Pediatrics

Neuromuscular diseases

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a neuromuscular disease? What are the typical findings for this disease?

Neuromuscular disorders in children comprise a broad group of diseases, which can affect skeletal muscle, the neuromuscular junction, the peripheral nerve and/or the anterior horn cells.

The clinical presentation of skeletal muscle weakness associated with an impairment to or inability to move extremities against gravity, with or without an elevated creatine kinase, is highly suggestive of a neuromuscular disorder.

Individuals with isolated peripheral muscle weakness generally do not show signs of cognitive impairment, although gross and fine motor skills can be delayed depending on the severity of the weakness and pattern of muscle involvement. The diagnostic evaluation for peripheral muscle weakness often requires electromyography (EMG) studies and a skeletal muscle biopsy. Some conditions warrant specific ancillary testing to aid in diagnosis, such as an echocardiogram and electrocardiogram in Pompe disease, or an echocardiogram and ophthalmology evaluation in Marfan syndrome. If a particular diagnostic entity is suspected, molecular genetic testing maybe available for diagnosis, prognosis, and prenatal testing options in future pregnancies.

The following text will highlight important aspects of specific disorders.

Key symptoms of various neuromuscular disorders presenting within the first few months of life:

Spinal muscular atrophy (SMA)

Clinical features of SMA include the following: peripheral hypotonia with proximal weakness, absent deep tendon reflexes, tongue fasciculations, and sometimes contractures. A specific form of SMA associated with respiratory distress caused by hemidiaphragmatic paralysis and more distal muscle weakness is called SMARD.

Congenital myotonic dystrophy

Clinical features include the following: peripheral hypotonia, facial diplegia, weak cry/poor suck, possible developmental delay/cognitive impairment, maternal family history of facial weakness and contraction myotonia, diabetes type II, and/or cataracts.

Congenital Muscular Dystrophies:

Congenital muscular dystrophy type 1A (MDC1A) presents with peripheral hypotonia, kyphoscoliosis, joint contractures, and increased signal intensity of white matter on magnetic resonance imaging (MRI) of the brain.

Ullrich congenital muscular dystrophy: Salient features include the following: peripheral hypotonia, joint contractures of proximal joints, joint hypermobility of distal joints, torticollis, and kyphoscoliosis.

Rigid spine with muscular dystrophy: Salient features of the disorder include axial hypotonia, progressive spinal rigidity, and scoliosis.

Congenital Myopathies:

Central core/multi-minicore disease: Salient features of the disease are peripheral hypotonia, congenital hip dislocation, and scoliosis.

Nemaline myopathy: Salient features of nemaline myopathy include peripheral hypotonia, facial weakness, scoliosis, and joint contractures.

Myotubular myopathy: Myotubular myopathy affects mainly males, causing severe to mild peripheral hypotonia, respiratory insufficiency when severe, macrocephaly, and arachnodactyly.

Congenital myasthenia syndrome presents with peripheral weakness, poor suck/weak cry, ptosis, facial weakness, and possible arthrogryposis.

Carnitine palmitoyltransferase deficiency type II/metabolic myopathies most often present with peripheral hypotonia, liver failure, hypoketotic hypoglycemia, cardiomyopathy, respiratory distress, liver calcifications, cystic/dysplastic kidneys, and neuronal migration defects.

Pompe disease presents with severe peripheral hypotonia, hypertrophic cardiomyopathy, hepatomegaly, and shortened P-R interval on the electrocardiogram.

Barth syndrome is an X-linked disorder which presents in males with peripheral hypotonia, cardiomyopathy, neutropenia, and growth delay.

Infantile Botulism is characterized by normal tone at birth with development of peripheral hypotonia, hyporeflexia, constipation, respiratory difficulties, and eye motility abnormalities.

Key symptoms of various neuromuscular disorders presenting in infancy/first few years of life:

Duchenne muscular dystrophy (DMD):

Boys with DMD have mutations in the dystrophin gene and can have mildly delayed motor milestones. Most are unable to run and jump properly due to proximal muscle weakness, which also results in the use of the classic Gowers' manoeuvre when arising from the floor. Most patients are diagnosed at approximately 5 years of age, when their physical ability diverges markedly from that of their peers.

A milder form of muscle weakness associated with mutations in dystrophin (but residual protein expression) is called Becker muscular dystrophy and can present at any age with mild to moderate muscle weakness. It can sometimes present as exercise induced rhabdomyolysis.

Charcot-Marie-Tooth Polyneuropathies are characterized by peripheral hypotonia with distal weakness, atrophy, sensory loss, and decreased deep tendon reflexes.

Marfan syndrome and Loeys-Dietz syndrome:

Salient features of Marfan syndrome include mild peripheral hypotonia, joint hypermobility, aortic root or dilatation, scoliosis, pectus excavatum or carinatum, arachnodactyly, and tall stature.

Salient features of Loeys–Dietz syndrome are mild peripheral hypotonia, hypertelorism bifid uvula or cleft palate, tortuous blood vessels on magnetic resonance angiography, and craniosynostosis.

What other disease/condition shares some of these symptoms?

There are a number of conditions involving the central nervous system that also present with muscle weakness. The most important group of disorders to consider here are the muscle-eye-brain disorders caused by abnormal post-translational processing of alpha-dystroglycan. In addition to muscle weakness (due to muscular dystrophy) these patients present with a wide variety of abnormal eye findings and structural brain abnormalities.

What caused this disease to develop at this time?

Most of the neuromuscular conditions mentioned above are inherited in an autosomal recessive pattern.

Duchenne muscular dystrophy is inherited in an X-linked manner.

Congenital myotonic dystrophy is an autosomal dominant condition, which demonstrates anticipation, in particular when the mutation is inherited from the mother. Thus, an infant with congenital myotonic dystrophy almost always has a mother with a milder form of myotonic dystrophy. It important to note that mothers of children with congenital myotonic dystrophy are often not aware that they have the disease, thus a thorough evaluation including family history, clinical exam (and sometimes EMG and direct gene testing) of the mother is necessary.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

One of the most important laboratory tests is assessment of serum creatine kinase (CK). CK levels are elevated in neuromuscular conditions associated with turnover of skeletal muscle tissue (muscle degeneration). CK levels are most often significantly elevated in a variety of muscular dystrophies (DMD, limb-girdle muscular dystrophies, congenital muscular dystrophies).

It important to note that boys with DMD can have a wide range of elevated CK levels (ranging from 3000-40.000 U/L), however, this does not provide any information about their current disease status. Boys with higher CK levels do not necessarily do worse than boys with lower CK levels. In fact, the more muscle tissue is replaced by fibrotic tissue the less degeneration occurs, thus lower CK levels are more common in these children. This is one of the reasons that CK levels are never as high in children with congenital muscular dystrophy. These patients are born with already high amounts of skeletal muscle fibrosis, are therefore weaker early on and don't necessarily demonstrate the wide range of CK levels.

It is very important to emphasize that "liver enzymes" such as ALT and AST are usually measured as total enzyme concentration, which includes isoforms of skeletal muscle. Thus, elevations of ALT and AST without any history or clinical evidence for liver disease should prompt evaluation for a skeletal muscle disorder including a serum CK.

Many laboratories automatically measure the cardiac isoform CKMB in case of elevated CK levels. These levels can be elevated in patients with muscular dystrophy. However, since CKMB is also released from regenerating muscle fibers (observed in a variety of neuromuscular conditions), this does not necessarily reflect cardiac damage. If there is a suspicion for cardiac damage in patients with neuromuscular disorders and elevated CK levels, assessment of troponin I will help distinguish cardiac from skeletal muscle damage.

Many neuromuscular conditions that are not characterized by muscle degeneration (e.g., SMA, some congenital myopathies, connective tissue disorders) can have normal CK levels. Thus, normal CK values do not rule out neuromuscular disorders.

Would imaging studies be helpful? If so, which ones?

Skeletal muscle ultrasound and magnetic resonance imaging (MRI) are sometimes performed to obtain information of skeletal muscle involvement and pattern of disease distribution, but does not play a role in the standard diagnostic workup for neuromuscular disorders.

Confirming the diagnosis

In case of a patient with severe muscle weakness and/or abnormal CK levels, one should first assess whether the patient has absent deep tendon reflexes. If absent reflexes are confirmed, then this patient has to undergo gene testing for SMA until proven otherwise. An EMG can be helpful in distinguishing a peripheral nerve and/or anterior horn cell disorder from a myopathic condition. Furthermore, it can be helpful in diagnosing myotonia and myasthenia syndromes. However, a normal EMG does not rule out a skeletal muscle disorder.

Once a suspicion for a skeletal muscle disorder has been established, a muscle biopsy must be performed. Patients with severe joint hypermobility require an echocardiogram to evaluate for aortic root dilation. An echocardiogram also must be performed in patients in whom Pompe disease is entertained as a differential diagnosis.

If you are able to confirm that the patient has a neuromuscular disease, what treatment should be initiated?

Most of the neuromuscular conditions do not have any specific treatment available. However, it is absolutely critical to monitor patients with muscle weakness for development of ankle and other joint contractures, scoliosis, respiratory difficulties and cardiac abnormalities. Recent advancements in monitoring and management for patients with respiratory distress (including night time ventilation) and pharmacological interventions to prevent and/or treat heart failure have led to tremendous improvement of quality of life and life expectancy of patients with a variety of neuromuscular disorders. Below are a few specific management and treatment recommendations for certain neuromuscular disorders.

Duchenne muscular dystrophy (DMD): Optimum management of DMD requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favorably alter the natural history of the disease and improve function, quality of life, and longevity.

Pharmacological intervention has begun to change the natural history of DMD, and further advances and more effective treatment of the underlying pathology of DMD. Glucocorticoids are the only medication currently available that slow the decline in muscle strength and function in DMD, which in turn reduces the risk of scoliosis and stabilizes pulmonary function. Cardiac function might also improve, with limited data to date indicating a slower decline in echocardiographic measures of cardiac dysfunction, although these measures are not necessarily predictive of the delay in cardiac symptoms, signs, or cardiac-related mortality.

Prednisone and deflzacort (only available in Europe and Canada) produce similar benefits, although some small studies suggest that deflazacort has fewer side effects. There are different dosing strategies for both medications ranging from daily administration to a 10-day on and 10-day off, as well as a high-dose weekend only schedule. Clinical trials are currently under way to establish whether any of these dosing regimens is superior and/or are associated with fewer side effects.

Physical Therapy Interventions: It is important to emphasize to the parents that physical therapy is essential in preventing/delaying further complications of muscle weakness. Effective stretching of the musculotendinous unit requires a combination of interventions, including active stretching, active-assisted stretching, passive stretching, and prolonged elongation using positioning, splinting, orthoses, and standing devices. 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.

Prevention of contractures also relies on resting orthoses, joint positioning, and standing programs. Resting ankle-foot orthoses (AFOs) used at night can help to prevent or minimize progressive equinus contractures and are appropriate throughout life.

Skeletal Management: Patients that are not treated with glucocorticoids have a 90% chance of developing significant progressive scoliosis and a small chance of developing vertebral compression fractures due to osteoporosis. While glucocorticoids have significantly reduced the occurrence of scoliosis, the incidence of vertebral fractures has increased. Therefore, bone health management are critical for the management of patients with DMD.

Respiratory Management: The aim of respiratory care is to allow timely prevention and management of complications. A structured, proactive approach to respiratory management that includes use of assisted cough and nocturnal ventilation has been shown to prolong survival.

Cardiac Management: 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. The recommendation to initiate echocardiographic screening at the time of diagnosis or by the age of 6 years was judged necessary, even though the incidence of echocardiographic abnormalities is low in children aged less than 8-10 years.

There is currently some debate about when to initiate pharmacological management of patients with DMD. Abnormalities of ventricular function on non-invasive cardiac imaging studies warrant increased surveillance (at least every 6 months) and should prompt initiation of pharmacological therapy, irrespective of the age at which they are detected. Consideration should be given to the use of angiotensin-converting-enzyme inhibitors as first-line therapy. Beta-blockers and diuretics are also appropriate, and published guidelines should be followed for the management of heart failure. Recent evidence suggests that pharmacological therapy should be initiated before abnormal cardiac function is detected in boys with DMD.

Pain management: Physicians need to adequately assess whether patients with DMD suffer from pain and initiate management in an appropriate time and manner.

Nutritional management: Maintaining good nutritional status, defined as weight for age or body-mass index for age from the 10th to 85th percentiles on national percentile charts is essential. Poor nutrition can potentially have a negative effect on almost every organ system. Anticipatory guidance and prevention of undernutrition/malnutrition and being overweight/obese should be goals from diagnosis throughout life.

Psychosocial Management: The medical care of a patient who has DMD and his family is not complete without support for their psychosocial well-being. DMD is a multilevel/multisystem disease. Biological factors (including the lack of dystrophin and/or its isoforms and the subsequent effect on brain development and functioning), social and emotional factors, and treatment factors (e.g., glucocorticoids) can all play a part in psychosocial health. Although most psychosocial issues are not unique to DMD, patients with DMD are at increased risk for problems in these areas.

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 maximize potential outcome.

Pompe disease: Pompe disease is caused by deficiencies of a lysosomal enzyme called alpha-glucosidase (GAA). A drug called alglucosidase alfa, replacing the missing enzyme (Myozyme), has received FDA approval for the treatment of infants and children with Pompe disease. Until recently, the severe infantile form of Pompe disease caused by complete lack of the enzyme has been a lethal condition. Enzyme replacement therapy (ERT) with Myozyme has changed the disease trajectory. However, it is important to emphasize to parents that while ERT for patients with the severe form of Pompe disease prolongs survival, the disease is still associated with a significant number of medical problems. In contrast, patients with residual enzyme activity have shown quite dramatic responses to ERT, with some patients achieving full ambulation.

Congenital muscular dystrophies: Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. The care for these patients is similar to many neuromuscular disorders as they involve supportive and multidisciplinary care in the areas of neurology, pulmonology, cardiology, orthopedics, gastroenterology and palliative care.

Marfan syndrome and Loeys-Dietz syndrome: Regular monitoring of aortic root size is essential for the management of patients with these disorders. Recent evidence suggest that losartan, an angiotensin II type 1 receptor blocker (ARB) is successful in preventing further growth of aortic root size and/or dissection of aortic aneurysms. A multi-center clinical trial is currently under way to support the initial findings.

What are the adverse effects associated with each treatment option?

Corticosteroid treatment in DMD:

Monitoring of 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.

What are the possible outcomes of neuromuscular diseases?

Duchenne muscular dystrophy (DMD):

The initiation of multidisciplinary care and the use of glucocorticoids significantly changed the trajectory of this disorder. Patients with DMD are now surviving to a much older age, and the disease is slowly changing to a more chronic rather than life limiting disorder. It is very important to discuss this with patients and families early as there is still a general notion among health-care providers and families that patients with DMD die by the age of 20. This change of disease trajectory has also led to new challenges, which need to be met. Some of them include appropriate and coordinated transition of care to adult health care providers, social issues as further education, and independent living.

Pompe disease:

ERT has changed the prognosis of this disorder. However, as mentioned above, the prognosis is significantly dependent on the amount of residual GAA enzyme activity.

Other neuromuscular conditions:

In general, initiation of multidisciplinary care has significantly improved longevity and quality of life of patients with a variety of different disorders.

What causes this disease and how frequent is it?

Duchenne muscular dystrophy is one of the most common forms of neuromuscular disease in children, all of the other forms are very rare.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

Administration of glucocorticoids requires careful monitoring for the following side effects: Growth retardation, osteoporosis, hypertension, glucose intolerance, cushingoid features, obesity, hirsutism, delayed puberty, adverse behavioral changes, immune/adrenal suppression, cataracts, GERD/peptic ulcer disease.

Are additional laboratory studies available; even some that are not widely available?

The only rare laboratory tests, which should be considered are for single genes, once a group of neuromuscular disorders has been identified.

How can neuromuscular diseases be prevented?

Once a primary gene defect is identified, prenatal testing can be offered to the families.

What is the evidence?

Bushby, K, Finkel, R, Birnkrant, DJ. "Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management". Lancet Neurol. vol. 9. 2010. pp. 77-93.

Bushby, K, Finkel, R, Birnkrant, DJ. "Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care". Lancet Neurol. vol. 9. 2010. pp. 177-89.

(Both of these articles represent a recent standard of care review for the diagnosis and management of Duchenne muscular dystrophy.)

Lisi, EC, Cohn, RD. "Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature". Dev Med Child Neurol. vol. 53. 2011. pp. 598-99.

(This paper provides a systematic review of the evaluation of the hypotonic infant, with a brief review of numerous neuromuscular disorders.)

Wang, CH, Bonnemann, CG, Rutkowski, A. "Consensus statement on standard of care for congenital muscular dystrophies". J Child Neruol. vol. 25. 2010. pp. 1559-81.

(This paper provides a consensus statement for the diagnosis and treatment of various forms of congenital muscular dystrophy.)

Angenlini, C, Semplicini, C. "Metabolic myopathies: the challenge of new treatments". Curr Opin Pharmacol. vol. 10. 2010. pp. 338-45.

(This paper summarizes numerous forms of metabolic myopathies.)

Ongoing controversies regarding etiology, diagnosis, treatment

N/A

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