Compartmentalized Cerebrospinal Fluid
Hanspeter E. Killer, MD Prem S. Subramanian, MD, PhD
Cerebrospinal Fluid Production, Dynamics, and Function
The brain, spinal cord, and the optic nerve are surrounded by and bathed in cerebrospinal fluid (CSF). CSF is produced mainly by the choroid plexus epithelium and ependymal cells of the ventricles from where it flows into interconnecting chambers—the cisterns and the subarachnoid spaces (SASs).1,2 It is assumed that there is a free and constant circulation of fluid from the sites of production in the third, fourth, and lateral ventricles to the cisterns and SASs. The mechanism by which CSF is driven from its site of production to reabsorption is not yet fully understood, but CSF flow is influenced by the release of newly produced CSF (causing a pressure gradient), the ventricular pulsations, and the pulse pressure of the vascular choroid. The main site of resorption is at the arachnoid villi. Additional possible sites of absorption are the lymphatic capillaries in the dura of the optic nerve and in the area of the olfactory bulb, as well as the dura of the spinal roots.3–5 A newly discovered mechanism for resorption of CSF acts by means of the meningoepithelial cells (MEC) that cover the arachnoid, the pia, and the trabecular meshwork as well as the septae in the SAS of the optic nerve.6,7 MECs are found to be more abundant in patients with primary open-angle glaucoma than in normal subjects.8 In addition, an in vitro study demonstrated MEC proliferation of up to 20% when MECs were exposed to extrinsic increased pressure.6 Proliferation of MECs was also demonstrated in an animal model after ligation of the optic nerve close to the optic canal.9 It may thus be postulated that an increase in both the number and volume of MECs will result in a narrowing of the SAS and potentially reduce free CSF flow. INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 1, 95–102 r 2014, Lippincott Williams & Wilkins
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CSF plays an important role in mechanical cushioning of the brain and in the nutrition of neurons, axons, and glial cells (astrocytes and oligodendrocytes). It also functions as a transport system for the removal of toxic metabolites such as Tau proteins.10 The major metabolic importance of the CSF is inferred from its composition and frequent turnover. Its impressive proteome contains >19,000 peptides.11 Studies demonstrate that CSF is turned over up to 5 times a day in normal individuals, and large volumes of CSF may be replenished rapidly after removal through lumbar puncture.1 CSF is widely thought to be of fairly homogenous composition and to be distributed evenly, with a continuous flow through all CSF spaces, such as ventricles, cisterns, and SASs, including that of the optic nerve (SAS-ON). A homogenous CSF pressure has for a long time been assumed, although variations in different CSF spaces have been described.12 Elevated intracranial pressure (ICP) is thought to be the cause of stasis of axoplasmic flow, which results in papilledema.13 The concept of continuity and homogeneity of CSF pressure in patients with papilledema is challenged by the observation of highly asymmetric or frankly unilateral papilledema.14–18 If indeed the locally measured pressure during lumbar puncture equals the ICP (ventricles, cisterns, and SAS) and if there is free communication between the suprasellar cistern and the SAS-ON, then both CSF pressure and content should be equal in the SAS of both optic nerves, and the papilledema should be symmetric. Various explanations such as ‘‘anatomic variants,’’ whereby CSF pressure is not transmitted to the optic nerve head because of putative termination of the dural sheath proximal to the back of the globe, have been proposed to explain the paradox of unilateral and highly asymmetric papilledema in patients with elevated ICP.19 Such theories do not explain other clinical observations, however, including the persistence of papilledema in some patients with pseudotumor cerebri (PTC) despite reduction of ICP and resolution of other symptoms including headache and pulsatile tinnitus. The SAS of the ON is extremely small, and it is variable along the length of the nerve. The largest diameter is found directly behind the lamina cribrosa in the bulbar section of the SAS, whereas the smallest diameter is within the optic canal.19 Although coronal magnetic resonance images (MRIs) show the SAS as being uniform, it is bridged by a multitude of trabeculae and septae.19 Because of these anatomic structures, measuring the local pressure in the SAS-ON is apt to be unreliable as it may vary from location to location within the SAS. ’
Measuring the Pressure in the SAS-ON
Lumbar puncture is still the preferred approach for estimating ICP. A communicating pathway between the site of lumbar puncture and the www.internat-ophthalmology.com
Compartmentation of the Subarachnoid Space in Papilledema CSF
intracranial CSF spaces is mandatory for the reliability of this approach.20 Nonetheless, even if the spinal pressure equals the ICP, we cannot extrapolate this relationship to the SAS of the ON because of its unique anatomy. Unlike the intracranial CSF spaces, which are more voluminous, the SAS surrounding the ON is extremely narrow and harbors numerous trabeculae and septae that reduce both CSF volume and CSF flow. Direct measurement of CSF pressure using a transducer probe would render false results, as the probe volume itself would displace a significant amount of CSF in these tiny spaces and cause local pressure alterations. Aside from this technical concern, such a technique would be highly invasive and carry risk for optic nerve injury and is therefore not suitable for clinical application. Alternative methods are therefore required. An indirect assessment of the SAS-ON pressure may be obtained by correlating the opening pressure during lumbar puncture with the optic nerve sheath diameter measured on MRI or computed tomography scan.21 Such a procedure is easily available and noninvasive. Keeping in mind the possible inaccuracies of this approach, such as individual variance in the modulus of elasticity of the dural tissue, this method still allows an estimate of the local CSF pressure in the SAS-ON. ’
As discussed above, the MECs that cover the arachnoid and the pia are very responsive to various stimuli (such as pressure and hypoxia). Changes in MEC volume will have a disproportionate effect on the volume of the SAS-ON, and dynamic alterations are expected. The rate of change may prove as important as the amount in producing changes over time. Overall ICP elevations occur multiple times a day during Valsalva maneuvers, driving CSF into closed spaces like the SAS-ON. It is possible that the arrangement of the septae in the SAS-ON can form a 1-way valve-like structure, allowing CSF influx during Valsalva maneuvers but subsequently inhibiting CSF outflow. This behavior would occur because of the large volume gradient between the intracranial CSF and the CSF in the SAS-ON and is a recognized feature of fluid dynamics. In addition to the above-mentioned mechanisms, variations in the viscosity of the CSF due to accumulation of large molecules such as b-trace protein will also influence the flow characteristics of CSF.22 ’
Evidence for Compartmentation
The first evidence for compartmentation of the CSF spaces was based on concentration gradients of CSF proteins.22 If CSF flows continuously and freely, then the content and the concentration of www.internat-ophthalmology.com
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CSF proteins would be expected to be the same in every location where CSF is present. In a cohort of patients with papilledema, the concentration of b-trace protein in the lumbar CSF differed markedly from the concentration of the CSF in the SAS-ON, where the b-trace proteins tended to accumulate.22 This difference in concentration strongly argues against a homogenous composition of CSF throughout all CSF spaces. A second study, using computer-assisted cisternography performed in patients with papilledema, has provided even stronger evidence for compartmentation of CSF in the SAS of the ON. A contrast agent (lopimidol) was introduced into the CSF during lumbar puncture, and the concentration of the contrast agent was measured in the suprasellar cistern and the SAS-ON (Fig. 1).23 In some patients with PTC, a large concentration gradient of contrast-loaded CSF was measured between these 2 sites. Measuring the contrast-loaded CSF at different anatomic locations allows determination of the flow characteristics of CSF. A low concentration of contrast-loaded CSF in the SAS-ON provides strong evidence of reduced CSF flow and thus CSF turnover in the SAS-ON of at least some PTC patients.23 Interestingly, similar findings were demonstrated in a cohort of normal tension glaucoma patients.24 Confirmation of these findings in a larger cohort of patients and normal controls is needed to bolster the results. Compartmentation of the CSF in the SAS-ON might help explain why some patients with normalized CSF pressure on lumbar puncture have persistent papilledema and progressive visual field loss. These observations reinforce the idea that pressure is only 1 component of a complex mechanism resulting in visual field loss and loss of visual acuity in patients with increased ICP. A metabolic disturbance due to reduced clearance of CSF might be involved as well. A damaging effect of high concentrations of b-trace protein has been demonstrated in astrocytes and astrocytic ATP production.25 Astrocytes are important for the biochemical support of endothelial cells that form the blood-brain barrier and for the support of axons. ’
Development of CSF Compartmentation
How does compartmentation develop? A compartment is defined as a space or a region that is separated from its environment. In the case of an optic nerve sheath compartment, the SAS of the ON becomes partly or completely separated from the suprasellar cistern from which CSF enters the SAS of the ON. Two main factors seem to be involved in the process of compartmentation: hydraulic pressure and MEC proliferation. If the pressure in the SAS of the ON increases, the lymphatic vessels in the dura will collapse, leading to reduced CSF outflow and thus turnover. MEC proliferation occurs in response to numerous stimuli, www.internat-ophthalmology.com
Compartmentation of the Subarachnoid Space in Papilledema CSF
Figure 1. A, T2-weighted magnetic resonance image of a patient with idiopathic intracranial hypertension. Note distention of both SAS-ON and good signal for fluid in both SAS. Signal strength in the SAS-ON is the same as in the pituitary cistern. B, Computed tomography cisternography of the same patient. Contrast-loaded CSF stops abrupt after the canalicular region in both SAS-ON rendering the intraorbital and the retrobulbar SAS-ON dark. CSF indicates cerebrospinal fluid; ON, optic nerve; SAS, subarachnoid space.
including local irritation and ICP elevation.6 Proliferation of MECs at the narrowest site, the canalicular portion of the optic nerve, can lead to obstruction of the CSF pathway and consequent reduction of CSF flow (Fig. 2). Given the reactivity of MECs, the anatomy in the SAS-ON is dynamic and depends on pressure gradients and biochemical influences. However, our ability to measure this dynamic change is limited. Although MRI shows CSF (best on T2-weighted images) it does not demonstrate fluid dynamics on standard sequences. Even cardiac-gated cine sequences show bulk flow and lack the resolution to study flow within the SASON. Thus, we rely on static evidence of elevated ICP on MRI such as distention of the SAS with accumulation of CSF especially in the bulbar region of the SAS-ON.26 Cisternography is at present the only method available to demonstrate CSF compartmentation. The radiodensity in Hounsfield units of contrast-loaded CSF in different CSF spaces shows the relative penetration of CSF into various compartments at specific time points after contrast injection. Because it is an invasive procedure, it should be used without a clear clinical indication. A PTC patient with normalized ICP after shunt placement or medical therapy but persistent papilledema and progressive visual field loss is the ideal candidate for cisternography. ’
Consequences of CSF Compartmentation
What are the consequences of compartmentation in the treatment of patients with idiopathic intracranial hypertension? Compartmentation may lead to prolonged local pressure elevation and to a change in the www.internat-ophthalmology.com
Killer and Subramanian
Figure 2. Cross-sections through optic nerve at various locations. Note the extremely narrow subarachnoid space in the canalicular region.
composition of the CSF, both of which may contribute to ongoing visual loss despite overall ICP reduction.27 For this reason, CSF diversion (either ventriculoperitoneal or lumboperitoneal shunting) may be ineffective in treating vision loss. In such patients, optic nerve sheath fenestration should be considered the first treatment option. Because both optic nerve sheath fenestration and CSF diversion are considered equivalent in terms of efficacy based on retrospective data alone, better recognition of compartmentation may allow us to recommend one procedure over the other for a given patient. The mechanism by which compartmentation damages the optic nerve is at least 2-fold. Direct damage to axons and reduced vascular perfusion results from elevated local pressure, in the same way as in elevated ICP. Compartmentation results in reduced CSF turnover and changes in CSF content.19 As discussed above, reduced CSF flow not only results in local depletion of nutrients but also allows accumulation of potentially toxic substances.8,22 The relative contribution of pressure and toxicity to papilledema is an area of ongoing research. ’
Pressure and content of CSF were thought to be homogenous throughout the ventricular, cisternal, and subarachnoid spaces. Anatomic studies in humans and animals as well as patients with unilateral and highly asymmetrical papilledema challenged this concept. Recent www.internat-ophthalmology.com
Compartmentation of the Subarachnoid Space in Papilledema CSF
research has demonstrated concentration gradients of CSF proteins between the lumbar CSF and the CSF surrounding the ON. CSF flow studies with computed tomography–assisted cisternography in PTC patients who did not improve with medical ICP reduction showed impaired contrast-loaded CSF flow into the SAS-ON, indicating CSF compartmentation. Further study is needed to understand the importance of SAS-ON composition and pressure in the wider cohort of PTC patients and to develop methods to diagnose and treat this condition in patients who fail standard disease management.
The authors declare that they have no conflicts of interest to disclose.
1. Davson H. Physiology of the Cerebrospinal Fluid. London: Churchill; 1967. 2. Dichiro G. Movement of the cerebrospinal fluid in human beings. Nature. 1964;204: 290–291. 3. Killer HE, Laeng HR, Groscurth P. Lymphatic capillaries in the meninges of the human optic nerve. J Neuroophthalmol. 1999;19:222–228. 4. Killer HE, Jaggi GP, Miller NR, et al. Does immunohistochemistry allow easy detection of lymphatics in the optic nerve sheath? J Histochem Cytochem. 2008;56: 1087–1092. 5. Johnston M. The importance of lymphatics in cerebrospinal fluid transport. Lymphat Res Biol. 2003;1:41–45. 6. Xin X, Fan B, Flammer J, et al. Meningothelial cells react to elevated pressure and oxidative stress. PLoS One. 2011;6:e20142. 7. Li J, Fang L, Killer HE, et al. Meningothelial cells as part of the central nervous system host defence. Biol Cell. 2013;105:304–315. 8. Pache M, Meyer P. Morphological changes of the retrobulbar optic nerve and its meningeal sheaths in glaucoma. Ophthalmologica. 2006;220:393–396. 9. Jaggi GP, Harlev M, Ziegler U, et al. Cerebrospinal fluid segregation optic neuropathy: an experimental model and a hypothesis. Br J Ophthalmol. 2010;94: 1088–1093. 10. Silverberg GD, Mayo M, Saul T, et al. Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2003;2:506–511. 11. Schutzer SE, Liu T, Natelson BH, et al. Establishing the proteome of normal human cerebrospinal fluid. PLoS One. 2010;5:e10980. 12. Mindermann T. Pressure gradients within the central nervous system. J Clin Neurosci. 1999;6:464–466. 13. Hayreh SS. Pathogenesis of oedema of the optic disc. Doc Ophthalmol. 1968;24: 289–411. 14. Killer HE, Flammer J. Unilateral papilledema caused by a fronto-temporo-parietal arachnoid cyst. Am J Ophthalmol. 2001;132:589–591. 15. Marcelis J, Silberstein SD. Idiopathic intracranial hypertension without papilledema. Arch Neurol. 1991;48:392–399. www.internat-ophthalmology.com
Killer and Subramanian
16. Huna-Baron R, Landau K, Rosenberg M, et al. Unilateral swollen disc due to increased intracranial pressure. Neurology. 2001;56:1588–1590. 17. Sedwick LA, Burde RM. Unilateral and asymmetric optic disk swelling with intracranial abnormalities. Am J Ophthalmol. 1983;96:484–487. 18. Maxner CE, Freedman MI, Corbett JJ. Asymmetric papilledema and visual loss in pseudotumour cerebri. Can J Neurol Sci. 1987;14:593–596. 19. Killer HE, Laeng HR, Flammer J, et al. Architecture of arachnoid trabeculae, pillars, and septa in the subarachnoid space of the human optic nerve: anatomy and clinical considerations. Br J Ophthalmol. 2003;87:777–781. 20. Lenfeldt N, Koskinen L-OD, Bergenheim AT, et al. CSF pressure assessed by lumbar puncture agrees with intracranial pressure. Neurology. 2007;68:155–158. 21. Watanabe A, Kinouchi H, Horikoshi T, et al. Effect of intracranial pressure on the diameter of the optic nerve sheath. J Neurosurg. 2008;109:255–258. 22. Killer HE, Jaggi GP, Flammer J, et al. The optic nerve: a new window into cerebrospinal fluid composition? Brain. 2006;129:1027–1030. 23. Killer HE, Jaggi GP, Flammer J, et al. Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional? Brain. 2007;130:514–520. 24. Killer HE, Miller NR, Flammer J, et al. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol. 2012;96:544–548. 25. Xin X, Huber A, Meyer P, et al. L-PGDS (betatrace protein) inhibits astrocyte proliferation and mitochondrial ATP production in vitro. J Mol Neurosci. 2009;39: 366–371. 26. Maralani PJ, Hassanlou M, Torres C, et al. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clin Radiol. 2012;67:656–663. 27. Kelman SE, Sergott RC, Cioffi GA, et al. Modified optic nerve decompression in patients with functioning lumboperitoneal shunts and progressive visual loss. Ophthalmology. 1991;98:1449–1453.