Diabetic Neuropathy

Last Updated: September 28, 2006

Dianna Quan, MD, Emad Soliman, MD, MSc

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"
(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 crestderived 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:

In the US: 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.

Internationally: 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.

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. 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.
o

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
shocklike 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.

o

Distal symmetric polyneuropathy

Most common manifestation of diabetic neuropathy
Chronic symmetrical symptoms affecting peripheral nerves in a lengthdependent 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 smalldiameter 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.
o

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.

o

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.

DIFFERENTIALS
Alcohol (Ethanol) Related Neuropathy
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Nutritional Neuropathy
Sarcoidosis and Neuropathy
Thyroid Disease
Toxic Neuropathy
Uremic Neuropathy
Vasculitic Neuropathy
Other Problems to be Considered:
Amyloid polyneuropathy
Spinal cord tumors
Vitamin B-12 deficiency
Differential diagnoses to consider in the following situations:
Cranial mononeuropathy
Intracranial aneurysms
Bell palsy
Thoracoabdominal neuropathy
Herpes zoster
Spinal tumors
Myocardial infarction
Acute cholecystitis
Acute appendicitis
Diverticulitis
Lumbosacral radiculoplexopathy
Anterior disk protrusion
Spinal cord tumors
Malignant nerve root infiltrations
Inflammatory neuropathies
WORKUP
Lab Studies:

The following basic studies are suggested to exclude common causes of neuropathy
other than diabetes:
o

Complete blood cell count

Complete metabolic panel (electrolytes and liver function panel)

Vitamin B-12 and folate levels

Thyroid-stimulating hormone and thyroxine

Erythrocyte sedimentation rate

Serum protein electrophoresis with immunofixation electrophoresis

Examples of other studies that can be ordered depending on the patient's history and
examination findings include the following:
o

Antinuclear antibody

Rheumatoid factor

Paraneoplastic antibodies

Patients with diabetic neuropathies will likely have elevated hemoglobin A1c levels,
although the severity of the elevation does not always correlate with the severity of the
diabetic neuropathy.

Imaging Studies:

In the appropriate clinical setting, MRI of the cervical, thoracic, and/or lumbar regions
may help to exclude another cause for symptoms mimicking diabetic neuropathy. For
patients who cannot have MRI, CT myelogram is an alternative to exclude compressive
lesions and other pathology in the spinal canal, eg, in lumbosacral radiculoplexopathy
and thoracoabdominal neuropathy. In cranial nerve palsies, brain imaging, usually with
MRI, is helpful to exclude intracranial aneurysms, compressive lesions, and infarcts.

Other Tests:

Electrophysiologic studies are the most sensitive, reliable, and reproducible measures of
nerve function. Electrophysiologic findings usually correlate with morphologic changes on
nerve biopsy. Common early findings are abnormal nerve conduction studies or reduced
variability of heart rate with deep breathing or Valsalva maneuver. Although
electrodiagnostic studies can characterize and quantitate nerve dysfunction, they cannot
distinguish diabetic neuropathy from neuropathy of other causes.
Composite scores, combining clinical, quantitative sensory, and electrophysiologic
measures, are often used in natural history and efficacy studies. Examples include the
Neuropathy Impairment Score in the Lower Limbs + 7 and the Michigan Diabetic
Neuropathy score.

Electromyography and nerve conduction studies

o

Findings on nerve conduction studies depend on the pattern of nerve damage.

Patients with distal symmetrical polyneuropathy from predominant axonal loss
have reduced or absent sensory nerve action potentials, especially in the legs.
With progression of neuropathy, compound motor action potential amplitudes may
also be reduced and abnormalities may be observed in the hands. These changes
reflect length-dependent degeneration of large-diameter myelinated nerve fibers.

Conduction velocities are generally within the normal range or only mildly slowed
in distal symmetrical polyneuropathy. If conduction velocities are less than 70%
the lower limit of normal, or if conduction block is present, the patient may have
superimposed peripheral nerve demyelination in addition to the more typical
axonal loss seen in distal symmetrical polyneuropathy. Generalized demyelinating
changes on nerve conduction studies should prompt further evaluation for CIDP.
Focal slowing of conduction velocity at common sites of entrapment may indicate
one of the mononeuropathy syndromes discussed above.

Nerve conduction study abnormalities may be found in patients with diabetes even
without clinical symptoms of polyneuropathy.

Electromyographic sampling of distal lower extremity muscles may reveal acute

and ongoing denervation in the form of positive sharp waves and fibrillation
potentials (spontaneous discharges). Reinnervation changes such as largeamplitude, long-duration, polyphasic motor unit potentials reflect chronicity.
Abnormalities in paraspinal muscles (eg, spontaneous discharges) usually reflect
disease in spinal nerve roots.

Procedures:

Sural nerve biopsy is now rarely indicated in the diagnosis or longitudinal assessment of
diabetic peripheral neuropathy (see Images 1-2). Reasons for this move away from
biopsies in clinical trials include the invasive nature of the procedure with its attendant
risks, discomfort to the patient, high cost, problems with reproducibility due to sampling
error, and availability of other methods to obtain similar information.

The following new diagnostic approaches for diabetic neuropathy are currently under
intense study. Details of these techniques are beyond the scope of this review.
o

Skin punch biopsy/intraepidermal nerve fiber density testing and

immunohistochemical staining of peripheral nerves

Quantitative sensory testing

Imaging using MRI and ultrasonography

Staging: Different clinical neurological scales can be used to assess the severity of diabetic
polyneuropathy. Examples include the Neuropathy Impairment Scale (NIS), Vibration Detection
Threshold (VDT), Code Detection Scale (CDT), and Heel Pain (HP).
A common staging scale of diabetic polyneuropathy follows.

NO - No neuropathy

N1a - Asymptomatic neuropathy detected as nerve conduction abnormality in at least 2

nerves

N1b - N1a and abnormal neurologic examination

N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic

symptoms; patient able to heel walk

N2b - Severe symptomatic diabetic polyneuropathy (as in N2a, but patient unable to heel
walk)

N3 - Disabling diabetic polyneuropathy

TREATMENT
Medical Care: Throughout this discussion on treatment, distinction is made between therapies
for symptomatic relief and those that may slow the progression of neuropathy.

General aspects of treatment

o Consider any patient with clinical evidence of diabetic peripheral neuropathy to be
at risk for foot ulceration and provide education on foot care. If necessary, a
podiatry referral should be provided.
o Patients with diabetic peripheral neuropathy require more frequent follow-up, with
particular attention to foot inspection to reinforce the need for regular self-care.
The provision of regular foot examinations and reinforcement of the educational
message on foot care have been shown in several studies to have a major impact
on rates of ulceration and even amputation.

Current treatments for pain

o Of all treatments, tight and stable glycemic control is probably the most important
for slowing the relentless progression of neuropathy. Because rapid swings from
hypoglycemia to hyperglycemia have been suggested to aggravate and induce
neuropathic pain, the stability of glycemic control may be as important as the
actual level of control in relieving neuropathic pain. The DCCT demonstrated that
tight blood sugar control decreased the risk of neuropathy by 60% in 5 years.
o Many medications are available for the treatment of diabetic neuropathic pain.
These include tricyclic antidepressants, gabapentin, pregabalin, topical lidocaine,
and duloxetine. Other medications such as carbamazepine, oxcarbazepine,
phenytoin, lamotrigine, and opioids may also be used. Topical therapy with
capsaicin or lidocaine patches may be useful in some patients, especially those
with more localized pain. Any of these medications may be associated with side
effects, and patients should be counseled on possible problems before initiating
treatment.
o Alternative and complementary therapies for pain (eg, acupuncture) are under
investigation.

Treatments for autonomic dysfunction

o Until now, the main therapy for erectile impotence of nonvascular or
nonpsychological origin has been the intracorporeal injection of vasoactive
substances such as papaverine. Encouraging results have been presented for the
oral agent sildenafil in the treatment of erectile dysfunction of diverse causes,
including diabetes. Sildenafil is a potent and competitive inhibitor of type V cyclic
guanosine monophosphate-specific phosphodiesterase enzyme, the predominant
isoenzyme in human corpus cavernosum. Clinical trials of this agent in diabetes
are currently underway.
o Glycopyrrolate is an antimuscarinic compound that is the first specific treatment
for diabetic gustatory sweating. When applied topically to the affected area, it
results in a marked reduction in sweating while eating a meal.

A number of medications to slow the progression of diabetic neuropathy are currently

undergoing evaluation in clinical trials. Some are licensed for use in other countries.
o Aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat): Although numerous
studies of aldose reductase inhibitors have been published in the past 30 years,
none is currently available in the United States. Aldose reductase inhibitors block
the rate-limiting enzyme in the polyol pathway that is activated in hyperglycemic
states. Many earlier aldose reductase inhibitor trials had problems related to poor
study design (eg, enrolling patients with advanced neuropathy who were unlikely
to benefit from treatment). Clinical trials are ongoing.
o Alpha-lipoic acid: Ziegler and colleagues conducted a multicenter placebocontrolled trial of the antioxidant alpha-lipoic acid in 382 patients with type 2
diabetes and symptomatic neuropathy. They reported short-term symptomatic
relief. A more recent trial in autonomic neuropathy suggested that this agent also
may have a beneficial effect in the natural history of autonomic dysfunction.
o Gamma-linolenic acid: The first step in the metabolism of the essential fatty acid
linolenic acid is impaired in diabetes, and this defect can be bypassed by
administration of gamma-linolenic acid. Several studies have suggested clinical
and electrophysiologic improvement in peripheral nerve function when gammalinolenic acid is administered to patients with neuropathy. Further studies are
needed.
o NGF: Deficiencies in endogenous NGFs, which are trophic to sensory and
autonomic nerve fibers, have been described in diabetic neuropathy. Treatment
with exogenous NGF may be beneficial. Trials of parenteral NGF are ongoing.

Surgical Care: Pancreatic transplantation in patients with diabetes and end-stage renal disease
can stabilize neuropathy and in some instances improve motor, sensory, and autonomic
function for as long as 48 months after uremia plateaus.
MEDICATION
The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Tricyclic antidepressants -- This complex group of drugs has central and
peripheral anticholinergic effects as well as sedative effects. They have central effects on pain
transmission. They also block the active reuptake of norepinephrine and serotonin.

Drug Name

Amitriptyline (Elavil) -- By inhibiting reuptake of

serotonin and/or norepinephrine by presynaptic
neuronal membrane, may increase synaptic
concentration in CNS. Useful as analgesic for
certain types of chronic and neuropathic pain.

Adult Dose

10-25 mg/d PO hs
Increase to 30-100 mg PO qhs over several wk as
needed

Pediatric Dose

Children: 0.1 mg/kg/d PO hs and increase, as

tolerated, over 2-3 wk to 0.5-2 mg/d hs
Adolescents: 10-25 mg/d PO; increase gradually
to 100 mg/d as needed

Contraindications Documented hypersensitivity; MAOIs in past 14 d

Interactions

Metabolized by P-450 2D6 system, thus drugs that

inhibit this enzyme system (eg, cimetidine,

quinidine) may increase tricyclic levels;

phenobarbital may increase metabolism,
decreasing its effects; may block uptake of
guanethidine, thus preventing its hypotensive
effects; may interact with thyroid medications,
alcohol, CNS depressants, barbiturates, and
disulfiram
Pregnancy

D - Unsafe in pregnancy

Precautions

Caution in patients with cardiac conduction

disturbances, cardiac arrhythmias, seizures,
glaucoma, urinary retention history,
hyperthyroidism, and renal or hepatic impairment;
because of its pronounced effects in
cardiovascular system, best to avoid in elderly
persons

Drug Name

Nortriptyline (Pamelor, Aventyl HCl) -- Has

demonstrated effectiveness in treatment of chronic
pain; by inhibiting reuptake of serotonin and/or
norepinephrine by presynaptic neuronal
membrane, may increase synaptic concentration
in CNS; pharmacodynamic effects such as
desensitization of adenyl cyclase and downregulation of beta-adrenergic receptors and
serotonin receptors also appear to be involved in
mechanisms of action.

Adult Dose

25 mg PO qhs and increase over several wk as

needed; not to exceed 150 mg/d

Pediatric Dose

Contraindications

<25 kg: Not established

25-35 kg: 10-20 mg/d PO
35-54 kg: 25-35 mg/d PO
>54 kg: Administer as in adults
Documented hypersensitivity; narrow-angle
glaucoma; MAOIs in past 14 d

Interactions

Cimetidine may increase levels; may increase PT

in patients whose coagulation parameters have
been stabilized with warfarin

Pregnancy

D - Unsafe in pregnancy

Precautions

Caution in renal or hepatic impairment, cardiac

conduction disturbances, or history of
hyperthyroidism

Drug Category: Anticonvulsants -- These agents likely have central and peripheral effects
on pain modulation.

Drug Name

Gabapentin (Neurontin) -- Has properties common

to other anticonvulsants and antineuralgic effects.
Exact mechanism of action not known. Structurally
related to GABA but does not interact with GABA
receptors.

Adult Dose

100 mg PO tid; titrate dose upward prn

Pediatric Dose

<12 years: Not established

>12 years: Administer as in adults

Contraindications Documented hypersensitivity

Interactions

Antacids may reduce bioavailability significantly

(administer >2 h following antacid); cimetidine may
reduce clearance, but this may not be of clinical
significance; may significantly increase
norethindrone levels

Pregnancy

C - Safety for use during pregnancy has not been

established.

Precautions

Caution in severe renal disease

Drug Name

Carbamazepine (Tegretol, Carbatrol, Epitol) -- Has

antineuralgic effects; may depress activity of
nucleus ventralis of thalamus or decrease synaptic
transmission or summation of temporal
stimulation, leading to neural discharge by limiting
influx of sodium ions across cell membrane or
other unknown mechanisms. Target blood serum
concentration 4-12 mg/L.

Adult Dose

200 mg PO bid initial dose; increase gradually prn

over 2 wk to 200 mg tid
SR form: Therapeutic dose bid

Pediatric Dose

<6 years: 10-20 mg/kg/d PO initial dose; titrate

dose prn
6-12 years: 100 mg PO bid initial dose; titrate
dose prn
>12 years: 200 mg PO bid initial dose; titrate dose
prn

Contraindications

Documented hypersensitivity; bone marrow

suppression; MAOIs within last 14 d

Interactions

Cyclosporine, oral contraceptives, TCAs, warfarin,

phenytoin, doxycycline, neuroleptics, fentanyl,
calcium channel blockers, macrolide antibiotics,
isoniazid, cimetidine, lamotrigine, propoxyphene

Pregnancy

C - Safety for use during pregnancy has not been

established.

Precautions

MAOIs should be discontinued for minimum of 14

d before starting this medication; use cautiously in
patients with history of cardiac damage or hepatic
disease; blood cell abnormalities have been
reported following this medication; may worsen
primary generalized epilepsy or atypical absence
seizures; 0.5-1% risk of spina bifida in children
born to mothers who take carbamazepine during
pregnancy

Drug Name

Phenytoin (Dilantin) -- May stabilize neuronal

membranes and treat neuralgia by increasing
efflux or decreasing influx of sodium ions across
cell membranes in motor cortex during generation
of nerve impulses. When serum level in or near

therapeutic range, adjust dose in 30- to 50-mg

increments. Small-dose increments may cause
greater than expected increases in serum
concentration (ie, Michaelis-Menten drug kinetics).
Steady-state serum levels may take up to 3 wk to
occur because half-life is concentration
dependent.
Adult Dose
Pediatric Dose
Contraindications

300 mg/d PO initial dose; adjust to maintain serum

levels of 10-20 mg/L
5 mg/kg/d PO bid
Documented hypersensitivity; heart block; sinus
bradycardia

Interactions

Rifampin, cisplatin, vinblastine, bleomycin, folic

acid, theophylline, and continuous NG feedings
may decrease serum levels and effects; may
decrease effects of oral contraceptives,
itraconazole, mebendazole, methadone, oral
midazolam, valproic acid, cyclosporine,
theophylline, doxycycline, quinidine, mexiletine,
and disopyramide; isoniazid, chloramphenicol, or
fluconazole may increase serum concentrations;
may increase warfarin effects and rate of
conversion of primidone to phenobarbital, resulting
in increased phenobarbital serum concentrations

Pregnancy

D - Unsafe in pregnancy

Precautions

Discontinue if rash or lymphadenopathy develops;

caution in patients with hepatic dysfunction; is
approximately 90% protein bound; during
pregnancy or low albumin states, better to adjust
PO dose to maintain free serum concentrations of
1-2 mg/L

Drug Name

Lamotrigine (Lamictal) -- Triazine derivative useful

in treatment of neuralgia. Inhibits release of
glutamate and inhibits voltage-sensitive sodium
channels, which stabilizes neuronal membrane.
Follow manufacturer's recommendation for dose
adjustments.

Adult Dose

50-100 mg/d PO divided bid initial dose; 100-400

mg/d PO qd or divided bid maintenance; not to
exceed 500 mg/d

Pediatric Dose

2-12 years
Weeks 1-2: 0.6 mg/kg/d PO divided bid, rounded
down to nearest 5 mg
Weeks 3-4: 1.2 mg/kg/d PO divided bid, rounded
down to nearest 5 mg
Maintenance: 5-15 mg/kg/d PO; not to exceed 400
mg/d divided bid; to achieve usual maintenance
dose, increase subsequent doses q1-2wk as
follows: calculate 1.2 mg/kg/d and round down to
nearest 5 mg; add this amount to previously
administered daily dose

>12 years
Weeks 1-2: 50 mg/d PO Weeks 3-4: 100 mg/d PO
divided bid
Maintenance: 300-500 mg/d PO divided bid; to
achieve maintenance, increase by 100 mg/d q12wk
Contraindications Documented hypersensitivity
Interactions

Acetaminophen increases renal clearance,

decreasing effects; phenobarbital and phenytoin
increase metabolism, causing decrease in levels;
concomitant valproic acid increases half-life

Pregnancy

C - Safety for use during pregnancy has not been

established.

Precautions

Caution in patients with impaired renal or hepatic

function

Drug Name

Pregabalin (Lyrica) -- Structural derivative of

GABA. Mechanism of action unknown. Binds with
high affinity to alpha2-delta site (a calcium channel
subunit). In vitro, reduces calcium-dependent
release of several neurotransmitters, possibly by
modulating calcium channel function. FDA
approved for neuropathic pain associated with
diabetic peripheral neuropathy or postherpetic
neuralgia and as adjunctive therapy in partialonset seizures.

Adult Dose

50 mg PO tid initially; if needed, may increase to

100 mg tid within 1 wk

Pediatric Dose

Not established

Contraindications Documented hypersensitivity

Interactions

May cause additive effects on cognitive and gross

motor functioning when coadministered with drugs
that cause dizziness or somnolence

Pregnancy

C - Safety for use during pregnancy has not been

established.

Precautions

Discontinue gradually (over a minimum of 1 wk) to

minimize increased seizure frequency in patients
with seizure disorders; may cause insomnia,
nausea, headache, or diarrhea with abrupt
withdrawal; common adverse effects include
dizziness, somnolence, blurred vision, weight
gain, and peripheral edema; may elevate
creatinine kinase level, decrease platelet count,
and increase PR interval; doses >300 mg/d
associated with higher rate of adverse effects and
treatment discontinuation; decrease dose with
renal impairment (ie, CrCl <60 mL/min)

Drug Category: Analgesics, topical -- Topical analgesics may provide localized, temporary
pain relief.

Drug Name

Lidocaine (Anestacon, Dermaflex gel, Dilocaine,

Lidoderm) -- Several recent studies have
advocated topical administration of lidocaine as
treatment of postherpetic neuralgia. Lidocaine gel
(5%) in placebo-controlled study showed
significant relief in 23 patients studied. Lidocaine
tape also decreases severity of pain.

Adult Dose

Apply to affected area prn

Pediatric Dose

Administer as in adults

Contraindications Documented hypersensitivity

Interactions

None reported

Pregnancy

B - Usually safe but benefits must outweigh the

risks.

Precautions

For external or mucous membrane use only; do

not use in eyes

Drug Name

Capsaicin cream (Dolorac, Capsin, Zostrix) -Natural chemical derived from plants of
Solanaceae family. By depleting and preventing
reaccumulation of substance P in peripheral
sensory neurons, may render skin and joints
insensitive to pain. Substance P thought to be
chemomediator of pain transmission from
periphery to CNS.

Adult Dose

Apply to skin tid/qid for 3-4 consecutive wk and

evaluate efficacy; not to exceed 4 applications per
day

Pediatric Dose
Contraindications

Administer as in adults
Documented hypersensitivity; do not use on areas
of broken or irritated skin

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been

established.

Precautions

Avoid contact with eyes; do not bandage tightly; if

condition worsens or symptoms persist for 14-28
d, discontinue use and consult physician; for
external use only

Drug Category: Selective serotonin and norepinephrine reuptake inhibitors -Potentiates serotonergic and noradrenergic activity in the CNS.
Drug Name

Duloxetine (Cymbalta) -- Indicated for diabetic peripheral neuropathic

pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Adult Dose

60 mg PO qd; may initiate with lower dose in patient unable to tolerate 60

mg/d

Pediatric Dose

Not established

Documented hypersensitivity; uncontrolled narrow-angle glaucoma; do not

Contraindications administer within 14 d after stopping MAOI use or initiate MAOIs within 5 d
after stopping duloxetine

Interactions

Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that

inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may
increase duloxetine blood levels and toxicity; coadministration with drugs
that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase
duloxetine blood levels and toxicity; duloxetine moderately inhibits
CYP2D6 and may decrease elimination of CYP2D6 substrates (eg,
tricyclic antidepressants, phenothiazines [eg, thioridazine], type 1C
antiarrhythmics [eg, propafenone, flecainide]); coadministration with
MAOIs may cause serious, sometimes fatal reactions that include
hyperthermia, rigidity, myoclonus, autonomic instability, mental status
changes including extreme agitation, delirium, and coma (see
Contraindications)

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Observe closely for clinical worsening and suicidality when initiating

treatment or following dosage change; gradually decrease dose when
discontinuing, do not abruptly discontinue; caution with hepatic impairment
or end-stage renal disease; may cause slight blood pressure increase;
may activate mania or hypomania; common adverse effects include
nausea, dry mouth, constipation, decreased appetite, fatigue,
somnolence, and increased sweating

FOLLOW-UP
Deterrence/Prevention:

The importance of protection and care of insensitive feet cannot be overemphasized.

Patients should be instructed to trim their toenails with great care and to be fastidious
about foot hygiene. Any fungal or bacterial infection mandates prompt medical attention.
The need for well-fitting shoes should be stressed. In addition, lack of sensation makes
insensitive feet more susceptible to damage from frostbite in winter, and patients should
be counseled on proper foot wear and limiting activities in extreme cold.

Diabetic polyneuropathy is usually associated with diabetic retinopathy and nephropathy.

Patients with neuropathy should be counseled to seek appropriate eye care and discuss
renal care and follow-up with their primary care physicians or endocrinologists.

Complications:

The presence of neuropathy increases the risk of foot ulceration and infection, which in
turn may lead to gangrene and the need for amputation.

The economic burden of taking care of patients with diabetic neuropathy is huge.

Prognosis:

Treating diabetic neuropathy is a difficult task for the physician and patient. Most of the
medicines mentioned above do not lead to complete symptom relief. Clinical trials are
underway to help in early diagnosis and better management.

Patient Education:

Patient education should begin in the primary care office with discussion of the following
issues:

What is diabetic neuropathy?

o Diabetic neuropathy is nerve damage caused by diabetes. Diabetic neuropathy is
a specific type of peripheral neuropathy.
o Diabetic neuropathy can also affect the nerves that regulate unconscious vital
functions, such as heart rate and digestion. This type of problem is called
autonomic neuropathy.

How does diabetic neuropathy occur?

o Doctors have been studying this problem for many years, but they do not yet
understand exactly how diabetes damages the nervous system. However, they
have observed that good control of blood sugar levels helps prevent diabetic
neuropathy and slows its progression.

What are the symptoms?

o Symptoms of diabetic neuropathy may include the following:
Numbness or loss of feeling (usually in the feet and legs first, then the
hands)
Pain ranging from minor discomfort or tingling in toes to severe pain: Pain
may be sharp or lightninglike, deep and aching, or burning. Extreme
sensitivity to the slightest touch can also occur (allodynia).
Muscle weakness.
o Symptoms of autonomic neuropathy may include the following:
Low blood pressure and dizziness when rising quickly from sitting or lying
down
Rapid or irregular heartbeats
Trouble having an erection
Nausea or vomiting
Difficulty swallowing
Constipation or diarrhea

How can I help prevent diabetic neuropathy?

The best way to help prevent diabetic neuropathy is to take the following
actions:
Control diabetes. Try to keep blood sugar at a normal level.
Maintain normal blood pressure.
Exercise regularly, according to the healthcare provider's recommendation.
Stop smoking.
Limit the amount of alcohol intake because excessive alcohol also can
cause neuropathy or make it worse.
Eat a healthy diet.
Keep follow-up appointments with the healthcare provider.

How is diabetic neuropathy treated?

No treatment is available to reverse neuropathy. The best approach is to
control the diabetes.
Muscle weakness is treated with support, such as braces. Physical therapy
and regular exercise may help patients maintain the muscle strength they
have.

Pain-killing drugs or medications applied to the skin may help make pain
more tolerable.
Medications can be used to treat nausea, vomiting, and diarrhea.
Men who have trouble having erections because of neuropathy should talk
to their healthcare providers. Prosthetic devices can be put in the penis and
medications can help a man achieve and maintain an erection
Preventing injuries such as burns, cuts, or broken bones is especially
important, because patients with neuropathy have more complications from
simple injuries and may not heal as quickly as healthy individuals.
For excellent patient education resources, visit eMedicine's Diabetes Center and
Erectile Dysfunction Center. Also, see eMedicine's patient education articles,
Diabetes, Impotence/Erectile Dysfunction, Erectile Dysfunction FAQs, and
Nonsurgical Treatment of Erectile Dysfunction.

How can I take care of myself?

o Work with primary care physicians and endocrinologists to control glucose levels.
o Look for injuries on the skin of feet and lower legs regularly.
o See a healthcare provider promptly for calluses, sores on the skin, or other
potential problems so they can be treated properly.
o Wear good-fitting, comfortable shoes that protect the feet.

How long will the problem last?

o Once a patient has neuropathy, the symptoms will persist indefinitely.
o Patients may be able to stop neuropathy from worsening by keeping blood sugar
under good control.

MISCELLANEOUS
Medical/Legal Pitfalls:

Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The
primary care physician is responsible for educating patients about the acute and chronic
complications of diabetes.
o

Failure to diagnose diabetic polyneuropathy can lead to serious consequences,

including disability and amputation.

Addressing the psychological impact of sexual dysfunction in both men and

women is also a responsibility of the primary care giver.

The importance of involving a neurologist (preferably with expertise in peripheral

neuropathy) in the treatment of patients with diabetic neuropathy cannot be
overemphasized.

Caption: Picture 1. Lymphocytic inflammation of a small epineurial artery in a

femoral cutaneous nerve biopsy from a 70-year-old man with type 2 diabetes, 4
months of weight loss, progressive asymmetric diabetic polyneuropathy, and
electrophysiologic evidence of axonopathy. Hematoxylin and eosin stain, original
magnification 200X.
Caption: Picture 2. Sural nerve biopsy with a collection of lymphocytes around a
small epineurial vessel.
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