Psychological test usage in duchenne muscular dystrophy: An EU multi-centre study

) study. Instruments and diagnoses being used were inventoried for three domains of functioning (cognition, behaviour and academics) and three age groups (3 – 5 years, 6 – 18 years and adulthood 18 + years). Results: Data show wide diversity of tests being used in the five centres at different age groups and different domains. For the intelligence testing there is consensus in using the Wechsler scales, but all other domains such as memory, attention, behavioural problems and reading are tested in very different ways by different instruments in the participating centres. Conclusion: The heterogeneity of tests and diagnoses being used in current clinical practice underlines the importance for developing a Standard Operating Procedure (SOP) to improve both clinical practice and scientific research over different countries and improve comparative work.


Introduction
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), are X-linked progressive muscular disorders occurring in a frequency of respectively about one case in 3500-9300, and one case in 16700-18500 new-born boys (Orpha: 98896; Orpha: 98895).Both diseases are caused by mutations in the dystrophin gene, resulting in partial expression of the dystrophin protein in BMD, and an absolute absence of dystrophin and in DMD (1)(2)(3).Lack of dystrophin causes progressive muscle weakness, and consequently fatal cardiac and pulmonary complications.Therefore, preservation of muscle plays a central role in daily functioning and has been the main focus of medical interest.In the last two decades there has been a growing interest in neurocognitive and behavioural comorbidities in dystrophinopathies.It has been shown that intellectual disability, autism spectrum disorders, attention deficit disorder and learning difficulties such as dyslexia, are more common in dystrophinopathies than in the typically developing population.Intellectual disability occurs approximately in 19-26% of the DMD patients, autistic features in up to 19%, obsessive compulsive features up to 25%, attention deficit disorder 11-32%, and language and speech delays almost to 25%.Moreover, males with DMD score one deviation below average on IQ (84.76) and significantly lower than males with BMD (92.11) [4].A brain based explanation for this higher prevalence has been reported.Several isoforms of dystrophin (including Dp427, Dp140, and Dp71) are present in the central nervous system (CNS) and are thought to contribute to several higher order functions such as memory and learning [5][6][7][8][9][10][11][12][13][14][15][16][17].
Consistent screening of frequently comorbid neuropsychiatric and cognitive conditions in DMD patients is therefore important, [18].This is to make sure that patients can be appropriately referred for psychiatric and psychological treatment and care, in accordance with the revised Standards of Care (SoC) in 2018 [19].These Standards of Care describe the importance of early and adequate assessment for neuropsychological functioning in dystrophinopathies, but lack a description of what assessment procedures should be used to make a formal diagnosis.
Looking at the current literature there is a large number of different psychological instruments being used in DMD.A review of 32 studies on intellectual functioning in DMD boys [16] reported over 8 different instruments being used, resulting in a mean IQ of 80.2.In another review of Hellebrekers [20], they found a total of 61 instruments being used in 51 DMD studies.They concluded that different diagnostic instruments may lead to different prevalence rates of comorbidity depending on which tests were used.
In 2020 seven neuromuscular centres in six European countries (UK, Denmark, France Italy, Netherlands, Spain) started a multicentre study on Brain INvolvement in Dystrophinopathies (BIND, Horizon 2020 (847826), https://bindproject.eu/).The aim of this project is to improve understanding and measurement of dystrophin in the brain and working towards better treatment, care, and outcomes for all those living with Duchenne and Becker muscular dystrophies.As part of this study, we describe which tests are used in clinical practice for boys and men with DMD for three domains of functioning [1]: intelligence/neurocognitive functioning [2], behavioural/psychiatric functioning, and [3] learning disabilities over three age groups [1] preschool i.e. 3-5 years [2], school age: 6-18 years and [3] adulthood i.e. 18 years and older.Our aim is to describe a baseline of current practice with respect to psychological assessment and diagnoses being made in current clinical practice in 7 centres located in 6 European countries.

Participants
This study is part of an ongoing European project, Brain INvolvement in Dystrophinopathies (BIND).Psychologists from seven neuromuscular centres participated: University College London (UCL), University of Newcastle Upon Tyne (UNEW), Kempenhaeghe Centre for Neurological Learning Disabilities (KEM), Universidad Complutense de Madrid (UCM), Department of Neurology, Rigshospitalet, Copenhagen (RegionH), Imagine Institute des maladies genetiques Necker Enfant maladies foundation Paris (NEM), Universita Cattolica del Sacro Cuore, Rome (UCSC).In two of the seven centres, patients are not (routinely) assessed by a psychologist or psychiatrist.When there are any concerns regarding the cognitive, behavioural or emotional functioning of a child, he or she is referred to another health service.These centres (UCL and RegionH) were excluded from the analysis.On a yearly basis, approximately 100 males with dystrophinopathies are seen at UCSC, 20 at UCM, 20 at KEM, 10 at UNEW, and 10 at NEM for neurocognitive and behavioural assessments.Patients are referred for clinical care by health care specialists (e.g.neurologist, paediatrician, psychiatrist)), research activities (e.g.Duchenne Parent Project -Spain), and longitudinal monitoring (e.g. at UCSC).

Measure
An open-ended questionnaire was sent via e-mail to psychologists of the participating centres asking for [1] how often tests are being used (per age group and per domain (i.e.intelligence/cognition, behaviour and academics) rated on a four point scale: always, often, sometimes, never [2], which tests are being used per domain and per age group (an open ended question), and [3] which diagnoses are being made on the basis of these instruments mentioned (per age group and per domain).

Statistical analysis
Data analysis was performed using Microsoft Excel (2019).Initially, frequencies were calculated (see Tables 1-4).The open-ended questions were analysed by manually coding and transcribing, and describing testname and psychiatric/neurodevelopmental diagnosis.

Results
With respect to how often testing was done on a regular basis, data on the combined five centres are described in Table 1.Boys in the age group 6 to 18 are most frequently assessed.For the age group over 18 years one of the five centres never assesses adults.
The number of different tests used in five centres is presented in Table 2.The names of the different tests are listed in addendum 1.As tests can be used in different age-groups and different domains, the number of 164 tests in Table 2 does not correspond with the number of 89 tests in the addendum.It can be seen that there is a vast majority of tests being used for the three domains of functioning and the different age groups.Especially for the domain learning and academics language specific instruments are being used.
For the age group 3-5 years of age on the cognitive domain the WPPSI (Wechsler Preschool and Primary Scale of Intelligence) is used most often: in the five centres).For the behavioural domain the CBCL (see addendum 1 for list of abbreviations) is used in three of the five centres.All other 32 test are used in only one of the centres and represent very different instrument e.g.Merrill Palmer Revised, Bells test, Griffith, and Leiter (cognition), ADOS, Conners-3.PARS-III, Vineland-II (behaviour) and Illinois test of psycholinguistic abilities, Prolexia (learning).
For the school aged boys [6][7][8][9][10][11][12][13][14][15][16][17][18] there is slightly more heterogeneity in the same tests being used at different centres.Of the 79 instruments being used in this age group (Table 2).Table 3 describes the tests being used in two or more centres.Also aim of the test, age ranges, and the normative samples available and/or used are described.
We also explored the diagnostic categories that are being made in the five centres on the basis of the instruments used via an open-ended question.In one of the five centres adults (older than 18) are referred to regular educational or health care services for diagnoses.The diagnosis of intellectual disabilities is made most often (in all of the centres).In Table 4 an overview of the most frequently made diagnoses is given for all three age groups.

Discussion
We found a tremendous heterogeneity in the assessments used: e.g.79 tests are used for psychological and cognitive assessment of school aged DMD boys in five centres.The most frequently used instruments were Wechsler intelligence Scales, Tower of London, Conners behaviour rating and Child behaviour checklist (CBCL).This wide variety of instruments is probably related to a combination of the increased attention that has been devoted to cognitive abilities in DMD, and to school concerns, as also demonstrated by the fact that cognitive abilities are most often assessed during school age.The assessment of cognitive abilities was often limited to general scales such as the Wechsler scale.More specific aspects of cognition, such as testing of language, which is P. Weerkamp et al. an important function in DMD, were only routinely performed in two centres.
Other aspects of neurobehavioral and neuropsychological functioning were often assessed with common tests, such as the CBCL, which provides information on a broad range of behavioural and emotional problems in children.However, the CBCL has recently been found to be not entirely suitable for DMD boys as some of the items are less applicable to them due to progressive muscle wasting [20].
When trying to identify the frequency of diagnoses made per age group, we observe that neurodevelopmental diagnoses (e.g.ADHD and ASD) are made more frequent in younger children with DMD, school aged boys are more often diagnosed with cognitive deficits or learning problems, and (young) adults more often with anxiety and depression.Different rates in diagnoses per age group may reflect a cumulative list of clinical symptoms when growing older and the possibility of already being diagnosed with a neurodevelopmental disorder, or reflect a change in psychological functioning (e.g. more anxiety and depression) during transition in adulthood.A longitudinal study design is needed to further investigate the relation between age and brain related comorbidities.
Different review studies [9,16,20] confirm our findings in seven EU neuromuscular centres showing an abundance of different tests being used for neuropsychological problems, resulting in different prevalence rates of brain related comorbidities in boys and young men with DMD.
The current analysis was extremely useful to understand the complexity of the topic.Despite the limitation of a relatively small number of centres participating to the survey, that may not reflect what is used in other centres or countries, the data collected are representative of expert centres for neuromuscular disorders who were selected because of proven experience in testing DMD boys and men.
The heterogeneity of tools used, highlights on one hand the complexity of brain related comorbidities in dystrophinopathies [18] and on the other hand the need to identify a kit of tools that would allow a comparison of the results.Clinical features of CNS involvement in DMD are complex and there is no "one size fits all" assessment procedure for the psychological functioning.The impact of brain related comorbidities on quality of life for both individuals with DMD and their carers, is becoming increasingly evident.Combined also with the fact that life expectancy is prolonged due to better anticipatory care of the musculoskeletal, cardiac and respiratory complications, makes the development of a Standard Operating Procedure (SOP) for assessment of psychological functioning in DMD imperative.
Work is in progress to finalize a tool kit to be used in the BIND study to uniform the procedures and to identify a core set of tools to be used in a clinical setting for clinical purposes, and other tests that may be more suitable for research settings to better understand the complexity of CNS involvement and the correlation among different cognitive and behavioural variables.The BIND test battery includes among others the Wechsler Intelligence Scales and tools that assess: (working) memory,

Table 1
Assessment frequency (1 = not at all; 2 = sometimes; 3 = often; 4 = always) on regular base in three age groups and domains of functioning.attention, executive functioning, language, academics, ASD, ADHD, OCD, anxiety and depression, as these domains seem predominantly affected in dystrophinopathies [9,18,21].Collecting population-specific information on utility, validity, and normative data in dystrophinopathies is ongoing.Methodological challenges that come with cross-cultural research in psychology need to be considered.When comparing measurement outcomes across multiple cultures it is hard to obtain equivalence, which refers to the comparability level of measurement outcomes [22,23].To address the issue of languages, and cultural differences, we aim to include instruments that show good psychometric properties of the different translated versions and normcores in multiple countries.Our proposed method in attempting to statistically control for cultural bias includes analysing confounding factors such as years of education or socioeconomic status of study populations [23].Nonetheless, gathering sufficient normative and generalizable data across multiple populations, languages, and especially minorities remains a challenge.
With this EU multi-centre study we hope to set a first step in standardizing assessment procedures to identify comorbidities, in a way that advances research and collaborations, and standards of care in dystrophinopathies.

Table 2
Number of tests being used over the three age groups and domains of functioning.

Table 3
Tests used in two or more centres.