Diabetic neuropathy

Diabetic neuropathies are nerve damaging disorders 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

Illustration depicting areas affected by diabetic neuropathy

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 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. Signs and 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 the following:

• Trouble with balance
• 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

The following factors are 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 small blood vessels is narrowing of the blood vessels. As the disease progresses, neuronal dysfunction correlates closely with the development of blood vessel 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. Blood vessel opening agents (e.g., ACE inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, small blood vessel 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 levels of glucose within cells 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.

Polyol pathway

Also called the sorbitol/aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina,^[1] kidney,^[2] and nerves.^[3]

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 a glove-stocking distribution of numbness, sensory loss, dysesthesia and night time pain. The pain can feel like burning, pricking sensation, achy or dull. A 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 that 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 the muscles that move the eye except for 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 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.^[4] 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.^[4] 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.^[5]

Classification

Diabetic neuropathy encompasses a series of different neuropathic syndromes which can be schematized in the following way:^[6]

• 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)

Treatment

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

Options for pain control include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs) and capsaicin cream.^[7]

A systematic review concluded that "tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants."^[8] 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.^[9]

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.^[10][11] Before trying a systemic medication, some doctors recommend treating localized diabetic peripheral neuropathy with lidocaine patches.^[5]

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 abnormal heart rhythms. 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,^[12] 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;^[13] improved diabetic control may improve this.^[14]

Erythropoietin

There are some in vito studies indicating the beneficial effect of erythropoietin on the diabetic neuropathy, however, One nerve conduction study in mild-moderate diabetic patient showed that erythropoietin alone or in cobination with Gabapentin does not have any beneficial effect on progression of diabetic neuropathy.^[15]

Natural remedies

Various studies have shown that the daily intake of high levels of certain B vitamins may help control the pain associated with neuropathy, particularly B1 in the Benfotiamine form and B12 in the Methylcobalamine form. Other studies reference success with high doses of alpha-lipoic acid as well as the amino acid l-arginine which is proven to help with nitric oxide production and subsequent vaso dilation which can help reduce inflammation and associated pain.

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.

Medical devices

Monochromatic infrared photo energy treatment (MIRE) has been shown to be an effective therapy in reducing and often eliminating pain associated with diabetic neuropathy. The studied wavelength of 890nm is able to penetrate into the subcutaneous tissue where it acts upon a specialized part of the cell called the cytochrome C. The infrared light energy prompts the cytochrome C to release nitric oxide into the cells. The nitric oxide in turn promotes vaso dilation which results in increased blood flow that helps nourish damaged nerve cells. Once the nutrient rich blood able to reach the affected areas (typically the feet, lower legs and hands) it promotes the regeneration of nerve tissues and helps reduce inflammation thereby reducing and/or eliminating pain in the area.

Physical therapy

Physical therapy can be an effective and alternative treatment option for patients with diabetes.^[16] 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.^[17]

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.^[18]

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.^[18] Off-loading techniques can include the use of mobility aids (e.g. crutches) or foot splints.^[18] Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis.^[18]

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.^[19] General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting.^[20] 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.^[21]

Heat, therapeutic ultrasound,^[18] hot wax^[18] and short wave diathermy^[16] are also useful for treating diabetic neuropathy.^[18] Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.

Tight glucose control

Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control.^[22] Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes are 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.^[23]

Epidemiology

Globally diabetic neuropathy affects approximately 132 million people as of 2010 (1.9% of the population).^[24]

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.

References

Further reading

• Bril, Vera; England, John D.; Franklin, Gary M.; Backonja, Miroslav; Cohen, Jeffrey A.; Del Toro, David R.; Feldman, Eva L.; Iverson, Donald J.; Perkins, Bruce; Russell, James W.; Zochodne, Douglas W. (June 2011). "Evidence-based guideline: Treatment of painful diabetic neuropathy-report of the american association of neuromuscular and electrodiagnostic medicine, the american academy of neurology, and the american academy of physical medicine & rehabilitation" (PDF). Muscle & Nerve. 43 (6): 910–917. doi:10.1002/mus.22092. PMID 21484835. 

External links

• Diabetic Neuropathy at WebMD
• Diabetic Polyneuropathy at Medscape
• Diabetic Neuropathy at Diabetes.co.uk
• Diabetic Nerve Problems. MedlinePlus' extensive reference list of pertinent sites.