LYMPHEDEMA PATHOPHYSIOLOGY

LYMPHEDEMA PATHOPHYSIOLOGY

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Pathophysiology of Lymphedema

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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

Unlike the blood system the lymphatic system works according to the one way principle, its main purpose is to transport "waste materials" from the interstitial tissues back into the blood 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.

Lymph capillaries collect lymphatic loads from the interstitial areas and gradually join together into bigger lymph vessels, so-called precollectors which then drain into collectors.

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)

Ultrafiltration:
      blood capillary pressure > COP of plasma proteins
Reabsorption:
      blood capillary pressure < COP of 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.

The reasons for mechanical insufficiencies are various and mainly caused by surgery, radiation, trauma or inflammation.

Accumulation of high protein fluid is the result which is then recognized as lymphedema or lymphostatic edema.

Classification of Lymphedema:

      Secondary                                                  Primary

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 :

1. Manual Lymph Drainage
2. Compression Therapy
3. Meticulous Skin and Nail Care
4. Remedial Exercises

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 affections.

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.

References:

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 Cancer
Lymphology 29, 1996 48-49

10. E.Foeldi, M.Foeldi, L.Clodius
The Lymphedema Chaos: A Lancet
Ann Plast Surg 22:505-515

http://www.naturalhealthweb.com/articles/Zuther.html

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Primary Lymphedema: A Review of Pathophysiology, Diagnosis & Management

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:

Organized lymph tissues: the spleen, thymus, tonsils, liver, and visceral lymphoid tissues in the gastrointestinal and pulmonary systems.
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.

Between 1950 and 1960 Kinmonth introduced x-ray lymphangiography and subsequently devised a radiological classification based on 100 lymphographs.2 He described three radiological appearances:

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.

Classification—Primary vs. Secondary Lymphedema
Primary lymphedema is lymphedema caused by a primary abnormality or disease of the lymph conducting elements of the lymph vessels or lymph nodes.

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 Ayndrome
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.

Differential Diagnosis
If lymphedema presents in a newborn, developmental disorders of the lymphatic system, as described in the previous section, must be considered.

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 be edema of the eyelids and hypertension. Diagnostic studies in patients with nephrotic syndrome reveal albuminuria and hypercholesterolemia.

Hypoproteinemia will cause peripheral edema in malnourished individuals. Diagnostic studies for hypoproteinemia include serum protein and electrophoresis

Venous insufficiency can cause unilateral or bilateral peripheral edema, most often in female patients. The edema is usually alleviated with recumbency, and varicose veins are found on physical exam.

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.

Treatment

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 lympedema 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.

Bandaging
Multilayer bandaging involves application of layers of strong nonelastic bandages to generate a high pressure during muscular contractions but low pressure at rest.

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

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

ilink no longer available

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Lymphedema Pathophysiology

http://www.nci.nih.gov/cancerinfo/pdq/supportivecare/lymphedema/healthprofessional/#Section_4

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Pathogenesis & lymphedema pathophysiology

http://www.emedicine.com/med/topic2722.htm

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Join us as we work for lymphedema patients everywehere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

http://health.groups.yahoo.com/group/AdvocatesforLymphedema/

Subscribe:

AdvocatesforLymphedema-subscribe@yahoogroups.com

Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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For information about Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema\

For Information about Lymphedema Complications

http://www.lymphedemapeople.com/wiki/doku.php?id=complications_of_lymphedema

For Lymphedema Personal Stories

http://www.lymphedemapeople.com/phpBB2/viewforum.php?f=3

For information about How to Treat a Lymphedema Wound

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound

For information about Lymphedema Treatment

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment

For information about Exercises for Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema

For information on Infections Associated with Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema

For information on Lymphedema in Children

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children

Lymphedema Glossary

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet? Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more. Come and take a stroll!

Lymphedema Glossary

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing

Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema

Arm Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema

Leg Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema

Acute Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema

The Lymphedema Diet

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet