Susan D. Apkon

Consensus statement on standard of care for congenital myopathies.

Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.

Bone mineral density in children with myelomeningocele

The aim of the present study was to document bone mineral density (BMD) in children with myelomeningocele and to identify variables that contribute to reduced BMD. The study included 24 children with myelomeningocele (nine males, 15 females; age range 4–18y), who had varied levels of neurological impairment (thoracic/high‐lumbar, n=6; mid‐lumbar, n=9; sacral, n=9) and ambulatory status (non‐ambulators, n=12; part‐time ambulators n=2; full‐time ambulators, n=10). BMD measurements of the femoral neck and whole body using dual energy X‐ray absorptiometry assessments of dietary calcium intake, and serum markers of bone metabolism were obtained. BMD is presented as standardized scores (z‐scores) which are age‐ and sex‐matched to normally developing children. The mean femoral‐neck z‐score was −2.41. Femoral‐neck z‐scores differed significantly according to ambulatory status, with lower z‐scores in children who were wheelchair‐dependent (p=0.03). The mean z‐score at the femoral neck demonstrated a trend toward lower z‐scores in children with higher levels of lesions. Almost all children met their recommended daily intake of calcium. Markers of bone metabolism were normal in all patients. This study demonstrates that reduced BMD is a major complication in children with myelomeningocele. There is a significant relationship with low BMD in children who are wheelchair‐dependent, a trend in those with higher neurological levels, and no relationship between fractures and reduced BMD.

Botulinum toxin type a in the treatment of children with congenital muscular torticollis.

Oleszek JL, Chang N, Apkon SD, Wilson PE: Botulinum toxin type A in the treatment of children with congenital muscular torticollis. Am J Phys Med Rehabil 2005;84:813–816. This is a retrospective case series describing the use of botulinum toxin type A in the treatment of children with congenital muscular torticollis who fail to progress with conservative management. A total of 27 children with congenital muscular torticollis, 6–18 mos of age, received 30 botulinum toxin type A injections into their sternocleidomastoid or upper trapezius muscle, or both, at a pediatric tertiary care center between 1995 and 2001. Three children received repeat injections. Twenty of 27 children (74%) had improved cervical rotation or head tilt after the injections, and 2 of 27 (7%) experienced transient adverse events, specifically, mild dysphagia and neck weakness. This series suggests that botulinum toxin type A may be a safe and effective treatment option for children with congenital muscular torticollis who are unresponsive to a traditional regimen of physical therapy and a home program. A prospective, randomized controlled trial is necessary to definitively assess the role of botulinum toxin type A in this population.

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. FINDINGS Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. INTERPRETATION Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. FUNDING PTC Therapeutics.

Biomarkers of Hypercoagulability and Inflammation in Childhood-Onset Arterial Ischemic Stroke

OBJECTIVE To test the hypothesis that acute elevations of biomarkers of hypercoagulability and inflammation are common in children with arterial ischemic stroke (AIS), particularly among etiologic subtypes that carry an increased risk of recurrent stroke. STUDY DESIGN In this prospective/retrospective institutional-based cohort study of acute childhood-onset AIS (n = 50) conducted between 2005 and 2009, D-dimer, factor VIII (FVIII) activity, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were serially evaluated at the time of clinical blood sampling. Patients were classified by stroke subtype as cardioembolic, moyamoya, non-moyamoya arteriopathy, or other. RESULTS Both D-dimer and CRP were frequently elevated in acute childhood-onset AIS and exhibited a decreasing trend with time. Acute D-dimer levels were significantly higher in cardioembolic AIS compared with noncardioembolic AIS (median, 2.04 microg/mL [range 0.54-4.54 microg/mL] vs 0.32 microg/mL [0.22-3.18 microg/mL]; P = .002). At an optimal threshold of > or = 0.50 microg/mL, the sensitivity and specificity of D-dimer for cardioembolic subtype were 78% and 79%, respectively. CONCLUSIONS Our findings identify D-dimer and CRP as candidate biomarkers for etiology and prognosis in childhood-onset AIS. Further studies should investigate the role of these and other biomarkers of hypercoagulability and inflammation in childhood-onset AIS.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

PALLIATIVE CARE SERVICES IN FAMILIES OF MALES WITH DUCHENNE MUSCULAR DYSTROPHY

Introduction: Palliative care services that address physical pain and emotional, psychosocial, and spiritual needs may benefit individuals with Duchenne muscular dystrophy (DMD). Methods: The objective of this study was to describe the palliative care services that families of males with DMD report they receive. A questionnaire was administered to families of males with DMD born prior to January 1, 1982. Thirty‐four families responded. Results: Most families (85%) had never heard the term palliative care. Only attendant care and skilled nursing services showed much usage, with 44% and 50% indicating receipt of these services, respectively. Receipt of other services was reported less frequently: pastoral care (27%); respite care (18%); pain management (12%); and hospice care (6%). Only 8 respondents (25%) reported having any type of directive document in place. Conclusion: The data suggest a need for improved awareness of palliative care and related services among families of young men with DMD. Muscle Nerve 44: 93–101, 2011

Electrical impedance myography in Duchenne muscular dystrophy and healthy controls: A multicenter study of reliability and validity.

Introduction: Electrical impedance myography (EIM) is a non‐invasive, painless, objective technique to quantify muscle pathology. Methods: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3–12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6‐minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand‐held dynamometry). Results: EIM was well tolerated and had good inter‐ and intrarater reliability (intraclass correlation coefficient 0.81–0.96). The averaged EIM phase value from all muscles was higher (P < 0.001) in controls (10.45 ± 2.29) than boys with DMD (7.31 ± 2.23), and correlated (P ≤ 0.001) with 6MWD (r = 0.55), NSAA (r = 0.66), TFTs (r = –0.56), and strength (r = 0.44). Conclusion: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted. Muscle Nerve 52: 592–597, 2015

Safety Considerations in the Use of Botulinum Toxins in Children With Cerebral Palsy

The use of botulinum toxins to decrease spasticity in children with cerebral palsy has become standard of care during the past decade. In 2008 reports of severe adverse events, including death, were reported in children who received injections of these medications. The following discussion focuses on the background of these reports, the response of the U.S. Food and Drug Administration, as well as the safety profile and pharmacokinetics of botulinum toxins. Finally, the authors will offer their perspective on the safe use of botulinum toxins.

Use of weekly alendronate to treat osteoporosis in boys with muscular dystrophy

Apkon S, Coll J: Use of weekly alendronate to treat osteoporosis in boys with muscular dystrophy. Am J Phys Med Rehabil 2008;87:139–143.Three boys with muscular dystrophy with known osteoporosis were each treated for 1 yr with weekly alendronate and daily calcium and vitamin D. Measurements of lumbar spine and proximal femur using dual-energy x-ray absorptiometry were obtained at the initiation of the alendronate, at 6 mos, and at 1 yr. All three boys demonstrated increases in bone mineral density, with z scores improving from baseline to 1-yr follow-up. Improvements were observed at the lumbar spine, femoral neck, and greater trochanter. In this small case series, weekly oral alendronate for 1 yr plus daily vitamin D and calcium was effective in improving bone mineral density.