Epidemiology and Disease Pathology of Diabetic Neuropathy

Epidemiology

Morbidity and mortality

Diabetic neuropathy is the most common complication of diabetes and the leading cause of morbidity and mortality in diabetic patients.[1] Neuropathy is responsible for more admissions to hospitals than all other diabetic complications combined and accounts for up to 75% of all nontraumatic amputations.[1] The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss.[2-4] Of the diabetic complications, diabetic neuropathy is considered to have the most detrimental effect on quality of life. In addition, mortality rates are high, approaching 50% at 5-10 years after the onset of autonomic neuropathy.[1,4,5]

Prevalence estimates

The heterogeneous nature of diabetic neuropathy makes it impossible to establish precisely its true prevalence. Reports range between 10-90% depending on the criteria and methods used to define neuropathy.[1,6] An estimated 7.5% of patients have neuropathy at the time of diabetes diagnosis, and according to recent epidemiological studies, approximately 30% of hospitalized patients and 20% of diabetic individuals in the community are affected by diabetic neuropathy.[7,11]

Risk factors

Hyperglycemia is the main risk factor for diabetic neuropathy.[6] The likelihood of developing neuropathy also increases with diabetes duration, although this is intrinsically linked to patient age which is itself a risk factor. Cigarette smoking, alcohol consumption, hypertension, height and hypercholesterolemia are independent risk factors for diabetic neuropathy.[11]

Economic burden

Overall, diabetic neuropathy constitutes a huge economic burden on the healthcare system, ranking third behind macrovascular disease and nephropathy in lifetime expenditures associated with diabetes complications.[2,8,9] In the US, the total annual cost of diabetic peripheral neuropathy (DPN) and its complications has been estimated at $4.6-13.7 billion. Almost 30% of the direct medical cost of diabetes may be attributed to DPN.[10]

Etiology and pathogenesis

Nearly every nerve fiber in the body is vulnerable to diabetic neuropathy, and every organ system that relies on innervation for function is subject to pathology.[11] Neuropathy affects sensory and motor neurons, as well as the autonomic nervous system (ANS), and gives rise to numerous syndromes that are primarily identified by the nerves affected.[11] Classification of the different forms of neuropathy can vary, but neuropathies are generally divided into symmetric and asymmetric types and classified as either diffuse, focal, or autonomic.[7,11,12]

Diffuse Neuropathies

Distal symmetric polyneuropathy (DSPN)

This is the most common form of neuropathy and the most widely recognized by physicians. Both large and small nerve fibers may be involved in DSPN, resulting in mixed sensory and motor symptoms.[1,13] DSPN typically manifests as pain and parasthesia in the fingers and toes, which progresses in a symmetrical pattern known as “stocking and glove distribution”. Patients complain of burning, tingling, aching, cold, lancinating pain, numbness, and allodynia. Negative symptoms of sensory loss include inability to feel or manipulate small objects and a reduced capacity to judge temperature or painful stimuli. Loss of innervation can eventually lead to atrophy of essential pedal muscles and result in deformities such as hammertoes or Charcot’s Joint. Deformities predispose patients to calluses and may ultimately lead to ulceration.[7,11,12]

Small fiber neuropathy

This is a less common distal symmetric neuropathy, mainly involving small-diameter sensory fibers – A delta and C fibers. The condition presents as painful parasthesias that are burning, crushing, aching or cramplike, with increased severity at night. Patients also experience loss of pain and temperature perception, with sparing of distal reflexes and proprioception.[7]

Large fiber neuropathy

This form of distal symmetric neuropathy involves large-diameter sensory or motor fibers and tends to be a neuropathy of signs rather than symptoms. Symptoms can be minimal and include painless electric tingling or a snug band-like sensation around the ankles and feet. Ataxia is prominent, along with proprioceptive sensory impairment. Patients may have absent ankle jerk reflexes and gait instability with eyes closed.[1,7]

Proximal neuropathy

Proximal neuropathy, also known as diabetic neuropathic cachexia, affects the thigh muscles. It primarily affects elderly patients, and a common feature is the inability to rise from a sitting position.[1] Proximal neuropathy is further classified according to the specific presentation. Femoral neuropathy is most common in people with type 2 diabetes and is characterized by pain in the front of one thigh followed by weakness and muscle atrophy.[12] Diabetic amyotrophy is the term used when weakness occurs in both thighs but without pain.[12]

Focal Neuropathies

Mononeuropathies occur mainly in older diabetic patients, have rapid onset, and follow a self-limiting course that resolves within 6 to 8 weeks.[1]

Cranial mononeuropathy

Cranial mononeuropathy commonly involves oculomotor, facial and optic nerves. Individuals with this condition experience headache and pain around the eye socket, followed by double vision. There may also be facial weakness and some impairment of sight.[7]

Compression/entrapment mononeuropathy

This common type of neuropathy is caused by compression of a nerve as it crosses a pressure point or by ischemia and subsequent infarction of the nerve.[7,12] Unlike other mononeuropathies, compression/entrapment mononeuropathies are progressive and persist without intervention.[1] Compressed nerves and sites of entrapment tend to be the same as those seen in nondiabetic patients – the median nerve at the wrist (carpal tunnel syndrome), ulnar nerve at the elbow, and common peroneal nerve at the fibular head are often affected. Symptoms characteristic of nerve infarction are acute focal pain associated with weakness and variable sensory loss in the distribution of the damaged nerve. Mononeuritis multiplex describes the condition where multiple nerves are affected sequentially and at random.[7]

Diabetic polyradiculopathy

Single or multiple contiguous spinal roots are involved in this type of neuropathy which includes 2 syndromes: thoracoabdominal neuropathy and lumbosacral radiculoplexopathy. It is more common in people with type 2 diabetes and patients aged over 50 and is associated with significant weight loss. Thoracoabdominal neuropathy manifests as a band of pain in the chest or abdomen which spreads bilaterally. Lumbosacral radiculoplexopathy begins as a sudden severe pain in the lower back or hips which spreads to the anterior thigh. Muscle weakness and lower limb atrophy may eventually result.[7]

Autonomic neuropathies

Diabetic autonomic neuropathy (DAN)

DAN typically occurs as a system-wide disorder, affecting long nerves first but eventually impacting on all parts of the ANS. As the vagus nerve (the longest of the ANS nerves) is responsible for around 75% of all parasympathetic activity, even the early effects of DAN can be widespread. The condition manifests clinically as dysfunction of one or more organ systems and is classified in categories accordingly.[14,15]

Cardiovascular autonomic neuropathy (CAN)

CAN is the most clinically important form of autonomic neuropathy due to its strong association with adverse outcomes such as cardiovascular death.[14] The 5-year mortality rate is increased 5-fold in diabetic patients with CAN.[15]

Table 1. Association between cardiovascular autonomic neuropathy and mortality [14]

CAN arises from damage to the autonomic nerves that innervate the heart and blood vessels and leads to abnormalities in heart rate control and vascular dynamics.[16] Reduced heart rate variation is the earliest indicator of CAN.[17] CAN manifests clinically as exercise intolerance, resting tachycardia, orthostatic hypertension, and silent myocardial ischemia.[14]

Gastrointestinal neuropathy

GI symptoms commonly occur in patients with diabetes and often reflect GI neuropathy. Autonomic neuropathy causes a diverse range of GI symptoms that are categorized according to the affected section of the GI tract.[14]

Erectile dysfunction (ED)

ED is the most common form of organic sexual dysfunction in diabetic males with an estimated incidence of 35-75%.[18] The etiology of ED in diabetes is mulifactorial and is caused not only by neuropathy, which is responsible for loss of cholinergic activation of the erectile process, but also vascular disease, metabolic control, nutrition, endocrine disorders, psychogenic factors and drugs.[18,19] ED is a marker for the development of generalized vascular disease and premature demise from myocardial infarction and may herald future, often preventable, cardiovascular events.[20]

Neurogenic bladder

Up to 50% of people with diabetes have symptoms of bladder dysfunction. The earliest autonomic bladder abnormalities are sensory and result in impaired bladder sensation, a higher threshold for micturition reflex, and increase in bladder capacity and retention. Damage to efferent parasympathetic fibers causes symptoms such as micturition hesitancy and weak stream which lead to incomplete bladder emptying. Eventually, overflow incontinence occurs due to denervation of the external and internal sphincter.[18]

Sudomotor dysfunction

Sudomotor dysfunction is a common feature of diabetic neuropathy and may be one of the earliest indications of DAN.[14] Clinical manifestations include anhidrosis, heat intolerance, gustatory sweating, and dry skin.[14] Sudomotor function reflects sympathetic cholinergic function and can be assessed using the following tests: quantitative sudomotor axon reflex test (QSART), sweat imprint, thermoregulatory sweat test (TST), and sympathetic skin response. 

Pupillary abnormalities

Autonomic neuropathy can lead to impairment of pupillomotor function causing effects such as decreased diameter of the dark-adapted pupil. Argyll-Robertson pupil, a small irregular pupil that does not react to light, may also occur.[14]

Pathogenesis

Multiple causative factors are implicated in the pathogenesis of diabetic neuropathy including metabolic insult to nerve fibers, neurovascular insufficiency, autoimmune damage, and neurohormonal growth-factor deficiency.[1] Specific focus has centered on the involvement of oxidative stress, advanced glycation end products (AGEs), protein kinase C and the polyol pathway in the pathophysiology of neuropathy.[11] Figure 1 summarizes how different factors may interact to give rise to neuropathy.

Figure 1. Pathogenesis of diabetic neuropathy [11]

Natural history

Neuropathies can be separated into 2 categories based on the natural course of the complication. Sensory and autonomic neuropathies generally progress gradually with increasing duration of diabetes, whereas mononeuropathies, radiculopathies and acute painful neuropathies are short-lived and tend to remit completely.[21] In both type 1 and 2 diabetes, progression of neuropathy is strongly linked to glycemic control. In type 1 diabetes, the most rapid deterioration of nerve function is seen soon after diabetes onset, with dysfunction slowing after 2–3 years. In contrast, in type 2 diabetes, slowing of nerve conduction velocity is often present at diagnosis and progresses at a steady rate thereafter.[1]

References

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3. Caputo GM, Cavanagh PR, Ulbrecht JS. Assessment and management of foot disease in patients with diabetes. N Engl J Med. 1994;331:854-860.
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