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Published in: Fluids and Barriers of the CNS 1/2004

Open Access 01-12-2004 | Research

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

Authors: Miles Johnston, Andrei Zakharov, Christina Papaiconomou, Giselle Salmasi, Dianna Armstrong

Published in: Fluids and Barriers of the CNS | Issue 1/2004

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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.
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Literature
1.
go back to reference Johanson CE: Ventricles and Cerebrospinal fluid. Neuroscience in Medicine. Edited by: Conn PM. 1995, Philadelphia, J.B. Lippincott Company, 171-196. Johanson CE: Ventricles and Cerebrospinal fluid. Neuroscience in Medicine. Edited by: Conn PM. 1995, Philadelphia, J.B. Lippincott Company, 171-196.
2.
go back to reference Papaiconomou C, Zakharov A, Azizi N, Djenic J, Johnston M: Reassessment of the pathways responsible for cerebrospinal fluid absorption in the neonate. Childs Nerv Syst. 2004, 20: 29-36. 10.1007/s00381-003-0840-z.CrossRefPubMed Papaiconomou C, Zakharov A, Azizi N, Djenic J, Johnston M: Reassessment of the pathways responsible for cerebrospinal fluid absorption in the neonate. Childs Nerv Syst. 2004, 20: 29-36. 10.1007/s00381-003-0840-z.CrossRefPubMed
3.
go back to reference Zakharov A, Papaiconomou C, Koh L, Djenic J, Bozanovic-Sosic R, Johnston M: Integrating the roles of extracranial lymphatics and intracranial veins in cerebrospinal fluid absorption in sheep. Microvasc Res. 2004, 67: 96-104. 10.1016/j.mvr.2003.08.004.CrossRefPubMed Zakharov A, Papaiconomou C, Koh L, Djenic J, Bozanovic-Sosic R, Johnston M: Integrating the roles of extracranial lymphatics and intracranial veins in cerebrospinal fluid absorption in sheep. Microvasc Res. 2004, 67: 96-104. 10.1016/j.mvr.2003.08.004.CrossRefPubMed
4.
go back to reference Bradbury MWB, Cserr HF: Drainage of cerebral interstitial fluid and of cerebrospinal fluid into lymphatics. Experimental Biology of the Lymphatic Circulation 9. Edited by: Johnston MG. 1985, Amsterdam, Elsevier, 355-394. Bradbury MWB, Cserr HF: Drainage of cerebral interstitial fluid and of cerebrospinal fluid into lymphatics. Experimental Biology of the Lymphatic Circulation 9. Edited by: Johnston MG. 1985, Amsterdam, Elsevier, 355-394.
5.
go back to reference Boulton M, Young A, Hay J, Armstrong D, Flessner M, Schwartz M, Johnston M: Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol Appl Neurobiol. 1996, 22: 325-333.CrossRefPubMed Boulton M, Young A, Hay J, Armstrong D, Flessner M, Schwartz M, Johnston M: Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol Appl Neurobiol. 1996, 22: 325-333.CrossRefPubMed
6.
go back to reference Boulton M, Armstrong D, Flessner M, Hay J, Szalai JP, Johnston M: Raised intracranial pressure increases CSF drainage through arachnoid villi and extracranial lymphatics. Am J Physiol. 1998, 275: R889-R896.PubMed Boulton M, Armstrong D, Flessner M, Hay J, Szalai JP, Johnston M: Raised intracranial pressure increases CSF drainage through arachnoid villi and extracranial lymphatics. Am J Physiol. 1998, 275: R889-R896.PubMed
7.
go back to reference Boulton M, Flessner M, Armstrong D, Hay J, Johnston M: Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep. Am J Physiol. 1998, 274: R88-R96.PubMed Boulton M, Flessner M, Armstrong D, Hay J, Johnston M: Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep. Am J Physiol. 1998, 274: R88-R96.PubMed
8.
go back to reference Boulton M, Flessner M, Armstrong D, Mohamed R, Hay J, Johnston M: Contribution of extracranial lymphatics and arachnoid villi to the clearance of a CSF tracer in the rat. Am J Physiol. 1999, 276: R818-R823.PubMed Boulton M, Flessner M, Armstrong D, Mohamed R, Hay J, Johnston M: Contribution of extracranial lymphatics and arachnoid villi to the clearance of a CSF tracer in the rat. Am J Physiol. 1999, 276: R818-R823.PubMed
9.
go back to reference Boulton M, Flessner M, Armstrong D, Hay J, Johnston M: Lymphatic drainage of the CNS: effects of lymphatic diversion/ligation on CSF protein transport to plasma. Am J Physiol. 1997, 272: R1613-R1619.PubMed Boulton M, Flessner M, Armstrong D, Hay J, Johnston M: Lymphatic drainage of the CNS: effects of lymphatic diversion/ligation on CSF protein transport to plasma. Am J Physiol. 1997, 272: R1613-R1619.PubMed
10.
go back to reference Bozanovic-Sosic R, Mollanji R, Johnston MG: Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol Regul Integr Comp Physiol. 2001, 281: R909-R916.PubMed Bozanovic-Sosic R, Mollanji R, Johnston MG: Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol Regul Integr Comp Physiol. 2001, 281: R909-R916.PubMed
11.
go back to reference Mollanji R, Bozanovic-Sosic R, Zakharov A, Makarian L, Johnston MG: Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure. Am J Physiol Regul Integr Comp Physiol. 2002, 282: R1593-R1599.CrossRefPubMed Mollanji R, Bozanovic-Sosic R, Zakharov A, Makarian L, Johnston MG: Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure. Am J Physiol Regul Integr Comp Physiol. 2002, 282: R1593-R1599.CrossRefPubMed
12.
go back to reference Mollanji R, Papaiconomou C, Boulton M, Midha R, Johnston M: Comparison of cerebrospinal fluid transport in fetal and adult sheep. Am J Physiol Regul Integr Comp Physiol. 2001, 281: R1215-R1223.PubMed Mollanji R, Papaiconomou C, Boulton M, Midha R, Johnston M: Comparison of cerebrospinal fluid transport in fetal and adult sheep. Am J Physiol Regul Integr Comp Physiol. 2001, 281: R1215-R1223.PubMed
13.
go back to reference Mollanji R, Bozanovic-Sosic R, Silver I, Li B, Kim C, Midha R, Johnston M: Intracranial pressure accommodation is impaired by blocking pathways leading to extracranial lymphatics. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R1573-R1581.PubMed Mollanji R, Bozanovic-Sosic R, Silver I, Li B, Kim C, Midha R, Johnston M: Intracranial pressure accommodation is impaired by blocking pathways leading to extracranial lymphatics. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R1573-R1581.PubMed
14.
go back to reference Papaiconomou C, Bozanovic-Sosic R, Zakharov A, Johnston M: Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics?. Am J Physiol Regul Integr Comp Physiol. 2002, 283: R869-R876.CrossRefPubMed Papaiconomou C, Bozanovic-Sosic R, Zakharov A, Johnston M: Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics?. Am J Physiol Regul Integr Comp Physiol. 2002, 283: R869-R876.CrossRefPubMed
15.
go back to reference Silver I, Li B, Szalai J, Johnston M: Relationship between intracranial pressure and cervical lymphatic pressure and flow rates in sheep. Am J Physiol. 1999, 277: R1712-R1717.PubMed Silver I, Li B, Szalai J, Johnston M: Relationship between intracranial pressure and cervical lymphatic pressure and flow rates in sheep. Am J Physiol. 1999, 277: R1712-R1717.PubMed
16.
go back to reference Silver I, Kim C, Mollanji R, Johnston M: Cerebrospinal fluid outflow resistance in sheep: impact of blocking cerebrospinal fluid transport through the cribriform plate. Neuropathol Appl Neurobiol. 2002, 28: 67-74. 10.1046/j.1365-2990.2002.00373.x.CrossRefPubMed Silver I, Kim C, Mollanji R, Johnston M: Cerebrospinal fluid outflow resistance in sheep: impact of blocking cerebrospinal fluid transport through the cribriform plate. Neuropathol Appl Neurobiol. 2002, 28: 67-74. 10.1046/j.1365-2990.2002.00373.x.CrossRefPubMed
17.
go back to reference Zakharov A, Papaiconomou C, Djenic J, Midha R, Johnston M: Lymphatic cerebrospinal fluid absorption pathways in neonatal sheep revealed by subarachnoid injection of Microfil. Neuropathol Appl Neurobiol. 2003, 29: 563-573. 10.1046/j.0305-1846.2003.00508.x.CrossRefPubMed Zakharov A, Papaiconomou C, Djenic J, Midha R, Johnston M: Lymphatic cerebrospinal fluid absorption pathways in neonatal sheep revealed by subarachnoid injection of Microfil. Neuropathol Appl Neurobiol. 2003, 29: 563-573. 10.1046/j.0305-1846.2003.00508.x.CrossRefPubMed
18.
go back to reference Zakharov A, Papaiconomou C, Johnston M: Lymphatic vessels gain access to cerebrospinal fluid through a unique association with olfactory nerves. Lymphatic Research and Biology. 2004. Zakharov A, Papaiconomou C, Johnston M: Lymphatic vessels gain access to cerebrospinal fluid through a unique association with olfactory nerves. Lymphatic Research and Biology. 2004.
19.
go back to reference Kida S, Okamoto Y, Higashi S, Futami K, Yamashima T, Yamashita J, Weller RO: Morphological aspects of interstitial fluid drainage from the rat brain. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 136-139. Kida S, Okamoto Y, Higashi S, Futami K, Yamashima T, Yamashita J, Weller RO: Morphological aspects of interstitial fluid drainage from the rat brain. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 136-139.
20.
go back to reference Brinker T, Botel C, Rothkotter HJ, Walter GF, Samii M: The perineural pathway of cerebrospinal fluid absorption into the cervical lymphatic system. Morphological findings in rats, cats, dogs and monkeys. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 132-135. Brinker T, Botel C, Rothkotter HJ, Walter GF, Samii M: The perineural pathway of cerebrospinal fluid absorption into the cervical lymphatic system. Morphological findings in rats, cats, dogs and monkeys. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 132-135.
21.
go back to reference Brinker T, Ludemann W, Berens R, Samii M: Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid. Acta Neuropathol (Berl). 1997, 94: 493-498. 10.1007/s004010050738.CrossRef Brinker T, Ludemann W, Berens R, Samii M: Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid. Acta Neuropathol (Berl). 1997, 94: 493-498. 10.1007/s004010050738.CrossRef
22.
go back to reference Weller RO, Kida S, Zhang ET: Pathways of fluid drainage from the brain--morphological aspects and immunological significance in rat and man. Brain Pathol. 1992, 2: 277-284.CrossRefPubMed Weller RO, Kida S, Zhang ET: Pathways of fluid drainage from the brain--morphological aspects and immunological significance in rat and man. Brain Pathol. 1992, 2: 277-284.CrossRefPubMed
23.
go back to reference Zhang ET, Richards HK, Kida S, Weller RO: Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol (Berl). 1992, 83: 233-239. 10.1007/BF00296784.CrossRef Zhang ET, Richards HK, Kida S, Weller RO: Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol (Berl). 1992, 83: 233-239. 10.1007/BF00296784.CrossRef
24.
go back to reference Kida S, Pantazis A, Weller RO: CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol. 1993, 19: 480-488.CrossRefPubMed Kida S, Pantazis A, Weller RO: CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol. 1993, 19: 480-488.CrossRefPubMed
25.
go back to reference Moinuddin SM, Tada T: Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic hydrocephalic mice. Neurol Res. 2000, 22: 215-222.PubMed Moinuddin SM, Tada T: Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic hydrocephalic mice. Neurol Res. 2000, 22: 215-222.PubMed
26.
go back to reference Erlich SS, McComb JG, Hyman S, Weiss MH: Ultrastructural morphology of the olfactory pathway for cerebrospinal fluid drainage in the rabbit. J Neurosurg. 1986, 64: 466-473.CrossRefPubMed Erlich SS, McComb JG, Hyman S, Weiss MH: Ultrastructural morphology of the olfactory pathway for cerebrospinal fluid drainage in the rabbit. J Neurosurg. 1986, 64: 466-473.CrossRefPubMed
27.
go back to reference Bradbury MW, Cserr HF, Westrop RJ: Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol. 1981, 240: F329-F336.PubMed Bradbury MW, Cserr HF, Westrop RJ: Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol. 1981, 240: F329-F336.PubMed
28.
go back to reference Gomez DG, Fenstermacher JD, Manzo RP, Johnson D, Potts DG: Cerebrospinal fluid absorption in the rabbit: olfactory pathways. Acta Otolaryngol. 1985, 100: 429-436.CrossRefPubMed Gomez DG, Fenstermacher JD, Manzo RP, Johnson D, Potts DG: Cerebrospinal fluid absorption in the rabbit: olfactory pathways. Acta Otolaryngol. 1985, 100: 429-436.CrossRefPubMed
29.
go back to reference Yoffey JM, Drinker CK: Some observations on the lymphatics of the nasal mucous membrane in the cat and monkey. Journal of Anatomy. 1939, LXXIV: 45-52. Yoffey JM, Drinker CK: Some observations on the lymphatics of the nasal mucous membrane in the cat and monkey. Journal of Anatomy. 1939, LXXIV: 45-52.
30.
go back to reference Brinker T, Botel C, Samii M: A species comparing radiological study on the absorption of cerebrospinal fluid into the cervical lymphatic system. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 559-560. Brinker T, Botel C, Samii M: A species comparing radiological study on the absorption of cerebrospinal fluid into the cervical lymphatic system. Intracranial pressure IX. Edited by: Nagai H, Kamiya K and Ishii K. 1994, Toyko, Springer, 559-560.
31.
go back to reference Arnold W, Ilberg CV: The connections of the cerebrospinal fluid (CSF) with the lymphatic system of the head and neck. Progress in Lymphology IV. Edited by: Mayall RC and Witte MH. 1973, Tucson, AZ, Plenum Press, 57-58. Arnold W, Ilberg CV: The connections of the cerebrospinal fluid (CSF) with the lymphatic system of the head and neck. Progress in Lymphology IV. Edited by: Mayall RC and Witte MH. 1973, Tucson, AZ, Plenum Press, 57-58.
32.
go back to reference McComb JG, Hyman S: Lymphatic drainage of cerebrospinal fluid in the primate. Pathophysiology of the blood-brain barrier. Edited by: Johansson BB, Owman C and Widner H. 1990, New York, NY, Elsevier, 421-438. McComb JG, Hyman S: Lymphatic drainage of cerebrospinal fluid in the primate. Pathophysiology of the blood-brain barrier. Edited by: Johansson BB, Owman C and Widner H. 1990, New York, NY, Elsevier, 421-438.
33.
go back to reference Caversaccio M, Peschel O, Arnold W: The drainage of cerebrospinal fluid into the lymphatic system of the neck in humans. ORL J Otorhinolaryngol Relat Spec. 1996, 58: 164-166.CrossRefPubMed Caversaccio M, Peschel O, Arnold W: The drainage of cerebrospinal fluid into the lymphatic system of the neck in humans. ORL J Otorhinolaryngol Relat Spec. 1996, 58: 164-166.CrossRefPubMed
34.
go back to reference Csanda E, Obal F, Obal FJ: Central nervous system and lymphatic system. Lymphangiology. Edited by: Foldi M and Casley-Smith JR. 1983, New York, F.K. Schattauer Verlag, 475-508. Csanda E, Obal F, Obal FJ: Central nervous system and lymphatic system. Lymphangiology. Edited by: Foldi M and Casley-Smith JR. 1983, New York, F.K. Schattauer Verlag, 475-508.
35.
go back to reference Lowhagen P, Johansson BB, Nordborg C: The nasal route of cerebrospinal fluid drainage in man. A light-microscope study. Neuropathol Appl Neurobiol. 1994, 20: 543-550.CrossRefPubMed Lowhagen P, Johansson BB, Nordborg C: The nasal route of cerebrospinal fluid drainage in man. A light-microscope study. Neuropathol Appl Neurobiol. 1994, 20: 543-550.CrossRefPubMed
36.
go back to reference Rudert M, Tillmann B: Lymph and blood supply of the human intervertebral disc. Cadaver study of correlations to discitis. Acta Orthop Scand. 1993, 64: 37-40.CrossRefPubMed Rudert M, Tillmann B: Lymph and blood supply of the human intervertebral disc. Cadaver study of correlations to discitis. Acta Orthop Scand. 1993, 64: 37-40.CrossRefPubMed
37.
go back to reference Egnor M, Zheng L, Rosiello A, Gutman F, Davis R: A model of pulsations in communicating hydrocephalus. Pediatr Neurosurg. 2002, 36: 281-303. 10.1159/000063533.CrossRefPubMed Egnor M, Zheng L, Rosiello A, Gutman F, Davis R: A model of pulsations in communicating hydrocephalus. Pediatr Neurosurg. 2002, 36: 281-303. 10.1159/000063533.CrossRefPubMed
38.
go back to reference Johnston M, Papaiconomou C: Cerebrospinal fluid transport: a lymphatic perspective. News Physiol Sci. 2002, 17: 227-230.PubMed Johnston M, Papaiconomou C: Cerebrospinal fluid transport: a lymphatic perspective. News Physiol Sci. 2002, 17: 227-230.PubMed
39.
go back to reference Johnston M: Relationship between cerebrospinal fluid and extracranial lymph. Lymphology. 2000, 33: 1-3.PubMed Johnston M: Relationship between cerebrospinal fluid and extracranial lymph. Lymphology. 2000, 33: 1-3.PubMed
40.
go back to reference Mann JD, Butler AB, Johnson RN, Bass NH: Clearance of macromolecular and particulate substances from the cerebrospinal fluid system of the rat. J Neurosurg. 1979, 50: 343-348.CrossRefPubMed Mann JD, Butler AB, Johnson RN, Bass NH: Clearance of macromolecular and particulate substances from the cerebrospinal fluid system of the rat. J Neurosurg. 1979, 50: 343-348.CrossRefPubMed
41.
go back to reference McComb JG, Hyman S, Weiss MH: Lymphatic drainage of cerebrospinal fluid in the cat. Hydrocephalus. Edited by: Shapiro K, Marmarou A and Portnoy H. 1984, New York, Raven, 83-98. McComb JG, Hyman S, Weiss MH: Lymphatic drainage of cerebrospinal fluid in the cat. Hydrocephalus. Edited by: Shapiro K, Marmarou A and Portnoy H. 1984, New York, Raven, 83-98.
42.
go back to reference McComb JG, Davson H, Hyman S, Weiss MH: Cerebrospinal fluid drainage as influenced by ventricular pressure in the rabbit. J Neurosurg. 1982, 56: 790-797.CrossRefPubMed McComb JG, Davson H, Hyman S, Weiss MH: Cerebrospinal fluid drainage as influenced by ventricular pressure in the rabbit. J Neurosurg. 1982, 56: 790-797.CrossRefPubMed
Metadata
Title
Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species
Authors
Miles Johnston
Andrei Zakharov
Christina Papaiconomou
Giselle Salmasi
Dianna Armstrong
Publication date
01-12-2004
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2004
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/1743-8454-1-2

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