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Journal of Glaucoma:
doi: 10.1097/IJG.0b013e318293498b
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Production and Circulation of Cerebrospinal Fluid With Respect to the Subarachnoid Space of the Optic Nerve

Killer, Hanspeter E. MD

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University of Basel, Head of Neuro-ophthalmology, Kantonsspital Aarau, Aarau, Switzerland

Disclosure: The author declares no conflict of interest.

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Abstract

The function of cerebrospinal fluid (CSF) is to protect the brain and optic nerve from mechanical damage, provide nutrition for axons/neurons, and remove of toxic metabilites. CSF is produced mainly by the choroid plexus epithelium and ependymal cells of the ventricles and flows into interconnecting chambers; namely, the cisterns and the subarachnoid spaces. Based on studies of CSF circulation and direction of flow using radioisotopes and other tracers injected into the CSF, it is thought that there is a bulk circulation of fluid from the sites of production in the third, fourth, and lateral ventricles to the arachnoid villi and probably to the lymphatic capillaries in the cranial dura mater. The mechanism by which CSF is propelled is incompletely understood, but probably is influenced by the release of newly produced CSF, ventricular pulsations, and the pulse pressure of the vascular choroid plexus. This mechanism would account for the steady CSF pressure. In addition to the steady CSF pressure, overlapping pressure spikes occur during trunk inclination, coughing and other valsalva.

Cerebralspinal fluid (CSF) is thought to be fairly homogeneous in composition and to be distributed evenly with a continuous flow through all CSF spaces, such as ventricles, cisterns and subarachnoid spaces (SAS) including the SAS of the optic nerve. CSF is renewed up to 4 times daily, indicating rapid turnover. CSF pressure is measured via lumbar puncture, which is thought to reflect as well the intracranial pressure and the pressure in the subarachnoid space of the optic nerve. There is reasonable doubt about this link. Even if lumbar pressure might equal the intracranial pressure, there is no guarantee that this extrapolation can be streched to the subarachnoid space of the optic nerve with a quite different anatomy.

For a thorough understanding of optic nerve physiology and pathology, CSF dynamics and content are of essential interest. CSF is produced at a constant rate of approximately 0.37 mL/min within the choroid plexus epithelium and ependymal cells of the ventricles. Based on studies of CSF circulation and direction of flow using radioisotopes and other tracers injected into the CSF, it is thought that there is a bulk circulation of fluid from the sites of production, the lateral ventricles through the interventricular foramina (of Monro) into the third ventricle, through the cerebral aqueduct of Sylvius into the fourth ventricle, and then out into the SAS through the foramina of Luschka and Magendie. In the SAS at the base of the brain, CSF flows rostrally from the posterior fossa through the lower ventral basal cistern to reach the interpeduncular and chiasmatic cisterns. The CSF then flows caudally through the communicating cisterns to reach the dorsal cisterns and laterally and superiorly from the suprachiasmatic and infrachiasmatic cisterns into the cisterns of the Sylvian fissure and via the optic canal into the intraorbital SAS of the optic nerve, a space that becomes a cul de sac at the back of the eye. The mechanism by which CSF is reabsorbed out of the SAS of the optic nerve is not yet fully understood. Because of a large CSF–volume gradient between the intracranial SAS and the SAS of the optic nerve, it is highly unlikely that the CSF can reverse its flow towards the intracranial SAS. A possible outflow route for CSF from the SAS of the optic nerve is a recently discovered lymphatic outflow system.1–5

The main function of CSF is to protect the brain and optic nerve from mechanical damage, to provide nutrition for axons/neurons, and to remove toxic metabolites from the central nervous system. The mechanism by which CSF is propelled is incompletely understood, but probably is influenced by the release of newly produced CSF, ventricular pulsations, and the pulse pressure of the vascular choroid plexus. This mechanism would account for the steady CSF pressure. In addition to the steady CSF pressure, overlapping pressure spikes occur during trunk inclination, coughing and other Valsalva maneuvers.

CSF is of high metabolic importance and contains more than 2500 proteins.6 It is thought to be fairly homogeneous in composition and to be distributed evenly, with a continuous flow through all CSF spaces, such as ventricles, cisterns, and SAS, including the SAS of the optic nerve. The SAS of the optic nerve is bridged by a variety of trabeculae and septa.7 Their number and morphology depend on their location within the SAS. While the retrobulbar portion of the optic nerve harbors delicate trabeculae, the midorbital SAS is bridged by broad septae. The canalicular portion harbours a combination of septae and trabeculae. In the pia mater as well as the arachnoid mater, the trabeculae and the septae are covered with a layer of meningothelial cells (MEC) which have a potential for phagocytosis.8 Current studies demonstrate that MEC are highly reactive to pressure and oxidative stress. Elevated pressure leads to proliferation of MEC and to diminished phagocytosis.9 Cisternography is the only possible way to demonstrate CSF dynamics in small spaces such as the SAS of the optic nerve. Unlike the current understanding that CSF flow is homogenous, impaired flow dynamics between the chiasmal cistern and the SAS of the optic nerve have been demonstrated in patients with normal-tension glaucoma (NTG) and in a series of patients with papilledema.10,11 In addition, CSF content was found to differ markedly between the lumbar CSF and the CSF in the SAS of the optic nerve in patients with NTG and papilledema.11 In patients with NTG, CSF flow is markedly reduced in the SAS of the ON, thus reflecting low CSF circulation.12 The optic nerve sheath diameter is enlarged in NTG, probably as a result of higher local pressure in the SAS of the optic nerve.

Compartmentalization of the SAS of the optic nerve, with either reduced CSF exchange or augmented production of lipocalin-type prostaglandin D2 synthase is postulated to explain this as a concentration gradient. As mentioned above, one can study compartmentalization through computed tomography (CT) cisternography after intrathecal injection of a contrast medium (Iopamidol, molecular weight 778 D) by lumbar puncture. The distribution of contrast-loaded CSF can be measured in Hounsfield units in various locations and gradients of contrast-loaded CSF are indicators for compartmentalization (Δ contrast density) (Fig. 1). According to the second law of thermodynamics, the injected contrast agent is expected to diffuse homogeneously throughout all CSF spaces. In a series of 18 patients with NTG, a large concentration gradient of contrast loaded CSF between the basal cisterns and the SAS of the contrast-loaded was demonstrated.11 The same findings have been published recently in patients with papilledema.10

FIGURE 1
FIGURE 1
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The cause for compartmentalization is currently under investigation. There are at least two mechanisms that may shed light onto its pathophysiology. First, failure of CSF drainage out of the SAS, probably due to an insufficiency of the draining lymphatic system,3 and second, changes in the volume and number of MECs that line the SAS.13

Several attempts have been made to construct a mathematical model for CSF flow; however, these models consider only the CSF dynamics between two large CSF spaces (e.g. two ventricles—large system model). To describe the fluid dynamics in such a model, the Navier–Stokes equation, a nonlinear partial differential equation, is applied. However, due to the complexity of the anatomy of the SAS the application of this equation is limited.

The important point of this discussion is that CSF does not flow continuously between the intracranial CSF spaces and the SAS of the optic nerve. CSF content varies between different locations. CSF pressure taken during lumbar puncture does not necessarily represent the pressure in the SAS of the optic nerve.

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