Jan 2012

Ostergaard PSimpson MAMendola AVasudevan PConnell FCvan Impel AMoore ATLoeys BLGhalamkarpour A,Onoufriadis AMartinez-Corral IDevery SLeroy JGvan Laer LSinger ABialer MGMcEntagart MQuarrell OBrice G,Trembath RCSchulte-Merker SMakinen TVikkula MMortimer PSMansour SJeffery S.


Medical Genetics Unit, Biomedical Sciences, St. George’s University of London, London SW17 0RE, UK.


We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated withlymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.

Cell Press

Posted by: patoconnor | February 9, 2012

Lymphangiogenesis: A Potential New Therapy for Lymphedema?

Lymphangiogenesis: A Potential New Therapy for Lymphedema?

Jan 2012


Stanford Cardiovascular Institute, Stanford, CA.


At the level of the capillaries, the systemic circulation loses about 2-4 liters of fluid and about 100g of protein into the interstitium daily. This ultrafiltrate of the systemic capillaries is returned to the circulatory system by the lymphatics. The lymphatic vasculature is highly specialized to perform this service, beginning with the blind-ended lymphatic capillaries. These vessels are highly permeable to protein, fluid and even cells, due to fenestrations in their basement membrane, and discontinuous button-like junctions rather than tight intercellular junctions as observed in the systemic capillaries(1). The lymphatic capillaries merge into collectors and larger lymphatic conduits that are invested with vascular smooth muscle (capable of contracting and propelling lymph forward) and valves for unidirectional flow. These conduits merge at lymph nodes, delivering antigens to the immune cells and serving as an early warning system of pathogen invasion. The lymph nodes drain into conduits that ultimately merge into the thoracic duct which empties into the left subclavian vein.

AHA Journal


Posted by: patoconnor | October 28, 2009

Understanding the Lymph System

Understanding the Lymph System

I thought it would be helpful for readers to understand the lymph system, the anatomy, what it does, and how it helps with immunity.

Listed below are information pages that should be quite helpful and each page has many additional links for more a more in depth study.

Anatomy of the Lymph System

Lymphatic System Functions

Lymphatic System and Immunity

Pathology of the Lymph Nodes and Lymphoma

Lymph Nodes

Lymph Fluid

Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer.

Aug 2009

Bennett Britton TM, Wallace SM, Wilkinson IB, Mortimer PS, Peters AM, Purushotham AD.
Department of Research Oncology, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, Bermondsey Wing, Guy’s Hospital, London, UK.

email: A. D. Purushotham (amy.byrtus@kcl.ac.uk)

BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet.

RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema.

CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery. Copyright 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Wiley InterScience

Posted by: patoconnor | September 22, 2009

Fibrosis is a key inhibitor of lymphatic regeneration.

Fibrosis is a key inhibitor of lymphatic regeneration.

Aug 2009

Avraham T, Clavin NW, Daluvoy SV, Fernandez J, Soares MA, Cordeiro AP, Mehrara BJ.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

BACKGROUND: Lymphedema is a common debilitating sequela of lymph node dissection. Although numerous clinical studies suggest that factors that lead to fibrosis are associated with the development of lymphedema, this relationship has not been proven. The purpose of these experiments was therefore to evaluate lymphatic regeneration in the setting of variable soft-tissue fibrosis.

METHODS: A section of mouse tail skin including the capillary and collecting lymphatics was excised. Experimental animals (n = 20) were treated with topical collagen type I gel and a moist dressing, whereas control animals (n = 20) underwent excision followed by moist dressing alone. Fibrosis, acute lymphedema, lymphatic function, gene expression, lymphatic endothelial cell proliferation, and lymphatic fibrosis were evaluated at various time points.

RESULTS: Collagen gel treatment significantly decreased fibrosis, with an attendant decrease in acute lymphedema and improved lymphatic function. Tails treated with collagen gel demonstrated greater numbers of lymphatic vessels, more normal lymphatic architecture, and more proliferating lymphatic endothelial cells. These findings appeared to be independent of vascular endothelial growth factor C expression. Decreased fibrosis was associated with a significant decrease in the expression of extracellular matrix components. Finally, decreased soft-tissue fibrosis was associated with a significant decrease in lymphatic fibrosis as evidenced by the number of lymphatic endothelial cells that coexpressed lymphatic and fibroblast markers.

CONCLUSIONS: Soft-tissue fibrosis is associated with impairment in lymphatic regeneration and lymphatic function. These defects occur as a consequence of impaired lymphatic endothelial cell proliferation, abnormal lymphatic microarchitecture, and lymphatic fibrosis. Inhibition of fibrosis using a simple topical dressing can markedly accelerate lymphatic repair and promote regeneration of normal capillary lymphatics.
Fibrosis is a key inhibitor of lymphatic regeneration.

Plastic and Reconstructive Surgery

Primary lymphoedema at an unusual location triggered by nephrotic syndrome.

Ann Acad Med Singapore. 2009 Jul

Tabel Y, Mungan I, Sigirci A, Gungor S.
Department of Paediatrics, Faculty of Medicine, Inonu University, Malatya, Turkey. yilmaztabel@yahoo.com

INTRODUCTION: Lymphoedema results from impaired lymphatic transport leading to the pathologic accumulation of protein-rich lymphatic fluid in the interstitial space, most commonly in the extremities. Primary lymphoedema, a developmental abnormality of the lymphatic system, may become evident later in life when a triggering event exceeds the capacity of normal lymphatic flow.

CLINICAL PICTURE: We present a 3-year-old nephrotic syndrome patient with an unusual localisation for primary lymphoedema.

TREATMENT AND OUTCOME: The patient was treated with conservative approach and she was cured. CONCLUSION: In this particular case, lymphoedema developed at an unusual localisation, which has not been recorded before.

Full length PDF Article

For additional information on Nephrotic Syndrome and how it might relate to lymphedema please see:

Lymphedema and Nephrotic Syndrome

Posted by: patoconnor | September 17, 2009

Adverse effects of compression in treatment of limb lymphedema

I am not a particular fan of lymphedema patients using off the shelf compression garments as in my personal opinion they can often present tremendous complications if they do not fit properly, if there is rubbing of the materials on the skin, the bunching often accompanying a compression sleeve or garment and various other problems.

This is a good little article on the possible damages that can occur in using “improper” compression in the treatment of lymphedema.

An excellent reminder too how important it is for us to work with our therapist in designing the correct maintenance program and system for each of us individually, based on our particular situation.

Pat O’Conrnor
September 16, 2009

Adverse effects of compression in treatment of limb lymphedema


Limb lymphedema, whether primary or secondary, is a chronic disease. Compression is the cornerstone of therapy and includes multilayer low-stretch bandages and elastic garments. Compression is usually well-tolerated. The aim of our study was to identify all the different types of adverse effects of compression.

Materials and methods

Since January 2005, we have recorded all adverse events occurring in outpatients and inpatients consulting in a single lymphology department, spontaneously reported by patient during consultations or physical examinations, and noted the type of compression material used.


Adverse effects were secondary to poor choice of therapeutic material, excessive pressure or contact dermatitis. For the arms, an elastic garment stopping at the wrist can be responsible for lymphedema of the hand and fingers. Rubbing of sleeve seams may cause pain and even ulcers between the thumb and forefinger. Open-toed elastic stockings may exacerbate digital lymphedema, leading to the formation of oozing lymph vesicles. Hyperpressure may cause severe pain localized to the first and fifth toes, overlapping toes, interdigital corns and/or ingrown toenails. Silicone-banded soft-fit elastic garments may cause painful phlyctena, urticaria or eczematiform lesions. Elastic bandages may induce pain or purpuric lesions.


Compression can be responsible for adverse effects, sometimes severe, requiring treatment change or withdrawal. Further studies are needed to precisely determine their frequency to improve prescriptions and currently available products.

EM Consulte

Compression therapy in breast cancer-related lymphedema: A randomized, controlled comparative study of relation between volume and interface pressure changes.

J Vasc Surg. 2009 May

Damstra RJ, Partsch H.
Department of Dermatology, Phlebology and Lymphology, Nij Smellinghe Hospital, Drachten, The Netherlands. r.damstra@nijsmellinghe.nl

OBJECTIVE: Short stretch bandages are very effective in the initial management of arm lymphedema. However, no studies to date have measured the pressure required to achieve specific amounts of volume reduction. The purpose of this study was to determine whether there is a difference between low and high-pressure bandaging in terms of therapeutically intended volume reduction of the compressed arm.

METHODS: Experimental, randomized and comparative study with two study-groups consisting of high and low initial interface pressure bandages. Thirty-six hospitalized patients in Nij Smellinghe hospital suffering from moderate to severe unilateral breast cancer-related lymphedema not responsive to outpatient treatment were included. Bilateral arm volume was measured by inverse water volumetry before, after two hours and after 24 hours of bandaging. The amount of edema was calculated by subtracting the volume of the diseased arm from that of the contralateral side. Sub-bandage pressure was measured after bandage application and two hours later. Bandages were then re-applied and the pressure was measured again. Twenty-four hours later, the pressure measurement was repeated and bandages were removed for final volumetry. Patients were randomized into two groups: group A received low pressure bandages (20-30 mm Hg) and group B received high pressure bandages (44-58 mm Hg). The main outcome measures were reduction of arm volume and edema volume in the affected arm in both study groups. Secondary outcome parameters were changes in sub-bandage pressure and patient comfort.

RESULTS: Median arm volume reduction after two and 24 hours was 104.5 mL (95% confidence interval [CI], 51.2-184.2) (-2.5%) (P < .0001) and 217 mL (95% CI, 143.9-280.2) (-5.2%) (P < .01) for group A and 56.5 mL (95% CI, -2.7-123.1) (n.s.) and 167.5 mL (95% CI, 105.2-316.1) (-4.2%) (P < .01) for group B, respectively. There was no statistically significant difference between the volume changes in group A and group B. After 24 hours, edema decreased by median percentage of 9.2% in group A and 4.8% in group B (n.s.). Bandages in group A were better tolerated. The sub-bandage pressure drop in the first two hours was between 41% and 48% in both treatment groups at both measuring sites. After 24 hours, the pressure drop was between 55% and 63%. No proximal swelling above the bandage was observed.

CONCLUSIONS: Inelastic, multi-layer, multi-component compression bandages with lower pressure (20-30 mm Hg) are better tolerated and achieve the same amount of arm volume reduction as bandages applied with higher pressure (44-58 mm Hg) in the first 24 hours.


Relationship between ultrasound imaging and traditional Chinese medicine syndrome in limb lymphedema

Zhong Xi Yi Jie He Xue Bao. 2009 May

Liu M, Zhang Y, Song FC, Cheng ZX.
Department of Peripheral Vascular Surgery, Affiliated Hospital, Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong Province, China; E-mail: liuming404@sina.com.

Objective: To study the correlation between traditional Chinese medicine (TCM) syndrome type and the ultrasound imaging changes in patients with limb lymphedema, and to provide evidence for TCM syndrome differentiation. Methods: Syndrome typing was done and ultrasonography was performed in 107 patients with limb lymphedema. The thickenings of derma, hypodermis and deep-fascia were measured. The ultrasound echo intensity and the morphology of the hypodermis were classified into five degrees according to the ultrasonogram. The ultrasound indexes in the limb lymphedema patients with different syndromes were compared, and the relationship between TCM syndromes and the ultrasound indexes was analyzed. Results: There were specific ultrasound image features in different TCM syndromes of limb lymphedema. The thickenings of derma, hypodermis and deep-fascia in the limb lymphedema patients with downward migration of damp-heat or phlegm stagnation and blood stasis were more significant than those in the patients with collateral obstruction due to cold-dampness (P<0.05, P<0.01). The thickenings of derma and hypodermis in the patients with phlegm stagnation and blood stasis were obviously more severe than those in the patients with downward migration of damp-heat (P<0.01). The maximum and minimum ultrasound echo intensities of hypodermis were in phlegm stagnation and blood stasis and downward migration of damp-heat respectively (P<0.05), and there was a significant difference in the hypodermal morphology among the three syndrome types (P<0.05). The most obvious structure disturbance was observed in the patients with phlegm stagnation and blood stasis syndrome. Conclusion: TCM syndrome type of limb lymphedema is related to ultrasound image changes. The imaging data can be regarded as new objective indexes for TCM syndrome defferentiation, and it has an important value for diagnosis and treatment of limb lymphedema.


http://tbn0.google.com/images?q=tbn:CtoEFk3_7jOsAM:http://florey.biosci.uq.edu.au/BIA/images/sfbsmall.gifQuantitative bioimpedance spectroscopy for the assessment of lymphoedema.
Breast Cancer Res Treat. 2008 Dec 11

Ward LC, Czerniec S, Kilbreath SL.
School of Molecular and Microbial Sciences, University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia, l.ward@uq.edu.au.

The aim was to make bioimpedance spectroscopy (BIS) quantitative for assessment of lymphoedema. Apparent resistivity coefficients were determined for the intra- and extracellular water of arms in a control cohort of women (n = 66). These coefficients were used to predict water volumes in the arms of women with lymphoedema (n = 23) and a separate control group without lymphoedema (n = 13) and to compare these with total arm size measured by perometry. Total arm volume was highly correlated (r = 0.80-0.90) with arm fluid volumes predicted by BIS and the proportional increase in arm size predicted by BIS was not significantly different to that measured by perometry. BIS predicted that the increased volume in the women with lymphoedema was predominantly (60%) due to increase in extracellular fluid. BIS is capable of quantifying the volume increase in limb size seen in lymphoedema.


Body fluid volumes measurements by impedance: A review of bioimpedance spectroscopy (BIS) and bioimpedance analysis (BIA) methods.

Med Eng Phys. 2008 Dec

Jaffrin MY, Morel H.
Department of Biological Engineering, Technological University of Compiegne, 60205 Compiegne Cedex, France.

This paper reviews various bioimpedance methods permitting to measure non-invasively, extracellular, intracellular and total body water (TBW) and compares BIA methods based on empirical equations of the wrist-ankle resistance or impedance at 50kHz, height and weight with BIS methods which rely on an electrical model of tissues and resistances measured at zero and infinite frequencies. In order to compare these methods, impedance measurements were made with a multifrequency Xitron 4200 impedancemeter on 57 healthy subjects which had undergone simultaneously a Dual X-ray absorptiometry examination (DXA), in order to estimate their TBW from their fat-free-mass. Extracellular (ECW) and TBW volumes were calculated for these subjects using the original BIS method and modifications of Matthie [Matthie JR. Second generation mixture theory equation for estimating intracellular water using bioimpedance spectroscopy. J Appl Physiol 2005;99:780-1], Jaffrin et al. [Jaffrin MY, Fenech M, Moreno MV, Kieffer R. Total body water measurement by a modification of the bioimpédance spectroscopy method. Med Bio Eng Comput 2006;44:873-82], Moissl et al. [Moissl UM, Wabel P, Chamney PW, Bosaeus I, Levin NW, et al. Body fluid volume determination via body composition spectroscopy in health and disease. Physiol Meas 2006;27:921-33] and their TBW resistivities were compared and discussed. ECW volumes were calculated by BIA methods of Sergi et al. [Sergi G, Bussolotto M, Perini P, Calliari I, et al. Accuracy of bioelectrical bioimpedance analysis for the assessment of extracellular space in healthy subjects and in fluid retention states. Ann Nutr Metab 1994;38(3):158-65] and Hannan et al. [Hannan WJ, Cowen SJ, Fearon KC, Plester CE, Falconer JS, Richardson RA. Evaluation of multi-frequency bio-impedance analysis for the assessment of extracellular and total body water in surgical patients. Clin Sci 1994;86:479-85] and TBW volumes by BIA methods of Kushner and Schoeller [Kushner RF, Schoeller DA. Estimation of total body water by bioelectrical impedance analysis. Am J Clin Nutr 1986;44(3):417-24], Lukaski et al. [Lukaski HC, Bolonchuk WW. Estimation of body fluid volumes using tetrapolar bioelectrical impedance measurements. Aviat Space Environ Med 1988;59:1163-9], Hannan et al. [Hannan WJ, Cowen SJ, Fearon KC, Plester CE, Falconer JS, Richardson RA. Evaluation of multi-frequency bio-impedance analysis for the assessment of extracellular and total body water in surgical patients. Clinical Science 1994;86:479-85], Deurenberg et al. [Deurenberg P, van der Koy K, Leenen R, Westrate JA, Seidell JC. Sex and age specific prediction formulas for estimating body composition from bioelectric impedance: a cross validation study. Int J Obesity 1991;15:17-25] These volumes were compared against those given by BIS method and, in the case of TBW, with those by DXA. For ECW, a good agreement was found between various BIS methods and that of Sergi while Hannan’s values were higher. Both Matthie’s and Moissl’s methods gave mean TBW resistivities and volumes lower than those of Jaffrin’s and DXA methods. Kushner et al. method gave values of TBW not significantly different from those of Jaffrin et al. and DXA, as Hannan’s method in men, but Lukaski and Deurenberg methods led to an underestimation.


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