Diabetic neuropathy afflicts up to 70% of patients with type 2 diabetes. Diabetic neuropathy does not represent one distinct disease but rather an adverse group of conditions that effect the peripheral nervous system, attacking the peripheral, proximal, and autonomic nerves, and causing both focal and systemic disease. Patients with diabetic neuropathy may have pain or impaired sensation in the feet and hands, slow digestion, carpal tunnel syndrome, or impaired cardiovascular responses (17).
Severe nerve damage is a major contributor to lower extremity amputation. Impaired alteration and sensation can lead the patient with diabetes to develop asymptomatic severe foot ulcerations, which could lead to subsequent severe infection and loss of limbs. Additionally, neuropathic arthropathy can become a major problem in diabetics with impaired sensation. Stansberry et al. (18) classifies diabetic neuropathy into the following categories:
1. Large-fiber neuropathy characterized by impairments to vibration and touch, loss of tendon reflexes, and occasionally, motor deficit loss involving the hands and both legs up to the mid-thigh.
2. Small-fiber neuropathy characterized by slight sensory loss, mostly thermal and allodynia. This can be just as painful as large-fiber neuropathy but is usually not associated with motor deficits and patients have normal to slightly decreased tendon reflexes. Small-fiber neuropathy involves the lower extremities from the mid-calf to the feet.
3. Proximal motor neuropathy, involving the shoulders and popliteal to mid-thigh areas bilaterally. Proximal motor neuropathy involves minimal sensory loss, can be significantly painful, and can have loss of deep tendon reflexes and significant proximal motor deficit.
4. Mononeuritis multiplex can involve the third or the sixth cranial nerves and is usually associated with truncal neuropathy with mild sensory loss, significant pain, normal deep tendon reflexes, and motor deficits of varying degrees.
5. Entrapment syndromes can involve either the ulnar or median nerves in the upper extremities and the lateral popliteal nerves in the lower extremities. Entrapment syndromes can be painful and are characterized by significant sensory loss in the nerves involved. Deep tendon reflexes are usually normal and motor deficits can be present to a varying degree.
6. Diabetic autoneuropathy includes cardiovascular abnormalities with fluctuating heart rates, orthostatic hypotension, gastrointestinal disturbances (including diabetic diarrhea and gastroparesis and genitourinary problems including bladder dysfunction), and sexual disturbances (19).
The specific pathogenic disturbances underlying the etiology of neuropathy has not been completely elucidated, although a recognized link exists between persistent hyper-glycemia or neurological dysfunction. As with retinopathy, the incidence of diabetic peripheral neuropathy correlates with the duration of diabetes and glycemic control. Some theories on the causes of neuropathy concern the accumulation of sorbitol in hyperglycemic states or the increased oxidation of sorbitol to fructose. Whether the culprit is fructose, sorbitol, or a combination of both, the end result is nerve damage and an imbalance of nicotinamide adenosine diphosphate (NADP) and its reduced form, NADPH.
Depletion of the cell's NADPH occurs during the conversion of glucose into sorbitol and the subsequent conversion of sorbitol into fructose. Decreased NADPH disrupts the intracellular oxidation-reduction potential, causing the accumulation of various oxidative free radicals that can cause nerve damage (20).
The hyperglycemic state results in the glycation of proteins, often leading to the formation of advanced glycosylation end products, which impair blood flow to the nerves and cause ischemia by enhancing the production of free radicals.
According to the San Antonio Convention (21), there are three main groups of neurological disturbance in diabetics. These include:
1. Subclinical neuropathy characterized by abnormalities in somatosensory testing and electrodiagnostic evaluations.
2. Focal neuropathic syndromes.
3. Distal symmetric sensory motor and autonomic syndromes with diffuse clinical neuropathy (22).
The diagnosis of subclinical neuropathy is based on the following:
1. Decreased amplitudes and conduction velocities in selective electrodiagnostic testing.
2. Abnormal quantitative sensory tests for thermal, sensory, and vibration thresholds.
3. Abnormalities in quantitative autonomic function testing, demonstrating decreased heart-rate variation in postural testing with Valsalva maneuver and deep breathing (23).
Focal mononeuropathies occur primarily in the elderly patient population and usually tend to be self-limited, resolving in 6-8 weeks. Focal mononeuropathies occur as the result of vascular occlusions causing infarction of the affected neurons. Focal mononeuropathies can be distinguished from other entrapment syndromes that tend to evolve more slowly and persist without intervention. The classic example of this is the third or sixth nerve palsies that can occur in patients with diabetes without warning. Nerve entrapment sites in patients with diabetes can involve radial, ulnar, or median nerves; the lateral-femoral cutaneous nerve of the thigh; peroneal, medial, and lateral plantar nerves; and the femoral nerve.
Patients with diabetes are twice as likely to develop carpal tunnel syndrome as a result of edema or accumulation of fluid within the carpal tunnel area. Diffuse clinical neuropathies can exist distally or proximally. Distal neuropathy usually presents after acute stressful phenomenon, but can also be insidious in onset. Distal neuropathy can involve either motor or sensory nerves, and small and/or large fibers.
Small nerve fiber dysfunction usually manifests with symptoms of pain and hypersensitivities in the lower extremities, followed by reduced light touch and pinprick, and loss of thermal sensitivities (24).
Patient symptoms can be varied, and include burning dysesthesias and occasional interruption of all stimuli (allodynia), decreased sweating, impaired vasodilation, dry skin, cold extremities, and defective thermal sensation. Patients have normal reflexes and motor strength and significantly reduced sensitivity to the 1 g monofilament and vibratory sensation with the 128-Hz tuning fork.
Acute painful neuropathy usually lasts less than 6 months, and is characterized by pain and paresthesia early in the course of the disease. These spontaneous episodes of pain can occasionally be severely disabling, with the pain varying in character and intensity. Patients may characterize these sensations as stabbing, lancinating, sharp, burning with concomitant altered sensations of pins and needles, coldness, numbness, and tingling (25).
The pain of acute painful neuropathy can be so annoying that even basic daily activities can be disrupted, and the extremities can be exquisitely sensitive to touch. Chronic painful polyneuropathy is far more common.
Chronic painful polyneuropathy usually occurs many years later in the course of the disease, lasts for more than 6 months, can be significantly disabling, and is associated with analgesia and narcotic tolerance. Although the exact mechanism for the severe pain in small-fiber neuropathy is not well-understood, damage, injury, and subsequent disrup tion of neurofiber registration of pain occurs in the cerebral cortex, rendering the painful stimulus more chronic. On occasion, disappearance of the pain may come with nerve death but is more likely to remain persistent and severely annoying.
Large-fiber neuropathy is usually associated with Charcot's neuroarthropathy. This can involve either the motor or sensory nerves or both. These large fibers are responsible for cold, thermal perception, position sense, vibratory sensation, and motor function. The larger fibers are myelinated, synapse in the medulla oblongata, and have rapid conduction beginning in the lower extremities. Subclinical abnormalities can be detected on electromyography and are characteristic of "dying back" neuropathy. These abnormalities can sometimes be seen with toxic chemical exposures to poly-chlorinated biphenyls or to tetrachlorodibenzoparadioxin.
Patients usually have minimal symptoms, characterized by a sensation of walking on cotton or an inability to discriminate among coins. These patients classically may have depressed tendon reflexes, impaired vibratory perception and position sense, sensory ataxia, shortening of the Achilles tendon with pes equinus, and wasting of the small muscles of the feet with weakness in the muscles of the extremities (26) (see Table 1).
Large-fiber neuropathy can progress to the point where the patients have a great deal of difficulty standing on their toes or their heels, with "stocking-glove" distribution of sensory loss a consistent finding.
Nerve conduction studies, somatosensory evoked potentials, and electromyography remain the mainstay of establishing the diagnosis of peripheral neuropathy, and help to distinguish the diabetic from the neoplastic, inflammatory, traumatic, vascular, toxic, autoimmune, and some of the other metabolic and endocrine abnormalities that can cause peripheral neuropathy, including acute intermittent porphyearsia, hypo-thyearsoidism, B12 deficiencies, and uremia.
Physical examination can give important diagnostic clues but proper equipment needs to be used. A tuning fork with a vibrating frequency of 128 Hz is preferable for diagnosing the duration of vibratory sensation. A 1 g monofilament increases sensitivity to 90% in detecting neuropathy.
To evaluate a patient for entrapment neuropathies, Tinel's sign can not only be used for carpal tunnel syndrome but can also be used for median, plantar, ulnar, peroneal, fibular, and ulnar notch neuropathies. On occasion, in particularly difficult cases, nerve biopsy may be helpful in excluding other causes of neuropathy, and special arginine staining can be used to diagnose dying-back neuropathy (9).
Diabetic autonomic neuropathy may present with varying signs and symptoms including (27):
1. Pupillary disturbances of the Argyll-Robertson type.
2. Metabolic disturbances, including hyperglycemic-unresponsiveness and unawareness.
3. Cardiovascular disturbances characterized by orthostatic hypotension, heat intolerance, cardiac autonomic disturbances and denervation, and inappropriate tachycardia with exercise.
4. Neurovascular abnormalities, including hyperhydrosis, alterations in the skin blood flow, gustatorial sweating in areas of symmetrical distribution, and hyperhydrosis.
Foot-Related Risk Conditions With an Increased Risk for Amputation
• Bone deformities
• Peripheral neuropathy
• Altered biomechanics
• Peripheral vascular disease
• Previous history of amputation or ulcerations
• Severe nail pathology
• Increased persistent pressure conditions with erythema and hemorrhagic callus formation
Cardiac autonomic neuropathy occurs in approximately 22% of patients with type 2 diabetes and can progress from an initial manifestation of increased heart rate as a result of vagal denervation to fixed heart rates. In diabetic patients with heart-rate variability, the 5-year mortality rate is five times greater than in patients with normal variability, and there is an increased risk for sudden death and silent myocardial infarctions.
Cardiovascular autonomic neuropathy can manifest with the following (29):
1. Resting tachycardia.
2. Beat-to-beat variations.
3. Accelerated heart-rate response to standing.
4. Postural hypotension with systolic blood pressure drops greater than 15 mmHg.
5. Increased diastolic blood pressure, greater than 16 mmHg, in response to hand grip for 5 minutes.
6. Prolongation of the Q-T interval to greater than 444 ms.
7. Nocturnal hypertension with early morning decreases in blood pressure.
Because of these disturbances, patients with cardiac autonomic neuropathy may be more prone to developing a myocardial infarction in the evening as compared with the morning, as we see in individuals with normal autonomic function.
Impaired blood flow to the extremities can cause worsening neuropathy and impaired exercise tolerance. Excessive facial and trunk sweating can be manifested to compensate for impaired lower-body sweating. Particularly common is facial sweating immediately after eating (gustatory sweating). Gastrointestinal symptoms in diabetic patients may be close to 80%, as a result of impairments of both sympathetic and parasympathetic innervations (30).
Patients may experience delayed gastric secretion and emptying, and present with episodes of nausea and vomiting. Other symptoms can include anorexia, bloating, epigastric discomfort, and alternating episodes of constipation and diarrhea (with diarrhea being more prominent in patients with autonomic neuropathy). Diarrhea can result from pancreatic insufficiency, bacterial overgrowth, malabsorption, or intestinal hyper-motility.
Diabetic diarrhea tends to present nocturnally, which can distinguish it from other causes of malabsorption, including inflammatory bowel disease, tropical and nontropical sprue, and infectious states.
Neurogenic abnormalities in the detrusor muscles or damaged afferent fibers impairing bladder sensation can cause impaired sensory and motor function in the urinary bladder. Dribbling, overflow incontinence, and urinary retention may occur.
Often, erectile dysfunction may be the first manifestation of a developing autonomic neuropathy, followed by episodes of diminished ejaculation, loss of ejaculatory effort, or retrograde ejaculation. Poor glycemic control has shown to be the chief risk factor for autonomic neuropathy, although, in the Pittsburgh Epidemiology Study, increased low-density lipoproteins and hypertension were also contributing factors. Other data has implied associations between neuropathies and systolic and diastolic blood pressure or lipid disturbances (31).
Clearly, exposures to other neurotoxins, including pesticides, herbicides, cigarette smoking, alcohol, and adverse medication side effects, and genetic predispositions can also increase the risk of neuropathy.
The cornerstone of treatment of neuropathy begins with tight glycemic control. Studies have indicated that the highest prevalence of diabetic peripheral neuropathy occurs in patients with poorest diabetic control. The DCCT trial also confirmed significant benefits with intensive insulin therapy in preventing and inhibiting progression of neuropathy. In the UKPDS trial, tight glycemic control was associated with an improvement in vibratory sensation.
Various clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors can improve some of the symptoms of peripheral neuropathy, increasing parasym-pathetic activity and improving heart-rate variability. Trandolapril therapy showed improvement in neuroamplitude, latency, and conduction velocities; and lisinopril usage showed improvement in electrophysiological and quantitative sensory tests after 12 weeks of therapy (32).
Other agents that have had mixed success include y-linolenic acid, a-lipoic acid and other combinations using these two chemical compounds. Daily infusion therapy of 600 or 1200 mg of a-lipoic acid showed significant symptom improvement compared with placebo in type 2 diabetic patients, with one 2-year trial in patients with diabetic poly-neuropathy showing statistically significant improvement in nerve conduction velocity.
Studies with immunosuppressant agents, such as azothiaprim, intravenous y-globu-lin, and plasmapheresis, have had mixed success. Although phase II trials showed some promise with recombinant nerve growth factor therapy, this was not fulfilled or demonstrated in phase III studies. Not only has this diminished the interest in neurotrophic factors, but these substances can also cause pressure discomforts at the injection sites with hyperalgesia (27).
Diabetic neuropathic pain can be severely debilitating and is generally resistant to acetaminophen, selective cyclo-oxygenase (COX)-2 inhibitors, and other nonsteroidal anti-inflammatory drugs. Treatment of diabetic neuropathic pain has centered on the use of tricyclic antidepressants, antiepileptic drugs, selective serotonin reuptake inhibitors, sodium-channel blockers, capsaicin, dextromethorphan, antiarrhythmics, and opioids.
Tricyclic antidepressants, including desipramine, nortriptyline, and amitriptyline have been considered first-line drugs in the treatment of neuropathic pain for many years. These agents work well in neuropathic pain by increasing serotonin, blocking sodium channels, and increasing postsynaptic concentrations of norepinephrine.
Of this group, amitriptyline is still the gold standard for pain relief and has demonstrated proven efficacy for a number of painful conditions. Unfortunately, as much as 50% of patients will not get significant relief from the severe pain experienced with neuropathic pain.
Amitriptyline may cause some unwanted side effects, including seizures, hypotension, increased sedation, hyperthermia, and other effects, including constipation and pseudodementia. This can be especially problematic in the elderly patient population, which may be prone to develop cardiac and other side effects.
Both first-generation agents (including carbamazepine, valproic acid, phenytoin, and clonazepam) and second-generation drugs (including gabapentin, topiramate, lamotri-gine, and oxcarbazepine) have had variable effectiveness in treating neuropathic pain.
Carbamazepine has been the drug of choice for treating trigeminal neuralgia for many years. Unfortunately, the multiple side effects of this drug, including hepatic enzyme induction, hyponatremia, thrombocytopenia, and multiple drug interactions have limited its use. Gabapentin has shown some significant promise in relieving neuropathic pain in total doses of 1800-3600 mg/day, taken at three equal intervals. Dose-related dizziness and somnolence can occur at the initiation of this type of treatment (33).
Topiramate has shown some inconsistent results, although some tests have been promising. One placebo-controlled, double-blind study of 323 patients with diabetic peripheral neuropathy found that 36% of patients treated with topiramate at doses up to 400 mg/day for 12 weeks had a greater than 50% reduction in symptoms. The dose of topiramate can be variable, although is usually given twice daily.
Lamotrigine has been used with some effectiveness in trigeminal neuralgia and in human immunodeficiency virus neuropathy, but is limited because of its significant effects, including rash and rare occurrence of Steven-Johnson's syndrome.
The selective serotonin reuptake inhibitors have not been particularly effective and have been somewhat disappointing in treating pain, with a lack of consistency of performance in clinical trials. Venlafaxine (Effexor) reduced pain by 75-100% in 11 patients with diabetic peripheral neuropathy.
Sodium-channel blockers, such as the topical agent, lidocaine (Lidoderm), and mexil-etine, have been beneficial. In doses as high as 675 mg, mexiletine demonstrated efficacy in diabetic peripheral neuropathy. The Food and Drug Administration approved the use of a 5% lidocaine patch in 2001 for the treatment of postherpetic neuralgia. The 5% lidocaine patch has had some effectiveness in relieving the symptoms of peripheral neuropathy, particularly when the neuropathy is confined to smaller (rather than diffuse) areas of the extremities (17).
Capsaicin has also been effective in postherpetic neuralgia and has had some benefit in diabetic peripheral neuropathy. However, the burning sensation and subsequent increased sensation of warmth can be very annoying to some patients who are already experiencing a burning sensation from diabetic neuropathy.
Some clinical trials have shown varying benefits with dextromethorphan, but dextro-methorphan is not available in formulations appropriate to deliver up to 600 mg/day, which seems to be the desired dose for achieving a benefit. Additionally, dextromethorphan has recently been a target for abuse and overdosing by adolescents.
Tramadol has been effective when given at doses of 200-400 mg/day for greater than 4 weeks. Tramadol shares properties with opioid analgesics but has a low affinity for the ^-opioid receptor. In controlled studies, the efficacy of tramadol is comparable to the tricyclics and levorphanol. The most common side effect is central nausea, similar to seasickness, which can be somewhat attenuated by being well-hydrated.
Controlled-release oxycodone was shown to be an effective treatment for diabetic peripheral neuropathy, with twice-daily doses of 30 mg needed to achieve the desired effect. Dose-dependence and drug abuse have raised some concern in primary circles about ultimate use of controlled-release oxycodone, particularly on a chronic basis. For patients who require narcotics, fentanyl patches have been shown to have opioid potency and significantly fewer central nervous system effects and constipation than the opioids. The patch also ensures compliance, with the smooth drug delivery causing less fluctuation of analgesic blood levels (23).
Peripheral nerve stimulation has also been of occasional benefit. Peripheral nerve stimulation includes percutaneous electrical nerve stimulation and vibratory stimulation. These methods have been effective only for short-term relief. Other alternative therapies include acupuncture and relaxation techniques.
Diabetic enteropathy can impair gastric acid secretion and motility, resulting in gastroparesis, which is found in approximately 25% of patients with diabetes. Typically, these patients present with early satiety, nausea, vomiting, epigastric pain, bloating, and anorexia. These episodes may last for several months on a cyclical basis, with vomiting of undigested food particles. Other conditions, such as gastric or duodenal ulcer, gastritis, and gastric cancers, should be excluded. Diabetic enteropathy can interfere with nutrient delivery to the small bowel and impair glucose absorption and even absorption of medication. Wide swings of glycemia occur commonly. Although severity of symptoms does not always correlate with scintographic imaging, consumption of radionucle-otide-labeled food can be valuable in making the diagnosis of diabetic enteropathy, demonstrating impaired gastric emptying.
Diabetic gastroenteropathy remains a difficult condition to treat, particularly with the withdrawal of cisapride from the market. Initial treatment should focus on tight glycemic control, with patients advised to eat multiple small meals of 4-6 oz with reduced fat intake (<40 g/day). Fiber intake should be reduced to prevent bezoar formation (30).
Metoclopramide (Reglan) is perhaps the best-studied drug and 10-40 mg is usually given in divided doses before meals and at bedtime. Although metoclopramide is generally well-tolerated, side effects can result in galactorrhea, irregular menses, or erectile dysfunction, and metoclopramide may exacerbate Parkinson's disease or cause symptoms of Parkinsonism in other individuals. Other common side effects include gynecomastia, tardive dyskinesia, and fatigue.
Macrolide antibiotics, including erythromycin, can be somewhat effective in improving gastric emptying. Very low doses of erythromycin (125 mg in divided doses daily) are often sufficient in relieving symptoms. This dose can easily be administered with a liquid suspension. This lower dose tends to minimize the typical side effects from macrolide antibiotics, which include abdominal pain, nausea, and vomiting. Another dopamine antagonist that has a central antiemetic effect (domperidone) is currently not available in the United States. Domperidone has side effects including diarrhea, galactorrhea, and headache. Levosulpiride, at dosages of 25 mg three times daily, can also be tried.
The topical clonidine patch seems to be a particularly useful agent in treatment of gastroparesis and diarrhea, whether as initial therapy or in individuals concomitantly needing clonidine for hypertension control.
Diabetic diarrhea affects 20% of patients with diabetes and is characterized by intermittent patterns of episodes lasting from several hours to several days. Here, nocturnal diarrhea and fecal incontinence are common. The patient may have up to 20-30 bowel movements in a 24-hour period.
Causes of diarrhea include the following (29):
1. Diminished sympathetic inhibition.
2. Hypomotility with bacterial overgrowth.
3. Pancreatic insufficiency.
5. Bile-salt malabsorption.
Three daily doses of 50 mg of octreotide, or four daily doses of 2 mg of loperamide may be helpful for diarrhea.
Diabetic sexual dysfunction and impotence is a common complaint in the male patient population and is usually caused by circulatory and/or nervous system abnormalities. Females may experience a lack of lubrication, painful intercourse, and difficulty achieving organism. Usually, most patients can be treated noninvasively with some success.
The three agents currently available for use in the United States in males are:
2. Tadalafil (Cialis).
Sildenafil can be taken in doses of 25, 50, or 100 mg, 1 hour before sexual activity. Sildenafil works best on an empty stomach, taken at least 4-5 hours after eating a meal. However, food can be ingested 1 hour after taking sildenafil on an essentially empty stomach (34).
Sildenafil results in increases in nitric oxide levels and has been extremely successful in restoring normal sexual dysfunction to many men. Sildenafil should not be used in patients taking nitroglycerin preparations or in individuals with active coronary ischemia. Sildenafil needs to be used with caution in patients who are taking medications that are metabolized through the cytochrome P-450 3-A4 system. Similar caveats exist with the other two sexual dysfunction medications, tadalafil and vardenafil.
Tadalafil (Cialis) has an onset of action similar to sildenafil, with a prolonged duration of action of up to 36 hours compared with the 4-6 hours with sildenafil and vardenafil. The use of these drugs have made other options, such as penile prosthesis, vacuum constriction devices, intracavernosal injection of vasoactive agents, and intraurethral insertions, less attractive.
Sildenafil, tadalafil, and vardenafil are phosphodiesterase type-5 inhibitors, and have several cardiovascular effects including the following:
1. Decreased blood pressure at rest.
2. Increased exercise time and oxygen consumption in congestive heart failure.
3. Decreased peak exercise heart rate in congestive heart failure.
4. Increased coronary flow reserve.
5. Increased coronary blood flow.
6. Improved endothelial function.
7. Decreased pulmonary artery blood pressure and vascular resistance in pulmonary hypertension.
The ease of use of these products makes normal sexual activity and performance a realistic possibility for many diabetic males who have been frustrated with this problem. Hopefully, some assistance will be provided for female patients with diabetes in the future.
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