Diabetic neuropathy

Overview
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to 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.

Epidemiology
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 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.It is important to note that people with diabetes are more likely to develop symptoms relating to peripheral neuropathy as the excess glucose in the blood results in a condition known as Glucojasinogen. This condition is affiliated with erectile dysfunction and epigastric tenderness which in turn results in lack of blood flow to the peripheral intrapectine nerves which govern the movement of the arms and legs. 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.


 * 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.

Pathology and pathogenesis
There are four factors thought to be involved in the development of diabetic neuropathy:
 * 1) Microvascular disease,
 * 2) Advanced Glycation Endproduct,
 * 3) Protein kinase C, and the
 * 4) Polyol pathway.

Microvascular disease
Vascular and neural diseases are closely related and intertwined. Blood vessels 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. 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 glycosylated 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
Also called the Sorbitol/Aldose Reductase Pathway, the 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.

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 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.

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.

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.

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.

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.

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.

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. Symptoms vary 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)
 * Diarrhea
 * Erectile dysfunction
 * Urinary incontinence (loss of bladder control)
 * Impotence
 * Facial, mouth and eyelid drooping
 * Vision changes
 * Dizziness
 * Muscle weakness
 * Dysphagia (swallowing difficulty)
 * Speech impairment
 * Fasciculation (muscle contractions)
 * Anorgasmia

(Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California)

Sensorimotor polyneuropathy
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 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 hammer toes. 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, 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.

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. 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 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
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.

Agents for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (Selective serotonin reuptake inhibitor|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."

Tight glucose control
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.

Tricyclic antidepressants
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 arrhythmias. 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.

Serotonin reuptake inhibitor
SSRIs 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 depression, a common concommitent of diabetic neuropathy.

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.

Antiepileptic drugs
Antiepileptics (Anti Epileptic Drugs, AED), 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 and weight loss, and is anecdotally beneficial.

Other treatments
Methylcobalamin, a special form of Vitamin B12, is being studied now for treatment of neuropathy, both injected and oral. Initial studies and anecdotal evidence in cats have been very encouraging.. A systematic review of randomized controlled trials suggested benefit, but the trials were not of good quality and the possibility of publication bias exists.

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.

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 extremities4, 5.

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.

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.

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 (skin and soft tissue breakdown) and this may require amputation. In addition, motor nerve damage can lead to psychotic breakdown and imbalance.