Diabetic Neuropathy: An Intensive Review

Jeremiah John Duby; R. Keith Campbell; Stephen M. Setter; John Raymond White; Kristin A. Rasmussen


Am J Health Syst Pharm. 2004;61(2) 

In This Article

Classification and Disease Course

Diabetic neuropathy affects sensory, autonomic, and motor neurons of the peripheral nervous system, which is to say that nearly every type of nerve fiber in the body is vulnerable. Moreover, every organ system in the body that relies on innervation for function is consequently subject to pathology. Therefore, diabetic neuropathy describes a number of unique syndromes that are primarily classified by the nerve fibers affected. As for the disease course, it is fortunate that only a minority of patients experience neuropathic pain but tragic that a majority do not report symptoms until the complications are severe or irreversible. It is beyond the scope of this article and the practice of pharmacy to formulate diagnoses; however, a practical understanding of the classification and course of neuropathy is an invaluable part of pharmaceutical care for diabetes patients. A simple classification and staging system is outlined in the appendix, and the disease courses for the most common diabetic neuropathies are detailed below.

The excruciating, refractory pain that can accompany sensorimotor neuropathy is what most health care providers recognize as diabetic neuropathy; however, the damage typically develops insidiously as a painless loss or change of sensation that may be detected and quantified only by clinical tests. Sensorimotor neuropathy affects large and small afferent nerve fibers to varying degrees, resulting in mixed symptoms and sensory loss.[1,9] Large afferent nerve fibers transmit proprioception (i.e., spatial limb location), cold, and vibration sensation. Small afferent fibers are responsible for conducting nociceptive stimuli, touch, and warmth sensation.[1] The manifestations of sensorimotor neuropathy classically progress from the most distal extremities (the fingers and toes) in a symmetrical pattern that is generally described as a glove-and-stocking distribution.[1,9,10] The positive symptoms are pain and paresthesia (abnormal sensations), and patients complain of burning, tingling, aching, cold sensation, lancinating (sharp) pain, numbness, or pain from normal touch (allodynia), such as clothing brushing the skin.[1,9,10,11] Painful symptoms occur in a minority (11-32%) of neuropathy patients with diabetes and do not correlate with diminished nerve conduction velocity (NCV) or function.[1,9,11] The negative symptoms of sensory loss are more common and occur throughout the course of diabetes.[1] Patients may experience an inability to feel, identify, or manipulate smaller objects. They can gradually lose the capacity to judge temperature or sense even painful or threatening stimuli.[1,9,10] Further, the loss of innervation can lead to atrophy of essential pedal muscles, resulting in deformities (e.g., hammertoes) that predispose the patient to calluses and ultimately to ulceration.[1,12] In fact, sensorimotor neuropathy is the primary risk factor for the development of diabetic foot ulcer, which is responsible for 85% of lower-extremity amputations in diabetes patients.[12]

Sensorimotor neuropathy is the most common type of neuropathy, but there is an increasing awareness of the prevalence and impact of autonomic neuropathies. CAN is rapidly emerging as a key cause of morbidity and mortality in diabetes. The incidence of CAN appears to be around 15% in type 1 and 20% in type 2 diabetes patients. A malities-conservative source determined the mately-10-year mortality rate for diabetic patients with CAN to be 27%, a remarkable 22 absolute percentage points higher than the mortality rate for diabetes patients without CAN.[13] It is hypothesized that the comorbidity of CAN with coronary artery disease results in synergistic cardiovascular dysfunction, decreased myocardial infarction survival rates, and increased incidence of malignant arrhythmia and sudden death.[1,13,14] CAN affects both the sympathetic and parasympathetic innervation of the heart and coronary vessels.[15] The hallmark symptoms are orthostatic hypotension and decreased heart-rate variability, and CAN may contribute to left ventricular dysfunction, silent or asymptomatic myocardial infarction, and exercise intolerance.[1,13,14,15] There is evidence that the disease process may begin early in the course of diabetes but remain asymptomatic until later stages.[1,13,15]

Gastroparesis is the GI complication most commonly associated with diabetes, but diabetic autonomic dysfunction can affect the entire GI system from the esophagus to the colon.[16,17] Subclinical abnormalities are relatively common, and symptoms do not typically occur until later in the course of diabetes.[16,17,18] The symptoms can range from mild discomfort to disabling impairment of daily activities. Gastroesophageal dysfunction manifests as gastroesophageal reflux disease (GERD) in roughly 30% of diabetes patients.[16,17] Delayed gastric emptying and gastric retention, which are present in 25- 50% of patients with diabetes, can cause early satiety, cramping, bloating, epigastric pain (heartburn), nausea and vomiting, and loss of appetite to the point of anorexia.[16,17,18,19,20,21] Gastroparesis can also complicate pharmacotherapy by delaying the absorption of glucose or antidiabetic medication, for example.[16,17] Colon abnorare symptomatic in approximately 25% of patients, resulting in severe constipation, diarrhea, and fecal incontinence.[15,17]

Male and female sexual function and urinary continence are fundamental quality-of-life issues that can be adversely affected by diabetes.[22,23] Erectile dysfunction affects more than 50% of men with diabetes over the age of 50 years and three out of every four male diabetes patients who are 60 or older.[17,24] The initiation of penile erection is directed by the autonomic nervous system, and neuropathic dysfunction may result in the gradual loss of rigidity to the point of complete impotence. Female sexual dysfunction may manifest as diminished libido as a result of vaginal dryness and pain during intercourse (dyspareunia).[16,17] Neurogenic bladder or cystopathy may also be caused by diabetic autonomic neuropathy and can result in the inability to sense bladder fullness or initiate micturition, resulting in urinary retention, bladder enlargement, and overflow incontinence.[15,17]


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