Peripheral Neuropathy Explained

Nerve damage is the most common complication of diabetes. It affects all types of nerves, the ones responsible for sensory perception, motor function and autonomic processes. The prevalence of which is relatively high, 7% suffer within a year of being diagnosed with diabetes and half of diabetics suffer from it by the time they harbor the disease for 25 years. The lifespan of such patients dramatically shortens once they suffer from cardiovascular complications. Once patients lose sensation in both their lower limbs, they become at high risk for limb amputation, which occurs in 1-2% of diabetics.

Symptoms of diabetic neuropathy vary depending on the nerve that is affected. But more often than not, lower limbs are affected prior to upper extremities. Patients often complain of numbness or loss of sensation in the limbs, more specifically, they have a  reduced ability to feel temperature or pain. Presence of tingling sensations, cramps and burning sensation, inappropriate sensitivity to touch, difficulty in moving, clumsiness and loss of balance have been well described. Since patients have impaired sensation on their limbs, they frequently develop cuts and wounds that poorly heal because they don’t notice it. This has a tendency to give rise to painless ulcers which may heal poorly due to poor circulation and uncontrolled blood sugar levels.

What are the risk factors in the progression of neuropathy?

Diabetics who have poor sugar control, as evidenced by chronically increased glycosylated hemoglobin (HbA1c) levels have high incidence of acquiring nerve damage. A large scale study by the European Diabetic group reported that aside from poor blood sugar control, the prolonged duration of diabetes, high blood pressure, high blood lipid levels and smoking are significant risk factors for the development of diabetic peripheral neuropathy. These risk factors also give rise to impaired blood circulation, affecting susceptible structures such as the nerves, eyes and kidneys causing other common complications of diabetes, namely neuropathy, retinopathy and nephropathy which contributes significantly to the morbidity of this disease.

Biochemistry of diabetic neuropathy

There are several biochemical pathways that may contribute to diabetic complications leading to macrovascular and microvascular consequences. The sorbitol pathway, also known as the polyol pathway is the pathway wherein excess glucose in the body is metabolized. Aldose reductaseand sorbitol dehydrogenase are enzymes, which metabolize the excess glucose when normal metabolic pathways have been already exhausted. The end products of these pathways are sorbitol and fructose. Since sorbitol cannot cross cell membranes, it accumulates in cells together with other proteins and substances causing impaired production of cellular energy. This biochemical event causes impairment in transmission of signals across nerves and ultimately causing nerve damage.

Another biochemical mechanism that gives rise to diabetic complications would be the formation of advanced glycation end products (AGEs). These end products are formed when there is excessive glucose, as seen in uncontrolled diabetes. The glycation end products alter the proteins and enzymes involved in important cellular metabolic pathways. This pathway is important because in animal studies, if the formation of these glycation end products is inhibited, the diabetic microvascular complications in the eyes and kidneys are prevented. This mechanism might be important in developing a pharmacologic strategy in the future that could prevent diabetic microvascular complications.

Uncontolled blood sugar levels stimulate the formation of protein kinase C. Protein kinase C is an important enzyme which is implicated in the formation of byproducts, which poses serious microvascular consequences. The main effects of these byproducts are poor blood flow, occlusion of small blood vessels and capillaries and the promotion increased inflammation. Protein kinase C induces diabetic neuropathy by altering nerve conduction due to impaired blood flow and by affecting nerve function due to altered neurochemical signaling.

Excess sugar in the body is also shunted to another biochemical pathway, called the hexosamine pathway. This pathway potentially contributes to diabetic complications by altering genetic expression and protein function. The byproducts of these pathway can cause increased cellular oxidative stress with resultant altered physiologic function of the peripheral nerves.

Recommendations for Diabetic Neuropathy

Unfortunately, there is no known cure for diabetic peripheral neuropathy. Clinicians manage it by slowing down its progression, managing symptoms and complications, strict sugar control and nutritional support.

Patient education is very important in the disease management. For patients who are 59 years old and younger with no other illnesses apart from diabetes, Mayo Clinic recommends maintaininga blood sugar of 80-120mg/dl. For individuals 60 years old and above, with other medical problems, Mayo Clinic recommends maintaining blood sugar of 100-140mg/dl.

The American Diabetes association recommends at least a yearly comprehensive foot exam for all diabetics, either by a foot specialist or by a general medical practitioner. For every office visit, feet should be checked for any ulcerations, wounds or sores that may warrant a specialist referral. Frequent self-preventive measures such as self-check would also be beneficial. Wearing therapeutic footwear, if started early may also prevent the formation of diabetic foot ulceration.

To slow down the progession of peripheral neuropathy, blood pressure should be maintained at normal levels. Proper nutrition and adequate exercise is also recommended. Avoidance, if not elimination of vices such as smoking and drinking alcohol should be done.

Medications to relieve painful diabetic neuropathy can be tailored to every patient. According to Practice Guidelines released in 2012, the only effective pharmacologic agent for painful diabetic neuropathy is Pregabalin (Lyrica). It was shown to improve quality of life with less sleep-related complications. Other agents which may be helpful for pain relief are:gabapentin (Neurontin) and sodium valproate, which are anti-convulsants; the antidepressants amitriptyline, venlafaxine (Effexor), and duloxetine (Cymbalta); the opioids morphine sulfate, tramadol (Ultram). Medications, which may improve quality of life are venlafaxine, duloxetine, and dextromethorphan. Studies show that gabapentin together with venlafaxine may have a better treatment response.

Alternative medications, which may help relieve pain are capscaicin cream, isosorbidedinitrate and lidocaine patch. They may lessen pain in selected patients and should be considered according to your physician’s clinical judgment. Nutritional supplementation with alpha-lipoic acid and gamma-linolenic acid may be for diabetic neuropathy.

Another treatment modality, which may help alleviate painful complication would be percutaneous electrical nerve stimulation, which is usually done by rehabilitation specialists.

References:

• Yagihashi,S., et al. (2010). Mechanism of diabetic neuropathy: Where are we now and where to go? Journal of Diabetes Investigation.Feb 2011.Vol 2:18-32.
• Brownlee, M. (2001). Biochemistry and molecular cell biology of diabetic complications.Nature. Dec 2001. Vol 414: 813-820.
• Oyenihi,A, et al. (2015). Antioxidant strategies in the Management of Diabetic Neuropathy.BioMed Research International.Vol 2015, Article ID 515042, 15 pages
• Senthil, K et al. (2013). Primary and Secondary prevention od diabetic neuropathy: an update. Indian Journal of Preventive Medicine.2013 Jan-June 1(1).
• Devitt, M. (2012). AAN, AANEM, and AAPMR Publish Guideline for the Treatment of Painful Diabetic Neuropathy. AmFam Physician. 2012 Sep 1:86(5):469-470.
• Tesfaye, S. (2011). Recent advances in the treatment of diabetic symmetrical polyneuropathy. Journal of Diabetes Investigation. Feb 2011. Vol 2:33-42.
• http://www.mayoclinic.org/diseases-conditions/diabetic-neuropathy/basics/treatment
• http://www.who.int/mediacentre/factsheets/fs312/en/