Published: August 2010
Myopathy refers to a clinical disorder of the skeletal muscles. Abnormalities of muscle cell structure and metabolism lead to various patterns of weakness and dysfunction. In some cases, the pathology extends to involve cardiac muscle fibers, resulting in a hypertrophic or dilated cardiomyopathy.
Disruption of the structural integrity and metabolic processes of muscle cells can result from genetic abnormalities, toxins, inflammation, infection, and hormonal and electrolyte imbalances.
Myopathies may be divided into two main categories: inherited and acquired. The temporal course, the pattern of muscle weakness, and the absence or presence of a family history of myopathy help distinguish between the two types. An early age of onset with a relatively longer duration of disease suggests an inherited myopathy, and a sudden or subacute presentation at a later age is more consistent with an acquired myopathy. Inherited myopathies can be further subclassified as muscular dystrophies, congenital myopathies, mitochondrial myopathies, and metabolic myopathies. Acquired myopathies can be subclassified as inflammatory myopathies, toxic myopathies, and myopathies associated with systemic conditions. The more commonly seen inherited and acquired myopathies are listed in Box 1.
|Box 1 Common Causes of Myopathy|
|Myopathy Associated with Systemic Diseases
Myopathies are characterized by motor symptoms in the absence of any sensory involvement. Most myopathies manifest with weakness involving the proximal muscles. Commonly, pelvic girdle muscles are involved before and much more severely than shoulder girdle muscles. Some myopathies are associated with atypical distributions of weakness, such as inclusion body myositis, an inflammatory myopathy seen typically in older men that manifests with weakness in the finger flexors and quadriceps. Table 1 gives the distribution patterns of specific muscle disorders.
|Myopathy||Epidemiology||Distribution of Weakness||Other Systemic Manifestations|
|Dermatomyositis||Female > male
Peak incidence: children and ages 40–60 yr
|Symmetrical proximal muscle weakness
pelvic girdle > shoulder girdle muscles
|Skin manifestations: heliotrope rash (purplish discoloration of the eyelids), Gottron’s papules (erythematous scaling rash of extensor surfaces of fingers), shawl sign (erythematous rash over the shoulder and exposed areas of the back)
Interstitial lung diseases
|Polymyositis||Female > male predominance
Peak incidence: 20–50 yr
|Symmetrical proximal muscle weakness
Pelvic girdle > shoulder girdle muscles
|Inclusion body myositis||Men
Peak incidence: >50 yr
|Asymmetrical quadriceps muscle weakness and finger flexor muscle weakness||Dysphagia|
|Hypothyroid myopathy||Affects 30%–80% of patients with hypothyroidism||Proximal symmetrical pelvic > shoulder girdle weakness
Pseudohypertrophy of muscles
Delayed relaxation of ankle jerks
Myoedema (mounding of muscle when firmly palpated)
|Hyperthyroid myopathy||Affects 52%–82 % of patients with hyperthyroidism||Symmetrical proximal weakness, atrophy, some distal muscle involvement||Peripheral neuropathy
Graves’ ophthalmopathy, extraocular muscle weakness
|Sarcoidosis myopathy||Asymptomatic muscle involvement in ≤50% sarcoidosis patients||Symmetrical proximal muscle weakness
Focal muscle weakness from sarcoid granuloma
Restrictive lung disease
|Critical illness myopathy||At least as prevalent as critical illness neuropathy
Affects approximately 60% of patients with prolonged ICU stay
|Symmetrical proximal > distal muscle weakness||Critical illness neuropathy
Failure to wean off ventilation
|Amyloid myopathy||Rare||Proximal > distal muscle weakness
Pseudohypertrophy of muscles
Palpable muscle nodules
|Duchenne muscular dystrophy||1 in 3500 male births
Age of onset <13 yr
|Symmetrical proximal girdle weakness
|Limb girdle muscular dystrophy||1 per 15,000 population||Proximal pelvic >shoulder girdle weakness
|Different subtypes may have variable extent of cardiomyopathy or cardiac arrhythmias, respiratory muscle weakness|
|Myotonic dystrophy 1 and 2 (DM1, DM2)||Approximately 2.5–5.5 per 100,000 population||Distal muscle weakness predominates in DM1; proximal muscle weakness is common in DM2
Clinical myotonia (difficulty relaxing after a forceful muscle contraction)
Pregnancy- and labor-related complications
Eyelid ptosis without extraocular muscle weakness
|Oculopharyngeal muscular dystrophy||Relatively rare||Rarely presents with distal muscle weakness||Mainly manifests with ophthalmoparesis and with bulbar weakness manifesting with dysarthria and dysphagia|
|Facioscapulohumeral muscular dystrophy||Approximately 4 per 100,000 population||Face and arm weakness, scapular winging, and later distal leg muscle weakness||Hearing loss
|Mitochondrial myopathies||1 per 8000 population||Exercise intolerance
Proximal girdle muscle weakness
|Extraocular muscle weakness
|Acid maltase deficiency or glycogen storage disorder type 2||Approximately 1 in 40,000 newborns||Proximal girdle weakness||Macroglossia, hepatomegaly in infancy
Severe ventilatory muscle weakness with adult presentation
CNS, central nervous system; GI, gastrointestinal; ICU, intensive care unit.
Cramps, myalgias, and exertional fatigue are other common presenting symptoms. Many patients complain of difficulty rising from a chair, climbing stairs, changing a light bulb, or washing and combing their hair. In metabolic myopathies associated with rhabdomyolysis (defined as creatine kinase elevation 10 times the normal value), patients may report tea-colored or dark urine, especially after intense exercise. Rhabdomyolysis may also be seen with infectious etiologies, alcohol, and toxic exposures.
On physical examination, many myopathy patients, especially those with acquired myopathies, demonstrate symmetrical muscle weakness in a proximal to distal gradient. Sensation is intact, and deep tendon reflexes are preserved unless there is severe weakness. In the muscular dystrophies, which tend to manifest in childhood or adolescence, dyspnea, cardiac abnormalities, contractures, scapular winging, calf hypertrophy, and skeletal deformities may be present in addition to slowly progressive weakness. Respiratory compromise is a common feature of critical illness myopathy, amyloid myopathy, interstitial lung disease associated with dermatomyositis, acid maltase deficiency, and, very rarely, a subtype of limb girdle muscular dystrophy (LGMD 2I). Myopathies with other extramuscular manifestations are listed in Table 1. Some patients actually have a normal examination, such as those with metabolic myopathies, in which symptoms are transiently present only after physical exertion.
The clinical history is essential in identifying the presence of a myopathy and narrowing down the differential diagnosis. In particular, the patient should be questioned about medication and recreational drug history (especially alcohol), chemical exposures, exercise intolerance, childhood development, and family history of muscle disease or developmental motor delay.
Serologic testing, which can indicate muscle damage, includes elevations in creatine phosphokinase (CPK), aldolase, lactate dehydrogenase (LDH), and liver function enzymes. A screening panel of laboratory tests may also be obtained to rule out more common causes of myopathy, which are listed in Box 2. In cases suspected to be a primary inflammatory myopathy, specific autoantibodies can be considered to determine the prognosis and rule out associated conditions. For example, the presence of anti-Jo antibody in dermatomyositis predicts a superimposed interstitial lung disease. In addition, these patients should also be evaluated for an underlying systemic autoimmune disease with an extensive autoimmune panel and angiotensin-converting enzyme (ACE) levels. In myopathies that are accompanied by polyneuropathy, renal involvement, and a restrictive cardiomyopathy, immunofixation electrophoresis studies in the serum and urine should be considered to rule out the possibility of amyloid disease. Genetic testing is available for some inherited myopathies. These are listed in Table 2.
|Box 2 Laboratory Evaluation for Suspected Myopathy|
|Confirm the Presence of Muscle Disease
|Suspected Inflammatory Etiology
|Suspected Mitochondrial or Metabolic Myopathy
|Suspected Amyloid Myopathy
|Myopathies with Known Genetic Defects||Gene Abnormalities||Pattern of Inheritance|
|Duchenne muscular dystrophy||Dystrophin gene||X-linked recessive|
|Becker muscular dystrophy||Dystrophin gene||X-linked recessive|
|Emery-Dreifuss muscular dystrophy||Emerin gene||X-linked recessive|
|Limb girdle muscular dystrophy||Lamin A/C
Fukutin related protein
|Some are autosomal dominant and others are recessive|
|Facioscapulohumeral muscular dystrophy||D4Z4 deletion||Autosomal dominant|
|Oculopharyngeal muscular dystrophy||GCG repeat expansion in poly A binding protein 2 gene||Autosomal dominant|
|Myotonic dystrophy 1 and 2||DMPK gene for type 1
CNBP (ZNF9) gene for type 2
|Mitochondrial myopathy||Specific point mutation analysis for diseases like MELAS
POLG1 sequencing for MERRF available
Southern blot analysis for mtDNA deletions and mtDNA sequencing
But other can be inherited as autosomal dominant or recessive disease
|Amyloid myopathy from familial causes||Transthyretin mutation||Autosomal dominant|
|Statin myopathy (predictor of increased susceptibility)||SLCO1B1 gene||Unknown|
MELAS, mitochondrial myopathy, lactic acidosis, and strokes; MERRF, myoclonic epilepsy and ragged red fibers; mtDNA, mitochondrial DNA.
A traditional test used in the evaluation of a suspected metabolic myopathy is the ischemic forearm test. This is performed by obtaining baseline serum ammonia and lactate levels taken from the forearm. The patient then exercises that arm for 1 minute, after which repeat serum lactate and blood ammonia levels are measured. This is repeated at several intervals (1, 2, 5, and 10 minutes). In normal muscle, the resultant ischemia causes a 3- to 5-fold rise in lactate levels. In contrast, patients with glycogen storage disorders demonstrate no change in lactate levels after exercise.
The electromyogram (EMG) is an electrical study of the nerves and muscles that plays an important role in confirming the presence, duration, and severity of a myopathy. The study can also disclose special findings such as myotonic potentials. This is the electrical equivalent of clinical myotonia, which is manifested as impaired relaxation of muscles after forceful contraction; for example, patients cannot release objects from their grip. Myotonic potentials have the characteristic sound of a dive bomb on EMG and can help point toward the diagnosis of myotonic dystrophy when found in the appropriate muscles.
Although integral in the evaluation of a myopathy, the EMG can be normal in mild myopathies, steroid myopathies, and a number of metabolic myopathies. Therefore, it is important to remember that a normal EMG does not exclude the presence of a myopathy.
Histopathologic examination of muscle may be helpful in determining the specific type of muscle disease, especially in patients with a suspected inflammatory or infectious myopathy. Selecting the optimal muscle to biopsy is very important because factors such as severe weakness and technical artifacts can hamper an accurate histologic diagnosis. The ideal muscle that should be sampled is one that is clinically involved but still antigravity in strength, because more-severe weakness can lead to unhelpful, nonspecific findings of fibrosis. Also avoid muscles that have been examined by an EMG because the needle portion of the electrical study might have caused local damage, which can result in spurious findings. Common biopsy sites include the biceps and deltoid muscles in the upper extremity and the quadriceps and gastrocnemius muscles in the lower extremity.
For most patients with congenital myopathy or muscular dystrophy, the treatment is largely supportive, with physical therapy, occupational therapy, management of contractures, nutrition, and genetic counseling. In patients with Duchenne muscular dystrophy, treatment with prednisone at a dose of 0.75 mg/kg/day has been shown to improve strength and muscle bulk and slow the rate of natural progression of the disease. Patients should also be monitored over time for complications related to kyphoscoliosis or involvement of cardiac, respiratory, or bulbar muscles. In patients with mitochondrial myopathy, small studies have shown some benefit with creatine monohydrate (5-10 g/day), but no consistent benefit was seen with coenzyme Q10 replacement. Finally, genetic counseling should be offered to all patients with inherited myopathy and their family members.
Myopathies that result from systemic diseases are best treated by correcting the underlying endocrine or electrolyte abnormality. In patients with drug- or toxin-induced rhabdomyolysis, withdrawal of the offending agent is key. Control of the underlying infection is important for bacterial, parasitic, or spirochete-related myopathies as well as postinfectious inflammatory myositis. In HIV-related myositis, treatment with the combination of highly active antiretriviral therapy (HAART) and steroids may be beneficial.
In patients with inflammatory myopathies or those related to underlying autoimmune diseases, a number of immune-modulating medications may be used for treatment. Oral and intravenous steroids are most commonly used, with favorable results in most cases. Regimens of daily prednisone at a dose of 1.5 mg/kg per day or intravenous methylprednisolone at 500 to 1000 mg for 3 to 5 days are often used. Intravenous immune globulin (IVIg), methotrexate, azathioprine, and cyclophosphamide may also be helpful. Unfortunately, inclusion body myositis, though classified as an inflammatory myopathy, is typically refractory to immunosuppressant treatment and continues to progress, with prominent dysphagia and more generalized weakness over time.
For patients who present with rhabdomyolysis, treatment is aimed at preventing kidney failure in the acute setting. Vigorous hydration with close monitoring of kidney function and electrolytes are paramount. In patients with an underlying metabolic myopathy, education about following a more moderate exercise program and avoiding intense exercise and fasting is necessary in preventing recurrent episodes. Measures that have been suggested to be helpful include sucrose loading before exercise in some glycogen storage disorders and a low-fat, high-carbohydrate diet in patients with lipid storage disorders.
The incidence of muscle symptoms in patients taking statins has ranged from 5% to 18% in large studies and are reported to be severe in 0.1%. Because statins are one of the most commonly prescribed medications worldwide, these percentages represent a significant number of affected patients. Symptoms can range from mild cramps to more-severe myalgias, pain, and weakness. Rhabdomyolosis has also been reported in rare cases. The exact mechanism by which statins cause myopathy is unknown, but mitochondrial dysfunction and decreased coenyzme Q10 levels have been postulated. Specific risk factors for the development of statin myopathy include higher doses, smaller body frame, liver and kidney disease, diabetes, hypothyroidism, and genetic factors that affect statin metabolism. The use of alcohol or drugs that interfere with statin metabolism, such as gemfibrozil, macrolide antibiotics, antifungals, and HIV protease inhibitors, are also noted risk factors.
Treatment depends on the patient’s symptoms and CPK levels. If the CPK is less than five times normal, reassurance will suffice. If CPK levels are between 5 and 10 times normal and the patient is asymptomatic or able to tolerate the symptoms, then the statin can still be continued. However, if the symptoms are intolerable, then the statin should be discontinued until the CPK normalizes. If CPK more than 10 times normal, the statin should be discontinued until levels return to normal. In these cases, once the CPK is again normal, either the same statin can be reintroduced at a lower dosage or on alternate-day dosing, or a different type of statin such as fluvastatin or pravastatin (which have been associated with a lower incidence of myalgias due to their pharmacologic properties) can be tried. But if the CPK ever exceeds 50 times normal, or if kidney failure develops, alternative lipid-lowering strategies like low-density lipoprotein (LDL) apheresis or red yeast rice should be considered. The addition of coenzyme Q10 at a dose of 200 mg/day may also be helpful in reducing the development of statin induced myalgias.
Statins have also been shown to cause an inflammatory myopathy by altering the immune system. This type of myositis does not resolve with statin discontinuation alone and requires immunosuppressive treatments.
Patients with prolonged stays in the intensive care unit (ICU) are at risk for developing critical illness myopathy, which typically results in a flaccid quadriparesis and is often accompanied by critical illness polyneuropathy. As this is a recently coined diagnosis; information on its exact incidence is unknown. A number of studies have shown it to be equal in prevalence to critical illness polyneuropathy, which affects up to 58% of patients with prolonged ICU stays and nearly 80% of patients with multiorgan failure or septic shock. It is thought that critical illness myopathy is the result of a hypercatabolic effect on the muscle or muscle membrane. It has also been associated with the use of high-dose steroids in the ICU setting. For patients with critical illness myopathy, optimization of nutrition and the initiation of intensive physical therapy over a period of several months have shown to be beneficial.
Malignant hyperthermia is a severe reaction to anesthetic agents and depolarizing muscle-blocking agents that manifests as muscle rigidity, fever, muscle necrosis, myoglobinuria, metabolic acidosis, kidney failure, and cardiac arrhythmias. It has been highly associated with central core disease, an inherited myopathy that arises from mutations in the ryanodine receptor gene. Although it is a congenital myopathy, central core disease can manifest in childhood and adulthood. Aggressive treatment with oxygen, intensive body-cooling measures, hydration, hyperkalemia management, and dantrolene can be life saving. Patients with known central core disease and their family members should be warned about the potential risk of malignant hyperthermia preoperatively.