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Calderwood et al. Plast Aesthet Res 2021;8:40 https://dx.doi.org/10.20517/2347-9264.2021.14 Page 11 of 14

Limitations
Despite its many advantages, MRL does pose some challenges, particularly in relation to its use of
gadolinium-based contrast. It should be noted that gadolinium has been shown to store within the body as
an inert substance bound to molecules, and the long-term effects are yet to be confirmed [42,43] . Numerous
studies have observed retention of gadolinium in the brain (specifically deep nuclei), bones, and skin
following GBCA use [42-44] . Furthermore, many contrast MRL studies report the use of gadobenate
dimeglumine for the contrast medium, which has a linear chemical structure [1-4,6,13,14,16-18,22,23,25,27-30] . Linear
GBCAs are reported to result in greater gadolinium retention for a longer time period than macrocyclic
GBCAs, likely relating to the chemical stabilities of these agents [44,45] . Although the health implications of
gadolinium retention are not known, the International Society of Magnetic Resonance in Medicine Safety
Committee recommends that the use of GBCAs are avoided when not necessary . Additionally, the FDA
[44]
has issued warnings relating to the retention of GBCAs and recommends that repeat use of GBCA is
[46]
minimised where possible . At this stage, as there is no strong evidence regarding the side effects of
GBCAs, the United States FDA and Australian TGA have not removed any agents from the market, whilst
the European Medicines Agency has removed the linear chelates gadodiamide, and gadopentetate from the
market . In current practice, linear GBCAs are rarely used and it should be noted that it is now common
[44]
practise to use macrocyclic agents for contrast-enhanced MRIs.

Due to its water solubility, gadolinium contrast is taken up into the venous system. It does not occur with
the colloid-binding tracers used in lymphoscintigraphy, which are more specific for the lymphatic system
than gadolinium [3,22,24] . Enhancement of the venous system may complicate analysis since it can be difficult
to distinguish veins from lymphatic vessels [3,6,8,9,18,19,22,30] . Additionally, unaffected limbs do not image well on
both enhanced and non-enhanced MRL owing to their faster lymphatic flow resulting in contrast washout
on enhanced T1-weighted scans and less signal intensity on T2-weighted scans (as signal intensity is caused
by static fluid) [19,20] . It limits the understanding of the location of healthy vessels in the affected limb, and
therefore it may be difficult to identify potential collateral drainage pathways. Furthermore, lymphatic
vessels must have a degree of function to uptake contrast. Several studies identified patients with clinical
lymphoedema that had completely non-functional lymphatics with no contrast uptake on MRL, most
commonly seen in aplasia/hypoplasia primary lymphoedema [3,4,13,16,27-29] . It has also been recognised in two
articles that the larger proximal lymphatic trunks do not enhance as well as the smaller distal vessels on
[8,9]
contrast-enhanced MRL likely also from contrast washout . There are a variety of protocols regarding the
exact location and number of sites for contrast injection, and the validity of these protocols has not been
compared to form a standard protocol for optimal anatomical detail .
[34]
As with all injections, there is a small risk of hypersensitivity to the contrast agent, injection site infection,
pain at the injection site, intra-vascular contrast administration, and pulmonary embolism. Some papers
excluded patients with renal insufficiency from their study cohort. However, there is insufficient evidence
on the effect that gadolinium-based contrasts have on renal function [11,14,16,17,18,22-24,26] . Nephrogenic systemic
fibrosis has been reported as a complication of GBCA exposure in patients with severe renal failure.
However, these reports are not specific to MRL [41-43] . Of note, it has s been found that only 3% of patients
with end-stage renal failure developed nephrogenic systemic fibrosis following the administration of
GBCAs . However, a review article of MRL described that no adverse events or allergic reactions were
[42]
noticed in primary and secondary lymphedema patients .
[47]
Contraindications for MRL are the same as for other types of MRI, including patients with severe
claustrophobia, pacemakers, ferromagnetic intracerebral clips, or any other electrically, magnetically, or
mechanically activated implants [21,24,25] . Some patients may have difficulty remaining still within the confined
[3]
space of an MRI machine due to discomfort, anxiety, chronic back pain, and movement disorders . Patient