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Background and Aim: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS., Methods: Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses., Results: rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously., Conclusions: This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.

Introduction: Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients., Development: At an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced., Conclusions: Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to monitor patients individually., (Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier España. All rights reserved.)

Background and Objectives: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate., Methods: Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls., Results: Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353)., Conclusions: Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p(M-H)=0.001; OR(M-H) (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: p(M-H)=0.03; OR(M-H) (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: p(M-H)=0.01; OR(M-H) (95% CI)= 0.89 (0.81-0.97)].

Background: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis., Objective: The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels., Methods: Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC., Results: Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels., Conclusions: These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.

The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Regional grey-matter atrophy is more sensitive to cognitive impairment than global grey-matter atrophy measures. In patients with clinically isolated syndrome cognitive impairment does not predict conversion to multiple sclerosis (MS) after 5-years of follow-up. Focusing on central nervous system plasticity and functional reorganization in MS, an early intervention can improve clinical aspects and enhances brain plasticity. Preservation of a potential for plasticity provides a rationale for rehabilitation interventions even in later stages of disease. Therapeutical strategies have focused on stem cell-mediated remyelination and immunomodulation functions, on cellular infiltration into the brain, and on new ways for immuno-modulation for the development of future therapies in MS. Encouraging findings from clinical trials with current and emerging disease-modifying therapy being developed was also a key theme at this edition. Positive results have been reported for rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab, teriflunomide, BG-12, and laquinimod, including a favorable safety profile. Since armamentarium for the treatment of MS is fast increasing, concerns exist about the risk of severe adverse events with their use. This aspect reinforces the importance of disease registries as a proactive tool for monitoring drug safety in the post-approval setting.

Background: The association between multiple sclerosis (MS) and the HLA-DRB1*15:01 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association., Objectives: 1) Test the association of MS with *15:01 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *15:01; 3) study whether *15:01, VDR variants and/or sex affect HLA II gene expression., Methods: Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *15:01 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP., Results: Our data confirms that the *15:01 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107-1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *15:01. Sex confers a much stronger modulation and the *15:01-MS association seems to be female specific. A higher *15:01 frequency has been observed in Basques (45.1%). *15:01 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *15:01 controls., Conclusions: We confirm the *15:01-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*15:01 seems to be a haplotype consistently linked to high HLA II gene expression.

Background and Objective: To estimate the prevalence of excess body fat in a cohort of children aged 2 to 14 years, and calculate the risk of overweight during adolescence when it was present in previous years., Subjects and Method: This was a retrospective study and review of clinical records including weight, height and body mass index in a cohort of 840 children at ages 2, 3, 4, 6, 8, 10, 12 y 14 years. The excess of body fat was calculated following the International Obesity Task Force criteria and showing the odds ratio of having overweight at age 14 years when it was present in any previous year., Results: The prevalence of overweight at age 2 was 8.5%, increased progressively to 32.6% at age 8, and then decreased to 22.5% at age 14. The prevalence of overweight was significantly higher (p<0.05) in females at age 2 and 3 years and lower (p<0.05) at age 12 and 14 with respect to males. The probability of presenting overweight/obesity in adolescence was 15 times higher when overweight was present at age 8., Conclusions: This study show that overweight at any paediatric age, especially school age, implies a high risk of overweight/obesity in adolescence., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Introduction: Recent studies have shown the need to optimise the management of patients after a first attack suggestive of multiple sclerosis (MS). Our aim is to determine whether the results from follow-ups in these studies are reproducible within a Spanish multi-centre context., Patients and Methods: The PREM study (observational prospective Spanish multi-centre study at 24 months) included patients in the first three months following a first event suggestive of MS with at least two typical lesions in a magnetic resonance scan. The Expanded Disability Status Scale (EDSS) was obtained and the presence of attacks was evaluated basally and at 3, 6, 9, 12, 18 and 24 months; a magnetic resonance scan was performed basally and at 6 and 24 months so as to be able to calculate the brain volume and the volumes of the lesions (T1, T2 and T1 after administering gadolinium). McDonald and Poser criteria were evaluated during the follow-up. A subgroup of patients was followed up for a total period of four years., Results: Altogether 110 patients (67% females) with a mean age of 30.2 years were included in the study; 22 patients dropped out of the study before it finished. Poser criteria were met by 19% and 45% of patients at 6 months and 24 months, respectively; 63% and 71% satisfied McDonald criteria. The EDSS decreased significantly (-0.94; p < 0.001) and development of atrophy was observed (-1.2%; p < 0.001) at 24 months., Conclusions: Results of the follow-up of patients with first attacks suggestive of MS within a Spanish multi-centre context are wholly comparable with those from international clinical trials performed in these patients.

A relative risk assessment of biosolids disposal alternatives for cruise ships is presented in this paper. The area of study encompasses islands and marine waters of the Caribbean Sea. The objective was to evaluate relative human health and ecological risks of (a) dewatering/incineration, (b) landing the solids for disposal, considering that in some countries land-disposed solids might be discharged in the near-shore environment untreated, and (c) deep ocean disposal. Input to the Bayesian assessment consisted of professional judgment based on available literature and modeling information, data on constituent concentrations in cruise ship biosolids, and simulations of constituent concentrations in Caribbean waters assuming ocean disposal. Results indicate that human health and ecological risks associated with land disposal and shallow ocean disposal are higher than those of the deep ocean disposal and incineration. For incineration, predicted ecological impacts were lower relative to deep ocean disposal before considering potential impacts of carbon emissions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The new insights presented at European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in the city of Gothenburg, Sweden, in October 2010, have been summarized at the third edition of Post-ECTRIMS meeting held in Madrid in November 2010. Encouraging findings from the 5-years follow up extension from PreCISe study confirm the benefit of early treatment with glatiramer acetate in patients with clinically isolated syndromes (CIS) against the conversion to clinically definitive multiple sclerosis and cerebral atrophy with an adequate safety and tolerability. Regarding treatment decision with escalation or induction therapy, different strategies have been proposed depending on to the characteristics of the individual patient with CIS. Findings from several of the reported studies have revealed the favorable role of combined therapy on relapse rate but not on magnetic resonance parameters in patients with recurrent-remittent multiple sclerosis. Novel therapies such as alemtuzumab, daclizumab ofatutumab or ocrelizumab have shown promising findings regarding efficacy. Nevertheless, safety findings for these emerging therapies have detected some severe adverse events, the main ones being potentially fatal opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus, mainly linked to natalizumab treatment. In this regard, clinicians will face the assessment of he benefit-risk ratio when deciding on the adequate treatment for each patient in the clinical setting. In this regard, determination of antibodies to JC virus by a novel two-step enzyme-linked immunosorbent assay (ELISA) could provide clinicians with a useful tool to stratify PML risk in patients. Regarding non pharmacologic therapies, behavioral intervention has emerged as an effective therapy in the treatment of depression in multiple sclerosis, showing additional benefits on fatigue, disability and adherence to treatment.

Introduction: Health-related quality of life (HRQoL) is a complex concept in which evaluation of physical, emotional and social domains of health are included. Since chronic diseases has raised, the importance of HRQoL evaluation has increased, overall in patients with multiple sclerosis (MS) whose HRQoL has shown to be worse than in other chronic diseases., Aim: To review the information available about the HRQoL in patients with MS to provide an overview of the current situation., Development: Previously performed clinical trials identified the main factors related to the HRQoL: physical factors (sensitive/motor deficits, fatigue, pain, sexual/bladder dysfunction), psychological factors (depression, anxiety, cognitive disturbances, coping strategies) and social factors (family/social relationships, work activity). The inclusion of HRQoL questionnaires in the patients' follow-up is a relevant issue to optimize its treatment, making easier treatment decision and improving adherence, as well as to reduce the inconveniences derived from medication such as adverse events., Conclusions: HRQoL evaluation is really complex in patients with MS, being difficult to identify the main domains that impact on HRQoL. However, its regular evaluation provides essential information to improve the symptomatic treatment, increase the adherence to treatment and modify the immunomodulating treatment.

A recent meta-analysis of genome-wide association screens coupled to a replication exercise in a combined US/UK collection led to the identification of 4 single nucleotide polymorphisms (SNPs) in three gene loci, i.e. TNFRSF1A, CD6 and IRF8, as novel risk factors for multiple sclerosis with genome-wide level of significance. In the present study, using a combined all-Spain collection of 2515 MS patients and 2942 healthy controls, we demonstrate significant association of rs17824933 in CD6 (P(CMH)=0.004; OR=1.14; 95% CI 1.04-1.24) and of rs1860545 in TNFRSF1A (P(CMH)=0.001; OR=1.15; 95% CI 1.06-1.25) with MS, while the low-frequency coding non-synonymous SNP rs4149584 in TNFRSF1A displayed a trend for association (P(CMH)=0.062; OR=1.27; 95% CI 0.99-1.63). This data reinforce a generic role for CD6 and TNFRSF1A in susceptibility to MS, extending to populations of southern European ancestry., (Copyright 2010 Elsevier B.V. All rights reserved.)

There cases of paediatric inflammatory myofibroblastic tumours in different locations are presented. This a rare benign disease, that can develop into malignant forms. Clinical features are associated with the location. Fever was the main symptom in all our cases. The symptoms that indicated the location of the tumour were, haematemesis in the first case, and respiratory disease in the third. In the third case our patient was diagnosed with tuberculosis due to mycobacterium avium. All cases had increased CRP, ESR, thrombocytosis and high levels of gamma globulins Surgery is curative if total resection is possible, and the diagnosis is made by histopathology. We would like to emphasise the early development in the second case as this was a 3 months-old infant.

Objectives: To perform a longitudinal study of anthropometric measurements in a cohort of healthy children, and a comparative analysis with one of the most accepted Spanish studies (M. Hernández et al, L. Serra-Majem et al and A. Carrascosa et al)., Material and Methods: Weight, height and body mass index (BMI) at birth and age 1, 2, 3, 4, 6, 8, 10, 12 and 14 years were recorded. The cohort was made up of children born in 1993 and living in Navarre until 2007. The sample consisted of 930 healthy Caucasian children (482 males and 448 females) whose parents were of Spanish origin., Results: Mean values of height, weight and BMI with percent distribution in both sexes are shown. Differences that increased significantly with age were observed when compared to the tables of M. Hernández et al. Height and weight values (50 percentile) for males in Navarre were 5.8 cm and 9.0 kg higher, respectively, and for females 4.2 cm and 3.6 kg higher, respectively, at age 14. Differences were not significant when these data were compared to the tables of L. Serra-Majem and A. Carrascosa., Conclusions: An increase in weight and height is corroborated. Despite the longitudinal design of this study, the data obtained is similar to the current anthropometric measurements of the Spanish paediatric population. This means that a definitive stabilization in growth may have been reached due to the favourable socioeconomic and health conditions.

Aim: To analyse the epidemiological characteristics and the relative distribution of the different types of epilepsy and epileptic syndromes during the first year of life., Patients and Methods: An analysis was performed of the patient records of all patients with epilepsy diagnosed during their first year of life who were submitted to a developmental check-up in the year 2007. The sample consisted of 60 patients (27 boys and 33 girls). Epidemiological and clinical data were collected, together with the findings from complementary examinations. The diagnostic criteria applied were those of the International League Against Epilepsy., Results: The mean age at the time of diagnosis was 6.3 months. The mean follow-up time was 7.6 years. The aetiology was symptomatic in 40 cases (66.7%), cryptogenic in 16 (26.7%) and idiopathic in four cases (6.7%). Neuroimaging tests detected abnormalities in 34 patients (56.7%). West's syndrome (30%), symptomatic focal epilepsies (23.3%) and epilepsies linked to specific syndromes (16.7%) were the epileptic syndromes with the highest prevalence. Learning disabilities were observed in 82.5% of the children., Conclusions: Most epilepsies that present during the first year of life are symptomatic and/or cryptogenic, and are accompanied by psychoneurological impairment and/or resistance to therapy, which condition cognitive disorders that are eligible for specialised psycho-pedagogical intervention.

Reversible posterior leukoencephalopathy syndrome is a clinical-radiological phenomenon associated with headache, vomiting, lethargy, visual disturbances and seizures, concomitant with radiological abnormalities predominantly within posterior cerebral white matter due to cerebral edema. There are multiple triggers as acute hypertension, cancer, hematological disease, renal pathology, red cells transfusions and different drugs. We present two patients with reversible posterior leukoencephalopathy under treatment for acute lymphoblastic leukemia because of the probable association with vinca alkaloids.

Introduction: Neuromyelitis optica is an inflammatory demyelination disease that selectively affects optic nerves and spinal cord. Recently it has been described that the NMO-IgG antibodies, are highly specific for the diagnosis, although they are also present in partial forms of the disease. The antigen responsible for this immune response seems to be aquaporin-4 water channel., Clinical Case: We describe the detection in our laboratory of NMO-IgG antibodies in two patients, one of them with a neuromyelitis optica and the other one with a recurrent myelitis and subclinical involvement of the optic nerve., Conclusions: By using dual immunostaining, confocal microscopy showed that the antibodies of both patients colocalized with that of an anti-aquaporin-4.

Introduction: Lamotrigine (LTG) is a new antiepileptic of habitual use in monotherapy as much in partial epileptic as in generalised, which presents among other adverse effects: slight rashes and less frequently severe rashes such as Stevens-Johnson syndrome and Lyell syndrome or toxic epidermal necrolysis, above all in combination with valproate (VPA)., Clinical Case: A 44-yr-old woman in toxico-alcoholic epileptic treatment with VPA, showed a neutropenia possibly of secondary type which it was intended to change to LTG, following an ascending dose of LTG joined to a descending dose of VPA. In the sixth treatment week, the patient developed an erythematous rash which after a week of solar exposure, presented temperature, general discomfort, and in the head, on the front and back part of the thoracic and upper and lower limbs, erythematous lesions with scabbed areas, loosening epidermis areas with a positive Nikolsky sign and severe mucous membrane involvement, being diagnostic of Lyell syndrome. The lesions got slowly better with serum therapy, antibiotherapy, parenteral corticoids and topical treatments., Conclusions: There is a probability of severe rash associated with lamotrigine which has to be taken into account, and we advise patients to suppress the medication when they present a minimum rash.

Objective: The aim of the present study is to examine the operative technique and results of the treatment of trigeminal neuralgia (TN) by percutaneous microcompression of the trigeminal ganglion (Mullan's technique) in 20 consecutive patients over 3 years., Patients and Methods: The average age of the patients was 63 years. There were 8 men and 12 women. The operative technique is similar to Mullan and Lichtor's original description with some modifications., Results: On average it takes 30 minutes to complete the procedure. On 2 occasions the catheter had to be replaced as the balloon burst without clinical repercussions. Detectable changes were noted in systemic blood pressure and cardiac rhythm in 10 cases. On 17 occasions the radiographic appearance of the balloon was pear-shaped and in the remaining cases it was oval or irregular. Follow-up ranged from 6 months to 3 years. All but 1 patient were initially relieved of pain and it was progressively possible to suspend treatment with carbamazepine. The recurrence rate was 25%. Mean time until recurrence was 18 months. There was no relation between pain location and recurrence. Morbidity: some degree of transient cheek discomfort, herpes simplex perioralis, hypesthesia and masseter weakness were the rule. Meningitis in one case., Conclusions: Early results indicate that Mullan's technique provides a reliable, safe, cheap and effective, with low morbidity and no mortality.