Background Biological evidence reported in the literature supports the role of CELSR1 as being essential for valvular function in murine lymphatics. Yet thus far, there have been no variants inCELSR1associated with lymphatic dysfunction in humans. Case Presentation In this report, a rare early inactivating mutation in CELSR1is found to be causal for non-syndromic, lower extremity lymphedema in a family across three generations. Near-infrared fluorescence lymphatic imaging shows that instead of being propelled within the lumen of well-defined lymphatic vessels, lymph moved in regions of both legs in an unusual fashion and within sheet-like structures. Conclusion CELSRImay be responsible for primary, non-syndromic lymphedema in humans.

Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical support and feasibility of clinical implementation. The manuscript proposes a grid framework for comparing the ability of each modality to quantify specific lymphedema characteristics, including distribution, dysmorphism, tissue composition and fluid content, lymphatic anatomy and function, metaplasia, clinical symptoms, and quality of life and function. This review additionally applies a similar framework approach to consider how well assessment tools support important clinical needs, including: (1) screening, (2) diagnosis and differential diagnosis, (3) individualization of treatment, and (4) monitoring treatment response. The framework highlights which clinical needs are served by an abundance of assessment tools and identifies others that have problematically few. The framework clarifies which tools have greater or lesser empirical support. The framework is designed to assist stakeholders in selecting appropriate diagnostic and surveillance modalities, gauging levels of confidence when applying tools to specific clinical needs, elucidating overarching patterns of diagnostic and quantitative strengths and weaknesses, and informing future investigation.

Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.

Previous studies have shown cost effectiveness and quality-of-life benefit of pneumatic compression therapy (PCT) for lymphedema (LE). Insurers, such as the Centers for Medicare/Medicaid (CMS), however, desire visual proof that PCT moves lymph. Near-infrared fluorescence lymphatic imaging (NIRFLI) was used to visualize lymphatic anatomy and function in four subjects with primary and cancer treatment-related LE of the lower extremities before, during, and after PCT. Optically transparent and windowed PCT garments allowed visualization of lymph movement during single, 1$$ h PCT treatment sessions. Visualization revealed significant extravascular and lymphatic vascular movement of intradermally injected dye in all subjects. In one subject with sufficient patent lymphatic vessels to allow quantification of lymph pumping velocities and frequencies, these values were significantly increased during and after PCT as compared to pre-treatment values. Lymphatic contractile activity in patent lymphatic vessels occurred in concert with the sequential cycling of PCT. Direct visualization revealed increased lymphatic function, during and after PCT therapy, in all LE-affected extremities. Further studies are warranted to assess the effects of PCT pressure and sequences on lymph uptake and movement.

Background: Absorbance of near-infrared (600–800 nm) light by the tissue components water, melanin, and hemoglobin is minimal. This property allows the use of near-infrared-emitting fluorophores for noninvasive, in vivo , real-time imaging of tissue, without the interference of autofluorescence experienced with imaging in other wavelength ranges. Near-infrared (NIR) fluorescence imaging has been used to noninvasively image lymphatic architecture and pumping function in animals, as well as in humans. The effects of different doses of a NIR dye, indocyanine green (ICG), on lymphatic function have been questioned. This study aims to address these concerns in the context of a mouse inguinal-to-axillary lymphatic imaging model. Methods and Results: We measured lymph propulsive velocity and frequency using an imaging system composed of a laser diode for excitation of the dye, an image intensifier, and an intensified charge-coupled device (ICCD) camera to capture real-time images. At 0.32, 0.645, and 1.3 m M ICG, no significant differences in lymphatic propulsive velocity or frequency were observed. Additionally, the use of other NIR imaging agents did not result in significant differences. Conclusions: The use of different concentrations of ICG and the use of other near-infrared fluorophores for optical imaging of lymphatics does not significantly affect lymphatic propulsive velocity or frequency.