Epidemiology and classification of diabetic neuropathy

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 resource abundant regions of the world. 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 [1-4]. In a landmark study, over 4400 patients with diabetes were serially evaluated over 25 years [5-7]. 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 mellitus and, by 25 years, 50 percent of patients had neuropathy. In a separate 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.

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) [9].

The estimated prevalence of neuropathy may vary depending on presenting symptoms. In a community-based study from northwest England of 15,692 patients with diabetes, the prevalence of sensory neuropathy, defined by the loss of pinprick, vibration, and temperature sensation, was 49 percent, while the prevalence of painful neuropathic symptoms was 34 percent [10]. The prevalence of painful neuropathy symptoms accompanied by sensory neuropathy was 21 percent. The risk of painful neuropathy was increased in patients with type 2 diabetes, women, and those of South Asian ethnicity.

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 [11]. 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 [12]. The incidence was increased in patients with hypertension (relative risk 4.1).

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 [13].

CLASSIFICATION — Diabetic neuropathy is classified into distinct clinical syndromes [14]. 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

●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 [15]. (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 [16].

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 (diabetic lumbosacral radiculoplexus neuropathy) — Diabetic amyotrophy, also called diabetic lumbosacral radiculoplexus neuropathy, is the most common type of diabetic polyradiculopathy. Diabetic amyotrophy is reviewed here briefly and discussed in detail elsewhere. (See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

Diabetic amyotrophy is not exclusively a 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".)

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 'Diagnostic evaluation'.)

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 amyotrophy, 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 [17].

Thoracic and upper limb involvement has also been observed as part of the syndrome 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'.)

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 [18].

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 [19,20]. (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 lumbar radicular or lumbosacral plexus involvement (diabetic amyotrophy). (See 'Diabetic amyotrophy (diabetic lumbosacral radiculoplexus neuropathy)' 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".)

Treatment-induced neuropathy of diabetes — Treatment-induced neuropathy of diabetes (TIND), also called insulin neuritis, is an uncommon small fiber neuropathy that occurs in patients with chronic hyperglycemia who experience rapid improvement in glycemic control [21-24]. 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 [24]. 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 glycolated hemoglobin A1C of ≥2 percentage points over three months). The following observations were made [24]:

●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 [21], apoptosis from glucose deprivation [25], and microvascular neuronal injury due to recurrent hypoglycemia [26]. Treatment is symptomatic [24].

Other diabetic neuropathies — Although uncommon, there are several types of diabetic neuropathy syndromes associated with weight loss. These include:

●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 [27-29]. 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.

●Diabetic anorexia – Diabetic anorexia is a typically painful polyneuropathy seen with intentional weight loss [30]. Symptoms may improve as weight is regained.

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

●Epidemiology – Diabetic polyneuropathy is the most common neuropathy in the resource abundant regions. Clinical and subclinical neuropathy has been estimated to occur in approximately 50 percent of patients with diabetes mellitus, depending upon the diagnostic criteria and patient populations examined. (See 'Epidemiology' above.)

●Classification – 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)