Clinical manifestations and diagnosis of diabetic polyneuropathy

Author: Eva L Feldman, MD, PhD

Section Editor: Jeremy M Shefner, MD, PhD
Deputy Editor: John F Dashe, MD, PhD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: Apr 2018. | This topic last updated: Dec 15, 2016.

INTRODUCTION — There are many forms of diabetic neuropathy including symmetric

polyneuropathy, autonomic neuropathy, radiculopathies, mononeuropathies, and
mononeuropathy multiplex (table 1). (See "Epidemiology and classification of diabetic
neuropathy".)

The clinical manifestations and diagnosis of diabetic polyneuropathy, also referred to as

diabetic neuropathy, will be reviewed here. The pathogenesis and treatment of this
disorder and the characteristics of the other forms of diabetic neuropathy are discussed
separately. (See "Pathogenesis and prevention of diabetic polyneuropathy" and
"Treatment of diabetic neuropathy".)

CLINICAL MANIFESTATIONS — Diabetic polyneuropathy is primarily a symmetrical

sensory polyneuropathy, initially affecting the distal lower extremities. Ten to 18 percent
of patients have evidence of nerve damage at the time their diabetes is diagnosed,
suggesting that even early impairment of glucose handling, classified as prediabetes, is
associated with neuropathy. 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 later and in more severe cases.

Symptoms and signs — The earliest signs of diabetic polyneuropathy probably reflect the
gradual loss of integrity of both large myelinated and small myelinated and unmyelinated
nerve fibers:

● Loss of vibratory sensation and altered proprioception reflect large-fiber loss

● Impairment of pain, light touch, and temperature is secondary to loss of small fibers

Decreased or absent ankle reflexes occur early in the disease, while more widespread
loss of reflexes and motor weakness are late findings.

Patients with prediabetes (defined by the American Diabetes Association as a fasting

glucose of 100 to 125 mg/dL [5.6 to 6.9 mmol/L] or a two-hour serum glucose between
140 and 199 mg/dL [7.8 and 11.0 mmol/L] on an oral glucose tolerance test) may
present with intensely painful feet. Patients with frank diabetic polyneuropathy may also
present with pain, paresthesias, or dysesthesias of their feet. Some patients, however,
have few complaints but the physical examination reveals mild to moderately severe
sensory loss [1,2].

Complications — Diabetic polyneuropathy is frequently insidious in onset and can lead to

formation of foot ulcers and muscle and joint disease. Progressive sensory loss
predisposes to ulcer formation. 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 neuropathy (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 [3]. This weight shift results in formation of calluses that can fissure, become
infected and ulcerate. There may also be other arthropathic changes 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 neuropathic arthropathy".)

Natural history — The rationale for regular monitoring (see 'Monitoring' below) is the
observation that the incidence of diabetic neuropathy (and other microvascular and
macrovascular complications) increases over time. This was illustrated by a study from
Finland that evaluated the natural history of peripheral neuropathy in patients with newly
diagnosed type 2 diabetes [3]. 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 8.3 percent at baseline to 41.9 percent at
10 years; comparable values in normal subjects were 2.1 and 5.8 percent, respectively.

In a later population-based study from Australia that evaluated patients with type 2
diabetes who had an average disease duration of about eight years, the prevalence of
painful diabetic polyneuropathy was 26.4 percent [4].

CRITERIA FOR DIAGNOSIS — 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'.)

Historically, the diagnosis of diabetic polyneuropathy was based on subjective

interpretation of a constellation of symptoms and signs such as loss of vibratory or light
touch sensation and reduced or absent ankle reflexes [5]. In 1988, a group of
diabetologists and neurologists proposed a comprehensive set of criteria, the San
Antonio Consensus statement, to diagnose and monitor diabetic neuropathy [6]. Using
similar symptom scores, quantitative examination, and electrophysiologic
measurements, investigators at the Mayo Clinic placed patients in one of three classes
of diabetic neuropathy.

In 2005, an expert panel developed a case definition of distal symmetric polyneuropathy;

most of the supporting evidence came from studies involving patients with diabetic
polyneuropathy [7]. This polyneuropathy definition is discussed separately. (See
"Overview of polyneuropathy", section on 'Diagnosis of polyneuropathy'.)

A third consensus panel convened in Toronto in 2009 and advocated that, for controlled
clinical trials and epidemiologic studies of diabetic neuropathy, nerve conduction studies
are needed for accurate assessment, and are coupled with assessments of symptoms
and signs [8].

Screening tests — The San Antonio Consensus [6], the Mayo Clinic criteria and the
Toronto criteria [8] are thorough and appropriate for research purposes. However, they
are not practical in routine clinical practice. The need to identify simplified criteria has
resulted in the development of several simple screening tests. Two will be discussed:
one from the United Kingdom [9] and one which we developed at Michigan [10]. These
simple tools used to diagnose diabetic neuropathy do not include electrodiagnostic
assessments with nerve conduction studies or quantitative sensory testing. These are
discussed later. (See 'Electrodiagnostic tests' below.)

Accurate assessment of symptoms in diabetic polyneuropathy is known to be difficult

[2]. In developing the Michigan Neuropathy Screening Test described below, we hoped to
assess both the symptoms as well as the key signs of diabetic neuropathy. A 15-item,
yes/no questionnaire which included 13 questions relevant to diabetic neuropathy, one to
general asthenia, and one to peripheral vascular disease was administered to all
patients. We found that a similar number of patients with and without neuropathy
answered positively on up to six questions, demonstrating that symptoms do not always
indicate underlying neuropathy.

Similarly, 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 [11]. We therefore now rely on clinical signs to
diagnose diabetic neuropathy.

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 [9]:
 ● 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 neuropathy

● 5 to 6 points: Moderate neuropathy

● 7 to 9 points: Severe neuropathy

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 signs score can then be determined:

● 0 to 2 points: Normal

● 3 to 5 points: Mild neuropathy

● 6 to 8 points: Moderate neuropathy

● 9 to 10 points: Severe neuropathy

Peripheral neuropathy 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.
 Michigan Neuropathy Screening Instrument — We have designed a simple screening
test to diagnose diabetic neuropathy in outpatient clinics (figure 1) [10]. We use this test
to screen large numbers of patients for the presence of diabetic neuropathy. In this
simple examination the following questions are addressed:

● 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 is the vibration sense on the dorsum of the great toes? Reduced (0.5 points);
absent (1 point).

● What is the Achilles tendon reflex? Absent (1 point); present with reinforcement (0.5
points).

This test was standardized against the San Antonio Consensus criteria. A score greater
than 2 indicated neuropathy with both a high specificity (95 percent) and sensitivity (80
percent) [10]. The Michigan Neuropathy Screening Instrument can be administered by
any health care professional involved in the treatment of diabetic patients.

Tuning fork test — A simple test using a 128 Hz tuning fork to examine vibration
perception can be used to screen for diabetic polyneuropathy [12]. (See "The detailed
neurologic examination in adults".)

A 128 Hz tuning fork is placed on the interphalangeal joint of the right hallux.

● The score is 2 points if the patient feels no vibration.

When the patient feels vibration at the hallux, the still vibrating tuning fork is
immediately placed at the dorsal wrist, and the patient is asked to compare the
strength of vibration at the two sites.

● The score is 1 point if the vibration feels stronger at the wrist.

● The score is 0 points if the vibration feels no different at the wrist.

● A normal score is 0 points, a mild to moderate deficit is 1, and a severe deficit is 2.

This tuning fork test has widespread utility in clinical practice because it is simple, brief,
valid, and reliable [12,13].

Electrodiagnostic tests — Electrodiagnostic testing is necessary when the clinical

presentation of neuropathy is atypical for diabetic neuropathy [14]. 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

 ● Proximal greater than distal signs and symptoms

● Rapidly progressive disease course

A patient with any constellation of these atypical presenting symptoms or signs requires
electrodiagnostic testing for an accurate diagnosis.

Staging test

Michigan Diabetic Neuropathy Score — The Michigan Diabetic Neuropathy Score

consists of a quantitative neurologic examination that assesses sensory impairment
(vibratory threshold perception, pain, and light touch), muscle strength, and reflexes
(table 2), and a set of five nerve conduction studies (sural, peroneal motor, median
sensory and motor, and ulnar sensory) that are graded separately [10]. This score
provides a means of diagnosing and staging diabetic neuropathy for clinical trials and
epidemiologic studies that is simpler and less time consuming than the San Antonio
criteria. In a study of 8757 diabetic patients in Italy, 32 percent screened positively on the
Michigan Neuropathy Screening Instrument (see 'Michigan Neuropathy Screening
Instrument' above), and these patients were administered the Michigan Diabetic
Neuropathy Score:

● 16 percent had no neuropathy by this assessment: Score ≤6 and abnormal

conduction in no or one nerve.

● 41 percent had mild neuropathy: Score ≤12 and abnormal conduction in two nerves.

● 29 percent had moderate neuropathy: Score ≤29 and abnormal conduction in three
or four nerves.

● 13 percent severe neuropathy: Score ≥ 29 and abnormal conduction in all five

nerves.

In each case, severity of neuropathy correlated with disease duration.

DIFFERENTIAL DIAGNOSIS — When evaluating diabetic patients with neuropathy, it is

important to appreciate that there are other causes of neuropathy (table 3). These
should be considered if there is any aspect of the history or clinical presentation
suggesting features atypical of diabetic neuropathy (eg, signs of a systemic disease
such as vasculitis).

Certain forms of neuropathy (other than diabetic neuropathy) occur more frequently in
patients with diabetes than in the general population and should be excluded. These
include chronic inflammatory demyelinating polyneuropathy (CIDP) and neuropathy due
to vitamin B12 deficiency, hypothyroidism, and uremia [14].

Although uncommon, there are several types of acute painful diabetic neuropathy
syndromes. These are:
 ● Treatment-induced diabetic neuropathy 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 diabetic neuropathy that occurs in the setting of

unintended severe weight loss (see "Epidemiology and classification of diabetic
neuropathy", section on 'Diabetic neuropathic cachexia')

● Diabetic anorexia, a diabetic neuropathy that is seen with intentional weight loss

In general, these conditions are characterized by severe neuropathic pain, autonomic

dysfunction, and a potentially reversible course that may last for many months. (See
"Epidemiology and classification of diabetic neuropathy", section on 'Acute painful
diabetic neuropathies'.)

MONITORING — Diabetic neuropathy should be suspected in any patient with type 1

diabetes of more than five years' duration and in all patients with type 2 diabetes [3,15].
In addition, neuropathy due to prediabetes should be suspected in any patient presenting
with "idiopathic" painful neuropathy. Both epidemiological and case-controlled studies
show that 40 to 50 percent of patients with idiopathic neuropathy have prediabetes
compared with 14 percent of the age-matched general population [16].

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 control, can decrease the morbidity of diabetic
neuropathy.

Our recommendations are in agreement with those of the American Diabetes

Association practice statement published in 2005 [14]:

● All patients with diabetes should be screened for neuropathy at diagnosis of type 2
diabetes and five years after diagnosis of type 1 diabetes.

● After initial screening, all patients should be screened at least annually by examining
sensory function in the feet and checking ankle reflexes. One or more of the
following tests can be used to assess sensory function:

• Pinprick

• Temperature

• Vibration perception (using a 128 Hz tuning fork)

• Pressure sensation (using a 10 g monofilament pressure sensation at the distal

halluces)
 ● A complete history and clinical examination focusing on symptoms and signs of
peripheral neuropathy should be performed annually. Any history of neuropathic
symptoms should be elicited. A careful clinical examination of the feet and lower
limbs should be performed.

● At each diabetes care clinic visit, the feet should be examined for neuropathic
deformities, infection and ulceration, and the footwear should be inspected. (See
"Evaluation of the diabetic foot".)

● The patient should carefully inspect his or her feet daily [10].

● All patients with neuropathy, including those who are asymptomatic, should receive
foot care education and consideration for podiatric referral.

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 5th to 6th 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 10th to 12th 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

● Diabetic neuropathy is primarily a symmetrical sensory polyneuropathy, initially

affecting the distal lower extremities. The earliest signs of diabetic neuropathy
probably reflect the gradual loss of integrity of both large myelinated and small
myelinated and unmyelinated nerve fibers (see 'Clinical manifestations' above):

• Loss of vibratory sensation and altered proprioception reflect large-fiber loss

• Impairment of pain, light touch, and temperature is secondary to loss of small

fibers
● Diabetic neuropathy is frequently insidious in onset and can lead to formation of
foot ulcers and muscle and joint disease. (See 'Complications' above.)

● The incidence of diabetic neuropathy (and other microvascular and macrovascular

complications) increases over time. (See 'Natural history' above.)

● For the diagnosis of diabetic polyneuropathy, both the San Antonio Consensus and
the Mayo Clinic criteria are thorough and appropriate for research purposes.
However, they are not practical in routine clinical practice. Simplified criteria have
been developed for clinical use (see 'Criteria for diagnosis' above):

• The Michigan Neuropathy Screening Instrument (figure 1) was designed to

diagnose diabetic neuropathy in outpatient clinics. Additional useful screening
assessments include the United Kingdom screening test and the tuning fork
test. (See 'Michigan Neuropathy Screening Instrument' above.)

• The Michigan Diabetic Neuropathy Score (table 2), which consists of a

quantitative neurologic examination and nerve conduction studies, is useful for
diagnosing and staging diabetic neuropathy for clinical trials and epidemiologic
studies. (See 'Michigan Diabetic Neuropathy Score' above.)

● Other causes of neuropathy (table 3) should be considered if there is any aspect of

the history or clinical presentation suggesting features atypical of diabetic
neuropathy. (See 'Differential diagnosis' above.)

● Diabetic neuropathy 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,
neuropathy due to prediabetes should be suspected in any patient presenting with
"idiopathic" painful neuropathy. Because of the potentially severe complications,
including amputation for infected, nonhealing ulcers, early detection of diabetic
polyneuropathy is important. (See 'Monitoring' above.)

REFERENCES

1. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various
types of diabetic neuropathy, retinopathy, and nephropathy in a population-
based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993;
43:817.
2. Franse LV, Valk GD, Dekker JH, et al. 'Numbness of the feet' is a poor indicator
for polyneuropathy in Type 2 diabetic patients. Diabet Med 2000; 17:105.
3. Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral
neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J
Med 1995; 333:89.
4. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of
painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006;
 29:1518.
5. MULDER DW, LAMBERT EH, BASTRON JA, SPRAGUE RG. The neuropathies
associated with diabetes mellitus. A clinical and electromyographic study of
103 unselected diabetic patients. Neurology 1961; 11(4)Pt 1:275.
6. Consensus statement: Report and recommendations of the San Antonio
conference on diabetic neuropathy. American Diabetes Association American
Academy of Neurology. Diabetes Care 1988; 11:592.
7. England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: a
definition for clinical research: report of the American Academy of Neurology,
the American Association of Electrodiagnostic Medicine, and the American
Academy of Physical Medicine and Rehabilitation. Neurology 2005; 64:199.
8. Dyck PJ, Albers JW, Andersen H, et al. Diabetic polyneuropathies: update on
research definition, diagnostic criteria and estimation of severity. Diabetes
Metab Res Rev 2011; 27:620.
9. Young MJ, Boulton AJ, MacLeod AF, et al. A multicentre study of the prevalence
of diabetic peripheral neuropathy in the United Kingdom hospital clinic
population. Diabetologia 1993; 36:150.
10. Feldman EL, Stevens MJ, Thomas PK, et al. A practical two-step quantitative
clinical and electrophysiological assessment for the diagnosis and staging of
diabetic neuropathy. Diabetes Care 1994; 17:1281.
11. Dyck PJ, Kratz KM, Lehman KA, et al. The Rochester Diabetic Neuropathy Study:
design, criteria for types of neuropathy, selection bias, and reproducibility of
neuropathic tests. Neurology 1991; 41:799.
12. Meijer JW, Smit AJ, Lefrandt JD, et al. Back to basics in diagnosing diabetic
polyneuropathy with the tuning fork! Diabetes Care 2005; 28:2201.
13. Kanji JN, Anglin RE, Hunt DL, Panju A. Does this patient with diabetes have
large-fiber peripheral neuropathy? JAMA 2010; 303:1526.
14. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the
American Diabetes Association. Diabetes Care 2005; 28:956.
15. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy:
mechanisms to management. Pharmacol Ther 2008; 120:1.
16. Singleton JR, Smith AG, Russell J, Feldman EL. Polyneuropathy with Impaired
Glucose Tolerance: Implications for Diagnosis and Therapy. Curr Treat Options
Neurol 2005; 7:33.

Topic 5272 Version 10.0

© 2018 UpToDate, Inc. All rights reserved.