Kevin Rostasy

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

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Publications (64)246.28 Total impact

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    ABSTRACT: In patients with isolated optic neuritis (ON), the presence of antibodies to aquaporin 4 (AQP4) has diagnostic and prognostic value. In the same clinical setting, the significance of antibodies to myelin-oligodendrocyte glycoprotein (MOG) or the glycine receptor α1 subunit (GlyR) is unclear. To investigate the frequency of antibodies to AQP4, MOG, and GlyR in patients with unilateral or bilateral, severe, or recurrent isolated ON and to determine their clinical and prognostic correlates. Retrospective case-control study from November 1, 2005, through May 30, 2014 with the detection of autoantibodies in a neuroimmunology referral center. We included 51 patients with ON but without clinical and magnetic resonance imaging findings outside the optic nerves and 142 controls (30 healthy individuals, 48 patients with neuromyelitis optica, and 64 patients with multiple sclerosis). Clinicoimmunologic analysis. We determined the presence of antibodies to AQP4, MOG, and GlyR using cell-based assays. The median age of the patients at the onset of ON symptoms was 28 (range, 5-65) years; 36 patients (71%) were female. Antibodies were identified in 23 patients (45%), including MOG in 10 patients, AQP4 in 6 patients, and GlyR in 7 patients (concurrent with MOG in 3 and concurrent with AQP4 in 1). Patients with AQP4 antibodies (median visual score, 3.5 [range, 1-9]) had a worse visual outcome than patients with MOG antibodies alone (median visual score, 0 [range, 0-5]; P = .007), patients with seronegative findings (n = 28) (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies alone (n = 3) (median visual score, 0 [range, 0-2]; P = .10).The median age of the 7 patients with GlyR antibodies was 27 (range, 11-38) years; 5 (71%) of these were female. Among the 3 patients with GlyR antibodies alone, 1 patient had monophasic ON, 1 had recurrent isolated ON, and 1 had conversion to multiple sclerosis. The 3 patients with GlyR antibodies concurrent with MOG antibodies had recurrent isolated ON, and the patient with concurrent AQP4 antibodies had conversion to neuromyelitis optica. Of the 48 controls with neuromyelitis optica, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. Of the 64 controls with multiple sclerosis, 5 (8%) had GlyR antibodies. Forty-five percent of patients with unilateral or bilateral, severe, or recurrent isolated ON had antibodies to MOG, AQP4, or GlyR. Patients with AQP4 antibodies had the poorest visual outcomes, whereas patients with MOG antibodies had a better outcome that was similar to that of patients with seronegative findings. The significance of GlyR antibodies in the setting of ON is unclear and deserves further study.
    JAMA Neurology 12/2014; · 7.58 Impact Factor
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis.
    JAMA Neurology 12/2014; · 7.58 Impact Factor
  • Clinical Neurology and Neurosurgery. 11/2014;
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    ABSTRACT: OBJECTIVE: We aimed to report the frequency and implications of antibodies to myelin oligodendrocyte glycoprotein (MOG-ab) in adults with demyelinating syndromes suspicious for neuromyelitis optica (NMO). METHODS: Samples from 174 patients (48 NMO, 84 longitudinally extensive myelitis (LETM), 39 optic neuritis (ON), and three acute disseminated encephalomyelitis (ADEM) who presented initially with isolated LETM) were retrospectively examined for AQP4-ab and MOG-ab using cell-based assays. RESULTS: MOG-ab were found in 17 (9.8%) patients, AQP4-ab in 59 (34%), and both antibodies in two (1.1%). Among the 17 patients with MOG-ab alone, seven (41%) had ON, five (29%) LETM, four (24%) NMO, and one (6%) ADEM. Compared with patients with AQP4-ab, those with MOG-ab were significantly younger (median: 27 vs. 40.5 years), without female predominance (53% vs. 90%), and the clinical course was more frequently monophasic (41% vs. 7%) with a benign outcome (median Expanded Disability Status Scale: 1.5 vs. 4.0). In eight patients with paired serum-cerebrospinal fluid (CSF) samples, five had MOG-ab in both samples and three only in serum. Antibody titres did not differ among clinical phenotypes or disease course. MOG-ab remained detectable in 12/14 patients (median follow-up: 23 months) without correlation between titres' evolution and outcome. CONCLUSION: MOG-ab identify a subgroup of adult patients with NMO, LETM and ON that have better outcome than those associated with AQP4-ab. MOG-ab are more frequently detected in serum than CSF and the follow-up of titres does not correlate with outcome.
    Multiple Sclerosis 10/2014; Oct 24. · 4.47 Impact Factor
  • Journal of Neuroimmunology. 10/2014; 275(s 1–2):13.
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    ABSTRACT: A serum antibody against the inward rectifying potassium channel KIR4.1 (KIR4.1-IgG) was recently discovered, which is found in almost half of adult patients with multiple sclerosis. We investigated the prevalence of KIR4.1-IgG in children with acquired demyelinating disease (ADD) of the CNS. We also compared antibody responses to KIR4.1 and myelin oligodendrocyte glycoproteins (MOGs), another potential autoantigen in childhood ADDs. We measured KIR4.1-IgG by ELISA in children with ADD (n = 47), other neurologic disease (n = 22), and autoimmune disease (n = 22), and in healthy controls (HCs) (n = 18). One hundred six samples were also measured by capture ELISA. Binding of KIR4.1-IgG human subcortical white matter was analyzed by immunofluorescence. Anti-MOG antibodies were measured using a cell-based assay. KIR4.1-IgG titers were significantly higher in children with ADD compared with all control groups by ELISA and capture ELISA (p < 0.0001, p < 0.0001). Overall, 27 of 47 patients with ADD (57.45%) but none of the 62 with other neurologic disease or autoimmune disease or the HCs (0%) were KIR4.1-IgG antibody positive by ELISA. Sera containing KIR4.1-IgG stained glial cells in brain tissue sections. No correlation among KIR4.1-IgG, age, or MOG-IgG was observed in the ADD group. Serum antibodies to KIR4.1 are found in the majority of children with ADD but not in children with other diseases or in HCs. These findings suggest that KIR4.1 is an important target of autoantibodies in childhood ADD.
    Neurology 01/2014; · 8.30 Impact Factor
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    ABSTRACT: Objectives Although previous studies suggest that valproate (VPA) may induce reproductive endocrine disorders, the effects of newer antiepileptic drugs (AEDs) on reproductive endocrine health have not been widely investigated and compared with those of older AEDs. Therefore, this multicenter cross-sectional study aimed to evaluate the prevalence of reproductive endocrine dysfunctions in pubertal females with epilepsy receiving VPA, lamotrigine (LTG), or levetiracetam (LEV) monotherapy. Patients and Methods Pubertal girls on VPA (n = 11), LTG (n = 8), or LEV (n = 13) monotherapy for at least 6 months were recruited. Healthy sex-matched and age-matched subjects were enrolled as controls (n = 32). Each participant underwent a comprehensive physical examination concerning signs of hyperandrogenism. The Ferriman-Gallwey score of hirsutism was assessed. In addition, all patients completed a standardized questionnaire regarding epilepsy, menstrual cycle, and hirsutism features. Adiposity indices were measured and weight gain was documented for each subject. Results Hirsutism score, occurrence of hyperandrogenism features, and adiposity indices were significantly higher in the VPA group when compared with LEV and control groups. VPA therapy was more frequently associated with weight gain when compared with LTG and controls, whereas no significant differences with regard to signs of hyperandrogenism were found between VPA and LTG groups. Furthermore, no differences in menstrual disorders were observed between groups. Conclusions Pubertal girls with epilepsy receiving VPA monotherapy were more likely to develop signs of hyperandrogenism, that is, hirsutism and acanthosis, than those on LEV or controls. However, no differences in occurrence of menstrual disorders and other reproductive dysfunctions were found between VPA, LTG, LEV, and control groups. These findings do not allow us to clearly determine whether or not VPA, LEV, and LTG monotherapies considerably affect reproductive endocrine health in pubertal girls with epilepsy. Therefore, further prospective studies of larger sample sizes are needed to establish if screening tests should be recommended.
    Neuropediatrics 01/2014; · 1.19 Impact Factor
  • Kevin Rostasy, Markus Reindl
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    ABSTRACT: The recent detection of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) autoantibodies in acquired inflammatory demyelinating diseases, such as neuromyelitis optica, or acute disseminated encephalomyelitis, and multiple sclerosis, in children strongly indicates that B-cell-dependent mechanisms contribute to the pathogenesis. This review aims to give an overview of the role of autoantibodies in inflammatory demyelinating pediatric diseases, with a focus on antibodies to AQP4 and MOG.
    Neuropediatrics 10/2013; · 1.19 Impact Factor
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    ABSTRACT: To determine the frequency of KCNQ2 mutations in patients with neonatal epileptic encephalopathy (NEE), and to expand the phenotypic spectrum of KCNQ2 epileptic encephalopathy. Eighty-four patients with unexplained NEE were screened for KCNQ2 mutations using classic Sanger sequencing. Clinical data of 6 additional patients with KCNQ2 mutations detected by gene panel were collected. Detailed phenotyping was performed with particular attention to seizure frequency, cognitive outcome, and video-EEG. In the cohort, we identified 9 different heterozygous de novo KCNQ2 missense mutations in 11 of 84 patients (13%). Two of 6 missense mutations detected by gene panel were recurrent and present in patients of the cohort. Seizures at onset typically consisted of tonic posturing often associated with focal clonic jerking, and were accompanied by apnea with desaturation. One patient diagnosed by gene panel had seizure onset at the age of 5 months. Based on seizure frequency at onset and cognitive outcome, we delineated 3 clinical subgroups, expanding the spectrum of KCNQ2 encephalopathy to patients with moderate intellectual disability and/or infrequent seizures at onset. Recurrent mutations lead to relatively homogenous phenotypes. One patient responded favorably to retigabine; 5 patients had a good response to carbamazepine. In 6 patients, seizures with bradycardia were recorded. One patient died of probable sudden unexpected death in epilepsy. KCNQ2 mutations cause approximately 13% of unexplained NEE. Patients present with a wide spectrum of severity and, although rare, infantile epilepsy onset is possible.
    Neurology 10/2013; · 8.30 Impact Factor
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    ABSTRACT: Epilepsy is a common finding in patients with chromosomal macro- and micro-rearrangements but only few aberrations show a constant pattern of seizures. DNA array-based studies have reported causative copy number variations (CNVs) in 5-30% of patients with epilepsy with or without co-morbidities. The interpretation of many of the detected CNVs remains challenging. In order to identify CNVs carrying epilepsy-related genes we investigated 43 children with various patterns of epileptic seizures, intellectual disability, and minor dysmorphism, using the Illumina® Infinium Human1M-DuoV1 array. In three patients we found likely causative de novo CNVs, i.e. deletions in 1q41q42.12 (3.4 Mb) and 19p13.2 (834 kb), and a mosaic two-segment duplication in 17p13.2 (218 kb) and 17p13.1 (422 kb). In 6 additional patients there were aberrations (a deletion in one and duplications in 5 patients) with uncertain clinical consequences. In total, the finding of causative chromosomal micro-rearrangements in 3 out of 43 patients (7%) and potentially causative CNVs in 6 additional patients (14%) with epilepsy and intellectual disability but without major malformations confirms the power of DNA arrays for the detection of new disease-related genetic regions.
    Clinical Genetics 09/2013; · 4.25 Impact Factor
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    ABSTRACT: Autoantibodies targeting conformationally intact myelin oligodendrocyte glycoprotein (MOG) are found in different inflammatory diseases of the CNS, but their antigenic epitopes have not been mapped. We expressed mutants of MOG on human HeLa cells and analyzed sera from 111 patients (104 children, 7 adults) who recognized cell-bound human MOG, but had different diseases, including acute disseminated encephalomyelitis (ADEM), one episode of transverse myelitis or optic neuritis, multiple sclerosis (MS), anti-aquaporin-4 (AQP4)-negative neuromyelitis optica (NMO), and chronic relapsing inflammatory optic neuritis (CRION). We obtained insight into the recognition of epitopes in 98 patients. All epitopes identified were located at loops connecting the β strands of MOG. The most frequently recognized MOG epitope was revealed by the P42S mutation positioned in the CC'-loop. Overall, we distinguished seven epitope patterns, including the one mainly recognized by mouse mAbs. In half of the patients, the anti-MOG response was directed to a single epitope. The epitope specificity was not linked to certain disease entities. Longitudinal analysis of 11 patients for up to 5 y indicated constant epitope recognition without evidence for intramolecular epitope spreading. Patients who rapidly lost their anti-MOG IgG still generated a long-lasting IgG response to vaccines, indicating that their loss of anti-MOG reactivity did not reflect a general lack of capacity for long-standing IgG responses. The majority of human anti-MOG Abs did not recognize rodent MOG, which has implications for animal studies. Our findings might assist in future detection of potential mimotopes and pave the way to Ag-specific depletion.
    The Journal of Immunology 09/2013; · 5.52 Impact Factor
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    ABSTRACT: Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope.
    Multiple Sclerosis 09/2013; 19(10):1261-1267. · 4.47 Impact Factor
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    ABSTRACT: Background In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched.Objectives The study aimed to investigate cognitive functions and behavioral problems in children after LNB.Patients and Methods A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/μL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered.Results Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints.Conclusion Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome.
    Neuropediatrics 08/2013; · 1.19 Impact Factor
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    ABSTRACT: This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.
    Neuropediatrics 07/2013; · 1.19 Impact Factor
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    ABSTRACT: Midbrain-hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features. Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20-44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain-hindbrain structures were visually assessed by three independent raters. MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p=0.004) in three categories of MCD (category I - to abnormal neuronal proliferation; category II - to abnormal neuronal migration; and category III - due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p=0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p<0.001) and hippocampal abnormalities (52% vs. 27%; p<0.001). Patients wMHM were younger (median 25 years vs. 30 years; p=0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p=0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p<0.001), delayed developmental milestones (68% vs. 35%; p<0.001) and neurological deficits (66% vs. 47%; p=0.049) compared to those w/oMHM. The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes.
    Epilepsy research 06/2013; · 2.48 Impact Factor
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    ABSTRACT: Myelin oligodendrocyte glycoprotein (MOG) has been identified as a target of demyelinating autoantibodies in animal models of inflammatory demyelinating diseases of the CNS, such as multiple sclerosis (MS). Numerous studies have aimed to establish a role for MOG antibodies in patients with MS, although the results have been controversial. Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of high-titre MOG antibodies in paediatric patients with acute disseminated encephalomyelitis, MS, aquaporin-4-seronegative neuromyelitis optica, or isolated optic neuritis or transverse myelitis, but only rarely in adults with these disorders. These studies indicate that MOG antibodies could be associated with a broad spectrum of acquired human CNS demyelinating diseases. This Review article discusses the current literature on MOG antibodies, their potential clinical relevance, and their role in the pathogenesis of MOG antibody-associated demyelinating disorders.
    Nature Reviews Neurology 06/2013; · 15.52 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them. METHODS: We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles. RESULTS: ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62-86%; specificity 56-79%) from MS serum (sensitivity 40-87%; specificity 62-86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides. CONCLUSIONS: Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.
    Multiple Sclerosis 04/2013; · 4.47 Impact Factor
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    ABSTRACT: OBJECTIVE: Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research. METHODS: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions. RESULTS: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge. CONCLUSION: Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.
    Neurology 03/2013; 80(12):1161-1168. · 8.30 Impact Factor
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    ABSTRACT: IMPORTANCE Given the high frequency of failure of first-line therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS). OBJECTIVE To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsing-remitting MS in adults. DESIGN Retrospective study. SETTING Eleven centers for neurology and pediatric neurology in Germany and Austria. PARTICIPANTS A total of 20 pediatric patients with MS who started treatment with natalizumab prior to 18 years of age. These patients underwent magnetic resonance imaging as clinically indicated, despite the fact that 19 of these 20 patients were undergoing first-line disease-modifying therapy. The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (SD) pretreatment period was 18 (10) months. INTERVENTION Natalizumab, 300 mg every 4 weeks. MAIN OUTCOME MEASURES Annualized relapse rates, Expanded Disability Status Scale scores, number of new T2/fluid-attenuated inversion recovery lesions and contrast-enhancing lesions on magnetic resonance imaging, number of adverse events, the prevalence of neutralizing antibodies against natalizumab, and serum JC virus-antibody status. RESULTS Treatment with natalizumab was associated with reductions in mean annualized relapse rates (3.7 without treatment vs 0.4 with treatment; P < .001), median Expanded Disability Status Scale scores (2 without treatment vs 1 with treatment; P < .02), and mean number of new T2/fluid-attenuated inversion recovery lesions per year (7.8 without treatment vs 0.5 with treatment; P < .001). Two patients developed high-titer neutralizing antibodies against natalizumab and had to stop therapy. Adverse events included headaches, asthenia, infections, and hypersensitivity. Abnormal laboratory results were found for 8 patients. JC virus antibodies were found in 5 of 13 patients. After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8 patients within 6 months. CONCLUSIONS AND RELEVANCE Our data indicate that natalizumab may be safe and effective against MS in pediatric patients with breakthrough disease.
    JAMA neurology. 02/2013;
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    ABSTRACT: This is the first investigation of MMPs in children with febrile seizures. In a prospective, cross sectional study, serum levels of matrix metalloproteinases (MMP8/9), tissue inhibitor of metalloproteinases (TIMP1/2), of children with FS (n=13), children with febrile infection (FI, n=13) and children with unprovoked generalized seizures (US, n=11) were compared. Neither provoked nor unprovoked seizures in FS and US seem to elevate levels of MMPs or TIMPs, whereas in case of febrile infection blood level of MMP8 was significant elevated. Seizures in general might have no influence on this distinctive inflammatory process or even might have suppressive impact.
    Epilepsy research 01/2013; · 2.48 Impact Factor

Publication Stats

860 Citations
246.28 Total Impact Points


  • 2014
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2008–2013
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2012
    • Medical University of Vienna
      • Universitätsklinik für Neurologie
      Vienna, Vienna, Austria
  • 2007–2012
    • Medizinische Universität Innsbruck
      • • Department für Pädiatrie II
      • • Department für Kinder- und Jugendheilkunde
      Innsbruck, Tyrol, Austria
  • 2009
    • New England Baptist Hospital
      Boston, Massachusetts, United States
    • University of Ottawa
      Ottawa, Ontario, Canada
  • 2003–2008
    • Universitätsmedizin Göttingen
      • • Division of Virology
      • • Department of Neurology
      • • Division of Neuropediatrics
      Göttingen, Lower Saxony, Germany
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 2003–2006
    • Georg-August-Universität Göttingen
      • Faculty of Medicine
      Göttingen, Lower Saxony, Germany