Microangiopathic Complications of Diabetes: Diabetic Peripheral Neuropathies

This article is the fifth in a continuing series on diabetes in the elderly. The fourth article in the series, “A Review and Update of Insulins in the Management of Elderly Patients with Diabetes,” was published in the July/August issue of the Journal. The remaining articles in the series will discuss such topics as the role of exercise and dietary supplements in the management of diabetes, and macrovascular complications of diabetes.

Introduction

In the United States, it is estimated by the Centers for Disease Control and Prevention (CDC) that more than 23 million adults meet the criteria for the diagnosis of diabetes mellitus. More than 90% of them have type 2 diabetes (noninsulin dependent). Sixty-five to seventy percent of all persons with type 2 diabetes are over 60 years old.¹

Diabetes mellitus is a disease with multiple system involvement. Common complications are neurological, cardiac, renal, and ocular. The most common forms of complications are the neuropathies, mostly peripheral neuropathies. It is estimated that 30-50% of persons with diabetes develop a significant degree of clinically symptomatic neuropathies after 15-20 years with the disease.² Detailed neurological examination and electroneuromyographical studies reveal evidence of subclinical neuropathy in an additional 10-20% of persons with diabetes. In the United States, at least $25 billion per annum of health services expenditures are used for the treatment of diabetic complications, with at least $15 billion used for the management of neurological complications.³ Diabetic neuropathies include the diabetic peripheral neuropathies (DPN) and the autonomic (visceral) neuropathies. This review will focus on DPN, which include the following:

• Chronic symmetrical (distal) neuropathy
• Mononeuropathy
• Mononeuritis multiplex
• Neuropathic arthropathy (Charcot’s joint)

In addition to the involvement of peripheral nerves, neurological consequences of diabetes mellitus may result from atherosclerosis and ischemic injury to the brain or the spinal cord. Before attributing a peripheral neuropathy in an older person to diabetes, however, it is important to rule out other causes of neuropathy. In some older persons with diabetes, neuropathy may result from one or more coexisting conditions (Table I).

Clinical Manifestations of Diabetic Peripheral Neuropathy

DPN may involve a single nerve (mononeuropathy), or two or more nerves in separate nonsymmetrical areas (mononeuritis multiplex). Polyneuropathy is said to exist if many nerves are involved simultaneously and symmetrically. The term neuropathy is often referred to as neuritis. Neuritis, denoting an inflammation of a nerve, is not appropriate, however, since in most cases there is no acute inflammatory process involved in DPN.⁴

The most common form of DPN is a distal symmetrical sensorimotor neuropathy, with the sensory features being predominant. Chronic DPN is more commonly seen in persons with diabetes who are in their middle and late years. Occasionally, neuropathy may manifest even before the diagnosis of diabetes mellitus has been made. In the vast majority of cases, however, neuropathy is seen late in the course of the disease. The longer the duration of diabetes mellitus, the higher the frequency of peripheral neuropathy.

DPN is typically associated with pain, sensory loss, and muscle weakness with or without muscular atrophy. In an older person with diabetes, the diagnosis of DPN may be delayed since early symptoms and physical signs, such as loss of ankle reflexes and impaired vibration sense, may simply be attributed to changes of normal aging. The diagnosis is basically made by obtaining a comprehensive history and performing a complete neurological exam, and can be verified with electroneuromyographical studies.

Common causes, symptoms, and signs of DPN are summarized in Tables I, II, and III.

Distal Neuropathy

Distal neuropathy is a DPN that is bilateral, involving upper and/or lower limbs in a “glove-and-stocking distribution.” Lower limbs are affected more commonly than upper limbs. The more distal the part of the body is, the more severe the involvement. In the lower extremities, the toes are affected more frequently than thighs and lower legs. Pain is more common in the feet, and less so in the hands. Such pains are more common during the night and can cause severe sleep disturbance. As the disease progresses, the pain may disappear because of severe sensation loss. A severe impairment of sensations makes the patient more susceptible to foot injuries.

Mononeuropathy

Mononeuropathy involves a single nerve. Complaints of pain, sensation of “pins and needles,” numbness, and tingling are frequent in the distribution of the affected nerve. Cranial nerves (most commonly III, VI, and VII) may be involved. Foot drop is a strong sign of mononeuropathy. Involvement of the median nerve may mimic carpal tunnel syndrome. Diabetic amyotrophy or proximal neuropathy can also be seen, usually in older persons with diabetes. Symptoms include pain and weakness of proximal muscle groups (eg, thighs), and the knee jerk reflex is sluggish or completely absent.

Mononeuritis Multiplex

Mononeuritis multiplex is defined as an asymmetrical involvement of more than one nerve. Symptoms of pain, burning, or “pins and needles” are seen in the distribution areas of different multiple nerve fibers. Although mononeuritis multiplex can be seen in persons with diabetes, several other diseases including sarcoidosis, cancer, rheumatoid arthritis, neurofibromatosis, and leprosy must be ruled out.

Neuropathic Arthropathy (Charcot’s Joint)

Neuropathic arthropathy most commonly affects the tarsal, tarsometatarsal, and metatarsophalangeal joints. Clinical findings include swelling, deformity, and instability of one or more joints, with loss of plantar arch and impaired sensations. The affected joints eventually become anatomically disorganized. Almost all cases are associated with coexisting DPN. Severe degrees of neuropathy lead to neuropathic ulcers, claw toes, calluses, and bunions.

Pathogenesis of Diabetic Neuropathy

The exact cause of DPN remains unknown. Sensory neuropathy is associated with reduction of motor and sensory nerve conduction velocity and structural changes in peripheral nerves. These include endoneurial microangiopathy, abnormal Schwann cell pathology, axonal degeneration, paranodal demyelination, and loss of myelinated and unmyelinated fibers, due to a dying-back of distal axons that presents clinically as reduced epidermal nerve fiber density.³

In recent years, a better understanding of metabolic abnormalities observed in persons with diabetes has helped us learn more about probable pathophysiologic mechanisms contributing to the development of DPN and autonomic neuropathy. Results, from animal studies in particular, have shown that excessive levels of sorbitol (a product of glucose conversion by aldolase reductase) in cells exposed to high glucose levels may lead to cellular damage. Persisting hyperglycemia has been noted to result in a decline in cellular myoinositol and Na⁺/K⁺ - ATPase levels. It is thought that these metabolic changes result in axonal degeneration and, also, affect the function of Schwann cells, leading to segmental loss of myelin in diabetic neuropathy. Furthermore, lower levels of Na⁺/K⁺ - ATPase may lead to membrane depolarization and delayed conduction in the affected nerves.⁴ Aldolase (aldose) reductase inhibitors have been shown to reduce sorbitol levels in affected cells and are leading to the development of new drugs.

It is now generally believed that oxidative stress is the key pathological process inducing nerve damage in persons with diabetes. Oxidative stress, possibly triggered by vascular abnormalities and associated microangiopathy in the nerve, is a key step in a cascade of changes leading to nerve damage.³ In cultured endothelial cells, high glucose levels may drive excessive electron donation to the electron transport chain in mitochondria, resulting in mitochondrial hyperpolarization and elevated production of reactive oxygen species (ROS). This theory suggests that high glucose levels in target tissues for diabetic complications lead to increased supply of NADH in the mitochondria, and that this increased electron availability and/or saturation may cause partial reduction of oxygen to superoxide radicals in the proximal part of the electron transport chain. Subsequent ROS elevation then induces degeneration of tissues.³ Others have proposed that mitochondrial dysfunction in sensory neurons in diabetes could be associated with impaired Ca²⁺ homeostasis. This includes increased steady-state intracellular Ca²⁺ concentration, increased frequency of high-threshold Ca²⁺ currents, and decreased depolarization-induced Ca²⁺ signals.³

Once DPN is present, other factors may affect the rate of progression of the disease. In a recently published study, it was found that in patients with mild-to-moderate DPN, elevated triglycerides correlated with myelinated fiber density loss independent of disease duration, age, diabetes control, or other variables studied.5 These data support the concept that hyperlipidemia is instrumental in the progression of diabetic neuropathy.

Prevention and Management

There is no treatment modality available to completely reverse symptoms and signs of DPN. All efforts are, therefore, focused on prevention first, and symptom control second.

Prevention
Based on the pathophysiology of DPN, we could expect that good glucose control can prevent or delay the development of DPN. Indeed, many studies support this expectation. There is, however, debate on which treatment modalities and what degree of glucose control are optimal. In a paper published very recently, the investigators reported on the long-term follow-up (13-14 yr) of persons with diabetes treated with two different regimens of insulin (intensive treatment vs conventional treatment) during the Diabetes Control and Complications Trial (DCCT).⁶ From each group, approximately 600 patients were investigated, 13-14 years after the completion of the original study, for the presence of symptoms and signs of DPN. Researchers found that the prevalence of neuropathy increased in the 13-14 years, from 9-25% in the intensive therapy group and from 17-35% in the conventional treatment group, but the difference between groups remained significant. Longitudinal analysis in overall glycemic control showed a significant association between mean HbA1c and measures of incident and prevalent neuropathy. They concluded that the benefits of intensive insulin treatment persisted for at least 13 years.

Another recent study, however, evaluated the association between different glycemic therapies and prevalence of DPN in 2368 patients with type 2 diabetes and coronary artery disease (CAD).¹ Researchers found that the use of insulin was significantly associated with more cases of DPN (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.15-2.13), as compared to patients receiving no treatment for diabetes. Patients taking sulfonylurea or a combination of sulfonylurea/metformin/thiazolidinedione (TZD) or metformin/TZD had rates that were not substantially different from the “no-treatment” group. They concluded that, “this cross-sectional study in patients with diabetes mellitus and CAD showed association of insulin use with higher DPN prevalence, independent of disease duration, glycemic control and other characteristics.”¹ A close inspection of the data, however, indicates that the mean duration of diabetes in the insulin group was 16 years versus 3.7 years for the no-treatment group and 5.3-10.9 years for the various oral treatment groups. Although mean age and HbA1c were nearly identical in all groups, the effect of disease duration should not be ruled out.

In summary, most experts agree that the best possible control of blood glucose levels is highly desirable and should, at least, delay the development of DPN in persons with type 2 diabetes.

Treatment
Efforts for the discovery of agents that are capable of reliably reducing DPN symptoms have been ongoing for over 50 years without any great breakthroughs. Many drugs can control symptoms in some patients (20-50% depending on the drug) for several weeks. Effectiveness of all agents, though, appears to be substantially reduced with prolonged treatment. DPN can seriously affect quality of life, leading clinicians to try many available drugs to achieve the best possible symptomatic improvement with as few side effects as possible. Available agents include:

1. Tricyclic antidepressants
This category includes well-known agents such as amitriptyline, desipramine, imipramine, and clomipramine, which have been used for almost 40 years. These psychoactive agents are thought to work through nonselective inhibition of norepinephrine and/or serotonin reuptake at synapses of central descending pain neural pathways.⁷ They appear to be effective in approximately one-third of patients for a few weeks to a few months.⁷ No reliable data of long-term effectiveness can be found in the elderly. It should be noted that at least one-third of patients over 60 years of age develop side effects such as fatigue, muscular weakness, sleepiness, and dry mouth. These not only impair the quality of life of elderly patients, but also can worsen gait and balance impairments that can lead to falls and serious injuries. This category of drugs should, therefore, be used with extreme caution in the elderly.

2. Selective serotonin reuptake inhibitors
This group of agents, which includes paroxetine and citalopram, has been reported to reduce pain significantly in approximately 30% of patients with DPN. They have been recently reported to moderately increase the risk for gastrointestinal bleeding, especially when combined with nonsteroidal anti-inflammatory drugs and/or aspirin.⁷ The Food and Drug Administration (FDA) has not approved these drugs for the treatment of neuropathic pain.⁷

3. Selective serotonin and norepinephrine reuptake inhibitors
In this group, duloxetine and venlafaxine have been reported to be effective in controlling pain for several weeks in 40-50% of patients. Long-term effectiveness is still unclear, and the side effects are similar (but somewhat less frequent) to those of the tricyclics. The most common side effects are nausea, sleepiness, muscle weakness, dizziness, dry mouth, and constipation. As discussed above, these side effects can be dangerous in the elderly, and therefore, extreme caution is advised if used.

4. Calcium-channel modulators (alpha₂-delta ligands)
This category includes gabapentin⁸ and pregabalin. Gabapentin is chemically similar to gamma-aminobutyric acid. It appears to be effective in 40-60% of the patients who can tolerate 3600 mg/day. At this dose, however, more than 25% of patients will experience significant dizziness, somnolence, and gait instability. Long-term effectiveness is not known. Pregabalin is a newer specific alpha₂-delta ligand, with a sixfold higher affinity than gabapentin. It is reported to be effective in approximately 50% of patients for several months. Its side-effect profile is somewhat better than that of gabapentin, but, again, includes dizziness and somnolence.⁷

5. Antioxidants: Alpha-lipoic acid
As noted above, oxidative damage of peripheral nerves from excessive ROS production is believed to be a key pathogenetic mechanism. Studies in Europe and Australia suggest that the antioxidant alpha-lipoic acid may be effective in controlling symptoms of DPN with no side effects.⁹ Another 4-year, placebo-controlled study appeared to indicate that alpha-lipoic acid (600 mg/day) can delay the progression of DPN.¹⁰ These data are promising, but more studies are needed.

6. Aldose reductase inhibitors
Aldose (or aldolase) reductase directly controls sorbitol levels. As described above, sorbitol is believed to play a key role in nerve damage. Early studies with two experimental aldose reductase inhibitors, epalrestat and ranirestat (neither are FDA-approved for use in the U.S.), appear promising, and side effects are minimal.¹¹ Many more controlled studies will be needed to prove effectiveness.

7. Opioids
Opioids can be used with extreme caution in cases of severe pain that does not respond to any other treatments.

8. Balance training
Persons with diabetes who have DPN have much higher falls risk as compared to age-matched nondiabetic controls. This is, in part, attributable to slower reaction times and increased postural sway. In a well-controlled study, all of these variables improved after resistance and balance training three times a week for 6 weeks. Such improvement could prevent falls and subsequent injuries.¹²

Summary

DPN is often a disabling complication of diabetes mellitus. The prevalence of DPN is significantly higher in older persons with diabetes. Unfortunately, failure to recognize this complication in an early stage results in needless suffering from chronic pain, injuries, and ulcerations associated with loss of sensation. While no definitive treatment is available, stricter control of diabetes appears to be essential in delaying DPN progression. In addition, many treatments to reduce symptoms are available.

Follow-up articles on other microangiopathic complications of diabetes, to be published in future issues of the Journal, will focus on autonomic neuropathy, diabetic nephropathy, and diabetic retinopathy.

The author reports no relevant financial relationships.

Dr. Tsitouras is Clinical Director, Kronos Longevity Research Institute, Phoenix, AZ.

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