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ISL
Consensus Documents on the Diagnosis and Treatment of Peripheral
Lymphedema
The document attempts to amalgamate the broad spectrum of protocols
advocated worldwide for the diagnosis and treatment of peripheral
lymphedema into a coordinated proclamation representing a "Consensus" of
the international community. The document is not meant to override
individual clinical considerations for problematic patients nor
to stifle progress. It is also not meant to be a legal formulation
from which variations define medical malpractice. The Society understands
that in some clinics the method of treatment derives from national
standards while in others Access to medical equipment and supplies
is limited and therefore the suggested treatments are impractical.
We continue to struggle to keep the document concise while balancing
the need for depth and details. With these considerations in mind,
we believe that this version of the Consensus represents the best
judgment of the ISL membership on how to approach patients with
peripheral lymphedema as of 2003. We anticipate that the document
will and should be challenged, debated in the pages of Lymphology
(e.g., as Letters to the Editor), and ideally become a continued
focal point for robust discussion at local, national and international
conferences in lymphology and related disciplines. We further anticipate
as experience evolves and new ideas and technologies emerge that
this "living document" will undergo periodic revision
and refinement.
Lymphedema is an external (or internal) manifestation of lymphatic
system insufficiency and deranged lymph transport. It may be an
isolated phenomenon or associated with a multitude of other disabling
local sequelae or even life-threatening systemic syndromes. In
its purest form, the central disturbance is a low output failure
of the lymphvascular system, that is, overall lymphatic transport
is reduced. This derangement arises either from congenital lymphatic
dysplasia (primary lymphedema) or anatomical obliteration, such
as after radical operative dissection (e g., axillary or retroperitoneal
nodal sampling), irradiation, or from repeated lymphangitis with
lymphangiosclerosis (secondary lymphedema) or as a consequence
of functional deficiency (e.g., lymphangiospasm, paralysis, and
valvular insufficiency) (primary or secondary lymphedema). The
common denominator, nonetheless, is that lymphatic transport has
fallen below the capacity needed to handle the presented load of
microvascular filtrate including plasma protein and cells that
normally leak from the bloodstream into the interstitium. Swelling
is produced by accumulation in the extracellular space of excess
water, filtered plasma proteins, extravascular blood cells and
parenchymal cell products. This process culminates in proliferation
of parenchymal and stromal elements with excessive deposition of
ground matrix substances. High output failure of the lymph circulation,
on the other hand, occurs when a normal or increased transport
capacity of intact lymphatics is overwhelmed by an excessive burden
of blood capillary filtrate. Examples include hepatic cirrhosis
(ascites), nephrotic syndrome (anasarca), and deep venous insufficiency
of the leg (peripheral edema). Although the final pathway is the
manifestation of tissue edema whenever lymph formation exceeds
lymph absorption, the latter entities should properly be distinguished
from lymphedema, which is characterized by decreased lymphatic
transport. In some syndromes where high output lymphatic transport
failure is longstanding, a gradual functional deterioration of
the draining lymphatics may supervene and thereby reduce overall
transport capacity. A reduced lymphatic circulatory capacity then
develops in the face of increased blood capillary filtration. Examples
include recurring infection, thermal burns, and repeated allergic
reactions. These latter conditions are associated with “safety
valve insufficiency” of the lymphatic system and can be considered
a mixed form of edema/lymphedema and as such are particularly troublesome
to treat.
Peripheral lymphedema associated with chylous and non-chylous
reflux syndromes is an infrequent but complex condition that requires
specific diagnostic measures and treatment methods.
In the treatment of "classical" lymphedema of the limbs
(that is, peripheral
lymphedema), improvement in swelling can usually be achieved by
non-operative therapy. Because lymphedema is a chronic, generally
incurable ailment, it requires, as do other chronic disorders,
lifelong care and attention along with psychosocial support. The
continued need for therapy does not mean a priori that treatment
is unsatisfactory, although often it is less than ideal. For example,
patients with diabetes mellitus continue to need drugs (insulin)
or special diet (low calorie, low sugar) in order to maintain metabolic
homeostasis. Similarly, patients with chronic venous insufficiency
require lifelong external compression therapy to minimize edema,
lipodermatosclerosis and skin ulceration. The compliance and commitment
of the patient is also essential to an improved outcome. For example,
in a patient with diabetes, poor compliance can result in weight
loss, polyuria, and even coma and, long-term, also blindness, renal
failure, and stroke. With chronic venous insufficiency, poor patient
cooperation may be associated with progressive skin ulceration,
hyperpigmentation, and other trophic changes in the lower leg.
Similarly, failure to control lymphedema may lead to repeated infections
(cellulitis/lymphangitis), progressive elephantine trophic changes
in the skin, sometimes crippling invalidism and on rare occasions,
the development of a highly lethal angiosarcoma (Stewart-Treves
syndrome).
Whereas most ISL members generally rely on a three stage scale
for classification of a lymphedematous limb, an increasing number
recognize Stage 0 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)
and subsides with limb elevation. Pitting may occur. 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. Within each Stage,
severity based on volume difference can be assessed as minimal
(<20% increase) in limb volume, moderate (20-40% increase),
or severe (>40% increase).
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.
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).
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 semi-quantitative 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), 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 and
terminal lymphatics and accordingly have limited clinical usefulness.
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 lymphedema-distichiasis (FOXC2) and some forms of Milroy
disease (VEGFR-3). 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.
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.
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 is also helpful to virtually all patients undergoing
treatment.
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, 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
highly trained and educated 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, velcro-assisted, quilted,
etc.) may relieve some patients of the bandaging burden and perhaps
facilitate compliance with the full treatment program. Some clinics
find that patient self-care and risk reduction strategies help
maintain edema reduction.
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.
-
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
a combination of heat, skin care, and external compression has
been advocated by some practitioners
in Europe and Asia, the role and value of thermotherapy in the
management of lymphedema remain unclear.
-
f. Elevation. Simple elevation of a lymphedematous limb often
reduces swelling particularly in the early stage 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 occasionally useful during
the initial treatment phase of CPT. 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 are thought 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 (and related rutin and
bioflavonoid compounds) 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.
-
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.
-
f. Immunological therapy.
Efficacy of boosting immunity by intraarterial injection of autologous
lymphocytes is unclear.
-
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. In chylous reflux syndromes
(e.g., intestinal lymphangiectasia), a diet low 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. 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 is probably useful in
treatment of advanced fibrosclerotic lymphedema (elephantiasis).
Caution should be exercised in removing enlarged lymph nodes or
soft-tissue 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. 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.
Liposuction has been reported to alleviate non-pitting, non-fibrotic
upper extremity lymphedema due to excess fat deposition (which
has not responded to non-operative therapy) as, for example, after
treatment of breast cancer. At this time, results are encouraging
but long-term management requires strict patient compliance with
dedicated wearing of a low-stretch elastic compression sleeve.
This operation should be performed by an experienced team of surgeon,
nurses and physiotherapists to obtain optimal outcomes.
2. 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. Although lympho-venous and lympho-nodal
venous shunt are promising, these procedures still require 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.
3. 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.
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 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 lymphedema-associated 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 non-invasive methods to measure lymph flow
dynamics and lymphangion activity. 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.
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 specialty
in which clinicians are carefully trained in the intricacies of
the lymphatic system, lymph circulation and its related disorders.
The emerging era of molecular lymphology should result in improved
understanding, evaluation and treatment in clinical lymphology.
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.
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