PUBLICACIONES

  • Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review.
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    Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review.

    PLoS One. 2017;12(4):e0175538

    Authors: Navas-Madroñal M, Valero-Mut A, Martínez-Zapata MJ, Simón-Talero MJ, Figueroa S, Vidal-Fernández N, López-Góngora M, Escartín A, Querol L

    Abstract
    INTRODUCTION: Antibodies targeting the inward-rectifying potassium channel KIR4.1 have been associated with multiple sclerosis (MS) but studies using diverse techniques have failed to replicate this association. The detection of these antibodies is challenging; KIR4.1 glycosylation patterns and the use of diverse technical approaches may account for the disparity of results. We aimed to replicate the association using three different approaches to overcome the technical limitations of a single technique. We also performed a systematic review to examine the association of anti-KIR4.1 antibodies with MS.
    METHODS: Serum samples from patients with MS (n = 108) and controls (n = 77) were tested for the presence of anti-KIR4.1 antibodies using three methods: 1) by ELISA with the low-glycosylated fraction of recombinant KIR4.1 purified from transfected HEK293 cells according to original protocols; 2) by immunocytochemistry using KIR4.1-transfected HEK293 cells; and 3) by immunocytochemistry using the KIR4.1.-transfected MO3.13 oligodendrocyte cell line. We developed a systematic review and meta-analysis of the association of anti-KIR4.1 antibodies with MS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
    RESULTS: We did not detect anti-KIR4.1 antibodies in the MS patients or in controls using ELISA. Neither did we detect any significant reactivity against the antigen on the cell surface using the KIR4.1-transfected HEK293 cells or the KIR4.1-transfected MO3.13 cells. We included 13 prospective controlled studies in the systematic review. Only three studies showed a positive association between anti-KIR4.1 and MS. Clinical and statistical heterogeneity between studies precluded meta-analysis of their results.
    CONCLUSION: We found no association between anti-KIR4.1 antibody positivity and MS. Although this lack of replication may be due to technical limitations, evidence from our study and others is mounting against the role of KIR4.1 as a relevant MS autoantigen.

    PMID: 28414733

  • Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Related Articles Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Ann Clin Transl Neurol. 2016 Jun;3(6):443-54 Authors: Lee JY, Stathopoulos P, Gupta S, Bannock JM, Barohn R...
  • Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

    Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

    JAMA Neurol. 2016 Jul 5;

    Authors: Cortés-Vicente E, Gallardo E, Martínez MÁ, Díaz-Manera J, Querol L, Rojas-García R, Illa I

    Abstract
    Importance: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG.
    Objective: To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies.
    Design, Setting, and Participants: A retrospective cross-sectional study was conducted at Hospital de la Santa Creu i Sant Pau, an institutional practice referral center in Barcelona, Spain, between May 1, 2015, and November 30, 2015. We included 250 patients with a definitive diagnosis of MG with available serum samples at the time of diagnosis. Descriptive and comparative data analyses were performed.
    Exposures: Cortactin antibodies were measured by enzyme-linked immunosorbent assay and Western blot; AChR, MuSK, and anti-striated muscle antibodies were detected using a standard method; and LRP4 antibodies were tested using a cell-based assay.
    Main Outcomes and Measures: The primary outcome was the frequency of patients with dSNMG who have cortactin antibodies. Secondary outcomes were demographic, clinical, neurophysiological, and laboratory data.
    Results: Of 250 patients (mean years; P = .03); the group with dSNMG and cortactin antibodies also more frequently had ocular MG at onset than those with MG and AChR antibodies, although the difference was not statistically significant (66.7% vs 40.8%; P = .17). Of 17 patients with ocular dSNMG, 4 (23.5%) had antibodies to cortactin.
    Conclusions and Relevance: In this study, patients with cortactin antibodies and dSNMG had an ocular or mild generalized phenotype of MG. Including the detection of cortactin antibodies in the routine diagnosis of dSNMG may be helpful in ocular MG.

    PMID: 27379450

  • Correlation of the patient’s reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.
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    Correlation of the patient's reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

    Eur J Neurol. 2016 Apr 29;

    Authors: Draak TH, Gorson KC, Vanhoutte EK, van Nes SI, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    BACKGROUND AND PURPOSE: There is increasing interest in using patient-reported outcome measures (PROMs) in clinical studies to capture individual changes over time. However, PROMs have also been criticized because they are entirely subjective. Our objective was to examine the relationship between a subjective PROM and an objective outcome tool in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and gammopathy-related polyneuropathy (MGUSP).
    METHODS: The Inflammatory Rasch-built Overall Disability Scale (I-RODS©, a multi-item scale that examines functionality) was completed by 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59) and MGUSP (23) who were serially examined (GBS/CIDP, T0/T1/T3/T6/T12 months; MGUSP, T0/T3/T12). Possible association between the I-RODS findings and the vigorimeter scores, an objective linear instrument to assess grip strength, was examined.
    RESULTS: A significant correlating trend was found between the I-RODS and grip strength scores for the overall group and in each illness, independently.
    CONCLUSION: The objectivity of patients' subjective report on their functional state based on a strong correlation between the I-RODS and grip strength in patients with GBS, CIDP and MGUSP has been demonstrated. These findings provide further support to use the I-RODS and grip strength in future clinical studies in these conditions.

    PMID: 27129110

  • Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Related Articles Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain. 2016 Mar 26; Authors: Manso C, Querol L, Mekaouche M, Illa I, Devaux JJ Abstract Paranodal axogl...
  • Does ability to walk reflect general functionality in inflammatory neuropathies?
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    Does ability to walk reflect general functionality in inflammatory neuropathies?

    J Peripher Nerv Syst. 2016 Mar 10;

    Authors: Draak TH, Gorson KC, Vanhoutte EK, van Nes SI, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    BACKGROUND: The "ability to walk" is considered a benchmark for good clinical recovery and prognosis, particularly in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, it has never been determined whether being "able to walk" represents general functionality.
    OBJECTIVE: To examine whether the ability to walk outside independently reflects general functional improvement in patients with GBS, CIDP, and gammopathy-related neuropathy (MGUSP).
    METHODS: A total of 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59), and MGUSP (23) were serially examined (1-year). Predefined arbitrary cut-offs (so-called patients' Functional-Acceptable-Clinical-Thresholds ) were taken at the 50th, 75th, and 90th percentile of the Inflammatory-Rasch-built-Overall-Disability-Scale (I-RODS(©) ). We determined the proportion of patients able to walk outside independently that reached the postulated cut-offs.
    RESULTS: A mean total of 85%, 39%, and 12% of all patients able to walk reached 50th, 75th, and 90th percentile thresholds, respectively. These findings were not neuropathy type related.
    CONCLUSION: Our findings show that assessing only one construct of functionality (e.g. walking ability) does not reflect the full scope of daily/social functional deficits perceived by patients. The ability to walk shows a patient is doing better, but not necessarily doing well. The I-RODS(©) bypasses these limitations.

    PMID: 26968437

  • [Retinal and brain infarctions secondary to acute carotid thrombosis in ovarian hyperstimulation syndrome].
    Related Articles

    .

    Neurologia. 2008 Jun;23(5):319-21

    Authors: Querol L, Martínez-Corral M, Martí E, Martí-Fábregas J

    Abstract
    INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is an uncommon but potentially life-threatening iatrogenic condition that may appear following ovulation induction in the course of some fertility treatments. This may lead to further complications, some of which may be severe, such as thromboembolic events. Though rarely, it can therefore be a potential cause of stroke.
    CLINICAL CASE: We report the case of a 34-year old woman under ovulation induction treatment who developed retinal and brain infarctions secondary to internal carotid occlusion. Oral anticoagulation was administered and recovery was good in spite of the persistence of carotid occlusion in follow-up magnetic ressonance imaging- angiographies.
    CONCLUSIONS: This is the first case of carotid occlusion following an OHSS reported in Spain and the eighth one published in the literature. Current literature on cerebrovascular complications in OHSS is also briefly reviewed.

    PMID: 18247184

  • PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Related Articles PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. J Autoimmun. 2013 Jun;43:1-9 Authors: Larman HB, Laserson U, Querol L, ...
  • Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.
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    Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.

    Ann Neurol. 2013 Mar;73(3):370-80

    Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J, Suárez-Calvet X, Navas M, Araque J, Gallardo E, Illa I

    Abstract
    OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling.
    METHODS: Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell-based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments.
    RESULTS: Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin-1 (CNTN1), and 1 precipitated both CNTN1 and contactin-associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin.
    INTERPRETATION: Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP.

    PMID: 23280477

  • Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.
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    Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.

    J Peripher Nerv Syst. 2012 Jun;17(2):158-68

    Authors: Rojas-García R, Querol L, Gallardo E, De Luna Salva N, Juarez C, Garces M, Fages E, Casasnovas C, Illa I

    Abstract
    There is as yet no consensus for considering pure acute sensory ataxic neuropathy (ASAN) as a variant of Guillain-Barré syndrome (GBS). Reactivity against gangliosides sharing disialosyl epitopes has been reported in these patients. The aim of this study was to determine the spectrum of reactivity against gangliosides in ASAN and to define the clinical pattern. From our database we identified patients with suspicion of ASAN. We defined ASAN as the presence of ataxia of peripheral origin with loss of proprioception, and areflexia, absence of ophthalmoplegia and no or minimal muscle weakness. Patients who met these criteria were retrospectively reviewed for their spectrum of reactivity against gangliosides and clinical features. We identified 12 patients fulfilling pre-defined criteria for ASAN. Reactivity against gangliosides containing disialosyl epitopes was present in seven patients. Concomitant reactivity against other gangliosides was present in 6/7 patients. All patients presented good prognosis and an antecedent illness was present in nine. Our results support the previously described clinico-immunological association between ASAN and disialosyl specificity, and widen the spectrum of reactivity against gangliosides. The acute presentation with a monophasic course, and good prognosis in all cases, together with transient immunoglobulin G antiganglioside antibodies and infectious antecedent in 7/12 patients support the inclusion of ASAN as a GBS variant.

    PMID: 22734901

  • Long-lasting treatment effect of rituximab in MuSK myasthenia.
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    Long-lasting treatment effect of rituximab in MuSK myasthenia.

    Neurology. 2012 Jan 17;78(3):189-93

    Authors: Díaz-Manera J, Martínez-Hernández E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, Muñoz-Blanco JL, Mazia C, Straasheijm KR, Gallardo E, Juárez C, Verschuuren JJ, Illa I

    Abstract
    OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients.
    METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied.
    RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3.
    CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone.
    CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

    PMID: 22218276

  • Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation.
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    Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation.

    Clin Neurophysiol. 2011 Dec;122(12):2537-9

    Authors: Díaz-Manera J, Querol L, Clarimón J, Yagüe S, Illa I

    PMID: 21640645

  • Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review. Related Articles Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review. Sex Transm Dis. 2010 Feb;37(2):123-5 Authors: Suarez-Cal...
  • Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.
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    Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.

    Biol Blood Marrow Transplant. 2009 Nov;15(11):1439-46

    Authors: Barba P, Piñana JL, Valcárcel D, Querol L, Martino R, Sureda A, Briones J, Delgado J, Brunet S, Sierra J

    Abstract
    Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140 mg/m(2) (n=119), cyclophosphamide (Cy) 120 mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval

  • Blood pressure is not associated with haematoma enlargement in acute intracerebral haemorrhage.
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    Blood pressure is not associated with haematoma enlargement in acute intracerebral haemorrhage.

    Eur J Neurol. 2008 Oct;15(10):1085-90

    Authors: Martí-Fàbregas J, Martínez-Ramírez S, Martínez-Corral M, Díaz-Manera J, Querol L, Suárez-Calvet M, de Juan M, Santaló M, Marín R, Martí-Vilalta JL

    Abstract
    BACKGROUND AND PURPOSE: We performed an observational study that compared baseline and subsequent blood pressure (BP) measurements and its association with haematoma enlargement (HE) in patients with intracerebral haemorrhage (ICH).
    METHODS: We prospectively studied consecutive patients with supratentorial spontaneous ICH within the first 6 h after the onset of symptoms. HE was defined as an increase >or=33% in the volume of haematoma on the CT obtained 24-48 h after the onset of symptoms as compared with the CT at admission. We recorded systolic BP (SBP), diastolic BP (DBP) and mean BP (MBP) at admission and at 6, 12, 18 and 24 h after onset; the maximum SBP, DBP and MBP during the study period; the maximum SBP and DBP within intervals; the mean of all BP readings; administration of antihypertensive agents.
    RESULTS: We studied 60 patients whose mean age was 72.1 +/- 11.3 years. HE was observed in 27 (45%) patients. No statistically significant differences were observed in any of the analyses that compared BP parameters between the HE and non-HE groups (two-way anova).
    CONCLUSIONS: In an exploratory analysis, we did not find an association between BP and HE within the first 24 h after an acute ICH.

    PMID: 18717722

  • Carotid thrombosis after in vitro fertilization: a relatively new thrombotic complication in women.
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    Carotid thrombosis after in vitro fertilization: a relatively new thrombotic complication in women.

    Br J Haematol. 2008 Jun;141(6):897-9

    Authors: Martí E, Santamaría A, Mateo J, Tolosa A, Querol L, Viscasillas P, Fontcuberta J

    PMID: 18355379

  • Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.
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    Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.

    J Hum Genet. 2014 Aug;59(8):465-6

    Authors: Díaz-Manera J, Querol L, Alejaldre A, Rojas-García R, Ramos-Fransi A, Gallardo E, Illa I

    Abstract
    Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by episodes of weakness. Although TPP has been described in patients all over the world, it is especially frequent in Asiatic patients. Recently, two genomewide association studies have found a susceptibility locus on chromosome 17q24.3 near the KCNJ2 gene, which is responsible for another cause of periodic paralysis, the Andersen-Tawil syndrome (ATS). We report the first patient diagnosed with ATS with a de novo c.G899C mutation in the KCNJ2 gene in 2010 who developed an autoimmune hyperthyroidism and TPP in 2013. At the time of the ATS diagnosis other causes of periodic paralysis, including thyroid dysfunction, were ruled out. The condition of the patient, who had mild episodes of proximal weakness at follow-up, deteriorated dramatically in 2013, presenting continuous episodes of severe generalized weakness associated with low levels of potassium requiring frequent admissions to the hospital. After a few months, he also presented signs of hyperthyroidism, and a diagnosis of Grave's disease was made. In our opinion, this case clearly demonstrates that a dysfunction of the Kir2.1 potassium channel encoded by the KCNJ2 gene is a risk factor to develop TPP, and can be a useful tool to identify patients at risk in daily clinics.

    PMID: 24849934

  • Analysis of serum miRNA profiles of myasthenia gravis patients.
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    Analysis of serum miRNA profiles of myasthenia gravis patients.

    PLoS One. 2014;9(3):e91927

    Authors: Nogales-Gadea G, Ramos-Fransi A, Suárez-Calvet X, Navas M, Rojas-García R, Mosquera JL, Díaz-Manera J, Querol L, Gallardo E, Illa I

    Abstract
    Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of autoantibodies, mainly against the acetylcholine receptor (AChR). The mechanisms triggering and maintaining this chronic disease are unknown. MiRNAs are regulatory molecules that play a key role in the immune system and are altered in many autoimmune diseases. The aim of this study was to evaluate miRNA profiles in serum of 61 AChR MG patients. We studied serum from patients with early onset MG (n = 22), late onset MG (n = 27) and thymoma (n = 12), to identify alterations in the specific subgroups. In a discovery cohort, we analysed 381 miRNA arrays from 5 patients from each subgroup, and 5 healthy controls. The 15 patients had not received any treatment. We found 32 miRNAs in different levels in MG and analysed 8 of these in a validation cohort that included 46 of the MG patients. MiR15b, miR122, miR-140-3p, miR185, miR192, miR20b and miR-885-5p were in lower levels in MG patients than in controls. Our study suggests that different clinical phenotypes in MG share common altered mechanisms in circulating miRNAs, with no additional contribution of the thymoma. MG treatment intervention does not modify the profile of these miRNAs. Novel insights into the pathogenesis of MG can be reached by the analysis of circulating miRNAs since some of these miRNAs have also been found low in MG peripheral mononuclear cells, and have targets with important roles in B cell survival and antibody production.

    PMID: 24637658

  • Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.
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    Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.

    J Pathol. 2014 Jul;233(3):258-68

    Authors: Suárez-Calvet X, Gallardo E, Nogales-Gadea G, Querol L, Navas M, Díaz-Manera J, Rojas-Garcia R, Illa I

    Abstract
    We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments(†) using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up-regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid-inducible gene 1 (RIG-I, DDX58) and the novel antiviral factor DDX60, which promotes RIG-I-mediated signalling, were significantly up-regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over-expression of RIG-I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG-I produced a significant secretion of interferon-β (IFNβ; p < 0.05) and up-regulation of class I MHC, RIG-I and TLR3 (p < 0.05) by IFNβ-dependent and TLR3-independent mechanisms. RIG-I-mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM.

    PMID: 24604766

  • Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Related Articles Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology. 2014 Mar 11;82(10):879-86 Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Diaz-Manera ...
  • Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.
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    Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.

    J Biol Chem. 2014 Mar 14;289(11):7907-18

    Authors: Labasque M, Hivert B, Nogales-Gadea G, Querol L, Illa I, Faivre-Sarrailh C

    Abstract
    Cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier and in the rapid propagation of the nerve impulses along myelinated axons. These CAMs are the targets of autoimmunity in inflammatory neuropathies. We recently showed that a subgroup of patients with aggressive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows autoantibodies to contactin (1). The complex of contactin·Caspr·neurofascin-155 (NF155) enables the formation of paranodal junctions, suggesting that antibody attack against paranodes may participate in the severity of CIDP. In the present study, we mapped the molecular determinants of contactin targeted by the autoantibodies. In three patients, immunoreactivity was directed against the Ig domains of contactin and was dependent on N-glycans. The serum of one patient was selectively directed against contactin bearing mannose-rich N-glycans. Strikingly, the oligomannose type sugars of contactin are required for association with its glial partner NF155 (2). To investigate precisely the role of contactin N-glycans, we have mutated each of the nine consensus N-glycosylation sites independently. We found that the mutation of three sites (N467Q/N473Q/N494Q) in Ig domain 5 of contactin prevented soluble NF155-Fc binding. In contrast, these mutations did not abolish cis-association with Caspr. Next, we showed that the cluster of N-glycosylation sites (Asn-467, Asn-473, and Asn-494) was required for immunoreactivity in one patient. Using cell aggregation assays, we showed that the IgGs from the four CIDP patients prevented adhesive interaction between contactin·Caspr and NF155. Importantly, we showed that the anti-contactin autoantibodies induced alteration of paranodal junctions in myelinated neuronal culture. These results strongly suggest that antibodies to CAMs may be pathogenic and induce demyelination via functional blocking activity.

    PMID: 24497634

  • Endothelial progenitor cells in acute ischemic stroke.
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    Endothelial progenitor cells in acute ischemic stroke.

    Brain Behav. 2013 Nov;3(6):649-55

    Authors: Martí-Fàbregas J, Crespo J, Delgado-Mederos R, Martínez-Ramírez S, Peña E, Marín R, Dinia L, Jiménez-Xarrié E, Fernández-Arcos A, Pérez-Pérez J, Querol L, Suárez-Calvet M, Badimon L

    Abstract
    OBJECTIVES: The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points.
    MATERIAL AND METHODS: We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0-2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry.
    RESULTS: We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large-artery atherosclerosis and small-vessel disease etiologic subtypes.
    CONCLUSIONS: After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large-artery atherosclerosis and small-vessel disease subtypes, higher counts were related to better outcome at 3 months.

    PMID: 24363968

  • Myasthenia gravis and the neuromuscular junction. Related Articles Myasthenia gravis and the neuromuscular junction. Curr Opin Neurol. 2013 Oct;26(5):459-65 Authors: Querol L, Illa I Abstract PURPOSE OF REVIEW: Myasthenic disorders are a well chara...
  • Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Related Articles Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology. 2013 Sep 10;81(11):956-63 Authors: Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Haf...
  • 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands. Related Articles 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands. Neuromuscul Disord. 2013 Nov;23(11):924-33 Authors: Vanhou...
  • Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.
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    Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.

    Muscle Nerve. 2013 Dec;48(6):870-6

    Authors: Querol L, Rojas-Garcia R, Casasnovas C, Sedano MJ, Muñoz-Blanco JL, Alberti MA, Paradas C, Sevilla T, Pardo J, Capablo JL, Sivera R, Guerrero A, Gutierrez-Rivas E, Illa I

    Abstract
    INTRODUCTION: The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
    METHODS: Response to therapy was defined as an improvement of ≥ 1 point on the modified Rankin score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder.
    RESULTS: Eighty-six patients were included; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up.
    CONCLUSIONS: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment.

    PMID: 23512566

  • Outcome measures in MMN revisited: further improvement needed.
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    Outcome measures in MMN revisited: further improvement needed.

    J Peripher Nerv Syst. 2015 Sep;20(3):306-18

    Authors: Pruppers MH, Draak TH, Vanhoutte EK, Van der Pol WL, Gorson KC, Léger JM, Nobile-Orazio E, Lewis RA, van den Berg LH, Faber CG, Merkies IS, PeriNomS study group

    Abstract
    The objectives of this study were to provide an overview of the outcome measures (OMs) applied in clinical trials in multifocal motor neuropathy (MMN) and to determine the responsiveness of a core set of selected OMs as part of the peripheral neuropathy outcome measures standardization (PeriNomS) study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous immunoglobulin (assessments: T0/T3/T12 months): 14 muscle pairs MRC (Medical Research Council) scale, the Neuropathy Impairment Scale motor-subset, a self-evaluation scale, grip strength, and MMN-RODS© (Rasch-built overall disability scale). All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (½ × SD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both the identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual SE (responder definition: MCID-SE ≥ 1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in one fourth to one third of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MMN.

    PMID: 26115442

  • Rasch-ionale for neurologists. Related Articles Rasch-ionale for neurologists. J Peripher Nerv Syst. 2015 Sep;20(3):260-8 Authors: Vanhoutte EK, Hermans MC, Faber CG, Gorson KC, Merkies IS, Thonnard JL, PeriNomS Study Group Abstract ...
  • Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.
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    Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.

    J Peripher Nerv Syst. 2015 Sep;20(3):289-95

    Authors: Vanhoutte EK, Draak TH, Gorson KC, van Nes SI, Hoeijmakers JG, Van der Pol WL, Notermans NC, Lewis RA, Nobile-Orazio E, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, Hahn AF, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

    PMID: 26114893

  • Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.
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    Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.

    J Peripher Nerv Syst. 2015 Sep;20(3):277-88

    Authors: Draak TH, Vanhoutte EK, van Nes SI, Gorson KC, Van der Pol WL, Notermans NC, Nobile-Orazio E, Lewis RA, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, Hahn AF, van den Berg LH, van Doorn PA, Cornblath DR, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.

    PMID: 26110493

  • The expanding field of IgG4-mediated neurological autoimmune disorders. Related Articles The expanding field of IgG4-mediated neurological autoimmune disorders. Eur J Neurol. 2015 Aug;22(8):1151-61 Authors: Huijbers MG, Querol LA, Niks EH, Plomp JJ, van der Maarel SM, Graus F, Dalmau J...
  • Balo concentric sclerosis: A presentation mimicking ischaemic stroke.
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    Balo concentric sclerosis: A presentation mimicking ischaemic stroke.

    Neurologia. 2015 May 11;

    Authors: Aracil-Bolaños I, Prats-Sánchez L, Gómez-Ansón B, Querol-Gutiérrez L, Núñez-Marín F, Martí-Fàbregas J

    PMID: 25976947

  • A one-year follow-up study of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting multiple sclerosis: an appraisal of comparative longitudinal sensitivity.
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    A one-year follow-up study of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting multiple sclerosis: an appraisal of comparative longitudinal sensitivity.

    BMC Neurol. 2015;15:40

    Authors: López-Góngora M, Querol L, Escartín A

    Abstract
    BACKGROUND: Neuropsychological batteries are infrequently used to assess cognitive impairment in multiple sclerosis because they are time-consuming and require trained personnel. The Symbol Digit Modalities Test (SDMT) is suggested to be a useful screening tool to measure cognitive impairment in multiple sclerosis patients and is more valid and reliable over time than the Paced Auditory Serial Addition Test (PASAT). The purpose of this study was to evaluate which of these tests was more sensitive to cognitive impairment at one-year follow-up.
    METHODS: A total of 237 patients with relapsing-remitting multiple sclerosis and 57 healthy controls underwent a complete neuropsychological assessment. One year later, we assessed 196 patients using the Brief Repeatable Battery of Neuropsychological Tests. We also administered other executive function and prospective memory tests, together with fatigue and depression questionnaires.
    RESULTS: A total of 33.8% of patients were classified as cognitively impaired. The SDMT and the PASAT 3 seconds test (PASAT3) had a sensitivity of 0.809 and 0.783, respectively, thereby classifying patients as cognitively impaired. Analysis of 196 patients one year later showed 31.6% had cognitive impairment compared with 27.6% at the first assessment. The sensitivity to detect cognitive impairment after one year was 0.824 for SDMT and 0.796 for PASAT3. When the predictors were removed from the comparative standard battery, SDMT still showed a slightly higher sensitivity. Both SDMT and PASAT3 correlated significantly with all tests, but SDMT showed higher correlation values. Furthermore, SDMT was completed by all subjects while PASAT3 was completed by 86.9% of patients and 94.7% of controls.
    CONCLUSIONS: SDMT is simpler to administer than PASAT3 and may be slightly more sensitive to MS cognitive impairment. It could thus be a suitable test to assess cognitive impairment routinely in people with relapsing-remitting multiple sclerosis.

    PMID: 25886168

  • Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry.
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    Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry.

    Eur J Neurol. 2015 Jul;22(7):1056-61

    Authors: Ramos-Fransi A, Rojas-García R, Segovia S, Márquez-Infante C, Pardo J, Coll-Cantí J, Jericó I, Illa I, Myasthenia NMD-ES Study Group

    Abstract
    BACKGROUND AND PURPOSE: Myasthenia gravis (MG) may become life-threatening if patients have respiratory insufficiency or dysphagia. This study aimed to determine the incidence, demographic characteristics, risk factors, response to treatment and outcome of these life-threatening events (LTEs) in a recent, population-based sample of MG patients.
    METHODS: A retrospective analysis of MG patients who presented with an LTE between 2000 and 2013 was performed. Participants were identified from a neuromuscular diseases registry in Spain that includes 648 patients with MG (NMD-ES).
    RESULTS: Sixty-two (9.56%) patients had an LTE. Thirty-two were classified as class V according to the MG Foundation of America, and 30 as class IVB. Fifty per cent were previously diagnosed with MG and median duration of the disease before the LTE was 24 months (3-406). The most common related factor was infection (n = 18). All patients received intravenous human immunoglobulin; 11 had a second infusion and six had plasma exchange. Median time to feeding tube removal was 13 days (1-434). Median time to weaning from ventilation was 12 days (3-176), and it was significantly shorter in late onset MG (≥50 years) (P = 0.019). LTEs improved <2 weeks in 55.8% but did not improve until after 1 month in 20% of patients. Four patients died. No other factors influenced mortality or duration of LTEs.
    CONCLUSIONS: The percentage of LTEs in MG patients was low, particularly amongst those previously diagnosed and treated for the disease. The significant percentage of treatment-resistant LTEs indicates that more effective treatment approaches are needed for this vulnerable sub-population.

    PMID: 25847221

  • Cortactin autoantibodies in myasthenia gravis.
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    Cortactin autoantibodies in myasthenia gravis.

    Autoimmun Rev. 2014 Oct;13(10):1003-7

    Authors: Gallardo E, Martínez-Hernández E, Titulaer MJ, Huijbers MG, Martínez MA, Ramos A, Querol L, Díaz-Manera J, Rojas-García R, Hayworth CR, Verschuuren JJ, Balice-Gordon R, Dalmau J, Illa I

    Abstract
    Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5.2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggests an underlying autoimmune mechanism, supporting the use of immune therapy.

    PMID: 25193850

  • [Toxic demyelinating neuropathy and leukoencephalopathy in patients who take the slimming products Thermatrim ® and Pura Alegria ®].
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    .

    Rev Neurol. 2015 Dec 1;61(11):527-8

    Authors: Osuna MT, Querol L, Olivas-Chacon CI, Lejarreta-Andres S, Robert J, Ailouti-Caballero N, Ramos-Duran L, Diaz-Manera J, Belvis R

    PMID: 26602810

  • Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.
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    Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.

    Neurol Neuroimmunol Neuroinflamm. 2015 Oct;2(5):e149

    Authors: Querol L, Rojas-García R, Diaz-Manera J, Barcena J, Pardo J, Ortega-Moreno A, Sedano MJ, Seró-Ballesteros L, Carvajal A, Ortiz N, Gallardo E, Illa I

    Abstract
    OBJECTIVE: To describe the response to rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against paranodal proteins and correlate the response with autoantibody titers.
    METHODS: Patients with CIDP and IgG4 anti-contactin-1 (CNTN1) or anti-neurofascin-155 (NF155) antibodies who were resistant to IV immunoglobulin and corticosteroids were treated with rituximab and followed prospectively. Immunocytochemistry was used to detect anti-CNTN1 and anti-NF155 antibodies and ELISA with human recombinant CNTN1 and NF155 proteins was used to determine antibody titers.
    RESULTS: Two patients had a marked improvement; another patient improved slightly after 10 years of stable, severe disease; and the fourth patient had an ischemic stroke unrelated to treatment and was lost to follow-up. Autoantibodies decreased in all patients after rituximab treatment.
    CONCLUSIONS: Rituximab treatment is an option for patients with CIDP with IgG4 anti-CNTN1/NF155 antibodies who are resistant to conventional therapies.
    CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is effective for patients with treatment-resistant CIDP with IgG4 anti-CNTN1 or anti-NF155 antibodies.

    PMID: 26401517

  • Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) ).
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    Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) ).

    J Peripher Nerv Syst. 2015 Sep;20(3):296-305

    Authors: Vanhoutte EK, Faber CG, van Nes SI, Cats EA, Van der Pol WL, Gorson KC, van Doorn PA, Cornblath DR, van den Berg LH, Merkies IS, PeriNomS Study Group

    Abstract
    Clinical trials in multifocal motor neuropathy (MMN) have often used ordinal-based measures that may not accurately capture changes. We aimed to construct a disability interval outcome measure specifically for MMN using the Rasch model and to examine its clinimetric properties. A total of 146 preliminary activity and participation items were assessed twice (reliability studies) in 96 clinically stable MMN patients. These patients also assessed the ordinal-based overall disability sum score (construct, sample-dependent validity). The final Rasch-built overall disability scale for MMN (MMN-RODS(©) ) was serially applied in 26 patients with newly diagnosed or relapsing MMN, treated with intravenous immunoglobulin (IVIg) (1-year follow-up; responsiveness study). The magnitude of change for each patient was calculated using the minimum clinically important difference technique related to the individually obtained standard errors. A total of 121 items not fulfilling Rasch requirements were removed. The final 25-item MMN-RODS(©) fulfilled all Rasch model's expectations and showed acceptable reliability and validity including good discriminatory capacity. Most serially examined patients improved, but its magnitude was low, reflecting poor responsiveness. The constructed MMN-RODS(©) is a disease-specific, interval measure to detect activity limitations in patients with MMN and overcomes the shortcomings of ordinal scales. However, future clinimetric studies are needed to improve the MMN-RODS(©) 's responsiveness by longer observations and/or more rigorous treatment regimens.

    PMID: 26329270

  • Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis.
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    Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis.

    PLoS One. 2015;10(8):e0136786

    Authors: López-Góngora M, Escartín A, Martínez-Horta S, Fernández-Bobadilla R, Querol L, Romero S, Mañanas MÀ, Riba J

    Abstract
    Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes.

    PMID: 26322632

  • Paranodal and other autoantibodies in chronic inflammatory neuropathies. Related Articles Paranodal and other autoantibodies in chronic inflammatory neuropathies. Curr Opin Neurol. 2015 Oct;28(5):474-9 Authors: Querol L, Illa I Abstract PURPOSE OF REVIEW: Autoimmune diso...
  • Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.
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    Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.

    J Peripher Nerv Syst. 2015 Sep;20(3):269-76

    Authors: Draak TH, Pruppers MH, van Nes SI, Vanhoutte EK, Bakkers M, Gorson KC, Van der Pol WL, Lewis RA, Notermans NC, Nobile-Orazio E, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, van den Berg LH, van Doorn PA, Cornblath DR, Hahn AF, Faber CG, Merkies IS, PeriNomS study group

    Abstract
    The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar

  • [Toxic demyelinating neuropathy and leukoencephalopathy in patients who take the slimming products Thermatrim ® and Pura Alegria ®].
    Related Articles

    .

    Rev Neurol. 2015 Dec 1;61(11):527-8

    Authors: Osuna MT, Querol L, Olivas-Chacon CI, Lejarreta-Andres S, Robert J, Ailouti-Caballero N, Ramos-Duran L, Diaz-Manera J, Belvis R

    PMID: 26602810

  • Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.
    Related Articles

    Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.

    Neurol Neuroimmunol Neuroinflamm. 2015 Oct;2(5):e149

    Authors: Querol L, Rojas-García R, Diaz-Manera J, Barcena J, Pardo J, Ortega-Moreno A, Sedano MJ, Seró-Ballesteros L, Carvajal A, Ortiz N, Gallardo E, Illa I

    Abstract
    OBJECTIVE: To describe the response to rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against paranodal proteins and correlate the response with autoantibody titers.
    METHODS: Patients with CIDP and IgG4 anti-contactin-1 (CNTN1) or anti-neurofascin-155 (NF155) antibodies who were resistant to IV immunoglobulin and corticosteroids were treated with rituximab and followed prospectively. Immunocytochemistry was used to detect anti-CNTN1 and anti-NF155 antibodies and ELISA with human recombinant CNTN1 and NF155 proteins was used to determine antibody titers.
    RESULTS: Two patients had a marked improvement; another patient improved slightly after 10 years of stable, severe disease; and the fourth patient had an ischemic stroke unrelated to treatment and was lost to follow-up. Autoantibodies decreased in all patients after rituximab treatment.
    CONCLUSIONS: Rituximab treatment is an option for patients with CIDP with IgG4 anti-CNTN1/NF155 antibodies who are resistant to conventional therapies.
    CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is effective for patients with treatment-resistant CIDP with IgG4 anti-CNTN1 or anti-NF155 antibodies.

    PMID: 26401517

  • Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) ).
    Related Articles

    Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) ).

    J Peripher Nerv Syst. 2015 Sep;20(3):296-305

    Authors: Vanhoutte EK, Faber CG, van Nes SI, Cats EA, Van der Pol WL, Gorson KC, van Doorn PA, Cornblath DR, van den Berg LH, Merkies IS, PeriNomS Study Group

    Abstract
    Clinical trials in multifocal motor neuropathy (MMN) have often used ordinal-based measures that may not accurately capture changes. We aimed to construct a disability interval outcome measure specifically for MMN using the Rasch model and to examine its clinimetric properties. A total of 146 preliminary activity and participation items were assessed twice (reliability studies) in 96 clinically stable MMN patients. These patients also assessed the ordinal-based overall disability sum score (construct, sample-dependent validity). The final Rasch-built overall disability scale for MMN (MMN-RODS(©) ) was serially applied in 26 patients with newly diagnosed or relapsing MMN, treated with intravenous immunoglobulin (IVIg) (1-year follow-up; responsiveness study). The magnitude of change for each patient was calculated using the minimum clinically important difference technique related to the individually obtained standard errors. A total of 121 items not fulfilling Rasch requirements were removed. The final 25-item MMN-RODS(©) fulfilled all Rasch model's expectations and showed acceptable reliability and validity including good discriminatory capacity. Most serially examined patients improved, but its magnitude was low, reflecting poor responsiveness. The constructed MMN-RODS(©) is a disease-specific, interval measure to detect activity limitations in patients with MMN and overcomes the shortcomings of ordinal scales. However, future clinimetric studies are needed to improve the MMN-RODS(©) 's responsiveness by longer observations and/or more rigorous treatment regimens.

    PMID: 26329270

  • Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis.
    Related Articles

    Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis.

    PLoS One. 2015;10(8):e0136786

    Authors: López-Góngora M, Escartín A, Martínez-Horta S, Fernández-Bobadilla R, Querol L, Romero S, Mañanas MÀ, Riba J

    Abstract
    Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes.

    PMID: 26322632

  • Paranodal and other autoantibodies in chronic inflammatory neuropathies. Related Articles Paranodal and other autoantibodies in chronic inflammatory neuropathies. Curr Opin Neurol. 2015 Oct;28(5):474-9 Authors: Querol L, Illa I Abstract PURPOSE OF REVIEW: Autoimmune diso...
  • Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.
    Related Articles

    Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar.

    J Peripher Nerv Syst. 2015 Sep;20(3):269-76

    Authors: Draak TH, Pruppers MH, van Nes SI, Vanhoutte EK, Bakkers M, Gorson KC, Van der Pol WL, Lewis RA, Notermans NC, Nobile-Orazio E, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, van den Berg LH, van Doorn PA, Cornblath DR, Hahn AF, Faber CG, Merkies IS, PeriNomS study group

    Abstract
    The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar

  • Outcome measures in MMN revisited: further improvement needed.
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    Outcome measures in MMN revisited: further improvement needed.

    J Peripher Nerv Syst. 2015 Sep;20(3):306-18

    Authors: Pruppers MH, Draak TH, Vanhoutte EK, Van der Pol WL, Gorson KC, Léger JM, Nobile-Orazio E, Lewis RA, van den Berg LH, Faber CG, Merkies IS, PeriNomS study group

    Abstract
    The objectives of this study were to provide an overview of the outcome measures (OMs) applied in clinical trials in multifocal motor neuropathy (MMN) and to determine the responsiveness of a core set of selected OMs as part of the peripheral neuropathy outcome measures standardization (PeriNomS) study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous immunoglobulin (assessments: T0/T3/T12 months): 14 muscle pairs MRC (Medical Research Council) scale, the Neuropathy Impairment Scale motor-subset, a self-evaluation scale, grip strength, and MMN-RODS© (Rasch-built overall disability scale). All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (½ × SD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both the identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual SE (responder definition: MCID-SE ≥ 1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in one fourth to one third of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MMN.

    PMID: 26115442

  • Rasch-ionale for neurologists. Related Articles Rasch-ionale for neurologists. J Peripher Nerv Syst. 2015 Sep;20(3):260-8 Authors: Vanhoutte EK, Hermans MC, Faber CG, Gorson KC, Merkies IS, Thonnard JL, PeriNomS Study Group Abstract ...
  • Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.
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    Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison.

    J Peripher Nerv Syst. 2015 Sep;20(3):289-95

    Authors: Vanhoutte EK, Draak TH, Gorson KC, van Nes SI, Hoeijmakers JG, Van der Pol WL, Notermans NC, Lewis RA, Nobile-Orazio E, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, Hahn AF, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

    PMID: 26114893

  • Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.
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    Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses.

    J Peripher Nerv Syst. 2015 Sep;20(3):277-88

    Authors: Draak TH, Vanhoutte EK, van Nes SI, Gorson KC, Van der Pol WL, Notermans NC, Nobile-Orazio E, Lewis RA, Léger JM, Van den Bergh PY, Lauria G, Bril V, Katzberg H, Lunn MP, Pouget J, van der Kooi AJ, Hahn AF, van den Berg LH, van Doorn PA, Cornblath DR, Faber CG, Merkies IS, PeriNomS Study Group

    Abstract
    We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.

    PMID: 26110493

  • The expanding field of IgG4-mediated neurological autoimmune disorders. Related Articles The expanding field of IgG4-mediated neurological autoimmune disorders. Eur J Neurol. 2015 Aug;22(8):1151-61 Authors: Huijbers MG, Querol LA, Niks EH, Plomp JJ, van der Maarel SM, Graus F, Dalmau J...
  • Balo concentric sclerosis: A presentation mimicking ischaemic stroke.
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    Balo concentric sclerosis: A presentation mimicking ischaemic stroke.

    Neurologia. 2015 May 11;

    Authors: Aracil-Bolaños I, Prats-Sánchez L, Gómez-Ansón B, Querol-Gutiérrez L, Núñez-Marín F, Martí-Fàbregas J

    PMID: 25976947

  • A one-year follow-up study of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting multiple sclerosis: an appraisal of comparative longitudinal sensitivity.
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    A one-year follow-up study of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting multiple sclerosis: an appraisal of comparative longitudinal sensitivity.

    BMC Neurol. 2015;15:40

    Authors: López-Góngora M, Querol L, Escartín A

    Abstract
    BACKGROUND: Neuropsychological batteries are infrequently used to assess cognitive impairment in multiple sclerosis because they are time-consuming and require trained personnel. The Symbol Digit Modalities Test (SDMT) is suggested to be a useful screening tool to measure cognitive impairment in multiple sclerosis patients and is more valid and reliable over time than the Paced Auditory Serial Addition Test (PASAT). The purpose of this study was to evaluate which of these tests was more sensitive to cognitive impairment at one-year follow-up.
    METHODS: A total of 237 patients with relapsing-remitting multiple sclerosis and 57 healthy controls underwent a complete neuropsychological assessment. One year later, we assessed 196 patients using the Brief Repeatable Battery of Neuropsychological Tests. We also administered other executive function and prospective memory tests, together with fatigue and depression questionnaires.
    RESULTS: A total of 33.8% of patients were classified as cognitively impaired. The SDMT and the PASAT 3 seconds test (PASAT3) had a sensitivity of 0.809 and 0.783, respectively, thereby classifying patients as cognitively impaired. Analysis of 196 patients one year later showed 31.6% had cognitive impairment compared with 27.6% at the first assessment. The sensitivity to detect cognitive impairment after one year was 0.824 for SDMT and 0.796 for PASAT3. When the predictors were removed from the comparative standard battery, SDMT still showed a slightly higher sensitivity. Both SDMT and PASAT3 correlated significantly with all tests, but SDMT showed higher correlation values. Furthermore, SDMT was completed by all subjects while PASAT3 was completed by 86.9% of patients and 94.7% of controls.
    CONCLUSIONS: SDMT is simpler to administer than PASAT3 and may be slightly more sensitive to MS cognitive impairment. It could thus be a suitable test to assess cognitive impairment routinely in people with relapsing-remitting multiple sclerosis.

    PMID: 25886168

  • Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry.
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    Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry.

    Eur J Neurol. 2015 Jul;22(7):1056-61

    Authors: Ramos-Fransi A, Rojas-García R, Segovia S, Márquez-Infante C, Pardo J, Coll-Cantí J, Jericó I, Illa I, Myasthenia NMD-ES Study Group

    Abstract
    BACKGROUND AND PURPOSE: Myasthenia gravis (MG) may become life-threatening if patients have respiratory insufficiency or dysphagia. This study aimed to determine the incidence, demographic characteristics, risk factors, response to treatment and outcome of these life-threatening events (LTEs) in a recent, population-based sample of MG patients.
    METHODS: A retrospective analysis of MG patients who presented with an LTE between 2000 and 2013 was performed. Participants were identified from a neuromuscular diseases registry in Spain that includes 648 patients with MG (NMD-ES).
    RESULTS: Sixty-two (9.56%) patients had an LTE. Thirty-two were classified as class V according to the MG Foundation of America, and 30 as class IVB. Fifty per cent were previously diagnosed with MG and median duration of the disease before the LTE was 24 months (3-406). The most common related factor was infection (n = 18). All patients received intravenous human immunoglobulin; 11 had a second infusion and six had plasma exchange. Median time to feeding tube removal was 13 days (1-434). Median time to weaning from ventilation was 12 days (3-176), and it was significantly shorter in late onset MG (≥50 years) (P = 0.019). LTEs improved <2 weeks in 55.8% but did not improve until after 1 month in 20% of patients. Four patients died. No other factors influenced mortality or duration of LTEs.
    CONCLUSIONS: The percentage of LTEs in MG patients was low, particularly amongst those previously diagnosed and treated for the disease. The significant percentage of treatment-resistant LTEs indicates that more effective treatment approaches are needed for this vulnerable sub-population.

    PMID: 25847221

  • Cortactin autoantibodies in myasthenia gravis.
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    Cortactin autoantibodies in myasthenia gravis.

    Autoimmun Rev. 2014 Oct;13(10):1003-7

    Authors: Gallardo E, Martínez-Hernández E, Titulaer MJ, Huijbers MG, Martínez MA, Ramos A, Querol L, Díaz-Manera J, Rojas-García R, Hayworth CR, Verschuuren JJ, Balice-Gordon R, Dalmau J, Illa I

    Abstract
    Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5.2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggests an underlying autoimmune mechanism, supporting the use of immune therapy.

    PMID: 25193850

  • Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.
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    Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.

    J Hum Genet. 2014 Aug;59(8):465-6

    Authors: Díaz-Manera J, Querol L, Alejaldre A, Rojas-García R, Ramos-Fransi A, Gallardo E, Illa I

    Abstract
    Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by episodes of weakness. Although TPP has been described in patients all over the world, it is especially frequent in Asiatic patients. Recently, two genomewide association studies have found a susceptibility locus on chromosome 17q24.3 near the KCNJ2 gene, which is responsible for another cause of periodic paralysis, the Andersen-Tawil syndrome (ATS). We report the first patient diagnosed with ATS with a de novo c.G899C mutation in the KCNJ2 gene in 2010 who developed an autoimmune hyperthyroidism and TPP in 2013. At the time of the ATS diagnosis other causes of periodic paralysis, including thyroid dysfunction, were ruled out. The condition of the patient, who had mild episodes of proximal weakness at follow-up, deteriorated dramatically in 2013, presenting continuous episodes of severe generalized weakness associated with low levels of potassium requiring frequent admissions to the hospital. After a few months, he also presented signs of hyperthyroidism, and a diagnosis of Grave's disease was made. In our opinion, this case clearly demonstrates that a dysfunction of the Kir2.1 potassium channel encoded by the KCNJ2 gene is a risk factor to develop TPP, and can be a useful tool to identify patients at risk in daily clinics.

    PMID: 24849934

  • Analysis of serum miRNA profiles of myasthenia gravis patients.
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    Analysis of serum miRNA profiles of myasthenia gravis patients.

    PLoS One. 2014;9(3):e91927

    Authors: Nogales-Gadea G, Ramos-Fransi A, Suárez-Calvet X, Navas M, Rojas-García R, Mosquera JL, Díaz-Manera J, Querol L, Gallardo E, Illa I

    Abstract
    Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of autoantibodies, mainly against the acetylcholine receptor (AChR). The mechanisms triggering and maintaining this chronic disease are unknown. MiRNAs are regulatory molecules that play a key role in the immune system and are altered in many autoimmune diseases. The aim of this study was to evaluate miRNA profiles in serum of 61 AChR MG patients. We studied serum from patients with early onset MG (n = 22), late onset MG (n = 27) and thymoma (n = 12), to identify alterations in the specific subgroups. In a discovery cohort, we analysed 381 miRNA arrays from 5 patients from each subgroup, and 5 healthy controls. The 15 patients had not received any treatment. We found 32 miRNAs in different levels in MG and analysed 8 of these in a validation cohort that included 46 of the MG patients. MiR15b, miR122, miR-140-3p, miR185, miR192, miR20b and miR-885-5p were in lower levels in MG patients than in controls. Our study suggests that different clinical phenotypes in MG share common altered mechanisms in circulating miRNAs, with no additional contribution of the thymoma. MG treatment intervention does not modify the profile of these miRNAs. Novel insights into the pathogenesis of MG can be reached by the analysis of circulating miRNAs since some of these miRNAs have also been found low in MG peripheral mononuclear cells, and have targets with important roles in B cell survival and antibody production.

    PMID: 24637658

  • Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.
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    Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.

    J Pathol. 2014 Jul;233(3):258-68

    Authors: Suárez-Calvet X, Gallardo E, Nogales-Gadea G, Querol L, Navas M, Díaz-Manera J, Rojas-Garcia R, Illa I

    Abstract
    We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments(†) using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up-regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid-inducible gene 1 (RIG-I, DDX58) and the novel antiviral factor DDX60, which promotes RIG-I-mediated signalling, were significantly up-regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over-expression of RIG-I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG-I produced a significant secretion of interferon-β (IFNβ; p < 0.05) and up-regulation of class I MHC, RIG-I and TLR3 (p < 0.05) by IFNβ-dependent and TLR3-independent mechanisms. RIG-I-mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM.

    PMID: 24604766

  • Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Related Articles Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology. 2014 Mar 11;82(10):879-86 Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Diaz-Manera ...
  • Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.
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    Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.

    J Biol Chem. 2014 Mar 14;289(11):7907-18

    Authors: Labasque M, Hivert B, Nogales-Gadea G, Querol L, Illa I, Faivre-Sarrailh C

    Abstract
    Cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier and in the rapid propagation of the nerve impulses along myelinated axons. These CAMs are the targets of autoimmunity in inflammatory neuropathies. We recently showed that a subgroup of patients with aggressive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows autoantibodies to contactin (1). The complex of contactin·Caspr·neurofascin-155 (NF155) enables the formation of paranodal junctions, suggesting that antibody attack against paranodes may participate in the severity of CIDP. In the present study, we mapped the molecular determinants of contactin targeted by the autoantibodies. In three patients, immunoreactivity was directed against the Ig domains of contactin and was dependent on N-glycans. The serum of one patient was selectively directed against contactin bearing mannose-rich N-glycans. Strikingly, the oligomannose type sugars of contactin are required for association with its glial partner NF155 (2). To investigate precisely the role of contactin N-glycans, we have mutated each of the nine consensus N-glycosylation sites independently. We found that the mutation of three sites (N467Q/N473Q/N494Q) in Ig domain 5 of contactin prevented soluble NF155-Fc binding. In contrast, these mutations did not abolish cis-association with Caspr. Next, we showed that the cluster of N-glycosylation sites (Asn-467, Asn-473, and Asn-494) was required for immunoreactivity in one patient. Using cell aggregation assays, we showed that the IgGs from the four CIDP patients prevented adhesive interaction between contactin·Caspr and NF155. Importantly, we showed that the anti-contactin autoantibodies induced alteration of paranodal junctions in myelinated neuronal culture. These results strongly suggest that antibodies to CAMs may be pathogenic and induce demyelination via functional blocking activity.

    PMID: 24497634

  • Endothelial progenitor cells in acute ischemic stroke.
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    Endothelial progenitor cells in acute ischemic stroke.

    Brain Behav. 2013 Nov;3(6):649-55

    Authors: Martí-Fàbregas J, Crespo J, Delgado-Mederos R, Martínez-Ramírez S, Peña E, Marín R, Dinia L, Jiménez-Xarrié E, Fernández-Arcos A, Pérez-Pérez J, Querol L, Suárez-Calvet M, Badimon L

    Abstract
    OBJECTIVES: The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points.
    MATERIAL AND METHODS: We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0-2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry.
    RESULTS: We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large-artery atherosclerosis and small-vessel disease etiologic subtypes.
    CONCLUSIONS: After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large-artery atherosclerosis and small-vessel disease subtypes, higher counts were related to better outcome at 3 months.

    PMID: 24363968

  • Myasthenia gravis and the neuromuscular junction. Related Articles Myasthenia gravis and the neuromuscular junction. Curr Opin Neurol. 2013 Oct;26(5):459-65 Authors: Querol L, Illa I Abstract PURPOSE OF REVIEW: Myasthenic disorders are a well chara...
  • Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Related Articles Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology. 2013 Sep 10;81(11):956-63 Authors: Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Haf...
  • 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands. Related Articles 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands. Neuromuscul Disord. 2013 Nov;23(11):924-33 Authors: Vanhou...
  • Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.
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    Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.

    Muscle Nerve. 2013 Dec;48(6):870-6

    Authors: Querol L, Rojas-Garcia R, Casasnovas C, Sedano MJ, Muñoz-Blanco JL, Alberti MA, Paradas C, Sevilla T, Pardo J, Capablo JL, Sivera R, Guerrero A, Gutierrez-Rivas E, Illa I

    Abstract
    INTRODUCTION: The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
    METHODS: Response to therapy was defined as an improvement of ≥ 1 point on the modified Rankin score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder.
    RESULTS: Eighty-six patients were included; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up.
    CONCLUSIONS: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment.

    PMID: 23512566

  • PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Related Articles PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. J Autoimmun. 2013 Jun;43:1-9 Authors: Larman HB, Laserson U, Querol L, ...
  • Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.
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    Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy.

    Ann Neurol. 2013 Mar;73(3):370-80

    Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J, Suárez-Calvet X, Navas M, Araque J, Gallardo E, Illa I

    Abstract
    OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling.
    METHODS: Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell-based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments.
    RESULTS: Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin-1 (CNTN1), and 1 precipitated both CNTN1 and contactin-associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin.
    INTERPRETATION: Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP.

    PMID: 23280477

  • Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.
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    Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies.

    J Peripher Nerv Syst. 2012 Jun;17(2):158-68

    Authors: Rojas-García R, Querol L, Gallardo E, De Luna Salva N, Juarez C, Garces M, Fages E, Casasnovas C, Illa I

    Abstract
    There is as yet no consensus for considering pure acute sensory ataxic neuropathy (ASAN) as a variant of Guillain-Barré syndrome (GBS). Reactivity against gangliosides sharing disialosyl epitopes has been reported in these patients. The aim of this study was to determine the spectrum of reactivity against gangliosides in ASAN and to define the clinical pattern. From our database we identified patients with suspicion of ASAN. We defined ASAN as the presence of ataxia of peripheral origin with loss of proprioception, and areflexia, absence of ophthalmoplegia and no or minimal muscle weakness. Patients who met these criteria were retrospectively reviewed for their spectrum of reactivity against gangliosides and clinical features. We identified 12 patients fulfilling pre-defined criteria for ASAN. Reactivity against gangliosides containing disialosyl epitopes was present in seven patients. Concomitant reactivity against other gangliosides was present in 6/7 patients. All patients presented good prognosis and an antecedent illness was present in nine. Our results support the previously described clinico-immunological association between ASAN and disialosyl specificity, and widen the spectrum of reactivity against gangliosides. The acute presentation with a monophasic course, and good prognosis in all cases, together with transient immunoglobulin G antiganglioside antibodies and infectious antecedent in 7/12 patients support the inclusion of ASAN as a GBS variant.

    PMID: 22734901

  • Long-lasting treatment effect of rituximab in MuSK myasthenia.
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    Long-lasting treatment effect of rituximab in MuSK myasthenia.

    Neurology. 2012 Jan 17;78(3):189-93

    Authors: Díaz-Manera J, Martínez-Hernández E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, Muñoz-Blanco JL, Mazia C, Straasheijm KR, Gallardo E, Juárez C, Verschuuren JJ, Illa I

    Abstract
    OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients.
    METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied.
    RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3.
    CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone.
    CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

    PMID: 22218276

  • Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation.
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    Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation.

    Clin Neurophysiol. 2011 Dec;122(12):2537-9

    Authors: Díaz-Manera J, Querol L, Clarimón J, Yagüe S, Illa I

    PMID: 21640645

  • Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review. Related Articles Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review. Sex Transm Dis. 2010 Feb;37(2):123-5 Authors: Suarez-Cal...
  • Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.
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    Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation.

    Biol Blood Marrow Transplant. 2009 Nov;15(11):1439-46

    Authors: Barba P, Piñana JL, Valcárcel D, Querol L, Martino R, Sureda A, Briones J, Delgado J, Brunet S, Sierra J

    Abstract
    Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140 mg/m(2) (n=119), cyclophosphamide (Cy) 120 mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval

  • Blood pressure is not associated with haematoma enlargement in acute intracerebral haemorrhage.
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    Blood pressure is not associated with haematoma enlargement in acute intracerebral haemorrhage.

    Eur J Neurol. 2008 Oct;15(10):1085-90

    Authors: Martí-Fàbregas J, Martínez-Ramírez S, Martínez-Corral M, Díaz-Manera J, Querol L, Suárez-Calvet M, de Juan M, Santaló M, Marín R, Martí-Vilalta JL

    Abstract
    BACKGROUND AND PURPOSE: We performed an observational study that compared baseline and subsequent blood pressure (BP) measurements and its association with haematoma enlargement (HE) in patients with intracerebral haemorrhage (ICH).
    METHODS: We prospectively studied consecutive patients with supratentorial spontaneous ICH within the first 6 h after the onset of symptoms. HE was defined as an increase >or=33% in the volume of haematoma on the CT obtained 24-48 h after the onset of symptoms as compared with the CT at admission. We recorded systolic BP (SBP), diastolic BP (DBP) and mean BP (MBP) at admission and at 6, 12, 18 and 24 h after onset; the maximum SBP, DBP and MBP during the study period; the maximum SBP and DBP within intervals; the mean of all BP readings; administration of antihypertensive agents.
    RESULTS: We studied 60 patients whose mean age was 72.1 +/- 11.3 years. HE was observed in 27 (45%) patients. No statistically significant differences were observed in any of the analyses that compared BP parameters between the HE and non-HE groups (two-way anova).
    CONCLUSIONS: In an exploratory analysis, we did not find an association between BP and HE within the first 24 h after an acute ICH.

    PMID: 18717722

  • Carotid thrombosis after in vitro fertilization: a relatively new thrombotic complication in women.
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    Carotid thrombosis after in vitro fertilization: a relatively new thrombotic complication in women.

    Br J Haematol. 2008 Jun;141(6):897-9

    Authors: Martí E, Santamaría A, Mateo J, Tolosa A, Querol L, Viscasillas P, Fontcuberta J

    PMID: 18355379

  • [Retinal and brain infarctions secondary to acute carotid thrombosis in ovarian hyperstimulation syndrome].
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    .

    Neurologia. 2008 Jun;23(5):319-21

    Authors: Querol L, Martínez-Corral M, Martí E, Martí-Fábregas J

    Abstract
    INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is an uncommon but potentially life-threatening iatrogenic condition that may appear following ovulation induction in the course of some fertility treatments. This may lead to further complications, some of which may be severe, such as thromboembolic events. Though rarely, it can therefore be a potential cause of stroke.
    CLINICAL CASE: We report the case of a 34-year old woman under ovulation induction treatment who developed retinal and brain infarctions secondary to internal carotid occlusion. Oral anticoagulation was administered and recovery was good in spite of the persistence of carotid occlusion in follow-up magnetic ressonance imaging- angiographies.
    CONCLUSIONS: This is the first case of carotid occlusion following an OHSS reported in Spain and the eighth one published in the literature. Current literature on cerebrovascular complications in OHSS is also briefly reviewed.

    PMID: 18247184

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