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Diabetic neuropathies are neuropathicdisorders that are associated with diabetes mellitus. These conditions usually result from diabetic microvascular injury involving small blood vesselsthat supply nerves (vasa nervorum). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painfulpolyneuropathy; autonomicneuropathy; and thoracoabdominal neuropathy.
- 1 Epidemiology
- 2 Pathology and pathogenesis
- 2.1 Microvascular disease
- 2.2 Advanced glycated end products
- 2.3 Protein kinase C (PKC)
- 2.4 Polyol pathway
- 3 Clinical manifestations
- 3.1 Sensorimotor polyneuropathy
- 3.2 Autonomic neuropathy
- 3.3 Cranial neuropathy
- 4 Treatment
- 5 Prognosis
- 6 See also
- 7 References
- 8 External links
Diabetes is the leading cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidityand mortalityin diabetes patients. It is estimated that the prevalenceof neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50-75% of nontraumatic amputations.
The main risk factor for diabetic neuropathy is hyperglycemia. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age, cigarettesmoking, hypertension, height and hyperlipidemiaare also risk factors for diabetic neuropathy.
Pathology and pathogenesis
There are four factor involved in the development of diabetic neuropathy:
- Microvascular disease,
- Advanced glycated end products,
- Protein kinase C, and the
- Polyol pathway.
Vascular and neural diseases are closely related and intertwined. Blood vesselsdepend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the microvasculature is vasoconstriction. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickeningand endothelial hyperplasia, which contribute to diminished oxygen tensionand hypoxia. Neuronal ischemiais a well-established characteristic of diabetic neuropathy. Vasodilatoragents (e.g., angiotensin-converting-enzyme inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.
Advanced glycated end products
Elevated intracellular levels of glucosecause a non-enzymatic covalent bondingwith proteins, which alters their structure and destroys their function. Certain of these glycated proteins are implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.
Protein kinase C (PKC)
PKCis implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerol, which activates PKC. PKC inhibitors in animal modelswill increase nerve conductionvelocity by increasing neuronal blood flow.
Increased glucose levels activates this alternative biochemical pathway, which in turn causes a decrease in glutathioneand an increase in reactive oxygen radicals. The pathway is dependent on the enzyme aldose reductase. Inhibitors of this enzyme have demonstrated efficacy in animal models in preventing the development of neuropathy.
Diabetic neuropathy affects all peripheral nerves: pain fibers, motor neurons, autonomic nerves. It therefore necessarily can affect all organs and systems since all are innervated. There are several distinct syndromes based on the organ systems and members affected, but these are by no means exclusive. A patient can have sensorimotor and autonomic neuropathy or any other combination. Symptomsvary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years.
Usual symptoms may be:
- Numbness and tingling of extremities
- Dysesthesia(decreased or loss of sensation to a body part)
- Urinary incontinence(loss of bladder control)
- Facial, mouth and eyelid drooping
- Vision changes
- Muscle weakness
- Disphagia(swallowing difficulty)
- Fasciculation(muscle contractions)
Longer nerve fibers are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve's length. In this syndrome, decreased sensation and loss of reflexes occurs first in the toes bilaterally, then extends upward. It is usually described as glove-stocking distribution of numbness, sensory loss, dysesthesiaand nighttime pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, that is, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk for developing ulcersand infections on the feet and legs, which can lead to amputation. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion contracturesof the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called hammertoes. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.
The autonomic nervous systemis composed of nerves serving the heart, gastrointestinal systemand urinary system. Autonomic neuropathycan affect any of these organ systems. The most commonly recognized autonomic dysfuction in diabetics is orthostatic hypotension, or the uncomfortable sensation of faintingwhen a patient stands up. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain. This symptom is usually accompanied by a loss of sinus respiratory variation, that is, the usual change in heart rate seen with normal breathing. When these 2 findings are present, cardiac autonomic neuropathy is present.
GI tract manifestations include delayed gastric emptying, gastroparesis, nausea, bloating, and diarrhea. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemiawhen an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small instestinecan cause bacterialovergrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea.
Urinary symptoms include urinary frequency, urgency, incontinenceand retention. Again, because of the retention of sweet urine, urinary tract infectionsare frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.
When cranial nervesare affected, oculomotor (3rd) neuropathies are most common. The oculomotor nervecontrols all of the muscles that move the eyewith the exception of the lateral rectusand superior oblique muscles. It also serves to constrict the pupiland open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia. All of the oculomotor muscles innervated by the third nerve may be affected, except for those that control pupil size. The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nervescan occur and lead to painful syndromes that mimic myocardial infarction, cholecystitisor appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome.
Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control. Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes is recent in onset. Conversely, painful symptoms of neuropathy in uncontrolled diabetics tend to subside as the disease and numbness progress. Of course, these uncontrolled patients are at great risk for diabetic foot ulcers and amputation because of neuropathy.
Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited by side effects and lack of efficacy. Thus, treatments are symptomatic and do not address the underlying problems. Agents for pain caused by sensorimotor neuropathy include tricyclic antidepressants(TCAs), serotonin reuptake inhibitors(SSRIs) and antiepileptic drugs (AEDs). None of these agents reverse the pathological processes leading to diabetic neuropathy and none alter the relentless course of the illness. They just treat the pain.
TCAs include imipramine, amitriptyline, desipramineand nortriptyline. These drugs are effective at decreasing painful symptoms but suffer from multiple side effects that are dosage dependent. One notable side effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicityis rare, but if symtoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects.
SSRIsinclude fluoxetine, paroxetine, sertralineand citalopram. They are less effective that TCAs in relieving pain, but are better tolerated. Side effects are rarely serious, and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetis's glycemic control. They can be used at dosages that also relieve the symptoms of depression, a common concommitent of diabetic neuropathy.
The SSNRIDuloxetine(Cymbalta) is approved for Diabetic neuropathy. By targeting both Serotonin and Norepinephrine. It targets the painful symptomes of diabetic neuropathy, and also treats depression if it exists. Typical dosages are between 60mg and 120mg.
AEDs, especially gabapentinand the related pregabalin, are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amytriptiline in terms of efficacy, and is clearly safer. Its main side effect is sedation, which does not diminish over time and may in fact worsen. It needs to be takes three times a day, and it sometimes causes weight gain, which can worsen glycemic control in diabetics. Carbamazepine(Tegretol®) is effective but not necessarily safe for diabetic neuropathy. Its first metabolite, oxcarbazepine, is both safe and effective in other neuropathic disorders, but has not been studied in diabetic neuropathy. Topiramatehas not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexiaand weight loss, and is anecdotally beneficial.
The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.
As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot). Small infectionscan progress to ulceration(skinand soft tissue breakdown) and this may require amputation. In addition, motor nerve damage can lead to musclebreakdown and imbalance.
- The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995;122:561-8. PMID 7887548.
- Diabetic Nerve Problems. MedlinePlus' extensive reference list of pertinent sites.
- Diabetic Neuropathy. Medical Encyclopedia, Medline Plus (US government public domain site, partially used here)
- Diabetic Neuropathy: An Intensive Reviewin Medscape from WebMD (partially used in summarized form).
- Diabetic Polyneuropathyin Medscape from WebMD (partially used in summarized form).
This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Diabetic+neuropathy Wikipedia article Diabetic neuropathy.