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Diabetic neuropathy

Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum ). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy ; mononeuropathy ; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Contents

Epidemiology

Diabetes is the leading cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients. It is estimated that the prevalence of 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, cigarette smoking, hypertension, height and hyperlipidemia are 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.

Microvascular disease

Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depends 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 thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (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 glucose cause a non-enzymatic covalent bonding with 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)

PKC is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerol, which activates PKC. PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.

Polyol pathway

Increased glucose levels activates this alternative biochemical pathway, which in turn causes a decrease in glutathione and 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.


Clinical manifestations

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.

Sensorimotor polyneuropathy

Longer nerve fibers are affected to a greated 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, dysesthesia and 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 ulcers and 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 contractures of 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.

Autonomic neuropathy

The autonomic nervous system is composed of nerves serving the heart, GI tract and urinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfuction in diabetics is orthostatic hypotension, or the uncomfortable sensation of fainting when 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 hypoglycemia when 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 instestine can cause bacterial overgrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea.

Urinary symptoms include urinary frequency, urgency, incontinence and retention. Again, because of the retention of sweet urine, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.

Cranial neuropathy

When cranial nerves are affected, oculomotor (3rd) neuropathies are most common. The oculomotor nerve controls all of the muscles that move the eye with the exception of the lateral rectus and superior oblique muscles. It also serves to constrict the pupil and 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 nerves can occur and lead to painful syndromes that mimic myocardial infarction, cholecystitis or appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome.

Treatment

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 inhibitor s (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, amytriptyline , desipramine and 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, toxicity is rare, but if symtoms warrant higher doses, complications are more common. Among the TCAs, amytriptylene is most widely used for this condition, but desipramine and nortyptilene have fewer side effects.

SSRIs include fluoxetine (Prozac), paroxetine (Paxil), sertralene (Zoloft) and citalopram (Celexa and Lexapro). 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.

AEDs, especially gabapentin (Neurontin®), 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 causes weight gain, which will worsen glycemic control in diabetics. Carbamazapine (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. Topimirate (Topamax®) has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexia and weight loss, and is anecdotally beneficial.

Prognosis

to be filled in

References

  • 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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
    ct&list_uids=7887548
    .
  • MEDLINE/PubMed http://www.ncbi.nlm.nih.gov/entrez/query.fcgi The National Library of Medicine or MeSH (medical subject heading) term
  • Diabetic Neuropathy: An Intensive Review http://www.medscape.com/viewarticle/467524_3 in Medscape from WebMD (summarized, not plagiarized).
  • Diabetic Polyneuropathy http://www.medscape.com/viewprogram/705 in Medscape from WebMD (summarized, not plagiarized).


Last updated: 02-07-2005 16:46:19
Last updated: 05-03-2005 09:00:33