Myopathies — The Dana Guide


by Jerry R. Mendell

March, 2007

sections include: symptoms of myopathiestesting and diagnosismuscular dystrophyinflammatory myopathies 

Myopathies are disorders of the skeletal muscles, involving changes in either the structure or the function of those muscles. Their major symptoms include muscle weakness, pain, and fatigue. In their early stages, they can resemble diseases of the nerves that control the muscles, such asperipheral neuropathymyasthenia gravis and amyotrophic lateral sclerosis. Therefore, even though myopathies do not necessarily involve the nervous system, physicians must consider them alongside nervous system disorders when trying to diagnose the cause of a person’s weakness or fatigue.

Many myopathies arise from problems in the muscle tissue itself, either through a genetic defect (as in the various forms of muscular dystrophy) or as an acquired condition (most commonly in what are called inflammatory myopathies). This book cannot cover all the myopathies in detail but will focus instead on how doctors distinguish them from neuromuscular disorders and how they can be linked to other neurological problems.

Symptoms of Myopathies

Muscle weakness. Most muscle disorders cause persistent weakness, with the muscles closest to the trunk (the proximal muscles) weaker than those farther away (the distal muscles). Some diseases affect the muscles of the eyes, causing eyelid drooping (ptosis) and double vision (diplopia), as in myasthenia gravis.

In certain disorders, the muscle weakness is intermittent. Symptoms may fluctuate drastically between severe weakness at one time to complete recovery at others. This is particularly characteristic of disorders in which the sources of energy for a muscle (fats and carbohydrates) are deficient and unable to support vigorous activity. Overworking the muscle causes its tissue to break down, accompanied by the release of a chemical called myoglobin into the bloodstream, which turns a person’s urine dark brown. Intermittent symptoms are also typical of myasthenia gravis, especially of the eye muscles late in the day; swallowing and limb muscle strength also varies during the day and from day to day.

A doctor’s examination may reveal a pattern of weakness that helps in diagnosing a specific myopathy. Gowers’ sign is particularly useful in revealing proximal weakness; individuals “climb their own limbs” as they get up from the floor.

When people’s trunk and hip muscles are weak, their gait reveals an arching of the back and a tendency to walk on the toes. These same individuals demonstrate a “waddling gait” caused by their muscles’ inability to hold the hips in a horizontal position; thus the hip drops or dips with each step.

Thigh muscle weakness causes a characteristic gait with a tendency for the knee to lock and curve backward (hyperextend) with each step.

If ankle muscles are weak, individuals tend to exhibit what is called foot drop—with each step, they have a hard time raising their moving foot. This predisposes an individual to tripping and falling (and perhaps breaking a bone).

Fatigue. Any disorder that causes muscle weakness can also bring on fatigue, which in this context means an inability to maintain a force. With weak muscles, individuals cannot sustain physical activities for very long; they become excessively tired. After all, they are attempting to perform the same movements with fewer or damaged muscle fibers. Such fatigue occurs in a variety of conditions: myasthenia gravis, disorders altering the energy production of the muscles, such as mitochondrial myopathies, and many of the myopathies that cause a significant loss of muscle (such as muscular dystrophy).

The fatigue from myopathies is different from the excess tiredness or lack of energy that many individuals experience, although people may confuse these conditions. Tiredness usually also involves feeling sleepy and having difficulty concentrating.

Muscle pain. Symptoms of muscle pain, also called myalgia, may or may not be accompanied by weakness or swelling. Certain drugs, particularly those taken to lower cholesterol, cause true myalgia (“true” meaning that the pain is in the muscle, not merely felt there). Two important painful muscle conditions are not associated with muscle weakness:

  • Fibromyalgia is a common but poorly understood pain syndrome. People with this condition complain of severe muscle pain and tenderness with specific trigger points, disturbed sleep and easy fatigability.
  • Polymyalgia rheumatica occurs in people over age 50 and is characterized by stiffness and pain in the shoulders, lower back, hips, and thighs. A blood test called the erythrocyte sedimentation rate (ESR) shows values that are well above normal. Blood vessels to the scalp (temporal arteries) and eyes may be inflamed, with a risk of blindness and strokes. It is important to recognize polymyalgia rheumatica because doctors can relieve the discomfort and risk of blindness and strokes with corticosteroids, medication that reduces the inflammation of the blood vessels.

Muscle cramps. These are painful, involuntary, localized muscle contractions with a visible hardening of the muscle. They are usually abrupt in onset and short in duration, but the muscle may remain sore for an extended period. Cramps often occur when a muscle is irritated from overwork, or if there is a pinched or damaged nerve. They can also accompany Duchenne and related forms of muscular dystrophy.

Myotonia is a distinct form of cramp consisting of a prolonged muscle contraction followed by slow muscle relaxation. Myotonia always follows muscle activation, usually voluntary, but a doctor can elicit myotonia by striking the muscle with a reflex hammer. Myotonia makes it difficult for a person to release an object after grasping it firmly. Usually it becomes worse in cold temperatures and eases with continued activity. Myotonic muscular dystrophy is named for its symptoms of muscle weakness and myotonia.

Muscle enlargement or atrophy. In most myopathies, fat and scar tissue replace lost muscle tissue, so the size of the muscle is usually not affected. However, in Duchenne muscular dystrophy a person’s calf muscles typically grow, due to increased fibrous tissue and fat replacement. A muscle can also appear enlarged when a tendon has ruptured, especially the biceps brachii tendon in the upper arm.

In contrast, atrophy refers to a decrease in the size of the muscle. It occurs slowly over time in long-standing myopathies. Muscle atrophy also occurs when there is nerve damage, as in polio, because the size of the muscle depends on nerve input.

Testing and Diagnosis

Doctors can diagnose any suspected myopathy with a limited battery of tests. Nearly all individuals require electrodiagnostic studies and blood tests. For some conditions, a muscle biopsy or DNA analysis may be very useful.

Electrodiagnostic studies. A very important test that measures the electrical activity of a person’s muscle is often called an EMG. In actual practice, however, the term EMG applies only to an electromyogram, a needle examination of muscle. An EMG can determine whether weakness is due to an inflamed muscle, or which muscle is appropriate to sample for biopsy, and is also especially helpful in detecting myotonia.

Nerve conduction studies are almost always done as part of the electrodiagnostic examination. By electrically stimulating a nerve, doctors can measure how fast that nerve conducts the impulse. This may indicate that weakness is due to nerve damage rather than muscle damage. In combination, the EMG and the nerve conduction studies provide enough information to differentiate myopathies from other conditions causing weakness.

Another component of the electrodiagnostic examination, called repetitive nerve stimulation, detects the type of fatigue in a muscle that is characteristic of myasthenia gravis. This requires that the nerve be stimulated at very high frequencies and can be uncomfortable.

Enzymes. Another standard part of testing for myopathies is to take a blood sample and look for certain enzymes. The most important is creatine kinase (CK), which leaks into the blood after damage to muscles.

DNA analysis. Molecular biology now allows us to precisely identify certain myopathies caused by genetic mutations and the resulting defective proteins. After a doctor takes a blood sample, laboratory technicians extract DNA from the person’s white blood cells and look for particular genetic markers. In some cases, a DNA test leads to a diagnosis without the need for other tests.

Muscle biopsies. Muscle biopsy analysis is an important step in establishing the final diagnosis of a suspected myopathy. This procedure requires removing a small sample of muscle for laboratory examination. The muscle selected depends on a variety of factors, including the degree of weakness and how the surgical procedure may affect the individual. Choosing a very weak muscle may show only scar tissue, so doctors try to avoid that.

A biopsy involves evaluating the muscle sample on a microscopic, cellular scale, using a combination of techniques.

  • Histochemistry, or chemical tests on the cells: this can identify certain disorders leading to energy failure or pain in the muscle.
  • Immune staining: a standard battery of antibodies can be applied to the sample to identify missing components of the muscle, thus helping to diagnose specific types of muscular dystrophies.
  • electron microscopy: viewing the cells at great magnification to spot structural changes.

A muscle biopsy is of particular value in diagnosing the inflammatory myopathies.

Muscular Dystrophy

Muscular dystrophy is an umbrella term for a group of hereditary progressive diseases affecting the muscles. All are neuromuscular disorders.

Duchenne Muscular Dystrophy

This inherited disorder affects only boys: about 30 out of every 100,000 male babies. It is usually recognized when a boy of about age 3 or 4 falls frequently and has difficulty keeping up with his friends when playing. The problem is progressive, and by age 12, most boys who suffer from Duchenne use wheelchairs. By age 16 to 18, young men are predisposed to serious, sometimes fatal pulmonary infections. Boys with Duchenne dystrophy commonly also have some intellectual impairment, more so than children with comparably disabling disorders. This usually affects verbal ability most but, unlike the muscular problems, does not get worse over time.

To diagnose Duchenne muscular dystrophy, doctors must perform a muscle biopsy or DNA blood test, looking for an abnormality in the protein dystrophin or the gene that creates it. If a mother has the defective gene, there is a 50 percent chance that it will be passed to a son or daughter. A son would develop the disease; a daughter would become a carrier. The DNA mutation can be identified in a fetus before birth through amniocentesis or chorionic villus sampling.

Becker Muscular Dystrophy

 Becker dystrophy results from defects of the same gene as in Duchenne dystrophy but is about ten times less frequent; it also strikes only boys. The defect is not as severe: though this condition also involves muscle wasting, it progresses much more slowly. Most people with Becker first experience difficulties between the ages of 5 and 15. By definition, those with Becker walk beyond age 15, while Duchenne boys are typically in a wheelchair by age 12. People with Becker dystrophy have a reduced life expectancy, but most survive into their fourth or fifth decade. The disorder affects the heart and in some cases leads to heart failure. Mental retardation in Becker dystrophy is not as common as in Duchenne.

Limb-Girdle Muscular Dystrophy

 Limb-girdle muscular dystrophy (LGMD) actually represents more than one disorder, now distinguished by genetics:

  • LGMD1 refers to cases that are dominantly inherited, with a child having a 50 percent chance of inheriting the disease if one parent is affected. Five forms have been identified.
  • LGMD2 indicates autosomal recessive transmission, meaning that both parents must carry the affected gene for a child to inherit it. It is rare for either parent to have the condition. Ten forms of LGMD2 have now been identified, with more added every few months.

Muscle weakness in LGMD of any type affects both males and females, with onset ranging from the first to the fourth decade. Most cases are progressive and affect the pelvic and shoulder girdle muscles. A person’s diaphragm may become so weak that he or she needs help to breathe. In some individuals the disorder weakens the heart muscle. The pattern of weakness and the rate of progression vary from person to person. Most people maintain normal intellectual function.

Myotonic Muscular Dystrophy

This disorder has an incidence of 13.5 per 100,000 live births, affecting males and females equally. It is the most common adult muscular dystrophy. Diagnosing the condition does not require a muscle biopsy. An EMG will show the myotonia, and a DNA test will easily reveal the genetic defect that causes it.

The symptom of myotonia usually appears by age 5, making it difficult for people to release objects after a firm grasp. The condition also produces weak neck muscles, wrists, hands, and fingers. Ankle weakness may cause foot drop. People’s proximal muscles remain stronger throughout the course of the disease, in contrast to most types of muscular dystrophy, although many individuals develop weakness and selective atrophy of the quadriceps (thigh) muscles.

It is common for people with myotonic dystrophy to develop a nasal voice and swallowing problems. Some suffer weakness in their diaphragm and chest muscles, which results in breathing problems. Affected adults typically have a narrow-faced appearance due to atrophy of muscles of the face and jaw. Men are usually bald, and woman may have thin hair; how these latter signs relate to the muscle weakness or the genetic defect is unknown.

Most people with myotonic dystrophy suffer disturbances in their heartbeat, and some require pacemakers. Other features associated with myotonic dystrophy include mild intellectual impairment, sleep apnea andexcessive daytime sleepiness and cataracts.

A very severe form of myotonic dystrophy occurs in about 25 percent of infants with affected mothers (not fathers). It is present at the time of birth and often causes swallowing and breathing problems. This congenital form of myotonic dystrophy is usually associated with mental retardation.

Facioscapulohumeral Muscular Dystrophy

This form of muscular dystrophy affects approximately 1 in 20,000 people. It is inherited as an autosomal dominant disorder affecting males and females. The condition typically comes on in a person’s teenage years or young adulthood. In most cases the first symptoms appear subtly in facial muscles: an inability to smile, whistle, or fully close the eyes. Later, individuals develop weakness of the shoulder girdles, making it hard to raise their arms. That weakness usually cues a young person to seek medical attention.

For most individuals, the weakness remains restricted to facial, upper extremity, and distal lower extremity muscles. In about 25 percent of cases, weakness progresses to involve the proximal lower extremities, producing great difficulty walking and perhaps necessitating the use of a wheelchair. Characteristically, people with facioscapulohumeral dystrophy do not have heart involvement. A few individuals develop nerve deafness or loss of vision from retinal detachment; why this disease affects these senses is unknown.

Researchers have located the gene for facioscapulohumeral dystrophy on chromosome 4 but have not detected the specific missing protein. Nevertheless, a very accurate diagnosis can be established by a DNA test.

Treating Muscular Dystrophies

The current treatment for muscular dystrophies is mostly supportive, aimed at improving people’s quality of life. Individuals need help tailored for their physical needs—for example, braces, canes, scooters, and wheelchairs to get around.

Prednisone, a powerful anti-inflammatory drug in the corticosteroid family, has been shown to delay the progression of Duchenne muscular dystrophy. It must be administered cautiously, however, because of potentially severe side effects. It has not been shown to be helpful for other types of muscular dystrophy, with the exception of rare individuals with LGMD.

Experimenters continue to seek a definitive way to replace the proteins that are missing or abnormal because of these genetic diseases. Attempts to replace the protein directly have not been successful; usually the protein breaks down before it reaches the muscle. Most researchers have turned their attention to gene replacement, trying to deliver to defective muscles a normal gene that will make the missing protein. Such treatment is not yet available for patients, but encouraging results in experimental animals with muscular dystrophy demonstrate that gene therapy looks promising for the future.

Inflammatory Myopathies

There are many forms of myopathies that are acquired during life rather than inherited. The three most prevalent all cause muscles to become inflamed and are grouped under the label “inflammatory myopathies.” They all tend to come on slowly and insidiously, with weakness developing over weeks or months. They usually affect the proximal muscles and cause difficulty swallowing, among other symptoms. Despite overlap in symptoms, the disorders are distinct.

Dermatomyositis

This disorder can begin at any age from childhood to late life. The slowly progressive weakness affects the proximal muscles more than the distal, but both are involved. The weakness is commonly accompanied by fatigue and muscle aching. Many myopathies can produce these symptoms, but dermatomyositis is distinguished from all other conditions by a skin rash. Its name in fact comes from the root words for “skin” (dermato-) and “muscle inflammation” (myositis). The rash may precede the muscle symptoms and involve the fingers, the backs of the hands, the elbows, and the skin around the eyes. Many people develop a purplish discoloration of the eyelids, with swelling around the eyes and the rash extending onto the cheeks and forehead. Some people develop small calcium deposits over pressure points on their buttocks, knees, and elbows. The inflammation can affect other organs, causing heart failure, fibrosis (scarring) of the lungs, and swelling of the joints.

People with dermatomyositis have an increased risk for cancer, especially in the lung, breast, and colon. Dermatomyositis patients should be tested for cancer and be especially careful to avoid known cancer risk factors, such as smoking.

The diagnosis requires blood tests showing an elevated CK level, an EMG demonstrating irritability of the muscles from inflammation, and a muscle biopsy showing characteristic changes. The findings on biopsy distinguish dermatomyositis from other inflammatory myopathies.

Treatment can be very effective. A new approach is to use intravenous immunoglobulin (IVIG) as the first treatment—an infusion of antibodies straight into the blood system, usually repeated over several weeks or even months. In many cases this treatment must be combined with prednisone or other anti-inflammatory drugs. Individuals must work closely with their physicians to be sure that side effects are kept to a minimum.

Polymyositis

This disorder mainly affects adults; it is relatively rare in children. As with dermatomyositis, the symptoms may include slowly progressing weakness of the proximal muscles and swallowing difficulties, but there is no skin rash. Polymyositis can cause heart failure, fibrosis of the lungs, and joint swelling accompanied by aching. The risk for cancer is not as high as with dermatomyositis, but individuals do need to be screened for underlying tumors. The diagnosis is established by a CK blood test, EMG, and muscle biopsy. Polymyositis responds to prednisone and other anti-inflammatory drugs, but not to IVIG.

Inclusion Body Myositis

The third major type of inflammatory myopathy is a disease of older adults: most people with the disorder develop symptoms over age 50. The weakness in inclusion body myositis (IBM) has some unique features. In addition to causing proximal muscle weakness and swallowing problems, it typically affects the distal muscles. Individuals have notable hand weakness and may exhibit foot drop. CK in the blood is usually not as elevated as in the other inflammatory disorders and may even be normal. An EMG reveals the inflammatory process. The final diagnosis of this disorder depends on a muscle biopsy; the microscopic features permit an unequivocal diagnosis distinct from other inflammatory myopathies.

Unfortunately, treatment for IBM has minimal benefits. Prednisone or other anti-inflammatory drugs may help to a small degree but not significantly for any length of time. IVIG does not help people with IBM any more than drugs. This lack of effective treatment is frustrating both for individuals and for their doctors. Many researchers are now studying IBM to find a way to help people with this disorder.  

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