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Neuromuscular Diseases

Neuromuscular Diseases

The motor unit

Causes of neuromuscular dysfunction

The neuropathies: symptoms and clinical findings

Muscular dystrophy

The neuromyopathies

Progressive muscular atrophy

Resources

When humans are in good health, the nervous system and musculature work together so smoothly there is little awareness of how efficiently this complicated biochemical machine functions. Neuromuscular diseases include a vast and bewildering array of related and unrelated disorders that have a certain similarity of symptoms in that both nerves and muscles are usually impaired. This term is usually applied to disorders of the motor unit and specifically excludes primary disorders of the central nervous system such as cerebral palsy.

The motor unit

The motor unit has four components: a motor neuron in the brain or spinal cord, its axon and related axons that comprise the peripheral nerve, the neuromuscular junction, and all the muscle fibers activated by the neuron. Like other cells, nerve and muscle cells have an external membrane that separates the inner fluids from those on the outside. The fluid on the inside is rich in potassium (K), magnesium (Mg), and phosphorus (P), whereas the fluid on the outside contains sodium (Na), calcium (Ca), and chloride (Cl). When all is quiet, the internal chemical composition of both nerve and muscle cells is remarkably constant and is called resting membrane potential. A primary reason for this constancy lies in the cells ability to regulate the flow of sodiumthanks to an enzyme in the membrane called Na+/K+ ATP-ase. Because the inside of the cell has less sodium than the outside, there is a negative potential (like a microscopic battery) of 70 to 90 mV. Under ordinary circumstances, the interior of the cell is 30 times richer in potassium than the extracellular fluid and the sodium concentration is 10 to 12 times greater on the outside of the cell. At rest, sodium tends to flow into cells and potassium oozes out.

When an impulse or current runs down a nerve and hits a muscle fiber, the action potential of the membrane is suddenly changed; K moves out of the cell and the permeability to Na keeps increasing so that the inside may become positive by as much as 40 mV. In a fraction of a second, however, K moves back again and restores the cell membrane to normal. This process of movement of ions in and out of cells is known as action potential and is the basis for both the transmission of nerve impulses and muscular contractions.

This action explains the biochemical processes involved, but anatomy also plays a role in movement. The critical spot is the synaptic cleft, the place where the nerve dips into the muscle. Here, the finely branched nerve fiber inserts into a microscopic bit of muscle tissue, and acetylcholine (ACh), the chemical responsible for the transmission of the nerve impulse, hooks onto the muscle fibers, stimulating them to contract. Enough calcium at the site makes the process go more smoothly, while magnesium slows the process. To keep ACh from accumulating in the cells, the enzyme cholinesterase destroys the excess.

To understand the physiological nature of muscle contractions, it is helpful to examine muscles microscopically. Muscle fibers have an outside membrane called the plasmalemma, an interior structure called a sarcolemma, transverse tubules across the fibers, and an inner network of muscle tissue called sarcoplasma. When a nerve impulse reaches the muscle, an action potential is set up and the current quickly travels in both directions from the motor end plate through the entire length of the muscle fiber. The whole inside of the muscle tissue becomes involved as the current spreads and, aided by calcium, the contractile protein called actin causes the muscle component (myosin) to contract. An enzyme, ATP-ase, helps provide the energy needed for the muscular filaments to slide past each other. Relaxation occurs promptly when Ca flows into the muscle tissue and the cycle is completed. The muscle fiber is now ready to be stimulated again by a nerve impulse.

A constant need for ready energy exists because muscles must be able to respond on demand. Compounds such as creatine, phosphate, adenosine triphosphate (ATP), myoglobin, creatine kinase (CK), calcium, and a host of oxidative enzymes are all involved. Red musculature is usually more efficient than pale muscle because it contains more myoglobin and more oxidative enzymes. In any one motor unit, however, all the muscle fibers are the same type.

Muscles acquire about 90% of the energy they need from glycogen, a starchy compound synthesized and stored in the muscles. A small amount of glucose and some free fatty acids also provide energy both in vigorous exercise and at rest. Many enzymes, too many to name, take part in these energy reactions, and some neuromuscular diseases are caused by a failure of these enzymes to function properly.

Causes of neuromuscular dysfunction

When a single nerve impulse strikes a muscle it causes a twitch, and ordinarily there is a brief refractory period of relaxation. If another impulse is received before relaxation is completed, the twitches can add up and cause a prolonged muscular spasm, or tetany. Normally, muscles continue to function properly because the ACh transmitted down the nerve is enzymatically eliminated. Certain drugs such as neostigmine and physostigmine can block this action and paralyze a muscle. Poisonous nerve gases and insecticides can also do the same. In a neuromuscular disease called myasthenia gravis, antibodies can block the passage of ACh to the end plate creating a similar paralysis. Leg cramps at night, on the other hand, are due to sustained muscular contractions (200 per second). They can be relieved by quinine or diphenhydramine.

Paralysis can take place anytime there is a failure or interference in the transfer of biochemical impulses from nerve to muscle. On the other hand, hyperactivity of neuromuscular transmission can lead to minor twitches and cramps or to severe spasms as in tetanus (lockjaw) or amyotrophic lateral sclerosis (Lou Gehrig disease). There is still much to learn about both hyperactive and paralytic cases, but new research on DNA (deoxyribonucleic acid) and immunology is proving helpful.

Abnormal levels of blood electrolytes such as sodium and potassium can also cause neuromuscular disturbances. When potassium is too high or too low, the muscles of the trunk, arms, and legs can be very weak, even to the point of paralysis. If the blood calcium is low (as in vitamin D deficiency or inadequate function of the parathyroid gland), twitching may occur. When blood calcium is too high, there may be profound weakness. Normal magnesium levels are also important for proper neuromuscular functioning.

Creatine is a nitrogenous organic acid normally present in muscle and other tissues. When muscle is injured, creatine leaks out and can be measured in the blood as creatine kinase (CK). Blood levels of CK are increased when heart muscle is damaged, but also in muscle trauma, polymyositis, rapidly worsening cases of muscular dystrophy, vigorous exercise, or for no apparent reason.

The neuropathies: symptoms and clinical findings

Various types of diseases involve both the nerves and muscles. Some pathologic processes destroy nerves; others primarily attack muscles. Although the cause (or causes) of practically all of them still remain unknown, all are under intensive study.

Muscular dystrophy

This primary degenerative process, first described by German neurologist Wilhelm Erb (18401921) in 1891, affects the muscular fibers, not the nerves or end plates. In spite of extensive research, the cause has not yet been firmly established, although genetic factors are receiving strong consideration. A variety of types and classifications have been proposed, but all are based on age of onset, symptomatology, and rate of progression. One simple classification system includes: progressive muscular dystrophy or Duchenne type; facioscapulohumeral or Landouzy and D´ jerine type; and limb-girdle dystrophies including distal muscular dystrophy, ocular myodystrophy, and myotonic dystrophy.

Progressive muscular dystrophy (Duchenne type) is the most important one of the group and the best studied. It accounts for almost 70% of all dystrophies, affects males five times more frequently than females, and almost always begins in the first five years of life. It is an inherited sex-linked recessive trait, and the abnormal gene is at the Xp21 locus. Its incidence is 1 in 3,600 in newborn males. Muscular weakness is noted first in the pelvis, shoulder girdle, and spine, and spreads peripherally to the extremities, especially to the legs. This weakness results in a waddling gait, an insecure stance on a wide base, and a lordotic (forward curved) posture. Weakness continues to spread all over the body, although some of the involved muscles appear to grow larger secondary to an invasion of muscle tissue by peculiar fat cells. This is especially evident in the calf muscles. Victims rarely survive to maturity.

Blood enzyme tests can detect the abnormalities associated with progressive muscular dystrophy early on, even before symptoms are clearly evident. Muscle tissue is rich in creatine and, when muscles are diseased, the creatine leaks into the blood and can be measured as creatine kinase (CK). The normal level of CK is about 160 IU/L, but an individual with Duchene muscular dystrophy may have CK levels as high as 15,000 to 35,000 IU/L. If the diagnosis is in doubt, genetic studies and muscle biopsy can also be done. The recent isolation of the Duchenne gene and the discovery that dystrophin is the abnormal encoded protein makes a precise molecular diagnosis possible. It also offers hope that the genetic basis for other dystrophies will be discovered soon.

Facioscapulohumeral muscular dystrophy or Landouzy-D´ jerine dystrophy differs from the more common types in that it involves primarily the upper extremities, face muscles, and shoulder girdle. The condition starts later in life (usually by age 10 years) and may appear even in the elderly. Because it has a slower progress and longer duration, patients may develop irregular cardiac rhythms or even damage to the heart muscle. CK enzymes vary greatly, and electromyograms (EMGs) are not diagnostic. A muscle biopsy is the only way to confirm the presence of this condition. As in all other dystrophies, no satisfactory therapy is yet available.

Limb-girdle dystrophies also follow a slow course and often cause only slight disability. When the disease begins in the fingers and then spreads centrally toward the body, the term distal is employed. When paralysis starts in the eyelids and facial muscles, it is classed as ocular. The causes of these conditions are obscure.

Although once considered rare, myotonic dystrophy is now being recognized with increasing frequency. It is an inheritable or familial condition that primarily affects young adults. The muscle groups of the hands, feet, and face (taper mouth is secondary to atrophy of face muscles) are most commonly involved. An individual with this condition may be easily able to shake hands but may have difficulty relaxing his grip. There are many accompanying glandular disturbances, changes in bones, and elevated blood cholesterol. Since so many body functions are affected by this disease, it is not surprising that death (from heart attacks) usually occurs before middle age.

The neuromyopathies

Neuromyopathies are similar to the dystrophies in that there is both nerve and muscular involvement, but there are also differences between the two categories. Some neuromyopathies start in childhood, while others begin later in life. Neuromyopathies involve more brain and spinal cord damage; causes can include infectious diseases, allergic conditions, immunologic problems, and toxic or traumatic injuries.

Amyotonia congenita of the Werdnig-Hoffmann type is the most prevalent condition in this group. In all types of amyotonia congenita, however, there is a failure of development or a degeneration of the motor neurons of the central nervous system or damage of the nerve pathways to the muscles. Since nerve activation of the muscles is diminished or lost completely, muscles atrophy. The condition is recognizable within the first few weeks of life. The child lies flaccid on his back with the head turned to one side, his cry is weak, and his reflexes are diminished or gone. In such severe cases, death occurs before the fifth year, but in some instances, a few years later. The condition is familial and affects both sexes equally. On biopsy the most striking microscopic characteristic of affected muscle tissue is the absence or loss of the development of end plates, where the twig-like branches of the motor nerves dip into the muscle fibers. The motor nerves

KEY TERMS

Acetylcholine (ACh) A white crystalline chemical compound (C7H17NO3) that transmits nerve impulses across intercellular gaps and activates muscular contraction.

Actin A muscle protein, active with myosin, in muscle contraction.

Action potential A transient change in the electrical potential across a membrane which results in the generation of a nerve impulse.

Cholinesterase An enzyme that destroys acetylcholine and keeps it from accumulating at neuro-muscular interfaces.

Creatine A nitrogenous, organic acid found in the muscle tissue of many vertebrates. Blood levels increase when muscle is damaged.

Creatine kinase A enzyme that is found and easily measured in blood and other tissues. It increases quantitatively when there is muscle destruction.

Dystrophin An abnormal encoded protein isolated from the Duchenne gene at the Xp21 locus.

Glycogen A starchy substance that is synthesized and stored in the muscles and a ready source of energy for muscular contraction.

Neuromuscular junction Where the nerve fibers terminate in the muscle tissue.

Neuron A nerve cell consisting of a nucleated portion from which there extrude smaller extensions called dendrites and longer processes called axons. Neurons may be either sensory or motor.

Plasmalemma Outer sheath or membrane of muscle tissue.

Sarcolemma Muscle tissue enclosed by muscle sheath and closely related to another substance called sarcoplasma.

or axons also show some typical thickening. Several blood enzyme tests are available for differentiating neuromyopathy from dystrophy but, since neither condition can be effectively treated, the distinction has little therapeutic value.

Progressive muscular atrophy

Although there are several variations of this disorder, they all show wasting of the muscles (atrophy) secondary to degeneration of the motor nerve system. The most common type is called amyotrophic lateral sclerosis and is popularly known as Lou Gehrig disease. Onset generally occurs between ages 40 to 70 years, but the disease can begin at other times in life. Although it may begin on one side, it always becomes bilateral. It is always fatal (within two to five years after diagnosis), since it spreads upward to involve throat and other vital muscles.

Charcot-Marie-Tooth disease (CMT) is named after the three doctors who first described it in 1886, Professor Jean-Martin Charcot (pronounced sharko) (18251893), his student, Pierre Marie (18531940), who both worked in Paris (France) at the Hospital de Salpetriere, and Dr. Howard Tooth (18561925) of London (England). It is also called peroneal muscular atrophy (PMA) because the peroneal muscle down the front of the shin that enables one to pull the foot up is usually the first muscle to be affected.

A weakened peroneal muscle can cause sloppy walking or drop foot, which causes tripping. CMT also has a third and more recent name, hereditary motor and sensory neuropathy (HMSN). This name more accurately describes the syndrome because it is hereditary, can affect both or either the ability to move (motor) or the ability to feel (sensory).

CMT is primarily a disease of the nerves whereby the myelin or insulating sheath of myelin on the nerves does not stay intact and the messages from the brain to the muscles through the nerves are not carried properly. It differs from muscular dystrophy in that people who have CMT are born with normal muscles. The muscles atrophy because the CMT affected nerves that serve them cannot properly send the message from the brain for them to move. Therefore, muscles can atrophy even though they are being used. People with muscular dystrophy have a problem with their muscles from the beginning. CMT is a muscular atrophy not a muscular dystrophy.

CMT is not well known but it is not rare. Many people do not know they have it even though it is carried in families sometimes for generations. CMT can be inherited three ways but most cases are inherited autosomal dominate pattern meaning it comes directly down a line from parent to child. In this form of inheritance there is a 50/50 chance at each conception that the child will have CMT.

Outward signs are what doctors look for to begin a diagnosis of CMT. The primary signs for CMT are: loss of muscle in the calf area giving the leg a very thin look from the knee down, a drop foot walk, high arches or very flat feet and other foot bone deformities, cocked or hammertoes, ankle weakness and loss of feeling and/or movement in the foot and ankle. Primary signs in the upper extremities are finger, hand and grip as well as wrist weakness, the loss of the muscle that lets the thumb move and a loss of feeling and/or movement in the hand and wrist. Balance is usually affected because the muscles of the feet are weak and cannot compensate for a sudden stop or a change in the terrain.

Fatigue is one of the prime symptoms that everyone who has CMT seems to experience. Scoliosis and other spinal deformities are often diagnosed in people who show CMT at an early age and some people experience hip and knee dislocations while some are born with deformed hip sockets. Diagnosis can also be made by doing an electromyogram (EMG) that measures the irritability and function of muscles and motor nerve-conduction velocity (MNCV) tests that establish the ability of nerves to send and receive impulses.

CMT does not affect life expectancy unless the phrenic nerves that help one breathe are badly involved. Also, some people who have CMT lose the ability to cough. Not being able to cough and weakened respiratory function can mean a person is more susceptible to life-threatening lung infections and disease. With an early diagnosis and by taking care of oneself over the years, most people with CMT will live a normal life span without too much difficulty, although there is no denying the fact that some people do have severe problems. Surgery can help foot, ankle, hand, finger, spine and hip problems. Ankle-foot orthotics (AFOs) can also help a person with footdrop walk without tripping and in-shoe orthotics can help alleviate pain experienced when walking and give a person an improved gait. Genetic research has already found the genes that cause some of the many types of CMT and is ongoing. Testing for some types is available.

See also Muscular system.

Resources

BOOKS

Brown, William F., Charles F. Bolton, and Michael J. Aminoff, eds. Neuromuscular Function and Disease: Basic, Clinical, and Electrodiagnostic Aspects. Philadelphia, PA: Saunders, 2002.

Benatar, Michael. Neuromuscular Disease: Evidence and Analysis in Clinical Neurology. Totowa, NJ: Humana Press, 2006.

Feldman, Eva L. Atlas of Neuromuscular Diseases: A Practical Guideline. New York: Springer, 2005.

Wilkinson, Iain M.S. Essential Neurology. Malden, MA: Blackwell Publishing, 2005.

Joseph D. Wassersug

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