean follow-up times of up to five years. However, a current challenge in the global application of established criteria for RIS involves the accurate classification of subjects with incidentally identified anomalies that are highly characteristic of MS, in comparison to those categorized in medical parlance as possessing "unidentified bright objects" or nonspecific T2-hyperintensities, which are commonly identified in patients with migraine headache who fulfill the spatial dissemination requirements for MS. The need for systematically acquired data for improvements in the classification of radiologically isolated syndrome (RIS) and the generation of risk algorithms are critically important, providing a basis for scientifically supported management and most importantly, minimizing the number of improperly classified subjects exposed to unnecessary medical testing, MS treatments, and psychological harm. In addition, brain atrophy is a common finding that can now be quantitatively assessed by MR volumetric measures. Further, integrated strategies that combine MRI and clinical markers in scoring systems have provided a potentially useful approach for the management of patients with MS.
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http://dx.doi.org/10.5152/npa.2015.12576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353228PMC
December 2015

Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorder Patients in Turkish Cohort: Demographic, Clinical, and Laboratory Features.

Neurologist 2015 Oct;20(4):61-6

Departments of *Neurology ∥∥Ophthalmology, Istanbul University Cerrahpasa Medical School ‡Department of Neurology, Haseki Training and Education Hospital ∥Department of Neurology, Bakirkoy Training and Education Hospital ¶Department of Neurology, Istanbul Medeniyet University Goztepe Training and Education Hospital, Istanbul †Department of Neurology, Hacettepe University Medical School §§Department of Neurology, Ankara University Medical School, Ankara §Department of Neurology, Ondokuz Mayis University Medical School, Samsun #Department of Neurology, Trakya University Medical School, Edirne **Department of Neurology, Ege University Medical School, Izmir ††Department of Neurology, Mustafa Kemal University Medical School, Hatay ‡‡Department of Neurology, Karadeniz Technical University Medical School, Trabzon, Turkey.

Background: Neuromyelitis optica (NMO) is an immune-mediated, chronic relapsing, inflammatory disease characterized by severe attacks of optic neuritis and myelitis.

Objective: To determine the demographic, clinical, and laboratory features; antibody status; and treatment modalities of patients with NMO and neuromyelitis optica spectrum disorders in a Turkish cohort from 11 centers.

Methods: A total of 182 patients were included in this study. Data on age at disease onset, sex, type of attacks, clinical presentation, analysis of cerebrospinal fluid, serum antiaquaporin-4 antibody status, annual progression index, and medical and family histories were collected.

Results: Mean age was 38.43±12.40 years (range, 13 to 75 y), and mean age at disease onset was 31.29±12.40 years (median, 29 y; range, 10 to 74 y). In NMO group, the rate of NMO immunoglobulin (Ig)G positivity was 62.5%. The annual progression index was significantly higher in the longitudinally extending spinal cord lesion. The mean Expanded Disability Status Scale score was higher in the late than early-onset NMO group.

Conclusion: Our results revealed a lower rate of NMO IgG positivity, more severe disability in patients with NMO/neuromyelitis optica spectrum disorders presenting with either transverse myelitis or late-onset NMO, and no correlation between disability and NMO IgG status.
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http://dx.doi.org/10.1097/NRL.0000000000000057DOI Listing
October 2015

Fulminant Central Plus Peripheral Nervous System Demyelination without Antibodies to Neurofascin.

Can J Neurol Sci 2016 Jan 14;43(1):149-56. Epub 2015 Aug 14.

1Hacettepe University Medical Faculty,Department of Neurology,Ankara,Turkey.

Background: Combined central and peripheral nervous system demyelination is a rare and poorly described phenomenon. Recently, anti-neurofascin antibodies were reported to be positive in 86% of these patients in a Japanese cohort. Yet, there seems to be a clinical, radiological, and serological heterogeneity among these patients. In this report, our aim is to describe characteristics of our patients with this entity and compare with others in the literature.

Methods: We report clinical, electrophysiological, radiological, and laboratory characteristics of five patients with both multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy from our institutional database containing 1890 MS patients.

Results: Three patients presented with extensive, active demyelination of both central nervous system and peripheral nervous system with hypertrophic peripheral nerves. Plexuses, trunks, division and cords were involved in the process. Oligoclonal band was negative. Conduction block was not detected. Corticosteroid treatment was not adequate. Others had a slowly progressive clinical course. Serum anti-neurofascin antibody was negative. Review of the literature revealed similar cases with active disease, early-onset hypertrophic peripheral nerves, and central demyelination, in addition to other cases with an insidious course.

Conclusions: Patients with combined central and peripheral demyelination form a spectrum. Some patients may have an antibody-mediated syndrome with or without anti-neurofascin antibodies and others seem to represent a coincidence.
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http://dx.doi.org/10.1017/cjn.2015.238DOI Listing
January 2016

Assessment of the effect of cigarette smoking on regional brain volumes and lesion load in patients with clinically isolated syndrome.

Int J Neurosci 2016 Sep 13;126(9):805-811. Epub 2015 Aug 13.

c 3 National Magnetic Resonance Research Center (UMRAM) , Bilkent University , Ankara , Turkey.

Purpose: Smoking has been associated with an increased risk of developing multiple sclerosis, disease progression and clinical disability. We detected the effects of smoking on regional brain volumes and lesion load in patients with clinically isolated syndrome using quantitative magnetic resonance imaging.

Materials And Methods: Smoker patients (n = 16), smoker healthy controls (n = 13), non-smoker patients (n = 17) and non-smoker healthy controls (n = 14) underwent magnetic resonance imaging and neocortical volumes were measured. Lesion load was calculated in terms of number and volume of white matter hyperintensities.

Results: Smoking was associated with increased gray matter volumes in several regions of the brain. A tendency towards greater lesion load in smoker patients was found. Smoking duration was significantly negatively correlated with intracranial volume and left hemisphere cortical gray matter volume. There was no relationship between regional brain volumes and clinical disability scores, lesion load duration of the disease and degree of smoking exposure.

Conclusions: Clinically isolated syndrome related regional brain atrophy might vary in extent and severity with smoking. Despite increased lesion load, less cortical and deep gray matter damage with a possible neuroprotective effect occurs in smoking.
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http://dx.doi.org/10.3109/00207454.2015.1073727DOI Listing
September 2016

Functional clinical outcomes in multiple sclerosis: Current status and future prospects.

Mult Scler Relat Disord 2015 May 23;4(3):192-201. Epub 2015 Mar 23.

Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.

For decades, the Expanded Disability Status Scale (EDSS) has been the principal measure of disability in clinical trials in patients with multiple sclerosis (MS) and in clinical practice. However, this test is dominated by effects on ambulation. Composite endpoints may provide a more sensitive measure of MS-related disability through the measurement of additional neurological functions. The MS Functional Composite (MSFC) includes a walking test (25-ft walk) plus tests of upper extremity dexterity (9-hole peg test) and cognitive function (Paced Auditory serial Addition test [PASAT]). Replacing PASAT with the Symbol Digit Modality test, a more sensitive test preferred by patients, may improve the clinical utility of the MSFC. In addition, disease-specific measures of QoL may be used alongside the MSFC (which does not include measurement of QoL). Clinical data suggest that disease-modifying therapies may delay or prevent relapse, and better composite measures will be valuable in the assessment of disease activity-free status in people with MS.
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http://dx.doi.org/10.1016/j.msard.2015.03.004DOI Listing
May 2015