Diabetic Neuropathy

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Diabetic Neuropathy

Author: Dianna Quan, MD, Director, Electromyography Laboratory, Department of Neurology, Assistant Professor, University of Colorado Health Sciences Center

Dianna Quan is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Coauthor(s): Emad Soliman, MD, MSc, Consulting Staff, Department of Neurology, St John's Riverside Hospital; Charles Gellido, MD, Laboratory Director, Assistant Professor, Department of Neurology, Jacobi Medical Center, Albert Einstein College of Medicine

Editors: Milind J Kothari, DO, Professor and Vice-Chair for Education and Training, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Hershey Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, University of Pittsburgh Medical Center - Shadyside, Clinical Associate Professor, Department of Neurology, University of Pittsburgh School of Medicine; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author and Editor Disclosure

Synonyms and related keywords: diabetic polyneuropathy, diabetic amyotrophy, proximal diabetic neuropathy, mononeuropathy multiplex, diabetic autonomic neuropathy, distal symmetric sensorimotor polyneuropathy, painful diabetic neuropathy, generalized sensorimotor polyneuropathy of diabetes mellitus, diabetic peripheral neuropathy, peripheral neuropathies, chronic hyperglycemia, entrapment neuropathies, diabetic neuropathy, carpal tunnel syndrome, numbness, feeling of wearing gloves, loss of balance, electric shocklike feelings, hypersensitivity to touch, foot slapping, toe scuffing, postural lightheadedness, fainting, urinary urgency, urinary dribbling, urinary incontinence, nocturnal diarrhea, constipation

erectile impotence, ejaculatory failure, nighttime painful paresthesias, impaired proprioception, impaired vibratory perception, sensory ataxia, anhidrosis, bladder atony, unreactive pupils, painless electric tingling, snug bandlike sensation around ankles, snug bandlike sensation around feet, absent ankle jerk reflexes, proprioceptive sensory impairment, gait instability, orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, sluggish light reflex

diabetic neuropathic cachexia, median neuropathy of the wrist, MNW, ulnar neuropathy of the elbow, UNE, single somatic mononeuropathies, multiple somatic mononeuropathies, single monoradiculopathies, multiple monoradiculopathies, diabetic lumbosacral radiculoplexoneuropathy, DLSRPN, diabetic thoracolumbar radiculoneuropathy, DTLRN, diabetic autonomia, cranial mononeuropathy, anterior ischemic optic neuropathy, diabetic oculomotor cranial mononeuropathies, acute periorbital pain, facial neuropathy, mononeuritis multiplex

diabetic polyradiculopathy, thoracoabdominal neuropathy, lumbosacral radiculoplexopathy, thoracolumbar neuropathy, thoracoabdominal radiculopathy, thoracic radiculopathy, truncal neuropathy, asymmetric proximal motorneuropathy, diabetic femoral neuropathy, femorosciatic neuropathy, diabetic myelopathy, Bruhn-Garland syndrome, poorly controlled diabetes, acute painful neuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, diabetes mellitus-CIDP, demyelinating neuropathy, diabetic neuropathy

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" (Boulton, 1998). 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). 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. Pathologically, numerous changes have been demonstrated in both myelinated and unmyelinated fibers.

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. The best-supported mechanisms include the following:

Metabolic theory

This theory proposes that 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.

Vascular (ischemic-hypoxic) theory

According to this theory, endoneurial ischemia develops because of increased endoneurial vascular resistance to hyperglycemic blood. Various metabolic factors, including formation of advanced glycosylation end products, also have been implicated. The end results are capillary damage, inhibition of axonal transport, reduced Na+/K+-ATPase activity, and finally axonal degeneration.

Altered neurotrophic support theory

Neurotrophic factors are important in the maintenance, development, and regeneration of responsive elements of the nervous systems. Nerve growth factor (NGF) is the best studied. This protein promotes survival of sympathetic and small-fiber neural crestÒderived elements in the peripheral nervous system. In animals with diabetes, both production and transport of NGF are impaired. Antioxidants have been used to enhance the effects of NGF.

Laminin theory

Laminin is a large, heteromeric, curariform glycoprotein composed of a large alpha chain and two smaller beta chains, beta 1 and beta 2. In cultured neurons, laminin promotes neurite extension. Lack of normal expression of the laminin beta 2 gene may contribute to the pathogenesis of diabetic neuropathy.

Autoimmune theory

Autoimmune diabetic neuropathy is postulated to result from immunogenic alteration of endothelial capillary cells. This is the basis for the use of intravenous immunoglobulin (IVIg) to treat some variants of diabetic neuropathy.

Frequency
United States
An estimated 10-65% of patients with diabetes have some form of peripheral neuropathy. Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. One half of patients have distal symmetric polyneuropathy, and one fourth have compression or entrapment neuropathies (mainly carpal tunnel syndrome).

The wide variability in diabetic neuropathy prevalence data is due to lack of consistent criteria for the diagnosis of peripheral neuropathy, variable methods of selecting patients for study, and differing assessment techniques. In addition, because most 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% patients already had neuropathy when diagnosed with diabetes. After 25 years, the number with neuropathy rose to 45%. 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
Male patients with diabetes usually have a higher incidence of diabetic neuropathy than female patients.

Age

Diabetic neuropathy can occur at any age but is more common with increasing severity and duration of diabetes.
Symptomatic presentation is most common in patients older than 50 years.
Some theories suggest that diabetic neuropathy begins early in the hyperglycemic process, often before the clinical diagnosis of diabetes is made.

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. Occasionally, patients with type 2 diabetes mellitus may 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 shockÒlike feelings, aching, tightness, or hypersensitivity to touch.
Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms 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.
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, and increased height. Establishing the diagnosis requires careful evaluation, since 5-10% of patients with diabetes have neuropathy from another cause.
Symmetric polyneuropathies involve multiple nerves diffusely and symmetrically.

Distal symmetric polyneuropathy
Most common manifestation of diabetic neuropathy
Chronic symmetrical symptoms affecting peripheral nerves in a length-dependent pattern (the longest nerves affected first)
Sensory, motor, and autonomic functions affected in varying degrees, with sensory abnormalities predominating
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
Weakness of foot muscles and decreased ankle and knee reflexes occur commonly
Loss of sensation predisposes to development of foot ulcers and gangrene
With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia)
Small-fiber neuropathy
Less common 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 hyperglycemia 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.
Asymmetric neuropathies include single or multiple cranial mononeuropathies (eg, median neuropathy of the wrist, ulnar neuropathy of the elbow, single or multiple somatic mononeuropathies, single or multiple monoradiculopathies, diabetic lumbosacral radiculoplexoneuropathy [DLSRPN], diabetic amyotrophy, diabetic thoracolumbar radiculoneuropathy). 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, DLSRPN) 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.
Common sites include median nerve at the wrist (carpal tunnel syndrome), ulnar nerve at the elbow, and common peroneal nerve at the fibular head. Symptoms often are bilateral.
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 polyradiculopathy
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 more commonly 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) or weakness of quadriceps muscles (L3-4 roots).
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 radiculoplexopathy
Synonyms include symmetric proximal motor neuropathy, diabetic amyotrophy, diabetic femoral neuropathy, femorosciatic neuropathy, and diabetic myelopathy (Bruhn-Garland syndrome).
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.
Symptoms begin unilaterally and later may spread to the opposite limb.
Starts as sudden, severe, unilateral pain and may occur in the hip/lower back or shoulder/neck.
Weakness develops days to weeks later. Atrophy of the limb musculature is common.
Reflexes in the affected limb may be depressed.
Numbness and paresthesias may occur.
Chronic inflammatory demyelinating polyneuropathy (CIDP) may be seen in patients with diabetes.

Krendel et al described 15 patients with polyneuropathy, amyotrophy, or mononeuropathy multiplex due to type 2 diabetes mellitus. Electrophysiologic and histologic analyses of nerve or muscle were performed. Perivascular and vascular lymphocytic infiltrates were noted in 7 patients. Neurological improvement with immunosuppressive therapy, often including IVIg, was noted among some patients. Six additional patients with type 1 diabetes mellitus had electrophysiologic evidence of demyelinating neuropathy. Although no vascular inflammation was seen on biopsy, "onion bulbs" were found, reflecting a chronic demyelinating process. These patients responded to immunosuppressive treatment. The authors postulated that these patients had CIDP and that type 1 diabetes mellitus may predispose patients to CIDP.

Patients with CIDP typically have a more chronic course (up to 180 months), do not lose weight, and are more likely to have a distal neuropathy, commonly involving the upper extremities. However, as in the case of inflammatory vasculopathy, the distribution is often asymmetric.


In patients with diabetes, demyelination on nerve conduction study should prompt evaluation for CIDP, just as it does in those without diabetes. Why patients with diabetes may be predisposed to CIDP is unknown. The fact that demyelination has been found more often in association with type 1 diabetes than with type 2 diabetes suggests autoimmune factors may be important, since these patients more often have other associated autoimmune diseases.

Patients with demyelinating neuropathy by nerve conduction study criteria can reasonably be assumed to have CIDP. The available data suggest that diabetic patients with these findings may improve with IVIG treatment. Nerve biopsy with immunohistochemistry to look for evidence of vasculitis or other causes of neuropathy is reasonable.

Overall, diabetes mellitus-CIDP differs from idiopathic CIDP in the following ways:

Older age at presentation in patients with diabetes
Duration of symptoms at the time of evaluation is longer in patients with diabetes
Prominent axonal loss in the diabetes group
Less response to therapy in the diabetes group

Physical

Diabetic polyneuropathy often develops as generalized asymptomatic dysfunction of peripheral nerve fibers. The first clinical sign that usually develops in tandem with abnormal nerve conductions is decrease or loss of ankle jerks, or decrease or loss of vibratory sensation over the great toes. With more severe involvement, the patient may lose deep tendon reflexes and develop weakness of small foot muscles. More focal findings may be seen with injury to specific nerves as described above.

Five criteria are needed to establish the diagnosis of diabetic polyneuropathy.

The patient has diabetes mellitus by National Diabetes Data Group criteria.
Diabetes mellitus has caused prolonged chronic hyperglycemia.
The patient has predominantly distal sensorimotor polyneuropathy in the lower extremities.

Diabetic retinopathy or nephropathy is approximately similar in severity to polyneuropathy.

Other causes of sensorimotor polyneuropathy have been excluded.