Diabetic polyneuropathy is a distal symmetric polyneuropathy (DSPN) characterized by numbness, tingling, pain, or weakness that affects the nerves in a stocking-and-glove pattern, beginning in the distal extremities. DSPN leads to substantial pain, morbidity, and impaired quality of life. A number of different classification schemes exist for diabetic neuropathy; a common one is outlined in Box 1.

DSPN

Distal symmetric polyneuropathy

Diabetic peripheral neuropathy

• Patients most commonly experience numbness and tingling, but they may also experience either feelings of tightness or a sensation of heat or cold.²
• Pain is common, is often worst at night, and can be burning, aching, shooting, or lancinating in nature.²
• Sensory symptoms begin in the feet and may slowly ascend over months to years. Symptoms in the hands do not generally occur until symptoms in the lower extremities have reached the level of the knees. In more severe cases, the symptoms can spread to the trunk and head.²
• Neurologic examination reveals early loss of small-fiber modalities resulting in decreased pinprick and temperature sensation and later involvement of large-fiber modalities leading to a reduction in vibratory and proprioceptive sensation. Ankle reflexes are usually reduced or absent, and more proximal reflexes may also become involved as the neuropathy progresses. Strength is usually normal, but there can be some motor involvement leading to mild weakness and atrophy, which is usually limited to intrinsic foot muscles and ankle dorsiflexors.

The precise etiology is unknown but most likely involves a complex interaction of metabolic derangements and microvascular insults occurring in the setting of diabetes.

Although diabetes is the leading cause of peripheral neuropathy in developed countries, there are numerous other causes requiring further investigation(s).

• A thorough history and neurologic examination are essential to confirm features consistent with a diabetic polyneuropathy and exclude other features suggesting alternative diagnoses.
• For some patients, neuropathy may be the presenting feature of previously undiagnosed diabetes.
• Electrodiagnostic evaluation to include nerve conduction studies and electromyography can be helpful in confirming the presence, extent, and severity of a neuropathy.
• Patients with DSPN typically have a reduction of amplitudes and slowing of conduction velocities involving sensory and possibly motor nerves in a length-dependent and symmetric fashion.
• Electromyographic examination of distal muscles may reveal fibrillation potentials, positive sharp waves, and large motor unit action potentials, all suggestive of denervation and reinnervation.
• Electrodiagnostic testing may be negative if the neuropathy is limited to small fiber involvement.
• Neither skin biopsy nor nerve biopsy is necessary in the vast majority of cases.
• Fig. 1 describes a diagnosis and treatment algorithm of diabetic autonomic neuropathy.

Figure 1 Diagnosis and Treatment Algorithm of Diabetic Autonomic Neuropathy

ACE, Angiotensin-Converting Enzyme; Arbs, Angiotensin Receptor Blockers; BP, Blood Pressure; DM, Diabetes Mellitus; GI, Gastrointestinal; HbA1c, Glycohemoglobin; Hrv, Heart Rate Variability; Ssr, Sympathetic Skin Response.

Modified from Larsen PR et al [eds]: Williams textbook of endocrinology, ed 11, Philadelphia, 2008, Saunders.

• Fasting blood sugar, hemoglobin A1c, and 2-hr oral glucose tolerance tests should all be considered in patients with peripheral neuropathy without a known history of diabetes.
• A focused laboratory evaluation for other common or potentially treatable causes of neuropathy is also indicated: CBC, comprehensive metabolic panel to include electrolytes and liver function tests, vitamin B₁₂ and folate levels, thyroid function tests, serum protein electrophoresis with immunofixation.
• Additional laboratory tests can be considered, based on either history or exam findings suggesting other underlying diagnoses, such as antinuclear antibodies, extractable nuclear antigens, ANCAs, rheumatoid factor, HIV, hepatitis B and C, and cryoglobulins.

Imaging is not necessary unless there is concern for an alternative or coexisting process based on the history and examination.

• Table 1 summarizes clinical features, diagnosis, and treatment of diabetic autonomic neuropathy.
• Glycemic control: The primary treatment for diabetic polyneuropathy is effective glycemic control, as this may either improve or at least slow progression of the neuropathy.
• Symptomatic management: Another aspect of treatment is the symptomatic management of pain and paresthesias. The American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation have together developed an evidence-based guideline for the treatment of painful diabetic neuropathy. Pregabalin, an anticonvulsant, is the only agent in the guideline that has been established as effective for painful diabetic neuropathy.³ Other probably effective agents are listed in the following:
  1. Topical agents: Lidocaine 5% patch can be applied to painful areas for 12 hr a day, capsaicin 0.075% applied qid.
  2. Anticonvulsants: Gabapentin (100 to 1200 mg tid), pregabalin (50 to 100 mg tid), carbamazepine (100 mg bid).
  3. Antidepressants: Amitriptyline (10-100 mg qhs), nortriptyline (25 to 150 mg qhs), duloxetine (60 to 120 mg/day).
  4. Tramadol (50 mg qid as needed) can be a useful adjunctive analgesic.
• Fig. 2 describes a treatment algorithm for neuropathic pain after exclusion of nondiabetic etiologies and stabilization of glycemic control.

Figure 2 Treatment Algorithm for Neuropathic Pain after Exclusion of Nondiabetic Etiologies and Stabilization of Glycemic Control

Ivig, Intravenous Immune Globulin; Snri, Serotonin-Norepinephrine Reuptake Inhibitors; Tca, Tricyclic Antidepressants.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

The distal sensory loss of diabetic polyneuropathy places patients at increased risk of trauma to the extremities, with the potential for ulceration and infection that could ultimately require amputation if not attended to in a timely fashion.

• A neurologist can assist in the diagnosis and management of diabetic polyneuropathy.
• Patients with diabetic polyneuropathy should also be evaluated at least annually by a podiatrist and ophthalmologist.
• Progression of diabetic polyneuropathy can be minimized by paying close attention to strict glycemic control as well as other risk factors such as hypertension and obesity.

• For many patients, either DSPN or another form of diabetic neuropathy may be the initial presentation of previously undiagnosed diabetes.
• In addition to regular visits with podiatry, patients with diabetic polyneuropathy should be educated on aggressive foot hygiene and the importance of examining their own feet.
• Cannabidiol (CBD) use for reduction of chronic pain has markedly increased over the past decade, but overall quality of evidence in patients with painful neuropathy remains low.⁴

The following website is recommended: www.mayoclinic.com/health/diabetic-neuropathy/DS01045