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Understanding Lymphedema Pathophysiology and Treatment
By: Joachim E. Suther
Lymphedema, a protein rich swelling which usually affects the extremities, is a very common condition worldwide. Complete Decongestive Physiotherapy is done successfully in Europe for decades in the treatment of primary and secondary Lymphedema and is now becoming widely recognized in the U.S.
UNDERSTANDING LYMPHEDEMA PATHOPHYSIOLOGY AND TREATMENT
Joachim E. Zuther
Chronic peripheral lymphedema, an accumulation of protein rich fluid in the superficial tissues, is a very common and serious condition with significant consequences for the patient.
One of the main reasons for the development of lymphedema are surgical interventions in combination with lymph node dissections, such as mastectomy or lumpectomy due to breast cancer, which is the number one cause for this disease in the U.S.
Although reliable statistics on the overall incidence of lymphedema are not available, conservative numbers estimate the incidence of secondary upper extremity lymphedema to be around 2.5 million. In addition to that there is a large number of patients suffering from primary lymphedema, which usually affects the lower extremities and is caused by congenital malformations of the lymphatic system.
Anatomy and Physiology of the Lymphatic System
These materials, also called lymphatic loads, consist of protein, water, cells and fat, are drained by the various vascular structures of the lymphatic system and filtered by a large number of regional and central lymph nodes before they enter the venous system. Part of these waste materials are also cell products and cell residues including foreign materials.
Initial lymphatic system: Lymph vessels start in almost every tissue as lymph capillaries. These initial lymphatics are made up of endothelial cells which overlap each other. Capillaries do not have a continuous connection like blood capillary endothelial cells do. A surrounding fiber net, anchoring filaments, arranged around the lymph capillaries, enables these small vessels to stay open, even under high tissue pressure.
Collectors: One segment of a lymph collector is called lymph angion. Contractions of smooth muscles situated in each lymph angion, generate the propulsive force of the lymph flow.
The pumping is aided by a large number of valves located inside the collectors which allow the lymph flow in only one direction. After passing a large number of lymph nodes, where foreign substances like bacteria are filtered out and necessary immune reactions are activated, the lymph fluid empties into the venous system, mainly via the thoracic duct.
The thoracic duct is the largest lymph vessel of the body. Under physiological conditions approximately 1-2 liters of lymph fluid drain in 24 hours via the thoracic duct into the left venous angle, formed by the left internal jugular and the left subclavian vein.
Starling's equilibrium: The amount of water and protein transported via the lymphatic system is depending on forces being active in the area of the blood capillaries.
Starling's equilibrium describes the balance of capillary filtration and capillary reabsorption. The transport of fluid through the membrane of blood capillaries depends on four variables:
1. blood capillary pressure (BCP) 2. colloidosmotic pressure (COP) of the plasma proteins 3. colloidosmotic pressure (COP) of the proteins located in the interstitial tissue 4. tissue pressure (TP)
blood [[glossary:capillaries|capillary]] pressure > COP of plasma proteins
blood capillary pressure < COP of [[glossary:plasma|plasma]] proteins
Under physiological conditions 10-15% of the ultrafiltrate remains in the interstitial tissues and is then drained by the lymphatic system.
Shifting of Starling's equilibrium towards an increase in ultrafiltration, e.g. increased blood capillary pressure (inflammation, venous hypertension) or decreased colloidosmotic pressure (hypoproteinemia), can cause an increased amount of water and proteins, thus creating a higher burden on the lymphatic system. A healthy lymphatic system is, for some time, able to prevent the onset of edema, under normal conditions the transport capacity (TC) of the lymphatic system is approximately 10 times higher than the physiological amount of the lymphatic loads (LL) of water and protein ⇒ functional reserve (FR) of the lymphatic system.
Pathophysiology of Lymphedema:
As long as the lymphatic loads remains lower than the transport capacity of the lymphatic system, the lymphatic compensation is successful.
If the amount of water and protein exceeds the transport capacity, edema will occur. This condition is called dynamic insufficiency of the lymphatic system, the lymph vessels are intact but overwhelmed. The result is an accumulation of fluid in the tissue which is usually treated successfully with elevation of the affected limbs, compression and decongestive exercises.
Lymphedema is caused by a mechanical insufficiency, or low-volume insufficiency of the lymphatic system.
In this case the transport capacity of the lymphatic system drops below the physiological level of the lymphatic loads of water and protein, that means the lymphatic system is not able to manage its main purpose which is to clear the interstitial spaces from excess water, protein and other chemical, organic and inorganic cell products.
Accumulation of high protein fluid is the result which is then recognized as lymphedema or lymphostatic edema.
Classification of Lymphedema:
1.Caused by lymph node dissections, 1.caused by malformations of the e.g. axilla, groin, pelvis or neck, lymphatic system (hyperplasia, radiation of lymph nodes, trauma or hypoplasia, aplasia or sclerosis infection ofthe lymphatic system. of lymph nodes)
2.Affects extremities, genitalia, 2.Can be present at birth (congenital abdomen or the face a lymph-edema), develop around the (lymphedema precox) or after age of puberty the age of 35 (lymphedema tardum)
Any lymphedema left untreated gradually worsens and will have significant consequences.The first stage of lymphedema (reversible stage) is characterized by a smooth texture of the tissue, the lymphedema is ”pitting” and may vanish more or less over night. If protein rich edema persists, the congested protein molecules are replaced by fibrotic tissue, i.e. the lymphedema becomes harder (stage II) and in addition to that patients are prone to developing frequent infections which additionally worsen the condition. Typical for the third stage of lymphedema, lymphostatic elephantiasis, is an extreme increase of the swelling combined with skin changes, loss of function and other complications.
Since lymphedema, primary or secondary, is a progressive condition, treatment should begin as early as possible. The goal of the treatment is to remove the excess lymphatic loads of water and protein and to restore the disturbed equilibrium in the interstitial tissues of the affected area.
Treatment of Lymphedema with Complete Decongestive Physiotherapy:
Complete Decongestive Physiotherapy (CDP), done successfully in Europe for decades, is a non-invasive therapy with long lasting results. CDP, which now becomes widely recognized in the U.S., is superior to all other approaches to treat lymphedema (pumps, medication, surgery) and designed to reduce and to maintain the reduction of the swollen extremity.
At the end of the last century Winiwarter, professor of surgery, already described the basic steps of this therapy. The technique was improved in the 1930s by Vodder, a physical therapist from Denmark, who successfully treated lymphedema.
In the 1980s Foeldi considerably improved this therapy by developing a technique called Complete Decongestive Physiotherapy, which even in advanced stages of lymphedema shows remarkable results.
CDP is done in two phases. The first phase, intensive phase, lasts between two and four weeks (in extreme cases longer), treatments are done twice a day, five days a week. The goal of this phase is to decongest the swollen extremity to a normal or near normal size. Simultaneously the patient is instructed in techniques designed to maintain and even improve the condition after the intensive phase of the therapy.
The first phase is immediately followed by phase two, the maintenance and improvement phase which the patients continues at home.
For the safety of the patients and to achieve good results it is absolutely mandatory that the therapist is thoroughly trained in all components of CDP. Only certified MLD/CDP therapists have a complete understanding of the pathophysiology of lymphedema and its treatment.
CDP consists of four basic steps :
Manual Lymph Drainage is a gentle manual treatment technique which improves the activity of intact lymph vessels by mild mechanical stimuli. The goal of this treatment is to move excess lymphatic loads of water and protein into areas with still sufficient lymphatics.
Since the elastic fibers of the skin are destroyed during the course of lymphedema it is mandatory to apply sufficient compression to the affected area in order to prevent reaccumulation of fluid. Compression therapy in phase one is achieved by short-stretch bandages applied after each treatment. After the extremity is decongested the patient is fitted with a sufficient compression garment that needs to be worn during the daytime. At night the patient applies mild compression using bandages.
Before treatment can be started the skin has to be free of infections or fungal infections.
During the treatment it is mandatory to apply a low-pH lotion to maintain the moisture of the skin.
Remedial exercises performed by the patient wearing the compression bandage or garment aid the lymphokinetic effects of the joint and muscle pumps.
1. Marvin Boris, et al. Lymphedema Reduction By Noninvasive Complex Lymphedema Therapy Cornell University School of Medicine and Lymphedema Therapy. Woodbury, NY
2. M.Foeldi, S.Kubik Lehrbuch der Lymphologie Gustav Fischer Verlag, Germany 1992
3. L.Clodius, M.Foeldi Therapy For Lymphedema Today Inter. Angio., 3 1984
4. S.Kubik The Lymphatic System Springer, NY 1985
5. M.Foeldi, E.Foeldi Das Lymphoedem Gustav Fischer Verlag, Germany 1991
6. G.Bringezu, O.Schreiner Die Therapieform Manuelle Lymphdrainage Otto Haase Verlag, Germany 1987
7. R.Lerner, J.Petrek Lymphedema Diseases Of The Breast, Lippincott - Raven, 1996
8. J.R. Casley-Smith Lymphedema, The Poor and Benzo-Pyrones: Proposed Amendments To The Consensus Document Lymphology 29, 1996 137-140
9. E.Foeldi Preventions of Dermatolymphangioadenitis By Combined Physiotherapy Of The Swollen Arm After Treatment For Breast CancerLymphology 29, 1996 48-49
10. E.Foeldi, M.Foeldi, L.Clodius The Lymphedema Chaos: A Lancet Ann Plast Surg 22:505-515
Family Physicians are key to treating developmental disorders
By Clare A. Green, DO
Abstract Lymphedema is the accumulation of lymph in the interstitial spaces caused by a fault in the lymphatic system. Failure of any part of the lymphatic system results in the accumulation of plasma proteins in the interstitial fluid,an increase in interstitial fluid colloid osmotic pressure and subsequent edema.
Primary lymphedema is caused by pathology affecting the lymphatics directly, rather than the lymphatics failing secondary to pathology of another organ system. The diagnosis of primary lymphedema is a diagnosis of exclusion, and many differential diagnoses must first be considered.
Lymphedema is associated with other anomalies of development and is a feature of several developmental syndromes. Primary lymphedema has a significant genetic inheritance pattern. The frequency at birth of those who will develop primary lymphedema is estimated to be about 1 in 6,000 with a sex ratio of about one male to three females.4
Imaging studies used to evaluate the lymphatic system include venography, lymphangiography and radio-isotopic tracers (lymphangioscintigraphy). Disease management is multifactorial, primarily focused on prevention, or slowing the rate of progression.
Patients must take an active role in controlling their disease by wearing the compression hosiery, frequently elevating the affected extremity, and following through with therapies recommended by their primary care physician. Drug therapy has not shown much benefit, and surgery is saved for extreme cases.
The Clinical Picture Lymphedema is defined as a swelling in some part of the body owing to a fault in the lymphatic system. Primary lymphedema is due to pathology affecting the lymphatics directly. The vast majority of patients complain of swelling of the lower limbs.
The swelling may be present in one or both legs and be present at birth or develop at any age afterwards, with a peak onset between the ages of 10 and 25 years. Lymphedema has a variable clinical onset, progress, and picture - it has a high incidence in females with an increased onset in the ages associated with the menarche and child bearing.
Despite the advances in technology and our knowledge of anatomy and physiology, the lymphatic system is almost as mysterious now as it was in the 1800s, when Milroy first described a family with lymphedema passing through six generations.6 Much of the pathophysiology discussed later is speculative, based on animal studies and theory.
Although there are centers that specialize in the treatment of lymphedema, most often it is diagnosed and managed by the primary care physician, along with a team of health care professionals. Primary lymphedema is a lifetime condition with no known medical cure.
The key to management is aggressive maintenance to slow disease progression. The maintenance, or preventative medicine,” is monitored by the patient’s primary care physician.
To give a complete overview of primary lymphedema, this paper will review the pathophysiology of the disease, the association with several developmental disorders, the genetic inheritance, and the management and treatment in clinical practice today.
Pathophysiology of Lymphedema Anatomy of the Lymphatic System The lymphatic system begins developing at approximately 20 weeks gestation, and continues to undergo changes until puberty. The three components of the lymphatic system are:
Lymph channels perfusing all the tissues of the body, the channels are connected by lymph nodes. The channels begin as blind thinly walled tubes, lymphatic capillaries, which join to form capillary plexus that in turn form larger trunks. The trunks eventually drain into two main trunks that empty into the venous system in the cervicothoracic area, either the right lymphatic duct, or the thoracic duct.
Lymph fluid the substance that leaks out of the arterial capillaries, into the interstitium, and into the single-cell lymphatic vessels. Lymph fluid contains proteins, salts, water soluble fats, and clotting factors. Bacteria and smaller viruses are found in the peripheral lymph before filtration through a lymph node or one of the organized lymphoid tissues. The primary cells of lymph are lymphocytes.
The primary function of the lymphatic system is to clear the interstitial spaces of excess water, large molecules and particles and to subsequently transport them from the tissues back to the intravascular circulation. Starling’s hypothesis states that the exchange of water and small molecules across the capillary membrane is largely governed by the transmural capillary hydrostatic and colloid osmotic pressures. The colloid osmotic pressure is dependent on the relative impermeability of the capillary membrane to plasma proteins.
It has been known since 1896 that a proportion of the plasma proteins pass through the capillary wall but not all of it returns directly to the circulation.2 The concept of the lymphatic system as absorbing vessels, whose main function is to return to the bloodstream those protein molecules that fail to return via the venular capillaries, was first elaborated by Drinker in 1931; a concept that has been confirmed repeatedly with experiments using radio-active labeled plasma proteins.2
Iodine labeled albumin studies in man indicate a daily exchange between the intra and extravascular pools of 140% of the total body albumin. Failure of any part of the lymphatic system will inevitably result in the accumulation of plasma proteins in the interstitial fluid and therefore lead to an increase in interstitial fluid colloid osmotic pressure and the movement of more water into the interstitial space, i.e., edema.
Lymphedema is the accumulation of lymph in the interstitial spaces, principally of the subcutaneous fat, caused by a fault in the lymphatic system. Although there are many descriptive classification of the causes of lymphedema there is no classification based on the disordered physiology because the etiology of primary lymphedema remains obscure.
No vessels visualized—which he called aplasia. True aplasia—no lymphatics—does occur but is very rare and likely only to be associated with those lymphedemas that are present at birth.
A reduced number of vessels visible–hypoplasia.
An increased number of dilated vessels visible—hyperplasia.
The mechanisms controlling the collection and passage of lymph, from the interstitial spaces to the blood system, remain largely unknown, however from the available research the various stages of lymph collection and transport can be discussed under the following descriptive functions:2
System Overload The capillary wall becomes more permeable in severe pathological conditions. Injury by trauma, heat, irradiation, and infections all cause edema secondary to increased capillary permeability. Venous congestion causes edema by preventing reabsorption in the venular capillaries. Provided the lymphatic pathways are normal this type of edema is eventually cleared, although this may take longer to resolve than the initial injury.
Inadequate Collection Like the venous system, the lymphatic vessels rely on unidirectional valves and exterior compressive forces to propel the fluid. The lymphatic terminal buds are in the tissues, the entry point for the extravascular fluid to enter the lymphatic system. It is hypothesized that when tissues are lax, the pores of the terminal buds are open to allow free flow inwards, and during tissue compression (caused by movement and exercise) the pores in the terminal segment are closed.
Work done by Guyton and Casley-Smith suggests that in lymphedema the minor changes of tissue pressure that effect the opening and closing of the pores are absent because the interstitial pressure is both postitive and relatively constant.2 The pores may be kept permanently closed by the increased tension in the filaments attached to the endothelial cells caused by increased tissue pressure and tissue fibrosis, a situation which will prevent their alternate opening and closing and so make the collection system inadequate or incompetent.
Abnormal Lymphatic Contractility The walls of all lymphatics, except the terminal segments, contain smooth muscle cells and nerves. Studies by Olsewski and Engeset (1979), suggest that there are rhythmic contractions of the lymphatics at rest and that lymph flow occurs during the waves of lymphatic contraction. They also claim that skeletal muscle contractions per se do not increase lymph flow but that muscular activity is associated with an increased number of intrinsic contractions.2
Autonomic Control The sympathetic nervous system plays an important role in controlling the rest of the vascular tree. In 1968 Browse showed that limb lymphatics contract in response to sympathetic nerve stimulation, so raising the possibility that lymphatic contractility and lymph propulsion may be under nervous control.2
Insufficient Lymphatics As confirmed by lymphangiography, the majority of patients with lymphedema have a reduced number of lymphatics. Whether the patient is born with this reduced number which manifests itself as lymphedema later in life or whether it reflects an acquired occlusion following some form of damage to the lymph vessels is often unclear. The reduced number of lymphatics are eventually inadequate, particularly following incidents which cause edema such as trauma or inflammation.
LymphNode Obstruction The two most obvious and well known examples of lymphatic obstruction are lymphedema following block dissection of nodes (as in breast cancer patients), and lymphedema caused by filarial tropical elephantiasis. Other studies have correlated non-filarial primary lymphedema to the deposition of silica particles from the soil, as well as the presence of shrunken, fibrotic lymph nodes.
Central Vessel Defects Congenital or acquired abnormalities of the central abdominal or thoracic collecting ducts may cause lymphedema. Congenital abnormalities may be without symptoms, however, usually they cause bilateral lymphedema with moderate dilatation of the vessels and nodes. Acquired obstruction of the thoracic duct, in children or adults, through trauma, mediastinitis, tumors, venous thrombosis or surgery is often symptomless. It may occasionally cause chylothorax but hardly ever causes peripheral edema.
Secondary lymphedema is edema caused by disease in the nodes or vessels that began elsewhere (neoplastic or filarial) or began in the cellular-nonconducting elements of the nodes (lymphocytic proliferative disorders). Secondary lymphedema may also occur following surgical removal of lymph nodes or vessels; such as in mastectomy for breast cancer.
Developmental Disorders of the Lymphatic System There are several different developmental disorders which are associated with lymphedema.5 Many of them present with lymphedema at birth, and should be considered when diagnosing a newborn with peripheral edema. As many of the syndromes are associated with other congenital anomalies, the presence of lymphedema may stimulate a more careful scrutiny of the other organ systems
Turner Syndrome Turner syndrome is a collection of anomalies linked to the XO karyotype. Among multiple malformation syndromes, Turner sydrome is most often associated with congenital lymphatic disorders. The manifestations may include cystic hygroma, hydrops fetalis and peripheral edema. More well known features of Turner syndrome are the short stature, webbed neck, infertility, poor pubertal development and shield chest.
Klinefelter Syndrome Klinefelter Syndrome also occasionally is associated with lymphatic blockage or fetal hydrops. This syndrome is associated with a 47XXY karyotype and occurs in 1/500 newborns. Other features of Klinefelter are tall stature, long upper extremities, poor pubertal development, microorchidism and sterility.
Trisomy 21 Cystic hygroma and lymphedema have been occasionally noted in children with Down Syndrome. Other features of Down Sydrome are characteristic facies, short broad hands, heart defects and mental retardation.
Klippel-Trenaunay-Weber-Syndrome Klippel-Trenaunay and Parkes Weber syndromes are panangiopathis associated with localized overgrowth of bone and soft tissue of a limb or portion of the trunk. A variety of blood and lymph vascular malformations may be seen, including hemangiomas, arteriovenous malformations, port-wine stains, varicose veins, lymphangiomas, and lymphedema.
Noonan Syndrome Noonan Syndrome has been suggested to have a “Turner-like” phenotype with similar manifestations that include peripheral lymphedema, hypoplastic nails, and shield chest. They often exhibit right sided cardiac abnormalities. Despite similarities, Noonan syndrome is distinct from Turner’s in that males and females are equally affected. Most cases of Noonan syndrome are likely due to an altered autosomal gene.
Noone-Milroy-Type Hereditary Lymphedema Also known as Lymphedema I, this disorder presents as brawny edema usually of the lower extremity. The diagnosis is usually made at birth. Tissue swelling occurs distally or proximally in the involved limbs, and either hypoplasia or hyperplasia of the lymphatics has been found.
Meige-Type Lymphedema Also known as Lymphedema II, this syndrome is similar to Lymphedema I but the onset of peripheral edema occurs during the second to the fifth decades. The legs are the most commonly involved, and lymphangiography reveals hypoplasia of peripheral lymphatics with dilation of lymphatic trunks.
Lymphedema-Hypoparathyroidism Syndrome The major diagnostic criteria for this syndrome include congenital lymphedema—which develops soon after birth, hypoparathyroidism, nephropathy, mitral valve prolapse, and brachytelephalangy.
Please refer toTable 1 and Table 2 for a comparison of the developmental disorders described.
The Inheritance of Primary Lymphedema The frequency at birth of those who will develop primary lymphedema is estimated to be about 1 in 6000 with a sex ratio of about one male to three females.4
It is clear from the studies done by Dale, that lymphedema passes from generation to generation.4 True dominant inheritance, recessive and sex linked inheritance were excluded. In those patients with a genetic origin of their lymphedema, the form of inheritance is that of a modified dominant single autosomal gene.
On average, half the offspring of these subjects will carry the gene. The expression of this dominant gene approaches 50 percent and in those patients who develop lymphedema the majority will have done so by the age of 30 years. The expression of lymphedema is sex influenced and is much higher in females than males, 66 percent and 30 percent respectively.
In those patients who have no preceding family history probably only a small proportion have received a new mutation, thus creating a risk to children in this group which is higher than to siblings. In those patients with no preceding family history the risk to children in about 1 in 12.4
The Diagnosis of Primary Lymphedema Diagnosis of primary lymphedema, as in all diseases, relies primarily on history and physical exam. A patient presenting with lower extremity edema and a family history of hereditary lymphedema will be easier to diagnose than an infant with no family history. Primary lymphedema is usually differentiated from secondary lymphedema by history as well.
Most cases of lymphedema, both primary and secondary, affect limbs. Presumably this is because there are reduced options for collateral lymph drainage. Swelling results in discomfort, heaviness, reduced mobility, and impaired function. Moderate to severe pain is not a feature of lymphedema and, if present, should suggest alternative pathology. However the size and weight of some limbs soon produce secondary complications such as musculoskeletal problems.
Difficulty in the clinical diagnosis of lymphedema is likely to be encountered in the early stages before the characteristic skin and subcutaneous tissue changes ensue. It is not uncommon for lymphedema to present with swelling which comes and goes.
Cancer rarely presents in the first instance with lymphedema because lymph flow is maintained remarkably well through malignant nodes. Lymphoma does not produce lymphedema, and it is only in circumstances of advanced cancer (prostate carcinoma) where swelling can be a presenting feature.
Filiariasis, causing lymphedema by obstruction of the lymphatics, is a diagnosis which must be investigated in persons living in the tropics or with a history of traveling to the tropics.
A condition often confused with filarial elephantiasis is podoconiosis or non filarial elephantiasis. The clinical manifestations of swollen feet and legs are no different from that of any other cause, but the cause in this condition is uptake of microparticles of silica through the soles of the feet. It exists in non-filarial areas of tropical Africa, Central America, and India, and occurs only in barefoot walkers.
Heart failure may cause bilateral peripheral edema, and should be considered first in a patient with known hypertension or coronary artery disease. Associated symptoms are dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. On physical examination there may be pulmonary rales, distended neck veins, tachycardia, cardiomegaly, or gallop. Diagnostic studies to rule out heart failure include a chest radiograph and echocardiogram.
Cirrhosis is also a cause of bilateral peripheral edema. Associated symptoms are alcoholism, ascites, jaundice, and abdominal swelling. On physical exam corresponding findings are hepatomegaly, jaundice, ascites, and gynecomastia. Diagnostic studies confirming cirrhosis include abnormal liver function tests, and liver biopsy.
Nephrotic syndrome is a cause of bilateral edema which is found primarily in children. Associated symptoms are polyuria and eyelid swelling. On physical exam there may also beedema of the eyelids and hypertension. Diagnostic studies in patients with nephrotic syndrome reveal albuminuria and hypercholesterolemia.
Thrombophlebitis is a cause of peripheral edema which usually presents with a sudden onset of swelling, redness and pain. Precipitating factors of thrombophlebitis are trauma, immobilization, childbirth, drugs, and birth control pills. On physical exam there is a tender cord, positive Homans’ sign, warmth, and low grade fever. Diagnostic studies are duplex/doppler ultrasonography, venogram, or computed tomography.
A ruptured gastrocnemius muscle will cause peripheral edema, usually with a sudden onset in runners. On physical exam the extremity will be painful, and have ecchymoses of the ankle. Computed tomography is used for diagnosis.
A Baker’s cyst may cause peripheral edema in the patient with rheumatoid arthritis, and is diagnosed by arthrogram.
Dependency of the lower extremity is a common cause of peripheral edema in post stroke patients. This type of edema is exacerbated by venous insufficiency, and improved by muscle activity of the legs.
Lipedema causes bilateral peripheral edema in the obese female. It is exacerbated by weight gain, and improved by weight loss. On physical exam it differs from the other types of lymphedema noted in that it spares the foot.
Salt retaining drugs are also a cause of bilateral peripheral edema. These include: estrogens, oral contraceptives, NSAIDs, lithium and vasodilators.
Making the Diagnosis Once the other etiologies in the differential for peripheral edema have been ruled out, primary lymphedema should be considered in any chronically swollen limb without pain or inflammation. Traditionally, lymphedema is described as a brawny edema that does not readily pit. This is not a reliable sign. Although most of the swelling occurs in the subcutaneous layer, it is the skin that exhibits the most changes. It becomes thicker as demonstrated by the Kaposi-Stemmer sign, a failure to pick up or pinch a fold of skin at the base of the second toe.
Skin creases become enhanced and hyperkeratosis develops. Skin changes occur most frequently in the lower limb, owing to the compounding effects of gravity. The term mossy foot is used when the skin changes are advanced, and secondary bacterial and fungal infections are common.7
Imaging studies used to evaluate the lymphatic system include venography, lymphangiography and radio-isotopic tracers (lymphangioscintigraphy). When evaluating someone with primary lymphedema, the risks of the imaging studies must also be considered.
Commonly, in uncomplicated cases, the invasive studies are not performed secondary to the risk of damaging the delicate lymphatic system. Usually, a venous doppler is performed to exclude venous obstruction. MRI is another nonanvasine imaging study which may be used to determine area of lymphatic blockage.
There is no laboratory study used to diagnose primary lymphedema. Genetic studies may be done if a physician suspects an associated developmental disorder.
Elastic Hosiery The cornerstone of limb lymphedema treatment is elastic hosiery. The hosiery is designed to limit capillary filtration by opposing capillary pressure and act as a counterforce to striated muscle contractions. Exercise, breathing and posture are important for clearance of central dilated and obstructed lymphatics in the thorax and abdomen, which will improve peripheral edema.
Massage Massage is controversial, despite being an accepted treatment for lymphedema in continental Europe. The problem is that most types of massage are used to increase blood flow to the tissue—therefore increasing the amount of fluid to be transported by the defective lymphatic system.
However, gentle tissue movement is a stimulus to lymph flow without increasing blood flow (and, therefore, capillary filtration). Manual lymphatic drainage (MLD) therapy is a specific form of manual massage that is directed primarily at normally draining lymph node regions via extremely gentle tissue manipulation. MLD is the only effective treatment for midline lymphedema where external compression is impractical.
Osteopathic Manipulative Therapy Osteopathic Manipulative Therapy is a therapy used by Osteopathic physicians to maximize the functions of all organ systems by working to improve the structure of the body through the musculoskeletal system. Improving lymphatic function is one of the cornerstone principles of Osteopathic Manipulative Therapy. There are several treatment modalities, all of which have shown to be extremely beneficial in improving lymphedema.9
Skin Care Prevention of infection is crucial to control of lymphedema, as cellulitis can lead to deteriorating, irreversible swelling. Patients with advanced lymphedema and recurrent cellulitis are recommended to be put on prophylactic penicillin. Care of the skin, good hygiene, control of tinea pedis, chronic dermatitis, and other inflammatory dermatoses, as well as good antisepsis following abrasions and minor wounds, are as important as in diabetes.
Compression Pumps Pneumatic compression therapy or intermittent/sequential pneumatic compression is another treatment of extremity lymphedema. It consists of an inflatable sleeve or boot connected to a motor driven pump. Immediately following the therapy a compressive stocking is fitted to prevent limb reswelling.
Drug therapy Diuretics alone have very little benefit in lymphedema because their main action is to limit capillary filtration by reducing circulating blood volume. Improvement from diuretics suggests that the predominant cause of the edema is not lymphatic.
The Rutoside group of drugs, Paroven, has been advocated for use in lymphedema and a recent controlled trial of benzopyrones showed benefit in a variety of forms of lymphedema. Currently these drugs have only been used in Europe, and present data shows that clinical effect is mimimal.7
There are several other alternative therapies that have not been reviewed by medical literature. Many herbal preparations, such as grape seed extract, have reported beneficial effect in lymphedema. Microwave heat therapy has been used in China, with mixed results. It is theorized that the heat helps to break down the chronic fibrosis.7
Surgery Surgery for lymphedema is usually used as a last resort, and used more commonly in countries in which the other therapies are not available. Unfortunately, since it cannot correct the problem, lymphedema will recur, and sometimes worsen following surgery. Surgery for lymphedema can be of two types: reconstructive and debulking. Associated risks of surgery include infection and inflammation, which greatly accelerate the progression of the disease and obliteration of the lymphatic vessels.
Extremity elevation Once started, treatment needs to be maintained; otherwise the edema will progress and become more and more difficult to reverse. Lymphedema of the lower limbs usually progresses even with treatment, however the rate and degree of progression is greatly reduced with treatment. Posture and limb positioning are important. Any dependent limb will swell as a result of increased intravascular hydrostatic pressure. Elevation of the affected limbs just above heart level is the most effective.
Weight Management There is some evidence that obesity exacerbates lymphedema, particularly in the lower leg, as it makes compression more difficult. A weight reduction diet may be indicated.
Coexsisting Depression Psychologically, many patients are affected by the disfigurement of lymphedema, and appropriate counseling may be a necessary part of management.
Physical handicap is another aspect. Even those patients with mild lymphedema cannot tolerate prolonged standing, long distance running, or areas of high heat and humidity, as these situations increase capillary permeability and lymphatic load. Patients should be counseled on supportive footwear, and the need to elevate the affected extremity as frequently as possible during the day.
Disease Progression Air travel can also exacerbate lymphedema, some patients may want to have the affected extremity bandaged before travel to prevent increased disability.
Lymphedema invariably requires the highest compression strength (>40mmHg) hosiery, and double hosiery may need to be worn on occasions to maintain control. Most garments last no more than 6 months, less in an active young patient.
Conclusion The patient presented in the case report is an example of the typical presentation of primary lymphedema. Her diagnosis had already been made, but it is evident that she could benefit from continued management and education.
During her subsequent visits, she was educated in the importance of preventing the progression of her disease, by frequent foot elevation, wearing the compression stockings and supportive footwear, and by avoiding prolonged standing. She was treated monthly with Osteopathic Manipulative Therapy to improve lymphatic drainage. Her tinea pedis was treated and she was counseled about skin care. She went to genetic counseling regarding the inheritance of the disease, and was told that the chance of her child developing the disease was 20 percent.
Her pregnancy was uncomplicated, with the edema being most significantly affected in the last four weeks of gestation. She delivered vaginally, and her son had no congenital abnormalities.
The exacerbation of the peripheral edema, which occurred during the last month of her pregnancy, slowly reversed to her pre-pregnancy state over the period of three months.
Summary The diagnosis of primary lymphedema, a disorder of the lymphatic system, is made primarily by family history and physical exam. The disease presentation is extremely variable, both in age of presentation, and severity of disease. Many times it is associated with other anomalies of development and is a feature of several developmental syndromes.
Primary lymphedema has a significant genetic inheritance pattern, although it can appear sporadically. Disease management is multifactorial, primarily focused on prevention, or slowing the rate of progression. Lymphedema is always progressive, but the discomfort and disability can be minimized by therapies which reduce the superfluous fluid as much as possible.
Patients must take an active role in controlling their disease by wearing the compression hosiery, frequently elevating the affected extremity, using supportive footwear, and having diligent skin care. Drug therapy has not shown much benefit, and surgery is saved for extreme cases.
The pathophysiology of lymphatic system disorders is not well understood. Hopefully further investigations will better elucidate the nature of the disease, so that treatment can be more directed at the cause of the disorder, rather than the symptom—peripheral edema.
Dr. Green recently completed a fellowship in OMM at Michigan State University College of Osteopathic Medicine, following a family practice residency in Muskegon, Michigan. She will practice family medicine in Oregon
An Overview of Lymphedema
Introduction Lymphedema is the accumulation of lymph in the interstitial spaces, principally in the subcutaneous fatty tissues, caused by a defect in the lymphatic system. It is marked by an abnormal collection of excess tissue proteins, edema, chronic inflammation, and fibrosis. Lymphedema is a frequent complication of cancer and its therapies, and can have long-term physical and psychosocial consequences for patients.
The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillary-like channels that drain into larger, secondary lymphatic vessels located in the subdermal space. These primary and secondary lymphatic vessels parallel the superficial veins and drain into a third, deeper layer of lymphatic vessels located in the subcutaneous fat adjacent to the fascia. A muscular wall and numerous valves aid active, unidirectional lymphatic flow in secondary and subcutaneous lymphatic vessels. Primary lymphatic vessels lack a muscular wall and do not have valves. An intramuscular system of lymphatic vessels that parallels the deep arteries and drains the muscular compartment, joints, and synovium also exists. While there is evidence that the superficial and deep lymphatic systems communicate near lymph nodes, they probably function independently except in abnormal states.  Lymph drains from the lower limbs into the lumbar lymphatic trunk, which joins the intestinal lymphatic trunk and cisterna chyli to form the thoracic duct that empties into the left subclavian vein. The lymphatic vessels of the left arm drain into the left subclavian lymphatic trunk and then into the left subclavian vein. Right arm lymph channels drain into the right subclavian lymphatic trunk and then into the right subclavian vein.
One function of the lymphatic system is to return excess fluid and protein from interstitial spaces to the blood vascular system. Since lymphatic vessels often lack a basement membrane, they can resorb molecules too large for venous uptake. Mechanisms of clinicaledema include increased arteriovenous capillary filtration and reduced interstitial fluid absorption. Causes of increased capillary filtration include increased hydrostatic pressure in capillaries, decreased tissue pressure, and increased membrane permeability. Reduced interstitial fluid resorption can be caused by decreased plasma oncotic pressure, increased oncotic pressure of tissue fluid, and lymphatic obstruction.
Lymphedema is categorized as either primary or secondary. Primary lymphedema is caused by congenital absence or abnormalities of lymphatic tissue and is relatively rare. Secondary lymphedema is generally caused by obstruction or interruption of the lymphatic system, which usually occurs at proximal limb segments (i.e., lymph nodes) due to infection, malignancy, or scar tissue (see Table 1).  The pelvic and inguinal groups of nodes in the lower extremities and the axillary nodes of the upper extremities are the primary sites of obstruction.
Table 1. Lymph Drainage Failure* Mechanism Reduced lymph-conducting pathways Hypertrophy or hyperplasia of lymphatic vessels Functional failure Obstructed lymphatics Possible causes Aplasia or hypoplasia of whole vessel Lymphangiomatosis, lymphatic malformations Valvular failure Lymph node abnormalities (e.g., fibrosis) Acquired obliteration of lymphatic lumen (e.g., lymphangio-thrombosis, lymphangitis) Megalymphatics Disordered contractility Scarring from lymphadenectomy, radiation therapy, or infection *Adapted from Mortimer PS: The pathophysiology of lymphedema. Cancer 83(12 suppl 2): 2798-2802, 1998.
It has been assumed that lymphedematous limbs contain interstitial fluids with higher protein concentrations than plasma. However, a recent report found a negative correlation between protein concentration and arm edema.  Concomitant venous obstruction has also been observed in patients with lymphedematous limbs. An investigation of venous outflow using duplex Doppler ultrasound revealed venous abnormalities in more than 60% of cases.  Additional studies suggest that local vasodilatory control may be altered, although not on a sustained basis.  Further work in this area is needed to better discern the pathophysiology of lymphedema.
Acute-Onset versus Insidious-Onset Lymphedema Secondary lymphedema may be categorized by its chronicity. Four patterns of acute lymphedema have been identified. The first occurs within a few days after surgery as a result of the cutting of lymphatic channels or injury to or manipulation of the subclavian lymphatic trunks or the associated subclavian veins. It is usually transient and mild, responding to limb elevation and muscle pumping of the associated limbs (e.g., making a fist and releasing it) within 1 week of onset. The affected area may be warm and slightly erythematous, but it is generally not painful.
A second type of acute lymphedema may occur within 6 to 8 weeks postoperatively, possibly as a result of acute lymphangitis or phlebitis. There is no associated venous thrombosis in these cases. This pattern of lymphedema may also be seen during the course of radiation treatment of a limb or its associated lymphatic drainage route. The affected area is tender, warm or hot, and erythematous. This type of lymphedema can usually be successfully treated with limb elevation and anti-inflammatory medication, although more involved treatments may be necessary. The first 2 acute forms do not necessarily portend chronic swelling after their resolution.
A third type of acute lymphedema is an erysipeloid form, occurring after an insect bite, or minor injury or burn. It is often superimposed on a chronic edematous limb. The affected area is erythematous, very tender and hot. This form of edema often requires limb elevation and antibiotics. Compression pumping or wrapping is contraindicated during acute stages of infection. Many clinicians will permit treatment once severe erythema or blistering has resolved. Mild erythema can persist following an infection.
The fourth and most common type of lymphedema is usually insidious and is not always associated with erythema. Discomfort of the skin or aching in the proximal segments (neck/shoulders for upper extremity, lumbar spine/hips for lower extremity) may be noted due to stretch of the soft tissues or muscular overuse and postural changes caused by increased limb weight. This type has a variable onset and is frequently apparent 18 to 24 months after surgery. It may appear a few months or many years after cancer treatment.
Transient versus Chronic Lymphedema Transient lymphedema is a temporary condition that lasts less than 6 months and is associated with pitting edema with tactile pressure and lack of brawny skin changes.  The following factors may place the patient at risk for acute-onset, transient lymphedema:
Surgical drains with extravasation of protein into the surgical site. Inflammation following injury, radiation, or infection leading to increased capillary permeability. Immobility of the limb(s) that results in decreased external compression by the musculature. Temporary absence of collateral lymphatics. Proximal venous occlusion by thrombosis or phlebitis. Reversal of equilibrium at the capillary bed that results in accumulation of third-space fluid. Chronic lymphedema is the most difficult of all types of edema to reverse, due to the nature of its pathophysiology. A cycle is started, in which the deficient lymphatic system of the limb is incapable of compensating for the increased demand for fluid drainage. This condition may occur subsequent to any of the following:
Tumor recurrence or progression in the nodal area. Infection and/or injury of lymphatic vessels. Immobility. Radiation injury to lymphatic structures. Surgery. Unsuccessful management of early lymphedema. Venous obstruction due to thrombosis.
Early in the course of developing lymphedema, the patient experiences soft, pitting edema that may be easily improved by limb elevation, gentle exercise, and elastic support. Continual and progressive lymphostasis, however, causes dilation of the lymph vessels and backflow of fluid to the tissue beds. Collagen proteins accumulate, further increasing colloid osmotic tissue pressure, leading to enhanced fluid flow from the vascular capillaries into the interstitial space. The stasis of fluid and protein stimulates inflammation and macrophage activity as the body attempts to degrade the excess proteins. Fibrosis of the interstitial connective tissue by fibrinogen and fibroblasts causes the development of the brawny, stiff, nonpitting lymphedema that no longer responds to elevation, gentle exercise, or elastic compression garments. Chronic lymphedema gradually becomes nonpitting.
Lymphedematous tissues have lower oxygen content, a greater distance between lymph vessels due to fluid accumulation and swelling, impaired lymphatic clearance, and depressed macrophage function, rendering patients at increased risk of infection and cellulitis. Since there is no other route for tissue protein transport,treatment for patients with advanced lymphedema with chronic fibrosis is more difficult than when treated earlier. Additionally, once these tissues are stretched, edema recurs more readily.
Generalized lymphedema may also occur subsequent to hypoalbuminemia with low plasma oncotic pressure due to:
Inadequate oral nutrition (secondary to anorexia, nausea, vomiting, depression, chemotherapy). Decreased intestinal absorption of protein or abnormal protein synthesis/anabolism. Protein loss due to leakage of blood, ascites, effusions, or surgical drains.
Contributing medical conditions leading to hypoalbuminemia (e.g., diabetes, kidney malfunction, hypertension, congestive heart failure, liver disease).
Incidence and Prevalence
The reported incidence of lymphedema varies, being subject to discrepancies in its definition and measurement, and differing time points since treatment in which subjects are assessed for this complication. The incidence also varies depending upon the treatment and limb involved. With these caveats understood, there appears to be an overall incidence of arm edema after breast cancer therapy of 26%.  A survey of 1151 women treated with radiation for breast cancer reported lymphedema in 23% of subjects at 0 to 2 years after treatment and 45% at 15 or more years after treatment. Among breast cancer patients treated with surgery alone, prevalence increased from 20% at 0 to 2 years to 30% at 15 or more years since surgery.  A study of 744 breast cancer patients found that patients with lymphedema had impaired quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire C-30. 
Factors that contribute to the development of lymphedema are irradiation of the dissected nodal basin, postoperative wound complications and subsequent cellulitis of the limb, the extent of node dissection, and advanced age.
Patients at risk for lymphedema are those with:
Breast cancer, if they have received radiation therapy or had node dissection. Radiation therapy to the axilla following axillary node dissection increases the incidence of lymphedema. A review of several studies reports lymphedema in approximately 41% (range, 21%-51%) of patients who underwent axillary radiation and surgery, compared to 17% (range, 6%-39%) of those receiving axillary surgery without radiation.  The extent of axillary dissection also increases the risk of lymphedema.
Nodal dissection of axillary, inguinal, or pelvic regions. Radiation therapy of axillary, inguinal, or pelvic regions, or supraclavicular (mantle field) radiation. Scarring of the left or right subclavian lymphatic ducts and veins by either surgical or radiation procedures. Advanced cancer causing bulky lymphadenopathy of the anterior cervical, thoracic, axillary, pelvic, or abdominal nodes.
Intrapelvic or intra-abdominal tumors that involve or directly compress lymphatic vessels and/or the cisterna chyli and thoracic duct.
There are disparate reports concerning the incidence of lymphedema, especially involving the upper extremities, due largely to a lack of uniform diagnostic criteria. Objective criteria are based on circumferential or volumetric measurements, but there is no agreement on the diagnostic criteria for lymphedema. Some studies utilize differences in the affected limb compared to the unaffected limb of 1 to 2 cm. Anatomical variation, handedness, and body habitus may make this a meaningless difference. Optimally, sequential measurements over time, including pretreatment measurements, should be made. Water displacement measurement 15 cm above the epicondyle has been suggested as the best objective criterion with which to judge lymphedema; a displacement value of 200 mL included 96.4% of patients with subjective lymphedema.  Some studies use 6 cm above the elbow; preferably, measurement of the upper extremities should be at consistent points along the arm, above and below the antecubital fossa, and across the hand or wrist. The lower extremities do not offer as precise a point, but may be measured at consistent points.  
Approximately 50% of patients with minimal edema report a feeling of heaviness or fullness of the extremity. Assessment of the patient with edema includes a history and physical examination. The history should include information regarding past surgeries, postoperative complications, prior radiation treatments, the time interval from radiation or surgery to the onset of symptoms, and intervening variables in the presence or severity of symptoms. The quality and behavior of the edema (fluctuation with position, progression over time) should be assessed. History of trauma or infection should be determined. In addition, information concerning current medications may be important.  Edema is not detectable clinically until the interstitial volume reaches 30% above normal. The following scale may be clinically useful:
1+ = Edema that is barely detectable. 2+ = A slight indentation is visible when the skin is depressed. 3+ = A deeper fingerprint returns to normal in 5 to 30 seconds. 4+ = The extremity may be 1.5 to 2 times normal size. References: Brennan MJ: Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment. J Pain Symptom Manage 7 (2): 110-6, 1992. Horsley JS, Styblo T: Lymphedema in the postmastectomy patient. In: Bland KI, Copeland EM, eds.: The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia, Pa: Saunders, 1991, pp 701-706. Bates DO, Levick JR, Mortimer PS: Change in macromolecular composition of interstitial fluid from swollen arms after breast cancer treatment, and its implications. Clin Sci (Lond) 85 (6): 737-46, 1993. Svensson WE, Mortimer PS, Tohno E, et al.: Colour Doppler demonstrates venous flow abnormalities in breast cancer patients with chronic arm swelling. Eur J Cancer 30A (5): 657-60, 1994. Stanton AW, Levick JR, Mortimer PS: Cutaneous vascular control in the arms of women with postmastectomy oedema. Exp Physiol 81 (3): 447-64, 1996. Erickson VS, Pearson ML, Ganz PA, et al.: Arm edema in breast cancer patients. J Natl Cancer Inst 93 (2): 96-111, 2001. Mortimer PS, Bates DO, Brassington HD, et al.: The prevalence of arm oedema following treatment for breast cancer. Q J Med 89: 377-380, 1996. Kwan W, Jackson J, Weir LM, et al.: Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. J Clin Oncol 20 (20): 4242-8, 2002. Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985. Petrek JA, Senie RT, Peters M, et al.: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92 (6): 1368-77, 2001. Deutsch M, Flickinger JC: Arm edema after lumpectomy and breast irradiation. Am J Clin Oncol 26 (3): 229-31, 2003. Kissin MW, Querci della Rovere G, Easton D, et al.: Risk of lymphoedema following the treatment of breast cancer. Br J Surg 73 (7): 580-4, 1986. Guyton AC: The lymphatic system, interstitial fluid dynamics, edema, and pulmonary fluid. In: Guyton AC: Textbook of Medical Physiology. 7th ed. Philadelphia, Pa : WB Saunders, 1986, pp 361-373. Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985. Management Prevention It is important to identify patients at risk for lymphedema early and to begin preventive monitoring and instruction for self care. Inadequate nutritional status, obesity, immobility, and other medical conditions may increase the risk of developing lymphedema. The following parameters may help facilitate early detection of the condition:
The ratio of actual to ideal weight. Extremity measurements. Ability to perform activities of daily living (at each physician examination). History of contributing factors (e.g., edema). Prior radiation therapy or surgery. Concurrent medical illnesses (e.g., diabetes, hypertension, kidney or cardiac disease, or phlebitis). Patients should also be assessed for knowledge of their disease and the potential for developing lymphedema. Deficient lymphatic drainage due to node dissection and/or radiation therapy predisposes the affected limb to serious infection. Even minor infection of the limb may lead to significant lymphedema.
Patients should understand the potential of developing lymphedema and should be instructed on limb and skin care following surgery and/or radiation therapy. (See list of Considerations for Patient Teaching below.) It should be stressed that there is no empirical evidence for these or similar recommendations, although advice to avoid injury and infection in the affected limb seems intuitive. Lymphedema may occur as late as 30 or more years after surgery. Breast cancer patients who comply with instruction on skin care and exercises following mastectomy show a significantly lower incidence of lymphedema. 
Lymphatic drainage is improved by tissue compression from muscular contractions during exercise. In exercise, muscles squeeze the soft tissue causing lymph to travel proximally to the vascular system.  Therefore, exercise is important in the prevention of lymphedema. Breast cancer patients should be instructed on hand and arm exercises following mastectomy. Patients who undergo operative procedures affecting pelvic lymph node drainage should be instructed in how to perform appropriate leg and ankle exercises. The physician should determine how soon the exercise is initiated following surgery. Physiatrists or therapy professionals should be consulted for a tailored program of exercises for each patient.
Because the recovery rate is increased when lymphedema is detected early,  patients should be taught to recognize the early signs of edema and to report any of the following symptoms to their doctor: feelings of tightness in the extremity; shoes that don’t fit; decreased strength; pain, aching, or heaviness; redness, swelling, or signs of infection. Rings may become tight as well, but patients are discouraged from wearing them on the side of risk.
Considerations for Teaching Patients Prevention and Control of Lymphedema Keep arm or leg elevated above the level of the heart, when possible. Avoid rapid circular movements that cause centrifugal pooling of fluid in distal parts of the limb. Clean and lubricate the skin of the extremity daily. Avoid injury and infection of the affected limb: Upper extremities: Use an electric razor for shaving. Wear gardening and cooking gloves; thimbles for sewing. Maintain good nail care; do not cut cuticles. Lower extremities: Wear foot coverings outdoors. Keep feet clean and dry; wear cotton socks. Cut toenails straight across; see a podiatrist as needed to prevent ingrown nails and infections. Either upper or lower extremities: Suntan gradually; use sunscreen. Clean breaks in skin with soap and water, then use antibacterial ointment. Use gauze wrapping instead of tape, but avoid a tourniquet effect. Consult physician about rashes. Avoid invasive venipuncture, including finger sticks and intravenous fluid administration, in affected extremity. Avoid extreme hot or cold (i.e., heating pads or ice packs) . Avoid prolonged and strenuous work with the affected extremity. Avoid constrictive pressure on the arm or leg: Do not cross legs while sitting. Wear loose jewelry and clothes with no constricting bands. Carry handbag on opposite arm. Do not use blood pressure cuffs on the vulnerable limb. Do not use elastic bandages and stockings with constrictive bands. Do not sit in one position without change for longer than 30 minutes. Watch for signs of infection (e.g., redness, pain, heat, swelling, fever). Call your physician immediately if signs or symptoms occur. Practice prescribed exercises, as instructed. Keep regular follow-up appointments with your physician. Closely observe all areas of the limb daily for signs of problems: Measure the circumference of the arm or leg at intervals suggested by your physician/therapist at 2 consistent levels on the limb and report any sudden increase in size to your physician. Sensation may be diminished. Use the unaffected extremity to test temperatures (e.g., for bath water, cooking). Treatment There are 2 broad categories of conservative management or treatment of lymphedema: mechanical and pharmacologic. Mechanical modalities include elevation of the affected limb; manual lymphatic drainage (a form of massage that mobilizes edema fluid from distal to proximal areas and from areas of stasis to areas of healthy lymphatics); use of multilayered compression bandages and custom-fitted pressure-graded garments; and meticulous skin hygiene to prevent infection. A number of these modalities have been combined in a strategy known as complex physical therapy (or complex decongestive therapy), which consists of manual lymphedema treatment, compression wrapping, individualized exercises, and skin care, followed by a maintenance program.    Complex physical therapy has been recommended by consensus panels and is an effective approach for lymphedema that is unresponsive to standard elastic compression therapy. It must be performed by a properly trained therapist.
Surgical interventions are not recommended as they are not generally successful in curing lymphedema. Several techniques have been tried, such as staged excision of the skin and subcutaneous tissue with or without skin grafting and the Thompson dermal flap, which combines excision of edematous tissue with burying a shaved dermal flap to establish continuity between the superficial and deep lymphatic vessels. These methods have minimal success and high complication rates of skin necrosis, infection, and sensory difficulties.  The oncology patient is usually not a suitable candidate for these techniques.
Compression Garments Compression garments should always cover the entire area of edema. For example, a stocking that reaches only to the knee tends to become tight and occludes lymphatic and venous return if there is significant edema in the thigh. Extremity pumps that use intermittent sequential pneumatic compression may also be helpful in the management of the edematous limb, though many feel such pumps are ineffective and potentially counterproductive. The cuff is alternately inflated and deflated according to a controlled time cycle. This action increases fluid flow in the veins and lymphatic vessels and prevents the accumulation of residual fluid in the limb. Compression pumps should be used only under the supervision of a trained health care professional. High external pressure can damage superficial lymphatic vessels. Furthermore, when using compression pumps and other techniques, caution should be taken if there is a potential for residual tumor which some theorize may be mobilized into venous or lymphatic channels.
Pharmacologic Therapy Pharmacologic therapy uses antibiotics to treat and prevent bacterial cellulitis and lymphangitis. Other drugs that have been used include diuretics, anticoagulants, pantothenic acid, pyridoxine, and hyaluronidase. These drugs have no proven therapeutic value and may cause adverse reactions. 
It is important to determine the specific etiology of the swelling and to treat it appropriately. Infection is a frequent sequela of edema and causes increased capillary permeability, which increases protein deposition in the tissues. If an infection is diagnosed, appropriate antibiotics should be given that are effective against gram-positive cocci and, less frequently, fungal infections. Laboratory data (e.g., complete blood cell count (CBC)) should be evaluated. Because massage and techniques to encourage drainage would be contraindicated if venous thrombosis is present, diagnostic tests may be indicated to distinguish vascular blockage from deep vein thrombosis. If thrombosis is found, anticoagulation therapy should be given.
Coumarin (Chemical Abstracts Service registry number 91-64-5; NSC 8774; systematic name 2H-1-Benzopyran-2-one, also referred to as 5,6-benzo-[a]-pyrone), is a compound that has been studied for the management of high-protein lymphedemas such as those associated with local and regional treatments for neoplastic diseases.  
In the United States, dietary supplements, such as coumarin, are regulated as food not drugs. Premarket approval by the Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not required to be reviewed for manufacturing consistency, and no specific standards for dose or purity exist, there may be considerable variation from lot to lot for all products marketed as dietary supplements.
Coumarin was formerly used in the United States as a fixative and flavoring agent in foods and as a pharmaceutical excipient. In response to investigations by coumarin manufacturers that demonstrated the compound caused liver toxicity in animals when used in amounts comparable to or greater than that appearing in human foods, it was reclassified by the U.S. Food and Drug Administration (FDA) in 1954 as a food adulterant. Since that time, its addition to human foods has been prohibited and importation of coumarin-containing foodstuffs from outside the United States is not permitted. Coumarin is marketed for medical use in several European countries, but its therapeutic use has not been approved in the United States or Canada.
Adverse effects commonly associated with coumarin include mild nausea and diarrhea.  Liver toxicity has been reported in up to 6% of treated patients.     Patients typically present with increased serum concentrations of hepatic transaminases, with or without coincidentally increased serum bilirubin.   Aberrant laboratory values generally resolve within a few weeks after coumarin treatment is discontinued; however, liver pathology may be progressive and fulminant despite withdrawal of the compound.  Long-term toxicity data are sparse for patients who have received continuous treatment for up to 2 years. The clinical toxicity of longer durations of coumarin treatment has not been investigated. Animal toxicology studies have shown that the incidence of coumarin-induced hepatotoxicity is highly variable between species.  Reports of hepatic toxicity in humans have led to coumarin’s removal from the market in some European countries as well as in Australia.
In one study, coumarin, administered as tablets for oral use at a daily dose of 400 mg, was shown to partially reverse edema fluid accumulation, to reduce the size of swollen extremities, and to decrease the discomfort associated with lymphedema.  A double-blind, placebo-controlled, crossover study in 140 women with lymphedema of the arm following treatment for breast cancer, however, demonstrated that coumarin was not more effective than placebo in the treatment of lymphedema. This study also found a higher (6%) incidence of coumarin-associated hepatic toxicity and concluded that coumarin was not a safe or effective treatment for lymphedema.  
Diuretics encourage vascular fluid depletion, but they do nothing for excess protein deposits and could hasten connective tissue fibrosis.  Therefore, diuretics should be used with caution and only for the treatment of excess vascular fluid due to other causes.
Dietary Management The nutritional status of the patient should be evaluated and supportive measures instituted as required. Hypoalbuminemia encourages fluid to pass into interstitial tissues with excess protein and higher colloid osmotic pressure. The serum albumin level should be kept above 2.5 g/dL. The patient’s weight should be monitored, and patients should be encouraged to eat protein-rich foods and supplements.
Pain Management Patients with lymphedema may experience pain as a result of pressure on nerve endings or as a result of atrophy or muscle contractures during movement.  Following assessment, pain may be managed with nonopioid analgesics, relaxation techniques, mild-to-strong opioid analgesics, adjuvant drugs (e.g., amitriptyline), and/or transcutaneous electrical nerve stimulation (TENS). The most successful treatment, however, is reduction of the lymphedema.
Complications Edematous tissues are less well nourished and more prone to necrosis during immobility. Therefore, patients with lymphedema should be monitored for areas of skin breakdown, especially over bony prominences.
Excess pressure on inguinal or pelvic lymphatics may indicate pelvic metastasis with subsequent interference of bladder emptying. Pressure, in conjunction with regular narcotics, may cause problems with bowel elimination. Patient bladder and bowel status should be monitored for signs of urinary retention or constipation.
Psychosocial Considerations There are multiple psychosocial and adjustment issues faced by cancer patients and survivors with lymphedema. Because lymphedema is disfiguring and sometimes painful and disabling, it can create problems in many aspects of functioning, e.g., psychologic, physical, and sexual. Until relatively recently, however, inadequate attention has been directed toward its psychosocial impact. Several articles have noted that women who develop lymphedema following treatment for breast cancer encounter more difficulties in each of these aspects than women who do not develop the condition after such treatment.    Additionally, because the treatments for upper extremity lymphedema can be uncomfortable, arduous, and timeconsuming, the presence of psychologic difficulties can significantly interfere with treatment efforts. Upper extremity pain in women following breast cancer can have a highly complex differential diagnosis. One study has highlighted the deleterious impact of pain on quality of life and coping in patients with upper extremity lymphedema. 
Another study highlighted the factors associated with psychologic distress within a group of patients who developed upper extremity lymphedema after breast cancer treatment. Risk factors for poor adjustment to the condition include poor social support, use of an avoidant and reclusive style of coping (some women seek to avoid social situations in which their lymphedema causes a constant reminder of their cancer experience), and the presence of pain of any intensity.  Group and individual counseling that provides specific information about preventive measures, the role of diet and exercise, advice for selecting comfortable and flattering clothing, and emotional support can be helpful to women coping with lymphedema.
References: Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985. Markowski J, Wilcox JP, Helm PA: Lymphedema incidence after specific postmastectomy therapy. Arch Phys Med Rehabil 62 (9): 449-52, 1981. Casley-Smith JR, Casley-Smith JR: Modern treatment of lymphoedema. I. Complex physical therapy: the first 200 Australian limbs. Australas J Dermatol 33 (2): 61-8, 1992. Boris M, Weindorf S, Lasinkski S: Persistence of lymphedema reduction after noninvasive complex lymphedema therapy. Oncology (Huntingt) 11 (1): 99-109; discussion 110, 113-4, 1997. Daane S, Poltoratszy P, Rockwell WB: Postmastectomy lymphedema management: evolution of the complex decongestive therapy technique. Ann Plast Surg 40 (2): 128-34, 1998. Savage RC: The surgical management of lymphedema. Surg Gynecol Obstet 160 (3): 283-90, 1985. Brennan MJ: Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment. J Pain Symptom Manage 7 (2): 110-6, 1992. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone. N Engl J Med 329 (16): 1158-63, 1993. Loprinzi CL, Kugler JW, Sloan JA, et al.: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 340 (5): 346-50, 1999. Casley-Smith JR, Casley-Smith JR: Frequency of coumarin hepatotoxicity. Med J Aust 162 (7): 391, 1995. Beinssen AP: Possible coumarin hepatotoxicity. Med J Aust 161 (11-12): 725, 1994 Dec 5-19. Cox D, O'Kennedy R, Thornes RD: The rarity of liver toxicity in patients treated with coumarin (1,2-benzopyrone). Hum Toxicol 8 (6): 501-6, 1989. Loprinzi CL, Sloan J, Kugler J: Coumarin-induced hepatotoxicity. J Clin Oncol 15 (9): 3167-8, 1997. Morrison L, Welsby PD: Side-effects of coumarin. Postgrad Med J 71 (841): 701, 1995. Faurschou P: Toxic hepatitis due to benzo-pyrone. Hum Toxicol 1 (2): 149-50, 1982. Bassett ML, Dahlstrom JE: Liver failure while taking coumarin. Med J Aust 163 (2): 106, 1995. Fentem JH, Fry JR: Species differences in the metabolism and hepatotoxicity of coumarin. Comp Biochem Physiol C 104 (1): 1-8, 1993. Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985. Passik SD, Newman ML, Brennan M, et al.: Predictors of psychological distress, sexual dysfunction and physical functioning among women with upper extremity lymphedema related to breast cancer. Psychooncology 4 (4): 255-63, 1995. Maunsell E, Brisson J, Deschênes L: Arm problems and psychological distress after surgery for breast cancer. Can J Surg 36 (4): 315-20, 1993. Tobin MB, Lacey HJ, Meyer L, et al.: The psychological morbidity of breast cancer-related arm swelling. Psychological morbidity of lymphoedema. Cancer 72 (11): 3248-52, 1993. Newman ML, Brennan M, Passik S: Lymphedema complicated by pain and psychological distress: a case with complex treatment needs. J Pain Symptom Manage 12 (6): 376-9, 1996. Complications In addition to the complications associated with chronic lymphedema noted in other sections of this summary, a rare but lethal complication is that of lymphangiosarcoma. The mean time between mastectomy and lymphangiosarcoma is 10.2 years, and the median survival is 1.3 years.
The cause of lymphangiosarcoma is unknown. Clinically, it presents as single or multiple, bluish-red hemorrhagic nodules on the edematous limb with proximal and distal progression. Initially, there is a solitary, purple-red focus in the skin of the limb, slightly raised, macular or nodular, and usually described by the patient as a bruise. Later, satellite tumors arise, and the nodules grow. Death usually results from metastatic (usually pulmonary) and residual growths. 
References: Stewart FW, Treves N: Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer 1: 64-81, 1948. Changes to This Summary (10/24/2003) The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Deutsch et al. as reference 11.
Questions or Comments About This Summary If you have questions or comments about this summary, please send them to Cancer.gov through the Web site’s Contact Form. We can respond only to email messages written in English.
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Date last modified: 2003-10-24 http://www.meb.uni-bonn.de/cancer.gov/CDR0000062735.html
Peter S Mortimer .
Lymph conducting pathways may become reduced in number, obliterated, obstructed, or dysfunctional (because of failure of contractility or valve incompetence). A lack of sensitive methods for investigation makes it difficult to distinguish between these mechanisms. A defect in the lymph conducting pathways leads to primary lymphoedema; in practice this means no identifiable outside cause can be found. Secondary lymphoedema is due to factors originating outside the lymphatic system
Congenital lymphoedema presenting at or soon after birth is rare. A family history suggests Milroy's disease. Swelling invariably affects both lower limbs, but the upper limbs and face may also swell.
Limb swelling may be the presenting and major manifestation of congenital lymphatic malformations either in a pure formfor example, diffuse lymphangiomaor in combination with a congenital vascular syndromefor example, Klippel-Trenaunay (varicose veins, excessive long bone growth, and vascular birthmark).
Most forms of primary lymphoedema present after puberty with foot and ankle swelling. Women are more often affected, and the condition may be familialfor example, Meige's disease. Lymph reflux due to lymphatic vessel hypertrophy or megalymphatics is clinically distinguishable.
Filariasis is probably the most common cause of secondary lymphoedema worldwide and should be considered in any patient with lymphoedema who has travelled or lived in an endemic area.
Clinical diagnosis of lymphoedema
The clinical diagnosis of lymphoedema depends on the history and characteristic skin changes. Although most swelling occurs in the subcutaneous layer, the skin becomes thicker (as demonstrated by the inablity to pinch a fold of skin at the base of the second toe), skin creases become enhanced, and a warty texture (hyperkeratosis) and papillomatosis develop. Such skin changes are termed “elephantiasis.”
The differential diagnosis includes venous oedema, “armchair legs,” and lipodystrophy or lipoedema, which is often misdiagnosed as lymphoedema.
Investigation of lymphoedema
Lymphoscintigraphy (isotope lymphography) Lymphoscintigraphy is the best investigation for identifying oedema of lymphatic origin. Radiolabelled colloid or protein is injected into the first web space of each foot and monitored using a gamma camera as it moves to the draining lymph nodes. Measurement of tracer uptake within the lymph nodes after a defined interval will distinguish lymphoedema from oedema of non-lymphatic origin. The appearance of tracer outside the main lymph routes, particularly in the skin (dermal backflow), indicates lymph reflux and suggests proximal obstruction. Poor transit of isotope from the injection site suggests hypoplasia of the peripheral lymphatic system
Direct contrast x ray lymphography (lymphangiography) After the lymph vessels have been identified with a vital dye, a contrast medium such as Lipiodol is administered directly into a peripheral lymphatic vessel, usually in the dorsum of the foot. In a normal limb the lymphangiogram will show opacification of five to 15 main collecting vessels as they converge on the lowermost inguinal lymph nodes. In patients with lymphatic obstruction the contrast medium will often reflux into the dermal network, so called “dermal backflow.”
Computed tomography and magnetic resonance imaging Both computed tomography and magnetic resonance imaging detect a characteristic “honeycomb” pattern in the subcutaneous compartment that is not seen with other causes of oedema. In post-thrombotic syndrome the muscle compartment deep to the fascia is enlarged, whereas in lymphoedema it is unchanged. Thickening of the skin is also characteristic of lymphoedema, although it is not diagnostic. Magnetic resonance imaging is more informative than computed tomography because it can detect water.
Management of lymphoedema
Most patients with lymphoedema are just told to live with it, but this is neither necessary nor acceptable.
Physical treatment to reduce swelling Treatment is aimed at controlling lymph formation and improving lymph drainage through existing lymphatic vessels and collateral routes by applying normal physiological processes which stimulate lymph flow.
Physical treatment for lymphoedema Process
Exercise Dynamic muscle contractions encourage both passive (movement of lymph along tissue planes and non-contractile lymph vessels) and active (increased contractility of collecting lymph vessels) drainage Compression (hosiery) Opposes capillary filtration Acts as a counterforce to muscle contractions (so generating greater interstitial pressure changes) Manual lymphatic drainage Form of massage that stimulates lymph flow in more proximal, normally draining lymphatics to “siphon” lymph from congested areas (particularly trunk) Multilayer bandaging Used as an intensive treatment in combination with exercise to reduce large, misshapen lower limbs and permit subsequent maintenance treatment with hosiery Pneumatic compression Softens and reduces limb volume but can forcibly displace fluid into trunk and genitalia. Hosiery must always be worn afterwards Elevation Does not stimulate lymph drainage but lowers venous pressure and therefore filtration, allowing lymph drainage to catch up
Prevention of infection Prevention of acute inflammatory episodes (cellulitis or lymphangitis) is crucial because they can cause severe constitutional upset and deterioration in swelling. Care of the skin, good hygiene, control of skin diseases such as tinea pedis, and careful antiseptic dressings after minor wounds are all important. Antibiotics must be given promptly when an acute inflammatory episode occurs. In recurrent cellulitis the only effective treatment is prophylactic antibioticsfor example, phenoxymethylpenicillin 500 mg daily, for an indefinite period.
Drug treatment for lymphoedema Diuretics are of little benefit in lymphoedema because their main action is to limit capillary filtration. Improvement in patients who are taking diuretics suggests that the predominant cause of the oedema is not lymphatic. The benefit of benzopyrones, such as coumarin or flavonoids, remains unproved.
Surgery Surgery is of value in a few patients in whom the size and weight of a limb inhibit its use and interfere with mobility after physical treatment. Surgery is aimed at either removing excessive tissue (reducing or debulking operations) or bypassing local lymphatic defects
Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment of lymphedema of the extremities. Arch Surg 1998;133:452-8. Mortimer PS. The swollen limb and lymphatic problems. In: Tibbs DJ, Sabiston DC, Davies MG, Mortimer PS, Scurr JH. Varicose veins, venous disorders and lymphatic problems in the lower limb. Oxford: Oxford University Press, 1997. Levick JR. An introduction to cardiovascular physiology. 2nd ed. Oxford: Butterworth-Henemann, 1995.
Peter S Mortimer is consultant skin physician, St George's Hospital and Royal Marsden Hospital, London.
The ABC of arterial and venous disease is edited by Richard Donnelly, professor of vascular medicine, University of Nottingham and Southern Derbyshire Acute Hospitals NHS Trust (firstname.lastname@example.org ) and Nick J M London, professor of surgery, University of Leicester, Leicester (email@example.com ). It will be published as a book later this year.
Anatomy & Pathophysiology of Lymphedema
Definitions and Lymphedema Pathophysiology
Carolyn Wadsworth, P.T., O.C.S., C.H.T. Department of Rehabilitation Therapies University of Iowa Hospitals and Clinics First Published: 2003 Last Revised: December 2003 Peer Review Status: Internally Reviewed
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