Myopathies and Neuromuscular Junction Disorders
Rebecca Elizabeth Traub
Neuromuscular disorders include all diseases of the peripheral nervous system that extends from the anterior horn of the spinal cord to the muscles and small peripheral nerves in the extremities. There are acute or emergency presentations of diseases at every level of the peripheral nervous system, including myopathies, neuromuscular junction disorders, peripheral neuropathies, disorders of the brachial and lumbosacral plexus, and spinal nerve root and motor neuron disease. This chapter focuses on primary diseases of muscle (myopathies) and the neuromuscular junction.
MYOPATHIES
Myopathies include a broad range of diseases primarily affecting muscle itself. Most, but not all, cause elevation in the serum creatine kinase (CK); however, there are nonmyopathic disease processes that can also cause the CK to be elevated (Table 7.1).
There are three broad categories of primary muscle disease: genetic or inherited, inflammatory, and toxic-metabolic. Inflammatory or toxic-metabolic myopathies are more likely to be seen in the emergency setting, but even patients with preexisting genetic myopathies may present with acute worsening of weakness affecting cardiac or respiratory function.
INFLAMMATORY MYOPATHIES
Inflammatory myopathies include the group of immune-mediated muscle diseases that cause inflammation and damage in skeletal muscle, and, in severe cases, may also affect cardiac or respiratory muscle. Types of myositis include polymyositis (PM), dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), and inclusion body myositis (IBM).
The Clinical Challenge
The incidence of DM and PM combined has been estimated at 2 per 100,000 annually. NAM is probably less common. DM, PM, and NAM share similar clinical features, with proximal muscle weakness being a hallmark feature, that are difficult to distinguish on initial presentation. Any patient presenting with subacute proximal muscle weakness without sensory symptoms and an
elevated CK on laboratory testing is suspicious for an inflammatory myopathy. The presence of typical rash suggests the specific diagnosis of DM.
elevated CK on laboratory testing is suspicious for an inflammatory myopathy. The presence of typical rash suggests the specific diagnosis of DM.
TABLE 7.1 Causes of Weakness with Elevations in the Serum Creatine Kinase (CK) | ||||||||||||||
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Uncommonly, inflammatory myopathies affect cardiac muscle and can cause cardiomyopathy or cardiac conduction abnormalities. Any patient in whom inflammatory myopathy is suspected should undergo cardiac testing to assess for myocardial involvement. It is also rare for respiratory function to be affected in inflammatory myopathies, but in severe cases, respiratory failure requiring mechanical ventilation can occur.
Interstitial lung disease (ILD) can occur in association with PM or DM in 10% of cases, most often with antisynthetase antibodies. In patients with a history of DM or PM and respiratory symptoms, ILD should be strongly considered.
Patients with known diagnosis of inflammatory myopathies are often on corticosteroid or other immune-suppressing medications. Such patients are at increased risk for infectious complications. Any patient with inflammatory myopathy on immune-suppressing therapy who presents in the emergency setting should be considered for infectious complications of treatment.
Pathophysiology
DM, PM, and NAM are autoimmune conditions causing inflammation in and destruction of muscle. DM is a vasculopathy of muscle and skin, typically presenting with rash, proximal muscle weakness, and high CK. Muscle pathology shows perimysial and perivascular inflammation involving the sheath of connective tissue that groups muscle fibers into bundles.
PM presents with clinical features similar to that of DM, without the associated rash. Pathology, however, shows primarily endomysial inflammation and muscle fiber necrosis involving the connective tissue that ensheathes each muscle fiber, or myocyte. DM, more than PM, can occur as a paraneoplastic syndrome, and thus patients should be screened for underlying cancer. NAM is a distinct autoimmune myopathy presenting with symptoms similar to that of PM, but often with more severe and treatment-refractory weakness. The pathology of NAM is distinct, with myofiber necrosis with little or no inflammatory response. It is often seen in association with anti-signal recognition particle (SRP) antibodies or 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase or HMGCR) antibodies, sometimes associated with statin medication exposure.
IBM is a distinct subset of acquired muscle disease that has both inflammatory and neurodegenerative features. The exact pathophysiology underlying IBM is not well understood. The clinical progression is much more indolent, often over many years. The typical pathology on muscle biopsy includes endomysial inflammation with congophilic rimmed vacuoles.
Prehospital Concerns
Prehospital concerns in inflammatory myopathies relate primarily to rare patients with cardiac or respiratory muscle involvement of the muscle disease. In these cases, supportive measures include mechanical ventilation, in rare cases, and close cardiac monitoring.
Approach/The Focused Examination
Inflammatory myopathies share clinical features of proximal muscle weakness, affecting the arms and legs. The history will often reveal difficulty getting up from a chair or toilet, or with reaching overhead, combing hair, or brushing teeth. Neurologic examination should include confrontation testing of both proximal and distal muscle groups, including ability to stand from a seated position and gait assessment. Muscle pain, or myalgias, may be present. Sensory symptoms and examination findings are absent unless there is a coexisting reason for the patient to have neuropathy (eg, diabetes). In more severe cases, there may be facial or bulbar weakness. Ocular muscles are typically spared. Respiratory weakness can be present in severe cases. In severe or more longstanding cases, muscle atrophy may be present. Deep tendon reflexes are typically normal.
IBM has distinct clinical features, with more indolent progression of weakness—often over many months to years. The distribution of weakness in IBM is also different from that of the other inflammatory myopathies, with the greatest weakness and atrophy in the forearm flexors, quadriceps, and peroneal compartment of the lower leg. In advanced cases, facial and bulbar weakness occurs.
The diagnosis of DM should be specifically considered in the patient presenting with proximal muscle weakness and rash. The typical skin findings of DM can include Gottron papules (erythematous papules or scaling over the dorsum of the hands and fingers), heliotrope eruption over the eyelids, facial erythema, and rash over sun-exposed sites—most typically over the chest and upper back (“shawl sign”).
PM should be more strongly considered as a diagnosis in patients with a previous history of connective tissue disorders. In these patients, the myositis “overlap syndrome” occurs in association with their other preexisting rheumatologic disorder.
Serum CK is nearly always elevated in inflammatory myopathies. Inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), may be variably elevated. In any patient with subacute proximal weakness and elevated serum CK, inflammatory myopathy should be highly considered. Additional tests used to confirm diagnosis include myositis-specific antibodies, electrodiagnostic testing, skin biopsy, and muscle biopsy.
Management
Treatment strategies for DM, PM, and NAM are similar. IBM is clinically distinct, does not typically respond well or at all to immunotherapy, and is addressed separately. The initial treatment for most inflammatory myopathies is glucocorticoids, either intravenous (IV) methylprednisolone or high-dose oral corticosteroids (usually prednisone); see Table 7.2. Pending clinical and laboratory response to corticosteroids, the doses are slowly tapered over many months, along with the addition of steroid-sparing therapy. Typical steroid-sparing medications used for inflammatory myopathies include methotrexate, mycophenolate, azathioprine, intravenous immunoglobulin (IVIG), and rituximab.
In the emergency setting, additional management is supportive, assessing for cardiac or respiratory muscle involvement, and treating associated muscle pain. In the acute setting, nonsteroidal anti-inflammatory medications and short-term opiate pain medications may be used. Long-term agents for neuropathic pain, such as gabapentin, pregabalin, duloxetine, and others are used for management of muscle pain. Patients on immunosuppressing treatment should be carefully monitored for infectious complications. Patients on IVIG treatment are at increased risk for venous and arterial thrombotic events.
TABLE 7.2 Treatments for Inflammatory Myopathies | ||||||||||||||||||||
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IBM has pathologic features shared with the inflammatory myopathies, but typically does not respond, or responds minimally to the immune-suppressing treatments used for the other autoimmune myopathies. Some patients with IBM do improve partially with immunotherapy and thus may be treated with corticosteroids, IVIG, or oral steroid-sparing treatments, but most patients ultimately will not be maintained on these medications and the management is primarily supportive. In late-stage disease, IBM often causes dysphagia and occasionally causes respiratory muscle weakness. Some patients elect to have a percutaneous gastrostomy tube placed and use noninvasive ventilation for respiratory support.
Pediatric Issues
Juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM) are inflammatory myopathies occurring in the pediatric population. NAM is rarely seen in the pediatric population. Clinical features are similar to the adult population, and diagnostic testing is similar, including laboratory antibody testing, electromyography (EMG), and muscle biopsy. The differential diagnosis emphasizes the genetic myopathies. Treatments for inflammatory myopathies in childhood are similar to those used in adults, including corticosteroids and steroid-sparing medications.
Viral myositis is also more common in childhood, most often associated with influenza and coxsackie infections. Typical viral syndrome symptoms accompanied or followed by myalgias and elevated serum CK levels are characteristic of viral myositis. The syndrome is transient and resolves within a week without intervention. Supportive measures, including IV fluids if there is associated rhabdomyolysis, and pain control as needed, are appropriate.
GENETIC MYOPATHIES
Genetic myopathies include a broad range of inherited muscle diseases, including muscular dystrophies, congenital myopathies, metabolic myopathies, and periodic paralysis disorders. Onset is usually in childhood, but some milder phenotypes can present in adulthood. They can demonstrate a range of phenotypes, with either proximal or distal weakness, typically without sensory symptoms. Depending on the genetic mutation, there may be involvement of cranial muscles. Cardiac involvement is present in some genetic subtypes. Most genetic myopathies will present for outpatient evaluation with slowly progressive weakness, but emergency presentations may occur with infectious or metabolic stressors or cardiopulmonary complications of disease. A list of genetic myopathies associated with cardiac involvement is shown in Table 7.3.
Of the muscular dystrophies, the most common relate to mutations in the dystrophin gene, with an X-linked inheritance pattern. Duchenne muscular dystrophy (DMD) presents in early childhood and causes proximal weakness, pseudohypertrophy of the calf muscles, and prominent cardiac and respiratory muscle involvement. Becker muscular dystrophy (BMD) also results from mutations in the dystrophin gene, but those resulting in a still partially functioning protein and thus a milder phenotype, often presenting later in childhood or adulthood. Treatment with corticosteroid
medications has been shown to slow decline in strength in DMD, and thus these patients can incur complications of long-term steroid treatment.
medications has been shown to slow decline in strength in DMD, and thus these patients can incur complications of long-term steroid treatment.
TABLE 7.3 Genetic Myopathies with Increased Risk of Cardiac Involvement | ||||||||||||||||
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Other muscular dystrophies and inherited myopathies include Emery-Dreifuss muscular dystrophy (EDMD); myotonic dystrophy, including types 1 and 2; limb girdle muscular dystrophy (LGMD); facioscapulohumeral muscular dystrophy (FSHD); myofibrillar myopathies; and genetically diverse congenital myopathies. Inherited myopathies associated with RYR1 mutations, or central core disease, is associated with an increased risk of malignant hyperthermia, for which anesthesia precautions must be taken.
Metabolic myopathies include the group of muscle diseases associated with genetic defects in energy storage and metabolism. Subgroups of metabolic myopathies include disorders of glycogen metabolism, disorders of lipid metabolism, and mitochondrial disorders. Disorders of glycogen metabolism can lead to episodes of acute rhabdomyolysis, often precipitated by physical activity, illness, or other metabolic stress, and must be treated supportively.
The common management strategies for all of the genetic myopathies include close monitoring for cardiac arrhythmia or associated cardiomyopathy, supportive measures for respiratory muscle weakness, high index of suspicion for pneumonia or aspiration in patients with respiratory muscle weakness, and avoidance of myotoxic medications.
PERIODIC PARALYSIS
Periodic paralysis syndromes are a rare group of neuromuscular disorders related to muscle channel ion defects that result in episodes of muscle weakness, often triggered by exercise, fasting, or high carbohydrate intake.
Hypokalemic periodic paralysis, related to either calcium channel or sodium channel mutations, presents with episodes of weakness associated with low serum potassium levels. Attacks can be precipitated by exercise, high-carbohydrate meals, and other metabolic stressors. Episodes of paralysis typically last hours to days at a time. Weakness is generalized, but typically spares ocular, bulbar, and respiratory muscles. During episodes of hypokalemia, cardiac arrhythmia can occur; thus, electrocardiogram and cardiac monitoring are indicated. Diagnosis is made on the basis of typical history and laboratory findings, family history, electrodiagnostic testing, and genetic testing.
Acute treatment of hypokalemic periodic paralysis involves potassium repletion and management of any underlying metabolic stressor. The recommended dosing regimen for acute hypokalemic periodic paralysis is 60 to 120 mEq of oral potassium chloride, given in 30 mEq doses every 30 minutes, with frequent laboratory checks to avoid rebound hyperkalemia. IV fluids containing dextrose should be avoided because they can worsen the hypokalemia. Long-term prophylactic
treatment may include acetazolamide (250 mg twice daily) or dichlorphenamide (50 mg twice daily), and sometimes potassium-sparing diuretics, such as spironolactone.
treatment may include acetazolamide (250 mg twice daily) or dichlorphenamide (50 mg twice daily), and sometimes potassium-sparing diuretics, such as spironolactone.
More common than the rare genetic hypokalemic periodic paralysis is generalized weakness seen in the setting of hypokalemia due to other medical causes, such as renal or gastrointestinal (GI) wasting. Hyperthyroidism can also cause a clinical picture mimicking hypokalemic periodic paralysis. In these cases of weakness due to hypokalemia of other causes, correction of the metabolic derangement will result in rapid improvement in strength.
Hyperkalemic periodic paralysis, a disease related to sodium channel mutations, presents with episodes of muscle weakness associated with high serum potassium levels. Attacks can be precipitated by cold exposure, fasting, following exercise, or potassium intake. Weakness during attacks is generalized, but usually spares cranial and respiratory muscles. Between attacks, physical examination may demonstrate clinical myotonia. Laboratory testing will usually demonstrate normal or mildly elevated serum potassium levels. Diagnosis is established on the basis of typical history, electrodiagnostic testing, and genetic testing.
Treatment of acute attacks in hyperkalemic periodic paralysis, when mild, can include oral sugar or brief exercise. More severe attacks can be treated with thiazide diuretics, inhaled albuterol, and IV calcium. Arrhythmia associated with episodes of hyperkalemia has been reported, so electrocardiogram and cardiac monitoring are indicated. Prophylactic treatment to avoid attacks includes dietary strategies and treatment with oral acetazolamide or dichlorphenamide.
TOXIC MYOPATHIES
Myopathies may occur as a result of direct toxicity of prescribed, illicit, or recreational medications and drugs. Glucocorticoids commonly cause a proximal myopathy, without elevation of CK, that improves with reduction in dose or cessation of the medications. Statin medications, prescribed for hyperlipidemia, commonly cause myalgias, but less often cause myopathy and elevated serum CK levels. Other commonly prescribed medications that can cause myopathy include hydroxychloroquine, chloroquine, colchicine, and some antiviral medications used for human immunodeficiency virus (HIV).
In addition to direct toxicity, some medications can induce an inflammatory myopathy. Rarely, statin medications can trigger a NAM associated with HMGCR antibodies. Tumor necrosis factor (TNF)-α inhibitor medications and penicillamine have also been reported to trigger inflammatory myopathies. More recently, checkpoint inhibitor chemotherapy agents have been associated with a broad range of autoimmune complications, including myositis.
Alcohol can cause either a chronic myopathy, with or without peripheral neuropathy, due to long-term use, or acute myopathy from binge drinking, sometimes causing rhabdomyolysis. Cocaine can also precipitate an acute episode of rhabdomyolysis.
In any patient presenting with weakness and elevated CK, the clinician must evaluate all prescribed medications and consider alcohol and illicit substances as possible contributors.
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