Diabetic Neuropathy

 

Diabetic neuropathies are nerve damaging disorders associated with diabetes mellitus. These conditions are thought to result from a diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum) in addition to macrovascular conditions that can accumulate in diabetic neuropathy. Relatively common conditions which may be associated with diabetic neuropathy include third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Diagnosis
Diabetic peripheral neuropathy is the most likely diagnosis for someone with diabetes who has pain in a leg or foot, although it may also be caused by vitamin B12 deficiency or osteoarthritis. A 2010 review in the Journal of the American Medical Association’s “Rational Clinical Examination Series” evaluated the usefulness of the clinical examination in diagnosing diabetic peripheral neuropathy. While the physician typically assesses the appearance of the feet, presence of ulceration, and ankle reflexes, the most useful physical examination findings for large fiber neuropathy are an abnormally decreased vibration perception to a 128-Hz tuning fork (likelihood ratio (LR) range, 16–35) or pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11–16). Normal results on vibration testing (LR range, 0.33–0.51) or monofilament (LR range, 0.09–0.54) make large fiber peripheral neuropathy from diabetes less likely. Combinations of signs do not perform better than these 2 individual findings. Nerve conduction tests may show reduced functioning of the peripheral nerves, but seldom correlate with the severity of diabetic peripheral neuropathy and are not appropriate as routine tests for the condition.

Classification
Diabetic neuropathy encompasses a series of different neuropathic syndromes which can be schematized in the following way:

Focal and multifocal neuropathies:
Mononeuropathy
Amyotrophy, radiculopathy
Multiple lesions “mononeuritis multiplex”
Entrapment (e.g. median, ulnar, peroneal)
Symmetrical neuropathies:
Acute sensory
Autonomic
Distal symmetrical polyneuropathy (DSPN), the diabetic type of which is also known as diabetic peripheral neuropathy (DPN) (most common presentation)

Treatment
Except for tight glucose control, treatments are for reducing pain and other symptoms.

Medication options for pain control include antiepileptic drugs (AEDs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and capsaicin cream. About 10% of people who use capsaicin cream have a large benefit.

A systematic review concluded that “tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants.” A further analysis of previous studies showed that the agents carbamazepine, venlafaxine, duloxetine, and amitriptyline were more effective than placebo, but that comparative effectiveness between each agent is unclear.

The only three medications approved by the United States’ Food and Drug Administration for diabetic peripheral neuropathy (DPN) are the antidepressant duloxetine, the anticonvulsant pregabalin, and the long-acting opioid tapentadol ER. Before trying a systemic medication, some doctors recommend treating localized diabetic peripheral neuropathy with lidocaine patches.

Antiepileptic drugs
Multiple guidelines from medical organizations such as the American Association of Clinical Endocrinologists, American Academy of Neurology, European Federation of Neurological Societies, and the National Institute of Clinical Excellence recommend AEDs, such as pregabalin, as first-line treatment for painful diabetic neuropathy. Pregabalin is supported by low-quality evidence as more effective than placebo for reducing diabetic neuropathic pain but its effect is small. Studies have reached differing conclusions about whether gabapentin relieves pain more effectively than placebo. Available evidence is insufficient to determine if zonisamide or carbamazepine are effective for diabetic neuropathy. The first metabolite of carbamazepine, known as oxcarbazepine, appears to have a small beneficial effect on pain. A 2014 systematic review and network meta-analysis concluded topiramate, valproic acid, lacosamide, and lamotrigine are ineffective for pain from diabetic peripheral neuropathy. The most common side effects associated with AED use include sleepiness, dizziness, and nausea.

Serotonin-norepinephrine reuptake inhibitors
As above, the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine are recommended in multiple medical guidelines as first or second-line therapy for DPN. A 2017 systematic review and meta-analysis of randomized controlled trials concluded there is moderate quality evidence that duloxetine and venlafaxine each provide a large benefit in reducing diabetic neuropathic pain. Common side effects include dizziness, nausea, and sleepiness.

Selective serotonin reuptake inhibitor
SSRIs include fluoxetine, paroxetine, sertraline, and citalopram have been found to be no more efficacious than placebo in several controlled trials and therefore are not recommended to treat painful diabetic neuropathy. Side effects are rarely serious and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic person’s glycemic control. They can be used at dosages that also relieve the symptoms of depression, a common comorbidity of diabetic neuropathy.

Tricyclic antidepressants
TCAs include imipramine, amitriptyline, desipramine, and nortriptyline. They are generally regarded as first or second-line treatment for DPN. Of the TCAs, imipramine has been the best studied. These medications are effective at decreasing painful symptoms but suffer from multiple side effects that are dose-dependent. One notable side effect is cardiac toxicity, which can lead to fatal abnormal heart rhythms. Additional common side effects include dry mouth, difficulty sleeping, and sedation. 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 side effects.

Opioids
Typical opioid medications, such as oxycodone, appear to be no more effective than placebo. In contrast, low-quality evidence supports a moderate benefit from the use of atypical opioids (e.g., tramadol and tapentadol), which also have SNRI properties. Opioid medications are recommended as second or third-line treatment for DPN.

Topical agents
Capsaicin applied to the skin in a 0.075% concentration has not been found to be more effective than placebo for treating pain associated with diabetic neuropathy. There is insufficient evidence to draw conclusions for more concentrated forms of capsaicin, clonidine, or lidocaine applied to the skin.

Other
Low-quality evidence supports a moderate-large beneficial effect of botulinum toxin injections. Dextromethorphan does not appear to be effective in treating diabetic neuropathic pain. There is insufficient evidence to draw firm conclusions for the utility of the cannabinoids nabilone and nabiximols. There are some in vitro studies indicating the beneficial effect of erythropoietin on the diabetic neuropathy; however, one nerve conduction study in mild-moderate diabetic individuals showed that erythropoietin alone or in combination with gabapentin does not have any beneficial effect on progression of diabetic neuropathy.

Prognosis
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 infections can progress to ulceration and this may require amputation.

Epidemiology
Globally diabetic neuropathy affects approximately 132 million people as of 2010 (1.9% of the population).

Diabetes is the leading known cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes. It is estimated that neuropathy affects 25% of people with diabetes. 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.

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