Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics

Abstract

Cerebrospinal fluid (CSF) is produced by the choroid plexuses within the ventricles of the brain and circulates through the subarachnoid space of the skull and spinal column to provide buoyancy to and maintain fluid homeostasis of the brain and spinal cord. The question of how CSF drains from the subarachnoid space has long puzzled scientists and clinicians. For many decades, it was believed that arachnoid villi or granulations, outcroppings of arachnoid tissue that project into the dural venous sinuses, served as the major outflow route. However, this concept has been increasingly challenged in recent years, as physiological and imaging evidence from several species has accumulated showing that tracers injected into the CSF can instead be found within lymphatic vessels draining from the cranium and spine. With the recent high-profile rediscovery of meningeal lymphatic vessels located in the dura mater, another debate has emerged regarding the exact anatomical pathway(s) for CSF to reach the lymphatic system, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves. In this review, a summary of the historical and contemporary evidence for the different outflow pathways will be presented, allowing the reader to gain further perspective on the recent advances in the field. An improved understanding of this fundamental physiological process may lead to novel therapeutic approaches for a wide range of neurological conditions, including hydrocephalus, neurodegeneration and multiple sclerosis.

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

“…The lymphatic system further evolved in flying birds and mammals to lose the lymph heart and instead acquire lymph nodes for immune functions. Similar lymphatic drainage was defined across many animal models ( Koh et al, 2005 ; Proulx, 2021 ), although there are differences between rodent models and humans ( Choi et al, 2012 ). In particular, arachnoid granulations are not found in lower vertebrates or human infants ( Proulx, 2021 ), creating some controversy in CSF drainage pathways in humans.…”

“…Similar lymphatic drainage was defined across many animal models ( Koh et al, 2005 ; Proulx, 2021 ), although there are differences between rodent models and humans ( Choi et al, 2012 ). In particular, arachnoid granulations are not found in lower vertebrates or human infants ( Proulx, 2021 ), creating some controversy in CSF drainage pathways in humans. This is reviewed by others ( Koh et al, 2005 ; Proulx, 2021 ) and briefly discussed later in this review in the context of recent in vivo imaging.…”

“…In particular, arachnoid granulations are not found in lower vertebrates or human infants ( Proulx, 2021 ), creating some controversy in CSF drainage pathways in humans. This is reviewed by others ( Koh et al, 2005 ; Proulx, 2021 ) and briefly discussed later in this review in the context of recent in vivo imaging.…”

“…Brain lymphatics were shown for the first time in 1787 by Mascagni ( Sandrone et al, 2019 ; Hsu et al, 2021 ; Proulx, 2021 ). Since the 1800s, several studies were aimed at characterizing the drainage pathways from the central nervous system (CNS) in which parallels were drawn between the subarachnoid space surrounding the brain and lymphatics in the periphery ( Rodriguez-Peralta, 1957 ; Földi et al, 1966 ; Andres et al, 1987 ; Cserr et al, 1992b ; Kida et al, 1993 ; Bozanovic-Sosic et al, 2001 ; Mollanji et al, 2001b ; Koh et al, 2005 ; Pollay, 2010 ; Weller et al, 2010 ; Laman and Weller, 2013 ; Brøchner et al, 2015 ; Engelhardt et al, 2017 ; Hannocks et al, 2018 ; Castro Dias et al, 2019 ).…”

Dorsal skull meningeal lymphatic vessels drain blood-solutes after intracerebral hemorrhage

“…Finally, we report a correlation between the levels of neuroinflammation and meningeal lymphangiogenesis, contributing to demonstrate that glia activation modulates the meningeal lymphatics. The role of dorsal meningeal lymphatics as a drainage pathway for the CNS has been disputed, with most of the studies providing indirect evidences of the transport through mLVs, and/or focusing on the cerebrospinal fluid (CSF) clearance (for a review see (Proulx, 2021)). In controlled and clinical-mimicking conditions, we found a unidirectional transport of blood-derived solutes through mLVs, which suggests a direct flow from the brain parenchyma to the mLV.…”