ImportanceAutologous hematopoietic stem cell transplant (AHSCT) is available for treatment of hig... more ImportanceAutologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS).ObjectiveTo compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials.Design, Setting, and ParticipantsThis comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics.ExposureAHSCT vs fingolimod, natalizumab, or ocrelizumab.Main outcomesPairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) sco...
ABSTRACTBackground and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typicall... more ABSTRACTBackground and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses and reach irreversible disability at a younger age than adult-onset patients. There have been few randomized placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry.MethodsThis retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021 (N=1218). The primary outcome was the time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse ra...
Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting... more Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosi...
Nöroloji Staj NotlarıBu kitap, Dönem V Nöroloji Stajı boyunca öğrencilerin elinde temel bir rehbe... more Nöroloji Staj NotlarıBu kitap, Dönem V Nöroloji Stajı boyunca öğrencilerin elinde temel bir rehber olmasını sağlamak amacıyla hazırlanmıştır. Hastaya, hikayesine ve bulgularına bir bilmece gibi yaklaşmak, lezyon “nerededir?” ve “nedir?” sorularının yanıtını aramak nörolojiyi zevkli kılan özelliklerdir. İyi bir hikaye almanın önemi hemen her bölümde vurgulanmıştır. Klinik nörolojinin temel ve güncel kavramlarını içermekle birlikte tüm bilgiyi 200 sayfalık bu kitapçığa sığdırmak mümkün değildir. Eksik konular için önerilen kaynaklar kitabın sonunda verilmiştir. Bu ikinci baskıda öğrencilerden ve öğretim üyelerinden gelen görüşler doğrultusunda düzeltmeler yapılmış, nöroanatomik kısa bilgiler ve güncel kavramlar eklenmiştir. Bilgiye ulaşmak için çok çeşitli kaynakların var olduğu bir dönemde, elde temel bir kitabın var olmasının, öğrencinin araştırmacı yönünü azaltmayacağını, aksine artıracağını umuyoruz
Anti-John Cunningham Virus antibody prevalence in multiple sclerosis patients in Turkey
Journal of Experimental & Clinical Medicine, 2014
Exposure to John Cunningham Virus (JCV) has been associated with Progressive Multifocal Leukoence... more Exposure to John Cunningham Virus (JCV) has been associated with Progressive Multifocal Leukoencephalopathy (PML) in Multiple Sclerosis (MS) patients under specific treatments. In order to assess the identifiable risks of Turkish relapsing-remitting multiple sclerosis (RRMS) patients, the seroprevalence rate of JCV antibodies was investigated and compared with demographic and therapy related factors. Serum samples were collected from 308 RRMS patients at 24 centers, and tested by STRATIFY JCV assay for the presence of anti-JCV antibodies. Also, demographic, disease and treatment data were collected at the same time and were used for analysis of associations with seropositivity. The prevalence of anti-JCV antibodies was observed to be 68.2%, which is higher than most countries. There was a trend in terms of higher seroprevalence of antibodies in older patients, and male patients. There was no association with previous natalizumab use, but there was a significantly higher seroprevalen...
Factors associated with fingolimod rebound: A single center real-life experience
Multiple Sclerosis and Related Disorders, 2021
Background It is still controversial whether the relapse experienced after discontinuation of fin... more Background It is still controversial whether the relapse experienced after discontinuation of fingolimod treatment is a rebound. Increasing cases of rebound have been reported in the literature. The rate of fingolimod rebound in patients after fingolimod cessation is reported between 5% and 52%. The present study aims to determine the rate of rebound after discontinuation of fingolimod treatment and the factors affecting the rebound. Methods This retrospective cohort study consists of adult MS patients who have been admitted to the Hacettepe University Hospital Neurology MS Center outpatient clinic between 2012 and 2020. Results During the study period, 642 patients received fingolimod and 23.1% discontinued the fingolimod treatment. Thirteen of 126 patients had a rebound (10.3%) after fingolimod discontinuation. The patients in the rebound group were significantly younger and washout period were significantly longer than those in the non-rebound group. After discontinuation of fingolimod treatment, the EDSS score of the rebound group was significantly higher than the non-rebound group, while Annualized Relapse Rates were similar. Conclusion Younger age, longer washout time, and previous treatment preferences may increase the occurrence probability of rebound. It is recommended that patients should be closely monitored after fingolimod discontinuation and appropriate disease-modifying therapy should be initiated as soon as possible.
The outcome of a national MS-Covid-19 study: What the Turkish MS cohort reveals?
Multiple Sclerosis and Related Disorders, 2021
Background The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect peo... more Background The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect people with Multiple Sclerosis (pwMS). Currently, the accumulating information on the effects of the infection regarding the demographic and clinical characteristics of the disease, as well as outcomes within different DMTs¸ enable us to have better practices on the management of the Covid-19 infection in pwMS. Objective To investigate the incidence of coronavirus disease 2019 (Covid-19) and to reveal the relationship between the demographic-clinical and therapeutic features and the outcome of Covid-19 infection in a multi-center national cohort of pwMS. Methods The Turkish Neurological Society-MS Study Group in association with the Italian MuSC-19 Study Group initiated this study. A web-based electronic Case Report Form (eCRF) of Study-MuSC-19 were used to collect the data. The demographic data and MS histories of the patients were obtained from the file tracking forms of the relevant clinics. Results 309 MS patients with confirmed Covid-19 infection were included in this study. Two hundred nineteen (219) were females (70.9%). The mean age was 36.9, ranging from 18 to 66, 194 of them (62.8%) were under 40. The clinical phenotype was relapsing-remitting in 277 (89.6%) and progressive in 32 (10.4%). Disease duration ranged from 0.2 years to 31.4 years. The median EDSS was 1.5, ranging from 0 to 8.5. The EDSS score was<= 1 in 134 (43%) of the patients. 91.6% of the patients were on a DMT, Fingolimod was the most frequently used drug (22.0%), followed by Interferon (20.1%). The comorbidity rate is 11.7%. We were not able to detect any significant association of DMTs with Covid-19 severity. Conclusion The Turkish MS-Covid-19 cohort had confirmed that pwMS are not at risk of having a more severe COVID-19 outcome irrespective of the DMT that they are treated. In addition, due to being a younger population with less comorbidities most had a mild disease further highlight that the only associated risk factors for having a moderate to severe COVID-19 course are similar with the general population such as having comorbid conditions and being older.
‘Is RLS a harbinger and consequence of MS?: Striking results of the ‘RELOMS-T’ study’
Multiple Sclerosis and Related Disorders, 2020
BACKGROUND Although studies report a high prevalence rate of restless legs syndrome (RLS) among p... more 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.
Cytomegalovirus (CMV) causes several neurological diseases in the late stages of AIDS, but their ... more Cytomegalovirus (CMV) causes several neurological diseases in the late stages of AIDS, but their ante-mortem diagnosis is problematic. Clinical criteria (defining a presumptive diagnosis) and polymerase chain reaction $4 (PCR) assay from cerebrospinal fluid (CSF) were blindly used to predict the involvement of CMV in neurological disorders of 164 consecutive AIDS patients undergoing a lumbar puncture. During the follow-up, a definite diagnosis based on viral culture of CSF, clinical outcome and/or CNS histology was allowed in 88 patients, 27 (16 %) of whom had a proven CMV related neurological disease. The concordance between the presumptive and definite diagnosis was of 60 %, inducing a moderate agreement kappa index of 0.40. In contrast, the sensitivity and specificity of PCR were respectively of 89 and 94 %, with a positive and negative predictive values of 86 and 95 %. Cytomegalovirus related neurological diseases appeared thus as a frequent complication of AIDS, and detection of viral DNA in CSF by means of PCR seems a reliable tool for their diagnosis, allowing its use for therapeutic decisions 20 99mTC-HMPAO LEUCOCYTE SCINTIGRAPHY IN DIAGNOSIS OF
Değerli meslektaşlarımızın okuduğu ilk nöroloji kitabı olacağı düşüncesiyle yazılmış ve Hacettepe... more Değerli meslektaşlarımızın okuduğu ilk nöroloji kitabı olacağı düşüncesiyle yazılmış ve Hacettepe stajyer ders notlarını kapsayan bu kitabın tüm ülkeye yararlı olması dileğiyle. H.Ü.T.F. Nöroloji Öğretim Üyeler
Multiple Sclerosis is an area of ever expanding research and escalating publications. Multiple Sc... more Multiple Sclerosis is an area of ever expanding research and escalating publications. Multiple Sclerosis and Related Disorders is a wide ranging international journal supported by key researchers from all neuroscience domains that focus on MS and associated disease of the central nervous system. The primary aim of this new journal is the rapid publication of high quality original research in the field. Important secondary aims will be timely updates and editorials on important scientific and clinical care advances, controversies in the field, and invited opinion articles from current thought leaders on topical issues. One section of the journal will focus on teaching, written to enhance the practice of community and academic neurologists involved in the care of MS patients. Summaries of key articles written for a lay audience will be provided as an on-line resource.
ImportanceAutologous hematopoietic stem cell transplant (AHSCT) is available for treatment of hig... more ImportanceAutologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS).ObjectiveTo compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials.Design, Setting, and ParticipantsThis comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics.ExposureAHSCT vs fingolimod, natalizumab, or ocrelizumab.Main outcomesPairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) sco...
ABSTRACTBackground and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typicall... more ABSTRACTBackground and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses and reach irreversible disability at a younger age than adult-onset patients. There have been few randomized placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry.MethodsThis retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021 (N=1218). The primary outcome was the time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse ra...
Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting... more Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosi...
Nöroloji Staj NotlarıBu kitap, Dönem V Nöroloji Stajı boyunca öğrencilerin elinde temel bir rehbe... more Nöroloji Staj NotlarıBu kitap, Dönem V Nöroloji Stajı boyunca öğrencilerin elinde temel bir rehber olmasını sağlamak amacıyla hazırlanmıştır. Hastaya, hikayesine ve bulgularına bir bilmece gibi yaklaşmak, lezyon “nerededir?” ve “nedir?” sorularının yanıtını aramak nörolojiyi zevkli kılan özelliklerdir. İyi bir hikaye almanın önemi hemen her bölümde vurgulanmıştır. Klinik nörolojinin temel ve güncel kavramlarını içermekle birlikte tüm bilgiyi 200 sayfalık bu kitapçığa sığdırmak mümkün değildir. Eksik konular için önerilen kaynaklar kitabın sonunda verilmiştir. Bu ikinci baskıda öğrencilerden ve öğretim üyelerinden gelen görüşler doğrultusunda düzeltmeler yapılmış, nöroanatomik kısa bilgiler ve güncel kavramlar eklenmiştir. Bilgiye ulaşmak için çok çeşitli kaynakların var olduğu bir dönemde, elde temel bir kitabın var olmasının, öğrencinin araştırmacı yönünü azaltmayacağını, aksine artıracağını umuyoruz
Anti-John Cunningham Virus antibody prevalence in multiple sclerosis patients in Turkey
Journal of Experimental & Clinical Medicine, 2014
Exposure to John Cunningham Virus (JCV) has been associated with Progressive Multifocal Leukoence... more Exposure to John Cunningham Virus (JCV) has been associated with Progressive Multifocal Leukoencephalopathy (PML) in Multiple Sclerosis (MS) patients under specific treatments. In order to assess the identifiable risks of Turkish relapsing-remitting multiple sclerosis (RRMS) patients, the seroprevalence rate of JCV antibodies was investigated and compared with demographic and therapy related factors. Serum samples were collected from 308 RRMS patients at 24 centers, and tested by STRATIFY JCV assay for the presence of anti-JCV antibodies. Also, demographic, disease and treatment data were collected at the same time and were used for analysis of associations with seropositivity. The prevalence of anti-JCV antibodies was observed to be 68.2%, which is higher than most countries. There was a trend in terms of higher seroprevalence of antibodies in older patients, and male patients. There was no association with previous natalizumab use, but there was a significantly higher seroprevalen...
Factors associated with fingolimod rebound: A single center real-life experience
Multiple Sclerosis and Related Disorders, 2021
Background It is still controversial whether the relapse experienced after discontinuation of fin... more Background It is still controversial whether the relapse experienced after discontinuation of fingolimod treatment is a rebound. Increasing cases of rebound have been reported in the literature. The rate of fingolimod rebound in patients after fingolimod cessation is reported between 5% and 52%. The present study aims to determine the rate of rebound after discontinuation of fingolimod treatment and the factors affecting the rebound. Methods This retrospective cohort study consists of adult MS patients who have been admitted to the Hacettepe University Hospital Neurology MS Center outpatient clinic between 2012 and 2020. Results During the study period, 642 patients received fingolimod and 23.1% discontinued the fingolimod treatment. Thirteen of 126 patients had a rebound (10.3%) after fingolimod discontinuation. The patients in the rebound group were significantly younger and washout period were significantly longer than those in the non-rebound group. After discontinuation of fingolimod treatment, the EDSS score of the rebound group was significantly higher than the non-rebound group, while Annualized Relapse Rates were similar. Conclusion Younger age, longer washout time, and previous treatment preferences may increase the occurrence probability of rebound. It is recommended that patients should be closely monitored after fingolimod discontinuation and appropriate disease-modifying therapy should be initiated as soon as possible.
The outcome of a national MS-Covid-19 study: What the Turkish MS cohort reveals?
Multiple Sclerosis and Related Disorders, 2021
Background The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect peo... more Background The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect people with Multiple Sclerosis (pwMS). Currently, the accumulating information on the effects of the infection regarding the demographic and clinical characteristics of the disease, as well as outcomes within different DMTs¸ enable us to have better practices on the management of the Covid-19 infection in pwMS. Objective To investigate the incidence of coronavirus disease 2019 (Covid-19) and to reveal the relationship between the demographic-clinical and therapeutic features and the outcome of Covid-19 infection in a multi-center national cohort of pwMS. Methods The Turkish Neurological Society-MS Study Group in association with the Italian MuSC-19 Study Group initiated this study. A web-based electronic Case Report Form (eCRF) of Study-MuSC-19 were used to collect the data. The demographic data and MS histories of the patients were obtained from the file tracking forms of the relevant clinics. Results 309 MS patients with confirmed Covid-19 infection were included in this study. Two hundred nineteen (219) were females (70.9%). The mean age was 36.9, ranging from 18 to 66, 194 of them (62.8%) were under 40. The clinical phenotype was relapsing-remitting in 277 (89.6%) and progressive in 32 (10.4%). Disease duration ranged from 0.2 years to 31.4 years. The median EDSS was 1.5, ranging from 0 to 8.5. The EDSS score was<= 1 in 134 (43%) of the patients. 91.6% of the patients were on a DMT, Fingolimod was the most frequently used drug (22.0%), followed by Interferon (20.1%). The comorbidity rate is 11.7%. We were not able to detect any significant association of DMTs with Covid-19 severity. Conclusion The Turkish MS-Covid-19 cohort had confirmed that pwMS are not at risk of having a more severe COVID-19 outcome irrespective of the DMT that they are treated. In addition, due to being a younger population with less comorbidities most had a mild disease further highlight that the only associated risk factors for having a moderate to severe COVID-19 course are similar with the general population such as having comorbid conditions and being older.
‘Is RLS a harbinger and consequence of MS?: Striking results of the ‘RELOMS-T’ study’
Multiple Sclerosis and Related Disorders, 2020
BACKGROUND Although studies report a high prevalence rate of restless legs syndrome (RLS) among p... more 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.
Cytomegalovirus (CMV) causes several neurological diseases in the late stages of AIDS, but their ... more Cytomegalovirus (CMV) causes several neurological diseases in the late stages of AIDS, but their ante-mortem diagnosis is problematic. Clinical criteria (defining a presumptive diagnosis) and polymerase chain reaction $4 (PCR) assay from cerebrospinal fluid (CSF) were blindly used to predict the involvement of CMV in neurological disorders of 164 consecutive AIDS patients undergoing a lumbar puncture. During the follow-up, a definite diagnosis based on viral culture of CSF, clinical outcome and/or CNS histology was allowed in 88 patients, 27 (16 %) of whom had a proven CMV related neurological disease. The concordance between the presumptive and definite diagnosis was of 60 %, inducing a moderate agreement kappa index of 0.40. In contrast, the sensitivity and specificity of PCR were respectively of 89 and 94 %, with a positive and negative predictive values of 86 and 95 %. Cytomegalovirus related neurological diseases appeared thus as a frequent complication of AIDS, and detection of viral DNA in CSF by means of PCR seems a reliable tool for their diagnosis, allowing its use for therapeutic decisions 20 99mTC-HMPAO LEUCOCYTE SCINTIGRAPHY IN DIAGNOSIS OF
Değerli meslektaşlarımızın okuduğu ilk nöroloji kitabı olacağı düşüncesiyle yazılmış ve Hacettepe... more Değerli meslektaşlarımızın okuduğu ilk nöroloji kitabı olacağı düşüncesiyle yazılmış ve Hacettepe stajyer ders notlarını kapsayan bu kitabın tüm ülkeye yararlı olması dileğiyle. H.Ü.T.F. Nöroloji Öğretim Üyeler
Multiple Sclerosis is an area of ever expanding research and escalating publications. Multiple Sc... more Multiple Sclerosis is an area of ever expanding research and escalating publications. Multiple Sclerosis and Related Disorders is a wide ranging international journal supported by key researchers from all neuroscience domains that focus on MS and associated disease of the central nervous system. The primary aim of this new journal is the rapid publication of high quality original research in the field. Important secondary aims will be timely updates and editorials on important scientific and clinical care advances, controversies in the field, and invited opinion articles from current thought leaders on topical issues. One section of the journal will focus on teaching, written to enhance the practice of community and academic neurologists involved in the care of MS patients. Summaries of key articles written for a lay audience will be provided as an on-line resource.
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