Direct venous spinal reabsorption of cerebrospinal fluid: a new ...

J Neurosurg Spine 16:394–401, 2012

Direct venous spinal reabsorption of cerebrospinal fluid: a new concept with serial magnetic resonance cisternography in rabbits Laboratory investigation Huseyin Biceroglu, M.D.,1 Sait Albayram, M.D., 2 Sabri Ogullar, M.D., 3 Zehra Isik Hasiloglu, M.D., 2 Hakan Selcuk, M.D., 4 Odhan Yuksel, M.D.,1 Burak Karaaslan, M.D.,1 Can Yildiz, M.D.,1 and Adem Kiris, M.D. 3 Departments of 1Neurosurgery and 2Neuroradiology, Cerrahpasa Medical Faculty, Istanbul University; 3 Department of Radiology, Haseki Training and Research Hospital; and 4Department of Radiology, Bakırköy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey Object. For nearly 100 years it has been believed that the main reabsorption of CSF occurs in arachnoid projections into the superior sagittal sinus, but a significant number of experiments and cases conflict with this hypothesis. According to recently published studies, CSF is permanently produced and absorbed in the whole CSF system. Clusters of arachnoidal villi, which are speculated to have a role in the reabsorption of CSF, have recently been revealed in the dorsal root of the spinal nerves. Huge absorptive surface areas of microvessels have been suggested to serve a putative role in reabsorption. The authors’ aim was to observe direct venous connections between the subarachnoid space and the perispinal veins. Methods. Eleven adult (6 months old) New Zealand white male rabbits weighing approximately 3.0 kg each were used in this experiment. After obtaining precontrast MR cisternography images, subarachnoid access was gained percutaneously via a cisternal approach by using a 20-gauge intravenous indwelling cannula. One rabbit died as a result of brainstem trauma during percutaneous cannulation before contrast administration, but contrast agent was still injected to see the possible MR imaging results of spinal CSF reabsorption after death. Magnetic resonance imaging was performed at 15, 60, 120, and 180 minutes after the administration of contrast agent. After intramuscular injections of anesthetic, 2 rabbits died 120 and 150 minutes after contrast injection, but the MR imaging study at 180 minutes after contrast injection was still performed. Results. Direct connections between the subarachnoid space and the perispinal veins were observed in all rabbits during serial MR cisternography. The enhancement power was not affected by the amount of injected contrast agent or by cervical or lumbar penetration but was increased at higher contrast concentrations or upon seizure (physical activity). Conclusions. Extracranial reabsorption of CSF has been finally proved with direct radiological confirmation of spinal venous reabsorption of CSF using serial MR cisternography. The authors believe that this study can help to develop a more accurate model of CSF dynamics, which will allow understanding of many CSF-related diseases, as well as the development of new strategies for treatment. (http://thejns.org/doi/abs/10.3171/2011.12.SPINE11108)

Key Words • spinal absorption • cerebrospinal fluid • reabsorption • magnetic resonance cisternography • technique

F

centuries humankind has been struggling to understand the hydrodynamics, formation, and absorption of CSF along with its pathological imbalances. The widely accepted theory of CSF hydrodynamics implies that CSF is mainly secreted from choroid plexuses in brain ventricles and is absorbed with unidirectional flow from arachnoid projections into the superior sagittal sinus.19,38,48 A significant number of experiments and cases conflict with this hypothesis, however.1,2,14,20–22,26 According to recently published studies, CSF is continuously pro394

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duced and absorbed in the whole cerebrospinal system.38,41 Filtration and reabsorption occur through the capillaries of cranial and spinal ependyma, the lymphatic system, and associated veins.6,16,18,38,41,44,45 Authors of various experiments have stated that the cranial and spinal lymphatic system could have a role in CSF reabsorption, but the This article contains some figures that are displayed in color online but in black and white in the print edition.

J Neurosurg: Spine / Volume 16 / April 2012

Direct venous spinal reabsorption with serial MR cisternography existence and participation of extracranial reabsorption is still a matter of debate.20,21,28–30,36,51 Spinal venous reabsorption is even more controversial, but clusters of arachnoidal villi have recently been revealed histologically in the dorsal root of spinal nerves and are speculated to have a role in the reabsorption of CSF.16,18,44,49,50,52,53 We studied MR cisternography results in 11 New Zealand white rabbits. Direct venous connections could be discerned in all rabbits. Despite the considerable number of histological and tracing studies that speculate extracranial reabsorption of CSF, the current study represents the first radiological confirmation via serial MR cisternography of direct spinal venous reabsorption.

Methods Eleven adult (6 months old) New Zealand white male rabbits weighing approximately 3.0 kg each were used for this experiment. Animals were sedated with ketamine (50 mg/kg) and xylazine (10 mg/kg) delivered intramuscularly. One milliliter of gadopentetate dimeglumine (Magnevist) was diluted with pure water, and different solutions (1/3– 1/20) for each rabbit were prepared to visualize the effect of the contrast agent’s intensity to the enhancement power. During the procedure, heart and respiration rates, behavioral alterations (including seizure activity), and changes in body temperature were periodically checked. After obtaining precontrast scans, subarachnoid access was gained percutaneously via a cisternal approach using a 20-gauge intravenous indwelling cannula. The contrast agent gadopentetate dimeglumine (Magnevist) was intrathecally administered through the craniovertebral junction by the cisternal pathway in 9 rabbits and by the lumbar pathway in 2 rabbits, at a flow rate of approximately 0.1 ml/second via manual injection. The rabbits were then gently rotated 3 times and were subjected to continuous passive movement to facilitate even distribution of the contrast agent. All images were obtained with the rabbits prone, with the vertex remaining at the top of the images. Magnetic resonance imaging was performed at 15, 60, 120, and 180 minutes after the administration of contrast agent. Axial, coronal, and sagittal MR images were obtained on a 1.5-T Achieva MR Unit (Philips Medical System) with an 8-channel SENSE neurovascular coil (Table 1). This study was approved by the Institutional Animal Care and Use Committee of Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey. TABLE 1: Summary of whole spine MR imaging characteristics* Angle

No. of Slices

Gap (mm)

Matrix

NSA

axial coronal sagittal

80 30 20

0–1 0 0

259/640 259/704 240/704

6 2 6

* All images had a field of view 300–400, TR 500 msec, TE 9 msec, and slice thickness of 2 mm. Abbreviation: NSA = number of signals averaged.


Results Connections Between Veins and Subarachnoid Space

Direct connections between the subarachnoid space and the perispinal veins were viewed in all 9 rabbits during serial MR cisternography. Cervical, thoracic, and lumbar veins were similarly affected even at different contrast concentrations. No difference between the right and left sides could be seen (Table 2).

Serial MR Cisternography Results

Contrast enhancement was visualized 15 minutes after the injection of contrast agent in 6 rabbits and persisted during the experiment (Fig. 1). We could not detect early enhancement at 15 minutes after contrast injection in 3 rabbits in which low contrast concentrations (1/10 and 1/20 dilutions) were applied, but the venous connection was visualized in all 3 after 60 minutes. We observed direct connections at 15 minutes after contrast injection through the lumbar approach even with low contrast concentrations. Rabbits 3 and 4 (Table 2) had a seizure immediately after contrast administration; the seizures were severe and resistant to medication. Rabbits experiencing seizure had severe tonic-clonic movements. The rabbits were sufficiently stable, even after the exhausting seizure experience, for the remaining images to be obtained. Interestingly, contrast enhancement was stronger in the seizure images compared with the nonseizure images, although the amount and concentration of contrast agent (0.5 ml, 1/4 dilution for Rabbits 3 and 4 compared with 0.8 ml, 1/3 dilution for Rabbits 1 and 2) were lower. Maximum enhancement power was obtained after seizure (Fig. 2). For subsequent experiments in Rabbits 5–11 the contrast agent was diluted, and the procedure was performed with an O2 inhaler (4 L/minute) to avoid further seizures. In these 6 seizure-free rabbits the degree of contrast enhancement in the direct subarachnoidvenous connections did not vary. One rabbit (Rabbit 2) died as a result of brainstem trauma during percutaneous cannulation before contrast administration, but the degree of contrast enhancement did not vary after the rabbit’s death. Two rabbits (Rabbits 1 and 5) died after intramuscular anesthetic injection after the 120th and 150th minutes, just before performing the MR cisternography studies, respectively, although the MR imaging study 180 minutes after contrast injection was still performed. The histopathological changes in spinal veins after contrast administration were not studied, but we believe that the death of the rabbits occurred because of the anesthetic agent, which suppressed respiration, and not as a result of contrast toxicity. None of the rabbits receiving O2 ventilation (4 ml/minute) during the procedures died.

Contrast Enhancement

The subarachnoid-venous connections in Rabbit 2, which died immediately after cisternal penetration, could be viewed just as well as in the live rabbits. Contrast visualization was weak in Rabbits 10 and 11 (1/20 dilutions) compared with that in the rabbits with higher concentrations (1/3, 1/4, and 1/10 dilutions). The subarachnoid space drained to the cervical venous plexuses of the rabbits, and 395

H. Biceroglu et al. TABLE 2: Summary of characteristics in 11 rabbits that underwent MR cisternography* Rabbit Alive After Contr Time of MR Image (min)‡ Contr Enhancement Contr Dilu- Amount of Contr No. Injection (min)† 15 60 120 180 Complication/Important Notes Power in Veins Approach tion Ratio§ Injected (ml) 1

150

+

+

+

+

death after IM anesthesia

high

cisternal

1/3

0.8

2

0

+

+

+

+

death during penetration

high

cisternal

1/3

0.8

3

60

NP

+

+

+

seizure

very high

cisternal

1/4

0.5

4

55

NP

+

+

+

seizure

very high

cisternal

1/4

0.5

5

120

−

+

+

+

death after IM anesthesia

high

cisternal

1/10

0.6

6

throughout study throughout study throughout study throughout study throughout study throughout study

−

+

+

+

high

cisternal

1/10

0.6

+

+

+

+

high

cisternal

1/10

0.8

+

+

+

+

high

lumbar

1/3

0.9

+

+

+

+

high

cisternal

1/3

0.9

−

+

+

+

moderate

cisternal

1/20

0.5

+

+

+

+

continuous 4 L/min O2 inhaler after IM anesthesia continuous 4 L/min O2 inhaler after IM anesthesia continuous 4 L/min O2 inhaler after IM anesthesia continuous 4 L/min O2 inhaler after IM anesthesia continuous 4 L/min O2 inhaler after IM anesthesia continuous 4 L/min O2 inhaler after IM anesthesia

moderate

lumbar

1/20

0.5

7 8 9 10 11

* All rabbits had cervical, thoracic, and lumbar enhancement on both the left and right sides. Abbreviations: Contr = contrast; IM = intramuscular; NP = imaging not performed; − = no; + = yes. † Precontrast images already obtained. ‡ After needle penetration for contrast injection. § Degree of dilution with distilled water.

connections to individual veins were seen in all rabbits (Fig. 3). The strength of contrast enhancement did not vary with regard to the injection amount, death, or agent distribution, although the enhancement power was significantly affected by seizure (physical activity) and by the initial agent concentration (Fig. 4).

Discussion

Classic CSF Absorption Theory

Cerebrospinal fluid is an essential physiological medium surrounding the CNS, providing mechanical support and transportation of wastes, chemicals, immunoglobu-

lins, and electrolytes.22,41 According to the classic hypothesis, the formation of CSF is an active, energy-consuming metabolic process that occurs mainly in the choroid plexuses within brain ventricles.16,38,43 Although it is believed that most CSF reabsorption occurs in the arachnoid villi of the dural venous sinuses, a significant number of studies in previous decades have supported absorption of CSF from the subarachnoid space to the extrasinusoidal spaces such as the cranial and spinal lymphatic system, choroid plexuses, ependyma, cranial perineural space, and spinal veins and directly into intrathecal blood vessels.16,38,41,44,49,50,52,53 It was very hard and complicated to determine the percentage of this partition.41

Fig. 1. Serial axial MR images revealing the spread of contrast agent from the spinal canal via the neural foraminal aperture and the periradicular area. Drainage to the neck veins can be clearly seen, which proves the direct venous connection from the subarachnoid space to the venous system. Images were obtained 15 (A), 120 (B), and 180 (C) minutes after contrast injection.

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Direct venous spinal reabsorption with serial MR cisternography in the whole CSF system to maintain normal intracranial pressure.19,38,41 Hydrodynamics and Distribution of CSF Reabsorption Under Physiological and Pathological Conditions

Fig. 2. Sagittal T1-weighted MR image obtained after seizure, demonstrating the lumbar spinal venous connection (arrows). The contrast enhancement power increased due to tonic-clonic contractions of muscles and possible increases in CSF pressure.

New Concepts of Spinal CSF Reabsorption

Orešković et al.38 state that CSF formation has not been correctly evaluated in the past, and they conclude that there is no net CSF formation in the brain ventricles. They have postulated that osmotic and hydrostatic forces are important for volume regulation and that the cerebral capillaries and, theoretically, venules could be the main sites of this exchange.38 More importantly, contrary to current hypotheses, a permanent fluid and substance exchange between the CSF system and surrounding tissue has been speculated in the last decade.15,38 The discovery that no net CSF is produced in the brain ventricles led to a new understanding—that CSF is permanently produced and absorbed J Neurosurg: Spine / Volume 16 / April 2012

Pollay41 states that the drainage system is engaged in 50–70 mm of CSF pressure and that the flow rate is approximately 0.35 ml/minute under a 3- to 4-mm Hg pressure gradient in normal conditions. The estimated maximum capacity of this CSF drainage system is 1.0 ml/ minute. Edsbagge et al.18 also checked these findings and calculated mean CSF production as 0.35 ml/minute based on a radionuclide cisternography study in healthy young humans. Draining studies with human serum tagged with 131 I (RISA) revealed olfactory connections that are believed to be active under low pressure conditions.7,10 Extracranial reabsorption of CSF was speculated to occur mostly through the lymphatic system.35 Previous tracer studies in animal models support a lymphatic connection.24,27 Some studies mention that the estimated drainage of CSF from the lymphatics is 30% in rabbits and 10%–15% in cats.6,8 Boulton et al.3 suggest that the clearance of CSF tracer from the cranial vault by lymphatics is almost 50%, but some studies ignore the importance of spinal absorption and support mostly cranial reabsorption.47 Some investigators established the fact that CSF escapes chiefly by way of the venous system and, to a lesser extent, along lymphatic pathways.46 Bozanovic-Sosic et al.4 separated cranial and spinal compartments and stated that the spinal subarachnoid compartment has an important role in CSF clearance and is responsible for approximately 25% of total CSF transport. Extravasation of radioactive red blood cells by lymphatic vessels into the orbit has been demonstrated.11 India ink filled the lymph nodes of the spinal region in rabbits after 4 hours as a result of intrathecal administration.13 Brierly12 found India ink in the cul-de-sac (terminations in the pole of the root ganglion) of rabbits and mentioned variations in the filling of the adjacent subarachnoid space with India ink. Edsbagge et al.18 performed a radionuclide cisternography study in healthy young humans and found that the rate of tracer activity decline was about 20% in the 1st hour; these authors added that this decline was affected by physical activity. The calculated spinal absorption was 0.11–0.23 ml/minute, but it remained unclear whether this flow was into the spinal veins or into a lymphatic plexus. Papaiconomou et al.39 found that arachnoid villi and granulations do not appear during fetal stages but instead begin to develop around the time of birth and increase in number with age. As a result of this discovery, they postulated that the lymphatics play a major role in neonatal CSF transport. At low pressure there is a constant flow through the lymphatics, especially in neonates, contrary to the classic view. It has also been shown that CSF can be absorbed directly into the venous system as a secondary drainage mechanism when intracranial pressures are very high.40 The percentage, distribution, and importance of reabsorption in fetal life and in adulthood, during both physiological and pathological conditions, are still a matter of debate and need more evaluation. We believe that elucidation of these matters will help in understanding the importance, participation, and development of spinal absorption. 397

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Fig. 3. Serial sagittal fat-saturated MR images demonstrating a direct connection between the subarachnoid space and the radicular veins. Note the enhancement of the contrast agent migrating from the spinal canal to the radicular veins and draining to the cervical and thoracic veins. Arrow indicates the direct venous connection of CSF from the subarachnoid space to the cervicothoracic junction of the rabbit. Note that the direct venous connection occurs before the venous plexus and big veins in the neck visualized with contrast enhancement. This is proof of a direct venous connection.

Proof of Spinal Venous Reabsorption

It was obvious that there was significant absorption in the extracranial region, but where and how this occurred remained a matter of debate. Elman19 first identified clusters of arachnoidal cells located near the dorsal root veins as potentially important for the reabsorption of CSF. Wisclocki50 used tracing methods to define the plexus around the spinal dorsal root, which was found to be similar to those in the cranial sagittal sinus. Histological and anatomical findings of extracranial reabsorption, especially from extracranial lymphatics, could not have a functional aspect for a long time, despite the considerable number of studies.5–13 Welch and Pollay49 studied spinal arachnoid granulations in monkeys, particularly the thinwalled veins found around the dorsal root ganglia, but they observed these granulations in only 5 (16%) of 32 roots.38 Some investigators found even higher numbers of arachnoid granulations in dogs and sheep.23,38 In fact, CSF absorption in chickens appears to be a very suitable animal

Fig. 4. Left: Axial preenhancement MR image demonstrating the spinal canal of the rabbit. Right: Axial postenhancement MR image demonstrating connection of the subarachnoid space with the perispinal veins.

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model for the mechanisms operative in arachnoid granulations in humans.31 Kido et al.33 observed spinal arachnoid villi located around the thoracic region in human cadavers,38 but Tubbs et al.44 mentioned that these were mostly related to the lumbosacral venous vessels and added that the increase in size in the adjacent radicular vein results in an increase in the number of arachnoid villi.38 Some investigators found no functional or anatomical relationship between the spinal arachnoid villi and the venous system.44 The spinal subarachnoid space contributed a great overall decrease in CSF pressure and volume in the early period after mannitol administration in some studies.34 Despite several histological and tracing experiments showing evidence of extracranial CSF absorption, a direct connection between the subarachnoid space and spinal veins has not yet been shown. Current Research Results Under New Conceptual Developments

We observed immediate net spinal venous flow in 6 of 9 rabbits 15 minutes post–contrast injection and in all rabbits 60 minutes postcontrast. (In 2 of 11 rabbits the initial postinjection imaging study could not be performed because of seizures.) The contrast percentage was lower (1/10) in 3 rabbits (Rabbits 5–7), and thus contrast could not be observed in the spinal veins after 15 minutes. A net spinal venous connection could be discerned at every level and in both the left and right sides. Edsbagge et al.18 state that spinal venous reabsorption increases with physical activity. Despite theories that the dural sinuses are the main place of CSF reabsorption during physiological conditions, we believe that the importance and drainage of CSF into the spinal veins increases under pathological conditions.38 J Neurosurg: Spine / Volume 16 / April 2012

Direct venous spinal reabsorption with serial MR cisternography These findings also explain why the rabbits undergoing seizures in our study absorbed more contrast agent. Although spinal arachnoid granulations in monkeys were directly associated with veins in only 5 of 32 nerve roots,49 we experienced venous absorption in all spinal ver tebral levels. Was this reabsorption through the lymphatics, the veins, or, in particular, the arachnoid granulations in perispinal vascular veins? We believe additional histopathological examinations must be done to make clear how the CSF entered the venous system, and further physiological studies are needed to discern the participation of different mechanisms in various physiological conditions correlating with MR imaging. On the other hand, according to literature on the dynamics of CSF in animals and humans, we speculated that both the lymphatics and the venous system play important roles in CSF reabsorption. In fact, the lymphatic system is probably responsible for low-pressure reabsorption of CSF, and the venous system is functioning mostly at high-pressure levels. Greitz and Hannerz25 studied the intracranial dynamics of CSF using MR and CT cisternography in 26 healthy volunteers and in 25 patients who had different CSF-related diseases. They declared that the main absorption of CSF does not occur through the pacchionian granulations, but instead a major part of the transportation to the bloodstream is likely to occur via the paravascular and extracellular spaces of the CNS, and they suggested revising the old accepted CSF circulation model.15 Interstitial fluid and CSF are formed by water filtration across the walls of arterial capillaries, resulting in the formation and absorption of CSF in balance.4 An acute occlusion in the aqueduct of Sylvius usually does not change CSF pressure in isolated ventricles, and the distribution of substances inside CSF and between CSF and interstitial fluid occurred by pulsations of these fluids.4 Absorption of CSF into venous sinuses and/or lymphatic reabsorption of CSF under physiological conditions is speculated to be of minor importance given the minute surface area of the vessels compared with the surface area of large cranial sinuses.4 Although spinal arachnoid granulations should have a role in the reabsorption of CSF like those in the sagittal sinus, it is clear from these granulations, as well as through the venous capillaries at all spinal vertebral levels, that there is an outflow of CSF. When the spinal nerve roots enter the intervertebral foramen, they are enveloped by dura mater, which is continuous with the perineural tissue of the root bundles immediately proximal to the ganglion.42 We noted CSF drainage starting at the level of all spinal nerve roots and continuing regular and straight, following the estimated pathways of the veins to reach cervical, thoracic, and lumbosacral venous plexuses. The contrast enhancement was seen at both the right and the left sides similarly. Contrast enhancement was seen in the perispinal veins before the cervical veins were visualized, which gives us strong proof of early and clear perispinal venous absorption of CSF. We demonstrated the speculated schematic view of a spinal nerve root in which the perispinal veins, arachnoid granulations, and lymphatic vessels interact collaboratively in the drainage of CSF, but we must remember that the morphology of the vessels that drain the spinal CSF clearly demonstrate the veins and not the lymphatics (Fig. 5). Moreover, possible ultrastructural J Neurosurg: Spine / Volume 16 / April 2012

Fig. 5. Schematic demonstrating the possible relationship between the periradicular structures in spinal CSF reabsorption. a = dorsal root ganglion; b = radicular artery; c = radicular vein; d = ventral root of spinal nerve; e = arachnoid granulations; f = cervicothoracic junction with venous plexus; g = periradicular lymphatic vessels; h = dura mater. Printed with the permission of H. Biceroglu, 2011.

evidence for pressure-dependent closed and open venous systems of CSF reabsorption has been identified in animals and humans by electron microscopy.17,32 Spinal reabsorption of CSF is affected after subarachnoid bleeding and causes acute or chronic hydrocephalus.37 Acute hydrocephalus is probably a simple mechanical obstruction, but chronic hydrocephalus is a result of arachnoid cap cell proliferation, which also must be studied to understand spinal reabsorption hydrodynamics.37 Our study represents the first MR imaging–guided confirmation of direct spinal venous reabsorption. We believe that our data can help in solving and understanding a long-standing debate about CSF reabsorption. New conceptual and experimental data will cause the present widely accepted beliefs to be reconsidered. Additional studies must be done to understand the overall significance of this pathway and its relative importance under physiological and pathological conditions.

Conclusions

Our data support recent publications postulating that CSF absorption occurs not only intracranially but also along the whole spinal axis. Additional studies must be conducted to reveal the importance of spinal reabsorption in CSF hydrodynamics. A more accurate model of CSF dynamics can help us to understand many CSF-related diseases and develop new strategies for treatment. Disclosure This study was supported by Istanbul University Research Projects Department. Author contributions to the study and manuscript preparation include the following. Conception and design: Biceroglu, Albayram, Kiris. Acquisition of data: Biceroglu, Albayram, Yuksel, Karaaslan, Yildiz. Analysis and interpretation of data: Biceroglu, Albayram, Ogullar, Hasiloglu, Kiris. Drafting the article: Biceroglu, Albayram, Hasiloglu. Critically revising the article: all authors. Reviewed sub-

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H. Biceroglu et al. mitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Biceroglu. Administrative/ technical/material support: Biceroglu, Albayram, Hasiloglu, Selcuk, Yuksel, Karaaslan, Yildiz, Kiris. Study supervision: Biceroglu, Albayram, Ogullar, Yildiz. Acknowledgments The authors gratefully acknowledge the valuable technical assistance provided by Sinan Unlu, Ali Serkan Yukceken, and Volkan Kutlu. References 1. 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 275:R889–R896, 1998 2. 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 272:R1613–R1619, 1997 3. 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 276:R818–R823, 1999 4. Bozanovic-Sosic R, Mollanji R, Johnston MG: Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol Regul Integr Comp Physiol 281:R909–R916, 2001 5. Bradbury M: Lymphatics and central nervous system. Trends Neurosci 4:100–101, 1981 6. Bradbury MW, Cole DF: The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. J Physiol 299:353–365, 1980 7. Bradbury MW, Cserr HF: Drainage of cerebral interstitial fluid and of cerebrospinal fluid into lymphatics, in Johnston M (ed): Experimental Biology of the Lymphatic Circulation. New York: Elsevier, 1985, pp 355–349 8. Bradbury MW, Cserr HF, Westrop RJ: Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329–F336, 1981 9. Bradbury MW, Deane R, Segal MB, Westrop RJ: Recovery of [125I] albumin in deep cervical lymph of the sheep after intraventricular injection. J Physiol 305 (Suppl):52P, 1980 10. Bradbury MW, Westrop RJ: Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J Physiol 339:519–534, 1983 11. Bradford FK, Johnson PCJ Jr: Passage of intact ironlabeled erythrocytes from subarachnoid space to systemic circulation in dogs. J Neurosurg 19:332–336, 1962 12. Brierley JB: The penetration of particulate matter from the cerebrospinal fluid into the spinal ganglia, peripheral nerves, and perivascular spaces of the central nervous system. J Neurol Neurosurg Psychiatry 13:203–215, 1950 13. Brierly JB, Field EJ: The connexions of the spinal sub-arachnoid space with the lymphatic system. J Anat 82:153–166, 1948 14. Brinker T, Lüdemann W, Berens von Rautenfeld D, Samii M: Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid. Acta Neuropathol 94:493–498, 1997 15. Bulat M, Klarica M: Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev 65:99–112, 2011 16. Dandy WE: Where is cerebrospinal fluid absorbed? JAMA 92:2012–2014, 1929 17. d’Avella D, Cicciarello R, Albiero F, Andrioli G: Scanning electron microscope study of human arachnoid villi. J Neurosurg 59:620–626, 1983 18. Edsbagge M, Tisell M, Jacobsson L, Wikkelso C: Spinal CSF absorption in healthy individuals. Am J Physiol Regul Integr Comp Physiol 287:R1450–R1455, 2004

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