A critical review of functional assessment tools for upper limbs in Duchenne muscular dystrophy

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW A critical review of functional assessment tools for upper limbs in Duchenne muscular dystrophy ELENA S MAZZONE 1 * GESSICA VASCO 1 * CONCETTA PALERMO 1 FLAVIANA BIANCO 1 CARMEN GALLUCCIO 1 VALERIA RICOTTI 2 ANTONELLA D CASTRONOVO 1 MARIA SOLE DI MAURO 1 MARIKA PANE 1 ANNA MAYHEW 3 EUGENIO MERCURI 1,2 1 Department of Paediatric Neurology, Catholic University, Rome, Italy. 2 Dubowitz Neuromuscular Centre, Institute of Child Health, London; 3 Institute of Genetic Medicine, Newcastle Upon Tyne, UK. Correspondence to Dr Eugenio Mercuri at Child Neurology Unit, Policlinico Gemelli, Largo Gemelli, 8, Rome, Italy. eumercuri@gmail.com *The first two authors contributed equally to the study. PUBLICATION DATA Accepted for publication 4th April Published online 19th June ABBREVIATIONS ADL Activities of daily living DMD Duchenne muscular dystrophy MFM Motor Function Measure The recent development of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify clinical outcome measures for planned efficacy studies. Although several studies have reported the value of functional scales, timed tests, and measures of endurance aimed at ambulant individuals, less has been done to identify reliable measures of function in individuals who have lost ambulation. The aim of this paper is to provide a critical review of the existing literature on functional measures assessing upper extremity function in DMD. Four observer-rated, performance-based measures and four self-reported scales have been previously used in DMD. Each scale provides useful information but none reflects all the different levels of functional ability in activities of daily living observed in individuals with DMD at different ages. The recent development of therapeutic treatment approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify clinical outcome measures for planned efficacy studies. A number of workshops have been held to find a consensus on possible outcome measures, encouraging collaborative multicentre studies in order to assess the suitability of the selected measures. 1 3 Several studies have reported the value of both quantitative and manual muscle strength testing measures in DMD, 4,5 but recently aspects of motor function that reflect activities of daily living (ADL), and are therefore thought to be more clinically relevant, have attracted increasing attention. 1,2,6 Until now, the majority of recently completed and ongoing clinical trials in DMD have targeted young ambulant participants, 7 9 and most of the efforts have been devoted to identifying reliable outcome measures in this group. A number of measures, including functional scales, timed tests, and, more recently, measures of endurance, such as the 6-minute walk test, 16,17 have been selected and validated, confirming the feasibility and reliability of repeated evaluations performed at multiple sites in multicentre studies These studies also produced an impressive number of data sets reporting natural history data on disease progression in a large number of children, reflecting contemporaneous standards of treatment, including steroids. 3,16,19 Less attention has been devoted to older individuals with DMD and, in general, to those who have lost ambulation. In addition there is increasing pressure from advocacy groups and regulatory agencies to identify functional outcome measures able to reflect the functional ability observed at different stages of the disorder, and to ensure that other populations of individuals with DMD are included in the target group for any new therapy. 2,3 This has produced new interest in identifying suitable functional assessments for very young children and, at the other end of the scale, for non-ambulant individuals. Assessments of upper limb function have been used to capture functional changes across different stages of the disease A number of these assessments have explored the effect of progressive weakness on upper limb and manual abilities and dexterity. 23,24,26 Other tools have investigated different aspects of ADL involving upper limb function, such as transfers, feeding, or washing, that provide a measure of the ability of the individuals to interact with the environments and of their level of independence. 21,27,28 In this paper we provide a critical review of the existing literature on functional measures assessing upper limb function in DMD in order to examine their applicability and reproducibility in non-ambulant individuals with DMD. METHOD Search strategy A comprehensive search of the following electronic databases wasperformed:medline,cinahl,psycinfo,andem- BASE. We also searched the web-based registry of measures ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press DOI: /j x 879

2 on the TREAT NMD website ( research/outcome-measures/rom/). The primary search terms duchenne muscular dystrophy or neuromuscular disorder or muscular dystrophies were combined with keywords assessment, outcome, measure, and function. We also ran a more specific search using upper limb or upper extremity. All electronic searches were limited to the English language owing to the lack of resources for translation, and to publication years 1980 to Reference listsofrelevantarticlesweresearchedtoidentifyanyother further assessment tool or other studies evaluating their properties. Inclusion exclusion criteria To be included, an assessment tool had to meet the following a priori inclusion criteria: (1) the primary aim was to assess upper extremity function or (2) at least 25% of the assessment items evaluated the upper extremity; (3) it had been reported in studies in males with DMD; and (4) the assessment was available for use. Data extraction and quality assessment The titles and abstracts of articles were screened by the first authors (EM GV). As it was not always possible from the abstract to ascertain details of the assessments and to distinguish between strength and function, we first identified all papers including assessments of upper limb or general functional assessments and the full text of articles were then scrutinized to obtain details of the methods and of their application. As the primary aim was to review functional assessments, we identified papers using functional assessments, either isolated or in conjunction with other measures, and excluded those using only measures of strength. We used a data extraction checklist to obtain data on topics, assessment tools used (e.g. function vs strength), study design, setting (observer-rated vs self-reported), studied population (DMD only, all neuromuscular disorders), numbers of participants, and relevant results. The selected papers were further subdivided into (1) those reporting observer-rated performance-based measures; and (2) those focused on self-reported questionnaires investigating aspects of ADL. Data extracted included the name of the assessment tool, publication details, purpose and description, and designated population. We analysed the number of items, time to complete evaluation, and possible overlaps between the selected measures. We also assessed if the available measures covered the full range of upper limb activities ranging from shoulder abduction and lifting the arms above the head to minimal distal movements, reflecting all the different levels of functional ability seen in individuals with DMD at different ages. We assessed if the items included bimanual tasks or the performance, such as writing or moving objects on a horizontal plane, required for many ADL. Finally, we searched for reliability and validity data reporting if the method had already been used in longitudinal studies in males with DMD. What this paper adds The paper provides the first critical review of the existing literature on functional measures assessing upper extremity function in DMD. The review suggests that none of the existing measures reflects the different levels of functional ability observed in in activities of daily living in individuals with DMD at different ages. RESULTS A total of eight assessment tools met the inclusion criteria as functional measures (Tables IandII). Four assessments were observer-rated, performance-based measures (Table I). Three of the four assessed upper limb only: the Brooke Upper Extremity Scale 26 and the Upper Limb Functional Ability Test, 29 specifically designed for individuals with neuromuscular disorders, and the Jebsen Hand Function Test, originally developed for individuals with cerebral palsy. 30,31 The fourth scale, the Motor Function Measure (MFM), is a general scale for the assessment of neuromuscular disorders assessing axial, proximal, and distal motor capacity, with one of the three domains dedicated to distal function (domain 3) and another (domain 2) including a few items assessing proximal upper limb function. 14 The other four measures, the Egen Klassification, the Activli, the ABILHAND, and the Muscular Dystrophy Functional Rating Scale (Table II), are self-rated measures that assess aspects of upper limb function related to ADL through a questionnaire. The ABILHAND was specifically developed for assessing upper limb activities; 32 the others are not, but include a significant number of activities (>26%) related to upper limb function. 22,27,28 In the Egen Klassifikation scale, the questions are combined with observed tasks. 27 Table III provides details of the papers reporting the use of the selected measures and of their use, in isolation or in combination with other measures. Reliability and validity studies Reliability and validity studies were available for all the selected studies (Table III). Table IV lists upper limb activities and the items from different observer-rated measures assessing the individual abilities, showing the overlap among individual measures. DISCUSSION In recent meetings of experts in outcome measures in neuromuscular disorders, advocacy groups, and regulatory agencies there was widespread consensus that measures for non-ambulant individuals with DMD should be clinically meaningful and address the varying levels of functional ability observed at different ages. 1 3 The most recent review highlights the need to identify assessments of upper limb function that can be used across the spectrum of abilities. 3 Individuals with DMD begin to experience weakness in the upper limbs when they are still ambulant, with difficulties gradually increasing in the proximal muscles and exhibiting a proximal to distal gradient of progression. A few years after loss of ambulation, antigravity movements are generally limited to the forearm and hands and there is loss of shoulder abduction and flexion. Subse- 880 Developmental Medicine & Child Neurology 2012, 54:

3 Table I: Details of the observer-rated measures Brooke Upper Extremity Scale Jebsen Hand Function Test Motor Function Measure (MFM) Upper Limb Functional Ability Test No. of items of the 32 items assess upper limb function 14 Items 1. Starting with arms at sides, can abduct arms in a full circle until they touch above head 2. Can raise arms above head only by flexing elbow or by using accessory muscles 3. Cannot raise arms above head but can raise a glass of water (=8oz) to mouth (using both hands if necessary) 4. Can raise hands to mouth but cannot raise a glass of water to mouth 5. Cannot raise hand to mouth but can use hands to hold pen or pick up pennies from table 6. Cannot raise hands to mouth and has no useful function of hands 1. Writing 2. Turning over 3 by 5 in card 3. Picking up small common objects 4. Simulated feeding 5. Stacking checkers 6. Picking up large objects 7. Picking up large heavy objects D2=Upper limb axial motor capacity 15. Forearms resting on table, place both hands on top of head 16. Hand resting on table, reach pencil with one hand and elbow in maximal extension 23. Arms along trunk, place forearms hands on table at same time D3=Upper limb distal motor capacity 17. Pick up and hold 10 coins in one hands (20s) 18. Go around edge of a CD with one finger, no contact of hand on table 19. Pick up a pencil and draw series of loops inside a horizontal frame 20. Tear a sheet of paper folded in four 21. Pick up a tennis ball and turn hand over completely holding the ball 22. Place finger in eight squares of 3 3diagram Administration time 5min 20 45min 10 15min Not applicable Scoring The score is given by the last item that has been fully performed Time necessary to complete each subtest (rounded the nearest second). Slow times reflect a less desirable performance Each item is scored on a 4-point scale. Scores are expressed as a percentage: total score achieved on a single dimension multiplied by the total number of items, divided by 100. For the MFM-32 the total score is the total sum of 32 items divided by 96 and multiplied by 100 Upper limb axial motor capacity 1. Raises himself and maintains the position for 2 3s 2. Shoulder extension 3. Shoulder internal external rotation 4. Shoulder flexion 5. Shoulder abduction adduction 6. Shoulder flexion abduction 7. Elbow flexion Upper limb distal motor capacity 8. Forearm pronation supination 9. Wrist flexion extension 10. Wrist ulnar deviation 11. Metacarpophalangeal flexion extension 12. Proximal interphalangeal joint flexion extension 13. Thumb opposition to other fingers 14. Finger tremors Each item has a maximum value of 1 point. Each item has two sub-items, each of which are tested separately contributing one-half of a point Review 881

4 Table II: Details of the self-reported measures Egen Klassifikation ABILHAND (questionnaire to measure manual ability in neuromuscular disorders) ACTIVLIM (self-reported scale of activity limitations) Muscular Dystrophy Functional Rating Scale Number of (UL) activities Items 4 of the 10 items assess upper limb function Ability to use wheelchair Ability to transfer from wheelchair Ability to move arms Ability to use the hands and arms for eating of the 22 items assess upper limb function Taking the cap off a bottle Cutting one s nails Buttoningupashirt Fastening the zipper of a jacket Turning a key in a keyhole Fastening a snap (jacket, bag) Opening a pack of chips Opening a pack of biscuits Inserting a key in a keyhole Turning off a tap Turning on a tap Filling a glass with water Sharpening a pencil Opening a bread box Squeezing toothpaste on to a toothbrush Spreading butter on a slice of bread Opening a toothpaste tube Counting banknotes Dealing cards Unwrapping a chocolate bar Wiping one s hands Washing one s hands Carrying a heavy load Taking a bath Putting on a backpack Dressing one s lower body Taking a shower Wiping one s upper body Putting on a T-shirt Hanging a jacket on a hat stand Sittingonthetoilet Washing one s upper body Opening a door Closing a door Washing one s face 15 of the 33 items assess upper limb function Mobility domain Indoor mobility Transferring from bed to chair Wheelchair manipulation Basic activities of daily living domain Feeding Combing hair Brushing teeth Dressing upper lower parts of body Bathing Arm function domain Managing objects overhead Carrying object Cleaning table Writing Turning books Picking up small objects Manipulating small objects Administration 10 NA NA NA Scoring 4-point grading 4-point grading system 3-point grading system 4-point grading system system UL, upper limb; NA, not applicable. quently, movements are limited to hand and wrist and, eventually, to fingers. The assessment of strength is a valuable indicator of the progression of weakness, but functional abilities such as lifting and reaching are also influenced by other variables, such as the severity of contractures or compensatory strategies. Because of this, ability to perform ADL does not always reflect the individual s level of strength. It has therefore been suggested that functional assessments should be used to provide useful additional information to strength measurements, including the ability to perform bimanual tasks. The aim of this review was not only to provide a list of measures used in DMD but also to provide a critical review aimed at identifying clinically meaningful tools that could be reliably used as outcome measures in clinical trials. Of the eight upper limb functional assessments already used in individuals with DMD, four are observer-rated, performance-based measures and the others are self-reported measures, based only or mainly on questionnaires. The advantage of the observer-rated measures is that the items are assessed using standardized procedures, instructions, and material. In recent years, increased attention has been devoted to overcoming difficulties in the use of observer-rated measures in multicentre settings. 10,13 Each measure was able to assess different stages of severity covering a variety of aspects of ADL with relatively little overlap among individual items on the four scales. The differences between the measures probably reflect the fact that they have been developed with different aims. The Brooke scale has been successfully used in clinical practice for over three decades. It was developed to categorize individuals according to their maximal level of activity in the upper limbs. 26,40 However, it is limited to six levels of function and is, therefore, not sensitive to relatively minor functional changes. Furthermore, it does not specifically assess hand function. The advantage of the MFM is that it covers a full range of activities from shoulder abduction to distal movements that can be measured in both ambulant and non-ambulant individuals. A number of items are related to distal function, and provide useful information on abilities, such as tracing a diagram or a circular path, that reflect the function needed to use a wheelchair joystick or a touchscreen, and are important for those with limited finger movements. However, only a few activities measure antigravity power in the forearm, such as moving the hand to the mouth or reaching, functions that are clinically important for a significant number of children with DMD in the years after they have lost ambulation. This is because only approximately 25% of the items of the MFM assess any aspect of upper limb function, as the scale was designed to assess function in individuals with a wider range of neuromuscular disorders, such as spinal muscular atrophy or distal neuropathies with a different pattern of weakness and contractures and different disease course. 882 Developmental Medicine & Child Neurology 2012, 54:

5 Table III: Main papers reporting observer-rated and self-reported measures in Duchenne muscular dystrophy (DMD) Measure Reference Ambulatory DMD Non-ambulatory DMD Other measures Content of the paper Observer-rated, performance-based scales Brooke Upper Extremity Scale Brooke et al. 26 ns ns MRC, ROM, FVC, HHD, Description of test Brooke Upper Extremity Scale Florence et al MRC, ROM, FVC, TT Intra- interobserver reliability Brooke Upper Extremity Scale Lord et al MMT Correlation with strength Brooke Upper Extremity Scale Wagner et al ROM, MRC, QMT Correlation with other scales Brooke Upper Extremity Scale Barr et al MMT, Vignos, ROM Inter- intra-evaluator reliability Brooke Upper Extremity Scale Lue et al Barthel, Vignos Cross-sectional, correlation with other measures Jebsen Hand Function Test Hiller and Wade Brooke Suitability, test retest, correlation with other scales Jebsen Hand Function Test Wagner et al ROM, MMT Cross-sectional Motor Function Measure Bérard et al FIM, Brooke Construction and interrater reliability, correlation with other scales Motor Function Measure Vuillerot et al Longitudinal, sensitivity to change Motor Function Measure Bartels et al ROM, HHD, MMT Cross-sectional study Upper Limb Functional Ability Test Zupan ROM, Brooke Inter- and intrarater reliability, correlation with other measures Self-reported scales Egen Klassifikation Steffensen et al MRC, ROM Content and construct validity, interrater reliability, correlation with other measures Egen Klassifikation Steffensen et al MRC, Brooke Longitudinal study ACTIVLIM Vandervelde et al FIM Correlation with other measures ACTIVLIM Vandervelde et al MMT, QMT Correlation with other measures ACTIVLIM Vandervelde et al Rasch analysis, longitudinal study ABILHAND Vandervelde et al ACTIVLIM, QMT Rasch analysis, correlation with other measures Muscular Dystrophy Functional Rating Scale Lue et al. 22 ns ns MMT, ROM, Barthel, Brooke Inter- and intrarater reliability, internal consistency, correlation with other scales +, present; ns, not specified; MRC, Muscle Research Council; ROM, range of movement; FVC, forced vital capacity; HHD, hand-held dynamometry; TT, timed test; MMT, manual muscle testing; QMT, quantitative muscle testing; FIM, Functional Independence Measure. Table IV: Clinically relevant abilities assessed in the individual measures Performance-based, observer-rated measure Clinically relevant activities Brooke Upper Extremity Scale Jebsen Hand Function Test Motor Function Measure Upper Limb Functional Ability Test Lifts hands above head Shoulder abduction + + Reaching at shoulder height) + + Lifting objects from table surface + Hands to mouth + + Bringing hands onto table (from lap) + Moving objects on horizontal plane + Write + + Bimanual activities + + Timed items + The Jebsen Hand Function Test is essentially a series of timed tests that assess movement in the horizontal plane and, as such, it does not explore activities, such as hand to mouth, that are important in everyday life. 24,30,31,35 A previous study using the Jebsen Hand Function Test in individuals with DMD highlighted the difficulties that such individuals have in performing some items of the test. The writing task was considered unsuitable, reflecting the learning difficulties often associated with DMD and not specifically poor hand function. 24,31 In addition, the scale, successfully used in the assessment of hemiplegia or other types of cerebral palsy, assesses only unimanual abilities and includes no bimanual tasks. 30 Furthermore, the scoring system is based on the time spent to complete the task only when this is successfully performed. According to the instructions, there is no possibility of scoring the level of ability if the participant is not able to complete the task and does not capture information regarding compensatory strategies. Review 883

6 Finally, the upper limb functional ability test includes a wide range of items assessing both proximal and distal movements and has been used in a large cohort of individuals with neuromuscular disorders including males with DMD. 29 The scale is specifically designed to assess functional movements, i.e. the strength required to perform movements, providing information on the level of impairment of individual groups of muscles and, despite its name, does not assess functional abilities or ability to perform ADL. Compared with the observer-rated measures, the selfreported measures have the advantage of including ADL that cannot always be observed in a clinical or research setting. The Egen Klassifikation has been successfully used in individuals with DMD, and also in longitudinal studies. 27,37 It assesses a variety of aspects, including ability to speak or to cough, and includes a number of items assessing upper limb function or the ability to perform activities requiring the use of upper limbs (ability to use manual wheelchair). Both the ACTIVLIM 20,28 and the Muscular Dystrophy Functional Rating Scale 22 also assess a wide range of abilities, whereas the ABILHAND is specifically designed to assess upper limb function. One of the advantages of the ABILHAND and ACTIVLIM is that they have been developed in recent years and the authors have pioneered the use of psychometric tests, such as Rasch analysis, to improve the measurement qualities of these scales. 20,28,38,39 The information provided by the self-reported measures is extremely valuable as it provides an understanding of individuals ability to interact with their environments and their degree of independence, but one should be aware of their limitations when used as a primary outcome measures in a trial. Some activities, such as transfer from wheelchair, depend on a number of variables that cannot easily be standardized (e.g. size of the wheelchair) and comparing results across participants can be difficult in a clinical trial. Other activities listed in the ABILHAND, such as closing a zipper or turning a tap on and off, also depend on the size and nature of the objects. CONCLUSION Our review suggests that a number of measures are available for assessing different and often complementary aspects of activities requiring upper limb function. For these measures there are some data concerning inter- and intraobserver reliability with more data on validation of construct or on the use of Rasch analysis for the MFM, the ABILHAND and the ACTIVLIM. 14,15,20,28,38,39 Each of these measures provides useful information but none appears to be able to fulfil the three requirements for an ideal measure: covering the full spectrum of abilities, to address all the issues related to clinical meaningfulness, and standardization of tasks. The difficulty in identifying a perfectly suitable measure among the ones selected reflects that they were not specifically designed for DMD. Because of this, the spectrum of activities assessed and their scoring system do not necessarily reflect the abilities or difficulties related to the DMD-specific pattern and progression of weakness and contractures. Further work is required to fill the gaps in the existing measures. A consortium of experts has recently devised a diseasespecific module for assessing upper limb function in nonambulant individuals with spinal muscular atrophy, modifying the most suitable items from existing scales and developing new items based on what was reported as clinically meaningful by individuals experiencing weakness and their families. 12 A similar approach may be used for assessing upper limbs in DMD. There is general agreement among experts that future development should prioritize not just the identification of an assessment for non-ambulant individuals with DMD but measures that could be used across spectrum of abilities. Recent or ongoing trials in ambulant DMD using the 6-minute walking test and timed items as the only motor outcome measures have highlighted the difficulty of following changes in the children who lost ambulation during the course of the trial. 41 One would therefore wish to identify measures of upper limb function that can already be used in ambulant children who are still able to perform antigravity movements but should also include aspects of more limited function to be used in older individuals who only have few residual movements, limited to hands and fingers. Further work is therefore required to develop a protocol including many of the items from the existing scales that appear to be more suitable for individuals with DMD and to validate new methods of assessment, such as electronic devices, that may provide an objective assessment of function and endurance. 42 ACKNOWLEDGEMENT Elena Mazzone is a TREAT NMD PT fellow funded by Telethon Italy. REFERENCES 1. 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