Elizabeth C. Malkus

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.

Quantitative ultrasound using backscatter analysis in Duchenne and Becker muscular dystrophy

Evaluation of ultrasound images of muscle with calibrated muscle backscatter (cMB) provides reproducible quantitative measurements of muscle pathology. Increased cMB is associated with greater muscle pathology. We used cMB to evaluate the severity of muscle pathology in 55 patients with Duchenne and Becker Muscular Dystrophy (D/BMD) compared to 77 controls. cMB was also compared to measurements of strength and function. cMB in DMD and BMD increased linearly with age and was higher than in controls when groups are compared. cMB increased twice as fast with age in DMD than in BMD. In DMD, cMB was higher with reduced function and strength. Ultrasound measurement of muscle pathology using cMB is a sensitive and objective quantitative technique for determining the severity of muscle pathology in dystrophinopathies. Longitudinal studies are required to determine the sensitivity of this measure to changes in pathology over time.

Outcome reliability in non-Ambulatory Boys/Men with duchenne muscular dystrophy

Introduction: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non‐ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Methods: Non‐ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. Results: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9‐hole peg test, and Jebsen‐Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Conclusions: Reliable assessment of non‐ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. Muscle Nerve 51: 522–532, 2015

Muscle ultrasound quantifies disease progression over time in infants and young boys with duchenne muscular dystrophy.

Introduction: Quantitative muscle ultrasound (QUS) in boys with Duchenne muscular dystrophy (DMD) shows increased echointensity as muscle is replaced with fat and fibrosis. Studies of quantitative ultrasound in infants/young boys with DMD over time have not been reported. Methods: We used calibrated muscle backscatter (cMB), a reproducible measure of ultrasound echointensity, to quantify muscle pathology in 5 young boys with DMD (ages 0.5–2.8 years) over 17–29 months. We compared the results with repeated assessments of function (n = 4) and with muscle ultrasound images from a cross‐section of 6 male controls (0.6–3.1 years). Results: cMB in boys with DMD increased (worsened) over time (P < 0.001), whereas function improved. After age 2 years, cMB in most (4 of 5) boys with DMD was higher than in any control. Conclusions: QUS measures disease progression in young boys with DMD despite functional improvements. QUS could be employed as an outcome measure for serial assessment of young boys with DMD. Muscle Nerve 52: 334–338, 2015

Qualitative and Quantitative Skeletal Muscle Ultrasound in Late-Onset Acid Maltase Deficiency

Introduction: Acid maltase deficiency (AMD, or Pompe disease) is an inherited myopathic disorder of glycogen degradation. Diagnosis is often delayed. Muscle ultrasound could improve diagnosis. Methods: We compared skeletal muscle ultrasound images from adults with AMD (n = 10) to other myopathies (n = 81) and, in AMD, compared qualitative (Heckmatt) and quantitative (backscatter) ultrasound measurements with strength and function. Results: Qualitative ultrasound was abnormal in at least one muscle in all AMD subjects. Ultrasound patterns specific for AMD were: normal triceps brachii despite abnormalities in elbow flexors (89% vs. 17%, P < 0.0001); focal abnormalities affecting deep more than superficial biceps brachii (40% vs. 4%, P = 0.002); and more severe involvement of vastus intermedius than rectus femoris (40 vs. 11%, P = 0.03). In AMD, both qualitative (Heckmatt) and quantitative (backscatter) ultrasound measures increased with decreasing strength and function. Conclusions: Muscle ultrasound identifies the presence and specific patterns of AMD pathology, measures disease severity, and can help in the diagnosis of AMD. Muscle Nerve 44: 418–423, 2011

One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

BACKGROUND The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. PATIENTS Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. RESULTS Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). CONCLUSION Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure.

Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA–DMD network follow-up

Introduction: Outcomes sensitive to change over time in non‐ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well‐established. Methods: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6‐month intervals for 2 years. We analyzed all subjects using an intent‐to‐treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. Results: Eight patients (12–33 years old) died during the study. Sixty‐six completed 12‐month follow‐up, and 51 completed 24‐month follow‐up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. Conclusion: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non‐ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681–689, 2016

Clinical trial readiness in non‐ambulatory boys and men with DMD: MDA‐DMD network follow‐up

Introduction: Outcomes sensitive to change over time in non‐ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well‐established. Methods: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6‐month intervals for 2 years. We analyzed all subjects using an intent‐to‐treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. Results: Eight patients (12–33 years old) died during the study. Sixty‐six completed 12‐month follow‐up, and 51 completed 24‐month follow‐up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. Conclusion: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non‐ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681–689, 2016

P.3.1 GNE myopathy functional activity scale (GNEM-FAS): Development of a disease-specific instrument for measuring function and independence

GNE myopathy or hereditary inclusion body myopathy (HIBM) is an autosomal recessive myopathy presenting with distal leg weakness in early adulthood. Progressive weakness results in greater dependence and disability over time. A disease-specific measurement of functional activity is needed to better understand the burden of illness, inform the design of clinical studies and optimize care. After clinical interview of patients, a 25-item questionnaire was developed to assess ability and independence in three domains: mobility, upper extremity (UE) use and self-care. Each item was rated from 0 to 4 with higher scores representing better function. Total scores range from 0 to 100; subscale scores range from 0 to 40 for Mobility, 0–32 for UE and 0–28 for Self-Care. The GNE Myopathy Functional Activity Scale (GNEM-FAS) was administered to 47 ambulatory subjects enrolled in a Phase 2 study of extended release sialic acid. Physical therapists completed the GNEM-FAS based on clinical observation and subject interview. Scores were compared to performance on volitional measures of strength and function, as well as scores on the Inclusion Body Myositis Functional Rating Scale (IBMFRS), a validated instrument for myositis. The mean GNEM-FAS total score was 69 out of 100 (23–94). Mobility subscores averaged 50%, UE, 81% and Self-Care, 82% of the maximum possible. Higher Mobility scores were associated with greater lower extremity strength ( r =0.83) and longer 6MWT distances ( r =0.83). A moderate association was seen between the UE domain scores and UE strength ( r =0.66). Self-care domain scores and the stair climb time were negatively related ( r =−0.68). There was a strong correlation between GNEM-FAS total scores and IBMFRS scores ( r =0.94). Mobility was limited more than UE or self-care function in this cohort of ambulatory subjects with GNE myopathy. Repeat administration in treated and untreated patients with varying degrees of severity is underway to further validate the instrument.

Characterization of Strength and Function in Ambulatory Adults With Gne Myopathy

Objective: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. Methods: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). Results: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. Conclusions: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.