Clinical aspects

Description

Management of chronic neuromuscular disease in children begins with neurologic and functional assessments as part of a multidisciplinary approach (33). This multidisciplinary approach should include a pulmonologist and a cardiologist because pulmonary and cardiac complications are common findings in patients with neuromuscular disease. Orthopedic surgery input for treatment of contractures and spine deformities such as scoliosis, which are commonly encountered in patients with chronic neuromuscular disease, is also an essential part of patient management. A physiatrist and a physical therapist are essential members of the clinic team because physical therapy is one of the mainstays of treatment in patients with chronic neuromuscular disease. Personnel with knowledge of durable medical equipment are also important contributors to care as assistive devices may be prescribed. The presence of a nutritionist, social worker, and genetic counselor is also desirable, if possible.

Management of cardiac complications. Cardiac involvement is variable in incidence and severity from one chronic neuromuscular disease to another. The main categories of cardiac affliction are dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmias (14). Recommended general screening procedures include annual electrocardiography and periodic echocardiography.

Cardiac conduction defects, resting tachycardia, and cardiomyopathy are frequently encountered in Duchenne muscular dystrophy. Mitral valve prolapse and pulmonary hypertension may also occur. Despite the lack of randomized controlled trials for treatment of cardiomyopathy in this condition, there are suggestions in the literature of a role for treatment of cardiomyopathy with angiotensin converting enzyme inhibitors (15). The use of mineralocorticoid receptor antagonist such as aldosterone or eplerenone can attenuate damage and minimize left ventricular strain in patients with Duchenne muscular dystrophy (31).

Cardiomyopathy is also common in Becker muscular dystrophy, but due to the milder degree of skeletal muscle involvement, cardiac transplantation could be considered in addition to medical therapy (25). Current guidelines recommend obtaining a transthoracic echocardiogram at the time of diagnosis or by 6 years of age, with subsequent evaluations every 2 years until 10 years of age (09), after which cardiac evaluation should be at least yearly. In a study of patients with Duchenne muscular dystrophy, steroid therapy was found to be associated with a substantial reduction in all-cause mortality and new-onset progressive cardiomyopathy (34).

In contrast, patients with myotonic muscular dystrophy rarely develop cardiomyopathy but do commonly have electrocardiographic abnormalities and left ventricular dysfunction on echocardiography (25). Standard 12-lead ECGs are useful in detecting the first of higher-degree heart block in susceptible patients; however, heart block may be intermittent initially. Twenty-four-hour ECG recordings are valuable in patients who may have underlying rhythm disturbance (14). Treatment of cardiac disease in muscular dystrophy patients involves placement of cardiac pacemakers for symptomatic conduction defects.

Emery-Dreifuss muscular dystrophy (X-Linked or autosomal dominant Lamin A/C mutations) patients may commonly suffer from atrial paralysis as well as atrial fibrillation or flutter and infranodal conduction system abnormalities leading to complete heart block. The atrial abnormalities may require chronic anticoagulation to avoid cardioembolism and permanent pacemaker placement for symptomatic bradycardia or complete heart block (25). Cardiac transplantation can be considered for ambulant patients with severe cardiomyopathy.

Management of nocturnal hypoventilation may also help prevent cardiac complications.

Management of pulmonary complications. Respiratory muscle weakness and fatigue, in addition to altered biomechanics from scoliosis, may result in respiratory failure in patients with chronic neuromuscular disease. Reduced capacity to generate an effective cough to clear secretions due to expiratory muscle weakness also may lead to respiratory compromise as well as airway obstruction and atelectasis. These complications are generally preventable with careful serial assessment of respiratory function (16; Finder et al 2009). Early interventions, such as mechanical or manual assistance with coughing and noninvasive positive pressure ventilation, may help prevent these complications (03; 29; 05). Careful monitoring of patient symptoms, such as exertional dyspnea or sleep-disordered breathing, as well as signs such as vital capacity and maximal inspiratory pressures, can aid greatly in clinical decisions regarding use of ventilatory support measures.

Patients with Duchenne muscular dystrophy should visit a pediatric pulmonologist twice a year following confinement to a wheelchair, vital capacity below 80%, or at 12 years of age (16). Earlier evaluations may be warranted to diagnose sleep disordered breathing. For vital capacity less than 45% of predicted value, maximal static inspiratory pressure of less than 30% of predicted value, dyspnea at rest, and hypercapnia, ventilatory support should be implemented (03). An FEV1 of 20% or less of predicted value has been associated with awake carbon dioxide retention in patients with Duchenne muscular dystrophy (21).

Manual assistance with coughing involves application of external positive pressure to the abdomen in order to generate a useful expiratory flow rate for effective coughing (cough peak flow more than 160 liters per minute) (06). Assisted cough should be initiated as soon as chest congestion occurs due to infection (06). Use of CoughAssist machines on a regular basis may help prevent infections and respiratory complications, may also prevent hospital admissions. Patients as young as 6 months of age may tolerate the use of such devices.

Noninvasive positive pressure ventilation can be accomplished with a nasal or full face mask or an adapted mouthpiece and a portable pressure- or volume-limited ventilator (30).

Initial interventions may include use of ventilatory support during sleep, allowing for a reduction in respiratory muscle work and ameliorating gas exchange disturbances and symptoms in patients with chronic respiratory failure (30). Limited information is available suggesting that nocturnal ventilatory support may improve respiratory muscle endurance but not strength (03). It is recommended that when the forced vital capacity falls to 12% of predicted value or less, as may occur in patients with Duchenne muscular dystrophy, ventilatory support should continue through the daytime as well (06).

The use of noninvasive positive pressure ventilation is recommended in symptomatic patients with diurnal PaCO2 greater than 45 mm Hg, nocturnal SaO2 less than or equal to 88% for more than 5 consecutive minutes, or severe pulmonary dysfunction (FVC less than 50% of predicted value or maximal inspiratory pressure less than 60 cm H2O) (30).

Nocturnal hypoventilation occurs in many children with progressive neuromuscular diseases such as spinal muscular atrophy (SMA). Children with spinal muscular atrophy may benefit from the use of nocturnal noninvasive ventilation or may require tracheostomy and positive pressure ventilation (35). Hypoventilation and high PaCo2 during sleep should be assessed through a sleep study and recommendations for noninvasive ventilation may be recommended based on results (01).

Care for perioperative management of respiratory complications may include the assessment for postoperative respiratory needs, such as the introduction of a CoughAssist device or the use of noninvasive ventilation following removal of endotracheal tube (07).

Management of limb contractures. Limb contractures are common impediments to maintenance of mobility in many patients with chronic neuromuscular disease and are more likely to occur in chronic muscular dystrophy than in inflammatory myopathies or neuropathies (27). Static limb positioning due to progressive weakness and reduced range of motion at a joint are important risk factors for contracture in any neuromuscular disease. Management strategies include early intervention following diagnosis with ongoing passive range of motion exercises in weak extremities. Lower extremity muscles are of particular concern as contractures in this region may have a profound effect on the patient's ability to ambulate. Joint range of motion should be monitored closely, and consideration should be given to bracing and splinting if mild contractures develop (27). Use of passive range of motion exercises and night splints along with weight-bearing exercise are important. Passive stretching exercises should allow the position of the muscle to be held for 10 to 15 seconds and repeated 10 to 15 times during a session. Intermittently positioning the patient in the prone position will help to prevent hip contractures in patients with proximal lower extremity weakness, such as in limb girdle muscular dystrophies, Duchenne muscular dystrophy, and Becker muscular dystrophy (27).

Splinting may slow progression of mild contractures and may include devices such as ankle foot orthotics. Splinting must be done in combination with continued passive stretching exercises to optimize benefit (12; 27). Knee ankle orthotics fix the knee joint in extension and may help patients with ambulation. Bracing and ankle foot orthotics should be used with caution in patients with proximal muscle weakness such as with Duchenne muscular dystrophy. For children who have neuromuscular foot deformities from inherited peripheral neuropathy such as Charcot-Marie-Tooth disease or from poliomyelitis, a combined surgical approach with V-osteotomy and the Ilizarov method has been shown to result in a painless, plantigrade foot (24). In all cases, careful assessment of an individual patient's lower extremity muscle strength, range of motion, and pre-surgical compensatory mechanisms employed for standing and balance must be done to ensure that any procedure will only enhance the patient's ability to maintain upright posture and ambulate as easily as possible. Once patients become wheelchair-bound, splinting and bracing procedures have limited benefits. They may still be used to minimize pain or to help with positioning and to minimize further progression of contractures.

Serial casting has been suggested by a study to help minimize plantar flexion contractures as well as prolong ambulation in patients with Duchenne muscular dystrophy (Glanzman et at 2011).

Management of scoliosis. Spinal deformities develop as a result of muscle weakness and consequent altered biomechanics in patients with neuromuscular disease. It generally requires surgical intervention to alleviate the deformity. The implications of scoliosis, if untreated, are those of respiratory compromise due to deformity of the chest cavity (in addition to respiratory muscle weakness), pain, and uneven weight bearing when sitting (26). Scoliosis due to chronic neuromuscular disease, as opposed to idiopathic scoliosis, is more likely to be severe in its degree of curvature and involve a larger segment of the spine and coincide with pelvic instability. It is also noted that there is a rapid increase usually in the degree of scoliosis that coincides with puberty. A molded thoracolumbosacral orthosis or brace may be used intermittently (when the patient is in an upright posture) to preserve function during periods of spinal growth until the patient can successfully undergo spinal fusion surgery to try to correct the deformity (26). Soft spinal orthoses have been used successfully in patients with spinal muscular atrophy for improved stability and postural positioning (Hart and 27; 26). Surgical correction is generally needed in particular with a pubertal growth spurt and is the definitive treatment for this complication, especially if the underlying muscle disease is a myopathy or muscular dystrophy (Hart and 27; 26); however, caution has to be taken to avoid respiratory restrictions. Scoliosis is common in Bethlem myopathy and early treatment with spinal fusion may help improve respiratory function (13). Surgery to stabilize the spine is usually recommended to be performed once the curvature is 35 degrees or more and before the patient's vital capacity declines (27). Clinical monitoring of patients in anticipation of surgery may include scheduled chest x-rays and pulmonary function tests, especially for patients such as those with Duchenne muscular dystrophy. Surgery should be performed in a specialized center with expertise in neuromuscular disease.

The currently accepted approaches to spinal fusion for neuromuscular scoliosis involve extensive, segmental spinal instrumentation that includes the pelvis and sacrum. Segmental hook-rod systems of various designs are used. A technique using lumbosacral fusion (spinopelvic transiliac fixation) with cinching together of the sacroiliac joints for greater stability of the base of the fusion has been described (23) with good results in terms of degree of curvature correction and pelvic stability. One study evaluated the effectiveness of posterior spinal fusion on the rate of decline of respiratory function and found that posterior spinal fusion for scoliosis in Duchenne muscular dystrophy is associated with a significant decrease in the rate of respiratory decline post-surgery compared with pre-surgery rates (38).

Management of mitochondrial myopathy. Patients with mitochondrial cytopathies are a heterogeneous population, with myopathy as a common manifestation of mitochondrial dysfunction due to the high energy metabolism of muscles. Management of these patients includes cardiac evaluation, neuro-ophthalmology evaluation, and long-term physical and occupational therapy to preserve muscle strength and mobility. Suggested treatments include supervised aerobic exercise and dietary management by frequent, smaller meals to maintain normoglycemia (18). Pharmacologic treatment is controversial, based to date primarily on anecdotal data, but may include dietary supplements such as coenzyme Q10 (4 to 15 mg/kg per day), levocarnitine (100 mg/kg per day for children in 3 divided doses), and antioxidants (selenium, 50 to 100 mcg/day; vitamin C, 250 to 4000 mg in divided doses; vitamin E, 400 to 1200 IU in divided doses; lipoic acid, 200 to 600 mg per day in divided doses) (18). Recognition of an energy or mitochondrial crisis and aggressive management may be life-saving in some patients with mitochondrial disease. A multidisciplinary approach, which may include a metabolic specialist, is advisable.

Future management strategies. Treatment of patients with Duchenne muscular dystrophy with corticosteroids, either prednisone (0.75 mg/kg per day) or deflazacort (0.9 mg/kg per day), prior to loss of independent ambulatory status, was recommended by the American Academy of Neurology in 2005 and found in many studies to maintain muscle strength by reducing any potential inflammatory component and prevent the muscle deterioration and, thus, helping to keep the child ambulatory for as long as possible (22; 37; 08; 04).

Gene therapy and RNA modifications (exon skipping) for different exon deletion mutations are currently undergoing study, and 1 product was FDA approved for exon 51 amenable mutations. Exon skipping, which utilizes antisense oligonucleotides to modify gene mutations at the RNA level, has resulted in promising preliminary results as a treatment modality for Duchenne muscular dystrophy patients (20; 28).

Gene therapy and RNA modifications (exon skipping) for different exon deletion mutations are now FDA approved for exon 51, 53, and 45 amenable mutations. Exon skipping, which utilizes antisense oligonucleotides to modify gene mutations at the RNA level, has resulted in promising results as a treatment modality for Duchenne muscular dystrophy patients (20; 28).

Gene replacement therapy for spinal muscular atrophy is currently FDA approved. Zolgensma, an adenoviral vector-based, 1-time gene therapy, has been approved by the FDA (02).

Gene replacement therapy for Duchenne muscular dystrophy is in clinical trials. Technical challenges, such as design of an efficient delivery system for the candidate replacement gene and control of the host immune response to this delivery system (usually a viral vector), as well as its protein product, have yet to be overcome. Modified vector systems (adeno-associated virus vectors) have been used to deliver small genes, such as those for specific sarcoglycans in limb girdle muscular dystrophy. Other nonmutation specific treatment trials are currently ongoing in Duchenne muscular dystrophy.

Antisense oligonucleotide medication designed to bind to the SMN2 pre-mRNA and promote inclusion of exon 7 for treatment of spinal muscular atrophy, which is related to SMN mutations, was also approved through the FDA’s Fast Track program (10). Although it appears to be efficacious, it requires lifetime treatment and raises many economic and ethical questions (32).

A second oral medication functions as SMN2-splicing modifier that increases the production of full-length SMN protein. This drug is also FDA approved and has the convenience of being oral and well tolerated; however, again, it would need to be administered lifelong (11).

Outcomes

Management of limb contractures. Minimizing contractures, especially those involving the lower extremities, will limit their effect on independent ambulation. Promotion of a balanced stance and functional range of motion in the lower extremities leads to an improved quality of life and reduces the chance for injury. In addition, surgical release of lower extremity contractures allows for more successful bracing with knee ankle foot orthotic devices. In patients with Duchenne muscular dystrophy, the amount of time the patient is able to continue walking may be prolonged with orthopedic surgical intervention and lower extremity bracing procedures (Hart and 27). Long-term corticosteroid therapy may also prolong time to orthopedic intervention or wheelchair use in patients with Duchenne Muscular Dystrophy (08).

Management of scoliosis. Surgical management of neuromuscular scoliosis has been shown to improve quality of life and pulmonary function.

Management of mitochondrial myopathy. Management of mitochondrial myopathy associated with mitochondrial cytopathy should result in improved muscle strength and endurance as well as pulmonary muscle strength. However, this may be hard to achieve secondary to the heterogenous nature of these diseases.

Management of cardiac complications. Successful management of cardiac complications of chronic neuromuscular disease should result in improved cardiac functioning and reduction of heart failure. Detection of asymptomatic bradycardia or tachycardia may allow patients at particular risk of sudden death to be identified, prompting treatment. Cardiac transplantation for patients with primarily cardiac involvement could be considered in some patients.

Management of pulmonary complications. Effective ventilatory support in chronic neuromuscular patients should result in improved oxygen saturation, reduced carbon dioxide levels, and lessening of symptoms of respiratory failure with improved quality of life. Successful intervention in this area should lead to reduced morbidity from recurrent respiratory infections and prolonged hospitalizations and from severe pulmonary disease such as pneumonia (03; 29; 06). Noninvasive measures to achieve positive pressure ventilation reduce the need for intubation and the risk of tracheostomy, if the patient has lost the ability to breathe independently (29; 06).

Management of underlying disease pathology. With the advent of genetic therapies and new treatment trials emerging, the role for medical management of some muscular dystrophies and other neuromuscular diseases is expanding. The hope that some of the drugs currently in trials could be offered to all patients holds the potential to change the epidemiologic geography of neuromuscular disease.

Adverse effects

Management of limb contractures. Use of lower extremity braces for treatment of contractures may lead to excessive energy expenditure in an already weak patient. There are also safety concerns regarding falling when braced. Orthopedic interventions, such as tendon release or transfer surgeries, may lead to prolonged immobilization of the affected limb due to postoperative casting, which may result in additional contractures or muscle wasting. Achilles tenotomies without concurrent bracing above the knee can lead to loss of walking ability in a previously ambulatory patient if there is proximal lower extremity weakness (Hart and 27).

Prolonging the time prior to wheelchair confinement in the neuromuscular disease population will help postpone some of the common co-morbidities such as scoliosis, obesity, disuse atrophy, osteoporosis, pathologic fractures, pressure sores, and severe contractures.

Use of chronic corticosteroids in patients with Duchenne muscular dystrophy may lead to complications from therapy such as weight gain, cataract formation, hypertension, osteoporosis, and short stature due to effects on linear bone growth (22; 37; 08; 04). These adverse effects seem to be minimized in patients receiving deflazacort compared to prednisone, without loss of benefit (08).

Management of scoliosis. Spinal orthotic devices may contribute to respiratory compromise on a restrictive basis as well as cause skin breakdown and be poorly tolerated by the patient if used continuously (Hart and 27). Loss of functional compensatory mechanisms may occur in patients who have adapted to use of their spinal instability to deal with their proximal weakness.

Spinal fusion surgery is a major surgical procedure and requires additional considerations in pediatric patients with chronic neuromuscular disease. Cardiac abnormalities known to occur in certain populations of chronic neuromuscular disease patients should be accounted for and monitored during surgery to avoid potential morbidity. Surgery should be performed in a well-equipped center that is experienced in treating patients with chronic neuromuscular disease.

Malignant hyperthermia may complicate surgical procedures, and preventive measures should be undertaken to avoid its development in patients with inherited chronic neuromuscular diseases--particularly in patients with Duchenne muscular dystrophy and central core myopathies.

Management of chronic neuromuscular disease in children can yield benefits in terms of improving quality of life. Appropriate management of cardiac complications and early intervention for ventilatory needs probably do serve to prolong survival in most patients. There is hope that gene therapy will improve the final outcome, at least in some patients.

Patients should be referred early on following diagnosis to a palliative/supportive care program to help manage daily challenges and improve overall quality of life.

Families should be aware of the variability among patients in the degree of disease progression and the variable complications.