PRIMARY LYMPHEDEMA

PRIMARY LYMPHEDEMA

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PRIMARY LYMPHEDEMA

PRIMARY LYMPHEDEMA can be hereditary. Milroy's Disease or Syndrome will generally express itself at birth or in the very early years. Meige Lymphedema, also known as lymphedema praecox generally begins sometime during puberty. Lymphedema tarda begins in or around middle age. Lymphedema that has not expressed itself in an active condition is referred to a latent lymphedema. Primary lymphedema can also be congenital. This means some either in utero or during birth caused lymphatic damage.

TYPES OF PRIMARY LYMPHEDEMA

MILROY'S SYNDROME

Related Terms: Nonne-Milroy lymphedema, Milroy's Disease, Primary congenital hereditary lymphedema, hereditary lymphedema I, Nonne-Milroy-Meige disease

Milroy's Syndrome is an old term used to describe hereditary congenital lymphedema. It is a congenital familial primary lymphedema which results from vertical autosomal inheritance of a single gene. The gene has been identified as VEGFC. The condition usually presents itself at birth with the swelling of one or even both legs.

If the condition is unilateral (single leg lymphedema), the other leg may continue in the latency stage for years before expressing itself. The same is indicated for arm lymphedema.

It is the rarest of the inherited lymphedema, accounting for approximately 2% of hereditary lymphedemas.

Hereditary lymphedema was first described by Nonne in 1891, however in 1892 Dr. William F. Milroy described a missionary who had returned from work in India who had swollen legs his entire life. His mother likewise was afflicted with the same condition. Milroy had also, previously studied the 250 year history of a family and had been able to identify 22 persons with this condition through 6 generations. He was also able to pinpoint when the condition entered the family through a marriage in 1768.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) presents at birth and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of Milroy's Syndrome is a break in the VEGFC gene.

Complications

The usual complications involved with the condition include fibrosis of the limb tissues, cellulitis (and or lymphangitis and erysipelas infections). Other complications made include involvement of the genitalia, pain, skin conditions and in very rare situations lymphangiosarcoma.

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for Milroy's but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent is the condition is identified early and treatment begins so after the diagnosis is made.

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MEIGE LYMPHEDEMA SYNDROME

See also: Nonne-Milroy-Meige Syndrome, Meige's lymphedema, Hereditary lymphedema II, familial lymphedema praecox

Form of primary hereditary lymphedema that starts at or around the time of puberty. The affected limbs are generally the legs.

Named after French physician Dr. Henri Meige who first described hereditary lymphedema in 1891. This form of lymphedema which usually presents itself at or during puberty is the most common of the hereditary lymphedemas, account for 65-80% of all diagnosed cases.

Meige-Type Lymphedema

Also known as Hereditary 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.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) presents during puberty and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of Lymphedema Praecox is a break (mutation) in the FOXC2 gene.

*Edito's note. Since this report came out, there are further studies that indicate FOXC2 does NOT cause Lymphedema Praecox, but only Lymphedema distichiasis.

Complications

Other Indications

Related conditions may also include yellow nail syndrome, pulmonary hypertension, cerebrovascular malformations and distichiasis

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for Lymphedema praecox but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent if the condition is identified early and treatment begins so after the diagnosis is made.

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LYMPHEDEMA TARDA

Form of primary hereditary lymphedema that expresses itself during middle age (generally onset 35+ years). Swelling generally occurs in the legs and may involve either one or both limbs. There is a higher incidence of lymphedema tarda among females than males.

This form of inherited lymphedema accounts for approximately 10% of those with primary lymphedema.

Diagnosis

Basic diagnosis can be made by the fact that swelling (generally of the legs) unexpectedly and there is a family history of similar swelling. Currently the most precise diagnosis can be made by a lymphoscintigraphy test. In this test a radioactive substance is injected into the limb and is traced on a computer screen. Through this method the exact location of the lymphatic blockages can be identified.

Etiology

The cause of lymphedema tarda is a break in the FOXC2 gene.

Complications

Treatment

Decongestive therapy is the most widely accepted form of treatment. There is no cure for lymphedema tarda but the condition can be managed by early diagnosis and treatment.

Prognosis

Long term prognosis is excellent is the condition is identified early and treatment begins so after the diagnosis is made.

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Primary Lymphedema: A Review of Pathophysiology, Diagnosis & Management

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 garments or 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.

Lymph Node 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 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 (Trisomy 21). Other features of Down Sydrome are characteristic facies, short broad hands, heart defects and mental retardation.

Klippel-Trenaunay-Weber- Syndrome

Klippel-Trenaunay-Webber Syndrome 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.

Congestive 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.

Chronic 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.

It is critical that massage physiotherapy specifically designed to treat lymphedema be used.

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 compression bandaging involves application of layers of strong nonelastic bandages to generate a high pressure during muscular contractions but low pressure at rest. This involved short stretch bandages. This also may involve the use of compression garments; and the wearing of compression "sleeves"

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. A healthy diet and systematic weight control are essential in the proper management of lymphedema.

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.

*Link no longer available*

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References
1. Beninson J, Jacobson H, Eyler W, DuSault L. “Additional Observations on Genetic Lymphedema as Studied by Venography, Lymphangiography and Radio-Isotopic Tracers Na22 and RISA.” American College of Angiology. April 21, 1966
2. Browse NL, Stewart G. “Lymphoedema: Pathophysiology and Classification.” J. Cardiovascular Surgery 1985;26:91-105.
3. Corbett M, Dale RF, Coltart DJ, Kinmonth MS. “Congenital Heart Disease in Patients with Primary Lymphedemas.” Lymphology 1982;15:85-96.4. Dale RF. “The inheritance of primary lymphoedema.” Journal of Medical Genetics 1985;22:274-278.
5. Greenlee R, Hoyme H, Witte M, Crowe P, Witte C. “Developmental Disorders of the Lymphatic System.” Lymphology 1993;26:156-168.
6. Milroy WF. “An undescribed variety of hereditary oedema.” NY Medical Journal 1892;56:505-8.
7. Mortimer PS. “Managing lymphoedema.” Clinical and Experimental Dermatology 1995;20:98-106.8. Wittlinger H. Textbook of Dr. Vodder’s Manual Lymph Drainage. Haug International, Brussels, 1990.
9. Ward R. Foundations for Osteopathic Medicine, Williams and Wilkins, Baltimore 1997. pp941-946.
10. Blaszo G. “Oedema-inhibiting effects of procyanidin.” Acta Physiologica Academiae Hungaricae, Tomus 65(2):235-240, 1980.
11. Robert L. “The effect of procanidolic oligomers on vascular permeability.” Pathol Biol (Paris);36(6):608-16.

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LYMPHOEDEMA ASSOCIATION OF AUSTRALIA

What Are the Different Kinds of Primary Lymphoedema?

There are many different kinds of primary lymphoedema. Some are hereditary, but most are not. The list is far from complete. There are many syndromes which include lymphoedema, but they are rare syndromes. Listed below are a few of the identified syndromes.

Idiopathic Lymphoedema -Not Running in Families

This is the most common form of primary lymphoedema. As the name implies, this is primary lymphoedema of an unknown origin, and is not a part of a syndrome of other symptoms. It appears at birth or later on in an individual (more often female). Although it most commonly affects one lower extremity, it can affect any part of the body. It is not found in other family members because it is not hereditary and cannot be passed on to children. Lymphoscintigram findings will not show an obstruction as it would in acquired/secondary lymphoedema. Instead usually it will indicate a hypoplasia (underdevelopment of lymphatic vessels).

Primary Hereditary Lymphoedemas: Lymphoedemas Which Run in Families

Milroy’s Syndrome : [also called Nonne-Milroy Syndrome]: Lymphoedema present at birth. Often the problem is a lack of initial lymphatics. [Autosomal Dominant,* chromosome 5]

Meige’s Syndrome : Like Milroy’s, but the lymphoedema does not appear until later: lymphoedema praecox (before 35) or lymphoedema tarda (after 35). [Autosomal Dominant]

Primary Hereditary Lymphoedemas with other symptoms

Yellow Nail Syndrome [Samman-White Syndrome]: Syndrome which includes discoloured thickened nails, pulmonary problems, and lymphoedema. Onset is usually childhood or early adulthood. [Autosomal Dominant]

Sharp-Aagenaes Syndrome: Distinguished by neonatal cholestasis (stoppage of bile excretion) with jaundice. The lymphoedema develops in early childhood and is equally seen in males and females. [Autosomal Recessive,* chromosome 15]

Lymphoedema with Distichiasis [Falls-Kertesz Syndrome]: As well as lymphoedema, there is an extra row of eyelashes (distichiasis); problems also include a widened spinal canal and other related problems. Onset is usually adolescence. [Autosomal Dominant, chromosome 16]

Avasthey-Roy Syndrome: As well as lymphoedema, there are arteriovenous malformations and pulmonary hypertension. Onset is usually adolescence. [Autosomal Dominant]

Hennekam’s Syndrome: Lymphoedema of face, genitals, and limbs; the face and nose are flat, the mouth narrow, the chin large, the ear malformed, the eyes protruding, the fingers can be webbed, the thumb large. There can be mild mental retardation. [Autosomal Recessive]

Noonan’s Syndrome: Includes webbed neck, protruding upper chest, receding lower chest, cardiomyopathy, short stature. Appears very similar to Turner’s Syndrome, below, except is not sex-linked.. [Autosomal dominant, chromosome 12]

Jeken’s Syndrome: Includes mental retardation, abnormal fat distribution at buttocks, and ataxia. Lymphoedema onset is during infancy. [Autosomal recessive, chromosome 16]

Figueroa Syndrome: Cleft palate; lymphoedema starts during childhood or adolescence. [Autosomal dominant]

Primary Lymphoedemas Associated with other Syndromes- Do Not Run In Families

Klippel-Trenaunay-[Weber] Syndrome: Venous and arterial alterations are present; when the lymph vessels are involved, they are frequently varicose. In Weber’s Syndrome, the bones of a limb are also hypertrophied (larger).[not hereditary]

Turner Syndrome: Affects only females because it is sex-linked.* Frequently the lymphatic system, (specifically the valves), is underdeveloped, resulting in childhood lymphoedema. This sometimes resolves by adolescence. Other features of Turner’s Syndrome include short stature, infertility, and sometimes problems with the heart, kidney, or thyroid.(XO instead of XX chromosome; not hereditary]

*Some Basic Genetics Terms:

Autosomal: a gene that is not on the sex-linked chromosome(x and y are the sex-linked chromosomes)

Dominant: only one of these genes must be present for the trait to exhibit itself

Recessive: the gene must be present from both parents for the trait to exhibit itself; a person with only one of the genes is said to be a carrier.

Incomplete penetrance: the situation when the dominant gene or two recessive genes are present, so the person should exhibit the trait, but in a certain percentage of cases, this does not happen

Ackowledgement

Lymphoedema Association of Australia

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INHERITANCE OF PRIMARY LYMPHEDEMA
University of Pittsburg

Lymphedema is the swelling, usually of an extremity, resulting from poor drainage of fluid out of the body's tissues. There are two types of lymphedema. Although the cause is not well understood, primary lymphedema is thought to result from an inherited abnormality of the lymphatic system. Secondary lymphedema is the result of a damaged or blocked lymphatic system caused by traumas such as surgery or injury.

Primary lymphedema has been estimated to occur in about one in six thousand people, more often in females than in males (Dale, 1985). Age of onset tends to be similar within families. Primary lymphedema can be present from birth (congenital lymphedema), symptoms can begin at the time of puberty (lymphedema praecox), or onset can occur in adulthood (lymphedema tarda) (Lewis and Wald, 1984).

Primary lymphedema seems to be inherited in several different ways. Milroy's and Meige's Disease are two forms of primary lymphedema that tend to show swelling below the waist and are dominantly inherited in some families. Milroy's Disease (congenital lyphedema) is characterized by swelling present from around the time of birth. Meige Disease, also known as lymphedema praecox, may appear suddenly around the time of puberty (Wheeler et al., 1981). When the first signs of swelling appear after age 35, this condition is called lymphedema tarda. A recessive form of lymphedema has also been described, as well as lymphedema in association with other traits.

Except for genes on the sex chromosomes, both men and women have two copies of each gene. If only one changed copy of a gene causes a condition, the condition will be inherited in what is called a dominant pattern. If an individual has a dominant condition such as Milroy's or Meige's Disease, the chance of passing the gene to a child is 1 in 2 or 50% with each pregnancy. These odds are the same as getting "heads" in a coin toss.

Dominant disorders are ones that run from generation to generation or are passed along through the family. If a person has the gene for a dominant form of primary lymphedema, there is usually a 50% or 1 in 2 chance of passing that gene on to his or her children. However, not everyone with the gene for this form of lymphedema will actually develop symptoms. Therefore, even if a child does not inherit lymphedema from a parent, he or she may still have inherited the gene and pass the gene that causes lymphedema on to a child. Although we do not yet understand why this "reduced penetrance" sometimes occurs, it is more common in men. In other words, a brother would be less likely than his sister to have symptoms of lymphedema even if they both inherit the same lymphedema gene.

We hope a new understanding of the genetic basis of inherited lymphedema will provide insights into its treatment and contribute to early identification of individuals at risk.

http://www.pitt.edu/AFShome/g/e/genetics/public/html/lymph/inherit.htm

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PRIOR STUDIES OF PRIMARY LYMPHEDMEA

Isolated congenital hereditary lymphedema, now known as Nonne-Milroy Disease, was described by Milroy in 1892. The diagnostic criteria consisted of hereditary, congenital, chronic, and permanent lymphedema, which is not present above the waist, is firm but pitting to the touch, and does not affect longevity. However, exceptions such as one case of lymphedema praecox and one with spontaneous recovery were noted. The original paper described a family of 97 members with 22 affected individuals in six generations (Milroy, 1892).

Milroy attempted a follow-up investigation of this family thirty-five years later, at which time he identified thirty additional descendants in the fifth, sixth, and seventh generations. Since only two of these individuals were affected, he concluded that the disease was disappearing from the family, quite possibly by reason of attenuation of the trait through marriage with normal persons." However, a truly autosomal dominant disease would not be expected to show attenuation, and Milroy conceded that because many family members were lost to follow-up, this data was neither complete nor dependable (Milroy, 1928).

The first and only linkage study of congenital hereditary lymphedema was reported by John R. Esterly in 1965. The family he reported consisted of fifteen congenitally affected individuals in three generations, which included a reportedly affected stillborn female. Esterly's group examined all living affected family members, and a diagnosis of Milroy's Disease was confirmed. No linkage was demonstrated to red blood cell antigens, haptoglobin, phenylthiocarbamide tasting, or rate of isoniazid inactivation: some of the few polymorphic markers which were available at that time (Esterly, 1965).

In addition Esterly analyzed the 22 previously documented pedigrees for inheritance pattern, sex ratio of affected individuals, and ratio of affected to unaffected family members. Including Esterly's family, there were 152 affected people, among an unknown total number, in 23 families. Although lymphedema has been shown to affect three times more females than males in the general population, the sex ratio of all affected individuals in these families was 66 males to 81 females (5 were of unknown sex). Among the offspring of affected individuals, the ratio of affected to unaffected was 82:91, which is compatible with a simple autosomal dominant trait (Esterly, 1965). However, there were several families with reduced penetrance, and much of the data was incomplete or relied entirely on family reports. In addition, mild lymphedema is often difficult to detect, even when it is familial and congenital.

If only the families without skipped generations were included, the ratio of affected to unaffected individuals in at risk sibships changed to 50:46, and the sex ratio became 24:25. Esterly concluded that although all pedigrees were consistent with simple autosomal dominant inheritance, a second mode of inheritance may explain the excess of females in some of the families (Esterly, 1965).

Several investigators have addressed the preponderance of affected females with primary lymphedema. Some researchers have suggested the possibility of a sex-linked (X chromosome) modifier gene. Hormonal factors such as pregnancy and menstruation may also result in a greater penetrance of lymphedema praecox and tarda in females or increased expression of congenital lymphedema after menarche. However, the most plausible explanation for the excess of females with lymphedema is ascertainment bias because females may be more likely to report symptoms and seek treatment. Although three times more females are affected with primary lymphedema in the general population, this ratio drops to below two in sibships of many families with Milroy's or Meige's Disease.

http://www.pitt.edu/~genetics/lymph/previous.htm

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Primary Lymphedema - Milroy's Disease

Excerpt from Milroy Disease

http://www.emedicine.com/med/byname/milroy-disease.htm

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MEIGE LYMPHEDEMA, LYMPHEDEMA, LATE-ONSET, LYMPHEDEMA PRAECOX

Online Mendelian Inheritance in Man

John Hopkins University

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=153200

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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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All About Lymphedema

For our Google fans, we have just created this online support group in Google Groups:

Homepage: http://groups-beta.google.com/group/All-About-Lymphedema

Group email: All-About-Lymphedema@googlegroups.com

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Lymphedema Friends

http://groups.aol.com/lymphedemafriend

If you an AOL fan and looking for a support group in AOL Groups, come and join us there.

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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