Jan Hillert

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (296)1741.23 Total impact

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    J Hillert, L Stawiarz
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    ABSTRACT: The Swedish MS registry (SMSreg) is designed to assure quality health care for patients with multiple sclerosis (MS). It has been active since 2001 and web-based since 2004. It runs on government funding only and is used in all Swedish neurology departments. The SMSreg currently includes data on 14,500 of Sweden's estimated 17,500 prevalent patients with MS. One important function of SMSreg, to which participation is voluntary, is to serve as a tool for decision support and to provide an easy overview of the patient information needed at clinical visits. This is its core feature and explains why the majority of Swedish MS specialists contribute data. Another success factor for SMSreg is that entered data can be readily accessed, either through a query function into Excel format or through a set of predesigned tables and diagrams in which parameters can be selected. Recent development includes a portal allowing patients to view a summary of their registered data and to report a set of patient-reported outcomes. SMSreg data have been used in close to 100 published scientific reports. Current projects include an incidence cohort (EIMS), post-marketing cohorts of patients on novel disease-modifying drugs (IMSE), and a prevalence cohort (GEMS). As these studies combine physical sampling and questionnaire data with clinical documentation and possible linkage to other public registries, together they provide an excellent platform for integrated MS research. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Acta Neurologica Scandinavica 07/2015; 132 Suppl S199:11-19. DOI:10.1111/ane.12425 · 2.44 Impact Factor
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    ABSTRACT: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing-remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. This study aims to provide real-world data on safety and discontinuation rates. Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011-2013, initiating treatment with NTZ (n=640) or FGL (n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGL(afterNTZ)). Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGL(afterNTZ) versus FGL(NTZ-naïve) patients. Proportion on drug after 1 year was high, NTZ=87%, FGL(NTZ-naïve)=83% and FGL(afterNTZ)=76%. Adverse events was the most frequent reason for discontinuing FGL (FGL(NTZ-naïve)=9%, FGL(afterNTZ)=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGL(NTZ-naïve)=3%, FGL(afterNTZ)=8%. FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics. © The Author(s), 2015.
    Multiple Sclerosis 04/2015; DOI:10.1177/1352458515579216 · 4.86 Impact Factor
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    ABSTRACT: A reduced cancer risk amongst patients with multiple sclerosis (MS) has been reported. Theoretically, this could represent a genuine reduction in risk or, alternatively, 'diagnostic neglect', where cancer is undiagnosed when symptoms are misattributed to MS. Assess all-cause mortality risk following a cancer diagnosis in patients with MS compared with a cohort without MS. A cohort of MS patients (n = 19 364) and a cohort of the general population (n = 192 519) were extracted from national Swedish registers from 1969 to 2005. All-cause mortality after cancer in MS was compared with the general population. Poisson regression analysis was conducted in the MS and non-MS cohorts separately. The models were adjusted for follow-up duration, year at entry, sex, region and socioeconomic index. The two cohorts were combined and differences in mortality risk were assessed using interaction testing. The adjusted relative risk (and 95% confidence interval) for all-cause mortality following a cancer diagnosis in MS patients (compared with MS patients without cancer) is 3.06 (2.86-3.27; n = 1768) and amongst those without MS 5.73 (5.62-5.85; n = 24 965). This lower magnitude mortality risk in the MS patients was confirmed by multiplicative interaction testing (P < 0.001). A consistent pattern of lower magnitude of all-cause mortality risk following cancer in MS patients for a range of organ-specific cancer types was found. It suggests that cancer diagnoses tend not to be delayed in MS and diagnostic neglect is unlikely to account for the reduced cancer risk associated with MS. The lower magnitude cancer risk in MS may be due to disease-associated characteristics or exposures. © 2015 EAN.
    European Journal of Neurology 04/2015; 22(7). DOI:10.1111/ene.12710 · 3.85 Impact Factor
  • European Psychiatry 03/2015; 30:616. DOI:10.1016/S0924-9338(15)30490-9 · 3.21 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is associated with reduced work capacity, but there is limited knowledge about MS patients' sources of income. The purpose of this study was to elucidate MS patients' earnings and social benefits compared to those of the general population. From nationwide registers of all residents in Sweden aged 21-64 years in 2010 (n=5,291,764), those with an MS diagnosis (n=13,979) were compared to a propensity score matched reference group (n=69,895). Descriptive statistics and regression models were used to estimate the percentage difference between the MS patients and the matched references regarding the following annual incomes: earnings, disability pension, sickness absence, disability allowance, unemployment compensation and social assistance. Both MS patients and the matched references received most of their income from earnings followed by disability pension and sickness absence. MS patients that were diagnosed in 2010 had 15% lower earnings than the matched references, while MS patients diagnosed before 2005 had 38% lower earnings. Corresponding figures regarding summed social benefits were 33% and 130% higher for MS patients, respectively. The results indicate that MS patients are overrepresented, in relative and absolute terms, regarding health-related benefits and have lower levels of earnings. However, the redistributing welfare systems appear to financially compensate the MS patients considerably. © The Author(s), 2015.
    Multiple Sclerosis 02/2015; DOI:10.1177/1352458515570767 · 4.86 Impact Factor
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    Molecular Psychiatry 02/2015; 20(2):207-214. DOI:10.1038/mp.2013.195 · 15.15 Impact Factor
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    ABSTRACT: Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 x 10-16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 x 10-7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 x 10-37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 x 10-22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 x 10-6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
    Brain 01/2015; DOI:10.1093/brain/awu405 · 10.23 Impact Factor
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    ABSTRACT: Background and purposeThe possible interaction between adolescent obesity and past infectious mononucleosis (IM) was investigated with regard to multiple sclerosis (MS) risk.Methods This report is based on two population-based case–control studies, one with incident cases (1780 cases, 3885 controls) and one with prevalent cases (4502 cases, 4039 controls). Subjects were categorized based on adolescent body mass index (BMI) and past IM and compared with regard to occurrence of MS by calculating odds ratios with 95% confidence intervals (CIs) employing logistic regression. A potential interaction between adolescent BMI and past IM was evaluated by calculating the attributable proportion due to interaction.ResultsRegardless of human leukocyte antigen (HLA) status, a substantial interaction was observed between adolescent obesity and past IM with regard to MS risk. The interaction was most evident when IM after the age of 10 was considered (attributable proportion due to interaction 0.8, 95% CI 0.6–1.0 in the incident study, and attributable proportion due to interaction 0.7, 95% CI 0.5–1.0 in the prevalent study). In the incident study, the odds ratio of MS was 14.7 (95% CI 5.9–36.6) amongst subjects with adolescent obesity and past IM after the age of 10, compared with subjects with none of these exposures. The corresponding odds ratio in the prevalent study was 13.2 (95% CI 5.2–33.6).Conclusions An obese state both impacts the cellular immune response to infections and induces a state of chronic immune-mediated inflammation which may contribute to explain our finding of an interaction between adolescent BMI and past IM. Measures taken against adolescent obesity may thus be a preventive strategy against MS.
    European Journal of Neurology 12/2014; 22(3). DOI:10.1111/ene.12620 · 3.85 Impact Factor
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    ABSTRACT: Background: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. Objectives: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. Methods: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. Results: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. Conclusions: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands. Keywords:
    Multiple Sclerosis 11/2014; DOI:10.1177/1352458514557305 · 4.86 Impact Factor
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    ABSTRACT: Objective: The objective of this paper is to study comorbidity between multiple sclerosis (MS) and bipolar disorder, schizophrenia and depression in a nationwide cohort and to determine whether shared genetic liability underlies the putative association. Methods: We identified ICD-diagnosed patients with MS , bipolar disorder , schizophrenia and depression in the Swedish National Patient Register and identified their siblings in the Multi-Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison. Results: The risk of MS was increased in patients with bipolar disorder (HR 1.8, 95% CI 1.6–2.2, p < 0.0001) and depression (HR 1.9, 95% CI 1.7–2.0, p < 0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4–0.9, p = 0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant. Conclusion: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration. Background
    European congress of neuropsychopharmacology, Berlin, Germany; 10/2014
  • Journal of Neuroimmunology 10/2014; 275(s 1–2):16–17. DOI:10.1016/j.jneuroim.2014.08.048 · 2.79 Impact Factor
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    ABSTRACT: Background: Identification of MS registries and databases that are currently in use in Europe as well as a detailed knowledge of their content and structure is important in order to facilitate comprehensive analysis and comparison of data.
    Multiple Sclerosis 10/2014; 20(11):1523-1532. DOI:10.1177/1352458514528760 · 4.86 Impact Factor
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    ABSTRACT: Background and purposeHereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported.MethodsCSF1R exons 12−22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced.ResultsOne patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS.Conclusions Our study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.
    European Journal of Neurology 10/2014; 22(2). DOI:10.1111/ene.12572 · 3.85 Impact Factor
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    ABSTRACT: Background: One of the major questions concerning the clinical progression of multiple sclerosis (MS), still insufficiently elaborated or confirmed, is if it can be slowed down or augmented by external factors such as disease modifying drugs (DMDs) beyond the 2 years of a typical randomized controlled trial. Objectives: The aim of the study was to investigate if DMD treatment affects the long term clinical progression of MS, measured as time from diagnosis to scores of 4 or higher of Expanded Disability Status Scale (EDSS). Methods: Longitudinal, prospective data concerning treatment status and EDSS are collected by health professionals in the Swedish MS Registry. This study cohort comprised newly diagnosed MS patients at the Karolinska University Hospital (Stockholm, Sweden) between 2001 and 2005. Survival analysis adjusted for suspected confounders was performed with the outcome variable time in months from the baseline EDSS at diagnosis to EDSS ≥4 in a comparison of patients selected for treatment early or late after onset of disease. Results: Patients were divided into two groups, i.e. those with early (205 patients that received the first treatment within 24 months from MS onset) or delayed treatment (299 patients that received the first treatment after 24 months from MS onset). Univariate Kaplan-Meier analysis showed a statistically significant difference for time to reach EDSS ≥4 between early and delayed treatment groups (p > 0.001) with those treated late doing worse (hazard ratio of 1.77 (95% CI: 1.15−2.73) to reach EDSS≥4). The difference remained statistically significant after adjusting for covariates (age at onset, the baseline EDSS and gender). However, further analysis revealed that the early and delayed treatment groups were very different at the mean of age at diagnosis (32.2 and 39.1 years respectively). When we chose to include age at diagnosis instead of age at onset in the Cox proportional hazard model, significance was lost (95% CI for hazard ratio to reach EDSS ≥4 were 0.94-2.35). Interestingly, gender was not a significant covariate in either model while the baseline EDSS remained significant in both analyses. Conclusions: Different approaches to analyze the clinical course of MS, expressed in increase of EDSS score, show the importance of chosen confounders. Thus, we cannot confirm the beneficiary effect of early treatment in a cohort of this size in spite of a followup time of at an average of 10 years.
    2014 Joint ACTRIMS-ECTRIMS Meeting (MSBoston 2014), Boston, USA; 09/2014
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    ABSTRACT: Multiple sclerosis (MS) has been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n = 3876). Specific KIR ligands were associated with MS patients when compared to controls (n = 3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.
    Journal of Neuroimmunology 09/2014; 274(1-2). DOI:10.1016/j.jneuroim.2014.06.024 · 2.79 Impact Factor
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    ABSTRACT: In an attempt to map chromosomal regions carrying rare gene variants contributing to the risk of multiple sclerosis (MS), we identified segments shared identical-by-descent (IBD) using the software BEAGLE 4.0's refined IBD analysis. IBD mapping aims at identifying segments inherited from a common ancestor and shared more frequently in case-case pairs. A total of 2106 MS patients of Nordic origin and 624 matched controls were genotyped on Illumina Human Quad 660 chip and an additional 1352 ethnically matched controls typed on Illumina HumanHap 550 and Illumina 1M were added. The quality control left a total of 441 731 markers for the analysis. After identification of segments shared by descent and significance testing, a filter function for markers with low IBD sharing was applied. Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS. However, all markers but for one were located telomerically, including the very distal markers. For methodological reasons, such segments have a low sharing of IBD signals and are prone to be false positives. One marker on chromosome 19 reached genome-wide significance and was not one of the distal markers. This marker was located within the GNA11 gene, which contains no previous association with MS. We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.European Journal of Human Genetics advance online publication, 27 August 2014; doi:10.1038/ejhg.2014.155.
    European journal of human genetics: EJHG 08/2014; 23(5). DOI:10.1038/ejhg.2014.155 · 4.23 Impact Factor
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    ABSTRACT: Background Psychiatric comorbidity is common among multiple sclerosis (MS) patients. The majority of MS patients of working ages are on disability pension. The aims of this study were to chart the prevalences of psychiatric diagnoses and medications among MS patients of working ages, and to investigate their association with the risk for future disability pension. Methods This nationwide, population-based prospective cohort study includes 10,750 MS patients and 5,553,141 non-MS individuals who in 2005 were aged 17–64 years. Psychiatric diagnoses and medications were identified using nationwide registers. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated adjusting for socio-demographics. Furthermore, a survival analysis with five-year follow-up was performed among the 4,571 MS patients not on disability pension in 2005, with psychiatric diagnoses and medication as risk factors, and disability pension as the outcome. Results Among MS patients, 35% had been prescribed psychiatric medication compared to 10% of non-MS individuals, adjusted OR 3.72 (95% CI 3.57 to 3.88). Ten percent of MS patients had received a psychiatric diagnosis, compared to 5.7% of non-MS individuals, OR 1.82 (95% CI 1.71 to 1.94). Serotonin reuptake inhibitors (SSRIs), were the most commonly prescribed drugs (17%) among MS patients, while depression (4.8%) was the most common psychiatric diagnosis. In the survival analysis, MS patients with any psychiatric diagnosis had a hazard ratio (HR) of 1.83 (95% CI 1.53 to 2.18) for disability pension compared to other MS patients. MS patients with any psychiatric drug prescription had a HR for disability pension of 2.09 (95% CI 1.84 to 2.33). Conclusion Psychiatric diagnoses and medications are common among MS patients and adversely affect risk for disability pension. This highlights the importance of correct diagnosis and management of psychiatric comorbidity, in a clinical as well as in a societal perspective.
    PLoS ONE 08/2014; 9(8):e104165. DOI:10.1371/journal.pone.0104165 · 3.53 Impact Factor
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    ABSTRACT: Psychiatric disorders are known to be prevalent in multiple sclerosis (MS).OBJECTIVE: The objective of this paper is to study comorbidity between MS and bipolar disorder, schizophrenia and depression in a nationwide cohort and to determine whether shared genetic liability underlies the putative association.METHODS: We identified ICD-diagnosed patients with MS (n = 16,467), bipolar disorder (n = 30,761), schizophrenia (n = 22,781) and depression (n = 172,479) in the Swedish National Patient Register and identified their siblings in the Multi-Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison.RESULTS: The risk of MS was increased in patients with bipolar disorder (hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.6-2.2, p < 0.0001) and depression (HR 1.9, 95% CI 1.7-2.0, p < 0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4-0.9, p = 0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant.CONCLUSION: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration.
    Multiple Sclerosis 07/2014; 20(14). DOI:10.1177/1352458514540970 · 4.86 Impact Factor

Publication Stats

10k Citations
1,741.23 Total Impact Points

Institutions

  • 1990–2015
    • Karolinska Institutet
      • • Department of Clinical Neuroscience
      • • Department of Radiology
      • • Department of Neurology
      Solna, Stockholm, Sweden
  • 1996–2014
    • Karolinska University Hospital
      • Department of Neurology
      Tukholma, Stockholm, Sweden
    • Regional Centre for Biotechnology
      Гургаон, Haryana, India
  • 2012–2013
    • Stockholm University
      Tukholma, Stockholm, Sweden
  • 2010
    • Institute of Biotechnology
      Nagar, Rajasthan, India
  • 2002–2009
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 2008
    • deCODE genetics, Inc.
      Reikiavik, Capital Region, Iceland
  • 2005
    • Lund University
      Lund, Skåne, Sweden
  • 2004
    • Università degli Studi dell'Insubria
      Varese, Lombardy, Italy
  • 1993–2004
    • University Hospital Linköping
      • Department of Neurology
      Linköping, Östergötland, Sweden
  • 2000
    • KU Leuven
      • Rega Institute for Medical Research
      Leuven, VLG, Belgium