Jan J Verschuuren

Curium-LUMC, Leyden, South Holland, Netherlands

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Publications (126)629.29 Total impact

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    ABSTRACT: Muscle weakness in MuSK myasthenia gravis (MG) is caused predominantly by IgG4 antibodies which block MuSK signalling and destabilize neuromuscular junctions. We determined whether the binding pattern of MuSK IgG4 antibodies change throughout the disease course (“epitope spreading”), and affect disease severity or treatment responsiveness.
    No preview · Article · Feb 2016

  • No preview · Article · Oct 2015 · Neuromuscular Disorders

  • No preview · Article · Oct 2015 · Neuromuscular Disorders
  • M. Hooijmans · B. Wokke · N. Goemans · G. Campion · J. Verschuuren · H. Kan · E. Niks

    No preview · Article · Oct 2015 · Neuromuscular Disorders
  • M. Hooijmans · B. Wokke · N. Goemans · G. Campion · J. Verschuuren · H. Kan · E. Niks

    No preview · Article · Oct 2015 · Neuromuscular Disorders

  • No preview · Article · Oct 2015 · Neuromuscular Disorders
  • Nils Erik Gilhus · Jan J Verschuuren
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    ABSTRACT: Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.
    No preview · Article · Sep 2015 · The Lancet Neurology
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    ABSTRACT: An N=1 study may consist of a sequence of (placebo) treatments followed by multiple measurements of an outcome variable. An example is the study by Vrinten, et al. who evaluate the effect of intravenous immunoglobulin G on inflammation in hereditary neuropathy with liability to pressure palsy. In this study there was a sequence of seven (placebo) treatments each followed by about seven measurements of pain every two to three days. The main hypothesis was that pain decreased more after treatment than after placebo treatment. The main hypothesis was formalized by means of informative hypotheses (Hoijtink, 2012) that stated that “the regression coefficients relating time to pain were smaller (decreasing pain) in the first week after treatment than in the first week after placebo treatment”. The competing hypothesis was the complement of the main hypotheses, that is all the sets of regression coefficients that are not in agreement with the main hypothesis. Both hypotheses were evaluated using the Bayes factor. This is a measure of the support in the data for the hypotheses under consideration. A Bayes factor of 10 means that the data support the main hypothesis ten times more than its complement. For pain the resulting Bayes factor was 33.22 which denotes strong support in the data for the first hypotheses. Conclusion: If informative hypotheses are formulated with respect to the outcomes of an N=1 study in which a sequence of (placebo) treatments followed by multiple measurements of outcome variables, even with a limited set of data strong support for the hypotheses entertained can be found. References: Hoijtink, H. (2012). Informative Hypotheses. Theory and Practice for Behavioural and Social Scientists. Boca Raton: Springer.
    Full-text · Conference Paper · Aug 2015
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    ABSTRACT: An N=1 study may consist of a sequence of (placebo) treatments followed by multiple measurements of an outcome variable. An example is the study by Vrinten, et al. who evaluate the effect of intravenous immunoglobulin G on inflammation in hereditary neuropathy with liability to pressure palsy. In this study there was a sequence of seven (placebo) treatments each followed by about seven measurements of pain every two to three days. The main hypothesis was that pain decreased more after treatment than after placebo treatment. The main hypothesis was formalized by means of informative hypotheses (Hoijtink, 2012) that stated that “the regression coefficients relating time to pain were smaller (decreasing pain) in the first week after treatment than in the first week after placebo treatment”. The competing hypothesis was the complement of the main hypotheses, that is all the sets of regression coefficients that are not in agreement with the main hypothesis. Both hypotheses were evaluated using the Bayes factor. This is a measure of the support in the data for the hypotheses under consideration. A Bayes factor of 10 means that the data support the main hypothesis ten times more than its complement. For pain the resulting Bayes factor was 33.22 which denotes strong support in the data for the first hypotheses. Conclusion: If informative hypotheses are formulated with respect to the outcomes of an N=1 study in which a sequence of (placebo) treatments followed by multiple measurements of outcome variables, even with a limited set of data strong support for the hypotheses entertained can be found. References: Hoijtink, H. (2012). Informative Hypotheses. Theory and Practice for Behavioural and Social Scientists. Boca Raton: Springer.
    Full-text · Conference Paper · Aug 2015
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    ABSTRACT: Introduction Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG. Methods and analysis Single-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. Treatment: 25 mg ephedrine or placebo, twice daily. Main outcome measure: Quantitative Myasthenia Gravis (QMG) test. Statistical analysis: fixed effects linear model for QMG for all patients combined. Secondary outcome measures: Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients’ and caregivers’ experiences. Ethics and dissemination This study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes. Trial registration number This study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.
    Full-text · Article · Jul 2015
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    Full-text · Dataset · Jun 2015
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    ABSTRACT: At least 13 different disease entities affecting the central nervous system, peripheral nervous system and connective tissue of the skin or kidneys are associated with immunoglobulin G4 (IgG4) immune reactivity. IgG4 has always been considered a benign, non-inflammatory subclass of IgG, in contrast to the well-known complement-activating pro-inflammatory IgG1 subclass. A comprehensive review of these IgG4 autoimmune disorders reveals striking similarities in epitope binding and human leukocyte antigen (HLA) associations. Mechanical interference of extracellular ligand-receptor interactions by the associated IgG4 antibodies seems to be the common/converging disease mechanism in these disorders. © 2015 EAN.
    Full-text · Article · May 2015 · European Journal of Neurology
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    ABSTRACT: Exon-skipping drugs in Duchenne muscular dystrophy (DMD) aim to restore truncated dystrophin expression, which is present in the milder Becker muscular dystrophy (BMD). MRI skeletal muscle T2 relaxation times as a representation of edema/inflammation could be quantitative outcome parameters for such trials. We studied T2 relaxation times, adjusted for muscle fat fraction using Dixon MRI, in lower leg muscles of DMD and BMD patients and healthy controls. T2 relaxation times correlated significantly with fat fractions in patients only (P<0.001). After adjusting for muscle fat, T2 relaxation times were significantly increased in 6 muscles of DMD patients (P<0.01), except for the extensor digitorum longus. In BMD, T2 relaxation times were unchanged. T2 relaxation times could be a useful outcome parameter in exon-skipping trials in DMD but are influenced by fat despite fat suppression. This should be accounted for when using quantitative T2 mapping to investigate edema/inflammation. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Apr 2015 · Muscle & Nerve
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    ABSTRACT: Analysing the type and frequency of patient specific mutations that give rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. Locus specific databases (LSDBs) allow for the collection, organization, storage and analysis of genetic variants of disease. Here we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed genetic data for 7149 DMD mutations held within the database. 5682 large mutations were observed (80% of total mutations), of which 4894 (86%) were deletions (1 exon or larger), and 784 (14%) were duplications (1 exon or larger). There were 1445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · Human Mutation
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    ABSTRACT: Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Experimental Neurology
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    ABSTRACT: Myasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated. To assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes. On 17 November 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched reference lists of articles, conference proceedings of relevant conferences, and prospective trial registers. In addition, we contacted manufacturers and researchers in the field. We considered randomised controlled trials (RCTs) and quasi-RCTs comparing ephedrine as a single or add-on treatment with any other active treatment, placebo, or no treatment in adults or children with autoimmune MG, NMG, or CMSs. Two review authors independently assessed study design and quality, and extracted data. We contacted study authors for additional information. We collected information on adverse effects from included articles, and contacted authors. We found no RCTs or quasi-RCTs, and therefore could not establish the effect of ephedrine on MG, NMG and CMSs. We describe the results of 53 non-randomised studies narratively in the Discussion section, including observations of endurance, muscle strength and quality of life. Effects may differ depending on the type of myasthenia. Thirty-seven studies were in participants with CMS, five in participants with MG, and in 11 the precise form of myasthenia was unknown. We found no studies for NMG. Reported adverse effects included tachycardia, sleep disturbances, nervousness, and withdrawal symptoms. There was no evidence available from RCTs or quasi-RCTs, but some observations from non-randomised studies are available. There is a need for more evidence from suitable forms of prospective RCTs, such as series of n-of-one RCTs, that use appropriate and validated outcome measures.
    Preview · Article · Dec 2014 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Objective The aim of this study was to evaluate age-related changes in metabolic walking energy expenditure in ambulant boys affected by Duchenne muscular dystrophy over a follow-up period of 12 months. Methods At baseline (T1) and 12 months later (T2), metabolic walking energy expenditure was assessed during a 6-minute walk test at comfortable speed in 14 ambulant boys with Duchenne (age range: 6.0-12.5 years, mean 8.2). Outcome measures derived from the assessment included the 6-minute comfortable walking distance (m) and net-nondimensional energy cost relative to speed-matched control cost (SMC-EC, %). Statistical comparisons were made using a two-way repeated measures ANOVA (factors: time (T1 versus T2) and age (<8 years of age (yoa) versus ≥8 yoa)). Results Over the course of the study, a significant decrease of -28m (−8.2%, p = 0.043) was noted in the walked distance at comfortable speed. Besides, SMC-EC increased with 4.4%, although this change was not significant (p = 0.452). Regarding age groups, boys below 8 yoa showed a smaller annual decrease in the walked distance (−15 m) compared to boys above 8 yoa (−37 m). SMC-EC increased with 10% in the older boys, while in the younger boys it decreased (−2.1%). The main effect of age group on walking distance and SMC-EC however was not significant (p>0.158), and also there were no interaction effects (p>0.248). Conclusions The results of our small study suggest that the natural course of walking performance in ambulant boys with Duchenne is characterized by a decrease in comfortable walking distance and an increase in walking energy cost. The rate of energy cost seems to increase with age, while walking distance decreases, which is opposite from the trend in typically developing children.
    Full-text · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and 31P MRS. MRI and 31P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ≤ 0.05). The Pi/ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that 31P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. Copyright © 2014 John Wiley & Sons, Ltd.
    No preview · Article · Nov 2014 · NMR in Biomedicine
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    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, suggest an underlying autoimmune mechanism, supporting the use of immune therapy.
    Full-text · Article · Oct 2014 · Autoimmunity Reviews

  • No preview · Conference Paper · Oct 2014

Publication Stats

3k Citations
629.29 Total Impact Points

Institutions

  • 2010-2015
    • Curium-LUMC
      Leyden, South Holland, Netherlands
  • 1999-2015
    • Leiden University Medical Centre
      • Department of Neurology
      Leyden, South Holland, Netherlands
  • 1998-2015
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1994-1998
    • Memorial Sloan-Kettering Cancer Center
      • Department of Neurology
      New York City, New York, United States
  • 1997
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 1993
    • Maastricht University
      • MHeNS School for Mental Health and Neuroscience
      Maestricht, Limburg, Netherlands
  • 1988
    • Transnationale Universiteit Limburg
      SCE, Pennsylvania, United States