Muscular Dystrophy Guidelines

In 2013, the American Academy of Pediatrics (AAP) published a clinical report from a multidisciplinary expert panel that developed an algorithm for the screening of children for motor delays with guidance for the initial workup and referral. Identification of motor delays includes ongoing surveillance of the following milestones ^[72] :

• Sitting
• Standing
• Walking
• Running
• Going up stairs

The report recommends that developmental screenings take place at well-child visits at 9, 18, 30, and 48 months of age. The following motor skills are typically acquired at earlier ages, and their absence at these ages signifies delay:

• 9-month visit - Roll to both sides, sit well without support, and demonstrate motor symmetry without established handedness; ability to grasp and transfer objects hand to hand
• 18-month visit - Sitting, standing, and walking independently; ability to grasp and manipulate small objects; mild motor delays undetected at the 9-month screening visit may now be apparent
• 30-month visit - Most motor delays will have already been identified and more subtle gross motor, fine motor, speech, and oral motor impairments may emerge; progressive neuromuscular disorders may manifest as a loss of previously attained gross or fine motor skills
• 48-month visit -  Elementary school skills, with emerging fine motor, handwriting, gross motor, communication, and feeding abilities that promote participation with peers in group activities; loss of skills should alert to the possibility of a progressive disorder

The Centers for Disease Control and Prevention (CDC) also supports early identification and evaluation of motor delays to enable a quicker referral to a specialist for diagnosis. In collaboration with the National Task Force for Early Identification of Childhood Neuromuscular Disorders, the CDC developed a Web-based diagnostic tool, www.childmuscleweakness.org, to assist providers in primary care, rehabilitation medicine, and physical and occupational therapy in the evaluation of children with motor delay and early manifestations of neuromuscular disorders. The website content was endorsed by the AAP. ^[73]

ChildMuscleWeakness.org provides guidance on motor surveillance and screening and includes an aid to the assessment of motor development milestones and recommendations for evaluating the following milestones ^[74] :

• Infant+: Head lag on pull to sit
• Age 6+ months: Achieving and maintaining sitting
• Age 12+ months: Rising to stand from the floor and gait (walking and running)

If a delay is found by using the surveillance aid, a motor delay algorithm provides guidance on testing and referral. The following findings are red flags that indicate the need for an urgent referral to a neurologist:

• Tongue fasciculations
• Loss of motor milestones
• Creatine phosphokinase (CK) level higher than three times normal (however, children with some neuromuscular disorders have normal CK levels)

Many neuromuscular conditions increase the risk for malignant hyperthermia with anesthesia use, and anticipated surgery should increase the urgency of a diagnostic evaluation.  

Creatine phosphokinase testing

Peripheral neuromuscular conditions in which the CK concentration is always elevated from birth include Duchenne muscular dystrophy (MD) and Becker MD, as well as some congenital and limb-girdle MDs. Conditions in which CK is mildly elevated or normal include spinal muscular atrophy, neuropathies, and congenital myopathies. ^[74]

According to AAP guidelines, CK testing should be performed for all children with motor delay and low tone. The CK concentration is significantly elevated in Duchenne MD (DMD), usually  above 1000 U/L. DMD is an X-linked disorder, and there may be a family history of affected males on the maternal side. However, approximately 30% of cases are new mutations in patients with no family history. ^[72]

According to ChildMuscleWeakness.org, any of the following findings are indications for CK testing ^[74] :

• Proximal muscle weakness
• Loss of motor milestones
• Isolated gross motor delay without other developmental difficulties

Additionally, ChildMuscleWeakness.org recommended evaluation of children with mild to moderate developmental delay and motor delays.  Although an elevated CK level warrants prompt referral to a neurologist, a normal level does not rule out neuromuscular disease, and a mildly elevated CK (1-2 times normal) also requires follow-up.

Genetic testing

If the CK concentration is elevated, AAP guidelines suggest that the diagnosis of DMD can usually be confirmed with molecular sequencing of the DMD gene. Testing for other neuromuscular disorders should be performed by subspecialists, because they often require electrodiagnostic or specific genetic testing.

In 2009 and 2010, the CDC published a comprehensive set of DMD care recommendations that included the following topics ^{[75, 76]} :

• Rehabilitation
• Orthopedic
• Respiratory
• Cardiovascular
• Gastroenterology/nutrition
• Pain issues
• General surgery and emergency room precautions

Part 1 of the CDC guidelines focused on diagnosis and pharmacologic and psychosocial management. ^[75] Part 2 outlined the implementation of multidisciplinary care for DMD patients. ^[76]  These guidelines were affirmed by the American Academy of Neurology (AAN) and endorsed by the Muscular Dystrophy Association (MDA) and the TREAT-NMD Neuromuscular Network.

The guidelines required a multidisciplinary approach due to the range of expertise needed to care for DMD patients. The role of coordinating clinical care could be assumed by a neurologist or pediatric neurologist, rehabilitation specialist, neurogeneticist, pediatric orthopedist, pediatrician or other primary care physician. This physician must have access to information on health maintenance and proper monitoring of disease progression and complications to provide anticipatory, preventive care, and optimum management. ^[75]

In addition, the guidelines noted that logistical management of the patient in the clinic requires a physically accessible environment with proper equipment (eg, mechanical hoist or sliding board) and trained personnel available for the safe transfer of the nonambulatory patient. Appropriately trained staff with the expertise and means to obtain accurate measures of weight, height, and vital signs is also needed. ^[75]

These guidelines were subsequently updated in 2018. ^{[77, 78, 79]}

Confirmation of diagnosis

In patients with increased CK levels, the following steps should be taken to confirm the diagnosis of DMD ^[75] :

• If muscle biopsy shows presence of dystrophin protein, DMD is excluded
• If muscle biopsy show absence of dystrophin protein, dystrophin deletion/duplication testing is performed, and deletion or duplication mutation confirms diagnosis of DMD
• If deletion/duplication testing is negative, then dystrophin genetic sequencing is performed to look for point mutations or small deletions/insertions
• A muscle biopsy is not necessary if genetic testing is done, but may be useful to distinguish milder phenotypes

Electromyography and nerve conduction studies are no longer considered necessary for the assessment of DMD. Neuromuscular assessments (ie, strength, range of motion, posture, gait, timed testing, activities of daily living, motor function) are made after diagnosis to inform intervention decisions and are subsequently repeated to monitor response to therapy.

Pharmacologic intervention

The CDC guidelines recommended considering glucocorticoid therapy in all patients who have DMD, based on findings that glucocorticoids are the only medication available that effectively slows decline in muscle strength and function, offers reduced risk of scoliosis, and stabilizes pulmonary function. ^[75]

Additional recommendations for initiation of steroid therapy include the following:

• Timing of initiation of glucocorticoid therapy must be individualized on the basis of functional state, age, and pre-existing risk factors for adverse effects
• Recommended immunizations should be completed and varicella immunity established before therapy is initiated
• Glucocorticoid therapy is not recommended for children still gaining motor skills, especially those under the age of 2 years
• Once motor skills have plateaued (usually between ages 4-8), children should be started on steroids unless there are substantial reasons (eg, a major pre-existing risk factor for adverse effects) to delay therapy until motor skills decline
• Initiation of steroids when the child’s condition is in full decline may provide limited benefits but is still recommended

Further CDC guidance on glucocorticoid regimes and dosing included the following ^[75] :

• Daily use is preferred over alternative regimens
• Neither prednisone nor deflazacort has been proved superior in altering the decline in motor, respiratory, or cardiac functioning, but deflazacort may be preferred for some patients because of the lower risk of weight gain
• Starting doses: Prednisone, 0.75 mg/kg daily; deflazacort, 0.9 mg/kg daily; higher doses have not been found more effective
• The minimum effective dose that shows some benefit is believed to be 0.3 mg/kg daily for prednisone
• The dose is increased as the child grows, as long as adverse effects are manageable and tolerable, until a weight of 40 kg is reached
• The maximum daily dose is 40 mg for prednisone and 36-39 mg for deflazacort
• For children who experience transient behavioral effects, administration of the medication after school may be preferred
• Use of the anabolic steroid oxandrolone was not considered appropriate either with or without glucocorticoid therapy

Psychosocial assessment and interventions

CDC recommendations for emotional adjustment/coping included the following ^[75] :

• Brief screening of emotional status at every clinic visit or on an annual basis at a minimum
• Emotional adjustment screening can be informal and does not require a comprehensive assessment
• Use of short standardized rating scales might be helpful
• Can be completed by a social worker or mental health professional or by other clinical staff with sufficient training (eg, attending physician, nurse)

Neurocognitive assessment recommendations included the following:

• Comprehensive developmental (in children ≤4 years old) or neuropsychological (in children ≥5 years old) assessment at or near time of diagnosis and before the start of formal schooling by a neuropsychologist or other professional with expertise in brain functioning and development, within the context of medical conditions
• Standardized performance-based tests and parent/patient rating scales should be used

Assessment for speech and language therapy should be performed in the following cases:

• Younger children 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

Recommendations regarding autism spectrum disorders included the following:

• Screening in children suspected of having language delays, restricted or repetitive behavior patterns, or deficits in social functioning (as identified by caregiver or because of professional concerns)
• 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 should be performed by a clinical social worker or other professional with the following qualifications:

• Sufficiently trained and qualified to assess and address emotional adjustment and coping
• Understanding/awareness of DMD
• Access to financial resources, programs and social support networks

Interventions will depend on the individual patient, but should be available to meet a broad spectrum of needs. Development of an individual education plan in collaboration with the patient’s parents and school is necessary to address potential learning problems. Promoting patient independence and involvement in decision making (ie, as it relates to medical care) is also essential. Additional recommendations cover psychotherapy, pharmacologic, social interaction, and care/support interventions. ^[75]

Psychotherapy recommendations included the following:

• Parental management training for externalizing behaviors (eg, noncompliance/disruptive behavior, parent–child conflict)
• Individual therapy  for internalizing behaviors (eg, low self-esteem and depression, anxiety, and obsessive-compulsive disorder, adjustment, and coping difficulties)
• Group therapy for social skills deficits
• Family therapy for adjustment and coping difficulties and parent-child conflict
• Applied behavior analysis for specific behaviors related to autism

Pharmacologic intervention recommendations included the following:

• Selective serotonin reuptake inhibitors (SSRIs) for depression, anxiety, obsessive-compulsive disorder
• Mood stabilizers for aggression, anger/emotional dysregulation
• Stimulants for attention deficit/hyperactivity disorder

Social interaction intervention recommendations included the following:

• Increased DMD awareness and knowledge among school personnel
• Peer education
• 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 programs, and internet/chat rooms, among others

Care/support intervention recommendations included the following:

• A care coordinator with sufficient training in clinical care for DMD should serve as a point of contact for the family (eg, to meet family information needs, schedule and coordinate appointments, facilitate communication with clinicians)
• Home health-care services should be used if a patient's health is at risk because sufficient care cannot be provided in the current setting or circumstances; may also be appropriate when the current care providers cannot sufficiently meet the patient's care needs
• Transition planning and self-advocacy in medical care, facilitating transfer to a new medical care team, and developing educational and vocational opportunities
• Palliative care for pain management, as needed; emotional and spiritual support; and guidance for treatment and medical decisions
• Hospice care for end-stage patients

Management of joint contractures

The CDC guidelines for the management of joint contractures require input from neuromuscular specialists, physical therapists, rehabilitation physicians, and orthopedic surgeons. Programs to prevent contractures are usually monitored and implemented by a physical therapist and tailored to individual needs, stage of the disease, response to therapy, and tolerance. ^[76]

Additional recommendations for physical therapy included the following:

• Active, active-assisted, and/or passive stretching to prevent or minimize contractures should be done a minimum of 4-6 days per week for any specific joint or muscle group
• Stretching should be done at home and/or school, as well as in the clinic
• Regular stretching at the ankle, knee, and hip is necessary
• During the non-ambulatory phase, regular stretching of the upper extremities, including the long finger flexors and wrist, elbow, and shoulder joints, also becomes necessary
• Additional areas that require stretching can be identified by individual examination

Swimming may have benefits for aerobic conditioning and respiratory exercise, is highly recommended from the early ambulatory to early non-ambulatory phases, and could be continued in the non-ambulatory phase as long as it is medically safe. Additional benefits may be provided by low-resistance strength training and optimization of upper body function. Significant muscle pain in the 24-hour period after a specific activity is a sign of overexertion and contraction-induced injury, and if this occurs the activity should be modified.

The guidelines found no absolute situations in which lower-limb contracture surgery is invariably indicated. While surgical options exist, none could be recommended above any other. Options for surgery depend on individual circumstances, but can be utilized in both the ambulatory and non-ambulatory phases. Surgical options based on stage are provided below. ^[76]

Early ambulatory phase

Procedures include the following:

• Heel cord (Achilles tendon) lengthening for equinus contractures
• Hamstring tendon lengthening for knee-flexion contractures
• Anterior hip-muscle releases for hip-flexion contractures
• Excision of the iliotibial band for hip-abduction contractures

Middle ambulatory phase

Approaches to lower-extremity surgery to maintain walking include the following:

• Bilateral multi-level (hip-knee-ankle or knee-ankle) procedures
• Bilateral single-level (ankle) procedures
• Unilateral single-level (ankle) procedures for asymmetric involvement (rarely used)

The surgeries may involve the following:

• Tendon lengthening
• Tendon transfer
• Tenotomy (cutting the tendon)
• Release of fibrotic joint contractures (ankle)
• Removal of tight fibrous bands (iliotibial band at lateral thigh from hip to knee)

Equinus foot deformity (toe-walking) and varus foot deformities (severe inversion) can be corrected by heel-cord lengthening and tibialis posterior tendon transfer through the interosseous membrane onto the dorsolateral aspect of the foot to change plantarflexion-inversion activity of the tibialis posterior to dorsiflexion-eversion. Hamstring lengthening behind the knee is generally needed if the patient has a knee-flexion contracture of more than 15°.

After tendon lengthening and tendon transfer, postoperative bracing may be needed, which should be discussed preoperatively. Following tenotomy, bracing is always needed. When surgery is performed to maintain walking, the patient must be mobilized using a walker or crutches on the first or second postoperative day to prevent further disuse atrophy of lower-extremity muscles. Postoperative walking must continue throughout limb immobilization and post-cast rehabilitation. Close coordination between and an experienced team (eg, orthopedic surgeon, physical therapist, and orthoptist) is required.

Late ambulatory and early nonambulatory phase

Surgery in the late ambulatory phase has generally been ineffective. Likewise, extensive lower-extremity surgery and bracing to regain ambulation within 3-6 months after walking ability is lost is generally ineffective and not considered appropriate.

Late nonambulatory phase

Severe equinus foot deformities of more than 30° can be corrected with heel-cord lengthening or tenotomy. Varus deformities (if present) can be corrected with tibialis posterior tendon transfer, lengthening, or tenotomy. These procedures are performed for specific symptomatic problems, to alleviate pain and pressure, to allow the patient to wear shoes, and to permit correct placement of the feet on wheelchair footrests. They are not recommended as routine care.

Skeletal management

Daily glucocorticoid treatment reduces the risk of scoliosis, but increases the risk of vertebral fracture. Spinal care by an experienced spinal surgeon comprises the following:

• In the ambulatory phase, scoliosis monitoring by clinical assessment, with spinal radiography only if scoliosis is observed
• In the nonambulatory phase, clinical assessment for scoliosis at each visit; spinal radiography is indicated as a baseline assessment for all patients and should consist of a sitting anteroposterior (AP) full-spine radiograph and lateral projection film
• An AP spinal radiograph is warranted annually for curves of less than 15-20° and every 6 months for curves of more than 20°, irrespective of glucocorticoid treatment, until skeletal maturity
• Support of spinal/pelvic symmetry and spinal extension by the wheelchair seating system
• Monitoring for painful vertebral body fractures
• Spinal fusion to straighten the spine, prevent further worsening of deformity, eliminate pain due to vertebral fracture with osteoporosis, and slow the rate of respiratory decline
• Anterior spinal fusion is inappropriate in DMD
• Posterior spinal fusion is warranted only in nonambulatory patients who have spinal curvature of more than 20°, are not taking glucocorticoids, and have yet to reach skeletal maturity
• In patients on glucocorticoids, surgery may be warranted if curve progression continues and is associated with vertebral fractures and pain after optimization of medical therapy to strengthen the bones, irrespective of skeletal maturation

Internal fixation is warranted for severe lower-limb fractures in ambulatory patients, to allow prompt rehabilitation and the greatest possible chance of maintaining ambulation. In the nonambulatory patient, the requirement for internal fixation is less acute. Splinting or casting of a fracture is necessary for the nonambulatory patient, and is appropriate in an ambulatory patient if it is the fastest and safest way to promote healing and does not compromise ambulation during healing.

Respiratory management

The CDC guidelines suggested that respiratory care should allow for timely prevention and management of complications. A structured, proactive approach that includes use of assisted cough and nocturnal ventilation has been found to prolong survival. The guidelines provide an outline of respiratory intervention steps for older teenage and adult patients, which are listed below. ^[76]

Step 1: Volume recruitment/deep lung inflation technique

Volume recruitment/deep lung inflation technique (by self-inflating manual ventilation bag or mechanical insufflation-exsufflation) is used when the forced vital capacity (FVC) reaches < 40% predicted.

Step 2: Manual and mechanically assisted cough techniques

These techniques are necessary in any of the following situations:

• Respiratory infection is present and baseline peak cough flow < 270 L/min
• Baseline peak cough flow < 160 L/min or maximum expiratory pressure < 40 cm H ₂O
• Baseline FVC < 40% predicted or < 1.25 L in older teenager/adult

Step 3: Nocturnal ventilation

Nocturnal ventilation is indicated in patients who have any of the following:

• Signs or symptoms of hypoventilation (patients with FVC < 30% predicted are at especially high risk)
• Baseline oxygen saturation by pulse oximetry (SpO ₂) < 95% and/or blood or end-tidal CO ₂ >45 mm Hg while awake
• Apnea–hypopnea index >10 per hour on polysomnography or four or more episodes of SpO ₂ < 92% or drops in SpO ₂ of at least 4% per hour of sleep

Use of lung volume recruitment and assisted cough techniques should always precede initiation of noninvasive ventilation.

Step 4: Daytime ventilation

In patients already using nocturnally assisted ventilation, daytime ventilation is indicated for any of the following:

• Self-extension of nocturnal ventilation into waking hours
• Abnormal deglutition due to dyspnea, which is relieved by ventilatory assistance
• Inability to speak a full sentence without breathlessness
• Symptoms of hypoventilation with baseline SpO ₂ < 95% and/or blood or end-tidal CO ₂ >45 mm Hg while awake

Continuous noninvasive assisted ventilation (with mechanically assisted cough) can facilitate endotracheal extubation for patients who were intubated during acute illness or during anesthesia, followed by weaning to nocturnal noninvasive assisted ventilation, if applicable.

Step 5: Tracheostomy 

Indications for tracheostomy include the following:

• Patient and clinician preference
• Patient cannot successfully use non-invasive ventilation
• Inability of the local medical infrastructure to support non-invasive ventilation
• Three failures to achieve extubation during critical illness despite optimum use of non-invasive ventilation and mechanically assisted cough
• The failure of noninvasive methods of cough assistance to prevent aspiration of secretions into the lung and drops in oxygen saturation below 95% or the patient's baseline, necessitating frequent direct tracheal suctioning via tracheostomy

Cardiac management

The CDC guidelines recommended that a cardiac specialist be involved with the patient and family after confirmation of the diagnosis to initiate a relationship to ensure long-term cardiovascular health. Baseline assessment of cardiac function should be done at diagnosis or by the age of 6 years, especially if this can be done without sedation. Clinical judgment should be used for patients under the age of 6 years who require sedation.

Echocardiographic screening at the time of diagnosis or by the age of 6 years is deemed necessary even though the incidence of echocardiographic abnormalities is low in children younger than 8 to 10 years. A baseline echocardiogram allows for screening for anatomic abnormalities (eg, atrial or ventricular septal defects, patent ductus arteriosus) that might affect long-term cardiovascular function. ^[76]

Additional recommendations for cardiac management include the following:

• Minimum assessment should include electrocardiography (ECG) and a noninvasive cardiac imaging study (eg, echocardiography)
• Assessment of cardiac function should be performed at least once every 2 years until the age of 10 years
• Annual complete cardiac assessments should begin at the age of 10 years, or earlier if cardiac signs and symptoms arise
• Abnormalities of ventricular function on non-invasive cardiac imaging studies warrant increased surveillance (at least every 6 months) and should prompt initiation of pharmacologic therapy, irrespective of the age at which they are detected
• Consider the use of angiotensin-converting enzyme (ACE) inhibitors as first-line therapy; beta blockers and diuretics are also appropriate
• Signs or symptoms of cardiac rhythm abnormalities should be investigated with Holter or event monitoring and should be treated
• New-onset sinus tachycardia in the absence of a clear cause should prompt assessment, including that of left ventricular function
• Patients receiving glucocorticoids need additional monitoring for hypertension, which might necessitate adjustment in the glucocorticoid dose; systemic arterial hypertension should be treated
• Prevention of systemic thromboembolic events by anticoagulation therapy can be considered in patients with severe cardiac dysfunction, but is inappropriate in earlier cardiac dysfunction

Digestion and nutritional care

The guidelines recommend access to a dietitian or nutritionist, a swallowing/speech and language therapist, and a gastroenterologist, for the following reasons:

• To guide the patient to maintain good nutritional status to prevent both undernutrition/malnutrition and overweight/obesity
• To provide a well-balanced, nutrient-complete diet (adding tube feeding, if necessary)
• To monitor and treat dysphagia and prevent aspiration and weight loss
• To assess and treat delayed speech and language problems
• To treat the common problems of constipation and gastroesophageal reflux with both medication and nonmedication therapies

Pain management

CDC recommendations for pain management interventions included the following ^[76] :

• Physical therapy
• Postural correction
• Orthoses, wheelchair, and bed enhancements
• Pharmacologic approaches (eg, muscle relaxants and anti-inflammatory medications)

Pharmacologic interventions must take into account possible interactions with other medications (eg, steroids and nonsteroidal anti-inflammatory drugs [NSAIDs]) and their adverse effects, particularly those that might negatively affect cardiac or respiratory function.

Surgical precautions

In 2007 the American College of Chest Physicians (ACCP) published a consensus statement of recommendations for preoperative, intraoperative, and postoperative respiratory support for DMD patients undergoing procedures requiring anesthesia or sedation. ^[80]

Preoperative respiratory support

Anesthesiology and pulmonology consultations should be obtained, according to the ACCP. Pulmonary evaluation should include measurement of the following:

• FVC
• Maximum inspiratory pressure (MIP)
• Maximum expiratory pressure (MEP)
• Peak cough flow (PCF)
• Oxyhemoglobin saturation by pulse oximetry (SpO ₂) in room air; if < 95%, measure the blood and/or end-tidal carbon dioxide level
• Consider preoperative training in the use of noninvasive positive pressure ventilation (NPPV) for patients at increased risk of respiratory complications (FVC < 50% of predicted) and especially for patients at high risk (FVC < 30% of predicted)
• Consider preoperative training in manual and mechanically assisted cough, emphasizing use of mechanical insufflation-exsufflation (MI-E) with a bronchial secretion clearance device for patients at high risk of ineffective cough (adults with PCF < 270 L/min or MEP < 60 cm H ₂O)

Other preoperative measures should include the following:

• Refer the patient to a cardiologist for clinical evaluation and optimization of cardiac therapies
• Nutritional assessment and optimization of nutritional status is required
• Consider strategies to manage dysphagia
• Discuss the risks and benefits of general anesthesia or procedural sedation with the patient and guardians, and help them to decide on and implement their decisions regarding resuscitation parameters and, if applicable, advance directives

Intraoperative support

Intraoperative measures include the following:

• Consider use of a total intravenous anesthesia technique for induction and maintenance of general anesthesia (eg, propofol and short-acting opioids)
• The use of depolarizing muscle relaxants such as succinylcholine is absolutely contraindicated because of the risk of fatal reactions
• Have an intensive care unit bed available for postprocedure care

Options for providing respiratory support during maintenance of general anesthesia or procedural sedation for patients with DMD include the following:

• Endotracheal intubation, with use of NPPV to facilitate extubation for selected patients
• Mechanical ventilation via a mouthpiece with leak-proof seal
• Manual or mechanical ventilation (using conventional ventilators or bilevel positive pressure ventilators designed for noninvasive respiratory support) delivered via a full face mask or nasal mask interface
• Application of ventilation in the assisted or controlled modes should be considered for patients with FVC < 50% of predicted, and strongly considered for those with an FVC < 30% of predicted

Options for respiratory support during induction of and recovery from general anesthesia or procedural sedation include the following:

• Manual ventilation using a flow-inflated manual resuscitation bag (standard “anesthesia bag”) with a full face or nasal mask interface
• Mechanical support using a conventional or noninvasive positive pressure ventilator via a full face or nasal mask

Monitor SpO₂ continuously and, whenever possible, blood or end-tidal carbon dioxide levels.

Postoperative support

Postoperative measures include the following:

• Consider extubation directly to NPPV in DMD patients with FVC < 50% of predicted, and especially those with FVC < 30% of predicted
• Consider delaying extubation until respiratory secretions are well controlled and SpO ₂ is normal or baseline in room air; continuous use of NPPV can then be weaned as tolerated
• Use supplemental oxygen therapy cautiously; monitor Spo ₂ continuously
• Whenever possible, monitor blood or end-tidal carbon dioxide levels
• Assess whether hypoxemia is due to hypoventilation, atelectasis, or airway secretions and treat appropriately
• Use manually assisted cough and MI-E postoperatively for patients with impaired cough (PCF < 270 L/min or MEP < 60 cm H ₂O in adults)
• Optimize postoperative pain control in patients with DMD; if sedation and/or hypoventilation occurs, delay endotracheal extubation for 24 to 48 hours or use NPPV
• Obtain a cardiology consultation and closely monitor cardiac and fluid status postoperatively
• Initiate bowel regimens to avoid and treat constipation and consider prokinetic GI medications
• Consider gastric decompression with a nasogastric tube in patients with GI dysmotility
• Start parenteral nutrition or enteral feeding via a small-diameter tube if oral feeding is delayed for >24-48 hours postoperatively

The CDC guidelines concurred with the earlier guidelines of ACCP and include these additional recommendations for surgical precautions ^[76] :

• Surgery should be performed in a full-service hospital that has experience with DMD patients
• For patients on  long-term corticosteroid treatment, consider steroid coverage over the period of surgery
• To minimize blood loss and its intraoperative effects in major surgeries (eg, spinal fusion), use mildly hypotensive anesthetics, crystalloid bone allograft, and cell-saver technology
• Other interventions, such as the use of aminocaproic acid or tranexamic acid to diminish intraoperative bleeding, can be considered
• Postoperative anticoagulation with heparin and/or aspirin is inappropriate
• Use of compression stockings or sequential compression for prevention of deep venous thrombosis may be indicated
• An echocardiogram and electrocardiogram should be done before general anesthesia
• An echocardiogram should also be done if the patient is undergoing conscious sedation or regional anesthesia if the last investigation was more than 1 year ago or the patient has had an abnormal echocardiogram in the preceding 7-12 months
• For local anesthesia, an echocardiogram should be done if an abnormal result had been obtained previously
• Incentive spirometry is not indicated owing to potential lack of efficacy in patients with respiratory muscle weakness and the availability of preferred alternatives, such as mechanical insufflation-exsufflation (MI-E)

In 2015, the AAN and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) released joint evidence-based guidelines for the evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy (FSHD). The guidelines were also endorsed by the FSH Society and the Muscular Dystrophy Association. ^[81]

A clinical algorithm for diagnosis includes the following steps:

• When clinical presentation of FSHD is typical and the diagnosis of FSHD1 is genetically confirmed in a first-degree relative, genetic testing is not necessary in an affected individual
• In patients who have no first-degree relatives with genetic confirmation of the disease, test for D4Z4 contraction
• If negative for D4Z4 contraction, consider FSHD2,  limb-girdle muscular dystrophy type 2A, or other myopathies
• If positive for D4Z4 contraction and typical clinical presentation, FSHD1 diagnosis is confirmed
• If positive for D4z4 contraction and atypical clinical presentation, test for A allele; if positive for A allele, FSHD1 diagnosis is confirmed; if negative, consider other myopathies

There were no recommendations given a level A rating denoting that in almost all circumstances, adherence to the recommendation will improve health-related outcomes. Level B and C recommendations included the following ^[81] :

• Obtain genetic confirmation of FSHD1 in patients with atypical presentations and no first-degree relatives with genetic confirmation of the disease (level B)
• Patients with large D4Z4 deletion sizes (contracted D4Z4 allele of 10–20 kb) are more likely to develop more significant disability and at an earlier age as well as symptomatic extramuscular manifestations (level B)
• Obtain baseline pulmonary function tests (PFT); monitor regularly in patients with abnormal baseline PFT results or any combination of severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid conditions that may affect ventilation (eg, chronic obstructive pulmonary disease, cardiac disease) (level B)
• Refer patients with compromised PFT results (eg, forced vital capacity [FVC] < 60%) or symptoms of excessive daytime somnolence or nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches) for pulmonary or sleep medicine consultation, for consideration of nocturnal sleep monitoring or nocturnal non-invasive ventilation, to improve quality of life (level B)
• Patients who do not receive regular PFT should be tested prior to surgical procedures requiring general anesthesia, as such testing may uncover asymptomatic respiratory compromise (level B)
• Refer patients who develop overt signs or symptoms of cardiac disease (eg, shortness of breath, chest pain, palpitations) for cardiac evaluation; routine cardiac screening is not essential in the absence of cardiac signs or symptoms (level C)
• Refer patients with large deletions (contracted D4Z4 allele of 10-20 kb) to an experienced ophthalmologist (eg, retina specialist) for dilated indirect ophthalmoscopy (level B)
• The presence and severity of retinal vascular disease at initial screening should be used to determine the frequency of subsequent monitoring (level B)
• Screen all young children for hearing loss at diagnosis and yearly thereafter until these children start school; hearing loss may not be present at diagnosis and can be progressive (level B)
• Treating physicians should routinely inquire about pain; referral for a physical therapy evaluation may prove helpful as an initial nonpharmacologic intervention; in patients with persistent pain and no contraindications, a trial of nonsteroidal anti-inflammatory medications is appropriate for acute pain, and antidepressants or antiepileptics for chronic pain (level B)
• Albuterol, a corticosteroid, or diltiazem should not be prescribed for improving strength (level B)
• Surgical scapular fixation might be offered cautiously to selected patients after careful consideration of the overall muscle impairment in the involved arm, assessment of potential gain in range of motion by manual fixation of the scapula, the rate of disease progression, and the potential adverse consequences of surgery and prolonged postsurgical bracing (level C)
• Clinicians might encourage low-intensity aerobic exercise; an experienced physical therapist can help guide development of individualized exercise programs; clinicians might also use the practical physical activities guidelines for individuals with disabilities provided by the US Department of Health and Human Services when counseling patients about aerobic exercise (level C)
• Patients interested in strength training may be referred to physical therapists to establish a safe exercise program using appropriate low/medium weights/resistance that takes into consideration the patients' physical limitations (level C)

In 2010, the International Standard of Care Committee for Congenital Muscular Dystrophy published the first guidelines for children with congenital muscular dystrophies (CMDs) with consensus on care recommendations in seven areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/nutrition/speech/oral care, cardiology, and palliative care. The guideline development was funded by CureCMD, TREAT-NMD, AFM-Association Francaise contre les Myopathies and Telethon Italy. ^[82]

In 2015, the AAN and the AANEM released joint evidence-based guidelines for the evaluation, diagnosis and management of congenital muscular dystrophy. The guidelines were endorsed by the AAP, the American Occupational Therapy Association, the Child Neurology Society, and the National Association of Neonatal Nurses. ^[83]

The AAN/AANEM guidelines classify three major categories of CMDs:

• Collagenopathies (also known as collagen VI−related myopathies), including Ullrich CMD and Bethlem myopathy
• Merosinopathies (also known as merosin-deficient CMDs [MDCs], laminin α2 [ LAMA2]-related CMDs, and MDC1A
• Dystroglycanopathies (also known as α-dystroglycan–related MDs), including Fukuyama CMD, muscle-eye-brain disease, and Walker-Warburg syndrome

However, other rare CMDs do not fit into the three classic categories. These CMDs with their associated genes and clinical phenotypes include the following:

• Rigid spine syndrome (selenoprotein N, 1[ SEPN1], four-and-a-half LIM domain 1[ FHL1])
• Mutiminicore disease ( SEPN1)
•  L-CMD (Lamin A/C [ LMNA])

Other genes that have been associated with CMDs include the following ^[83] :

• GTDC2
• TMEM5
• B3GALNT2
• SGK196
• B3GNT1
• GMPPB]
• AG1

The authors of the AAN/AANEM guidelines base some recommendations in part on evidence from other neuromuscular disorders of childhood because of a lack of literature directly relevant to CMDs. As with other forms of muscular dystrophy, multidisciplinary teams should include the following:

• Neuromuscular specialists, particularly child neurologists and physiatrists with subspecialty training
• Physicians from other specialties (eg, cardiology, gastroenterology, neurology, ophthalmology, orthopedic surgery, pulmonology)
• Allied health professionals with relevant expertise (eg, dieticians, genetic counselors, nurses, nurse practitioners, occupational therapists, physical therapists, speech-language pathologists)

Like the 2015 FSHD guidelines, the AAN/AANEM contain no level A recommendations. The key recommendations include the following ^[83] :

• Physicians caring for children with CMD should consult a pediatric neuromuscular specialist for diagnosis and management (level B)
• Pediatric neuromuscular specialists should coordinate the multidisciplinary care of patients with CMD when such resources are accessible to interested families (level B)
• When genetic counselors are available to help families understand genetic test results and make family-planning decisions, help should be given to families to access such resources (level B)
• Physicians should use relevant clinical features such as ethnicity and geographic location, patterns of weakness and contractures, the presence or absence of central nervous system involvement, the timing and severity of other organ involvement, and serum creatine phosphokinase (CK) levels to guide diagnosis in collagenopathies and in dystroglycanopathies (level B)

Diagnosis

AAN/AANEM recommendations regarding diagnosis include the following:

• Immunohistochemical staining for relevant proteins in CMD cases may be included in muscle biopsies when the subtype-specific diagnosis is not apparent after initial diagnostic studies, if the risk associated with general anesthesia is determined to be acceptable (level C)
• When muscle biopsies are indicated, they should be performed and interpreted at centers experienced in this test modality; in some cases, optimal diagnostic information may be derived when the biopsy is performed at one center and interpreted at another (level B)
• Magnetic resonance imaging (MRI) may assist with the diagnosis of patients with clinically suspected CMD subtypes such as merosinopathies and dystroglycanopathies, if the potential risk associated with any sedation is determined to be acceptable and if a radiologist or other physician with the appropriate expertise is available to interpret the findings (level B)
• Consider muscle imaging studies of the lower extremities for individuals with suspected CMD subtypes such as collagenopathies (ultrasonography or MRI) and  SEPN1-related myopathy (MRI), if the risk associated with any sedation needed is determined to be acceptable and if a radiologist or other physician with the appropriate expertise is available to interpret the findings (level C)
• Consider targeted genetic testing for specific CMD subtypes that have well-characterized molecular causes when available and feasible (level C)
• In individuals who do not have a mutation identified in one of the commonly associated genes or who have a phenotype whose genetic origins have not been well characterized, whole-exome or whole-genome sequencing may be used if those technologies become more accessible and affordable for routine clinical use (level C)

Treatment

The AAN/AANEM guidelines note that there are no curative CMD subtype-specific interventions. Thus, all screening and interventions are intended to promote growth and potential development, mitigate cumulative morbidities, optimize function, and limit mortality while maximizing quality of life.

At the time of diagnosis, the family should be informed regarding areas of uncertainty such as clinical outcomes and the value of interventions as they pertain to both longevity and quality of life. Physicians should explain the multisystem implications of neuromuscular insufficiency and guide families as they make decisions regarding the monitoring for and treatment of CMD complications (level B).

Management of complications

Respiratory complications

The AAN/AANEM guidelines recommend the following ^[83] :

• Inform families of patients with CMD that respiratory insufficiency and associated problems may be inconspicuous at the outset (level B)
• Monitor pulmonary function tests such as spirometry and oxygen saturation in the awake and sleep states of patients, with monitoring levels individualized on the basis of the child's clinical status (level B)
• Refer to pulmonary or aerodigestive care teams, when available, that are experienced in managing the interface between oropharyngeal function, gastric reflux and dysmotility, and nutrition and respiratory systems, and can provide guidance concerning trajectory, assessment modalities, complications, and potential interventions (level B)

The International Standard of Care Committee consensus recommendations include the following ^[82] :

• Regularly scheduled physician visits and patient or family awareness of potential signs and symptoms are elements of a proactive approach to recognize early pulmonary problems prior to the onset of chronic respiratory compromise
• Pneumococcal and influenza vaccines are suggested for any patient with CMD
• Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus, should be given to children under 2 years of age as prophylaxis
• Spinal bracing is required to promote activities of daily living, ensure functional sitting posture, and delay the progression of scoliosis; this allows adequate thoracic growth until optimal timing for spinal surgery
• Spirometry both in and out of the brace is recommended to evaluate the impact on respiratory function
• Adjustment is needed between the degree of correction and the compression pressure on the thorax to avoid compromise of respiratory capacity

Complications from dysphagia

The AAN/AANEM guidelines recommend the following ^[83] :

• Neuromuscular specialists should coordinate with primary care providers to follow nutrition and growth trajectories in patients with CMD (level B)
• Multidisciplinary evaluations with swallow therapists, gastroenterologists, and radiologists if there is evidence of failure to thrive or respiratory symptoms (or both) (level B)
• A multidisciplinary care team, taking into account medical and family considerations, should recommend gastrostomy placement with or without fundoplication in the appropriate circumstances (level B)

The International Standard of Care Committee consensus recommends feeding and swallowing problems be regularly screened during routine clinic visits. Key screening issues are the following ^[82] :

• Length of mealtimes - More than 30 minutes per meal is considered to be prolonged
• Frequency of meals - Increased meal frequency may be needed and clinicians need to ensure that families can carry this out without difficulties
• Frequency of pulmonary infections
• Difficulties chewing; choking and coughing
• Food texture modification
• Family stress or enjoyment of mealtimes for the child and parents
• The ability to feed independently
• Position for feeding

Identification of difficulties in the above areas warrants assessment by a specialist qualified in feeding and swallowing evaluation. Assessment should include the following:

• Orofacial examination
• Observation and evaluation of feeding and swallowing skills
• Observation and evaluation of seating and positioning.

The use of a videofluoroscopic swallow assessment to objectively assess the swallow should be done by speech and language specialists. Endoscopic evaluation of swallow is an underused assessment in pediatrics, specifically in this population.

Additional consensus recommendations include the following ^[82] :

• Patients with muscle weakness are prone to gastroesophageal reflux and delayed gastric emptying; treatment with an H2-antagonist/proton pump inhibitor with or without a prokinetic agent can be indicated
• Speech and swallow evaluation should be considered for patients with symptoms of aspiration such as cough, choking, difficulty swallowing, poor feeding, or failure to thrive; thickened feeds or an alternate method of feeding are needed
• If symptomatic management is insufficient, the use of tube feeding has to be considered
• Nasogastric tube feeding should be reserved for short-term use such as before and after surgery or during acute illness
• Gastrostomy or jejunostomy is the treatment of choice for long-term enteral feeding

Cardiac complications

The AAN/AANEM guidelines recommend referral, regardless of subtype, for a baseline cardiac evaluation. The schedule for further evaluations should depend on the results of the baseline evaluation and the subtype-specific diagnosis (level B). ^[83]

The International Standard of Care Committee consensus recommendations include the following ^[82] :

• All patients with congenital muscular dystrophies should undergo cardiac screening beginning at diagnosis
• The initial evaluation can help with diagnosis of the type of CMD, provides reference values for follow-up, and assists follow-up planning
• The frequency of follow-up depends on the presence of cardiac risk factors such as diagnosis of laminopathy or dystroglycanopathy, cardiac symptoms, and abnormal previous cardiac tests
• In patients with laminopathies or dystroglycanopathies, cardiac examinations should be performed at least every year, and at least every 6 months in patients with symptoms, conductive abnormalities, or myocardial involvement
• In patients with other CMDs, follow-up should be performed at least every 2 years in asymptomatic patients and at least every year in patients with cardiac symptoms
• ECG and echocardiography are simple examinations and provide enough information in the majority of patients
• Twenty-four-hour ambulatory electrocardiogram should be considered in patients with laminopathies in order to detect paroxysmal conductive defects and arrhythmias
• Isotopic ventriculography can be useful to assess ventricular function in patients with poor echogenicity due to thoracic deformations
• Cardiac MRI could be useful in patients with laminopathies

Surgical complications

The AAN/AANEM guidelines recommend that before children undergo any surgical interventions and general anesthesia, physicians should discuss the potential increased risk of complications with patients' families, because these factors may affect decision-making regarding consent to certain elective procedures (level B). When children undergo procedures involving sedation or general anesthesia, physicians should monitor longer than usual in the immediate postoperative period to diagnose and treat respiratory, nutritional, mobility, and gastrointestinal mobility complications (level B). ^[83]

The International Standard of Care Committee recommends postoperative respiratory management by an experienced team including physical therapists to improve outcome. Nutritional aspects should be considered to ensure that maintenance of weight is achieved. Additional considerations for postoperative management and care include ^[82] :

• Intensive pulmonary treatment in the following 6 months (insufflation techniques, prolongation of mechanical ventilation) may be needed
• Self-feeding can be more difficult initially
• Wheelchairs may need to be adapted to the changed shape of the child
• Management of transfers, including the hoist and slings, must be considered
• All aspects of postoperative activities of daily living should be addressed preoperatively by an occupational or physical therapist
• Bracing may still be required after surgery, and it requires an experienced orthotist
• Support of the head may also be needed
• Pain management is needed
• Long-term follow-up by spinal surgeons is needed given the child’s changing status
• Increasing hyperextension of the neck is common in this group of disorders and needs to be monitored; strategies must be developed to alleviate the concomitant problems of function
• Extension of the spinal surgery into the neck may be required

Musculoskeletal complications

The AAN/AANEM guidelines recommend the following ^[83] :

• Refer to allied health professionals, including physical, occupational, and speech therapists; seating and mobility specialists; rehabilitation specialists; and orthopedic surgeons, to help maximize function and potentially slow the progression of musculoskeletal complications (level B)
• Range-of-motion exercises, orthotic devices, heel cord–lengthening procedures, or a combination of these interventions may be recommended in certain circumstances (level B)
• Avoid using neuromuscular blocking agents (eg, botulinum toxin), unless the contractures are determined to cause significantly greater impairment than would any potential worsening of weakness in the targeted muscle groups (level C)

The International Standard of Care Committee consensus recommends physical therapy be focused on the following ^[82] :

• Maintenance of function and mobility
• Prevention or treatment of joint contractures and spine deformities
• Activities to improve respiratory function, such as singing or playing a wind instrument
• Adequate seating and wheelchair support
• Nutrition and swallowing surveillance with optimal weight gain

Educational adjustments

The AAN/AANEM guidelines recommend referral to special education advocates, developmental specialists, and education specialists when appropriate for individual circumstances (level B). ^[83]

The International Standard of Care Committee consensus recommendations include the following ^[82] :

• Children with mental retardation and learning issues should undergo psychometric testing and be referred to early intervention and augmented/specialized school and communication programs with dedicated evaluations and monitoring
• For behavioral, emotional, and autistic problems, referrals to child psychology/psychiatry services
• In α-dystroglycanopathies, detailed eye examination and subsequent follow-ups are indicated; if the child is visually impaired, appropriate education and services should be provided, given that visual impairment negatively affects learning and quality of life
•  As coordinators of care, neurologists should act as advocates when working with day care, school, and other service providers and make sure that they understand the special needs of children with CMD

In 2014, guidelines for the diagnosis and management of patients with limb-girdle or distal muscular dystrophies were issued by the AAN and the AANEM. The guidelines were endorsed by the American Academy of Physical Medicine and Rehabilitation, the Child Neurology Society, the Jain Foundation, and the MDA. ^[84]

The guideline provides algorithms for diagnosis, with the clinical picture, ethnicity, family history, and cardiac and respiratory symptoms all considered in deciding whether genetic testing for MD is appropriate and which of the many individual tests to select. The guidelines call for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. The key recommendations are listed below.

Clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the following (level B):

• Pattern of muscle involvement
• Inheritance pattern
• Age at onset
• Associated manifestations (eg, early contractures, cardiac or respiratory involvement)

In patients with suspected MD in whom initial clinically directed genetic testing does not provide a diagnosis, clinicians may obtain genetic consultation or perform any of the following to identify the genetic abnormality (level C):

• Parallel sequencing of targeted exomes
• Whole-exome sequencing
• Whole-genome screening
• Next-generation sequencing

Other referral and assessment recommendations include the following:

• Clinicians should refer newly diagnosed patients for cardiology evaluation, even if they are asymptomatic, to guide appropriate management; the evaluation should include ECG and structural evaluation (echocardiography or cardiac MRI) (level B)
• If cardiology evaluation yields abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (eg, Holter monitor or event monitor) to guide appropriate management (level B)
• Refer patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation (level B)
• Referral of patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation is not obligatory unless they develop overt cardiac signs or symptoms (level B)
• Refer patients with dysphagia, frequent aspiration, or weight loss for swallowing evaluation or gastroenterology evaluation to assess and manage swallowing function and aspiration risk, to teach patients techniques for safe and effective swallowing (eg, chin tuck maneuver, altered food consistencies), and to consider placement of a gastrostomy/jejunostomy tube for nutritional support (level B)
• Refer for pulmonary function testing (PFT; spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or referral for pulmonary evaluation (to identify and treat respiratory insufficiency) at the time of diagnosis, or if the patient develops pulmonary symptoms (level B)
• In patients with a known high risk of respiratory failure (eg, those with LGMD2I or MFM), obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (level B)
• Referral of patients with LGMD2B and LGMD2L for pulmonary evaluation is not obligatory unless they are symptomatic (level C)
• Refer patients with excessive daytime somnolence, nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on PFTs for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (level B)
• Monitor patients for the development of spinal deformities to prevent resultant complications and preserve function (level B)
• Refer patients with musculoskeletal spine deformities to an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life (level B)
• Refer patients to a clinic that has access to multiple specialties (eg, physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics) designed specifically to care for patients with MD and other neuromuscular disorders in order to provide efficient and effective long-term care (level B)
• Clinicians should recommend that patients have periodic assessments by a physical and occupational therapist for symptomatic and preventive screening (level B)
• While respecting and protecting patient autonomy, clinicians should proactively anticipate and facilitate patient and family decision-making as the disease progresses, including decisions regarding loss of mobility, need for assistance with activities of daily living, medical complications, and end-of-life care (level B)
• Prescribe physical and occupational therapy, as well as bracing and assistive devices that are adapted specifically to the patient's deficiencies and contractures, in order to preserve mobility and function and prevent contractures (level B)
• Advise patients that aerobic exercise combined with a supervised submaximal strength training program is probably safe (level C)
• Advise patients that gentle, low-impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (level C)
• Counsel patients to hydrate adequately, not to exercise to exhaustion, and to avoid supramaximal, high-intensity exercise (level C)
• Educate patients who are participating in an exercise program about the warning signs of overwork weakness and myoglobinuria, which include feeling weaker rather than stronger within 30 minutes after exercise, excessive muscle soreness 24-48 hours after exercise, severe muscle cramping, heaviness in the extremities, and prolonged shortness of breath (level B)
• Clinicians should not offer patients gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine the efficacy and safety of the treatment (level R)