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Glaucoma and Cerebrospinal Fluid Pressure

Brandon Baartman, MD; Russell Swan, MD; R. Rand Allingham, MD; and John Berdahl, MD

Glaucoma is a spectrum of disorders resulting in the final common pathway of characteristic glaucomatous optic neuropathy. Initially, the pathogenesis of glaucomatous nerve damage was thought to occur due to a mechanical process, which postulated that elevated IOP led to deformation of the lamina cribrosa and resulted in retinal ganglion cell injury and death.¹ Historically, elevated intraocular pressure (IOP) was considered to be the most important and only modifiable risk factor for the development of glaucoma. However, the presence of clinically similar glaucomatous optic neuropathy in patients without elevated IOP, as well as the absence of glaucomatous nerve damage in patients with ocular hypertension, have led some investigators to search for other physiologic variables that may play a role in development of what we consider to be glaucoma. One of those physiologic variables is the cerebrospinal fluid pressure (CSFp).

An increasing body of literature has documented both clinical and experimental evidence of a relationship between CSFp and pathologic states at the optic nerve head, including glaucoma and, at the other end of the spectrum, papilledema from increased intracranial pressure (ICP). In this chapter, we will describe what is known about the relationship between glaucoma and CSFp and discuss burgeoning therapeutic methods that incorporate this idea.

CEREBROSPINAL FLUID AND THE OPTIC NERVE

The central nervous system is bathed in cerebrospinal fluid (CSF), a clear, protective, nutritive fluid that circulates throughout the intracranial cavity within the ventricles of the brain and subarachnoid space. The majority of CSF is produced by the choroid plexus at a rate of 25 mL/hrs, and a circulatory flow is created as the CSF traverses the ventricular system toward the subarachnoid space, where it is primarily drained by the arachnoid granulation tissue into venous circulation.² The CSFp is dependent on the balanced production and drainage of CSF from the intracranial space. As one might assume, this is one of the major determinants of ICP, the other being the cerebral blood flow.³ Cerebral blood flow is also thought to play a role in ICP determination, as outlined by the Monro-Kelli doctrine, suggesting a balanced relationship among the occupancy of CSF, blood, and the nervous tissue within the intracranial space. The exact contribution of the vascular component to ICP determination is much more difficult to define than CSF, but it is thought to involve variables such as arterial pressure, venous outflow, and the complex autoregulation of CSF.^3,4 For the purposes of this text, much as in clinical practice, we will discuss CSFp synonymously with ICP.

The optic nerve is intimately associated with the CSFp in its pathway toward the central nervous system. The retinal ganglion cells that exit the eye at the optic nerve head then traverse the lamina cribrosa, forming the orbital portion of the optic nerve. Posterior to the lamina cribrosa, the optic nerve is encased in meninges, including the optic nerve subarachnoid space, which contains CSF. The CSF surrounding the orbital portion of the optic nerve within the optic nerve subarachnoid space is continuous with the subarachnoid space throughout the central nervous system. The pressure within the retrolaminar optic nerve, or the retrolaminar tissue pressure, is the pressure that exerts force on the posterior surface of the lamina cribrosa (Figure 74-1). This retrolaminar tissue has a pressure that is strongly correlated to the CSFp within the lateral ventricle, measurable by lumbar puncture, when CSFp is > 0.⁵ Thus, ICP as measured by lumbar puncture has previously been used as a surrogate measure of the retrolaminar CSFp.^6,7 There are alternative methods of estimating this value utilizing noninvasive imaging methods and physical parameters, some of which will be discussed later in this chapter, though the validity of these techniques is not widely agreed upon.^8–10

GLAUCOMA AND CEREBROSPINAL FLUID PRESSURE

While the majority of clinical studies connecting the pathogenesis of glaucoma to variability in CSFp have appeared within the past 10 years, this idea was conceptualized more than 40 years ago by Volkov.¹¹ One of the earliest studies to provide any data implicating CSFp in the pathogenesis of glaucoma was by Yablonski in 1979. In the study, the CSFp in cats was decreased to -4 mm Hg, while the IOP of one eye was reduced to virtually 0 and the other remained unaltered. After 3 weeks, the eye with maintained physiologic IOP developed damage to the optic nerve similar to that seen in glaucoma,¹² suggesting that the relationship between IOP and CSFp may be of significant importance in the pathogenesis of glaucoma.

In one of the first studies to explore the clinical relationship between CSFp and glaucoma, Berdahl and colleagues retrospectively reviewed more than 30,000 charts of patients who had undergone lumbar puncture with documentation of opening pressure, identifying 29 patients with primary open-angle glaucoma (POAG) and 49 age-matched controls with no history of glaucoma. The authors discovered that patients with previously confirmed diagnosis of glaucoma had significantly lower CSFp than normal controls, and that a larger cup-to-disc ratio correlated with lower CSFp.⁷ A larger, case-control study from the same group included patients with normal-tension glaucoma and ocular hypertension in addition to patients with POAG.¹³ This study showed that patients with normal-tension glaucoma not only had significantly lower CSF pressure than controls, but also significantly lower CSF pressure compared to patients with POAG. Prospective studies by Ren and colleagues added clinical support for these findings, similarly noting that lumbar CSFp was significantly lower in patients with POAG compared to controls, and that CSFp in normal-tension glaucoma was lower than in patients with POAG.¹⁴ Perhaps one of the more compelling findings of these and other studies was that the patients with ocular hypertension, clinically defined as an elevated IOP without glaucomatous optic neuropathy, had significantly higher CSF pressure than controls.^13,15 This suggests a possible protective effect of elevated CSFp against the development of glaucoma from elevated IOP and would add support to the hypothesis that glaucoma and papilledema exist on a continuous spectrum and are directly related to the translaminar pressure difference, which is discussed in detail below. Table 74-1 summarizes the results from these 2 early studies correlating glaucoma to CSFp.

THE TRANSLAMINAR PRESSURE DIFFERENCE

The conceptualization of the role of CSFp in the development of glaucoma requires further explanation of the forces acting upon the optic nerve both in the eye (IOP) and in the orbit (CSFp). Both IOP and CSFp have a range of normal values, and their respective averages are approximately 15 mm Hg and 11 mm Hg. However, it is important to understand that the 2 values have not been shown to be correlated; an increase in either IOP or CSFp does not correspond to an increase in the other.^16–19 Thus, factors leading to an increase or decrease in IOP or CSFp may change the pressure difference across the lamina cribrosa and affect mechanical change at the optic nerve head. This concept is key to understanding how CSFp may be related to not only glaucoma but also other optic nerve disease processes such as papilledema.

The pressure difference of the 2 independently pressurized compartments (anteriorly, the IOP, and posteriorly, the CSFp) separated by the lamina cribrosa is known as the translaminar pressure difference, defined as IOP – ICP (see Figure 74-1). Using the approximate averages of both values, healthy individuals could thus be expected to have a translaminar pressure difference of about 4 mm Hg directed posteriorly at the optic nerve head.⁶ Within the body of literature connecting glaucoma to CSFp described above, the translaminar pressure difference has been correlated to objective findings in glaucoma (Figure 74-2). In the large retrospective study by Berdahl and colleagues identifying lower CSFp in patients with glaucoma, they also found a significant correlation between increased translaminar pressure differences and increasing cup-to-disc ratios.7 A similar finding in the study by Ren and colleagues demonstrated that the translaminar pressure difference was found to be significantly associated with both visual field loss (P = .008) and increased neuroretinal rim area (P = .006).²⁰ The latter was corroborated in a separate, small series of patients.²¹ These findings further implicate CSFp in glaucoma by demonstrating a relationship to the severity of glaucoma measured by objective means.

From experimental work using biomechanical models, investigators have begun to understand how alterations in either IOP or CSFp can induce this change at the optic nerve head. It has previously been noted that the optic nerve head becomes displaced by altering CSFp,22 likely the result of the change in translaminar pressure difference. However, physical displacement of the lamina cribrosa in response to pressure changes may also be in part related to the inherent biomechanical properties of it and the surrounding peripapillary sclera. These properties are dependent on the molecular and extracellular make-up of the tissue and may change with age and degree of strain.²³ The lamina cribrosa has been noted to be thinner in eyes with more advanced stages of glaucoma,²⁴ as well as in human eyes with high myopia and longer axial length,²⁵ which may explain the tendency toward more significant progression of retinal nerve fiber layer loss noted in these populations.

Attempts have been made to better visualize and understand the effects of deformation of the lamina cribrosa with variations in the CSFp. Feola and colleagues used synchrotron radiation phase-contrast microcomputed tomography to visualize the lamina cribrosa at a constant IOP while varying CSFp in porcine eyes, noting significant strain on both the lamina cribrosa and the retrolaminar neural tissue.²⁶ Villarruel and colleagues measured the position of the lamina cribrosa relative to Bruch membrane and found that, compared to healthy controls, patients with idiopathic intracranial hypertension had anteriorly displaced lamina cribrosa, while in patients with glaucoma the lamina cribrosa was posteriorly displaced.²⁷ In addition, the position of the lamina cribrosa was positively correlated to the translaminar pressure difference. While much has yet to be learned about the complex interplay between the biomechanical properties of eye and the translaminar pressure difference, these recent studies have advanced our understanding of how CSFp may be linked to glaucomatous optic neuropathy.

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