Essential Insights On Detecting The Etiology Of Peripheral Neuropathy

Peripheral neuropathy can be triggered by disparate causes such as diabetes, alcoholism, certain chemotherapy medications and HIV. Given the importance of identifying the correct etiology in order to facilitate appropriate treatment, these authors discuss pertinent clues in the patient history and physical exam, and share perspectives on helpful diagnostic testing.

   In podiatric practice, we commonly see peripheral neuropathy, the primary factor leading to ulceration, which can subsequently lead to infection and ultimately amputation. Neuropathy may also lead to Charcot osteoarthropathy, which occurs most commonly in those with diabetic neuropathy but can occur in those without diabetes.1-3

   Diabetes is the leading cause of peripheral neuropathy.4 However, peripheral neuropathy can be a complication of HIV, alcoholism, malnutrition and cancer. It can also be triggered by medication toxicities or hereditary causes.

   The prognosis of neuropathy can differ depending on the etiology. For some patients, neuropathy is reversible and in many cases, one can slow down or even stop the progression by implementing proper etiology-based treatment.5-13 Accordingly, it is crucial to determine the specific cause or causes of each patient’s neuropathy. By being aware of the type and degree of neuropathy, the physician is better able to assist the patient in preventing serious complications and improve the patient’s quality of life.

   Determining the cause of peripheral neuropathy is difficult for several reasons. There is no algorithm that has proven reliable and one leading neurologist has even opined that diagnosing neuropathy is a “mind game” wherein the physician must constantly be including and excluding diagnoses with each part of the examination.14 This is not only due to the fact that the same neuropathy can be caused by different diseases but also because the same disease can cause several different neuropathies.15

   While there is no definitive algorithm, there are guidelines on how to approach the history, physical exam and any additional testing.14,16,17

Key Considerations With The Patient History

   The most important diagnostic tool in determining the etiology of peripheral neuropathy is a thorough history. This requires knowledge of the different causes of neuropathy and their possible presentations. For a differential diagnosis of the more common etiologies, see “A Guide To The Differential Diagnosis Of Peripheral Neuropathy” on page 58.

   Having a disease that causes neuropathy clearly does not mean that a patient has or will have neuropathy. Therefore, the onset of the neuropathy and the onset of diabetes or other diseases are important historical components in determining correlation. While we have all certainly encountered patients in whom peripheral neuropathy was the presenting symptom of diabetes, this is rare.

   When peripheral neuropathy presents early in the disease progression of those who have their diabetes under good control, there is more than likely an alternate cause for the peripheral neuropathy.18 Since diabetic neuropathy is a microangiopathy, one would expect another microvascular disease, such as nephropathy and retinopathy, to be present during the same timeframe.4,14

   In a study of 100 consecutive patients with diabetes and symptomatic peripheral neuropathy, 97 patients had neuropathy related to diabetes. However, one-third of the patients had a second neuropathy of another etiology.19 In another study, 55 percent of 103 neuropathic patients with diabetes had one or more additional causes of neuropathy.20 Even diabetes-induced neuropathy has several different types and presentations.15

   Perhaps the most important aspect of a history for these patients is the patient’s family history. First, it is the only way to diagnose a hereditary neuropathy by means other than exclusion. Second, if the patient has a hereditary neuropathy, it is prudent to have other family members tested so they can take steps to reduce their risk of complications. Pertinent family history includes foot type, ulcers, amputations, mobility, the use of bracing, etc., among first-degree relatives. It is also important in the family history to note any diseases such as diabetes, vasculitis, amyloidosis and Charcot-Marie-Tooth disease, which are likely to cause neuropathy.

What To Look For In The Physical Exam

   The “anatomic-pathologic pattern” of neuropathy developed by Dyck, et al., helps to narrow the differential diagnosis and provides a baseline for monitoring the progression of the disease.14

   The first step is determining the pattern of the neuropathy. Then one should characterize positive and negative symptoms involving the small and large sensory, autonomic and somatic nerves. Combining the anatomic-pathologic pattern with the patient’s history will often result in a significantly narrowed differential diagnosis. This facilitates a more efficient choice of ancillary testing.

   Determining whether a neuropathy is symmetric or asymmetric can help differentiate the diagnosis. Lumbar compressive radiculopathy, primary vasculitic neuropathy, leprosy, nerve entrapments and nerve tumors are most commonly asymmetric neuropathies.

   Low back pain, for example, will primarily affect one side of the L5 or S1 nerve root — sensory, motor or autonomic. Any sensory deficiency would follow the L5 (lateral thigh, lateral leg and dorsal foot) or S1 (buttocks, posterior thigh, posterior leg, lateral foot) dermatomal distribution.21

   Conversely, diabetic, alcoholic, HIV-induced, secondary vasculitic and most of the other neuropathies in the aforementioned sidebar (see “A Guide To The Differential Diagnosis Of Peripheral Neuropathy” on page 58) most commonly present in length-dependent symmetric patterns.

Pertinent Signs And Symptoms Of Motor Neuropathy

   The peripheral nervous system can be divided into four parts based on what groups are primarily affected in neuropathy: motor, sensory large fibers, sensory small fibers and autonomic. One, some or all of these groups can be affected in any given neuropathic process.

   Motor neuropathy. Progressive muscle atrophy and weakness can result from motor neuropathy, and can cause gait impairment, increased falling risk and foot deformity leading to ulceration, especially in later stages.22,23 Clinical testing includes visual examination of intrinsic and extrinsic foot and hand musculature, gait analysis and muscle strength testing.

   Positive motor symptoms include fasciculations and cramps. Negative signs are atrophy, weakness and hyporeflexia. One can accomplish more objective testing with an electromyography/nerve conduction velocity (EMG/NCV) study, which we will discuss a bit later in the article.

   The condition dubbed “intrinsic minus foot” is caused primarily by motor neuropathy, leading to atrophy of the small intrinsic muscles of the feet. Since these muscles are the most distal muscles, they are usually the first to be affected by a length-dependent process.24 Researchers have quantified this atrophy on MRI.25 This leads to the development of hammertoes, prominent metatarsal heads and distal migration of plantar fat pad.24

   Similarly, the interosseus and thenar muscles of the hand can atrophy secondary to motor neuropathy. Atrophy of the thenar muscles may also be due to carpal tunnel syndrome, which can be an underlying condition in diabetic neuropathy, although not at a greater frequency.4

   Distal leg weakness often occurs in late stage, length-dependent neuropathy and one can test this by having the patient walk on his or her heels (anterior compartment strength) or on his or her toes (posterior compartment). Since the anterior compartment muscles represent a smaller muscle group, they are more likely to exhibit weakness before the posterior compartment, and one can use this relationship to track progression of the neuropathy.

   A length-dependent process results in weaker anterior muscles first, leading to the inability to walk on the heels. The inability to walk on the toes (with spared heel walking) may signify intraspinal pathology and is termed the “Pierre Bourque” sign.26 One can test muscle strength clinically in the standard manner for the foot and ankle.

Does The Neuropathy Involve Large Fibers Or Small Fibers?

   Sensory large fibers. Vibration, joint position, light touch, two-point discrimination and pressure sensations are all carried by large nerve fibers. The afferent arcs of the deep tendon reflexes are also carried by large fibers. In peripheral neuropathy, large fiber disease most often presents with negative sensory symptoms.

   Sensory small fibers. Small nerve fibers transmit pain and temperature sensations. Neuropathy may cause positive (pain, burning, tingling, electric) and negative (numbness) symptoms. Any complaint along these lines indicates small fiber involvement. Clinical examination includes pinprick (sharp/dull), warm/cold threshold testing and heat-pain testing. One would most often perform these exams as screening tests. The CASE-IV system can quantify small fiber disease and skin biopsy is a fairly recent development.27

   Skin biopsy may be useful in quantifying small fiber neuropathy and tracking its progression. This exam is not very useful for diagnosing specific neuropathies at this point in time and it cannot replace nerve biopsy in this role.28

What You Should Know About Autonomic Neuropathy

   Autonomic. Autonomic neuropathies affect the skin, heart, vasculature, eyes, gastrointestinal system and genitourinary system in any combination. Autonomic dysfunction in the skin can result in hyperhidrosis or anhidrosis, as well as abnormal nail and hair growth. Poor vasculature exacerbates skin atrophy and hair loss. Other vascular changes include orthostatic hypotension and arteriovenous shunting.

   Testing vagal nerve function by monitoring changes in the patient’s pulse rate with the valsalva maneuver or deep breathing is a test that one can easily perform clinically. The examiner takes the radial pulse and instructs the patient to inhale and exhale slowly. A normal vagal response increases heart rate with inhalation and decreases with exhalation. If the pulse rate (rhythm) remains constant, then there is no heart rate variability to deep breathing. This signifies autonomic neuropathy.

What About Medications That Cause Neuropathy?

   There are several drugs that are known to cause peripheral neuropathy. Most of these are chemotherapy agents and include: vincristine (Oncovin), cisplatin and paclitaxel (Taxol, Bristol-Myers Squibb).9 Also bear in mind that highly active anti-retroviral therapy (HAART) for HIV is known to cause neuropathy.10 Statins are also implicated in neuropathy though epidemiological figures are in the range of 1 in 14,000.5 Finally, linezolid (Zyvox, Pfizer) and a few other antibiotics (quinolones, nitrofurantoin, polymyxin B) have been known to cause neuropathy.28

   Although it is difficult to generalize, acute onset neuropathy associated with prescription medications is usually reversible a few weeks to months after cessation of the drug. More chronic cases and late onset neuropathy, on the other hand, seem to be more permanent and improve only slightly, if at all.5,9

A Pertinent Overview Of Helpful Lab Tests

   Laboratory tests can greatly enhance the etiological diagnosis by providing the physician with knowledge about specific disease processes in the patient. After taking a careful history, one can pursue specific lab tests in a more focused and cost-effective manner. Interpreting results is also easier with a thorough patient history and one should further delve into any abnormal values.

   Complete blood count (CBC). Although rare in recent years, neuropathy caused by lead poisoning can occur. Anemia may be the first indication of this. Eosinophilia is a common finding in Churg-Strauss syndrome, a vasculitis in which neuropathy occurs in 65 to 80 percent of cases.30

   Basic metabolic panel (BMP). Testing kidney function can assist in diagnosing etiology since peripheral neuropathy is a common complication of end-stage renal disease or uremia. It is estimated that 60 to 100 percent of patients on renal dialysis have neuropathy and that the only current remedy is renal transplant.31

   Aspartate aminotransferase test/ alanine aminotransferase test (AST/ALT). Liver dysfunction may be indicative of alcoholic neuropathy but one should follow this up with a hepatitis panel. If hepatitis C is present, elevated serum cryoglobulins are associated with neuropathy.20

   Erythrocyte sedimentation rate/ C-reactive protein (ESR/CRP). Elevated inflammatory markers may be indicative of a vasculitis-induced neuropathy.

   Accordingly, one should check for primary vasculitidies such as polyarteritis nodosa, Churg-Strauss syndrome and Wegener’s granulomatosis as well as connective tissue disorders, such as Sjogren’s syndrome or cryoglobulinemia, that may cause vasculitis.20

   Thyroid-stimulating hormone (TSH). Peripheral neuropathy can develop as a complication of low thyroid hormones.7 Symptoms usually resolve fairly readily with thyroid hormone replacement therapy. Other compression neuropathies such as carpal tunnel syndrome can develop from complications with myxedema.

   Vitamin B12. A deficiency in vitamin B12 is potentially causative of neuropathy.13 The deficiency is usually a result of pernicious anemia. If the disease is not longstanding, B12 supplementation should result in symptom reversal.

   HIV testing. If the patient’s history dictates, perform HIV testing. Neuropathy from HIV can be a result of disease complications and HAART therapy.10

   Serum electrophoresis. Serum electrophoresis can detect abnormalities related to multiple myeloma, macroglobulinemia and amyloidosis. Perform this test when you suspect these diseases.32

Understanding The Benefits Of The EMG/NCV Study

   An EMG/NCV study performed by a neurologist with peripheral neuropathy expertise can greatly aid the diagnosis of the neuropathy. The objective study can determine sensory versus motor dysfunction; axonal versus demyelinative injury; and whether the injury is focal, multifocal or generalized. In some cases, the exam can determine the duration of the disease, particularly in axonal injury.33 An EMG/NCV study can also monitor progression or regeneration of nerve function.

   The EMG/NCV cannot, by itself, determine etiology or the mechanism of injury. It also cannot provide objective measures in painful versus non-painful neuropathy and it has no diagnostic value for small fiber epidermal nerves. There are several components to an EMG/ NCV study and a brief description of each is listed below.

   EMG. Electromyography examines motor nerve function by measuring motor unit recruitment. A motor unit consists of an anterior horn cell, its axon and the muscle fibers it innervates. One would examine the muscle at rest and during activity. There should be no motor activity when the muscle is at rest so any electrical activity will be pathologic.

   During muscle contraction, the neurologist would examine the morphology of the electrical activity for pathology, and measure the motor unit recruitment pattern for any abnormalities.34 Motor nerve damage will typically show up on EMG three weeks after the initial injury.17

   Sensory nerve action potentials (SNAP). This test measures the function of large sensory fibers. This exam distinguishes between preganglionic and postganglionic lesions. For example, if the lesion is preganglionic as in spinal radiculopathy, the nerve distal to the lesion should transmit impulses normally as it is anatomically unaffected by the lesion.

   Compound muscle action potentials (CMAP). This test measures the function of individual motor nerves by measuring muscle activity after nerve stimulation. One may differentiate the conduction velocity of the nerve from the neuromuscular junction and the muscle fibers by measuring the velocity from both a distal and a proximal site, and subtracting the difference between them. The exam is useful for determining the existence and extent of motor neuropathy.

   H-reflex. The H-reflex is a non-standard part of the EMG/NCV study and can help in localizing an S1 lumbar radiculopathy.

   Sural nerve biopsy. One would choose this nerve because of its peripheral nature. It is strictly sensory and autonomic. Therefore, there will not be any motor deficits upon harvesting. Bevilacqua, et al., have described proper technique.35 Histologic nerve changes associated with different conditions can help determine the etiology.

   The primary conditions that one can uncover with this nerve biopsy are: inflammatory conditions (inflammatory demyelination, vasculitis, granuloma); infiltrative conditions (amyloidosis, malignancy); infectious conditions (leprosy); and unique reactions (glycogen storage, etc.).14

   Due to risks associated with surgery, one should perform this only when the information gleaned from the biopsy is not attainable with another exam. A secondary benefit of sural nerve biopsy is the elimination of pain (if the sural nerve is involved) distal to the biopsy site.

In Conclusion

   The treatment of neuropathy should be based on its etiology. Bear in mind that up to 10 percent of those with diabetes and neuropathic symptoms have an etiology other than diabetes for their neuropathy.4 Proper diagnosis of hereditary neuropathies can aid both the patient and family members. Discovering a reversible cause of neuropathy can reduce pain and the risk for ulcers and amputations.

   Once one has addressed the causal factor(s), neuropathic symptoms can improve. However, when improvement of symptoms is not attainable, there are prescription medications available that often help alleviate pain and discomfort.36 In certain cases in which sensory loss is the primary sign, concentrating on preventing ulceration is paramount.

Mr. Tilton is a fourth-year student at the College of Podiatric Medicine and Surgery at Des Moines University in Des Moines, Iowa.

Dr. Rogers is the Director of the Amputation Prevention Center at Broadlawns Medical Center in Des Moines.

For further reading, see “A Closer Look At Motor Neuropathy In Patients With Diabetes” in the September 2008 issue, “Diabetic Neuropathy: Is Surgery An Option?” in the August 2005 issue or “How To Diagnose Peripheral Neuropathy” in the March 2006 issue.

References:

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