imported>Robert Badgett |
imported>Robert Badgett |
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| {{subpages}}{{Infobox Disease |
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| Name = Diabetic neuropathy |
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| ICD10 = E10.4, E11.4, E12.4, E13.4, E14.4 |
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| ICD9 = {{ICD9|250.6}} |
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| }}
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| '''Diabetic neuropathies''' are [[neuropathy|neuropathic]] disorders that are associated with [[diabetes mellitus]]. These conditions are thought to result from diabetic microvascular injury involving small [[blood vessel]]s 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 [[Pain and nociception|painful]] polyneuropathy; [[autonomic]] neuropathy; and thoracoabdominal neuropathy.
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| ==Epidemiology==
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| {{Diabetes}}
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| Diabetes is the leading known* cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of [[morbidity]] and [[death|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 [[amputation]]s.
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| 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, [[senescence|age]], [[cigarette]] smoking, [[hypertension]], height and [[hyperlipidemia]] are also risk factors for diabetic neuropathy.
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| *The largest group of neuropathy patients are of unknown cause, referred to as [[idiopathic]] in origin. Of the roughly 100 known causes, diabetes is by far the largest. Other known causes include genetic factors, damaging chemical agents such as chemotherapy drugs, and HIV.
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| ==Pathology and pathogenesis==
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| There are four factors thought to be involved in the development of diabetic neuropathy:
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| #[[Microvascular disease]],
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| #[[Advanced glycation endproduct|Advanced Glycation Endproduct]],
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| #[[Protein kinase C]], and the
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| #[[Polyol pathway]].
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| ===Microvascular disease===
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| Vascular and neural diseases are closely related and intertwined. [[Blood vessel]]s depend 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 thickening]] and [[endothelial hyperplasia]], which contribute to diminished [[oxygen tension]] and [[Hypoxia (medical)|hypoxia]]. [[Neuronal ischemia]] is a well-established characteristic of diabetic neuropathy. [[Vasodilator]] agents (e.g., [[angiotensin-converting-enzyme inhibitor]]s, α1-antagonists) can lead to substantial improvements in neuronal [[blood flow]], with corresponding improvements in [[Nerve conduction velocity|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.
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| ===Advanced glycated end products===
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| Elevated intracellular levels of [[glucose]] cause a non-enzymatic [[covalent bond]]ing with [[protein]]s, which alters their structure and destroys their function. Certain of these glycosylated proteins are implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.
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| ===Protein kinase C (PKC)===
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| [[PKC]] is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular [[diglyceride|diacylglycerol]], which activates PKC. PKC inhibitors in [[animal model]]s will increase [[nerve conduction]] velocity by increasing neuronal blood flow.
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| ===Polyol pathway===
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| Also called the Sorbitol/Aldose Reductase Pathway, the [[Polyol pathway|Polyol Pathway]] may be implicated in diabetic complications that result in microvascular damage to nervous tissue, and also to the retina and kidney which also have lots of microvasculature themselves.
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| Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body to react with. Increased glucose levels, like those seen in Diabetes, activates this alternative [[biochemical pathway]], which in turn causes a decrease in [[glutathione]] and an increase in reactive [[oxygen radical]]s. 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.
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| While most body cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin-independent. Therefore there is a free interchange of glucose from inside to outside of the cell, regardless of the action of insulin, in the eye, kidney and neurons. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway and be converted into sorbitol. Under normal blood glucose levels, this interchange will cause no problems, as aldose reductase has a low affinity for glucose at normal concentrations.
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| However, in a hyperglycemic state (Diabetes), the affinity of aldose reductase for glucose rises, meaning much higher levels of sorbitol and much lower levels of [[NADPH]], a compound used up when this pathway is activated. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water into the cell. Fructose does essentially the same thing, and it is created even further on in the chemical pathway.
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| The NADPH, used up when the pathway is activated, acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen molecules. Glutathione deficiencies can lead to hemolysis caused by oxidative stress, and we already know that nitric oxide is one of the important vasodilators in blood vessels. NAD+, which is also used up, is necessary to keep reactive oxygen species from forming and damaging cells.
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| In summary, excessive activation of the Polyol pathway leads to increased levels of sorbitol and reactive oxygen molecules and decreased levels of nitric oxide and glutathione, as well as increased osmotic stresses on the cell membrane. Any one of these elements alone can promote cell damage, but here we have several acting together.
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| Experimental evidence has yet to confirm that the polyol pathway actually is responsible for microvasculature damage in the retina, kidney and/or neurons of the body. However, physiologists are fairly certain that it plays some role in neuropathy.
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| ==Clinical manifestations==
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| 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. [[Symptom]]s vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years.
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| Usual symptoms may be:
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| * Numbness and tingling of extremities
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| * [[Dysesthesia]] (decreased or loss of sensation to a body part)
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| * [[Diarrhea]]
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| * [[Constipation]]
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| * [[Urinary incontinence]] (loss of bladder control)
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| * [[Impotence]]
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| * Facial, mouth and eyelid drooping
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| * Vision changes
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| * [[Dizziness]]
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| * Muscle weakness
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| * [[Dysphagia]] (swallowing difficulty)
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| * [[Speech]] impairment
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| * [[Fasciculation]] (muscle contractions)
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| ===Sensorimotor polyneuropathy===
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| 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, [[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 [[ulcer]]s 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 [[contracture]]s of the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called [[hammer toe]]s. 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.
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| ===Autonomic neuropathy===
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| The [[autonomic nervous system]] is composed of nerves serving the [[heart]], [[gastrointestinal system]] and [[urinary-genital system]]. [[Autonomic neuropathy]] can affect any of these organ systems. The most commonly recognized autonomic dysfunction 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]][failure of the sensitivty of the baroreceptors]. 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.
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| 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 [[bacteria]]l overgrowth, made worse by the presence of [[hyperglycemia]]. This leads to [[bloating]], gas and [[diarrhea]].
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| Urinary symptoms include urinary frequency, urgency, [[Urinary incontinence|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]].
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| ===Cranial neuropathy===
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| When [[cranial nerve]]s 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 muscle|lateral rectus]] and [[superior oblique muscle]]s. 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. This is because pupillary function within CNIII is found on the periphery of the nerve (in terms of a cross sectional view), which makes it less susceptible to ischemic damage (as it is closer to the vascular supply). 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 nerve]]s 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]].
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| ==Screening== | | ==Screening== |
| The [[National Institute for Health and Clinical Excellence]] (NICE) has addressed screening and recommends annually:<ref>(2004) [http://guidance.nice.org.uk/CG10/Guidance/pdf/English CG10 Type 2 diabetes - footcare]. National Institute for Health and Clinical Excellence</ref><br/> | | The [[National Institute for Health and Clinical Excellence]] (NICE) has addressed screening and recommends annually:<ref>(2004) [http://guidance.nice.org.uk/CG10/Guidance/pdf/English CG10 Type 2 diabetes - footcare]. National Institute for Health and Clinical Excellence</ref><br/> |
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| | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19595541 | doi=10.1016/j.jvs.2009.05.017 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref> of studies<ref name="pmid10417599">{{cite journal| author=Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL| title=Clinical examination for the detection of protective sensation in the feet of diabetic patients. International Cooperative Group for Clinical Examination Research. | journal=J Gen Intern Med | year= 1999 | volume= 14 | issue= 7 | pages= 418-24 | pmid=10417599 | | | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19595541 | doi=10.1016/j.jvs.2009.05.017 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref> of studies<ref name="pmid10417599">{{cite journal| author=Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL| title=Clinical examination for the detection of protective sensation in the feet of diabetic patients. International Cooperative Group for Clinical Examination Research. | journal=J Gen Intern Med | year= 1999 | volume= 14 | issue= 7 | pages= 418-24 | pmid=10417599 |
| | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10417599 | pmc=PMC1496604 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>. | | | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10417599 | pmc=PMC1496604 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>. |
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| ==Treatment==
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| 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, with the exception of tight glucose control, treatments are for reducing pain and other symptoms and do not address the underlying problems.
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| Agents for pain control include [[tricyclic antidepressant]]s (TCAs), [[serotonin reuptake inhibitor]]s (SSRIs) and antiepileptic drugs (AEDs). A [[systematic review]] concluded that "[[tricyclic antidepressants]] and traditional [[anticonvulsants]] are better for short term pain relief than newer generation anticonvulsants." <ref name="pmid17562735">{{cite journal |author=Wong MC, Chung JW, Wong TK |title=Effects of treatments for symptoms of painful diabetic neuropathy: systematic review |journal=BMJ |volume=335 |issue=7610 |pages=87 |year=2007 |pmid=17562735 |doi=10.1136/bmj.39213.565972.AE}}</ref>
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| ===Tight glucose control===
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| Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control.<ref name="pmid7887548">{{cite journal |author= |title=The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group |journal=Ann. Intern. Med. |volume=122 |issue=8 |pages=561-8 |year=1995 |pmid=7887548 |doi=}}</ref> 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.
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| ===Tricyclic antidepressants===
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| TCAs include [[imipramine]], [[amitriptyline]], [[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 [[arrhythmia]]s. At low dosages used for neuropathy, [[toxicity]] is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer [[adverse effect (medicine)|side effects]].
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| In a [[randomized controlled trial]] of patients with diabetic neuropathy, [[amitriptyline]] was better than [[fluoxetine]] <ref name="pmid1560801">{{cite journal |author=Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R |title=Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy |journal=N. Engl. J. Med. |volume=326 |issue=19 |pages=1250–6 |year=1992 |month=May |pmid=1560801 |doi= |url= |issn=}}</ref> In this trial, amitriptyline was effective in patients regardless of whether they had [[depression]], whereas fluoxetine was effective only in depressed patients.
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| In a randomized crossover trial of patients with diabetic neuropathy, [[amitriptyline]] provided moderate or greater pain relief in 67% of patients as compared to 52% with [[gabapentin]]. In this small study, this result was statistically insignificant.<ref name="pmid10493324">{{cite journal |author=Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA |title=Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain |journal=Arch. Intern. Med. |volume=159 |issue=16 |pages=1931–7 |year=1999 |month=September |pmid=10493324 |doi= |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=10493324 |issn=}}</ref>
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| ===Serotonin reuptake inhibitor===
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| [[SSRI]]s include [[fluoxetine]], [[paroxetine]], [[sertraline]] and [[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 diabetic's glycemic control. They can be used at dosages that also relieve the symptoms of [[clinical depression|depression]], a common concommitent of diabetic neuropathy.
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| The [[SSNRI]] [[duloxetine]] (Cymbalta) is approved for diabetic neuropathy. By targeting both serotonin and norepinephrine, it targets the painful symptoms of diabetic neuropathy, and also treats depression if it exists. Typical dosages are between 60mg and 120mg.
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| ===Antiepileptic drugs===
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| [[Antiepileptic|AED]]s, especially [[gabapentin]] and the related [[pregabalin]], are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amitriptyline 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 taken 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. [[Topiramate]] has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild [[anorexia (symptom)|anorexia]] and [[weight loss]], and is anecdotally beneficial.
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| ===Other treatments===
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| [[Methylcobalamin]], a special form of [[Vitamin B12]], is being studied now for treatment of neuropathy, both injected and oral. Initial studies[http://laurieulrich.com/jasper/methylcobalaminarticle.htm] and anecdotal evidence in cats[http://laurieulrich.com/jasper/] have been very encouraging.[http://www.delano.com/ReferenceArticles/Xobaline-for-Diabetic.html]. A [[systematic review]] of [[randomized controlled trials]] suggested benefit, but the trials were not of good quality and the possibility of [[publication bias]] exists.<ref name="pmid16008162">{{cite journal |author=Sun Y, Lai MS, Lu CJ |title=Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials |journal=Acta neurologica Taiwanica |volume=14 |issue=2 |pages=48-54 |year=2005 |pmid=16008162 |doi=}}</ref>
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| [[α-lipoic acid]], an [[anti-oxidant]] that is a non-prescription dietary supplement has shown benefit in a [[randomized controlled trial]] that compared once-daily oral doses of 600 mg to 1800 mg compared to [[placebo]], although nausea occurred in the higher doses.<ref name="pmid17065669">{{cite journal |author=Ziegler D, Ametov A, Barinov A, ''et al'' |title=Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial |journal=Diabetes Care |volume=29 |issue=11 |pages=2365-70 |year=2006 |pmid=17065669 |doi=10.2337/dc06-1216}}</ref>
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| In addition to pharmacological treatment there are several other modalities that help some cases. While lacking double blind trials, these have shown to reduce pain and improve patient quality of life particularly for chronic neuropathic pain: Interferential Stimulation; Acupuncture; Meditation; Cognitive Therapy; and prescribed exercise. In more recent years, Photo Energy Therapy devices are becoming more widely used to treat neuropathic symptoms. Photo Energy Therapy devices emit near infrared light typically at a wavelength of 890nm. This wavelength is is believed to stimulate the release of [[Nitric Oxide]], an [[Endothelium-derived relaxing factor ]] into the bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in various clinical studies to decrease pain and improve sensation in diabetic and non-diabetic patients. Photo Energy Therapy devices seem to address the underlying problem of neuropathies, poor [[microcirculation]], which leads to pain and numbness in the extremities[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14693984 4], [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15251618 5].
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| While it is quite true that recognized treatment modalities backed up by double blind trials do not address the underlying causality of diabetic neuropathy, two other programs have had substantial although still anecdotal results. The first involves a program of nutritional supplements put forth in an Internet article researched and published by diabetic neuropathy patients themselves (although heavily referencing peer-reviewed research articles). This article is entitled "A Multidisciplinary Approach to Diabetic Neuropathy Treatment" and its treatment regimen has been instrumental in substantial reversal in individuals throughout the world.<ref>{{cite web |url=http://www.geocities.com/bsy53/dn/neuropat.html |title=A MULTIDISCIPLINARY APPROACH TO DIABETIC NEUROPATHY TREATMENT |accessdate=2007-07-25 |format= |work=}}</ref>
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| The second method involves a combination of a vegan diet combined with moderate walking exercise. It has been used over several decades to affect both Type II diabetes as well as diabetic peripheral neuropathy.
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| ==Prognosis==
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| 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.
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| As a complication, there is an increased risk of injury to the feet because of loss of sensation (see [[diabetic foot]]). Small [[infection]]s can progress to [[ulcer]]ation ([[skin]] and soft tissue breakdown) and this may require [[amputation]]. In addition, motor nerve damage can lead to [[muscle]] breakdown and imbalance.
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| ==References==
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| <references/>
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| ==External links==
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| *[http://health.groups.yahoo.com/group/Neuropathy_Treatment_Testemonials/ Join a Neuropathy Support Group on Yahoo!]
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| *[http://www.diabetesincontrol.com/annodyne/burkeseries.php Nitric Oxide and its Role in Diabetes, Wound Healing and Peripheral Neuropathy]
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| *[http://www.nlm.nih.gov/medlineplus/diabeticnerveproblems.html Diabetic Nerve Problems]. MedlinePlus' extensive reference list of pertinent sites.
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| * [http://www.nlm.nih.gov/medlineplus/ency/article/000693.htm Diabetic Neuropathy]. Medical Encyclopedia, Medline Plus (US government public domain site, partially used here)
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| *[http://www.medscape.com/viewarticle/467524_3 Diabetic Neuropathy: An Intensive Review] in Medscape from WebMD (partially used in summarized form).
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| *[http://www.medscape.com/viewprogram/705 Diabetic Polyneuropathy] in Medscape from WebMD (partially used in summarized form).
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| *[http://diabetes.niddk.nih.gov/ National Diabetes Information Clearinghouse]
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| {{Endocrine pathology}}
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