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    The cognitive profile of myotonic dystrophy type 1: protocol for systematic

    review and meta-analysis

    Authors: *Cornelis P Okkersen1,4, *Melanie HM Buskes1, Johannes MM Groenewoud2, Roy PC

    Kessels3,4, Hans Knoop5, Baziel GM van Engelen1,4, Joost Raaphorst1,4

    1. Department of Neurology, Radboud University Medical Centre, Nijmegen 2. Department for Health Evidence, Radboud University Medical Centre, Nijmegen 3. Department of medical psychology, Radboud University Medical Centre, Nijmegen 4. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 5. Nijmegen Expert Centre for Chronic Fatigue, Radboud University Medical Centre, Nijmegen

    *Both authors contributed equally

    Corresponding author Joost Raaphorst, MD, PhD Department of Neurology, Radboud Univeristy Medical Centre Postbus 9101, 6500 HB Nijmegen Reinier Postlaan 4 Telephone: 024-361 66 00

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    Myotonic dystrophy type 1 (DM1) is a chronic progressive multi-system disorder with autosomal

    dominant inheritance.1 The disorder is characterised by progressive distal more than proximal

    extremity muscle weakness and atrophy , as well as weakness of facial, jaw and neck flexor muscles.

    Other muscular symptoms include myotonia and cardiac conduction defects. Non-muscular features

    include gastrointestinal, endocrine and central nervous system dysfunction.2, 3 Traditionally, DM1 has

    primarily been regarded a muscle disease. However, cognitive and behavioural dysfunction are

    increasingly recognized to have a significant impact on quality of life, and the importance of

    understanding DM1 as a brain disorder has recently been stressed.4, 5

    Cognitive dysfunction in DM1 is well established, but poorly characterised.1 In this systematic review

    and meta-analysis, we carefully characterise the cognitive profile in myotonic dystrophy type 1. A

    synthesis of data will be made from studies that administered neuropsychological tests in patients

    with DM1 and compared the results with those from (matched) healthy controls. To accommodate

    for an anticipated large variety of different neuropsychological tests used in studies, we will use the

    standardised mean difference as a method to aggregate data.

    This review is, to the best of our knowledge, the first to examine cognitive changes in DM1 in a

    systematic way. We hypothesize that DM1 demonstrates a cognitive profile with deficits in multiple

    domains, such as executive functioning, visuospatial functioning, psychomotor speed and attention.

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    Search strategy

    Authors MB and CO will search Embase (1974-2015), Medline (1946-2015), and PsycInfo (1806-2015)

    without language restrictions. Cross-referencing will identify studies potentially missed by our

    search. We identified 30 articles of potential interest through a preliminary search in PubMed. These

    articles will be used to optimize our search strategy, which will be coordinated with local information

    specialists. All databases will be searched for free text or subject headings for myotonic dystrophy

    type 1, cognition and related terms. For details, the reader is referred to table S1 in the Appendix.

    Eligibility Criteria

    Eligible studies will be identified through predefined criteria (table 1). Only studies with myotonic

    dystrophy type 1, with a genetically proven diagnosis will be included. For studies conducted before

    or shortly after gene discovery in 1992, a clinical diagnosis is acceptable. Studies have to report

    results of at least one validated neuropsychological test. We anticipate that most studies will be

    cross-sectional, but longitudinal studies will also considered for review. For longitudinal studies, only

    data from the first assessment will be included in our analysis. Only studies will be included with

    participants free from significant co-morbidity possibly interfering with neuropsychological test

    performance, according to authors’ statement.

    We will exclude studies that provide insufficient information for analysis, such as studies without

    abstracts or without available full-text. Conference abstracts will be considered for inclusion if

    providing essential information. We will consider studies published in English, Dutch, French or

    German language for inclusion in our study. In case of multiple articles reporting on the same patient

    cohort, the article reporting on the largest sample will be selected, to avoid double inclusion of the

    same individuals. Studies not including a control group are excluded. For the purpose of meta-

    analysis, studies should report means or SD/variance for the neuropsychological tests, or report

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    exact effect sizes and appropriate statistics (such as t-values and/or their associated exact p-values;

    F-ratios) that enables conversion to the standardized mean difference.6 For studies reporting these

    values for significant results only, effect sizes for non-significant results will be set at 0.00, adopting a

    conservative approach.7 Eligibility assessment will be performed independently by MB and CO in an

    unblinded standardized manner. Disagreements between reviewers are to be resolved by consensus.

    If articles provide insufficient or unclear information, additional information will be requested from

    the authors.

    Eligibility criteria for review

    Inclusion criteria (Study Characteristics)

    - Type of patients: patients with genetically proven DM1*

    - Type of studies: cross-sectional, occasionally longitudinal$

    - Types of outcome measures: ≥1 validated neuropsychological test reported for patients and

    control group

    - Absence of significant co-morbidity that might interfere with outcome measures, according to

    authors’ statement

    *For studies conducted before or shortly after gene discovery (1992), clinical diagnosis is acceptable

    $ in case of longitudinal design, only data from the first visit will be included in this review

    Exclusion criteria (Report Characteristics)

    - Unavailable full-text

    - Language restrictions (articles not published in English, Dutch, French or German)

    - Double reportingⱡ

    - Absence of control group§

    - Absence of reporting of exact statistics for the neuropsychological tests for patients or control


    ⱡ In case of multiple articles reporting on the same patient cohort, the article reporting on the largest sample will be

    considered for review

    § Technically a study characteristic, but if studies complied with inclusion criteria, full text was always evaluated for the

    presence of a control group (even if not mentioned in title and abstract)

    Table 1. Eligibility criteria for review

    Data extraction

    We developed a data extraction sheet (table S2, appendix) that will be piloted on 5 randomly

    selected included studies. The form will be adapted after discussion during consensus meetings. Data

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    will be independently extracted, and subsequently compared, by MB and CO, in order to minimise

    extraction errors.8 We will extract demographic (age; education) and clinical variables (DM1 class

    (congenital/juvenile/adult/late-onset), disease severity, presence of depressive symptoms). Study

    characteristics such as number of patients, main inclusion criteria and reported outcomes will also be

    extracted. Additional items to assess the risk of bias are added to the data extraction sheet (see risk

    of bias).

    To facilitate the extraction of data, neuropsychological tests identified in a set of articles identified

    through a preliminary PubMed search were categorized into different cognitive domains based on a-

    priori theory and convention (e.g. in accordance with established handbooks such as Lezak et al.,

    2012 and Strauss, Spreen & Strauss, 2006).9, 10 This approach is comparable to published meta-

    analyses on cognition in other disease fields .11, 12 Additional tests to be found in included studies will

    be classified following consultation with an experienced clinical neuropsychologist (RK). If a single

    study reports multiple tests within the same domain, an average effect size will be calculated for that

    domain from that particular study. If multiple subtests leading to one overall score are reported, only

    subtests that can be classified in a domain from the aggregated score will be used in our analysis. In

    case multiple subscores of a single test are reported without an aggregate test score, we will either

    use the most frequently or most general subscore , or pool different subscores, as considered

    appropriate. Direction of test scores will be obtained from method sections or deducted from the

    results or discussion sections of respective papers. Results of individual neuropsychological tests will

    be reported separately if they are reported in a minimum of five studies.

    Risk of bias

    MB and CO will assess the risk of bias for all of the included articles. The bias assessment form is

    based on a modified ve

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