I. Flashlights of Lymphology

Abstract

Manuel Cornely¹, Jean-Paul Belgrado², Christian Ure³, Andreas Wittlinger⁴, Christina Buder⁴, Walter Gruenwald³, Christine Hemmann-Moll⁵, Ljiljana Jelica⁶, Elisabeth Kleinpaul⁷, Cornelia Kuegele³, Tanja Lenk-Killinger⁴, Katrin Maennel-Emra⁸, Johannes Poppmeier³, Susan Schlums⁹, Bettina Sommer¹⁰, Eva-Maria Streicher¹¹, Erich Brenner¹², Zsombor Ocskay^{13, 14}, László Bálint¹³, Carolin Christ¹³, Mark L. Kahn¹⁵, Zoltán Jakus¹³, Bernard Ho¹⁶, Walter Doeller¹⁷, Chieh-Han John Tzou^{18, 19, 20}

¹LY.SEARCH gGmbH, Duesseldorf, Germany

²Lymphology Research and Rehabilitation Unit, Université libre de Bruxelles, Brussels, Belgium

³Wolfsberg Lymphology Clinic at the LKH Wolfsberg, Austria

⁴Wittlinger Therapiezentrum GmbH, Walchsee, Austria

⁵Master Bandagist, Bad Rappenau, Germany

⁶Institute for Physical Medicine and Rehabilitation, Mein Hanusch-Krankenhaus, Vienna, Austria

⁷Massage Therapist, MLD-Therapist, Vienna, Austria

⁸Physiotherapy Maennel-Emra, Neumarkt, Germany

⁹Lymphgesundheitszentrum (LGZ) Ried im Innkreis, Austria

¹⁰MissNutri e.U., Vienna, Austria

¹¹Physiotherapy practice, Lymph Centre Großhadern, Munich, Germany

¹²Institute for Clinical-Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria

¹³Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary

¹⁴Department of Vascular and Endovascular Surgery, Semmelweis University School of Medicine, Budapest, Hungary

¹⁵Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA

¹⁶St George's University Hospitals NHS Foundation Trust, London, UK

¹⁷Wolfsberg Lymph Clinic, LKH Wolfsberg, Wolfsberg, Austria

¹⁸Department of Plastic and Reconstructive Surgery, Department of Surgery, Hospital of the Divine Savior, Vienna, Austria

¹⁹Faculty of Medicine, Sigmund Freud University Vienna, Austria

²⁰TZOU MEDICAL., Lymphology Center, Vienna, Austria

The opening of the 5^th International Lymphology Symposium from November 21^st-23^rd, 2024 in Vienna will focus on the latest insights on the organisation of oedema in tissue, in particular in the lower extremity the findings on the ageing of the lymphatic vascular system and the possible influence on these processes, embedded in the evolutionary developments of lymphedema treatment, which has received considerably more attention from self-help groups. The latter leads to an optimisation of therapies and greater awareness of Lymphangiology.

Before the first lecture block, Jean-Paul Belgrado will demonstrate ‘ICG-assisted decision-making and visualisation of lymphoedema’ and ‘Pressure profile under various compression systems real-time display’ in two workshops. In the third workshop before the first session, Christian Ure and Andreas Wittlinger will give tips and tricks for conservative treatments in a workshop entitled ‘Physical (self-)therapy for oedema patients’.

In this first lecture block, the focus will be placed directly on the lymphatic vascular system and its function as a guarantor for maintaining fluid balance, draining interstitial fluid, and breaking down the proteoglycans and glucosamines formed. Erich Brenner explains this masterpiece of nature explicitly using the vascular system of the legs. He emphasises that the arterial system supplies oxygen, nutrients, signalling molecules and free cells to the tissue, while the venous and lymphatic vessels are responsible for removing “waste products” and transporting them back out of the interstitium. “All cells in the body swim in a fluid that surrounds them”. This interstitial fluid can only be called lymph once it has entered the initial lymphatic vessels. Disruptions to this transport lead to oedema and the associated clinical pictures.

However, such disorders can also develop biologically as age-related changes. The lymphatic system also ages, resulting in immune system impairment. The molecular mechanisms of these age-related changes are still the subject of research. Zsombor Ocskay showed that the presence of lymphatic vessels decreases with age and explains this using the induced detection of CCB1E in animal experiments as an example. This may open up a way of therapeutically influencing the health of the lymphatic system by intervening in the mechanisms induced by CCB1E.

Bernard Ho explains the considerable progress in treating lymphedema. He covers everything from historical developments to modern therapeutic strategies. Of course, compression techniques play an essential role, but the introduction of manual lymphatic drainage in the 1930s and its systematic dissemination by Johannes Asdonk's schools was a quantum leap. The modern surgical procedures of the 21st century, the diagnostic developments in the classification of primary lymphedema, the development of specific imaging techniques and genetic studies show that the dynamic development of lipoedema and lymphedema treatment is distinguished by its futuristic character.

Walter Doeller focuses on the development of lymphedema therapy in Austria. He places lymphedema therapy in the context of worldwide scientific developments in lymphology. Unfortunately, lymphangiology, i.e. the study of the lymphatic vessels, is neglected in university education. Lymphology is most likely to be taught and researched in connection with immunology. In addition to the academisation of therapists, affected individuals and self-help groups are joining forces with doctors, scientists, therapists and patients to open up a new perspective on conservative and surgical therapy. The commitment of self-help groups of patients complements the significant advances in diagnostics and therapy of the last century. However, there is still a lack of scientific studies (RCTs) in the therapeutic field of lymphology.

Number: 1

Workshop: ICG-guided decisions and visualization of lymphedema

Jean-Paul Belgrado

Lymphology Research and Rehabilitation Unit, Université libre de Bruxelles, Belgium

ORCID Number: 0000-0001-6774-1725

The lymphatic system is invisible to the human eye because of its transparency. After an intradermal injection of highly diluted ICG, the superficial lymphatic system draining the injected area appears visible, thanks to a dedicated infrared camera.

The workshop aims to show typical steps of ICG lymphography exam in real time, on two volunteers, one affected with lymphedema and one without. Based on observable evidence, we will show and discuss: the diffusion of the dye from the injection point, the lymph progression in normal and pathological conditions, the contingencies of lymphangion valves and other characteristics of updated knowledge of lymphatic physiology and physiopathology.

Believe your eyes: In this workshop you will see the superficial lymphatics and the lymph flow in real time in normal and pathological conditions. Invisible lymphatics become visible, thanks to Indocyanine green (ICG) lymphography. It can be used in the diagnosis of lymphedema and for the planning of surgical therapy and also for the physical treatment.

Topics

ICG lymphography provides specific dynamic images to help diagnose lymphedema.

Dynamic testing of the physiology of the superficial lymphatic collectors

Clinical cases of primary and secondary lymphedema were observed in ICG lymphography.

Number: 2

Workshop: Pressure profile under different compression systems – Illustration in real time

Jean-Paul Belgrado

Lymphology Research and Rehabilitation Unit, Université libre de Bruxelles, Belgium

ORCID Number: 0000-0001-6774-1725

Today's technology provides reliable measuring instruments that enable us to record pressure profiles in real time on surfaces with constantly- changing temperature.

One of these surfaces can be the largest organ of the human body, the skin. Pressure sensors under various compression systems, such as elastic compression stockings, multi-component bandages of different materials, or static and dynamic wraps, wirelessly evaluate and communicate pressure data in real time. This technology enables the analysis of various pressure profiles in static and dynamic positions, such as standing, lying down or during activities, e.g. walking, running, cycling, etc.

Measurement qualities of these instruments will be evaluated and discussed, followed by live demonstrations on volunteer participants, whose limbs will be analyzed under various static and dynamic compression systems. Exciting real time observations of pressure profiles during simple activities such as walking, running and cycling will be the basis for further dialogue in this workshop.

Number: 3

Workshop: Physical (self) therapy for edema patients

Christian Ure¹, Andreas Wittlinger², Christina Buder², Walter Gruenwald¹, Christine Hemmann-Moll³, Ljiljana Jelica⁴, Elisabeth Kleinpaul⁵, Cornelia Kuegele¹, Tanja Lenk-Killinger², Katrin Maennel-Emra⁶, Johannes Poppmeier¹, Susan Schlums⁷, Bettina Sommer⁸, Eva-Maria Streicher⁹

¹Wolfsberg Lymphology Clinic at the LKH Wolfsberg, Austria

² Wittlinger Therapiezentrum GmbH, Walchsee, Austria

³Master Bandagist, Bad Rappenau, Germany

⁴Institute for Physical Medicine and Rehabilitation, Mein Hanusch-Krankenhaus, Vienna, Austria

⁵Massage Therapist, MLD-Therapist, Vienna, Austria

⁶Physiotherapy Maennel-Emra, Neumarkt, Germany

⁷Lymphgesundheitszentrum (LGZ) Ried im Innkreis, Austria

⁸MissNutri e.U., Vienna, Austria

⁹Physiotherapy practice, Lymph Centre Großhadern, Munich, Germany

As part of this workshop, experts will provide insight into the various therapy options, some of which are also learned by the patient and can be continued independently in the sense of self-management, such as breathing techniques, bandaging, skin care, manual lymphatic drainage, intermittent pneumatic compression,

Possibilities in compression garments and others.

One focus is also on complicated care situations for genital and head lymphedema.

For example, many cancer patients often develop complicated lymphedema that is not easy to treat postoperatively, e.g. after abdominal carcinoma, after prostate cancer, but also after tumors in the head area such as mouth/jaw or ENT tumors.

Radiotherapy and chemotherapy can also intensify the blockage of lymphatic drainage. As a result, lymphedema can develop or increase even years after cancer treatment has been completed.

In the case of tumors in the head/neck area, the removal of numerous important lymphatic drainage pathways is unavoidable, as a result of which massive lymphedema often develops in the facial area, which also affects the tongue and oral mucosa. Although improvements have been achieved through new surgical techniques, more effective handling of recurrences and consequent radiation-related damage, as well as through rehabilitative speech therapy measures, adequate lymphological care is still a major challenge.

In the case of abdominal cancer, a distinction is made between uterine cancer, ovarian cancer, cervical cancer and cancer of the external genitals, depending on the frequency of occurrence in women. Prostate cancer is the most common cancer in men in Western industrialized countries.

Depending on the stage of the tumour, this diagnosis requires radical surgery and radical removal of the lymph nodes of the pelvis along the large pelvic vessels. This and accompanying radiotherapy as well as chemotherapy lead to leg lymphedema (approx. 25% of cases) by blocking the lymphatic drainage, but sometimes also to genital lymphedema (labia, mons pubis and, in men, penis, foreskin and scrotum) and to lymphedema in the adjacent lower torso quadrant. In these cases, too, adequate lymphological care is a major challenge.

Lymphedema causes both a mechanical disability in the leg and, especially genital lymphedema, a severe impairment of the quality of life and a psychological burden that should not be underestimated. In addition, lymphatic congestion in the legs and genitals weakens the local immune system and thus makes it susceptible to inflammation, especially erysipelas. However, every infection inevitably aggravates lymphedema. Therefore, the avoidance of potential germ entry ports is also a central challenge in the lymphological care of these patients.

Of course, the workshop also offers a lot of freedom for your questions and for a lively exchange of experiences through practical demonstrations.

Number: 4

A masterpiece of nature: The vascular system of the legs

Erich Brenner

Institute for Clinical and Functional Anatomy, Medical University of Innsbruck, Austria

The central function of this system is to deliver oxygen, nutrients, signaling molecules, and ‘free’ cells to the tissues. Additionally, the system plays a crucial role in removing “waste” products through venous and lymphatic pathways. Whereas oxygen is transported via erythrocytes, plasma facilitates fluid circulation. The drainage from tissues is managed through the interstitium and lymphatic vessels.

The vascular system is a dynamic and adaptive network, which is not fixed but constantly adjusts to physiological demands. Starling's equation, a critical principle governing microvascular fluid exchange, best summarizes this exchange between capillaries and interstitium. It explains how hydrostatic pressure, colloid osmotic pressure, and vessel wall permeability dictate fluid movement between capillaries and tissues.

There is almost no free fluid within the interstitium, but most of it is reversibly bound to gel-forming proteoglycans and glycosaminoglycans. These substances vary in size and, therefore, can adapt to the amount of fluid within the interstitium.

The lymphatic system is critical in maintaining fluid balance, focusing on interstitial fluid drainage and degradation of gel-formers. It shows structural adaptations, such as anchoring filaments and valves within the lymphatic vessels, as essential mechanisms for facilitating centripetal fluid transport and preventing backflow.

The development and variation of arterial, venous, and lymphatic anatomy express the status of a dynamic and adaptive network.

Conclusion: The leg's vascular structures are highly efficient and adaptive. They are essential in maintaining homeostasis and supporting the metabolic needs of the tissues in the lower extremities.

Number: 5

Age-dependent changes in the lymphatic system

Zsombor Ocskay^{1, 3}, László Bálint¹, Carolin Christ¹, Mark L. Kahn², Zoltán Jakus¹

¹Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary

²Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA

³Department of Vascular and Endovascular Surgery, Semmelweis University School of Medicine, Budapest, Hungary

Introduction/Background: The general functions of lymphatic vessels, including fluid balance and immune surveillance, are well recognized. Recent studies have suggested that the lymphatic system progressively regresses with age, contributing to impaired immunity and increased risk of age-related diseases. However, the molecular mechanisms involved in the maintenance of organ-specific lymphatic structures remain unclear. Here we aim to summarize recent findings on lymphatic aging in this field and present our results on the potential role of CCBE1 in the aging process of lymphatic vessels of the meninges and other organs.

Material and Methods: To characterize lymphatic structural changes with age, we used lymphatic endothelial cell-specific immunostaining in both wild-type and CCBE1 conditional knockout mouse strains.

Results: Our findings indicate that the presence of lymphatic vessels declines with age. Additionally, the inducible deletion of CCBE1 leads to a pronounced regression of lymphatic structures, suggesting that CCBE1 plays a crucial role in maintaining lymphatic structures over time.

Conclusion: Collectively, our results suggest that aging induces regression in the lymphatic system. Our study highlights the essential role of CCBE1-dependent mechanisms in preventing age-related regression of meningeal lymphatics. These findings suggest that targeting CCBE1 may be a promising therapeutic strategy to maintain lymphatic health and prevent age-associated regression of meningeal lymphatic structures

Reference:

Ocskay et al. Biomed Pharmacother., 2024

Number: 6

History and evolution of lymphedema treatment

Bernard Ho

St George's University Hospitals, NHS Foundation Trust, London, UK

The treatment of lymphedema has undergone significant evolution, reflecting advances in medical understanding and technology. This presentation traces the historical development of lymphedema management from ancient practices to modern therapeutic strategies. Historically, compression techniques were employed by Ancient Egyptian, Greek, and Roman civilisations for wound management and recovery. The 20th century saw pivotal advancements with the introduction of Manual Lymphatic Drainage (MLD) by Emil and Estrid Vodder in the 1930s, leading to the establishment of the first MLD school in Germany by Johannes Asdonk in 1969. The development of Complete Decongestive Therapy in the 1980s further advanced treatment paradigms.

Surgical interventions have also evolved from drastic measures such as amputation to more refined techniques like Lymphaticovenous Anastomosis (LVA) and Vascularized Lymph Node Transfer (VLNT). Diagnostic approaches have progressed from primary classifications of congenital lymphedema to sophisticated imaging and genetic studies. The integration of artificial intelligence and novel pharmacological therapies promises to enhance diagnostic precision and therapeutic outcomes. This comprehensive overview underscores the dynamic nature of lymphedema treatment and highlights future directions for research and clinical practice.

Number: 7

Evolution of lymphedema therapy in Austria

Walter Doeller

Wolfsberg Lymphology Clinic at the LKH Wolfsberg, Austria

Introduction/Background: The treatment of lymphedema in Austria, as in many European countries, is not as well-established as it should be. This article aims to highlight the development of lymphedema therapy in Austria over the past decades.

Material and Methods: To better understand the evolution of lymphedema therapy in Austria, we first examine the (social) environment, the development of science in lymphology, and advancements in diagnostics.

Results: Lymphology, as the study of the lymphatic system, is taught and researched in Austrian universities only in the context of immune organs. Lymphangiology, the study of lymphatic vessels, is often overlooked in education and research. Only a few scientists have focused on lymphedema in the past century, leading to the condition's being underrecognized or ignored.

Since 1970, self-help groups for women post-breast cancer have formed in Austria, focusing on education and counseling regarding postoperative arm lymphedema. This increased awareness led to the establishment of the “Austrian Lymph League” in 1993, a coalition of doctors, scientists, therapists, and patients. In the now-changed social environment regarding lymphedema, all involved parties called for a review and adaptation of care situations and needs.

Over the past 50 years, it has become possible to introduce conservative therapy, at least in the inpatient rehabilitation setting, in Austria. In the last 20 years, surgical, particularly microsurgical treatment options have also been established.

Conclusion: Austrian physicians have made significant strides in diagnostics and therapy over the last century. The Austrian Lymph League has played a key role in facilitating optimal lymphedema treatment development by motivating affected patients and igniting scientific interest in the field of lymphangiology. This has resulted in a broad knowledge base regarding diagnostics and therapy. However, there remains a need for studies (RCTs) to optimize and potentially further develop therapy in both conservative and surgical areas.