Lymphedema

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In medicine, lymphedema exhibits as fluid retention due to damage to, or dysfunction of the lymphatic system. There may be multiple comorbid causes of fluid retention, such as metabolic disturbances.
The standard of care for lymphedema encompasses risk reduction, early detection, Phase-I Complete Decongestive Therapy in a clinical setting, and Phase-II Self Management at home. [1]

The disorder presents as fullness or swelling of soft tissues, most often in the arms or legs but potentially in other body parts, such as the neck, trunk, face or genitals. Significant swelling or soreness of soft tissues always must be diagnosed. Lymphadema is a chronic disorder requiring lifetime care, but also can coexist or resemble other causes of soft tissue swelling and pain, such as cellulitis or deep vein thrombosis, which can progress to urgent threats to life or limb.

Etiology

Lymphedema may be primary, with a genetic etiology, or secondary, as a result of another disorder or physical damage.[2]

Lymphedema may be due to:[3]

  • Obliterative disease of lymph nodes
  • Hyperplastic disease of lymph nodes

Secondary lymphedema

"Secondary lymphedema has an identifiable cause that destroys or renders inadequate the otherwise normal lymphatics."[4] Besides cancer treatment or tumor effects, other causes include vein stripping for treatment of varicose veins[5] or obtaining arterial grafts, peripheral vascular surgery, lipectomy, burns, burn scar excision, and insect bites. Minimally invasive techniques for harvesting venous grafts are being used, in part, to reduce the risk of postoperative lymphedema. [6]

Primary lymphedema

Lymphedema may have a genetic cause.[7] Several types have been reported in the literature. They vary in in age of onset, site of edema, associated features, inheritance patterns, and underlying genetic cause. Determining the representative phenotype for different types of genetically determined primary lymphedema has been successfully achieved with Milroy's disease and the lymphedema-distichiasis syndrome. Phenotype characterization facilitates the identification of causative genes, as has been demonstrated with VEGFR3 and FOXC2, in Milroy's disease and lymphedema-distichiasis respectively.

Using transgenic and gene transfer techniques, the defects have been produced in mice, giving "initial clues to the development of a biologically based therapy for primary lymphedema. Of more importance from a public health perspective is the fact that manipulation of this pathway may lead to effective therapies for the more prevalent forms of secondary lymphedema."[8] The known mutations leading to lymphatic phenotypes, however, explain fewer than half the cases of lymphedema.[9] Nevertheless, there are research directions for treatment, based on lymphangiogenesis, the triggering of new lymphatic system growth.[10]

Meige disease

Meige disease, also called lymphedema praecox, occurs after birth but before 35 years; the age of onset is generally in adolescence is the most common form of primary lymphedema. By definition, it becomes clinically evident after birth and before age 35 years. This condition accounts for 65-80% of all primary lymphedema cases and most often arises during puberty. Females are affected 4 times as often as males. About 70% of cases are unilateral, with the left lower extremity being involved more often than the right. [4]

Milroy's disease

"Congenital lymphedema that is present at birth and associated with an autosomal dominant familial history is called Milroy disease."[11] The differential diagnosis includes: Some additional diagnostic techniques may be useful for confirming this syndrome. Color Doppler ultrasonography is fairly routine to all investigation of lymphedema, but there are methods that demonstrate the characteristic absence of lymphatics in this disorder. Biopsy also has a role.

Lymphoscintigraphy remains preferred to lymphangiography, but, if lymphangiography is attempted, a prior subcutaneous injection of dye shows lymphatic vessels that cannot be cannulated, as does fluorescence microlymphography using a light fluorescence microscope following subepidermal infection of FITC-dextran 150,000 demonstrates a lack of microlymphatics.

In these young patients, it can be wise to do plain radiographs to exclude bone disease.

Lymphedema-distichiasis syndrome

Caused by mutations in the FOXC2-gene, the lymphedema-distichiasis syndrome involves malformations of both the lymphatic and vascular systems. It "is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis (double row of eyelashes). While the latter is the most common expression of LD, venous insufficiency occurs in half of the patients. Other associations have been reported, including congenital heart disease, ptosis, cleft lip/palate and spinal extradural cysts"[12]

Lymphedema Tarda

Present in 10% of the cases of primary lymphedema, the lymphadema aspect of this disease manifests after age 35.[11] Histologically, patients are likely to demonstrate a hyperplastic pattern, with tortuous lymphatics increased in caliber and number. They often display absent or incompetent valves.[4]

The initial indication of the genetic disorder may be cleft palate.[13]

Yellow nail syndrome

Yellow nail syndrome, the cause of which is unknown, combines lymphedema, yellow discoloration of the nails, pleural effusion, often with chronic lower respiratory infection and sinusitis. It is a rare disorder, with only 51 partial and 13 complete cases reported by 1980. Cancer and thyroiditis have been reported as part of the syndrome.[14]

Diagnosis

Lymphedema should be distinguished from edema, myxedema, and lipedema.[15] Lipedema is more likely to spare the dorsum of the foot.

It is possible, however, to have comorbid edema and lymphedema. For example, a vasodilator used to treat hypertension can cause edema in a patient with cardiac disease. If that patient has had the lymphatics of the lower leg damaged by stripping the saphenous vein for use as an arterial graft, that damage can cause lymphedema to coexist with edema.

Physical examination

On physical examination, fast recovery of pitting is associated with lower serum albumin levels.[16] Fast recovery within 2-3 seconds, is more sensitive than specific at detecting hypoalbuminemia. Presumably this is related to the viscosity of the interstitial fluid thus hypoalbuminemic interstitial fluid can reform more quickly.[16]

Imaging

Imaging should begin with the least invasive methods, such as Color Doppler duplex ultrasound is useful in evaluating venous abnormalities; it is also key to ruling out deep venous thrombosis, along with D-dimer determinations.

X-ray-contrast lymphography[17] was long the gold standard mode of demonstrating lymphatic collectors and lymph nodes, but the technique is invasive as it involves direct cannulation of the lymphatics, and, with oil-based contrast media, has been associated with complications. [18] It is rarely used since the advent of.lymphangioscintigraphy [19] Whole-body lymphangioscintigraphy is now the main imaging method, usually following color Doppler ultrasound. [20]

Magnetic resonance imaging may help in the diagnosis, but is usually considered an additional study after lymphangioscintigraphy. [21] It is most useful in secondary than primary lymphedema, to visualize lymph trunk anatomy and causes of obstructive secondary lymphedema.[11] "MRI of lymphatic vessels in lymphoedematous patients is safe and feasible after intracutaneous injection of gadoteridol if the diagnosis of lymphoedema necessitates a better definition for optimal therapeutic planning or an objective, diagnostic baseline is required." [22]

Biopsy

Biopsy, if only minimally-invasive skin-punch, may be appropriate for some specific confirmatory diagnoses, as in Milroy's Disease. "Biopsy of the skin is performed using standard techniques. A 25-gauge needle is used to infiltrate the skin with local anesthesia. The skin is stretched perpendicular to the desired line of the scar. A punch biopsy tool is rotated into the skin to obtain a small circle of tissue, which is sent to pathology for histologic staining. Bleeding is controlled by the application of pressure to the area or by the use of a single suture. Topical antibiotics applied twice daily speed wound healing." [11]

Treatment

Dermatologists refer to "complex physical therapies" asthe core of treatment:

  • External compression, using bandaging, multilayer compression wraps, and compression pumps
  • Periodic leg elevation
  • Exercise
  • Skin care
  • Massage

Drugs are controversial for lymphedema proper, although they may be useful with comorbidities.

Direct drug treatment

There is no universally accepted drug therapy. Benzpyrones such as coumarin and flavonoids have been used, but have a risk of toxicity. There have been case reports of benefit from retinoids, as well as Topical emollients and keratolytics, such as ammonium lactate, urea, and salicylic acid, have been recommended to improve secondary epidermal changes.[23]

Benzpyrones

They decrease "excess edematous fluid, softening the limb, decreasing skin temperature, and decreasing the number of secondary infections. The benzopyrones successfully increase the number of macrophages, leading to proteolysis and protein reabsorption. Of note, however, is that hepatotoxicity has been associated with coumarin therapy"[23]

The Cochrane reviews were unable to perform meta-analysis.[24] One review suggested pharmacogenomics may identify the patients likely to be harmed by coumadin. [25]

Retinoids

Oral and topical retinoids, such as acetretin and tazarotene, may normalize keratinization and decrease inflammatory and fibrotic changes. [26]

Keratolytics

Ammonium lactate and urea have been used. [23]

Free radical scavengers

Research suggests a possible value to selenium. [27]

Drug treatment of cormormidities

Diuretics, for example, have no role in the disorder, but are indicated in comorbid edema from vascular disorders or medication effects. Antibiotics, of course, are relevant in treating active infections, but are appropriate propylactically in selected patients.

Surgery is generally palliative but has a role.

Compression

Use of compression stockings takes specialized knowledge. The area to be compressed must be measured, and the stocking size needs to change if limb volume changes, as often takes place in the first part of therapy. As opposed to commercial support hose, the compression applied is not even, but designed to help spread fluid.

Multilayer compression bandaging for 2-3 weeks followed by hosiery may reduce the size of limbs with lymphedema.[28] The innermost layer of these bandages is a thin conformal mesh, followed by padding, followed by mildly elastic bandages — much less elastic than those used for musculoskeletal injuries.

Exercise

Exercise had traditionally been avoided, but more recent data show that careful exercise, even strength training, may increase well-being and not increase risk. The patient, however, must be scrupulous about seeking care for even minor injuries. Symptoms did not exacerbate in a randomized controlled trial of 45 breast cancer survivors.[29] Several comments were made that limb volume measurements are more accurate than limb circumference as a possible warning of problems, although muscle mass can also increase volume.

Drugs

If there is more than one episode of infection annually, prophylactic oral antibiotics are indicated. [30]

References

  1. Mayrovitz HN (2009), "The standard of care for lymphedema: current concepts and physiological considerations", Lymphat Res Biol 7 (2): 101-8, DOI:10.1089/lrb.2009.0006
  2. Browse NL, Stewart G (1985). "Lymphoedema: pathophysiology and classification.". J Cardiovasc Surg (Torino) 26 (2): 91-106. PMID 3884629[e]
  3. Wolfe JH (1984). "The prognosis and possible cause of severe primary lymphoedema.". Ann R Coll Surg Engl 66 (4): 251-7. PMID 6742737. PMC PMC2492713[e]
  4. Cite error: Invalid <ref> tag; no text was provided for refs named EmedSurg
  5. Lahl W, Richter J, Neppach V, Massel R. (1981), "[Leg oedema after surgery of varicose veins (author's transl)] [Article in German]", Zentralbl Chir 106 (23): 1535-42
  6. G J Carrizo, J J Livesay, and L Luy (1999), "Endoscopic harvesting of the greater saphenous vein for aortocoronary bypass grafting.", Tex Heart Inst J. 26 (2): 120–123
  7. Connell F, Brice G, Mortimer P. (2008), "Phenotypic characterization of primary lymphedema", Ann N Y Acad Sci 1131: 140-6.
  8. Ferrell RE (2002 Dec), "Research perspectives in inherited lymphatic disease.", Ann N Y Acad Sci 979: 39-51; discussion 76-9
  9. Ferrell RE, Finegold DN (2008), "Research perspectives in inherited lymphatic disease: an update.", Ann N Y Acad Sci 1131: 134-9
  10. Nakamura K, Rockson SG (2008), "Molecular targets for therapeutic lymphangiogenesis in lymphatic dysfunction and disease.", Lymphat Res Biol 6 ((3-4)): 181-9
  11. 11.0 11.1 11.2 11.3 Raphael J Kiel (16 October 2008), "eMedicine Specialties > Pulmonology > Idiopathic Lung Disorders: Milroy Disease", eMedicine
  12. Vreeburg M, Heitink MV, Damstra RJ, Moog U, van Geel M, van Steensel MA (2008 Nov), "Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene.", Int J Dermatol 47 (Suppl 1): 52-5
  13. Figueroa AA, Pruzansky S, Rollnick BR (1983 Apr), "Meige disease (familial lymphedema praecox) and cleft palate: report of a family and review of the literature", Cleft Palate J. 20 (2): 151-7
  14. Mambretti-Zumwalt J, Seidman JM, Higano N (1980 Aug), "Yellow nail syndrome: complete triad with pleural protein turnover studies.", South Med J. 73 (8): 995-7.
  15. Loughlin V (May 1993). "Massive obesity simulating lymphedema". N. Engl. J. Med. 328 (20): 1496. PMID 8479476.
  16. 16.0 16.1 Henry JA, Altmann P (April 1978). "Assessment of hypoproteinaemic oedema: a simple physical sign". British medical journal 1 (6117): 890–1. PMID 638510. PMC 1603695[e] PubMed Central
  17. Kinmonth JB (1952), "Lymphangiography in man: a method of outlining lymphatic trunks at operation", Clin Sci 11: 13-20
  18. Koehler PR (1968), "Complications ol lvmphographv.", Lymphology 1: 117-120
  19. Witte CL; Witte MH; Unger EC; Williams WH; Bernas MJ; McNeill GC; Stazzone AM (2000), "Advances in imaging of lymph flow disorders.", Radiographics 20 (6): 1697-719
  20. McNeill GC, Witte MH, Witte CL, et al. (August 1989). "Whole-body lymphangioscintigraphy: preferred method for initial assessment of the peripheral lymphatic system". Radiology 172 (2): 495–502. PMID 2748831[e]
  21. Case TC, Witte CL, Witte MH, Unger EC, Williams WH (1992). "Magnetic resonance imaging in human lymphedema: comparison with lymphangioscintigraphy". Magn Reson Imaging 10 (4): 549–58. PMID 1501525[e]
  22. Lohrmann C, Foeldi E, Bartholomae JP, Langer M (2007 Jul), "Gadoteridol for MR imaging of lymphatic vessels in lymphoedematous patients: initial experience after intracutaneous injection.", Br J Radiol 80 (955): 569-73
  23. 23.0 23.1 23.2 Kathleen M Rossy, Noah S Scheinfeld (1 February 2008), "Lymphedema: Treatment & Medication", eMedicine Specialties > Dermatology > Diseases of the Vessels
  24. Badger C, Preston N, Seers K, Mortimer P (2004), "Benzo-pyrones for reducing and controlling lymphoedema of the limbs", Cochrane Database Syst Rev (no. 2): CD003140
  25. Farinola N, Piller NB (2007 Feb), "CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?", Pharmacogenomics 8 (2): 151-8
  26. Feind-Koopmans A, van de Kerkhof PC. Successful treatment of papillomatosis cutis lymphostatica with acitretin. Acta Derm Venereol. Sep 1995;75(5):411
  27. Bruns F, Micke O, Bremer M (2003 Jul-Aug), "Current status of selenium and other treatments for secondary lymphedema.", J Support Oncol 1 (2): 121-30
  28. Badger CM, Peacock JL, Mortimer PS (June 2000). <2832::AID-CNCR24>3.0.CO;2-U "A randomized, controlled, parallel-group clinical trial comparing multilayer bandaging followed by hosiery versus hosiery alone in the treatment of patients with lymphedema of the limb". Cancer 88 (12): 2832–7. PMID 10870068[e]
  29. Ahmed RL, Thomas W, Yee D, Schmitz KH (2006 Jun 20 (2006 May 15 ePub)), "Randomized controlled trial of weight training and lymphedema in breast cancer survivors", J Clin Oncol 24 (18 pages = 2765-72)
  30. Vignes S, Dupuy A. Recurrence of lymphoedema-associated cellulitis (erysipelas) under prophylactic antibiotherapy: a retrospective cohort study. J. Eur. Acad. Dermatol. Venereol. 20(7), 818-822 (2006).