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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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Background

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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Methods

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

group

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 version of the Newcastle-Ottawa quality assessment scale.13 The NOS evaluates

selection of participants, comparability of the participants and data collection (table S3, Appendix).

We plan to assess whether risk of bias due to motor deficits and dysarthria was addressed in studies.

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Furthermore, we will examine studies for reporting on respiratory dysfunction, depression and

anxiety and use of psychoactive medication, as these factors themselves may lead to cognitive

deficits. Risk of publication bias will be explored using funnel and Galbraith plots.14, 15

Statistical analysis

Effect sizes from each study for different neuropsychological domains will be expressed as the

standardised mean differences expressed as Hedges g. A random effects model was chosen to obtain

an average weighted effect size across the studies. Effect sizes will be interpreted as small, medium

and large for values of 0.2, 0.5 and 0.8 respectively, as previously described.11 A negative effect size

(<0) indicates worse performance in DM1 patients compared to controls and higher effect sizes will

always indicate better cognitive performance. Effect sizes will be considered significant when the

confidence interval (CI) does not contain 0. We will explore statistical heterogeneity among results

from included studies using τ2 and I2 statistics as well as the prediction interval. τ2 is the standard

deviation of between study effects, whereas I2 provides an estimate of the proportion of

heterogeneity among studies that can be attributed to real heterogeneity rather than to chance.

Low, moderate and substantial heterogeneity cut-off points have been previously defined at 25%,

50% and 75%, respectively.16 We also calculate prediction intervals because their interpretation with

regards to the true effect is more straightforward than those of τ2 and I2, and they offer the most

sensible way to summarize the results of heterogeneous studies.17 Sensitivity analysis will be done to

assess the influence of individual studies on our results, and possible causes in the case of

heterogeneity will be explored. Subgroup analysis is planned to analyse studies that did not include

congenital cases of DM1, meaning all studies not explicitly reporting to have excluded patients with

congenital DM1 will be left out. We will use R (version 3.1.3, R Foundation for statistical computing,

Vienna, Austria) for statistical analysis.18

Funding

We have no sources of funding to report for this review.

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Systematic Review Status

In process of data extraction

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References

1. Harper PS. Myotonic dystrophy, 3rd ed. / with a chapter on molecular and cell biology by J. David Brook and Emma Newman. ed. London: W.B. Saunders, 2001. 2. Bird TD. Myotonic Dystrophy Type 1. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)1993. 3. Hilton-Jones D, Turner MR. Oxford textbook of neuromuscular disorders, First edition. ed. 4. Rakocevic-Stojanovic V, Peric S, Madzarevic R, et al. Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1. Clinical neurology and neurosurgery 2014;126:76-81. 5. Axford MM, Pearson CE. Illuminating CNS and cognitive issues in myotonic dystrophy: Workshop report. Neuromuscular disorders : NMD 2013;23:370-374. 6. Lipsey MW, Wilson DB. Practical meta-analysis. Thousand Oaks, Calif. ; London: Sage, 2001. 7. Rosenthal R. Meta-analysis: a review. Psychosomatic medicine 1991;53:247-271. 8. Gotzsche PC, Hrobjartsson A, Maric K, Tendal B. Data extraction errors in meta-analyses that use standardized mean differences. Jama 2007;298:430-437. 9. Strauss E, Sherman EMS, Spreen O, Spreen O. A compendium of neuropsychological tests : administration, norms, and commentary, 3rd ed. Oxford ; New York: Oxford University Press, 2006. 10. Lezak MD. Neuropsychological assessment, 5th ed. ed. Oxford ; New York: Oxford University Press, 2012. 11. Beeldman E, Raaphorst J, Klein Twennaar M, de Visser M, Schmand BA, de Haan RJ. The cognitive profile of ALS: a systematic review and meta-analysis update. Journal of neurology, neurosurgery, and psychiatry. Published online first: August 17, 2015. doi:10.1136/jnnp-2015-310734. 12. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes care 2005;28:726-735. 13. Wells GA SB, O’Connell D, Peterson J, Welch V, Losos M. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. [online]. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 24-03-2016. 14. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj 1997;315:629-634. 15. Anzures-Cabrera J, Higgins JP. Graphical displays for meta-analysis: An overview with suggestions for practice. Research synthesis methods 2010;1:66-80. 16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Bmj 2003;327:557-560. 17. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. Journal of the Royal Statistical Society Series A 2009;172:137-159. 18. R: A language and environment for statistical computing. [computer program]. Version 3.1.3. R Foundation for Statistical Computing, Vienna, Austria: 2015.

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Supplementary material

Table S1. Search terms

Search terms

Myotonic Dystrophy

Free text myoton* dystroph* dystroph* myoton* Steinert*

EMTREE myotonic dystrophy

MeSH myotonic dystrophy

Psycinfo muscular dystrophy myotonia

Cognition

Free text cogniti* neuropsychologic* intelligence dementia mental processes visuospatial visuoperceptive language thinking brain comprehension learning decision making speech verbal recall social recognition

EMTREE cognition cognitive defect social cognition neuropsychological test intelligence intelligence test memory memory disorder aptitude test language

MeSH mental processes cognition disorders cognition memory memory disorders neuropsychological tests aptitude tests intelligence intelligence tests language

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language disorders

Psycinfo cognition cognitive impairment neuropsychological assessment social cognition intelligence intelligence measures psychometrics cognitive processes memory memory disorders aptitude measures language language disorders

Table S2. Data extraction form

Systematic Review & Meta-analysis Data Extraction Form

Data extractor name: Date:

Study ID

Author

Title

Year

Language

Patients Controls

Number (male/female)

Age (years)

Education (years of formal education/ISCED)

Main in-/exclusion criteria

DM1 classes included

CTG repeat length mean (SD)

Neuropsychological tests (mean (SE))

Global cognition

Intelligence

Language

Executive functions

Overall memory

Verbal memory

Visual memory

Visuoperceptive functions

Visuoconstructive functions

Psychomotor speed

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Attention

Social cognition

Legend: ISCED internation standard classification of education DM1 classes congenital present at birth, juvenile presenting after birth-17 years, adult 18-60 years, late-onset >60 years of age

Table S3. Risk of bias assessment form

Assessment of risk of bias (modified from NOS case-control form for risk of bias)

Selection bias

Is case definition adequate?

□ Yes, with independent validation (1)

□ Yes, e.g. record linkage or self report (2)

□ No description (3)

Representativeness of cases

□ Consecutive or obviously representative series of cases (1)

□ Potential for selection bias, or not stated (2)

Selection of controls □ Community controls (1)

□ Hospital controls (2) □ No description (3)

Definition of controls □ No history of disease (1)

□ No description of source (2)

Comparability

Correction for respiratory dysfunction?

□ Study assesses respiratory function (1)

□ Respiratory dysfunction exclusion criterion (2)

□ No assessment/ criterion or not reported (3)

Correction for dysartria and motor disabilities?

□ Study assesses dysarthria/motor skill (1)

□ Significant dysarthria or motor dysfunction exclusion criterion (2)

□ No assessment/ criterion or not reported (3)

Depression and anxiety

□ Study assesses/ reports depression and/or anxiety in patients and controls (1)

□ Depression and/or anxiety exclusion criterion for patients and controls OR exclusion criterion in one and assessed/ reported in other group (2)

□ Depression and/or anxiety exclusion criterion for patients or only reported in patients (3)

□ Depression and/or anxiety exclusion criterion for controls or only reported in controls (4)

□ No assessment or criterion or not reported (5)

Psychoactive medication use

□ Use of psychoactive medication reported (1)

□ Use of medication exclusion criterion for patients and controls (2)

□ Use of medication exclusion criterion for patients (3)

□ Use of medication exclusion criterion for controls (4)

□ Not reported or unclear (5)

Data collection

Same method of ascertainment for cases and controls

□ Yes (1) □ No (2)

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Non-response rate □ Non-response rate reported and non-respondents described (1)

□ Non-response rated reported, not described (2)

□ Non-response rate not reported (3)