Andrei Zakharov

Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species

BackgroundThe parenchyma of the brain does not contain lymphatics. Consequently, it has been assumed that arachnoid projections into the cranial venous system are responsible for cerebrospinal fluid (CSF) absorption. However, recent quantitative and qualitative evidence in sheep suggest that nasal lymphatics have the major role in CSF transport. Nonetheless, the applicability of this concept to other species, especially to humans has never been clarified. The purpose of this study was to compare the CSF and nasal lymph associations in human and non-human primates with those observed in other mammalian species.MethodsStudies were performed in sheep, pigs, rabbits, rats, mice, monkeys and humans. Immediately after sacrifice (or up to 7 hours after death in humans), yellow Microfil was injected into the CSF compartment. The heads were cut in a sagittal plane.ResultsIn the seven species examined, Microfil was observed primarily in the subarachnoid space around the olfactory bulbs and cribriform plate. The contrast agent followed the olfactory nerves and entered extensive lymphatic networks in the submucosa associated with the olfactory and respiratory epithelium. This is the first direct evidence of the association between the CSF and nasal lymph compartments in humans.ConclusionsThe fact that the pattern of Microfil distribution was similar in all species tested, suggested that CSF absorption into nasal lymphatics is a characteristic feature of all mammals including humans. It is tempting to speculate that some disorders of the CSF system (hydrocephalus and idiopathic intracranial hypertension for example) may relate either directly or indirectly to a lymphatic CSF absorption deficit.

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

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.

Subarachnoid injection of Microfil reveals connections between cerebrospinal fluid and nasal lymphatics in the non-human primate

Based on quantitative and qualitative studies in a variety of mammalian species, it would appear that a significant portion of cerebrospinal fluid (CSF) drainage is associated with transport along cranial and spinal nerves with absorption taking place into lymphatic vessels external to the central nervous system. CSF appears to convect primarily through the cribriform plate into lymphatics associated with the submucosa of the olfactory and respiratory epithelium. However, the significance of this pathway for CSF absorption in primates has never been established unequivocally. In past studies, we infused Microfil into the subarachnoid compartment of numerous species to visualize CSF transport pathways. The success of this method encouraged us to use a similar approach in the non‐human primate. Yellow Microfil® was injected post mortem into the cisterna magna of 6 years old Barbados green monkeys (Cercopithecus aethiops sabeus, n = 6). Macroscopic and microscopic examination revealed that Microfil was (1) distributed throughout the subarachnoid compartment, (2) located in the perineurial spaces associated with the fila olfactoria, (3) present within the olfactory submucosa, and (4) situated within an extensive network of lymphatic vessels in the nasal submucosa, nasal septum and turbinate tissues. We conclude that the Microfil distribution patterns in the monkey were very similar to those observed in many other species suggesting that significant nasal lymphatic uptake of CSF occurs in the non‐human primate.

Lymphatic cerebrospinal fluid absorption pathways in neonatal sheep revealed by subarachnoid injection of Microfil

There is mounting evidence that a significant portion of cerebrospinal fluid drainage is associated with transport along cranial and spinal nerves with absorption taking place into lymphatic vessels external to the central nervous system. To characterize these pathways further, yellow Microfil® was infused into the cisterna magna of 2–7‐day‐old lambs post mortem to perfuse either the cranial or spinal subarachnoid compartments. In some animals, blue Microfil was perfused into the carotid arteries simultaneously. Microfil was observed in lymphatic networks in the nasal mucosa, covering the hard and soft palate, conchae, nasal septum, the ethmoid labyrinth and the lateral walls of the nasal cavity. Many of these lymphatics drained into vessels located on the lateroposterior wall of the nasopharynx and from this location drained to the retropharyngeal lymph nodes. Additionally, lymphatics containing Microfil penetrated the lateral wall of the nasal cavity and joined with superficial lymphatic ducts travelling towards the submandibular and preauricular lymph nodes. In two cases, lymphatic vessels were observed anastomosing with deep veins in the retropharyngeal area. Microfil was also distributed within the nerve trunks of cranial and spinal nerves. The contrast agent was located in longitudinal channels within the endoneurial space and lymphatics containing Microfil were observed emerging from the mesoneurium. In summary, Microfil distribution patterns in neonatal lambs illustrated the important role that cranial and spinal nerves play in linking the subarachnoid compartment with extracranial lymphatics.

Cerebrospinal fluid transport across the cribriform plate into extracranial lymphatics in rats: development and quantification

Bifida Meeting abstracts - A single PDF containing all abstracts in this supplement is available here .