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Clinical Management of Dystrophinopathies: A Systematic Approach
Introduction
This chapter reviews the current management recommendations for the skeletal muscle predominant disorders caused by mutations in the dystrophin gene: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and manifesting carriers of dystrophinopathy. Duchenne muscular dystrophy is the most common form of dystrophinopathy, affecting around 1 in 5000 male births. The incidence of Becker muscular dystrophy is around 1 in 14,000. Figures for manifesting carrier status are variable depending on the definition of this condition, which can be highly heterogeneous, ranging from minor symptoms to full-blown disease as seen in males. However, around 10% of female carriers of a dystrophin mutation have some kind of symptoms at some stage in their lives. Rarely, male and female patients have an isolated cardiomyopathy without any skeletal muscle manifestations at all. The management of these cases depends on the nature of their cardiac disease, and they are not discussed in detail here.
Diagnosis is dealt with in detail in Chapter 30 . The age of diagnosis of DMD remains a crucial factor to improve patient management and ensure appropriate genetic counselling. Only by recognizing the primary manifestations and promptly identifying possible complications of this disorder we can ensure optimal treatment. Although still controversial, recent data suggest that early initiation of steroid treatment could be associated with better long-term outcomes. Moreover, it is intuitive to think that any interventions that potentially modify the natural history of the condition may be of greater benefit in younger children with less damaged muscles. Early diagnosis will therefore potentially allow early access to investigational drugs.
While newborn screening has been suggested to reduce the diagnostic delay in DMD, this is not widely available and raises ethical issues due to the current lack of a curative treatment. Earlier consideration of DMD in the differential diagnosis of boys with motor or speech developmental delay may expedite diagnosis and improve management and quality of life of these patients.
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy remains a devastating diagnosis with inexorable and relatively predictable progression and development of complications. Internationally generated standardized recommendations for the diagnosis and management of DMD were published in 2010 and are also available in a simplified version for families in many languages. As outlined in the 2010 publications, there are many areas where patient care can be dramatically improved. The standards of care recognize that DMD is a multisystemic and progressive condition needing a multidisciplinary approach, timed and adapted to disease stage-specific needs. The natural course of DMD can be subdivided into five major stages: presymptomatic, early ambulatory, late ambulatory, early and late nonambulatory phases. Although the age of onset and duration of each stage can vary from patient to patient and may be affected by pharmacological and nonpharmacological interventions, each boy with DMD passes through each of these stages sequentially. A stage-specific approach therefore addresses specific needs and areas of interventions better than one based on age alone.
A comprehensive approach to management must be multidisciplinary and should be coordinated with the family by a neuromuscular specialist with a genetic, pediatric, or neurological background. Although a multidisciplinary approach is required throughout the lifespan, depending on the stage of the condition, the relative involvement of genetic counselors, physiotherapist, cardiologist, respiratory clinician, orthopedic surgeon, endocrinologist, dietician, gastroenterologist, psychologist, and speech and language therapist will vary (see Table 31.1 ). Management should be anticipatory, preventing complications wherever possible. Access to advice on social care issues is also imperative at all stages. Ideally, social and medical issues should be addressed in a holistic manner within a recognized center of excellence. The prolonged survival of DMD patients has highlighted the need to adapt a proactive approach to transition services and the engagement of appropriate adult-based specialists to assume the patient ongoing care into adulthood.
Table 31.1
Care Recommendations Based on Disease Stages
| Stage 1: Pre-symptomatic | Stage 2: Early Ambulatory | Stage 3: Late Ambulatory | Stage 4: Early Nonambulatory | Stage 5: Late Nonambulatory | |
|---|---|---|---|---|---|
| Diagnostics |
|
– | – | – | |
| Neuromuscular Specialist assessment |
|
|
|
||
| Treatment consideration (corticosteroids) | Start discussion about effects of corticosteroids | Initiation of treatment recommended during the plateau phase (age 2–5) | Dose and regime to be adjusted balancing growth and side effects |
|
Carefully evaluate benefits and side effect profile |
| Rehabilitation management | Encourage adequate exercise and activity |
|
|
|
|
| Orthopedic Management | Orthopedic interventions rarely needed | Consideration of surgical correction of contractures (Achilles tendons) if necessary | Monitoring spinal deformities |
|
|
| Cardiac management | ECG and echocardiogram at diagnosis to exclude dilated cardiomyopathy | Cardiac assessment every 2 years until age of 10, annually thereafter | Continue cardiac assessments to monitor development of early signs of cardiac dysfunction |
|
|
| Respiratory Management | Normal respiratory function |
|
|
|
Increased risk of respiratory complications; Establish respiratory physiotherapy and consider cough assist devices; Promptly trigger respiratory investigations and interventions (e.g. antibiotics) |
| Gastrointestinal management | Monitor for normal growth for age | Monitor weight; Consider gastro protection with corticosteroid treatment |
Monitor weight; Nutritional assessment for over/underweight |
Monitor for possible dysphagia and aspiration pneumonia | |
| Psychological management | Family support; Early evaluation and interventions for speech developmental delay, learning difficulties, and behavioral problems |
Assess educational needs and establish interventions at school; Monitoring and management of behavioral issues Support coping strategies |
Promote independence and social development; Monitor coping strategies; Consider interventions (psychological support) |
Promote independence and social participation; Transition planning to adult service; Consider pharmacological treatment if necessary |
|
Although there are no specific treatments currently available for DMD, the application of the care recommendations to include corticosteroids, respiratory, cardiac, orthopedic, and rehabilitative interventions has contributed to a “new natural history” altering the characteristic progression of the condition. A recent comprehensive review of the burden of illness in DMD across the USA, the UK, Italy, and Germany showed that, while annual direct health costs are approximately ten times the national average for a comparable age group, these are just a small proportion of the overall burden of the disease. Although the generation of an international publication on standards of care has significantly improved the diagnosis and management of DMD worldwide, variable and inconsistent health care is still reported in different countries and even among different specialized centers within the same country
Assessments
Patients should be seen by the neuromuscular specialist at least once every six months. The aim of these assessments is to recognize manifestations of the condition, prevent and promptly address disease complications, inform decisions about therapeutic and physiotherapy interventions, and monitor response to treatments. More frequent evaluations might be required in transitional phases, such as initiation of steroid treatment, in the late ambulatory and early nonambulatory phases. A three- and six-month follow-up visit should be offered after initiation of corticosteroid treatment to closely monitor individual response and side effects.
Assessments should include medical and physiotherapy examinations. The involvement of a psychologist, a social care advisor, and an occupational therapist at each assessment ensures early interventions for specific issues raised by the patient and family ( Table 31.2 ).
Table 31.2
Assessments in DMD: Standard Recommendations
| Assessments | Frequency (Minimum) | Aims |
|---|---|---|
| Neuromuscular specialist | Every 6 months |
|
| Physiotherapist | Every 4 months |
|
| Cardiac specialist | At diagnosis, every 2 years until age of 10, annually thereafter |
|
| Pulmonary evaluation | Every 6 months |
|
| Gastrointestinal assessment | Every 6 months |
|
| Speech and language therapist | As indicated |
|
| Rehabilitation and orthoses | As indicated |
|
| Orthopedic surgeon | As indicated |
|
| Psychologist | As indicated |
|
| Occupational therapist | As indicated |
|
Questions about family history should be included in the patient’s first evaluation and at each follow-up, to identify subjects at risk of developing the condition or of being carriers and to ensure appropriate counseling and cardiac surveillance for female carriers.
Vital signs and physical examination are of particular importance for subjects on corticosteroids to monitor side effects.
Physiotherapy assessments should monitor muscle strength and function, posture, gait, and range of joint motion in a standardized manner to allow comparison over time. Scales and assessments commonly used in DMD are listed in Table 31.3 . Essential requirements for any evaluation scale are feasibility, safety, reliability, reproducibility, and sensitivity to change. These assessments should be used to guide steroid dosing, physiotherapy interventions, and needs for aids and appliances. In a clinical setting, important factors are also ease of use, familiarity of clinical staff with the tests, restrictions related to clinic setting and timing, and the ways in which the results of the testing will influence patient care.
Table 31.3
Physiotherapy Scales and Assessments
| Scale | Advantages | Disadvantages | |
|---|---|---|---|
| Muscle strength testing | Manual muscle testing | Ambulatory and nonambulatory stages; easy to perform in clinic | Evaluator sensitive; value of the testing uncertain in late nonambulatory patients |
| Quantitative myometry | Reliable | Requirement of specific equipment; length of the assessment | |
| Muscle function testing | North Star Ambulatory Assessment (NSAA) | Reliable and reproducible if trained personnel; clinically meaningful; minimal equipment required | Limited to ambulatory patients |
| Motor Function Measure (MFM) | It includes function related to activities of daily living | Poor sensibility; not specific for DMD | |
| Brooke upper extremity scale | Easy to perform | Poor sensitivity, especially for late ambulatory stage | |
| Egen Klassification (EK) functional assessment | It can be performed in nonambulatory patients | Poor reliability and sensitivity | |
| Hammersmith motor scale | It can be performed in ambulatory and nonambulatory patients | Poor sensibility | |
| Performance of the Upper Limb (PUL) | It can be performed across stages (from ambulatory to late nonambulatory phases) | Not fully validated yet | |
| Timed functional testing | 6 minute walking test (6MWT) | Integrated measure of ambulatory function; reliable and reproducible if trained personnel | Difficult to perform in a clinical setting due to space and equipment requirements; limited to ambulatory patients |
| Time to rise from the floor | Clinically meaningful; easy to perform in clinic | Limited to ambulatory patients | |
| Time to run 10 meters | Clinically meaningful; easy to perform in clinic | Limited to ambulatory patients | |
| Time to climb 4 stairs | Clinically meaningful; easy to perform in clinic | Requirement of standardized stairs; limited to ambulatory patients | |
| Time to descend 4 stairs | Clinically meaningful; easy to perform in clinic | Requirement of standardized stairs; limited to ambulatory patients | |
| Range of motion | Goniometry | Minimal equipment required | Poor sensitivity |
For clinical trials, a wider range of measures may be mandated, depending on the study design, to demonstrate reliability, validity, and responsiveness to interventions. Although the aim of these assessments is different in the two situations, some consistency across the two settings is desirable in order to ensure clinical relevance of the measures used in trials.
Manual muscle testing (Medical Research Council [MRC] scale) is used clinically to assess muscle strength in the limbs, monitor disease progression, and evaluate response to treatment. Advantages of the MRC scale include its ease of use, as it does not require any equipment and can easily be performed at any clinic. However, the assessment is highly evaluator-sensitive and should be performed only by clinicians with experience in neuromuscular diseases to ensure reliability. Quantitative muscle testing (QMT) has been shown to be a valid and reliable outcome measure in DMD trials, but quantitative measurement systems are expensive and available only in a limited number of centers.
The North Star Ambulatory Assessment (NSAA) is a widely used 17-item rating scale specifically developed by the North Star Clinical Network for Paediatric Neuromuscular Disease for children with DMD. The scale assesses 17 motor skills ( Table 31.2 ) considered both clinically meaningful and sensitive to change, with scores summed to generate a total ambulatory function score (higher scores indicate better motor function). The assessment can be completed in approximately 10 minutes and requires minimal equipment, making it both feasible and practical. As long as adequate training is provided, the scale is reliable and reproducible.
Timed function tests (i.e. time to climb stairs, run 10 meters, rise from the floor) are also clinically relevant endpoints that have been shown to be sensitive, reliable, and strong predictors of decline in ambulation in DMD. The 10 m run and rise from floor are included in the NSAA.
NSAA and timed function testing have shown good correlation with clinically meaningful outcomes for ambulatory DMD patients, and can therefore be used as predictive factors of motor decline. A total NSAA score higher than 18 infers a lower risk of losing ambulation within the following 2 years. Similar correlations have been found for times to rise from the floor of less than 7 seconds, and run 10m in less than 10 seconds. Inability to rise from the floor predicts loss of ambulation within 12 months in 40% of cases.
Other scales, including the Motor Function Measure, Hammersmith Motor Ability Scale, Vignos and Brooke scales have been largely replaced by the NSAA or are not in current use in clinical practice due to their lower sensitivity and length of the assessment.
Based on the assumption that gait abnormalities are a major disease manifestation with great importance to patients and families, McDonald et al. developed a modified 6-minute Walk Test (6MWT) for DMD boys. This integrated measure of ambulatory function in DMD is influenced by lower limb strength, joint contractures, fatigability, and cardiorespiratory dysfunction. In recent years, the 6MWT has been used as primary outcome measure in several clinical trials involving ambulatory DMD patients. Natural history and clinical trial data suggest a good correlation of the 6-minute walk distance (6MWD) with age and disease progression as measured by patient-reported outcomes and timed functional tests. A threshold 6MWD below 50–55% predicted for age, height, and weight, or approximately 325 meters, is predictive of more rapid decline in motor function with a 40% risk of loss of ambulation over the subsequent year. The 6MWT requires a 25-m length, quiet straight corridor, which limits its applicability in routine clinical practice.
All of these assessments are focused on lower limb muscle strength and are therefore applicable only during the ambulatory stages of the disease. Moreover, the complexity of some of these scales requires patient compliance, limiting their application in very young children. The importance of outcome measures able to reflect functional abilities across different stages of DMD has been recently emphasized by advocacy groups and regulatory agencies. With this aim, a number of upper limb functional tests have been developed to evaluate muscle weakness, manual abilities, and dexterity in DMD, and to explore the impact of upper limb involvement on daily activities such as transfers, feeding, or washing. These scales are still under development but are likely to provide a useful addition to the currently available assessments by allowing follow-up across the disease spectrum. Meanwhile there is some experience with other measures in the nonambulant population, such as the (mainly patient-reported) Egen Klassifikation (EK) scale.
International collaborations have been developed over the last few years to find a consensus on outcome measures and assessment in DMD, with an aim to collect consistent natural history data, monitor disease progression, and assess the impact of therapies. Moreover, standardized and validated assessment of muscle strength and motor function are essential for assessment of efficacy of new investigational drugs. Until an agreement on standardized assessment is reached, training and experience of the assessor and consistency in the tests performed within an individual clinic are essential to allow monitoring of disease progression.
Pharmacological Interventions
Corticosteroids are the only pharmacological treatment to have been proven effective in DMD. Corticosteroids improve muscle strength and function in DMD their prescriptions in routine clinical practice has dramatically changed the natural history of the disease.
Several additional pharmacological approaches have been developed over the last 10 years to modify the underlying pathology of DMD; none has yet been proven effective, but several remain under investigation in clinical trials.
Corticosteroids
Although the precise mechanism of action of corticosteroids in DMD remains unknown, it is now well recognized that corticosteroids slow the natural decline in muscle strength and function in DMD. Several studies have shown that corticosteroids improve muscle strength and reduce the progression of weakness, preserving important functions such as independent walking and ability to stand from supine, rise from a chair, and climb stairs. In the longer term, corticosteroids also improve upper limb function by prolonging the ability to raise hands to the mouth and respiratory function, maintaining respiratory muscle strength and possibly reducing ventilatory dependency in later stages.
Corticosteroids also slow the development of scoliosis, leading to a significant reduction in the number of patients needing to undergo spinal surgery. It remains unclear whether corticosteroids truly prevent scoliosis or simply delay its onset by prolonging ambulation and maintaining axial and trunk muscle strength, but increasing experience in the adult age group suggests that the protection against the development of scoliosis is long-lasting.
Recent studies support previous evidence from cohort observations that corticosteroids impact cardiac function, reducing the development of cardiomyopathy and slowing progression of left ventricular dysfunction, further reducing mortality. The cardioprotective mechanism of corticosteroids remains unclear. Although this may relate to reduction of inflammation and fibrosis in the heart, such changes are not seen in steroid-treated mdx mice. The improvement in cardiac function following steroid therapy might simply represent a secondary effect from improved skeletal muscle and respiratory function and reduced risk of scoliosis.
Although corticosteroids have been prescribed in DMD for over 20 years, there is still clear equipoise about their use in routine clinical practice, due mainly to their significant side effects. Moreover, it is anecdotally known that some DMD boys do not respond to corticosteroids, although how often patients are truly nonresponders is unknown. Treatment with corticosteroids should be routinely offered unless there are substantial contraindications such as major pre-existing risk factors for steroid side effects or poor family compliance. As risk of developing side effects and effectiveness seem to be independent responses, discontinuation of steroid therapy is recommended if there is no improvement or stabilization of muscle strength and function within 6 to 12 months of initiation of treatment. No predictive factors for steroid nonresponsiveness have yet been identified, but several groups are currently investigating biomarkers and genetic modifiers that might also be useful in predicting response to steroids and minimizing side effects.
Initiation of Corticosteroid Therapy
Exactly when corticosteroids should be initiated in DMD is still debated. Current guidelines recommend commencing treatment during the plateau phase of the child’s motor development, when there is no longer ongoing acquisition of new motor skills, but before the decline and development of muscle weakness. In the early stages of DMD, a “honeymoon phase” is often described, during which children continue to acquire motor skills due to growth and improved motor coordination. Recent systematic studies in young children show that this is a misnomer, because even at a young age there is an increasing disparity in motor performance between patients with DMD and their peers, even though they are gaining skills. The plateau phase can be identified by assessment and parental report when children are no longer gaining skills but not yet deteriorating. This typically occurs around the age of 4, and rarely continues beyond age 5–6. This should not be confused with the plateau in motor performance that can be seen later with the use of steroids.
Concerns about the long-term side effects of corticosteroids have, to date, limited their prescriptions while new skills are still being achieved, and certainly in children younger than 2; equally, starting treatment during the decline phase is not optimal as this is probably less effective. Recent data suggest that boys beginning corticosteroids before the age of 5 have a trend to a slower functional decline compared to boys starting treatment later. Some studies also suggest that earlier treatment—even before the age of 4—might better preserve strength in the long term, possibly prolonging ambulation. Concerns regarding the increased risk of long-term side effects have so far prevented large-scale early prescription of corticosteroids, but further study would be valuable to better define long-term outcomes in larger cohorts of patients.
Current recommendations are for steroid initiation between 3 and 5 years of age, but their applicability is limited by the fact that in most countries, the average age of diagnosis is about 4 years.
Steroid Formulations, Doses, and Regimes
A number of different steroid dosage regimes are in use for DMD worldwide. The main formulations used are prednisolone/prednisone and deflazacort. Typical starting doses are 0.75mg/kg/day for prednisolone/prednisone and 0.9mg/kg/day for deflazacort. The use of higher daily doses (1.5 mg/kg/day) is not associated with greater benefits, while doses of 0.3 mg/kg/day are less effective. Daily, alternate day, 10 days on/off, and high dose weekend regimes all have their advocates, and there are distinct regional differences in how steroids are prescribed.
Prednisolone/prednisone represents the first choice in several countries due to low cost and availability in tablet and liquid formulations, which might be preferable in younger children. Deflazacort is more expensive and is not currently approved for use in DMD in all countries (e.g. USA), though its use is relatively widespread.
In ambulant boys, the dose is usually increased according to growth, taking into account changes in strength and development of side effects, which should be regularly monitored ( Figure 31.1 ). Doses are usually increased according to weight when there is a decline in motor performance, and if side effects are acceptable to the child and family. The aim is to reach the minimum effective dose; therefore, doses can be maintained at the initial levels where strength remains stable.
Regimes—Equipoise
Since the initial publications on the use of corticosteroids in DMD in 1974, concerns about the side effects of daily regimens have led to the development of alternative regimens trying either to give a lower dosage of corticosteroids or to allow “steroid holidays.” This has led to lack of consistency of dosage and regimes in different countries and centers. Few large randomized studies on corticosteroids in DMD have been published so far; therefore, comparison between different regimes or different corticosteroids is difficult. Prednisolone and deflazacort have shown similar effect on muscle strength as well as respiratory and cardiac function. Compared to prednisolone, deflazacort seems to be associated with less weight gain but more frequent development of cataracts.
Daily administration seems to be more effective than alternate day treatment. An intermittent regime of 10 days on followed by 10 days off steroids seems less effective in preserving muscle strength and function but may cause fewer side effects (weight gain, behavioral problems, hypertension, and vertebral fractures) compared to daily treatment. A weekend high-dose regime was suggested to minimize side effects. A double-blind clinical trial comparing high-dose weekend prednisone (10 mg/kg/week) with standard daily regime (0.75 mg/kg/day) over 12 months showed that high-dose weekend prednisone was well tolerated, equally effective in preserving muscle function, and possibly had less negative impact on growth and weight gain ; however, the long-term outcomes of these regimens remain unclear.
Unfortunately, today, the choice of glucocorticoid and regime often depends on availability, cost, and personal experience of the clinician prescribing the treatment, rather than clinically based evidence. The lack of a standard regimen may result in patients being treated suboptimally or exposed to higher risk of side effects, and may confound efficacy evaluation in clinical trials of new therapeutic approaches. An international clinical trial funded by the National Institutes of Health (FOR-DMD: Finding the Optimum Regimen of Corticosteroids for DMD) is currently comparing different steroid regimes in a young (4–7 years) steroid-naïve DMD population with respect to efficacy, treatment satisfaction, side effects, tolerability, and quality of life (ClinicalTrials.gov #NCT01603407). The study is designed to generate the data that will allow standardization of treatment of DMD, ensuring harmonization of care, improving management, and preparing a population for current and future studies with new investigational drugs.
Nonambulant Patients
The use of corticosteroids in nonambulatory patients is controversial. Further research is needed to investigate the long-term effects of late corticosteroid treatment, especially in view of the increasing adult population with DMD. In nonambulatory patients, the potential benefits of ongoing steroid therapy (preservation of respiratory and cardiac function and prevention of scoliosis) must be carefully balanced against the risk of side effects, in particular in fractures and obesity, which can negatively impact cardiorespiratory and upper limb function.
A recent study showed that older boys continuing corticosteroid treatment following loss of independent ambulation are more likely to preserve muscle function in the lower and upper limbs compared to those who discontinued treatment. Maintenance of the ability to self-feed improves independence and health-related quality of life. The probable cardioprotective effects of corticosteroids are also important at this stage.
Together, these data support continuation of treatment after the loss of ambulation in patients who have used corticosteroids while ambulatory. No controlled or long-term data are available on the effect of commencing treatment in patients who are already nonambulatory. Stabilization of respiratory function in early nonambulatory patients has been suggested in small and short-term studies; presence of cardiomyopathy does not represent a contraindication to corticosteroid therapy, but the impact of treatment in patients with severe left ventricular dysfunction is unclear. Currently, the prescription of corticosteroids in steroid-naïve nonambulatory cases is based on the experience and judgment of the clinician.
Administration
Corticosteroids are usually administered in the morning, with breakfast, to mimic the natural diurnal variation in endogenous steroid production. Although evening administration is sometimes tried in children who develop behavioral issues (emotional lability, hyperactivity, and temper) in the hours after steroid administration, evening administration may cause insomnia. Corticosteroids should never be taken on an empty stomach due to the risk of gastrointestinal complications. Sudden discontinuation of corticosteroids must be avoided as it can cause acute adrenal failure. Although the risk seems to be related to duration and cumulative dose of steroids, all children who have received systemic glucocorticoid therapy at a dose ≥0.3mg/kg daily for more than three weeks should be considered at risk of adrenal insufficiency. A slow, tapered reduction must therefore be planned if discontinuation is required.
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