Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption?

Abstract

In most tissues and organs, the lymphatic circulation is responsible for the removal of interstitial protein and fluid but the parenchyma of the brain and spinal cord is devoid of lymphatic vessels. On the other hand, the literature is filled with qualitative and quantitative evidence supporting a lymphatic function in cerebrospinal fluid (CSF) absorption. The experimental data seems to warrant a re-examination of CSF dynamics and consideration of a new conceptual foundation on which to base our understanding of disorders of the CSF system. The objective of this paper is to review the key studies pertaining to the role of the lymphatic system in CSF absorption.

Figure 1

Anatomical relationships between cerebrospinal fluid and lymphatic vessels. A – Illustration of cribriform plate and lymphatic vessels in the rat. In this example, yellow Microfil has been injected into the cisterna magna. An extensive network of lymphatics filled with yellow Microfil can be observed in the olfactory submucosa. Black arrows-cribriform plate; OB – olfactory bulb. B – Lymphatics filled with yellow Microfil (injected into the cisterna magna) in the ethmoid turbinates of the pig. C – Lymphatics filled with yellow Microfil (injected into the cisterna magna) in the ethmoid turbinates of the sheep. Blood vessels (red) can be seen interspersed between the lymphatic networks. D – Lymphatics filled with yellow Microfil (injected into the cisterna magna) converge on several lymph nodes. In this example, prenodal lymphatic vessels can be observed converging onto one of the retropharyngeal nodes in sheep. E – When Evans blue dye is injected into the spinal subarachnoid space in sheep, it enters the epidural tissues around the spinal cord. F – Lymphatic vessels filled with Evans blue dye (injected into the spinal subarachnoid space) can be observed draining to the intercostal lymph nodes in sheep.

Figure 2

Anatomical connections between the olfactory nerve and extracranial lymphatic vessels. In schematic (A) the lymphatics are connected directly with the CSF space. In A1, the lymphatic vessels form a collar around the emerging olfactory nerve root with the lymphatic endothelium fusing to the perineural sheath of the nerve and the periosteum or dura associated with the cribriform plate. In effect this lymphatic collar provides a 'seal' that ensures that little or no CSF enters the submucosal interstitium. In A2, the lymphatics join with the cribriform plate and nerve as above but in this scenario, a collar of CSF follows the nerve some distance into the submucosa. This CSF collar is delimited by the lymphatic vessel. As in the scenario outlined in A1, no CSF is permitted to enter the interstitium. In (B), the lymphatics are not connected directly with the olfactory nerves or cribriform plate but are interspersed throughout the olfactory submucosa. In this proposal, CSF must convect first into the interstitium of the submucosa from which it is absorbed into blind ending lymphatic vessels. (C) Uptake of Microfil by lymphatic vessels adjacent to cribriform plate. This histological section was stained with hematoxylin and eosin. In this example, yellow Microfil was infused into the CSF space (appears dark brown in section) and blue Microfil was injected into the arterial circulation. Distended lymphatic vessels containing Microfil are especially prominent in the area surrounding the olfactory nerve roots as they emerge from the cribriform plate (red arrows). Lymphatics are also observed fused to the olfactory nerves at discrete locations away from the cribriform plate (yellow arrows). Microfil is not observed free within the interstitium of the submucosa. Regarding the relationship between cranial CSF and lymph, examples such as this would appear to support the schema illustrated in A. BV – blood vessels.