Diabetic Neuropathy

Author: Dianna Quan, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP

Practice Essentials

Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting as many as 50% of patients with type 1 and type 2 DM. Diabetic peripheral neuropathy involves the presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes after other possible causes have been excluded. ^[1] 

Signs and symptoms

In type 1 DM, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia, whereas in type 2, it may be apparent after only a few years of known poor glycemic control or even at diagnosis. Symptoms include the following:

• Sensory – Negative or positive, diffuse or focal; usually insidious in onset and showing a stocking-and-glove distribution in the distal extremities
• Motor – Distal, proximal, or more focal weakness, sometimes occurring along with sensory neuropathy (sensorimotor neuropathy)
• Autonomic – Neuropathy that may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands

Physical examination should include the following assessments:

• Peripheral neuropathy testing – Gross light touch and pinprick sensation; vibratory sense; deep tendon reflexes; strength testing and muscle atrophy; dorsal pedal and posterior tibial pulses; skin assessment; Tinel testing; cranial nerve testing
• Autonomic neuropathy testing – Objective evaluation of cardiovagal, adrenergic, and sudomotor function in a specialized autonomic laboratory; may be preceded by bedside screening to assess supine and upright blood pressure and heart rate, with measurement of sinus arrhythmia ratio

Two classification systems for diabetic neuropathy are the Thomas system and the symmetrical-versus-asymmetrical system. The Thomas system (modified) is as follows:

• Hyperglycemic neuropathy
• Generalized symmetrical polyneuropathies
• Sensory neuropathy
• Sensorimotor neuropathy
• Autonomic neuropathy
• Focal and multifocal neuropathies
• Superimposed chronic inflammatory demyelinating polyneuropathy

Distal symmetrical sensorimotor polyneuropathy is commonly defined according to the following 3 key criteria:

• The patient must have diabetes mellitus consistent with a widely accepted definition
• Severity of polyneuropathy should be commensurate with duration and severity of diabetes
• Other causes of sensorimotor polyneuropathy must be excluded

Pure autonomic diabetic neuropathy is rare.

Asymmetrical neuropathies include the following:

• Median neuropathy of the wrist (carpal tunnel syndrome)
• Other single or multiple limb mononeuropathies
• Thoracic radiculoneuropathy
• Lumbosacral radiculoplexus neuropathy
• Cervical radiculoplexus neuropathy

Diabetic polyneuropathy is commonly staged as follows:

• NO – No neuropathy
• N1a – Signs but no symptoms of neuropathy
• N2a – Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient is able to heel-walk
• N2b – Severe symptomatic diabetic polyneuropathy; patient is unable to heel-walk)
• N3 – Disabling diabetic polyneuropathy

See Clinical Presentation for more detail.

Diagnosis

Laboratory tests that may be helpful include the following:

• Fasting plasma glucose
• Hemoglobin A1c
• Complete blood count
• Complete metabolic panel (electrolytes and liver function panel)
• Vitamin B-12 and folate levels
• Thyroid function tests
• Erythrocyte sedimentation rate
• C-reactive protein
• Serum protein electrophoresis with immunofixation electrophoresis
• Antinuclear antibody
• Anti-SSA and SSB antibodies
• Rheumatoid factor
• Paraneoplastic antibodies
• Rapid plasma reagin
• Genetic screens
• Hematology screen (for anemia)
• Sequential multiple analysis-7 (renal function and electrolyte imbalances)/complete metabolic panel (CMP)

Other diagnostic modalities that may be considered are as follows:

• Electromyography and nerve conduction velocity testing
• Electrophysiologic studies
• Magnetic resonance imaging
• Computed tomography (including single-photon emission computed tomography)
• Nuclear imaging
• Doppler imaging
• Microdialysis
• Electrocardiography
• Nerve and skin biopsy (now rarely recommended for clinical purposes)

See Workup for more detail.

Management

Key components of the management of diabetic neuropathy include the following:

• Foot care, including regular follow-up, patient education, and referral as appropriate
• Tight, stable glycemic control (most important for slowing progression of neuropathy)
• Pain management (eg, with pregabalin, gabapentin, sodium valproate, dextromethorphan, morphine sulfate, tramadol, oxycodone, duloxetine, topical capsaicin, transdermal lidocaine)
• Treatment of diabetic gastroparesis (eg, with erythromycin, cisapride [not available in the United States], metoclopramide, polyethylene glycol 3350, tegaserod [currently available only on an emergency basis])
• Experimental therapies include aldose reductase inhibitors, alpha-lipoic acid, actovegin, and spinal cord stimulators.

Treatment of autonomic dysfunction must address the following:

• Erectile dysfunction
• Orthostatic hypotension
• Gustatory sweating

Surgical treatment may be considered as follows:

• Aggressive debridement or amputation for recalcitrant foot necrosis or infection
• Jejunostomy for intractable gastroparesis
• Implantation of a penile prosthesis for ongoing impotence
• Bracing, special boots, or, in some cases, surgery for Charcot foot
• Pancreatic transplantation for diabetes with end-stage renal disease

See Treatment and Medication for more detail.

Background

Neuropathies are characterized by a progressive loss of nerve fiber function. 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.” ^[2, 3] 

Neuropathies are the most common complication of diabetes mellitus (DM), affecting up to 50% of patients with type 1 and type 2 DM. In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, patients with type 2 diabetes mellitus may present with distal polyneuropathy after only a few years of known poor glycemic control; sometimes, these patients already have neuropathy at the time of diagnosis. (See Clinical Presentation.)

Neuropathies severely decrease patients’ quality of life (QOL). Furthermore, while the primary symptoms of neuropathy can be highly unpleasant, the secondary complications (eg, falls, foot ulcers, cardiac arrhythmias, and ileus) are even more serious and can lead to fractures, amputations, and even death in patients with DM.

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 (see History). Physical examination of patients with suspected distal sensory motor or focal (ie, entrapment or noncompressive) neuropathies should include assessments for both peripheral and autonomic neuropathy (see Physical Examination).

Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected. (See Workup.)

Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The primary care physician needs to be alert for the development of neuropathy—or even its presence at the time of initial diabetes diagnosis—because failure to diagnose diabetic polyneuropathy can lead to serious consequences, including disability and amputation. In addition, the primary care physician is responsible for educating patients about the acute and chronic complications of diabetes (see Patient Education). Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. (See Treatment Strategies and Management.)

Management of diabetic neuropathy includes 2 approaches: therapies for symptomatic relief and those that may slow the progression of neuropathy. Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy. Many medications are available for the treatment of diabetic neuropathic pain, although most of them are not specifically approved by the United States Food and Drug Administration for this use. Nonpharmacologic treatment includes rehabilitation, which may comprise physical, occupational, speech, and recreational therapy. (See Medication.)

Anatomy

A review of the anatomy of the peripheral nervous system can facilitate understanding of the classification of diabetic peripheral neuropathy. Peripheral neurons can be categorized broadly as motor, sensory, or autonomic.

Motor neurons originate in the central nervous system (CNS) and extend 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 in 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 below).

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.

The smaller fibers are affected first in DM. With continued exposure to hyperglycemia, the larger fibers become affected. Fibers of different size mediate different types of sensation, as shown in the table below.

Table. Subdivisions of Sensory Neurons (Open Table in a new window)

The factors leading to the development of diabetic neuropathy are not understood completely, and multiple hypotheses have been advanced. ^{[4, 5, 6, 7, 8, 9, 10, 11, 12, 13]} It is generally accepted to be a multifactorial process. Development of symptoms depends on many factors, such as 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. Genetic factors may also play a role. ^[14] Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the polyol pathway, advanced glycation end products, and oxidative stress.Pathophysiology

For more information, see Type 2 Diabetes and TCF7L2.

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. ^[15] 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. ^[16] 

Advanced glycation end products

The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advanced glycation end products (AGEs) that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.^[17] 

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. ^{[18, 19, 20]} 

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 neurotrophins, and nerve ischemia. ^[21] Clinical trials of the best-studied neurotrophin, human recombinant nerve growth factor, were disappointing. With future refinements, however, pharmacologic intervention targeting one or more of these mechanisms may prove successful.

In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles. ^[22] 

Etiology

Risk factors that are associated with more severe symptoms include the following ^[23] :

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

Development of symptoms depends on many factors, such as 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. Genetic factors may also play a role. ^[14] 

Peripheral neuropathies have been described in patients with primary DM (types 1 and 2) and in those with 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). ^[24] 

An association between impaired glucose tolerance and peripheral neuropathy has been construed as further evidence of a dose-dependent effect of hyperglycemia on nerves, although this relationship remains an area of some controversy for type 2 diabetes and prediabetes. ^{[25, 26, 27, 28]} 

A study by Jende et al indicated that in patients with type 1 diabetes, the predominant nerve lesions of distal symmetrical diabetic neuropathy develop in relation to poor glycemic control and nerve conduction loss, while in type 2 diabetes, these lesions arise in association with lipid metabolism changes. ^[109] 

A study by Pai et al indicated that in adults with type 2 diabetes, an association exists between variability in fasting plasma glucose and the risk for painful diabetic peripheral neuropathy. Using the coefficient of variation (CV) for fasting plasma glucose, the investigators found that, after consideration of HbA1c, the odds ratios for the development of painful diabetic peripheral neuropathy were 4.08 and 5.49 for the third and fourth CV quartiles, respectively, compared with the first quartile. ^[108] 

A study by Altaf et al indicated that obstructive sleep apnea (OSA) is linked to small-fiber neuropathy in type 2 diabetes, with poly–adenosine diphosphate ribose polymerase activation being a possible mechanism behind OSA’s association with diabetic peripheral neuropathy and endothelial dysfunction. ^[29] 

A study by Dabelea et al found that among teenagers and young adults who had been diagnosed with type 1 or type 2 diabetes during childhood or adolescence, the age-adjusted prevalence of peripheral neuropathy was greater in those with type 2 diabetes than in patients with type 1 diabetes (17.7% vs 8.5%, respectively). After modifications had been made for established risk factors measured over time, the odds ratio for peripheral neuropathy in patients with type 2 diabetes versus those with type 1 was 2.52. ^[30] 

Epidemiology

United States statistics

A large American study estimated that 47% of patients with diabetes have some peripheral neuropathy. ^[31] Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. More than half of cases are distal symmetric polyneuropathy. Focal syndromes such as carpal tunnel syndrome (14-30%), ^{[32, 33, 34]} 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. The use of additional diagnostic techniques, such as autonomic or quantitative sensory testing, might result in a higher recorded prevalence. ^[35, 36] 

International statistics

In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients already had neuropathy when diagnosed with diabetes. ^[37] 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%. ^[38] 

Diabetic neuropathy in racial minorities

No definite racial predilection has been demonstrated for diabetic neuropathy. However, members of minority groups (eg, Hispanics, African Americans) have more secondary complications from diabetic neuropathy, such as lower-extremity amputations, than whites. ^[23] They also have more hospitalizations for neuropathic complications.

Sex differences in diabetic neuropathy

DM affects men and women with equal frequency. However, male patients with type 2 diabetes may develop diabetic polyneuropathy earlier than female patients, ^[39] and neuropathic pain causes more morbidity in females than in males.

Diabetic neuropathy and advancing age

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

Prognosis

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.

Treating diabetic neuropathy is a difficult task for the physician and patient. Most of the medicines mentioned in the Medication section do not lead to complete symptom relief. Clinical trials are under way to help find new ways to treat symptoms and delay disease progression.

Mortality is higher 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 with 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. In patients with diabetic peripheral neuropathy, the prognosis is good, but the patient’s QOL is reduced.

In a Canadian study of patients with painful diabetic neuropathy being managed in a tertiary care setting, Mai et al found that at 12-month follow-up, significant improvement in pain and function had been achieved in almost one third of these individuals. That included pain reduction of 30% or greater in 37.2% of patients, functional improvement (reduction of 1 or greater on the Pain Interference Scale) in 51.2% of patients, and achievement of both of these measures in 30.2% of patients. Polypharmacy was found to be essential to symptom management and included the use of analgesic antidepressants and anticonvulsants. ^[40] 

For more information, go to Diabetic Foot.

for more information, go to Diabetic Foot Infections.

Patient Education

Controlling diet and nutrition are paramount to improving the secondary complications of diabetes, including neuropathy. Patients with diabetic neuropathy should work with nutritionists or their primary care physicians to develop a realistic diet for lowering blood glucose and minimizing large fluctuations in blood glucose.

Patients with diabetic neuropathy should be encouraged to remain as active as possible. However, those with significant sensory loss or autonomic dysfunction should be cautioned about exercising in extreme weather conditions, which may result in injury. For example, patients with extremity numbness may not be aware of frostbite injuries during prolonged cold exposure, or those with abnormal sweating may become easily overheated in hot conditions. In most cases, consultation with the patient’s regular physician is reasonable before the initiation of a regular exercise program.

Patients with diabetic neuropathy need to be educated on all aspects of their condition, and they need to know that it is very much affected by poor glycemic control. Prevention of diabetic neuropathy is potentially best achieved by having near-euglycemic control from the onset of DM. Even in patients with symptoms of diabetic neuropathy, controlling blood glucose to euglycemic levels reduces pain significantly. When a person has poor control and becomes euglycemic quickly, pain may be exacerbated (possibly due to an insulin effect), but this pain disappears in a few days. The bottom line for patients is that medications are imperfect. Many result in no pain relief for certain patients. However, glucose control is something that the patient can achieve that may reduce pain.

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.

Diabetic polyneuropathy is often associated with diabetic retinopathy and nephropathy. Patients with neuropathy should be counselled to seek appropriate eye care and discuss renal care and follow-up with their primary care physicians or endocrinologists.

Patient education should begin in the primary care office. The following outline reviews some common questions and answers that can serve as a springboard for discussion.

What is diabetic neuropathy?

Diabetic neuropathy is nerve damage caused by diabetes. In the United States, diabetes is one of the most common causes of nerve damage, also known as peripheral neuropathy. Diabetic neuropathy can affect nerves that supply feeling and movement in the arms and legs. It can also affect the nerves that regulate unconscious vital functions such as heart rate and digestion.

How does diabetic neuropathy occur?

Doctors have been studying this problem for many years, but they do not yet understand exactly how diabetes damages nerves. However, they have observed that good control of blood sugar levels helps prevent diabetic neuropathy and slows its progression, especially in patients with type 1 diabetes.

What are the symptoms?

Symptoms of diabetic neuropathy may include the following:

• Numbness or loss of feeling (usually in the feet and legs first, then the hands)
• Pain
• Muscle weakness
• 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

Pain from diabetic neuropathy may range from minor discomfort or tingling in toes to severe pain. Pain may be sharp or lightning-like, deep and aching, or burning. Extreme sensitivity to the slightest touch can also occur (allodynia).

A study by D’Amato et al indicated that among diabetes-related complications and comorbidities, painful diabetic polyneuropathy is the greatest determinant of depression in patients with diabetes. The study involved 181 patients, including 25 with painful diabetic polyneuropathy and 46 with the painless form of the condition. ^[41] 

How can I help prevent diabetic neuropathy?

The following steps may help to prevent or slow the worsening of diabetic neuropathy ^[42] :

• 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 and avoid elevated levels of triglycerides in the blood
• Maintain a healthy weight
• Keep follow-up appointments with the healthcare provider

How is diabetic neuropathy treated?

No treatment is currently available to reverse neuropathy. The best approach is to control the diabetes and other risk factors.

Muscle weakness is treated with support, such as braces. Physical therapy and regular exercise may help patients maintain the muscle strength they have.

Pain medications 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. Medications can help a man achieve and maintain an erection, or prosthetic devices can be put in the penis.

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.

How can I take care of myself?

Diabetes patients can take the following self-care measures:

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

How long will the problem last?

Once a person has neuropathy, the symptoms will persist indefinitely, but most people with diabetic neuropathy are able to lead active, fulfilling lives. Keeping blood sugar under good control may stop neuropathy from worsening.

For excellent patient education resources, visit eMedicineHealth’s Diabetes Center and Men’s Health Center. Also, see eMedicineHealth’s patient education articles, Diabetes Mellitus and Diabetic Foot Care.

Diabetic Neuropathy Clinical Presentation

Author: Dianna Quan, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP

History

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

Since diabetic neuropathy can manifest as 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

Sensory neuropathy usually is insidious in onset and shows a stocking-and-glove distribution in the distal extremities. 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 symptoms

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; 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. Motor neuropathy may occur along with sensory neuropathy (sensorimotor neuropathy).

Autonomic symptoms

Autonomic neuropathy may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands. Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. In addition, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage—gastrointestinal, cardiovascular, bladder, or sudomotor.

Gastrointestinal autonomic neuropathy may produce the following symptoms ^[43] :

• Dysphagia
• Abdominal pain
• Nausea/vomiting
• Malabsorption
• Fecal incontinence
• Diarrhea
• Constipation

Cardiovascular autonomic neuropathy may produce the following symptoms ^[44] :

• Persistent sinus tachycardia
• Orthostatic hypotension
• Sinus arrhythmia
• Decreased heart variability in response to deep breathing
• Near syncope upon changing positions from recumbent to standing

Bladder neuropathy (which must be differentiated from prostate or spine disorders) may produce the following symptoms:

• Poor urinary stream
• Feeling of incomplete bladder emptying
• Straining to void

Sudomotor neuropathy may produce the following symptoms:

• Heat intolerance
• Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
• Gustatory sweating

Physical Examination

Physical examination of patients with suspected distal sensory, motor, or focal (ie, entrapment or noncompressive) neuropathic symptoms should include assessments for both peripheral and autonomic neuropathy. ^[45] 

Peripheral neuropathy testing

Testing for peripheral neuropathy begins with assessment of gross light touch and pinprick sensation. The first clinical sign that usually develops in diabetic symmetrical sensorimotor polyneuropathy 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 from the hands into the 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.

Vibratory sense in the feet is tested with a 128-Hz tuning fork placed at the base of the great toenail. Test protective sensation with 5.07 Semmes-Weinstein monofilament, briefly applying the tip perpendicular to the plantar surface of the foot, using sufficient force (10 g) to buckle the monofilament. Inability to perceive the tuning fork or the monofilament identifies patients who are at increased risk (ie, 60% in the next 3 years) of developing a foot ulcer. ^[46] The 2 tests should be performed at least every year. ^[47] 

Test deep tendon reflexes. With neuropathy, these are commonly hypoactive or absent. Perform strength testing and examine for distal intrinsic extremity muscle atrophy, since weakness of small foot muscles may develop. Check dorsal pedal and posterior tibial pulses.

Examine the skin for dryness, tinea pedis, cracks, onychomycoses, acute erythema and tenderness, and fluctuance under calluses.

Perform Tinel testing. Paresthesias or pain suggests median nerve injury.

Perform cranial nerve testing. Have the patient walk on the heels and toes; heel-toe walking tests not only distal lower-extremity strength but balance, as well.

Perkins et al recommended conducting annual screening for diabetic neuropathy using superficial pain sensation testing, monofilament testing, or vibration testing by the on-off method. These researchers also validated a scoring system to document and monitor neuropathy in the clinic. ^[48] 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. ^[49] 

Autonomic neuropathy testing

Testing for autonomic neuropathies is performed objectively in a specialized autonomic laboratory, evaluating cardiovagal, adrenergic, and sudomotor function. However, the clinician may first perform bedside screening to assess if further, more specialized testing is necessary.

Blood pressure and heart rate measurements with the patient supine and upright are compared. Blood pressure measurements in patients with autonomic neuropathy may show orthostatic hypotension with reduced compensatory tachycardia. Testing for orthostatic hypotension is particularly important in patients with longstanding diabetes mellitus. ^[50] 

The sinus arrhythmia (SA) ratio is measured with the patient breathing 6 times per minute while the heart rate is monitored with a continuous ECG strip. The longest R-R interval during expiration and the shortest R-R interval during inspiration are measured, and the average of the 6 breaths is taken. The SA ratio is R-R expiration/R-R inspiration. The normal ratio is 1:2.

Classification of Diabetic Neuropathy

Diabetic neuropathies are heterogeneous in type; thus, several classifications of diabetic neuropathy have been created and recognized. ^{[51, 2, 45]} Two classification systems will be presented here: the Thomas system and symmetrical-versus-asymmetrical neuropathies.

Thomas system

A classification system by Thomas ^[52] combines anatomy and pathophysiology. It is presented below with a few modifications:

• Hyperglycemic neuropathy (acute)
• Generalized symmetrical polyneuropathies
• Sensory neuropathy
• Sensorimotor neuropathy (chronic, symmetric)
• Autonomic neuropathy (cardiovascular, gastrointestinal, genitourinary, sudomotor)
• Focal and multifocal neuropathies: this category includes cranial neuropathy, proximal motor neuropathy (amyotrophy), thoracic or lumbar radiculopathies, and focal limb neuropathies (entrapment neuropathies)
• Superimposed chronic inflammatory demyelinating polyneuropathy (CIDP)

Symmetrical versus asymmetrical neuropathies

Another generally accepted classification of diabetic neuropathies divides them broadly into symmetrical and asymmetrical neuropathies.

Symmetrical polyneuropathies involve multiple nerves diffusely and symmetrically. Distal symmetrical sensorimotor polyneuropathy is the most common manifestation of diabetic neuropathy. The syndrome has been defined in many ways, but 3 key 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 ^[53, 54] 
• The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes
• Other causes of sensorimotor polyneuropathy must be excluded

Distal symmetrical sensorimotor polyneuropathy affects sensory, motor, and autonomic functions in varying degrees, with sensory abnormalities predominating. Chronic symmetrical symptoms affect peripheral nerves in a length-dependent pattern, with the longest nerves affected first. Patients commonly present with painful paresthesias and numbness, which begin in the toes and ascend proximally in a stocking-like distribution over months and years.

When sensory symptoms ascend above the knees, similar symptoms develop in the hands, progressing proximally in a glove-like distribution. At a very late stage, the anterior aspect of the trunk and vertex of the head may be affected. The loss of sensation in the feet predisposes to development of foot ulcers and gangrene. ^[55] In addition, mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly. With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia).

Small-fiber neuropathy is a distal symmetrical neuropathy involving predominantly small-diameter sensory fibers (A delta and C fibers). It manifests as painful paresthesias that patients perceive as burning, stabbing, crushing, aching, or cramplike, with increased severity at night. There is loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception.

Although some degree of autonomic involvement is present in most patients with distal symmetrical diabetic polyneuropathy, patients may not notice autonomic problems, and pure autonomic diabetic neuropathy is rare. Manifestations of autonomic neuropathy may include orthostatic hypotension, resting tachycardia, loss of normal sinus arrhythmia ratio, anhidrosis, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.

In diabetic neuropathic cachexia, the patient experiences a precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fiber neuropathy, and autonomic dysfunction. This condition occurs more often in older men; impotence is common. Muscle weakness is uncommon. The condition usually improves with prolonged glycemic control; however, 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

Asymmetrical neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include the following:

• Median neuropathy of the wrist (carpal tunnel syndrome)
• Other single or multiple limb mononeuropathies
• Thoracic radiculoneuropathy
• Lumbosacral radiculoplexus neuropathy
• Cervical radiculoplexus neuropathy

These syndromes are distinguished from typical distal diabetic polyneuropathy by the following characteristics:

• They often have a monophasic course
• Some are associated with inflammatory angiitis and ischemia (eg, lumbosacral radiculoplexus neuropathy) and may appear acutely or subacutely
• They have a weaker association with total hyperglycemic exposure than symmetrical polyneuropathies

Cranial mononeuropathy most often involves cranial nerves (CN) III, IV, VI, VII, or II. Disease of CN III, IV, and VI 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 affected) and can be recurrent or bilateral. Most patients recover spontaneously in 3-6 months.

Anterior ischemic optic neuropathy manifests as acute visual loss or visual-field defects (usually inferior altitudinal). The optic disc appears pale and swollen; flame-shaped hemorrhages may be present.

For more information, see Macular Edema, Diabetic.

Somatic mononeuropathies include 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, usually 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 presents as burning, stabbing, boring, beltlike, or deep aching pain that usually begins unilaterally and may subsequently become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness follows 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, such as 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. There isoftencoexistingdiabeticdistalsymmetrical polyneuropathy.

Diabetic radiculoplexus neuropathy 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. 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.

For more information, see Diabetic Lumbosacral Plexopathyhere.

Staging

Different clinical neurologic scales can be used to assess the severity of diabetic polyneuropathy. ^[51] 

A common staging scale of diabetic polyneuropathy is as follows ^[56] :

• NO – No neuropathy
• N1a – Signs but no symptoms of neuropathy
• 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

Diabetic Neuropathy Differential Diagnoses

Author: Dianna Quan, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP

Diagnostic Considerations

Establishing the diagnosis of diabetic neuropathy requires careful evaluation, because in 10-26% of diabetic patients with neuropathy, the neuropathy may have another cause. ^{[31, 57, 58, 59, 60]} 

The differential diagnoses to consider vary with the presentation.

Cranial mononeuropathy includes the following:

• Intracranial aneurysms
• Bell palsy

Thoracoabdominal neuropathy includes the following:

• Herpes zoster
• Spinal tumors
• Myocardial infarction
• Acute cholecystitis
• Acute appendicitis
• Diverticulitis

Lumbosacral radiculoplexopathy includes the following:

• Anterior disk protrusion
• Spinal cord tumors
• Malignant nerve root infiltrations
• Inflammatory neuropathies

Peripheral neuropathy includes the following:

• Pernicious anemia
• Vitamin B-6 intoxication
• Alcoholism
• Uremia
• Chemical toxins
• Nerve entrapment and compression of benign etiology
• Hepatitis
• Idiopathic
• Congenital (various hereditary sensory motor neuropathies)
• Paraneoplastic syndrome
• Syphilis
• HIV/AIDS
• Medication (eg, chemotherapy, isoniazid)
• Spine disease (eg, radiculopathy, stenosis, arteriovenous [AV] fistula)

Cardiovascular autonomic neuropathy (in addition to some listed above) includes the following:

• Myocardial infarction
• Neuropathic arrhythmias (eg, Wolff-Parkinson–White syndrome, sick sinus syndrome)
• Volume depletion
• Drugs

Gastrointestinal neuropathy includes the following:

• Gastrointestinal malignancy
• Peptic ulcer disease
• Postsurgical vagotomy
• Electrolyte imbalance

Bladder dysfunction includes the following:

• Bladder outlet obstruction
• Prostate cancer
• Spinal cauda equine syndrome

Mononeuropathy includes the following:

• Vasculitides
• Acromegaly
• Coagulopathies
• Hypothyroidism

For more information, see Diabetic Lumbosacral Plexopathy.

Differential Diagnoses

• Alcohol (Ethanol) Related Neuropathy
• Amyloid polyneuropathy
• Chronic Inflammatory Demyelinating Polyradiculoneuropathy
• Chronic Myelogenous Leukemia (CML)
• Neurosarcoidosis
• Nutritional Neuropathy
• Spinal Cord Tumors
• Toxic Neuropathy
• Uremic Neuropathy
• Vasculitic Neuropathy
• Vitamin B-12 deficiency

Diabetic Neuropathy Workup

Author: Dianna Quan, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP

Approach Considerations

Fasting plasma glucose and hemoglobin A1c are important laboratory screening tests for diabetic neuropathy.

Imaging studies rarely help the physician diagnose or manage diabetic neuropathy. However, in the appropriate clinical setting, MRI of the cervical, thoracic, and/or lumbar regions may help exclude another cause for symptoms mimicking diabetic neuropathy.

Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.

In a systematic review of 5 studies of noninvasive screening tools for detecting peripheral neuropathies in pediatric patients with type 1 diabetes, Hirschfeld and colleagues found that the diagnostic utility of the Rydel-Seiffer tuning fork and 10-g Semmes-Weinstein monofilament was low, while that of biothesiometry and a finer (1-g) monofilament was acceptable. Sensitivities and specificities of these screening tools were as follows: ^[61, 62] 

• Tuning fork: 87-99% (sensitivity); 1-19% (specificity)
• Coarse monofilament: 16% (sensitivity); 64% (specificity)
• Fine monofilament: 73% (sensitivity); 87% (specificity)
• Biothesiometer: 61-80% (sensitivity); 64-76% (specificity)

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