Distal Neuropathies

When it comes to identifying types of pain, there are two types: acute and chronic. Acute pain comes on quickly, can be severe but only lasts a relatively short time. It is typically experienced after an injury or trauma, and self-resolves.

Unlike acute pain, chronic pain is pain that lasts for a long time, and doesn't seem to get better or go away. This time period can vary but is typically defined as a three- to six-month period after symptoms begin. Chronic pain is often a debilitating symptom of many diseases and is considered a disease itself when it persists beyond recovery from an injury or illness. Chronic pain is a frequent component of many neurological disorders.

Pain warns you that something is not quite right in your body and can cause you to take certain actions and avoid others. Pain can significantly impact your quality of life—by adversely affecting your physical and emotional well-being; upsetting relationships with family, coworkers and friends; and limiting your mobility and participation in daily activities.

Hundreds of pain syndromes or disorders make up the spectrum of pain. One cause of pain are distal neuropathies, which are progressive disorders affecting nerve cells often resulting in cramps, muscle weakness and movement. The main types of distal neuropathies are diabetic neuropathy, B12 deficiency, chemotherapy-induced peripheral neuropathy (CIPN) and immune-mediated peripheral neuropathy (IMPN).

Diabetic neuropathy is nerve damage that can occur in people with diabetes. Over time, high blood glucose levels, also called blood sugar, and high levels of fats, such as triglycerides, in the blood from diabetes can damage your nerves. Symptoms depend on which type of diabetic neuropathy you have. The four types of diabetic neuropathies are peripheral neuropathy, autonomic neuropathy, focal neuropathy and proximal neuropathy.

Vitamin B12 is a vital nutrient that keeps your blood and nerve cells healthy. B12 deficiency is clinically associated with neurological disorders, such as dementia, cognitive impairment and depression. B12 deficiency may cause demyelination of nerves (damage to the nerve’s insulating layer or the cells that form them), in the peripheral and central nervous system and has been associated with peripheral neuropathy, loss of sensation in peripheral nerves, and weakness in lower extremities in older adults. Vitamin B12 is associated with both sensory and motor peripheral nerve function.

B12 deficiency is also associated with peripheral neuropathies, resulting in nerve damage—particularly to sensory and motor fibers in the nerves, affecting both sensory and motor function.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by drugs used in cancer treatment and their effects on the nervous system. CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers to prevent and treat symptoms.

Immune-mediated peripheral neuropathy (IMPN) is a group of peripheral nerve disorders caused by immune-mediated response to antigens in the peripheral nerves. There are two major groupings of IMPNs: Acute immune-mediated neuropathy (such as Guillain-Barré syndrome) and chronic immune-mediated polyneuropathy.

The most common immune-mediated neuropathy is Guillain-Barré syndrome, a rare neurological disorder in which your immune system mistakenly attacks part of the peripheral nervous system—the network of nerves located outside of the brain and spinal cord. GBS can range from a very mild case with brief weakness to nearly devastating paralysis, leaving you unable to breathe independently.

Diabetic neuropathy is nerve damage that is caused by diabetes. Over time, high blood glucose levels, also called blood sugar, and high levels of fats, such as triglycerides, in the blood from diabetes can damage your nerves. High blood glucose levels can also damage the small blood vessels that nourish your nerves with oxygen and nutrients. Without enough oxygen and nutrients, your nerves cannot function well.

Deficiency in B12 is typically related to diet. Those who eat meat, fish and dairy products usually have healthy amounts of vitamin B12, but impaired vitamin absorption, autoimmune metaplastic atrophic gastritis (an inherited autoimmune disease that attacks parietal cells) and age-related low levels of stomach acid (impairing food digestion) can cause a deficiency.

Additionally, gastritis (inflammation of the stomach lining), digestive diseases (celiac and Crohn’s disease) and genetic disorders like transcobalamin II deficiency contribute to B12 deficiencies.

Cancer treatments like chemotherapy can cause nerve damage to the brain and spine’s peripheral nerves that control the bladder and bowels, and movement of the arms and legs.

IMPNs are commonly caused by the immune system’s response to antigens in the peripheral nerves. The most common among immune-mediated neuropathies is Guillain-Barré syndrome (GBS). The exact cause of GBS isn't known. Researchers don't know why it strikes some people and not others.

What they do know is that the affected person's immune system begins to attack the body itself. It may be that this immune attack starts as a fight against an infection and that some chemicals on infecting bacteria and viruses resemble those on nerve cells, which, in turn, also become targets of attack. Since the body's own immune system does the damage, GBS is called an autoimmune disease (“auto” meaning “self”). Normally the immune system uses antibodies (molecules produced in an immune response) and special white blood cells to protect us by attacking infecting microorganisms (bacteria and viruses). In Guillain-Barré syndrome, however, the immune system mistakenly attacks the healthy nerves.

Risk factors for diabetic neuropathies are the duration of diabetes, age, blood sugar levels, diabetic retinopathy (growth of abnormal blood vessels in the retina), smoking and body mass index (BMI).

Although different types of diabetic neuropathy can affect people who have diabetes, research suggests that up to one-half of people with diabetes have peripheral neuropathy. More than 30 percent of people with diabetes have autonomic neuropathy.

Risk factors for B12 deficiency and its resultant anemia include family history, age and some medicines. Additionally strict vegetarian and vegan diets result in low levels of B12. Those diagnosed with Crohn’s disease, autoimmune diseases and HIV also are at risk for low B12 absorption.

Certain drugs used in chemotherapy such as oxaliplatin, taxanes, vinca alkaloids and myeloma treatments can increase risk of developing CIPN. Risks increase with higher doses and the number of courses. Older patients and those with diabetes or vitamin deficiencies are more likely to develop CIPN. Some studies show that risk is reduced with a healthy, vitamin-rich diet, regular exercise, and abstaining from alcohol.

Many IMPNs have autoimmune disorders as increased risk factors, including Sjögren’s syndrome, lupus and rheumatoid arthritis. Additionally, connections between infections and influenza-A and Zika virus have been observed, as have certain cancer treatments and Guillain-Barré syndrome.

The most commonly known immune-mediated neuropathy is Guillain-Barré syndrome (GBS). GBS can affect anyone. It can strike at any age (although it is more frequent in adults and older people) and both sexes are equally prone to the disorder. GBS is estimated to affect about one person in 100,000 each year. It is not contagious or inherited.

Most GBS cases usually start a few days or weeks following a respiratory or gastrointestinal viral infection. Occasionally surgery will trigger the syndrome. In rare cases vaccinations may increase the risk of GBS (there have been reports of a few people who received a vaccine for the SARS-CoV-2 virus developing GBS, but the chance of this occurring is very low). Some countries worldwide reported an increased incidence of GBS following infection with the Zika virus.

To prevent diabetic neuropathy, it is important to manage your diabetes by managing your blood glucose, blood pressure and cholesterol levels.

You should also take the following steps to help prevent diabetes-related nerve damage:

• be physically active
• follow your diabetes meal plan
• get help to quit smoking
• limit alcoholic drinks to no more than one drink per day for women and no more than two drinks per day for men
• take any diabetes medicines and other medicines your doctor prescribes

Blood tests can determine if you are experiencing a B12 deficiency. Your doctor may opt to run these tests if you are displaying symptoms such as anemia, mental changes, loss of balance, numbness, weakness, pain or tingling in the arms and legs.

In many cases, B12 deficiencies can be prevented with a diet rich in vitamins and minerals—specifically red meat, fish, poultry, eggs and dairy products—and by avoiding alcohol.

Physicians typically diagnose CIPN based on symptoms. There are no specific tests that determine CIPN, but patients have shown that the following measures can be helpful in prevention or at least symptom relief:

• Acupuncture
• Exercise
• Ganglioside-monosialic acid
• Cryotherapy
• Compression therapy

There is no known prevention for immune-mediated inflammatory neuropathy. Screenings for immune-mediated neuropathies such as Guillain-Barré syndrome include:

• A spinal tap, during which a small amount of fluid is taken from the spinal canal in the lower back.
• Electromyography, where thin-needle electrodes are inserted into the muscles to be studied.
• Electrodes are taped to the skin above your nerves to study conductivity.

Your symptoms depend on which type of diabetic neuropathy you have. In peripheral neuropathy, some people may have a loss of sensation in their feet, while others may have burning or shooting pain in their lower legs. Most nerve damage develops over many years, and some people may not notice symptoms of mild nerve damage for a long time. In some people, severe pain begins suddenly.

Common symptoms of a vitamin B12 deficiency include weakness, mental changes, loss of balance, pain, numbness or tingling in the arms and legs, or anemia. Signs of anemia—when the body is not producing enough healthy red blood cells to carry oxygen to tissues—may include fatigue, nausea, diarrhea, shortness of breath or loss of appetite.

Symptoms of CIPD are determined by the nerves affected, and tend to arise hours to days or even weeks after treatment. CIPN patients typically complain of:

• Muscle weakness
• Sensitivity to touch, pressure, pain, and temperature
• Tingling, or a “pins-and-needles” sensation
• Pain, including constant and severe or passing
• Decreased sensation

• Weakness—The weakness seen in GBS usually comes on quickly and worsens over hours or days. Symptoms are usually equal on both sides of the body (called symmetric). You may first notice weakness and difficulty climbing stairs or walking. Symptoms often affect the arms, breathing muscles and even the face, reflecting more widespread nerve damage. Symptoms occasionally start in the upper body and move down to the legs and feet. Muscles controlling breathing can weaken to the point that you might need a machine to help you breathe.

Most people reach the greatest stage of weakness within the first two weeks after symptoms appear; by the third week 90 percent of affected individuals are at their weakest.

• Sensation changes—Since nerves are damaged in GBS, your brain may receive abnormal sensory signals from the rest of your body. This results in unexplained, spontaneous sensations, called paresthesias, that you may feel as tingling, a sense of insects crawling under the skin (called formications), and pain. Deep muscular pain may be experienced in the back and/or legs.

Unexplained sensations often occur first, such as tingling in the feet or hands, or even pain (especially in children), often starting in the legs or back. Children will also show symptoms with difficulty walking and may refuse to walk. These sensations tend to disappear before the major, longer-term symptoms appear.

• Other symptoms may include:
  • Difficulty with eye muscles and vision
  • Difficulty swallowing, speaking or chewing
  • Pricking or pins and needles sensations in the hands and feet
  • Pain that can be severe, particularly at night
  • Coordination problems and unsteadiness
  • Abnormal heartbeat/rate or blood pressure
  • Problems with digestion and/or bladder control

The assessment of diabetic neuropathy depends on the individual’s symptoms, but typically involves a monofilament examination, which determines nerve damage. A strand of nylon is attached to a plastic base and used to check for loss of feeling in the feet.

To screen for vitamin B12 deficiency, your healthcare provider may order blood tests to see whether you have low hemoglobin or vitamin B12 levels. A complete blood count (CBC) test measures hemoglobin, and another blood test measures vitamin B12 levels in the blood.

Working with your care team and oncologist to communicate your symptoms, you may be diagnosed with CIPN following a physical examination and a screening questionnaire. The assessment process may result in adjusting the chemotherapy regimen, levels and frequency.

For most immune-mediated neuropathies, nerve biopsies (including motor nerve biopsies and sensory nerve biopsies) are useful to determine the type of neuropathy. Additionally, autonomic testing, pulmonary function tests and telemetry are used in more severe cases.

The initial signs and symptoms of Guillain-Barré syndrome are varied, and there are several disorders with similar symptoms. Therefore, doctors may find it difficult to diagnose GBS in its earliest stages and may perform the following tests.

• Physical exam—Your physician will look at your physical symptoms, ask about your medical history and conduct exams to assess how your muscles and nerves are functioning. Your physician or a specialist will note whether your symptoms appear on both sides of the body (the typical finding in Guillain-Barré syndrome) and the speed with which the symptoms appear (in other disorders, muscle weakness may progress over months rather than days or weeks). Your reflexes also will be checked: in GBS, deep tendon reflexes in the legs, such as knee jerks, are usually lost. Reflexes may also be absent in the arms.
• Nerve conduction velocity test (NCV)—This test measures the nerve's ability to send a signal. In GBS, the signals traveling along the damaged nerves are slow, and this can provide clues to aid the diagnosis.
• fluid analysis—Your doctor also may remove and have analyzed a small sample of the cerebrospinal fluid that bathes the spinal cord, since the fluid in people with GBS contains more protein than usual but very few immune cells (measured by white blood cells).

Key diagnostic findings include:

• Recent onset, within days to at most four weeks of symmetric weakness, usually starting in the legs
• Abnormal sensations such as pain, numbness and tingling in the feet that accompany or even occur before weakness
• Absent or diminished deep tendon reflexes in weak limbs
• Elevated cerebrospinal fluid protein without elevated cell count (this may take up to 10 days from onset of symptoms to develop)
• Abnormal nerve conduction velocity findings, such as slow signal conduction
• Sometimes, a recent viral infection or diarrhea

If you have diabetic neuropathy, you should manage your diabetes, which means managing your blood glucose, blood pressure, cholesterol levels and weight to keep nerve damage from getting worse.

Foot care is very important for all people with diabetes, and it’s even more important if you have peripheral neuropathy. Check your feet for problems every day, take good care of your feet. See your doctor for a neurological exam and foot exam at least once a year—more often if you have foot problems.

Since the body does not produce vitamin B12 on its own, it’s important to eat a diet rich in vitamins and minerals to build up healthy nutrients. Animal products, like meat, dairy and eggs, are typically rich in B12.

Oral medication, including a synthetic form of B12 known as cyanocobalamin, is often prescribed to elevate B12 deficiencies. Other options include B12 injections, nasal gels and nasal spray.

While CIPN-related nerve damage cannot be improved, managing symptoms can be an effective treatment.

Treatment guidelines for acute neuropathies differ depending on the disease stages. While there is no known cure for neuropathies like Guillain-Barré syndrome, some therapies can lessen the severity of the illness and shorten your recovery time. There are also several ways to treat the complications of the disease.

If you have GBS, you are usually admitted to and treated in the hospital's intensive care unit due to possible complications of muscle weakness, problems that can affect any paralyzed person (such as pneumonia or bed sores), and the need for sophisticated medical equipment.

There are currently two treatments commonly used to interrupt immune-related nerve damage. Both are equally effective if started within two weeks of GBS symptoms.

• Plasma exchange (PE), also called plasmapheresis, involves removing some of your blood through a catheter. The blood cells from the liquid part of the blood (plasma) are extracted and treated and returned to your body. Plasma contains antibodies and PE removes some plasma; PE may work by removing the bad antibodies that have been damaging the nerves.
• Intravenous immunoglobulin therapy (IVIg) involves intravenous injections of immunoglobulins—proteins that your immune system naturally makes to attack infecting organisms. The immunoglobulins are developed from a pool of thousands of healthy donors. IVIg can lessen the immune attack on the nervous system and shorten recovery time. Investigators believe this treatment also lowers the levels or effectiveness of antibodies that attack the nerves by both “diluting” them with non-specific antibodies and providing antibodies that bind to the harmful antibodies and take them out of commission.

Anti-inflammatory steroid hormones called corticosteroids have also been tried to reduce the severity of GBS, but controlled clinical trials showed this treatment is not effective.

Supportive care is very important to address the many complications of paralysis as your body recovers, and damaged nerves begin to heal. Since respiratory failure can occur in GBS, your breathing should be closely monitored. Sometimes a mechanical ventilator is used to help support or control breathing. The autonomic nervous system (that regulates the functions of internal organs and some of the muscles in your body) can also be disturbed, causing changes in heart rate, blood pressure, toileting or sweating, so you should be put on a heart monitor or equipment that measures and tracks body function. You also may need help with any difficulty from secretions in the mouth and throat. In addition to choking and/or drooling, secretions can fall into your airway and cause pneumonia.

As you begin to improve, you may be transferred from the acute care hospital to a rehabilitation setting. Here, you can regain strength, receive physical rehabilitation and other therapy to resume activities of daily living, and prepare to return to pre-illness life.

Because GBS can affect several parts of your body, you may need different methods and approaches to prevent or treat complications. For example, you may need a physical therapist to manually move and position your limbs to help keep the muscles flexible and prevent muscle shortening. Injections of blood thinners can help prevent dangerous blood clots from forming in leg veins. Inflatable cuffs may also be placed around your legs to provide intermittent compression. All or any of these methods helps prevent blood stagnation and sludging (the buildup of red blood cells in veins), which could lead to reduced blood flow in the leg veins. Muscle strength may not return uniformly; some muscles that get stronger faster may tend to take over a function that weaker muscles normally perform—called substitution. A physical therapist can select specific exercises to improve the strength of weaker muscles so their original function can be regained.

Occupational and vocational therapy helps you learn new ways to handle everyday functions that may be affected by the disease, as well as work demands and the need for assistive devices and other adaptive equipment and technology.

Guillain-Barré syndrome can be a devastating disorder because of its sudden and rapid, unexpected onset of weakness—and usually actual paralysis. Fortunately, most people with GBS have a full recovery. With careful intensive care and successful treatment of infection, autonomic dysfunction and other medical complications, even those individuals with respiratory failure usually survive.

Your recovery can be slow or incomplete–anywhere from as little as a few weeks up to a few years. Some individuals still report ongoing improvement after two years. About 30 percent of those with Guillain-Barré have residual weakness after three years. About 3 percent may suffer a relapse of muscle weakness and tingling sensations many years after the initial attack. About 15 percent of individuals experience long-term weakness; some may require ongoing use of a walker, wheelchair or ankle support. Muscle strength may not return uniformly.

Ongoing fatigue, pain and other annoying sensations can sometimes be troublesome. You may face physical difficulties and emotionally painful periods. You might find it extremely difficult to adjust to sudden paralysis and dependence on others for help with routine daily activities. Some people with GBS need psychological counseling to help them adapt. Support groups can often ease emotional strain and provide valuable information.

Peripheral neuropathy can lead to foot complications, such as sores, ulcers and infections, because nerve damage can make you lose feeling in your feet. As a result, you may not notice that your shoes are causing a sore or that you have injured your feet. Nerve damage can also cause problems with balance and coordination, leading to falls and fractures.

These problems may make it difficult for you to get around easily, causing you to lose some of your independence. In some people with diabetes, nerve damage causes chronic pain, which can lead to anxiety anddepression<.

Autonomic neuropathy can cause problems with how your organs work, including problems with your heart rate and blood pressure, digestion,urination and ability to sense when you have low blood glucose.

Depending on how early the deficiency is diagnosed and treatment begins, most can quickly recover from the symptoms of B12 deficiency. Medication may be required for life in cases caused by co-occurring disorders.

Symptoms for peripheral neuropathy typically fade over several months following treatment and/or cessation of chemotherapy treatments. Depending on the severity of symptoms, your care team may opt to delay treatments or use smaller doses of the drugs causing CIPN and symptoms.

Living with immune-mediated neuropathies like Guillain-Barré syndrome can be devastating because of its sudden and rapid, unexpected onset of weakness—and usually actual paralysis. Fortunately, most people with GBS have a full recovery. With careful intensive care and successful treatment of infection, autonomic dysfunction and other medical complications, even those individuals with respiratory failure usually survive.

Your recovery can be slow or incomplete–anywhere from as little as a few weeks up to a few years. Some individuals still report ongoing improvement after two years. About 30 percent of those with Guillain-Barré have residual weakness after three years. About 3 percent may suffer a relapse of muscle weakness and tingling sensations many years after the initial attack. About 15 percent of individuals experience long-term weakness; some may require ongoing use of a walker, wheelchair or ankle support. Muscle strength may not return uniformly.

Ongoing fatigue, pain and other annoying sensations can sometimes be troublesome. You may face physical difficulties and emotionally painful periods. You might find it extremely difficult to adjust to sudden paralysis and dependence on others for help with routine daily activities. Some people with GBS need psychological counseling to help them adapt. Support groups can often ease emotional strain and provide valuable information.

Occupational and vocational therapy helps you learn new ways to handle everyday functions that may be affected by the disease, as well as work demands and the need for assistive devices and other adaptive equipment and technology.

Persistent fatigue and residual disabilities are common long-term symptoms for immune-mediated neuropathies. Some may require inpatient rehab, while others benefit from aerobic conditioning, gait training, resistance exercises as well as speech and language therapies as necessary.