Role of Intracranial Pressure (in Glaucoma)

Authors:  Arthur J. Sit, SM, MD

A better understanding of translaminar pressure differences and pressure gradients may elucidate glaucoma pathogenesis. 

Elevated intraocular pressure (IOP) is the greatest risk factor for glaucoma, but IOP alone is not sufficient to explain glaucoma pathogenesis. It is possible that intracranial pressure (ICP) may play some role.

The optic nerve is subject to a variety of forces, as described by Morgan and colleagues (see Figure 1).1 There is IOP from the anterior side of the optic nerve head; retrolaminar tissue pressure (RLTP) within the optic nerve, just behind the laminar cribrosa; orbital pressure from the sides; and finally, there is the fluid pressure of the optic nerve subarachnoid space (ONSAS) surrounding the optic nerve. The ONSAS is filled with cerebral spinal fluid (CSF), and is in communication with the intracranial cerebral spinal fluid, so presumably the ONSAS pressure is in some way related to ICP.

Given that the most obvious changes in glaucoma occur in the laminar cribrosa, we would ideally like to know what is happening to the RLTP. However, RLTP is obviously quite difficult to measure in humans—or in animals, for that matter.

However, research in dogs has correlated the RLTP with CSF pressure in the ventricles. That is, above a CSF pressure of 2.0 mmHg, RLTP is virtually identical to the CSF ventricular pressure.2 Below 2.0 mmHg, the tissue pressure is approximately constant, perhaps reflecting the orbital tissue pressing against the nerve when the CSF pressure drops very low.

This research is very useful because it allows us to simplify our analysis of the pressures that act on the laminar cribrosa. The translaminar pressure difference can simply be described as IOP minus ICP. In normal eyes, assuming an IOP of 16 mmHg and an ICP of 12 mmHg, the translaminar pressure difference is about 4 mmHg. This can be refined by taking into account the thickness of the laminar cribrosa to determine the pressure gradient. Normal eyes have a laminar cribrosa thickness of about 450 µm, for a pressure gradient of approximately 10 mmHg/mm. As the laminar cribrosa gets thinner, the translaminar pressure gradient increases.

MECHANISMS OF DAMAGE

There are two potential mechanisms for glaucomatous damage related to translaminar pressure differences and gradients. The most direct mechanism would be deformation of the laminar cribrosa. In monkeys, acute elevation of intraocular pressure leads to posterior bowing of the optic nerve head (ONH), axial thinning and radial expansion of the posterior scleral portion of the neural canal, and laminar thinning, which increases the translaminar pressure gradient.3 Anterior or posterior deformation of the anterior laminar cribrosa surface may also occur.

In combination, these changes exert direct compression, expansion, and shear forces, which act on the axons, the astrocytes and the laminar and posterior ciliary blood supply to the optic nerve. Any of these forces could potentially contribute to glaucoma pathogenesis.

The second potential mechanism of action for ICP in glaucoma is that pressure forces may impair axonal transport. Normally, CSF pressure is lower than IOP, and retrograde transport from the lateral geniculate nucleus to the retinal ganglion cell bodies must cross a pressure barrier. However, an increase in IOP, a decrease in ICP, or a decrease in the laminar cribrosa thickness may increase the pressure barrier against which transport needs to occur (see Table 1).

Table 1: Potential mechanism for impairment of axonal transport. With acute changes in the IOP, ICP and/or laminar thickness, there can be a greater than four-fold increase in the pressure difference and pressure gradient compared with normal eyes.

These changes could cause a significant increase (more than four-fold, in the example in Table 1) in the pressure difference and pressure gradient compared to normal eyes. In theory, this would be sufficient to impair axonal transport, at least in the peripheral nerves, and presumably would have similar effects on central nervous system axons.4

The first clinical evidence that this might play a role in humans was described in a case- controlled study at the Mayo Clinic from Berdahl and colleagues involving 31,786 patients who underwent lumbar puncture over a 10-year period. Of that group, researchers were retrospectively able to identify 28 patients who had been diagnosed by glaucoma specialists as having characteristic optic nerve changes and visual field loss consistent with primary open- angle glaucoma (POAG).5 They also identified a control group of 49 subjects who had been seen by an ophthalmologist within a year of having a lumbar puncture, had documented cup/disc ratios, and no history of glaucoma, elevated IOP or optic nerve abnormality.

CSF pressure in the controls (13.0 ±4.2 mmHg) was significantly higher than in the POAG group (9.2 ±2.9 mmHg). Not surprisingly, IOP in the control group was lower than in the POAG group (16.4 ±2.8 mmHg vs. 24.3 ±6.1 mmHg).5 A subsequent study also included normal-tension glaucoma (NTG) and ocular hypertension (OHT) patients.6 There was a much larger translaminar pressure difference in the POAG patients than in the NTG patients who, in turn, had a higher translaminar pressure difference than in the controls. The OHT group also had a greater translaminar pressure difference than controls, whether one looked at the maximum IOP or the IOP closest to the date of the lumbar puncture.

More recently, Ren and colleagues prospectively compared CSF pressures in a cohort of patients with open-angle glaucoma to those of a control group slated for lumbar puncture for other reasons.7 Within the POAG group, patients were divided into normal-tension glaucoma (IOP ≤ 21 mmHg) and high pressure glaucoma (>21 mmHg). The results were very similar to those in the retrospective studies, with the control group having the highest CSF pressure and the smallest translaminar pressure difference (see Table 2).7

Table 2: Translaminar pressure differences between controls and patients with primary open- angle glaucoma. Ren R, Jonas JB, Tian G, et al. Ophthalmology 2010;117:259–66.

To answer the central question of whether patients with high translaminar cribrosa pressure barriers are more likely to develop glaucoma, we need longitudinal data in addition to the prospective, cross-sectional data available thus far. There are also a number of other issues that need to be explored in this emerging field. For example, what are the normal circadian variations in ICP? What effect does body position (e.g. supine vs. standing erect) have on ICP? As we move forward in trying to understand the role of ICP and glaucoma pathogenesis, is it possible to imagine a role for intracranial hypertensive agents?

Ultimately, ICP may serve primarily as an additional risk factor. Particularly in that subset of patients who continue to get worse despite significant IOP lowering, lumbar puncture to measure CSF pressure may provide another way to analyze risk. There are some patients who have abnormally low CSF pressures, related to CSF leaks in the skull base or other factors. Whether those patients are more susceptible to glaucoma is being investigated. If they are, treatment could safely raise the intracranial pressure. It is much less likely that clinicians would attempt to raise intracranial pressure in someone with normal ICP.

In conclusion, there is a clear theoretical basis for the importance of translaminar cribrosa pressure gradients in glaucoma. Early clinical evidence does suggest a relationship between intracranial or cerebrospinal fluid pressure and glaucoma, but further investigation is needed to understand the exact role of intracranial pressure, its diagnostic or therapeutic value in glaucoma, and the implications for clinical practice.

REFERENCES

  1. Morgan WH, Yu DY, Balaratnasingam C. The role of cerebrospinal fluid pressure in glaucoma pathophysiology: the dark side of the optic disc. J Glaucoma 2008;17:408-13.
  2. Morgan WH, Yu DY, Alder VA, et al. The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure. Invest Ophthalmol Vis Sci 1998; 39:1419-28.
  3. Yang H, Downs JC, Sigal IA, et al. Deformation of the normal monkey optic nerve head connective tissue after acute IOP elevation within 3-D histomorphometric reconstructions. Invest Ophthalmol Vis Sci 2009;50(12):5785-99.
  4. Hahnenberger RW. Inhibition of fast anterograde axoplasmic transport by a pressure barrier. The effect of pressure gradient and maximal pressure. Acta Physiol Scand 1980;109(2):117-21.
  5. Berdahl JP, Allingham P, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmol 2008;115:763-8.
  6. Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci. 2008;49(12):5412-8.
  7. Ren R, Jonas JB, Tian G, et al. Cerebrospinal fluid pressure in glaucoma. Ophthalmol 2010;117:259-66.
     

Managing Glaucoma: Beyond Intraocular Pressure. 2011. RELEASE DATE: SEPTEMBER, 2011EXPIRATION DATE: SEPTEMBER 30, 2012

Source: Review of Opthalmology