The myopathies are neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of muscle fiber. In pediatric patients, myopathies can be inherited (such as the muscular dystrophies) or acquired. The distribution of muscle weakness is proximal but it could be generalized or distal. Patients may also complain of muscle pain and cramps. Presentation of weakness may be acute or insidious (Figure 15-1). Acute weakness can occur in neuromuscular junction disorders. Some diseases are present since childbirth, and in this group the differential diagnosis is important to distinguish the disorders from other causes of hypotonic infants. Figure 15-2 shows a diagnostic algorithm in infants with suspected neuromuscular hypotonia. Evidence of reduced fetal movement and polyhidroamnios could be found early. Also respiratory and feeding difficulties can occur. Other physical signs such as joint contractures (severe arthrogryposis), foot deformities, and facial, palatal, and pharyngeal abnormalities are also useful in detecting an inherited myopathy.

This chapter includes the principal inherited myopathies: congenital and acquired neuromuscular junction disorders, congenital myopathies, congenital muscular dystrophies, muscular dystrophies, inherited metabolic myopathies, mitochondrial myopathies, inflammatory myopathies, muscle channelopathies, and endocrine and toxic myopathies.

Myasthenia Gravis

Definitions and Epidemiology

Myasthenia gravis (MG) is a disorder involving the neuromuscular junction that results in fatigable weakness as its primary symptom. The onset can be insidious, and it is often difficult to make the diagnosis initially (Table 15-1).1

Myasthenia gravis is a relatively common disorder, affecting approximately 2 to 10 per 100,000 people in the United States. Before age 40 years, MG is three times more common in women than men. It may begin at any age but is rare before age 10 years or after age 60 to 70 years. There are bimodal age-related peaks, with the earlier peak involving more women between ages 10 and 40 years and slightly more men between ages 50 and 70 years. The older patients more often have associated thymomas.

The male-to-female ratio is essentially equal in prepubertal patients of Northern European decent. Myasthenia gravis is usually a less severe disease in this group, with more spontaneous remissions and shorter disease duration. More patients in this group are seronegative (50%). The disease becomes more common in females during and after puberty, taking on more of the characteristics associated with myasthenia in the adult. The female-to-male ratio is 4.5:1 in the postpubertal group. Females in this group tend to have more severe disease than males. Thirty-two percent of prerpubertal children are seronegative, and 9% of postpubertal children are antibody negative. The disease appears more common in female African Americans of all ages than in males (2:1). The percentage of African-American children negative for AChR antibodies is the same as for whites.1,2

Patients and their first-degree relatives have an increased incidence of other autoimmune disorders (eg, systemis lupus erythematosus [SLE], rheumatoid arthritis [RA], thyroiditis, Grave disease) and hyperthyroidism (3-8%). Therefore, these disorders should be screened for on the initial evaluation.1,2

Children with MG are at an increased risk for a seizure disorder, with seizures occurring in 3% to 12% of patients. Neoplasms are rare but have also been associated with juvenile myasthenia.

Pathogenesis

Myasthenia arises as the result of the abnormal production of autoantibodies to nicotinic acetylcholine receptors (AChR). Overall, 80% to 90% of patients with MG are positive for AChR antibodies. Children less often have detectable AChR antibodies. Only 40% of children with ocular myasthenia are Ab+ as compared to 50% in adults. Only 58% of children with generalized MG are Ab+, as compared to 80% to 90% in adults. It is thought that the 10% to 20% of patients who have “antibody-negative” MG do have autoantibodies that may be directed at epitopes not present in the AChR extract used in testing, or they may have too low an affinity for detection in the assay system.2

The AChR antibodies are synthesized by B-cells in the thymus gland. The thymus gland of MG patients is almost always abnormal. Most of the pateints (>75%) have lymphoid hyperplasia of the thymus. Thymomas occur in approximately 15% of myasthenia patients (slightly more common in older patients).

Clinical Presentation/Diagnosis

The three cardinal features of MG are (1) fluctuating weakness, (2) weakness varies from day to day or during the course of a single day, and (3) excessive fatigability with exercise. There are several areas that are commonly affected by the weakness. Ocular muscle weakness is common, with ocular muscles affected at presentation in 40% of patients and are eventually affected in 85%. This produces the characteristic symptoms of diplopia and ptosis. Purely ocular myasthenia is relatively uncommon and differs from generalized myasthenia. Only 50% of these patients have AChR antibodies (as opposed to 80% to 90% with generalized MG). If myasthenia remains restricted to the eye muscles for more than 3 years, it is likely to remain restricted.

Bulbar muscle weakness is also a common finding. This results in complaints of dysphagia, dysarthria, and facial weakness. Speech may be “mushy” or nasal. Limb and neck weakness is common. Limb weakness is usually more prominent in the proximal muscles than the distal ones. Limbs are almost never affected alone.

Diagnostic Tests

The history must be compatible and supported by physical examination findings. The sensory, cerebellar, and reflex examinations should be unremarkable.

The Tensilon test is performed with the administration of the short-acting acetylcholinesterase inhibitor edrophonium. The onset of action is approximately 30 seconds and the duration is about 5 minutes. The adult form of the test is described below.

1. 
   

   Decide on a readily observable sign of weakness that you can measure (eg, ptosis, FVC [forced vital capacity]).

   
   
2. 
   

   Make sure that the patient has a functioning IV line.

   
   
3. 
   

   Keep 10-mg Tensilon and 1-mg atropine at bedside.

   
   
4. 
   

   Inject 2-mg Tensilon and watch for side effects (bradycardia, hypotension, arrhythmias).

   
   
5. 
   

   If patient tolerates the test dose well, inject the remaining 8-mg Tensilon.

   
   
6. 
   

   Observe the patient for improvement and continue watching for side effects.

   
   
7. 
   

   If at any point during the test the patient has serious side effects or becomes unstable, abort the test and give atropine 0.5- to 1-mg IV.

Placebo injections with NS are sometimes used in evaluation of limb weakness, but are not usually necessary when evaluating cranial muscle weakness, as this is difficult for most patients to simulate.

An alternate test is the ice-pack test. Cooling the eyelids can improve ptosis.

The repetitive nerve stimulation (Jolly test) is the most commonly used electrodiagnostic test for MG. Trains for electrical stimuli are applied for stimulation of the orbicularis oculi or the ADQ muscle in the hand. A decremental response to low rates of stimulation (2-5 Hz) suggests a defect in neuromuscular transmission (MG).

The most important laboratory test for MG is the acetylcholine receptor antibody (AChRAb) assay. It is positive in 80% to 90% of patients with generalized MG and in 50% with pure ocular MG. Antibody titers do not correlate with severity of disease.

Additional antibody testing may also be helpful for diagnosis in some cases. Muscle-specific tyrosine kinase antibodies (MuSK) are positive in 71% of AChR antibody-negative patients.3 Antistriated muscle antibodies are positive in 85% of patients with a thymoma.

Chest x-ray and chest CT scan are important studies during the initial evaluation of MG. These studies help screen for infection and thymoma. The chest CT should be performed without contrast, since the contrast agent can exacerbate MG and potentially result in a myasthenic crisis.

The single-fiber EMG may be helpful in difficult cases. On this needle EMG study, increased “jitter” and blocking is seen. It is positive in about 90% of patients but is very nonspecific.

Additional evaluation of the newly diagnosed myasthenia patient should include ANA, RF, and ESR, ± anti–double stranded DNA (screen for SLE, RA, etc.). Thyroid studies should also be obtained, since hyperthyroidism is a common comorbid disorder. The CBC with differential and a urinalysis should be obtained since infection can exacerbate MG. Blood sugar and electrolytes must be studied.

Treatment

After the diagnosis of MG has been made, the patient’s medication list should be reviewed to eliminate or avoid medications that may exacerbate MG. Box 15-1 gives an overview of medications that can worsen MG.

Acetylcholinesterase inhibitors (anticholines-terases) are the mainstay of therapy. Pyridostigmine (Mestinon) is the most commonly used agent. It has an onset of 30 minutes, a peak dose of 2 hours, and a duration of approximately 3 to 6 hours. The dosage is usually 30 to 90 mg every 3 to 4 hours. The IV dose is 1/30 of the oral dose. Potential side effects include diarrhea, nausea/ vomiting, sweating, increased salivation, miosis, bradycardia, and hypotension. The oral agent glycopyrrolate (Robinul), which is an anticholinergic, can be used for the GI side effects caused by pyridostigmine. The dosage is typically 1 to 2 mg orally three times daily.4,5

Immunosuppressive agents are used when symptoms are not adequately controlled by anticholinesterases alone.4,5 Prednisone can help suppress the autoimmune activity. Patients should be hospitalized when high-dose steroids are initiated because they can precipitate weakness. After the initially high dosing, the dose should be tapered to the lowest dose needed to maintain the patient’s functional status. As with any patient being treated with steroids, the patient should be monitored for side effects including hyperglycemia, sodium abnormalities and water retention (hypertension, edema, heart failure), psychosis, ulcers, osteoporosis, aseptic necrosis, and so forth.

A number of other immunosuppressive agents can be used when steroids prove ineffective.

Thymectomy is recommended for virtually all patients with thymoma.6 The exceptions include those with poor surgical risk, the elderly, and those with limited life expectancy, because it may take years before a benefit is noted. It may also be beneficial for patients with severe generalized myasthenia without thymoma and for selected patients with severe, disabling ocular myasthenia requiring immunosuppressants.

Myasthenic Crisis

A myasthenic crisis occurs when respiratory weakness becomes severe enough to require mechanical ventilation. This can also result from severe dysphagia with airway compromise secondary to inability to clear secretions. The myasthenic crisis may be provoked by an infection (particularly respiratory), surgical procedures, drugs, IV contrast dye, emotional stress, or systemic illness.

There are two types of crisis: myasthenic crisis due to underlying disease, and cholinergic crisis due to overmedication. Symptoms include miosis, increased salivation and secretions, diarrhea, cramps, and fasciculations. Cholinergic crisis is treated by withdrawal of medications.

If unsure which type the patient has, you can challenge with edrophonium. If the patient improves, this is myasthenic crisis, and the patient needs more medication. If the patient worsens, this is cholinergic crisis, and the patient needs less medication. (Be prepared for marked worsening with this approach!)

In addition to aggressive management with acetylcholinesterase inhibitors such as pyridostigmine, there are several approaches to the patient in myasthenic crisis. The choice of the treatment depends in part on what therapies are available at that particular hospital. Total plasma exchange (TPE)/plasmapheresis and intravenous immuno-globulin (IVIg) therapy can both provide significant and fairly rapid improvement in the degree of weakness.4,5 At present, IVIg given every 4 to 8 weeks until remission is the preferred treatment. TPE is usually reserved for cases in which IVIg fails or “tuning-up” is required prior to an intervention, surgery, or when the child is ventilator dependent and requires immediate attention.

Myasthenic Exacerbation

For myasthenic exacerbation, but not yet in crisis, close monitoring and aggressive management are warranted.2,,4,5 Since respiratory compromise can occur, the patient should be monitored with forced vital capacity (FVC) every 4 to 6 hours. Intubatation should be considered for those with FCV less than 12 to 15 mL/kg. FVC is the best indicator of respiratory weakness, and not arterial blood gas or pulse oximetry! Blood gases can remain unremarkable until just prior to respiratory failure, but the FVC will show a decline as the weakness worsens. Patients can decompensate quickly and must be monitored very closely. In addition to the respiratory status, the patient’s bulbar function must be monitored closely.

Botulism

Pathogenesis

Botulism is caused by the exotoxin of Clostridium botulinum. The toxin interferes with the presynaptic release of AChR from the nerve terminal. There are three types of botulism: foodborne, wound-related, and infant.7,8

Foodborne botulism is most often due to ingestion of C botulinum in home-preserved foods. It is much less commonly caused by improperly canned commercial products. Public health authorities must be notified. Wound-related botulism is secondary to a penetrating injury or IV drug abuse. C botulinum from the soil colonizes the wound. Gas production in the wound can often be seen on x-ray. Infant-related botulism has a peak incidence 2 to 7 months of age and arises secondary to colonization of the GI tract by C botulinum after ingestion of spores or during periods of constipation. It may be a cause of sudden infant death syndrome (SIDS).

Clinical Presentation/Diagnosis

Symptoms usually appear within 12 to 36 hours after ingestion of contaminated food and evolve rapidly over 2 to 4 days. The characteristic progression of symptoms begins with ophthalmoparesis, progresses to loss of pupillary reactions, bulbar weakness (dysphagia, dysarthria), and finally results in generalized weakness and respiratory compromise. Pupils are often unreactive. Severe constipation and paralytic ileus frequently occur, which would be unusual in MG. The infantile form also has a similar progression of symptoms.

Diagnostic Tests

C. botulinum toxin assays are available for stool and serum.9 Furthermore, stool can be sent for C. botulinum culture. Repetitive nerve stimulation testing reveals an incremental response to high rates of stimulation. As with MG, single-fiber needle EMG reveals increased jitter and blocking.

Treatment

Trivalent antiserum (antitoxin) can be obtained from the Centers for Disease Control and Prevention. This is a horse serum product and can cause serum sickness or anaphylaxis. Guanidine can help with the weakness. Penicillin may help in both the wound and infant forms. Supportive care is vital regardless of the subtype of botulism. Improvement, in those who recover, begins within a few weeks, but complete recovery may take many months. Recovery mirrors symptom onset, with ocular movement typically improving first followed by other cranial nerves and finally limb/trunk and respiratory muscles.

Neonatal Myasthenia

Pathogenesis

Neonatal myasthenia is a transient disorder seen in 15% of infants born to mothers with MG. It is caused by placental transfer of AChR antibodies.10,11 Symptomatic infants are thought to synthesize the antibodies de novo as well.

Clinical Presentation/Diagnosis

Symptoms may appear prenatally with intrauterine hypotonia, and affected infants can be born with arthrogryposis. Symptoms usually become evident within the first 24 hours of life and always by day of life 3. The mean duration of symptoms is 18 days. The most common symptoms include weakness of bulbar muscles with a weak cry, weak suck, and difficulty feeding. Approximately half of patients have generalized hypotonia. Respiratory insufficiency is uncommon.

Diagnostic Testing

The mother should have a diagnosis of MG; however, it would be possible for the mother to be previously undiagnosed. Patients are usually AChR-antibody positive. The Tensilon test is positive.

Treatment

For those with severe generalized weakness and respiratory distress, exchange transfusion may be of benefit. For others, administer Neostigmine IM 0.01 to 0.04 mg/Kg/ dose (or oral dose of 0.2 mg, 20 minutes before feeding). Recall that this is a self-limited disease.10,11

Pathogenesis

Congenital myasthenia is a heterogeneous disorder due to genetic defects in the presynaptic or postsynaptic neuromuscular junction.11 It is not associated with antibodies to the AChR (Tables 15-2 and 15-3).

Clinical Presentation/Diagnosis

Symptoms usually begin in the neonatal period. Ocular, bulbar, and respiratory weakness, worse with crying or activity, are common symptoms. Congenital myasthenia is a heterogeneous set of disorders, however, and some disorders may not cause symptoms until the second or third decade of life (eg, slow channel syndrome).

Diagnostic Testing

There is a positive family history in some, but this is not required. The AChRAb tests must be negative.11 Most forms are also Tensilon-test negative. The repetitive nerve stimulation test shows a decremental response, and the single-fiber needle EMG has increased jitter.

Treatment

The course is usually protracted, with mild to moderate symptoms refractory to both medical and surgical treatments.11

There exists a flourishing knowledge about inherited muscle diseases derived from myopathology including immunofluorescence and Western blotting analysis, and from identification of errors in many genes involved in structural protein complexes of muscle cells. Due to this increasing molecular and clinical understanding, the array of inherited myopathies is continuously increasing, so that any attempt to classify them is difficult. But classifications that combine in different degrees the clinical features with pathologic, genetic, and molecular findings are useful to study a child with suspected myopathy. The clinical features are discussed in more detail in Chapter 30.

Congenital myopathies show distinctive and specific morphologic abnormalities in skeletal muscles (within the myofibril) as the main pathologic feature. They are grouped into subtypes depending on the predominant pathologic finding in light and/or electronic microscopic biopsy study. Although weakness and hyptonia occur at birth or in the first year of life, there exists a wide clinical variation within each subtype including adult onset. Genetic diagnosis is available for the majority of these conditions, but they are genetically heterogeneous; one gene can result in multiple pathologies or multiple genes can result in only one myopathic phenotype. Therefore clinical study and muscle biopsy are very important in directing genetic testing. A morphologic classification of the main congenital myopathies is outlined in Table 15-4.

Myopathies with Cores: Central Core Myopathy

Central core myopathy is probably the most common congenital myopathy.12-14 It arises because of a mutation in the skeletal muscle ryanodine receptor (RYR1) gene at chromosome 19 q13.1, which is also implicated in the malignant hyperthermia susceptibility trait. RYR1 mutations associated with myopathies can occur as either dominant or recessive traits.15 Genotype-phenotype correlations associated with the RYR1 gene are complex, with some dominant mutations being related to malignant hyperthermia and others to congenital myopathy.

Clinical Description