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Am J Physiol Regul Integr Comp Physiol 282: R1593-R1599, 2002. First published January 31, 2002; doi:10.1152/ajpregu.00695.2001
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Vol. 282, Issue 6, R1593-R1599, June 2002

Blocking cerebrospinal fluid absorption through the cribriform plate increases resting intracranial pressure

R. Mollanji, R. Bozanovic-Sosic, A. Zakharov, L. Makarian, and M. G. Johnston

Trauma Research Program, Department of Laboratory Medicine and Pathobiology, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario M4N 3M5, Canada


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Cerebrospinal fluid (CSF) drains through the cribriform plate (CP) in association with the olfactory nerves. From this location, CSF is absorbed into nasal mucosal lymphatics. Recent data suggest that this pathway plays an important role in global CSF transport in sheep. In this report, we tested the hypothesis that blocking CSF transport through this pathway would elevate resting intracranial pressure (ICP). ICP was measured continuously from the cisterna magna of sheep before and after CP obstruction in the same animal. To block CSF transport through the CP, an external ethmoidectomy was performed. The olfactory and adjacent mucosa were removed, and the bone surface was sealed with tissue glue. To restrict our analysis to the cranial CSF system, CSF transport into the spinal subarachnoid compartment was prevented with a ligature tightened around the thecal sac between C1 and C2. Sham surgical procedures had no significant effects, but in the experimental group CP obstruction elevated ICP significantly. Mean postobstruction steady-state pressures (18.0 ± 3.8 cmH2O) were approximately double the preobstruction values (9.2 ± 0.9 cmH2O). These data support the concept that the olfactory pathway represents a major site for CSF drainage.

lymphatic vessels; olfactory pathway; arachnoid villi; hydrocephalus


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE TENETS that form the basis of our understanding of cerebrospinal fluid (CSF) absorption do not appear to have received critical appraisal in recent years. The arachnoid projections into the cranial venous sinuses are believed to represent the primary sites for CSF absorption, and current views on the pathophysiology of hydrocephalus focus on impaired CSF transport to or through these elements. However, there are numerous observations that are inconsistent with an arachnoid villus-centered view of CSF drainage (reviewed in Ref. 22). Additionally, the possibility that CSF may transport through the cribriform plate (CP) into extracranial lymphatic vessels has been generally ignored even though an association between CSF and lymph has been known for many years.

The CP is located at the base of the anterior skull and supports the olfactory bulbs. Olfactory nerves penetrate this bone through holes or foramina and terminate in the olfactory epithelium in the nasal mucosa. Investigators have known for some time that CSF tracers convect along the extensions of the subarachnoid compartment associated with the olfactory nerves, transport through the CP, and are ultimately absorbed by lymphatics in the nasal mucosa (9, 23). From this location, the cervical lymphatic ducts transport the CSF tracers to the venous system. Additionally, there is evidence that human immunodeficiency virus (HIV) antigens within the CSF can be carried to the cervical lymph nodes via this pathway (11).

Estimates of the clearance of CSF through extracranial lymphatics in sheep and rats based on studies employing radioactive protein tracers and mathematical modeling suggested that a significant portion of the total volume of CSF removed from the cranial vault was cleared into cervical lymphatic vessels (3-7). In addition, intracranial pressure (ICP) was closely related to cervical lymph pressure and lymph flow rate (39). In experiments in which we challenged the ICP regulatory system with intracisternal infusions of artificial CSF, CP obstruction elevated CSF outflow resistance significantly (38) and reduced CSF absorption appreciably (31). Remarkably, even though arachnoid villi exist in adult sheep, the data suggested that the majority of cranial CSF transport occurred through the CP at low CSF pressures and that other undefined clearance sites (possibly arachnoid villi) were recruited only when pressures were elevated (31).

These data challenge the conventional view that CSF is absorbed principally via arachnoid villi and provided further support for the existence of several anatomically distinct cranial CSF transport pathways. One would predict, therefore, that obstruction of the CP would remove a significant number of CSF absorption sites and result in an elevation of ICP. The objective of the experiments outlined here was to test this hypothesis.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Randomly bred sheep weighing 20-40 kg were used for this investigation. They were fed hay, pellets, and water ad libitum but were fasted 24 h before surgery. Experiments were approved by the ethics committee at Sunnybrook and Women's College Health Sciences Centre and conformed to the guidelines set by the Canadian Council on Animal Care and the Animals for Research Act of Ontario.

Blocking CSF transport pathways to the spinal CSF compartment. The sheep were anesthetized initially by intravenous infusion of 5% pentothal sodium solution with consequent endotracheal administration of halothane through a respirator (either Narkomed 2 or A.D.S. 1000). For continuous monitoring of systemic arterial pressure, femoral artery cannulation was performed. We prevented CSF transport into the spinal cord by performing a C1-C2 laminectomy. A 0-silk ligature was passed around the thecal sac between C1 and C2 and tied tightly to compress the meninges and spinal cord, thereby separating the cranial and spinal subarachnoid compartments. In all animals, systemic arterial pressure increased immediately after the cord was ligated, but blood pressure returned to baseline or slightly lower and remained stable for the duration of the experiment. Similar effects of spinal compression on systemic blood pressure have been described in the literature (16, 21). The cisterna magna was cannulated with an angiocatheter connected to a vinyl cannula filled with artificial CSF (13). Artificial CSF contained (in mM) 125 NaCl, 2.8 KCl, 1.2 CaCl2, 0.9 MgCl2, 25 NaHCO3, and 0.5 Na2HPO4/KH2PO4. The catheter was secured to the dura with tissue glue (mixture of ethyl cyanoacrylate and polymethylmethacrylate, Surehold, Chicago, IL) and exteriorized. The CSF and arterial catheters were connected to Cobe CDX disposable pressure transducers. All pressure data were recorded on a computer-based data-acquisition system (A-Tech Instruments, Toronto, Ontario, Canada; Visual Designer software, Tucson, AZ).

Blocking CSF transport pathways to extracranial lymphatic vessels. To gain access to the extracranial side of the CP, the skin over the frontal-nasal area was reflected to reveal the frontal and nasal bones. Approximately a 3 × 3-cm nasal bone was removed to expose the nasal mucosa with the upper edge approximately at the level of a line bisecting the medial canthi. In the experimental group, an external ethmoidectomy was performed; the nasal mucosa, olfactory nerves, and all soft tissue on the extracranial surface of the CP were scraped away with a curette, and the bone surface was sealed with the aforementioned tissue glue. At the end of each experiment, an Evans blue dye-protein complex was injected into the CSF compartment to check for possible CSF leaks.

In the sham surgery group, all surgical procedures were the same (spinal cord ligated and section of nasal bone removed) with the exception that the nasal mucosa and CP were left intact. The experimental group lost more blood than the sham surgery group. We estimated this volume by weighing the surgical gauze before and after surgery in several of the experimental group preparations. We used the weight difference to calculate the blood loss associated with scraping the nasal mucosa from the CP. The estimated blood volume (average 118 ml) was removed from four of the seven sham surgery preparations over a period of time equivalent to that needed to seal the CP.

Experimental protocol and data analysis. ICP was measured continuously during the experiments. After spinal cord ligation, the pressure was monitored until a new equilibrium pressure was attained (when ICP remained stable for 30 min). At this point, the animal was subjected to a sham surgical procedure or CP obstruction, and ICP was monitored until a new equilibrium was achieved (stable ICP for 30 min).

To simplify the analysis, we found that it was helpful to reduce the number of data points captured by the data-acquisition system. Therefore, all systolic, diastolic, and mean ICPs were averaged over 10-min intervals, and these values were plotted against time. From this graph, three consecutive pretreatment and three consecutive posttreatment equilibrium values were identified by visual inspection of the pressure record. To calculate a before-treatment pressure, the three consecutive equilibrium points immediately before surgery were averaged to generate a single number. Similarly, the three consecutive points from the second equilibrium period after CP obstruction/sham surgery were averaged. These values were used for statistical analysis. All values were expressed as means ± SE. The impact of CP obstruction and the sham surgery procedure was assessed with two-way repeated-measures ANOVA. We interpreted P < 0.05 as significant. A similar approach was used for analysis of systemic arterial pressure.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Twenty sheep were used in this investigation. Of these, three animals were excluded from data analysis because of CSF leaks or other technical problems. For reasons unknown to us, three additional animals demonstrated high initial ICP and will be discussed separately. We considered that 14 experiments were successful (7 sham surgical preparations and 7 in the CP obstruction group).

In every experiment, the spinal cord was ligated to separate the cranial and spinal subarachnoid compartments. This resulted in an initial 5- to 10-cmH2O increase in ICP followed by a decline. After between 10 and 50 min, an equilibrium pressure was achieved. Systemic arterial pressure also increased after spinal ligation and then decreased to a level ~70% of the initial value. This was due presumably to the loss of spinal control of blood pressure. Additionally, in both the CP obstruction and sham surgery preparations, average arterial pressures declined significantly from time 0 to the period in which the second equilibrium ICP was established (79.6 ± 7.2 to 69.0 ± 6.1 cmH2O in the CP obstruction group and 68.4 ± 5.1 to 55.2 ± 4.3 cmH2O in the sham surgery group). However, the arterial pressure pattern was very similar in both groups. A two-way, repeated-measures ANOVA (group by time) illustrated no significant differences in arterial pressures between the CP obstruction group and the sham surgery series.

ICP in the sham surgery group. In the control animals, the ICP after sham surgery did not change to any significant extent. Figure 1 illustrates an example from this group. In this and in five other sham surgery experiments, ICP remained stable. In one experiment, ICP increased moderately. Overall, mean, systolic, and diastolic pressures declined slightly after the surgical procedure (Fig. 2 illustrates averaged data).


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  		Fig. 1.   Example of the effects of sham surgical procedures on resting intracranial pressure in an adult sheep.



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  		Fig. 2.   Relationship between intracranial pressure and mean, systolic, and diastolic pressure before and after sham surgical procedures (n = 7).

ICP in the cribriform seal group. Immediately after external ethmoidectomy, ICP decreased presumably, as some CSF was lost from the cranial compartment. After CP obstruction, ICP then rose as new CSF was synthesized. In six of the seven preparations, ICP increased above the presurgery value, and after 3-5 h, a new equilibrium pressure was achieved. An example from this series is illustrated in Fig. 3. Mean, systolic, and diastolic pressures were all elevated relative to the initial levels. In one sheep, no changes in ICP were observed. The averaged data are illustrated in Fig. 4. For each of the mean, systolic, and diastolic pressures, ICP essentially doubled after the CP had been sealed. In addition, the amplitude of the pulse pressure was greater after CP obstruction (the difference between systolic and diastolic pressures averaged 6.2 ± 1.0 cmH2O before and 15.1 ± 2.0 cmH2O after obstruction; in the sham surgery group, pulse pressures were the same, i.e., 5.6 ± 0.9 cmH2O before and 5.0 ± 1.2 cmH2O after sham surgery).


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  		Fig. 3.   Example of the effects of extracranial cribriform plate (CP) obstruction on resting intracranial pressure in an adult sheep.



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  		Fig. 4.   Relationship between intracranial pressure and mean, systolic, and diastolic pressure before and after extracranial CP obstruction (n = 7). A 2-way, repeated-measures ANOVA revealed a significant interactive effect between the terms group (CP obstruction vs. sham-operated animals) and time (pre- vs. posttreatment) for the mean and systolic pressure data. This was due to the fact that equilibrium mean and systolic intracranial pressure levels increased in the CP obstruction group but not in the sham surgery animals. No significant differences were observed in diastolic pressure values. * Significant differences.

Statistical analysis. Details of the statistical analysis are provided in Table 1. A two-way, repeated-measures ANOVA on seven sham surgery and seven CP-obstructed animals demonstrated a significant interactive effect between the terms group (CP obstruction vs. sham-operated animals) and time (pre- vs. posttreatment) for the mean and systolic pressure data. This effect was due to the observation that there was an increase in equilibrium mean (P = 0.0259) and systolic (P = 0.0063) ICP levels after CP obstruction but not after sham surgery. Diastolic pressure values were not significantly different between the CP obstruction and sham surgery groups (P = 0.0886).

                              
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  		Table 1.   Statistical analysis using 2-way, repeated-measures ANOVA on 7 sham surgery and 7 CP-obstructed animals

Animals with high initial ICP. After spinal cord ligation, ICP generally stabilized between 8 and 9 cmH2O. From our experience in this species, these pressures would fall within the normal range. However, three animals exhibited very high initial ICP (>= 20 cmH2O). Of these, one was in the sham surgery series and ICP did not change during the course of the experiment. With the two animals in the cribriform seal group, we did not observe any changes in ICP after CP obstruction. Because these three sheep exhibited higher than normal ICPs, they were excluded from data analysis.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In previous studies, we determined that sealing the CP had a significant impact on CSF transport. We demonstrated that extracranial obstruction of the plate reduced CSF clearance from the cranial vault (31) and elevated CSF outflow resistance (38). In both of these previous investigations, we challenged the cranial ICP regulatory mechanisms with continuous or bolus infusions into the CSF compartment. In this report, we hypothesized that prevention of CSF transport through the CP would elevate resting ICP. We reasoned that CSF would be formed continuously in the choroid plexus during the experimental period. Because CP obstruction would remove a significant CSF absorption site, ICP would increase to a new equilibrium level.

The hypothesis was supported by the data. When the CP was sealed, ICP rose to a value that was approximately double that observed in the preseal period. Additionally, the amplitude of the pulse pressure increased. The latter effect was likely due to compliance issues. As volume increases in the cranial vault, pressures rise exponentially (15). By reducing CSF clearance from the cranial CSF system, obstruction of the CP elevated ICP and forced the cranial pressure-regulating mechanisms to work further up the pressure-volume curve where compliance is reduced. Under these conditions, any change in CSF volume (or displacement due to vascular pulse pressures and respiration) increases the amplitude of ICP pulsations.

The effects of CP obstruction we observed were dependent on the separation of the cranial and spinal CSF compartments. We know from past studies that ~25% of global CSF transport in adult sheep occurs from the spinal subarachnoid compartment (8). Additionally, our analysis suggested that the proportional CSF clearance that occurred through noncribriform routes was greater when CSF had access to spinal absorption sites. Therefore, if the spinal subarachnoid compartment were in continuity with its cranial counterpart, obstruction of CSF outflow through the CP would likely result in the recruitment of additional CSF drainage sites in the spinal compartment. This recruitment would blunt any attempt to understand the dynamics of cranial CSF transport systems.

What is most remarkable about the elevation of ICP we observed is that CSF transport was altered by an extracranial manipulation. The CP was sealed on the nasal mucosal side, thereby avoiding complications associated with intracranial access. We did consider the possibility that changes in blood pressure due to ligation of the spinal cord could alter ICP independently of any effects the CP obstruction would have on CSF transport. Spinal ligation increased systemic arterial pressure transiently followed by a decline to below normal values. Additionally, during the course of the experiment, arterial pressures dropped 10-14 cmH2O in both the experimental and sham surgery groups. However, ICP increased only in the CP-obstructed animals, and therefore, it is very unlikely that vascular parameters contributed to the elevation in ICP observed after CP obstruction.

Magnitude of CSF transport by the olfactory pathway. In previously published studies, we estimated the volumetric transport of CSF into cervical lymphatic vessels and the thoracic duct using radioactive protein tracers. The cranial and spinal subarachnoid compartments were left in communication. At resting ICPs, we estimated that between 40 and 48% of global CSF transport occurred into extracranial lymphatics (5). We probably underestimated the lymphatic contribution in these experiments because we likely failed to identify all of the relevant cervical lymphatic vessels. In a more recent investigation with the spinal subarachnoid compartment excluded, we compared cranial CSF conductance with the CP intact and with the plate obstructed. The data suggested that the proportion of CSF transport that occurred through olfactory and nonolfactory pathways was dependent on ICP (31). At pressures close to the opening pressure (i.e., the ICP at which CSF absorption was initiated), the majority of cranial CSF drainage occurred through the olfactory pathway. As ICP was elevated, other absorption sites were recruited progressively.

In the study reported here, a new equilibrium pressure was established after negating the olfactory/cervical lymphatic pathway. Therefore, CSF clearance must have continued through some other cranial transport system. Clearly, this alternative pathway did not have the volumetric capacity to deal with normal CSF production. If this had been the case, ICP would not have increased. In this regard, it is of interest to note that in several animals in which ICP was abnormally elevated before CP obstruction, ICP did not increase further once the plate had been sealed. Therefore, this alternative system is independent of cribriform lymphatic transport, and its function is determined solely by ICP. It is possible that this clearance occurred through the arachnoid villi and granulations that project into the cranial venous system. However, we must also consider the possibility that other lymphatic networks play a role in CSF transport.

Arachnoid projections into the cranial venous sinuses. The arachnoid projections into the cranial venous sinuses are believed to represent the primary sites for CSF absorption. The anatomic evidence seems persuasive. Arachnoid projections are found in close proximity to several of the cranial venous sinuses and thus seem strategically located to function as CSF transport sites (reviewed in Ref. 15). While no consensus seems to have been reached, suggested mechanisms for CSF to venous transport include arachnoid cell phagocytosis (37), pressure-dependent pinocytosis (1, 20), transport via giant vacuoles and/or transcellular channels (40, 41), or a labyrinth of open tubes that are presumed to connect the subarachnoid space with the venous sinuses in the dura (42). Arachnoid proliferations resembling the villi and granulations of the cranial system have been described in association with the spinal arachnoid membrane (18, 24, 43). It is puzzling, however, that these structures are not always linked with veins. In one study, arachnoid projections were associated directly with the venous system in only 5 of 32 nerve roots investigated (43). Without a venous connection, it is unclear how these structures would function.

There are few studies in which the role of the arachnoid villus has been quantified directly. Dura mater containing arachnoid villi has been positioned between two watertight chambers. In monkeys (42, 43) and dogs (34), transport occurred from the subarachnoid side to the venous side, but little transport was observed in the opposite direction. However, the preparation was inherently unstable with transport increasing over time. It seems possible that a portion of the fluid movement was an artifact caused by tissue deterioration. Furthermore, in some preparations, arachnoid villi were present but no transport was observed. Additionally, while the demonstration of more rapid appearance of a CSF tracer in the cranial venous blood than in the systemic circulation would tend to support CSF-to-cranial venous transport (27), it should be noted that not everyone has been able to observe this phenomenon (28).

There are additional observations that are inconsistent with an arachnoid villus-centered view of CSF drainage especially when attempting to correlate hydrocephalus with absent or dysfunctional arachnoid villi (reviewed in Ref. 22). Perhaps the most difficult factor to reconcile with the conventional view is that arachnoid villi do not appear to exist before birth in humans. In two microscopic studies of autopsy specimens from individuals up to 56 days old (33) and from 18 wk gestation to 80 yr (17), no arachnoid villi or granulations were observed before birth. Indeed, our recent data suggest that the olfactory/lymphatic pathway plays an important role in CSF transport in the late-gestation fetus (32). Therefore, the role of arachnoid projections in CSF transport requires further clarification.

Other lymphatic transport systems. If the role of arachnoid villi in CSF transport is questionable, perhaps other lymphatic vessels were responsible for the residual CSF clearance we observed when the CP was obstructed. The most important lymphatic CSF transport pathway is no doubt the olfactory route leading to cervical lymphatic vessels, but there are other nerves that may conduct CSF extracranially (9). One possible location for lymphatic CSF transport that has been ignored generally is the dura itself. In rats, lymphatics exist around the wall of the sagittal sinus, in the areas of the confluence of sinuses in proximity to the mesothelial cells of the subdural spaces and close to the vasculature of the dural tissues (2). Depending on where these vessels empty, our CP obstruction method may not have eliminated this potential CSF transport.

There is, however, at least one theoretical objection to a possible role for dural lymphatics in CSF drainage. The cellular architecture and the presence of tight junctions between arachnoid cells are believed to contribute to the blood-brain/CSF barrier (35). Without this barrier function, the extravasated fluid and solutes from the permeable dural capillaries would enter the dura interstitium and possibly gain access to CSF. However, for any dural CSF transport to occur, presumably CSF would have to pass through the supposed barrier provided by the arachnoid membrane to enter dural tissues. Such transport is thought to occur through specialized areas of the membrane where it projects into the venous sinuses (arachnoid villi). CSF transport through the arachnoid membrane at other locations has not been given much consideration, although there is some evidence to support this concept. CSF transport is known to occur through the olfactory nerve arachnoid membrane (or its perineural epithelial equivalent) into the nasal mucosa and through the arachnoid of the optic nerve. India ink injected into the subarachnoid space of the optic nerve was observed to penetrate the arachnoid and entered the interstitial compartment and lymphatics in the dura of the nerve (25). Therefore, it seems theoretically possible that dural lymphatic vessels will play some role in CSF transport.

In summary, past attempts from our group to investigate the importance of the olfactory pathway in CSF absorption have relied on tracer studies incorporating mass balance equations and experiments in which the CSF compartment was challenged with bolus or continuous infusions. In the study reported here, we provide direct physical evidence that the olfactory pathway is important in CSF transport under normal circumstances. CSF drainage through the CP into nasal mucosal lymphatic vessels helps to counterbalance the addition of new fluid into the subarachnoid compartment provided by the regular production of CSF.

Perspectives

Evidence linking extracranial lymphatics with CSF transport exists in several species, including sheep (3-5, 7, 26, 27, 33, 34), rabbits (10, 19, 28), rats (6, 23), and mice (11, 30). In these species, it is perhaps surprising to consider that there are noticeably more data supporting a role for extracranial lymphatics in volumetric CSF transport than exist to support a function for arachnoid villi. This is not to say that arachnoid projections have no role in CSF transport. However, new experimental approaches need to be developed to investigate their role more directly. The outcome of such studies could have a major impact on how we view the pathophysiology of hydrocephalus in humans. Indeed, there are some circumstantial data that cribriform-lymphatic CSF transport occurs in humans as well (12, 14, 26, 36, 44), although it is too early to say whether the cribriform route has the same quantitative significance. For example, in human autopsy material, intracranially administered India ink was observed to fill the perineural spaces around the olfactory nerve branches and was found in the nasal submucosal tissue (26). Similarly, with subarachnoid hemorrhage, red blood cells were observed around the olfactory nerves and within the nasal mucosa. Additionally, in nonhuman primates, the injection of radioactive albumin into the CSF compartment leads to elevated concentrations of tracer in the cervical lymph nodes (29).


    FOOTNOTES

Address for reprint requests and other correspondence: M. G. Johnston, Dept. of Laboratory Medicine and Pathobiology, Neuroscience Research, Sunnybrook & Women's College Health Sciences Centre, Univ. of Toronto, Research Bldg. S-111, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada (E-mail: miles.johnston{at}swchsc.on.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published January 31, 2002;10.1152/ajpregu.00695.2001

Received 21 November 2001; accepted in final form 17 January 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 282(6):R1593-R1599
0363-6119/02 $5.00 Copyright © 2002 the American Physiological Society


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