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InternalMed_Harrison. which there is a stenosis or occlusion in the aorta or the arteries of the limbs. Atherosclerosis is the leading cause of PAD in patients >40 years old. Other causes include thrombosis, embolism, vasculitis, fibromuscular dysplasia, entrapment, cystic adventitial disease, and trauma. The highest prevalence of atherosclerotic PAD occurs in the sixth and seventh decades of life. As in patients with atherosclerosis of the coronary and cerebral vasculature, there is an increased risk of developing PAD in cigarette smokers and in persons with diabetes mellitus, hypercholesterolemia, hypertension, or renal insufficiency.


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InternalMed_Harrison. Pathology (See also Chap. 291e) Segmental lesions that cause steno-sis or occlusion are usually localized to large and medium-size vessels. The pathology of the lesions includes atherosclerotic plaques with calcium deposition, thinning of the media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic lamina, and thrombi composed of platelets and fibrin. The primary sites of involvement are the abdominal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80–90% of patients), and the more distal vessels, including the tibial and peroneal arteries (40– 50% of patients). Atherosclerotic lesions occur preferentially at arterial branch points, which are sites of increased turbulence, altered shear stress, and intimal injury. Involvement of the distal vasculature is most common in elderly individuals and patients with diabetes mellitus.


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InternalMed_Harrison. Clinical Evaluation Fewer than 50% of patients with PAD are symp-1643 tomatic, although many have a slow or impaired gait. The most common symptom is intermittent claudication, which is defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it occurs during exercise and is relieved by rest. The site of claudication is distal to the location of the occlusive lesion. For example, buttock, hip, thigh, and calf discomfort occurs in patients with aortoiliac disease, whereas calf claudication develops in patients with femoral-popliteal disease. Symptoms are far more common in the lower than in the upper extremities because of the higher incidence of obstructive lesions in the former region. In patients with severe arterial occlusive disease in whom resting blood flow cannot accommodate basal nutritional needs of the tissues, critical limb ischemia may develop. Patients complain of rest pain or a feeling of cold or numbness in the foot and toes. Frequently, these


InternalMed_Harrison

InternalMed_Harrison. cannot accommodate basal nutritional needs of the tissues, critical limb ischemia may develop. Patients complain of rest pain or a feeling of cold or numbness in the foot and toes. Frequently, these symptoms occur at night when the legs are horizontal and improve when the legs are in a dependent position. With severe ischemia, rest pain may be persistent.


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InternalMed_Harrison. Important physical findings of PAD include decreased or absent pulses distal to the obstruction, the presence of bruits over the nar rowed artery, and muscle atrophy. With more severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature, and pallor or cyanosis are common physical signs. In patients with critical limb ischemia, ulcers or gangrene may occur. Elevation of the legs and repeated flexing of the calf muscles produce pallor of the soles of the feet, whereas rubor, secondary to reactive hyperemia, may develop when the legs are dependent. The time required for rubor to develop or for the veins in the foot to fill when the patient’s legs are transferred from an elevated to a dependent position is related to the severity of the ischemia and the presence of collateral vessels. Patients with severe ischemia may develop peripheral edema because they keep their legs in a dependent position much of the time. Ischemic neuropathy can result in numbness


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InternalMed_Harrison. of collateral vessels. Patients with severe ischemia may develop peripheral edema because they keep their legs in a dependent position much of the time. Ischemic neuropathy can result in numbness and hyporeflexia.


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InternalMed_Harrison. Noninvasive Testing The history and physical examination are often sufficient to establish the diagnosis of PAD. An objective assessment of the presence and severity of disease is obtained by noninvasive techniques. Arterial pressure can be recorded noninvasively in the legs by placement of sphygmomanometric cuffs at the ankles and the use of a Doppler device to auscultate or record blood flow from the dorsalis pedis and posterior tibial arteries. Normally, systolic blood pressure in the legs and arms is similar. Indeed, ankle pressure may be slightly higher than arm pressure due to pulse-wave amplification. In the presence of hemodynamically significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the ankle and brachial artery pressures (termed the ankle:brachial index, or ABI) is 1.00–1.40 in normal individuals. ABI values of 0.91–0.99 are considered “borderline,” and those <0.90 are abnormal and diagnostic of PAD. ABIs >1.40 indicate


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InternalMed_Harrison. the ankle:brachial index, or ABI) is 1.00–1.40 in normal individuals. ABI values of 0.91–0.99 are considered “borderline,” and those <0.90 are abnormal and diagnostic of PAD. ABIs >1.40 indicate noncompressible arteries secondary to vascular calcification.


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InternalMed_Harrison. Other noninvasive tests include segmental pressure measurements, segmental pulse volume recordings, duplex ultrasonography (which combines B-mode imaging and Doppler flow velocity waveform analysis examination), transcutaneous oximetry, and stress testing (usually using a treadmill). Placement of pneumatic cuffs enables assessment of systolic pressure along the legs. The presence of pressure gradients between sequential cuffs provides evidence of the presence and location of hemodynamically significant stenoses. In addition, the amplitude of the pulse volume contour becomes blunted in the presence of significant PAD. Duplex ultrasonography is used to image and detect stenotic lesions in native arteries and bypass grafts. Treadmill testing allows the physician to assess functional limitations objectively. Decline of the ABI immediately after exercise provides further support for the diagnosis of PAD in patients with equivocal symptoms and findings on examination.


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InternalMed_Harrison. Magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and conventional catheter-based angiography should not be used for routine diagnostic testing but are performed before potential revascularization (Fig. 302-1). Each test is useful in defining the anatomy to assist planning for endovascular and surgical revascularization procedures. FIGURE 302-1 Magnetic resonance angiography of a patient with intermittent claudication, showing stenoses of the distal abdominal aorta and right iliac common iliac artery (A) and stenoses of the right and left superficial femoral arteries (B). (Courtesy of Dr. Edwin Gravereaux, with permission.)


InternalMed_Harrison

InternalMed_Harrison. Prognosis The natural history of patients with PAD is influenced primarily by the extent of coexisting coronary artery and cerebrovascular disease. Approximately one-third to one-half of patients with symptomatic PAD have evidence of coronary artery disease (CAD) based on clinical presentation and electrocardiogram, and over one-half have significant CAD by coronary angiography. Patients with PAD have a 15–30% 5-year mortality rate and a twoto sixfold increased risk of death from coronary heart disease. Mortality rates are highest in those with the most severe PAD. Measurement of ABI is useful for detecting PAD and identifying persons at risk for future atherothrombotic events. The likelihood of symptomatic progression of PAD is lower than the chance of succumbing to CAD. Approximately 75–80% of nondiabetic patients who present with mild to moderate claudication remain symptomatically stable. Deterioration is likely to occur in the remainder, with approximately 1–2% of the group


InternalMed_Harrison

InternalMed_Harrison. 75–80% of nondiabetic patients who present with mild to moderate claudication remain symptomatically stable. Deterioration is likely to occur in the remainder, with approximately 1–2% of the group ultimately developing critical limb ischemia each year. Approximately 25–30% of patients with critical limb ischemia undergo amputation within 1 year. The prognosis is worse in patients who continue to smoke cigarettes or have diabetes mellitus.


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InternalMed_Harrison. Patients with PAD should receive therapies to reduce the risk of associated cardiovascular events, such as myocardial infarction and death, and to improve limb symptoms, prevent progression to critical limb ischemia, and preserve limb viability. Risk factor modification and antiplatelet therapy should be initiated to improve cardiovascular outcomes. The importance of discontinuing cigarette smoking cannot be overemphasized. The physician must assume a major role in this lifestyle modification. Counseling and adjunctive drug therapy with the nicotine patch, bupropion, or varenicline increase smoking cessation rates and reduce recidivism. It is important to control blood pressure in hypertensive patients. Angiotensin-converting enzyme inhibitors may reduce the risk of cardiovascular events in patients with symptomatic PAD. β-Adrenergic blockers do not worsen claudication and may be used to treat hypertension, especially in patients with coexistent CAD. Treatment of hypercholesterolemia


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InternalMed_Harrison. in patients with symptomatic PAD. β-Adrenergic blockers do not worsen claudication and may be used to treat hypertension, especially in patients with coexistent CAD. Treatment of hypercholesterolemia with statins is advocated to reduce the risk of myocardial infarction, stroke, and death. The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high intensity statin treatment in patients with atherosclerotic disorders, including peripheral artery disease. Platelet inhibitors, including aspirin and clopidogrel, reduce the risk of adverse cardiovascular events in patients with atherosclerosis and are recommended for patients with symptomatic PAD, including those with intermittent claudication or critical limb ischemia or prior lower extremity revascularization. Dual antiplatelet therapy with both aspirin and clopidogrel is not more effective than aspirin alone in reducing cardiovascular morbidity and mortality


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InternalMed_Harrison. or prior lower extremity revascularization. Dual antiplatelet therapy with both aspirin and clopidogrel is not more effective than aspirin alone in reducing cardiovascular morbidity and mortality rates in patients with PAD. The anticoagulant warfarin is as effective as antiplatelet therapy in preventing adverse cardiovascular events but causes more major bleeding; therefore, it is not indicated to improve outcomes in patients with chronic PAD.


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InternalMed_Harrison. Therapies for intermittent claudication and critical limb ischemia include supportive measures, medications, nonoperative interventions, and surgery. Supportive measures include meticulous care of the feet, which should be kept clean and protected against excessive drying with moisturizing creams. Well-fitting and protective shoes are advised to reduce trauma. Elastic support hose should be avoided, as it reduces blood flow to the skin. In patients with critical limb ischemia, shock blocks under the head of the bed together with a canopy over the feet may improve perfusion pressure and ameliorate some of the rest pain.


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InternalMed_Harrison. Patients with claudication should be encouraged to exercise regularly and at progressively more strenuous levels. Supervised exercise training programs for 30to 45-min sessions, three to five times per week for at least 12 weeks, prolong walking distance. Patients also should be advised to walk until nearly maximum claudication discomfort occurs and then rest until the symptoms resolve before resuming ambulation. The beneficial effect of supervised exercise training on walking performance in patients with claudication often is similar to or greater than that realized after a revascularization procedure. Pharmacologic treatment of PAD has not been as successful as the medical treatment of CAD (Chap. 293). In particular, vasodilators as a class have not proved to be beneficial. During exercise, peripheral vasodilation occurs distal to sites of significant arterial stenoses. As a result, perfusion pressure falls, often to levels lower than that generated in the interstitial tissue by the


InternalMed_Harrison

InternalMed_Harrison. peripheral vasodilation occurs distal to sites of significant arterial stenoses. As a result, perfusion pressure falls, often to levels lower than that generated in the interstitial tissue by the exercising muscle. Drugs such as α-adrenergic blocking agents, calcium channel antagonists, and other vasodilators have not been shown to be effective in patients with PAD.


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InternalMed_Harrison. Cilostazol, a phosphodiesterase inhibitor with vasodilator and antiplatelet properties, increases claudication distance by 40–60% and improves measures of quality of life. The mechanism of action accounting for its beneficial effects is not known. Pentoxifylline, a substituted xanthine derivative, increases blood flow to the micro-circulation and enhances tissue oxygenation. Although several placebo-controlled studies have found that pentoxifylline increases the duration of exercise in patients with claudication, its efficacy has not been confirmed in all clinical trials. Statins and angiotensinconverting enzyme inhibitors appear promising for treatment of intermittent claudication in initial clinical trials, but more studies are needed to confirm the efficacy of each class of drugs. There is no definitive medical therapy for critical limb ischemia, although several studies have suggested that long-term parenteral administration of vasodilator prostaglandins decreases pain and


InternalMed_Harrison

InternalMed_Harrison. There is no definitive medical therapy for critical limb ischemia, although several studies have suggested that long-term parenteral administration of vasodilator prostaglandins decreases pain and facilitates healing of ulcers. Enthusiasm for therapy with angiogenic growth factors abated when clinical trials of intramuscular gene transfer of DNA encoding vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, or hypoxia-inducible factor 1α failed to demonstrate improvement in symptoms or outcomes in patients with intermittent claudication or critical limb ischemia. Clinical trials assessing the ability of bone marrow–derived vascular progenitor cells to promote angiogenesis and preserve limb viability in patients with critical limb ischemia are ongoing.


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InternalMed_Harrison. Revascularization procedures, including catheter-based and surgical interventions, are usually indicated for patients with disabling, progressive, or severe symptoms of intermittent claudication despite medical therapy and for those with critical limb ischemia. MRA, CTA, or conventional angiography should be performed to assess vascular anatomy in patients who are being considered for revascularization. Nonoperative interventions include percutaneous transluminal angiography (PTA) and stent placement (Chap. 296e). PTA and stenting of the iliac artery are associated with higher success rates than are PTA and stenting of the femoral and popliteal arteries. Approximately 90–95% of iliac PTAs are initially successful, and the 3-year patency rate is >75%. Patency rates may be higher if a stent is placed in the iliac artery. The initial success rates for femoralpopliteal PTA and stenting are approximately 80%, with 60% 3-year patency rates. Patency rates are influenced by the severity of


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InternalMed_Harrison. is placed in the iliac artery. The initial success rates for femoralpopliteal PTA and stenting are approximately 80%, with 60% 3-year patency rates. Patency rates are influenced by the severity of pretreatment stenoses; the prognosis of occlusive lesions is worse than that of nonocclusive stenotic lesions. The role of drug-eluting stents and drug-coated balloons in PAD is under investigation.


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InternalMed_Harrison. Several operative procedures are available for treating patients with aortoiliac and femoral-popliteal artery disease. The preferred operative procedure depends on the location and extent of the obstruction(s) and the general medical condition of the patient. Operative procedures for aortoiliac disease include aortobifemoral bypass, axillofemoral bypass, femoro-femoral bypass, and aortoiliac endarterectomy. The most frequently used procedure is the aortobifemoral bypass using knitted Dacron grafts. Immediate graft patency approaches 99%, and 5and 10-year graft patency rates in survivors are >90% and 80%, respectively. Operative complications include myocardial infarction and stroke, infection of the graft, peripheral embolization, and sexual dysfunction from interruption of autonomic nerves in the pelvis. The operative mortality rate ranges from 1–3%, mostly due to ischemic heart disease.


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InternalMed_Harrison. Operative therapy for femoral-popliteal artery disease includes in situ and reverse autogenous saphenous vein bypass grafts, placement of polytetrafluoroethylene (PTFE) or other synthetic grafts, and thromboendarterectomy. The operative mortality rate ranges from 1–3%. The long-term patency rate depends on the type of graft used, the location of the distal anastomosis, and the patency of runoff vessels beyond the anastomosis. Patency rates of femoral-popliteal saphenous vein bypass grafts approach 90% at 1 year and 70–80% at 5 years. Five-year patency rates of infrapopliteal saphenous vein bypass grafts are 60–70%. In contrast, 5-year patency rates of infrap-1645 opliteal PTFE grafts are <30%.


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InternalMed_Harrison. Preoperative cardiac risk assessment may identify individuals who are especially likely to experience an adverse cardiac event during the perioperative period. Patients with angina, prior myocardial infarction, ventricular ectopy, heart failure, or diabetes are among those at increased risk. Stress testing with treadmill exercise (if feasible), radionuclide myocardial perfusion imaging, or echocardiography permits further stratification of risk in these patients (Chap. 296e). Patients with abnormal test results require close supervision and adjunctive management with anti-ischemic medications. β-Adrenergic blockers and statins reduce the risk of postoperative cardiovascular complications. Coronary angiography and coronary artery revascularization compared with optimal medical therapy do not improve outcomes in most patients undergoing peripheral vascular surgery, but cardiac catheterization should be considered in patients with unstable angina and angina refractory to medical therapy


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InternalMed_Harrison. improve outcomes in most patients undergoing peripheral vascular surgery, but cardiac catheterization should be considered in patients with unstable angina and angina refractory to medical therapy as well as those suspected of having left main or three-vessel CAD.


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InternalMed_Harrison. Fibromuscular dysplasia is a hyperplastic disorder that affects medium-size and small arteries. It occurs predominantly in females and usually involves the renal and carotid arteries but can affect extremity vessels such as the iliac and subclavian arteries. The histologic classification includes intimal fibroplasia (also classified as focal), medial dysplasia (multifocal), and adventitial hyperplasia. Medial dysplasia is subdivided into medial fibroplasia, perimedial fibroplasia, and medial hyperplasia. Medial fibroplasia is the most common type and is characterized by alternating areas of thinned media and fibromuscular ridges. The internal elastic lamina usually is preserved. The iliac arteries are the limb arteries most likely to be affected by fibromuscular dysplasia. It is identified angiographically by a “string of beads” appearance caused by thickened fibromuscular ridges contiguous with thin, less-involved portions of the arterial wall, which is typical of medial fibroplasia.


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InternalMed_Harrison. angiographically by a “string of beads” appearance caused by thickened fibromuscular ridges contiguous with thin, less-involved portions of the arterial wall, which is typical of medial fibroplasia. When limb vessels are involved, clinical manifestations are similar to those for atherosclerosis, including claudication and rest pain. PTA and surgical reconstruction have been beneficial in patients with debilitating symptoms or threatened limbs.


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InternalMed_Harrison. Thromboangiitis obliterans (Buerger’s disease) is an inflammatory occlusive vascular disorder involving small and medium-size arteries and veins in the distal upper and lower extremities. Cerebral, visceral, and coronary vessels may be affected rarely. This disorder develops most frequently in men <40 years of age. The prevalence is higher in Asians and individuals of Eastern European descent. Although the cause of thromboangiitis obliterans is not known, there is a definite relationship to cigarette smoking in patients with this disorder.


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InternalMed_Harrison. In the initial stages of thromboangiitis obliterans, polymorphonuclear leukocytes infiltrate the walls of the small and medium-size arteries and veins. The internal elastic lamina is preserved, and a cellular, inflammatory thrombus develops in the vascular lumen. As the disease progresses, mononuclear cells, fibroblasts, and giant cells replace the neutrophils. Later stages are characterized by perivascular fibrosis, organized thrombus, and recanalization.


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InternalMed_Harrison. The clinical features of thromboangiitis obliterans often include a triad of claudication of the affected extremity, Raynaud’s phenomenon, and migratory superficial vein thrombophlebitis. Claudication usually is confined to the calves and feet or the forearms and hands because this disorder primarily affects distal vessels. In the presence of severe digital ischemia, trophic nail changes, painful ulcerations, and gangrene may develop at the tips of the fingers or toes. The physical examination shows normal brachial and popliteal pulses but reduced or absent radial, ulnar, and/or tibial pulses. MRA, CTA, and conventional arteriography are helpful in making the diagnosis. Smooth, tapering segmental lesions in the distal vessels are characteristic, as are


InternalMed_Harrison

InternalMed_Harrison. Arterial Diseases of the Extremities 1646 collateral vessels at sites of vascular occlusion. Proximal atherosclerotic disease is usually absent. The diagnosis can be confirmed by excisional biopsy and pathologic examination of an involved vessel. There is no specific treatment except abstention from tobacco. The prognosis is worse in individuals who continue to smoke, but results are discouraging even in those who stop smoking. Arterial bypass of the larger vessels may be used in selected instances, as well as local debridement, depending on the symptoms and severity of ischemia. Antibiotics may be useful; anticoagulants and glucocorticoids are not helpful. If these measures fail, amputation may be required. Other vasculitides may affect the arteries that supply the upper and lower extremities. Takayasu’s arteritis and giant cell (temporal) arteritis are discussed in Chap. 385.


InternalMed_Harrison

InternalMed_Harrison. Other vasculitides may affect the arteries that supply the upper and lower extremities. Takayasu’s arteritis and giant cell (temporal) arteritis are discussed in Chap. 385. Acute limb ischemia occurs when arterial occlusion results in the sudden cessation of blood flow to an extremity. The severity of ischemia and the viability of the extremity depend on the location and extent of the occlusion and the presence and subsequent development of collateral blood vessels. Principal causes of acute arterial occlusion include embolism, thrombus in situ, arterial dissection, and trauma.


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InternalMed_Harrison. The most common sources of arterial emboli are the heart, aorta, and large arteries. Cardiac disorders that cause thromboembolism include atrial fibrillation, both chronic and paroxysmal; acute myocardial infarction; ventricular aneurysm; cardiomyopathy; infectious and marantic endocarditis; thrombi associated with prosthetic heart valves; and atrial myxoma. Emboli to the distal vessels may also originate from proximal sites of atherosclerosis and aneurysms of the aorta and large vessels. Less frequently, an arterial occlusion results paradoxically from a venous thrombus that has entered the systemic circulation via a patent foramen ovale or another septal defect. Arterial emboli tend to lodge at vessel bifurcations because the vessel caliber decreases at those sites; in the lower extremities, emboli lodge most frequently in the femoral artery, followed by the iliac artery, aorta, and popliteal and tibioperoneal arteries.


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InternalMed_Harrison. Acute arterial thrombosis in situ occurs most frequently in atherosclerotic vessels at the site of an atherosclerotic plaque or aneurysm and in arterial bypass grafts. Trauma to an artery may disrupt continuity of blood flow and cause acute limb ischemia via formation of an acute arterial thrombus or by disruption of an artery’s integrity and extravasation of blood. Arterial occlusion may complicate arterial punctures and placement of catheters; it also may result from arterial dissection if the intimal flap obstructs the artery. Less common causes include thoracic outlet compression syndrome, which causes subclavian artery occlusion, and entrapment of the popliteal artery by abnormal placement of the medial head of the gastrocnemius muscle. Polycythemia and hypercoagulable disorders (Chaps. 131 and 141) are also associated with acute arterial thrombosis.


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InternalMed_Harrison. The symptoms of an acute arterial occlusion depend on the location, duration, and severity of the obstruction. Often, severe pain, paresthesia, numbness, and coldness develop in the involved extremity within 1 hour. Paralysis may occur with severe and persistent ischemia. Physical findings include loss of pulses distal to the occlusion, cyanosis or pallor, mottling, decreased skin temperature, muscle stiffening, loss of sensation, weakness, and/or absent deep tendon reflexes. If acute arterial occlusion occurs in the presence of an adequate collateral circulation, as is often the case in acute graft occlusion, the symptoms and findings may be less impressive. In this situation, the patient complains about an abrupt decrease in the distance walked before claudication occurs or of modest pain and paresthesia. Pallor and coolness are evident, but sensory and motor functions generally are preserved. The diagnosis of acute limb ischemia is usually apparent from the clinical presentation.


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InternalMed_Harrison. and paresthesia. Pallor and coolness are evident, but sensory and motor functions generally are preserved. The diagnosis of acute limb ischemia is usually apparent from the clinical presentation. In most circumstances, MRA, CTA, or catheter-based arteriography is used to confirm the diagnosis and demonstrate the location and extent of arterial occlusion.


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InternalMed_Harrison. Once the diagnosis is made, the patient should be anticoagulated with intravenous heparin to prevent propagation of the clot. In cases of severe ischemia of recent onset, particularly when limb viability is jeopardized, immediate intervention to ensure reperfusion is indicated. Catheter-directed thrombolysis/thrombectomy, surgical thromboembolectomy, and arterial bypass procedures are used to restore blood flow to the ischemic extremity promptly, particularly when a large proximal vessel is occluded.


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InternalMed_Harrison. Intraarterial thrombolytic therapy with recombinant tissue plasminogen activator, reteplase, or tenecteplase is most effective when acute arterial occlusion is recent (<2 weeks) and caused by a thrombus in an atherosclerotic vessel, arterial bypass graft, or occluded stent. Thrombolytic therapy is also indicated when the patient’s overall condition contraindicates surgical intervention or when smaller distal vessels are occluded, thus preventing surgical access. Meticulous observation for hemorrhagic complications is required during intraarterial thrombolytic therapy. Another endovascular approach to thrombus removal is percutaneous mechanical thrombectomy using devices that employ hydrodynamic forces or rotating baskets to fragment and remove the clot. These treatments may be used alone but usually are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss or when symptoms


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InternalMed_Harrison. usually are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss or when symptoms of occlusion have been present for more than 2 weeks. Amputation is performed when the limb is not viable, as characterized by loss of sensation, paralysis, and the absence of Doppler-detected blood flow in both arteries and veins.


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InternalMed_Harrison. If the limb is not in jeopardy, a more conservative approach that includes observation and administration of anticoagulants may be taken. Anticoagulation prevents recurrent embolism and reduces the likelihood of thrombus propagation; it can be initiated with intravenous heparin and followed by oral warfarin. Recommended doses are the same as those used for deep vein thrombosis (Chap. 300). Emboli resulting from infective endocarditis, the presence of prosthetic heart valves, or atrial myxoma often require surgical intervention to remove the cause.


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InternalMed_Harrison. Atheroembolism is another cause of limb ischemia. In this condition, multiple small deposits of fibrin, platelets, and cholesterol debris embolize from proximal atherosclerotic lesions or aneurysmal sites. Large protruding aortic atheromas are a source of emboli that may lead to limb ischemia, as well as stroke and renal insufficiency. Atheroembolism may occur after intraarterial procedures. Since atheroemboli to limbs tend to lodge in the small vessels of the muscle and skin and may not occlude the large vessels, distal pulses usually remain palpable. Patients complain of acute pain and tenderness at the site of embolization. Digital vascular occlusion may result in ischemia and the “blue toe” syndrome; digital necrosis and gangrene may develop (Fig. 302-2). Localized areas of tenderness, pallor, and livedo reticularis (see below) occur at sites of emboli. Skin or muscle biopsy may demonstrate cholesterol crystals.


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InternalMed_Harrison. Ischemia resulting from atheroemboli is notoriously difficult to treat. Usually neither surgical revascularization procedures nor thrombolytic therapy is helpful because of the multiplicity, composition, and distal location of the emboli. There is limited evidence that anti-thrombotic therapy with platelet inhibitors or anticoagulants prevents atheroembolism. Statins may stabilize plaque and potentially reduce the risk of atheroembolism. Surgical intervention to remove or bypass the atherosclerotic vessel or aneurysm that causes the recurrent atheroemboli may be necessary.


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InternalMed_Harrison. This is a symptom complex resulting from compression of the neurovascular bundle (artery, vein, or nerves) at the thoracic outlet as it courses through the neck and shoulder. Cervical ribs, abnormalities of the scalenus anticus muscle, proximity of the clavicle to the first rib, or abnormal insertion of the pectoralis minor muscle may compress the subclavian artery, subclavian vein, and brachial plexus as these structures pass from the thorax to the arm. Depending on the structures affected, thoracic outlet compression syndrome is divided into arterial, venous, and neurogenic forms. Patients with neurogenic thoracic outlet compression may develop shoulder and arm pain, weakness, and paresthesias. Patients with arterial compression may experience claudication, Raynaud’s phenomenon, and even ischemic tissue loss and gangrene. Venous compression may cause thrombosis of the subclavian and axillary veins; this is often associated with effort and is referred to as Paget-Schroetter syndrome.


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InternalMed_Harrison. FIGURE 302-2 Atheroembolism causing cyanotic discoloration and impending necrosis of the toes (“blue toe” syndrome). Examination of a patient with arterial thoracic outlet compression syndrome is often normal unless provocative maneuvers are performed. Occasionally, distal pulses are decreased or absent and digital cyanosis and ischemia may be evident.


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InternalMed_Harrison. Several maneuvers that support the diagnosis of arterial thoracic outlet compression syndrome may be used to precipitate symptoms, cause a subclavian artery bruit, and diminish arm pulses. These maneuvers include the abduction and external rotation test, in which the affected arm is abducted by 90° and the shoulder is externally rotated; the scalene maneuver (extension of the neck and rotation of the head to the side of the symptoms); the costoclavicular maneuver (posterior rotation of shoulders); and the hyperabduction maneuver (raising the arm 180°). A chest x-ray will indicate the presence of cervical ribs. Duplex ultrasonography, MRA, and contrast angiography can be performed during provocative maneuvers to demonstrate thoracic outlet compression of the subclavian artery. Neurophysiologic tests such as the electromyogram, nerve conduction studies, and somatosensory evoked potentials may be abnormal if the brachial plexus is involved, but the diagnosis of neurogenic thoracic outlet


InternalMed_Harrison

InternalMed_Harrison. tests such as the electromyogram, nerve conduction studies, and somatosensory evoked potentials may be abnormal if the brachial plexus is involved, but the diagnosis of neurogenic thoracic outlet syndrome is not necessarily excluded if these tests are normal owing to their low sensitivity.


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InternalMed_Harrison. Most patients can be managed conservatively. They should be advised to avoid the positions that cause symptoms. Many patients benefit from shoulder girdle exercises. Surgical procedures such as removal of the first rib and resection of the scalenus anticus muscle are necessary occasionally for relief of symptoms or treatment of ischemia. Popliteal artery entrapment typically affects young athletic men and women when the gastrocnemius or popliteus muscle compresses the popliteal artery and causes intermittent claudication. Thrombosis, 1647 embolism, or popliteal artery aneurysm may occur. The pulse examination may be normal unless provocative maneuvers such as ankle dorsiflexion and plantar flexion are performed. The diagnosis is confirmed by duplex ultrasound, CTA, MRA, or conventional angiography. Treatment involves surgical release of the popliteal artery or vascular reconstruction.


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InternalMed_Harrison. Popliteal artery aneurysms are the most common peripheral artery aneurysms. Approximately 50% are bilateral. Patients with popliteal artery aneurysms often have aneurysms of other arteries, especially the aorta. The most common clinical presentation is limb ischemia secondary to thrombosis or embolism. Rupture occurs less frequently. Other complications include compression of the adjacent popliteal vein or peroneal nerve. Popliteal artery aneurysm can be detected by palpation and confirmed by duplex ultrasonography. Repair is indicated for symptomatic aneurysms or when the diameter exceeds 2–3 cm, owing to the risk of thrombosis, embolism, or rupture.


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InternalMed_Harrison. Abnormal communications between an artery and a vein, bypassing the capillary bed, may be congenital or acquired. Congenital arteriovenous fistulas are a result of persistent embryonic vessels that fail to differentiate into arteries and veins; they may be associated with birthmarks, can be located in almost any organ of the body, and frequently occur in the extremities. Acquired arteriovenous fistulas either are created to provide vascular access for hemodialysis or occur as a result of a penetrating injury such as a gunshot or knife wound or as complications of arterial catheterization or surgical dissection. An uncommon cause of arteriovenous fistula is rupture of an arterial aneurysm into a vein.


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InternalMed_Harrison. The clinical features depend on the location and size of the fistula. Frequently, a pulsatile mass is palpable, and a thrill and a bruit lasting throughout systole and diastole are present over the fistula. With long-standing fistulas, clinical manifestations of chronic venous insufficiency, including peripheral edema; large, tortuous varicose veins; and stasis pigmentation become apparent because of the high venous pressure. Evidence of ischemia may occur in the distal portion of the extremity. Skin temperature is higher over the arteriovenous fistula. Large arteriovenous fistulas may result in an increased cardiac output with consequent cardiomegaly and high-output heart failure (Chap. 279).


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InternalMed_Harrison. The diagnosis is often evident from the physical examination. Compression of a large arteriovenous fistula may cause reflex slowing of the heart rate (Nicoladoni-Branham sign). Duplex ultrasonography may detect an arteriovenous fistula, especially one that affects the femoral artery and vein at the site of catheter access. CTA and conventional angiography can confirm the diagnosis and are useful in demonstrating the site and size of the arteriovenous fistula.


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InternalMed_Harrison. Management of arteriovenous fistulas may involve surgery, radiotherapy, or embolization. Congenital arteriovenous fistulas are often difficult to treat because the communications may be numerous and extensive, and new communications frequently develop after ligation of the most obvious ones. Many of these lesions are best treated conservatively using elastic support hose to reduce the consequences of venous hypertension. Occasionally, embolization with autologous material, such as fat or muscle, or with hemostatic agents, such as gelatin sponges or silicon spheres, is used to obliterate the fistula. Acquired arteriovenous fistulas are usually amenable to surgical treatment that involves division or excision of the fistula. Occasionally, autogenous or synthetic grafting is necessary to reestablish continuity of the artery and vein.


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InternalMed_Harrison. Raynaud’s phenomenon is characterized by episodic digital ischemia, manifested clinically by the sequential development of digital blanching, cyanosis, and rubor of the fingers or toes after cold exposure Arterial Diseases of the Extremities FIGURE 302-3 Vascular diseases associated with temperature: (A) Raynaud’s phenomenon; (B) acrocyanosis; (C) livedo reticularis; (D) pernio; (E) erythromelalgia; and (F) frostbite.


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InternalMed_Harrison. FIGURE 302-3 Vascular diseases associated with temperature: (A) Raynaud’s phenomenon; (B) acrocyanosis; (C) livedo reticularis; (D) pernio; (E) erythromelalgia; and (F) frostbite. and subsequent rewarming. Emotional stress may also precipitate Raynaud’s phenomenon. The color changes are usually well demarcated and are confined to the fingers or toes. Typically, one or more digits will appear white when the patient is exposed to a cold environment or touches a cold object (Fig. 302-3A). The blanching, or pallor, represents the ischemic phase of the phenomenon and results from vasospasm of digital arteries. During the ischemic phase, capillaries and venules dilate, and cyanosis results from the deoxygenated blood that is present in these vessels. A sensation of cold or numbness or paresthesia of the digits often accompanies the phases of pallor and cyanosis.


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InternalMed_Harrison. With rewarming, the digital vasospasm resolves, and blood flow into the dilated arterioles and capillaries increases dramatically. This “reactive hyperemia” imparts a bright red color to the digits. In addition to rubor and warmth, patients often experience a throbbing, painful sensation during the hyperemic phase. Although the triphasic color response is typical of Raynaud’s phenomenon, some patients may develop only pallor and cyanosis; others may experience only cyanosis. Raynaud’s phenomenon is broadly separated into two categories: idiopathic, termed primary Raynaud’s phenomenon, and secondary Raynaud’s phenomenon, which is associated with other disease states or known causes of vasospasm (Table 302-1).


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InternalMed_Harrison. Primary Raynaud’s Phenomenon This appellation is applied when the secondary causes of Raynaud’s phenomenon have been excluded. Over 50% of patients with Raynaud’s phenomenon have the primary form. Women are affected about five times more often than men, and the age of presentation is usually between 20 and 40 years. The fingers are involved more frequently than the toes. Initial episodes may involve only one or two fingertips, but subsequent attacks may involve the entire finger and may include all the fingers. The toes are affected in 40% of patients. Although vasospasm of the toes usually occurs in patients with symptoms in the fingers, it may happen alone. Rarely, the earlobes, the tip of the nose, and the penis are involved. Raynaud’s phenomenon occurs frequently in patients who also have migraine headaches or variant angina. These associations suggest that there may be a common predisposing cause for the vasospasm.


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InternalMed_Harrison. Results of physical examination are often entirely normal; the radial, ulnar, and pedal pulses are normal. The fingers and toes may Collagen vascular diseases: scleroderma, systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, polymyositis, mixed connective tissue disease, Sjögren’s syndrome Arterial occlusive diseases: atherosclerosis of the extremities, thromboangiitis obliterans, acute arterial occlusion, thoracic outlet syndrome Neurologic disorders: intervertebral disk disease, syringomyelia, spinal cord tumors, stroke, poliomyelitis, carpal tunnel syndrome, complex regional pain syndrome Blood dyscrasias: cold agglutinins, cryoglobulinemia, cryofibrinogenemia, myeloproliferative disorders, lymphoplasmacytic lymphoma Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury, typing, piano playing


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InternalMed_Harrison. Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury, typing, piano playing Drugs and toxins: ergot derivatives, methysergide, β-adrenergic receptor blockers, bleomycin, vinblastine, cisplatin, gemcitabine, vinyl chloride be cool between attacks and may perspire excessively. Thickening and tightening of the digital subcutaneous tissue (sclerodactyly) develop in 10% of patients. Angiography of the digits for diagnostic purposes is not indicated. In general, patients with primary Raynaud’s disease have milder clinical manifestations. Fewer than 1% of these patients lose a part of a digit. After the diagnosis is made, the disease improves spontaneously in approximately 15% of patients and progresses in about 30%.


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InternalMed_Harrison. Secondary Causes of Raynaud’s Phenomenon Raynaud’s phenomenon occurs in 80–90% of patients with systemic sclerosis (scleroderma) and is the presenting symptom in 30% (Chap. 382). It may be the only symptom of scleroderma for many years. Abnormalities of the digital vessels may contribute to the development of Raynaud’s phenomenon in this disorder. Ischemic fingertip ulcers may develop and progress to gangrene and autoamputation. About 20% of patients with systemic lupus erythematosus (SLE) have Raynaud’s phenomenon (Chap. 378). Occasionally, persistent digital ischemia develops and may result in ulcers or gangrene. In most severe cases, the small vessels are occluded by a proliferative endarteritis. Raynaud’s phenomenon occurs in about 30% of patients with dermatomyositis or polymyositis (Chap. 388). It frequently develops in patients with rheumatoid arthritis and may be related to the intimal proliferation that occurs in the digital arteries.


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InternalMed_Harrison. Atherosclerosis of the extremities is a common cause of Raynaud’s phenomenon in men >50 years. Thromboangiitis obliterans is an uncommon cause of Raynaud’s phenomenon but should be considered in young men, particularly those who are cigarette smokers. The development of cold-induced pallor in these disorders may be confined to one or two digits of the involved extremity. Occasionally, Raynaud’s phenomenon may follow acute occlusion of large and medium-size arteries by a thrombus or embolus. Embolization of atheroembolic debris may cause digital ischemia. The latter situation often involves one or two digits and should not be confused with Raynaud’s phenomenon. In patients with thoracic outlet compression syndrome, Raynaud’s phenomenon may result from diminished intravascular pressure, stimulation of sympathetic fibers in the brachial plexus, or a combination of both. Raynaud’s phenomenon occurs in patients with primary pulmonary hypertension (Chap. 304); this is more than coincidental


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InternalMed_Harrison. of sympathetic fibers in the brachial plexus, or a combination of both. Raynaud’s phenomenon occurs in patients with primary pulmonary hypertension (Chap. 304); this is more than coincidental and may reflect a neurohumoral abnormality that affects both the pulmonary and digital circulations.


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InternalMed_Harrison. A variety of blood dyscrasias may be associated with Raynaud’s phenomenon. Cold-induced precipitation of plasma proteins, hyper-viscosity, and aggregation of red cells and platelets may occur in patients with cold agglutinins, cryoglobulinemia, or cryofibrinogenemia. Hyperviscosity syndromes that accompany myeloproliferative disorders and lymphoplasmacytic lymphoma (Waldenström’s macroglobulinemia) should also be considered in the initial evaluation of patients with Raynaud’s phenomenon. Raynaud’s phenomenon occurs often in patients whose vocations require the use of vibrating hand tools, such as chain saws or jackhammers. The frequency of Raynaud’s phenomenon also seems to be increased in pianists and keyboard operators. Electric shock injury to the hands or frostbite may lead to the later development of Raynaud’s phenomenon.


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InternalMed_Harrison. Several drugs have been causally implicated in Raynaud’s phenomenon. They include ergot preparations, methysergide, β-adrenergic receptor antagonists, and the chemotherapeutic agents bleomycin, vinblastine, cisplatin, and gemcitabine. Most patients with Raynaud’s phenomenon experience only mild and infrequent episodes. These patients need reassurance and should be instructed to dress warmly and avoid unnecessary cold exposure. In addition to gloves and mittens, patients should protect the trunk, head, and feet with warm clothing to prevent cold-induced reflex vasoconstriction. Tobacco use is contraindicated.


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InternalMed_Harrison. Drug treatment should be reserved for severe cases. 1649 Dihydropyridine calcium channel antagonists such as nifedipine, isradipine, felodipine, and amlodipine decrease the frequency and severity of Raynaud’s phenomenon. Diltiazem may be considered but is less effective. The postsynaptic α1-adrenergic antagonist prazosin has been used with favorable responses; doxazosin and terazosin may also be effective. Phosphodiesterase type 5 inhibitors such as sildenafil and tadalafil may improve symptoms in patients with secondary Raynaud’s phenomenon, as occurs with systemic sclerosis. Digital sympathectomy is helpful in some patients who are unresponsive to medical therapy.


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InternalMed_Harrison. In this condition, there is arterial vasoconstriction and secondary dilation of the capillaries and venules with resulting persistent cyanosis of the hands and, less frequently, the feet. Cyanosis may be intensified by exposure to a cold environment. Acrocyanosis may be categorized as primary or secondary to an underlying condition. In primary acrocyanosis, women are affected much more frequently than men, and the age of onset is usually <30 years. Generally, patients are asymptomatic but seek medical attention because of the discoloration. The prognosis is favorable, and pain, ulcers, and gangrene do not occur. Examination reveals normal pulses, peripheral cyanosis, and moist palms (Fig. 302-3B). Trophic skin changes and ulcerations do not occur. The disorder can be distinguished from Raynaud’s phenomenon because it is persistent and not episodic, the discoloration extends proximally from the digits, and blanching does not occur. Ischemia secondary to arterial occlusive disease can


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InternalMed_Harrison. phenomenon because it is persistent and not episodic, the discoloration extends proximally from the digits, and blanching does not occur. Ischemia secondary to arterial occlusive disease can usually be excluded by the presence of normal pulses. Central cyanosis and decreased arterial oxygen saturation are not present. Patients should be reassured and advised to dress warmly and avoid cold exposure. Pharmacologic intervention is not indicated.


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InternalMed_Harrison. Secondary acrocyanosis may result from hypoxemia, vasopressor medications, connective tissue diseases, atheroembolism, antiphospholipid antibodies, cold agglutinins, or cryoglobulins and is associated with anorexia nervosa and postural orthostatic tachycardia syndrome. Treatment should be directed at the underlying disorder.


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InternalMed_Harrison. In this condition, localized areas of the extremities develop a mottled or rete (netlike) appearance of reddish to blue discoloration (Fig. 302-3C). The mottled appearance may be more prominent after cold exposure. There are primary and secondary forms of livedo reticularis. The primary, or idiopathic, form of this disorder may be benign or associated with ulcerations. The benign form occurs more frequently in women than in men, and the most common age of onset is the third decade. Patients with the benign form are usually asymptomatic and seek attention for cosmetic reasons. These patients should be reassured and advised to avoid cold environments. No drug treatment is indicated. Primary livedo reticularis with ulceration is also called atrophie blanche en plaque. The ulcers are painful and may take months to heal. Secondary livedo reticularis can occur with atheroembolism (see above), SLE and other vasculitides, anticardiolipin antibodies, hyper-viscosity, cryoglobulinemia, and


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InternalMed_Harrison. and may take months to heal. Secondary livedo reticularis can occur with atheroembolism (see above), SLE and other vasculitides, anticardiolipin antibodies, hyper-viscosity, cryoglobulinemia, and Sneddon’s syndrome (ischemic stroke and livedo reticularis). Rarely, skin ulcerations develop.


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InternalMed_Harrison. Pernio is a vasculitic disorder associated with exposure to cold; acute forms have been described. Raised erythematous lesions develop on the lower part of the legs and feet in cold weather (Fig. 302-3D). They are associated with pruritus and a burning sensation, and they may blister and ulcerate. Pathologic examination demonstrates angiitis characterized by intimal proliferation and perivascular infiltration of mononuclear and polymorphonuclear leukocytes. Giant cells may be present in the subcutaneous tissue. Patients should avoid exposure to cold, and ulcers should be kept clean and protected with sterile dressings. Sympatholytic drugs and dihydropyridine calcium channel antagonists may be effective in some patients.


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InternalMed_Harrison. Arterial Diseases of the Extremities 1650 ERYTHROMELALGIA This disorder is characterized by burning pain and erythema of the extremities (Fig. 302-3E). The feet are involved more frequently than the hands, and males are affected more frequently than females. Erythromelalgia may occur at any age but is most common in middle age. It may be primary (also termed erythermalgia) or secondary. Mutations in the SCN9A gene, which encodes the Nav1.7 voltage-gated sodium channel expressed in sensory and sympathetic nerves, has been described in inherited forms of erythromelalgia. The most common causes of secondary erythromelalgia are myeloproliferative disorders such as polycythemia vera and essential thrombocytosis. Less common causes include drugs, such as calcium channel blockers, bromocriptine, and pergolide; neuropathies; connective tissue diseases such as SLE; and paraneoplastic syndromes. Patients complain of burning in the extremities that is precipitated by exposure to a warm


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InternalMed_Harrison. and pergolide; neuropathies; connective tissue diseases such as SLE; and paraneoplastic syndromes. Patients complain of burning in the extremities that is precipitated by exposure to a warm environment and aggravated by a dependent position. The symptoms are relieved by exposing the affected area to cool air or water or by elevation. Erythromelalgia can be distinguished from ischemia secondary to peripheral arterial disorders because the peripheral pulses are present. There is no specific treatment; aspirin may produce relief in patients with erythromelalgia secondary to myeloproliferative disease. Treatment of associated disorders in secondary erythromelalgia may be helpful.


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InternalMed_Harrison. In this condition, tissue damage results from severe environmental cold exposure or from direct contact with a very cold object. Tissue injury results from both freezing and vasoconstriction. Frostbite usually affects the distal aspects of the extremities or exposed parts of the face, such as the ears, nose, chin, and cheeks. Superficial frostbite involves the skin and subcutaneous tissue. Patients experience pain or paresthesia, and the skin appears white and waxy. After rewarming, there is cyanosis and erythema, wheal-and-flare formation, edema, and superficial blisters. Deep frostbite involves muscle, nerves, and deeper blood vessels. It may result in edema of the hand or foot, vesicles and bullae, tissue necrosis, and gangrene (Fig. 302-3F).


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InternalMed_Harrison. Initial treatment is rewarming, performed in an environment where reexposure to freezing conditions will not occur. Rewarming is accomplished by immersion of the affected part in a water bath at temperatures of 40°–44°C (104°–111°F). Massage, application of ice water, and extreme heat are contraindicated. The injured area should be cleansed with soap or antiseptic, and sterile dressings should be applied. Analgesics are often required during rewarming. Antibiotics are used if there is evidence of infection. The efficacy of sympathetic may exhibit increased sensitivity to cold. lymphedema CHRONIC VENOUS DISEASE 303 blocking drugs is not established. After recovery, the affected extremity Mark A. Creager, Joseph Loscalzo


InternalMed_Harrison

InternalMed_Harrison. Mark A. Creager, Joseph Loscalzo Chronic venous diseases range from telangiectasias and reticular veins, to varicose veins, to chronic venous insufficiency with edema, skin changes, and ulceration. This section of the chapter will focus on identification and treatment of varicose veins and chronic venous insufficiency, since these problems are encountered frequently by the internist. The estimated prevalence of varicose veins in the United States is approximately 15% in men and 30% in women. Chronic venous insufficiency with edema affects approximately 7.5% of men and 5% of women, and the prevalence increases with age ranging from 2% among those less than 50 years of age to 10% of those 70 years of age. Approximately 20% of patients with chronic venous insufficiency develop venous ulcers.


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InternalMed_Harrison. Veins in the extremities can be broadly classified as either superficial or deep. The superficial veins are located between the skin and deep fascia. In the legs, these include the great and small saphenous veins and their tributaries. The great saphenous vein is the longest vein in the body. It originates on the medial side of the foot and ascends anterior to the medial malleolus and then along the medial side of the calf and thigh, and drains into the common femoral vein. The small saphenous vein originates on the dorsolateral aspect of the foot, ascends posterior to the lateral malleolus and along the posterolateral aspect of the calf, and drains into the popliteal vein. The deep veins of the leg accompany the major arteries. There are usually paired peroneal, anterior tibial, and posterior tibial veins in the calf, which converge to form the popliteal vein. Soleal tributary veins drain into the posterior tibial or peroneal veins, and gastrocnemius tributary veins drain into the


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InternalMed_Harrison. tibial veins in the calf, which converge to form the popliteal vein. Soleal tributary veins drain into the posterior tibial or peroneal veins, and gastrocnemius tributary veins drain into the popliteal vein. The popliteal vein ascends in the thigh as the femoral vein. The confluence of the femoral vein and deep femoral vein form the common femoral vein, which ascends in the pelvis as the external iliac and then common iliac vein, which converges with the contralateral common iliac vein at the inferior vena cava. Perforating veins connect the superficial and deep systems in the legs at multiple locations, normally allowing blood to flow from the superficial to deep veins. In the arms, the superficial veins include the basilic, cephalic, and median cubital veins and their tributaries. The basilic and cephalic veins course along the medial and lateral aspects of the arm, respectively, and these are connected via the median cubital vein in the antecubital fossa. The deep veins of the arms


InternalMed_Harrison

InternalMed_Harrison. and cephalic veins course along the medial and lateral aspects of the arm, respectively, and these are connected via the median cubital vein in the antecubital fossa. The deep veins of the arms accompany the major arteries and include the radial, ulnar, brachial, axillary, and subclavian veins. The subclavian vein converges with the internal jugular vein to form the brachiocephalic vein, which joins the contralateral brachiocephalic vein to form the superior vena cava. Bicuspid valves are present throughout the venous system to direct the flow of venous blood centrally.


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InternalMed_Harrison. Pathophysiology of Chronic Venous Disease Varicose veins are dilated, bulging, tortuous superficial veins, measuring at least 3 mm in diameter. The smaller and less tortuous reticular veins are dilated intradermal veins, which appear blue-green, measure 1 to 3 mm in diameter, and do not protrude from the skin surface. Telangiectasias, or spider veins, are small, dilated veins, less than 1 mm in diameter, located near the skin surface, and form blue, purple, or red linear, branching, or spider-web patterns.


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InternalMed_Harrison. Varicose veins can be categorized as primary or secondary. Primary varicose veins originate in the superficial system and result from defective structure and function of the valves of the saphenous veins, intrinsic weakness of the vein wall, and high intraluminal pressure. Approximately one-half of these patients have a family history of varicose veins. Other factors associated with primary varicose veins include aging, pregnancy, hormonal therapy, obesity, and prolonged standing. Secondary varicose veins result from venous hypertension, associated with deep venous insufficiency or deep venous obstruction, and incompetent perforating veins that cause enlargement of superficial veins. Arteriovenous fistulas also cause varicose veins in the affected limb.


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InternalMed_Harrison. Chronic venous insufficiency is a consequence of incompetent veins in which there is venous hypertension and extravasation of fluid and blood elements into the tissue of the limb. It may occur in patients with varicose veins but usually is caused by disease in the deep veins. It also is categorized as primary or secondary. Primary deep venous insufficiency is a consequence of an intrinsic structural or functional abnormality in the vein wall or venous valves leading to valvular reflux. Secondary deep venous insufficiency is caused by obstruction and/or valvular incompetence from previous deep vein thrombosis (Chap. 300). Deep venous insufficiency occurs following deep vein thrombosis, as the delicate valve leaflets become thickened and contracted and can no longer prevent retrograde flow of blood and the vein itself becomes rigid and thick walled. Although most veins recanalize after an episode of thrombosis, the large proximal veins may remain occluded. Secondary incompetence


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InternalMed_Harrison. flow of blood and the vein itself becomes rigid and thick walled. Although most veins recanalize after an episode of thrombosis, the large proximal veins may remain occluded. Secondary incompetence develops in distal valves because high pressures distend the vein and separate the leaflets. Other causes of secondary deep venous insufficiency include May-Thurner syndrome, where the left iliac vein is occluded or stenosed by extrinsic compression from the overlapping right common iliac artery; arteriovenous fistulas resulting in increased venous pressure; congenital deep vein agenesis or hypoplasia; and venous malformations as may occur in Klippel-Trénaunay-Weber and Parkes-Weber syndromes.


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InternalMed_Harrison. Clinical Presentation Patients with venous varicosities are often asymptomatic but still concerned about the cosmetic appearance of their legs. Superficial venous thrombosis may be a recurring problem, and, rarely, a varicosity ruptures and bleeds. Symptoms in patients with varicose veins or venous insufficiency, when they occur, include a dull ache, throbbing or heaviness, or pressure sensation in the legs typically after prolonged standing; these symptoms usually are relieved with leg elevation. Additional symptoms may include cramping, burning, pruritus, leg swelling, and skin ulceration.


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InternalMed_Harrison. The legs are examined in both the supine and standing positions. Visual inspection and palpation of the legs in the standing position confirm the presence of varicose veins. The location and extent of the varicose veins should be noted. Edema, stasis dermatitis, and skin ulceration near the ankle may be present if there is superficial venous insufficiency and venous hypertension. Findings of deep venous insufficiency include increased leg circumference, venous varicosities, edema, and skin changes. The edema, which is usually pitting, may be confined to the ankles, extend above the ankles to the knees, or involve the thighs in severe cases. Over time, the edema may become less pitting and more indurated. Dermatologic findings associated with venous stasis include hyperpigmentation, erythema, eczema, lipodermatosclerosis, atrophie blanche, and a phlebectasia corona. Lipodermatosclerosis is the combination of induration, hemosiderin deposition, and inflammation, and typically occurs in


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InternalMed_Harrison. eczema, lipodermatosclerosis, atrophie blanche, and a phlebectasia corona. Lipodermatosclerosis is the combination of induration, hemosiderin deposition, and inflammation, and typically occurs in the lower part of the leg just above the ankle. Atrophie blanche is a white patch of scar tissue, often with focal telangiectasias and a hyperpigmented border; it usually develops near the medial malleolus. A phlebectasia corona is a fan-shaped pattern of intradermal veins near the ankle or on the foot. Skin ulceration may occur near the medial and lateral malleoli. A venous ulcer is often shallow and characterized by an irregular border, a base of granulation tissue, and the presence of exudate (Fig. 303-1).


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InternalMed_Harrison. Bedside maneuvers can be used to distinguish primary varicose veins from secondary varicose veins caused by deep venous insufficiency. With the contemporary use of venous ultrasound (see below), however, these maneuvers are employed infrequently. The Brodie-Trendelenburg


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InternalMed_Harrison. FIGURE 303-1 Venous insufficiency with active venous ulcer near the medial malleolus. (Courtesy of Dr. Steven Dean, with permission.) test is used to determine whether varicose veins are secondary to deep 1651 venous insufficiency. As the patient is lying supine, the leg is elevated and the veins allowed to empty. Then, a tourniquet is placed on the proximal part of the thigh and the patient is asked to stand. Filling of the varicose veins within 30 s indicates that the varicose veins are caused by deep venous insufficiency and incompetent perforating veins. Primary varicose veins with superficial venous insufficiency are the likely diagnosis if venous refilling occurs promptly after tourniquet removal. The Perthes test assesses the possibility of deep venous obstruction. A tourniquet is placed on the midthigh after the patient has stood, and the varicose veins are filled. The patient is then instructed to walk for 5 min. A patent deep venous system and competent perforating veins


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InternalMed_Harrison. is placed on the midthigh after the patient has stood, and the varicose veins are filled. The patient is then instructed to walk for 5 min. A patent deep venous system and competent perforating veins enable the superficial veins below the tourniquet to collapse. Deep venous obstruction is likely to be present if the superficial veins distend further with walking.


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InternalMed_Harrison. Differential Diagnosis The duration of leg edema helps to distinguish chronic venous insufficiency from acute deep vein thrombosis. Lymphedema, as discussed later in this chapter, is often confused with chronic venous insufficiency, and both may occur together. Other disorders that cause leg swelling should be considered and excluded when evaluating a patient with presumed venous insufficiency. Bilateral leg swelling occurs in patients with congestive heart failure, hypoalbuminemia secondary to nephrotic syndrome or severe hepatic disease, myxedema caused by hypothyroidism or pretibial myxedema associated with Graves’ disease, and with drugs such as dihydropyridine calcium channel blockers and thiazolidinediones. Unilateral causes of leg swelling also include ruptured leg muscles, hematomas secondary to trauma, and popliteal cysts. Cellulitis may cause erythema and swelling of the affected limb. Leg ulcers may be caused by severe peripheral artery disease and critical limb ischemia;


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InternalMed_Harrison. secondary to trauma, and popliteal cysts. Cellulitis may cause erythema and swelling of the affected limb. Leg ulcers may be caused by severe peripheral artery disease and critical limb ischemia; neuropathies, particularly those associated with diabetes; and less commonly, skin cancer, vasculitis, or rarely as a complication of hydroxyurea. The location and characteristics of venous ulcers help to differentiate these from other causes.


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InternalMed_Harrison. Classification of Chronic Venous Disease The CEAP (clinical, etiologic, anatomic, pathophysiologic) classification schema incorporates the range of symptoms and signs of chronic venous disease to characterize its severity. It also broadly categorizes the etiology as congenital, primary, or secondary; identifies the affected veins as superficial, deep, or perforating; and characterizes the pathophysiology as reflux, obstruction, both, or neither (Table 303-1).


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InternalMed_Harrison. Diagnostic Testing The principal diagnostic test to evaluate patients with chronic venous disease is venous duplex ultrasonography. A venous duplex ultrasound examination uses a combination of B-mode imaging and spectral Doppler to detect the presence of venous obstruction and venous reflux in superficial and deep veins. Color-assisted Doppler ultrasound is useful to visualize venous flow patterns. Obstruction may be diagnosed by absence of flow, the presence of an echogenic thrombus within the vein, or failure of the vein to collapse when a compression maneuver is applied by the sonographer, the last implicating the presence of an intraluminal thrombus. Venous reflux is detected by prolonged reversal of venous flow direction during a Valsalva maneuver, particularly for the common femoral vein or saphenofemoral junction, or after compression and release of a cuff placed on the limb distal to the area being interrogated.


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InternalMed_Harrison. Some vascular laboratories use air or strange gauge plethysmography to assess the severity of venous reflux and complement findings from the venous ultrasound examination. Venous volume and venous refilling time are measured when the legs are placed in a dependent position and after calf exercise to quantify the severity of venous reflux and the efficiency of the calf muscle pump to affect venous return. Magnetic resonance, computed tomographic, and conventional venography are rarely required to determine the cause and plan treatment for chronic venous insufficiency unless there is suspicion for pathology that might warrant intervention. These modalities are used to identify obstruction or stenosis of the inferior vena cava and iliofemoral veins, as may occur in patients with previous proximal TABlE 303-1 CEAP (CliniCAl, ETiologiC, AnAToMiC, PATHoPHYSiologiC) ClASSiFiCATion


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InternalMed_Harrison. TABlE 303-1 CEAP (CliniCAl, ETiologiC, AnAToMiC, PATHoPHYSiologiC) ClASSiFiCATion C0 No visible or palpable signs of venous disease C1 Telangiectasias, reticular veins C2 Varicose veins C3 Edema without skin changes C4 Skin changes, including pigmentation, eczema, lipodermatosclerosis, and Pr Reflux Po Obstruction Pr,o Reflux and obstruction Pn No venous pathophysiology identifiable Source: B Eklöf et al: J Vasc Surg 40:1248, 2004. deep vein thrombosis; occlusion of inferior vena cava filters; extrinsic compression from tumors; and May-Thurner syndrome.


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InternalMed_Harrison. Source: B Eklöf et al: J Vasc Surg 40:1248, 2004. deep vein thrombosis; occlusion of inferior vena cava filters; extrinsic compression from tumors; and May-Thurner syndrome. Varicose veins usually are treated with conservative measures. Symptoms often decrease when the legs are elevated periodically, prolonged standing is avoided, and elastic support hose are worn. External compression with elastic stockings or stretch bandages provides a counterbalance to the hydrostatic pressure in the veins. Although compression garments may improve symptoms, they do not prevent progression of varicose veins. Graduated compression stockings with pressures of 20–30 mmHg are suitable for most patients with simple varicose veins, although pressures of 30–40 mmHg may be required for patients with manifestations of venous insufficiency such as edema and ulcers.


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InternalMed_Harrison. Patients with chronic venous insufficiency also should be advised to avoid prolonged standing or sitting; frequent leg elevation is helpful. Graded compression therapy consisting of stockings or multilayered compression bandages is the standard of care for advanced chronic venous insufficiency characterized by edema, skin changes, or venous ulcers defined as CEAP clinical class C3– C6. Graduated compression stockings of 30–40 mmHg are more effective than lesser grades for healing venous ulcers. The length of stocking depends on the distribution of edema. Calf-length stockings are tolerated better by most patients, particularly elderly patients; for patients with varicose veins or edema extending to the thigh, thigh-length stockings or panty hose should be considered. Overweight and obese patients should be advised to lose weight via caloric restriction and exercise.


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InternalMed_Harrison. In addition to a compression bandage or stocking, patients with venous ulcers also may be treated with low adherent absorbent dressings that take up exudates while maintaining a moist environment. Other types of dressings include hydrocolloid (an adhesive dressing comprised of polymers such as carboxymethylcellulose that absorbs exudates by forming a gel), hydrogel (a nonabsorbent dressing comprising over 80% water or glycerin that moisturizes wounds), foam (an absorbent dressing made with polymers such as polyurethane), and alginate (an absorbent, biodegradable dressing that is derived from seaweed), but there is little evidence that these are more effective than low adherent absorbent dressings. The choice of specific dressing depends on the amount of drainage, presence of infection, and integrity of the skin surrounding the ulcer. Antibiotics are not indicated unless the ulcer is infected. The multilayered compression bandage or graduated compression garment is then put over the


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InternalMed_Harrison. and integrity of the skin surrounding the ulcer. Antibiotics are not indicated unless the ulcer is infected. The multilayered compression bandage or graduated compression garment is then put over the dressing.


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InternalMed_Harrison. There are no drugs approved by the U.S. Food and Drug Administration for the treatment of chronic venous insufficiency. Diuretics may reduce edema, but at the risk of volume depletion and compromise in renal function. Topical steroids may be used for a short period of time to treat inflammation associated with stasis dermatitis. Several herbal supplements, such as horse chestnut seed extract (aescin); flavonoids including diosmin, hesperidin, or the two combined as micronized purified flavonoid fraction; and French maritime pine bark extract, are touted to have venoconstrictive and anti-inflammatory properties. Although meta-analyses have suggested that aescin reduces edema, pruritus, and pain and that micronized purified flavonoid fraction in conjunction with compression therapy facilitates venous ulcer healing, there is insufficient evidence to recommend the general use of these substances in patients with chronic venous insufficiency.


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InternalMed_Harrison. Ablative procedures, including endovenous thermal ablation, sclerotherapy, and surgery, are used to treat varicose veins in selected patients who have persistent symptoms, great saphenous vein incompetency, and complications of venous insufficiency including dermatitis, edema, and ulcers. Ablative therapy may also be indicated for cosmetic reasons.


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InternalMed_Harrison. Endovenous thermal ablation procedures of the saphenous veins include endovenous laser therapy and radiofrequency ablation. To ablate the great saphenous vein, a catheter is placed percutaneously and advanced from the level of the knee to just below the saphenofemoral junction via ultrasound guidance. Thermal energy is then delivered as the catheter is pulled back. The heat injures the endothelium and media and promotes thrombosis and fibrosis, resulting in venous occlusion. Average 1and 5-year occlusion rates exceed 90% following endovenous laser therapy and are slightly less after radiofrequency ablation. Deep vein thrombosis of the common femoral vein adjacent to the saphenofemoral junction is an uncommon but potential complication of endovenous thermal ablation. Other adverse effects of thermal ablation procedures include pain, paresthesias, bruising, hematoma, and hyperpigmentation.


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InternalMed_Harrison. Sclerotherapy involves the injection of a chemical into a vein to cause fibrosis and obstruction. Sclerosing agents approved by the U.S. Food and Drug Administration include sodium tetradecyl sulfate, polidocanol, sodium morrhuate, and glycerin. The sclerosing agent is administered as a liquid or mixed with air or CO2/O2 to create a foam. It first is injected into the great saphenous vein or its affected tributaries, often with ultrasound guidance. Thereafter, smaller more distal veins and incompetent perforating veins are injected. Following completion of the procedure, elastic bandages are applied, or 30–40 mmHg compression stockings are worn for 1–2 weeks. Average 1and 5-year occlusion rates are 81% and 74%, respectively, following sclerotherapy. Complications are uncommon and include deep vein thrombosis, hematomas, damage to adjacent saphenous or sural nerves, and infection. Anaphylaxis is a very rare but severe complication.


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InternalMed_Harrison. Surgical therapy usually involves ligation and stripping of the great and small saphenous veins. The procedure is performed under general anesthesia. Incisions are made at the groin and the upper calf. The great saphenous vein is ligated below the saphenofemoral junction, and a wire is inserted into the great saphenous vein and advanced distally. The proximal part of the great saphenous vein is secured to the wire and retrieved, i.e., stripped, via the calf incision. Stripping of the great saphenous vein below the knee and stripping of the small saphenous vein usually are not performed because of the respective risks of saphenous and sural nerve injury. Complications of great saphenous vein ligation and stripping include deep vein thrombosis, bleeding, hematoma, infection, and nerve injury. Recurrent varicose veins occur in up to 50% patients by 5 years, due to technical failures, deep venous insufficiency, and incompetent perforating veins.


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InternalMed_Harrison. Stab phlebectomy is another surgical treatment for of varicose veins. A small incision is made alongside the varicose vein, and it is avulsed by means of a forceps or hook. This procedure may be performed in conjunction with saphenous vein ligation and stripping or thermal ablation. Subfascial endoscopic perforator surgery (SEPS) uses endoscopy to identify and occlude incompetent perforating veins. It also may be performed along with other ablative procedures.


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InternalMed_Harrison. Endovascular interventions, surgical bypass, and reconstruction of the valves of the deep veins are performed when feasible to treat patients with advanced chronic venous insufficiency who have not responded to other therapies. Catheter-based interventions, usually involving placement of endovenous stents, may be considered to treat some patients with chronic occlusions of the iliac veins. Technical success rates exceed 85% in most series, and long-term patency is achieved in approximately 75% of these patients. Iliocaval bypass, femoroiliac venous bypass, and femorofemoral crossover venous bypass are procedures used occasionally to treat iliofemoral vein occlusion; saphenopopliteal vein bypass can be used to treat chronic femoropopliteal vein obstruction. Long-term patency rates for venous bypass procedures generally exceed 60% and are associated with improvement in symptoms. Surgical reconstruction of the valves of the deep veins and valve transfer procedures are used to treat


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InternalMed_Harrison. venous bypass procedures generally exceed 60% and are associated with improvement in symptoms. Surgical reconstruction of the valves of the deep veins and valve transfer procedures are used to treat valvular incompetence. Valvuloplasty involves tightening the valve by commissural apposition. With valve transfer procedures, a segment of vein with a competent valve, such as a brachial or axillary vein, or adjacent saphenous or deep femoral vein, is inserted as an interposition graft in the incompetent vein. Both valvuloplasty and vein transfer operations result in ulcer healing in the majority of patients, although success rates are somewhat better with valvuloplasty.


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InternalMed_Harrison. Lymphedema Lymphedema is a chronic condition caused by impaired transport of lymph and characterized by swelling of one or more limbs and occasionally the trunk and genitalia. Fluid accumulates in interstitial tissues when there is an imbalance between lymph production and lymph absorption, a process governed in large part by Starling forces. Deficiency, reflux, or obstruction of lymph vessels perturbs the ability of the lymphatic system to reabsorb proteins that had been filtered by blood vessels, and the tissue osmotic load promotes interstitial accumulation of water. Persistent lymphedema leads to inflammatory and immune responses characterized by infiltration of mononuclear cells, fibroblasts, and adipocytes, leading to adipose and collagen deposition in the skin and subcutaneous tissues.


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InternalMed_Harrison. Lymphatic Anatomy Lymphatic capillaries are blind-ended tubes formed by a single layer of endothelial cells. The absent or widely fenestrated basement membrane of lymphatic capillaries allows access to interstitial proteins and particles. Lymphatic capillaries merge to form microlymphatic precollector vessels, which contain few smooth muscle cells. The precollector vessels drain into collecting lymphatic vessels, which comprise endothelial cells, a basement membrane, smooth muscle, and bileaflet valves. The collecting lymphatic vessels in term merge to form larger lymphatic conduits. Analogous to venous anatomy, there are superficial and deep lymphatic vessels in the legs, which communicate at the popliteal and inguinal lymph nodes. Pelvic lymphatic vessels drain into the thoracic duct, which ascends from the abdomen to the thorax and connects with the left brachiocephalic vein. Lymph is propelled centrally by the phasic contractile activity 1653 of lymphatic smooth muscle and


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InternalMed_Harrison. duct, which ascends from the abdomen to the thorax and connects with the left brachiocephalic vein. Lymph is propelled centrally by the phasic contractile activity 1653 of lymphatic smooth muscle and facilitated by the contractions of contiguous skeletal muscle. The presence of lymphatic valves ensures unidirectional flow.


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InternalMed_Harrison. Etiology Lymphedema may be categorized as primary or secondary (Table 303-2). The prevalence of primary lymphedema is approximately 1.15 per 100,000 persons less than 20 years of age. Females are affected more frequently than males. Primary lymphedema may be caused by agenesis, hypoplasia, hyperplasia, or obstruction of the lymphatic vessels. There are three clinical subtypes: congenital lymph-edema, which appears shortly after birth; lymphedema praecox, which has its onset at the time of puberty; and lymphedema tarda, which usually begins after age 35. Familial forms of congenital lymphedema (Milroy’s disease) and lymphedema praecox (Meige’s disease) may be inherited in an autosomal dominant manner with variable penetrance; autosomal or sex-linked recessive forms are less common. Mutations in genes expressing vascular endothelial growth factor receptor 3 (VEGFR3), which is a determinant of lymphangiogenesis, have been described in patients with Milroy’s disease. A mutation on


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InternalMed_Harrison. Mutations in genes expressing vascular endothelial growth factor receptor 3 (VEGFR3), which is a determinant of lymphangiogenesis, have been described in patients with Milroy’s disease. A mutation on chromosome 15q is associated with the cholestasis-lymphedema syndrome. A mutation in the FOXC2 gene, which encodes a transcription factor


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InternalMed_Harrison. Klinefelter’s syndrome Trisomy 13, 18, or 21 Noonan’s syndrome Infection Bacterial lymphangitis (Streptococcus pyogenes, Staphylococcus aureus) Lymphogranuloma venereum (Chlamydia trachomatis) Filariasis (Wucheria bancrofti, Brugia malayi, B. timori) Tuberculosis Neoplastic infiltration of lymph nodes Lymphoma Prostate Others Surgery or irradiation of axillary or inguinal lymph nodes for treatment of cancer


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InternalMed_Harrison. Iatrogenic Lymphatic division (during peripheral bypass surgery, varicose vein surgery, or harvesting of saphenous veins) 1654 that interacts with a signaling pathway involved in the development of lymphatic vessels, has been reported in patients with the lymphedema-distichiasis syndrome, in which lymphedema praecox occurs in patients who also have a double row of eyelashes. A mutation of SOX18, a transcription factor upstream of lymphatic endothelial cell differentiation, has been described in patients with lymphedema, alopecia, and telangiectasias (hypotrichosis, lymphedema, telangiectasia syndrome). Patients with a chromosomal aneuploidy, such as Turner’s syndrome, Klinefelter’s syndrome, or trisomy 18, 13, or 21, may develop lymphedema. Syndromic vascular anomalies associated with lymphedema include Klippel-Trénaunay syndrome, Parkes-Weber syndrome, and Hennekam’s syndrome. Other disorders associated with lymphedema include Noonan’s syndrome, yellow nail syndrome, intestinal


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InternalMed_Harrison. lymphedema include Klippel-Trénaunay syndrome, Parkes-Weber syndrome, and Hennekam’s syndrome. Other disorders associated with lymphedema include Noonan’s syndrome, yellow nail syndrome, intestinal lymphangiectasia syndrome, lymphangiomyomatosis, and neurofibromatosis type 1. Secondary lymphedema is an acquired condition that results from damage to or obstruction of previously normal lymphatic channels. Recurrent episodes of bacterial lymphangitis, usually caused by streptococci, are a very common cause of lymphedema. The most common cause of secondary lymphedema worldwide is lymphatic filariasis, affecting approximately 129 million children and adults worldwide and causing lymphedema and elephantiasis in 14 million of these affected individuals (Chap. 258). Recurrent bacterial lymphangitis by Streptococcus may result in chronic lymphedema. Other infectious causes include lymphogranuloma venereum and tuberculosis. In developed countries, the most common secondary cause of lymphedema


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InternalMed_Harrison. by Streptococcus may result in chronic lymphedema. Other infectious causes include lymphogranuloma venereum and tuberculosis. In developed countries, the most common secondary cause of lymphedema is surgical excision or irradiation of axillary and inguinal lymph nodes for treatment of cancers, such as breast, cervical, endometrial, and prostate cancer, sarcomas, and malignant melanoma. Lymphedema of the arm occurs in 13% of breast cancer patients after axillary node dissection and in 22% after both surgery and radiotherapy. Lymphedema of the leg affects approximately 15% of patients with cancer after inguinal lymph node dissection. Tumors, such as prostate cancer and lymphoma, also can infiltrate and obstruct lymphatic vessels. Less common causes include contact dermatitis, rheumatoid arthritis, pregnancy, and self-induced or factitious lymph-edema after application of tourniquets.


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InternalMed_Harrison. Clinical Presentation Lymphedema is generally a painless condition, but patients may experience a chronic dull, heavy sensation in the leg, and most often they are concerned about the appearance of the leg. Lymphedema of the lower extremity initially involves the foot and gradually progresses up the leg so that the entire limb becomes edematous (Fig. 303-2). In the early stages, the edema is soft and pits easily with pressure. Over time, subcutaneous adipose tissue accumulates, the limb enlarges further and loses its normal contour, and the toes appear square. Thickening of the skin is detected by Stemmer’s sign, which is the inability to tent the skin at the base of the toes. Peau d’orange is a term used to describe dimpling of the skin, resembling that of an orange peel, caused by lymphedema. In the chronic stages, the edema no longer pits and the limb acquires a woody texture as the tissues become indurated and fibrotic. The International Society of Lymphology describes four


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InternalMed_Harrison. lymphedema. In the chronic stages, the edema no longer pits and the limb acquires a woody texture as the tissues become indurated and fibrotic. The International Society of Lymphology describes four clinical stages of lymphedema (Table 303-3).


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InternalMed_Harrison. Differential Diagnosis Lymphedema should be distinguished from other disorders that cause unilateral leg swelling, such as deep vein thrombosis and chronic venous insufficiency. In the latter condition, the edema is softer, and there is often evidence of a stasis dermatitis, hyperpigmentation, and superficial venous varicosities, as described earlier. Other causes of leg swelling that resemble lymphedema are myxedema and lipedema. Lipedema usually occurs in women and is caused by accumulation of adipose tissue in the leg from the thigh to the ankle with sparing of the feet. Diagnostic Testing The evaluation of patients with lymphedema should include diagnostic studies to clarify the cause. Abdominal and pelvic ultrasound and computed tomography (CT) can be used to detect obstructing lesions such as neoplasms. Magnetic resonance imaging (MRI) of the affected limb may reveal a honeycomb pattern


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InternalMed_Harrison. FIGURE 303-2 A. Lymphedema characterized by swelling of the leg, nonpitting edema, and squaring of the toes. (Courtesy of Dr. Marie Gerhard-Herman, with permission.) B. Advanced chronic stage of lymphedema illustrating the woody appearance of the leg with acanthosis and verrucous overgrowths. (Courtesy of Dr. Jeffrey Olin, with permission.) characteristic of lymphedema in the epifascial compartment and identify enlarged lymphatic channels and lymph nodes. MRI also is useful to distinguish lymphedema from lipedema. Lymphoscintigraphy and lymphangiography are rarely indicated, but either can be used to confirm the diagnosis or differentiate primary from secondary lymph-edema. Lymphoscintigraphy involves the injection of radioactively labeled technetium-containing colloid into the distal subcutaneous tissue of the affected extremity, which is imaged with a scintigraphic camera to visualize lymphatic vessels and lymph nodes. Findings indicative of primary lymphedema include absent or


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InternalMed_Harrison. subcutaneous tissue of the affected extremity, which is imaged with a scintigraphic camera to visualize lymphatic vessels and lymph nodes. Findings indicative of primary lymphedema include absent or delayed filling of the lymphatic vessels or dermal back flow caused by lymphatic reflux. Findings of secondary lymphedema include dilated lymphatic vessels distal to an area of obstruction. In lymphangiography, iodinated radio-contrast material is injected into a distal lymphatic vessel that has been isolated and cannulated. In primary lymphedema, lymphatic channels are absent, hypoplastic, or ectatic. In secondary lymphedema, lymphatic channels often appear dilated beneath the level of obstruction.


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InternalMed_Harrison. A latent or subclinical condition where swelling is not evident despite impaired lymph transport. It may exist for months or years before overt edema occurs. Early accumulation of fluid relatively high in protein content that subsides with limb elevation. Pitting may occur. An increase in proliferating cells may also be seen. Limb elevation alone rarely reduces tissue swelling, and pitting is manifest. Late in stage II, the limb may or may not pit as excess fat and fibrosis supervene. Lymphostatic elephantiasis where pitting can be absent and trophic skin changes such as acanthosis, further deposition of fat and fibrosis, and warty overgrowths have developed. Source: Adapted from The 2013 Consensus Document of the International Society of Lymphology: Lymphology 46:1, 2013.


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InternalMed_Harrison. Source: Adapted from The 2013 Consensus Document of the International Society of Lymphology: Lymphology 46:1, 2013. The complexities of lymphatic cannulation and the risk of lymphangitis associated with the contrast agent limit the utility of lymphangiography. A novel technique of optical imaging with a near-infrared fluorescence dye may enable quantitative imaging of lymph flow. Patients with lymphedema of the lower extremities must be instructed to take meticulous care of their feet to prevent recurrent lymphangitis. Skin hygiene is important, and emollients can be used to prevent drying. Prophylactic antibiotics are often helpful, and fungal infection should be treated aggressively. Patients should be encouraged to participate in physical activity; frequent leg elevation can reduce the amount of edema. Psychosocial support is indicated to assist patients cope with anxiety or depression related to body image, self-esteem, functional disability, and fear of limb loss.


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InternalMed_Harrison. Physical therapy, including massage to facilitate lymphatic drainage, may be helpful. The type of massage used in decongestive physiotherapy for lymphedema involves mild compression of the skin of the affected extremity to dilate the lymphatic channels and enhance lymphatic motility. Multilayered, compressive bandages are applied after each massage session to reduce recurrent edema. After optimal reduction in limb volume by decongestive physiotherapy, patients can be fitted with graduated compression hose. Occasionally, intermittent pneumatic compression devices can be applied at home to facilitate reduction of the edema. Diuretics are contraindicated and may cause depletion of intravascular volume and metabolic abnormalities.


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InternalMed_Harrison. Liposuction in conjunction with decongestive physiotherapy may be considered to treat lymphedema, particularly postmastectomy lymphedema. Other surgical interventions are rarely used and often not successful in ameliorating lymphedema. Microsurgical lymphaticovenous anastomotic procedures have been performed to rechannel lymph flow from obstructed lymphatic vessels into the venous system. Limb reduction procedures to resect subcutaneous tissue and excessive skin are performed occasionally in severe cases of lymphedema to improve mobility.


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InternalMed_Harrison. Therapeutic lymphangiogenesis has been studied in rodent models of lymphedema, but not as yet in humans. Overexpression of vascular endothelial growth factor (VEGF) C generates new lymphatic vessels and improves lymphedema in a murine model of primary lymphedema, and administration of recombinant VEGF-C or VEGF-D stimulated lymphatic growth in preclinical models of post-surgical lymphedema. Clinical trials in patients with lymphedema are required to determine efficacy of gene transfer (cell-based) therapies for lymphedema. Pulmonary Hypertension Aaron B. Waxman, Joseph Loscalzo Pulmonary hypertension (PH) is a spectrum of diseases involving the pulmonary vasculature, and is defined as an elevation in pulmonary arterial pressures (mean pulmonary artery pressure >22 mmHg). Pulmonary arterial hypertension (PAH) is a relatively rare form of 304


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InternalMed_Harrison. PH and is characterized by symptoms of dyspnea, chest pain, and syncope. If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure. There have been significant advances in this field in regard to understanding the pathogenesis, diagnosis, and classification of PAH. Despite these significant advances, there is still a substantial delay in diagnosis of up to 2 years. In many cases, patients whose primary complaint is dyspnea on exertion are frequently misdiagnosed with more common diseases such as asthma or chronic obstructive pulmonary 1655 disease. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality. A delay in diagnosis results in an obvious delay in the initiation of appropriate treatment. Clinicians should be able to recognize the signs and symptoms of PH and to complete a systematic workup


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InternalMed_Harrison. A delay in diagnosis results in an obvious delay in the initiation of appropriate treatment. Clinicians should be able to recognize the signs and symptoms of PH and to complete a systematic workup in patients suspected of having it. In this way, early diagnosis, prompt treatment, and improved outcomes for patients become achievable.