Screening for diabetic polyneuropathy

INTRODUCTION — There are many forms of diabetic neuropathy including distal symmetric polyneuropathy, autonomic neuropathy, radiculopathies, mononeuropathies, and mononeuropathy multiplex (table 1). (See "Epidemiology and classification of diabetic neuropathy".)

The risk factors, clinical manifestations, and diagnosis of diabetic distal symmetric polyneuropathy will be reviewed here. Other aspects of diabetic neuropathy are discussed separately.

●(See "Pathogenesis of diabetic polyneuropathy".)

●(See "Epidemiology and classification of diabetic neuropathy".)

●(See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

●(See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

●(See "Management of diabetic neuropathy".)

RISK FACTORS — Several risk factors have been associated with the risk of developing diabetic neuropathy in multiple large clinical cohorts including the following [1-8]:

●Longer duration of diabetes mellitus

●Higher glycated hemoglobin levels

●Hypertension

●Obesity

●Dyslipidemia

●Tobacco use

●Chronic alcohol use

●Taller patient height

●Older age

Older age and the duration and severity of hyperglycemia are the major risk factors for the development of diabetic neuropathy in patients with both type 1 and type 2 diabetes [1,2].

Obesity and metabolic syndrome are significant and independent risk factors for diabetic neuropathy, particularly in type 2 diabetes. Clinical studies from varied patient populations [3,9-12] all strongly suggest that one or more components of the metabolic syndrome are critical drivers of diabetic neuropathy [3,9-12].

The association between neuropathy and metabolic syndrome is not limited to type 2 diabetes [13]. Among 1172 participants in the EURODIAB study with type 1 diabetes and no neuropathy at baseline, a distal symmetric polyneuropathy developed over a mean follow-up of 7.3 years in 276 patients (24 percent) [7]. In addition to duration of diabetes and glycolated hemoglobin values, the incidence of neuropathy in these type 1 patients was significantly associated with increased triglyceride levels, body mass index, and the presence of hypertension at baseline, all markers of the metabolic syndrome. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

CLINICAL MANIFESTATIONS — Diabetic polyneuropathy is primarily a distal symmetric sensory polyneuropathy. The earliest signs of diabetic polyneuropathy probably reflect the gradual loss of integrity of both large myelinated and small myelinated and unmyelinated nerve fibers (table 2):

●Large nerve fiber loss leads to impairment of vibratory sensation and proprioception, and reduced ankle reflexes

●Small nerve fiber loss leads to impairment of pain, light touch, and temperature sensation

Neuropathic signs and symptoms — The main symptoms of diabetic polyneuropathy include negative symptoms (those related to nerve fiber loss or dysfunction), such as numbness and loss of balance, and positive symptoms (those related to abnormal function of surviving nerve fibers), such as tingling and pain. Symptoms start distally in the toes and feet [14], and positive symptoms are usually worse at night. Some patients, however, have few complaints. Up to one-half of patients with diabetic polyneuropathy may be asymptomatic [15], but the physical examination reveals mild to moderately severe sensory loss [16,17]. Decreased or absent ankle reflexes occur early in the disease, while more widespread loss of reflexes is a late finding.

With disease progression, sensory loss ascends and, when reaching approximately mid-calf, appears in the hands. This gradual evolution causes the typical "stocking-glove" sensory loss. This pattern reflects preferential damage according to axon length; the longest axons are affected first. Motor involvement with frank weakness occurs in the same pattern, but only much later and in more severe cases.

Skin and joint signs — Diabetic polyneuropathy is frequently insidious in onset and can lead to formation of foot ulcers and muscle and joint disease. Progressive loss of protective sensation predisposes to ulcer formation [14]. Foot ulcers are usually classified into two groups: acute ulcers secondary to dermal abrasion from poorly fitting shoes and chronic plantar ulcers occurring over weight-bearing areas. Chronic ulceration is probably multifactorial, due to a combination of diabetic polyneuropathy (with decreased pain sensation), autonomic dysfunction, and vascular insufficiency. (See "Evaluation of the diabetic foot".)

Distal motor axonal loss results in atrophy of intrinsic foot muscles and an imbalance between strength in toe extensors and flexors. This ultimately leads to chronic metatarsal-phalangeal flexion (claw-toe deformity) which shifts weight to the metatarsal heads [18]. This weight shift results in formation of calluses that can fissure, become infected and ulcerate. Other arthropathic changes may also develop, including collapse of the arch of the midfoot and bony prominences leading to Charcot arthropathy, fragmentation and sclerosis of bone, new bone formation, subluxation, dislocation, and stress fractures. (See "Diabetic neuroarthropathy".)

APPROACH TO SCREENING — The discussion that follows regarding the diagnosis of diabetic polyneuropathy applies primarily to patients with an established diagnosis of diabetes mellitus. An overview of the diagnostic approach to suspected polyneuropathy in patients without diabetes or in those who have not yet been evaluated for diabetes is found elsewhere. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation'.)

Prevalence — The prevalence of diabetic polyneuropathy (and other microvascular and macrovascular complications) increases with disease duration. This was illustrated by a study from Finland that evaluated the natural history of peripheral polyneuropathy in patients with newly diagnosed type 2 diabetes [18]. Polyneuropathy was diagnosed on the basis of both clinical (pain and paresthesia) and electrodiagnostic (nerve conduction velocity and response-amplitude values) criteria. The prevalence of definite or probable polyneuropathy progressively increased from 8 percent at baseline to 42 percent at 10 years; comparable values in normal subjects were 2 and 6 percent, respectively.

The duration and severity of hyperglycemia and components of the metabolic syndrome are major risk factors for the development of diabetic neuropathy, as discussed separately. (See 'Risk factors' above.)

Who should be screened? — Our recommendations are in agreement with those of the 2017 ADA position statement [15]:

●All patients with diabetes should be screened for polyneuropathy at the time of diagnosis of type 2 diabetes and five years after the diagnosis of type 1 diabetes [18,19].

●Patients with prediabetes (ie, impaired fasting glucose and/or impaired glucose tolerance) who have symptoms of polyneuropathy should also be screened [20].

●After initial screening, all patients with type 2 or type 1 diabetes who do not have polyneuropathy should be screened at least annually for the development of neuropathy [15].

Screening assessment includes the following essential elements [15]:

●A careful history

●Assessment of small nerve fiber function by testing thermal or pin prick sensation and light touch perception with a 10 g monofilament on the dorsal aspect of the distal great toe

●Assessment of large nerve fiber function by testing vibration sensation with a 128 Hz tuning fork, proprioception (joint position sensation), and deep tendon reflexes at the ankle as compared with more proximal locations

In the Rochester Diabetic Neuropathy Study, assessment of symptoms by either the Neuropathy Symptom Score or the Neuropathy Symptom Profile was poorly reproducible, and significant differences in judging symptom severity occurred even among highly trained neurologists [21]. We therefore now rely on clinical signs to diagnose diabetic polyneuropathy but adhere to the 2017 American Diabetes Association (ADA) guidelines of obtaining a careful history of polyneuropathy symptoms [15].

The recommended ADA assessments can be met by using one or more simple screening tests (see 'Simple screening tests' below). These screening tests used to diagnose diabetic neuropathy do not require electrodiagnostic assessments with nerve conduction studies or quantitative sensory testing. The use of electrodiagnostic studies is not indicated for the routine diagnosis of diabetic polyneuropathy, but may be helpful when clinical features are atypical (eg, motor greater than sensory neuropathy, rapid onset, asymmetrical presentation), when the diagnosis is unclear, or when a different etiology is suspected [15]. (See 'Who should be referred to a specialist?' below.)

Because of the potentially severe complications, including amputation for infected, nonhealing ulcers, early detection of diabetic polyneuropathy is important. Early detection, if followed by therapeutic interventions including patient education, regular foot surveillance, and improved glycemic and metabolic control, may decrease the morbidity of diabetic polyneuropathy.

All patients with polyneuropathy, including those who are asymptomatic, should receive foot care education and consideration for podiatric referral. The patient should be instructed to carefully inspect his or her feet every day [22].

History and examination — The history and examination should focus on identifying the typical symptoms and signs that support the diagnosis of diabetic polyneuropathy, as well as atypical features that suggest another etiology [14]:

The examiner should ask about the following:

●Where did symptoms start? Symptoms of diabetic polyneuropathy typically start in the toes.

●What are the symptoms? Numbness, tingling, and pain are typical early symptoms.

●Are these symptoms worse at night? Is it painful when bedsheets touch the feet? Is the pain stabbing, burning, or lightening-like?

●Is there any weakness present? Weakness typically develops late and usually first affects toe extension and ankle dorsiflexion.

●How have symptoms changed over time? Proximal spread is typical.

●What is the pace of symptom progression? Slow progression is typical.

●Are there any differences from one foot to the other? Symmetry of symptoms is typical.

●For patients with hand symptoms, how much of the legs were involved by the time hand symptoms occurred? Symptoms typically ascend from the toes to the knees before affecting the fingertips.

●Are any autonomic symptoms present (eg, lightheadedness, constipation, urinary retention, change in sweating patterns, blurry vision, abdominal bloating)? Prominent autonomic involvement is atypical, especially early in the disease course.

●Is there a history of alcohol use? Prolonged excessive alcohol use is a common cause of symmetric polyneuropathy.

●Is there a family history of similar symptoms, or a family history of high arches or hammer toes? A family history suggests the possibility of a hereditary neuropathy; high arches or hammer toes in particular suggest Charcot-Marie-Tooth disease.

●What other medical problems are present? Many medical conditions are associated with polyneuropathy, as outlined in the table (table 3).

A careful clinical examination of the feet and legs should be performed. The feet should be examined for neuropathic deformities, infection and ulceration, and the footwear should be inspected. (See "Evaluation of the diabetic foot".)

The neurologic examination should test the following:

●Pinprick and temperature sensation at the toes compared with the knees to assess small nerve fiber function

●Vibration, pressure sensation, and proprioception at the toes to assess large nerve fiber function

●Ankle and patellar deep tendon reflexes

●Extension of the big toe, ankle dorsiflexion, and walking on heels to test motor strength

●Romberg test, normal gait, and tandem gait to assess balance and fall risk

Simple screening tests, described below, have been devised to assess important symptoms and signs of diabetic polyneuropathy.

Simple screening tests

Michigan Neuropathy Screening Instrument — Accurate assessment of symptoms in diabetic polyneuropathy is known to be difficult [17]. We designed a simple screening test, the Michigan Neuropathy Screening Instrument (MNSI), to diagnose diabetic polyneuropathy in outpatient clinics (table 4) [22]. The MNSI assesses both the key symptoms and signs of diabetic polyneuropathy in two separate parts [22]:

●The history/symptom portion of the MNSI (table 4) consists of a 15-item, self-administered, yes/no questionnaire [22]. Patients with a total score >4 points are considered to have neuropathy [23].

●The physical part of the MNSI (table 4) consists of a lower extremity inspection and examination that addresses the following signs [22]:

•Do the feet show dry skin, callus, fissure, infection or deformities? The presence of any of these indicators of neuropathy is scored as one point and an additional point is added if an ulcer is present.

•What are the ankle tendon reflexes? These are scored as 0 if present, 0.5 if present with reinforcement, and 1 point if absent

•What is the vibration sense on the dorsum of the great toes using a 128 Hz tuning fork? This is scored as 0 if present, 0.5 if reduced and 1 point if absent.

A physical assessment score ≥2.5 indicates a diagnosis of clinical neuropathy with a sensitivity and specificity of 61 and 95 percent, respectively [23].

The MNSI can be administered by any health care professional involved in the treatment of diabetic patients. However, to align with the 2017 ADA guidelines [15], the physical assessment should be coupled with an examination of either thermal or pin prick sensation on the great toe to assess small fiber function.

Utah Early Neuropathy Scale — The Utah Early Neuropathy Scale (UENS) is a simple screening tool that assesses both large and small fiber nerve function [24], and aligns with the 2017 ADA recommendations [15]. The use of the UENS is described in the figure (figure 1). A score of ≥4 defines clinical neuropathy.

This UENS is similar to the MNSI (see 'Michigan Neuropathy Screening Instrument' above), with the addition of measuring small fiber function by assessing pin prick sensation in a distal to proximal pattern, as well as determining the presence of allodynia or hyperesthesia in the toes or foot. Finally, there is an assessment of great toe strength, which can be impaired in severe diabetic polyneuropathy.

United Kingdom Screening Test — In the United Kingdom, investigators have developed a two-part diagnostic test, consisting of a simple symptom score and physical examination [25]:

●What is the sensation felt? Burning, numbness, or tingling in the feet (2 points); fatigue, cramping, or aching (1 point). Maximum is 2 points.

●What is the location of symptoms? Feet (2 points); calves (1 point); elsewhere (0 points). Maximum is 2 points.

●Have the symptoms ever awakened you at night? Yes (1 point).

●What is the timing of symptoms? Worse at night (2 points); present day and night (1 point); present only during the day (0 points). Maximum is 2 points.

●How are symptoms relieved? Walking around (2 points); standing (1 point); sitting or lying or no relief (0 points). Maximum is 2 points.

The total symptom score can then be determined:

•0 to 2 points: Normal

•3 to 4 points: Mild polyneuropathy

•5 to 6 points: Moderate polyneuropathy

•7 to 9 points: Severe polyneuropathy

A similar quantitative score can be made for the physical findings:

●What is the Achilles tendon reflex? Absent (2 points for each foot); present with reinforcement (1 point for each foot).

●What is vibration sense? Absent or reduced (1 point for each foot).

●What is pin prick sensation? Absent or reduced (1 point for each foot).

●What is temperature sensation? Reduced (1 point for each foot).

The neurologic sign score can then be determined:

•0 to 2 points: Normal

•3 to 5 points: Mild polyneuropathy

•6 to 8 points: Moderate polyneuropathy

•9 to 10 points: Severe polyneuropathy

Peripheral polyneuropathy is considered to be present if there are moderate or severe signs (≥6 points), even in the absence of symptoms, or if there are at least mild signs (≥3 points) in the presence of moderate symptoms (≥5 points). A neurologic sign score of 8 or more indicates that the patient's feet are at high risk for ulceration.

Laboratory tests — Patients with diabetes or another known cause of distal symmetric polyneuropathy (eg, alcoholism, chemotherapy) do not require further testing. Electrodiagnostic testing is necessary only when the clinical presentation of polyneuropathy is atypical for diabetic polyneuropathy [15].

For patients with diabetes who have an unclear cause of neuropathy despite a detailed clinical history and examination, suggested laboratory tests include serum B12 and serum protein immunoelectrophoresis with immunofixation [14]. For patients with distal symmetric polyneuropathy without a known diagnosis of diabetes, particularly those with multiple risk factors, it is reasonable to obtain a fasting serum glucose level and a glucose tolerance test. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation'.)

Who should be referred to a specialist? — Patients with typical symptoms and signs of diabetic symmetric polyneuropathy (ie, symmetry, distal onset, predominant sensory loss, slow progression) generally do not need referral for specialist consultation. However, to help obtain an accurate diagnosis, patients with atypical presenting symptoms or signs should be referred to a neurologist or neuromuscular specialist, who can direct further investigations including electrodiagnostic testing. Atypical presenting features suggesting a cause other than diabetes include the following:

●Asymmetry of symptoms or signs

●Initial presentation with weakness more than sensory loss

●Rapidly progressive disease course

Diagnostic criteria — The diagnosis of diabetic polyneuropathy is based primarily on clinical findings in a patient with diabetes, as outlined in the 2017 ADA position statement; these are [15]:

●A combination of typical symptoms with typical signs (table 2), particularly symmetric distal sensory loss

●Typical signs on examination (table 2) in the absence of symptoms or with only the presence of a painless foot ulcer

These ADA criteria can be applied in routine clinical practice. Note that the diagnosis of diabetic polyneuropathy is one of exclusion; nondiabetic neuropathies can exist in this patient population (table 3), especially polyneuropathy associated with B12 deficiency [15]. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Other causes of polyneuropathy, and clues to their diagnosis, are reviewed in the table (table 3). These should be considered if there is any aspect of the history or clinical presentation suggesting features that are atypical of diabetic polyneuropathy (eg, asymmetry, non–length dependence, predominant motor involvement, rapid onset).

Certain forms of polyneuropathy (other than diabetic polyneuropathy) that are relatively common in patients with diabetes or the general population should be excluded. These include vitamin B12 deficiency, alcohol use, chronic kidney disease, chemotherapy, hereditary neuropathies, paraproteinemia, and chronic inflammatory demyelinating polyneuropathy (CIDP) [15]. The cause remains unknown (idiopathic) despite extensive evaluation in approximately 25 percent of cases [14].

Although uncommon, there are several types of acute painful diabetic neuropathy syndromes. These are:

●Treatment-induced diabetic polyneuropathy that presents in the setting of rapid glycemic control (see "Epidemiology and classification of diabetic neuropathy", section on 'Treatment-induced neuropathy of diabetes')

●Diabetic neuropathic cachexia, a polyneuropathy that occurs in the setting of unintended severe weight loss

●Diabetic lumbosacral polyradiculopathy (aka diabetic amyotrophy), which typically presents with acute, asymmetric, focal onset of pain followed by weakness involving the proximal leg, with associated weight loss (see "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy")

In the absence of atypical features, the differential diagnosis of bilateral distal symmetric pain in the toes and feet is neuropathy or peripheral arterial disease. The physical examination is helpful (decreased sensation or loss of deep tendon reflexes), but these signs of neuropathy do not necessarily mean that the pain is due to the neuropathy. Several clues that the patient has neuropathic pain are the location of pain (feet more than calves), the quality of the pain, and the timing of pain (present at rest, improves with walking) (table 5). Each of these features is different from those of the pain due to peripheral arterial disease. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Lower extremity pain'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Nerve damage caused by diabetes (The Basics)")

●Beyond the Basics topics (see "Patient education: Diabetic neuropathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors – The duration and severity of hyperglycemia are major risk factors for the development of diabetic neuropathy in patients with both type 1 and type 2 diabetes. Additional risk factors include older age, metabolic syndrome, and obesity. (See 'Risk factors' above.)

●Clinical manifestations – Diabetic polyneuropathy is primarily a distal symmetric sensory polyneuropathy. The main symptoms are numbness, tingling, pain, and weakness, starting distally in the toes and feet. The symptoms are usually worse at night. Up to one-half of patients with diabetic polyneuropathy may be asymptomatic, but the physical examination reveals mild to moderately severe sensory loss. (See 'Clinical manifestations' above.)

●Patient selection for screening – Diabetic polyneuropathy should be suspected in any patient with type 1 diabetes of more than five years duration and in all patients with type 2 diabetes. In addition, polyneuropathy due to prediabetes should be suspected in any patient presenting with "idiopathic" painful polyneuropathy. (See 'Who should be screened?' above.)

●Evaluation

•History and examination – The history and examination should focus on identifying the typical symptoms (eg, numbness, tingling, and pain starting in the toes, with slow progression and proximal spread) and signs (eg, symmetric distal sensory loss) that support the diagnosis of diabetic polyneuropathy (table 2), as well as identifying any atypical features that suggest another etiology. (See 'History and examination' above.)

•Screening tests – Simple screening tests have been developed for the diagnosis of diabetic polyneuropathy in outpatient clinics, including the Michigan Neuropathy Screening Instrument (table 4), the Michigan Diabetic Neuropathy Score (table 6), the Utah Early Neuropathy Screening Instrument (figure 1), and the United Kingdom Screening Test. (See 'Simple screening tests' above.)

●Diagnostic criteria – The diagnosis of diabetic polyneuropathy is based primarily on clinical findings in a patient with diabetes; these are a combination of typical symptoms with typical signs (table 2), typical signs on examination in the absence of symptoms, or with only the presence of a painless foot ulcer. (See 'Diagnostic criteria' above.)

●Differential diagnosis – Other causes of polyneuropathy (table 3) should be considered if there is any aspect of the history or clinical presentation suggesting features atypical of diabetic polyneuropathy, such as rapid onset, asymmetrical presentation, or motor greater than sensory neuropathy. (See 'Differential diagnosis' above.)