Lymphomics; improving the understanding of the anatomy of the lymphatic system and the direction and velocity of lymph flow

Lymph is part of the fluid that is in the interstitium of the body. It
circulates via the lymphatic vessels and is connected to the venous system, in
particular the subclavian veins. Lymph contains lymphocytes and has a role in
the immune system. Lymph from the liver and bowels is called chyle and contains
a large amount of triglycerides and peptids, and this has an important function
in feeding the body.
The knowledge of lymph is limited. The organ of lymph, consisting of vessels en
nodes, seems to be a much forgotten or neglected one for the last decades.
Knowledge of the embryology, etiology and anatomy as well as knowledge of lymph
function and etiopathogenesis of lymphatic disorders is largely unknown and
much is to be discovered yet. This goes especially for the (patho)physiology of
the flow of lymph in the central lymph vessels.
Primary edema of a limb, ascites, chylothorax or leakage of lymph or chyle can
be impairing for normal development, daily activities and quality of life. The
cause can be found in a congenital anatomic or conducting disorder of the
lymph. The types can be divided per cause (congenital or acquired) or per
location (central or peripheral). In fetuses, a central conducting disorder can
result in fetal hydrops and this can be lethal. Central lymph flow disorders
may be acquired after (retroperitoneal or mediastinal) disease or surgery, due
to extensive removal of lymph nodes or injury to the thoracic duct. If the
lymph cannot flow into its mouth in the subclavian vein, it may leak in a more
upstream level, either as chylothorax, chyloascites or lymphedema or even
chylus leaking from the scrotum or vagina. Peripheral lymph flow abnormalities
can result in edema of an extremity, which can be congenital (primary) or
postoperative (mostly after lymphadenectomy for oncologic reasons).
It is not known how many people are impaired with lymph flow disorders, as many
of these patients have unrecognized symptoms and remain without diagnosis. This
goes especially for the patients with congenital central lymph flow disorders.
For instance, patients with Noonan syndrome may have abdominal swelling and low
proteins without complaining and without being aware that this is an
abnormality called protein losing enteropathy caused by retrograde flow of
chyle into the bowels. Also, patients with the diagnosis primary lymphedema
(which implies to be without known cause) may have an anatomic or functional
abnormality of the lymph vessels, that is not diagnosed as the causative lymph
flow problem. Patients with a cardiac condition called Fontan circulation may
have ascites and protein losing enteropathy while others have not. It is
unknown what the causative mechanism is.
Currently, there is no protocol for diagnosing lymph flow disorders. In many
cases the diagnosis is based on the symptoms and not on the underlying abnormal
lymph anatomy or flow. There are tests for the lymph flow, such as lymph
scintigraphy, however this has a very low spatial and temporal resolution. Some
institutions use MR T2 images, which images fluid (lymph), but not flow.
Recently the dynamic MR lymphangiography (DMRL) with intranodal contrast
injection was introduced in the Radboudumc, based on the scan invented in
Philadelphia. With this DMRL scan the flow of lymph in the central lymph
vessels is visualized, to diagnose anatomic and flow abnormalities. This
dynamic imaging is the gate to improving therapy such as minimal invasive
embolization of leakages. However the DMRL has not been validated yet and it
has not been studied what the additive value is compared to conservative or
non-invasive tests.
With the diagnosis being based on the symptoms and not on the underlying cause,
as a consequence the therapy will focus on diminishing symptoms and not healing
the pathological cause. For primary lymph edema, the current therapy is
bandaging; however the probable cause is found in abnormal retrograde lymph
flow and aberrant lymph vessels. For chylothorax, the current therapy is
drainage, however the cause being a leak in the thoracic duct is rarely
examined nor subject of therapy. It is important to gain more knowledge of the
pathophysiology in order to improve therapy.
This study is researching several aspects of lymph, as described in the
objective. The aim of this study is to help the patients with lymph flow
disorders. Due to the lack of current research, this is accomplished by first
aiming for improving the basic knowledge of lymph anatomy, lymph flow and lymph
velocity in healthy volunteers. Thereafter, abnormalities could be easier
recognized and possibly treated.

To improve the knowledge and understanding of the (patho)physiology of lymph
disorders
Main objective: the anatomy of the central lymph vessels, the velocity and
direction of lymph flow and its influencers and thoracic duct outlet location
and patency.

This is a single center, prospective collection of data of MR lymphangiography
and contrast-enhanced ultrasound imaging in our center. The anatomy of the
central lymph vessels will be studied. The MR lymphangiography scans will also
be reviewed for measurements such as the width of the thoracic duct and the
location of inflow into the subclavian vein. The velocity of the lymph flow
will be measured on the MR images that were made after intranodal contrast
injection. In addition, thoracic duct outlet location and patency will be
determined using contrast-enhanced ultrasound imaging of the left and right
neck.

Participation places subjects at minimal risk. The health benefit of this study
for the healthy volunteers is zero, the incentive is the benefit for the
subjects. Subjects will undergo placement of a small needle in an inguinal
lymph node on both sides , with very little risk of bleeding and/or infection,
as with other minimal invasive procedures. The contrast agent used for the DMRL
and used for contrast-enhanced ultrasound imaging carries minimal risk of
adverse reaction. The dynamic MR lymphangiography will take approximately two
hours. In the Radboudumc, around 70 patients undergone the DMRL, all without
complications.

During this study, there may be incidental findings that are not relevant for
the study, but are for the subject. If this is important for the subjects
health, . the primary care physician will be informed by de study coordinator
in case of an incidental finding. The subject will also consent to this.