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Once neuropathy begins, reversal is difficult to achieve.5 Perkins and colleagues6 demonstrated that patients with diabetic neuropathy have a 30% reduction in sural nerve fiber density compared with patients who have no evidence of the disease. Nerve conduction slows as the hemoglobin A1c (HbAlc) value surpasses 9% (the target recommended by the American Diabetes Association is an A1c of less than 7%).7 Once nerve fibers are destroyed, conduction is altered, which leads to painful and irreversible neuropathy. This illustrates the importance of early intervention and intensive management of patients with diabetes to prevent neuropathic complications.
Studies show that surveillance for evidence of neuropathy and intensive diabetes management can reduce the incidence of complications. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive management of patients with type 1 diabetes reduced the risk of neu- ropathy, as well as retinopathy and nephropathy, by 60%.2 The Kumamato University trial8 revealed that, compared with twice-daily injections of insulin, intensive therapy with multiple daily injections (preprandial, regular, and bedtime) of intermediate-acting insulin resulted in a decrease in HbA1c values from 9.4% to 7.1% in patients with type 2 diabetes. Two-step progression of retinopathy decreased by 69%, nephropathy progression decreased by 70%, and nerve conduction velocities improved. Furthermore, although neuropathy was not one of the primary end points of the United Kingdom Prospective Diabetes Study (UKPDS), the study showed that intensive glucose control led to a 40% relative response rate in association with sensory nerve function deterioration as measured by a biothesiometer.9
In this article, I describe the pathophysiology of neuropathy and provide information on diagnostic screening for neuropathy, as well as on diagnosis and treatment of a range of mononeuropathies seen in the diabetic patient.
PATHOPHYSIOLOGY OF NEUROPATHY
Diabetic neuropathy is directly related to the length of time that nerve fibers are exposed to hyperglycemia. The mechanism by which hyperglycemia mediates vascular and neuronal cell dysfunction is not completely understood. A number of biochemical mechanisms may be involved, including nonenzymatic glycosylation, increases in oxidative stress, activation of the polyol pathway, and activation of the protein kinase C (PKC) pathway.
Nonenzymatic glycosylation and oxidation of proteins and lipids are natural phenomena of aging that occur at a very slow rate. As glucose becomes incorporated into proteins, advanced glycated end products (AGEs) are formed in an irreversible chemical reaction. During this process, reactive oxygen species, such as superoxide and hydrogen peroxide, also are produced. In patients with diabetes, hyperglycemia results from the production of higher levels of AGEs and reactive oxidants. The formation of AGEs in connective tissue and matrix components causes alterations in collagen structure, basement membrane thickening, and arterial stiffness. AGEs also can bind to AGE receptor sites on endothelial cell surfaces. This can lead to increased inflammatory responses, vascular permeability, and procoagulant activity.10
An increase in oxidative stress also may result in neuropathy. Hyperglycemia can increase intracellular sorbitol and fructose levels within neuronal tissue, which may lead to the production of harmful free radicals and an alteration of neuronal function.11
Research into treatment strategies for diabetic neuropathy is focusing on PKC--a family of enzymes that play an important role in intracellular signal transduction for hormones and cytokines. Hyperglycemia activates PKC production, which initiates a complex intracellular signaling cascade that affects gene expression and enzymes in many organs and tissues throughout the body. PKC inhibitor drugs, once developed, may suppress the activation of these enzymes and reduce diabetes-related complications.12,13
DEFINITION AND CLASSIFICATION
The common neuropathies associated with both type 1 and type 2 diabetes mellitus can be divided into 2 broad categories: peripheral, which can be subdivided into focal and generalized, and autonomic (Table 1). Generalized neuropathies represent an insidious and progressive process. Peripheral sensory neuropathy can initiate the pathophysiologic pathways that lead to distal extremity ulceration and amputation (Table 2). Autonomic impairments can lead to erectile dysfunction, gastropathy, and cardiovascular complications.
SCREENING AND DIAGNOSIS
Although complex electrophysiologic and autonomic function tests are required to confirm the diagnosis of diabetic neuropathies, routine clinical examination in the primary care office often can be used for screening.
Because there are no detectable findings in most diabetic patients with mild sensory neuropathy, screening for neuropathy is an important component of routine diabetes care. All patients with newly diagnosed diabetes should be evaluated annually for peripheral neuropathy. Screening at an early stage may forestall progression to more severe, disabling, or irreversible disease.
Inspection of the feet This is mandatory for all diabetic patients at their initial visit and annually thereafter. Dry skin, distended veins, callosity, and multiple deformities (such as clawfoot and prominent metatarsal heads) may suggest Charcot neuroarthropathy. Impaired peripheral sensation and increased pressure on the plantar surface may lead to ulceration. Foot ulceration and amputation are the most common consequences of diabetic neuropathy and are major causes of morbidity and disability (Figure).
Monofilament test This is the most commonly used method for assessing risk of foot ulcers. Most screening is performed with the 10-g monofilament. The device is placed perpendicular to a foot surface until it bends, and the patient is asked whether he or she perceives the sensation. Protocols differ as to the number of sites on the foot that are tested and the criteria for a positive test for ulcer risk.
Quantitative sensory testing Risk of ulceration also can be determined by using the Neuropathy Disability Score (Table 3)14 to quantify the results of sensory testing. One sensory test is performed by touching a 128-Hz tuning fork to the hallux and asking the patient whether he can feel the vibration. Loss of ability to perceive vibration indicates that the patient has significant sensory neuropathy. The same tuning fork can be used to assess sensitivity to hot or cold, which is altered in diabetic neuropathy. In addition, check for loss of ankle reflexes--a sign of advanced peripheral neuropathy.
Self-inspection Educate patients who have clinical evidence of neuropathic disease about how to prevent the development of foot ulcers. Discuss self-inspection of the feet and the use of properly fitting footwear.
Cardiovascular evaluation Simple tests for evaluation of cardiovascular autonomic neuropathy have also been developed. Table 4 lists the measures and the normal values; the abnormal values are signs of autonomic neuropathy.15
Small unmyelinated C fibers, when damaged by neuropathic disease, produce typical symptoms and clinical findings on general examination. The loss of large myelinated neurons results in loss of ankle jerks, difficulty with proprioception and balance, and abnormalities in nerve conduction studies. When examining patients with peripheral neuropathy, the extent of the disease can be ascertained from the patient's neurologic history and physical examination, as depicted in Table 5.
MANAGEMENT OF PERIPHERAL GENERALIZED AND AUTONOMIC NEUROPATHY
Improved metabolic control This is the primary goal of management. The DCCT research group reported a 64% reduction in electrophysiologic evidence of neuropathy in patients treated with intensive insulin therapy (3 or 4 injections per day or use of an insulin pump) compared with patients treated with conventional therapy (2 injections daily).2 In the UKPDS, patients with type 2 diabetes who received intensive treatment showed improvement in vibration perception compared with patients managed with diet and exercise alone.16 Care must be taken to manage not only glycemia but also lipid levels, blood pressure, weight, and lifestyle factors (smoking and alcohol cessation), while encouraging the use of aspirin.
Magnesium supplementation Observational studies suggest that intracellular magnesium deficiency in patients with diabetes may account for abnormal nerve conduction studies.17 Oral magnesium oxide supplements have been shown to improve nerve conduction velocities in patients who have type 1 diabetes mellitus of short duration. In my practice, supplemental oral magnesium oxide (250 to 750 mg, taken on an empty stomach at bedtime) has been effective in eliminating paresthesias and reducing pain in patients with diabetic neuropathy.
Treatment of painful diabetic neuropathy Because peripheral sympathetic nerve fibers use substance P as their neurotransmitter pain inducer, drugs that can reduce substance P can reduce neuropathic pain. Over-the-counter capsaicin ointment can be applied to a neuropathic painful limb. The ointment must be applied with a gloved hand and rubbed in for 5 minutes twice daily for 2 weeks. Contact with the face and eyes should be avoided. Patients who complain of burning pain usually respond well to a combination of oral magnesium and topical capsaicin.
For pain described as gnawing or deep-seated ("toothache-like"), oral tramadol (Ultram, Ortho-McNeil) may be required. This nonopioid, centrally acting analgesic is used to treat moderate to severe pain. A tricyclic antidepressant also may be effective.
Carbamazepine can be used for "lancinating" pain; however, higher doses may be difficult for some patients to tolerate. The neuromodulator gabapentin (Neurontin, Pfizer) has shown promise in treating painful neuropathies.18
Other anticonvulsants, such as topiramate (Topamax, Ortho-McNeil), may be useful in treating diabetic neuropathy.19,20 Although topiramate can cause an increase in numbness as well as some cognitive dysfunction, studies of topiramate in patients with type 2 diabetes have demonstrated positive secondary metabolic effects, such as weight reduction,21 lower HbA1c levels,22 and improved blood pressure control.23
Within the past year, 2 drugs have been approved by the FDA for the treatment of diabetic peripheral neuropathic pain (DPNP): pregabalin (Lyrica, Pfizer) and duloxetine (Cymbalta, Eli Lilly).
Pregabalin is an analog of the neurotransmitter gamma-aminobutyric acid. It has analgesic, anticonvulsant, and anxiolytic activity. As pregabalin binds to volted calcium channels at nerve terminals,20 pain-promoting neurotransmitters (glutamate, noradrenaline, and substance P) are inhibited from propagating peripheral pain.21
Approved on December 31, 2004, pregabalin will be available for treatment of DPNP in the fall of 2005. Recommendations are that the dosage be titrated, beginning at 50 mg/d tid and increased to a maximum dosage of 100 mg/d tid according to need and tolerability. The dosage should be tapered upon discontinuation as well.
Duloxetine is a selective serotonin and norepinepherine reuptake inhibitor that was approved by the FDA in 2004 for treatment of both major depressive disorder and DPNP. Although its exact mechanism of action is uncertain, the drug appears to increase the levels of norepinephrine and serotonin in the central inhibitory pain pathway of the CNS, thereby blocking the sensation of pain. However, no agent that reverses hyperglycemia-associated neurotoxicity has yet been found. Nevertheless, the pain relief provided by duloxetine may bring about rapid improvement in sleep, quality of life, ambulation, balance, anxiety, and depression.
Clinicians should, however, be aware of duloxetine's black-box warning. Patients who are new to antidepressant therapy, or whose dosage has been changed, should be closely observed for signs of clinical worsening or suicidality.
Management of autonomic neuropathy This involves treatment of the associated symptoms. Erectile dysfunction can be successfully managed with a variety of oral medications (phosphodiesterase-5 inhibitors), transurethral alprostadil pellets, and intracavernosal injections.24 Encourage women with vaginal dryness to use vaginal lubricants before sexual intercourse.
Avoid medications (antihypertensives, antidepressants, cardiac drugs, a-blockers) that may cause syncope in patients who have autonomic dysfunction. Restrict excessive outdoor exercise regimens, and instruct patients in whom anhidrosis is evident to replace fluids to avoid dehydration.
Advise patients with hypoglycemic unawareness to check their blood glucose levels more frequently, especially before driving, to detect low blood sugar levels. Frequently discuss with patients the proper treatment of hypoglycemia. Use of continuous subcutaneous insulin infusion therapy (insulin pumping) may help reestablish hypoglycemic awareness in patients with autonomic dysfunction.25
Cardiac autonomic neuropathy Prevention of cardiac autonomic neuropathy is often difficult because few effective therapies are available once neuropathic changes develop. However, the overall risk of cardiac autonomic neuropathy can be reduced by 70% with physiologic management of hyperglycemia, hyperlipidemia, and hypertension, as well as with the use of angiotensin-converting enzyme (ACE) inhibitors.4 Effective glycemic control may reverse cardiac autonomic neuropathy in the early stages of development.
The symptoms of postural hypotension may be reduced by increasing water consumption and by using gradient compression stockings.26 Fludrocortisone can increase blood pressure in patients with orthostatic hypotension; however, it may also potentiate congestive heart failure, edema, and hypertension. Antihypertensive drugs may produce a paradoxical increase in blood pressure by activating or antagonizing a- or b-adrenergic receptors that are expressed as a result of autonomic denervation or dysfunction.27
Use clonidine with extreme caution in patients with cardiac autonomic neuropathy. Imbalances in sympathetic and parasympathetic activities may be corrected with ACE inhibitors and b-blockers.10 Dihydroergotamine, midodrine, caffeine, and octreotide are the drugs of choice for refractory cardiac autonomic neuropathy.28
GI autonomic neuropathy Improvement in overall glycemic control is the primary goal in treating diabetic GI autonomic neuropathy. Hyperglycemia retards gastric emptying and reduces GI motility.29 Management of insulin therapy can be challenging in patients with delayed gastric emptying, because matching the timing of the injection with the anticipated rise in postprandial glucose absorption is difficult, if not impossible. Advise patients with delayed gastric emptying who use an insulin pump to take an "extended wave bolus" at mealtime. Extended administration allows insulin to be absorbed over 2 to 3 hours rather than as a large dose with a meal. This reduces the incidence of postprandial hypoglycemia in patients with GI autonomic neuropathy.25
Metoclopramide is effective in treating severe diabetic gastropathy; however, long-term use of this agent increases the risk of CNS adverse effects.30 Pharmacologic management of diabetic gastroesophageal reflux, constipation, and diarrhea has not been successful. Moreover, treatment of GI autonomic dysfunction and acceleration of gastric emptying may not reduce or resolve symptoms. The best approach is to target physiologic insulin replacement therapy and improve overall glycemic control.
Focal and multifocal neuropathies are confined to the distribution of a single peripheral nerve (mononeuropathy) or multiple peripheral nerves (mononeuropathy multiplex). Mononeuropathies are caused by vasculitis and subsequent ischemia or nerve infarcts.27 Commonly, a cranial nerve (III, IV, VI, or VII) or a peroneal, sural, sciatic, femoral, ulnar, or median nerve is involved. A typical mononeuropathy begins acutely, is associated with pain, and resolves spontaneously within 6 weeks.
Nerve entrapment syndromes Such disorders affect up to 30% of patients with diabetes and should be evaluated carefully in persons with signs and symptoms of neuropathy.31 They begin gradually and may become disabling over time without intervention. Commonly, the median, ulnar, or peroneal nerve, or the lateral cutaneous tibial nerve within the tarsal tunnel, is involved.
Carpal tunnel syndrome This syndrome, also known as median neuropathy, is a clinically relevant problem in 6% of patients with diabetes.32 Painful paresthesias of the fingers may progress to a deep-seated ache that radiates up the forearm. Symptoms are worse at night. Motor weakness can be progressive, and thenar wasting occurs over time.
Two clinical tests with a high false-positive rate are commonly used to detect carpal tunnel syndrome. The Phalen maneuver--forearms held vertically and hands held in complete flexion for 1 minute--is positive if paresthesia develops in the median nerve distribution within 30 seconds. The Tinel sign--percussion over the median nerve that induces paresthesia over the distribution of the nerve--is suggestive of carpal tunnel syndrome. However, nerve conduction studies are required to confirm the diagnosis.
Treatment options include wrist splints for nocturnal symptoms. Cortisone injections into the carpal tunnel may provide relief of symptoms; however, these injections often need to be repeated. Surgical intervention is required for pain relief and to prevent the acceleration of muscle wasting.
Ulnar neuropathy This condition occurs in only 2% of diabetic patients and results from nerve compression immediately distal to the ulnar groove beneath the edge of the flexor carpi ulnaris aponeurosis in the cubital tunnel.32 Alcoholism is a risk factor. Typical symptoms include painful paresthesias in the fourth and fifth digits associated with hypothenar and interosseous muscle wasting. Treatment should be conservative; however, patients with motor loss and muscle wasting may require surgical intervention.
Tarsal tunnel syndrome This is a painful lower limb entrapment that involves the tibial nerve. Patients may experience severe burning pain in the plantar aspect of the foot when standing or walking. A Tinel sign on the underside of the medial malleolus, with atrophy of the muscles of the sole, is typical. Treatment options include nighttime splinting in a neutral position and targeted injections of local anesthetics and corticosteroids into the tarsal tunnel.31
Cranial neuropathy This is rare in diabetic patients and typically affects older persons who have a long history of diabetes.33 Cranial nerve III, IV, or VI may be involved. The classic presentation is acute-onset diplopia with ptosis and papillary sparing associated with ipsilateral headache. Neurologic deficits resolve within an average of 2.5 months. Recurrence is rare but has been noted in 25% of diabetic patients.33 Advise patients with a cranial neuropathy to wear a patch over the affected eye and to adhere to strategies that improve glycemic control.
Diabetic amyotrophy This condition typically occurs in patients aged 50 to 60 years who have type 2 diabetes mellitus. Presenting symptoms include severe pain and unilateral or bilateral muscle weakness associated with atrophy of the proximal thigh muscles.34 The cause is unknown; however, it may be related to infarcts in the lumbosacral plexus.35 It results in significant pain and difficulty in climbing stairs or getting out of cars, but it can be managed with drugs such as tramadol and gabapentin. Improvement in overall glycemic control is imperative in these patients.
Diabetic truncal radiculoneuropathy The primary feature is pain of acute onset that resolves spontaneously within 4 to 6 months. The pain--worse at night--is an aching or burning sensation with superimposed lancinating stabs. Patients describe pain as being in a girdlelike distribution across the lower thoracic or abdominal wall. The pain may be unilateral or bilateral. Patients, who typically are middle-aged or elderly men, may experience profound weight loss associated with the onset of their symptoms. Clinical findings range from no abnormalities to sensory loss and hyperesthesia in a complete dermatomal pattern.
Diabetic truncal radiculoneuropathy shares many features with diabetic amyotrophy, except the latter is more painful and occurs in patients whose glycemic control is worse.36 Therapy is directed at improving glycemic control and pain management. *
Editor's Note: An earlier version of this
article was published in the October 2004 issue of Consultant. It has been updated and revised for Applied Neurology.
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