eMedicine Specialties > Neurology > Neuromuscular Diseases

Diabetic Neuropathy

Author: Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

Neuropathies are characterized by a progressive loss of nerve fibers that can be assessed noninvasively by several tests of nerve function, including nerve conduction studies and electromyography, quantitative sensory testing, and autonomic function tests. A widely accepted definition of diabetic peripheral neuropathy is "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes."¹ Diabetic neuropathy is classified into several syndromes, each with a distinct pattern of involvement of peripheral nerves. Patients often have multiple or overlapping syndromes.

Peripheral neuropathies have been described in patients with primary (types 1 and 2) and secondary diabetes of diverse causes, suggesting a common etiologic mechanism based on chronic hyperglycemia. The contribution of hyperglycemia has received strong support from the Diabetes Control and Complications Trial (DCCT).² The dose-dependent effect of hyperglycemia on nerves has been supported further in recent years by increasing recognition of an association between impaired glucose tolerance (prediabetes) and peripheral neuropathy.³ Pathologically, numerous changes have been demonstrated in both myelinated and unmyelinated fibers.

For related information, see Medscape's Incretin Hormones in Diabetes and Metabolism and Diabetic Microvascular Complications Resource Centers.

Pathophysiology

The factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced. It is generally accepted to be a multifactorial process. Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the following:

Polyol pathway

Hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased membrane Na⁺/K⁺ -ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation. This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction.⁴

Advanced glycation end products (AGE)

The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advance glycation end products that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.⁵   

Oxidative stress

The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha lipoic acid may hold promise for improving neuropathic symptoms.⁶

Related contributing factors

Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotropins, and nerve ischemia. Clinical trials of the best studied neurotropin, human recombinant nerve growth factor were disappointing. However, with future refinements, one or more of these mechanisms may provide reasonable targets for pharmacological intervention.

In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles.

Frequency

United States

A large American study estimated that 47% of patients with diabetes have some peripheral neuropathy.⁷ Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. More than half of patients have distal symmetric polyneuropathy. Focal syndromes such as carpal tunnel syndrome (14-30%)⁸ , radiculopathies/plexopathies, and cranial neuropathies account for the rest. Solid prevalence data for the latter 2 less common syndromes is lacking.   

The wide variability in symmetric diabetic polyneuropathy prevalence data is due to lack of consistent criteria for diagnosis, variable methods of selecting patients for study, and differing assessment techniques. In addition, because many patients with diabetic polyneuropathy are initially asymptomatic, detection is extremely dependent on careful neurologic examination by the primary care clinician.

International

In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients already had neuropathy when diagnosed with diabetes.⁹ After 25 years, the number with neuropathy rose to 45%. In the United Kingdom, the prevalence of diabetic neuropathy among the hospital clinic population was noted to be around 29%.¹⁰ Using additional methods of detection, such as autonomic or quantitative sensory testing, the prevalence may be higher.

Mortality/Morbidity

Patients with untreated or inadequately treated diabetes have higher morbidity and complication rates related to neuropathy than patients with tightly controlled diabetes. Repetitive trauma to affected areas may cause skin breakdown, progressive ulceration, and infection. Amputations and death may result.

Race

No definite racial predilection has been demonstrated for diabetic neuropathy.

Sex

Age

Diabetic neuropathy can occur at any age but is more common with increasing age and severity and duration of diabetes.

Clinical

History

In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, in type 2, it may present after only a few years of known poor glycemic control. Patients with type 2 diabetes mellitus may sometimes already have neuropathy at the time of diagnosis.

• Since diabetic neuropathy can manifest with a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy.
  • Sensory symptoms may be negative or positive, diffuse or focal. Negative sensory symptoms include feelings of numbness or deadness, which patients may describe as being akin to wearing gloves or socks. Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common. Positive symptoms may be described as burning, prickling pain, tingling, electric shock-like feelings, aching, tightness, or hypersensitivity to touch.
  • Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms may include impaired fine hand coordination and difficulty with tasks such as opening jars or turning keys. Foot slapping and toe scuffing or frequent tripping may be early symptoms of foot weakness. Symptoms of proximal limb weakness include difficulty climbing up and down stairs, difficulty getting up from a seated or supine position, falls due to the knees giving way, and difficulty raising the arms above the shoulders. In the most common presentation of diabetic neuropathy with symmetrical sensorimotor symptoms, minor weakness of the toes and feet may be seen, but severe weakness is uncommon and should prompt investigation into other causes, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or vasculitis. More severe weakness may be observed in asymmetrical diabetic neuropathy syndromes (see Asymmetric neuropathies). 
  • Autonomic symptoms may be sudomotor (dry skin due to lack of sweating or excessive sweating in defined areas), pupillary (poor dark adaptation, sensitivity to bright lights), cardiovascular (postural lightheadedness, fainting), urinary (urgency, incontinence, dribbling), gastrointestinal (diarrhea, constipation, nausea, or vomiting), and sexual (erectile impotence and ejaculatory failure in men, loss of ability to reach sexual climax in women).
• A generally accepted classification of diabetic neuropathies divides them broadly into symmetric and asymmetric neuropathies. Development of symptoms depends on total hyperglycemic exposure and other risk factors such as elevated lipids, blood pressure, smoking, increased height, and high exposure to other potentially neurotoxic agents such as ethanol. Establishing the diagnosis requires careful evaluation since patients with diabetes may have neuropathy from another cause. Depending on the physician practices studied, this group may represent 10-26% of diabetic patients with neuropathy.^7,12  
• Symmetric polyneuropathies involve multiple nerves diffusely and symmetrically.
  • Distal symmetric polyneuropathy
    • Most common manifestation of diabetic neuropathy
    • Sensory, motor, and autonomic functions affected in varying degrees, with sensory abnormalities predominating
    • Chronic symmetrical symptoms affecting peripheral nerves in a length-dependent pattern (the longest nerves affected first). 
    • Commonly presents as painful paresthesias and numbness, which begin in the toes and ascend proximally in a stockinglike distribution over months and years
    • When sensory symptoms reach the knees, hands develop similar symptoms, progressing proximally in a glovelike distribution
    • Anterior aspect of the trunk and vertex of the head may be affected at a very late stage
    • Mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly
    • Loss of sensation predisposes to development of foot ulcers and gangrene¹³
    • With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia)
  • Small-fiber neuropathy
    • Distal symmetrical neuropathy involving predominantly small-diameter sensory fibers (A delta and C fibers)
    • Manifests as painful paresthesias that patients perceive as burning, stabbing, crushing, aching, or cramplike, with increased severity at night
    • Loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception
  • Diabetic autonomic neuropathy
    • Pure autonomic is neuropathy rare.
    • Some degree of autonomic involvement is present in most patients with diabetic polyneuropathy.
    • Signs may include orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, anhydrosis, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.
  • Diabetic neuropathic cachexia
    • Precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fiber neuropathy, and autonomic dysfunction
    • Occurs more often in older men; impotence is common.
    • Muscle weakness is uncommon.
    • Symptoms usually improve with prolonged glycemia control.
    • Symptoms are often refractory to other pharmacologic treatment. Limited anecdotal improvement is reported with nonpharmacologic treatments such as sympathectomy, spinal cord blockade, and electrical spinal cord stimulation.
    • Recovery may be incomplete and prolonged over many months
• Asymmetric neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include median neuropathy of the wrist (carpal tunnel syndrome), single or multiple somatic mononeuropathies, thoracic radiculoneuropathy, lumbosacral radiculoplexus neuropathy, and cervical radiculoplexus neuropathy. These syndromes are distinguished from typical distal diabetic polyneuropathy by the following characteristics: (1) they often have a monophasic course, (2) some are associated with inflammatory angitis and ischemia (eg, lumbosacral radiculoplexus neuropathy) and may appear acutely or subacutely, and (3) they have a weaker association with total hyperglycemic exposure than symmetrical polyneuropathies.
  • Cranial mononeuropathy
    • Cranial nerves (CN) III, IV, VI, VII, and II are most often involved.
    • CN III, IV, and VI disease manifests as acute or subacute periorbital pain or headache followed by diplopia. Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared. Complete spontaneous recovery usually occurs within 3 months.
    • Facial neuropathy manifests as acute or subacute facial weakness (taste is not normally involved) and can be recurrent or bilateral. Most recover spontaneously in 3-6 months.
    • Anterior ischemic optic neuropathy manifests as acute visual loss or visual field defects (usually inferior altitudinal). The optic disk appears pale and swollen; flame-shaped hemorrhages may be present.
  • Somatic mononeuropathies
    • Focal neuropathies in the extremities caused by entrapment or compression at common pressure points or by ischemia and subsequent infarction.
    • Entrapment and compression tend to occur in the same nerves and at the same sites as in individuals without diabetes.
    • Median nerve entrapment at the wrist (carpal tunnel syndrome) is more common in patients with diabetes and can be treated in the same manner as in patients without diabetes. Symptoms are often bilateral. The susceptibility to ulnar nerve entrapment at the elbow or common peroneal nerve entrapment at the fibular head is not definitely increased among patients with diabetes.
    • Neuropathy secondary to nerve infarction presents acutely with focal pain associated with weakness and variable sensory loss in the distribution of the affected nerve. Multiple nerves may be affected (mononeuritis multiplex).
  • Diabetic thoracic radiculoneuropathy
    • Burning, stabbing, boring, belt-like, or deep aching pain usually begins unilaterally; then may become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness in a dermatomal distribution, most prominent in distal distribution of intercostal nerves.
    • Single or multiple spinal roots are involved. Contiguous territorial extension of symptoms may occur in a cephalad, caudal, or contralateral direction.
    • In the trunk, thoracoabdominal neuropathy or radiculopathy may cause chest and/or abdominal pain in the distribution of thoracic and/or upper lumbar roots.
    • Weakness presents in the distribution of the affected nerve root, eg, bulging of the abdominal wall from abdominal muscle paresis (thoracic root).
    • Patients older than 50 years are affected most often; it is more common in diabetes mellitus type 2 and is often associated with significant weight loss.
    • Coexisting diabetic distal symmetrical polyneuropathy often is present.
  • Diabetic radiculoplexus neuropathy 
    • The syndrome may occur in the cervical or lumbosacral distributions and is referred to in the literature by various designations including diabetic amyotrophy, Bruns-Garland syndrome, and diabetic plexopathy, among others.
    • The most frequent initial symptom is sudden, severe, unilateral pain in the hip/lower back or shoulder/neck. Weakness then develops days to weeks later. Atrophy of the limb musculature may occur. Allodynia, paresthesias, and sensory loss are common. 
    • Symptoms usually begin unilaterally and may later spread to the opposite side.
    • Reflexes in the affected limb may be depressed or absent.
    • This condition often occurs in patients older than 50 years with poorly controlled diabetes. It is more common in men than in women.
    • Significant weight loss occurs in 50% of patients.
    • The course is generally monophasic with improvement over many months;  however, some residual deficits often remain.

Physical

• The first clinical sign that usually develops is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then into the hands and arms, a pattern often referred to as "stocking and glove" sensory loss. Very severely affected patients may lose sensation in a shield distribution on the chest. Deep tendon reflexes are commonly hypoactive or absent and weakness of small foot muscles may develop. More focal findings may be seen with injury to specific nerves as described above.
• Distal symmetrical sensorimotor polyneuropathy due to diabetes has been defined in many ways but a few criteria are commonly accepted.
  • The patient must have diabetes mellitus by one of the widely accepted definitions such as those outlined by the American Diabetes Association or World Health Organization.^14,15
  • The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes. 
  • Other causes of sensorimotor polyneuropathy have been excluded.

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