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1 Trauma Research Program, We demonstrated previously
that about one-half of cerebrospinal fluid (CSF) removed from the
cranial vault was cleared by extracranial lymphatic vessels. In this
report we test the hypothesis that lymphatic drainage of CSF increases
as intracranial pressure (ICP) is elevated in anesthetized sheep.
Catheters were inserted into both lateral ventricles, cisterna magna,
cervical lymphatics, and jugular vein. A ventriculocisternal perfusion
system was employed to regulate CSF pressures and to deliver a protein
tracer (125I-labeled human serum
albumin) into the CSF compartment.
131I-labeled human serum albumin
was injected intravenously to permit calculation of plasma tracer loss
and tracer recirculation into lymphatics. ICP was controlled by
adjusting the height of the inflow reservoir and the cisterna magna
outflow catheter appropriately. The experimental design consisted of a
3-h period of lower pressure followed by a 3-h period of higher
pressure in the same animal (10-20 or 20-30
cmH2O). We determined that
incremental changes in ICP were associated with higher CSF transport
through lymphatic and arachnoid villi routes in all eight animals
tested (P = 0.004).
cervical lymphatics; sheep; brain; spinal cord; lymph nodes
DESPITE THE FACT that a physiological association
between extracellular fluid in the brain and extracranial lymph has
been appreciated for over 100 years (reviewed in Ref. 5), this concept has never been embraced by the biomedical community. Because the drainage of central nervous system (CNS) interstitial fluid could be
accounted for by clearance through specialized structures termed arachnoid villi, there seemed little need to incorporate lymphatics into the conceptual framework that has driven investigation in this
area. The development of methods that allow quantitation of
cerebrospinal fluid (CSF) volumetric absorption into extracranial lymphatic vessels by our group has led to studies that challenge this
conventional view.
In sheep, as in some other species, multiple lymphatic drainage
pathways for CSF exist, but a major route involves clearance through
the retropharyngeal/cervical vessels (4). We determined the relative
roles of arachnoid villi and lymphatics in the clearance of a CSF
tracer by comparing the plasma recovery of an intraventricularly administered protein before and after diversion of thoracic duct and
cervical lymph and ligation of the smaller cervical vessels. Approximately one-half of the protein tracer transported from the CSF
compartment into plasma was removed by extracranial lymphatics (3).
Nonetheless, tracer recovery studies can be problematic. The transport
of a CSF tracer to the plasma complicates measurements of the CSF
tracer in lymph, since the human serum albumin (HSA) that was
transported from the CSF into plasma by the arachnoid villi would
filter back into the lymphatic compartment, resulting in an
overestimate of the lymphatic contribution to CSF absorption. To
overcome this problem, we used tracer recovery data to develop a
mathematical model that permitted estimates of volumetric CSF absorption into lymphatics. An important element in the design of the
model was the ability to correct the recovery data for errors
introduced by filtration as was mentioned above. We estimated conservatively that 40-48% of the total volume of CSF absorbed from the cranial compartment was removed by extracranial lymphatic vessels (2).
The numerous studies using ventriculocisternal or ventriculolumbar
perfusion methods, beginning with the work of Heisey et al. (11), have
demonstrated clearly that the absorption of CSF behaves as a convective
flow driven by a pressure drop. This is observed in goats (11), dogs
(1), and humans (8, 21). However, the impact of raised intracranial
pressure (ICP) on volumetric drainage of CSF by extracranial lymphatic
pathways has not been investigated adequately. Just as increased CSF
absorption through arachnoid villi is believed to play a role in the
regulation of ICP, the same may also be true of CSF clearance through
extracranial lymphatics. The purpose of this investigation was to test
whether elevations in ICP increase CSF drainage into cervical lymphatic vessels in sheep. To achieve this, we utilized tracer recovery data and
mass balance equations derived earlier to compare estimates of CSF
volumetric clearance through arachnoid villi and extracranial lymphatics under conditions of low and high CSF pressures in the same
animals.
Surgery.
Randomly bred female sheep (24-40 kg) were used in these studies.
Experiments were approved by the Ethics Committee at the Sunnybrook
Health Science Centre and conformed to the guidelines set by the
Canadian Council on Animal Care and the Animals for Research Act of
Ontario. Access to the CSF, blood, and lymph compartments was achieved
as described previously (3). A minimum of 3 days before the experiment,
catheters were inserted into both lateral ventricles under halothane
anesthesia. On the day of the experiment, multiple cervical lymphatics
were cannulated (0.58 mm ID, 0.96 mm OD; Critchley, Silverwater,
Australia), and lymph was collected into a single heparinized tube.
Lymphatic vessels too small to cannulate were ligated. The left jugular
vein was cannulated, and a solid-state pressure transducer (model
9815-F7, Honeywell) was advanced into the superior vena cava. For
access to the cisterna magna, a laminectomy of
C1 was performed. A 14-gauge
angiocatheter was used to puncture the dura and arachnoid, leaving the
catheter in the subarachnoid space. Free movement of CSF within
the catheter assembly confirmed placement.
Tracers and solutions.
125I-HSA (0.93 MBq/ml, 10 mg/ml)
and 131I-HSA (37 MBq/ml, 10 mg/ml)
were obtained from Frosst (Kirkland, PQ, Canada). All tracer solutions
were purified before use by passage through a Centricon centrifugal
concentrator (10,000-mol wt cutoff) to remove free 125I or
131I before infusion. To ensure
that the measured radioactivity in any collected sample was protein
associated, a second set of aliquots was assayed after precipitation
with 10% TCA. Free or non-protein-associated 125I or
131I represented <1% of the
total radioactivity in any sample. Macrodex saline solution (6%
Dextran 70, Baxter) was purchased from Pharmacia (Quebec, PQ, Canada).
Artificial CSF was made as described by Chodobski et al. (7).
Experimental design.
Tracer administration into the CSF compartment and control of CSF
pressure was achieved with a ventriculocisternal perfusion system. A
constant-pressure reservoir supplied artificial CSF to a lateral
ventricle, and because the height of this reservoir was elevated above
the outflow catheter placed in the cisterna magna, CSF flowed through
the system at 0.2-0.7 ml/min. ICP was determined by the height of
the reservoir and outflow catheter relative to the animal. Just before
the experiment, the autologous nonradioactive CSF was exchanged with
radioactive artificial CSF via a low-pressure perfusion. At
time 0 (beginning of experiment), ventriculocisternal perfusion with a flow marker
(125I-HSA) was initiated for 3 h
at the chosen lower pressure. A second label of the same CSF flow
marker (131I-HSA) was injected
intravenously to allow correction of the data for filtration errors.
After 3 h, the heights of the reservoir and outflow catheter were
elevated to achieve the desired higher pressure. Two series of
experiments were performed with low to high pressures set at 10 and 20 cmH2O in one series and 20-30 cmH2O in another. In two
additional animals, pressure-drainage parameters were compared between
0 and 30 cmH2O and between 5 and
15 cmH2O.
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Ro + h, where Po is outflow pressure (in
cmH2O), is
flow (in µl/min), Ro is outflow
catheter resistance (in
cmH2O · l
1 · min),
and h is height of the outflow end of
the cervical lymphatic catheter (in cm above the lymphatic in the
animal) (9). The total resistance of the lymphatic catheter was
determined experimentally by measuring the flow of artificial CSF at
different outflow heights. Flow varied linearly with perfusion
pressure, and the gradient of this relationship gave a resistance
factor that could be incorporated into the expression noted above along
with the measured value of Po,
which was taken to be equal to CVP. From this, we were able to
calculate the appropriate height of the outflow tip of the cervical
lymphatic catheter to achieve the desired level of Po.
Mathematical model. The CSF drainage rate through arachnoid villi and cervical lymphatics can be roughly estimated by dividing the total amount of radioactivity recovered in the plasma or lymph compartments by the concentration of tracer in the CSF. However, this approach does not take into consideration potential problems associated with tracer filtration. Because plasma recoveries in lymph-diverted animals were used to estimate arachnoid villi drainage, tracer loss through blood capillary filtration would result in this pathway being underestimated. Similarly, the transport of tracer to the plasma complicates measurements of the CSF tracer in lymph, since the HSA that was transported from the CSF into plasma by the arachnoid villi would filter back into the lymphatic compartment, resulting in an overestimate of the lymphatic contribution to CSF drainage.
To correct tracer recovery data for problems caused by filtration, we developed previously a three-compartment mathematical model. Tracer data were inserted into derived mass balance equations to provide estimates of the CSF flow rates through the arachnoid villi and lymphatic drainage pathways (2). This model integrates brain lymph and arachnoid villi drainage systems with the CSF and vascular compartments. It is assumed that there is no direct transport of tracer into CNS capillaries and that all tracer is removed from the CNS by arachnoid villi or extracranial lymphatics. All tracer concentrations (C) are dependent on time. Intercompartmental flow rates [observed lymph flow rate (L), volumetric transfer rate of CSF tracer from the plasma (F), and estimated CSF drainage rates (D)] are assumed to remain constant. At the initiation of the experiment, a flow marker (125I-HSA) was infused into both lateral ventricles. The flow marker transfers to the plasma via the arachnoid villi at a flow rate DAV. Drainage also occurs to the cervical lymphatics at a flow rate DCT. The cervical lymphatics (tracer concentration = CCT) receive fluid and solutes from the plasma at a rate FCT, while lymph flows to the plasma at rate LCT. Flow marker concentrations within the plasma are designated CP and distribute to the volume of distribution of the marker (VP). A second label of the same flow marker injected into the CSF (131I-HSA) is infused into the plasma space to estimate the flow from the plasma into cervical lymph (FCT). The rate of transfer of a marker protein from the plasma is taken from the observed plasma disappearance rate of 131I-HSA and is designated Kexp. Plasma concentrations of 131I-HSA were divided by the initial concentration at time 0, and Kexp was calculated from the slope of the logarithmically transformed data. It is assumed that neither 125I-HSA nor 131I-HSA crosses the blood-brain barrier from the plasma into the CSF. The compartmental concentrations of the tracer have been designated by the superscripts 125 and 131 as appropriate. A mass balance around the cervical lymph compartment assumes that the mass of tracer into the compartment equals the mass flowing out. All concentrations are a function of time (t). The mass balance yields
![D<SUB>CT</SUB> = <FR><NU><LIM><OP>∫</OP><LL><IT>t</IT><SUB>i</SUB></LL><UL><IT>t</IT><SUB>f</SUB></UL></LIM>[L<SUB>CT</SUB>C<SUP>125</SUP><SUB>CT</SUB>(<IT>t</IT>) − F<SUB>CT</SUB>C<SUP>125</SUP><SUB>P</SUB>(<IT>t</IT>)]d<IT>t</IT></NU><DE><LIM><OP>∫</OP><LL><IT>t</IT><SUB>i</SUB></LL><UL><IT>t</IT><SUB>f</SUB></UL></LIM>C<SUP>125</SUP><SUB>SA</SUB>(<IT>t</IT>)d<IT>t</IT></DE></FR> (ml/h)](/content/vol275/issue3/fulltext/R889/img001.gif)
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(1) |
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(2) |
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(3) |
Analysis of data. Values are means ± SE. P < 0.05 was considered statistically significant. The mean changes in various parameters as a function of time were analyzed through repeated-measures ANOVA. To test the consistency of the expected direction of change in increased CSF clearance through cervical lymphatic vessels and arachnoid villi as a function of elevated ICP, the test of binomial distribution was used (20).
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RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Distribution of tracers. Figure 1 illustrates the distribution of the tracers in the CSF, plasma, and lymph compartments in sheep 7. After the exchange of autologous CSF with artificial CSF containing 125I-HSA, tracer concentrations in the cisterna magna remained relatively stable over the 6-h duration of the experiment. No significant changes in CSF tracer concentrations were observed over this period (Fig. 2). The plasma tracer 131I-HSA was not detected in CSF. Both radioactive isotopes were detected in cervical lymph and blood. The highest concentration of intraventricularly administered 125I-HSA outside the CNS was always observed in cervical lymph. The plasma concentration of 131I-HSA injected intravenously declined exponentially, appeared in cervical lymph, but maintained its highest concentration in plasma. The background physiological data for all animals are illustrated in Table 1.
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Cervical lymph flow rates. Average cervical lymph flow rates (i.e., lymph flow from all tissues, not just lymph originating as CSF) tended to increase with elevation of ICP (Fig. 1). At 10, 20, and 30 cmH2O ICP, cervical flow rates averaged 3.1 ± 0.5, 4.8 ± 0.6, and 6.9 ± 1.5 ml/h, respectively. However, over the course of the 3-h measurement at each ICP, the lymph flows remained relatively stable, indicating that a steady state had been achieved for each 3-h monitoring period (Fig. 3).
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Estimates of volumetric CSF drainage via arachnoid villi and extracranial lymphatic vessels before and after elevations of ICP. Tables 2 and 3 illustrate the calculated CSF drainage rates through arachnoid villi and cervical lymphatics, respectively, in each animal at initial and raised pressures. Two values have been illustrated for each pressure: 1) estimates of CSF drainage rates based on raw data uncorrected for filtration errors and 2) values derived from the mass balance equations that have been corrected for filtration anomalies. Calculated as flow rates (ml/h), the differences in the values estimated by the two methods seem quite small. However, the mass balance correction of the data becomes more significant when CSF clearance volumes are determined over longer periods. Table 4 illustrates the total CSF clearance for each animal (sum of arachnoid villi and lymphatic contributions estimated from the mass balance equations).
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The demonstration that extracranial lymphatic pathways remove about one-half of the draining CSF in normal conscious sheep leaves little doubt that lymphatics contribute to the regulation of extracellular fluid in the CNS of sheep (2, 3). What remains unclear is the response of the lymphatic pathways to conditions of raised ICP. By diverting known lymphatic pathways from emptying into the blood and monitoring the appearance of a CSF tracer in plasma and lymph compartments, we were able to separate the arachnoid villi and lymphatic contributions to total CSF clearance. Combining this approach with ventriculocisternal perfusion allowed assessment of CSF drainage through the two pathways at several levels of ICP. The major conclusion from this study is that elevations of ICP increase CSF clearance into cervical lymphatic vessels. However, several key parameters incorporated into the experimental design require some comment before the implications of this result are discussed.
Physiological requirements for the use of the mathematical model. The suitability of HSA as the CSF tracer and the derivation of the mass balance equations used in this study have been described in detail previously (2). In deriving the equations, we assumed that the volumetric flow rates defined by the letters L, D, and F remained constant for the duration of the experiment. Although the observed cervical lymphatic flow rates tended to be greater at the higher of the two pressures tested in each animal, the flow rates observed at 10, 20, and 30 cmH2O were relatively stable (Fig. 3). Therefore, a steady-state condition was achieved for all the monitoring periods, and as a consequence, we believed that this requirement had been met. The slope of the plasma disappearance curve of intravenously injected 131I-HSA was used to calculate a coefficient of elimination for labeled HSA and to permit correction for the plasma tracer and accompanying volume that refiltered into the lymphatics. The disappearance of tracer followed a typical exponential decline. The amount of tracer entering the lymphatic compartment from the plasma would be defined by the filtration coefficient for each tissue compartment. Changes in ICP over the range of pressures used in this study would not be expected to alter the volumetric transfer of 131I-HSA (F).
Experimental factors that could adversely affect CSF drainage. In previous reports, we estimated the relative roles of arachnoid villi and extracranial lymphatics in CSF clearance in conscious sheep (2, 3). To simplify the study under consideration here, we chose to use a ventilated-anesthetized preparation. This approach resulted in CSF clearance parameters that were reduced compared with our earlier study. Contractions of lymphatics provide a major source of the energy required to transport lymph from its collection at the interstitial level to delivery into the plasma. Anesthetic agents are known to depress active lymphatic contractility (19). In addition, the motion of the head and neck, which could potentially produce passive compression of lymphatic vessel segments, would be abolished in our experimental preparation. Cervical lymph flow rates at all three pressures in the present study were below previously documented values of 9.1 ± 3.3 ml/h in conscious sheep (2). Higher cervical flow rates would be expected to have directly increased lymphatic drainage values.
The ventilated-anesthetized preparation would also have an impact on CSF drainage through arachnoid villi. CSF absorption across the arachnoid villi is a pressure-driven process that does not begin until CSF pressure is greater than sagittal sinus pressure (Pss). Any increases in Pss would be expected to decrease CSF absorption by diminishing the hydrostatic pressure gradient. In our study, CVP was measured continuously at the level of the superior vena cava (7.0 ± 1.0 cmH2O, n = 10). As expected, the CVP closely paralleled end-expiratory pressure during mechanical ventilation and was assumed to estimate closely Pss values (15). With experimental CSF pressure set at 10 cmH2O and Pss approximating 7 cmH2O, the CSF pressure-blood hydrostatic pressure gradient was quite small, ~3 cmH2O. This driving force likely produced the low total CSF drainage rates observed under these conditions (sum of arachnoid villi and lymphatic = 1.5 ± 0.2 ml/h). Elevations of ICP to 20 and 30 cmH2O increased the CSF pressure-Pss gradients and yielded increased total CSF drainage rates at each increment (4.8 ± 1.3 and 12.6 ± 5.0 ml/h, respectively). Using a similar model in resting, conscious sheep, we reported earlier an average total CSF clearance in resting animals of ~4.0 ml/h (2). In the anesthetized-ventilated group of animals studied in the present report, we had to use an ICP of ~20 cmH2O to achieve CSF clearances of similar magnitude. CVP may also have an important role in determining the clearance of CSF by extracranial lymphatics. Unlike the case with arachnoid villi, which were intact with regard to their drainage target (veins), determination of a lymphatic drainage rate required the direct cannulation of multiple lymphatic vessels in the neck and collection of lymph exterior to the animal. Therefore, the normal outflow pressure sensed by these vessels would be altered. To account for this, we assumed that the outflow pressure would be equivalent to the CVP. The tip of the outflow end of the catheter was raised, such that the total resistance experienced by the cannulated vessels matched CVP. Therefore, arachnoid villi and extracranial lymphatics would be provided with the appropriate pressure gradient for CSF clearance.Effects of ICP changes on CSF drainage into extracranial cervical lymphatics. In every animal subjected to an increase in ICP, an increase in lymphatic drainage followed (n = 8). The most striking example was sheep 7. At 20 cmH2O, total CSF drainage was 11.44 ml/h, with arachnoid villi and lymphatic drainage contributing in approximately equal amounts (5.62 and 5.82 ml/h, respectively). With an increase to 30 cmH2O, arachnoid villi and lymphatic drainage increased to 12.08 and 18.04 ml/h, respectively, to yield a total CSF drainage of 30.12 ml/h. This example illustrates the magnitude of lymphatic drainage that is possible. However, considerable variability existed between animals in terms of the magnitude of clearance through arachnoid villi and lymphatics. In some sheep, CSF clearance into cervical lymph was small but, as noted earlier, always increased when ICP was elevated. This pattern of individual variability appeared in our earlier studies of CSF drainage under normal pressures in conscious sheep (2-4). This suggests that some adults are more dependent on the lymphatic drainage pathways for CSF removal, whereas others rely primarily on the arachnoid villi. Pathological consequences of a dependence on one pathway over the other remain unknown.
From the data illustrated in Figs. 1 and 3 it is also apparent that total cervical lymph flow (i.e., flow from all tissues, not just from the CSF compartment) tended to increase as ICP were elevated. This is to be expected if a portion of cervical lymph has its origins as CSF. However, in a given experiment we did not always observe an increase in the directly measured cervical lymph flow rate. This was no doubt due to the fact that even though the estimated CSF clearance into cervical lymph increased in all sheep, in six of eight animals the increase was considerably <1 ml/h. Therefore, as a percentage of the total lymph formed in the drainage basin of the cervical lymphatic vessels, in some cases the contribution from the CSF compartment was minor and the changes induced with elevations in ICP were likely lost within the normal variation in lymph flow. Incremental ICP changes of >10 cmH2O would probably elicit greater changes in directly measured cervical lymph flow rates. Bradbury and Westrop (6) cannulated a single cervical lymphatic in rabbits and concluded that absolute lymphatic recovery of an intraventricularly administered albumin tracer increased but that the fractional recovery compared with blood decreased. An increase in total cervical lymph flow has been observed after elevations of ICP in cats (16) and dogs (10). In addition, the increased distribution of radiolabeled albumin in postmortem peripheral tissues of rabbits with raised ICP compared with normal-pressure controls suggests that more CSF tracer was being distributed outside the CNS under conditions of elevated CSF pressures, where it would be accessible to lymphatic absorption (18). Each of these studies provides indirect evidence to support the importance of lymphatics in the volumetric removal of CSF. However, cervical lymphatics collect flow from a wide variety of tissues and not just fluid originating as CSF. Furthermore, tracer recovery data can be misleading because of the "cross-contamination" of tracer. Our model permits the separate calculation of CSF drainage via arachnoid villi and lymphatic pathways from tracer recovery data and provides the first direct evidence that CSF transport into extracranial lymphatics is enhanced by incremental changes in ICP. One must be cautious in commenting on the magnitude of the ICP-induced changes in CSF clearance because of the large variation between animals. With this in mind, the data in Fig. 4 suggest that for each 1.0-cmH2O elevation in ICP, arachnoid villi drainage increased ~0.36 ml/h and lymphatic clearance increased ~0.20 ml/h. On average, an ICP increase of 10 cmH2O elevated arachnoid villi and lymphatic CSF clearance 2.7- and 3.9-fold, respectively. It is of interest to note that by plotting the average values for arachnoid villi drainage at each pressure, the extrapolated line at the x-intercept approximates CVP and therefore Pss (8.1 cmH2O; Fig. 4). CSF pressures greater than this value would be expected to result in CSF drainage that increases linearly with increases in ICP, a result that was suggested from the data in Fig. 4. Similarly, the extrapolated x-intercept (9.9 cmH2O) for cervical flow may represent the average opening pressure to facilitate cervical clearance. This suggests that the pressure gradients responsible for transport of CSF via arachnoid villi and extracranial lymphatic pathways may be similar, although additional experiments at numerous ICP levels are required to address this issue appropriately. It is difficult to interpret the concept of a break point pressure that initiates CSF transport to cervical lymphatics. In rats, CSF seems to pass directly through subarachnoid channels into the lymphatics of the nasal submucosa (14). A CSF pressure gradient of ~10 cmH2O may drive CSF through the cribriform plate into the nasal submucosa and, ultimately, into the initial cervical lymphatics. Alternatively, CSF may not transport directly to cervical lymph but, rather, may mix in the fluid volume of the nasal submucosa. Unfortunately, the exact anatomic relationships between CSF and cervical lymph in sheep are unknown. For the mathematical analysis of the data, we have used a relatively simple three-compartment model (CSF, plasma, and extracranial lymph). It was assumed that fluid transfer occurred directly from one compartment to another. However, this may not be the case, and CSF may first empty into the nasal submucosal interstitial space. The mechanisms that control the uptake of interstitial fluid by lymphatics are still being debated. In some tissue compartments, interstitial pressures are subatmospheric, and a pressure gradient between the interstitium and lymphatic appears to be created partly by contractions of the initial lymphatic (12, 13). During the diastolic phase of contractions, a suction force may be generated to draw tissue fluid into the vessel. A more detailed analysis of the CSF pressure-clearance relationships in conscious sheep at multiple pressures may permit more accurate determination of the opening pressures for both pathways. Additionally, the development of a more complex four-compartment model may facilitate our understanding of this process. In this study a determination of the relative roles of arachnoid villi and cervical lymphatics in the quantitative clearance of CSF was not an important objective. Reports to this end have been published previously (2-4). In this study, arachnoid villi appeared to be responsible for the majority of CSF drainage at all pressures investigated. However, lymphatic drainage was clearly underestimated. Small lymphatic vessels that were difficult to cannulate were ligated and not monitored for the appearance of CSF tracer, and unidentified vessels that contained tracer would have emptied into the blood, adding to the arachnoid villi rates. Additionally, increased CSF pressures would have distributed tracer along the spinal canal (6), to be drained ultimately by the thoracic duct (4). The thoracic duct was left undisturbed and potentially could have delivered tracer to the blood. In our previous reports, we estimated the contribution of uncannulated cervical ducts and determined conservatively that lymphatics were responsible for about one-half of all CSF absorbed from the cranial vault. Rather than revisit this issue in this report, we focused our attention on testing the hypothesis that elevations in ICP resulted in increases in lymphatic CSF clearance. Many issues related to the relationship between ICP and CSF clearance into extracranial lymphatics remain to be elucidated. The proportional distribution of CSF drainage into arachnoid villi and lymphatic vessels over a wide range of ICP levels, including levels of pressure associated with intracranial hypertension and pathology, needs to be investigated. Other investigators have speculated that the potential resistance offered by the cribriform plate as CSF moves from the subarachnoid space into the nasal submucosa may limit substantially the transport of CSF into cervical lymphatics (6). Additionally, at a high ICP, some CSF may be shunted into the spinal canal and may be taken up by lymphatics that connect with lumbar and intercostal nodes. In earlier studies of sheep we demonstrated high levels of labeled HSA in these lymph nodes after the injection of the tracer into spinal CSF (4).Perspectives
Current understanding of the factors that regulate ICP can be summarized by the following expression: ICP = If × Rout + Pss, where If is the CSF formation rate and Rout is the resistance to CSF outflow (17). Because CSF formation is known to remain constant throughout a wide ICP range (8, 11), the Rout and Pss terms assume the greatest importance. However, as originally conceived, this expression assumes that all CSF drainage occurs via the arachnoid villi, an assumption that ignores the important contribution of extracranial lymphatics in this process.First, the Rout term is meant to represent the total resistance imparted by the anatomy of all CSF outflow pathways, but it has been generally assumed that resistance is determined by the arachnoid villi, and investigation of perceived anomalies in CSF drainage has quite naturally focused primarily on these structures. It now appears likely that a lymphatic component figures prominently in the physiological parameters defined by the Rout designation. Second, Pss provides not only a potential impediment to CSF transport through arachnoid villi, but the equivalent pressure in the veins located in the base of the neck also provide an outflow pressure into which cervical lymphatics are forced to pump. Clearly, we have to rethink ICP regulation and begin to test hypotheses that integrate ICP with CSF drainage into lymphatics.
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ACKNOWLEDGEMENTS |
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This research was funded by the Medical Research Council of Canada.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests: M. G. Johnston, Trauma Research Program and Dept. of Pathology, University of Toronto, Research Bldg., S-111, Sunnybrook Health Science Centre, 2075 Bayview Ave., Toronto, ON, Canada M4N 3M5.
Received 4 February 1998; accepted in final form 28 April 1998.
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REFERENCES |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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) or
131I-HSA concentration (
) in
cerebrospinal fluid (CSF, A), plasma
(B), and cervical lymph
(C).
D: directly measured cervical lymph
flow rates. Data are from sheep 7 in
Tables 
,
n = 8), and 30 cmH2O (
,
n = 5) over 3 h of perfusion at each
pressure. Repeated-measures ANOVA with Greenhouse-Geisser adjusted
P values revealed no significant
changes in cervical lymph flow rates at any of tested pressures over
time: 10 cmH2O
(P = 0.622), 20 cmH2O
(P = 0.411), or 30 cmH2O
(P = 0.323).
