Myopathy – Causes, Symptoms, Diagnosis, Treatment

Myopathy is derived from the Greek words “myo” for muscle, and “pathy” for suffering which means muscle disease. The most common signs and symptoms of myopathies include weakness, stiffness, cramps, and spasms. Myopathies are a heterogeneous group of disorders primarily affecting the skeletal muscle structure, metabolism, or channel function. They usually present with muscle weakness interfering in daily life activities. Muscle pain is also a common finding and some myopathies are associated with rhabdomyolysis.

Causes of Myopathy

The etiology of the myopathies is usually caused by a disruption in the muscle tissue integrity, and metabolic stability which may be triggered by inherited genetic diseases, or metabolic errors, certain drugs and toxins, bacterial or viral infections, inflammation, besides minerals, electrolytes, and hormonal irregularities:

 Inherited Myopathies

• Mitochondrial Myopathies[rx]

  • Mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome (MELAS)
  • Kearns-Sayre syndrome
  • Others (Leber hereditary optic neuropathy; Myoclonic epilepsy with ragged red fibers; Leigh syndrome and neuropathy, ataxia, and retinitis pigmentosa; mtDNA deletion and depletion syndromes; Chronic progressive external ophthalmoplegia; etc.)[rx]

• Congenital Myopathies

  • Nemaline myopathies[rx]
  • Core myopathies
  • Centronuclear myopathies
  • Others[rx]

• Metabolic Myopathies

  • Lipid myopathies (most common are carnitine palmitoyltransferase II deficiency, very-long-chain-acyl-CoA dehydrogenase deficiency, trifunctional protein deficiency)
  • Glycogen storage disease myopathy (Acid maltase deficiency – Pompe disease, Debrancher deficiency – Cori disease – and muscle phosphorylase deficiency – McArdle disease – are the most frequently encountered)[rx]

• Channelopathies

  • Periodic paralysis (Hypokalemic, hyperkalemic, Andersen-Tawil syndrome)
  • Nondystrophic myotonias (p.e. paramyotonia congenita, Thomsen disease)

• Muscular Dystrophies[rx]

  • Dystrophinopathies (Duchenne muscular dystrophy, Becker muscular dystrophy, Intermediate phenotype)
  • Myotonic muscular dystrophies (type 1 and type 2)
  • Facioscapulohumeral muscular dystrophies (type 1 and type 2)
  • Emery-Dreifuss muscular dystrophy
  • Limb-girdle muscular dystrophies
  • Oculopharyngeal muscular dystrophy
  • Congenital muscular dystrophy (most common being LAMA2-related, collagen VI-related and alfa-dystroglycan-related)
  • Distal myopathies

Acquired Myopathies

• Toxic Myopathies

  • Necrotizing myopathies (statins, fibrates, immune checkpoint inhibitors, labetalol, propofol, alcohol, cyclosporine)[rx][rx]
  • Mitochondrial myopathies (some antiretrovirals)
  • Amphiphilic myopathies (chloroquine, hydroxychloroquine, amiodarone)
  • Antimicrotubular myopathies  (vincristine)
  • Hypokalemic myopathies (diuretics, steroids, laxatives, alcohol, etc.)
  • Critical care-associated myopathies (corticosteroids, neuromuscular blockers)
  • Inflammatory myopathy (tumor necrosis alfa inhibitors, immune checkpoint inhibitors, statins, IFN-alfa, D-penicillamine, L-tryptophan, hydroxyurea, imatinib lamotrigine, phenytoin)
  • Unknown mechanism (finasteride, omeprazole, isotretinoin)[rx]

• Immune-mediated or Idiopathic Inflammatory Myopathies

  • Dermatomyositis
  • Antisynthetase syndrome
  • Immune-mediated necrotizing myopathy
  • Inclusion body myopathy
  • Overlap myositis (association with other connective tissue diseases as systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis, and rheumatoid arthritis)
  • Polymyositis[rx]

• Infectious Myopathies 

  • Bacterial infections (Lyme disease, pyomyositis – Staphylococcus aureus)
  • Viral infections (Human immunodeficiency virus (HIV), Coxsackie A and B viruses, Influenza)
  • Parasitic infections (trichinosis, toxoplasmosis, cysticercosis)[rx][rx][rx]
  • Fungal infection (Candida, Coccidiomycosis)[rx]

• Endocrine Myopathies [rx]

  • Thyroid and parathyroid dysfunction (hyperthyroidism, hypothyroidism, hyperparathyroidism)
  • Adrenal dysfunction (Addison’s disease, Cushing syndrome)
  • Diabetic muscle infarction

• Electrolyte-mediated Mopathies (hypo- and hyperkalemia, hypercalcemia, hypermagnesemia, hypophosphatemia)
• Myopathies associated with systemic disease (amyloidosis, sarcoidosis, vitamin D deficiency, critical care myopathy, idiopathic eosinophilic myopathy, paraneoplastic)

NOTE: Rhabdomyolysis is a syndrome defined by skeletal muscle damage with CK elevation. It can occur with or without underlying muscle disease and should not be considered as a primary myopathy.[rx]

Other types of acquired myopathies will represent within a group of symptoms associated with that particular disease like for example sarcoidosis myopathy, amyloid myopathy, and critical illness myopathy. Duchenne muscular dystrophy, myotonic dystrophy 1,2, mitochondrial myopathies, Glycogen storage diseases like (McArdle, Pompe’s disease, etc) are inherited myopathies affect children and it is rare, and accompanied with severe systemic complications. These patients’ life expectancy is relatively limited depending on the severity of the disease and the complications.[rx]

Symptoms Of Myopathy

The signs and symptoms consistent with are^[rx]

Diagnosis of Myopathy

Myopathies are typically involving motor impairment without any sensory symptoms. It presents as proximal muscle weakness, mainly in the pelvic girdle or the shoulder girdle muscle groups.

Hypothyroid and hyperthyroid myopathies – Both of them are associated with thyroid disease whether it is a hypo- or hyperthyroid disease, and both present with proximal muscle weakness and peripheral neuropathy. Hypothyroid myopathy is associated with pseudohypertrophy, myxoedema, and delayed deep tendon reflexes. Hyperthyroid myopathy is associated with Grave’s ophthalmopathy, goiter, and extraocular muscle weakness as well.[rx][rx][rx]

The complementary evaluation should be guided by clinical suspicion. Useful tests include:

 1) Laboratory studies

• Complete blood count
• Blood urea nitrogen and serum creatinine
• Electrolytes (sodium, magnesium, potassium, calcium, phosphorus)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), y-glutamyltransferase (GGT)
• Creatine kinase (CK), myoglobin, and aldolase: CK the most useful blood test but levels may not correlate with the degree of muscle weakness. Myopathies with enhanced regeneration or spared myofibers, such as in antisynthetase syndrome, dermatomyositis, and critical care myopathy, may present with normal CK and selectively elevated aldolase.
• C-reactive protein and erythrocyte sedimentation rate
• Thyroid function tests
• Anti-nuclear antigen (ANA) and myositis associated antibody panel (importantly -Jo1, -PL7, -PL12, -OJ for antisynthetase syndrome; TIF1-gamma, – NXP2, -Mi2, -SAE, – MDA5 for dermatomyositis, – HMG-CoA, -SRP for immune-mediated necrotizing myopathy)
• Urinalysis: positive hemoglobin dipstick without erythrocytes on microscopic evaluation is a sign of myoglobinuria

2) Electromyography (EMG) and nerve conduction study (NCS)

In this context electrodiagnostic testing has many objectives:

• it is useful to exclude alternative diagnoses such as neuromuscular junction or motor neuron disorders.
• it can confirm the myopathic nature of the process if there is an identifiable pattern.
• it helps characterized and stratify the severity of the disease
• it can help to choose the best location to perform a muscle biopsy.  [rx]

3) Electrocardiography (ECG): Findings suggestive of hypokalemia include the following:

• Diffuse nonspecific ST-T wave changes
• Increased PR interval
• U waves
• Wide QRS

4) Muscle biopsy – The muscle biopsy shows muscle fibers of varying sizes as well as small groups of necrotic and regenerating fibers. Connective tissue and fat replace lost muscle fibers.  Muscle biopsy usually shows nonspecific dystrophic features, although cases associated with FHL1 mutations have features of myofibrillar myopathy.[rx] Muscle biopsy shows muscle atrophy involving Type 1 fibers selectively in 50 percent of cases.[rx] Muscle biopsies are categorized by three major components:[rx]

• Histological/histochemical
• Myopathic vs. neuropathic patterns of disease
• Presence of unique features that are clues to underlying pathophysiology and diagnosis
• Myopathic pattern
• Rounding and variation of myofiber size
• Internal nuclei, fiber atrophy, degeneration and regenerating myofibers
• Fatty replacement
• Neuropathic pattern
• Evidence of denervation and re-innervation
• Small, atrophic, angular fibers and target fibers
• Re-innovation results in fiber type grouping

5) Muscle MRI: Magnetic resonance imaging of the muscles

• Increased signal intensity within muscle tissue
• May see muscle necrosis, degeneration, and/or inflammation
• May see fatty replacement, an indicator of chronic muscle damage
• Findings may help guide site selection for muscle biopsy
• MRI offers a less invasive assessment tool in pediatric populations[rx]

Laboratory Tests

• Blood and urine tests – can detect defective genes and help identify specific neuromuscular disorders. For example:
• Creatine kinase – is an enzyme that leaks out of the damaged muscle. Elevated creatine kinase levels may indicate muscle damage, including some forms of myopathy before physical symptoms become apparent. Levels are significantly increased in the early stages of myopathy. Testing can also determine if a young woman is a carrier of the disorder.[rx] The level of serum aldolase an enzyme involved in the breakdown of glucose, is measured to confirm a diagnosis of skeletal muscle disease. High levels of the enzyme, which is present in most body tissues, are noted in people with myopathy and some forms of myopathy. [rx]
• Myoglobin – is measured when injury or disease in skeletal muscle is suspected. Myoglobin is an oxygen-binding protein found in cardiac and skeletal muscle cells. High blood levels of myoglobin are found in people with myopathy.
• Polymerase chain reaction (PCR) – can detect some mutations in the dystrophin gene. Also known as molecular diagnosis or genetic testing, PCR is a method for generating and analyzing multiple copies of a fragment of DNA.
• Serum electrophoresis – is a test to determine quantities of various proteins in a person’s DNA. A blood sample is placed on specially treated paper and exposed to an electric current. The charge forces the different proteins to form bands that indicate the relative proportion of each protein fragment. [rx]
• Exercise tests – can detect elevated rates of certain chemicals following exercise and are used to determine the nature of myopathy or other muscle disorders. Some exercise tests can be performed bedside while others are done at clinics or other sites using sophisticated equipment. These tests also assess muscle strength. They are performed when the person is relaxed and in the proper position to allow technicians to measure muscle function against gravity and detect even slight muscle weakness. If weakness in respiratory muscles is suspected, respiratory capacity may be measured by having the person take a deep breath and count slowly while exhaling.[rx]
• Genetic testing – looks for genes known to either cause or be associated with inherited muscle disease. DNA analysis and enzyme assays can confirm the diagnosis of certain neuromuscular diseases, including myopathy. Genetic linkage studies can identify whether a specific genetic marker on a chromosome and a disease are inherited together. They are particularly useful in studying families with members of different generations who are affected. An exact molecular diagnosis is necessary for some of the treatment strategies that are currently being developed. Advances in genetic testing include whole-exome and whole-genome sequencing, which will enable people to have all of their genes screened at once for disease-causing mutations, rather than have just one gene or several genes tested at a time. Exome sequencing looks at the part of the individual’s genetic material, or genome, that “code for” (or translate) into proteins. [rx]
• Genetic counseling – can help parents who have a family history of myopathy determine if they are carrying one of the mutated genes that cause the disorder. Two tests can be used to help expectant parents find out if their child is affected.
• Amniocentesis – done usually at 14-16 weeks of pregnancy, tests a sample of the amniotic fluid in the womb for genetic defects (the fluid and the fetus have the same DNA). Under local anesthesia, a thin needle is inserted through the woman’s abdomen and into the womb. About 20 milliliters of fluid (roughly 4 teaspoons) is withdrawn and sent to a lab for evaluation. Test results often take 1-2 weeks.
• Chorionic villus sampling, or CVS –  involves the removal and testing of a very small sample of the placenta during early pregnancy. The sample, which contains the same DNA as the fetus, is removed by a catheter or a fine needle inserted through the cervix or by a fine needle inserted through the abdomen. The tissue is tested for genetic changes identified in an affected family member. Results are usually available within 2 weeks. [rx]
• Alanine Aminotransferase (ALT, SGPT) – The normal range in males is 10 to 40 U/L. The normal range in females is 8 to 35 U/L; it is elevated in muscular dystrophy.[rx]
• Aldolase (Serum) – The normal range is 0 to 6 U/L. It is elevated in muscular dystrophy but decreases in later stages of muscular dystrophy.[rx]
• Arterial Blood Gases (ABG) – Normal ranges: PO2 is 75 to 100 mmHg; PCO2 is 35 to 45 mm Hg; HCO3- is 24 to 28 mEq/L; pH is 7.35 to 7.45. Respiratory acidosis can develop if there are defects in muscles involved in respiration.[rx]
• Aspartate Aminotransferase (AST) – Normal ranges from 0 to 35 U/L. Elevated in muscular dystrophy.[rx]
• Creatine Kinase (CK, CPK) and Creatine Kinase Isoenzymes (CK-MB and CK-MM) – Normal ranges from 0 to 130 U/L. Elevated in muscular dystrophy (hyperkalemia).[rx] The serum enzymes, especially creatine phosphokinase (CPK), is increased to more than ten times normal, even in infancy and before the onset of weakness.[rx][rx] Serum CK levels are invariably elevated between 20 and 100 times normal in myopathy.[rx] The levels are abnormal at birth, but values decline late in the disease because of inactivity and loss of muscle mass.[rx] Elevated CPK levels at birth are diagnostic indicators of myopathy.[rx]
• Lactate Dehydrogenase (LDH) – Normal ranges from 50 to 150 U/L. Elevated in muscular dystrophy. LDH 4: 3 to 10%, LDH 5: 2 to 9%.[rx]
• Urinalysis (UA) – Glucose in urine is commonly associated with muscular dystrophy due to the high incidence of diabetes mellitus within this population.[rx] Myoglobinuria may also be present.[rx]

Other Tests

• Chromosomal Analysis – DNA testing for common mutations and chromosomal analysis can now rule out Down syndrome, myotonic dystrophy, and other disorders. In both Becker and Duchenne dystrophies, the DNA deletion size does not predict clinical severity.[rx] [rx]
• Electrocardiogram (ECG) – Often, patients will have annual echocardiograms to stay ahead of any developing cardiomyopathy. This study will demonstrate atrial and atrioventricular rhythm disturbances. The typical electrocardiogram shows an increased net RS in lead V1; deep, narrow Q waves in the precordial leads.[rx] A QRS complex too narrow to be right bundle branch block; and tall right precordial R waves in V1.[rx] Dominant R wave in lead V1 is the best clue to the actual diagnosis.[rx] Normal PR interval, QRS duration.
• Electromyography (EMG) – Allows assessment for denervation of muscle, myopathies, and myotonic dystrophy, motor neuron disease. EMG demonstrates features typical of myopathy.[rx] Clinical examination, electromyography changes are found in almost any muscle: waxing and waning of potentials termed the dive bomber effect.[rx]
• Genetic Testing – A definitive diagnosis of muscular dystrophy can be established with mutation analysis on peripheral blood leukocytes.[rx] Genetic testing demonstrates deletions or duplications of the dystrophin gene in 65% of patients with Becker dystrophy, which is approximately the same percentage as in Duchenne dystrophy.[rx] [rx]
• Immunocytochemistry – A definitive diagnosis of muscular dystrophy can be established based on dystrophin deficiency in a biopsy of muscle tissue.[rx] Also, staining of muscle with dystrophin antibodies can demonstrate the absence or deficiency of dystrophin localizing to the sarcolemmal membrane.[rx] DIsease carriers may demonstrate a mosaic pattern, but dystrophin analysis of muscle biopsy specimens for carrier detection is not reliable.[rx]
• Immunofluorescence testing – can detect specific proteins such as dystrophin within muscle fibers. Following the biopsy, fluorescent markers are used to stain the sample that has the protein of interest.
• Electron microscopy – can identify changes in subcellular components of muscle fibers. Electron microscopy can also identify changes that characterize cell death, mutations in muscle cell mitochondria, and an increase in connective tissue seen in muscle diseases such as MD. Changes in muscle fibers that are evident in a rare form of distal MD can be seen using an electron microscope.[rx]
• Nerve conduction velocity test –  measure the speed and strength with which an electrical signal travels along a nerve. A small surface electrode stimulates a nerve, and a recording electrode detects the resulting electrical signal either elsewhere on the same nerve or on a muscle controlled by that nerve. The response can be assessed to determine whether nerve damage is present. Repetitive stimulation studies involve electrically stimulating a motor nerve several times in a row to assess the function of the neuromuscular junction. The recording electrode is placed on a muscle controlled by the stimulated nerve, as is done for a routine motor nerve conduction study.[rx]
• Motor NCS  – are usually normal unless there is a concomitant neuropathy. Exceptions to this include distal myopathies and critical care myopathy where low compound muscle action potentials (CMAPs) with normal latencies and conduction velocities are seen. Sensory NCS are within the normal range. Inclusion body myositis is the exception since it can cause sensory abnormalities.
• Needle EMG –  is the most sensitive examination for myopathy. The presence of myotonic discharges and muscle membrane irritability (increased insertional activity, fibrillation potentials, and positive sharp waves) helps to narrow the differential diagnosis as it is generally present in necrotizing myopathies (inflammatory or toxic), myotonic dystrophies, and a few metabolic and congenital myopathies. Repetitive stimulation and correlation with exercise may be needed in the special case of channelopathies. In some metabolic, congenital, endocrine myopathies, electrodiagnostic tests may be normal. Of note, electrodiagnostic testing is not always needed if there is a strong suspicion of a myopathic disorder (p.e. suggestive clinical features with elevated CK or positive family history), especially in the pediatric population. [rx]
• Polysomnogram – Excessive daytime somnolence with or without sleep apnea is not uncommon. Sleep studies, noninvasive respiratory support (biphasic positive airway pressure [BiPAP]), and treatment with modafinil may be beneficial.[rx]
• Slit Lamp – An examination for cataracts that may be present in patients with muscular dystrophy.[rx]
• Western Blot – A diagnosis of Duchenne dystrophy can also be made by Western blot analysis of muscle biopsy specimens, revealing abnormalities on the quantity and molecular weight of dystrophin protein. On Western blot, Becker muscular dystrophy individuals dystrophin levels will appear normal, although the protein itself is abnormal; this is in comparison to Duchenne muscular dystrophy affected individuals who have a significantly decreased dystrophin on Western blot.[rx]

Treatment of Myopathy

Surgical Treatment

• Contracture Release – Surgical release of contracture deformities is used to maintain normal function as long as possible.[rx] Massage and heat treatments also may be helpful.
• Defibrillator or Cardiac Pacemaker – Cardiac function requires monitoring, and pacemaker placement may be a consideration if there is evidence of heart block.[rx]  Individuals with either Emery-Dreifuss or myotonic dystrophy may require a pacemaker at some point to treat cardiac problems. Management of cardiomyopathy and arrhythmias may be life-saving.[rx] In patients with severe syncope, established conduction system disorders with second-degree heart block previously documented, or tri-fascicular conduction abnormalities with significant PR interval lengthening, consideration needs to be given towards placement of a cardiac pacemaker.[rx] An advanced cardiac block is also an indication to install a pacemaker.[rx]
• Shoulder Surgery – Individuals with facioscapulohumeral muscular dystrophy and myopathy may benefit from surgery to stabilize the shoulder.[rx]
• Spinal Correction – Scoliotic surgery is an option when curves exceed 20 degrees to prolong respiratory function or walking ability or both.[rx]
• Tendon or muscle-release surgery – is recommended when a contracture becomes severe enough to lock a joint or greatly impair movement. The procedure, which involves lengthening a tendon or muscle to free movement, is usually performed under general anesthesia. Rehabilitation includes the use of braces and physical therapy to strengthen muscles and maintain the restored range of motion.  A period of immobility is often needed after these orthopedic procedures, thus the benefits of the procedure should be weighed against the risk of this period of immobility, as the latter may lead to a setback.
• Surgery to reduce the pain and postural imbalance – caused by scoliosis may help some individuals. Scoliosis occurs when the muscles that support the spine begin to weaken and can no longer keep the spine straight. The spinal curve, if too great, can interfere with breathing and posture, causing pain. One or more metal rods may need to be attached to the spine to increase strength and improve posture. Another option is spinal fusion, in which bone is inserted between the vertebrae in the spine and allowed to grow, fusing the vertebrae together to increase spinal stability.
• Cataract surgery – involves removing the cloudy lens to improve the person’s ability to see.

Prevention

• Yearly influenza vaccine
• Pneumococcal vaccine (PPS 23)[rx]
• Assess for, in the presence of corticosteroid intake, weight gain, dysphagia, constipation, malnutrition or prior main surgeries
• Physical therapy to prevent muscle contractures. Promote daily or regular exercise, but if there is muscle pain, reduce activity intensity or frequency
• Monitor for serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D (per semester), magnesium, PTH, urine calcium, and creatinine; Dual-energy x-ray absorptiometry at age three and annually; spine x-rays; bone age, especially if under corticosteroid therapy[rx]
• Consider biphosphonates if there is a history of symptomatic vertebral fractures, not as prophylaxis
• Cardiac evaluation every two years, from the time of diagnosis (electrocardiogram and echocardiogram or cardiac MRI)[rx][rx]; On heterozygous asymptomatic females, observation, and work up as considered by symptoms; routine cardiac surveillance every five years from age 25
• Baseline pulmonary function tests and biannually along with pediatric pulmonologist if the patient uses a wheelchair, age 12, or has a reduction of vital capacity of less than 80%
• Family members or caregivers should be educated regarding manual ventilation bags, mechanical insufflation-exsufflation device.