9/28/2020 Epidemiology and classification of diabetic neuropathy - UpToDate

Author: Eva L Feldman, MD, PhD

Section Editor: Jeremy M Shefner, MD, PhD
Deputy Editor: Richard P Goddeau, Jr, DO, FAHA

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2020. | This topic last updated: Apr 01, 2020.

INTRODUCTION

Involvement of the peripheral and autonomic nervous systems is probably the most common
complication of diabetes. Clinical diabetic neuropathy is categorized into distinct syndromes
according to the neurologic distribution, although many overlap syndromes occur. In both type 1 and
type 2 diabetes, the prevalence varies with both the severity and duration of hyperglycemia.

This topic will review the epidemiology and classification of diabetic neuropathy. Other aspects of
diabetic neuropathy are discussed separately. (See "Pathogenesis of diabetic polyneuropathy" and
"Screening for diabetic polyneuropathy" and "Diabetic autonomic neuropathy" and "Management of
diabetic neuropathy" and "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus
neuropathy".)

EPIDEMIOLOGY

Diabetic polyneuropathy is the most common neuropathy in developed countries. Prevalence is a

function of disease duration, and a reasonable figure, based upon several large studies, is that
approximately 50 percent of patients with diabetes will eventually develop neuropathy [1-3].

The prevalence and incidence of diabetic polyneuropathy can be illustrated by the following
observations:

● In a landmark study, over 4400 patient with diabetes were serially evaluated over 25 years [4-
6]. Neuropathy was defined as decreased sensation in the feet and depressed or absent ankle
reflexes. The onset of neuropathy correlated positively with the duration of diabetes and, by 25
years, 50 percent of patients had neuropathy.

● In a community-based study from northwest England of 15,692 patients with diabetes, the
prevalence of clinical neuropathy, defined by the loss of pinprick, vibration, and temperature
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sensation, was 49 percent, while the prevalence of painful neuropathic symptoms was 34
percent [7]. The prevalence of painful neuropathy symptoms accompanied by clinical
neuropathy was 21 percent. The risk of painful neuropathy was increased in patients with type
2 diabetes, women, and those of South Asian ethnicity.

● In a cross-sectional multicenter study of 6487 diabetic patients in the United Kingdom, the
overall prevalence of diabetic neuropathy was 28.5 percent [8]. There was a correlation with
disease duration such that the prevalence reached 44 percent in patients between 70 and 79
years of age.

● Two reports evaluated the incidence of new cases of diabetic neuropathy. In one, 231 patients
with type 2 diabetes but no peripheral neuropathy were followed for a mean of 4.7 years [9].
The incidence of new cases of distal symmetric sensory neuropathy was 6.1 per 100 person-
years. As expected, the occurrence of neuropathy was associated with the level of hemoglobin
A1C. A similar rate of new cases was described in a series of patients with type 1 diabetes [10].
The incidence was increased in patients with hypertension (relative risk 4.1).

● A population-based study of 329 adolescents with type 1 diabetes and 70 with type 2 diabetes
found that the prevalence of diabetic polyneuropathy was significantly higher with type 2
compared with type 1 diabetes (26 versus 8 percent) [11].

The high rate of diabetic neuropathy results in substantial morbidity, including recurrent lower
extremity infections, ulcerations, and subsequent amputations. (See "Management of diabetic foot
ulcers".)

Diabetic patients with foot problems occupy more hospital beds than do those with all other diabetic
complications [3]. The cumulative risk of lower extremity amputation in one report was 11 percent 25
years after diagnosis of diabetes [12].

CLASSIFICATION

Diabetic neuropathy is classified into distinct clinical syndromes [13]. A characteristic set of
symptoms and signs exist for each syndrome, depending on the component of the peripheral
nervous system that is affected. The most frequently encountered neuropathies include (table 1):

● Distal symmetric polyneuropathy

● Autonomic neuropathy

● Thoracic and lumbar nerve root disease, causing polyradiculopathies

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● Individual cranial and peripheral nerve involvement causing focal mononeuropathies, especially
affecting the oculomotor nerve (cranial nerve III) and the median nerve

● Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy multiplex

In the Rochester diabetic study, for example, approximately 50 percent of patients had distal
symmetric polyneuropathy; about 14 percent had symptoms and a few percent had difficulty
walking. Other neuropathies included median mononeuropathies (25 percent), autonomic
neuropathy (7 percent), and other neuropathies, including thoracic and lumbar polyradiculopathy
and cranial mononeuropathies (3 percent) [1].

Symmetric polyneuropathy — Distal symmetric sensorimotor polyneuropathy is the most common

type of diabetic neuropathy and is often considered synonymous with the term diabetic neuropathy.
It is characterized by a progressive loss of distal sensation correlating with loss of sensory axons,
followed, in severe cases, by motor weakness and motor axonal loss. Classic "stocking-glove"
sensory loss is typical in this disorder. (See "Screening for diabetic polyneuropathy".)

Autonomic neuropathy — Diabetic autonomic neuropathy is a common complication of diabetes.

It is a diagnosis of exclusion and may be unnoticed because of multiorgan involvement and
insidious onset. It can, however, cause severe dysfunction of a single organ. Among the problems
that can occur are postural hypotension, gastroparesis, and enteropathy with constipation or
diarrhea. (See "Diabetic autonomic neuropathy".)

Polyradiculopathies — The term asymmetric proximal neuropathy was initially used to describe
injury to proximal limb and nerve roots. Because of the pleiotropic presentation of this type of
diabetic neuropathy, several other terms appeared in the literature, most prominently diabetic
amyotrophy and diabetic thoracic polyradiculopathy. These forms of diabetic neuropathy are
probably subtypes of diabetic polyradiculopathy [14].

Diabetes frequently injures the nerve roots at one or more thoracic or high lumbar levels with
subsequent axonal degeneration and frequent contralateral, cephalad, or caudal extension. The
various subgroups of polyradiculopathy present as distinct syndromes but also share certain
features in common. Affected patients are typically older, have coexisting peripheral
polyneuropathy, and have weakness and atrophy in the distribution of one or more contiguous nerve
roots with frequent territorial expansion.

Diabetic amyotrophy (lumbar polyradiculopathy) — Diabetic amyotrophy is reviewed here

briefly and discussed in detail elsewhere. (See "Diabetic amyotrophy and idiopathic lumbosacral
radiculoplexus neuropathy".)

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The most common type of diabetic polyradiculopathy is a syndrome frequently called diabetic
amyotrophy. Diabetic amyotrophy is not a pure lumbosacral plexopathy because it also affects the
lumbosacral nerve roots and peripheral nerves. The etiology is debated, and several
pathophysiologic mechanisms (ischemic, metabolic, and/or inflammatory) have been proposed as
the cause. Of these, the most likely cause is ischemic injury from a nonsystemic microvasculitis.
(See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy", section on
'Background'.)

The traditional features of diabetic amyotrophy include the acute, asymmetric, focal onset of pain
followed by weakness involving the proximal leg, with associated autonomic failure and weight loss.
Progression occurs over months and is followed by partial recovery in most patients. The same
process can occur in the contralateral leg, immediately following (within days) or much later than
(months to years) the initial attack. The diagnosis of diabetic amyotrophy is mainly based upon the
presence of suggestive clinical features in a patient with known or newly diagnosed diabetes
mellitus. Appropriate laboratory investigations, particularly electrodiagnostic studies, and
neuroimaging in select patients, are useful to exclude other peripheral and central nervous system
etiologies as a cause of the neurologic symptoms and signs. (See "Diabetic amyotrophy and
idiopathic lumbosacral radiculoplexus neuropathy", section on 'Clinical features' and "Diabetic
amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy", section on 'Diagnosis'.)

No treatments are proven to be effective for diabetic amyotrophy. There is limited and conflicting
data regarding the benefit of immunosuppressive therapies including oral prednisone, intravenous
methylprednisolone, intravenous immune globulin, cyclophosphamide, and plasma exchange. (See
"Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy", section on
'Treatment'.)

Thoracic polyradiculopathy — Although less common than diabetic lumbar polyradiculopathy,

thoracic polyradiculopathy can cause marked symptoms. Affected patients present with severe
abdominal pain, sometimes in a band-like pattern, and frequently have undergone extensive
gastrointestinal diagnostic studies in attempts to identify the etiology of their pain [15].

Thoracic and upper limb involvement has also been observed as part of the syndrome of diabetic
amyotrophy in a minority of patients. Some have symptoms and signs suggesting a thoracic
radiculopathy, a brachial plexopathy, or mononeuropathies of the ulnar and median nerves. Most
upper limb symptoms occur in association with lumbosacral plexus involvement. (See "Diabetic
amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy", section on 'Cervical and
thoracic involvement'.)

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Diabetic neuropathic cachexia — Another rare but identifiable syndrome is diffuse diabetic
polyradiculopathy superimposed upon severe peripheral neuropathy. This syndrome is associated
with unintended severe weight loss and depression and is known as diabetic neuropathic cachexia
[16-18]. It most frequently occurs in men with type 2 diabetes on oral hypoglycemic agents who are
middle-aged or older. Most patients improve spontaneously within 12 to 24 months, although some
have residual neurologic deficits. There is no specific therapy, and management is supportive.

Mononeuropathies — There are two types of mononeuropathy associated with diabetes: cranial
and peripheral, as discussed in the sections that follow.

Cranial mononeuropathy — The most common cranial mononeuropathies occur in those

nerves which supply the extraocular muscles, especially cranial nerves III (oculomotor), VI
(abducens), and IV (trochlear). Patients with diabetic ophthalmoplegia typically present with
unilateral pain, ptosis, and diplopia, with sparing of pupillary function [19].

Facial mononeuropathy (Bell's palsy) occurs more frequently in diabetic than in nondiabetic
patients. This observation suggests that the disorder is due to diabetes in some patients [20,21].
(See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults".)

Peripheral mononeuropathy — The most common peripheral mononeuropathy in diabetic

patients is median mononeuropathy at the wrist. While estimates vary, it is likely that at least one-
quarter to one-third of patients develop either symptomatic or asymptomatic median
mononeuropathy [1]. Ulnar mononeuropathy, either at the elbow or, less commonly, at the wrist can
also occur [1].

In the lower extremities, peroneal mononeuropathies with compression at the fibula are a well-
recognized complication of diabetes. Common peroneal palsy, for example, can result in foot drop.
It is probable, however, that isolated femoral mononeuropathies are rare in diabetes; many of these
patients, after careful clinical and electrodiagnostic examinations, are found to have a high lumbar
radiculopathy (diabetic amyotrophy). (See 'Diabetic amyotrophy (lumbar polyradiculopathy)' above.)

Mononeuropathy multiplex — Multiple mononeuropathies in the same patient are known as

mononeuropathy multiplex (or asymmetric polyneuropathy). The other major disorder that can
produce this syndrome is vasculitis, which should also be considered in affected patients [1]. (See
"Clinical manifestations and diagnosis of vasculitic neuropathies".)

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

● Treatment-induced diabetic neuropathy (see 'Treatment-induced neuropathy of diabetes'

below)
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● Diabetic neuropathy that occurs in the setting of unintended severe weight loss (see 'Diabetic
neuropathic cachexia' above)

● Diabetic neuropathy that is seen with intentional weight loss (diabetic anorexia) [22]

In general, these conditions are characterized by severe neuropathic pain, autonomic dysfunction,
and a potentially reversible course that may last for many months.

Treatment-induced neuropathy of diabetes — Treatment-induced neuropathy of diabetes

(TIND), also called insulin neuritis, is a small fiber neuropathy that occurs in patients with chronic
hyperglycemia who experience rapid improvement in glycemic control [23-26]. The main clinical
manifestations are severe, treatment-resistant pain and autonomic dysfunction, along with
worsening of retinopathy and nephropathy. Although historically considered rare, data from a
retrospective study of 954 patients referred to a tertiary care center for diabetic neuropathy
evaluation suggest that TIND is more common than previously suspected [26]. The investigators
defined the condition by the acute onset of neuropathic pain or autonomic dysfunction within eight
weeks of a large improvement in glycemic control (ie, a decrease in glycosylated hemoglobin A1C
of ≥2 percentage points over three months). The following observations were made [26]:

● TIND was present in 104 patients (11 percent).

● The risk of developing TIND and the severity of neuropathic pain and autonomic dysfunction
correlated with the magnitude of decrease in hemoglobin A1C.

● The risk of TIND was increased with type 1 diabetes or a history of eating disorders.

● TIND occurred with treatment using insulin or oral hypoglycemic agents.

The pathogenesis of TIND is uncertain, but proposed mechanisms include endoneurial edema and
ischemia [23], apoptosis from glucose deprivation [27], and microvascular neuronal injury due to
recurrent hypoglycemia [28].

Management of TIND is symptomatic. Although there are no proven prevention strategies, one
suggestion is to limit hemoglobin A1C reduction to <2 percentage points over three months [26].

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
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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

● Diabetic polyneuropathy is the most common neuropathy in the Western world. Clinical and
subclinical neuropathy has been estimated to occur in 10 to 100 percent of diabetic patients,
depending upon the diagnostic criteria and patient populations examined. (See 'Epidemiology'
above.)

● Diabetic neuropathy is classified into distinct clinical syndromes. A characteristic set of

symptoms and signs exist for each syndrome, depending on the component of the peripheral
nervous system that is affected. The most frequently encountered diabetic neuropathies include
(table 1):

• Distal symmetric polyneuropathy (see 'Symmetric polyneuropathy' above)

• Autonomic neuropathy (see 'Autonomic neuropathy' above)

• Thoracic and lumbar nerve root disease, causing polyradiculopathies (see

'Polyradiculopathies' above)

• Individual cranial and peripheral nerve involvement causing focal mononeuropathies,

especially affecting the oculomotor nerve (cranial nerve III) and the median nerve (see
'Cranial mononeuropathy' above and 'Peripheral mononeuropathy' above)

• Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy

multiplex (see 'Mononeuropathy multiplex' above)

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REFERENCES

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