Abstract: ABSTRACT: BACKGROUND: A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TOR) were applied to our database of patients treated with IFN B1a IM. Patient data were assessed during year 1 for disease activity and patients assigned to 2 groups according to TOR: " change treatment " (C) and " no change treatment " (N). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The " change treatment " status was assigned to 22 patients, and " no change treatment " to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9 and 84.4%. During the following years, the Relapse Rate was always higher in the " change treatment " group (C) than in the " no change treatment " group (N) (5y; C: 0.7, N: 0.07; p<0.001, 12 m - last visit; C: 0.536, N: 0.34). We obtained the same results with the EDSS (4y; C: 3.53, N: 2.55, annual progression rate in 12 m - last visit; C: 0.29, N: 0.13). CONCLUSIONS: Applying TOR to the first year of therapy allowed for accurate edition of continued disease activity in relapses and in disability progression.
Abstract: Event-related potentials (ERPs) and power spectral density (PSD) were registered during an auditory-oddball paradigm in 11 MS patients. These patients showed a decrease in the amplitude of P2 and N2 components and a delayed P3 latency compared to control subjects suggesting that the attentional orienting mechanism in the auditory modality is affected in MS. The PSD analysis showed that MS patients exhibited an increased power in beta and gamma bands. The combined analysis of frequency and time domain suggested diverse phenomena that occurred in the MS patient group related with the EEG background or the motivational status.
Abstract: BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis. Materials and METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two SNPs (rs4728142, rs3807306) and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with p-values <0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele-specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
Abstract: Some polymorphisms in the FCRL3 gene, a member of the Fc-receptor like family, have been associated with several autoimmune diseases and recently with multiple sclerosis (MS). We performed a case-control study of three SNPs in FCRL3 gene in 645 MS patients and 786 controls, all Caucasians from the South of Spain. Genotype and allele frequencies of two SNPs (rs7528684/FCRL3_3 and rs7522061/N28D), which were in high linkage disequilibrium (r(2)=0.87), differed between MS cases and controls. The C allele of FCRL3_3 was found to be protective for MS (per allele OR=0.81, 95% C.I.=0.70-0.94; P-value=0.007) as was the G variant of N28D, but no association was found for rs11264799/FCRL3_4. Haplotype analysis confirmed these associations with highly consistent effect sizes for haplotypes carrying the C allele of FCRL3_3.
Abstract: INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is an infrequent pathology affecting the central nervous system (about 1/1,000000) that has a subacute progression and, for the time being, a fatal prognosis. The familial forms account for between 5-10% of cases and one of the most frequent is that produced by the E200K mutation of prion protein gene (PRNP), which has not been reported in Spanish families although Spain is considered to be part of the expansion circuit of the mutation. CASE REPORTS: We report on a Spanish family with three cases of CJD. The disease affected three females (our patient and two paternal aunts), who started with dementia, myoclonias, gait disorders and cortical blindness at the ages of 61, 53 and 55 years. Progress in all three cases was torpid and the symptoms advanced in a short time. Results of the complementary tests that were carried out were normal, except for the electroencephalogram, which was compatible with CJD in all three cases, and the imaging tests, which revealed cortical-subcortical atrophy. A confirmatory diagnosis was reached from a biopsy, the clinical picture and the family history in the cases of the paternal aunts and from a genetic study of our patient, which confirmed the E200K mutation. CONCLUSIONS: This family confirms the presence of familial forms of CJD in Spain, more specifically the E200K mutation, and highlights the role of Spain in the possible transmission of this mutation.
Abstract: Vanishing white matter (VWM) is a childhood leukoencephalopathy with central hypomyelination, white matter rarefaction, and cystic degeneration. Adult onset, variable phenotype, and high frequency characterize Arg113His mutation caused by G338A polymorphism associated with VWM. A patient with trauma-associated onset, and clinical features compatible with multiple sclerosis (MS), was homozygous for G338A mutation of eukaryotic translation initiation factor (eIF2B5). The authors checked a cohort of 101 MS patients, including 19 with head/neck trauma-associated onset, and failed to find the mutation, described above, in MS chromosomes. Our report does not exclude the presence in MS chromosomes of other mutations in the eIF2B gene family.
Abstract: OBJECTIVE: We aimed to study clinical, radiological and molecular genetic features of patients with cerebral cavernous malformations (CCMs) from the Iberian Peninsula. METHODS: We screened Krit1(CCM1), MGC4607(CCM2), and PDCD10(CCM3) by systematic SSCP and direct sequencing of coding exons in 48 nuclear families and 30 sporadic cases of CCM from Spain and Portugal. RESULTS: Screening of CCM patients detected nine different mutations in 19 families. We found four new mutations in Krit1. Three of them were caused by either a small insertion or deletion, which lead to frameshift and premature termination codons. We also found a missense L308H mutation located in a highly conserved sequence within the ankyrin domain of Krit1. In CCM2, we found a redundant 14 bp deletion in exon 5 of MGC4607 which predicts a truncated protein at residue 230. We did not find mutations in CCM3. CONCLUSIONS: Finding that the 14 bp deletion was present in eleven families from the Iberian Peninsula indicates a high prevalence of this mutation. This redundant CCM2 mutation is worth considering in molecular diagnosis and genetic counselling of cerebral cavernous malformations.
Abstract: Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform--MSBase--has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.
Abstract: This cost-of-illness analysis is based on information from 1.848 patients in Spain and is part of a Europe-wide study on the costs of multiple sclerosis. The objective was to analyze the costs and quality of life (QOL) related to the level of disease severity and progression. Patients were identified by the Asociación Española de Esclerosis Múltiple (AEDEM) and participated in the survey by answering a mail questionnaire (response rate 31.8%). In addition to details on the disease (type of disease, relapses, level of functional disability), the questionnaire asked for information on all resource consumption, medical, non-medical, work absence and informal care, as well as utility (QOL). The mean age of the cohort was 45 years, and only 5.5% of patients were 65 years of age or more. Approximately 36% of patients had mild disease (Expanded Disability Status Scale [EDSS] score of 0-3), 44.8% had moderate disease (EDSS score of 4-6.5) and 17.7% had severe disease (EDSS score > or =7). The mean EDSS score in the sample was 4.5 (median 5.0), with a utility of 0.554. Costs and utility are highly correlated with disease severity. Workforce participation decreases from around 70% in early disease to less than 5% in the very late stages. Hospitalization is very infrequent in early disease, representing less than euro 1.300 per patient per year for patients at EDSS scores <6, but increases steeply for patients at scores > or =7. Ambulatory care increases fivefold between early and late disease, while investments and services increase from basically no cost to just over euro 6.000 at EDSS scores > or =7. Productivity losses increase more than eightfold, and informal care increases from euro 593 at EDSS scores of 0-1 to nearly euro 34.228 at scores of 8-9. Hence, total mean costs per patient are driven by the distribution of the severity levels in the sample, increasing from euro 10.425 at EDSS scores of 0-1 to euro 45.264 at a score of 7, and euro 65.693 at scores of 8-9. The same is true for utility, which decreases from 0.865 to 0.084 as patients progress from the mildest to the most severe disability levels. However, the utility loss compared to the age- and gender-matched general population is high at all levels of the disease ( approximately 0.25 in patients below 30 years of age with an EDSS score of 2-3, and approximately 0.4 in patients over 60 years of age and a score of > or =6), leading to an estimated annual loss of 0.276 quality-adjusted life-year per patient. Relapses for patients with an EDSS score below 5 are associated with a cost of approximately euro 2.750 and a utility loss of 0.1 during the quarter in which they occur.
