What is peripheral neuropathy?
Peripheral neuropathy refers to the many conditions that involve damage to the peripheral nervous system, which is a vast communications network that sends signals between the central nervous system (the brain and spinal cord) and all other parts of the body.
Peripheral nerves send many types of sensory information to the central nervous system (CNS), such as the message that your feet are cold. They also carry signals from the CNS to the rest of the body. Best known are the signals to the muscles that tell them to contract, which is how we move, but there are different types of signals that help control everything from our heart and blood vessels, digestion, urination and sexual function to our bones and immune system.
More than 20 million people in the U.S. are estimated to have some form of peripheral neuropathy, but this figure may be significantly higher as not all people with symptoms of neuropathy are tested for the disease and tests currently do not look for all forms of neuropathy.
Nerve signal interruption
The peripheral nerves are like cables that connect different parts of a computer or connect to the Internet. When they malfunction, complex functions can grind to a halt.
Nerve signaling in neuropathy is disrupted in three ways:
- Loss of signals normally sent
- Inappropriate signaling when there shouldn't be any
- Errors that distort the messages being sent
Some forms of neuropathy involve damage to only one nerve (mononeuropathy). Neuropathy affecting two or more nerves in different areas is called multiple mononeuropathy or mononeuropathy multiplex. More often, many or most of the nerves are affected (polyneuropathy).
Classifying the nerves and peripheral neuropathies
More than 100 types of peripheral neuropathy have been identified, each with its own symptoms and prognosis. Symptoms vary depending on the type of nerves—motor, sensory, or autonomic—that are damaged.
- Motor nerves control the movement of all muscles under conscious control, such as those used for walking, grasping things, or talking
- Sensory nerves transmit information such as the feeling of a light touch, temperature, or pain from a cut
- Autonomic nerves control organs to regulate activities that people do not control consciously, such as breathing, digesting food, and heart and gland functions
Most neuropathies affect all three types of nerve fibers to varying degrees; others primarily affect one or two types. Doctors use terms such as predominantly motor neuropathy, predominantly sensory neuropathy, sensory-motor neuropathy, or autonomic neuropathy to describe different conditions.
About 75 percent of polyneuropathies are “length-dependent,” meaning the farthest nerve endings in the feet are where the symptoms develop first or are worse. In severe cases, these neuropathies can spread upwards toward the central parts of the body. In non-length dependent polyneuropathies, the symptoms can start around the torso, or are patchy.
Symptoms can range from mild to disabling, but are rarely life-threatening. The symptoms depend on the type of nerve fibers affected and the type and severity of damage. Symptoms may develop over days, weeks, or years. In some cases, symptoms improve on their own and may not require advanced care. Unlike nerve cells in the CNS, peripheral nerve cells continue to grow throughout life.
Symptoms are related to the type of nerves affected.
Motor nerve damage is most commonly associated with muscle weakness. Other symptoms include:
- Painful cramps
- Fasciculations (uncontrolled muscle twitching visible under the skin)
- Muscle shrinking
Sensory nerve damage causes various symptoms because sensory nerves have a broad range of functions.
- Damage to large sensory fibers harms your ability to feel vibrations and touch, especially in the hands and feet. You may feel as if you are wearing gloves and stockings when you are not. This damage may contribute to the loss of reflexes (as can motor nerve damage). Loss of position sense often makes people unable to coordinate complex movements like walking, fastening buttons, or maintaining their balance when their eyes are shut.
- The “small fibers” without myelin sheaths (protective coating) include fiber extensions called axons that transmit pain and temperature sensations. Small-fiber polyneuropathy can interfere with your ability to feel pain or changes in temperature. It is often difficult for medical caregivers to control, which can seriously affect your emotional well-being and overall quality of life. Neuropathic pain is sometimes worse at night, disrupting sleep. It can be caused by pain receptors firing spontaneously without any known trigger, or by difficulties with signal processing in the spinal cord that may cause severe pain (allodynia) from a light touch that is normally painless. For example, you might experience pain from the touch of your bedsheets, even when draped lightly over your body.
Autonomic nerve damage affects the axons in small-fiber neuropathies. Common symptoms include:
- Excess sweating
- Heat intolerance
- Inability to expand and contract the small blood vessels that regulate blood pressure
- Gastrointestinal symptoms
- Problems eating or swallowing if the nerves that control the esophagus are affected (although this is rare)
Types of peripheral neuropathy
There are several types of peripheral neuropathies, including
- Diabetic neuropathy (a consequence of diabetes)
- Guillain-Barré syndrome, which occurs when the body's immune system mistakenly attacks the nerves in the body
- Carpal tunnel syndrome, which affects the hand and the wrist and is caused by pressure on the median nerve that runs from the forearm into the hand
- Meralgia paresthetica, which causes numbness and tingling on one thigh
- Complex regional pain syndrome, involving small-nerve fiber damage that causes excessive and prolonged pain in an affected arm or leg
Who is more likely to get peripheral neuropathy?
Most instances of neuropathy are either acquired, meaning the neuropathy or the inevitability of getting it isn't present from the beginning of life, or genetic. Acquired neuropathies are either symptomatic (the result of another disorder or condition) or idiopathic (meaning it has no known cause).
Acquired peripheral neuropathy causes include:
- Physical injury (trauma), such as injury from automobile accidents, falls, sports, and medical procedures that can stretch, crush, or compress nerves, or detach them from the spinal cord. Less severe traumas also can cause serious nerve damage. Broken or dislocated bones can exert damaging pressure on neighboring nerves and slipped disks between vertebrae can compress nerve fibers where they emerge from the spinal cord. Arthritis, prolonged pressure on a nerve (such as by a cast) or repetitive, forceful activities can cause ligaments or tendons to swell, which narrows slender nerve pathways. Carpal tunnel syndrome is a common type of neuropathy from a compressed nerve at the wrist. In some cases, there are underlying medical causes (such as diabetes) that prevent the nerves from tolerating the stresses of everyday living.
- Diabetes is the leading cause of polyneuropathy in the U.S. About 60 to 70 percent of people with diabetes have mild to severe forms of nerve problems that can cause numb, tingling, or burning feet, one-sided bands or pain, and numbness and weakness on the trunk or pelvis.
- Vascular and blood problems that decrease oxygen supply to the peripheral nerves can lead to nerve tissue damage. Diabetes, smoking, and narrowing of the arteries from high blood pressure or atherosclerosis (fatty deposits on the inside of blood vessel walls) can lead to neuropathy. Blood vessel wall thickening and scarring from inflammation of blood vessels can impede blood flow and cause patchy nerve damage in which isolated nerves in different areas are damaged.
- Systemic (body-wide) autoimmune diseases, in which the immune system mistakenly attacks a number of the body's own tissues, can directly target nerves or cause problems when surrounding tissues compress or entrap nerves.
- Autoimmune diseases that exclusively attack nerves are often triggered by recent infections. They can develop quickly or slowly, while others become chronic and fluctuate in severity. Damage to the motor fibers that go to the muscle includes visible weakness and muscle shrinking, which can produce chronic pain and autonomic symptoms.
- Hormonal imbalances can disturb normal metabolic processes, leading to swollen tissues that can press on peripheral nerves.
- Kidney and liver disorders can lead to high amounts of toxic substances in the blood that can damage nerve tissue. Most individuals on dialysis because of kidney failure develop varying levels of polyneuropathy.
- Nutritional or vitamin imbalances, alcoholism, and exposure to toxins can damage nerves and cause neuropathy. Vitamin B12 deficiency and excess vitamin B6 are the best-known vitamin-related causes. Several medications have been shown to occasionally cause neuropathy.
- Certain cancers and benign tumors cause neuropathy in various ways. Tumors sometimes infiltrate or press on nerve fibers. Paraneoplastic syndromes, a group of rare degenerative disorders that are triggered by the immune system's response to a cancer, can indirectly cause widespread nerve damage.
- Chemotherapy drugs used to treat cancer cause polyneuropathy in an estimated 30 to 40 percent of people. However, not all chemotherapy drugs cause neuropathy and not everyone receiving chemotherapy will develop neuropathy. Chemotherapy-induced peripheral neuropathy may continue long after stopping chemotherapy. Radiation therapy also can cause nerve damage, sometimes starting months or years later.
- Infections can attack nerve tissues and cause neuropathy. Viruses such as varicella-zoster virus (which causes chickenpox and shingles), West Nile virus, cytomegalovirus, and herpes simplex target sensory fibers, causing attacks of sharp, lightning-like pain. Lyme disease, carried by tick bites, can cause a range of neuropathic symptoms, often within a few weeks of being infected. The human immunodeficiency virus (HIV), which causes AIDS, can extensively damage the central and peripheral nervous systems. An estimated 30 percent of people who are HIV-positive develop peripheral neuropathy; 20 percent develop distal (away from the center of the body) neuropathic pain.
Genetically caused polyneuropathies are rare. Genetic mutations can either be inherited or arise "de novo," meaning they are completely new to an individual and are not present in either parent. Some genetic mutations lead to mild neuropathies with symptoms that begin in early adulthood and result in little, if any, significant impairment. More severe hereditary neuropathies often appear in infancy or childhood. The small-fiber neuropathies that present with pain, itch, and autonomic symptoms can be genetic.
How is peripheral neuropathy diagnosed and treated?
Diagnosing peripheral neuropathy
The variability of symptoms that neuropathies can cause often makes diagnosis difficult. A diagnosis of neuropathy can include:
- Medical history—A doctor will ask questions about your symptoms and any triggers or relieving factors throughout the day, work environment, social habits, exposure to toxins, alcohol use, risk of infectious diseases, and family history of neurological diseases.
- Physical and neurological exams—A doctor will look for any evidence of body-wide diseases that can cause nerve damage, such as diabetes. A neurological exam includes tests that may identify the cause of the neuropathic disorder as well as the extent and type of nerve damage.
- Body fluid tests—Various blood tests can detect diabetes, vitamin deficiencies, liver or kidney dysfunction, other metabolic disorders, infections, and signs of abnormal immune system activity. Less often, other body fluids are tested for abnormal proteins or the abnormal presence of immune cells or proteins associated with some immune-mediated neuropathies.
- Genetic tests—Gene tests are available for some inherited neuropathies.
Additional tests may be ordered to help determine the nature and extent of the neuropathy.
Physiologic tests of nerve function
- Nerve conduction velocity (NCV) tests measure signal strength and speed along specific large motor and sensory nerves. They can reveal nerves and nerve types affected and whether symptoms are caused by degeneration of the myelin sheath or the axon. During this test, a probe electrically stimulates a nerve fiber, which responds by generating its own electrical impulse. An electrode placed further along the nerve's pathway measures the speed of signal transmission along the axon. Slow transmission rates tend to indicate damage to the myelin sheath, while a reduction in the strength of impulses at normal speeds is a sign of axonal degeneration. Inability to elicit signals can indicate severe problems with either.
- Electromyography (EMG) involves inserting fine needles into specific muscles to record their electrical activity at rest and during contraction. EMG tests irritability and responsiveness, detects abnormal muscular electrical activity in motor neuropathy, and can help differentiate between muscle and nerve disorders.
Neuropathology tests of nerve appearance
- Nerve biopsy involves removing and examining a sample of nerve tissue, usually a sensory nerve from the lower leg (sural nerve biopsy). Although a nerve biopsy can provide the most detailed information about the exact types of nerve cells and cell parts affected, it can further damage the nerve and leave chronic neuropathic pain and sensory loss.
- Neurodiagnostic skin biopsy allows specialists to examine nerve fiber endings following removal of a tiny piece of skin (usually three millimeters in diameter) under local anesthesia. Skin biopsies have become the standard for diagnosing small fiber neuropathies that don't affect standard nerve conduction studies and electromyography.
- Several different types of autonomic testing can evaluate peripheral neuropathies, one of which is a QSART test that measures the ability to sweat in several sites in the arm and leg. Abnormalities in QSART are associated with small fiber polyneuropathies
Radiology imaging tests
- Magnetic resonance imaging (MRI) of the spine can reveal nerve root compression (pinched nerve), tumors, or other internal problems. MRI of the nerve (neurography) can show nerve compression.
- Computed tomography (CT) scans of the back can show herniated disks, spinal stenosis (narrowing of the spinal canal), tumors, bone and vascular irregularities that may affect nerves.
Muscle and nerve ultrasound is a noninvasive experimental technique for imaging nerves and muscles for injury such as a severed nerve or a compressed nerve. Ultrasound imaging of the muscles can detect abnormalities that may be related to a muscle or nerve disorder. Certain inherited muscle disorders have characteristic patterns on muscle ultrasound.
Treating peripheral neuropathy
Treatments depend entirely on the type of nerve damage, symptoms, and location. Your doctor will explain how nerve damage is causing your specific symptoms and how to minimize and manage them. You may be able to reduce your medication dose or manage your neuropathy without medications. Definitive treatment can allow for functional recovery over time, as long as the nerve cell itself has not died.
Correcting underlying causes can result in the neuropathy resolving on its own as the nerves recover or regenerate. Nerve health and resistance can be improved by healthy lifestyle habits such as maintaining optimal weight, avoiding toxic exposures, eating a balanced diet, and correcting vitamin deficiencies.
Smoking constricts the blood vessels that supply nutrients to the peripheral nerves and can worsen neuropathic symptoms. Exercise can deliver more blood, oxygen, and nutrients to far-off nerve endings, improve muscle strength, and limit muscle atrophy. Self-care skills in people with diabetes and others who have an impaired ability to feel pain can alleviate symptoms and often create conditions that encourage nerve regeneration. Strict control of blood glucose levels can reduce neuropathic symptoms and help people with diabetic neuropathy avoid further nerve damage.
Inflammatory and autoimmune conditions leading to neuropathy can be controlled using immunosuppressive drugs such as prednisone, cyclosporine, or azathioprine. Plasmapheresis—a procedure in which blood is removed, cleansed of immune system cells and antibodies, and then returned to the body—can help reduce inflammation or suppress immune system activity. Agents such as rituximab that target specific inflammatory cells, large intravenously administered doses of immunoglobulins, and antibodies that alter the immune system, also can suppress abnormal immune system activity.
- For motor symptoms, mechanical aids such as hand or foot braces can help reduce physical disability and pain. Orthopedic shoes can improve gait disturbances and help prevent foot injuries. Splints for carpal tunnel problems can help position the wrist to reduce pressure of the compressed nerve and allow it to heal. Some people with severe weakness benefit from tendon transfers or bone fusions to hold their limbs in better position, or to release a nerve compression.
- Autonomic symptoms require detailed management depending on what they are. For example, people with orthostatic hypotension (significant drop in blood pressure when standing quickly) can learn to prevent drops by standing up slowly and taking medications to improve blood pressure swings. Many people use complementary methods and techniques such as acupuncture, massage, herbal medications, and cognitive behavioral or other psychotherapy approaches to cope with neuropathic pain.
- Sensory symptoms, such as neuropathic pain or itching caused by injury to a nerve or nerves, are more difficult to control without medication. Behavioral strategies can help some people to cope with chronic pain as well as depression and anxiety that many may feel following nerve injury.
Medications recommended for chronic neuropathic pain are also used for other medical conditions. Among the most effective are a class of drugs first marketed to treat depression. Nortriptyline and newer serotonin-norepinephrine reuptake inhibitors such as duloxetine hydrochloride modulate pain by increasing the brain's ability to inhibit incoming pain signals.
Another class of medications that quiets nerve cell electrical signaling is also used for epilepsy. Common drugs include gabapentin, pregabalin, and less often topiramate and lamotrigine. Carbamazepine and oxcarbazepine are particularly effective for trigeminal neuralgia, a focal neuropathy of the face.
Local anesthetics and related drugs that block nerve conduction may help when other medications are ineffective or poorly tolerated. Medications put on the skin (topically administered) are generally appealing because they stay near the skin and have fewer unwanted side effects. Lidocaine patches or creams applied to the skin can be helpful for small painful areas, such as localized chronic pain from mononeuropathies such as shingles. Another topical cream is capsaicin, a substance found in hot peppers that can desensitize peripheral pain nerve endings. Doctor-applied patches that contain higher concentrations of capsaicin offer longer term relief from neuropathic pain and itching, but they worsen small-fiber nerve damage. Weak over-the-counter formulations also are available. Lidocaine or longer acting bupivacaine are sometimes given using implanted pumps that deliver tiny quantities to the fluid that bathes the spinal cord, where they can quiet excess firing of pain cells without affecting the rest of the body. Other drugs treat chronic painful neuropathies by calming excess signaling.
Narcotics (opioids) can be used for pain that doesn't respond to other pain-control medications and if disease-improving treatments aren't fully effective. Because pain relievers that contain opioids can lead to dependence and addiction, their use must be closely monitored by a physician. One of the newest drugs approved for treating diabetic neuropathy is tapentadol, which has both opioid activity and norepinephrine-reuptake inhibition activity of an antidepressant.
Surgery is the recommended treatment for some types of neuropathies. Protruding disks (pinched nerve) in the back or neck that compress nerve roots are commonly treated surgically to free the affected nerve root and allow it to heal. Injuries to a single nerve (mononeuropathy) caused by compression, entrapment, or rarely tumors or infections may require surgery to release the nerve compression. Polyneuropathies that involve more scattered nerve damage, such as diabetic neuropathy, are not helped by surgical intervention. Surgeries or interventional procedures that attempt to reduce pain by cutting or injuring nerves are not often effective as they worsen nerve damage and the parts of the peripheral and central nervous system above the cut often continue to generate pain signals (“phantom pain”). More sophisticated and less damaging procedures such as electrically stimulating remaining peripheral nerve fibers or pain-processing areas of the spinal cord or brain have largely replaced these surgeries.
Transcutaneous electrical nerve stimulation (TENS) is a noninvasive intervention used for pain relief in a range of conditions. TENS involves attaching electrodes to the skin at the site of pain or near associated nerves and then administering a gentle electrical current. Although data from controlled clinical trials are not available to broadly establish its efficacy for peripheral neuropathies, in some studies TENS has been shown to improve neuropathic symptoms associated with diabetes.
The best treatment is prevention, and strategies for reducing injuries are highly effective and well tested. Since medical procedures ranging from casting fractures to injuries from needles and surgery are another cause, unnecessary procedures should be avoided.
The new adjuvanted vaccine (an adjuvant is an ingredient used in some vaccines that helps create a stronger immune response in people receiving the vaccine) against shingles prevents more than 95 percent of cases and is widely recommended for people over 50, including those who have had previous shingles or vaccination with the older, less effective vaccine.
Diabetes and some other diseases are common preventable causes of neuropathy. People with neuropathy should ask their doctors to minimize use of medications that are known to cause or worsen neuropathy where alternatives exist. Some families with very severe genetic neuropathies use in vitro fertilization (IVF) to prevent transmission to future generations.
What are the latest updates on peripheral neuropathy?
The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is a component of the National Institutes of Health (NIH), a leading supporter of biomedical research in the world.
NINDS-funded research ranges from clinical studies of the genetics and the natural history of hereditary neuropathies to discoveries of new cause and treatments for neuropathy, to basic science investigations of the biological mechanisms responsible for chronic neuropathic pain. Together, these diverse research areas will advance the development of new therapeutic and preventive strategies for peripheral neuropathies. Understanding the causes of neuropathy provides the foundation for finding effective prevention and treatment strategies.
Genetic mutations have been identified in more than 80 distinct hereditary neuropathies. NINDS supports studies to understand the disease mechanisms of these conditions and to identify other genetic defects that may play roles in causing or modifying the course of disease. The Inherited Neuropathies Consortium (INC)—a group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research in Charcot-Marie-Tooth disease and improving the care of people with the disease—is working to characterize the natural history of several different forms of neuropathy and to identify genes that modify clinical features in these disorders. Knowing which genes are mutated, and what their normal function is, allows precise diagnosis and leads to new therapies that can prevent or reduce nerve damage. INC is also developing and testing biomarkers (signs that can indicate the diagnosis or progression of a disease) and clinical outcome measures that will be needed in future clinical trials to determine whether individuals respond to candidate treatments.
Rapid communication between the peripheral nervous system and the central nervous system often depends on myelination, a process through which special cells called Schwann cells create an insulating coating around axons. Several NINDS-funded studies focus on understanding how myelin protein and membrane production and maintenance in Schwann cells is regulated and how mutations in genes involved in these processes cause peripheral neuropathies. Schwann cells play a critical role in the regeneration of nerve cell axons in the peripheral nervous system. By better understanding myelination and Schwann cell function, researchers hope to find targets for new therapies to treat or prevent nerve damage associated with neuropathy.
In inflammatory peripheral neuropathies such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP), the body's immune system mistakenly attacks peripheral nerves, damaging myelin and weakening signaling along affected nerves. NINDS-supported researchers hope to better understand how antibodies to cell membrane components cause peripheral nerve damage and how the effects of these antibodies can be blocked. Researchers are also studying how mutations in the Autoimmune Regulator (AIRE) gene in a mouse model of CIDP cause the immune system to attack peripheral nerves. NINDS research has helped discover that some types of small-fiber polyneuropathy appear to be immune-caused, particularly in women and children.
NINDS-supported researchers are also exploring the use of tissue engineered from the cells of humans with peripheral neuropathy as models to identify specific defects in the transport of cellular components along axons and the interactions of nerves with muscles. Such tissue engineering approaches may eventually lead to new therapeutics for peripheral neuropathies.
In addition to efforts to treat or prevent underlying nerve damage, other NINDS-supported studies are informing new strategies for relieving neuropathic pain, fatigue, and other neuropathy symptoms. Researchers are investigating the pathways that carry pain signals to the brain and are working to identify substances that will block this signaling.
For research articles and summaries on peripheral neuropathy, search PubMed, which contains citations from medical journals and other sites.
How can I or my loved one help improve care for people with peripheral neuropathy?
Consider participating in a clinical trial so clinicians and scientists can learn more about peripheral neuropathy and other nerve disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.
All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.
For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with peripheral neuropathy at Clinicaltrials.gov, a database of current and past trials, some of which have research results.
Where can I find more information about peripheral neuropathy?
Information and resources on peripheral neuropathy and nerve disease are available from the following organizations:
Hereditary Neuropathy Foundation
Neuropathy Commons at Mass General Brigham Nerve Unit
National Diabetes Information Clearinghouse (NDIC)