presentation of diabetic peripheral neuropathy

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Diabetic peripheral neuropathy.

Myron A. Bodman ; Mark A. Dreyer ; Matthew Varacallo .

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Last Update: February 25, 2024 .

• Continuing Education Activity

Peripheral neuropathy encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction. Patients with peripheral neuropathy often present with varying degrees of numbness, tingling, aching, burning sensation, weakness of limbs, hyperalgesia, allodynia, and pain. Neuropathic pain has been characterized as superficial, deep-seated, or severe, unremitting pain with exacerbation at night. While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying peripheral neuropathy clinical pathology, broad clinical consideration is given to many clinical conditions. There are many possible causes of peripheral neuropathy; the most prevalent subtype, diabetic peripheral neuropathy (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life. 

Because peripheral neuropathy is so common in patients with diabetes, the American Diabetes Association (ADA) recommends clinicians evaluate patients with type 2 diabetes when they are diagnosed; in patients with type 1 diabetes, clinicians should assess for peripheral neuropathy 5 years after diagnosis and then annually. Peripheral neuropathy is primarily diagnosed clinically. Diabetic peripheral neuropathy management consists of several strategies. The aim of this activity is to enhance healthcare learners' competence in selecting appropriate diagnostic tests, managing peripheral neuropathy, and fostering effective interprofessional teamwork to improve outcomes.

• Identify the pathophysiology of diabetic peripheral neuropathy.
• Implement evidence-based treatment strategies for diabetic peripheral neuropathy.
• Determine the potential complications of diabetic peripheral neuropathy.
• Implement collaboration strategies with interprofessional team members to provide well-coordinated care and enhance patient outcomes.
• Introduction

Peripheral neuropathy encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction. [1]  Patients with peripheral neuropathy often present with varying degrees of numbness, tingling, aching, burning sensation, weakness of limbs, hyperalgesia, allodynia, and pain. This pain has been characterized as superficial, deep-seated, or severe, unremitting pain with exacerbation at night. [2] While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying peripheral neuropathy clinical pathology, broad clinical consideration is given to many clinical conditions.

Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life. [2] Early assessment of symptoms of peripheral polyneuropathy helps avoid neuropathic foot ulcers to combat potential morbidity and mortality resulting from the pathophysiologic poor wound healing potential, which can lead to limb compromise, local to systemic infection, septicemia, and even death. [3] [4] [5]  DPN is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament. Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation). [6]

The exact cause of DPN is not known. Proposed theories include metabolic, neurovascular, and autoimmune pathways have been proposed. Mechanical compression (eg, carpal tunnel), genetics, and social and lifestyle factors such as chronic alcohol consumption and smoking have all been implicated. Perpetually high blood serum glucose leads to insulin resistance, promoting oxidative stress, inflammation, and cell damage. [7] First, the distal sensory and autonomic nerve fibers are damaged; the damage continues with proximal progression, leading to a gradual loss of protective sensation in the skin and foot joints. DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Half of the diabetic peripheral neuropathies may be asymmetric. [6] If not recognized and preventative foot care is not implemented, patients have an increased risk of injury due to their insensate feet. [8] [9]

Metabolic disorders represent the most common clinical category of etiologies, causing extremity pain from underlying peripheral neuropathy conditions. Several causes of PN exist, but diabetes mellitus is the most common etiology. Other underlying etiologies include:

• Alcohol use disorder  [10]
• Nutritional deficiencies (eg, low B12, high B6)  [11]
• Guillain-Barre syndrome  [12]
• Toxins (eg, chemotherapy) and overdose  [13] [14] [15] [16]
• Hereditary or genetic conditions (eg, Charcot Marie Tooth disease, amyloidosis, porphyria)  [17] [18] [19] [20] [21] [22]
• Infection (eg, HIV) [23] [24] [25]
• Inflammatory conditions (eg, lupus and rheumatoid arthritis)  [26] [27] ] [28]
• Hypothyroidism  [29] [30] [31] [32]
• Trauma  [33] [34]

Diabetic Peripheral Neuropathy Risk Factors 

Risk factors for DPN include:

• Advanced age
• Hypertension
• Peripheral vascular disease
• Dyslipidemia
• Poor glucose control
• Long-standing diabetes
• Excessive alcohol consumption
• Positive HLA-DR3/4 genotype
• Epidemiology

At the time a patient is diagnosed with diabetes, the literature estimates that 10% to 20% of these patients are concomitantly diagnosed with DPN; however, studies analyzing patients with long-standing diabetes mellitus report that DPN has a higher prevalence in those patients. After 5 years, 26% have peripheral neuropathy, and 41% of patients with diabetes have neuropathy at 10 years. The literature reports that 50% to 66% of patients with diabetes mellitus will eventually develop DPN during their lifetime. [35]  DPN can occur in both type 1 and type 2 diabetes, but the prevalence is higher in individuals with type 2 diabetes due to the longer duration and higher rates of comorbidities. [36]  Diabetes mellitus is also the most common cause of Charcot neuroarthropathy, with an incidence of 0.1% to 0.4% and as high as 29% in patients with peripheral neuropathy. [37]

About half of patients with DPN can clinically present with asymmetric sensory changes. [38] [39]  Obesity and genetic factors increase the risk of developing diabetes. Peripheral and autonomic neuropathies are some of the leading causes of morbidity in diabetes mellitus. At 5 years, the risk of death for patients with a diabetic foot ulcer is 2.5 times as high as the risk of death for a patient with diabetes who does not have a foot ulcer. The rate of emergency department visits for diabetic foot ulcers and associated infection exceeds the rates for congestive heart failure, renal disease, depression, and most forms of cancer. [40] [41] [42]

• Pathophysiology

DPN encompasses sensory, motor, and autonomic neuropathy. Increased serum glucose leads to insulin resistance, dyslipidemia, and oxidative stress of the endoplasmic reticulum and mitochondria. These processes contribute to accumulating reactive oxygen species (ROS), inflammation, and cellular damage. The infiltrated macrophages inside peripheral nerve cells trigger cytokine and chemokine production, promoting inflammation and nerve fiber damage. [7] In addition, implicated causes of peripheral nerve damage include advanced glycosylation end products and disturbance of hexosamine, protein kinase C, and polymerase pathways. Neurovascular impairment with poor repair processes and endothelial dysfunction also have been implicated. [39]

• Toxicokinetics

Transient hyperglycemia is often tolerated by normal compensatory physiological function and homeostatic mechanisms of blood sugar control. However, serum glucose can have toxic effects such as neuropathy in chronically elevated states. For patients diagnosed early with type 1 diabetes, tight glucose control can reduce the risk of diabetic peripheral neuropathy by 78%. [36]  In contrast, typically, with a later diagnosis of long-standing hyperglycemia or type 2 diabetes, tight glucose control only reduces the risk by 5% to 9%. [36] [43]

• History and Physical

Because peripheral neuropathy is so common in patients with diabetes, the American Diabetes Association (ADA) recommends clinicians evaluate patients with type 2 diabetes when they are diagnosed; in patients with type 1 diabetes, clinicians should assess for peripheral neuropathy 5 years after diagnosis and then annually. Peripheral neuropathy is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament. [6]

Clinical History

Clinicians should perform a complete medical history, including diabetes, obesity, dyslipidemia, and hypertension. Furthermore, a review of systems and medications captures most of the underlying causes of DPN. Other risk factors for peripheral neuropathy should also be noted (eg, older age and diabetes control). Characteristic symptoms of peripheral neuropathy include burning, numbness, or tingling in the feet that worsens at night. [6] Patients with pedal paresthesias and dysesthesia often describe a nonspecific constellation of symptoms resulting in difficulty with ambulation and other basic activities of daily living (ADL). Clinical features of peripheral neuropathy and distal sensory peripheral neuropathy are present in about 80% of DPN patients, often described as a "stocking-glove distribution," which can take several years to develop. [44]

Physical Examination

A lower extremity neurological physical exam should include muscle strength, reflex, and sensation evaluation, including light touch with a monofilament, vibratory sensation, and proprioception. A dermatological exam demonstrating dry/cracked skin may point to autonomic neuropathy, while pedal deformities (eg, hammertoes) suggest motor neuropathy. [44]

Small fiber sensation is assessed with temperature changes or pinprick testing. A patient's risk for developing ulcers is evaluated by determining the individual's ability to feel pressure. Since the protective sensation is lost after sensory impairment, the standard Semmes-Weinstein 5.07 monofilament 10 g of pressure protective sensation test may be accurately sensed even after developing a neurotrophic ulcer. [6]

Large fibers are assessed through vibratory sensation. [6] Simply timing the duration that a vibrating 128 Hz tuning fork is felt at the dorsal hallux interphalangeal joint, normally 18 seconds in most individuals, can be used to detect sensory deficits earlier and quantify severity. Decreased light touch sensation or loss of ankle reflexes tend to occur earlier in the disease process. In contrast, the detectable loss of protective sensation tends to occur later in the disease, sometimes even after a neuropathic ulcer develops. Needle electromyography (EMG) and nerve conduction velocity testing can be both painful and expensive and mainly test the large myelinated fibers. Epidermal nerve fiber density testing can be performed to evaluate the small unmyelinated fibers. [45]

Autonomic Symptoms

Autonomic neuropathy is also prevalent in diabetes and can affect the gastrointestinal, cardiovascular, and genitourinary organs. Common symptoms in each organ system include:

• GI: Abdominal discomfort, dysphagia, nausea, fecal incontinence, constipation, diarrhea
• Cardiac: Hypotension, sinus tachycardia, variable heart rate, syncope
• Bladder: Weak urinary stream, straining to void, incomplete emptying of bladder, 
• Skin: Heat intolerance, gustatory sweating, extreme diaphoresis
• Nervous: Carpal tunnel syndrome, radiculopathy, lumbosacral, cervical neuropathy, and impairment of cranial nerves III, IV, VI, and VII

Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation). [6]  Electromyography and nerve conduction studies are suggested for severe or rapidly progressive symptoms or motor weakness.

Intraepidermal nerve fiber density is the preferred test for small fiber neuropathy evaluation. Intraepidermal nerve fiber density measurement by skin biopsy can be considered in patients with idiopathic cases. The number and morphology of axons within the epidermis can be evaluated, and intraepidermal nerve fiber density is compared to age-dependent normal values. [46] [47]

Minor symptoms may not need laboratory workup. Persistent unexplained symptoms may warrant laboratory investigation, including serum glucose, hemoglobin A1c, complete blood count, erythrocyte sedimentation rate, rapid plasma reagin, serum electrophoresis, and vitamin B1, B6, and B12 levels.

• Treatment / Management

DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Many patients with neuropathy have mild to moderate numbness symptoms yet retain protective sensation in their feet. Patients may only need reassurance and education regarding the cause of the numbness. Periodic follow-up is essential. Peripheral arterial disease and radiculopathy should be ruled out. With improved glycemic control, paresthesias and dysesthesias may diminish within one year. In 2022, the Current Pain and Headache Reports proposed a treatment algorithm for painful diabetic neuropathy. [48] The algorithm is divided into conservative, pharmacologic, and interventional therapies, subcategorized as first, second, and third-line treatment.

Conservative Therapy

• Weight-bearing exercises
• Tai chi massage therapy
• Optimization of glucose
• Properly manage comorbidities
• Weight loss
• Healthy diet
• Acupuncture
• Transcutaneous electrical nerve stimulation (TENS)

  Pharmacological Therapy

• Gabapentinoids (eg, pregabalin and gabapentin)
• Serotonin and norepinephrine reuptake inhibitors (eg, venlafaxine)
• Tricyclic antidepressants (eg, amitriptyline)
• Capsaicin patch 8%
• Lidocaine patch 5%
• Intravenous agents (eg, lidocaine, ketamine)

Interventional Therapy

• Typically 10 kHz
• Tonic waveforms
• Burst spinal cord stimulation
• Dorsal root ganglion spinal cord stimulation
• Peripheral nerve stimulation
• Intrathecal morphine, fentanyl, or hydromorphone
• Intrathecal ziconatide

DPN can affect other body areas, including the digestive, endocrine, and vascular systems. Diabetic gastroparesis may be managed with erythromycin and metoclopramide. [49] [50]  Tegaserod is a newer agent but is only available on an emergency basis because of serious adverse cardiac effects. [51]  Erectile dysfunction is managed with phosphodiesterase inhibitors, but not everyone has a response. A penile prosthesis may be of benefit. [52]  Orthostatic hypotension may be managed by increased salt and fluid intake and compression stockings. If that fails, steroids may be required. Glycopyrrolate is used to manage sweating but often does not work. [53]

Alternative Therapies

Some patients may also benefit from supplements, but studies are scarce. Omega-3 polyunsaturated fatty acid oral supplements (ie, fish oil) have perhaps the best evidence in attenuating sensory loss and reducing the incidence of peripheral neuropathy. [54] One randomized controlled trial reported a significant increase in corneal nerve fiber length in patients with dry eye disease compared to placebo. [55]  Several studies have linked vitamin D deficiency with an increased risk for diabetic peripheral neuropathy, diabetic ulcer, and cardiovascular autonomic neuropathy. [56] In addition, a single high-dose intramuscular injection of vitamin D supplementation 600,000 IU has significantly improved patients' quality of life and perception of foot problems. [57] There is moderate evidence that alpha lipoic acid supplementation decreases pain with little to no adverse effects. [58] [59] [60]  

Additionally, although classified as a medical food, the prescription containing L-methyl folate, pyridoxal 5'-phosphate, and methylcobalamin for the dietary management of endothelial dysfunction has significantly improved nerve fiber density and monofilament sensation. [61]  Scant evidence shows that supplementation with vitamins C and E prevents diabetic complications. There is no evidence that taking vitamin B12 oral supplements improves DPN. [62]  Depleting substance P with topical capsaicin cream may help some patients who can tolerate the initially increased burning. [63] [64] [65]  For patients with painful diabetic peripheral neuropathy, a capsaicin 8% patch in serial treatments can provide modest improvements in pain and sleep quality. [66] [67]

• Differential Diagnosis

Differential diagnoses of DPN include the following:

• Alcohol-associated neuropathy
• Nutritional linked neuropathy
• Uremic neuropathy
• Vasculitic linked neuropathy
• Vitamin B12 deficiency
• Toxic metal neuropathy

While numerous classifications have attempted to categorize different types of diabetic neuropathies, most experts agree that a classification based on the clinical manifestation is the most appropriate. [68] The following classification of diabetic neuropathies described initially by Thomas is the most accepted today:

• hyperglycemic neuropathy
• Chronic sensorimotor 
• Acute sensory
• Prediabetic or impaired glucose tolerance neuropathy
• Thoracolumbar radiculoneuropathy
• Proximal motor (eg, amyotrophy)
• Superimposed chronic inflammatory demyelinating neuropathy  [69]

The most common type of DPN is generalized symmetrical sensorimotor polyneuropathy. [70]  The staging of diabetic neuropathy was described by Dyck and divided into 4 stages: [71]

• Stage 0: no neuropathy
• Stage 1: asymptomatic neuropathy
• Stage 2: symptomatic neuropathy
• Stage 3: disabling neuropathy

Poorly treated diabetics have higher morbidity and complication rates associated with DPN than well-controlled diabetics. DPN often leads to skin breakdown, infection, ulceration, and eventually to amputation. Further, the treatment of DPN is not satisfactory, and adverse cardiac events are common. Less than a third of patients achieve reasonable pain control. For most patients with DPN, the quality of life is poor.

• Complications

Common complications of DPN include the following:

• Amputations of the toes, foot, or leg
• Infections of the foot
• Falls secondary to dizziness
• Diarrhea, failure to thrive, and dehydration
• Cardiovascular neuropathy can cause death
• Deterrence and Patient Education

Preventative strategies are an essential aspect of DPN management. According to the American Diabetes Association, people with diabetes should have a complete foot examination annually and a visual examination of the feet at each visit, usually every 3 to 4 months. Patients should be educated on monitoring blood sugar levels and self-examining their feet daily to look for ulcers, wounds, or broken skin. They should also follow a diet plan and take medications on time, as advised by the doctor. Clinicians should make patients aware of the contributing role of alcohol and smoking in peripheral neuropathy and recommend a plan to quit as needed. Moreover, abnormally fitting shoes should not be worn by the patient.

• Pearls and Other Issues

The lower extremities are especially prone to the repetitive microtrauma-induced complications of polyneuropathy. There is an increased propensity to develop not only recurrent neuropathic ulcers but also Charcot neuroarthropathy and, to a lesser extent, motor neuropathy. Additionally, as patients age, their nails become dystrophic, and the risk of subungual ulcerations, gangrene, and osteomyelitis increases with decreased protective sensation. Periodic pedal-focused examinations are essential. Professional foot care and therapeutic shoes and insoles have helped reduce the lower limb amputation rates in patients with diabetes mellitus.

• Enhancing Healthcare Team Outcomes

Diabetic neuropathy affects many organ systems and is best managed by an interprofessional team. Because there is no cure for the disorder, the key is prevention. All people with diabetes should have a dietary consult and receive education on what foods they should eat and what to avoid. The diet should be realistic and focused on lowering blood glucose levels. The patients should also enter a rehabilitation program or some exercise. Losing weight makes it easier to control blood sugars and lowers blood pressure and lipids. A podiatry consult is vital as protection of the foot is necessary. Further, all people with diabetes should be informed about avoiding trauma and undergoing any invasive procedure on the feet without prior clearance from the endocrinologist. In addition, the patient should be told to avoid cold or hot temperatures.

A nurse proficient in diabetes management should educate the patient about all aspects of diabetes and the importance of euglycemia. Patients should be taught how to monitor their blood glucose and use portable glucose monitors. The pharmacist should offer education about the medications, their benefits, and their adverse effects.

Compliance with medication therapy to treat diabetes is vital. Finally, patients who develop neuropathy also tend to have nephropathy and retinopathy; hence, all people with diabetes should be referred to a nephrologist and ophthalmologist. There should be open communication between the interprofessional team so that all patients are provided with the available standard of care with minimal morbidity. Foot and nail care nurses monitor patients, provide education, and inform the team of the patient's condition. Pharmacists educate patients about the use of medications and the importance of compliance. [72] [73]  

In general, patients with diabetes mellitus who are not compliant with treatment or undertreated usually tend to have a poorer outcome than patients who undergo treatment. The neuropathy frequently results in skin breakdown, ulceration, and, eventually, an infection. Amputation of the toes and limbs is not uncommon. However, the actual treatment of diabetic neuropathy is not perfect, and often, most treatments do not work. Complete relief from symptoms of neuropathy is rare. Overall, the mortality rates are highest in patients with diabetes mellitus with autonomic neuropathy, especially those who have cardiac dysfunction. The overall mortality rates are 15% to 30% over 10 years, but there is also significant morbidity from limb amputation. Other symptoms that make the quality of life poor include syncopal attacks, diarrhea, constipation, and continuous pain. [70] [74]

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Disclosure: Myron Bodman declares no relevant financial relationships with ineligible companies.

Disclosure: Mark Dreyer declares no relevant financial relationships with ineligible companies.

Disclosure: Matthew Varacallo declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Bodman MA, Dreyer MA, Varacallo M. Diabetic Peripheral Neuropathy. [Updated 2024 Feb 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Diabetic neuropathy

On this page, when to see a doctor, risk factors, complications.

Diabetic neuropathy is a type of nerve damage that can occur if you have diabetes. High blood sugar (glucose) can injure nerves throughout the body. Diabetic neuropathy most often damages nerves in the legs and feet.

Depending on the affected nerves, diabetic neuropathy symptoms include pain and numbness in the legs, feet and hands. It can also cause problems with the digestive system, urinary tract, blood vessels and heart. Some people have mild symptoms. But for others, diabetic neuropathy can be quite painful and disabling.

Diabetic neuropathy is a serious diabetes complication that may affect as many as 50% of people with diabetes. But you can often prevent diabetic neuropathy or slow its progress with consistent blood sugar management and a healthy lifestyle.

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• A Book: The Essential Diabetes Book

There are four main types of diabetic neuropathy. You can have one type or more than one type of neuropathy.

Your symptoms depend on the type you have and which nerves are affected. Usually, symptoms develop gradually. You may not notice anything is wrong until considerable nerve damage has occurred.

Peripheral neuropathy

This type of neuropathy may also be called distal symmetric peripheral neuropathy. It's the most common type of diabetic neuropathy. It affects the feet and legs first, followed by the hands and arms. Signs and symptoms of peripheral neuropathy are often worse at night, and may include:

• Numbness or reduced ability to feel pain or temperature changes
• Tingling or burning feeling
• Sharp pains or cramps
• Muscle weakness
• Extreme sensitivity to touch — for some people, even a bedsheet's weight can be painful
• Serious foot problems, such as ulcers, infections, and bone and joint damage

Autonomic neuropathy

The autonomic nervous system controls blood pressure, heart rate, sweating, eyes, bladder, digestive system and sex organs. Diabetes can affect nerves in any of these areas, possibly causing signs and symptoms including:

• A lack of awareness that blood sugar levels are low (hypoglycemia unawareness)
• Drops in blood pressure when rising from sitting or lying down that may cause dizziness or fainting (orthostatic hypotension)
• Bladder or bowel problems
• Slow stomach emptying (gastroparesis), causing nausea, vomiting, sensation of fullness and loss of appetite
• Difficulty swallowing
• Changes in the way the eyes adjust from light to dark or far to near
• Increased or decreased sweating
• Problems with sexual response, such as vaginal dryness in women and erectile dysfunction in men

Proximal neuropathy (diabetic polyradiculopathy)

This type of neuropathy often affects nerves in the thighs, hips, buttocks or legs. It can also affect the abdominal and chest area. Symptoms are usually on one side of the body, but may spread to the other side. Proximal neuropathy may include:

• Severe pain in the buttock, hip or thigh
• Weak and shrinking thigh muscles
• Difficulty rising from a sitting position
• Chest or abdominal wall pain

Mononeuropathy (focal neuropathy)

Mononeuropathy refers to damage to a single, specific nerve. The nerve may be in the face, torso, arm or leg. Mononeuropathy may lead to:

• Difficulty focusing or double vision
• Paralysis on one side of the face
• Numbness or tingling in the hand or fingers
• Weakness in the hand that may result in dropping things
• Pain in the shin or foot
• Weakness causing difficulty lifting the front part of the foot (foot drop)
• Pain in the front of the thigh

More Information

• Types of diabetic neuropathy

Call your health care provider for an appointment if you have:

• A cut or sore on your foot that is infected or won't heal
• Burning, tingling, weakness or pain in your hands or feet that interferes with daily activities or sleep
• Changes in digestion, urination or sexual function
• Dizziness and fainting

The American Diabetes Association (ADA) recommends that screening for diabetic neuropathy begin immediately after someone is diagnosed with type 2 diabetes or five years after diagnosis with type 1 diabetes. After that, screening is recommended once a year.

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The exact cause of each type of neuropathy is unknown. Researchers think that over time, uncontrolled high blood sugar damages nerves and interferes with their ability to send signals, leading to diabetic neuropathy. High blood sugar also weakens the walls of the small blood vessels (capillaries) that supply the nerves with oxygen and nutrients.

Anyone who has diabetes can develop neuropathy. But these risk factors make nerve damage more likely:

• Poor blood sugar control. Uncontrolled blood sugar increases the risk of every diabetes complication, including nerve damage.
• Diabetes history. The risk of diabetic neuropathy increases the longer a person has diabetes, especially if blood sugar isn't well controlled.
• Kidney disease. Diabetes can damage the kidneys. Kidney damage sends toxins into the blood, which can lead to nerve damage.
• Being overweight. Having a body mass index (BMI) of 25 or more may increase the risk of diabetic neuropathy.
• Smoking. Smoking narrows and hardens the arteries, reducing blood flow to the legs and feet. This makes it more difficult for wounds to heal and damages the peripheral nerves.

Diabetic neuropathy can cause a number of serious complications, including:

• Hypoglycemia unawareness. Blood sugar levels below 70 milligrams per deciliter (mg/dL) — 3.9 millimoles per liter (mmol/L) — usually cause shakiness, sweating and a fast heartbeat. But people who have autonomic neuropathy may not experience these warning signs.
• Loss of a toe, foot or leg. Nerve damage can cause a loss of feeling in the feet, so even minor cuts can turn into sores or ulcers without being noticed. In severe cases, an infection can spread to the bone or lead to tissue death. Removal (amputation) of a toe, foot or even part of the leg may be necessary.
• Urinary tract infections and urinary incontinence. If the nerves that control the bladder are damaged, the bladder may not empty completely when urinating. Bacteria can build up in the bladder and kidneys, causing urinary tract infections. Nerve damage can also affect the ability to feel the need to urinate or to control the muscles that release urine, leading to leakage (incontinence).
• Sharp drops in blood pressure. Damage to the nerves that control blood flow can affect the body's ability to adjust blood pressure. This can cause a sharp drop in pressure when standing after sitting or lying down, which may lead to lightheadedness and fainting.
• Digestive problems . If nerve damage occurs in the digestive tract, constipation or diarrhea, or both are possible. Diabetes-related nerve damage can lead to gastroparesis, a condition in which the stomach empties too slowly or not at all. This can cause bloating and indigestion.
• Sexual dysfunction. Autonomic neuropathy often damages the nerves that affect the sex organs. Men may experience erectile dysfunction. Women may have difficulty with lubrication and arousal.
• Increased or decreased sweating. Nerve damage can disrupt how the sweat glands work and make it difficult for the body to control its temperature properly.

You can prevent or delay diabetic neuropathy and its complications by closely managing your blood sugar and taking good care of your feet.

Blood sugar management

The American Diabetes Association (ADA) recommends that people living with diabetes have a glycated hemoglobin (A1C) test at least twice a year. This test indicates your average blood sugar level for the past 2 to 3 months.

glycated hemoglobin (A1C) goals may need to be individualized, but for many adults, the ADA recommends an A1C of less than 7.0%. If your blood sugar levels are higher than your goal, you may need changes in your daily management, such as adding or adjusting your medications or changing your diet or physical activity.

Foot problems, including sores that don't heal, ulcers and even amputation, are common complications of diabetic neuropathy. But you can prevent many of these problems by having a thorough foot exam at least once a year. Also have your health care provider check your feet at each office visit and take good care of your feet at home.

Follow your health care provider's recommendations for good foot care. To protect the health of your feet:

• Check your feet every day. Look for blisters, cuts, bruises, cracked and peeling skin, redness, and swelling. Use a mirror or ask a friend or family member to help examine parts of your feet that are hard to see.
• Keep your feet clean and dry. Wash your feet every day with lukewarm water and mild soap. Don't soak your feet. Dry your feet and between your toes thoroughly.
• Moisturize your feet. This helps prevent cracking. But don't get lotion between your toes because it might encourage fungal growth.
• Trim your toenails carefully. Cut your toenails straight across. File the edges carefully so that you have smooth edges. If you can't do this yourself, a specialist in foot problems (podiatrist) can help.
• Wear clean, dry socks. Look for socks made of cotton or moisture-wicking fibers that don't have tight bands or thick seams.
• Wear cushioned shoes that fit well. Wear closed-toed shoes or slippers to protect your feet. Make sure your shoes fit properly and allow your toes to move. A foot specialist can teach you how to buy properly fitted shoes and to prevent problems such as corns and calluses. If you qualify for Medicare, your plan may cover the cost of at least one pair of shoes each year.

Apr 29, 2022

• Ferri FF. Diabetic polyneuropathy. In: Ferri's Clinical Advisor 2022. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 17, 2021.
• Diabetic neuropathy. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/nerve-damage-diabetic-neuropathies/all-content. Accessed Jan. 10, 2020.
• American Diabetes Association. Standards of medical care in diabetes — 2021. Diabetes Care. 2021. https://care.diabetesjournals.org/content/44/Supplement_1. Accessed Nov. 11, 2021.
• AskMayoExpert. Peripheral neuropathy (adult). Mayo Clinic; 2021.
• Feldman EL, et al. Management of diabetic neuropathy. https://www.uptodate.com/contents/search. Accessed Dec. 17, 2021.
• Diabetes and foot problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/foot-problems#healthyfeet. Accessed Jan. 10, 2020.
• Jankovic J, et al., eds. Disorders of peripheral nerves. In: Bradley and Daroff's Neurology in Clinical Practice. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Jan. 11, 2020.
• Baute V, et al. Complementary and alternative medicine for painful peripheral neuropathy. Current Treatment Options in Neurology. 2019; doi:10.1007/s11940-019-0584-z.
• Feldman EL, et al. Diabetic neuropathy. Nature Reviews — Disease Primers. 2019; doi:10.1038/s41572-019-0092-1.
• Cutsforth-Gregory (expert opinion). Mayo Clinic. Dec. 24, 2021.
• Castro MR (expert opinion). Mayo Clinic. Jan. 21, 2022.
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• Diabetic neuropathy - Symptoms & causes - Mayo Clinic
• Diabetic neuropathy and dietary supplements

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When viewing this topic in a different language, you may notice some differences in the way the content is structured, but it still reflects the latest evidence-based guidance.

Diabetic neuropathy

• Overview  
• Theory  
• Diagnosis  
• Management  
• Follow up  
• Resources  

Hyperglycaemia contributes to the pathogenesis of neuropathy in both type 1 and type 2 diabetes. Other metabolic and vascular factors, particularly hypertriglyceridaemia, are important.

The clinical presentation comprises a broad constellation of symptoms and deficits, involving sensory, motor, and autonomic nerve fibres, and multiple organ systems.

Diabetic peripheral neuropathy is the most common chronic complication of diabetes, characterised by the presence of peripheral nerve dysfunction, diagnosed after the exclusion of other causes. Pain is the outstanding complaint in most patients, but many patients are completely asymptomatic.

Treatment has traditionally focused on control of hyperglycaemia as a means of slowing progression or delaying onset, on targeting potential pathogenic mechanisms, and on pain reduction.

Although pain is generated principally by peripheral nerve injury, there is recent evidence that the central nervous system may play a significant role in the disinhibition and amplification of pain. Indeed, the most effective drugs in treating painful diabetic neuropathy are centrally acting.

Diabetic neuropathy (DN) is a highly prevalent complication of diabetes (type 1 or type 2) and is characterised by the presence of symptoms and/or signs of peripheral nerve dysfunction and/or autonomic nerve dysfunction. It is diagnosed after the exclusion of other causes. Frequently, however, people with DN are asymptomatic.

History and exam

Key diagnostic factors.

• presence of risk factors
• asymptomatic
• pain (peripheral)
• loss of sensation (peripheral)
• dysaesthesia (peripheral)
• reduced or absent ankle reflexes (peripheral)
• painless injuries (peripheral)
• resting tachycardia (autonomic)
• impaired heart rate variability (autonomic)
• urinary frequency, urgency, nocturia, incontinence, hesitancy, weak stream, or retention (autonomic)
• erectile dysfunction (autonomic)
• decreased sexual desire and increased pain during intercourse (autonomic)
• orthostatic hypotension (autonomic)

Other diagnostic factors

• constipation (autonomic)
• faecal incontinence (autonomic)
• anhidrosis, heat intolerance, dry skin, or hyperhidrosis (autonomic)
• hypoglycaemia unawareness (autonomic)
• weakness (peripheral)
• history of recent falls (peripheral)
• gait ataxia (peripheral)
• nausea, postprandial vomiting, bloating, loss of appetite, early satiety (autonomic)
• heartburn and dysphagia for solids (autonomic)
• profuse and watery diarrhoea (autonomic)
• specific mononeuropathy (peripheral)
• cranial neuropathy (peripheral)
• pain over lower thoracic or abdominal wall (peripheral)
• thigh muscle atrophy, pain, and weakness (peripheral)

Risk factors

• poorly controlled hyperglycaemia
• prolonged duration of diabetes
• older age (e.g., >70 years)
• tall stature
• hypertension
• dyslipidaemia with elevated triglycerides
• co-existence of multiple cardiovascular disease (CVD) risk factors (type 2 diabetes)
• immune dysregulation

Diagnostic investigations

1st investigations to order.

• clinical diagnosis
• fasting blood glucose
• serum thyroid-stimulating hormone
• serum vitamin B12
• electrolytes, urea, creatinine
• serum lipid profile
• FBC and erythrocyte sedimentation rate
• serum/urine immunoelectrophoresis
• corneal confocal microscopy

Investigations to consider

• 2-hour plasma glucose
• nerve conduction studies (nerve conduction velocity [NCV])
• electromyography (EMG)
• quantitative sensory testing (QST)
• skin biopsy
• cardiovascular reflex testing
• heart rate variability (HRV)
• gastric emptying studies
• gastroduodenoscopy
• barium meal
• gastrointestinal manometry
• hydrogen breath tests
• gastric ultrasonography
• gastric MRI
• anorectal manometry
• d-xylose test
• urine culture
• cystometry, voiding cystometrogram
• post-void urinary tract ultrasound
• video-urodynamics
• measurement of nocturnal penile tumescence and of penile and brachial BP
• serum LH, testosterone, free testosterone, prolactin (morning tests, 8.00-9.00 a.m.)

Treatment algorithm

Diabetic peripheral neuropathy, cranial neuropathies, limb or truncal mononeuropathies, diabetic amyotrophy, diabetic autonomic neuropathy, contributors, rayaz a. malik, bsc (hons), msc, mbchb, frcp, phd.

Professor of Medicine

Organizational Official for the Human Research Protection Program

Weill Cornell Medicine - Qatar

Disclosures

RAM has been reimbursed for being on the advisory board for an epidemiological study on cardiovascular disease in type 2 diabetes and to give educational lectures on treatment of diabetes undertaken by Novo Nordisk. RAM has been reimbursed for educational lectures on diabetes treatment for Sanofi Aventis, Lilly, and Proctor and Gamble (P&G). RAM has reviewed an investigator-initiated grant to study long COVID from P&G. RAM is an author of a number of references cited in this topic.

Uazman Alam, BSc, MBChB, MPHe, PhD

Senior Lecturer and Consultant Physician

University of Liverpool

UA serves on advisory boards for Eli Lilly.

Shazli Azmi, MBchB, MRCP

Consultant Physician

Diabetes and Endocrinology

Central Manchester Foundation Trust

University of Manchester Manchester

SA declares that she has no competing interests.

Acknowledgements

Dr Rayaz Malik, Dr Uazman Alam, and Dr Shazli Azmi would like to gratefully acknowledge Dr Rodica Pop-Busui and Dr Eva Feldman, the previous contributors to this topic.

RPB declares that she has received speaking honoraria from Pfizer and research support from Amylin Pharmaceuticals; National Institutes of Health/National Heart, Lung, and Blood Institute; National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association; and Juvenile Diabetes Research Foundation. RPB and EF are authors of references cited in this topic.

Peer reviewers

Zachary t. bloomgarden, md.

Clinical Professor

Department of Medicine

Mount Sinai School of Medicine

ZTB declares that he has no competing interests.

Rajesh K. Garg, MD

Assistant Professor of Medicine

Harvard Medical School

Division of Endocrinology

Diabetes and Hypertension

Brigham and Women's Hospital

RKG has received consultant fees from Aventis and Novartis, and speaker fees from Novartis.

Edward Jude, MBBS, MD, MRCP, DNB

Consultant and Honorary Senior Lecturer

Tameside General Hospital

Diabetes Centre

Ashton Under Lyne

EJ has received funding for conferences and lectures from Pfizer and Boehringer Ingelheim.

Differentials

• Cyanocobalamin deficiency
• Hypothyroidism
• Diabetes (type 1 and type 2) in children and young people: diagnosis and management
• Standards of care in diabetes - 2023

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SCOTT BRAGG, PharmD, SARAH TUCKER MARRISON, MD, PhD, AND SEAN HALEY, MD, MPH

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2024;109(3):226-232

Author disclosure: No relevant financial relationships.

Diabetic peripheral neuropathy occurs in up to 50% of patients with diabetes mellitus and increases the risk of diabetic foot ulcers and infections. Consistent screening and clear communication are essential to decrease disparities in assessment of neuropathic symptoms and diagnosis. Physicians should address underlying risk factors such as poor glycemic control, vitamin B 12 deficiency, elevated blood pressure, and obesity to reduce the likelihood of developing neuropathy. First-line drug therapy for painful diabetic peripheral neuropathy includes duloxetine, gabapentin, amitriptyline, and pregabalin; however, these medications do not restore sensation to affected extremities. Evidence for long-term benefit and safety of first-line treatment options is lacking. Second-line drug therapy includes nortriptyline, imipramine, venlafaxine, carbamazepine, oxcarbazepine, topical lidocaine, and topical capsaicin. Periodic, objective monitoring of medication response is critical because patients may not obtain desired pain reduction, adverse effects are common, and serious adverse effects can occur. Opioids should generally be avoided. Nondrug therapies with low- to moderate-quality evidence include exercise and neuromodulation with spinal cord stimulation or transcutaneous electrical nerve stimulation. Peripheral transcutaneous electrical nerve stimulation is well tolerated and inexpensive, but benefits are modest. Other treatments, such as acupuncture, alpha-lipoic acid, acetyl-L-carnitine, cannabidiol, and onabotulinumtoxinA need further study in patients with diabetic peripheral neuropathy.

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