Diabetic neuropathy

Author(s): Jarron I. Tilghman, MD, Kevin Komes, MD, Michael Khadavi, MD, Ebby Varghese, MD

Originally published:07/25/2012

Last updated:07/25/2012



Diabetic neuropathy (DN) is a group of syndromes resulting from the disturbances in nerve function caused by diabetes mellitus.1

Epidemiology including risk factors and primary prevention

Seven million Americans are diagnosed with diabetes mellitus, and of those who carry this diagnosis for longer than 25 years, 50% will develop DN. The primary risk factor for DN is the hyperglycemia of poorly controlled diabetes mellitus, and strict glycemic control may retard its progression. Controlling blood glucose can decrease the risk of developing DN by 60% over 5 years.1,2


The etiology of DN is multifactorial. Elevated blood glucose levels in diabetes mellitus alters numerous metabolic pathways involved in nerve function. Long-term hyperglycemia inhibits uptake of myo-inositol and other essential molecules within the nerve, leading to the slowing of nerve conduction. The excess glucose is converted into sorbitol, which is then metabolized into fructose, which are 2 sugars that cause osmotic stress on individual neurons when they accumulate. Microvascular disease in diabetes mellitus may result in ischemic injury to peripheral nerves. A complete understanding of the pathophysiology of DN is yet to be revealed. DN is a heterogeneous group of syndromes, categorized and described by their anatomic distribution of involvement. The generalized symmetric polyneuropathies include distal symmetric polyneuropathy, which accounts for two-thirds of DN cases, as well as acute sensory neuropathy, small fiber neuropathy, autonomic neuropathy, and diabetic cachexia. Focal and multifocal neuropathies consist of mononeuropathies (especially carpal tunnel syndrome), cranial neuropathies, truncal radiculoneuropathies, and radiculoplexopathies (diabetic amyotrophy). The latter 2 categories of DN appear to carry a more vasculitic pathophysiology.1

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Generalized symmetric polyneuropathy is a length-dependent process initially producing sensory disturbances of the distal limbs in a stocking glove distribution, and it may subsequently demonstrate distal motor weakness and absent ankle reflexes. While up to 50% of individuals with DN are insensate in their distal lower limbs, a much smaller proportion have motor involvement. This form of DN is insidious, irreversible, and progresses proximally if blood glucose is not tightly controlled. Autonomic neuropathy predominantly disrupts the cardiovascular, genitourinary, and gastrointestinal systems. Common presentations include orthostatic hypotension, absence of fluctuations in heart rate, and resting tachycardia. Small fiber neuropathy causes decreased pain and temperature sensation with normal vibration and proprioception, reflexes, and electrodiagnostic studies and is characterized by burning pain, usually in the feet. Diabetic lumbosacral radiculoplexus neuropathy may present insidiously or suddenly and often begins with unilateral proximal lower limb pain, followed by intense proximal weakness. While it can evolve into a widespread paralytic disorder affecting the lower limbs, it carries a favorable prognosis, with the majority of affected patients reporting resolution of pain and weakness after several years.1,3,4

Specific secondary or associated conditions and complications

Loss of pedal sensation from DN may result in skin wounds and ulceration. The concomitant vascular and immunologic disorders make these wounds susceptible to infection that may progress to osteomyelitis or gangrene. There are many other secondary complications including autonomic dysfunction, erectile dysfunction, gastroparesis, and neuropathic arthropathies (Charcot joints). DN may also contribute to common entrapment neuropathies, such as carpal tunnel syndrome.



DN may produce painful positive symptoms like squezing, throbbing, freezing, burning, or lancinating sensations. Nonpainful positive symptoms include a feeling of stiffness and thickness. Negative symptoms include numbness. History should also assess for gait disturbances, skin lesions, hypotensive symptoms, sexual dysfunction, changes in bowel or bladder function, and progressive weakness.

Distal symmetric polyneuropathy generally presents insidiously and involves the distal lower limbs in a symmetric pattern. Neurogenic or vascular claudication and other length-dependent neuropathies may mimic DN. Diabetic distal symmetric polyneuropathy generally presents insidiously and involves the distal lower limbs in a symmetric pattern, while diabetic lumbosacral radiculoplexus neuropathy has an abrupt, painful onset, is generally accompanied by weight loss, and often is a presenting finding in newly diagnosted diabetics. It is characterized by sharp, burning, and asymmetric pain that more often presents proximally in the hip and thigh before later spreading distally.1,3

Physical examination

Gait and skin evaluations are mandatory. Proprioceptive deficits should be exposed with Romberg, tandem gait, and one-leg stand tests. Examinations with a 128 Hz tuning fork and a 10-g monofilament test carry sensitivities of 62.5 and 62.8%, respectively, and specificities of 95.3 and 92.9%, respectively. Vibratory sensation is often the first sensory finding in DN,5 and pinprick and light touch examinations may also suggest a pattern of sensory deficit. Ankle deep tendon reflexes and strength should be documented. A skin examination should detect erythema, callouses, and ulcers, and inspection should also look for boney irregularities and muscle atrophy. Diabetic distal symmetric polyneuropathy shows sensory loss in all modalities with progression to weakness and atrophy in a distal to proximal distribution. Examination in small fiber neuropathy can show allodynia and loss of sensation to various modalities. Warm, dry skin and orthostasis may signify underlying autonomic neuropathy.

Diabetic lumbosacral radiculoplexus neuropathy generally presents with proximal deficits; motor findings are greater than sensory findings. Physical examination should be documented and serially monitored to accurately assess disease progression.1

Functional assessment

History should emphasize mobility, transfers, and other activities of daily living. Functional independence measures and the 36-item short form health survey may assist in functional assessments.

Laboratory studies

Basic laboratory evaluation of polyneuropathy includes: complete blood count, erythrocyte sedimentation rate, vitamin B12, folate, comprehensive metabolic panel (including fasting blood glucose and both renal and liver function tests), thyroid function tests, and serum protein immunofixation electrophoresis. Depending on the results of these studies and the patient’s history, other studies may include: methylmalonic acid with or without homocysteine, drug and toxin screens, urinalysis, and urine protein electrophoresis with immunofixation. Whether these routine studies need to be performed in known diabetics or prediabetics is unclear. Prediabetics can be identified with a fasting glucose, HbA1c, or glucose tolerance test.6


Magnetic resonance imaging of the lumbar spine and arterial studies may identify spinal or vascular etiologies of symptoms that mimic DN. Plain films may diagnose and follow the progression of neuroarthropathies, such as Charcot foot. When osteomyelitis is suspected, advanced imaging may assist in confirming the diagnosis.7

Supplemental assessment tools

Electrodiagnostic studies, including electromyography (EMG) and nerve conduction studies, may facilitate the diagnosis, monitor progression, and investigate other pathologies within the differential diagnosis of DN. In diabetic distal symmetrical polyneuropathy, conduction slowing is evidenced by prolonged latencies for distal and late responses and decreased conduction velocities. Axonal loss shows small motor and sensory amplitudes. Fibrillation potentials and positive sharp waves on needle EMG examination reveal active axonal loss. Large amplitude motor unit action potentials indicate a chronic component to the individual’s DN. Diabetic amyotrophy often shows evidence of axonal loss in affected nerve distribution. Small fiber neuropathies frequently have normal standard electrodiagnostic studies, and skin biopsy may be useful in this diagnosis. This involves a 3 mm diameter punch biopsy usually taken from the lower extremity, which has 88% sensitivity. Autonomic neuropathy can be diagnosed with specialized neurophysiologic methods including the sympathetic skin response and R-R variability testing on electrocardiogram.1,8

Early predictions of outcomes

DN increases the risk of amputation 1.7-fold, and more than 80% of amputations are related to a foot ulcer or other injury. Following a diabetes-related amputation of one limb, the risk of amputation for the corresponding limb is 50% over five years. If autonomic neuropathy is diagnosed in a diabetic individual, the chance of death increases by 25-50% over 10 years.1,9


It is important to ensure that the living environment of a patient with DN is accessible. Proper lighting at night and avoidance of throw rugs should be encouraged in order to minimize fall risk.


Available or current treatment guidelines

Ultimate goals of treatment are maintenance of function, quality of life, and limb preservation. There is strong evidence that anticonvulsants are beneficial, particularly pregabalin. There is moderate evidence supporting antidepressants (tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors), capsicin, isosorbide dinitrate spray, and opioids (dextromethorphan, morphine sulfate, tramadol, and oxycodone) to treat the pain associated with DN. Medication selection generally depends on their roles in treating comorbid conditions, contraindications, and on their interactions with other medications. Patients with neuropathic pain refractory to the above treatments may be candidates for spinal cord stimulators. There is moderate evidence that percutaneous electrical nerve stimulation is beneficial.1,10

At different disease stages

Evalulations and treatments must be tailored to the specific complications and functional needs of each patient.

Coordination of care

The physiatrist coordinates diagnostic and treatment plans among orthotists, prosthetists, podiatrists, physical and occupational therapists, and surgical specialists.4

Patient & family education

The patient and family must be educated about the relationship between glycemic control and the course of diabetic neuropathies. Patients and their caretakers should be encouraged to perform daily foot inspections and bring any skin lesions to the attention of their physician. They must be educated on the complications of DN and effective methods of prevention. Routine podiatry visits must be recommend for nail care.

Emerging/unique Interventions

Function should be monitored subjectively by the patient. Skin lesions must be carefully observed to resolution. For pain and other subjective neuropathic complaints, the Visual Analogue Scale, Neuropathic Pain Scale, Mcgill Pain Questionaire, and the Leeds Assessment of Neuropathic Symptoms and Signs may also assist in assessing treatment efficacy.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

The importance of glycemic control cannot be overstated, and patients should be continually educated about this. As vibratory sensation is lost early in DN, an examination of this should be performed if DN is suspected and serially monitored. Physiatrists must coordinate effectively with primary care and other involved physicians, providing education as appropriate for prevention and treatment techniques.


Cutting edge concepts and practice

Alpha-lipoic acid is a promising treatment for the stabbing, burning pain associated with distal symmetric DN. It is a nonprescription antioxidant with proven benefits in a randomized controlled trial.11


Gaps in the evidence-based knowledge

Etiologies for DN remain controversial. Several novel theories for the pathogenesis of DN are currently in development. Neurotrophic factors, such as vascular endothelial growth factor, nerve growth factor, and insulin-like growth factor, promote the maintenance and regeneration of neurons, and low levels in diabetics may lead to neuronal apoptosis.1

The relationship between prediabetes and neuropathy remains unproven, as does the relationship between chronic inflammatory demyelinating polyneuropathy and DN.


  1. Wooten K. Clinical features and electrodiagnosis of diabetic peripheral neuropathy in the dysvascular patient. Phys Med Rehabil Clin N Am. 2009;20:657-676.
  2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatement of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med. 1993;329:977-986.
  3. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve. 2002;25:477-491.
  4. DeLisa JA, Gans BM, et al. Physical Medicine and Rehabilitation: Principles and Practice. 14th ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2005:873-911.
  5. Vibratory perception in diabetics. Acta Medica Scand. 1963;173:22-37.
  6. England JD, Gronseth GS, Franklin G, et al. Evaluation of distal symmetrical polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle Nerve. 2009;39:116-125.
  7. Frykberg R, Zgonis T, Armstrong DG, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg. 2006;45(5 Suppl):S1-S66.
  8. England JD, Gronseth GS, Franklin G, et al. Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve. 2009;39:106-115.
  9. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Harris M, Cowie CC, Stearn MP, eds. Diabetes in America. 2nd ed. Bethesda, MD: National Diabetes Data Group of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; 1995:409-428.
  10. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy–report of the American Association of Neuromuscular and Electrodiagnostic Medicine, The American Academy of Physical Medicine & Rehabilitation. Muscle Nerve. 2011;43; 910-917.
  11. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 Trial. Diabetes Care. 2006;29:2365-2370.

Author Disclosure

Jarron I. Tilghman, MD
Nothing to Disclose

Kevin Komes, MD
Nothing to Disclose

Michael Khadavi, MD
Nothing to Disclose

Ebby Varghese, MD
Nothing to Disclose

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