Chapter 173. Cutaneous Changes in Peripheral Arterial Vascular Disease

Epidemiology

Although atherosclerotic obstructive peripheral arterial disease (PAD) has a prevalence of only 3% in patients of age 40–59 years, this rises to 15% in the age group older than 65 years. This translates into approximately 9 million cases in the United States in 2005, and this number is expected to increase along with the aging demographics of our population.1,2 PAD is often unrecognized clinically and more than one-half of all patients are asymptomatic. Gender predisposition shows preponderance in males, although the incidence in females rises rapidly after menopause. Anatomically, superficial femoral artery disease predominates, with development of symptoms typically in the seventh decade. Interestingly, symptoms from aortoiliac disease usually present a decade earlier.

Etiology and Pathogenesis

Atherosclerotic risk factors are similar to those identified for coronary artery disease and include diabetes mellitus, hypertension, hyperlipidemia, smoking, family history of vascular disease, and obesity. Among these, diabetes mellitus and smoking are the most significant and are associated with a fourfold and doubling of relative risk, respectively. Patients with diabetes mellitus develop the disease at an earlier age than nondiabetics and have more severe and progressive disease. The anatomic distribution of obstruction differs from nondiabetics with less aortoiliac involvement and more extensive disease of the runoff vessels below the knees; however, superficial femoral artery disease is similar in both populations. Approximately 50% of patients have hyperlipidemia. PAD is also more commonly encountered in patients with hypertension.

The pathologic findings in atherosclerosis occur in large- and medium-sized arteries, and are morphologically diverse, with focal accumulation of lipids and lipoproteins, mucopolysaccharides and collagen, smooth muscle cells and macrophages, and calcium deposits in variable quantities. Localized areas of intimal thickening secondary to smooth muscle cell proliferation and lipid-laden macrophages are seen in early stages with disruption of the internal elastic lamina. The media is often atrophic with thin strands of smooth muscle, lipid pools, collagen tissue, and calcium deposits. Enlarging plaques encroach on the lumen despite dilation of the artery, and the plaques may ulcerate. Hemorrhages occur in the arterial wall. Thrombi may form and occlude the narrowed arterial lumen.

The etiology of atherosclerosis is complex and multifactorial, but progressive buildup of plaque narrows the vessel lumen, and complete occlusion may develop acutely secondary to thrombosis. Because disease progression is usually over an extended time period, collateral blood vessels have time to develop and are usually robust. Tissue perfusion to the affected limb is often adequate at rest, but the blood pressure distal to the occlusions is decreased secondary to high resistance and limited flow through collateral vessels. Under resting conditions, normal blood flow to extremity muscle groups averages 300–400 mL/min. Once exercise begins, blood flow increases up to tenfold owing to the increase in cardiac output and compensatory vasodilation at the tissue level. When exercise ceases, the blood flow returns to normal within minutes. In patients with PAD, resting blood flow may be similar to that of a healthy person. However, during exercise, blood flow cannot maximally increase in muscle tissue because of fixed proximal arterial stenoses. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated. Dermatologic changes imply severe compromise of tissue perfusion, often secondary to tandem high-grade stenoses or occlusions present at multiple levels in the arterial tree.

Clinical Findings

(Fig. 173-1)

History

The most classical symptom of PAD is intermittent claudication, which is usually described as pain, fatigue, or tiredness in the muscles distal to the diseased vascular segment on walking. The location of the pain differs depending on the anatomical location of the arterial lesions. Since the disease is most common in the distal superficial femoral artery, patients most commonly present with claudication in the calf muscle area (the muscle group just distal to the arterial disease). When the disease affects the more proximal aortoiliac vessels, thigh and buttock muscle claudication predominates. The discomfort tends to be highly reproducible within the same muscle groups and is precipitated by the same level of exertion. It is crucial to determine the amount of walking distance before the onset of symptoms; this helps to quantify patients with some standard measure of walking distance before and after therapy. Resolution within several minutes of rest is an expected finding. Patients with inadequate collateral circulation may complain of cold extremities, hyperesthesia, rest pain, discolored toes, or skin breakdown. Ischemic rest pain typically affects the foot and may interfere with sleep or necessitate sleeping with the leg in a dependent position. Peripheral edema may then occur.

Acute limb ischemia secondary to vessel thrombosis or embolism presents more dramatically with (1) severe pain, usually persistent at rest, (2) pallor, (3) pulselessness, (4) paresthesias, and (5) paralysis (the five Ps). Poikilothermia (a cold extremity) may be added to this pentad of clinical findings (Box 173-1). The presence of neurologic symptoms indicates severe ischemia and need for emergent evaluation.

Since atherosclerosis is a systemic disease process, patients who present with claudication due to PAD can be expected to have atherosclerosis elsewhere. Hence, it is common for patients to present with symptoms related to disease affecting the other vascular territories.

Cutaneous Findings

The cutaneous findings in PAD will vary depending on the severity of arterial obstruction and tissue ischemia (Table 173-1). Limbs in patients with intermittent claudication may appear normal, although associated clinical findings may include hair loss, coldness, and cyanosis, or thickened and malformed toenails. In patients with severe ischemia, the skin is apt to be atrophic, dry, and shiny. In patients with rest pain, the foot is usually bright red and cold in dependency. Ulcerations most often start at the tips of the toes or on the heel of the foot and are extremely painful except when diabetic neuropathy is also present (Fig. 173-2). Ulcers also occasionally start on the lower calves or lateral aspect of the heel. They frequently demonstrate irregular borders and a pale base. The heels may show cracks in the skin with numerous fissures. When gangrene occurs, usually one or more toes become black, dry, and mummified (Fig. 173-3). Superimposed infection is a major concern, and important associated signs include purulent discharge or decay (wet gangrene) or surrounding tissue erythema and swelling.

Related Physical Findings

The hallmark characteristic is decreased or absent pulses distal to the stenotic arterial segment, and there may be bruits on auscultation over the diseased segment of vessel secondary to turbulent flow. It is also possible to find normal palpable pulses in a patient who presents with a history consistent with typical intermittent claudication. In such a case, the clinician can have the patient walk around the office (or perform toe raises) until the symptoms are reproduced and then palpate for pulses. The exercise may “unmask” a stenosis causing the atherosclerotic lesion to become significant and should diminish the strength of the pulses distal to the lesion. The collateral circulation to limbs affected by PAD can be evaluated by simple bedside exam. With the patient supine, elevation of the limb at a 45° angle for 2 minutes should not produce pallor. Collateral circulation is deemed inadequate if the toes and feet become pale. The patient then assumes a sitting position with the legs dependent and the times for filling of the foot veins and flushing of the feet measured. The veins should fill within 20 seconds and the feet flush immediately in a warm environment. When these times exceed 30 seconds, the collateral circulation is deemed inadequate, and the patient must be observed frequently for the development of rest pain, ulcers, or gangrene. Venous filling times are of limited value when varicose veins coexist.

Special Tests

A simple objective test comparing systolic blood pressure in the arms and ankles is sufficient to document the severity of arterial obstruction. The ankle systolic pressure in the supine position should be equal to or greater than the brachial artery systolic pressure. An ankle-to-arm systolic pressure ratio is calculated (ankle-brachial index, or ABI); values greater than 0.9 are generally considered normal, whereas those less than 0.4 are indicative of severe disease (see Chapter 174 for details of ABI measurements). This information is of prognostic use for determination of wound healing or the need for revascularization. One important caveat to note is that occasional patients with heavily calcified or “noncompressible” vessels, most commonly diabetics, may have falsely elevated ABIs (greater than 1.3) despite the presence of significant PAD. Under this circumstance, alternate tests, including toe pressures (as smaller vessels are rarely affected) or segmental volume plethysmography, are helpful. Duplex ultrasound scanning can be time-consuming, but further helps to define physiology and anatomic extent of disease. Magnetic resonance angiography (MRA) and computed tomographic angiography are competitive technologies used to demonstrate precise anatomic location and extent of disease in the arteries but supply limited hemodynamic information. MRA is often preferred because of lack of ionizing radiation or need for iodine-based contrast dye, but may not be tolerated by claustrophobic individuals. Conventional catheter-based arteriography is usually reserved for definitive evaluation in patients about to undergo vascular surgery or as a necessary component of percutaneous angioplasty or stenting procedures (Fig. 173-4).

Differential Diagnosis

The diagnosis of PAD can usually be made by the typical history of intermittent claudication and palpation for diminished or absent pulses in the limbs. The ABI is usually diminished, although occasional patients may have normal values at rest. When the diagnosis remains in doubt, a helpful provocative maneuver to increase blood flow is to exercise the patient. Postexercise blood flow may be limited by the arterial obstructive disease, and repeat ABI will then be diminished. The differential diagnosis of PAD includes both local factors and systemic disorders (Box 173-2). Arterial obstructive disease is just one of several potential etiologies for the development of a foot ulcer (Box 173-3). In some patients with diabetes mellitus or other disease resulting in neuropathy, ulcers may develop on the heel, toes, or anterior calf in the presence of normal pulses. These painless (neurotrophic) ulcers are due to repetitive trauma not noticed by the patient because of the peripheral neuropathy. Surrounding callus formation is a typical finding.

Thromboangiitis obliterans also causes intermittent claudication, ulcers, and gangrene. It occurs in young smokers (onset of symptoms before the age of 45 years) and is often associated with superficial thrombophlebitis and vasospasm. In contrast to PAD, it affects medium and smaller arteries and the upper extremities more commonly.

Occlusive vascular disease confined to focal anatomic locations in young patients with minimal traditional risk factors for atherosclerosis should raise suspicion for alternative etiologies. For example, popliteal artery occlusion may occur secondary to entrapment by calf muscles or cystic adventitial disease. In the former, an abnormal anatomical insertion of the medial gastrocnemius muscle head causes compression of the popliteal artery, with the tibial pulses disappearing on plantar (or dorsi) flexion of the foot and full extension of the knee. Pain is aggravated with walking but less with running because knee extension is not as severe with running. In the latter condition, adventitial cysts of unclear etiology compress the vessel lumen, most commonly in the popliteal artery (85%) or rarely, in the external iliac or femoral arteries, presenting as intermittent claudication. Surgical excision of the cysts usually alleviates symptoms although, in the event of complete vessel occlusion, an interposition graft may be necessary.

Neurogenic claudication (pseudoclaudication) is often a difficult diagnosis to distinguish and is due to compression or intermittent ischemia of the lower spinal cord or cauda equina with exercise. Etiologic factors are prolapsed intervertebral discs, congenital stenosis, or hypertrophic bony ridging of the spinal canal. In contrast to PAD, leg pain may occur in the erect position without exercise and be affected by changes in posture, neurologic signs may be present before or after exercise, and peripheral pulses are normal. The pain is frequently relieved by leaning forward against a solid surface or by sitting. Dilemmas in diagnosis and management can occur when both conditions coexist. MRI or computed tomography scan of the spine is used to confirm the diagnosis.

Complications

The major direct complications of PAD relate to limb loss from progressive severe ischemia or superimposed infection. In patients with rest pain or tissue loss, the risk of infection is high and wound healing slow or absent. Under these circumstances, the need for revascularization is more urgent to avoid the need for amputation. Superimposed infection needs to be aggressively treated with antibiotics, wound débridement, and local foot care and, if rapidly progressive, presents a medical emergency.

Prognosis and Clinical Course

The most feared consequence of PAD is a severe limb-threatening ischemia leading to amputation. Fortunately, the peripheral vascular outcomes in patients with intermittent claudication as a consequence of PAD tend to be relatively benign, with studies showing that 60%–90% of such patients remained stable over a period of 5–9 years.3 In a large prospective study of 1,440 patients with intermittent claudication, only 12.2% patients were reported to require amputation during a follow-up period of 10 years. Occasional patients show spontaneous improvement in symptoms, most likely secondary to enhanced collateral blood flow, although plaque regression is possible. However, patients with diabetes mellitus tend to have progressive disease, and their amputation rate is fourfold greater than for patients without diabetes. In patients with diabetic neuropathy, trauma to the limbs must be avoided, and special shoes may be required. Ongoing smokers also have greater amputation and vascular graft occlusion rates than nonsmokers.

In contrast with the limb-related outcomes, because patients with PAD often have advanced atherosclerosis present in multiple vascular beds, the risk of associated cardiovascular morbidity and mortality is high.1,2 The 5-year mortality in patients with intermittent claudication is 30%, with death largely attributed to cardiovascular causes. In addition, another 20% of patients will incur a nonfatal myocardial infarction or stroke. The association between PAD and cardiovascular morbidity and mortality has been shown to be independent of prior history of cardiovascular disease and independent of known cardiovascular risk factors. Studies have also shown that more severe PAD, as indicated by a lower ABI value, is associated with greater risk of cardiovascular mortality than mild PAD, as evidenced by a higher ABI value. It should be emphasized that PAD of any severity (as documented by an abnormal ABI) may be used to identify the individuals with an increased risk of cardiovascular events and mortality.4

Treatment

The goal of medical management should include measures to halt the progression of the disease in addition to alleviating the symptoms. The measures to halt the progression of disease include cessation of smoking and optimization of risk factors, such as diabetes mellitus, hypertension, and hyperlipidemia. For patients with symptoms of intermittent claudication, an exercise program is often the treatment of choice (Box 173-4).2 Patients are instructed to exercise to the threshold of tolerable pain, briefly rest, and then exercise again for a total duration of 30–60 minutes a day in excess of their normal activity. The exercise period must be performed in one session, with walking being the preferred modality. Drawing on data from several studies, approximately 80% of patients may be expected to show significant improvements in exercise tolerance through these techniques. While the exact mechanism for improvement in walking distance with exercise remains unknown, regular exercise is thought to condition the muscles to work more efficiently (more extraction of blood) and increase collateral vessel formation. The magnitude of benefit associated with exercise programs for claudication appears to be greater than that reported for clinical trials of pharmacologic therapy. Patients should be further instructed to keep their feet warm, clean, and dry; and extremes of temperature should be avoided because ischemic tissue is more susceptible to burning and to frostbite than normal tissue. Cuts or severe bruises of the limbs or feet should be treated immediately. Conventional vasodilators appear to have no value in treatment.

Two agents have been approved for the indication of intermittent claudication in the United States. Cilostazol, a phosphodiesterase inhibitor with antiplatelet and vasodilatory properties, has been shown in several studies to have consistent benefits on treadmill walking distance and quality of life.5 However, its benefits are balanced by high frequency of side effects, principally gastrointestinal symptoms or headaches. Furthermore, it is contraindicated in patients with congestive heart failure. Pentoxifylline affects red cell deformability and blood viscosity but has been shown to be relatively ineffective in the treatment of claudication2. Other agents, such as propionyl-l-carnitine an agent with metabolic effects, are under study in the United States for this indication.

Endovascular intervention with angioplasty or stenting is highly effective for aortoiliac disease and is often indicated for moderate, or lifestyle-limiting claudication. Angioplasty or stenting of the superficial femoral artery is technically feasible but limited in applicability by high restenosis rates, particularly in the setting of long occlusions, a common scenario in this location. Despite this limitation, it is a valid therapeutic option for patients with focal disease, severe claudication, or tissue loss. Endovascular management of infrapopliteal (below the knee) disease is associated with extremely high restenosis rates, and is usually a temporizing measure to allow increased blood flow for wound healing. Surgical bypass techniques are effective but are generally high-risk procedures in a population with frequent comorbidities and are usually reserved for patients with severe intermittent claudication or rest pain, or to allow healing of ulcers and gangrene. Sympathectomy is not of value for intermittent claudication, but has been used in the past to allow small ulcers or areas of gangrene to heal. In patients with rest pain, ulcers, or gangrene who are technically unrevascularizable or very high risk for surgery, treatment options are limited. A period of rest with legs dependent may improve some patients, but amputation is a frequent outcome. Parenterally administered prostacyclin or prostaglandin E1 despite some favorable reports of success, has not yet been thoroughly evaluated and is an expensive mode of therapy.

Dry gangrene of the digits or lower limbs should be allowed to spontaneously demarcate. Soaking or ointments are unnecessary. The edges of the gangrenous areas should be kept open if possible and observed frequently for infection. Pain medication is usually necessary for 2–3 months with digital gangrene. A conservative approach and patience will save many digits and extremities. Infected (wet) gangrenous areas must be actively débrided and appropriate antibiotics administered. Amputations may be necessary.

Prevention

The grim statistics regarding cardiovascular outcomes in these patients emphasize the need for aggressive secondary prevention by modifying appropriate cardiovascular risk factors when possible. Tobacco smoking is absolutely contraindicated. Continued smoking has been identified as the most consistent adverse risk factor associated with the progression of the disease. Smoking even one or two cigarettes a day can interfere with PAD treatments. Smoking is also associated with significantly higher rates of amputation compared with nonsmokers. The rate of in-hospital amputation was shown to be 23% in smokers and 10% in nonsmokers. On the other hand, quitting smoking has been shown to slow the progress of PAD and also to reduce the rates of amputation required. Hypertension and diabetes mellitus should be controlled, and hyperlipidemias should be treated with a target low-density lipoprotein <100 mg/dL (or <70 mg/dL with uncontrolled or multiple risk factors) as per recent guidelines for secondary prevention. Evidence is accumulating that aggressive lipid management will prevent progression of PAD, in addition to prevention of myocardial infarction and stroke. Similarly, antiplatelet use with aspirin is used for prevention of cardiovascular events but some controversy of effectiveness in diabetics with PAD. The use of thienopyridines such as clopidogrel (Plavix) may be of additional benefit, but may be associated with higher bleeding rates (particularly with combined therapy) and expense. Use of antiplatelet therapy is a must for those with PAD but should be individualized.

Epidemiology

The epidemiology of atheromatous embolism is poorly defined due to underreporting and difficulties establishing a clinical diagnosis.6 Routine autopsy series of the adult population suggest an incidence of atheromatous embolism of between 0.15% and ∼4%. The incidence increases dramatically in the presence of severe atherosclerotic disease. Atheromatous embolism has been found in more than 20% of deaths following cardiac surgery or angiography. However, it should be emphasized that the rate of clinically detected atheromatous embolism appears to be reasonably low (less than 1%). The atheromatous embolism appears to be more common in males than in females with a reported male-to-female ratio of approximately 3.4:1. It is strongly associated with older age, with the mean age reported to range from 66 to 72 years.

Etiology and Pathogenesis

The pathogenesis of atheromatous embolism involves the occlusion of small arteries and arterioles (of 50–900 μm in diameter) by atheromatous debris (or so-called cholesterol crystals) that are dislodged from a proximal atherosclerotic plaque, with this material inciting an inflammatory cascade characterized by leukocyte infiltration followed by monocytes. This inflammatory process leads to further occlusion with thrombus formation, endothelial cell proliferation, and intimal fibrosis, which may result in ischemia, infarction, and necrosis. The clinical picture is characterized by impaired perfusion of the skin and muscle due to small vessel occlusion, although nearly any organ of the body may be involved.

The major risk factor for the development of atheromatous embolism is atherosclerotic disease of the thoracic or abdominal aorta. The risk is higher with more extensive atheroma burden (defined by increased thickness above 4 mm) or unfavorable plaque features such as protruding mobile plaque.7 Coexistent vascular disease including coronary artery disease, PAD, and even an abdominal aortic aneurysm are risk factors. The more traditional atherosclerotic risk factors also increase the risk of atheromatous embolism, with older age (more than 60 years) being prominent.

Atheromatous embolism often occurs after an invasive procedure.8 Angiography, endovascular procedures, and both cardiac and vascular surgeries may create mechanical trauma to the vessel and destabilize an atherosclerotic plaque. Anticoagulation, primarily with Coumadin, and even thrombolytic therapy are potential risk factors. It has been postulated that anticoagulation may delay the healing of irregular or ulcerated plaque. Embolic events may occur spontaneously although minor stressors such as coughing or straining may be provocative factors.

Clinical Findings

History

The clinical presentation of atheromatous embolism, although it can occur spontaneously, usually follows an invasive procedure such as an invasive angiographic or vascular surgical procedure. The clinical manifestations may be immediate, or delayed by several days to weeks after the inciting event. The precise clinical syndrome depends on the location of the source of embolism and the pattern and distribution of flow downstream. This may range from subtle clinical findings to catastrophic systemic embolic complications. Nearly any organ of the body may be involved. Involvement of the ascending aorta may result in systemic complications including transient ischemic attacks, strokes, or retinal manifestations, while involvement of the descending or abdominal aorta may lead to lower extremity ischemia, renal failure, mesenteric ischemia, or hemorrhagic pancreatitis. Since more common sites for severe atheromatous disease are in abdominal aorta and iliac arteries, the signs and symptoms more commonly result from embolism to the lower half of the body. The lower extremity involvement typically presents with manifestations of discolored or ulcerated painful toes and tender calf muscles.

In addition, constitutional symptoms including fever and weight loss may be seen due to hypermetabolism associated with the inflammatory process.

Cutaneous Lesions

The dermatologic manifestations are often the presenting complaint (Table 173-2). The most common of these findings are related to tissue or digital ischemia and include cyanosis, necrosis, gangrene, ulcerations, and fissures. The finding of tender, cool, blue, or purple toes with normal pulses, found in the “blue toe syndrome,” is common (Fig. 173-5A). About 50% of patients will have livedo racemosa, which typically involves the foot and leg but may extend into the trunk or buttocks. Erythematous lesions are often seen on the lateral aspect of the foot and calcaneal region. Although advanced ischemic manifestations such as ulcers or gangrene may be present (see Fig. 173-5B), the surrounding areas are normally perfused tissue. There may be other cutaneous manifestations, often hemorrhagic in nature, including petechiae, ecchymosis, purpura, and splinter hemorrhages. Raised painful inflammatory nodules may occur.

Related Physical Findings

Examination of the vascular system often reveals normal pedal and proximal pulses, but systolic bruits may be heard on auscultation over the aorta or common femoral arteries. Tenderness of skeletal muscles, particularly in the calf, may be detected. Funduscopic examination revealing Hollenhorst plaques is a specific but insensitive finding because most atheromatous emboli arise from a source distal to the aortic arch. Fever may be present.

Laboratory Tests

The laboratory tests are typically nonspecific and depend upon the organ involved and the severity of disease. An elevated erythrocyte sedimentation rate, thrombocytopenia, hypocomplementemia, leukocytosis, and anemia may all been seen due to the systemic inflammatory response. With renal involvement azotemia, proteinuria, microscopic hematuria, eosinophilia, and even eosinophiluria may be seen. Transient eosinophilia has been reported in up to 80% of those with renal involvement. Involvement of the gastrointestinal tract may lead to anemia and blood in the stools. Injury to the liver, gallbladder, or pancreas may lead to abnormal liver function tests and elevated pancreatic enzymes.

Special Tests

Contrast angiography may reveal diffuse atherosclerotic involvement of the vessels proximal to the lesions, but is typically avoided due to the risk of precipitating further embolic events. Noninvasive imaging techniques such as computed tomographic angiography or MRA are useful to evaluate for atherosclerotic disease within the aorta or other large vessels. Although stenotic atherosclerotic disease is the most common finding, aneurysmal disease may also be present. Transthoracic echocardiography is often helpful to evaluate for a cardiac source, but the more definitive transesophageal echocardiography can also assess the thoracic aorta for plaque.

Definitive diagnosis of cholesterol embolization requires demonstration of cholesterol crystals, which are birefringent under polarized light. However, due to the solubility of cholesterol with typical solvents used in processing of tissue for histopathology, cholesterol crystals appear as empty clefts. Skin, muscle, or renal biopsies may reveal these characteristic elongated, needle-shaped clefts in small arterial vessels. There may also be inflammatory infiltrates, intimal thickening, and perivascular fibrosis as well as giant cells. The sensitivity of the biopsy depends upon the site. Muscle biopsy seems to be the most sensitive test, reportedly being positive in >95% of cases, but is technically difficult, painful, and risky to obtain. The sensitivity of skin biopsy has varied from 40% to 90%. Skin biopsies offer maximum yield when obtained directly from areas of suspected emboli, such as those with livedo racemosa, but should be cautiously obtained or avoided in areas of more overt ischemic injury.

Differential Diagnosis

Because of its clinical similarity to other systemic diseases, atheromatous embolism is often misdiagnosed. The diagnosis of atheromatous emboli is suggested by blue or ulcerated painful digits, livedo racemosa, petechiae, and tender calf muscles in the presence of normal pulses. However, it is difficult to establish the diagnosis, when the clinical features are subtle and nonspecific. Thus, a high index of suspicion is needed, especially in the setting of a history of preexisting atherosclerotic disease and a specific precipitating event. Definitive diagnosis can be made by skin, muscle, or even renal biopsies. Several other entities must be considered in the differential diagnosis of atheromatous embolism (Box 173-5).

Moreover, among patients who develop acute renal failure, it is important to distinguish from contrast nephropathy, which is typically reversible. Renal failure due to atheromatous emboli usually develops over 1–4 weeks after angiographic procedure and shows partial recovery, whereas contrast-induced renal failure typically appears soon after testing and begins to recover within 3–5 days.

Complications

There are numerous ischemic complications depending upon the organ involved. These include the kidneys, mesenteric circulation, and central nervous system. Renal atheroembolic disease is a consequence of showering of emboli to the renal parenchymal branch vessels. An intense inflammatory process may ensue, producing glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Although there is a variable timing of onset and progression of disease, there typically is a several-week delay after the inciting event before the development of renal dysfunction. New onset of hypertension or overt renal failure may ensue. It is rare to develop gross hematuria or frank renal infarction. The development of renal failure is one of the more ominous complications with a high mortality in affected individuals.

The central nervous system is another feared site of involvement with atheromatous embolism. There is concern for ischemic manifestations such as transient ischemic attacks, stroke, and paralysis. However, other less readily appreciated manifestations may ensue, such as a confusional state or a progressive neurologic decline.

The gastrointestinal tract is perhaps the third most common organ system involved with atheromatous embolism. The manifestations may be nonspecific abdominal complaints such as abdominal pain, nausea, vomiting, or diarrhea. More severe ischemic manifestations may be seen with gastrointestinal bleeding or bowel infarction. The colon is the most common site in the gastrointestinal tract to be affected. Establishing a diagnosis may be difficult as endoscopy findings are often nonspecific, and biopsy may miss the classic findings. Splenic infarction, cholecystitis, gangrene of the gall bladder, pancreatitis, and pancreatic necrosis have also been reported.

Prognosis and Clinical Course

The prognosis of cholesterol embolism is generally poor, in part because of the severe underlying atherosclerosis. The outcome also depends upon the organ system affected with the emboli. Estimates of mortality range from 20% to 30% for 1-year mortality. The poorest outcomes have been reported in those with emboli arising from a suprarenal location.

The syndrome usually subsides, and lesions heal following successful surgical or medical treatment, although spontaneous resolution may occur. Recurrent embolism may result in limb loss in the absence of surgical or interventional management options. In the “malignant multisystem” disease, most patients die within 1 year if treatment is unsuccessful. The prognosis is extremely poor in the presence of systemic complications, particularly renal failure or stroke. The development of end-stage renal disease due to atheromatous embolism is a strong predictor of death.

Treatment

Early recognition is essential to minimize end-organ damage and improve the clinical outcomes.6 Preventing further ischemic insult, supportive care, and removal of the atheromatous source are the mainstays of therapy.9 Elimination of the source of the emboli can often be accomplished by surgical bypasses or endarterectomy although many of these patients have contraindications to major surgery. Endovascular procedures with covered stents may also be considered; however, this approach may carry significant risk with the potential to exacerbate further embolization.

Medical therapies have not been well studied, and recommendations are based on the results from small series or anecdotal reports. Antiplatelet agents, such as aspirin, dipyridamole, or clopidogrel, are most often tried and, if successful, should be continued long term. Antithrombotic therapy such as subcutaneous heparin or low-molecular-weight heparin may be beneficial with some, suggesting that these agents may reduce the secondary small vessel thrombosis. Warfarin is usually avoided due to potential for exacerbating the process, but this concern has limited basis. There is even a proposed beneficial effect of long-term anticoagulation to prevent embolic events in those with extensive mobile aortic atheroma. The use of statins may aid in plaque stabilization and has clear established benefits in prevention of cardiovascular ischemic events in those with vascular disease. Other agents such as iloprost and cilostazol have limited evidence to suggest benefit but have been tried in those with renal dysfunction and cutaneous lesions, respectively. Systemic corticosteroids are not recommended. Since most of these patients have severe underlying atherosclerosis, they should be aggressively treated for secondary prevention of cardiovascular disease with optimization of the risk factors.

Prevention

Because of the rarity of the disease and the difficulties in establishing the diagnosis, increased awareness of the problem is important. Primary prevention in high-risk patients, targeted to avoid the development of atherosclerotic plaque, should be performed. Once atherosclerosis develops, avoiding unnecessary invasive procedures is advised. When angiography is necessary, more cautious techniques with the use of soft-tipped guidewires and more flexible catheters help to reduce the risk. In addition, protective devices such as filters, baskets, and balloon occlusion have been used. In patients with atheromatous disease of abdominal aorta and iliac arteries, use of brachial artery approach is often considered. Surgical techniques have also been refined with less aortic manipulation and circulation arrest, which may help to minimize the chance of developing this disorder.

Epidemiology

The prevalence of this disease is greatest in the Mediterranean, Middle East, and Asia, and it is relatively less common in people of northern European descent.10 Males are afflicted with a higher prevalence than females (with a male-to-female ratio of 3:1), although an increased incidence in females has occurred in recent years, likely reflecting the pattern of tobacco use. Patients are usually between the ages of 20 and 40 years. Over the last three decades, there has been a marked decline in the reported prevalence of thromboangiitis obliterans in the United States, possibly reflecting the impact from adoption of strict diagnostic criteria for this disease entity, although declining smoking prevalence may also play a role. In 1947, the prevalence of the disease in the United States was estimated at 104 cases per 100,000, however, more recently the prevalence has been estimated at 12–20 cases per 100,000.11

Etiology and Pathogenesis

The etiology of thromboangiitis obliterans remains unknown. The disease occurs almost exclusively in smokers and often abates with the cessation of tobacco smoking. An increased cellular sensitivity to types I and III collagen has been reported in comparison to a group of normal individuals and patients with atherosclerotic disease. An increased prevalence of HLA-A9, HLA-A54, and HLA-B5 has been observed in these patients, suggesting a genetic component to the disease.12 Tissue ischemia is produced by an inflammatory reaction involving medium and small arteries of the extremities and superimposed obstruction by thrombi. Despite the inflammatory process, thromboangiitis obliterans is considered serologically silent, and even during active disease inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein levels, are usually normal. In one report, serum antiendothelial cell antibody titers were found to be high, and impaired endothelial-dependent vasodilation to acetylcholine has been demonstrated to occur even in nonobstructed limbs. Veins may also be involved. Occasionally, cardiac, intestinal, and cerebral vessels are involved.

Clinical Findings

(Fig. 173-6)

History

The most common initial complaints are claudication of the foot or lower calf, digital cyanosis or gangrene, or rest pain. Involvement of multiple limbs is typical. Patients may present with ulcers of the toes or fingers. Although the lower extremities are affected most often, more than one-third of patients have upper-extremity involvement. Ulcerations or gangrenous areas are characteristically extremely painful. Superficial thrombophlebitis, often migratory, may occur in up to 40% of patients. Cold sensitivity or even classical Raynaud phenomenon may be observed.

Cutaneous Findings

The cutaneous findings of thromboangiitis obliterans are similar to that of PAD. Common findings include ulceration or gangrene of digits (feet worse than hands) (Fig. 173-7), peripheral cyanosis or Raynaud phenomenon, and superficial thrombophlebitis, often migratory, with indurated red nodules.

Related Physical Findings

The hands and feet of patients with the disease are usually cold and mildly edematous. They may develop cyanotic, ulcerated, or gangrenous, and very painful digits. Typically, the distal pulses (dorsalis pedis, posterior tibial, and ulnar pulses) are often absent, while the more proximal pulses are preserved. During episodes of thrombophlebitis, small-indurated red, tender nodules will be found, which follow the course of superficial veins and are common on the thigh or calf. Typical changes of Raynaud phenomenon, with well-demarcated pallor or cyanosis of the digits, may be seen on exposure to cold; one or more extremities may be involved. Sensory abnormalities reflecting ischemic neuropathy have been observed in advanced cases. Nail fold examination with capillaroscopy may reveal multiple dilated capillary loops.

Laboratory and Special Tests

No specific laboratory tests confirm or exclude the diagnosis of thromboangiitis obliterans. The primary goal of a laboratory workup is to exclude other disease processes in the differential diagnosis. A complete serologic profile must be obtained and an echocardiography should be performed to exclude a proximal source of emboli as the cause of distal vessel occlusion. Classical findings on contrast arteriography include segmental occlusions of medium and small blood vessels interspersed with normal appearing wall segments. Corkscrew configuration of collateral vessels originating from the occluded vessels is a classic finding; however, these findings are not pathognomonic, as similar lesions may be seen in patients with other disorders. More proximal and larger caliber vessels are usually spared.

Pathology

In the acute stage, there is a panvasculitis of arteries and veins; the diagnostic findings include the presence of segmental, occlusive thrombi with minimal inflammation in the walls of the affected blood vessels. Microscopic examination typically demonstrates the polymorphonuclear-predominant cellular aggregates with foci of microabscesses and multinucleated giant cells. In contrast to systemic vasculitis (see Chapter 162) and atherosclerosis, normal architecture of the vessel wall is usually well preserved, and there is no early disruption of the internal elastic lamina.13 In the chronic stage, only fibrotic obliteration of the arteries may be observed. The diagnosis can then only be surmised in the absence of hallmark pathologic changes to support atherosclerosis.

Differential Diagnosis

The same differential diagnoses as for PAD must be considered in thromboangiitis obliterans (see Box 173-2). In particular, the disease must be distinguished from distal arterial obstructive disease often seen in diabetes mellitus or end-stage chronic kidney disease. Other considerations include autoimmune disease, particularly scleroderma or CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), and ergotamine abuse.

The diagnosis should be considered in young male smokers presenting with symptoms and signs of distal extremity ischemia, migratory thrombophlebitis, or Raynaud phenomenon. An abnormal Allen test (with compromised perfusion of the fingers and blanching secondary to an occluded ulnar artery or incomplete palmar arch following manual compression of the radial artery) in a young smoker with lower extremity ulceration is very suggestive of this disease. The distal nature of disease and associated upper extremity involvement are particularly helpful clues to differentiate from atherosclerotic PAD. Arteriographic findings may support the diagnosis but only biopsy of an artery or vein during the active phase of the disease showing the characteristic pathologic picture is truly diagnostic. Atherosclerosis is the major differential but tends to occur in an older age group, usually more than 45 years of age, and larger vessels are involved. Raynaud phenomenon (see Chapter 168) is infrequent, and upper extremities are rarely involved. Occasional patients with long-standing diabetes mellitus or end-stage renal disease may exhibit arteriosclerosis affecting medium-sized and distal vessels, but these diagnoses are usually obvious. Raynaud phenomenon associated with scleroderma or CREST syndrome may present with a similar picture, but systemic symptoms, proximal skin changes, and presence of antinuclear antibodies will assist in the diagnosis.

Complications

Major clinical complications of this disease include progression of the disease necessitating amputation of the affected limbs and superimposed infection of the ischemic tissue. Rarely, involvement of other vessels may result in myocardial infarction, stroke, or mesenteric ischemia.

Prognosis and Clinical Course

The disease often continues to progress unabated in patients who continue to smoke. Amputations of digits or even extremities may be necessary. The course of the disease is marked by exacerbations and remissions, but usually becomes quiescent after many years. However, in those who manage to quit smoking, remission is common and progression to amputation is unusual unless critical limb ischemia with tissue loss is already present. Patients generally have a normal life expectancy.

Treatment

There is no specific treatment (Box 173-6) other than smoking cessation. Local wound care is imperative, and adequate analgesic therapy is emphasized. In the absence of data from large randomized trials, antiplatelet agents and vasodilators may play a role and are usually initiated. Similarly, pentoxifylline or cilostazol, both agents used for improving walking distances in claudicants with atherosclerotic disease, may be tried. In one study, daily intravenous infusions of iloprost, a prostaglandin analog, were shown to relieve rest pain, heal ulcers, and prevent amputation more frequently than aspirin. Bypass surgery or angioplasty have been reported but are suboptimal therapeutic options because of the small size and distal location of the vessels affected. Sympathectomy may help patients with a prominent vasospastic component. Vascular endothelial growth factor gene therapy may prove of value, but has not been well studied yet. In those with refractory disease with nonhealing ulcers, gangrene, or intractable pain, surgical amputation of the affected distal limbs is often unavoidable.

Prevention

Absolute discontinuation of tobacco use is the only strategy proven to prevent the progression of thromboangiitis obliterans. Smoking as few as one or two cigarettes daily, using chewing tobacco, or even using nicotine replacements may keep the disease active.14 The following strategies are important in prevention of complications from the disease: use of well-fitting protective footwear to prevent foot trauma and thermal or chemical injury, avoidance of cold environments, and avoidance of drugs that lead to vasoconstriction.

Epidemiology

Livedo reticularis is typically a primary disorder that affects young to middle-aged females (20–50 years of age) who are otherwise healthy.15 Amantadine-induced livedo reticularis is also more common in females. The epidemiologic factors of livedo racemosa are dependent on the underlying condition. It is the most frequent dermatologic manifestation in patients with antiphospholipid syndrome, present in 25% of patients with primary APS and in up to 70% of patients with SLE-associated APS.16 The distinction between livedo racemosa and livedo reticularis is an evolving concept, which is not universally quoted, and is not referred to in most of the older literature.

Etiology and Pathogenesis

In both disorders, the characteristic ring-like mottling results from (patho)physiologic changes within the cutaneous microvascular system. Anatomically, the dermis is perfused via perpendicularly oriented ascending arterioles. Individual arterioles arborize into a capillary bed at the skin surface. Ultimately, the capillary beds empty into a conical appearing, peripherally located subpapillary venous plexus.

Pathophysiologically, livedo arises from either deoxygenation or venodilatation within the venous plexus.17 Decreased arteriolar perfusion is the predominant cause of deoxygenation within the venous plexus. Diminished arteriolar flow can result from vasospasm, hyperviscosity, and/or thrombosis. Physiologic arteriolar vasospasm produces the reversible cutaneous discoloration of livedo reticularis. The livedo reticularis can occur as a physiological reaction to cold exposure, when it is known as cutis marmorata, or the skin color changes may be unrelated to ambient temperature. Protracted arteriolar vasospasm, thrombosis, and/or hyperviscosity underlie the pathologic skin changes of livedo racemosa. Venodilatation of the venous plexus may be provoked by hypoxia or autonomic dysfunction.

A possible role for the endothelial cells (EC) has also been suggested in the subset of patients of APS with livedo racemosa. The interaction of aPL antibodies with EC could induce livedo racemosa and also lead to increased production of procoagulant substances such as tissue factor (TF), plasminogen activator inhibitor 1, and endothelin. Increased TF expression on EC induced by aPL could be responsible, in part, for hypercoagulability and might explain the thrombosis in both arterial and venous circulation that characterizes these patients.

Amantadine-induced livedo reticularis has traditionally been ascribed to catecholamine provoked arteriolar vasospasm; however, an interaction between amantadine and N-methyl-d-aspartic acid receptors in the skin may be responsible in some unexplained fashion.18

Livedoid vasculopathy is a rare ulcerative subtype of livedo racemosa due to fibrinolytic abnormalities and microcirculatory thrombosis.

Clinical Findings

History

With the exception of a subjective feeling of coldness, the majority of patients with livedo reticularis are asymptomatic. Patients often present with concerns regarding their skin discoloration. A minority describes mild pain and numbness. The symptoms are worse during winter months. Livedo racemosa-associated symptoms are related to the causative secondary disorder.

Cutaneous Lesions

In livedo reticularis, a symmetric, fishnet-like red or purple mottling surrounds a pallorous conical core (Fig. 173-8). This discoloration is aggravated by cold exposure and may completely dissipate with warming. The livid rings are most pronounced on the lower extremities yet the abdomen and upper extremities can be affected.

In contradistinction to the symmetric and uniform reticular pattern of livedo reticularis, the discoloration of livedo racemosa is asymmetric, irregular, and “broken” (Fig. 173-9). Although it may improve with warming, it does not resolve completely. Attendant skin manifestations of livedo racemosa may include purpura, nodules, macules, ulcerations, and/or atrophie blanche-type scarring. When associated with livedoid vasculitis, painful ulcerations about ankles and forefeet may occur.

In both livedo reticularis and racemosa, the skin is palpably cool.

Related Physical Findings

Livedo reticularis and livedo racemosa are often associated with vasospastic digits or acrocyanosis. With exception of the characteristic skin changes, the examination in livedo reticularis is otherwise unremarkable. Patients with livedo racemosa may have concurrent abnormal physical findings related to their underlying disease (e.g., aphasia and lateralizing neurologic signs associated with Sneddon syndrome).

Laboratory and Special Tests

In livedo reticularis, laboratory testing is typically negative and consequently is unwarranted. An antiphospholipid antibody panel should be obtained on all patients presenting with livedo racemosa. A complete thrombophilia panel is warranted in the rare patient with livedoid vasculopathy (see Chapter 163). The need for additional laboratory analysis in a patient with livedo racemosa should be directed by the clinical assessment.

A skin biopsy is not required in livedo reticularis as the findings are nonspecific. A large punch or wedge biopsy of the deep reticular dermis and subcutaneous fat is sometimes helpful in identifying the secondary cause of livedo racemosa. Selection of the correct biopsy site (seemingly uninvolved skin in the center of the lesion) is essential for detection of relevant vascular pathology. The biopsy findings are highly variable and reflect the associated livedo racemosa etiology. For instance, cholesterol clefts suggest atheroembolic disease, calcification of the vessels and interstitium indicate calciphylaxis, noninflammatory arteriolar obstruction occurs with Sneddon syndrome, livedoid vasculopathy is associated with extensive fibrin deposition and microthrombi (see Chapter 163), whereas fibrinoid necrosis is present in polyarteritis nodosa (see Chapter 164).

Differential Diagnosis

The diagnosis of livedo is easily made by identifying the characteristic mottled skin discoloration. It is paramount that the clinicians distinguish between livedo reticularis and livedo racemosa. Once a diagnosis of livedo racemosa is established, the secondary cause (Table 173-3) should be sought by appropriate clinical laboratory tests. Diagnostic difficulties may occur when no other pathological signs except livedo racemosa are found. This clinical condition, known as “idiopathic livedo racemosa,” may represent a very early stage of Sneddon syndrome.

Prognosis and Clinical Course

The prognosis for livedo reticularis is excellent as this is primarily a cosmetic condition. Livedo racemosa-associated prognosis is less favorable and parallels the associated disease. Of interest, livedo racemosa has been identified as a marker for predicting multisystem thrombosis in the antiphospholipid antibody syndrome. Additionally, up to 40% of patients manifest livedo racemosa as the initial sign of the antiphospholipid antibody syndrome.19 In addition, increased rate of pregnancy loss has been recognized in patients with widespread livedo racemosa who were seronegative for antiphospholipid antibodies, suggesting that livedo racemosa may be an independent risk factor for pregnancy loss in the absence of APS. Livedoid vasculopathy tends to be a relapsing condition marked by recurrent painful ulcerations and subsequent atrophie blanche-type scars.

Treatment

Other than cold avoidance, medical treatment for primary livedo reticularis is typically unwarranted. As a last resort, vasodilator therapy may be tried in the patient that is socially inhibited by the cosmetic appearance of the disorder. The symptoms may improve spontaneously with age.

Therapy of livedo racemosa should be directed toward the underlying disorder. Patients with livedo racemosa and the antiphospholipid antibody syndrome with thrombosis require anticoagulation. Treatment of livedoid vasculopathy is often unsatisfactory but potentially beneficial medications include anticoagulants, antiplatelet agents, immunosuppressants, pentoxifylline, danazol, and tissue plasminogen activator. Alternatively, hyperbaric oxygen and psoralen and ultraviolet A light therapy have also been successfully utilized to treat livedoid vasculopathy.

Epidemiology

This is a rare disorder with limited epidemiologic data available.20 In Norway, the incidence is estimated to be 0.25 for 100,000 population with a prevalence of 2 per 100,000. In the United States, extrapolation from a series of erythromelalgia patients at the Mayo Clinic suggests an incidence of 1 case per 40,000 patients; however, this could overestimate the incidence in general population. Primary erythromelalgia may occur at any age with an uncertain gender predilection, although recent studies seem to suggest a female predominance.21 In contrast, secondary erythromelalgia has an equal sex distribution and occurs mostly after the third decade.

Etiology and Pathogenesis

The etiology and pathogenesis of the erythromelalgia are unknown. Several mechanisms have been postulated for primary erythromelalgia, including arteriovenous shunting and a small fiber neuropathy. It has been speculated that precapillary sphincters may be constricted while arteriovenous shunts are open, leading to an increased total perfusion but a deficient nutritive blood flow.22 Substances produced by local hypoxia lead to increased local blood flow, warmth, redness, and pain. In contrast, the genetics of erythromelalgia appears to be supporting a neuropathic basis. A mutation in a voltage-gated sodium channel of sensory nerves has been reported in inherited erythromelalgia.

Secondary erythromelalgia occurs in polycythemia, thrombocythemia, and autoimmune disorders and is hypothesized to be caused by platelet breakdown products based on the response to aspirin therapy.

Clinical Findings

History

The disorder is characterized by red, hot, painful extremities with characteristic intense burning pain. It most commonly affects the lower extremities but may affect the upper extremities as well as other body parts, such as the face and ears. Involvement is usually symmetric, although it can be unilateral in secondary cases. The symptoms are typically intermittent in nature but may be constant. Their onset may be gradual or abrupt, usually precipitated by activities that increase the body temperature, such as exercise, ambient temperature, or the use of heavy blankets at night. The episodes can also be triggered by dependency of the limb, wearing socks, or tight shoes, and sometimes with the ingestion of alcohol or spicy foods. There are also reports of episodes triggered by ingestion of some drugs, such as pergolide, bromocriptine, and calcium channel blockers (nifedipine, felodipine, and nicardipine). In contrast, cold exposure (e.g., standing on a cold floor) or immersion in ice water often relieves the flares.

Patients have also been described who have both erythromelalgia and Raynaud phenomenon. During the hyperemic phase of Raynaud phenomenon, patients often complain of erythromelalgic-like symptoms. It is postulated that both syndromes have a common basis in a dysfunction of the regulation of vasomotor tone.23

Cutaneous Lesions

Examination during attacks reveals warm, red, extremely sensitive extremities with normal pulses (Fig. 173-10). Between flares, the extremities may appear normal. The constant use of ice water leads to maceration of the skin, secondary infection, ulcers, and necrosis.

Physical Findings

Physical examination is usually unremarkable in primary type of erythromelalgia, however may reveal signs of an underlying disorder in the secondary erythromelalgia. The peripheral pulses are usually normal or bounding.

Pathology

In patients with secondary erythromelalgia associated with thrombocythemia, skin biopsy results have shown arteriolar endothelial cell swelling, with sparing of venules, capillaries, and nerves. A thickening of the vessel wall and luminal narrowing due to fibromuscular dysplasia and thrombotic occlusions of arterioles are present.

Biopsy specimens in patients with primary erythromelalgia show mild mononuclear perivascular infiltrates with edema, thickened vascular basement membranes, and moderate endothelial swelling. The intimal thickening and thrombi seen in secondary erythromelalgia are lacking.

Laboratory and Special Tests

There are no confirmatory tests. Thermography reveals elevated skin temperatures in the affected area, but this finding is not necessary to establish diagnosis. Striking differences in surface temperature can occur between involved and uninvolved areas. It has been reported that warm water immersion at 32°C–36°C (89.6°F –96.8°F) may induce attacks.

Secondary disease must be evaluated with a complete blood cell count, looking for evidence of a myeloproliferative disorder and antinuclear antibodies, to help distinguish autoimmune diseases. Nerve conduction studies may be necessary to rule out neuropathies. Triple-phase technetium bone scanning has been used in patients with a history of trauma or stroke if reflex sympathetic dystrophy is strongly considered (particularly if the symptoms are unilateral).

Differential Diagnosis

The diagnosis must be made from the history and clinical manifestations. Skin injury is sometimes present from the constant cold-water immersion. The main differential diagnosis is regional complex pain syndrome (or reflex sympathetic dystrophy) during the early warm phase, but this is usually unilateral, and there is a history of trauma.

Complications

Complications are often related to treatment used by patients to provide relief of symptoms. Immersion or thermal injury may ensue due to prolonged soaks in ice water. This may lead to trophic changes of the skin, ulcers, and infection and even the need for amputation.

Prognosis and Clinical Course

The natural history of erythromelalgia is extremely variable.24 Symptoms may be mild for several years or totally disabling within weeks. It has been reported that with long-term follow-up, symptoms were worse in 32%, unchanged in 27%, improved in 31%, and resolved in 10% of patients. Many patients become disabled being unable to work or carry on daily activities. As a result of the profound impact upon their life with intractable symptoms, patients have even been known to commit suicide. There is a decrease in survival compared with age- and gender-matched controls.

Treatment

There are limited data available to guide therapy, primarily based upon case reports or small series.24 Behavioral modifications should include efforts to keep the limbs cool and avoid the use of ice water or prolonged soaking. Additional measures including biofeedback and even hypnosis have been tried. Pharmacologic therapy has varied but often has focused on vasoactive drugs and drugs that affect the nervous system. Most vasoactive drugs, including calcium-channel blockers and β blockers, have been minimally effective in treating this disorder. Drugs used to treat neuropathy, such as serotonin reuptake inhibitors, tricyclic antidepressants, and gabapentin, have been used and may provide some relief. Aspirin is often of great benefit but only in secondary cases. Topical therapies, such as lidocaine patch or capsaicin cream, may reduce the pain. The prostaglandin E1 analog misoprostol has been evaluated in a double-blind, crossover trial and found to be superior to placebo. Numerous other agents, including lorazepam, cycloheptadine, methysergide, piroxicam, and pizotifen, have been tried in selected cases. Surgical or medical sympathectomies have also been tried but have been found to have mixed results.

Prevention

There are no established measures to prevent the development of erythromelalgia. The focus has been to prevent flares once the disorder occurs. The key to prevention is to avoid exacerbating factors and to prophylactically cool the involved extremity. The other preventive measures are to prevent the development of secondary complications often as a result of prolonged soaking in ice water. It is important to limit the duration of soaking and to use cool, not ice-cold, water.