Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head‐down tilt using near‐infrared fluorescence imaging

Abstract

Evidence overwhelmingly suggests that the lymphatics play a critical role in the clearance of cerebrospinal fluid (CSF) from the cranial space. Impairment of CSF outflow into the lymphatics is associated with a number of pathological conditions including spaceflight‐associated neuro‐ocular syndrome (SANS), a problem that limits long‐duration spaceflight. We used near‐infrared fluorescence lymphatic imaging (NIRFLI) to dynamically visualize the deep lymphatic drainage pathways shared by CSF outflow and disrupted during head‐down tilt (HDT), a method used to mimic the cephalad fluid shift that occurs in microgravity. After validating CSF clearance into the lymph nodes of the neck in swine, a pilot study was conducted in human volunteers to evaluate the effect of gravity on the flow of lymph through these deep cervical lymphatics. Injected into the palatine tonsils, ICG was imaged draining into deep jugular lymphatic vessels and subsequent cervical lymph nodes. NIRFLI was performed under HDT, sitting, and supine positions. NIRFLI shows that lymphatic drainage through pathways shared by CSF outflow are dependent upon gravity and are impaired under short‐term HDT. In addition, lymphatic contractile rates were evaluated from NIRFLI following intradermal ICG injections of the lower extremities. Lymphatic contractile activity in the legs was slowed in the gravity neutral, supine position, but increased under the influence of gravity regardless of whether its force direction opposed (sitting) or favored (HDT) lymphatic flow toward the heart. These studies evidence the role of a lymphatic contribution in SANS.

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

“…To date, we have not imaged dermal backflow in the external lymphatics of treatment-naive HNC patients with known or suspected LN metastases, probably because these external lymphatics are typically not in the same lymphatic watershed directly draining interior oropharynx, larynx, and oral cancers. However, in preliminary studies of internal lymphatic drainage of treatment-naive HNC patients, few exhibited drainage into the lympho-jugular chain after mucosal administration of ICG [29], as was seen in normal-health subjects (Figure 4 above) [27]. This observation is preliminary and needs more carefully controlled studies to underscore changes in internal lymphatic drainage from the cranium with head and neck cancer progression.…”

“…Instead, intrathecal injections of Gd-contrast in humans and of ICG in animals show that cervical lymphatics are the major conduits of CSF outflow [25,26]. In humans, the possible neurological consequences of Gd deposits in the brain limit its use for assessing CSF outflow [27]. While intrathecal ICG administration has not been cleared by the FDA, we have conducted off-label administration of ICG into the mucosal lymphatics of the palatine tonsils under FDA clearance [26,28].…”

“…While the venous arachnoid granulations in the subarachnoid space have been traditionally credited for its clearance, the low transmural pressure suggests little, if any, venous reabsorption occurs [25]. Instead, intrathecal injections of Gd-contrast in humans and of ICG in animals show that cervical lymphatics are the major conduits of CSF outflow [26,27]. In humans, the possible neurological consequences of Gd deposits in the brain limit its use for assessing CSF outflow [28].…”

“…In humans, the possible neurological consequences of Gd deposits in the brain limit its use for assessing CSF outflow [ 28 ]. While intrathecal ICG administration has not been cleared by the FDA, we have conducted off-label administration of ICG into the mucosal lymphatics of the palatine tonsils under FDA clearance [ 27 , 29 ]. This administration enables imaging of the ipsilateral lympho-jugular lymphatic chain that drains into the cervical ( Figure 5 a) and supraclavicular LNs ( Figure 5 b) when subjects are sitting upright.…”

<p>Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions</p>

“…Salerni et al 19 reported a mathematical model of fluid flow in the eyes and brain which predicted increased ICP and IOP in microgravity, as well as decreased ocular blood flow in the choroid and ciliary body. As noted above, the lymphatic system has been proposed to play a role in contributing to SANS, and Rasmussen et al 32 described a technique that could be used to further our understanding of this. The authors reported subdermal indocyanine green (ICG) injections with near infrared fluorescent lymphatic imaging to visualize deep lymphatic outflow shared by CSF and in a small group of healthy human volunteers showed its disruption during HDT.…”