Diabetic neuropathy

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) in addition to macrovascular conditions that can culminate in diabetic neuropathy. 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.

Signs and symptoms
Diabetic neuropathy affects all peripheral nerves including pain fibers, motor neurons and the autonomic nervous system. It therefore can affect all organs and systems, as all are innervated. There are several distinct syndromes based upon 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.

Symptoms may include:
 * Numbness and tingling of extremities
 * Dysesthesia (abnormal sensation to a body part)
 * Diarrhea
 * Erectile dysfunction
 * Urinary incontinence (loss of bladder control)
 * Facial, mouth and eyelid drooping
 * Vision changes
 * Dizziness
 * Muscle weakness
 * Difficulty swallowing
 * Speech impairment
 * Fasciculation (muscle contractions)
 * Anorgasmia
 * Retrograde ejaculation (in males)
 * Burning or electric pain

Pathogenesis
There are four factors thought to be involved in the development of diabetic neuropathy:

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., ACE 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 inhibits their function. Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.

Protein kinase C
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.

Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body with which to react. 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 not insulin-dependent. 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, 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.

Furthermore, the high levels of sorbitol are believed to reduce the cellular uptake of another alcohol, myoinositol, decreasing the activity of the plasma membrane Na+/K+ ATPase pump required for nerve function, further contributing to the neuropathy.

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.

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), also known as diabetic peripheral neuropathy (DPN) (most common presentation)

Effects on nerve types
Different nerves are affected in different ways

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 on each foot, then extends upward. It is usually described as glove-stocking distribution of numbness, sensory loss, dysesthesia and night time pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, 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 of 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, lungs, blood vessels, bone, adipose tissue, sweat glands, gastrointestinal system and genitourinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension, or fainting when standing 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 respiratory sinus arrhythmia - the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy.

GI tract manifestations include 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 intestine 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 urine, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.

Cranial neuropathy
When cranial nerves are affected, neuropathies of the oculomotor nerve (cranial nerve #3) 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, but those that control pupil size are usually well-preserved early on. This is because the parasympathetic nerve fibers within CNIII that influence pupillary size are found on the periphery of the nerve (in terms of a cross sectional view), which makes them less susceptible to ischemic damage (as they are 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.

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 recent 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.

Treatment
Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.

Options for pain control include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), microcurrent 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." A combination of these medication (gabapentin + nortriptyline) may also be superior to a single agent.

The only three drugs approved by the FDA for diabetic peripheral neuropathy 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 periperal neuropathy with lidocaine patches.

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-norepinephrine reuptake inhibitors
The SSNRI duloxetine (Cymbalta) is approved for diabetic neuropathy, while venlafaxine is also commonly used. By targeting both serotonin and norepinephrine, these drugs target the painful symptoms of diabetic neuropathy, and also treat depression if it exists. On the other hand, selective serotonin reuptake inhibitors are not useful.

Selective Serotonin reuptake inhibitor
SSRIs include fluoxetine, paroxetine, sertraline and citalopram and are not recommended to treat painful neuropathy because they have been found to be no more efficacious than placebo in several controlled trials. 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 comorbidity of diabetic neuropathy.

Antiepileptic drugs
AEDs, 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. Clinical studies have differed regarding its effectiveness; improved diabetic control may improve this.

Classic analgesics
The above three categories of drugs fall under the heading of "atypical, adjuvant and potentiators" and are often combined with opioids and/or NSAIDs, usually having effects greater than the sum of their parts.

Duloxetine + extended release morphine ± naproxen ± hydroxyzine (esp. with oxycodone) ± morphine or hydromorphone immediate release for breakthrough pain is a common recipe in cases where diabetic neuropathy is a complicating factor in a debilitating chronic pain condition — amitriptyline may be more effective than Duloxetine in some. Opioids requiring Cytochrome P-450 activation (e.g. codeine, dihydrocodeine) should perhaps be used with an agent not chemically related to the SSRIs; conversely, they may impact parts of the Liberation, Absorption, Distribution, Metabolism & Elimination profile for morphine, hydromorphone, oxymorphone &c the other way.

Physical therapy
Physical therapy can be an effective and alternative treatment option for patients with diabetes. This may help reduce dependency on pain relieving drug therapies. Certain physiotherapy techniques can help alleviate symptoms brought on from diabetic neuropathy such as deep pain in the feet and legs, tingling or burning sensation in extremities, muscle cramps, muscle weakness, sexual dysfunction, and diabetic foot.

Transcutaneous electrical nerve stimulation (TENS) and interferential current (IFC) use a painless electric current and the physiological effects from low frequency electrical stimulation to relieve stiffness, improve mobility, relieve neuropathic pain, reduce oedema, and heal resistant foot ulcers.

Gait training, posture training, and teaching these patients the basic principles of off-loading can help prevent and/or stabilize foot complications such as foot ulcers. Off-loading techniques can include the use of mobility aids (e.g. crutches) or foot splints. Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis.

Exercise programs, along with manual therapy, will help to prevent muscle contractures, spasms and atrophy. These programs may include general muscle stretching to maintain muscle length and a person’s range of motion. General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting. Aerobic exercise such as swimming and using a stationary bicycle can help peripheral neuropathy, but activities that place excessive pressure on the feet (e.g. walking long distances, running) may be contraindicated.

Heat, therapeutic ultrasound, hot wax and short wave diathermy are also useful for treating diabetic neuropathy. Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.

Other treatments
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.

Methylcobalamin, a specific form of Vitamin B-12 found in spinal fluid, has been studied and shown to have significant effect, taken orally or injected, in treating and improving diabetic neuropathy.

Though not yet commercially available, C-peptide has shown promising results in treatment of diabetic complications, including neuropathies. Once thought to be a useless by-product of insulin production, it helps to ameliorate and reverse the major symptoms of diabetes.

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 (NIR Therapy) typically at a wavelength of 880 nm. This wavelength 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 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,.

Sativex, a cannabis based medicine has not been found to be effective for diabetic neuropathy. Along with Sativex, Cesamet (Nabilone) a synthetic THC medication has also shown benefits for DPN as an adjuvant therapy. There has been experimental work testing the efficacy of sildenafil (Viagra) but this study described itself as an "isolated clinical report" and cited a need for further clinical investigation. There is no evidence of sufficient quality to show that Chinese herbal medicines are either safe or effective for treating DPN.

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.

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 131 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 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.