So this time I'm back on home territory, I'm going to discuss some of the knowledge and work on genetic forms of primary lymphoedema, in particular the work we've been pursuing here at St George's for the last few years. This section should probably also be entitled "sssssshhhhhhhh, don't tell anyone because we haven't published it all yet ". Before discussing the specific types of lymphoedemas I'll give a brief overview of genetics.

Genetics 101
Every cell in the body contains DNA, the structure which contains genes - the codes for life. The genes impact on every aspect of life whether it be the colour of our eyes, hair or which hand we use to write. For each gene in the body there are 2 copies. Each of these copies is called an allele. One allele we get from our mother, the other from our father.When an individual has a baby each allele has a 50:50 chance of being the one passed onto the child, and this is the crucial thing for understanding genetics.

There are 2 types of genetic conditions that I want to mention, the first is a dominant condition, whilst the second is a recessive condition. In dominant conditions, mutations (a slight alteration in the coding of the gene) only need to occur in one allele for the result of the mutation to present as a clinical alteration. In a recessive condition, both alleles of a particular gene need to contain mutations for the result to be expressed clinically. If an individual has a dominant condition, they have a 50:50 chance of their children having the condition (the same chance as inheriting the affected allele).With a recessive condition, both parents need to have a mutated allele to pass on, although the parents may not exhibit the condition themselves as they may be carriers (have 1 mutated allele and 1 normal allele). One of the most well known examples of a recessive genetic condition is Haemophilia, a condition that most famously affected the royal family around the 1900s.

Genetic forms of primary lymphoedema
At present, there are only 3 forms of primary lymphoedema for which genetic cause is identified. Identified means that mutations in a specific gene cause the condition. Although there may be other lymphoedemas that also have a genetic component, identifying a specific gene has not been successful. The three known lymphoedemas (as discussed last time) are:

• Lymphoedema distichiasis syndrome (LDS): A dominant hereditary lymphoedema with swelling below the knee that usually develops during or after puberty. The condition is also associated with a second row of eye lashes growing on the inside of the eye lid. Caused by a mutation in the gene FOXC2.
• Milroy disease: Another dominant hereditary lymphoedema, with below knee swelling that is present from birth. Caused by a mutation in the gene VEGFR.
• Hypotrichosis-lymphoedema-telangiectasia syndrome. A lymphoedema currently found in only one family. Caused by a mutation in the gene SOX18.

Lymphoedema distichiasis syndrome
Our aim was to determine how the mutations in the specific genes alter the clinical phenotype (physical characteristics) of these lymphoedemas.We examined both the lymphatic vessels and the veins. These vessels have a common embryological origin (during development the cells that later form the lymphatic vessels bud off from the veins) and have some common features (i.e. the presence of valves to ensure flow in one direction towards the centre of the body).

The veins of the leg were examined by venous ultrasound. Using this technique it is possible to determine the direction of blood flow. For example, when examining the thigh veins of an individual when they are standing, a squeeze of the calf will cause blood to flow up the leg (termed proximal flow), and the valves prevent gravity pulling the blood back down the leg. In patients with LDS, however, the venous valves did not stop this backflow properly meaning that blood "refluxed " (or flowed retrogradely) back down the leg and pooled in the feet (see Figure 1).

     
Figure 1: Scans of the direction of blood flow using colour Doppler ultrasound on a vein in the thigh. Peaks above the line represent normal flow following calf squeeze, whilst peaks below the line represent abnormal reflux back down the vein. Left: Control volunteer with only flow up the leg following calf squeeze. Right: Lymphoedema distichiasis volunteer showing venous reflux due to failure of valves.

To examine the lymphatics we used a technique called fluorescence microlymphography (FML) which uses an injection of a large fluorescent sugar. Large molecules are exclusively removed from tissues by the lymphatic system. Utilising this, the fluorescent tracer enters the first lymphatic vessels which then become visible on the skin surface when viewed using a fluorescent microscope (Figure 2).We are then able to determine how many lymphatics are functioning in a region of skin. This allows comparisons to be made between skin regions on the same volunteer or between groups of volunteers.We found that the lymphatics in the feet could function normally when at heart level (lying down), but did not work as well when below heart level (sitting or standing).

Figure 2: Image of the lymphatic vessels filled during an FML study.

Our findings show that dependency (when a tissue or organ is below heart level) affects the function of both the lymphatic vessels and the veins.When the feet and legs were below heart level (i.e. sitting upright or standing) the veins do not return the blood to the heart adequately, which leads to a pooling of the blood in the feet and consequently filtration of more fluid from the blood into the tissue. In addition to this increase in fluid filtering into the tissue there is a reduction in the amount of fluid being removed by the lymphatic system. Combined together these results mean that when below heart level, not only is less fluid being removed from the tissue by the dysfunctional lymphatic system, but there is also more being filtered into the tissue from the dysfunctional veins as well. This partially explains the increase in volume that occurs during the day, and the reduction overnight that is reported by lymphoedema distichiasis patients.

One possible cause of the simultaneous lymphatic and venous failures would be the development of dysfunctional valves. Our current hypothesis is that the gene FOXC2 is involved in valve development and maintenance in both systems and that mutations in this gene cause their failure. Interestingly, all those volunteers (few in number) who had mutations in the gene but no swelling (carriers) still had venous abnormalities but normal lymphatic function. This suggests that the mutations firstly affect the venous system over the lymphatic system, but that a dysfunctional lymphatic system is required to ensure the development of swelling.

Milroy disease
The gene involved in Milroy disease, VEGFR-3, is very important for lymphangiogenesis (the growth and development of lymphatic vessels). Milroy disease has, therefore, traditionally been considered a problem due to a lack of lymphatic vessels. A reduction in the function of this gene is thought to reduce lymphatic numbers. This hypothesis agreed with what occurred in lymph scan images, where injections of radioactive tracer to examine deep lymphatic routes demonstrated no movement of tracer (i.e. no uptake into the lymphatic vessels).

When we used FML, as previously described for LDS, we found no uptake of tracer into the lymphatic vessels in the swollen feet of volunteers with Milroy disease, irrespective of whether the volunteer was lying down or sitting. Gravity, therefore, does not alter lymphatic function in the same way as shown in lymphoedema distichiasis. Lymphatic filling was normal in skin regions with no swelling (we examined the forearm). This is a little strange given that the mutation must be present in all cells of the body, but only seems to alter lymphatic function below the knee whilst leaving normal lymphatic function at other sites on the body.

Further complications were found when we examined skin biopsy sections from the feet of those with Milroy disease. Expecting to be unable to see any lymphatic vessels at all, we were surprised to see some vessels within the skin (possibly a normal level although this analysis is still ongoing). This means that the mutation must be causing a reduction in lymphatic function rather than solely preventing lymphatic vessels from forming.

Conclusion
Our work has shown that different types of lymphoedema, even those that may look similar, can have different pathologies underlying the swelling.We have also shown that simply understanding the exact genetic mutation is not enough to understand lymphoedema. As with most research, this work has aided our understanding of these conditions, but has also raised more questions that now need answering. Research is very much a rolling process, but gradually we are getting there.

In 2001, LymphLine announced that Professor Mortimer's team at St George's Hospital in London (together with a research team at Addenbrooke's Hospital in Cambridge) had been awarded a 5 year Wellcome Trust grant, for research into breast cancer-related lymphoedema (BCRL).With less than a year of the grant remaining, here's a reminder of the puzzles which the team were originally presented with, together with an update on the progress that has been made towards solving them.

Treatment for breast cancer and the link to lymphoedema
Lymph (which consists of mainly water and proteins) drains through a network of connecting lymphatic vessels (lymphatics), from the arm and the breast, towards a group of axillary lymph nodes, which are found mainly in the armpit. The lymphatics which transport lymph in these regions are the main routes for metastases of malignant breast cancer cells, so axillary lymph nodes are usually removed during breast cancer surgery. The removed lymph nodes are examined under a microscope to determine if the cancer cells have spread. Removal of axillary lymph nodes and radiotherapy (which can cause scarring of lymph nodes and lymphatics) may interfere with lymph draining out of the arm. In some cases, this results in a swollen arm, otherwise known as breast cancerrelated lymphoedema.

Progress in understanding the mechanisms underlying breast cancer-related lymphoedema
It's only really in the last 15 years that research aimed at improving the understanding of BCRL, has started to progress. The traditional and widely accepted view of BCRL is that the damage to the axillary lymph nodes prevents lymph from properly draining from the arm, much like a blocked drain, resulting in swelling. However, this view appears to be too simplistic as it fails to fully explain certain puzzles which relate to BCRL, including:

• Why do only approximately a quarter of women who have similar breast cancer treatment develop BCRL?
• Why can BCRL develop when just a single lymph node is removed and why does swelling not necessarily occur when all lymph nodes are removed?
• Why can the arm seem normal for months or years after surgery and then suddenly swell for no obvious reason?
• Why can certain parts of the arm be more swollen than others which may have no swelling at all?

How is lymphatic function in breast cancer-related lymphoedema investigated?
One of the ways we can assess how well the lymphatic system is working is to measure lymph flow. This is important so that we can find out the reason why lymph drainage is obstructed. Lymph flow cannot be measured directly (unlike blood flow), so investigating lymphoedema is difficult. A technique called 'lymphoscintigraphy' can be used to measure lymph 'drainage' as a surrogate for lymph flow. This method involves the injection of a large radioactive protein into the tissue of the arm. The size of this protein means that the only way for it to leave the tissue is via the lymphatics. The fact that this protein is radioactive means it is possible to measure how quickly it leaves the tissue through the lymphatics, giving us a way of actually measuring lymph flow. The faster it leaves the tissue, the faster the lymph flow.

Does axillary surgery damage lymph flow?
In one of our current studies, we are testing if there is any blockage to lymph flow in women who have so far not developed lymphoedema following recent breast cancer surgery. As the incidence of BCRL is around 25%, we would expect approximately one quarter of these women to eventually develop BCRL. Using lymphoscintigraphy, we measure lymph drainage in two places as soon as possible after axillary surgery. Firstly in the subcutis, which is just under the surface of the skin and secondly in the muscle, to identify any obstruction to lymph drainage before lymphoedema becomes apparent. This could potentially lead to a way of identifying which women are most at risk of developing lymphoedema. These women could then be monitored more closely, enabling earlier management, and perhaps even prevention of the swelling. The results of this study, so far, show that even when all axillary lymph nodes have been removed, we cannot identify any obstruction in lymph drainage on the operated side. It may be that changes in lymph drainage only become apparent when swelling occurs. This test will be repeated using the same volunteers 2-3 years after the first study so that we can determine if there have been any changes in lymph drainage over time.

Why can the arm swell after months or years with no swelling?
It is not known how long it takes from the time of deterioration in lymphatic function to the development of BCRL. Although there have been reports of swelling developing as much as 20 years after surgery, around 90% of women who develop swelling will do so within 3 years. Occasionally, a factor such as an infection, a cut or a greater degree of exercise using the arm is reported to have led to the swelling, but in many cases there is no obvious cause.
One of the ideas we are currently investigating is the idea of a gradual failure of the ability of lymphatics to pump. Large lymphatics in the arm actively contract in order to pump lymph along the arm towards axillary lymph nodes. After the removal of axillary lymph nodes, these lymphatics may have to pump harder than normal to drain lymph out of the arm past the axilla. Eventually the lymphatics may start to fail in their ability to pump and this failure may happen months or years after the surgery, leading to swelling in the arm. The study which we are currently undertaking aims to see if the lymphatic pumps of women with BCRL are working less well than those individuals without lymphoedema.

Why can some regions of the lymphoedematous arm be spared from swelling?
Some lymphatics, or parts of lymphatics, may be weaker than others. The weaker lymphatics presumably fail first in their ability to pump lymph, resulting in greater swelling in these regions compared with others. A particularly unusual feature of BCRL is that the whole forearm can be swollen whilst the hand can be spared of swelling. Lymphatic drainage in the non-swollen hand of an otherwise swollen arm has shown to be normal (or even slightly increased). This is very surprising given the lymphatics in the hand and forearm drain to the same damaged axillary lymph nodes. In swollen arms, lymph often uses the skin as an alternative drainage route if normal drainage routes are blocked (like a road diversion). So why is the hand not swollen? It could be the case that lymph in the non-swollen hand is draining through alternative pathways (perhaps those closer to the surface of the skin). Other studies have suggested that there are additional routes which allow certain lymphatics, such as those travelling from the hand, to bypass the damaged axillary region, perhaps via a route over the shoulder or above the collar bone. It is a possibility that women who do not have these additional 'bypass' routes are most at risk of developing lymphoedema.

Where is the lymph blocked in the swollen arm?
In one of our current studies we are measuring lymph drainage in two layers of the swollen forearm - in the subcutis (i.e. in superficial lymphatics) and in the muscle (i.e. in deep lymphatics). Superficial and deep lymphatics are connected at certain points along the arm. The subcutis (just below the skin) is where most of the swelling is visible so it is unsurprising that, here, superficial lymph drainage has shown to reduce by 25%.When lymph drainage is measured in the deep lymphatics of the muscle, the reduction is greater even though the muscle itself doesn't actually swell. Furthermore, the degree to which lymph drainage is reduced in the muscle is very tightly correlated to the extent of swelling in the subcutis. So, what could be happening to lymph flow in these two layers of the swollen arm and where exactly is lymph drainage blocked?
If there is an obstruction to superficial lymph flow, it could be that lymph which normally drains through the muscle cannot do so and has to divert into the subcutis which is more expandable than the muscle - like an overflow. Alternatively, lymph from the superficial lymphatics which would normally use the deep lymphatics as an additional drainage route can no longer do so. Both scenarios would result in swelling in the subcutis.

Can the bloodstream give us any clues?
Eventually, all lymph will drain into the bloodstream via veins in the neck (this is why manual lymphatic drainage starts in the neck). The time it takes for the lymph to empty into the blood is an additional way of checking how well the lymphatics are working. Research has shown that the time it takes for lymph to empty into the blood is surprisingly quicker in swollen arms compared with non-swollen arms. One possible explanation is that after axillary surgery, the lymphatic system tries to develop ways of coping with the swelling by opening 'bridges' (called lymphovascular communications) between the blood and the lymphatic system. These 'bridges' would effectively allow the lymph to take a short-cut back to the blood, bypassing the damaged axillary region. It may be that those who do not develop swelling have more of these bridges than women who do not. However, more evidence is needed to substantiate this idea.

Are some people predisposed to developing lymphoedema after axillary surgery?
The sentinel node is the name given to the first node which lymph from the tumour drains into, and it may be removed as a way of determining if cancer cells have metastasised. It is surprising therefore that BCRL can develop when just one lymph node is removed (figures quoted range from 0-22% of breast cancer patients). In other women, all axillary lymph nodes may be removed and BCRL may not develop. One possible explanation is that natural genetic differences influence lymph drainage. These genetic differences would be expected to affect the whole body, including the legs. To see if this is the case, we are currently investigating the possibility that women with BCRL experience more ankle swelling than those without BCRL.We also plan to do studies to check if the genes which are normally involved in the growth and repair of lymphatics may be altered, or not working properly, in women who develop BCRL.
As you can see, the traditional 'blocked drain' view that BCRL is simply caused by the removal of axillary lymph nodes is too simplistic to explain all the unusual features associated with it.We plan to report the results of all the studies in this 5 year programme at the end of 2006. Continued research into lymphoedema is vital. Finding out more about the causes and mechanisms underlying BCRL will hopefully shed some light on the puzzles associated with this condition and advance the steps we are taking towards finding a cure.
If you would like further information on our current research into BCRL, please email: Smodi@sgul.ac.uk or call Stephanie Modi on 0208 725 5439/5437.

It has been suggested that an article about research into growth of new lymphatic vessels would be useful. Obviously this topic appeals to anyone with lymphoedema because it sounds like the perfect way to improve a condition caused by an underlying lymphatic problem. It would seem to be of potential help to lymphoedema caused by both internal sources (primary lymphoedema) or external sources (secondary lymphoedema). The scientific term for growing new lymphatics is 'lymphangiogenesis'. Although there is a lot of research to be done to understand lymphangiogenesis, it is one of the most actively researched fields in lymphatic biology at present, mainly due to its role in cancer spread, but also because of its role in swelling.

Lymphatic biology
Before I launch into lymphangiogenesis, it is important to have an understanding of the lymphatic system. Sandy Ellis wrote an article in the Spring 2005 issue of LymphLine titled "What is the lymphatic system?" covering some of this issue, and this article is accessible on the LSN website in the Medical Articles section. All I'm going to cover here is a brief overview that will aid in the understanding of lymphatics with regards to lymphangiogenesis. If you already have an understanding of the make up of the lymphatic system, you may want to skip the next paragraph and move onto the next section.

I picture the lymphatic system as a river, starting off with many small tributaries which gradually join together forming larger and larger rivers until they finally flow into the sea. In the case of the lymphatics, the tributaries (and springs) are the initial lymphatic capillaries, these are the site at which fluid is first taken into the lymphatic system. These vessels are very small, and have very thin walls that allow the uptake of tissue fluid. These join together to form firstly pre-collectors and then collectors, each larger than the last, with the collectors having thick walls that can actively contract to pump the lymph fluid along the lymphatic network. The lymphatic system contains valves to ensure that the lymph fluid continues to flow centrally. Finally, the lymphatic system empties into the blood circulation in the veins just before the heart. This process is continual, and allows the maintenance of tissue fluid levels.

Lymphangiogenesis
OK, now that all those that skipped ahead have rejoined us, I'll get on to the main part of the article. Lymphangiogenesis is usually referred to in two ways; i) developmental lymphangiogenesis, referring to lymphatic growth when the lymphatic system is first formed in an embryo during pregnancy, and ii) adult lymphangiogenesis, referring to lymphatic growth that occurs after development, usually as a response to injury or tissue growth.With regards to primary lymphoedema, it is important to have knowledge of how lymphatic vessels first develop and function normally, hopefully allowing better identification of the underlying cause of the lymphatic disruption when it occurs. For secondary lymphoedema, understanding adult lymphangiogenesis is just as important. For example, understanding how surgery removing the lymph nodes and vessels in the axilla during breast cancer treatment disturbs normal lymphatic function and may interrupt repairing lymphatic vessels growth, could aid future treatments. Obviously, adult lymphangiogenesis is also the type of lymphatic growth which may be of interest in future treatments (see later).

It is important to note that only a small amount of work in understanding the mechanisms behind lymphangiogenesis has yet been completed in humans. Most of the work discussed below has been done on animal models (for example mouse models, where particular genes are inactivated to determine their role in lymphatic development) or in cell cultures (where lymphatic cells are grown in Petri dishes to see how they react to various stimuli).

Developmental lymphatic growth
During development, cells have to go through a number of processes to form a functional lymphatic system. If any of the processes are not completed properly then lymphatic function will be reduced.When the blood vessels initially appear in the very early days of development, there are no lymphatic vessels. The first step in the lymphatic development pathway is that some of the cells lining the main veins in the neck and trunk begin to express (show on their surface) a molecule which marks them for a lymphatic fate. This phase is termed differentiation, and if it does not occur, then no lymphatic system forms. Once marked in such a way, the cells increase in number and migrate away from the veins to form small lymph sacs. These are essentially groups of cells all marked for a lymphatic fate, although not yet forming vessels. This stage is reached by weeks 6-7 of pregnancy in humans. The lymph sacs further multiply and spread to form vessels all over the body, forming a primitive lymphatic network. This primitive network is composed of only lymphatics capillaries (small thin walled vessels) irrespective of the site in the body. At this point, there are still many links between the veins and the lymphatics (termed lympho-venous anastomoses). It is important for the production of a functional system that these links are broken in all but those sites where the adult lymphatic system rejoins the blood circulation just before the heart.

During late pregnancy, and even after birth, the primitive lymphatic network undergoes remodelling and maturation. These processes turn the lymphatic vessels into those seen in a complete adult network, with the structure of vessels altering to match their site and role in the system (i.e. that described previously), from initial lymphatic capillaries to large collecting vessels.

Some examples of what can go wrong
In many types of primary lymphoedema it is almost impossible to know exactly which part of the development/maturation pathways has gone wrong, other than knowing that lymphatic function is reduced. It is sometimes possible to find out, by using techniques such as lymphoscintigraphy, where in the lymphatic system the failing occurs (e.g. the lymphatic capillaries), but not necessarily the cause. There are, however, 3 known genetic causes of specific types of primary lymphoedema. Although only making up a very small percentage of primary lymphoedemas, they indicate the importance of each step in development. I will go into the genetics of lymphoedema in a future article, but briefly, the 3 types are caused by changes in the genes:

1. SOX18. A gene involved in the proliferation and migration of cells to the lymph sacs from the veins, mutations in which cause a primary lymphoedema called hypotrichosislymphoedema- telangiectasia due to an early malformation in lymphatic development.
2. FOXC2. This is involved in remodelling and maturation of the lymphatic system (we believe specifically the valves) and changes in the gene cause lymphoedema distichiasis (swelling below the knee after puberty, and a second row of eye lashes on the inside of the eyelid). It is known to be a transcription factor, which means that it controls other genes, but which genes it controls are unknown, and therefore how exactly it controls remodelling and maturation are also unknown.
3. VEGFR-3. Probably of most interest to scientists at present. Changes in the gene VEGFR-3 cause Milroy disease (bilateral below knee swelling present from birth). VEGFR-3 is the main known trigger on lymphatic cells that when stimulated causes cell multiplication and lymphangiogenesis. To scientists it forms a good model to look at, and it is from this model that many of the works on lymphangiogenesis have been completed (see later).

These are only 3 of the many factors involved in developmental lymphangiogenesis, and a reduction in any of them causes lymphoedema. Even though we only have limited knowledge of these factors, there are many more factors where even less is known, and it is also likely that more factors have not been discovered which are also important.

Adult lymphangiogenesis
Studies on adult lymphangiogenesis in humans have been limited to examining biopsies taken from various tissues and situations (i.e. skin cancer or lymphoedema) and measuring whether there are more lymphatics present than normal, or whether there are any markers of new growth. It is difficult from these studies to determine exactly what processes are involved. It is assumed that a similar process to that which takes place for blood vessel growth (angiogenesis), of which there is more knowledge, must take place. If this assumption is true then the lymphatic vessels that are already present must be de-stabilised so that they are primed for multiplication and spread. The cells and vessels must then undergo multiplication and migration through the tissue (probably using a number of factors such as VEGFR-3). Once multiplied, they must then be re-stabilised (matured) so that they form functioning lymphatics with normal characteristics.

Most of the work on adult lymphangiogenesis has mainly concerned adding substances that lead to new lymphatic vessels growth without truly understanding the underlying triggers and causes, or whether the result is maintainable.

Animal models and lymphangiogenesis treatment
The most exciting study of recent years on the possibilities of lymphangiogenesis as a treatment for lymphoedema came from an eminent research lab in Finland. They used a mouse model of Milroy disease that has had the VEGFR-3 gene mutated so that no lymphatic vessels grow properly. They showed that by adding molecules that stimulate lymphangiogenesis they could cause the formation of new lymphatics. Unfortunately, it also made more blood vessels grow, causing more swelling, and potentially other problems. Following this they slightly altered the molecule they were adding to the mice, introduced to the tissues using gene therapy, and caused lymphangiogenesis alone. This sounds wonderful on the surface, but there are some major drawbacks to the research that still need to be answered:

1. The research caused alterations to the veins, potentially causing problems that will make any swelling worse.
2. The mouse model may not be an accurate representation of the human condition it is meant to mimic. Milroy disease has always been considered a hypoplastic (meaning lack of vessels) condition, and this is seen in the mouse model. Some of our own recent work suggests that the lymphatics may actually be present but not functioning properly. The issue is then raised that if new lymphatic vessels were grown would they work properly.
3. In the mouse model, the swelling caused by the mutation is actually very rare, unlike in humans when the swelling is nearly always present if the gene is altered.

There are also some points that are relevant to treatments developed from mouse models in this way for use in humans:

1. The model used is only of Milroy disease, whilst there are many different types of lymphoedema. Many lymphoedemas (as stated in previous articles) have other alterations in addition to the lymphatic changes. It is likely that these problems will also need to be corrected before the lymphoedema can properly be treated.
2. It is possible that a treatment of this type may only benefit specific lymphoedemas rather than a catch all treatment.
3. The work involves genetic therapy, an issue that raises ethical issues with many people. This needs to be discussed in depth by the population and the individuals involved, along with many other issues regarding genetics in medicine.

Conclusions
At the moment, trying to understand lymphangiogenesis (and its potential for treating lymphoedema) can be like doing a jigsaw with only 2 sides completed.We have an impression of where we are going, but as yet there is still a long way to go. It is most likely that this type of treatment is many years away, at least until many of the questions raised above are answered, but the research is being completed by some of the most eminent scientists in the developmental field, and is gradually edging in the right direction.

Next time, I'm going to come back to an issue closer to home for me, genetic causes of lymphoedema (an issue we work on here at St George's), and why they are not as simple as we previously expected.

We all know that lymphoedema occurs, but just how common is lymphoedema? This is a question asked by patients, clinicians and scientists alike, and the simple answer is that we don't truly know. The studies examining the levels of lymphoedema in any given populations are patchy and differences occur due to the type of lymphoedema being examined (not all lymphoedemas are studied to the same degree), the area of study (there are differences in study type, and the type of lymphoedema examined both across the UK and internationally) and the criteria for diagnosing lymphoedema (see below). In this article I'm going to reference several papers that give some information on how common is lymphoedema, and try to show if there is any consensus between research articles. At the bottom there will be a list of references that I've mentioned here, and these will form a good starting point for anyone interested in finding out more.

General knowledge
There is a remarkable lack of studies examining the total level of lymphoedema in the general population. One of the only studies asked healthcare professionals how many cases of long term swelling they saw (a surrogate for lymphoedema) (Moffatt et al., 2003). It showed that 1.3 % of the study population had swelling, suggesting that in the UK at least 100,000 people would be affected. This figure would most likely be an underestimation given that the study could not include those people not being seen by a healthcare worker. In addition, the paper also showed that swelling was more common in the elderly, and more so in women than men. It is important to note that these results include both primary and secondary lymphoedema, but it gives a good idea of the overall levels of lymphoedema.

Secondary lymphoedema - breast cancer related lymphoedema
Secondary lymphoedemas, in particular breast cancer related lymphoedema (BCRL), have been subject to the greatest number of studies examining the levels of lymphoedema and treatment. This is most likely due to the ease with which patients can be followed over time, and the knowledge of when the intervention that caused the swelling occurred. According to a very good review paper by Williams et al. (Williams et al., 2005), since it's first mention in a scientific paper in 1921 there have been many papers examining the number of patients developing swelling. Unfortunately, levels of BCRL range from 89 % down to 0.4 % of those treated for breast cancer, depending on the paper. As you can see this poses quite a problem, and shows the difficulty when comparing results. Some of the causes of these huge differences are:

1. Era of study. It is commonly held that treatment for breast cancer has become more conservative over the years, and therefore lymphoedema levels will have dropped. This usually means that earlier studies (1950s and 60s) have higher levels of BCRL than more recent studies.
2. Type of cancer treatment. It is known that radiotherapy and the degree of axillary surgery can increase the risk of developing lymphoedema after breast cancer treatment. Studies which do not include these treatments will therefore show low levels of lymphoedema, whilst those including such treatments would be expected to have higher levels.
3. Time since treatment. Some researchers have done prospective studies over many years, whilst others have only looked up to 6 months after treatment. Given that there can be a period of time (sometimes many years) after cancer treatment before the development of swelling, those studies which only look over a short period may have artificially low levels of lymphoedema.
4. Criteria for defining lymphoedema. This is a big problem. Even if the first 3 points are taken into account, many studies utilise different criteria for determining the presence of lymphoedema (e.g. 10 % increase in limb volume compared to the opposite arm, or 2 cm increase in circumference) because there is no set differential diagnosis. Depending upon the criteria used, this will obviously affect results, those with criteria that are more difficult to meet (e.g. 20 % increase in arm volume) showing lower levels of lymphoedema in a given population.

1. Decreased visibility of veins. The skin is thickened in lymphoedema and veins are more difficult to see.
2. Greater roundness or fullness of the elbow contours. This is the region where swelling is most common.
3. Increased skin and subcutis thickness. By pinching the skin between fingers and thumb the limb may feel different due to increased thickness.
4. Pitting oedema. When the site of swelling is pressed for 60 seconds a pit remains upon pressure removal.

Problems with 'possible' lymphoedema
To complicate matters further, we have noted a number of patients who seem to have 'incipient' lymphoedema after breast cancer treatment. These patients have been volunteers for our research who have had breast cancer treatment but are believed to have no swelling. On examination there was a small difference in volume (often only 1-5 %) between the arms, and when the arms were examined the contours of the arm on the side of treatment were slightly altered. The hypothesis that there is a group of individuals with small changes in arm size that would otherwise be missed from many quoted figures suggests that lymphoedema may be further underestimated.

Other secondary lymphoedemas
Although BCRL has been the most frequently studied secondary lymphoedema, in theory any cancer treatment that causes damage to the lymph tissue (usually lymph nodes) can cause lymphoedema. Frequently, lymphoedema is the most common long-term complication following these treatments. Again, the levels vary depending upon the study type and the cancer being studied, with values ranging from 8 - 100 % when there is lymph node involvement. Surgery involving treatment of the groin lymph nodes seems to be particularly prone to developing lymphoedema, and studies indicate that a higher degree of lymphoedema is recorded following groin lymph node surgery than axillary surgery.

Lymphoedema filariasis
Internationally, lymphoedema filariasis is a common problem, particularly in developing countries. Unlike other forms of lymphoedema, filariasis is more dependent upon the mode of transmission (i.e. the mosquito). In regions where stagnant water allows large mosquito populations, the lymphoedema filariasis can become endemic in the population. The largest endemic population is India (40 % of worldwide cases). In 2001, 45 % of the Indian population lived in endemic regions, and 48 million people had swelling caused by filariasis in India alone, with a further 68 million being infected with the worm that causes the condition but without swelling (Das et al., 2001). Attempts to decrease levels have included mass insecticide spraying of mosquito breeding areas, or more recently the World Health Organisation (WHO) plans to administer chemotherapy-like drugs to all people in an affected region, breaking the life-cycle of the filarial worm involved. The long term goal by the WHO is to eradicate this condition by 2020, although whether they can meet the administration problems of treating patients in rural areas of affected countries, and the lack of compliance to treatment regimes, is yet to be seen.

Primary lymphoedema
Unfortunately, there have been no complete studies examining the levels of primary lymphoedema, a frustrating position given that this is my main area of interest. Some studies have suggested that those clinics that are allowed to see primary lymphoedema are made up of 75 % secondary and 25 % primary lymphoedema patients. This is unlikely to be the true numbers. Many primary lymphoedema patients are still not seen in lymphoedema clinics, suggesting that much higher numbers are affected.
Having now worked on two forms of inherited lymphoedema (lymphoedema distichiasis syndrome and Milroy disease), both of which are thought to be rare types of primary lymphoedema, it has been surprising how many of these patients have not been seen by any lymphoedema service. Although these conditions run in families, roughly half of those volunteers being recruited were having no active lymphoedema treatment, pointing out the difficulty of measuring how many people suffer from these conditions. Regrettably, primary lymphoedema can still be called a hidden condition, and until this is altered, the exact numbers of people affected will be difficult to ascertain.

Conclusions and next time
Looking back over the article I can see that, yet again, I seem to be pointing out the gaps in knowledge regarding lymphoedema, although the consensus would seem to be that lymphoedema is a very significant problem.
Next time I hope to take a more positive view and concentrate on some of the good research underway that is examining the underlying causes of some specific types of lymphoedema.

Reference List

Armer,J., Fu,M.R.,Wainstock,J.M., Zagar,E., and Jacobs,L.K. (2004). Lymphedema following breast cancer treatment, including sentinel lymph node biopsy. Lymphology 37, 73-91.

Das,P.K., Ramaiah,K.D., Augustin,D.J., and Kumar,A. (2001). Towards elimination of lymphatic filariasis in India. Trends Parasitol. 17, 457-460.

Kissin,M.W., Querci della,R.G., Easton,D., and Westbury,G. (1986). Risk of lymphoedema following the treatment of breast cancer. Br. J. Surg. 73, 580-584.

Moffatt,C.J., Franks,P.J., Doherty,D.C.,Williams,A.F., Badger,C., Jeffs,E., Bosanquet,N., and Mortimer,P.S. (2003). Lymphoedema: an underestimated health problem. QJM. 96, 731-738.

Mortimer,P.S., Bates,D.O., Brassington,H.D., Stanton,A.W.B., Strachan,D.P., and Levick,J.R. (1996). The prevalence of arm oedema following treatment for breast cancer. Q J Med 89, 377-380.

Querci della,R.G., Ahmad,I., Singh,P., Ashley,S., Daniels,I.R., and Mortimer,P. (2003). An audit of the incidence of arm lymphoedema after prophylactic level I/II axillary dissection without division of the pectoralis minor muscle. Ann. R. Coll. Surg Engl. 85, 158-161.

Williams,A.F., Franks,P.J., and Moffatt,C.J. (2005). Lymphoedema: estimating the size of the problem. Palliat.Med 19, 300-313.

When Anita asked me to write an article on lymphoedema research, it became evident that there was little information out there for those affected by lymphoedema. I suggested, some would say foolishly, that it may be interesting to produce a series of articles, reviewing what has previously been shown and what is happening at the moment. Of course, Anita then told me it was a great idea, so this article will be the first of a series, looking at what we know and, more importantly some would say, what we don't know. In this first article I aim to give a brief overview of the different types of research done on lymphoedema. I should say at the start that this is not an exhaustive list of lymphoedema research, and is obviously written from my own point of view as a scientific researcher.

Where is the research being done?

Although not as many researchers around the world are interested in lymphoedema as in some other conditions, there are at least a few people in each country. This varies from those just 'dabbling' in lymphoedema for a short period (e.g. a clinician who has seen an interesting trend in their clinic) to those groups that have a proven track record, whether clinically, treatment related or the science behind the swelling.

What are researchers in lymphoedema interested in?

Research into lymphoedema can be split into roughly 3 areas:

1. Incidence/prevalence: This research is interested in finding out how common lymphoedema is, and each year a good number of papers are published covering this area. These are population studies examining the number of people affected by chronic swelling/ lymphoedema, or more local studies, examining the prevalence of specific types of lymphoedema, such as secondary lymphoedema following breast cancer treatment in south London or lymphoedema filariasis (lymphoedema caused by a nematode worm infection) in tropical regions. Usually, these studies rely upon individuals filling out questionnaires, or audits of clinics which see affected individuals. Unfortunately, there is no definite measure of lymphoedema, so studies frequently use differing descriptions (i.e. 10 % increase in volume, 2cm increase in circumference, presence of pitting oedema) and care has to be taken when comparing incidence across areas and between countries.
   
   
2. Treatments. Obviously, a crucial aspect of research is determining the effectiveness of treatments. Unfortunately, at present there is no cure for lymphoedema, and most current treatments are aimed at controlling the swelling. Commonly, population studies examining the effects of a particular treatment (e.g. MLD) are most likely to be completed by treatment providers (i.e. lymphoedema therapists/nurses). Interestingly, although most people would admit the importance of hosiery, there is little published evidence showing the effect of hosiery alone. It would now be very difficult to perform a study examining the usefulness of this treatment, as it would require the withdrawal of hosiery provision to a large number of patients for comparison.
   Research is also conducted on new treatments and strategies, such as hyperbaric oxygen therapy or liposuction and studies to show how well they work, often partially working for some individuals but not others. Studies of patients' involvement in treatments and patients' own strategies in self management of the condition, can be included here. In the countries affected by lymphoedema filariasis, this will include work on anti-worm treatments and other methods of reducing the transmission of the infection causing the lymphoedema.
   Attempts are also underway to produce cures to the underlying causes of lymphoedema. One possible future treatment (still some way off) may be gene therapy to stimulate growth of new functioning lymphatic vessels. If this does become available, then obviously discussion on genetic therapies, and the ethics thereof, become all important.
   
   
3. Understanding the pathophysiology. Understanding the underlying causes of lymphoedema is crucial to any future treatment. Be it studies on volunteers, animal models or genetic studies, research in this area usually depends upon the particular researcher's field of interest.When looking at research from around the world, many different aspects of lymphoedema are examined, from the genes that cause lymphatic vessels to grow, through to how they are functioning in the patient, and all need to be drawn together to give an overall picture of lymphoedema. Research is further complicated by the different types of lymphoedemas that are examined, for example within the broad definitions of primary and secondary lymphoedema, there are further splits (e.g. primary lymphoedema of genetic origin compared with secondary lymphoedema after breast cancer treatment). This usually means that only a small number of scientists are working on any specific type of lymphoedema.

As I'm sure you will readily agree, at the moment with lymphoedema, there are infinitely more questions than answers, and often research will answer one question but also raise two more.

Do researchers know of each other, or are we all working alone?

Most of those involved in lymphoedema research know of at least a few other people working in the same field. Journals such as Lymphatic Research and Biology and Lymphology are well known internationally for specialising in lymphodema research, whilst other journals in the fields of nursing, cancer, surgery, and circulation have also published papers regarding particular aspects of lymphoedema. One sure way of keeping track of current work is to use internet referencing services (such as PubMed and Medline) where abstracts and information of many published works are available.

Conferences provide an important place for discussion with fellow researchers. The International Lymphology Society meeting that is held every 2 years (this year in Brazil) is attended by scientists, nurses and doctors alike from around the world.More locally, the British Lymphology Society conference (this year in Glasgow) can play a similar role. At these conferences it is possible to see and ask questions of others in the field, determine just how all the work fits together, and gain inspiration for future work.

Collaboration and communication

Collaboration can be crucial for the increase in understanding of any condition. With our own research, past collaborations have often lead to good results due to the pooling of resources within a small field of expertise and we continue to collaborate with other institutions across the country and internationally. For example, with our work on primary lymphoedema, we collaborate with St Thomas'Hospital, London, whilst for secondary lymphoedema we collaborate with Addenbrookes Hospital, Cambridge.

There does seem, however, to be a lack of collaboration between the clinical and science aspects of lymphoedema research, and with the patients. This is something that needs to be addressed, as it is important for scientists like myself to be grounded in our thoughts of lymphoedema with regards to our volunteers and those providing front line treatment. Hopefully, we can build and strengthen these links in the future.

Limitations on research

Unfortunately, despite saying that research is ongoing in lymphoedema, there is still a long way to go to be able to provide a true understanding of the condition. Research can be very expensive (salaries, equipment and consumables) and most scientific research is dependent upon charitable funding. For example, we have been funded by the British Heart Foundation, the Medical Research Council and the Wellcome Trust amongst others. There is difficulty in getting funding for lymphoedema because of the lack of interest from funding bodies, and when funding does occur it is often on a specific type of lymphoedema. Various agencies such as the National Lymphoedema Framework Project are attempting to increase awareness of lymphoedema, and we all hope that this will help in the future.

Conclusions

I have only touched the surface of research in lymphoedema in this article, hopefully giving the impression that research, although limited, is ongoing. In future articles I hope to touch more specifically on certain aspects of lymphoedema research, how it is conducted, and how it fits together.

Introduction

When Anita first asked me to write an article for the LSN about my particular interest in venous access and lymphoedema, I was thrilled, but after I'd put the phone receiver down, the realisation set in that I had a difficult task ahead.
Needles and Lymphoedema is often an emotive issue. I know the LSN have many queries about injections and I have attempted to answer many of the frequently asked questions. As you read on, my hope is that you will see how complex an issue this is and that the answers are not always straight forward.

So why have I been asked to talk about this issue?
I am a nurse whose main speciality has been cancer treatment and giving chemotherapy treatments for the cure or palliation of cancer patients. I love nursing and remain passionate about excellence in nursing practice and provision of the highest quality patient care. Over the years, I have gained a lot of experience in venous access in patients receiving cancer treatments. I have been putting needles into patients' veins for many years and believe me, I have heard every nickname you can imagine!
I first became interested in lymphoedema back in 1998 when I worked for the vascular access team at the Royal Marsden. The standard advice given to patients at the time of their breast surgery is to avoid having blood pressure measurements and injections on their "at risk of lymphoedema" arm. I was informed that the reason for this is that it may reduce the likelihood of swelling developing. For my BSc dissertation, I decided to conduct a systematic review of the evidence relating to the risk factors for lymphoedema development with a particular focus on the subject of needles and lymphoedema. There is anecdotal evidence where patients have reported swelling developing after blood pressure recordings and injections, however, I found that there was little good research based evidence relating to this subject. I have been working within the field of lymphoedema for nearly 18 months now and am currently attempting to write guidelines for professionals on the subject of injections in patients at risk of lymphoedema, however, the process is taking longer than I expected, but I'm nearly there!

"At risk" versus those with existing lymphoedema
Those who have lymphoedema are people who have swelling present in their arm (or other body part, but for this instance we will be discussing arm lymphoedema). Those who are at risk of lymphoedema are people who have had one or more of their axillary nodes removed. If someone has never had their nodes removed but has disease present in their axillary nodes, they are also at risk. People who have undergone axillary radiotherapy are also at risk, due to the scarring of the nodes which can occur years after radiotherapy.

Some useful definitions and explanation of terms you may hear:

Venepuncture

• The procedure for taking a blood test is known as venepuncture. The needle only remains in the vein for as long as is needed to withdraw blood. It is then promptly removed.

• A cannula is a flexible tube which is placed into a vein for purposes of administering medication or fluids. It is introduced using a needle and the cannula can remain in the vein for a few days.

• A subcutaneous injection is an injection which goes into the tissues of the limb, for example, a local anaesthetic to numb an area.
• An intramuscular injection goes into the muscle of the arm, for example, a flu vaccination.

• This is a very fine needle which pierces the finger tip in order to produce a droplet of blood to find out the level of sugar in one's blood.

• This is a device which is inserted into one of the larger veins near the heart and they can remain in place for extended periods of time. There are three main types of central venous catheters; a peripherally inserted central catheter (inserted via a large vein in the arm), a skin tunnelled catheter and an implanted port (inserted via the chest).

So what should you do?
In the first instance, always offer your unaffected arm for injections of any type. Educating practitioners is not forbidden! Let staff conducting procedures involving needles know that it should be avoided so they can look into this in more detail. I have been attempting to spread the word by talking to district nurses and speaking at conferences. It is not uncommon for medical, nursing and phlebotomy staff to have never heard of lymphoedema, let alone know what it is and its implications on someone's life. The purchase of a medic alert bracelet may be a useful tool to help people who are conducting these procedures know that use of the patient's affected arm should be avoided.

Practitioner competency?
Everyone has to learn somehow. Contrary to popular opinion, nurses generally don't enjoy hurting people. Conducting such a procedure needs confidence and expertise. How do you become an expert if you don't start somewhere? It is important that if practitioners are having problems accessing your veins for either a blood test or a cannula, you ask for an experienced member of staff to conduct the procedure. Our rule is to try twice and refer on, as after two attempts, both the patient and the practitioner are getting anxious and this will not help. Ensure that warming the limb has been tried before gaining venous access as this helps enormously. It is worth spending a few extra minutes warming the arm in order to achieve a successful result!

Problematic veins?
Patients who need repeated chemotherapy treatments may develop problems with their veins. The veins may become hard to find and the walls of the veins can become hardened and phlebitis may occur. This is when the wall of the vein can become inflamed causing discomfort and the vein may need to be avoided for further cannulation attempts. Some people are born with "bad veins", often members of the same family have difficult veins. It isn't that the veins aren't there (otherwise the arm would not be a very good colour!) but it is that the veins may be deeper within the tissues and harder to access.

What happens when there are no suitable veins left in the unaffected side?
This is a common question. The most important thing to do in this situation is to discuss any problems with your medical team or your general practitioner. Until we have percentage risk figures then we have to look at the whole picture and each patient's medical history.

Some questions to consider may be:

• What is the regularity of having to have needles in the affected arm?
• What type of treatments are you receiving?
• Is an occasional blood test needed or regular intravenous treatment?
• Can foot veins be used instead for blood tests?
• Should a central venous access device be placed?
• What are the risks of these devices and do they outweigh the risk of potentially developing or worsening lymphoedema?

What happens if both arms have had their associated axillary nodes affected?
If you only require the occasional blood test, then the feet may be able to be assessed for suitable veins. Venepuncture can sometimes be more painful in the top of the foot. By heating the foot and using anaesthetic creams, the procedure can be carried out more comfortably. Some phlebotomists (practitioners who are specifically trained to take blood) are instructed not to use the feet, especially in the general hospital setting. If this occurs, ask your breast care specialist nurse or your GP for advice on who to contact for a blood test should the need arise. Often, blood tests in the feet can be carried out by staff in the chemotherapy day unit. If no suitable veins are present in the foot then a choice needs to be made on which arm should be offered for such procedures. If longer term treatment and/or frequent blood tests are required, then further venous assessment may be necessary. Consensus on the issue of venous access in patients who have had bilateral axillary node treatment can be problematic. Some medical centres advocate early placement of a central venous access device, while others advocate using the arm which had its associated axillary nodes operated on first (providing that side had not undergone axillary radiotherapy). Again, the regularity of the need to gain intravenous access needs to be considered, as well as the potential risks of central venous access devices.

Conclusions
There are still a lot of questions as to why some people develop swelling and others do not. Unfortunately, we still have a lot to learn and medicine does not always have the answers we want. By medical and nursing staff working together with patients, we give the best advice we have at the time and give you the high quality care you deserve. By raising awareness in avoiding the use of the affected side, we can reduce the likelihood of swelling occurring. Prompt and early detection of potential problems means that decisions regarding someone's venous access can be made earlier so that the most appropriate device is selected for the job!

Editor's note: If you have had personal experience of having an injection in the arm and subsequently developed persistent arm swelling we would like to hear from you. Conversely, if you have had an injection of any type in the affected limb and not developed or exacerbated existing swelling, we would also like to hear from you. Your letters will increase our knowledge base in this area and help professionals and patients make informed decisions.

What are the differences between arteries, veins and lymphatics and how do they all connect?

The circulation of blood and other fluids around the body is performed by the circulatory system and this is broadly divided into three parts: the arterial system, the venous system and the lymphatic system.

The arterial system consists of arteries which transport blood, rich in oxygen (carried by red blood cells) and nutrients, to the tissues (muscles and organs) of the body. As this blood passes through the tissues, the nutrients and oxygen are taken up and used by the tissues. Afterwards, the blood is channelled into the venous system which is made up of veins. The blood is then transported through the veins with the help of valves placed along the inside of the veins. These valves push the blood along the veins and away from the tissues, directing it back to the heart and onwards through the arterial system and so the cycle begins again.

It is the arterial system which carries the blood to cleansing organs such as the liver and kidneys, where the unwanted substances can be filtered out. The blood is also replenished with new oxygen as it passes through the lungs and with nutrients as it passes through the gut. It is the heart which pushes the blood through the arteries by its strong pumping action. This pumping action is so strong and achieves such a high pressure in the arteries that, unlike the veins, they do not require valves to help the blood along.

If you think about how we measure somebody's heart rate, we don't usually listen to their heart and count what we hear. We feel their pulse at certain parts of the body where an artery can be felt (usually the wrist) and we simply count what we feel and what we are feeling is the blood passing along the artery with each beat of the heart.

Similarly, when we measure somebody's blood pressure it is the pressure within the arteries that we are actually measuring. If you have ever had your blood pressure taken you may have seen that two numbers are recorded. The top number is the pressure within your arteries during a beat (pump) of your heart and the bottom number is the pressure within your arteries when the heart is resting between beats (pumps).

In addition to the arteries and veins, the circulatory system also involves what is referred to as the microcirculation and it is here where the cells of the tissues or organs gain access to the nutrients brought there in the blood. It is also where the debris, unwanted substances and waste materials are collected and the drainage process begins. Tissue uptake of oxygen results in carbon dioxide which is transported back to the veins. Waste materials and excess fluid drains into the lymphatic system.

The term micro means tiny or very small and this gives us a clue as to what happens in the microcirculation. Because tissue cells are so tiny, they need their blood supply to be brought to them in tiny blood vessels. Arteries, which are very big, divide into a network of tiny vessels at the points where they need to supply the tissues. Once this blood is 'used' by the tissues it has to be taken away and this is done via another network of tiny blood vessels. This network is attached to the veins (venous system) so the blood can be transported away by the veins as described earlier.

So that the tissue cells have access to the nutrients and substances in the blood which has been brought to them, the blood passes from the tiny arterial vessels into highly specialised blood vessels called capillaries. Capillaries are attached at one end to the tiny arterial vessels and at the other end to the tiny vessels leading to the veins, so forming the link between the arterial and venous systems.

As blood passes through a capillary it allows fluid, nutrients and other substances to leak out through its walls and fill the spaces between the cells. (The spaces between the cells contain special proteins which bind themselves to water, and also contains fibres and collagen type substances.) So the spaces between the cells become a kind of reservoir and the cells can absorb what they need from the fluid surrounding them. The cells will also push out any waste matter and excess fluid back into the spaces between the cells and it is here that we first encounter the lymphatics.

How do the lymphatics work?

As nutrient rich fluid flows out through the walls of the capillaries into the spaces between the cells, so an equal amount of fluid, laden with waste substances, drains back into the circulation via tiny vessels. These vessels are the initial lymphatics, so called because they form the beginning of the lymphatic system. Fluid is directed into the initial lymphatics through channels which occur in the spaces between cells. These channels are known as the prelymphatic channels, so called because they occur just before the beginning of the lymphatic system.

The capillaries, initial lymphatics and the combined components of the spaces between tissue cells all work in partnership and this is what we are referring to when we talk about the microcirculation.

Lymph flow

Once fluid enters the initial lymphatics it is referred to as lymph or lymph fluid.

The initial lymphatics are a network of literally millions of hollow tubes, which cover the whole body. As lymph fills the initial lymphatics it flows down away from the skin surface into slightly deeper lymph vessels called the precollectors. These precollectors can also take up some extra fluid from the tissues, in addition to the lymph draining into them from the initial collectors.

So far, the lymph has been gathered by two types of lymph vessels, forming a network of a kind of three dimensional mesh, designed to fill as much space between the cells as is necessary to collect the waste fluid etc.

The precollectors deliver the lymph to vessels (tubes) even deeper and these are known as the collecting lymphatics or collectors (sometimes referred to as the true collectors).

The collecting lymphatics are rather like a chain where each link of the chain is a chamber, separated from the next chamber by a valve. This valve only allows lymph to travel in one direction and the lymph is squeezed from one chamber to the next by the muscular contraction of each chamber in turn.When a chamber has emptied into the next one, it relaxes and because it is empty, the pressure within it drops. This means that when the chamber behind it contracts it has a higher pressure than the empty chamber. This pressurised lymph forces open the next valve and the lymph passes from the full chamber to the empty chamber. As this process is repeated all the way along the chain, so lymph is forced in one direction, towards the lymph nodes (lymph glands).

The body of these lymphatic vessels sends out chemical messages which act on the microcirculation and regulate how much lymph is produced. They also send chemical messages to other chambers (other links in their own chain) which make the chambers contract and relax (pump) faster or slower, depending on the amount of lymph passing through them.

The collecting lymphatics use their valves to direct lymph to clusters of lymph nodes situated in certain regions of the body. There are hundreds of lymph nodes of different sizes (between 0.5 - 3cm in diameter) all around the body. If we look at Figure 1 we can see the direction of the flow of lymph represented by the arrows. It is being directed to clusters of lymph nodes, shown as black dots on the diagram.

Figure 1. Normal lymph flow in skin, towards the lymph nodes

You will notice from the diagram that the direction of the flow of lymph within the skin is different in different areas or zones of the body. For example: look at how the arrows on the left side of the chest show lymph being directed to the nodes in the left armpit; whereas lower down on the left side of the body we can see arrows indicating lymph flow being directed towards the nodes in the left groin area. These zones are called lymphatic basins or lymph territories and are separated from each other by borders which are known as watersheds. This means that the amount of lymph being transported around a particular zone at any one time is controlled to a certain extent.

Once the lymph arrives at the lymph nodes it enters the nodes and is cleansed by a filtering process as it passes through the node. The cleansed lymph then passes out of the other side of the node into new collecting lymphatics. These collecting lymphatics join up with others along the way and form larger vessels called lymph trunks.

So far we have seen that the journey taken by lymph starts in the free spaces between tissue cells and then into tiny little vessels and continues along through bigger and bigger vessels, being filtered by the nodes en route, until this point; where all the lymph produced by the body ends up in the lymph trunks. True to form, these lymph trunks then pass the lymph into even bigger lymph vessels known as the lymphatic ducts, which are the largest lymph vessels in the system and represent the end of the line for the transport of lymph.

The body has two lymphatic ducts situated between the collar bone and the upper part of the chest: one on the left side of the body and one on the right. The right lymphatic duct is only about 1.3cm long because it only takes the lymph drained from the right side of the head and neck, the right arm and hand and the right side of the chest, including the right lung and the right side of the heart. It also takes lymph drained from that small part of the liver that sits in the right side of the chest.

The lymph that enters the right lymphatic duct is finally emptied into the venous bloodstream via a large vein just below the right collar bone.

The left lymphatic duct is also known as the thoracic duct and it takes all the lymph produced from all the other areas of the body, including the right side of the body from the waist down. This means that the majority of the body's lymph trunks drain into it, so it is much longer than the right lymphatic duct, at about 42cm.

The lymph that enters the left lymphatic duct is finally emptied into the venous bloodstream via a large vein just below the left collar bone.

What happens when it goes wrong?

Some people are born with some of their lymphatic system missing or not working properly. Swelling may be obvious at birth or become apparent when a child or adolescent develops. Sometimes it is necessary to surgically remove lymph nodes and surrounding lymph vessels. Damage to the lymphatics may occur through injury, or treatments such as radiotherapy. Other problems in the body may also cause Lymphoedema such as untreated venous disease in the legs, which may increase the amount of fluid in the tissues; eventually overwhelming the superficial lymphatics, which fail from exhaustion.

We know that our bodies can cope without some lymphatics to a certain extent. Our superficial lymphatics seem to be able to reroute some lymph where an original route is blocked, or there are nodes missing. Normal lymphatics can cope with a greater than usual volume of lymph for a while but they do reach a kind of saturation point. At this point there will be more fluid in the spaces between the cells than the lymphatics can cope with and that is when we see swelling appear. The swelling is the visible sign of excess fluid in the tissues. This is Lymphoedema.

Increased lymph in the tissues means an increase of proteins, fluid, fibres and other substances found there. Over time, these substances cause changes in the skin, making it feel tougher and less pliable.

Factors influencing management

Management of Lymphoedema involves the removal of as much excess fluid, proteins, fibres etc. and the prevention of them building up again. This can be achieved by compression garments, massage, bandaging, exercising and addressing any other factors which are contributing to the problem. The approach used will depend on the degree and nature of the swelling and other factors such as what is acceptable to the person with Lymphoedema. Management may be with compression garments only, or with a combination of the other approaches.

Can we retrain our bodies to redirect lymph?

We cannot really retrain our bodies, but we can exploit what we know about lymph drainage and the structure of the lymphatic system. Simple lymphatic drainage, or SLD, guides some excess fluid away from the area of swelling via the superficial lymphatics in the skin.

Manual Lymphatic Drainage, or MLD, opens up new drainage routes in the superficial lymphatics in the skin. It breaches the watersheds, those barriers between the different zones (lymphatic basins or territories) of the body and the fluid is guided to lymph nodes which will be able to drain and filter the excess lymph. MLD also helps to break down the build up of excess fibres within the skin (fibrosis).

Exercise plays an important role in the management of lymphoedema

Exercise is a most important part of managing lymphoedema. Walking is excellent because it helps to pump fluid back up the venous system. Also, as the leg muscles contract and relax they change the pressures in and around the lymphatics, causing a kind of siphoning effect in the superficial lymphatics and helping the initial and collecting lymphatics to pump more effectively. Specific exercises for the arms and hands also employ this technique. Wearing a compression garment during exercise enhances the effect considerably.

Any exercising in water is excellent for reducing swelling, because water pressure exerts a force on the body which is greater then the pressure in the superficial and initial lymphatics. This results in excess lymph flowing into the lymphatic system. If Lymphoedema is present in the lower body or legs, simply walking through chest high water will have excellent results. This is because water pressure increases, the deeper the water; so the feet and lower legs are in a more pressurised (compressive) environment than higher up the body; thus transporting lymph upwards and inwards. The pressure of the water massages the tissues and can act like a sleeve or stocking. Swimming is very good as it uses muscle pumps without putting any load bearing strain on the joints.

Author's note: The lymphatic system also plays a vital role in the body's defences against infection, which is an entire subject in its own right. This article has only looked at the circulatory functions of the lymphatics.

Changes in a Normal Pregnancy
The cardiovascular system undergoes considerable changes during pregnancy with an increase in blood output from the heart by at least 50%. Blood vessels generally enlarge creating a relatively 'under filled' circulation and so to compensate, the kidneys try and conserve salt and water. This leads to fluid retention amounting to some 6-8 litres in the body. The dilution of the plasma proteins encourages fluid to leak from the blood vessels into the tissues. A fall in the threshold of the hormone that encourages a fluid diuresis maintains a fluid retention state. By the end of the pregnancy, 80% of healthy women will have some degree of oedema.
Very little is known about what happens to the lymphatic system during pregnancy. If blood vessels enlarge, i.e. relax, then by implication, lymphatic vessels are likely to do the same, in which case they will not be as efficient at draining fluid. Normally there is sufficient reserve in lymphatic transport so that any increases in tissue fluid will be compensated for by increases in lymph drainage. If the lymph drainage is already working close to capacity because of a genetic or constitutional weakness in the lymphatic system (but not so severe as to have produced lymphoedema before), then the extra demands of pregnancy may be all that is needed to manifest swelling for the first time.
Other factors that potentially increase the risk of oedema during pregnancy are weight gain and a reduction in exercise levels.While fluid retention will increase weight, so will obesity. Lean women who eat to appetite gain as much as 1kg in the first 10 weeks and women with a tendency to obesity will gain much more. Such weight gain will probably have an adverse effect on lymph drainage, particularly in the legs. It is difficult to maintain exercise levels during pregnancy because of tiredness and the awkwardness the pregnancy brings to walking. Exercise is, of course, crucial for good lymph drainage in the legs.
Like other blood vessels, the veins in the leg tend to enlarge during pregnancy. Varicose veins often develop, which will result in a further filtration of fluid from the blood into the tissues of the leg and so make oedema worse.

Pre-eclampsia
Pre-eclampsia (used to be called toxaemia of pregnancy) is specific to pregnancy and manifests with hypertension (raised blood pressure), a leak of protein by the kidney, and oedema. The cause is not known, but the syndrome of pre-eclampsia usually develops from the mid-point in the pregnancy (20 weeks onwards), and resolves completely after delivery. Generalised oedema is an inconsistent feature. It may develop suddenly and is associated with accelerated weight gain (due to fluid retention). Although the ankles and feet will be the commonest site for the swelling due to the effects of gravity, oedema can occur anywhere in the body including the chest and the abdomen (ascites is free fluid in the abdominal cavity). The generalised nature of the oedema would suggest that the fault lies with the blood vessels leaking more fluid into the tissues rather than any failure of the lymphatic system, but nobody knows. As mentioned earlier, any such increase in tissue fluid will inevitably demand more of the lymphatic vessels to drain the fluid and any failure to do so will increase the oedema further.
Diuretics are best avoided in pregnancy because they result in an even greater 'under fill' of the blood circulation. Drugs called 'calcium channel blocking agents' are recommended for the raised blood pressure, but do tend to interfere with the working of lymphatic vessels and may increase ankle oedema.

Lymphoedema in Pregnancy
A major concern of any young female patient with lymphoedema is "What will happen to my lymphoedema if I become pregnant?" The answer is that it is likely to get worse because of the fluid retention, but it should be manageable and fully recover once the baby is born. The extra bodily fluid retained during the pregnancy will include the part of the body affected by the lymphoedema; so extra effort will be required to ensure that this extra fluid is drained by the local lymphatic system that is already failing. So if a leg is affected by lymphoedema, for example, then extra measures to control the swelling may be necessary. These measures may include longer periods of rest with the leg elevated, manual lymphatic drainage, or an additional compression garment. Not every woman with lymphoedema suffers any exacerbation of swelling during pregnancy. In many, the lymphoedema remains unaffected, and so what is described here is the worst case scenario.
There is no reason to believe pregnancy harms the lymphatic system, and so a full recovery would be expected following delivery. Nevertheless, as with returning to one's original weight and bodily shape, recovery of the lymphoedematous limb may take a bit of time and effort. Increasing levels of exercise and dieting may be necessary.

Genetics, Lymphoedema and Pregnancy
Primary lymphoedema is due to an underlying abnormality in the lymphatics. Although the swelling may not be present until later in life, the abnormality is probably present at birth. It is now recognised that there are some causes of primary lymphoedema that are inherited. Therefore a woman (or man) with primary lymphoedema may have a child with the same condition.

Family History
The best indicator that there is a genetic cause of lymphoedema is the presence of other affected individuals in the family. The commonest way that primary lymphoedema is inherited is from parent to child. This mode of inheritance is called autosomal dominant inheritance. There are two copies of most genes. An autosomal dominant condition is due to an alteration, or 'spelling mistake', in one of the copies. The baby can inherit either the affected gene or the unaffected gene, so the risk to the offspring of inheriting an autosomal dominant condition is 1 in 2, or 50%. Some of the genetic causes of primary lymphoedema are well recognised and are described in more detail below.

Milroy's Disease
Milroy first described a large family with lymphoedema presenting at birth in 1892. It was clear from the family history that this condition was autosomal dominant, and therefore being transmitted from parent to child.Milroy's disease presents predominantly at birth with swelling of the lower limbs, usually the feet. The swelling can increase, or improve, or remain stable. Boys sometimes have extra fluid in the scrotum, but this rarely causes any problems. Milroy's disease is not usually associated with any other abnormalities.Most of the carriers of this condition have some swelling of the lower limbs, but it is recognised that some carriers of the condition are not affected, but may have affected offspring. The lymphoedema in Milroy's disease is due to a lack of lymphatic channels in the lower limbs (hypoplasia or aplasia). The gene for this condition, Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) was identified only recently. This gene is important in the development of the lymphatics of the baby.

Lymphoedema-Distichiasis Syndrome
This condition is another autosomal dominant cause of primary lymphoedema. However, the lymphoedema usually presents in late childhood or puberty. The age of onset and severity of the swelling varies even within families. The swelling is usually associated with the presence of extra eyelashes on the inner side of the eyelids.
Although the swelling presents later, it is still due to an underlying abnormality of the lymphatic channels. Lymph scans in affected individuals have shown that there are a normal or excess number of lymphatic channels with delayed uptake of lymph in the inguinal lymph nodes, suggesting an abnormality in the function of the lymphatic channels. The mechanism is still unknown. This condition is sometimes associated with other congenital abnormalities. About one third of affected individuals have drooping of the eyelid (ptosis) which occasionally requires surgical correction. There is a slightly increased risk of heart disease at birth (8%). This is not usually severe, but may require surgical repair. A few affected individuals also have a cleft palate (3%).
The gene for this condition has been identified; it is a very small gene called FOXC2. It clearly has a role in the development of the lymphatics and eye, but very little is understood about its function.

Risk of Inheriting Lymphoedema
The risk of inheriting lymphoedema for those types where the gene is known and in which a family history exists, is approximately 50%, i.e. 1 in every 2 births. There are, of course, many other causes of primary lymphoedema.Many of these may be genetic but not inherited. Often the underlying cause is not known. The baby is at an increased risk of inheriting the lymphoedema if any of the following are present:

1. If one parent is affected and has a family history of lymphoedema
2. If the affected parent has distichiasis (extra eyelashes)
3. If the lymphoedema is symmetrical and bilateral.

1. The affected parent has no family history of lymphoedema
2. There is no distichiasis
3. The swelling is unilateral (including lower limbs)
4. The swelling is not in the lower limbs.

How Can You Tell If the Baby is Affected
Ultrasound examinations performed during the pregnancy may pick up oedema in a foot or around the back of the neck, both signs that the child may be affected. In the majority of cases, no abnormalities will be observed, and it may only be after birth or sometime later in life that the lymphoedema becomes obvious. In the future it may be possible to test the baby for the offending gene during the pregnancy, but this is not possible at present.

Prevention of Lymphoedema
In the years to come, we hope it will be possible to correct the faulty gene before the baby is born so that the lymphoedema can be reversed. This has been achieved in animals, but not yet in humans. Insertion of the normal gene instead of the faulty one is called gene therapy. It may be possible to do this in adults already affected by lymphoedema. There is hope!

Lipoedema and Pregnancy
Pregnancy may trigger or exacerbate lipoedema and worsen the lymphoedema component of lipoedema.
Lipoedema is a condition that results in swelling of the hips, thighs or legs in females. Fluid does contribute to the swelling, but the main component is fat, but in a way different from obesity. In addition to swelling, which gives rise to a 'bottom heavy' or 'chunky, shapeless legs' appearance, symptoms of tissue tenderness and easy bruising are commonplace. Lipoedema tends to develop or deteriorate at times of hormonal change, e.g. puberty, pregnancy and menopause. The condition may not be apparent during the pregnancy because of all the other changes that take place. Following the pregnancy, however, weight loss may prove difficult from the lower half of the body (bottom, thighs and legs). Dieting tends to result in fat loss from face, neck and chest, but not the legs. Treatment is difficult, but a vigorous exercise regimen and healthy eating are recommended. The fluid component of lipoedema appears to be related to poor lymph drainage from the areas of fat deposition. As the fluid increases, so more noticeable oedema develops, particularly in the feet. This is called lipoedemalymphoedema syndrome (lipolymphoedema). Pregnancy may therefore trigger or exacerbate lipoedema.

Conclusions
In summary, in female patients with lymphoedema, pregnancy may create additional concerns with regard to adverse effects on the swelling and the fear of passing on the condition to any offspring. In most cases these concerns are unfounded. Any increase in swelling can usually be managed satisfactorily with the help of a lymphoedema therapist, with a full return to normal once the baby is born. In many individuals the lymphoedema will not change. In the event of a child inheriting lymphoedema, it does not follow that their condition will be the same or worse than that of the parent. The recent upsurge in our knowledge of the genes and proteins involved in lymphatic growth and development means that the possibility of curative or even preventative treatment for primary lymphoedema is greater than ever before.

Hyperkeratosis	Papillomatosis

What are hyperkeratosis and papillomatosis?
These are changes which can take place within the skin and present as thickening and solidness (described as fibrosis*) of the tissues.
The cause of these characteristic changes is the result of untreated lymphoedema and are generally found on lower limbs.

How can they be recognised?
Hyperkeratosis is a warty scaly change in the skin due to an increased production of keratin, a surface protein.
Papillomatosis is a cobblestone change in the skin surface due to dilated surface lymphatic vessels or focal accumulations of lymph; they are non-compressible due to thickening and fibrosis of surrounding tissues. Warty hyperkeratosis and papillomatosis often coexist in which case the skin resembles elephant skin (known as elephantiasis).

How can they be prevented?
As already stated, these changes generally appear as a result of oedema being untreated. The fitting of good quality compression hosiery and meticulous daily skin care, including the use of moisturising cream, should help to prevent changes occurring within the skin and tissues.

How can these changes be treated?
It is important to moisturise the affected area twice daily with 50% white soft paraffin and 50% liquid paraffin mixed, until the skin improves. In more severe cases, salicylic acid 5% in an ointment base may be used, this will help to lift the scales from the skin surface. This must be discussed with the health care professional responsible for your care.
When the skin condition has improved, daily application of aqueous cream can be applied at night in order to keep the skin well hydrated and supple. Appropriate class and size of compression hosiery must be worn daily to maintain the improved skin condition.
If the limb is very swollen and distorted in shape it will be essential to receive an intensive course of treatment known as decongestive lymphatic therapy (DLT) from a qualified lymphoedema specialist.

NB * Fibrosis is an increase in the thickness and amount of collagen in the skin. It conveys a harder consistency to the tissues concerned.

Lymphoedema of the genital region is relatively uncommon, but is extremely uncomfortable and distressing for the patients who suffer with this condition. It can affect both men and women alike, but is seen more frequently in males due to the anatomical differences between the genders and effects of gravity. Around ten percent of people who develop leg oedema will have associated genital swelling, but some patients can have genital oedema alone.
In some circumstances, genital oedema can occur acutely due to trauma or cellulitis and may be able to resolve completely by itself. Far more usual however, is the chronic genital oedema, which is unfortunately irreversible, but can be controlled and reduced through appropriate lymphoedema management. The main cause of genital oedema is either due to primary or secondary lymphoedema.

Primary lymphoedema affecting only the genitals is rare. It can be noticed from birth or during the teens, and as the affected individual grows, the involved lymphatic system becomes ever more under pressure to drain the tissue fluid and the swelling becomes far more obvious. The main reasons for primary genital lymphoedema are that the lymph vessels are absent or reduced in number or simply don't work as well as they should i.e. functional failure. It has also been thought that primary lymphoedema patients who are obese, have an increased risk of genital swelling due to greater pressure on the groin from the enlarged abdomen.

Secondary lymphoedema more commonly affects the genital region than primary lymphoedema. In Africa, India and other tropical countries, genital swelling is frequently seen due to infectious diseases like filariasis. This can lead to gross elephantiasis of the penis and scrotum. In the Western world, the majority of genital oedemas are from trauma or surgery to remove gynaecological, urological, abdominal or prostatic cancers. It has been reported that up to 70% of patients treated for carcinoma to the vulva will have lower body swelling. Radiotherapy to the lymph nodes in the groin or abdominal region can also cause genital lymphoedema. The incidence also increases if there has been surgery and radiotherapy plus episodes of cellulitis.

Clinical Features
Swelling - Various parts of the genital anatomy can become swollen. In males, both the penis and scrotum, or each, can swell independently. Very few patients just have penile oedema, but it does happen, as can be seen from the case study. Sometimes, the scrotum becomes so swollen, that the patient has difficulty in walking. As the swelling increases, it can involve the area above the base of the penis (called the pubic area), thus causing the penis to retract into the scrotum. This clearly causes problems for micturition (urination)and sexual activity.
In females, the inner and outer lips of the vagina (labia) can become so swollen that they extend out of the vagina by up to 6 inches; again this creates problems for sexual activity and urination. In both genders, the pubic area on the lower abdomen alone can become oedematous, with associated skin changes and fibrosis.

Genital swelling can occur due to other causes. Palliative patients who have renal, cardiac or hypoproteinaemia (high output failure due to low protein) and patients who have had venous problems, could develop genital oedema. A clear diagnosis and medical investigations are needed, prior to lymphoedema management.

Pain is a problem for some patients, who describe a dragging, heavy, bursting sensation or an ache around the genital region. This is usually eased when the area is decongested or lifted by a jock straplike support or cycling shorts.

Skin changes are readily seen in genital oedema. Thickening and dry, flaking skin (hyperkeratosis) or warty blisters (papillamatosis) do occur as the swelling progresses.

Acute Inflammatory Episodes (cellulitis) are commonly seen in oedematous skin, which is the ideal medium for bacteria as it is generally warm, moist and has numerous crevices. The bacteria multiply in the protein rich oedema fluid, and infections can spread throughout the genital region, causing it to be red, hot, tender and swell even further. More often than not, an infection is seen as the precipitating factor in causing the swelling.

Fungal Infections do occur, due to the area being moist, warm and having so many crevices. Sweating also can trigger fungal infections.

Lymphorrhoea occurs when the tissue pressure increases and causes leakage of fluid from the thin layer of skin. Lymphorrhoea can continue for a few days or weeks and carries a high risk of developing infections. It can be very distressing for patients, as some have to wear incontinence/sanitary pads to absorb the copious fluid. Lymphoedema treatment is necessary to stop this leakage.

Sexual Dysfunction happens as the oedema increases. In males, impotence or painful erections impede sexual intercourse. Females find that the presence of oedema dampens sexual activity, due to decreased libido and pain.

Lymphoedema Treatment and Management
The four cornerstones of lymphoedema care can be modified to treat genital oedema.

Skin Care and meticulous hygiene of the genitals is imperative. Daily bathing with an antibacterial soap and drying the area afterwards is very important to reduce the likelihood of infections. Regular moisturising with an aqueous cream will deter any areas of dry, flaky skin and keep the area soft.
As this area is prone to fungal infections and cellulitis, regular inspection will enable the patient to detect any early signs of inflammation. If an infection occurs, prompt anti- fungal or antibiotic treatment is required. If a patient suffers from recurring cellulitis episodes, then longterm prophylactic antibiotics may be required.

Compression Garments or Multi- Layered Bandaging techniques are needed to give the genital area support and compression. The penis, scrotum and labia areas will continue to swell until a firm outer casing prevents them from doing so. This outer casing works by providing the muscles with a base to press against, thereby, reducing the swelling.
The best form of compression garment comes in the form of custom-made tights or shorts. Spandex or padded cycling shorts and sports jock straps are also very useful to provide more comfort to the oedematous areas. Under garments must be firm and supportive, not loose. In some instances, two pairs, or an under garment plus swimming trunks, have been found to be effective.
Foam inserts also can increase the amount of compression to the penis, scrotum or female genital area. Ladies may find that the addition of a sanitary towel underneath garments is also helpful. For male patients with significant penile and scrotum swelling, a regime of multi-layered bandaging may be appropriate. This will consist of washable or disposable bandages and padding/foam being applied to the scrotum and penis separately. Your lymphoedema specialist will need to have had additional training in managing lymphoedema of the genitals, as bandaging the genital area can be very awkward, particularly in getting the bandages to stay in place once the oedema has reduced. Occasionally, bandaging can cause an irritation at the base of the penis and the edge of the scrotal bandaging, thus care must be taken to ensure adequate padding is in place.
Simple solutions that have helped, include creating a harness for the swollen scrotum, using a soft pliable material like splint foam or 'Velfoam' prior to padding and bandaging. The harness creates more uplift for the scrotum and patients find it more comfortable as the bandages don't tend to slip. The harness and the penile bandaging can be kept in place using Velcro strips, as it is much easier to apply and reapply and does, therefore, tend to stay in place better. The use of compression shorts, post bandaging, also draws the genitals close to the body and also keeps the bandages in place. All bandages can be easily removed for micturition or if soiled, and the patient taught how to apply/reapply them. The use of bandages can significantly reduce the oedema, which would be maintained by compression garments such as shorts or tights.

Exercise in any form is important, as it keeps all the joints and muscles working adequately. If there are no areas of broken skin, then an excellent form of exercise is swimming or walking in the water. The genital area will have some support from the swimming attire and the pressure from the water assists too. Other forms of aerobic exercise that are also useful are cycling and walking, but it is important that compression garments and padding are worn when cycling.
A specific form of exercise for female genital oedema is the pelvic floor exercise. Together with abdominal exercises and diaphragmatic breathing, pelvic floor exercises can help in reducing the oedema. Ask your lymphoedema specialist or physiotherapist for further advice.

Lymph Drainage is an important part of lymphoedema management. Manual Lymphatic Drainage (MLD) and Simple Lymphatic Drainage (SLD) are massage techniques designed to move fluid away from the swollen genital region, to parts that are not affected, to drain freely. The massage itself is very light and is not painful. It is also very useful in softening hard, fibrosed tissue. MLD is a technique that is carried out by trained therapists. SLD is a simplified form of MLD and can be taught to the patient or carer to do themselves.

Surgical Management
In some cases where conservative treatment does not control the swelling, surgical intervention may be required. Surgery could involve reducing the scrotum, penis or labia with the aid of plastic surgery skin grafting.

Case Study
Mr A is a 68-year-old gentleman who has suffered with genital oedema since November 2001.Whilst on holiday in 2001, Mr A developed a painful spot on the right buttock possibly from an insect bite. Unfortunately, this blemish continued to increase in size and eventually became an abscess. He was operated on 3 times in a generalist hospital and due to infections and gangrenous tissue, some of his inguinal lymph nodes were removed. Mr A's genital swelling started soon after the surgery and was sited in the penis area alone. He unluckily had numerous cellulitis episodes, which in turn increased the penile swelling. The scrotum area was severely distorted due to the previous operations and in December 2002, Mr A underwent plastic surgery to graft and lower the testicle area, which although improved the cosmetic appearance of the testicles increased the penile swelling.
Mr A was referred to the lymphoedema service and assessed in June 2003. On examination, the genital area was red, inflamed and had a discharge from the shaft of the penis, which was grossly oedematous. The lymphorrhoea had been present for the last 6 months and Mr A had to pad the area to stop it staining his under garments. Severe skin changes were apparent with brown discolouration patches, hyperkeratosis and fibrosis all over the penis. The pubic area was also swollen and fibrosed.
Functionally, Mr A felt all forms of activity were limited, as well as travelling and socialising. He suffered an extreme amount of discomfort and pain, which hindered his mobility, and psychologically he felt that the oedema had greatly affected his quality of life and the way in which he viewed himself as a man.
Treatment commenced immediately, with Mr A starting a 2-week course of antibiotics to manage the infection. Information regarding hygiene and daily moisturising with an aqueous cream was initiated to help the skin changes, and antibacterial talc was recommended to reduce friction in the groin region. A simple technique of bandaging was also taught to the patient to reduce penis size and stop the leaking fluid. MLD was started and SLD was taught, to improve the fibrosis and create collateral drainage.
Mr A was reassessed four weeks later and was delighted with the results. His penile swelling had reduced significantly, making it look far more normal. The skin condition was greatly improved with all areas of hyperkeratosis and leaking diminished. His mobility was normal due to the pain being relieved and he informed me that he had booked a holiday. He is continuing with his lymphoedema regime, consisting of SLD, multi-layered bandaging and daily use of his compression padded cycling shorts, which will keep him in control of his genital oedema.

For further information regarding genital oedema, ask your lymphoedema specialist or medical practitioner.

Antibiotics are often recommended on a long term basis in patients who have recurrent attacks of cellulitis. The reason is quite simply because nothing else works (unless there has been a substantial improvement in the swelling following decongestive lymphatic therapy). Cellulitis results from the compromised local immunity within the swollen region (but not your overall body).

Treating with antibiotics as and when each attack of cellulitis occurs is a bit like 'shutting the stable door after the horse has bolted'! Each attack of cellulitis can not only make you ill but tends to cause a deterioration in the swelling and make the tissues (skin and underlying fat layer) harder (fibrotic). This does not help the long term control of the lymphoedema. Experience has shown that the best way of controlling recurrent attacks of cellulitis is with a low dose of antibiotic taken every day (usually penicillin or erythromycin). Unfortunately this approach, nor any other for that matter, may not necessarily cure the infection and an attack could start immediately if you inadvertently stop the antibiotic. Therefore please only comply with the recommendations made by your GP or lymphoedema therapist.

There is no reason to believe that long term antibiotics are harmful or affect your whole body's immunity. For decades penicillin has been given life long without a problem to patients who have had their spleen removed. Therefore safety seems assured providing you are not allergic.

What is Lymphorrhoea?

Lymphorrhoea is the leakage, or weeping, of lymph fluid through the skin surface. Large beads of fluid appear on the skin and trickle from the affected areas.

Causes of Lymphorrhoea

• May be the result of lacerations, abrasions, or trauma of the altered dry skin of longstanding oedema e.g. graze/cut
• It may result from the rupture (bursting) of lymphangiomas (described more fully below)
• It may also occur in a sudden or acute oedema (swelling) where the shiny, taut skin has stretched so rapidly that it splits, forming a leak.

Lymphorrhoea - the problems it causes

• The skin feels very cold, wet and uncomfortable
• The fluid can soak through dressings which may need changing many times a day to cope with the large amounts of leakage
• The fluid can collect in shoes/slippers… clothing and bed linen can become soaked and require frequent changes
• Lymphorroea will increase the risk of cellulitis - the break in the skin acts as an entry for bacteria. Infection will cause further problems (pain/inflammation/flu-like symptoms and increased amounts of fluid leakage)
• If left to leak and dressings are not regularly changed the lymph (being an excellent culture medium) may grow bacteria causing odour and discolouration
• Lymphorrhoea may cause social difficulties and embarassement. Lymphorrhoea not uncommonly affects the genital area and may be difficult to distinguish from urinary incontinence.

Treatment of Lymphorrhoea

In order to stop the fluid leaking, a series of steps are essential.
Your Lymphoedema nurse/therapist or other nurse involved in your care should be able to help you with these steps following a full assessment of the cause of the leakage:

• The area around the 'leak' needs to be cleaned carefully to ensure the risk of infection is reduced.
• An emollient (moisturising cream/lotion) should be applied to the skin to improve the condition and protect it (by acting as a barrier) against further skin breakdown.
• A non-adherent (non sticky), absorbent, (e.g. Allevyn/Cutinova/lyofoam) sterile dressing should be applied to the leaking area to prevent further trauma to the skin - and to absorb the leakage.
• Pressure should be applied. For example a limb should be supported with appropriate bandaging e.g. Multi Layer Lymphoedema Bandaging (MLLB) with short stretch compression bandages. This normally stops the flow of leakage within 24-48 hours. Bandages may have to be replaced frequently during this period of time to remove wet bandages/ dressings and to prevent further skin breakdown. MLLB should continue until the skin condition has improved enough to wear your stockings/sleeve again.
• At rest, the affected limb should be elevated to reduce the effects of gravity.
• Once the leakage has stopped, and the skin condition has improved, your usual compression garment should once again be applied. The garment will keep the swelling to a minimum and prevent any further 'leaks' appearing.

Lymphangiomas

Lymphangiomas are often referred to as 'lymph blisters'.
They consist of enlarged, or bulging lymphatic vessels just under the surface of the skin, which give the appearance of a blister.
Lymphangiomas can occur as a result of damage to the deep lymphatic vessels e.g. following radiotherapy, or surgery and they generally contain clear lymph fluid (though sometimes it can be blood stained).
If Lymphangiomas burst, they result in wetness around the area… or even profuse leakage which is a risk of potential infection.
Treatment involves strict skin hygiene and the usual lymphoedema cornerstones of treatment - especially compression.
If left untreated, the lymph blisters may become harder and firmer and begin to look like firm skin nodules.
Lymphangiomas are not cancerous.

Many patients suffering from oedema/lymphoedema will have heard about electrical compression pumps at some point when trying to find a suitable treatment programme to reduce their swelling. The LSN frequently receives calls about the differing types of machines available and also for information/advice about how and when they should be used. The following information may prove beneficial to some of you who maybe thinking of using PCT to control your oedema.
Pneumatic Compression Therapy (PCT) has been used for over 25years in the treatment of lymphoedema and until the last decade or so, pumps and compression garments were the only real treatments available to patients. They were used commonly for people who had developed an oedema following a Deep Vein Thrombosis (DVT) and also for women who had oedema following mastectomy.
PCT consists of a small electrical compression pump, or device, which is attached by plastic tubing to an inflatable plastic sleeve/boot. This fits over the affected arm or leg. The machine pumps air into the sleeve/boot, causing it to inflate, and then after a set number of seconds, it turns off and allows the sleeve/boot to deflate. The cycle of inflation and deflation goes on as long as the machine is switched on. Varying pressures maybe selected which will allow the sleeve/boot to fill up with more, or less air.
There are various makes and models available that range from small portable pumps with single or 3-chambered sleeves/boots, to larger models with multichambered sleeves/boots. Functionally, they fall into 2 categories:

• SEGMENTAL (sequential, multi-chambered) - the plastic sleeve/boot has several compartments (3, 5 or 10), which inflate (and compress) in sequence. The same pressure is applied to each segment of the garment in turn, and is said to mimic the natural pressure changes that occurs in the limb.
• NON-SEGMENTAL (single chambered) - a single continuous sleeve/boot that is inflated (compressed) all at once, then released.