Charcot-Marie-Tooth disease

Definition

The term peripheral neuropathy encompasses a wide range of disorders in which the nerves outside of the brain and spinal cord--peripheral nerves--have been damaged. Peripheral neuropathy may also be referred to as peripheral neuritis, or if many nerves are involved, the terms polyneuropathy or polyneuritis may be used.

Description

Peripheral neuropathy is a widespread disorder, and there are many underlying causes. Some of these causes are common, such as diabetes, and others are extremely rare, such as acrylamide poisoning and certain inherited disorders. The most common worldwide cause of peripheral neuropathy is leprosy. Leprosy is caused by the bacterium Mycobacterium leprae, which attacks the peripheral nerves of affected people. According to statistics gathered by the World Health Organization, an estimated 1.15 million people suffer from leprosy worldwide.

Leprosy is extremely rare in the United States, where diabetes is the most commonly known cause of peripheral neuropathy. It has been estimated that more than 17 million people in the United States and Europe suffer from diabetes-related polyneuropathy. Many neuropathies are idiopathic, meaning that no known cause can be found. The most common of the inherited peripheral neuropathies in the United States is Charcot-Marie-Tooth disease, which affects approximately 125,000 persons.

Another of the better known peripheral neuropathies is Guillain-Barré syndrome, which arises from complications associated with viral illnesses, such as cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus (HIV), or bacterial infection, including Campylobacter jejuni and Lyme disease. The worldwide incidence rate is approximately 1.7 cases per 100,000 people annually. Other well-known causes of peripheral neuropathies include chronic alcoholism, infection varicella-zoster virus, botulism, and poliomyelitis. Peripheral neuropathy may develop as a primary symptom, or it may be due to another disease. For example, peripheral neuropathy is only one symptom of diseases such as amyloid neuropathy, certain cancers, or inherited neurologic disorders. Such diseases may affect the peripheral nervous system (PNS) and the central nervous system (CNS), as well as other body tissues.

To understand peripheral neuropathy and its underlying causes, it may be helpful to review the structures and arrangement of the PNS.

Nerve cells and nerves

Nerve cells are the basic building block of the nervous system. In the PNS, nerve cells can be threadlike--their width is microscopic, but their length can be measured in feet. The long, spidery extensions of nerve cells are called axons. When a nerve cell is stimulated, by touch or pain, for example, the message is carried along the axon, and neurotransmitters are released within the cell. Neurotransmitters are chemicals within the nervous system that direct nerve cell communication.

Certain nerve cell axons, such as the ones in the PNS, are covered with a substance called myelin. The myelin sheath may be compared to the plastic coating on electrical wires--it is there both to protect the cells and to prevent interference with the signals being transmitted. Protection is also given by Schwann cells, special cells within the nervous system that wrap around both myelinated and unmyelinated axons. The effect is similar to beads threaded on a necklace.

Nerve cell axons leading to the same areas of the body may be bundled together into nerves. Continuing the comparison to electrical wires, nerves may be compared to an electrical cord--the individual components are coated in their own sheaths and then encased together inside a larger protective covering.

Peripheral nervous system

The nervous system is classified into two parts: the CNS and the PNS. The CNS is made up of the brain and the spinal cord, and the PNS is composed of the nerves that lead to or branch off from the CNS.

The peripheral nerves handle a diverse array of functions in the body. This diversity is reflected in the major divisions of the PNS--the afferent and the efferent divisions. The afferent division is in charge of sending sensory information from the body to the CNS. When afferent nerve cell endings called receptors are stimulated, they release neurotransmitters. These neurotransmitters relay a signal to the brain, which interprets it and reacts by releasing other neurotransmitters.

Some of the neurotransmitters released by the brain are directed at the efferent division of the PNS. The efferent nerves control voluntary movements, such as moving the arms and legs, and involuntary movements, such as making the heart pump blood. The nerves controlling voluntary movements are called motor nerves, and the nerves controlling involuntary actions are referred to as autonomic nerves. The afferent and efferent divisions continually interact with each other. For example, if a person were to touch a hot stove, the receptors in the skin would transmit a message of heat and pain through the sensory nerves to the brain. The message would be processed in the brain and a reaction, such as pulling back the hand, would be transmitted via a motor nerve.

Neuropathy

When an individual suffers from a peripheral neuropathy, nerves of the PNS have been damaged. Nerve damage can arise from a number of causes, such as disease, physical injury, poisoning, or malnutrition. These agents may affect either afferent or efferent nerves. Depending on the cause of damage, the nerve cell axon, its protective myelin sheath, or both may be injured or destroyed.

There are hundreds of peripheral neuropathies. Reflecting the scope of PNS activity, symptoms may involve sensory, motor, or autonomic functions. To aid in diagnosis and treatment, the symptoms are classified into principal neuropathic syndromes based on the type of affected nerves and how long symptoms have been developing. Acute development refers to symptoms that have appeared within days, and subacute refers to those that have evolved over a number of weeks. Early chronic symptoms are those that take months to a few years to develop, and late chronic symptoms have been present for several years.

The classification system is composed of six principal neuropathic syndromes, which are subdivided into more specific categories. By narrowing down the possible diagnoses in this way, specific medical tests can be used more efficiently and effectively. The six syndromes and a fewa ssociated causes are listed below:

• Acute motor paralysis, accompanied by variable problems with sensory and autonomic functions. Neuropathies associated with this syndrome are mainly accompanied by motor nerve problems, but the sensory and autonomic nerves may also be involved. Associated disorders include Guillain-Barré syndrome, diphtheritic polyneuropathy, and porphyritic neuropathy.
• Subacute sensorimotor paralysis. The term sensorimotor refers to neuropathies that are mainly characterized by sensory symptoms, but also have a minor component of motor nerve problems. Poisoning with heavy metals (e.g., lead, mercury, and arsenic), chemicals, or drugs are linked to this syndrome. Diabetes, Lyme disease, and malnutrition are also possible causes.
• Chronic sensorimotor paralysis. Physical symptoms may resemble those in the above syndrome, but the time scale of symptom development is extended. This syndrome encompasses neuropathies arising from cancers, diabetes, leprosy, inherited neurologic and metabolic disorders, and hypothyroidism.
• Neuropathy associated with mitochondrial diseases. Mitochondria are organelles--structures within cells--responsible for handling a cell's energy requirements. If the mitochondria are damaged or destroyed, the cell's energy requirements are not met and it can die.
• Recurrent or relapsing polyneuropathy. This syndrome covers neuropathies that affect several nerves and may come and go, such as Guillain-Barré syndrome, porphyria, and chronic inflammatory demyelinating polyneuropathy.
• Mononeuropathy or plexopathy. Nerve damage associated with this syndrome is limited to a single nerve or a few closely associated nerves. Neuropathies related to physical injury to the nerve, such as carpal tunnel syndrome and sciatica, are included in this syndrome.

Causes & symptoms

Typical symptoms of neuropathy are related to the type of affected nerve. If a sensory nerve is damaged, common symptoms include numbness, tingling in the area, a prickling sensation, or pain. Pain associated with neuropathy can be quite intense and may be described as cutting, stabbing, crushing, or burning. In some cases, a nonpainful stimulus may be perceived as excruciating or pain may be felt even in the absence of a stimulus. Damage to a motor nerve is usually indicated by weakness in the affected area. If the problem with the motor nerve has continued over a length of time, muscle shrinkage (atrophy) or lack of muscle tone may be noticeable. Autonomic nerve damage is most noticeable when an individual stands upright and experiences problems such as light-headedness or changes in blood pressure. Other indicators of autonomic nerve damage are lack of sweat, tears, and saliva; constipation; urinary retention; and impotence. In some cases, heart beat irregularities and respiratory problems can develop.

Symptoms may appear over days, weeks, months, or years. Their duration and the ultimate outcome of the neuropathy are linked to the cause of the nerve damage. Potential causes include diseases, physical injuries, poisoning, and malnutrition or alcohol abuse. In some cases, neuropathy is not the primary disorder, but a symptom of an underlying disease.

Disease

Diseases that cause peripheral neuropathies may either be acquired or inherited; in some cases, it is difficult to make that distinction. The diabetes-peripheral neuropathy link has been well established. A typical pattern of diabetes-associated neuropathic symptoms includes sensory effects that first begin in the feet. The associated pain or pins-and-needles, burning, crawling, or prickling sensations form a typical "stocking" distribution in the feet and lower legs. Other diabetic neuropathies affect the autonomic nerves and have potentially fatal cardiovascular complications.

Several other metabolic diseases have a strong association with peripheral neuropathy. Uremia, or chronic kidney failure, carries a 10-90% risk of eventually developing neuropathy, and there may be an association between liver failure and peripheral neuropathy. Accumulation of lipids inside blood vessels (atherosclerosis) can choke-off blood supply to certain peripheral nerves. Without oxygen and nutrients, the nerves slowly die. Mild polyneuropathy may develop in persons with low thyroid hormone levels. Individuals with abnormally enlarged skeletal extremities (acromegaly), caused by an overabundance of growth hormone, may also develop mild polyneuropathy.

Neuropathy can also result from severe vasculitides, a group of disorders in which blood vessels are inflamed. When the blood vessels are inflamed or damaged, blood supply to the nerve can be affected, injuring the nerve.

Both viral and bacterial infections have been implicated in peripheral neuropathy. Leprosy is caused by the bacteria M. leprae, which directly attack sensory nerves. Other bacterial illness may set the stage for an immune-mediated attack on the nerves. For example, one theory about Guillain-Barré syndrome involves complications following infection with Campylobacter jejuni, a bacterium commonly associated with food poisoning. This bacterium carries a protein that closely resembles components of myelin. The immune system launches an attack against the bacteria; but, according to the theory, the immune system confuses the myelin with the bacteria in some cases and attacks the myelin sheath as well. The underlying cause of neuropathy associated with Lyme disease is unknown; the bacteria may either promote an immune-mediated attack on the nerve or inflict damage directly.

Infection with certain viruses is associated with extremely painful sensory neuropathies. A primary example of such a neuropathy is caused by shingles. After a case of chickenpox, the causative virus, varicella-zoster virus, becomes inactive in sensory nerves. Years later, the virus may be reactivated. Once reactivated, it attacks and destroys axons. Infection with HIV is also associated with peripheral neuropathy, but the type of neuropathy that develops can vary. Some HIV-linked neuropathies are noted for myelin destruction rather than axonal degradation. Also, HIV infection is frequently accompanied by other infections, both bacterial and viral, that are associated with neuropathy.

Several types of peripheral neuropathies are associated with inherited disorders. These inherited disorders may primarily involve the nervous system, or the effects on the nervous system may be secondary to an inherited metabolic disorder. Inherited neuropathies can fall into several of the principal syndromes, because symptoms may be sensory, motor, or autonomic. The inheritance patterns also vary, depending on the specific disorder. The development of inherited disorders is typically drawn out over several years and may herald a degenerative condition--that is, a condition that becomes progressively worse over time. Even among specific disorders, there may be a degree of variability in inheritance patterns and symptoms. For example, Charcot-Marie-Tooth disease is usually inherited as an autosomal dominant disorder, but it can be autosomal recessive or, in rare cases, linked to the X chromosome. Its estimated frequency is approximately one in 2,500 people. Age of onset and sensory nerve involvement can vary between cases. The main symptom is a degeneration of the motor nerves in legs and arms, and resultant muscle atrophy. Other inherited neuropathies have a distinctly metabolic component. For example, in familial amyloid polyneuropathies, protein components that make up the myelin are constructed and deposited incorrectly.

Physical injury

Accidental falls and mishaps during sports and recreational activities are common causes of physical injuries that can result in peripheral neuropathy. The common types of injuries in these situations occur from placing too much pressure on the nerve, exceeding the nerve's capacity to stretch, blocking adequate blood supply of oxygen and nutrients to the nerve, and tearing the nerve. Pain may not always be immediately noticeable, and obvious signs of damage may take a while to develop.

These injuries usually affect one nerve or a group of closely associated nerves. For example, a common injury encountered in contact sports such as football is the "burner," or "stinger," syndrome. Typically, a stinger is caused by overstretching the main nerves that span from the neck into the arm. Immediate symptoms are numbness, tingling, and pain that travels down the arm, lasting only a minute or two. A single incident of a stinger is not dangerous, but recurrences can eventually cause permanent motor and sensory loss.

Poisoning

The poisons, or toxins, that cause peripheral neuropathy include drugs, industrial chemicals, and environmental toxins. Neuropathy that is caused by drugs usually involves sensory nerves on both sides of the body, particularly in the hands and feet, and pain is a common symptom. Neuropathy is an unusual side effect of medications; therefore, most people can use these drugs safely. A few of the drugs that have been linked with peripheral neuropathy include metronidazole, an antibiotic; phenytoin, an anticonvulsant; and simvastatin, a cholesterol-lowering medication.

Certain industrial chemicals have been shown to be poisonous to nerves (neurotoxic) following work-related exposures. Chemicals such as acrylamide, allyl chloride, and carbon disulfide have all been strongly linked to development of peripheral neuropathy. Organic compounds, such as N-hexane and toluene, are also encountered in work-related settings, as well as in glue-sniffing and solvent abuse. Either route of exposure can produce severe sensorimotor neuropathy that develops rapidly.

Heavy metals are the third group of toxins that cause peripheral neuropathy. Lead, arsenic, thallium, and mercury usually are not toxic in their elemental form, but rather as components in organic or inorganic compounds. The types of metal-induced neuropathies vary widely. Arsenic poisoning may mimic Guillain-Barré syndrome; lead affects motor nerves more than sensory nerves; thallium produces painful sensorimotor neuropathy; and the effects of mercury are seen in both the CNS and PNS.

Malnutrition and alcohol abuse

Burning, stabbing pains and numbness in the feet, and sometimes in the hands, are distinguishing features of alcoholic neuropathy. The level of alcohol consumption associated with this variety of peripheral neuropathy has been estimated as approximately 3 liters of beer or 300 milliliters of liquor daily for 3 years. However, it is unclear whether alcohol alone is responsible for the neuropathic symptoms, because chronic alcoholism is strongly associated with malnutrition.

Malnutrition refers to an extreme lack of nutrients in the diet. It is unknown precisely which nutrient deficiencies cause peripheral neuropathies in alcoholics and famine and starvation victims, but it is suspected that the B vitamins have a significant role. For example, thiamine (vitamin B₁) deficiency is the cause of beriberi, a neuropathic disease characterized by heart failure and painful polyneuropathy of sensory nerves. Vitamin E deficiency seems to have a role in both CNS and PNS neuropathy.

Diagnosis

Clinical symptoms can indicate peripheral neuropathy, but an exact diagnosis requires a combination of medical history, medical tests, and possibly a process of exclusion. Certain symptoms can suggest a diagnosis, but more information is commonly needed. For example, painful, burning feet may be a symptom of alcohol abuse, diabetes, HIV infection, or an underlying malignant tumor, among other causes. Without further details, effective treatment would be difficult.

During a physical examination, an individual is asked to describe the symptoms very carefully. Detailed information about the location, nature, and duration of symptoms can help exclude some causes or even pinpoint the actual problem. The person's medical history may also provide clues as to the cause, because certain diseases and medications are linked to specific peripheral neuropathies. A medical history should also include information about diseases that run in the family, because some peripheral neuropathies are genetically linked. Information about hobbies, recreational activities, alcohol consumption, and work place activities can uncover possible injuries or exposures to poisonous substances.

The physical examination also includes blood tests, such as those that check levels of glucose and creatinine to detect diabetes and kidney problems, respectively. A blood count is also done to determine levels of different blood cell types. Iron, vitamin B₁₂ and other factors may be measured as well, to rule out malnutrition. More specific tests, such as an assay for heavy metals or poisonous substances, or tests to detect vasculitis, are not typically done unless there is reason to suspect a particular cause.

An individual with neuropathy may be sent to a doctor that specializes in nervous system disorders (neurologist). By considering the results of the physical examination and observations of the referring doctor, the neurologist may be able to narrow down the possible diagnoses. Additional tests, such as nerve conduction studies and electromyography, which tests muscle reactions, can confirm that nerve damage has occurred and may also be able to indicate the nature of the damage. For example, some neuropathies are characterized by destruction of the myelin. This type of damage is shown by slowed nerve conduction. If the axon itself has suffered damage, the nerve conduction may be slowed, but it will also be diminished in strength. Electromyography adds further information by measuring nerve conduction and muscle response, which determines whether the symptoms are due to a neuropathy or to a muscle disorder.

In approximately 10% of peripheral neuropathy cases, a nerve biopsy may be helpful. In this test, a small part of the nerve is surgically removed and examined under a microscope. This procedure is usually the most helpful in confirming a suspected diagnosis, rather than as a diagnostic procedure by itself.

Treatment

Treat the cause

Attacking the underlying cause of the neuropathy can prevent further nerve damage and may allow for a better recovery. For example, in cases of bacterial infection such as leprosy or Lyme disease, antibiotics may be given to destroy the infectious bacteria. Viral infections are more difficult to treat, because antibiotics are not effective against them. Neuropathies associated with drugs, chemicals, and toxins are treated in part by stopping exposure to the damaging agent. Chemicals such as ethylenediaminetetraacetic acid (EDTA) are used to help the body concentrate and excrete some toxins. Diabetic neuropathies may be treated by gaining better control of blood sugar levels, but chronic kidney failure may require dialysis or even kidney transplant to prevent or reduce nerve damage. In some cases, such as compression injury or tumors, surgery may be considered to relieve pressure on a nerve.

In a crisis situation, as in the onset of Guillain-Barré syndrome, plasma exchange, intravenous immunoglobulin, and steroids may be given. Intubation, in which a tube is inserted into the trachea to maintain an open airway, and ventilation may be required to support the respiratory system. Treatment may focus more on symptom management than on combating the underlying cause, at least until a definitive diagnosis has been made.

Supportive care and long-term therapy

Some peripheral neuropathies cannot be resolved or require time for resolution. In these cases, long-term monitoring and supportive care is necessary. Medical tests may be repeated to chart the progress of the neuropathy. If autonomic nerve involvement is a concern, regular monitoring of the cardiovascular system may be carried out.

Because pain is associated with many of the neuropathies, a pain management plan may need to be mapped out, especially if the pain becomes chronic. As in any chronic disease, narcotics are best avoided. Agents that may be helpful in neuropathic pain include amitriptyline, carbamazepine, and capsaicin cream. Physical therapy and physician-directed exercises can help maintain or improve function. In cases in which motor nerves are affected, braces and other supportive equipment can aid an individual's ability to move about.

Prognosis

The outcome for peripheral neuropathy depends heavily on the cause. Peripheral neuropathy ranges from a reversible problem to a potentially fatal complication. In the best cases, a damaged nerve regenerates. Nerve cells cannot be replaced if they are killed, but they are capable of recovering from damage. The extent of recovery is tied to the extent of the damage and a person's age and general health status. Recovery can take weeks to years, because neurons grow very slowly. Full recovery may not be possible and it may also not be possible to determine the prognosis at the outset.

If the neuropathy is a degenerative condition, such as Charcot-Marie-Tooth disease, an individual's condition will become worse. There may be periods of time when the disease seems to reach a plateau, but cures have not yet been discovered for many of these degenerative diseases. Therefore, continued symptoms, potentially worsening to disabilities are to be expected.

A few peripheral neuropathies are eventually fatal. Fatalities have been associated with some cases of diphtheria, botulism, and others. Some diseases associated with neuropathy may also be fatal, but the ultimate cause of death is not necessarily related to the neuropathy, such as with cancer.

Prevention

Peripheral neuropathies are preventable only to the extent that the underlying causes are preventable. Steps that a person can take to prevent potential problems include vaccines against diseases that cause neuropathy, such as polio and diphtheria. Treatment for physical injuries in a timely manner can help prevent permanent or worsening damage to nerves. Precautions when using certain chemicals and drugs are well advised in order to prevent exposure to neurotoxic agents. Control of chronic diseases such as diabetes may also reduce the chances of developing peripheral neuropathy.

Although not a preventive measure, genetic screening can serve as an early warning for potential problems. Genetic screening is available for some inherited conditions, but not all. In some cases, presence of a particular gene may not mean that a person will necessarily develop the disease, because there may be environmental and other components involved.

Key Terms

Afferent

Refers to peripheral nerves that transmit signals to the spinal cord and the brain. These nerves carry out sensory function.

Autonomic

Refers to peripheral nerves that carry signals from the brain and that control involuntary actions in the body, such as the beating of the heart.

Autosomal dominant or autosomal recessive

Refers to the inheritance pattern of a gene on a chromosome other than X or Y. Genes are inherited in pairs--one gene from each parent. However, the inheritance may not be equal, and one gene may overshadow the other in determining the final form of the encoded characteristic. The gene that overshadows the other is called the dominant gene; the overshadowed gene is the recessive one.

Axon

A long, threadlike projection that is part of a nerve cell.

Central nervous system (CNS)

The part of the nervous system that includes the brain and the spinal cord.

Efferent

Refers to peripheral nerves that carry signals away from the brain and spinal cord. These nerves carry out motor and autonomic functions.

Electromyography

A medical test that assesses nerve signals and muscle reactions. It can determine if there is a disorder with the nerve or if the muscle is not capable of responding.

Inheritance pattern

Refers to dominant or recessive inheritance.

Motor

Refers to peripheral nerves that control voluntary movements, such as moving the arms and legs.

Myelin

The protective coating on axons.

Nerve biopsy

A medical test in which a small portion of a damaged nerve is surgically removed and examined under a microscope.

Nerve conduction

The speed and strength of a signal being transmitted by nerve cells. Testing these factors can reveal the nature of nerve injury, such as damage to nerve cells or to the protective myelin sheath.

Neurotransmitter

Chemicals within the nervous system that transmit information from or between nerve cells.

Peripheral nervous system (PNS)

Nerves that are outside of the brain and spinal cord.

Sensory

Refers to peripheral nerves that transmit information from the senses to the brain.

Further Reading

For Your Information

Books

• Adams, Raymond D., Maurice Victor, and Allan H. Ropper. "Diseases of the Peripheral Nerves." In Principles of Neurology, 6th Edition. New York: McGraw-Hill, 1997.

  Periodicals

• Chalk, Colin H. "Acquired Peripheral Neuropathy." Neurologic Clinics 15, no. 3 (August 1997): 501.
• Feinberg, Joseph H., Scott F. Nalder, and Lisa S. Krivickas. "Peripheral Nerve Injuries in the Athlete." Sports Medicine 24, no. 6 (December 1997): 385.
• Morgenlander, Joel C. "Recognizing Peripheral Neuropathy: How to Read the Clues to an Underlying Cause." Postgraduate Medicine 102, no. 3 (September 1997): 71.
• Pascuzzi, Robert M. and James D. Fleck. "Acute Peripheral Neuropathy in Adults." Neurologic Clinics 15, no. 3 (August 1997): 529.
• Perkins, A. Thomas, and Joel C. Morgenlander. "Endocrinologic Causes of Peripheral Neuropathy." Postgraduate Medicine 102, no. 3 (September 1997): 81.

  Organizations

• American Diabetes Association. 1660 Duke St., Alexandria, VA 22314. (800) DIABETES. http://www.diabetes.org.
• Charcot-Marie-Tooth Association. Crozer Mills Enterprise Center, 601 Upland Ave., Upland, PA 19015. (800) 606-2682. http://www.charcot-marie-tooth.org.
• Guillain-Barré Syndrome Foundation International. P.O. Box 262, Wynnewood, PA 19096. (610) 667-0131. http://www.webmast.com/gbs.
• The Myelin Project. 1747 Pennsylvania Ave., NW, Ste. 950, Washington, DC 20006. (202) 452-8994. http://www.myelin.org.
• The Neuropathy Association. 60 E. 42nd St., Suite 942, New York, NY 10165. (800) 247-6968. http://www.neuropathy.org/association.html.

Gale Encyclopedia of Medicine. Gale Research, 1999.