Cerebrospinal fluid a major player in glaucoma?

Take-home message: Imbalance between IOP and cerebrospinal fluid pressure may influence the risk of normal-tension glaucoma or the susceptibility of the optic nerve to ocular hypertension.

By Lynda Charters; Reviewed by R. Rand Allingham, MD

Durham, NC-Elevated IOP has always been thought to be one of the primary factors in the development of glaucoma, in addition to age, race, and family history.

More recently, the role of lower cerebrospinal fluid (CSF) pressure is being investigated as a contributing factor to increased pressure differences across the lamina cribrosa-the tissue that the retinal axons cross as they leave the eye and enter the optic nerve.

R. Rand Allingham, MD, and colleagues hypothesize this may increase the risk of glaucoma.

“Normal IOP is commonly present in people found to have glaucoma when screened in population-based studies,” said Dr. Allingham, who is the Richard and Kit Barkhouser Distinguished Professor, Department of Ophthalmology, Duke University Medical Center, Durham, NC,

“One-third of European and African American individuals with primary open-angle glaucoma (POAG), the most common form in the world, have normal IOP at the initial exam,” he said. “Over three-fourths of Hispanics and Japanese with open-angle glaucoma have normal IOPs.”

Humans have two circulating pressurized fluid compartments that are separated by the lamina cribrosa.

In addition to the importance of pressure on the optic nerve over time, Dr. Allingham also noted it is helpful to recognize how close the CSF within the subarachnoid space of the optic nerve is to the intraocular aqueous humor and that the lamina cribrosa separating these fluid spaces can dramatically thin in people with glaucoma.

The groundwork for this line of thought was laid more than 15 years ago, when Morgan et al. investigated the relationship between the IOP and the subarachnoid space in a canine model (Invest Ophthalmol Vis Sci. 1998;39:1419-1428) by altering the pressure in the intraocular and subarachnoid spaces and studying the effect of that change on the translaminar pressure across the lamina cribrosa. Investigators found that changing the pressure of the CSF had a similar effect to changing the IOP on the lamina cribrosa and proposed that the CSF pressure may be involved in the pathogenesis of glaucoma.

“Morgan and associates found that 85% of the pressure drop was within 400 µm of the lamina cribrosa,” Dr. Allingham recounted. “Those investigators concluded in that study that the CSF pressure was the major determinant of the post-laminar pressure and that the effect of altering the CSF pressure was biomechanically equivalent to altering the IOP. They concluded: ‘These factors can influence the development of normal tension glaucoma or the susceptibility of the optic nerve to ocular hypertension.’”

A decade later, Berdahl and colleagues reported in a retrospective study that intracranial pressure was significantly lower in patients with POAG than in patients with no glaucoma. They reported their findings in Ophthalmology (2008;115:763-768).

However, and interestingly, they found in a subsequent study (Invest Ophthalmol Vis Sci. 2008;49:5412-5418) that patients with ocular hypertension had significantly higher CSF pressure compared with control patients.

Ren and associates corroborated these findings in a prospective study (Ophthalmology. 2010;117:259-266). In addition, they also found a strong nonrandom correlation between these two pressures and between blood pressure and CSF pressure.

Clinically, the translaminar pressure difference was the factor found most strongly correlated with visual field loss, Dr. Allingham explained.

He also pointed that there is a sustained and significant reduction of the CSF pressure with age that occurs after the age of 50 years (Fleishman et al., PloS One, Dec. 26, 2012 DOI: 10.1371/journal.pone.0052664).

“The pressure is remarkably stable prior to this age then drops about 33% through age 80,” he said. “Interestingly, the prevalence of POAG typically starts to rise around the same age. Throughout this age range, the IOP is relatively stable in most people.”

A study to determine if there is internal regulation of IOP and CSF was conducted (Samuels et al. Invest Ophthalmol Vis Sci. 2012;53:7328-7335).

“We are aware that the IOP appears to have a circadian rhythm, although there is not a great deal of supporting data to confirm this. Brian has found that the dorsomedial and perifornical hypothalamic neurons are highly involved in the diurnal curve; when stimulated with GABA receptor antagonists, there was a rapid and almost instant increase in the mean arterial pressure and CSF pressure. The IOP also increased but, surprisingly, 20 minutes after the stimulation,” Dr. Allingham commented.

When those two responses are mapped, there is a period when there is a striking difference in the translaminar pressure difference, he noted. This raises the question about whether this difference is clinically relevant.

“This is a new finding and that question is an important one to answer,” he said.

Summary

“The CSF pressure is lower in some patients with POAG. IOP, CSF pressure, and blood pressure are highly correlated in patients who do not have glaucoma but not in those who have POAG. The central nervous system may be involved in all of these parameters.

“It appears that maintaining a physiologic balance between the pressures across the lamina cribrosa is important,” he said. “This balance is likely to be important to the health of retinal ganglion cells and their axons.

“Dysregulation of this process may play a pivotal role in the pathogenesis of glaucoma,” Dr. Allingham said. “To better understand this process, we need to understand IOP better, but we also need to investigate the role of CSF pressure in the equation.”

R. Rand Allingham, MD

E: rand.allingham@duke.edu

This article was adapted from Dr. Allingham’s presentation at the 2015 meeting of the American Glaucoma Society. Dr. Allingham has no financial interest in the subject matter.