J Castilló

University Hospital Vall d'Hebron, Barcelona, Catalonia, Spain

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Publications (14)60.07 Total impact

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    ABSTRACT: We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.
    Multiple sclerosis (Houndmills, Basingstoke, England). 11/2014;
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    ABSTRACT: Recent studies have suggested a role of the cation channel TRPM4 in mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis (MS). We aimed to extrapolate central nervous system findings to the blood compartment by determining TRPM4 expression in peripheral blood mononuclear cells from 12 healthy controls (HC) and 64 untreated MS patients. TRPM4 mRNA expression levels were comparable between HC and MS patients with primary progressive MS (n=17), secondary progressive MS (n=19), and relapsing-remitting MS during clinical remission (n=21) and relapses (n=7). These findings do not support a role of TRPM4 in the peripheral blood compartment of MS patients.
    Journal of neuroimmunology 06/2013; · 2.84 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Ubiquitin specific peptidase 18 (USP18) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of USP18 in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls. METHODS: Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse-onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non-responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for USP18 and its target ISG15 were performed by real-time polymerase chain reaction. RESULTS: Two USP18 haplotypes were significantly associated with MS, TG and CG. Additional experiments revealed that CG carriers were characterized by lower USP18 gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, AA homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, USP18 expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes. CONCLUSIONS: Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ.
    European Journal of Neurology 05/2013; · 4.16 Impact Factor
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    ABSTRACT: BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.
    Multiple Sclerosis 05/2013; · 4.47 Impact Factor
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    ABSTRACT: BACKGROUND: Sialic acid binding immunoglobulin-like lectins (Siglecs) are cell surface receptors that recognize sialic acids and may attenuate immune responses and reduce inflammation. OBJECTIVE: The purpose of this study was to investigate the role of two members of the Siglec family, SIGLEC1 and SIGLEC7, in the clinical course and disease activity of patients with multiple sclerosis (MS). METHODS: SIGLEC1 and SIGLEC7 expression was determined by flow cytometry in the blood monocytes of 16 healthy controls and 55 untreated MS patients (13 primary progressive MS (PPMS) patients, 13 secondary progressive MS (SPMS) patients and 29 relapsing-remitting MS (RRMS) patients (18 during clinical remission and 11 during relapse)). RESULTS: SIGLEC1 expression by CD14+ monocytes was significantly increased in MS patients compared with controls (p=0.025 for percentage of positive cells; p=0.007 for mean fluorescence intensity (MFI)). Stratification of patients into different clinical forms revealed increased SIGLEC1 expression in patients with progressive forms of the disease, particularly in those with PPMS (p=0.003 for percentage of positive cells and p=0.001 for MFI when compared with controls; p=0.031 for percentage of positive cells when compared with RRMS patients). Both inflammatory and resident monocytes contributed to the increase in SIGLEC1 expression observed in PPMS patients. SIGLEC7 expression was significantly up-regulated in blood monocytes from RRMS during relapse compared with patients during clinical remission (p=0.001 for MFI). CONCLUSIONS: These findings suggest roles for SIGLEC1 in the chronic progressive phases of MS and for SIGLEC7 in acute disease activity.
    Multiple Sclerosis 08/2012; · 4.47 Impact Factor
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    ABSTRACT: Despite the availability of diagnostic criteria, an overlap between neuromyelitis optica (NMO) and multiple sclerosis (MS) exists, particularly in the early stage of the disease. To study the value of NMO-immunoglobulin G (IgG) determination in Caucasian patients with a first demyelinating episode who develop a relapsing form of optic neuritis or myelitis. This study was based on a prospectively acquired cohort of patients regarded as having a clinically isolated syndrome (CIS) at the time of presentation. From this cohort, 2 different groups were selected: group 1 (NMO phenotype), consisting of a first attack involving the optic nerve or the spinal cord, and at least a second event affecting either topography, and group 2 (negative control group), consisting of a first attack involving the brainstem or the cerebral hemispheres and at least 1 relapse in any topography. Group 3 was composed of patients with NMO according to the 2006 revised diagnostic criteria. Serum NMO-IgG was determined by indirect immunofluorescence. A total of 3.1 of the group 1 patients were positive for NMO-IgG in comparison to 3.9% of group 2 and 44.5% of group 3, NMO. One of the positive patients in group 1 evolved to NMO. NMO-IgG determination is crucial in detecting patients who will develop NMO; however, its value as a routine test in cases presenting with symptoms of the type seen in MS is low, and should only be performed in those patients in which the initial diagnosis is not clear.
    Neurology 05/2012; 78(20):1608-11. · 8.30 Impact Factor
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    ABSTRACT:   Therapy for multiple sclerosis (MS) has a partial efficacy, and a significant proportion of treated patients will develop a suboptimal response with first-line disease-modifying drugs (DMD). Therapy switch in patients with MS can be a strategy after a treatment failure. We studied the change in clinical activity after switching of first-line DMD because of a treatment failure.   Relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-beta (IFNB) or glatiramer acetate (GA) were divided into (i) patients without change in DMD, (ii) patients with a change in DMD because of a poor response, and (iii) those with a change in DMD without relation with response. Annualized relapse rate (ARR) and relapse-free proportions were analyzed.   We identified 923 patients with RRMS. Of the 180 who experienced a change because of suboptimal response, 90 switched to another first-line DMT, 38 to mitoxantrone, and 52 to natalizumab. Median ARR in the pre-DMD period on first DMD and second DMD was the following: 1, 1, and 0 for switchers from IFNB to another IFNB (P = 0.0001); 0.67, 1, and 0 for switchers from GA to IFNB (P = 0.01); 1, 1, and 0 for switchers from an IFNB to GA (P = 0.02); 1.1, 1.5, 0.2 for switchers from IFNB or GA to mitoxantrone (P = 0.0001); 0.9, 1, 0 for switchers from IFNB or GA to natalizumab (P = 0.0001).   In patients with RRMS who have a poor response, switch to another DMD may reduce the clinical activity of the disease.
    European Journal of Neurology 01/2012; 19(6):899-904. · 4.16 Impact Factor
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    ABSTRACT: To analyse the safety and effectiveness of natalizumab in the treatment of multiple sclerosis in a real clinical practice setting and according to the approved indications. All patients with multiple sclerosis treated with natalizumab in our centre were evaluated. The clinical and radiological disease activity during the first year of treatment was analyzed in patients who received at least 12 doses of the drug. The data regarding moderate and severe adverse events in the entire study sample was also evaluated. A total of 112 patients were included in the study, of which 110 had been previously treated with other drugs and 76 had received at least 12 doses of natalizumab. In this group, the annualized relapse rate was reduced by 89% compared to the preceding year and 80% of patients were free from relapses after one year of treatment. Nine percent of patients exhibited 3-month confirmed disability progression. At month 12, the mean number of gadolinium-enhancing lesions on brain MRI was decreased by 99% compared to the pre-treatment MRI. During the first year of treatment, 76% of patients remained free from clinical activity and 33% remained free from both clinical and radiological disease activity. Twenty-nine percent of patients had at least one moderate or severe adverse event, which led to treatment discontinuation in 6%. Four percent of patients experienced immediate hypersensitivity reactions. This study suggests that natalizumab is effective in reducing disease activity in patients with relapsing multiple sclerosis and inadequate response to other therapies, with a favorable risk-benefit ratio.
    Revista de neurologia 03/2011; 52(6):321-30. · 1.18 Impact Factor
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    ABSTRACT: Number of baseline lesions has been shown to predict future attacks and disability in clinically isolated syndromes (CIS). To investigate the role of baseline infratentorial lesions in long-term prognosis. Subjects were included in a prospective cohort of patients with CIS. Patients underwent brain MRI within 3 months after CIS onset. Number and location of lesions at baseline were prospectively studied. Retrospective scan analysis was conducted to specifically look at number and location of infratentorial lesions. We analyzed the time to a second attack and to reach EDSS 3.0. We included 246 patients with CIS followed for a median of 7.7 years. Patients with infratentorial lesions had both a higher risk of conversion (71.4% vs 29.6%; hazard ratio [HR] 3.3; 95% confidence interval [CI] 2.2-4.8; p < 0.001) and of developing disability (32.5% vs 12.4%; HR 2.4; 95% CI 1.3-4.3; p = 0.003). Presence of at least one cerebellar lesion was associated with an increased risk of conversion (HR 2.4; 95% CI 1.3-4.5; p = 0.007). Presence of at least one brainstem lesion increased both the risk of conversion (HR 2.9; 95% CI 1.7-5.0; p < 0.001) and disability (HR 2.5; 95% CI 1.1-5.4; p = 0.026). Broken down into number of lesions, the presence of infratentorial lesions increased both the risk of conversion (83% vs 61%) (HR 22.3; 95% CI 9.7-51.1; p < 0.001) and of reaching EDSS 3.0 (40% vs 19%) (HR 3.2; 95% CI 1.3-7.4; p = 0.008) only in patients with 9 or more lesions. Presence of infratentorial lesions increases the risk for disability. Brainstem rather than cerebellar lesions may be responsible for poor prognosis.
    Neurology 11/2010; 75(21):1933-8. · 8.30 Impact Factor
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    ABSTRACT: The role of multimodal evoked potentials (MMEPs) in establishing multiple sclerosis (MS) diagnosis and prognosis has diminished nowadays. The objective of this article is to evaluate whether MMEPs add information to MRI in identifying patients with higher risk of relapse or development of disability after a clinically isolated syndrome (CIS). Patients who underwent visual, somato-sensory and brainstem auditory evoked potentials (EPs) were identified from a cohort of consecutive CIS. Patients also underwent brain MRI within 3 months of first attack. We analysed time to second attack and to Expanded Disability Status Scale (EDSS) score of 3.0 according to number of Barkhof criteria and number of abnormal MMEPs. A complete study was performed in 245 patients who were followed for a mean of 76.4 months (interquartile range: 61 to 96). Seventy-one patients (29%) had the three EPs normal, 115 patients (47%) had one abnormal EP; 40 patients (16%) had two; and 19 patients (8%) had three abnormal EPs. Baseline MRI determined the risk for converting to clinically definite MS and correlated with disability according to previous studies. EPs individually did not modify the risk of conversion or disability. However, the presence of three abnormal EPs increased the risk of reaching moderate disability (hazard ratio 7.0; 1.4-34.9) independently of baseline MRI. In conclusion, in the presence of three abnormal EPs could help identify CIS patients with a higher risk of developing disability, independently of MRI findings. However, the utility of MMEPs is limited by the low percentage of CIS patients having the three abnormal at baseline.
    Multiple Sclerosis 12/2009; 16(1):55-61. · 4.47 Impact Factor
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    ABSTRACT: Recognition of multiple sclerosis (MS) attacks relies mostly on clinical assessment. However, their definition based on McDonald criteria refers mostly to timing and when dealing with clinical features is rather ambiguous: "...of the kind seen in multiple sclerosis." This is heightened in clinically isolated syndromes of the brainstem/cerebellum (CISB), where clinical manifestations can be manifold. This study aimed to describe the clinical features of patients with CISB to improve clinical recognition of patients with brainstem manifestations at the onset of their MS. To this end, we conducted a retrospective analysis of case notes of consecutively recruited patients with CISB assessed within 3 months of symptoms onset. Seventy-five patients were included. Most common brainstem-specific symptoms were: diplopia (68%), facial sensory symptoms (32%) and gait disturbance (31%). Adjusting for follow-up times, total number of symptoms and presence of other brainstem-specific symptoms, only the presence of facial sensory symptoms was predictive of (a lower risk of) conversion to clinically definite (CD) MS (Odds ratio: 0.086; p = 0.007). Neither the total number of brainstem-specific, non brainstem-specific nor the sum of both predicted conversion to CDMS. Results indicate that diplopia, facial sensory symptoms and gait disturbance occur in more than 30% of patients with CISB. Facial sensory symptoms are less associated with conversion to CDMS.
    Journal of Neurology 11/2009; 257(5):742-6. · 3.58 Impact Factor
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    ABSTRACT: Plasma exchange (PE) is used to treat severe episodes of CNS demyelination unresponsive to corticosteroids. Predictors of long-term response are not well known. We retrospectively reviewed the medical records of 41 patients consecutively treated by PE between January 1995 and July 2007. The primary outcome was improvement at 6 months after PE defined as decrease of >or=1 point in the Expanded Disability Status Scale (EDSS) score for patients with EDSS <or=7.5 or 1.5 points with EDSS >or=8.0 or improvement of more than 2 lines in the visual acuity chart for patients with optic neuritis (ON). Twenty-five patients (61%) were women, and the median age was 33 years (range 14-57 years). Twenty-three (56%) had multiple sclerosis, 2 (5%) had clinically isolated syndrome, 2 (5%) had Marburg disease, 7 (17%) had acute disseminated encephalomyelitis, 4 (10%) had neuromyelitis optica, 2 (5%) had idiopathic ON, and 1 (2%) had idiopathic transverse myelitis. The median EDSS score before the attack was 1.0 (range 0-6.5). At PE onset, the median EDSS score was 7.0 (range 3.0-9.5). Sixteen patients (39%) improved at discharge, and 26 (63%) improved at 6 months. In the multivariate analysis, early initiation of PE (odds ratio [OR] 6.29, 95% confidence interval [CI] 1.18-52.96) and improvement at discharge (OR 7.32, 95% CI 1.21-44.38) were significantly associated with response at 6 months. Plasma exchange (PE) was associated with clinical improvement in 63% of patients at 6 months. Early initiation of PE and improvement at discharge were predictors of this response. Twelve patients (48%) who did not improve early did so during follow-up.
    Neurology 09/2009; 73(12):949-53. · 8.30 Impact Factor
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    ABSTRACT: Several criteria for treatment response to interferon beta (IFNbeta) have been proposed, although there is no consensus among different investigators. Hence, the aim of this study was to investigate magnetic resonance imaging (MRI) and clinical predictors of response during the first 12 months of therapy. This is a prospective and longitudinal study of relapsing-remitting multiple sclerosis (RRMS) patients treated with IFNbeta. Patients were classified based on the presence of new lesions on MRI, relapses, confirmed disability increase, or combinations of all these variables after 1 year of therapy. Regression analysis was performed in order to identify variables of response after a follow-up of 3 years. We included 222 RRMS patients. The logistic model demonstrated that only the combination of new active lesions on MRI with the presence of relapses (OR 4.4; 95% CI 1.6-12.5) or disability progression (Odds Ratio (OR) 7.1; 95% Confidence Interval (CI) 1.6-33.9), or both (OR 6.5; 95% CI 1.9-23.4) achieved significant values to identify those patients with a poor outcome. In RRMS patients treated with IFNbeta, the combination of measures of disease activity and the presence of new active lesions on MRI may have a prognostic value for identifying patients with disease activity in the second and third year of therapy.
    Multiple Sclerosis 08/2009; 15(7):848-53. · 4.47 Impact Factor
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    ABSTRACT: Acute disseminated encephalomyelitis (ADEM) is an uncommon disease characterized by inflammation and demyelination of the central nervous system (CNS). It typically occurs after a viral infection or vaccination and is more frequent in children. Its immediate and longterm prognosis is expected to be good (20% of cases with sequelae). Although ADEM is typically monophasic, occasional relapses may occur. Differential diagnosis, mostly in the early phases, is established with multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS that may have worse prognosis. Traditionally it has been believed that 10% of ADEM patients develop MS. However, this percentage could be higher according to several recently published clinical series. Some clinical and paraclinical patterns are considered to confer risk of developing MS when present in ADEM patients. Our study has aimed to: a) describe a series of 29 patients (22 children and 9 adults) admitted in our hospital and diagnosed of ADEM between 1990 and 2005; b) study those patients considered to have risk patterns of developing MS, and c) compare the child and adult populations of our series. After a median 55 month follow-up, 6 children (27%) and no adults developed MS. In our series, risk patterns for developing MS predicted conversion to MS more accurately in children than in adults. Eight patients (6 children and 2 adults) had sequelae, cognitive in 6 of them. Our work supports that also observed in recent publications: that both conversion to MS or presence of sequelae after an episode of ADEM are more frequent than traditionally considered.
    Neurologia (Barcelona, Spain) 10/2008; 23(9):546-54. · 1.35 Impact Factor