Commonly available outcome measures for use in Indian boys with Duchenne muscular dystrophy
Keywords: Duchenne muscular dystrophy, functional tests, outcome measures, strength tests
Duchenne Muscular Dystrophy (DMD) is currently incurable, but many potential therapies are undergoing clinical trials., These therapies have been successful pre-clinically in animals and are in different phases of clinical trials. All these clinical trials need sensitive and reliable outcome measures that can detect the disease progression and the potential effects of therapeutic drugs. These clinical outcome measures should also have the ability to detect changes even in young patients with DMD. As DMD is a rare disease with heterogeneous manifestations, the design of a clinical trial for it is often difficult. A lack of sensitive clinical outcome measures makes it even more challenging. Most of these clinical outcome measures have been designed in Western countries. However, in India, the clinical features are observed without using the outcome measures. There is a need to use clinical outcome measures which are commonly used in rest of the world in the Indian DMD population. This would help in comparing the natural history of disease progression of Indian patients with patients from other parts of the world. This manuscript will review the commonly used clinical outcome measures used globally, which can also be specifically used in the Indian boys with DMD.
Functional tests, which are commonly used by a physiotherapist for evaluating function of lower limbs and upper limbs, have been used in clinical trials. These functional tests are low-cost tests that are reproducible, and easy to use in clinical trials. These tests can give a quick assessment of how the disease is progressing in boys with DMD. It has already been shown that disease progression in India is comparable to that of Western population. Thus, similar tests can be used in India as well as in western countries to track the progression of the disease. Different tests are used for assessing lower limb and upper limb function as described below.
Most clinical trials related to DMD focus on changes in lower limb muscle function since they target the ambulatory population. Due to this, many functional tests have been developed by physiotherapists and clinicians over the years to assess the function of lower limbs. These tests have been extensively used in the DMD population, both clinically and in the research studies; clinical trials are, therefore, using them for testing the efficacy of their drugs. It has been observed that there is lower limb muscle weakness often with contractures present in patients with DMD, that was demonstrable in the study done in the South Indian population. Clinically, it has been observed that the proximal lower limb muscles are affected before the upper limb muscles. Thus, lower limbs have been the focus of attention for a long time. Below are some of the functional tests that can be used to assess the function of lower limbs in the Indian DMD population:
Timed function tests
Different timed function tests (TFTs) are used for assessing lower limb function in the DMD population. Some of the recently used TFTs measure the time taken: to walk/run 10 meters, to get up from the floor (supine-to-stand test), and to climb four stairs. In the 10 meter walk/run test, the subject is asked to either walk or run for 10 meters, whichever he thinks is faster, while the time is recorded. In the climbing four stairs test, the subject is asked to climb four stairs, either with or without the use of railings, while the time is recorded. In the supine-to-stand test, the subject is asked to get up from a lying down position on the floor and the time is recorded until he is standing upright with his hands at his sides. Qualitative grades ranging from 1 to 6 are used to assess each TFT, with grade 1 being an inability to perform the test and grade 6 indicating an ability to perform the test without any compensatory movement. These tests have been used to illustrate the disease progression in DMD. For example, it has been reported that if the time taken to walk/run 10 meters is more than 12 seconds or the time taken to climb four stairs is greater than 8 seconds, then the subject has a higher chance of losing ambulation within 12 months., TFTs have also been demonstrated to be reliable outcome measures for use in multi-center clinical trials., They have been used to test the efficacy of corticosteroids in DMD.,,, However, these tests are limited to ambulatory DMD patients. Moreover, the performance on these tests is dependent upon the motivation and co-operation of the patients, which makes them unsuitable for use in the younger age groups.
Six-minute walk test
The six-minute walk test (6 MWT) is another functional test commonly used in the DMD population, which has shown its reliability, validity, and reproducibility in assessing DMD patients.,,,, It is presently a primary endpoint for clinical trials in ambulatory DMD patients.,,, In the 6 MWT, the subject is asked to walk as far as possible without running in six minutes, and the total distance covered is recorded. To achieve a clinically meaningful functional change, a therapeutic drug in clinical trials has to show a difference of 30 meters in 6 MWT within a time period of one year between the treatment and placebo groups., This test can demonstrate disease progression in DMD. For example, it has been reported that a baseline 6 MWT distance of 330 meters and above decreases the chances of ambulation loss within 2 years in DMD patients.
Though 6 MWT is commonly used in clinical trials, it is dependent on the motivation and age of the patient. Alfano et al., demonstrated a performance improvement of 44m in the 6 MWT distance, with a financial reward of $50 in boys with DMD. This distance exceeds the clinical meaningful threshold targeted in several clinical trials., Moreover, over a one-year period, DMD patients less than 7 years old show improvement in their 6 MWT distance, due to maturational effects, compared to those who are 7 years or older.,,, Both these age groups would, therefore, require different clinical outcome measures for clinical trials. This shows that the 6 MWT is not a good test for use in younger DMD patients. Like TFTs, the 6 MWT can only be used in ambulatory DMD patients and cannot be used in clinical trials for non-ambulatory patients.
Since most of the literature concerning DMD has focused on assessing the function and strength of lower limbs, very little is known about the rate of loss of upper limb functions. Researchers and the DMD community have recently started focusing on evaluating upper limb functions. This is necessary so that non-ambulatory DMD patients can also participate in the clinical trials., Upper limb functions are necessary for performing daily living activities like eating, brushing teeth, and bathing., These functions are maintained for a period of time after a DMD patient loses his ambulation., It has been observed that there is a wasting of shoulder girdle muscles and weakness in upper limb muscles such as deltoid, biceps, triceps, and pectorals in the DMD patients. Below is a summary of some of the upper limb function tests that can be used by physiotherapists to assess the function in the Indian DMD population:
Performance of upper limb
The performance of upper limb (PUL) has recently been developed to evaluate the function of upper limbs in the DMD population. This is a reliable and valid scale that can be used for both ambulatory and non-ambulatory DMD patients. It has the ability to assess the extent and the severity of the disease. It consists of 22 items, divided into 3 level dimensions – shoulder, elbow, and wrist, which can help in tracking impairments in upper limb function.,, The scores can vary from 0 to 1 or from 0 to 6, depending upon the item being evaluated. PUL has shown good intra-observer and inter-observer reliability in a multi-center study. This test is suitable for use in DMD patients of age 5 years and older. The results of PUL have shown that impairment in the upper limbs starts even while DMD patients are still ambulatory.
Jebsen hand function test
Jebsen Hand Function Test (JHFT) is a timed test, that has shown its sensitivity in evaluating hand function in DMD patients., In this test, the subject performs 7 tasks that include activities that are commonly used in daily living.,,, The tasks include: “writing a sentence, turning over cards, picking up small common objects, simulating eating, stacking checkers, moving large light objects, and moving large heavy objects”, which are commonly used in the activities of daily living.,,, However, it does not include tasks that measure the function of proximal muscles of the upper limb, which are important for activities such as bathing, grooming, etc. The writing task in JHFT is also not very reliable, since its results may be indicative of learning disabilities rather than poor hand function in patients with DMD.
9-Hole peg test
The 9-hole peg test is a quantitative measure for evaluating upper limb function., Subjects are asked to put the 9 pegs in holes, one at a time, and then take them out the same way. It is a timed test and is done for each hand. The use of this reliable and valid test has been reported in DMD patients.,
Microsoft kinect gaming
Microsoft kinect gaming is a newly developed outcome measure for assessing upper limbs in DMD., It is a reliable and valid test that has the ability to evaluate upper limb impairment in both ambulatory and non-ambulatory patients with DMD or Becker muscular dystrophy [BMD].,,, Kinect gaming can be used to determine the reachable workspace  or the functional reaching volume, the velocity of movement, and the fatigue rate while playing video games. However, the major disadvantages of this outcome measure are the cost and the complexity of the setup. The complexity of the setup makes it harder for physiotherapists and clinicians to easily use this tool in clinics for assessing upper limb function in the DMD population.
Arm elevation assessment
The arm elevation assessment (AREA) has been used for evaluating the range of motion (ROM) of upper limbs, which is required for the performance of activities of daily living. It is also used to evaluate the quality of movement of upper limbs in patients with neuromuscular (NMD) diseases. There are 10 levels, ranging from 0 to 9, of normal 180 degrees of range of movement (ROM) of arm elevation. In this test, the subjects sit up straight on a chair, with arms by their sides. They are then instructed to elevate their arms (abduction-flexion) without bending the elbows. The ROM of arm elevation is measured by a goniometer and then scoring is done, which is called the “arm elevation score (AES).”, Further, the movement quality is evaluated by noticing any compensatory movement during elevation of the arm and the score obtained is called “arm elevation quality score (AEQS).” A movement with compensation is scored as 1, and a movement without compensation is scored as 2., The total score is obtained by multiplying AES and AEQS of the movement. The total score can vary anywhere from 0 (minimum score where there is an inability of arms to elevate from the trunk level) to 18 (maximum score where the ROM of arm elevation is 161-180 degrees without the presence of any compensatory movement). In a preliminary study in DMD patients, AREA has shown its validity for evaluating the range and quality of movement of the upper limbs.
The functional scales are used to determine the quality of movements. They are very easy to use in clinics by physiotherapists and give a quick assessment of the quality of movements of both upper and lower limbs. Below are some of the functional scales used in DMD:
The Brooke scale is used for grading both upper limb and lower limb functions. These scales are commonly used outcome measures in DMD., The Brooke scale for upper limb has grades ranging from 1 to 6. Grade 1 is given to the subject who can keep both his arms by his sides in the starting position and is then able to abduct the arms fully so that both the arms are touching over the head. Grade 6 is given when the subject is unable to raise his hands to his mouth, and the hands show no functional usefulness. [12, 27, 33, 41-44] The Brooke scale for the lower limbs has grades ranging from 1 to 10, with grade 1 being that the subject can walk and climb stairs without any support, and grade 10 being that the subject is confined to a bed. [12, 41, 42, 44-46] They are very easy to use and are a quick way to evaluate the quality of movements to determine whether or not the patient is performing compensatory movements. However, these scales are very subjective and do not provide much information about the ability to perform various activities of daily living.
North star ambulatory assessment
The North Star Ambulatory Assessment (NSAA) is a relatively new scale, developed in Europe over the last decade. The purpose for designing this scale was to include tasks that are focused more on activities of daily living in the DMD population. This clinical outcome measure contains 17 activities involving lower limbs, varying from easy tasks such as standing, to difficult tasks like running a distance of 10 meters., Each activity is scored from 0 to 2, with a score of 0 indicating an inability to perform the activity and a score of 2 indicating that the activity is performed normally, without any compensatory movement.,, The total score varies from 0 (inability to perform any of the activities) to 34 (all activities are performed normally)., It is a valid and reliable scale, and is used in ambulatory DMD patients to evaluate functional performance. [16, 39, 47, 49-51] For example, it has been reported that a baseline NSAA score of 18 or above indicates a reduced risk of losing ambulation within a 2-year period in DMD patients., This scale has also been frequently used in new clinical trials. This scale has the disadvantage of being age-dependent. It has been shown that NSAA scores tend to increase for DMD patients who are less than 7 years old, and decrease for those who are of 7 years of age or will become older than that age within one year. Therefore, this scale might not be useful for younger DMD patients.
Motor function measure
The motor function measure (MFM) scale was developed for objectively evaluating motor function in neuromuscular diseases., This scale was developed so that it can be easily used by physiotherapists and clinicians for determining function of patients with neuromuscular diseases. This scale has the advantage that it can be used for both ambulatory and non-ambulatory patients.,, It consists of 32 items, which are divided into three dimensions; dimension 1 (13 items) assesses standing position and transfers, dimension 2 (12 items) evaluates axial and proximal motor function, and dimension 3 (7 items) tests distal motor function.,,, Scores range from 0 to 3 where a score of 0 represents no initiation of the movement and a score of 3 denotes ability to perform the task normally. The total score can vary from 0 to 96. In patients with DMD, MFM is valuable in indicating the disease stage and in assessing whether the patient's motor function is improving, stabilizing, or declining. MFM can be used to assess the effect of steroids or other therapies on DMD patients. However, since physiotherapists determine the assignment of grades in this scale, its results can be subjective and are prone to inter-rater variability. Moreover, this test is time consuming, and may be physically tiring for patients who are weak, and may be mentally exhausting for those who have attention deficit disorder. However, the standard MFM scale has not been validated for subjects less than 6 years of age. This is because some of the items in this scale are not appropriate for young children since some motor and cognitive skills have not been developed by that age. A shorter version of MFM with 20 items has been validated for use in very young NMD patients.
The Egen-Klassification (EK) scale is a valid scale for use in non-ambulatory DMD patients. [8, 14, 16, 27, 40, 56] This scale is comprised of 10 categories ranging from the use of a wheelchair to overall physical well-being. Each category is scored from 0 to 3 and the total score ranges from 0 to 30. A higher score indicates a lower functional level in a patient.
Muscular dystrophy functional rating scale
The muscular dystrophy functional rating scale (MDFRS) was developed to evaluate function in muscular dystrophy patients. This scale is comprised of 33 items which are further subdivided into the 4 domains of mobility, basic daily living activities, arm function, and impairment. MDFRS has shown its reliability and validity for use in muscular dystrophy patients of age 6 years and above.
Hammersmith Functional Motor Scale
The Hammersmith functional motor scale (HFMS) was first developed for DMD. It has good inter-observer reliability in DMD. This scale is comprised of 20 items and is scored from 0 to 2, with 0 being an inability to perform the activity and 2 being unassisted performance of the activity. The total score varies from 0 (inability to perform any of the activities) to 40 (ability to perform all the activities independently). This scale is reliable and reproducible, and can be used in non-ambulatory patients with either spinal muscular atrophy or other NMDs.,
The Barthel index (BI) is a reliable and valid scale which is used for determining function in personal care and mobility domains in muscular dystrophy patients. This scale consists of 10 items with the total score varying from 0 (inability to perform any activity) to 100 (ability to perform all activities without any assistance). BI has been used to evaluate the problems in activities of daily living experienced by DMD patients.
Bayley-III scale of infant and toddler development
Since there are delayed developmental milestones in DMD, neither 6 MWT nor NSAA are suitable for DMD patients under the age of four. Therefore, the Bayley-III scale of infant and toddler development could be an appropriate alternative in very young patients with DMD. This scale evaluates cognitive function, language, and motor function skills. It is a reliable measure to evaluate development in infants and very young patients with DMD over a period of time. It is being used in clinical trials which are determining the effects of steroids in very young patients with DMD.
Muscle strength can be measured either manually or by using quantitative devices. Manual muscle testing (MMT) has been used to measure muscle strength manually for a long time. MMT is used to clinically evaluate the muscle strength of patients with neuromuscular diseases. It has been used to evaluate the muscle strength for both upper and lower limb muscles, [32, 43, 44, 65-68] and subsequently, to assess changes in muscle strength in patients with DMD over a period of time., It was used as one of the outcome measures to determine the efficacy of therapeutic drugs in DMD, like in the earlier clinical trials evaluating the efficacy of prednisone in treating DMD., A high intra-rater reliability is found in the MMT grades. The major disadvantage of using MMT is that it is too subjective in nature.,, The MMT grades greater than 3 depend heavily on the resistance provided by individual physiotherapists to the patient. Thus, there is a lot of inter-rater variability, making MMT a less accurate and a less sensitive method of assessment. Extensive training and experience is required to decrease the variability in using the MMT method.,, Moreover, it is difficult to apply MMT in young boys with DMD as they are unable to cooperate.
Quantitative muscle testing is an alternative to traditional MMT for evaluating muscle strength. It is a validated outcome measure for assessing muscle strength in patients with DMD. Being a sensitive outcome measure, it has the capability of recording even small changes in muscle strength and is thereby able to test specific muscles. It has been demonstrated that this is a reliable and accurate tool for assessing muscle strength and can be used for multi-center clinical trials. The hand-held dynamometer can be objectively used to measure muscle strength., 73, ,, Its ease of use and limited space requirement make it a desirable option. It has shown intra-rater reliability  and can thus be used in measuring isometric muscle strength in patients with DMD.,,, It is, however, not sensitive enough to detect the measurements in weak patients. A myometer can quantitatively measure muscle strength for various upper and lower limb muscles. [9, 10, 13, 74, 81, 82] Being lightweight and small in size, it can easily be used anywhere. However, it is not a very sensitive tool for measuring strength in the weak DMD patients. An isokinetic dynamometer (Biodex system) has been used to measure isometric peak torque of hip flexors, hip extensors, knee flexors, knee extensors, plantar flexors, and dorsiflexors. For this test, the patients are asked to push or pull as hard as they can for a few seconds, while their performance is simultaneously being viewed on a computer screen. This visual feedback motivates the patients to give their best effort. Although the test objectively measures the strength of different muscles, the elaborate set up required is a major disadvantage. The set up also requires a lot of space and so it cannot be easily used by physiotherapists in clinics.
All the above described quantitative tools have been used by physiotherapists for a long time for assessing muscle strength of upper and lower limbs. However, there was a need to develop easy-to-use tools that do not require a lot of space, and may be used even in very weak non-ambulatory DMD patients. To meet these requirements, new tools have recently been developed for assessing upper limb strength in non-ambulatory patients with DMD. They measure the isometric grip strength using a myogrip, and the key pinch force using a myopinch device., 82, ,, These tools have been proposed as outcome measures in non-ambulatory patients with DMD because of their sensitivity and reliability. They are easy to use and do not require a lot of space. They have the ability to detect strength in weak non-ambulatory patients with DMD. The only disadvantage of these tools is their cost. Being very costly, they may not be easily available for physiotherapists to use in clinics.
In conclusion, it can be said that there are many different clinical outcome measures, which can be used for assessing the function and strength of the patients with Duchenne muscular dystrophy. Neurologists and physiotherapists in India can use these tests to assess the disease progression in DMD patients. It is important that parents bring their children to the physiotherapists at regular intervals of 6 months to 1 year so that disease progression can be tracked and proper management can be provided. An increased awareness regarding DMD and its management practices is needed to overcome the prevalent psychosocial issues in the Indian society. The tests described here will improve our understanding of the disease progression and provide tools to detect the efficacy of the potential therapeutic drugs.