eMedicine Specialties > Physical Medicine and Rehabilitation > Peripheral Neuropathy

Diabetic Neuropathy

Author: Andrew L Sherman, MD, MS, Associate Professor of Clinical Rehabilitation Medicine, Vice Chairman, Chief of Spine and Musculoskeletal Services, Program Director, SCI Fellowship and PMR Residency Programs, Department of Rehabilitation Medicine, Leonard A Miller School of Medicine, University of Miami
Coauthor(s): Diana Echeverry, MD, MPH, Assistant Professor, Department of Endocrinology, Charles Drew University of Medicine and Science
Contributor Information and Disclosures

Updated: Oct 19, 2009

Introduction

Background

Neuropathies are the most common complication of diabetes mellitus (DM). Neuropathies related to DM affect up to 50% of patients both with type 1 and type 2 DM. Neuropathies also cause great morbidity because the symptoms severely decrease patients' quality of life (QOL). While the primary symptoms of neuropathy may be highly unpleasant, the secondary complications such as falls, foot ulcers,¹ cardiac arrhythmias, and ileus are even more serious and can lead to fractures, amputations, and even death in patients with DM. Increasing evidence indicates that electrophysiologic, quantitative, and clinical measures of neuropathy can predict endpoints of morbidity.

Diabetic neuropathies are heterogeneous in type; thus, several classifications of diabetic neuropathy were created and recognized. A classification system by Thomas combines both anatomy and pathophysiology, is the most intuitive, and is presented below with a few modifications:

• Hyperglycemic neuropathy (acute)
• Generalized symmetric polyneuropathies
  • Sensory
  • Sensorimotor (chronic, symmetric)
  • Autonomic
    • Cardiovascular autonomic neuropathy
    • Gastrointestinal neuropathy
    • Genitourinary neuropathy
    • Sudomotor neuropathy
• Focal and multifocal neuropathies
  • Cranial
  • Proximal motor (amyotrophy)
  • Thoracic or lumbar radiculopathies
  • Focal limb (entrapment neuropathies)
• Superimposed chronic inflammatory demyelinating polyneuropathy (CIDP)

Understanding of the classifications becomes easier with a review of the anatomy of the peripheral nervous system. Peripheral neurons can be categorized broadly as motor, sensory, or autonomic.

• Motor neurons originate in the central nervous system (CNS) and then go to the anterior horn of the spinal cord. From the anterior horn, they exit the spinal cord (via ventral roots) and combine with other fibers to go through the brachial or lumbar plexuses and innervate their target organs through peripheral nerves.
• Sensory neurons originate at the dorsal root ganglia (which lie outside the spinal cord) and follow a similar course with motor neurons. Sensory neurons are subdivided into categories according to the sensory modality they convey (see the Table).
• Autonomic neurons consist of sympathetic and parasympathetic types. In the periphery, preganglionic fibers leave the CNS and synapse on postganglionic neurons in the sympathetic chain or in sympathetic ganglia.

Subdivisions of Sensory Neurons

Open table in new window

Sensory neuropathy usually is insidious in onset and shows a stocking and glove distribution in the distal extremities. Sensorimotor neuropathy involves both sensory and motor function; pain, numbness, and paresthesias occur along with decreased strength and atrophy in the lower limb muscles. The feet of patients with DM often become insensate and are highly susceptible, not only to ulcers, but also to the Charcot foot (ie, a foot that loses its structure secondary to trauma and acute arthropathy, see Charcot-Marie-Tooth Disease) from frequent and multiple traumas. Autonomic neuropathy involves the cardiovascular system, gastrointestinal system, and the genitourinary system.

Diabetic amyotrophy affects the proximal lower extremities and leads to muscle atrophy and weakness. The focal and multifocal neuropathies can be separated into ischemic (presumed) and entrapment neuropathies. The ischemic focal neuropathies can occur after a single acute event of ischemia to a single blood vessel or group of blood vessels that serve a single nerve or group of nerves. Cranial nerve palsies, such as oculomotor neuritis and Bell palsy, are sudden and asymmetric and generally are self-limited.

Diabetic amyotrophy also can be classified under focal neuropathy because primarily the femoral nerve or upper lumbar plexus is affected. Entrapment neuropathies are more gradual in onset and usually are asymmetric. These disorders occur more frequently in the diabetic population than in the general population. Entrapment neuropathies include carpal and cubital tunnel syndromes and meralgia paresthetica. The table above demonstrates that the smaller fibers are affected first in DM, and with continued exposure to hyperglycemia, the larger fibers become affected.

Pathophysiology

The cause of diabetic neuropathy continues to be studied in both basic and clinical sciences. Thus far, diabetic neuropathy is known to be multifactorial and there is a large basis for prevention. Both basic science research and large prospective clinical studies, such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetic Study (UKPDS) have shown that tight glucose control and euglycemia (or near euglycemia) can prevent the onset or slow progression of diabetic neuropathy.

Currently, the factors recognized in the pathogenesis of diabetic neuropathy are metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of small unmyelinated nerves (C fibers) in a visceral and cutaneous distribution. The 2 main features that explain symptoms and complications of diabetic neuropathy are believed to be the degeneration of nerve fibers and grossly diseased blood vessels that supply those nerve fibers. Proper circulation determines whether or not nerve fibers repair themselves or proceed to total degeneration.

Metabolic failure can affect several pathways, greatly contributing to diabetic neuropathy. Hyperglycemia causes several biological changes, including an increase in the production of advanced glycosylated end products, a defect in the polyol pathway and involvement of aldose reductase enzyme, and impaired resistance to oxidative stress. All the above biological changes are closely related and work together to initiate the neuropathic complications.

Glucose is converted to sorbitol in cells by the aldose reductase enzyme. In hyperglycemia, sorbitol accumulates and results in the swelling of cells and increased activity of protein kinase C, which is implicated in the damage of blood vessels related to increasing basement membrane synthesis and vascular permeability. This sorbitol accumulation also results in a decrease in the intracellular levels of myoinositol (an important membrane component) and taurine to the extreme that they become rate limiting for intracellular metabolism. Nonspecific glycosylation of axon and microvessel proteins may cause reduction of endoneural blood flow and nerve ischemia, causing nerve and ganglia hypoxia and oxidative stress.

Derangement of the polyol pathway and vascular ischemia converge through oxidative stress. The conversion of glucose to sorbitol and sorbitol to fructose results in the depletion of reduced nicotinamide adenine dinucleotide (NADPH) and oxidized nicotinamide adenine dinucleotide (NAD⁺) stores in the cell, making the cell more vulnerable to reactive stresses. Ischemia induces reactive oxygen species, so the increase in these and the increase in vulnerability cause nerve injury. These processes are the basis of antioxidant therapy.

Another factor involved in the pathogenesis of diabetic neuropathy is the need for nerve regeneration after injury. Studies have suggested that loss of neurotrophic support contributes to the pathogenesis. Neurotrophic factors are proteins that promote the development, survival, and maintenance of specific neuronal populations. Sensory neuropathy involves the smallest nerve fibers (ie, C fibers). These small nerve fibers are supported by neurotrophic factor and nerve growth factor (NGF); hence, there is active research on this factor. Several studies have demonstrated that levels of NGF are reduced significantly and its action is impaired.

Other factors implicated in diabetic neuropathy are neurotrophin-3 and insulin growth factors. Autoimmune damage has been postulated, and one study demonstrated that serum autoantibodies against sulfatide and phospholipid in patients with type 2 DM were higher in patients with documented neuropathy than in those with no neuropathy. In summary, the etiology of neuropathy is multifactorial. Therapy for patients with diabetic neuropathy needs to encompass these factors to increase the yield of a successful treatment.

Frequency

United States

Diabetic neuropathy occurs in 10-20% of patients newly diagnosed with DM, and its prevalence is up to 50% in elderly patients with DM. Most studies agree that the overall prevalence of symptomatic diabetic neuropathy is approximately 30% of all patients with DM. The incidence of diabetic neuropathy is 2% of the general population. Diabetic neuropathy is more common in smokers, people older than 40 years, and those who have uncontrolled DM.

International

Diabetic neuropathy is found around the world in 20-30% of individuals with type 2 DM. This number depends on the type of fiber that is being sensed and the sensitivity of the measure. Individuals with type 1 DM usually develop neuropathy after more than 10 years of living with DM.

Mortality/Morbidity

Mortality increases in people with cardiovascular autonomic neuropathy (CAN). The overall mortality rate over periods up to 10 years was 27% in patients with DM and CAN detected, compared to a 5% mortality rate in those without evidence of CAN. Morbidity results from foot ulceration and lower extremity amputation. These 2 complications are the most common causes of hospitalization among people with DM in Western countries. Severe pain, dizziness, diarrhea, and impotence are common symptoms that decrease the QOL of a patient with DM.

Race

Members of minority groups (eg, Hispanics, African Americans) have more secondary complications from diabetic neuropathy, such as lower extremity amputations, than whites. They also have more hospitalizations for neuropathic complications.

Sex

DM affects men and women with equal frequency. Neuropathic pain causes more morbidity in females than in males.

Age

Diabetic neuropathy is more common in elderly patients. Up to 50% of patients with type 2 DM have peripheral neuropathy.

Clinical

History

Diabetic neuropathy is more common in patients with a longer duration of DM. Symptoms can vary significantly based on the type of neuropathy.

• Patients with the most common neuropathy, generalized sensorimotor peripheral neuropathy, most often report symptoms related to altered sensation in the distal feet or hands. The most common words used to describe the symptoms are pain, numbness, and pins and needles (ie, paresthesia). The distribution of symptoms is stronger distally and less proximally and is termed a glove-stocking distribution. The symptoms include the following:
  • Dysesthetic pain in the hands and feet
    • Burning sensations
    • Skin tingling
    • Allodynia - Painful sensation on contact with something that typically would not hurt (eg, bed sheets)
    • Hyperalgesia - Abnormally exaggerated response to painful stimuli
  • Paresthetic pain
    • Sensation of pins and needles
    • Electric shock–like sensation
    • Numbness and aching
    • Knifelike pain
    • Sensation like feet have been in ice water
    • Shooting and lancinating pain
  • Muscular pain (much less common)
    • Dull ache
    • Night cramps
    • Bandlike sensation
    • Drawing sensation
    • Deep aches
    • Spasms
    • Toothachelike pain
• Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. Also, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage.
  • Gastrointestinal neuropathy
    • Dysphagia
    • Abdominal pain
    • Nausea/vomiting
    • Malabsorption
    • Fecal incontinence
    • Diarrhea
    • Constipation
  • Cardiovascular autonomic neuropathy
    • Persistent sinus tachycardia
    • Orthostatic hypotension
    • Sinus arrhythmia
    • Decreased heart variability in response to deep breathing
    • Valsalva maneuver
    • Near syncope upon changing positions from supine to standing
  • Bladder neuropathy (must differentiate from prostate or spine disorders)
    • Poor urinary stream
    • Feeling of incomplete bladder emptying
    • Straining to void
  • Sudomotor neuropathy
    • Heat intolerance
    • Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
    • Gustatory sweating
• Mononeuropathy may involve the following:
  • Cranial nerves III (oculomotor), VI (abducens), and IV (trochlear)
  • Diplopia and eye pain
  • Third nerve palsy (pupil usually spared when secondary to diabetic neuropathy)
  • Seventh nerve palsy
  • Bell palsy

Physical

Physical examination of patients with suspected distal sensory motor or focal (ie, entrapment or noncompressive) neuropathies should include at least the following:

• Peripheral neuropathy
  • Gross light touch and pinprick sensation
  • Distal proprioception
  • Reflexes (ankle)
  • Vibratory sense (128-Hz tuning fork) at base of great toenail and monofilament (5.07) to test larger sensory fibers: Inability to perceive the 128-Hz tuning fork or to feel a 10-g (5.07) monofilament on the plantar surfaces of the foot identifies patients who are at increased risk (ie, 60% in next 3 y) of developing a foot ulcer.¹ The 2 tests should be performed at least every year.
  • Dorsal pedal and posterior tibial pulses
  • Skin examination for dryness, tinea pedis, cracks, onychomycoses, foot deformities, acute erythema and tenderness, and fluctuance under calluses
  • Tinel testing
  • Strength testing and examination for distal intrinsic extremity muscle atrophy
  • Cranial nerve testing
  • Heel-toe walk
• Autonomic neuropathies: In 2001, Perkins et al described a number of simple screening tests in outpatient clinics and validated a scoring system to document and monitor neuropathy in the clinic.² In 2002, Dyck et al described case report forms for recording symptoms and signs of neuropathy that might be useful in longitudinal follow-up of individual patients.³
  • Blood pressure and heart rate: Measure blood pressure and heart rate while the patient is supine and standing.
  • Sinus arrhythmia (SA) ratio: Have the patient breathe 6 times per minute while monitoring the heart rate in a continuous strip. Measure the longest R-R interval during expiration and the shortest R-R interval during inspiration. Take the average of 6 breaths. The SA ratio is R-R expiration/R-R inspiration. The normal response is 1:2.
  • Romberg sign testing
  • Gait analysis

Causes

Risk factors that are associated with more severe symptoms include the following⁴ :

• Poor glycemic control
• Advanced age
• Hypertension
• Long duration of DM
• Dyslipidemia
• Smoking
• Heavy alcohol intake
• HLA-DR3/4 phenotype
• Tall height

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