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. 2004 Dec 10;1(1):2.
doi: 10.1186/1743-8454-1-2.

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

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Free PMC article

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

Miles Johnston et al. Cerebrospinal Fluid Res. .
Free PMC article

Abstract

BACKGROUND: The 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. METHODS: Studies 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. RESULTS: In 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. CONCLUSIONS: The 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.

Figures

Figure 1
Microfil distribution patterns in the head of mice and rats. All images are presented in sagittal plane with gradual magnification of the olfactory area adjacent to the cribriform plate. Reference scales are provided either as a ruler in the image (mm) or as a longitudinal bar (1 mm). A-C illustrates images of the mouse and D-F images of rat. The Microfil can be viewed in the perineurial space of the olfactory nerves external to the cranium and a network of lymphatic vessels containing yellow Microfil can be observed in the ethmoid turbinal systems of both species. In the example illustrated in 1C, the image was captured before fixation. The reddish spots are areas of hemorrhage in this particular animal. b – brain; cp – cribriform plate; et – ethmoid turbinates; ob – olfactory bulbs; on – olfactory nerves; ns – nasal septum.
Figure 2
Microfil distribution patterns in the head of rabbits and sheep. All images are presented in sagittal plane with gradual magnification of the olfactory area adjacent to the cribriform plate. Reference scales are provided either as a ruler in the image (mm) or as a longitudinal bar (1 mm). A-C illustrates images of the rabbit and D-F images of sheep. In both species, the Microfil can be viewed in the perineurial spaces of the olfactory nerves external to the cranium, which merge into network of lymphatic vessels in the ethmoid turbinal systems. b – brain; cp – cribriform plate; et – ethmoid turbinates; on – olfactory nerves; ns – nasal septum; arrow in D – portion of cribriform plate removed for histology.
Figure 3
Microfil distribution patterns in the head of pigs and Barbados green monkeys. All images are presented in sagittal plane with gradual magnification of the olfactory area adjacent to the cribriform plate. Reference scales are provided either as a ruler in the image (mm) or as a longitudinal bar (1 mm). A-C illustrates images of the pig and D-F images of the monkey. In both species, the Microfil can be viewed in the perineurial spaces of the olfactory nerves external to the cranium, which merge into network of lymphatic vessels in the ethmoid turbinal systems. In A, Microfil can be observed penetrating the dura and entering the cavernous sinus with partial filling of the retromandibular vein (arrow). b – brain; cp – cribriform plate; et – ethmoid turbinates; ob – olfactory bulbs; on – olfactory nerves.
Figure 4
Microfil distribution patterns in the head of a human (A-F). All images are presented in sagittal plane with gradual magnification of the olfactory area adjacent to the cribriform plate. Reference scales are provided either as a ruler in the image (mm) or as a longitudinal bar (1 mm). As in the other species, Microfil introduced into the subarachnoid space was observed around the olfactory bulb (A), in the perineurial spaces of the olfactory nerves (B, C) and in the lymphatics of the nasal septum (D), ethmoid labyrinth (E) and superior turbinate (F). Due to tissue deterioration, some of the lymphatic vessels had ruptured and Microfil was noted in the interstitium of the submucosa of the nasal septum (D). In (E), Microfil is observed in the subarachnoid space and the perineurial space of olfactory nerves. The perineurial Microfil is continuous with that in lymphatic vessels (arrows). Intact lymphatic vessels containing Microfil are outlined with arrows (D, E, F). b – brain; fs – frontal sinus; cp – cribriform plate; et – ethmoid turbinates; ob – olfactory bulbs; on – olfactory nerves; ns – nasal septum; sas – subarachnoid space.
Figure 5
Visualization of lymphatic vessels containing Microfil. Reference scales are provided as a longitudinal bar (1 mm). A – illustrates the ability to separate blood vessels (blue) from lymphatics (yellow) using differently coloured Microfil preparations (sheep). B – demonstrates lymphatic networks that have taken up Microfil that was injected into the subarachnoid compartment (pig). These networks ultimately connect with various lymph nodes (C – retropharyngeal node example in sheep; D – submandibular node example in mouse). The prenodal vessels can be visualized converging on the lymph nodes with the lymphatics congregating into a labyrinth of small ducts or foot processes on the node capsule. Blood vessels containing blue Microfil can be observed proximal to the node in C. The functional contractile unit of lymphatic vessels is the lymphangion, which is a segment of vessel between 2 valves (valves illustrated by arrows in C). n – lymph node; L – lymphangion.

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