The Multidisciplinary Team and the Toolkit
The toolkit of assessments and interventions applicable to Duchenne muscular dystrophy (DMD) management is described in Figure 1 of the original guideline document.
The multidisciplinary approach to caring for patients with DMD and the range of expertise required are key features of this process. The patient and family should actively engage with the medical professional who coordinates clinical care. Depending on the patient's circumstances, such as area/country of residence or insurance status, this role might be served by, but is not limited to, a neurologist or paediatric neurologist, rehabilitation specialist, neurogeneticist, paediatric orthopaedist, paediatrician, or primary-care physician. This physician must be aware of the potential issues and be able to access the interventions that are the foundations for proper care in DMD. These include health maintenance and proper monitoring of disease progression and complications to provide anticipatory, preventive care and optimum management. Input from different specialties and the emphasis of interventions will change as the disease progresses (see Figure 2 in the original guideline document).
At a practical level, management of the patient with DMD in the clinic requires a physically accessible environment and parking structure, with proper equipment (e.g., mechanical hoist or sliding board) and trained personnel available for the safe transfer of the non-ambulatory patient. The expertise and means to obtain accurate measures of weight, height, and vital signs with appropriately trained staff are essential. Special weight scales that accommodate wheelchairs are available. Height measurements in patients with severe scoliosis are not accurate and can be replaced by arm-span measurements.
Diagnosis of DMD
The aim of care around diagnosis is to provide an accurate and prompt diagnosis, allowing initiation of appropriate interventions, continuing support and education, and minimising the length and impact of a potentially protracted diagnostic process. Diagnosis should be done by a neuromuscular specialist who can assess the child clinically and can rapidly access and interpret appropriate investigations in the context of the clinical presentation. Family follow-up and support after diagnosis will often be augmented by support from geneticists and genetic counsellors.
When to Suspect DMD
Suspicion of the diagnosis of DMD (see Figure 3 of the original guideline document) should be considered irrespective of family history and is usually triggered in one of three ways: (1) most commonly, the observation of abnormal muscle function in a male child; (2) the detection of an increase in serum creatine kinase tested for unrelated indications; or (3) after the discovery of increased transaminases (aspartate aminotransferase and alanine aminotransferase, which are produced by muscle as well as liver cells). The diagnosis of DMD should thus be considered before liver biopsy in any male child with increased transaminases. Initial symptoms might include delayed walking, frequent falls, or difficulty with running and climbing stairs. Although DMD is typically diagnosed at around 5 years of age, the diagnosis might be suspected much earlier because of delays in attainment of developmental milestones, such as independent walking or language; such delays have been documented prospectively by following patients with DMD identified by newborn screening. The presence of Gowers' sign in a male child should trigger the diagnostic investigation of DMD, especially if the child also has a waddling gait. Toe walking might be present but is not additionally helpful in deciding whether to suspect DMD. In the presence of a positive family history of DMD, there should be a low threshold for testing creatine kinase, although this will be influenced by the age of the child. In a child less than 5 years of age, suspicion of DMD probably cannot be excluded completely by a normal muscle examination. However, with increasing age, a normal muscle examination renders the chance of a child having DMD progressively less likely. A boy older than 10 years of age with normal muscle function is thus highly unlikely to have DMD.
Confirming the Diagnosis
Testing for a DMD mutation in a blood sample is always necessary even if DMD is first confirmed by the absence of dystrophin protein expression on muscle biopsy. The results of genetic testing provide the clinical information required for genetic counselling, prenatal diagnosis, and consideration for future mutation-specific therapies. Different types of mutations in DMD can be the genetic basis for DMD. The genetic tests commonly used to identify dystrophin mutations are multiplex polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification, single-condition amplification/internal primer, and multiplex amplifiable probe hybridisation. Multiplex PCR is widely available and the least expensive, but only detects deletions and does not cover the whole gene, so that a deletion might not always be fully characterised. Multiplex ligation-dependent probe amplification and amplifiable probe hybridisation will detect deletions and duplications and cover all exons, and single-condition amplification/internal primer will detect deletions and provide sequence data. None of these techniques is universally available.
If analysis by one or more of these techniques leads to the identification and full characterisation of a dystrophin mutation, then no further testing is required. If deletion/duplication testing is negative, then dystrophin gene sequencing should be done to look for point mutations or small deletions/insertions.
A muscle biopsy could be done, depending on the clinical situation, availability of genetic testing, and the facilities in the centre where the patient is seen. An open muscle biopsy is necessary if the differential diagnosis includes DMD among other diagnostic possibilities, such as other types of muscular dystrophy, so that adequate amounts of tissue will be available for further analysis. A needle biopsy might be appropriate if testing is only for DMD or if the clinician is skilled in taking multiple cores of tissue from paediatric patients. In those centres where it is done, the conchotome technique has the advantage of providing a larger sample than a single-core needle biopsy, and does not require an open surgical procedure.
The key tests done on the muscle biopsy for DMD are immunocytochemistry and immunoblotting for dystrophin, and should be interpreted by an experienced neuromuscular pathologist.
Genetic testing after a positive biopsy diagnosis of DMD is mandatory. A muscle biopsy is not necessary if a genetic diagnosis is secured first, particularly as some families might view the procedure as traumatic. However, if genetic testing has been done and no mutation identified, but creatine kinase concentrations are increased and signs or symptoms consistent with DMD are present, then the next necessary diagnostic step is to do a muscle biopsy. This is also the case if there is a family history of DMD and a suspicion of the diagnosis, but no family mutation is known.
Neuromuscular and Skeletal Assessments
Clinical assessment in DMD includes taking a standard medical and family history and undertaking a physical examination, with a focus on the musculoskeletal system and related functional impairments. The neuromuscular specialist should be experienced in the expected disease course for DMD to understand the implications of a deviation from this course (e.g., the possibility that a milder course might indicate a less severe dystrophinopathy or that more severe disease might suggest concomitant morbidity). This judgment will be informed by the results of regular assessments of disease progression (i.e., strength, range of motion, posture, gait, timed testing), monitoring of ability to cope with activities of daily living, and application of motor function scales. These assessments, which are also used to inform decisions about therapeutic interventions and monitor response to therapy, are described in Table 1 of the original guideline document. These tests require training and experience to maintain competence. Choice of tests to use in any particular category will be influenced by local factors; consistency within an individual clinic is important to allow comparison over time.
Pharmacological Interventions for Muscle Strength and Function
Glucocorticoids are the only medication currently available that slows the decline in muscle strength and function in DMD, which in turn reduces the risk of scoliosis and stabilises pulmonary function.
On the basis of convincing literature, practice parameter guidelines, and personal experience, the panel strongly urges consideration of glucocorticoid therapy in all patients who have DMD.
The goal of the use of glucocorticoids in the ambulatory child is the preservation of ambulation and the minimisation of later respiratory, cardiac, and orthopaedic complications, taking into account the well-described risks associated with chronic glucocorticoid administration. If such issues are pre-existing, the risk of side-effects might be increased (see Table 2 in the original guideline document). Particular care needs to be taken with such patients in deciding which glucocorticoid to choose, when to initiate treatment, and how best to monitor the child for any problems. A high index of suspicion for steroid-related side-effects needs to be maintained at all times. Prevention and management of side-effects needs to be proactive. Families should be provided with a steroid card or similar notification that the child is on steroids, listing emergency-care considerations in the setting of acute medical presentation, fracture, serious infection, need for surgery, or general anaesthesia, to alert any medical professional with whom the child might come into contact.
Initiation of Glucocorticoid Therapy
No generally accepted guidelines exist in the literature about the best time to initiate glucocorticoid therapy in an ambulatory boy with DMD. The panel's opinion, derived through the RAND Corporation–University of California Los Angeles Appropriateness Method (RAM) process, is that the timing of initiation of glucocorticoid therapy must be an individual decision, based on functional state and also considering age and pre-existing risk factors for adverse side-effects. Recognition of the three phases of motor function in DMD (making progress, plateau, and decline) helps the clinician to make this decision (see figure 4 in the original guideline document). In all cases, the recommended national immunisation schedule should be complete and varicella immunity should be established before steroids are started.
Initiation of glucocorticoid treatment is not recommended for a child who is still gaining motor skills, especially when he is under 2 years of age. The typical boy with DMD continues to make progress in motor skills until approximately age 4 to 6 years, albeit at a slower rate than his peers. The eventual use of glucocorticoids should be discussed with caregivers at this stage, in anticipation of the plateau in motor skills and subsequent decline. The plateau phase, which might last only a few months, can be identified when there is no longer progress in motor skills, but prior to decline, as determined by history and timed testing (see Table 1 of the original guideline). Once the plateau phase has been clearly identified, usually at age 4 to 8 years, the clinician should propose initiation of glucocorticoids unless there are substantial reasons (such as major pre-existing risk factors for side-effects) to wait until the decline phase. Starting steroids when in the full decline phase or when ambulation is more marginal is still recommended, but might be of more limited benefit.
These recommendations for when to initiate glucocorticoid treatment should be interpreted as a minimum threshold. Some practitioners favour a more aggressive approach with earlier initiation of treatment when clinical symptoms first appear, although there are no published data to support this, so the panel did not believe it appropriate to endorse earlier glucocorticoid treatment.
If glucocorticoids are initiated at a first visit, it is suggested that a physician be identified at that time who will be in charge of monitoring the child, particularly if the physician making the recommendation cannot fulfill this role.
Use of Glucocorticoids After Loss of Ambulation
In patients who have used glucocorticoids while ambulatory, many experts continue medication after loss of ambulation with the goal of preserving upper limb strength, reducing progression of scoliosis, and delaying decline in respiratory and cardiac function.
Indications for initiation of glucocorticoids in non-ambulatory patients are more relative than absolute. The effectiveness of glucocorticoid treatment in preventing scoliosis or in stabilising cardiac or respiratory function in this setting is not known.
If the patient and caregiver request the initiation of steroids, daily dosing is indicated if there is a stable functional course. A daily dose is also appropriate in the presence of declining function. However, there is greater need in this group to consider the effect of pre-existing risk factors, such as behavioural issues, fracture risk, or obesity; side-effects require close monitoring.
Glucocorticoid Regimens and Dosing
Daily use of a glucocorticoid is preferred to alternative regimes (i.e., alternate day, high-dose weekend, or a 10-day "on" cycling with 10 or 20 days "off"; see Table 3 of the original guideline document).
Prednisone (prednisolone) and deflazacort are believed to work similarly and neither one has a clearly superior effect on altering the decline in motor, respiratory, or cardiac function in DMD. The choice of which glucocorticoid to use depends on legal availability, cost, formulation, and perceived side-effect profiles (see Figure 4 in the original guideline document). Prednisone is inexpensive and available in a tablet and liquid formulation. Deflazacort, where available, is more expensive and available in fewer tablet sizes, and the liquid formulation is not widely available. Deflazacort might be preferred to prednisone for some patients because of the likely lower risk of weight gain.
The recommended starting dose for prednisone in ambulatory boys is 0.75 mg/kg daily and for deflazacort is 0.9 mg/kg daily, given in the morning. Some patients experience transient behavioural issues (e.g., hyperactivity, emotional lability) for a few hours after the medication is given. For these children, administration of the medication in the afternoon following school might be preferred. In general, higher doses of glucocorticoid are no more effective. The minimum effective dose that shows some benefit (albeit not to the maximum extent possible) is believed to be 0.3 mg/kg daily for prednisone. On the basis of the usual doses used in those who have continued use of steroids from the ambulatory phase, 0.3 to 0.6 mg/kg daily might be an option. There are no data or a panel consensus on the optimum dose of glucocorticoid medication for non-ambulatory steroid-naive patients.
For ambulatory patients, the dose of glucocorticoid is commonly increased as the child grows, provided side-effects are manageable and tolerable, until he reaches approximately 40 kg in weight, with a prednisone cap of approximately 30 to 40 mg/day and a deflazacort cap of 36 to 39 mg/day. Non-ambulatory teenagers maintained on chronic glucocorticoid therapy are usually above 40 kg bodyweight and the dose per kilogram is often allowed to drift down to the 0.3 to 0.6 mg/kg daily range for prednisone or deflazacort, which still leads to substantial benefit. An alternative approach is to not increase the dose of glucocorticoids as the child grows, maintaining the initial dose.
For patients on a relatively low dose of glucocorticoids (less than the starting dose per kg bodyweight) and showing functional decline, the panel felt that it is necessary to consider a functional-rescue adjustment. The dose of glucocorticoids is increased to the target dose and the patient is then re-assessed for benefit and tolerability in 2 to 3 months. It might also be reasonable to increase the dose in an individual patient beyond the typical target dose in this setting to see whether a boost in strength might prolong ambulation, but there are no data or consensus opinion to support this position at present. However, an increase in glucocorticoid dose might also increase the risk of side-effects and this needs to be taken into consideration.
Attentive management of steroid-related side-effects is crucial once a child has started chronic steroid therapy. Although steroid therapy is currently the mainstay of medication for DMD, it should not be undertaken casually by the health-care provider or family and should be managed in clinics with appropriate expertise. Setting parameters for the management of the growing child with DMD on chronic glucocorticoid therapy can help to determine the frequency of dosing and dose adjustment see Figure 4 in the original guideline document). Table 2 in the original guideline summarises the main side-effects to be monitored and useful interventions to counteract them.
Maintenance of a daily schedule is appropriate when the child's motor function is stable or in decline and if any glucocorticoid side-effects are manageable and tolerable. If a daily-dosing schedule generates unmanageable and/or intolerable side-effects that are not ameliorated by a reduction in dose at least once, then it is appropriate to change to an alternative regimen (see Table 3 in the original guideline). If, however, any glucocorticoid side-effects are unmanageable and/or not tolerable, then an increase in glucocorticoid dose for growth or declining function is inappropriate, and in fact, a decrease in dose is necessary, whether motor function is stable or in decline. This applies to all dosing regimens. A reduction of approximately 25% to 33% is suggested, with a reassessment by phone or clinical visit in 1 month to determine whether side-effects have been controlled. If obesity is of concern, then the physician should consider switching treatment from prednisone to deflazacort (see Table 2 in the original guideline document). Glucocorticoid therapy should not be abandoned even if side-effects are not manageable and/or tolerable until at least one dose reduction and change to an alternative regimen has been pursued. This recommendation holds for both ambulatory and non-ambulatory patients. However, should adjustments to the glucocorticoid dosing and/or schedule regimens prove ineffective in making any significant side-effects sufficiently manageable and tolerable, then it is necessary to discontinue glucocorticoid therapy, irrespective of the state of motor function. These decisions need to be made individually in partnership with the child and family, because tolerability of side-effects compared to perceived benefit is an individual judgment. Figure 4 and Table 2 of the original guideline provide more details on specific issues and management recommendations.
Other Drugs and Dietary Supplements
The use of oxandrolone, an anabolic steroid, was not considered necessary or appropriate, either with or without glucocorticoid therapy. The safety of botulinum toxin A has not been studied for the treatment or prevention of contractures in individuals with DMD and is thought to be inappropriate. No recommendations for the use of creatine were established. If a patient is taking creatine and has evidence of renal dysfunction, it is necessary to discontinue this supplement.
Supplements, such as coenzyme Q10, carnitine, amino acids (glutamine, arginine), anti-inflammatories/anti-oxidants (fish oil, vitamin E, green-tea extract), and others, are being used by some parents and are endorsed by some practitioners. In the absence of supportive data from the literature or expert opinion consensus from these panels, the panels make no recommendations for the use of supplements. The expert panels also did not rate the value of potential disease-modifying drugs, such as pentoxifylline or various herbal or botanical agents. This was identified as an area for which additional research is needed. Active involvement of families in activities that help with the advancement of knowledge about DMD, such as patient registries and clinical trials, was encouraged.
The medical care of a patient who has DMD and his family is not complete without support for their psychosocial wellbeing.
The psychosocial difficulties that are observed in DMD should be treated with the same effective, evidence-based interventions that are used in the general population, with a strong emphasis on prevention and early intervention, because this will maximise potential outcome.
Crucial times to consider assessments include the time around diagnosis (for some families, a 6- to 12-month window will be needed for some assessments to allow for adjustment after diagnosis), before entering school, and after a change in function.
Assessments are targeted at the areas of emotional adjustment and coping, neurocognitive functioning, speech and language development, the possible presence of autism spectrum disorders, and social support. Routine screening of psychosocial wellbeing in the patient, parents, and siblings is necessary.
- Brief screening of emotional status is strongly recommended at every clinic visit or on an annual basis at a minimum.
- Emotional adjustment screening can be informal in nature and does not require a comprehensive assessment.
- Use of short standardized rating scales is appropriate and might be helpful.
- Could be completed by a social worker or mental health professional or by other clinical staff with sufficient training in this area (e.g., attending physician, nurse).
- Comprehensive developmental (children ≤4 years old) or neuropsychological (children ≥5 years old) assessment is recommended at or near time of diagnosis and prior to entering formal schooling.
- Standardised performance-based tests and parent/patient rating scales should be used.
- Should be done by a neuropsychologist or other professional with expertise in brain functioning and development within the context of medical conditions.
Speech and Language
Assessment for speech and language therapy services is necessary for:
- Younger children who present with suspected delays in speech and/or language development (as identified by caregiver or because of professional concerns).
- Older patients who present with loss or impairment of functional communication ability.
Autism Spectrum Disorders
- Screening is necessary in children with DMD who are suspected of having language delays, restricted or repetitive behaviour patterns, or deficits in social functioning (as identified by caregiver or because of professional concerns).
- Necessary to refer to an experienced professional for comprehensive assessment and management of an autism spectrum disorder following positive screening or if ongoing concerns exist.
- Assessment of the caregivers and family by a social services professional is necessary.
- A social services professional is defined as a clinical social worker or other professional who is sufficiently trained and qualified to assess and address emotional adjustment and coping, who has access to financial resources and programs and social support networks, and who has an understanding/awareness of DMD.
Interventions will depend on the individual, but should be available to meet a broad spectrum of needs. Of crucial importance to patient/family psychosocial health is the designation of a care coordinator who can serve as a point of contact for families and who has sufficient knowledge and background in neuromuscular disorders to be able to meet the family's information needs. Proactive intervention to help families and patients avoid the social problems and social isolation that occur in the context of DMD is necessary.
Development of an individual education plan for all children with DMD in collaboration with their parents and schools is necessary to address potential learning problems.
Promoting patient independence and involvement in decision making (i.e., as it relates to their medical care) is also necessary.
Psychopharmacological interventions should be considered for the treatment of moderate to severe psychiatric symptoms as part of a multimodal treatment plan that includes appropriate psychotherapies and educational interventions. Standard prescribing practices and guidelines apply, with additional considerations focused on the patient's cardiac status and drug interactions and side-effects when combined with other medications (e.g., weight gain and glucocorticoids), and the patient's general medical condition. Close monitoring with systematic, routine follow-up is highly recommended, including consultation with the appropriate specialist if concerns arise.
Palliative care is appropriate to relieve or prevent suffering and to improve quality of life in patients who have DMD, as needed. In addition to pain management, palliative care teams might also be able to provide emotional and spiritual support, assist families in clarifying treatment goals and making difficult medical decisions, facilitate communication between families and medical teams, and address issues related to grief, loss, and bereavement.
- Parental management training: recommended for externalizing behaviours (e.g., noncompliance/disruptive behaviour and parent–child conflict)
- Individual therapy: recommended for internalizing behaviours (e.g., low self-esteem and depression, anxiety, and obsessive-compulsive disorder, adjustment and coping difficulties)
- Group therapy: recommended for social skills deficits
- Family therapy: recommended for adjustment and coping difficulties and parent–child conflict
- Applied behaviour analysis: recommended for specific behaviours related to autism
- Selective serotonin re-uptake inhibitors for depression, anxiety, obsessive-compulsive disorder
- Mood stabilisers for aggression, anger/emotional dysregulation
- Stimulants for attention-deficit hyperactivity disorder
Social Interaction Interventions
- Increasing DMD awareness and knowledge among school personnel
- Peer education about DMD
- Social skills training (as needed to address deficits in this area)
- Modified/adapted sports, summer camps, and youth groups/programs
- Art groups, equestrian, and aqua therapies; use of service dogs, nature programmes, and internet/chat rooms, among others
- Promoting patient independence and self-advocacy
- Neuropsychological assessment at diagnosis and before entering school
- Individualised education program on entering school
- Measures to address deficits as they are identified
- Care coordinator: serves as a point of contact for the family to meet family information needs, schedule and coordinate appointments, and facilitate communication with clinicians, etc; should be a professional with a sufficient level of training regarding clinical care for DMD
- Home health-care services: should be used if a patient's health is at risk because sufficient care cannot be provided in their current setting or circumstances; might also be appropriate in other situations when the current care providers cannot sufficiently meet the patient's care needs
- Transition planning: encouraging self-advocacy in medical care, facilitating transfer to a new medical care team, and developing educational and vocational opportunities
- Palliative care: appropriate for pain management, as needed; emotional and spiritual support; and guidance for treatment and medical decisions
- Hospice care: necessary for end-stage patients