Publications by authors named "Csilla Rozsa"

41 Publications

Population-based head-to-head comparison of the clinical characteristics and epidemiology of AQP4 antibody-positive NMOSD between two European countries.

Mult Scler Relat Disord 2021 Mar 3;51:102879. Epub 2021 Mar 3.

Department of Neurology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas.

Methods: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO).

Results: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria.

Conclusions: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.
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http://dx.doi.org/10.1016/j.msard.2021.102879DOI Listing
March 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884998PMC
February 2021

Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease.

Ther Adv Neurol Disord 2020 7;13:1756286420975223. Epub 2020 Dec 7.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.
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http://dx.doi.org/10.1177/1756286420975223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724259PMC
December 2020

Jobb oldali videoasszisztált thoracoscopos thymectomia a thymoma nélküli, felnőttkori myasthenia gravis sebészi kezelésében.

Magy Seb 2020 Dec 12;73(4):125-139. Epub 2020 Dec 12.

1 Országos Korányi Pulmonológiai Intézet, 1121 Budapest, Korányi Frigyes út 1.

Összefoglaló. Bevezetés: A myasthenia gravis javallatával végzett csecsemőmirigy-eltávolítás sebésztechnikai szempontból lényegesen megváltozott az elmúlt közel 30 évben. A standard műtétnek számító transsternalis és transcervicalis thymectomia mellett elterjedt a videoasszisztált thoracoscopos sebészeti (VATS), később pedig a robot sebészeti megoldás is. Két intézetünkben 2011-2012-ben vezettük be a VATS thymectomiát. Módszer: A többféle technikai megoldás közül a mediastinumot a jobb mellüreg felől megközelítő utat választottuk. Eleinte 3, később 2 pontos perimammaris portot készítettünk a thymus elérésére a beteg háton fekvő helyzetében. Minden esetben ultrahangos vágóeszközt alkalmaztunk. Kiterjesztett thymectomiára törekedve a perithymikus zsírszövetet is eltávolítottuk, szélesen megnyitva a bal oldali mellüreget is. A betegek kiválasztásában az átlagos testsúlyú vagy soványabb betegeket részesítettük előnyben. Eredmények: 8 év és 4 hónap alatt 92 beteget műtöttünk a fenti módszerrel thymoma nélküli myasthenia gravis alapbetegséggel. 20 férfi és 72 nő. Átlagéletkor 33,1 év (19-75 év). A műtéti idő 35-160 percig terjedt, átlagosan 82,3 perc volt. A tömegesebb mediastinalis zsírszövet néhány betegnél nehezítette a tájékozódást és a maradéktalan eltávolítást. Műtét alatt 4 esetben érsérülés és 3 ellenoldali tüdősérülés következett be. Két konverziót végeztünk (1-1 sternotomia és thoracotomia). Idegsérülés nem történt. Tíz beteg igényelt néhány órás művi lélegeztetést a műtét után, a többi beteget a műtőasztalon extubáltuk. Reintubáció, tracheostomia, légzési elégtelenség, műtéti halálozás nem volt. Az intenzív ápolási idő átlaga: 1,1 (0-11) nap. A teljes kórházi ápolási idő átlaga: 4,8 (3-15) nap. A drenázsidő 1-4 nap, átlagosan 1,16 nap. Két beteg (2,41%) halt meg a műtétet követően 1 és 5 éven belül. További 81 beteg 12-108 (átlag: 48) hónapos követése során a myastheniás állapotban 21 (25,3%) betegnél komplett, 4 (4,82%) betegnél gyógyszeres remisszió, 20 (24,1%) betegnél minimális manifesztáció, 28 (33,73%) betegnél egyéb javulás volt megállapítható. 4 (4,82%) beteg állapota változatlan maradt, 4 (4,82%) betegé pedig romlott. Következtetés: A VATS thymectomia teljesen új utat jelent a transsternalis módszerben járatos sebészek számára. A tömegesebb mediastinalis zsírszövet nagyon megnehezíti a műtétet. A perioperatív szak nagyon kedvező a betegek számára, és a késői eredmények is elfogadhatóak. Kérdéses, hogy a thymus minden esetben maradéktalanul eltávolítható-e ezzel a módszerrel.

Summary:

Introduction: Surgical technique of thymectomy performed for treatment of myasthenia gravis has considerably changed in the last almost 30 years. In addition to standard interventions - transsternal and transcervical thymectomy -, video-assisted thoracoscopic interventions (VATS), later on robotic surgery came into general use. In our two institutions, we apply VATS thymectomy since 2011.

Methods: There are several different surgical techniques for this purpose; we approached the mediastinum through the right thoracic cavity. We prepared initially 3, later on 2 perimammal ports for the access of the thymus; the patients were in supine position during surgery. We used an ultrasonic cutting device in all cases. In order to perform extended thymectomy, we removed the fatty tissue around the thymus and opened widely the left thoracic cavity, too. During patient enrollment, we preferred patients with normal or lower body weight.

Results: During 8 years and 4 months, we operated on 92 patients using this method for myasthenia gravis without thymoma; there were 20 male and 72 female patients at the age of 33 years on average (19-75 years). Duration of surgery was 35-160 minutes, 82.3 minutes on average. The bulky fatty tissue around the thymus made the orientation and the complete removal more difficult in a few patients. We experienced vascular injury in 4 cases and injury of the contralateral lung in 3 cases. Conversion was necessary in 2 cases (1 sternotomy and 1 thoracotomy), there were no nerve injuries. Assisted ventilation was necessary in case of ten patients in the postoperative period for a few hours; all other patients were extubated on the operating table. There was no need for repeated intubation and tracheostomy; there was no respiratory insufficiency and perioperative mortality. Duration of ICU care was 1.1 days on the average (0-11 days), that of the total hospital care 4.8 days on average (3-15 days). Duration of thoracic drainage was 1.16 days on average (1-4 days). Two patients (2.41%) died within one and five years after surgery. During 12-108 months (48 months on average) follow-up of 81 patients, 21 patients (25.3%) suffering from myasthenia total recovery was observed, pharmacologic remission was achieved in 4 patients (5.3%), minimal manifestation remained in 23 patients (24.1%), while in 28 patients (33.73%) other improvement was observed. The status of 4 patients (4.82%) remained unchanged and that of 4 patients (5.3%) worsened.

Conclusion: VATS thymectomy represents a completely new surgical method for surgeons having experience in transsternal surgical technique. Bulky mediastinal fatty tissue makes surgery very difficult. The perioperative period is advantageous for the patients and also the long term follow-up results are acceptable. It is questionable that the thymus can be completely removed with this method in all cases.
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http://dx.doi.org/10.1556/1046.73.2020.4.1DOI Listing
December 2020

[Family planning in multiple sclerosis: conception, pregnancy, breastfeeding].

Authors:
Csilla Rózsa

Ideggyogy Sz 2020 05;73(05-06):161-169

Jahn Ferenc Dél-pesti Hospital, Department of Neurology, Budapest.

Family planning is an exceptionally important question in multiple sclerosis, as women of childbearing age are the ones most often affected. Although it is proven that pregnancy does not worsen the long-term prognosis of relapsing-remitting multiple sclerosis, many patients are still doubtful about having children. This question is further complicated by the fact that patients - and often even doctors - are not sufficiently informed about how the ever-increasing number of available disease-modifying treatments affect pregnancies. Breastfeeding is an even less clear topic. Patients usually look to their neurologists first for answers concerning these matters. It falls to the neurologist to rationally evaluate the risks and benefits of contraception, pregnancy, assisted reproduction, childbirth, breastfeeding and disease modifying treatments, to inform patients about these, and then together come to a decision about the best possible therapeutic approach, taking the patients' individual family plans into consideration. Here we present a review of relevant literature adhering to international guidelines on the topics of conception, pregnancy and breastfeeding, with a special focus on the applicability of approved disease modifying treatments during pregnancy and breastfeeding. The goal of this article is to provide clinicians involved in the care of MS patients with up-to-date information that they can utilize in their day-to-day clinical practice.
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http://dx.doi.org/10.18071/isz.73.0161DOI Listing
May 2020

Utilization of acute vascular imaging and neurointervention for acute ischaemic stroke patients in 20 Hungarian stroke centers.

Ideggyogy Sz 2019 Nov;72(11-12):407-412

Semmelweis University, Faculty of Medicine, Department of Neurology, Budapest.

Background And Purpose: Acute mortality rate of stroke in Hungary is significantly higher than in Western Europe, which is likely to be partially attributable to suboptimal treatment.

Methods: We examined the use of acute vascular imaging and mechanical thrombectomy for acute ischaemic stroke patients. We collected data on 20 consecutive patients from Hungarian stroke centers before 31st August 2016.

Results: Out of the reported 410 patients, 166 (40.4%) underwent CT angiography and 44 (10.7%) had mechanical thrombectomy.

Conclusion: Only about 1/3 of acute ischaemic stroke patients eligible for thrombectomy actually had it. The underlying reasons include long onset-to-door time, low utilization of acute vessel imaging and a limited neuro-intervention capacity needing improvement.
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http://dx.doi.org/10.18071/isz.72.0407DOI Listing
November 2019

Contributing factors to health-related quality of life in multiple sclerosis.

Brain Behav 2019 12 11;9(12):e01466. Epub 2019 Nov 11.

Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.

Background: Health-related quality of life (HRQoL) is lower in people with multiple sclerosis (PwMS) compared to the healthy population, psychological symptoms accompanying multiple sclerosis (MS) have a serious impact on the HRQoL of PwMS. Data regarding the subject, however, remain conflicting.

Objectives: To evaluate the patients' sociodemographic attributes, education, fatigue, depression, and cognitive impairment level of impact on the HRQoL for the whole cohort as well as comparing the sexes.

Materials And Methods: Three hundred and twenty-two relapse-remitting MS patients filled out the Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI), MS Quality of Life-54 (MSQoL-54) questionnaires, cognitive impairment were identified using Brief International Cognitive Assessment for MS (BICAMS) test. The patients' data were acquired from our clinic's MS registry or from patients' files.

Results: Depression and fatigue were found to have the most ubiquitous and robust effect on the overall and any given subdivision of the HRQoL composite. Other factors had a slight effect on some of the subscales when the whole cohort was evaluated. When the genders were compared, differences were found on 10 domains.

Conclusion: Psychopathological symptoms have a more powerful influence on the HRQoL of MS patients than physical impairment, also these symptoms influence men's and women's HRQoL with different power. This invokes the need for complex and personalized care in the treatment of PwMS. Ours is the first study to show a difference between the sexes in this regard.
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http://dx.doi.org/10.1002/brb3.1466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908891PMC
December 2019

[Myasthenia gravis: perioperative complications of 1002 transsternal thymectomies - historical overwiev of 34 years long practice at one institution].

Magy Seb 2019 Sep;72(3):83-97

Mellkassebészet, Budai MÁV Kórház Budapest.

Thymectomy became an important part of the treatment of myasthenia gravis, since Alfred Blalock reported about his first surgery 80 years ago. Despite of several different surgical techniques already accepted abroad, sternal approach was the almost exclusive exposure for thymectomy in Hungary till 2006. In this publication, we analyze the direct surgical consequences and complications of this method. At the Surgical Department of Budai MÁV Hospital, 1002 transsternal thymectomies were performed during 34 years on patients suffering from myasthenia gravis. Surgeries were performed for neurological indications, following careful medical investigations, involving specialists in neurology and internal medicine. In cases associated with thymoma, surgery was indicated for two reasons: removal of the thymus and the tumor at the same time. Neurological indications, patient preparation, perioperative treatment and surgical technique have considerably changed during these 34 years. We interpret the results according to the two eras based on the most frequently applied surgical techniques (simple and extended thymectomy); we publish the data separately of the patients with thymoma and those who underwent repeated surgery, focusing basically on breath-related complications. The patients' age was 32 years on the average (8-73 years). Women/men ratio: 3.5:1. Myasthenia gravis was associated with thymoma in 12.7% of the patients. Repeated thymectomy was necessary in case of 11 patients; further two patients required repeated sternotomy after cardiac surgery. Respiratory failure occurred in 21,3% out of 525 myasthenic patients operated in the first 19-year-old era, emergency re-intubation and tracheostomy happened in 12,8% and in 11,2% as well. In the second 15-year-old period postoperative respiratory failure occurred in 12,7% with emergency re-intubation in 7,1% and tracheostomy only in 1,2% out of 338 myasthenic patients. Respiratory failure occurred in 19.1% out of 126 patients operated for thymoma; re-intubation was necessary in 12.8% of the cases and tracheostomy was performed in 20.6% of the patients. Respiratory failure occurred in 13 patients, who underwent repeated surgery (46.1%); the ratio of re-intubation was 15.4% and that of tracheostomies 46.1%. Serious surgical complications were infrequent also in the entire group of patients: 2 patients required repeated surgery due to sternal bleeding; one more patient underwent repeated surgery due to rupture of the drainage tube, 4 cases of mediastinitis in the first group, two cases of heart injury and one case of sternal disruption occurred in the second period. The overall mortality was 1.4%: 1.3% in the first period, 0.3% in the second period, 4% in the thymoma group and 7.7% after repeated surgeries. In a historical overview, the ratio of serious respiratory and airway complications and the mortality after transsternal thymectomies has considerably decreased, but the postoperative respiratory failure and the surgical risk of transsecting the sternum still pose a real risk.
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http://dx.doi.org/10.1556/1046.72.2019.3.1DOI Listing
September 2019

Management of multiple sclerosis patients in central European countries: current needs and potential solutions.

Ther Adv Neurol Disord 2018 22;11:1756286418759189. Epub 2018 Feb 22.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Multiple sclerosis (MS) experts in Europe are facing rapidly rising demands of excellence due to the increasing complexity of MS therapy and management. A central European expert board of MS experts met to identify needs and obstacles with respect to raising quality of MS care in central and Eastern European countries. There are substantial variations across countries regarding delivery of care and its cost structure, as well as access to treatment. To date, Eastern European countries are often less able to afford reimbursement of immunomodulatory agents than Western countries. Overall, approximately 40% of working-age patients are not working due to MS. Costs rise steeply with increasing disability; indirect costs constitute the bulk of the financial burden in patients with severe MS. Magnetic resonance imaging (MRI) assessment is meanwhile obligatory as the diagnostic interface in the management of MS patients. Recommended measures directed at improving quality of care include the collection of patient data in registries, enhanced education of healthcare professionals, implementation of national strategies aiming at reducing regional variation, optimization of approval processes, and removal of administrative barriers. Local partnerships with authorities such as those that represent the interests of employees can contribute to leverage the importance of epidemiological data. The need for education extends to (neuro)radiologists who are responsible for reporting MRI findings in expert quality. Dissemination of the Magnetic Resonance Imaging in MS (MAGNIMS) protocol would be an important step in this context. Also, clinical freedom of choice is rated as essential. Physicians should have access to a range of treatment options due to the complexity of disease. Guidelines such as the upcoming EAN-ECTRIMS clinical practice guideline also aim at providing a basis for argumentation in negotiations with national health authorities.
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http://dx.doi.org/10.1177/1756286418759189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826096PMC
February 2018

Prevalence of cognitive impairment among Hungarian patients with relapsing-remitting multiple sclerosis and clinically isolated syndrome.

Mult Scler Relat Disord 2017 Oct 1;17:57-62. Epub 2017 Jul 1.

Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u 6., H-6725 Szeged, Hungary. Electronic address:

Background: Cognitive impairment (CI) is a frequent symptom of multiple sclerosis (MS); its prevalence is reported to be 43-70%. It is one of the most important determinants of MS patients' quality of life, as it is one of the main factors for MS patients becoming unemployed.

Aim: We aimed to determine the prevalence of CI among the relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS) patients in Hungary, to evaluate the predicting factors of CI and to assess the differences between sexes and patients with different educational levels.

Patients And Methods: Five-hundred and fifty-three CIS and RRMS patients were enrolled to our study from three Hungarian MS centers. Age at screening, age at disease onset, disease duration, EDSS score, sex and educational levels were analyzed as socio-demographic factors. The BICAMS battery was used to assess their cognitive state, the BDI-II battery to assess depression. For statistical analysis, we utilized logistical regression, and used Fisher exact tests, chi-square tests and one-way ANOVA.

Results: The mean age of our patients was 44.93 ± 11.69 years, mean age at disease onset was 31.95 ± 10.01 years, the mean disease duration was 13.05 ± 8.05 years and the median EDSS score 2.0 (Range: 6.5, IQR:2.0) points. Three-hundred and sixteen (57.1%) patients had CI. Sex, educational level and EDSS score proved to be significant predictors of CI (OR: 2.71, p < 0.001; OR: 1.94, p = 0.023; OR: 0.47, p = 0.003 respectively). CI was significantly (p < 0.001) more frequent among men (70.1%) than women (52.0%). We found, that educational level and EDSS score were only a significant predicting factor among women. Thus, the prevalence of CI among women with college or university degree was significantly (p < 0.001) less common (39.4%) than women with 12-15 years of education (57.4%) and women without a high school degree (66.7%). Also, we found that among women with higher EDSS score than 2 points, the prevalence of CI is 69.9% as compared to women with EDSS score between 0 and 2 points, where the prevalence is 42.8% (p < 0.001). No such differences were observed among man.

Discussion: Our prevalence data is similar to those reported in the literature (43-70%), and almost identical to the one assessment using the BICAMS battery. We found that men are more vulnerable to CI than women in MS, as was reported recently. We are the first to report however, that higher educational level and lower EDSS scores are only associated with better cognitive performance in women.
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http://dx.doi.org/10.1016/j.msard.2017.06.017DOI Listing
October 2017

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

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

Lancet Neurol 2017 04 11;16(4):271-281. Epub 2017 Feb 11.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.

Methods: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.

Findings: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006).

Interpretation: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.

Funding: National Health and Medical Research Council, and the University of Melbourne.
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http://dx.doi.org/10.1016/S1474-4422(17)30007-8DOI Listing
April 2017

Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis.

J Neurol Neurosurg Psychiatry 2017 Mar 28;88(3):196-203. Epub 2016 Sep 28.

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

Objective: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy.

Methods: The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6 and 6-6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted.

Results: For the EDSS 3-6, 4-6 and 6-6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92-1.11) and postbaseline (2.15-2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58-3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72-0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results.

Conclusions: Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.
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http://dx.doi.org/10.1136/jnnp-2016-313976DOI Listing
March 2017

The effects of fatigue, depression and the level of disability on the health-related quality of life of glatiramer acetate-treated relapsing-remitting patients with multiple sclerosis in Hungary.

Mult Scler Relat Disord 2016 May 12;7:26-32. Epub 2016 Feb 12.

Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, 6 Semmelweis Str., 6725 Szeged, Hungary. Electronic address:

Background: The common symptoms of multiple sclerosis are fatigue, depression, cognitive dysfunction, pain and sexual dysfunction, which influence the health-related quality of life of the patients.

Objective: We aimed to determine the correlations between the health-related quality of life, the level of disability, fatigue and depression in glatiramer acetate-treated patients with multiple sclerosis in Hungary.

Methods: The Hungarian versions of the Multiple Sclerosis Quality of Life-54, Fatigue Impact Scale and Beck Depression Inventory questionnaires were completed by 428 relapsing-remitting multiple sclerosis patients treated with glatiramer acetate from 19 Hungarian centers.

Results: The prevalence of fatigue was found to be 62.4%. The prevalence of depression was lower (13.4%) than that described in previous studies (36-54%) among patients with multiple sclerosis. Significant differences in the health-related quality of life were found between fatigued and non-fatigued patients. The level of disability, fatigue, depression and the duration of the disease correlated significantly with the quality of life. However, linear regression analysis indicated that the quality of life was predicted by the level of disability, depression, social and cognitive fatigue, but not by physical fatigue.

Conclusions: Decreasing the disease activity in multiple sclerosis with immunomodulatory therapy, together with improvements of the diagnostics and treatment of the accompanying depression and fatigue are of high priority to improve the health-related quality of life of patients with multiple sclerosis.
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http://dx.doi.org/10.1016/j.msard.2016.02.006DOI Listing
May 2016

Predictors of long-term disability accrual in relapse-onset multiple sclerosis.

Ann Neurol 2016 07 1;80(1):89-100. Epub 2016 Jun 1.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).

Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
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http://dx.doi.org/10.1002/ana.24682DOI Listing
July 2016

Contribution of different relapse phenotypes to disability in multiple sclerosis.

Mult Scler 2017 Feb 11;23(2):266-276. Epub 2016 Jul 11.

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

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis.

Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted.

Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25-0.29)), cerebellar (β = 0.35 (0.30-0.39)) and bowel/bladder (β = 0.42 (0.35-0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains.

Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.
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http://dx.doi.org/10.1177/1352458516643392DOI Listing
February 2017

[TERIFLUNOMIDE: A NEW ORAL IMMUNOMODULATING AGENT FOR MULTIPLE SCLEROSIS].

Ideggyogy Sz 2015 Mar;68(3-4):79-87

Multiple sclerosis (MS) is the autoimmune, demyelinating, neurodegenerative disorder of the central nervous system (CNS). There are nine drugs available in Hungary reimbursed by the National Health Insurance Fund of Hungary (OEP) to reduce the activity of the disease, from which seven can be used as first line therapies. We have approximately 20 years of experience with the interferon beta-1a/1b and glatiramer-acetate products. Though in case of approximately 30% of the patients using one of the first line drugs, the disease remains active, that we call break-through disease. The reasons for breakthrough disease could be the insufficient adherence and compliance, the appearance of neutralizing antibodies or the high activity of the disease. One of the oral immunomodulating drugs for MS, teriflunomide, was registered in Europe in 2013. Because of the anti-proliferative and anti-inflammatory effect of teriflunomide, it can be used for the reduction of the disease activity in the relapsing-remitting course of MS. The effect of teriflunomide was proved in one Phase II. and four Phase III. (TEMSO, TOWER, TENERE, TOPIC) studies. Teriflunomide 14 mg once daily was able to demonstrate in two consecutive placebo-controlled phase 3 clinical trials that significantly reduces the relapse rate (31.5% and 36.3%) and in both studies significantly reduces the sustained disability progression (29.8% and 31.5%) moreover delays the appearance of the clinically definitive MS in patients with clinically isolated syndrome (CIS). According to the TENERE study there were no significant differences observed between teriflunomide 14 mg and IFNβ-α a s.c. in time to failure and annualized relapse rate but the treatment satisfaction domains of global satisfaction, side-effects and convenience were significantly improved with teriflunomide compared with s.c. IFNβ-α.
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March 2015

CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY--DISEASE OR MISDIAGNOSIS?

Ideggyogy Sz 2015 May;68(5-6):179-82

Background And Purpose: Former studies reported internal jugular vein stenosis in patients with multiple sclerosis. We aimed to evaluate if these venous stenoses were real and cerebral venous outflow of patients with multiple sclerosis differed from that of normal controls.

Methods: 20 controls were prospectively investigated by angiography and duplex ultrasound. Seven patients with multiple sclerosis underwent angiography at other centers; we reviewed these registrations and performed venous ultrasound examinations.

Results: Angiography displayed > 50% stenosis of internal jugular vein in 19 controls (69 ± 17% on the right and 73 ± 13% on the left side) and < 50% stenosis in 1 control (43.5% and 44.6%). All 7 patients had at least one-sided stenosis. The mean degree of stenosis was 63 ± 16% on the right and 67 ± 13% on the left side. There was no significant difference in the degree of stenosis between patients and controls. However, these "stenoses" disappeared if the contrast agent was injected at a catheter position below the orifice of the subclavian vein during venography. The venous flow volume was also similar between groups: 479.7 ± 214.1 and 509.8 ± 212.0 ml/min (right and left side) in the patients and 461.3 ± 224.3 and 513.6 ± 352.2 ml/min in the control group; p = 0.85 and 0.98 (right and left). Color and power duplex imaging also revealed normal blood flow of the internal jugular vein in all patients and controls.

Conclusion: The cerebral venous status of patients with multiple sclerosis and controls were similar. The angiographic "stenoses" were virtual, caused by the contrast dilution effect of the non-contrast blood stream of the subclavian vein.
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http://dx.doi.org/10.18071/isz.68.0179DOI Listing
May 2015

[Extending therapeutic possibilities in relapsing-remitting multiple sclerosis: dimethyl fumarate].

Ideggyogy Sz 2015 Jan;68(1-2):7-14

Dimethyl fumarate (DMF) is a novel oral therapy that has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate shows anti-inflammatory and cytoprotective properties that are thought to be mediated primarily via activation of the nuclear factor (erythroid-derived 2)-like 2- Nrf2 transcriptional pathway, which up-regulates the genes involved in the cellular response to oxidative stress. The drug was evaluated in 2 large, randomized, double-blind, multicentric, multinational, 2-year, phase III clinical trials. The DEFINE and CONFIRM trials, conducted with over 2600 adult patients suffering from RRMS, unequivocally confirmed the efficacy of DMF (2 x 240 mg daily) in reducing the annualized relapse rate (ARR) and reducing the proportion of patients with MS relapse at 2 years. Significantly reduced sustained disability progression was observed with the drug versus placebo in DEFINE, while the same tendency was seen in CONFIRM. The MRI results of the studies were also convincing: DMF significantly reduced the number of new/enlarging T2-hyperintense lesions and the number of Gd-enhancing lesions compared to placebo. Dimethyl fumarate was generally well tolerated and no safety concern has been raised. Adverse events that occurred most frequently included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating the same results as the two previous studies. In conclusion, although further, mostly comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, dimethyl-fumarate is a valuable addition to the therapeutic options available for RRMS.
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January 2015

Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis.

JAMA Neurol 2015 Apr;72(4):405-13

Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia2Department of Medicine, University of Melbourne, Melbourne, Australia.

Importance: After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain.

Objective: To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS.

Design, Setting, And Participants: Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted.

Exposures: Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy.

Main Outcomes And Measures: Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression.

Results: Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P=.009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P=.04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P=.02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P=.005), and lower hazard of treatment discontinuation (HR, 0.55; P=.04) compared with the injectable group.

Conclusions And Relevance: Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.
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http://dx.doi.org/10.1001/jamaneurol.2014.4147DOI Listing
April 2015

Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis.

Ann Neurol 2015 Mar 17;77(3):425-35. Epub 2015 Jan 17.

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

Objective: In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents.

Methods: Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses.

Results: Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p < 0.001).

Interpretation: This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.
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http://dx.doi.org/10.1002/ana.24339DOI Listing
March 2015

Pathological and biochemical investigation of a woman diagnosed with genetic Creutzfeldt-Jakob disease shortly after parturition.

Neuropathol Appl Neurobiol 2015 Aug 2;41(5):676-80. Epub 2015 May 2.

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/nan.12204DOI Listing
August 2015

Risk of relapse phenotype recurrence in multiple sclerosis.

Mult Scler 2014 Oct 28;20(11):1511-22. Epub 2014 Apr 28.

Royal Melbourne Hospital, AustraliaUniversity of Melbourne, Australia.

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype.

Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis.

Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease.

Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
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http://dx.doi.org/10.1177/1352458514528762DOI Listing
October 2014

A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission.

Mol Immunol 2014 Feb 26;57(2):200-9. Epub 2013 Oct 26.

3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.

Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS, but the three complement pathways have not been systematically investigated. We evaluated the overall activation of the classical, alternative, and MBL-lectin pathways in the peripheral blood of 25 patients with AQP4-seropositive NMO spectrum during remission and 113 healthy controls by three ways: (1) we measured the concentrations of native complement proteins of the three pathways [C1-inhibitor (C1-inh), C1q, C4, C3, C5, factor I, factor B, properdin]; (2) the concentrations of complement products suggesting in vivo activation (C1rC1sC1-inh, C3a, C3bBbP, and SC5b-9); and (3) the total activity of the three complement pathways. Additionally we measured levels of C1rC1sC1-inh, C3a, C3bBbP in cerebrospinal fluid (CSF) of 6 patients with relapsing NMO and of 18 patients with relapsing multiple sclerosis (MS). The serological studies indicated that total complement activity of the classical [median (interquartile range) 72 (61-82) vs. 65 (56-73) CH50/mL; p=0.0122] and of the lectin pathways [73 (59-111) vs. 49 (3-92)%; p=0.0078)] were elevated compared with the controls, whereas that of the alternative pathway was not significantly different. The levels of C3 [1.1 (0.9-1.3) vs. 1.4 (1.2-1.5)g/L; p<0.0001], factor B [89 (77-115) vs. 103 (93-113)%; p=0.0397] and factor I [85 (69-95) vs. 101 (93-107)%; p=0.0007], as well as of properdin [92 (74-104) vs. 108 (97-122)%; p=0.0028] were significantly lower in the patients than in the controls. The only increase in the patients was ascertained in the relative concentration of C1rC1sC1-inh vs. the C1-inhibitor (42.3 [31.9-65.0] vs. 30.8 [13.5-43.5] AU/mg; p=0.0007). The absolute and relative levels of the other complement activation products were not elevated in the patients. On the contrary, the serum concentrations of C3a, C3bBbP, and SC5b-9 of the patients were lower than those of the controls. The absolute concentration of the complement activation products (C1rC1sC1-inh, C3bBbP, C3a) and the ratio of C3bBbP/C1rC1sC1-inh did not differ in NMO and MS CSF samples. The ratio of C3bBbP/C1rC1sC1-inh was similar in NMO plasma and CSF samples. We found a higher ratio of C3bBbP/C1rC1sC1-inh in the plasma of control subjects compared to those in any pathological samples. Our results do not indicate substantial systemic complement activation if NMO activity is adequately controlled; nevertheless, the complement system is abnormally affected even during remission. The relative ancillarity of the alternative compared to the classical pathway may also suggest that suppression of the alternative pathway by treatment may be important to achieve remission.
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http://dx.doi.org/10.1016/j.molimm.2013.09.010DOI Listing
February 2014

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase.

Hum Immunol 2013 Dec 7;74(12):1701-4. Epub 2013 Aug 7.

Division of Clinical and Experimental Neuroimmunology, Department of Neurology, University of Pecs, Pecs, Hungary.

Introduction: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders.

Methods: The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls.

Results: The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01).

Discussion: The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.
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http://dx.doi.org/10.1016/j.humimm.2013.07.016DOI Listing
December 2013

Recommendations for the use of prolonged-release fampridine in patients with multiple sclerosis (MS).

CNS Neurosci Ther 2013 May;19(5):302-6

Department of Neurology and Center for Clinical Neuroscience, Charles University, General Hospital, Prague, Czech Republic.

Prolonged-release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system. Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis. This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management.
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http://dx.doi.org/10.1111/cns.12101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493348PMC
May 2013

Health status and costs of ambulatory patients with multiple sclerosis in Hungary.

Ideggyogy Sz 2012 Sep;65(9-10):316-24

Health Economics and Health Technology Assessment Research Centre, Corvinus University of Budapest.

Background And Purpose: Data on disease burden of multiple sclerosis from Eastern-Central Europe are very limited. Our aim was to explore the quality of life, resource utilisation and costs of ambulating patients with multiple sclerosis in Hungary.

Methods: Cross-sectional questionnaire survey was performed in two outpatient neurology centres in 2009. Clinical history, health care utilisation in the past 12 months were surveyed, the Expanded Disability Status Scale and the EQ-5D questionnaires were applied. Cost calculation was conducted from the societal perspective.

Results: Sixty-eight patients (female 70.6%) aged 38.0 (SD 9.1) with disease duration of 7.8 (SD 6.7) years were involved. Fifty-five (80.9%) had relapsing-remitting form and 52 (76.5%) were taking immunomodulatory drug. The average scores were: Expanded Disability Status Scale 1.9 (SD 1.7), EQ-5D 0.67 (SD 0.28). Mean total cost amounted to 10 902 Euros/patient/year (direct medical 67%, direct nonmedical 13%, indirect costs 20%). Drugs, disability pension and informal care were the highest cost items. Costs of mild (Expanded Disability Status Scale 0-3.5) and moderate (Expanded Disability Status Scale 4.0-6.5) disease were 9 218 and 17 634 Euros/patient/year respectively (p<0.01), that is lower than results from Western European countries.

Conclusion: Our study provides current inputs for policy making and contributes to understanding variation of cost-of-illness of multiple sclerosis in Europe.
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September 2012

Ultrasonography of MADSAM neuropathy: focal nerve enlargements at sites of existing and resolved conduction blocks.

Neuromuscul Disord 2012 Jul 16;22(7):627-31. Epub 2012 Apr 16.

Dept. of Neurology, Semmelweis University, Budapest, Hungary.

Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies.
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http://dx.doi.org/10.1016/j.nmd.2012.03.005DOI Listing
July 2012

Interleukin-4 receptor alpha polymorphisms in autoimmune myasthenia gravis in a Caucasian population.

Hum Immunol 2012 Feb 12;73(2):193-5. Epub 2011 Nov 12.

Clinical and Research Centre for Molecular Neurology, Semmelweis University, Budapest, Hungary.

Autoimmune myasthenia gravis is a T-cell-dependent, antibody-mediated, rare neuromuscular disorder. Interleukin-4, acting via interleukin-4 receptor alpha, plays a pivotal role in B-cell differentiation and antibody production and has been implicated to influence disease progression in experimental autoimmune myasthenia gravis. Polymorphisms of the interleukin-4 receptor alpha gene have been shown to be associated with various autoimmune diseases. We compared the distribution of three polymorphisms of the interleukin-4 receptor alpha gene (S503P, rs1805015, Q576R, rs1801275, I75V, rs1805010), all affecting interleukin-4 signaling, in two cohorts of myasthenia gravis patients with ethnically matched controls. Although the distribution of the S503P and Q576R polymorphisms did not differ significantly between the groups, the frequency of the GG rare homozygote genotype of the I75V polymorphism was significantly higher in patients with myasthenia gravis. Our data suggest that the reduced responsiveness to interleukin-4 because the I75V polymorphism may contribute to the pathogenesis of myasthenia gravis.
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http://dx.doi.org/10.1016/j.humimm.2011.11.001DOI Listing
February 2012

APOE epsilon status in Hungarian patients with primary progressive multiple sclerosis.

Swiss Med Wkly 2010 26;140:w13119. Epub 2010 Nov 26.

Department of Neurology, University of Szeged, Semmelweis u. 6., 6725 Szeged, Hungary.

Principles: Apolipoprotein E (ApoE), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The APOE gene (APOE) is involved in neurodegenerative diseases, the best-known association being that between the APOE ε4 allele and Alzheimer's disease. Multiple sclerosis (MS) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the APOE gene on the susceptibility of primary progressive MS (PPMS) in Hungary.

Methods: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers.

Results: The number of PPMS patients without the ε2 allele was found to be remarkably high, whilst the ε2 allele was overrepresented in the RRMS group. A markedly high frequency of the ε4 allele was found in the PPMS group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the ε2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of MS.

Conclusions: Our findings suggest that the presence of the ε2 and ε4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters.
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http://dx.doi.org/10.4414/smw.2010.13119DOI Listing
February 2011