Current Perspectives On The Differential Diagnosis For Peripheral Neuropathy

An estimated 20 million people in the United States have some form of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system.¹ Peripheral neuropathies can present in a variety of forms and follow different patterns. Patients may experience symptoms over a period of days, weeks or years. They could be acute or chronic. In acute neuropathies, such as Guillain-Barre syndrome, symptoms appear suddenly, progress rapidly and resolve slowly. Many chronic neuropathies worsen over time but very few forms are fatal.

In general, peripheral neuropathies are classified according to damage to the nerves. Some forms of neuropathy involve damage to only one nerve and they are called mononeuropathies. However, more frequently, there is polyneuropathy, which involves multiple nerves.

Some peripheral neuropathies are due to damage to the axons (the long, threadlike portion of the nerve cell) while others are due to damage to the myelin sheath, that fatty protein that coats and insulates the axon. Peripheral neuropathies may also be caused by a combination of both axonal damage and demyelination.

Symptoms vary depending on whether motor, sensory or autonomic nerves are damaged. Motor nerves control voluntary movement of muscles such as those we use for walking, grasping things or talking. Sensory nerves transmit information such as feeling of a light touch or the pain from a cut. Autonomic nerves control organ activities that are regulated autonomically such as breathing, digesting food and heart and gland functions.

Motor neuropathy is most commonly associated with muscle weakness, muscle twitching, cramps and fasciculations, muscle atrophy and decreased reflexes.

Sensory nerve damage causes a variety of symptoms because sensory nerves have a broad range of functions. Larger sensory nerve fibers enclosed in myelin register vibration, light touch and position sense. Damage to large sensory nerve fibers impairs touch, resulting in a general decrease in sensation. Since people feel this most in the feet and hands, they feel as if they are wearing gloves and stockings even when they are not. This damage to larger sensory nerve fibers may contribute to the loss of reflexes. Loss of position sense often makes people unable to coordinate complex movements like walking, fastening buttons or maintaining their balance when their eyes are closed.

Smaller sensory fibers without myelin sheaths transmit pain and temperature sensations. Damage to these fibers can interfere with the ability to feel pain or changes in temperature. People may fail to sense that they have been injured from a cut or a wound that is becoming infected. Others may not detect pain that warns of an impending heart attack or other acute conditions. Loss of pain sensation is a particularly serious for patients with diabetes, which may contribute to the higher rate of lower limb amputations.

Neuropathic pain is a common, often difficult to control symptom of sensory nerve damage, which can affect emotional well-being and overall quality of life. Often worse at night, neuropathic pain disrupts sleep and adds to the emotional burden of sensory nerve damage. Some folks may experience pain from bedsheets draped lightly over the body. Over many years, sensory neuropathy may lead to changes in the skin and hair as well as joint and bone damage. Unrecognized injuries due to poor sensation contribute to these changes so it is important for podiatrists to inspect numb areas for injury or damage.

Autonomic nerve damage symptoms are diverse since the parasympathetic and sympathetic nerves of the peripheral nervous system control nearly every organ in the body. Common symptoms of autonomic nerve damage include an inability to sweat normally, which may lead to heat intolerance, a loss of bladder control and the inability to control muscles that expand or contract blood vessels to regulate blood pressure. When a person moves suddenly from a seated to standing position, a corresponding drop in blood pressure (a condition known as postural or orthostatic hypotension) may result in dizziness, lightheadedness or fainting. Irregular heartbeats may also occur with this condition.

Patients who have cardiac arrhythmia may receive a prescription for oral amiodarone from their cardiologist. These patients, who may take this medication between two to four years, may not realize that this drug, in high concentrations, can accumulate, resulting in bilateral, symmetrical peripheral neuropathy. This condition is called amiodarone toxicity, which is also known as cardiovascular autonomic neuropathy (CAN).

Reviewing The Possible Etiologies Of Peripheral Neuropathy

Peripheral neuropathy may be either inherited or acquired through disease processes or trauma. Causes of acquired neuropathy include physical injury or trauma. Trauma is the most common cause of acquired nerve damage. Automobile accidents, falls, sport-related activities and surgical procedures can cause nerves to be partially or completely severed, crushed, compressed or stretched so as to be detached from the spinal cord.

Repetitive stress frequently leads to entrapment neuropathies, a form of compression injury. In podiatry, the most common example is Morton’s neuroma in the foot. Damage can become worsened by repetitive activities that may further result in irritation of ligaments, tendons and muscles. This may subsequently lead to inflamed and swollen narrow passageways that nerves pass through. Tarsal tunnel syndrome medially and sural nerve compression are two common types of neuropathy caused by trapped or compressed nerves in the foot.

Diseases and their related processes, such as inflammation, can be associated with peripheral neuropathy. Endocrine disorders impair the body’s ability to transform nutrients into energy and process waste products, which can lead to nerve damage. Diabetes mellitus, characterized by chronically high blood glucose levels, is a leading cause of peripheral neuropathy in the United States. About 60 to 70 percent of people with diabetes have mild to severe forms of nervous system damage that affects sensory, motor and autonomic nerves.¹ Endocrine disorders lead to hormonal imbalances, causing neuropathies such as hypothyroidism. With hypothyroidism, there is an underproduction of thyroid hormones that causes a slower metabolism, which tends to lead to fluid retention and swollen tissues in the feet and ankles that can exert pressures on peripheral nerves.

Small vessel disease can decrease oxygen supply to the peripheral nerves, leading to serious nerve tissue damage. Diabetes frequently leads to impaired blood flow to nerves. Various forms of vasculitis (blood vessel inflammation) cause vessel walls to harden, thicken and develop scar tissue, hence decreasing their diameter and impeding blood flow. Vasculitis is an example of nerve damage called mononeuritis multiplex.

Autoimmune diseases, in which the immune system attacks the body’s own tissue, can lead to nerve damage. Sjogren’s syndrome, lupus and rheumatoid arthritis are among the autoimmune diseases associated with peripheral neuropathy. When the tissue surrounding nerves becomes inflamed, the inflammation spreads directly into the nerve fibers. Over time, these chronic autoimmune conditions destroy joints, organs and connective tissues, thus making nerve fibers more vulnerable to compression injuries and entrapment.

Kidney disorders may cause neuropathies. Kidney dysfunction can lead to abnormally high amounts of toxic substances in the blood that can damage nerve tissue. Also, patients with kidney failure and require dialysis are known to develop polyneuropathy.

Neuromas are benign tumors that are caused by an overgrowth of nerve tissue that develops after a penetrating injury that can sever nerve fibers. Neuromas are often associated with intense pain and sometimes include neighboring nerves, leading to even greater pain. This widespread neuropathic pain condition is also referred to as reflex sympathetic dystrophy, which can be caused by traumatic injuries or surgical trauma. Then there is a widespread polyneuropathy that is associated with neurofibromatosis, a genetic disorder in which multiple benign tumors grow on nerve tissue. Upon examination of the patient, the podiatrist may find the tumors are often attached to the central and medial bands of the plantar fascia of the foot.

Exposure to environmental or industrial toxins such as lead, mercury, insecticides and solvents may lead to nerve damage and cause neuropathies.²

Medication toxicity usage can cause peripheral neuropathy. The use of amiodarone in 400 to 600 mg daily dosages is one example of this. The antiarrhythmic medication amiodarone was first reported as a cause of peripheral neuropathy in 1974.² Cardiologists use this medication to treat cardiac arrhythmias, especially in patients who just had an implantable cardioverter defibrillator (ICD) installed for cardiac arrhythmias, such as ventricular tachycardia with cardiomegaly of the heart tissue and a resultant enlarged left ventricle chamber. In most cases, neuropathy resolves when the prescribing physician adjusts the medication dosing.

Amiodarone is very beneficial in treating and managing cardiovascular autonomic neuropathy. Cardiovascular autonomic neuropathy occurs when damage to the peripheral nerves disrupts the automatic functions that control blood circulation and heartbeat. The two main noticeable symptoms of cardiovascular autonomic neuropathy are an inability to exercise for more than a short time period and orthostatic hypotension.

Autonomic neuropathy is a group of symptoms that occur when there is damage to nerves that manage everyday body functions, which include blood pressure, heart rate, sweating, bowel and bladder emptying, and digestion. Podiatrists may note or diagnose autonomic neuropathy in patients with alcohol abuse, diabetes, scarring and adhesions around nerves, HIV/AIDS, multiple sclerosis, Parkinson’s disease, spinal cord injuries, and surgeries involving the nerves.

Autonomic neuropathy may increase osteoclastic activity, resulting in reduced bone density. Therefore, Charcot arthropathy will reflect the severity of autonomic neuropathy. Nerve function involves large nerve fibers that one can test and assess proprioception and loss of protective sensation, deep tendon reflexes, muscle strength and two-point discrimination.

Heavy alcohol consumption is also a common cause of peripheral neuropathy. Chronic alcohol abuse frequently leads to nutritional deficiencies including B12, B1 and folate, which are also called cyanacobalamin, thiamine and folic acid respectively. All of these deficiencies contribute to the development of peripheral neuropathy.

Keys To Diagnosing Peripheral Neuropathy

The first step in understanding the cause of any neuropathy is obtaining a comprehensive history from the patient, which includes a past medical history, a family history, social history and current medications.

Certain medications can lead to numbness and tingling in the hands and feet. Adjusting certain medications can reduce the numbness to the feet. Common medications that may cause neuropathy are amiodarone, vincristine, metronidazole, nitrofuratonin and colchicine.²

An annual lower extremity physical exam is always recommended in patients with known neuropathy. A physical exam may reveal the presence of a systemic disease causing the nerve damage. Testing of vibratory sensation at the level of the hallux is important. Also, testing of protective sensation with a 10 g Semmes-Weinstein monofilament, ankle reflex testing, proprioception testing and sharp/dull discrimination testing are all elements of a comprehensive physical examination for neuropathy.

Blood tests can detect diabetes, vitamin deficiencies, liver and kidney dysfunction and signs of abnormal immune system activity. Lab tests should include a fasting blood sugar (glucose) and hemoglobin A1c, which will aid in a diagnosis of diabetes.

Based on the results of the neurological exam, physical exam, patient history and testing, there are additional tests that one may order to help determine the nature and extent of the neuropathy. The nerve conduction velocity (NCV) test can measure the degree of damage in large nerve fibers, revealing whether symptoms are caused by degeneration of the myelin sheath of the axon. The myelin covering is responsible for the very fast speed of nerve conduction. One can use an electrical probe to stimulate a nerve fiber, which responds by generating its own electrical impulse. This electrode measures the speed of impulse transmission along the axon further down the nerve’s pathway. Slow transmission rates and impulse blockage indicate damage to the myelin sheath while a reduction in the strength of impulses at normal speed is a sign of axonal degeneration.

Electromyography (EMG) involves inserting a fine needle into a muscle to record electrical activity when muscles are at rest and when they contract. EMG tests detect abnormal electrical activity in patients with motor neuropathy.
Magnetic resonance imaging (MRI) can illustrate muscle quality and size, and help rule out tumors, herniated discs and other abnormalities that cause neuropathy.

Nerve biopsy involves removing and examining a sample of nerve tissue, most often from the lower leg.

In Conclusion

All podiatric patients with diagnosed neuropathy should receive a referral to their primary physician or neurologist for long-term management of their conditions. That said, when it comes to peripheral neuropathy, it is important to be aware of the array of potential etiologies beyond diabetes in order to ensure accurate diagnosis and effective treatment. From a personal standpoint, I developed peripheral neuropathy after taking amiodarone 200 to 400 mg BID over the past 18 months. My doctor prescribed this medication following the installation of a pacemaker/defibrillator for cardiac arrhythmia for the past two years.

Although my cardiac arrhythmia was well-managed with amiodarone, I began experiencing unsteadiness while walking, muscle weakness in the legs and numbness along the dorsum of both feet. I had developed the large fiber segmental demyelination form of peripheral neuropathy. Clinically, the neuropathy was bilateral and symmetrical, and traveled from the toes upward to the ankle.

My cardiologist diagnosed me with “amiodarone toxicity” due to the aforementioned symptoms as well as amiodarone deposits in the back of the eye, dizziness, orthostatic hypotension, photosensitivity to sunlight, extreme tiredness, trouble sleeping, low back pain and loss of appetite. The cardiologist recommended lowering the dosages of amiodarone to 100 mg every other day and 200 mg daily for four days.

Dr. Chromey is based in Plains, Pa.

References

1.     American Diabetes Association. National Diabetes Statistics Report, 2017. Available at https://www.diabetes.org/assets/pdfs/basics/cdc-statistics-report-2017.pdf .
2.     Jasmin L. Neuropathy secondary to drugs. Medline Plus. Available at https://medlineplus.gov/ency/article/000700.htm .
3.     Ziegler D, Fonseca V. A review of recommendations for pharmacotherapy of painful diabetic neuropathy. Diabetes Complications. 2015; 29(1):146–56.
4.     Bolton AJM, Gries FA, Jervell J. Guidelines to the diagnosis and outpatient management of diabetic peripheral neuropathy. Diab Med. 1998; 24(Suppl 3):55–65.
5.     Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc. 2004; 79(12):1533–45.
6.     Kapur D. Neuropathic pain and diabetes. Diabetes Metab Res Rev. 2003; 19(Suppl 1):S9–15.

For further reading, see “Current And Emerging Insights On Treating Diabetic Peripheral Neuropathy” in the March 2013 issue of Podiatry Today or “Emphasizing Patient Awareness Of The Serious Complications Of Diabetes” in the February 2018 issue.