Causes of peripheral neuropathy: Diabetes and beyond

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶