Chronic peripheral oedema and lymphoedema

Chronic peripheral oedema and lymphoedema - technical

Topics covered:

  • Summary
  • Introduction
  • Pathophysiology
  • Aetiology
  • Epidemiology
  • Prevention
  • Clinical features
  • Differential diagnosis of the swollen limb
  • Clinical investigation
  • Treatment
  • Genital lymphoedema
  • Facial lymphoedema

Summary

Lymph transport, not venous capillary reabsorption, is the main process responsible for interstitial fluid drainage. Oedema develops when the microvascular filtration rate exceeds lymph drainage for a sufficient period, either because the filtration rate is high or because lymph flow is low, or a combination of the two. In the United Kingdom the prevalence of lymphoedema is just over 0.1%, rising to 0.5% in those over 65 years of age.

Causes of lymphoedema

Lymph drainage may fail either because of a defect intrinsic to the lymph conducting pathways (primary lymphoedema), or because of irreversible damage from some factor(s) originating from outside the lymphatic system (secondary lymphoedema).

Primary lymphoedema—can be caused by mutations in the vascular endothelial growth factor receptor-3 gene (Milroy’s disease) or in the forkhead transcription factor gene FOXC2 (lymphoedema—distichiasis), but for most forms the genetic cause is unknown. Congenital lymphoedema may occur in isolation or as part of a syndrome.

Secondary lymphoedema—filariasis is by far the most common cause of lymphoedema worldwide. In the United Kingdom 25% of cases are due to malignancy.

Clinical features and management

Lymphoedema causes persistent swelling that does not resolve with overnight elevation and is associated with cellulitis. Response to diuretics is poor. The oedema does pit, but prolonged pressure is required to do so, and the skin is thickened and warty. The investigation of choice for confirming that oedema is primarily of lymphatic origin is lymphoscintigraphy (isotope lymphography).

No drug or surgical therapy is known to improve lymph drainage. Treatment relies on improving lymph drainage through the application of simple physiological principles known to stimulate lymph flow, while at the same time restoring any excessive capillary filtration to as near normal as possible. Patients with leg lymphoedema often notice that walking reduces swelling, and the addition of a bandage or stocking can enhance the effect of movement by creating an outer collar to the leg that resists expansion of the calf muscle during contraction. This generates a high interstitial pressure during muscle contractions to drive lymph filling and drainage, but allows low pressures during skeletal muscle relaxation and hence permits lymphatic vessel refilling before further muscle contraction repeats the cycle. Compression without movement (active or passive exercises) does not improve lymph drainage. Manual lymphatic drainage therapy, a specific form of lymphatic massage, operates on the same principle of stimulating alternating rises and falls in interstitial pressure and is used to decongest more proximal regions of the body.

Prevention and prompt treatment of cellulitis is crucial to the control of lymphoedema, because this contributes to further decline in lymph drainage, which in turn encourages more infection.

Introduction

Oedema is an excess of interstitial fluid and is an important sign of ill health in clinical medicine. In medical practice peripheral oedema tends to be pigeon holed according to possible systemic or peripheral causes, e.g. heart failure, nephrotic syndrome, venous obstruction, or lymphoedema. This view point fails to appreciate the many dynamic physiological forces contributing to oedema development and in particular the central role of the lymphatic drainage system in tissue fluid (and consequently plasma volume) homeostasis. Hence the clinician’s approach to peripheral oedema is often misguided and the necessary medical intervention inappropriate, e.g. empirical use of diuretics. Management of peripheral oedema is better based on physiological principles that can then guide treatment.

Pathophysiology

Lymph transport, not venous capillary reabsorption, is the main process responsible for interstitial fluid drainage.

Oedema develops when the microvascular (from capillaries and venules) filtration rate exceeds lymph drainage for a sufficient period, either because the filtration rate is high or because lymph flow is low, or a combination of the two. Filtration rate is governed by the Starling principle of fluid exchange, which is described succinctly and quantitatively by the Starling equation for flow across a semipermeable membrane.

In simple terms, filtration of fluid from capillary into interstitium is driven by the hydraulic (water) pressure gradient across the wall (Pc – Pi) and is opposed by the osmotic pressure gradient (πp – πi), which is the ‘suction’ force keeping fluid in the circulation.

The Starling equation provides a logical approach for classifying oedema that is due to increased filtration:

1 Raised capillary pressure. Capillary pressure is more susceptible to changes in venous pressure than systemic (arterial) blood pressure because postcapillary resistance is much lower than precapillary resistance. Peripheral venous pressure is raised in:

  • right ventricular failure
  • salt and water overload (e.g. overtransfusion)
  • venous obstruction
  • venous reflux (chronic venous disease) e.g. following deep vein thrombosis, primary varicose veins
  • dependency (the effect of gravity)

2 Reduced plasma osmotic pressure (COP). This essentially means hypoalbuminaemia, which can arise from:

  • malnutrition
  • intestinal disease (malabsorption or protein loss)
  • nephrotic syndrome
  • hepatic failure to synthesize albumin—due to liver disease or chronic inflammatory states

3 Increased capillary permeability

Inflammation can cause a breakdown in the endothelial barrier, facilitating the passage of both plasma proteins and water across the capillary wall. In addition, vasodilatation causes a rise in capillary pressure (and blood flow).

Traditionally it has been taught that the arterial end of capillaries filter fluid while the venous end reabsorbs the bulk of fluid filtered. This view is not supported by modern evidence, which demonstrates that in most vascular beds there is a net but dwindling filtration along the entire length of well-perfused capillaries. The sum of all Starling forces is not an absorptive force in venous capillaries but a slight filtration force, except e.g. following haemorrhage, when capillary pressure drops sufficiently for transient absorption to occur. Even under such circumstances Starling forces soon re-equilibrate and slight filtration is restored. Sustained reabsorption of fluid is a normal feature of some microcirculatory beds, namely intestinal mucosa, renal peritubular, and lymph node capillaries, but not peripheral tissues. Since the old concept of sustained fluid absorption by venous capillaries is no longertenable, the major responsibility for drainage of interstitial fluid is through the lymphatic system.

Restraining factors against oedema include (1) elevation of interstitial fluid pressure, (2) fall in interstitial COP, and (3) increased lymph flow. Stiffness in tissues resists swelling. A small increase in interstitial fluid in a stiff tissue (low compliance) will cause a relatively large increase in interstitial pressure (Pi), which then opposes filtration, e.g. subfascial muscle compartment. Placing a bandage or rigid stocking around a leg will reduce compliance and resist stretch. Consequently Pi will increase more steeply for a given interstitial volume increase and the increased Pi will oppose filtration. Relating to interstitial COP, an increase in filtration rate will dilute the interstitial protein concentration and consequently reduce the osmotic pressure (π immediately outside the semipermeable membrane). The resulting increase in the osmotic pressure gradient will raise the suction force keeping fluid within the blood compartment.

Increases in interstitial fluid pressure and volume stimulate lymph flow. Lymph drainage is a complex process involving absorption of protein and fluid (as well as other macromolecules, microorganisms, immune cells, and cancer cells) from the interstitium into initial lymphatic vessels (also known as lymphatics) and then downstream through vessels of ever-enlarging diameter until reaching the main collecting lymphatics that pump lymph to the sentinel lymph nodes. Valves ensure unidirectional flow. Transport of interstitial fluid into and along initial lymphatics is largely a passive process dependent upon changes in tissue (interstitial) pressure from movement (active and passive exercise), massage, and local arterial pulsation and—in more central tissues—breathing. The larger collecting lymphatics contract and are mainly responsible for pumping lymph against gravity. Successive segments of collecting lymphatics behave like ‘mini hearts’ in series, and their contractile cycle bears striking similarities to the cardiac cycle. Sympathetic input influences the pumping rate, while the diastolic filling (preload or supply from upstream lymphatics) controls the force of contraction. Flow in collecting lymphatics is only as good as the supply from initial (noncontractile) lymphatics. Influx of calcium ions is important for smooth muscle contraction in the walls of the collecting lymphatics, hence calcium channel blocking agents are likely to work at least in part on the lymphatic system in causing peripheral oedema.

The lymph vessels return the capillary filtrate back to the bloodstream via the lymph nodes and eventually the thoracic duct. This completes the extravascular circulation of fluid and protein and maintains tissue volume homeostasis. Lymph flow should respond to increases in capillary filtration and so prevent oedema. By failing to compensate for increased capillary filtration and so permitting swelling, the lymphatic is to some extent failing in its duty in all types of oedema. This could help explain differences in the degree of leg oedema seen in patients with right-sided heart failure. True lymphoedema is strictly oedema arising from reduced lymph transport that is unable to cope with normal levels of capillary filtration. Most oedema arises from increased capillary filtration overwhelming lymph transport capacity for a sustained period of time. Once high lymph flow cannot be sustained and transport capacity fails, ‘true’ lymphoedema ensues. This pathophysiology is comparable with that occurring in high-output cardiac failure.

Aetiology

Lymph drainage may fail either because of a defect intrinsic to the lymph conducting pathways (primary lymphoedema) or because of irreversible damage from some factor(s) originating from outside the lymphatic system (secondary lymphoedema).

Physiologically there are only a limited number of ways that lymphatics can fail. They may be reduced in number (aplasia/hypoplasia), obliterated or damaged without repair (failed lymphangiogenesis), obstructed, lose contractility (pump failure), or become incompetent (valvular reflux). A lack of sensitive methods for investigation makes it difficult to distinguish between these mechanisms.

Primary lymphoedema

A defining moment in lymphatic research came with the discovery of the receptor vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligands VEGF-C and VEGF-D as the main signalling mechanism for lymphangiogenesis. Lymph sacs appear in humans at 6 to 7 weeks of gestation, with lymphatic endothelial cells arising from embryonic veins with the PROX1 gene committing to a lymphatic lineage and VEGFC driving lymphatic capillary sprouting and migration. In mice, deletion of Flt4 (= VEGFR-3) leads to defects in blood as well as lymphatic vessels and embryonic death, indicating an early role in both cardio- and lymphovascular function for this gene. Heterozygous missense point mutations leading to tyrosine-kinase inactivation have been found in FLT4 in patients with congenital familial lymphoedema (Milroy’s disease, OMIM 153100). The phenotype manifests with lymphoedema at or soon after birth, with swelling confined to one or both feet and ankles due to a reduction in functioning initial lymphatics.

The forkhead transcription factor FOXC2 is involved in the specification of the lymphatic capillary vs collecting lymphatic vessel phenotype. It is also important for the development and maintenance of lymphatic (and venous) valves. Heterozygous loss-of-function mutations in FOXC2 cause lymphoedema–distichiasis (LD, OMIM 153400), a dominantly inherited late-onset (postpubertal) lymphoedema associated with a double row of (ingrowing) eyelashes (distichiasis). Unlike Milroy’s disease the lymphatic vasculature is well formed or even hyperplastic, but a defect in lymphatic valves results in lymph reflux. Swelling may not manifest until the fifth decade, indicating how genetic abnormalities can cause late-onset lymphoedema. The phenotype may possess congenital heart disease, emphasizing the close relationship between cardiovascular and lymphatic development.

Congenital lymphoedema may be sporadic and involve several limbs, genitalia, or even the face. A failure in lymphatic development may also manifest with internal lymphatic abnormalities such as pleural effusion, pulmonary or intestinal lymphangiectasia. Obstruction to intestinal lymph drainage may result in chylous reflux, with chyle re-routing to various parts of the body, e.g. chylous effusion or ascites. The fat as well as protein content of such fluids should be measured for diagnosis. Congenital lymphoedema may occur in isolation or as part of a syndrome, e.g. Turner’s, Noonan’s or Proteus. It is not unusual for lymphoedema to associate with hypertrophy of other tissues giving rise to increased limb girth or length.

For most forms of primary lymphoedema the genetic cause remains unknown. Swelling usually presents at or after puberty, particularly in females, and affects the distal leg. Familial forms in which lymphangiograms demonstrate a reduction in size and number of superficial lymphatic collecting vessels are called Meige’s disease (OMIM 153200). Lymphoedema of the proximal obstructive type with unilateral whole-limb swelling is sporadic in type. Lymphangiograms of this form of lymphoedema demonstrate obstruction at the inguinal nodes, but no cause can be found. In such cases it is of the utmost importance to exclude tumour or iliac vein thrombosis.

Those cases of unilateral limb swelling associated with vascular abnormalities such as port wine stain and/or varicose veins are likely to be a form of Klippel–Trenaunay syndrome. The yellow nail syndrome, although given an OMIM number (153300), rarely has a family history and is of unknown cause.

Secondary lymphoedema

Filariasis is by far the most common cause of lymphoedema worldwide (filarial elephantiasis). It is endemic in eastern Asia, the Indian subcontinent, west and east Africa, Brazil, and the Caribbean. Microfilaria introduced into the skin by mosquitoes migrate towards and enter initial lymphatics. Adult worms develop within the main collector vessels close to the nodes, resulting in lymphatic dilatation and lymphadenitis.

In developed countries surgical removal or irradiation (or both) of lymph nodes for cancer treatment results in lymphoedema. In breast-cancer-related lymphoedema the exact mechanisms for development are unclear, but a simple ‘stopcock’ obstruction in the axilla from scarring seems unlikely. Lymphoedema can develop in some patients after one (sentinel) node removal, but not in others who have had a complete auxiliary clearance. Nevertheless, in general the more extensive the damage to lymph-conducting pathways from elective surgery or accidental trauma, the more likely is permanent swelling to occur. It is probably the failure of lymphatics to regrow or reconstitute functional channels (lymphangiogenesis) that represents the fundamental cause.

Cancer rarely presents with lymphoedema, except in advanced disease, but relapsed tumour frequently results in lymphoedema due to obstruction or infiltration of collateral lymphatic routes that have hitherto permitted escape of lymph. Kaposi’s sarcoma is a neoplasm characterized by vascular plaques in skin such that lymphoedema can result. The condition is associated with infection by human herpesvirus 8. The transcriptional profile of Kaposi’s sarcoma cells is closely related to normal lymphatic endothelial cells.

Lymphangitis or cellulitis probably only cause lymphoedema when the lymphatics are perilously vulnerable. Any patient suffering recurrent lymphangitis/cellulitis in the same region is likely to have impaired lymphatic function. Recurrent attacks of cellulitis frequently head to a stepwise deterioration in swelling.

Podoconiosis (endemic elephantiasis) is a form of endemic nonfilarial lymphoedema caused by microparticles of silica that penetrate the feet during barefoot walking in soil containing silica and aliminosilicates in tropical west and east Africa, certain volcanic islands, and Central America.

Functional lymphoedema may develop as a result of immobility and dependency due to infirmity following stroke, severe arthritis, or respiratory disease, with long periods spent in a chair. It is probably the lack of exercise as much as increased weight that causes lymphoedema to develop with obesity and sleep apnoea syndrome.

Lymphoedema is a common consequence of post-thrombotic syndrome (following deep vein thrombosis) and severe long-standing venous reflux due to varicose veins. High filtration rates from the ambulatory venous hypertension slowly exhaust lymph drainage in a manner equivalent to high output cardiac failure. Irreversibly impaired lymph drainage eventually results. Lymphoedema can also result from long-term inflammatory states such as rheumatoid arthritis and chronic hand or foot dermatitis (with or without infection).

Epidemiology

An estimated 15 million people suffer from leg lymphoedema in filariasis-endemic areas of the world. Other lymphatic manifestations such as genital lymphoedema and hydrocoele are equally common.

In the United Kingdom secondary forms of lymphoedema, particularly cancer-related lymphoedema, are generally considered more frequent than primary forms. However, lymphoedema is more common than is usually recognized, and noncancer forms are commoner than those related to malignancy. A study investigating lymphoedema in south-west London ascertained a prevalence of 1.33 per 1000 population, rising to 1 in 200 over 65 years of age, and with three noncancer patients for every cancer patient identified. 29% of the cases had experienced cellulitis in the preceding year, with one-quarter of them requiring admission. Time off work was attributed to the lymphoedema in 80% of cases, with employment status affected in 9%. Quality of life suffered. with clear deficits in many domains of the well-validated SF-36 questionnaire.

In cancer practice the prevalence of lymphoedema following breast cancer treatment is approximately 25% lifetime risk, reducing to approximately 7% with sentinel node techniques. Other cancers such as gynaecological, prostate, head and neck, melanoma, testicular, and sarcoma have smaller numbers presenting with lymphoedema as a result of treatment or through progressive disease. One study of lower limb lymphoedema in gynaecological cancer identified an overall prevalence of 18%, but 47% following treatment for vulval cancer.

Prevention

Identification of patients at risk of lymphoedema relies on awareness of its causes. Nevertheless, as cancer-related lymphoedema epidemiology demonstrates, it is difficult to predict who will develop lymphoedema, particularly as there may be several years delay between causative event and onset of swelling. Known risk factors are genetic predisposition, infection (e.g. cellulitis), advanced venous disease, immobility, and obesity.

Clinical features

Lymphoedema is rarely considered at presentation and consequently diagnosis is usually delayed while other possible causes of swelling are investigated and excluded. Any chronic oedema, irrespective of cause, will mean some degree of lymphatic failure.

Lymphoedema most commonly affects the extremities, particularly the leg, although midline swelling affecting head and neck or genitalia can be an isolated finding. Truncal oedema is often observed in the adjoining quadrant of the trunk to an affected limb because of the shared lymph drainage route. Oedema that is symmetrical (equal between right and left legs) is more likely to have systemic origins, e.g. right-sided heart failure or hypoproteinaemia. Oedema that is asymmetrical (more in one leg than the other) implies a local cause, e.g. impaired venous or lymph drainage, but both systemic and local causes can coexist. In a patient with advanced cancer leg oedema may result from a combination of hypoproteinaemia (liver metastases), impaired lymph drainage (original lymphadenectomy and/or lymphatic infiltration by tumour), venous obstruction (deep vein thrombosis or vein compression by tumour), immobility, and dependency.

History

Swelling frequently develops rapidly—within a day—but may be mild and intermittent at first. Pain may feature initially, prompting diagnoses such as deep vein thrombosis, soft tissue injury, or infection (although cellulitis often triggers lymphoedema). With time, oedema becomes more permanent and painless, although discomfort, aching and heaviness are common symptoms. Functional impairment is slight until swelling becomes more severe (Figure 1).

Figure 1: Lymphoedema of lower leg and arm

Lymphoedema does not respond to elevation or diuretics, except in the early stages or when it is compounded by increased capillary filtration. Chronic oedema that does not reduce significantly overnight is likely to be lymphatic in origin.

Clinical signs

It is often said that lymphoedema does not pit, but this is not true until the advanced stages of fibrosis (elephantiasis). To demonstrate pitting in lymphoedema sustained pressure for some 20 s may be necessary, owing to the firmer (and thicker) nature of the skin and subcutaneous tissues. The skin may double in thickness in lymphoedema, particularly at the base of the second toe, where it may be impossible to pinch up a fold of skin, which is called the (Kaposi–) Stemmer sign (Figure 2, Table 1). Skin creases become enhanced and a warty texture (hyperkeratosis) develops.

Figure 2: Kaposi-Stemmer sign

Table 1 Criteria for diagnosis of lymphoedema
Symptoms Persistent swelling (can be intermittent at first)
Oedema does not resolve with overnight elevation
Poor response to diuretics
Associated with cellulitis
Signs Pitting oedema (but difficult to pit)
Thickened, warty skin
Kaposi–Stemmer sign
Investigation Abnormal lymph drainage routes or impaired transport on lymphoscintigraphy

Accumulation of lymph under pressure in dermal lymphatics can result in lymph blisters that bulge on the surface (lymphangiectasia) and weep lymph. When associated with dermal fibrosis the surface bulges are firmer and resemble cobblestones (papillomatosis). The resemblance of the skin texture to elephant hide explains the term elephantiasis. Intestinal lymph that is rerouted or refluxes into more dependent regions of the body will appear milky (chyle) due to its high fat content. Chyle may reflux into the lower limbs, genitalia, peritoneal cavity, urinary and genital tracts, pleural cavity, and other cavities such as synovial joints and pericardium. Chyle will only appear if the lymphatic incompetence extends up to the preaortic lymphatics and cisterna chyli.

Cellulitis

In addition to swelling, impaired lymph drainage also predisposes to infection because of the role the lymphatic system plays in immunosurveillance. Acute inflammatory episodes identical to cellulitis can often be recurrent and frequent. In filarial lymphoedema secondary bacterial infections appear to be important for the progression of the condition. ‘Acute attacks’ manifest with increased oedema, pain, fever, or flu-like symptoms and can be largely prevented with long-term penicillin and improvements in skin hygiene. In primary and cancer-related lymphoedema recurrent cellulitis can be an equally common and difficult problem to that seen in filariasis, suggesting that altered immunity associated with lymphoedema is the fundamental cause.

Differential diagnosis of the swollen limb

Both excessive capillary filtration and compromised lymph drainage frequently coexist.

‘Venous’ oedema

Most cases of chronic venous disease giving rise to venous hypertension do not manifest with oedema because of increased lymph flow in response to increased capillary filtration. This suggests that the development of oedema in post-thrombotic syndrome and venous ulceration is as much a failure of lymph drainage to compensate as it is due solely to overwhelming filtration. Chronic ‘congestion’ in the lower leg resulting from both increased capillary filtration and impaired lymph drainage will often result in lipodermatosclerosis, usually seen just above the medial malleolus or anterior gaiter region (Fig. 3). The expansion of the venous pool in the leg due to dilatation of the veins will also contribute to an increase in limb girth.

Figure 3: Lipodermatosclerosis, a consequence of chronic congestion, manifests with fixed plum-red discolouration of skin, subcutaneous induration, and oedema—and is often mistaken for cellulitis.

‘Armchair’ legs (dependency syndrome)

This syndrome refers to those patients who sit in a chair day and night with their legs dependent. Immobility results in minimal lymph drainage and ‘functional lymphoedema’ ensues, i.e. there is no stimulation of lymph drainage from movement, compounded by increased capillary filtration from gravitational forces. Predisposed are those suffering cardiac or respiratory failure who cannot lie flat, those paralysed from stroke or spinal damage including spina bifida, and those with crippling arthritis, particularly rheumatoid. An increasing problem is excessively obese individuals with or without obstructive sleep apnoea.

Lipoedema (lipodystrophy, lipohypertrophy, lipidosis)

Frequently misdiagnosed as lymphoedema, lipoedema is almost exclusive to females with onset at or after puberty. Lipoedema (lip = fat, oedema = swelling) results in excessive fat deposition below the waist (and sometimes upper arms), but not affecting the feet. A disproportionate large pear-shaped lower half with thick, heavy, chunky legs results (Figure 4). The skin is soft, tender, and bruises easily. Pain may be a striking feature, Lipoedema is not influenced by dieting and is distinct from morbid obesity.

Figure 4: Lipoedema, a condition almost exclusive to women resulting in excess subcutaneous fat on hips, buttocks, thighs, or legs giving rise to disproportionately large lower limbs and often mistaken for lymphoedema.

Clinical investigation

The investigation of choice for confirming that oedema is primarily of lymphatic origin is lymphoscintigraphy (isotope lymphography). Traditional direct-contrast radiographic lymphography is now rarely undertaken to investigate lymphoedema. MRI or CT is of value in identifying a cause for lymphatic obstruction, e.g. cancer.

Lymphoscintigraphy

A radiolabelled protein or colloid is administered via a subcutaneous or intradermal injection and its absorption and transport through lymphatic vessels to lymph nodes is imaged by gamma camera. Theoretically lymphoscintigraphy permits examination of lymph drainage from any site to which radiolabelled tracer can be administered, as has happened with sentinel node mapping for melanoma, breast, and genital cancer management. For the investigation of a swollen limb tracer is administered bilaterally into feet or hands. Lymph drainage routes can be crudely imaged and abnormalities identified (Figure 5). Offline calculation of time–activity curves over regions of interest permit quantitative analysis of lymph drainage. Lymphoscintigraphy is very specific, i.e. there are few false positives, but only 90% sensitive and may miss lymphoedema.

lymphoscinitigraphy of lower limbs

Figure 5: Lymphoscintigraphy: Swollen limb indicates impaired lymph drainage. Lymphoscintigraphy is the investigation of choice for determining if limb swelling is due to lymphoedema. Following a web space injection (hand or foot) of a radiolabelled colloid (99mTc–antimony sulphide colloid) the transport of radioactivity is imaged by gamma camera. Image abnormalities or a quantitative reduction in radioactivity in a region of interest within draining lymph nodes indicates lymphoedema.

MRI

MRI (or CT) demonstrates a thicker skin and a ‘honeycomb’ pattern in the swollen subcutaneous compartment of lymphoedema. Following deep vein thrombosis of the leg the subfascial muscle compartment is enlarged, but not so in lymphoedema. MRI and CT are more sensitive than ultrasonography for identifying enlarged lymph nodes or pathology responsible for lymphatic obstruction such as pelvic tumour, and to differentiate lipoedema (fat) from lymphoedema (fluid).

Colour Doppler duplex ultrasound

Venous disease (primary varicose veins or post-thrombotic syndrome) may cause or contribute to lower limb swelling. Venous duplex ultrasonography is helpful for identifying venous reflux. Iliac vein thrombosis or compression can be a cause of whole-leg swelling.

Gene testing

Gene testing for Milroy’s disease (FLT4 mutations) and lymphoedema–distichiasis (FOXC2 mutations) is now available if the phenotype is appropriate.

Treatment

Physical therapy

No drug or surgical therapy is known to improve lymph drainage. The treatment of lymphoedema relies on improving lymph drainage through the application of simple physiological principles known to stimulate lymph flow, while at the same time restoring any excessive capillary filtration to as near normal as possible. The principles of treatment are generic, but obviously vary according to individual circumstances dependent on site, e.g. facial vs leg lymphoedema, and cause, e.g. genetic lymphoedema in a child vs lymphoedema in advanced cancer.

Unlike blood flow, which is predominantly driven by the heart, lymph flow falls to low levels unless stimulated by movement and in particular exercise. Alternating changes in interstitial fluid pressure (by active or passive exercise or massage) increase initial lymphatic filling and flow within initial lymphatics. Increases in lymph load to collecting lymphatics will stimulate greater contractility within these main pumping vessels. Patients with leg lymphoedema often notice that walking reduces swelling. The addition of a bandage or stocking will enhance the effect of movement. The idea of compression is not to squeeze fluid out of the limb with force like squeezing toothpaste out of a tube, but to create an outer collar to the leg that resists expansion of the calf muscle during contraction. This generates a high interstitial pressure during muscle contractions to drive lymph filling and drainage, but allows low pressures during skeletal muscle relaxation and hence permits lymphatic vessel refilling before further muscle contraction repeats the cycle. Compression without movement (active or passive exercises) does not improve lymph drainage. Such treatment as provided by compression will be particularly helpful in circumstances where lymphatic collector contractility is impaired. It has the added benefit of lowering venous pressure in the leg, so reducing filtration.

Manual lymphatic drainage therapy (MLD), a specific form of lymphatic massage, operates on the same principle of stimulating alternating rises and falls in interstitial pressure and is used to decongest more proximal regions of the body, e.g. the adjoining quadrant of the trunk to a swollen limb, through which lymph from the limb needs to pass before being directed to a normally functioning lymphatic basin. In right-arm lymphoedema MLD would serve to direct collateral lymph drainage to normally draining lymph routes in the contralateral left axilla and so complement the effect of any compression and exercise to the right arm.

In moderate to severe lymphoedema treatment with an intensive course of MLD, multilayer lymphoedema bandaging and exercise can reverse more or less all the comorbidity from swelling, including ‘elephantiasis’ skin changes. Once swelling has been reduced and limb shape improved, control is maintained through exercise while wearing appropriately fitted compression hosiery. In elderly and infirm individuals the application and removal of hosiery can be problematic, but technique can be helped and aids to application provided.

Elevation of the legs is often wrongly chosen over exercise as treatment. Elevation helps oedema by lowering venous pressure and consequently reducing capillary pressure, not by improving lymph drainage. While exercise is preferred to elevation as treatment, elevation is recommended during periods of rest.

Pneumatic compression pumps probably displace fluid as much as improve lymph flow. Nevertheless, they may prove helpful for patients spending considerable time in chairs and in cases of oedema associated with high filtration.

Drug therapy

Too often diuretics are prescribed for oedema on an empirical basis without due thought for the underlying pathophysiology. Diuretics have very little effect in established lymphoedema because their main action is to reduce capillary filtration. They should only be prescribed in circumstances of salt and water retention, whereupon spironolactone may be preferred. Rutoside (a glycoside) has been advocated, but clinical effect is minimal.

Calcium channel blockers should be avoided in lymphoedema because they encourage oedema. The mechanism is unclear, but lymphatic pumping is paralysed in animal studies.

Prevention of infection

Prevention of cellulitis is crucial to the control of lymphoedema because it contributes to further decline in lymph drainage, which in turn encourages more infection. Care of the skin, good hygiene, treatment of any dermatitis or fungal infection, and antisepsis following minor wounds are important. Consensus recommendations for the treatment of cellulitis with lymphoedema are given in Table 2.

Table 2 Treatment of cellulitis in lymphoedema a
Situation First-line antibiotics If allergic to penicillin Second-line antibiotics Comments
Acute infectious episode + septicaemia (inpatient admission)
  • Amoxicillin IV 2 g every 8 h
  • or benzylpenicillin 1.2–2.4 g every 6 h + flucloxacillin 500 mg every 6 h
Clindamycin IV 600 mg q6 h Clindamycin IV 600 mg every 6 h (if poor or no response by 48 h)
  • Switch to amoxicillin 500 mg every 8 h or clindamycin 300 mg every 6 h when:
  • Temperature down for 48 h
  • Inflammation much resolved
  • Falling CRP
  • Then continue as below
Acute infectious episode (home care) Amoxicillin 500 mg every 8 h b Clarithromycin 500 mg every 12 h If fails to resolve, convert to IV regimen as in row 1, column 2
  • Give for a minimum of 2 weeks
  • Continue antibiotics until the acute inflammation has completely resolved; this may take 1–2 months
Prophylaxis if 2+ acute infectious episodes per year Phenoxymethylpenicillin 500 mg o.d. (1 g if weight >75 kg)
  • Erythromycin 250 mg o.d. or
  • clarithromycin 250 mg o.d
Clindamycin 150 mg o.d. or clarithromycin 250 mg o.d. After 1 year, halve the dose of phenoxymethylpenicillin; if an acute infectious episode develops after discontinuation, treat the acute episode and then commence lifelong prophylaxis
Emergency supply of antibiotics ‘in case of need’ (when away from home) Amoxicillin 500 mg every 8 h Clindamycin 300 mg every 6 h If fails to resolve, or constitutional symptoms develop, convert to IV regimen as in row 1, column 2 above  

IV, intravenous; o.d., once daily.

a By mouth unless stated otherwise.

b If Staphylococcus aureus infection suspected (pus formation, crusted dermatitis), add flucloxacillin 500 mg every 6 h.

Adapted from Twycross RG, et al. (2007). Palliative care formulary, 3rd edition. palliativedrugs.com, Nottingham.

Surgery

Surgery can involve removal of excess tissue (reducing/debulking operations or liposuction) or bypassing of local lymphatic defects. Availability of centres offering microsurgical lymphovenous, lymphatic–lymphatic anastomoses remains limited. Surgery rarely if ever obviates the need for long-term compression hosiery.

Genital lymphoedema

Genital lymphoedema may arise from a genetic fault in lymphatic development, in which case internal lymph problems, e.g. intestinal lymphangiectasia, may coexist. Acquired forms may result from cancer treatment, infection (cellulitis), Crohn’s disease, and hidradenitis suppurativa. Control of any inflammation is essential for control of oedema.

Facial lymphoedema

Impaired lymph drainage within skin and subcutaneous local lymphatics is likely to be a factor in cases of facial swelling, particularly periorbital oedema associated with rosacea, dermatomyositis, and thyroid disease.