Diabetic Neuropathy Disease Background

Introduction

Diabetic neuropathy is a group of progressive, degenerative conditions involving autonomic, motor, or sensory peripheral nerves that develop in patients with diabetes mellitus (DM) and cannot be attributed to other causes of peripheral neuropathy, thus making it a diagnosis of exclusion.  

Epidemiology

Diabetic neuropathy is the most common chronic complication of diabetes, affecting about 50% of DM patients. It is noted to be more common in adults >50 years of age and in patients with type 2 DM. It is also the most common form of neuropathy observed in developed countries. Notably, the prevalence of diabetic neuropathy is a function of disease severity and duration; the prevalence increases with disease duration. Among the different forms of diabetic neuropathies, diabetic peripheral neuropathy (DPN) is the most common and the most studied. While the noted prevalence for DPN in type 1 DM patients is roughly 11 to 13%, more than half of all individuals with type 2 DM develop DPN.  

Studies in Malaysia show diabetic neuropathy has an estimated prevalence of around 10 to 30%. In the Philippines, DM is also the leading cause of neuropathy, 42% of DM patients suffering from it.

Pathophysiology

The pathogenesis of diabetic neuropathy is multifactorial and is mainly due to oxidative and inflammatory stress in association with metabolic dysfunction, which ultimately causes nerve cell damage.

Diabetic Neuropathy_Disease Background

Risk Factors

Risk factors for diabetic neuropathy include both unmodifiable and modifiable components. Unmodifiable risk factors include advanced age and the duration of diabetes, with the risk of developing neuropathy increasing as both age and disease duration progress. Height is also an independent predictor of neuropathy in both type 1 and type 2 DM patients.  

Modifiable risk factors include hyperglycemia, abdominal obesity, dyslipidemia (particularly hypertriglyceridemia, which increases the risk of distal symmetric polyneuropathy by 2.1 times), elevated low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C). Additional modifiable risk factors include hypertension, obesity (body mass index [BMI], weight, and waist circumference are associated with neuropathy), smoking, and heavy alcohol consumption.

Classification

Classification of Diabetic Neuropathies  

Diffuse or Generalized Neuropathies  

Diabetic sensorimotor polyneuropathy is a symmetrical, length-dependent sensorimotor polyneuropathy that is due to metabolic and microvessel alterations resulting from chronic hyperglycemia exposure and cardiovascular risk covariates. It is the most common form of diabetic neuropathy, affecting about 75% of DM patients. Diabetic sensorimotor polyneuropathy affects up to 50% of type 2 DM patients with >10 years of diabetes, and at least 20% of type 1 DM patients with long-standing diabetes (≥20 years). It may be present in at least 10–15% of newly diagnosed type 2 DM patients. Diabetic sensorimotor polyneuropathy follows a chronic and progressive course and is the most common cause of foot ulceration and lower extremity amputation. It must be noted that Charcot neuroarthropathy may also predispose patients to ulceration and amputation. Diabetic sensorimotor polyneuropathy typically has an insidious onset, beginning from distal and progressing proximally to the extremities affecting the toes and soles of the feet first then gradually ascending the legs. Symptoms at the fingertips and hands manifest usually when the distal extremity symptoms have reached the knees. Painful diabetic sensorimotor polyneuropathy is more common in patients with a longer duration of diabetes and poor glycemic control.  

Diabetic autonomic neuropathies usually occur in patients with long-term diabetes (≥20 years). They affect the sympathetic, parasympathetic, and enteric nerves. One form is cardiovascular autonomic neuropathy (CAN), which involves impairment of the autonomic control of the cardiovascular system. The prevalence of CAN increases with the duration of diabetes. It may cause prolonged QT interval in type 1 DM patients, leading to life-threatening cardiac arrhythmias and sudden cardiac death. Additionally, CAN may delay the diagnosis of silent or asymptomatic myocardial infarction due to reduced recognition of ischemic pain. Gastrointestinal (GI) autonomic neuropathy, which may involve any portion of the GI tract, tends to occur later in the course of diabetes. Urogenital autonomic neuropathy can manifest as diabetic cystopathy or neurogenic bladder, erectile dysfunction, or female sexual dysfunction. Sudomotor dysfunction manifests as distal hypohidrosis or anhidrosis, or as gustatory sweating. Another rare form of diabetic neuropathy is acute sensory diabetic neuropathy which may be subdivided into treatment-induced neuropathy and neuropathic cachexia. Treatment-induced neuropathy, or insulin neuritis, is an iatrogenic form of neuropathy caused by rapid glycemic control in the setting of chronic hyperglycemia. Diabetic neuropathic cachexia is a rare form of symmetrical painful neuropathy that usually affects the lower extremities and lower trunk.  

Mononeuropathy or Focal Neuropathies  

Mononeuropathy or focal neuropathies include isolated cranial neuropathies (eg cranial nerves [CN] III, IV, VI, VII) which usually occur in older DM patients with long-term diabetes. These also encompass isolated peripheral nerve neuropathies (eg ulnar, median, femoral, peroneal nerves). Entrapment neuropathies are estimated to occur in approximately one-third of DM patients. Most common of which is carpal tunnel syndrome, which is seen in 30% of patients with diabetic polyneuropathy and ulnar neuropathy, which is seen in 2.1% of patients with diabetes. Additionally, mononeuritis or mononeuropathy multiplex may occur, wherein multiple nerves are involved.  

Radiculopathy or Polyradiculopathy or Multifocal Neuropathies

Radiculopathy, polyradiculopathy, or multifocal neuropathies include diabetic radiculoplexus neuropathy, which may present as cervical radiculoplexus neuropathy, thoracic radiculoneuropathy, or lumbosacral polyradiculopathy. Both cervical and thoracic forms affect motor, sensory, and autonomic nerve fibers. Thoracic radiculoneuropathy primarily affects type 2 DM patients. Lumbosacral polyradiculopathy, or proximal motor amyotrophy, is the most frequent type of diabetic radiculoplexus neuropathy and affects about 1% of middle-aged patients with type 2 DM who have mild glucose metabolism impairment.