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The outpatient with unilateral leg swelling
COMMON MEDICAL PROBLEMS IN AMBULATORY CARE
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THE OUTPATIENT WITH UNILATERAL LEG SWELLING Geno J. Merli, MD, and John Spandorfer, MD
Approaching the patient with unilateral leg swelling presents a challenge to the physician in ambulatory practice. Contributing to the difficulty is the lack of studies that have assessed a population of patients presenting with unilateral leg swelling. The purpose of this article is to discuss unilateral leg swelling with respect to the chronicity of the presentation and the most common differential diagnoses based on a review of the current literature and personal clinical experience (Table 1). HISTORY AND PHYSICAL EXAMINATION
To focus better on the possible causes for unilateral leg swelling, key questions need to be elicited in the history as well as important signs noted on the physical examination. The primary points in the history are related to the different aspects of leg swelling: 1. 2. 3. 4. 5.
Causes of leg swelling. Location of the swelling. Initial onset of the swelling. Progression of the swelling. Swelling characteristics.
First, asking the patient for a possible cause for his or her leg swelling may elicit such causes as previous surgery, trauma, radiation, infections, From the Division of Internal Medicine, and Clinical Research Group, Section of Vascular Medicine, Thomas Jefferson University Hospital, Jefferson Medical College, Philadelphia, Pennsylvania MEDICAL CLINICS OF NORTH AMERICA VOLUME 79 • NUMBER 2 • MARCH 1995
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Table 1. CAUSES OF UNILATERAL LOWER EXTREMITY SWELLING Acute swelling <72 h Deep vein thrombosis Popliteal cyst Rupture of medial head of the gastrocnemius Bacterial cellulitis Erythema nodosum
Chronic swelling> 72 h Lymphedema Chronic venous insufficiency Reflex sympathetic dystrophy Congenital venous malformations Malignancy
or malignancy. Second, the location of the swelling identifies the underlying structures involved. Knee swelling with involvement of the calf may be an indication of a popliteal cyst. Leg swelling involving the entire extremity including the dorsum of the foot is compatible with lymphedema. Third, documenting the chronicity of the edema may aid in the differential diagnosis. For example, a patient developing unilateral leg swelling 2 weeks following total knee replacement focuses the cause on either deep vein thrombosis or residual leg swelling secondary to surgery. The aforementioned symptoms of progression identify an ongoing versus a static or localized process as a cause for leg swelling. Fourth, the presence of pitting, warmth, or pain may also help differentiate the type of leg swelling. Pitting or nonpitting refers to the character of the swelling, which may be a differential point in the diagnosis of lower extremity edema. For example, in acute deep vein thrombosis and chronic venous insufficiency, the edema is pitting caused by retrograde pressure at the capillary level of the venous system owing to obstruction from clot in the former and valvular incompetence in the latter. This increased retrograde pressure results in an interstitial fluid that has low viscosity and readily pits. The swelling of lymphedema is nonpitting secondary to impaired lymphatic drainage resulting in a highly viscous fluid in the interstitial space. The concomitant presence of warmth or pain with swelling leads to the consideration of cellulitis, erythema nodosum, and reflex sympathetic dystrophy. The physical examination of the lower extremity should focus on the size, presence of joint effusions, circulation (venous and arterial), tenderness to palpation, and skin changes. The circumference of the lower extremity should be measured from a designated point, such as the patella, tibial tubercle, or medial tibial plateau to the midportion of the thigh and calf. A difference of greater than 1 cm when compared with the contralateral extremity is considered a significant change suggesting further investigation for an underlying cause. In addition to circumference measurement, inspection of the extremity for localized enlargement, which frequently occurs with tumors of the bone or soft tissue, should be completed. Patients with congenital venous malformations have hypertrophy of the tissues and bone of the involved limb, giving it an enlarged appearance or a leg length discrepancy.26 Assessment of the knee joint for excess fluid is an important part of the examination of unilateral leg swelling. Popliteal cysts frequently present with knee effusion in addition to lower extremity swelling. Assessing the patient's popliteal space in the standing
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position often enhances the appearance of a cyst. The lower extremity should be examined for distention of the superficial venous circulation both in the lying and in the standing position. The presence of chronic venous insufficiency is manifest by distended or varicosed vessels over the surface of the lower extremity following the distribution of the greater or lesser saphenous veins. Often there are multiple small superficial veins over the foot that are secondary to increased venous pressure caused by retrograde blood flow from incompetent valves. Congenital venous malformations are noted as raised, bluish colored vessels isolated to the calf or thigh and do not follow the distribution of the major veins of the extremity. If there is an arterial component to the venous malformation, a bruit can be heard. Tenderness of the extremity may be elicited as a localized or diffuse pattern. Patients with an underlying bone or soft tissue tumor manifest a localized enlargement and tenderness. Thrombosis of the popliteal vein may result in tenderness on examination of the popliteal space. On occasion, this popliteal thrombosis may be palpable as a cord. In patients with cellulitis, there is more of a diffuse tenderness experienced by the patient. As the cellulitis progresses, the tenderness becomes magnified. Patients with reflex sympathetic dystrophy have a diffuse tenderness with marked hyperesthesia. These patients cannot tolerate any contact to their skin either by clothing or physical examination. The final sign of skin changes should be directed to the location, size, and color of the lesions. In patients with cellulitis, there is either red streaking up the extremity or a diffuse redness with increased temperature of the skin. The presentation of discrete, nummular, red, warm, tender areas over the anterior aspect of the extremity below the knee signals the diagnosis of erythema nodosum. On occasion, patients presenting with acute onset of calf pain and swelling develop a bluish purple discoloration below the medial malleolus. This crescent-shaped skin discoloration is caused by the downward gravitation of blood from either a ruptured popliteal cyst or a tear of the gastrocnemius muscle. J3 , 14, 18 In addition, patients with the latter injury are noted to have a sunken area where the muscle is torn on the medial side of the midcalf on standing. IS Patients with a history of chronic lower extremity swelling have skin changes commensurate with the duration of the underlying disease. The skin of patients with lymphedema is dry and scaling. The longer the duration of swelling, the greater thickening of the tissues occurs, with an elephant skin texture and multiple verrucous-like changes. In chronic venous insufficiency, the golden brown hemosiderin deposition is either localized to the distal medial aspect of the ankle or diffuse over the calf. The skin of patients with reflex sympathetic dystrophy has more trophic changes the longer the duration of the illness. In the early stages of this disease, the skin is indurated, cool, and hyperhidrotic, but as the disease progresses, it becomes taut, shiny, and thin.2s Patients with congenital venous malformations often have either flat angiomata that are purplish red or discrete, verrucous, textured, dark purple le-
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sions. 26 These findings are present in localized areas of the extremity where underlying venous or arteriovenous malformation is located. Lastly, the skin changes associated with malignancy resulting in lower extremity swelling are caused primarily by lymphatic obstruction. The retroperitoneal, pelvic, inguinal, or distal lymphatics are either compressed or infiltrated by tumor, causing induration of the skin with peau d'orange appearance. These important areas of the history and physical examination provide the clinician with the key database to proceed with further investigation to confirm the cause of unilateral leg swelling. ACUTE-ONSET UNILATERAL LEG SWELLING (24 TO 72 HOURS) Acute Deep Vein Thrombosis
Deep vein thrombosis remains one of the major medical problems in the United States. This diagnosis accounts for more than 260,000 acute hospital admissions per year. 2 In the patient presenting to the outpatient office with unilateral leg swelling, consideration of deep vein thrombosis in the differential diagnosis is significant because of the risk of thromboembolic events. The solicitation of key points in the history is of paramount importance in considering deep vein thrombosis as a cause of unilateral leg swelling. First, an inciting event should always be sought, such as a recent surgery, prolonged immobilization, or trauma. Further questioning should probe for previous episodes of thrombosis and their inciting events, medications, personal history of malignancy, a family history of thrombosis, and concomitant medical illnesses. The most common presentation of deep vein thrombosis is the acute onset of unilateral leg swelling and pain. The pain may be exacerbated by weight bearing or ambulation. Patients often describe their extremity as either tight, knot-like or vice-like pain or aching pain deep in the extremity. The edema is localized in the foot and ankle but progresses upward depending on the extent of the underlying thrombosis. This edema is pitting in character but develops a peau de orange consistency when the venous return is severely impaired. The extremity has an increased warmth and may often be red or discolored. The measurement of the leg circumference from a designated point, such as the patella, tibial tubercle, or medial tibial plateau to the midportion of the calf and thigh, documents the degree of enlargement compared with the opposite extremity. Although many of these signs are poorly sensitive and specific, they may help raise a clinical suspicion of deep vein thrombosis warranting further diagnostic testing. 8 At present, noninvasive Doppler ultrasonography is the most widely used test for detecting proximal vein thrombosis in symptomatic patients. The cardinal sign is the identification of an area of noncom-
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pressibility along the course of the studied vessels. 16 Venography remains the invasive gold standard for assessing both the distal and the proximal venous system. In some presentations of unilateral leg swelling, the Doppler ultrasound study may be negative, but if the suspicion of calf vein thrombosis is high, venography or serial Doppler ultrasound studies should be performed. Popliteal Cyst
Popliteal cyst (Baker's cyst) is another cause to be considered in the differential diagnosis of unilateral leg swelling. The manifestation of this anatomic abnormality is identical to deep vein thrombosis; hence the frequently used designation pseudothrombophlebitis syndrome. 14 When considering this diagnosis, attention must be focused on the concomitant medical problems, specific symptoms and signs, and imaging modalities for confirming the presence of popliteal cysts. The incidence of this anatomic abnormality of the knee has been reported by magnetic resonance (MR) imaging to be approximately 5%.6 These cysts are more commonly observed in patients with inflammatory joint disease, such as rheumatoid arthritis.14 Among patients with rheumatoid arthritis, there is no correlation between the degree or duration of disease and the presence of a popliteal cyst. Noninflammatory diseases constitute the second major group, with entities such as degenerative joint disease, tears of the posterior horn of the medial meniscus, and trauma the leading causes.13, 14 The most frequent clinical manifestation of popliteal cysts are calf pain, swelling, and knee effusion. These symptoms and signs result because popliteal cysts are connected to the gastrocnemius-semimembranous bursa in the calf. Evidence has shown a one-way valve effect in which fluid can go from the knee to the popliteal synovial bursa but not in the reverse direction. l l These cysts are usually seen along the medial side of the popliteal fossa, distal to the transverse skin crease. Occasionally a crescent sign has been observed along the base of the medial malleolus. These signs and symptoms occur acutely with a large number of cysts either dissecting into the calf or rupturing with blood traversing downward to the ankle via the fascial planes. Arthrography has been considered to be the gold standard, but Doppler ultrasound and MR imaging have demonstrated a nearly equal sensitivity and specificity and are noninvasive. Doppler ultrasound is the test that may be useful initially because this would rule out the diagnosis of thrombosis and allow interrogation of the popliteal space. If knee derangement is the major concern, MR imaging can be performed. Rupture of the Medial Head of the Gastrocnemius Muscle
An acute tear of the medial head of the gastrocnemius muscle closely mimics acute thrombosis of the deep vein system of the calf.
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Important points in the history and physical examination may help make this differentiation easier for the clinician. Frequently, this injury occurs in middle-aged patients during the process of sudden dorsiflexion of the ankle while extending the knee joint or dorsiflexion while the foot is planted on the ground. 27 Pain in the medial aspect of the midcalf area is acute in onset. This pain may be described by some patients as a sensation of tearing or being hit in the midportion of the calf. Over a 24- to 48-hour period, swelling develops in the calf and ankle areas. Occasionally a bluish discoloration of the lower medial aspect of the ankle may occur owing to the downward movement of blood along the fascial planes from the initial tear. Performing Homan's sign, palpating the gastrocnemius muscle for cords, standing, and walking all produce pain and tenderness in the central portion of the calf. Sometimes a small sunken area may be visible or palpable on the medial side of the midcalf, where there is pain and tenderness. IS The diagnosis of a tear of the medial head of the gastrocnemius muscle is primarily made by the history and physical examination. If testing is indicated, venous duplex scanning is recommended to rule out deep vein thrombosis or popliteal cyst. MR imaging and computed tomography have been used to evaluate this process but are costly for routine use. Cellulitis
Bacterial skin infections are common and may vary in presentation from mild infections to life-threatening necrotizing cellulitis. These infections may be the result of a primary process or secondary to a preexisting condition (e.g., previous episodes of cellulitis, saphenous venectomy for bypass surgery) that predisposes the skin and subcutaneous tissue to bacterial invasion. Group A streptococci and Staphylococcus aureus are the most common causes.? Frequently, cellulitis presents as unilateral leg swelling early on in the course of the infection. As the tissues become more inflamed, a spreading erythema and edema become more pronounced in the involved limb. The swelling often becomes indurated in texture. The area involved is red and warm with regional lymph node enlargement and tenderness. The margins of the infected areas are blurred and do not provide a high yield of organisms along the leading edge. lO Unrecognized, this process progresses resulting in chills, fever, and sepsis. Erythema Nodosum
Erythema nodosum is an inflammatory disease in which delayed hypersensitivity reactions involve the large blood vessels of the skin and the fibrous septa of the subcutaneous tissue. 4 These changes often result in either unilateral or bilateral swelling of the lower extremities.
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This inflammatory process is usually manifested by early constitutional symptoms, such as fever, malaise, and pain in the muscles and joints. Initially the nodules appear unilaterally or bilaterally below the knees. These areas vary in diameter from 1 to 5 cm with a red, smooth, shiny surface. A number of causative factors have been associated with erythema nodosum, including the following: streptococcal infections, tuberculosis, sarcoidosis, inflammatory bowel disease, acute monocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, and drugs (sulfonamides, oral contraceptives).4 LATE-ONSET UNILATERAL LEG SWELLING (GREATER THAN 72 HOURS) Chronic Venous Insufficiency
More than 1.6 million Americans have some form of chronic venous insufficiency, which accounts for 30,000 hospitalizations. 17, 30 In assessing patients with unilateral leg swelling, understanding the pathophysiology of this disease is important to making the diagnosis. The term chronic venous insufficiency is the descriptive heading under which diseases that result in valvular incompetency and regurgitation are listed (Table 2). Patients with primary varicose veins often have bilateral involvement and a family history. Secondary varicose veins are often related to pregnancy or obesity but may be associated with occupations that require prolonged standing or walking. These patients do not have a family history and manifest bilateral involvement. Patients with postphlebitic syndrome have unilateral leg varicosities, and in only 20% is a history of previous deep vein thrombosis recalled. s The final category is that of venous malformations, which include the KlippelTable 2. CLASSIFICATION OF LYMPHEDEMA Primary Lymphedema Hereditary (Milroy's disease) Congenital Iymphedema Lymphedema praecox Lymphedema tarda Secondary Lymphedema Obstructive Tumor Trauma (crush injury) Obliterative Surgery Tumor Radiation Sarcoid Inflammatory Filarial infecton Bacterial infection
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Trenaunay and Parkes-Weber syndromes. The former has unilateral varicosities, leg enlargement, and port wine skin lesions, whereas the latter has unilateral varicosities, leg enlargement, and venous bruits secondary to arteriovenous malformations. 26 These syndromes appear at an early age. Patients within any of these categories frequently describe their lower extremities as heavy, tight, fatigued, aching, or painful. These symptoms begin on arising and assuming the upright posture and gradually increase as the day progresses. These symptoms result mainly from valvular incompetence with retrograde flow resulting in an increased pressure at the capillary level. The retrograde venous flow translates into a greater volume of venous blood in the extremity and extrusion of red cells, fluid, and protein into the interstitial space, causing pitting edema and the golden brown discoloration of hemosiderin in the skin. 3 The protein in the subcutaneous tissue and skin causes an inflammatory response and subsequent fibrosis. Any injury to the skin can then lead to ulceration. These ulcers may or may not be painful. Sometimes, stasis dermatitis accompanies venous ulceration and resembles macerated tissue around the ulcer periphery. These pathophysiologic changes sometimes can be exacerbated by prolonged standing or sitting. Patients seek care because of this unilateral change. The first concern is whether a deep or superficial thrombosis is present. The presence of a superficial thrombosis can be diagnosed by physical examination, but noninvasive testing is required for evaluation of the deep system. Noninvasive testing to exclude a deep vein thrombosis would be warranted for a superficial phlebitis involving the greater saphenous vein above the knee. Recurrent unilateral leg swelling may be common with this disease. If leg swelling or pain occurs, the patient should be instructed to elevate the extremity for 24 hours, and if no improvement occurs in either pain or swelling, an office visit is mandatory. A clear understanding by the patient of the underlying disease helps avoid frequent visits for the common manifestation of leg swelling, which is part of the underlying pathophysiology of this disease.
Lymphedema
The diagnosis of lymphedema should be confined to patients with swelling of an extremity secondary to a malformation or obstruction of lymphatic channels. Lymphedema can be classified into primary and secondary categories (Table 3).9 In this section, the clinical manifestations and assessment of lymphedema are reviewed. The primary function of the lymphatics is to clear the interstitial space of excess proteinaceous fluid and return it to the blood circulation. When this protein-rich fluid (1 to 5 g/ dL) is not adequately removed, lymphedema develops. This edema is primarily painless and nonpitting. Understanding the classification of lymphedema and each of the specific
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Table 3. CLASSIFICATION OF CHRONIC VENOUS INSUFFICIENCY Varicose veins Primary varicose veins Secondary varicose veins (pregnancy, obesity, occupational) Postphlebitic syndrome Congenital thrombotic disorders Acquired thrombotic disorders Congenital venous malformations Klippel-Trenaunay syndrome (venous) Parkes-Weber syndrome (arteriovenous)
factors of each category is important when assessing the patient with unilateral leg edema. The first category includes congenital and hereditary forms.1 The congenital form often presents in an individual without a family history of lymphedema. The hereditary form (Milroy's disease) is transmitted as an autosomal dominant trait. The clinical characteristics of each are predominantly an enlargement of an extremity at birth with firm, nonpitting edema. The child's development and activities are not impaired. The second category is lymphedema praecox.] This group is composed primarily of women in the second and third decades of life. Lymphedema praecox presents spontaneously without an apparent cause. The edema is initially soft and pitting but becomes firm and nonpitting over time. There is no pain or ulceration, but recurrent infection can occur in this group. The lymphedema tarda category comprises patients who develop lymphedema after the age of 35 years. 15 This condition also occurs without an obvious cause. The edema is nonpitting and firm. Pain and ulceration do not occur, but recurrent infections are common. Both the praecox and tarda forms of lymphedema may represent congenital lymphatic disease with delayed onset of symptoms. On a worldwide basis, secondary lymphedema is the most frequent type. 28 Infection is the predominant cause in Third-World countries, whereas malignancy is the major cause in the Western world. The pathophysiology of secondary lymphedema is the obstruction or removal of lymphatic channels, by extranodal malignant disease, radiation, surgical excision, trauma, or infection. Therefore, three groups exist under the heading of secondary lymphedema: obstructive, obliterative, and inflammatory. The obstructive and obliterative types are caused predominantly by malignancy. Lymphedema results from tumor invasion or compression, surgical removal, or radiation. Prostate cancer in men and lymphoma in women are the most frequent causes. Lymphedema may precede the diagnosis of malignancy. The edema is predominantly unilateral, is pitting or nonpitting, and regresses slightly with elevation. The inflammatory type may result from frequent infections with residual limb edema, which becomes firm and nonpitting over time. Filariasis, tuberculosis, typhoid fever, and influenza have all been re-
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ported as causes for this process. 9 Rarely, sarcoidosis has been reported as a cause of lymphatic obstruction. 21 Swelling often precedes the other manifestations of sarcoidosis. The patient history is probably the most important factor in differentiating primary from secondary lymphedema. The physical examination, although often not specific, is important in distinguishing lymphedema from other causes of edema. The workup of these patients requires a thorough history and physical examination, supplemented by laboratory tests as indicated. Computed tomography or MR imaging of the abdomen and pelvis may supplement the physical examination in differentiating primary versus secondary lymphedema. Reflex Sympathetic Dystrophy
The incidence of reflex sympathetic dystrophy (RSD) has been reported to vary between 10% and 15%.24 This disease entity has been precipitated by a number of factors and disease processes. The mechanism by which all these entities cause this clinical syndrome is not yet known. The syndrome is characterized by burning pain, hyperesthesia, hyperhydrosis, and trophic change in the skin and bone of the affected extremity. Swelling is often an early sign of this syndrome and a frequent presenting complaint in the outpatient setting. Commonly the onset of unilateral lower extremity RSD follows a traumatic event or a concomitant disease process (Table 4). A few weeks after the initiating event, pain is experienced in the extremity as either burning or aching in character; swelling may be precipitated by dependency of the extremity, and physical contact or emotional upset may be followed by the onset of swelling. This symptom complex is designated as stage I of three stages of RSD.25 As the disease progresses to stage Il, the edematous tissue of the lower extremity becomes indurated and the skin cool, hyperhydrotic with livedo reticularis or cyanosis. 25 The pain is constant and made worse by any stimulus to the extremity. Stage III is manifested by the thinning of the skin with thickening of the fascia causing contractures, bony demineralization, and proximal spread of the pain and edema of stage 11.25 The differentiating points for diagnosing RSD are the association Table 4. PRECIPITATING FACTORS AND DISEASE ASSOCIATED WITH REFLEX SYMPATHETIC DYSTROPHY Peripheral Causes Fracture, sprains, dislocations Soft tissue injury Immobilization with cast or splint Venous or arterial thrombosis Myelography, venography, arteriography Infections Idiopathic
Central Causes Cervical cord injury Brain tumors Cerebral infarction
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with an initiating event, the character of the pain, and progression of swelling. Clinicians frequently observe the early stage of this disease in outpatient practice. It is difficult to differentiate this disease from some of the other causes of lower extremity swelling that have been described. Because there is no diagnostic test for RSD, good clinical assessment and follow-up observation are the primary approach. Congenital Venous Malformations
Klippel-Trenaunay syndrome is a congenital malformation of the venous system. 26 It predominantly involves the lower extremities with a variety of clinical manifestations. This syndrome is not common, but its presentation as unilateral lower extremity edema in 84% of patients makes this entity a consideration in the differential diagnosis of leg swelling. Klippel-Trenaunay syndrome is characterized by a port wine nevus involving the extremity, unilateral varicose veins, and hypertrophy of all of the tissues and bones of the impaired limb. The skin texture of the port wine nevus has been reported to be verrucous or smooth in quality. These patients frequently present with unilateral varicose veins early in life. The edema noted in this syndrome is located below the knee and may be manifested at birth, puberty, or adult life. This swelling can sometimes mask the varicose veins mentioned previously, leading the clinical assessment away from this diagnosis. A third factor is that of leg length discrepancy, which is a result of bone hypertrophy. The key point in the physical examination is the auscultation of the lower extremity varicosities for bmits. This finding indicates the presence of arteriovenous malformations as a component of congenital venous abnormality. The approach to managing a patient with arteriovenous malformations is to assess the extent of vascular involvement. Surgical intervention is the best strategy for long-term care of these patients. Malignancy
In this section, the most common bone and soft tissue tumors are discussed. Each individual tumor is reviewed featuring the most important clinical points for assisting the differential diagnosis of unilateral leg swelling. Osteochondromas are the most common benign bone tumors, representing 50% of these lesions.23 This tumor is primarily observed in adolescence, in which it presents as a mildly painful swelling along the metaphyseal region of the femur around the knee joint. Osteogenic sarcoma is the most common primary malignant bone tumor occurring in the second decade.23 These are usually characterized by pain and swelling in the area of the lesion. The pain is progressive
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and not related to the time of day. Swelling occurs locally and progresses as the tumor expands the bony cortex stretching the periosteum and above tissues. Chondrosarcomas represent 20% of all primary bone lesions.23 They commonly present in patients over the age of 40 years with lesions found predominately in the pelvis and femur. The tumor may cause localized pain and swelling at and distal to the lesion. Liposarcoma is the most common malignant soft tissue tumor in adults, constituting 7% to 10% of lesions. 20 They most commonly occur in the thigh and adjacent popliteal space, the inguinal and gluteal regions, and the retroperitoneum. If the lower extremity is involved, localized unilateral leg swelling and pain are observed. Kaposi's sarcoma is a tumor classically occurring spontaneously in Jewish and Italian men both in Europe and the United States. 20 There are three other variants of this tumor: endemic in parts of Africa in children, postrenal transplant, and associated with acquired immunodeficiency syndrome. This tumor is often manifested early by a raised bluish skin lesion. As the disease progresses, more tissues become involved, resulting in further swelling, redness, and pain in the extremity. Tissue biopsy confirms the diagnosis.
References 1. Allen E: Lymphedema of the extremities: Classification, etiology, and differential diagnosis. A study of three hundred cases. Arch Intern Med 54:606-624, 1934 2. Anderson F, Wheeler H, Goldberg R, et al: A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: The Worcester DVT study. Arch Intern Med 151:933-938, 1991 3. Angel M, Ramasastry S, Swartz W, et al: The causes of skin ulcerations associated with venous insufficiency: A unifying hypothesis. Plast Reconstr Surg 79:289, 1987 4. Arnold H, Odom R, James W: Andrews' Diseases of the Skin: Clinical Dermatology, ed 8. Philadelphia, WB Saunders, 1990, pp 142-143 5. Browse N, Clemenson G, Thomas L: Is the postphlebitic leg always postphlebitic? Relationship between phlebographic appearance of DVT and late sequelae. BMJ 281:1167, 1980 6. Fielding J, Franklin P, Kustan J: Popliteal cysts: A reassessment using magnetic resonance imaging. Skel Radiol 20:433-435, 1991 7. File T, Tan J: Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet 172:17-24 8. Haeger K: Problems of acute deep venous thrombosis: The interpretation of signs and symptoms. Angiology 20:219, 1969 9. Hammond M, Merli G, Zierler R: Rehabilitation of the patient with peripheral vascular disease of the lower extremity. In DeLisa J (ed): Rehabilitation Medicine: Principles and Practice, ed 2. Philadelphia, JB Lippincott, 1993, pp 1082-1098 10. Hook E: Acute cellulitis. Arch Dermatol 123:460-461, 1987 11. Jayson M, Dixon A: Valvular mechanisms in juxta-articular cysts. Ann Rheum Dis 29:415, 1970 12. Kahn R, Goldstein E: Common bacterial skin infections: Diagnostic clues and therapeutic options. Postgrad Med 93:175-182, 1993 13. Katz R: The key to diagnosing pseudothrombophlebitis. Intern Med 15:33-41, 1994 14. Katz R, Zizic T, Arnold P, et al: The pseudothrombophlebitis syndrome. Medicine 56:151-164, 1977
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15. Kinmonth J, Taylor G, Tracy C, et al: Primary lymphedema: Clinical and lymphographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 45:1, 1957 16. Lensing A, Prandoni P, Brandjes D, et al: Detection of deep vein thrombosis by realtime B-mode ultrasonography. N Engl J Med 320:342-345, 1989 17. Linder D, Edwards J, Phinney E, et al: Long-term hemodynamic and clinical sequelae of lower extremity DVT. J Vasc Surg 4:436,1986 18. McClure J: Gastrocnemius musculotendinous rupture: A condition confused with thrombophlebitis. South Med J 77:1143-1145, 1984 19. Menz M, Lucas G: Magnetic resonance imaging of a rupture of the medial head of the gastrocnemius muscle. J Bone J Surg Am 73:1260-1262,1991 20. Morton D, Antman K, Tepper J: Soft tissue sarcoma. In Holland J, Frei E, Bast R, et al (eds): Cancer Medicine, ed 3. Philadelphia, Lea & Febiger, 1993, pp 1858-1887 21. Nathan M, Pinsker R, Chase P, et al: Sarcoidosis presenting as Iymphedema. Arch Dermatol 109:543-544, 1974 22. Philips G, Godon D, Martin E: The Klippel and Trenaunay syndrome: Clinical and radiological aspects. Radiology 128:429-434, 1978 23. Rosen G: Neoplasms of the bone and soft tissue. In Holland J, Frei E, Bast R, et al (eds): Cancer Medicine, ed 3. Philadelphia, Lea & Febiger, 1993, pp 1825-1858 24. Rothberg J, Tahmoush A, Oldakowski R: The epidemiology of causalgia among soldiers wounded in Vietnam. Milit Med 148:347-350, 1983 25. Schwartzman R, McLellan T: Reflex sympathetic dystrophy. Arch Neurol 44:555-561, 1987 26. Servelle M: Klippel and Trenaunay's syndrome. Ann Surg 201:365-373, 1985 27. Shields C, Redix L, Brewster C: Acute tears of the medial head of the gastrocnemius. Foot Ankle 5:186-190,1985 28. Smith R, Spittell J, Schirger A: Secondary Iymphedema of the leg: Its characteristics and diagnostic implications. JAMA 185:80-82, 1963 29. Staraehely D, Jones W: Acute compartment syndrome following tear of the medial head of the gastrocnemius muscle. Am J Sports Med 14:96-99, 1986 30. Strandness D, Langlois Y, Cramer M, et al: Long-term sequelae of acute venous thrombosis. JAMA 280:1289, 1983
Address reprint requests to Geno J. Merli, MD Division of Internal Medicine Section of Vascular Medicine Walnut Towers 211 South 9th Street Philadelphia, PA 19107
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THE OUTPATIENT WITH UNILATERAL LEG SWELLING Geno J. Merli, MD, and John Spandorfer, MD
Approaching the patient with unilateral leg swelling presents a challenge to the physician in ambulatory practice. Contributing to the difficulty is the lack of studies that have assessed a population of patients presenting with unilateral leg swelling. The purpose of this article is to discuss unilateral leg swelling with respect to the chronicity of the presentation and the most common differential diagnoses based on a review of the current literature and personal clinical experience (Table 1). HISTORY AND PHYSICAL EXAMINATION
To focus better on the possible causes for unilateral leg swelling, key questions need to be elicited in the history as well as important signs noted on the physical examination. The primary points in the history are related to the different aspects of leg swelling: 1. 2. 3. 4. 5.
Causes of leg swelling. Location of the swelling. Initial onset of the swelling. Progression of the swelling. Swelling characteristics.
First, asking the patient for a possible cause for his or her leg swelling may elicit such causes as previous surgery, trauma, radiation, infections, From the Division of Internal Medicine, and Clinical Research Group, Section of Vascular Medicine, Thomas Jefferson University Hospital, Jefferson Medical College, Philadelphia, Pennsylvania MEDICAL CLINICS OF NORTH AMERICA VOLUME 79 • NUMBER 2 • MARCH 1995
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Table 1. CAUSES OF UNILATERAL LOWER EXTREMITY SWELLING Acute swelling <72 h Deep vein thrombosis Popliteal cyst Rupture of medial head of the gastrocnemius Bacterial cellulitis Erythema nodosum
Chronic swelling> 72 h Lymphedema Chronic venous insufficiency Reflex sympathetic dystrophy Congenital venous malformations Malignancy
or malignancy. Second, the location of the swelling identifies the underlying structures involved. Knee swelling with involvement of the calf may be an indication of a popliteal cyst. Leg swelling involving the entire extremity including the dorsum of the foot is compatible with lymphedema. Third, documenting the chronicity of the edema may aid in the differential diagnosis. For example, a patient developing unilateral leg swelling 2 weeks following total knee replacement focuses the cause on either deep vein thrombosis or residual leg swelling secondary to surgery. The aforementioned symptoms of progression identify an ongoing versus a static or localized process as a cause for leg swelling. Fourth, the presence of pitting, warmth, or pain may also help differentiate the type of leg swelling. Pitting or nonpitting refers to the character of the swelling, which may be a differential point in the diagnosis of lower extremity edema. For example, in acute deep vein thrombosis and chronic venous insufficiency, the edema is pitting caused by retrograde pressure at the capillary level of the venous system owing to obstruction from clot in the former and valvular incompetence in the latter. This increased retrograde pressure results in an interstitial fluid that has low viscosity and readily pits. The swelling of lymphedema is nonpitting secondary to impaired lymphatic drainage resulting in a highly viscous fluid in the interstitial space. The concomitant presence of warmth or pain with swelling leads to the consideration of cellulitis, erythema nodosum, and reflex sympathetic dystrophy. The physical examination of the lower extremity should focus on the size, presence of joint effusions, circulation (venous and arterial), tenderness to palpation, and skin changes. The circumference of the lower extremity should be measured from a designated point, such as the patella, tibial tubercle, or medial tibial plateau to the midportion of the thigh and calf. A difference of greater than 1 cm when compared with the contralateral extremity is considered a significant change suggesting further investigation for an underlying cause. In addition to circumference measurement, inspection of the extremity for localized enlargement, which frequently occurs with tumors of the bone or soft tissue, should be completed. Patients with congenital venous malformations have hypertrophy of the tissues and bone of the involved limb, giving it an enlarged appearance or a leg length discrepancy.26 Assessment of the knee joint for excess fluid is an important part of the examination of unilateral leg swelling. Popliteal cysts frequently present with knee effusion in addition to lower extremity swelling. Assessing the patient's popliteal space in the standing
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position often enhances the appearance of a cyst. The lower extremity should be examined for distention of the superficial venous circulation both in the lying and in the standing position. The presence of chronic venous insufficiency is manifest by distended or varicosed vessels over the surface of the lower extremity following the distribution of the greater or lesser saphenous veins. Often there are multiple small superficial veins over the foot that are secondary to increased venous pressure caused by retrograde blood flow from incompetent valves. Congenital venous malformations are noted as raised, bluish colored vessels isolated to the calf or thigh and do not follow the distribution of the major veins of the extremity. If there is an arterial component to the venous malformation, a bruit can be heard. Tenderness of the extremity may be elicited as a localized or diffuse pattern. Patients with an underlying bone or soft tissue tumor manifest a localized enlargement and tenderness. Thrombosis of the popliteal vein may result in tenderness on examination of the popliteal space. On occasion, this popliteal thrombosis may be palpable as a cord. In patients with cellulitis, there is more of a diffuse tenderness experienced by the patient. As the cellulitis progresses, the tenderness becomes magnified. Patients with reflex sympathetic dystrophy have a diffuse tenderness with marked hyperesthesia. These patients cannot tolerate any contact to their skin either by clothing or physical examination. The final sign of skin changes should be directed to the location, size, and color of the lesions. In patients with cellulitis, there is either red streaking up the extremity or a diffuse redness with increased temperature of the skin. The presentation of discrete, nummular, red, warm, tender areas over the anterior aspect of the extremity below the knee signals the diagnosis of erythema nodosum. On occasion, patients presenting with acute onset of calf pain and swelling develop a bluish purple discoloration below the medial malleolus. This crescent-shaped skin discoloration is caused by the downward gravitation of blood from either a ruptured popliteal cyst or a tear of the gastrocnemius muscle. J3 , 14, 18 In addition, patients with the latter injury are noted to have a sunken area where the muscle is torn on the medial side of the midcalf on standing. IS Patients with a history of chronic lower extremity swelling have skin changes commensurate with the duration of the underlying disease. The skin of patients with lymphedema is dry and scaling. The longer the duration of swelling, the greater thickening of the tissues occurs, with an elephant skin texture and multiple verrucous-like changes. In chronic venous insufficiency, the golden brown hemosiderin deposition is either localized to the distal medial aspect of the ankle or diffuse over the calf. The skin of patients with reflex sympathetic dystrophy has more trophic changes the longer the duration of the illness. In the early stages of this disease, the skin is indurated, cool, and hyperhidrotic, but as the disease progresses, it becomes taut, shiny, and thin.2s Patients with congenital venous malformations often have either flat angiomata that are purplish red or discrete, verrucous, textured, dark purple le-
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sions. 26 These findings are present in localized areas of the extremity where underlying venous or arteriovenous malformation is located. Lastly, the skin changes associated with malignancy resulting in lower extremity swelling are caused primarily by lymphatic obstruction. The retroperitoneal, pelvic, inguinal, or distal lymphatics are either compressed or infiltrated by tumor, causing induration of the skin with peau d'orange appearance. These important areas of the history and physical examination provide the clinician with the key database to proceed with further investigation to confirm the cause of unilateral leg swelling. ACUTE-ONSET UNILATERAL LEG SWELLING (24 TO 72 HOURS) Acute Deep Vein Thrombosis
Deep vein thrombosis remains one of the major medical problems in the United States. This diagnosis accounts for more than 260,000 acute hospital admissions per year. 2 In the patient presenting to the outpatient office with unilateral leg swelling, consideration of deep vein thrombosis in the differential diagnosis is significant because of the risk of thromboembolic events. The solicitation of key points in the history is of paramount importance in considering deep vein thrombosis as a cause of unilateral leg swelling. First, an inciting event should always be sought, such as a recent surgery, prolonged immobilization, or trauma. Further questioning should probe for previous episodes of thrombosis and their inciting events, medications, personal history of malignancy, a family history of thrombosis, and concomitant medical illnesses. The most common presentation of deep vein thrombosis is the acute onset of unilateral leg swelling and pain. The pain may be exacerbated by weight bearing or ambulation. Patients often describe their extremity as either tight, knot-like or vice-like pain or aching pain deep in the extremity. The edema is localized in the foot and ankle but progresses upward depending on the extent of the underlying thrombosis. This edema is pitting in character but develops a peau de orange consistency when the venous return is severely impaired. The extremity has an increased warmth and may often be red or discolored. The measurement of the leg circumference from a designated point, such as the patella, tibial tubercle, or medial tibial plateau to the midportion of the calf and thigh, documents the degree of enlargement compared with the opposite extremity. Although many of these signs are poorly sensitive and specific, they may help raise a clinical suspicion of deep vein thrombosis warranting further diagnostic testing. 8 At present, noninvasive Doppler ultrasonography is the most widely used test for detecting proximal vein thrombosis in symptomatic patients. The cardinal sign is the identification of an area of noncom-
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pressibility along the course of the studied vessels. 16 Venography remains the invasive gold standard for assessing both the distal and the proximal venous system. In some presentations of unilateral leg swelling, the Doppler ultrasound study may be negative, but if the suspicion of calf vein thrombosis is high, venography or serial Doppler ultrasound studies should be performed. Popliteal Cyst
Popliteal cyst (Baker's cyst) is another cause to be considered in the differential diagnosis of unilateral leg swelling. The manifestation of this anatomic abnormality is identical to deep vein thrombosis; hence the frequently used designation pseudothrombophlebitis syndrome. 14 When considering this diagnosis, attention must be focused on the concomitant medical problems, specific symptoms and signs, and imaging modalities for confirming the presence of popliteal cysts. The incidence of this anatomic abnormality of the knee has been reported by magnetic resonance (MR) imaging to be approximately 5%.6 These cysts are more commonly observed in patients with inflammatory joint disease, such as rheumatoid arthritis.14 Among patients with rheumatoid arthritis, there is no correlation between the degree or duration of disease and the presence of a popliteal cyst. Noninflammatory diseases constitute the second major group, with entities such as degenerative joint disease, tears of the posterior horn of the medial meniscus, and trauma the leading causes.13, 14 The most frequent clinical manifestation of popliteal cysts are calf pain, swelling, and knee effusion. These symptoms and signs result because popliteal cysts are connected to the gastrocnemius-semimembranous bursa in the calf. Evidence has shown a one-way valve effect in which fluid can go from the knee to the popliteal synovial bursa but not in the reverse direction. l l These cysts are usually seen along the medial side of the popliteal fossa, distal to the transverse skin crease. Occasionally a crescent sign has been observed along the base of the medial malleolus. These signs and symptoms occur acutely with a large number of cysts either dissecting into the calf or rupturing with blood traversing downward to the ankle via the fascial planes. Arthrography has been considered to be the gold standard, but Doppler ultrasound and MR imaging have demonstrated a nearly equal sensitivity and specificity and are noninvasive. Doppler ultrasound is the test that may be useful initially because this would rule out the diagnosis of thrombosis and allow interrogation of the popliteal space. If knee derangement is the major concern, MR imaging can be performed. Rupture of the Medial Head of the Gastrocnemius Muscle
An acute tear of the medial head of the gastrocnemius muscle closely mimics acute thrombosis of the deep vein system of the calf.
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Important points in the history and physical examination may help make this differentiation easier for the clinician. Frequently, this injury occurs in middle-aged patients during the process of sudden dorsiflexion of the ankle while extending the knee joint or dorsiflexion while the foot is planted on the ground. 27 Pain in the medial aspect of the midcalf area is acute in onset. This pain may be described by some patients as a sensation of tearing or being hit in the midportion of the calf. Over a 24- to 48-hour period, swelling develops in the calf and ankle areas. Occasionally a bluish discoloration of the lower medial aspect of the ankle may occur owing to the downward movement of blood along the fascial planes from the initial tear. Performing Homan's sign, palpating the gastrocnemius muscle for cords, standing, and walking all produce pain and tenderness in the central portion of the calf. Sometimes a small sunken area may be visible or palpable on the medial side of the midcalf, where there is pain and tenderness. IS The diagnosis of a tear of the medial head of the gastrocnemius muscle is primarily made by the history and physical examination. If testing is indicated, venous duplex scanning is recommended to rule out deep vein thrombosis or popliteal cyst. MR imaging and computed tomography have been used to evaluate this process but are costly for routine use. Cellulitis
Bacterial skin infections are common and may vary in presentation from mild infections to life-threatening necrotizing cellulitis. These infections may be the result of a primary process or secondary to a preexisting condition (e.g., previous episodes of cellulitis, saphenous venectomy for bypass surgery) that predisposes the skin and subcutaneous tissue to bacterial invasion. Group A streptococci and Staphylococcus aureus are the most common causes.? Frequently, cellulitis presents as unilateral leg swelling early on in the course of the infection. As the tissues become more inflamed, a spreading erythema and edema become more pronounced in the involved limb. The swelling often becomes indurated in texture. The area involved is red and warm with regional lymph node enlargement and tenderness. The margins of the infected areas are blurred and do not provide a high yield of organisms along the leading edge. lO Unrecognized, this process progresses resulting in chills, fever, and sepsis. Erythema Nodosum
Erythema nodosum is an inflammatory disease in which delayed hypersensitivity reactions involve the large blood vessels of the skin and the fibrous septa of the subcutaneous tissue. 4 These changes often result in either unilateral or bilateral swelling of the lower extremities.
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This inflammatory process is usually manifested by early constitutional symptoms, such as fever, malaise, and pain in the muscles and joints. Initially the nodules appear unilaterally or bilaterally below the knees. These areas vary in diameter from 1 to 5 cm with a red, smooth, shiny surface. A number of causative factors have been associated with erythema nodosum, including the following: streptococcal infections, tuberculosis, sarcoidosis, inflammatory bowel disease, acute monocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, and drugs (sulfonamides, oral contraceptives).4 LATE-ONSET UNILATERAL LEG SWELLING (GREATER THAN 72 HOURS) Chronic Venous Insufficiency
More than 1.6 million Americans have some form of chronic venous insufficiency, which accounts for 30,000 hospitalizations. 17, 30 In assessing patients with unilateral leg swelling, understanding the pathophysiology of this disease is important to making the diagnosis. The term chronic venous insufficiency is the descriptive heading under which diseases that result in valvular incompetency and regurgitation are listed (Table 2). Patients with primary varicose veins often have bilateral involvement and a family history. Secondary varicose veins are often related to pregnancy or obesity but may be associated with occupations that require prolonged standing or walking. These patients do not have a family history and manifest bilateral involvement. Patients with postphlebitic syndrome have unilateral leg varicosities, and in only 20% is a history of previous deep vein thrombosis recalled. s The final category is that of venous malformations, which include the KlippelTable 2. CLASSIFICATION OF LYMPHEDEMA Primary Lymphedema Hereditary (Milroy's disease) Congenital Iymphedema Lymphedema praecox Lymphedema tarda Secondary Lymphedema Obstructive Tumor Trauma (crush injury) Obliterative Surgery Tumor Radiation Sarcoid Inflammatory Filarial infecton Bacterial infection
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Trenaunay and Parkes-Weber syndromes. The former has unilateral varicosities, leg enlargement, and port wine skin lesions, whereas the latter has unilateral varicosities, leg enlargement, and venous bruits secondary to arteriovenous malformations. 26 These syndromes appear at an early age. Patients within any of these categories frequently describe their lower extremities as heavy, tight, fatigued, aching, or painful. These symptoms begin on arising and assuming the upright posture and gradually increase as the day progresses. These symptoms result mainly from valvular incompetence with retrograde flow resulting in an increased pressure at the capillary level. The retrograde venous flow translates into a greater volume of venous blood in the extremity and extrusion of red cells, fluid, and protein into the interstitial space, causing pitting edema and the golden brown discoloration of hemosiderin in the skin. 3 The protein in the subcutaneous tissue and skin causes an inflammatory response and subsequent fibrosis. Any injury to the skin can then lead to ulceration. These ulcers may or may not be painful. Sometimes, stasis dermatitis accompanies venous ulceration and resembles macerated tissue around the ulcer periphery. These pathophysiologic changes sometimes can be exacerbated by prolonged standing or sitting. Patients seek care because of this unilateral change. The first concern is whether a deep or superficial thrombosis is present. The presence of a superficial thrombosis can be diagnosed by physical examination, but noninvasive testing is required for evaluation of the deep system. Noninvasive testing to exclude a deep vein thrombosis would be warranted for a superficial phlebitis involving the greater saphenous vein above the knee. Recurrent unilateral leg swelling may be common with this disease. If leg swelling or pain occurs, the patient should be instructed to elevate the extremity for 24 hours, and if no improvement occurs in either pain or swelling, an office visit is mandatory. A clear understanding by the patient of the underlying disease helps avoid frequent visits for the common manifestation of leg swelling, which is part of the underlying pathophysiology of this disease.
Lymphedema
The diagnosis of lymphedema should be confined to patients with swelling of an extremity secondary to a malformation or obstruction of lymphatic channels. Lymphedema can be classified into primary and secondary categories (Table 3).9 In this section, the clinical manifestations and assessment of lymphedema are reviewed. The primary function of the lymphatics is to clear the interstitial space of excess proteinaceous fluid and return it to the blood circulation. When this protein-rich fluid (1 to 5 g/ dL) is not adequately removed, lymphedema develops. This edema is primarily painless and nonpitting. Understanding the classification of lymphedema and each of the specific
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Table 3. CLASSIFICATION OF CHRONIC VENOUS INSUFFICIENCY Varicose veins Primary varicose veins Secondary varicose veins (pregnancy, obesity, occupational) Postphlebitic syndrome Congenital thrombotic disorders Acquired thrombotic disorders Congenital venous malformations Klippel-Trenaunay syndrome (venous) Parkes-Weber syndrome (arteriovenous)
factors of each category is important when assessing the patient with unilateral leg edema. The first category includes congenital and hereditary forms.1 The congenital form often presents in an individual without a family history of lymphedema. The hereditary form (Milroy's disease) is transmitted as an autosomal dominant trait. The clinical characteristics of each are predominantly an enlargement of an extremity at birth with firm, nonpitting edema. The child's development and activities are not impaired. The second category is lymphedema praecox.] This group is composed primarily of women in the second and third decades of life. Lymphedema praecox presents spontaneously without an apparent cause. The edema is initially soft and pitting but becomes firm and nonpitting over time. There is no pain or ulceration, but recurrent infection can occur in this group. The lymphedema tarda category comprises patients who develop lymphedema after the age of 35 years. 15 This condition also occurs without an obvious cause. The edema is nonpitting and firm. Pain and ulceration do not occur, but recurrent infections are common. Both the praecox and tarda forms of lymphedema may represent congenital lymphatic disease with delayed onset of symptoms. On a worldwide basis, secondary lymphedema is the most frequent type. 28 Infection is the predominant cause in Third-World countries, whereas malignancy is the major cause in the Western world. The pathophysiology of secondary lymphedema is the obstruction or removal of lymphatic channels, by extranodal malignant disease, radiation, surgical excision, trauma, or infection. Therefore, three groups exist under the heading of secondary lymphedema: obstructive, obliterative, and inflammatory. The obstructive and obliterative types are caused predominantly by malignancy. Lymphedema results from tumor invasion or compression, surgical removal, or radiation. Prostate cancer in men and lymphoma in women are the most frequent causes. Lymphedema may precede the diagnosis of malignancy. The edema is predominantly unilateral, is pitting or nonpitting, and regresses slightly with elevation. The inflammatory type may result from frequent infections with residual limb edema, which becomes firm and nonpitting over time. Filariasis, tuberculosis, typhoid fever, and influenza have all been re-
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ported as causes for this process. 9 Rarely, sarcoidosis has been reported as a cause of lymphatic obstruction. 21 Swelling often precedes the other manifestations of sarcoidosis. The patient history is probably the most important factor in differentiating primary from secondary lymphedema. The physical examination, although often not specific, is important in distinguishing lymphedema from other causes of edema. The workup of these patients requires a thorough history and physical examination, supplemented by laboratory tests as indicated. Computed tomography or MR imaging of the abdomen and pelvis may supplement the physical examination in differentiating primary versus secondary lymphedema. Reflex Sympathetic Dystrophy
The incidence of reflex sympathetic dystrophy (RSD) has been reported to vary between 10% and 15%.24 This disease entity has been precipitated by a number of factors and disease processes. The mechanism by which all these entities cause this clinical syndrome is not yet known. The syndrome is characterized by burning pain, hyperesthesia, hyperhydrosis, and trophic change in the skin and bone of the affected extremity. Swelling is often an early sign of this syndrome and a frequent presenting complaint in the outpatient setting. Commonly the onset of unilateral lower extremity RSD follows a traumatic event or a concomitant disease process (Table 4). A few weeks after the initiating event, pain is experienced in the extremity as either burning or aching in character; swelling may be precipitated by dependency of the extremity, and physical contact or emotional upset may be followed by the onset of swelling. This symptom complex is designated as stage I of three stages of RSD.25 As the disease progresses to stage Il, the edematous tissue of the lower extremity becomes indurated and the skin cool, hyperhydrotic with livedo reticularis or cyanosis. 25 The pain is constant and made worse by any stimulus to the extremity. Stage III is manifested by the thinning of the skin with thickening of the fascia causing contractures, bony demineralization, and proximal spread of the pain and edema of stage 11.25 The differentiating points for diagnosing RSD are the association Table 4. PRECIPITATING FACTORS AND DISEASE ASSOCIATED WITH REFLEX SYMPATHETIC DYSTROPHY Peripheral Causes Fracture, sprains, dislocations Soft tissue injury Immobilization with cast or splint Venous or arterial thrombosis Myelography, venography, arteriography Infections Idiopathic
Central Causes Cervical cord injury Brain tumors Cerebral infarction
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with an initiating event, the character of the pain, and progression of swelling. Clinicians frequently observe the early stage of this disease in outpatient practice. It is difficult to differentiate this disease from some of the other causes of lower extremity swelling that have been described. Because there is no diagnostic test for RSD, good clinical assessment and follow-up observation are the primary approach. Congenital Venous Malformations
Klippel-Trenaunay syndrome is a congenital malformation of the venous system. 26 It predominantly involves the lower extremities with a variety of clinical manifestations. This syndrome is not common, but its presentation as unilateral lower extremity edema in 84% of patients makes this entity a consideration in the differential diagnosis of leg swelling. Klippel-Trenaunay syndrome is characterized by a port wine nevus involving the extremity, unilateral varicose veins, and hypertrophy of all of the tissues and bones of the impaired limb. The skin texture of the port wine nevus has been reported to be verrucous or smooth in quality. These patients frequently present with unilateral varicose veins early in life. The edema noted in this syndrome is located below the knee and may be manifested at birth, puberty, or adult life. This swelling can sometimes mask the varicose veins mentioned previously, leading the clinical assessment away from this diagnosis. A third factor is that of leg length discrepancy, which is a result of bone hypertrophy. The key point in the physical examination is the auscultation of the lower extremity varicosities for bmits. This finding indicates the presence of arteriovenous malformations as a component of congenital venous abnormality. The approach to managing a patient with arteriovenous malformations is to assess the extent of vascular involvement. Surgical intervention is the best strategy for long-term care of these patients. Malignancy
In this section, the most common bone and soft tissue tumors are discussed. Each individual tumor is reviewed featuring the most important clinical points for assisting the differential diagnosis of unilateral leg swelling. Osteochondromas are the most common benign bone tumors, representing 50% of these lesions.23 This tumor is primarily observed in adolescence, in which it presents as a mildly painful swelling along the metaphyseal region of the femur around the knee joint. Osteogenic sarcoma is the most common primary malignant bone tumor occurring in the second decade.23 These are usually characterized by pain and swelling in the area of the lesion. The pain is progressive
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and not related to the time of day. Swelling occurs locally and progresses as the tumor expands the bony cortex stretching the periosteum and above tissues. Chondrosarcomas represent 20% of all primary bone lesions.23 They commonly present in patients over the age of 40 years with lesions found predominately in the pelvis and femur. The tumor may cause localized pain and swelling at and distal to the lesion. Liposarcoma is the most common malignant soft tissue tumor in adults, constituting 7% to 10% of lesions. 20 They most commonly occur in the thigh and adjacent popliteal space, the inguinal and gluteal regions, and the retroperitoneum. If the lower extremity is involved, localized unilateral leg swelling and pain are observed. Kaposi's sarcoma is a tumor classically occurring spontaneously in Jewish and Italian men both in Europe and the United States. 20 There are three other variants of this tumor: endemic in parts of Africa in children, postrenal transplant, and associated with acquired immunodeficiency syndrome. This tumor is often manifested early by a raised bluish skin lesion. As the disease progresses, more tissues become involved, resulting in further swelling, redness, and pain in the extremity. Tissue biopsy confirms the diagnosis.
References 1. Allen E: Lymphedema of the extremities: Classification, etiology, and differential diagnosis. A study of three hundred cases. Arch Intern Med 54:606-624, 1934 2. Anderson F, Wheeler H, Goldberg R, et al: A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: The Worcester DVT study. Arch Intern Med 151:933-938, 1991 3. Angel M, Ramasastry S, Swartz W, et al: The causes of skin ulcerations associated with venous insufficiency: A unifying hypothesis. Plast Reconstr Surg 79:289, 1987 4. Arnold H, Odom R, James W: Andrews' Diseases of the Skin: Clinical Dermatology, ed 8. Philadelphia, WB Saunders, 1990, pp 142-143 5. Browse N, Clemenson G, Thomas L: Is the postphlebitic leg always postphlebitic? Relationship between phlebographic appearance of DVT and late sequelae. BMJ 281:1167, 1980 6. Fielding J, Franklin P, Kustan J: Popliteal cysts: A reassessment using magnetic resonance imaging. Skel Radiol 20:433-435, 1991 7. File T, Tan J: Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet 172:17-24 8. Haeger K: Problems of acute deep venous thrombosis: The interpretation of signs and symptoms. Angiology 20:219, 1969 9. Hammond M, Merli G, Zierler R: Rehabilitation of the patient with peripheral vascular disease of the lower extremity. In DeLisa J (ed): Rehabilitation Medicine: Principles and Practice, ed 2. Philadelphia, JB Lippincott, 1993, pp 1082-1098 10. Hook E: Acute cellulitis. Arch Dermatol 123:460-461, 1987 11. Jayson M, Dixon A: Valvular mechanisms in juxta-articular cysts. Ann Rheum Dis 29:415, 1970 12. Kahn R, Goldstein E: Common bacterial skin infections: Diagnostic clues and therapeutic options. Postgrad Med 93:175-182, 1993 13. Katz R: The key to diagnosing pseudothrombophlebitis. Intern Med 15:33-41, 1994 14. Katz R, Zizic T, Arnold P, et al: The pseudothrombophlebitis syndrome. Medicine 56:151-164, 1977
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15. Kinmonth J, Taylor G, Tracy C, et al: Primary lymphedema: Clinical and lymphographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 45:1, 1957 16. Lensing A, Prandoni P, Brandjes D, et al: Detection of deep vein thrombosis by realtime B-mode ultrasonography. N Engl J Med 320:342-345, 1989 17. Linder D, Edwards J, Phinney E, et al: Long-term hemodynamic and clinical sequelae of lower extremity DVT. J Vasc Surg 4:436,1986 18. McClure J: Gastrocnemius musculotendinous rupture: A condition confused with thrombophlebitis. South Med J 77:1143-1145, 1984 19. Menz M, Lucas G: Magnetic resonance imaging of a rupture of the medial head of the gastrocnemius muscle. J Bone J Surg Am 73:1260-1262,1991 20. Morton D, Antman K, Tepper J: Soft tissue sarcoma. In Holland J, Frei E, Bast R, et al (eds): Cancer Medicine, ed 3. Philadelphia, Lea & Febiger, 1993, pp 1858-1887 21. Nathan M, Pinsker R, Chase P, et al: Sarcoidosis presenting as Iymphedema. Arch Dermatol 109:543-544, 1974 22. Philips G, Godon D, Martin E: The Klippel and Trenaunay syndrome: Clinical and radiological aspects. Radiology 128:429-434, 1978 23. Rosen G: Neoplasms of the bone and soft tissue. In Holland J, Frei E, Bast R, et al (eds): Cancer Medicine, ed 3. Philadelphia, Lea & Febiger, 1993, pp 1825-1858 24. Rothberg J, Tahmoush A, Oldakowski R: The epidemiology of causalgia among soldiers wounded in Vietnam. Milit Med 148:347-350, 1983 25. Schwartzman R, McLellan T: Reflex sympathetic dystrophy. Arch Neurol 44:555-561, 1987 26. Servelle M: Klippel and Trenaunay's syndrome. Ann Surg 201:365-373, 1985 27. Shields C, Redix L, Brewster C: Acute tears of the medial head of the gastrocnemius. Foot Ankle 5:186-190,1985 28. Smith R, Spittell J, Schirger A: Secondary Iymphedema of the leg: Its characteristics and diagnostic implications. JAMA 185:80-82, 1963 29. Staraehely D, Jones W: Acute compartment syndrome following tear of the medial head of the gastrocnemius muscle. Am J Sports Med 14:96-99, 1986 30. Strandness D, Langlois Y, Cramer M, et al: Long-term sequelae of acute venous thrombosis. JAMA 280:1289, 1983
Address reprint requests to Geno J. Merli, MD Division of Internal Medicine Section of Vascular Medicine Walnut Towers 211 South 9th Street Philadelphia, PA 19107