Publications by authors named "Ricardo Fernandez-Bolaños"

22 Publications

  • Page 1 of 1

Prognostic indicators in pediatric clinically isolated syndrome.

Ann Neurol 2017 May;81(5):729-739

Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients.

Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data.

Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening.

Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.
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http://dx.doi.org/10.1002/ana.24938DOI Listing
May 2017

Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis.

Mult Scler 2018 04 6;24(5):642-652. Epub 2017 Apr 6.

Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.

Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation.

Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time.

Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics.

Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143; 16.8%), moderate ( n = 378; 44.3%), or severe ( n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively.

Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.
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http://dx.doi.org/10.1177/1352458517703800DOI Listing
April 2018

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2016 Dec 3;87(12):1343-1349. Epub 2016 Nov 3.

Groene Hart Ziekenhuis, Gouda, The Netherlands.

Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process.

Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression.

Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10).

Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.
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http://dx.doi.org/10.1136/jnnp-2016-314013DOI Listing
December 2016

Defining reliable disability outcomes in multiple sclerosis.

Brain 2015 Nov 10;138(Pt 11):3287-98. Epub 2015 Sep 10.

26 Hospital Italiano, Buenos Aires, Argentina.

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.
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http://dx.doi.org/10.1093/brain/awv258DOI Listing
November 2015

Multiple sclerosis in Latin America: A different disease course severity? A collaborative study from the MSBase Registry.

Mult Scler J Exp Transl Clin 2015 Jan-Dec;1:2055217315600193. Epub 2015 Aug 17.

Francicus Ziekenhuis, The Netherlands.

Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions.

Methods: Centers from 18 countries with >20 cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of >1 year and <30 years at time of EDSS measurement were evaluated. The MS Severity Score (MSSS) was used as a measure of disease progression. Comparisons among regions (North America, Europe, Australia and LA), hemispheres and countries were performed.

Results: A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%); North America, 1609 (16.7%); Australia, 1119 (11.6%); and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres ( = 0.68), regions ( = 0.96) or countries ( = 0.50).

Conclusions: Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.
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http://dx.doi.org/10.1177/2055217315600193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408755PMC
August 2015

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Mult Scler 2016 Apr 21;22(4):520-32. Epub 2015 Jul 21.

INEBA, Buenos Aires, Argentina.

Objective: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS).

Methods: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence.

Results: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation.

Conclusion: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.
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http://dx.doi.org/10.1177/1352458515594041DOI Listing
April 2016

Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS.

PLoS One 2015 5;10(6):e0122686. Epub 2015 Jun 5.

AORN San Giuseppe Moscati, Avellino, Italy.

Background: Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females.

Methods: Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS.

Results: In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change.

Conclusion: Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457630PMC
March 2016

Predictors of disability worsening in clinically isolated syndrome.

Ann Clin Transl Neurol 2015 May 27;2(5):479-91. Epub 2015 Mar 27.

Geelong Hospital Geelong, Australia.

Objective: To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS).

Methods: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression.

Results: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening.

Interpretation: This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.
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http://dx.doi.org/10.1002/acn3.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435703PMC
May 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

Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.

Ann Neurol 2015 Mar 30;77(3):447-57. Epub 2015 Jan 30.

Department of Immunology, Ramón y Cajal University Hospital, Institute Ramon y Cajal for Biomedical Research, Madrid, Spain; Spanish Network for the Research in Multiple Sclerosis, Spain.

Objective: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML.

Methods: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain.

Results: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2).

Interpretation: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.
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http://dx.doi.org/10.1002/ana.24345DOI Listing
March 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

Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing-remitting multiple sclerosis.

Mult Scler 2015 Aug 5;21(9):1159-71. Epub 2014 Dec 5.

Department of Neurology and Center of Clinical Neuroscience, 1st Faculty of Medicine, General University Hospital and Charles University in Prague, Czech Republic.

Background: The results of head-to-head comparisons of injectable immunomodulators (interferon β, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed.

Objective: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators.

Methods: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted.

Results: Of the 3326 included patients, 345-1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon β-1a relative to intramuscular interferon β-1a and interferon β-1b (p≤0.001). No differences in 12-month confirmed progression of disability were observed.

Conclusion: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.
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http://dx.doi.org/10.1177/1352458514559865DOI Listing
August 2015

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.

Ann Neurol 2014 Dec 20;76(6):880-90. Epub 2014 Oct 20.

Department of Neurology, Royal Melbourne Hospital, Parkville, Australia.

Objective: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude.

Methods: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak.

Results: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028).

Interpretation: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.
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http://dx.doi.org/10.1002/ana.24287DOI Listing
December 2014

Risk of relapse phenotype recurrence in multiple sclerosis.

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

University of Melbourne, AustraliaRoyal Melbourne Hospital, AustraliaUniversity of Melbourne, AustraliaUniversity of Bari, ItalyHôpital Notre Dame, Montreal, CanadaHospital Universitario Virgen Macarena, Sevilla, SpainHôpital Notre Dame, Montreal, CanadaMS Centre, University 'G. d'Annunzio', Chieti, ItalyHotel-Dieu de Levis, Quebec, CanadaNeuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, CanadaUniversity Hospital San Carlos, IdISSC, Madrid, SpainKaradeniz Technical University, Trabzon, TurkeyOrbis Medical Centre, Sittard, The NetherlandsAarhus University Hospital, Aarhus C, DenmarkOspedale di Macerata, Macerata, ItalyOspedali Riuniti di Salerno, Salerno, ItalyJohn Hunter Hospital, Newcastle, AustraliaAORN San Giuseppe Moscati, Avellino, ItalyRoyal 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

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

Brain 2013 Dec 18;136(Pt 12):3609-17. Epub 2013 Oct 18.

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

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
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http://dx.doi.org/10.1093/brain/awt281DOI Listing
December 2013

Predictors and dynamics of postpartum relapses in women with multiple sclerosis.

Mult Scler 2014 May 9;20(6):739-46. Epub 2013 Oct 9.

Department of Neurology, Royal Victoria Hospital, Belfast, UK.

Background: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies.

Objective: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse.

Methods: An observational case-control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses.

Results: The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model.

Conclusion: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.
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http://dx.doi.org/10.1177/1352458513507816DOI Listing
May 2014

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis.

PLoS One 2013 21;8(5):e63480. Epub 2013 May 21.

Departments of Medicine and Neurology, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.

Objectives: To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics.

Methods: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded.

Results: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages.

Conclusions: Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660604PMC
December 2013

Oxidative stress and inflammation biomarkers in the blood of patients with Huntington's disease.

Neurol Res 2012 Sep;34(7):721-4

Servicio de Neurología, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofía de Córdoba, Córdoba, España.

Objectives: Huntington's disease (HD) is a neurodegenerative disorder for which there is no effective treatment. Oxidative stress and inflammation are known to be involved in HD, but the precise relationship between the two remains unclear. The aim of this study was to analyze oxidative stress and inflammation biomarkers in blood of patients with HD with a view to identifying potential links between them.

Methods: Blood samples were collected from 13 patients with HD and from 10 age- and sex-matched controls, and the following were measured: C-reactive proteins, myeloperoxidase (MPO)/white blood cell (WBC) ratio, interleukin-6 (IL-6), thioredoxin reductase-1 (TrRd-1), thioredoxin-1 (Trx-1), total nitrites (NOx), nitric oxide synthase (NOS) and nitrotyrosine.

Results: Results showed that HD is associated to a reduction of TrRd-1 and Trx-1 levels in plasma and erythrocytes, and with an increase in the MPO/WBC ratio. A positive correlation was observed between global oxidative stress (GOS) and MPO/WBC. No changes were found in NOS and Nox levels with respect to controls.

Conclusion: Oxidative damage may be linked to the inflammatory response in HD, via a peripheral immune response.
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http://dx.doi.org/10.1179/1743132812Y.0000000073DOI Listing
September 2012

Country, sex, EDSS change and therapy choice independently predict treatment discontinuation in multiple sclerosis and clinically isolated syndrome.

PLoS One 2012 29;7(6):e38661. Epub 2012 Jun 29.

Department of Neurology, Royal Melbourne Hospital, Victoria, Australia.

Objectives: We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS).

Methods: The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation.

Results: A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation.

Conclusion: In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387159PMC
November 2012

NGF and nitrosative stress in patients with Huntington's disease.

J Neurol Sci 2012 Apr 16;315(1-2):133-6. Epub 2012 Jan 16.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Universidad de Córdoba, Córdoba, Spain.

Introduction: Huntington's disease (HD) is a neurodegenerative genetic disorder caused by expansion of polyglutamine repeats in the huntingtin gene and characterised by the loss of striatal and cortical neurons. Few studies to date have focussed on peripheral neurotrophic-factor levels in patients with HD.

Objective: To measure plasma NGF levels in Huntington's disease and investigate their correlation with disease intensity.

Materials And Methods: Nineteen patients with HD and nineteen age- and sex-matched healthy subjects took part in this cross-sectional study. Plasma levels of NGF, BDNF, GDNF, nitrotyrosine, and myeloperoxidase (MPO) were measured; lactate dehydrogenase (LDH) levels were determined and white blood cell (WBC) counts were evaluated.

Results: NGF levels were significantly lower, nitrotyrosine levels were higher and LDH activity was greater in HD patients than in healthy subjects. There was no significant difference in MPO levels or WBC counts, whereas the MPO/WBC ratio was considerably higher in HD patients. The data obtained suggested that biochemical and haematological changes correlated with disease severity.

Conclusion: NGF levels are lower in HD patients than in healthy subjects. However, further research is required to confirm the role of NGF in HD.
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http://dx.doi.org/10.1016/j.jns.2011.12.014DOI Listing
April 2012

Important role of oxidative stress biomarkers in Huntington's disease.

J Med Chem 2011 Aug 7;54(15):5602-6. Epub 2011 Jul 7.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Universidad de Córdoba, Córdoba, Spain.

This study examined global oxidative stress (GOS) and antioxidant system and their correlation with disease stage in 19 patients with HD. The results revealed an increase in oxidative stress biomarkers and a reduction in antioxidant systems in HD patients. The effects were more intense in HD1 than in HD2 patients. Additionally, carbonylated proteins and GOS were correlated with disease stage. These findings suggest that oxidative stress plays an important role in the pathogenesis of HD.
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http://dx.doi.org/10.1021/jm200605aDOI Listing
August 2011

Electrolytes disturbances and seizures.

Epilepsia 2006 Dec;47(12):1990-8

Department of Internal Medicine, Hospital de la Merced, Osuna, Spain.

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http://dx.doi.org/10.1111/j.1528-1167.2006.00861.xDOI Listing
December 2006