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.

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The textbook view that projections of the arachnoid membrane into the cranial venous sinuses represent the primary cerebrospinal fluid (CSF) absorption sites seems incompatible with many clinical and experimental observations. On balance, there is more quantitative evidence suggesting a function for extracranial lymphatic vessels than exists to support a role for arachnoid villi and granulations in CSF transport.

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.

Arachnoid villi and granulations are thought to represent the primary sites where cerebrospinal fluid (CSF) is absorbed. However, these structures do not appear to exist in the fetus but begin to develop around the time of birth and increase in number with age. With the use of a constant pressure-perfusion system in 2-to 6-day-old lambs, we observed that global CSF transport (0.012 Ϯ 0.003 ml ⅐ min Ϫ1 ⅐ cmH2O Ϫ1 ) and CSF outflow resistance (96.5 Ϯ 17.8 cmH2O ⅐ ml Ϫ1 ⅐ min) were very similar to comparable measures in adult animals despite the relative paucity of arachnoid villi at this stage of development. In the neonate, the recovery patterns of a radioactive protein CSF tracer in various lymph nodes and tissues indicated that CSF transport occurred through multiple lymphatic pathways. An especially important route was transport through the cribriform plate into extracranial lymphatics located in the nasal submucosa. To investigate the importance of the cribriform route in cranial CSF clearance, the cranial CSF compartment was isolated surgically from its spinal counterpart. When the cribriform plate was sealed extracranially under these conditions, CSF transport was impaired significantly. These data demonstrate an essential function for lymphatics in neonatal CSF transport and imply that arachnoid projections may play a limited role earlier in development. arachnoid villi; arachnoid granulations; intracranial pressure; cerebrospinal fluid outflow resistance; cerebrospinal fluid conductance; cribriform plate; hydrocephalus THE MICROSCOPIC ARACHNOID villi and macroscopic granulations are herniations of the arachnoid membrane into the dural venous sinuses of the brain. Based primarily on anatomic studies of adult human or animal specimens, it has been generally assumed that these structures represent the primary locations where cerebrospinal fluid (CSF) absorption occurs. However, earlier in development, this conventional view would not seem to apply. Several studies failed to observe arachnoid villi/granulations in the human fetus. In two microscopic studies of autopsy specimens from individuals up to 56 days old (38) and from 18 wk gestation to 80 yr (21), no arachnoid villi or granulations were observed before birth. At or around the time of birth, arachnoid projections start to become visible in the dura (24) and some of these appear to be associated with veins (23). As the infant ages, the villi and granulations increase in number, and in the adult, they exist in abundance (16). The role of the arachnoid projections in the neonate is important because reduced CSF transport to these absorption sites or impaired clearance through these structures is believed to constitute the principal defect in hydrocephalus (26).If arachnoid projections do not exist (or exist in very small numbers or in an immature form), we are left with the question of how CSF is drained in the neonatal period. We believe that current evidence favors a role for the lymphatic circulation. The central nervous system parenchyma does not con...

The data suggests that neonatal CSF can be absorbed directly into the cranial venous system. However, contrary to the classical view, this route may represent an auxiliary system that is recruited to compliment lymphatic transport when intracranial pressures are very high.

Lymphatic vessels gain access to the brain extracellular fluid (CSF) in an unusual anatomical association with the olfactory nerves external to the cranial vault. This study highlights the important role played by lymphatic vessels in CSF absorption.

We quantified cerebrospinal fluid (CSF) transport (conductance) and CSF outflow resistance in late-gestation fetal and adult sheep using two methods, a constant pressure infusion method and a bolus injection technique into the lateral ventricles. No significant differences in CSF conductance (fetus 0.013 +/- 0.002, adult 0.014 +/- 0.003 ml x min(-1) x cm H(2)O(-1)) or CSF outflow resistance (fetus 83.7 +/- 9.8, adult 84.7 +/- 19.7 cm H(2)O x ml(-1) x min) were observed. To confirm CSF transport to plasma in fetal animals, (125)I- or (131)I-labeled human serum albumin (HSA) was injected into the lateral ventricles. The tracer entered fetal plasma with an average mass transport rate of 1.91 +/- 0.47% injected/h (n = 9). In two fetuses, we monitored the tracer appearance in plasma and cervical and thoracic duct lymph after injection of radioactive HSA into the ventricular CSF. As was the case in adult animals, fetal tracer concentrations increased in all three compartments over time, with the highest concentrations measured in lymph collected from the cervical lymphatics. These results 1) indicate that global CSF transport parameters in the late-gestation fetus and adult sheep are similar and 2) suggest an important role for extracranial lymphatic vessels in CSF transport before birth.