International Guidelines on Lymphedema and lymphatic desorders

II. STAGING OF LYMPHEDEMA Whereas most ISL members generally  rely on a three stage scale for classification  of a lymphedematous limb, an increasing  number recognize Stage 0 (or Ia) which  refers to a latent or sub-clinical condition  where swelling is not evident despite  impaired lymph transport. It may exist  months or years before overt edema occurs  (Stages I-III). Stage I represents an early  accumulation of fluid relatively high in  protein content (e.g., in comparison with  “venous” edema) which subsides with limb  elevation. Pitting may occur. An increase in  proliferating cells may also be seen. Stage II  signifies that limb elevation alone rarely  reduces tissue swelling and pitting is  manifest. Late in Stage II, the limb may or  may not pit as tissue fibrosis supervenes.  Stage III encompasses lymphostatic  elephantiasis where pitting is absent and  trophic skin changes such as acanthosis, fat  deposits, and warty overgrowths develop.  These Stages only refer to the physical  condition of the extremities. A more detailed  and inclusive classification needs to be  formulated in accordance with improved  understanding of the pathogenetic mechanisms  of lymphedema (e.g., nature and degree of  lymphangiodysplasia, lymph flow  perturbations and nodal dysfunction as  defined by anatomic features and physiologic  imaging and testing) and underlying genetic  disturbances, which are gradually being  elucidated. Recent publications incorporating  both physical (phenotypic) findings with  functional imaging (by LAS at this point) into  a combined staging may be forecasting the  future changes in staging. In addition,  incorporation of genotypic information  available in the future may further advance  staging and classification of patients with  peripheral (and other) lymphedema.  Within each Stage, an inadequate but  functional severity assessment has been  utilized based on simple volume differences  assessed as minimal (<20% increase) in limb  volume, moderate (20-40% increase), or  severe (>40% increase). Clinicians also  incorporate factors such as extensiveness,  presence of erysipelas attacks, inflammation,  and other complications to their own  individual severity determinations.  Some healthcare workers examining  disability utilize the World Health  Organization’s guidelines for the International  Classification of Functioning, Disability, and  Health (ICF). Quality of Life issues (social,  emotional, physical disabilities, etc.) may also  be addressed by individual clinicians and can  favorably impact therapy and compliance  (maintenance).

III. DIAGNOSIS An accurate diagnosis of lymphedema is  essential for appropriate therapy. In most  patients, the diagnosis of lymphedema can be  readily determined from the clinical history  and physical examination. In other patients  confounding conditions such as morbid  obesity, venous insufficiency, occult trauma,  and repeated infection may complicate the  clinical picture. Moreover, in considering the  basis of unilateral extremity lymphedema,  especially in adults, an occult visceral tumor  obstructing or invading more proximal  lymphatics needs to be considered. For these  reasons, a thorough medical evaluation is  indispensable before embarking on  lymphedema treatment. Co-morbid  conditions such as congestive heart failure,  hypertension, and cerebrovascular disease  including stroke may also influence the  therapeutic approach undertaken.

A. Imaging If the diagnosis of lymphedema is  unclear or in need of better definition for  prognostic considerations, consultation with  a clinical lymphologist or referral to a  lymphologic center if accessible is  recommended. The diagnostic tool of isotope  lymphography (also termed  lymphoscintigraphy or  lymphangioscintigraphy) has proved  extremely useful for depicting the specific  lymphatic abnormality. Where specialists in  nuclear medicine are available,  lymphangioscintigraphy (LAS) has largely  replaced conventional oil contrast  lymphography for visualizing the lymphatic  network. Although LAS has not been  standardized (various radiotracers and  radioactivity doses, different injection  volumes, intracutaneous versus subcutaneous  injection site, epi-or subfascial injection, one  or more injections, different protocols of  passive and active physical activity, varying  imaging times, static and/or dynamic  techniques), the images, which can be easily  repeated, offer remarkable insight into  lymphatic (dys)function.  LAS provides both images of  lymphatics and lymph nodes as well as semiquantitative  data on radiotracer (lymph)  transport, and it does not require dermal  injections of blue-dye (as used for example in  axillary or groin sentinel node visualization  i.e., lymphadenoscintigraphy). Dye injection  is occasionally complicated by an allergic skin  reaction or serious anaphylaxis. Moreover,  clinical interpretation of lymphatic function  after vital dye injection alone (“the blue test”)  is often misleading. Direct oil contrast  lymphography, which is cumbersome and  occasionally associated with minor and major  complications, is usually reserved for complex  conditions such as chylous reflux syndrome  and thoracic duct injury. Non-invasive  duplex-Doppler studies and occasionally  phlebography are useful for examining the  deep venous system and supplement or  complement the evaluation of extremity  edema. Other diagnostic and investigational  tools used to elucidate  lymphangiodysplasia/lymphedema syndromes  include magnetic resonance imaging (MRI) –  includingMR angiography and newer MR  lymphography techniques, computed  tomography (CT), ultrasonography (US),  indirect (water soluble) lymphography (IL)  and fluorescent microlymphangiography  (FM). DEXA, or bi-photonic absorptiometry,  may help classify and diagnose a  lymphedematous limb but its greatest  potential use may be to assess the chemical  components of limb swelling (% fat, water,  lean mass) before and after treatment. IL and  FM are best suited to depict initial lymphatics  and accordingly have limited clinical  usefulness albeit valuable in research. US has  found its most practical value in depicting the  dance of the living adult worms in scrotal  lymphatic filariasis.

B. Genetics Genetic testing is almost becoming  practical to define a limited number of  specific hereditary syndromes with discrete  gene mutations such as lymphedemadistichiasis  (FOXC2), some forms of Milroy  disease (VEGFR-3), and hypotrichosislymphedema-  telangiectasis (SOX18). The  future holds promise that such testing  combined with careful phenotypic  descriptions will become routine to classify  familial lymphangiodysplastic syndromes  and other congenital/genetic-dysmorphogenic  disorders characterized by lymphedema,  lymphangiectasia, and lymphangiomatosis.  In addition, there are many other clinical  syndromes with lymphedema as a component  and these may have genes identified in the  future.

C. Biopsy Caution should be exercised before  removing enlarged regional lymph nodes in  the setting of longstanding peripheral  lymphedema as the histologic information is  seldom helpful, and such excision may  aggravate distal swelling. Fine needle  aspiration with cytological examination by a  skilled pathologist is a useful alternative if  malignancy is suspected. Use of sentinel node  biopsy in the groin or axilla in staging  malignancy such as breast and melanoma, if  validated for determining metastasis, may  lessen the incidence of peripheral  lymphedema by discouraging removal of  normal lymph nodes.

IV. TREATMENT Therapy of peripheral lymphedema is  divided into conservative (non-operative) and  operative methods. Applicable to both  methods is an understanding that meticulous  skin hygiene and care (cleansing, low pH  lotions, emollients) is of upmost importance  to the success of virtually all treatment  approaches. Basic range of motion exercises  of the extremities, especially combined with  external limb compression, and limb elevation  (specifically bed rest) is also helpful to  virtually all patients undergoing treatment. As  previously stated, even widely used methods  have yet to undergo sufficient meta-analysis  of multiple studies which have been rigorous,  well-controlled, and with sufficient followup.

A. Non-operative Treatment 1. Physical therapy

a. Combined physical therapy (CPT)  (also known as Complete or Complex  Decongestive Therapy (CDT) or Complex  Decongestive Physiotherapy (CDP) among  others) is backed by longstanding experience  and generally involves a two-stage treatment  program that can be applied to both children  and adults. The first phase consists of skin  care, a specific light manual massage (manual  lymph drainage), range of motion exercise and  compression typically applied with  multi-layered bandage-wrapping. Phase 2  (initiated promptly after Phase 1) aims to  conserve and optimize the results obtained in  Phase 1. It consists of compression by a  low-stretch elastic stocking or sleeve, skin  care, continued “remedial” exercise, and  repeated light massage as needed.  Prerequisites of successful  combined physiotherapy are the availability of  physicians (i.e., clinical lymphologists),  nurses, and therapists specifically trained,  educated, and experienced in this method,  acceptance of health insurers to underwrite the  cost of treatment, and a biomaterials industry  willing to provide high quality products.  Compressive bandages, when applied  incorrectly, can be harmful and/or useless.  Accordingly, such multilayer wrapping should  be carried out only by professionally trained  personnel. Newer manufactured devices to  assist in compression (i.e. pull on, velcroassisted,  quilted, etc.) may relieve some  patients of the bandaging burden and perhaps  facilitate compliance with the full treatment  program and some clinics find that patient  self-care and risk reduction strategies help  maintain edema reduction (although neither  of these has undergone rigorous study).  CPT may also be of use for  palliation as, for example, to control  secondary lymphedema from tumor-blocked  lymphatics. Treatment is typically performed  in conjunction with chemo- or radiotherapy  directed specifically at producing tumor  regression. Theoretically, massage and  mechanical compression could promote  metastasis in this setting by mobilizing  dormant tumor cells, although only diffuse  carcinomatous infiltrates which have already  spread to lymph collectors as tumor thrombi  might be mobilized by such treatment.  Because the long-term prognosis for such an  advanced patient is already dismal, any  reduction in morbid swelling is nonetheless  decidedly palliative.  A prescription for low stretch  elastic garments (custom made with specific  measurement if needed) to maintain  lymphedema reduction after CPT is essential  for long-term care. Preferably, a physician  should prescribe the compression garment to  avoid inappropriate usage in a patient with  medical contraindications such as arterial  disease, painful postphlebitic syndrome or  occult visceral neoplasia. Generally the  highest compression level tolerated (~20-60  mm Hg) by the patient is likely to be the  most beneficial.  Failure of CPT is confirmed only  when intensive non-operative treatment in a  clinic specializing in management of  peripheral lymphedema and directed by an  experienced clinical lymphologist has been  unsuccessful.

b. Intermittent pneumatic compression. Pneumomassage is usually a  two-phase program. After external  compression therapy is applied, preferably by  a sequential gradient “pump,” form-fitting  low-stretch elastic stockings or sleeves are  used to maintain edema reduction.  Displacement of edema more proximally in  the limb and genitalia and the development of  a fibrosclerotic ring at the root of the  extremity with exacerbated obstruction of  lymph flow needs to be assiduously avoided  by careful observation. Combining pneumatic  compression with MLD has been reported but  not sufficiently evaluated. Some published  reports support the use of MLD as a  monotherapy in newly established and/or mild  lymphedema without fibrosis.

c. Massage alone. Performed as an  isolated technique, classical massage or  effleurage usually has limited benefit.  Moreover, if performed overly vigorously,  massage may damage lymphatic vessels.

d. Wringing out. “Tuyautage” or  wringing out performed with bandages or  rubber tubes is probably injurious to lymph  vessels and should seldom if ever be  performed.

e. Thermal therapy. Although  combinations of heat, skin care, and external  compression have been advocated by  practitioners in Europe and Asia, the role and  value of thermotherapy in the management of  lymphedema remains unclear without further  rigorous studies.

f. Elevation. Simple elevation  (particularly by bed rest) of a  lymphedematous limb often reduces swelling  particularly in stage I of lymphedema. If  swelling is reduced by antigravimetric means,  the effect should be maintained by wearing of  a low-stretch, elastic stocking/sleeve.

2. Drug therapy

a. Diuretics. Diuretic agents are of  limited use during the initial treatment phase  of CPT and should be reserved for patients  with specific co-morbid conditions or  complications. Long-term administration of  diuretics, however, is discouraged for it is of  marginal benefit in treatment of peripheral  lymphedema and potentially may induce fluid  and electrolyte imbalance. Diuretic drugs  maybe helpful to treat effusions in body  cavities (e.g., ascites, hydrothorax) and with  protein-losing enteropathy. Patients with  peripheral lymphedema from malignant  lymphatic blockage may also derive benefit  from a short course of diuretic drug  treatment.

b. Benzopyrones. Oral benzopyrones,  which have been reported to hydrolyze tissue  proteins and facilitate their absorption while  stimulating lymphatic collectors, are neither  an alternative nor substitute for CPT. The  exact role for benzopyrones (which include  those termed rutosides and bioflavonoids) as  an adjunct in primary and secondary  lymphedema treatment including filariasis is  still not definitively determined including  appropriate formulations and dose regimens.  Coumarin, one such benzopyrone, in higher  doses has been linked to liver toxicity. Recent  research has linked this with poor CYP2A6  enzymatic activity in these individuals.

c. Antimicrobials. Antibiotics should  be administered for bona fide superimposed  acute inflammation (cellulitis/lymphangitis or  erysipelas). Typically, these episodes are  characterized by erythema, pain, high fever  and, less commonly, even septic shock. Mild  skin erythema without systemic signs and  symptoms does not necessarily signify  bacterial infection. If repeated limb “sepsis”  recurs despite optimal CPT, the  administration of a prophylactic antibiotic  (usually broad spectrum) is recommended.  Fungal infection, a common complication of  extremity lymphedema, can be treated with  antimycotic drugs (e.g., flucanozole,  terbinafine). In most instances, washing the  skin using a mild disinfectant followed by  antibiotic-antifungal cream is helpful.

d. Filariasis. To eliminate  microfilariae from the bloodstream in patients  with lymphatic filariasis, the drugs  diethylcarbamazine, Albendazole, or  Ivermectin are recommended. Killing of the  adult nematodes by these drugs  (macrofilaricidal effect) is variable and may  be associated with an inflammatory-immune  response by the host with aggravation of  lymphatic blockage. Short and long-term  efficacy of antibiotics (e.g., penicillin or  doxycyclin) separate from skin hygiene in  patients with lymphatic filariasis to prevent  elephantine trophic changes remains to be  determined.

e. Mesotherapy. The injection of  hyaluronidase or similar agents to loosen the  extracellular matrix is of unclear benefit and  may actually be harmful.

f. Immunological therapy. Efficacy of  boosting immunity by intraarterial injection of  autologous lymphocytes is unclear and needs  independent, reproducible evidence.

g. Diet. No special diet has proved to  be of therapeutic value for uncomplicated  peripheral lymphedema. In an obese patient,  however, reducing caloric intake combined  with a supervised exercise program is of  distinct value in decreasing limb bulk.  Restricted fluid intake is not of demonstrated  benefit for peripheral lymphedema. In chylous  reflux syndromes (e.g., intestinal  lymphangiectasia), a diet as low as possible or  even free in long-chain triglycerides (absorbed  via intestinal lacteals) and high in short and  medium chain triglycerides (absorbed via the  portal vein) is of benefit especially in children.

3. Psychosocial rehabilitation.  Psychosocial support with a quality of  life assessment-improvement program is an  integral component of any lymphedema  treatment.

B. Operative Treatment Operations designed to alleviate  peripheral lymphedema by enhancing lymph  return have not as yet been accepted  worldwide and often require combined  physiotherapy after the procedure to maintain  edema reduction. In selected patients, these  procedures may act as an adjunct to CPT or  be undertaken when CPT has clearly been  unsuccessful. In some specialized centers,  operative treatment within specific guidelines  may be a preferred approach.

1. Surgical Resection The simplest operation is “debulking”,  that is, removal of excess skin and  subcutaneous tissue of the lymphedematous  limb. The major disadvantage is that  superficial skin lymphatic collaterals are  removed or further obliterated. After  aggressive CPT, redundant skin folds may  require excision. Debulking has been  reported to be useful in treatment of  advanced fibrosclerotic lymphedema  (elephantiasis). Caution should be exercised  in removing enlarged lymph nodes or softtissue  masses (e.g., lymphangiomas) in the  affected extremity as lymphedema may  worsen thereafter.  Omental transposition, enteromesenteric  bridge operations, and the implantation of  tubes or threads to promote perilymphatic  spaces (substitute lymphatics) have not  shown long-term value and should be  avoided without further published evidence.  Chylous and other reflux syndromes are  special disorders which may benefit from  CT-guided sclerosis, operative ligation of  visceral dysplastic lymphatics, and/or  lymphatic to venous diversion.

2. Liposuction Liposuction has been reported to  completely reduce non-pitting, non-fibrotic,  extremity lymphedema due to excess fat  deposition (which has not responded to nonoperative  therapy) in both primary and  secondary lymphedema. Just like conservative  treatment, long-term management requires  strict patient compliance with dedicated  wearing of a low-stretch elastic compression  garments. This operation and follow-up  should be performed by an experienced team  of surgeon, nurses and physiotherapists to  obtain optimal outcomes.

3. Microsurgical procedures This operative approach is designed to  augment the rate of return of lymph to the  blood circulation. The surgeon should be  well-schooled in both microsurgery and  lymphology.

a. Reconstructive methods. These  sophisticated techniques involve the use of a  lymphatic collector or an interposition vein  segment to restore lymphatic continuity.  Autologous lymph vessel transplantation  generally has been restricted to unilateral  peripheral lymphedema due to the need for  one healthy leg to harvest the graft.

b. Derivative methods.  Lymphatic-venous and lymphatic-nodal  venous shunt are currently in use and these  procedures are undergoing confirmation of  long-term patency and demonstration of  improved lymphatic transport (i.e., objective  physiologic measurements of long-term  efficacy). Experience with these procedures  over the last 20 years suggests that improved  and more lasting benefit is forthcoming if  performed early in the course of lymphedema.

4. Treatment Assessment In each patient undergoing therapy, an  assessment of limb volume should be made  before, during and after treatment. This  volume can be measured by water  displacement, derived from circumferential  measurements using the truncated cone  formula, by perometer, or by other means. It  is desirable, however, that treatment  outcomes be reported in a standardized  manner in order to compare and contrast the  effectiveness of various treatment protocols.  Additional assessments by imaging  modalities such as lymphangioscintigraphy to  document functional changes in lymphatic  drainage and DEXA or magnetic resonance  imaging to determine volume and tissue  compositional changes would add scientific  rigor to analysis of the different treatment  approaches. Tissue alterations and fluid  changes may also be examined by tonometry  and bio-electrical impedance. Psychosocial  indices and visual analog scales of patient  perceptions are also useful.

C. Molecular Therapy Despite ongoing research, molecular  treatments (e.g. administration of VEGF-C  by various methods) has not yet been  translated to the clinic. While the addition of  growth (or inhibitory) factors is attractive,  the availability of these treatments in the  future is uncertain at this time and should be  conducted in the context of co-morbid  conditions (e.g. cancer and drug regimens).

V. RESEARCH AGENDA While recognizing and encouraging  individual investigators to pursue many  different avenues of investigation, some  general directions can be formulated.  Ongoing epidemiologic studies on the  incidence and prevalence of lymphedema  regionally and worldwide will benefit from the  further development and establishment of  standardized, secure, intercommunicating  database-registries. Assessment of  lymphedema risk and steps for lymphedema  prevention in different groups of at risk  patients need to be determined. Studies might  include research on minimizing or preventing  secondary lymphedema through altered  operative/sampling techniques (e.g., sentinel  node biopsy or precise anatomical knowledge  of derivative pathways), vector control (as  demonstrated in China) and prophylactic  drugs for filariasis, identification of patients  with heritable genetic defects for  lymphangiodysplasia (lymphedema), and use  of massage or compression where lymphatic  drainage is subclinically impaired as  documented by imaging techniques (e.g.,  LAS). Research in molecular lymphology  including lymphatic system genomics and  proteomics should be encouraged. With the  cellular and molecular basis of lymphedemaassociated  syndromes better defined, an array  of specific biologically-based treatments  including modulators of lymphatic growth and  function should become available. Improved  imaging techniques and physiological testing  need to be devised to allow more precise noninvasive  methods to measure lymph flow  dynamics and lymphangion activity.  Continuous improvement in imaging  techniques as well as development of new  technologies (e.g. near infrared) to visualize  the superficial and deep lymphatic system. As  knowledge accrues, the current crude  classification of lymphedema should be  revisited and modified to include a more  encompassing clinical description based on  genetic, anatomic, and functional disability.  Accordingly, treatment, whether by designer  drugs, gene or stem cell therapy, tissue  engineering, physical methods or new  operative approaches, should be directed at  preventing, reversing or ameliorating the  specific lymphatic defect and restoring  function and quality of life.  VI. CONCLUSION Lymphedema may be simple or  complex but should not be neglected.  Accurate diagnosis and effective therapy is  now available, and lymphology itself is now  recognized as an important speciality in  which clinicians are carefully trained in the  intricacies of the lymphatic system, lymph  circulation, and related disorders. The  emerging era of molecular lymphology  should result in improved understanding,  evaluation and treatment in clinical  lymphology.

REFERENCES 1. International Society of Lymphology  Executive Committee. The Diagnosis and  Treatment of Peripheral Lymphedema.  Lymphology 28 (1995), 113-117.  2. Witte MH, CL Witte, and M Bernas for  the Executive Committee. ISL Consensus  Document Revisited: Suggested  Modifications. Lymphology 31 (1998),  138-140.  3. International Congress of Lymphology,  Chennai, India. General Assembly  discussion. ISL Consensus Document  Revisited. September 25, 1999.  4. ISL Executive Committee Meeting, Földi  Klinik, Hinterzarten, Germany.  Discussions on modification of the ISL  Consensus Document. August 30, 2000.  5. Discussions at the XVIII ICL in Genoa,  Italy, September 2001 and over 50 written  and verbal comments submitted to  Executive Committee members. Changes  discussed, modified, deleted, and  confirmed at 2002 ISL Executive  Committee meeting, May 2002, Cordoba,  Argentina.  6. Consensus and dissent on the ISL  Consensus Document on the diagnosis and  11  treatment of peripheral lymphedema (M.  Bernas and M.H. Witte); Remarks (M  Földi); Liposuction and the Concensus  Document (H. Brorson); Adipose tissue in  lymphedema (H. Brorson); Liposuction in  the Concensus Document (S. Slavin); A  search for consensus on staging and  lymphedema (T.J. Ryan); and Guidelines of  the Societá Italiana Di Linfangiologia:  Excerpted sections (C. Campisi, S.  Michelini, F. Boccardo). Lymphology 37  (2004), 165-184.  7. Changes discussed, modified, deleted, and  confirmed at 2008 ISL Executive  Committee meeting, June 2008, Naples,  Italy.

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1 Comment

  1. by Jo Bershenyi on 14 November 2011  03:03 Reply

    I am trying to find a copy of the article published by W. Luedermann, G. Kuether, D. Berens von Rautenfeld: regarding Manual Lymph Drainage and its influence on intercranial pressure in severe head injury Published in the proceedings of the XIX International Congress of Lymphology, Freiburg, Germany 2003.
    If possible can you help me with how to gain access to this article?
    Many Thanks,
    Jo Bershenyi
    Vodder School International Certified MLD CDT Therapist

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