Dr Da Zhao
BMed China MVisSci
Dr Christine Tram Oanh Nguyen
Dr Zheng He
BMed China PhD
Professor Algis J Vingrys
BScOptom PGCertOcTher PhD FARVO FAAO
Associate Professor Bang Bui
BScOptom MOptom PGCertOcTher PhD
Department of Optometry and Vision Sciences, The University of Melbourne
It is widely accepted that glaucoma is associated with elevated intraocular pressure (IOP) elevation.
There are some patients who develop glaucoma without IOP elevation (normal tension glaucoma [NTG]) and in some patients, vision loss keeps progressing despite successful IOP reduction. Recent studies suggest that many non-IOP factors can also have important roles in glaucoma, such as diet,1 diabetes,2 blood pressure3 and intracranial pressure.4,5
The optic nerve head is thought to be the site of injury to the optic nerve axons. It is biomechanically the most susceptible part of the eye to stress because it is the thinnest part of a pressurised chamber; therefore, it is prone to displacement when subjected to changes in the pressure gradient across the lamina cribrosa.
Two key forces exert their effects at the optic nerve head: intraocular pressure from inside the eye and intracranial pressure (ICP) from the retro-laminar subarachnoid space.6 Elevated IOP has been well-established to cause backward bowing of the lamina cribrosa, which is consistent with the increased cupping seeing in glaucoma.7 Conversely an increase in retro-laminar pressure will cause the nerve to move forward.
For example, intracranial hypertension can manifest in the eye as papilloedema, which is associated with a forward displacement of the optic nerve tissue. This is because cerebrospinal fluid fills the subarachnoid space that surrounds the optic nerve all the way up to the sclera (Figure 1A). As such, the balance between IOP and ICP can affect the ganglion cells that exit the eye at the optic nerve head.
The balance between IOP and ICP creates a pressure gradient across the lamina cribrosa known as trans-laminar pressure (TLP = IOP - ICP). It stands to reason that a higher ICP should help to counteract the detrimental effects of IOP elevation on the optic nerve.
A recent study by our group shows that this is the case.5 In a rodent model, we demonstrate that progressive deformation of the optic nerve head and peripapillary retinal surface can be induced by increasing IOP. The effect of IOP elevation was made worse in animals that had low ICP and conversely, raising ICP prevented much of the detrimental effects of IOP elevation. This is in agreement with studies conducted in canine eyes, where significant posterior movement of the optic disc surface has been found with IOP elevation and anterior displacement with ICP increase.8
These structural changes to the optic nerve affect retinal function. Using the electroretinogram we show that loss of the ganglion cell response to light caused by IOP elevation could be modified by the ICP level (Figure 1). A higher ICP was protective against IOP elevation, whereas the converse was true for lower ICP levels.
Figure 1. Intracranial pressure can counteract the effect of IOP on optic nerve structure and function. A. Intraocular and intracranial pressure are forces that oppose each other across the lamina cribrosa. Using optical coherence tomography, we show that there was more backward bowing of the optic nerve surface (arrow lines) and retinal compression (arrowheads) with IOP elevation when ICP was normal (B. ICP 5 mmHg) compared with a high ICP (D. 30 mmHg). Using the electroretinogram we show that high ICP prevents ganglion cell dysfunction caused by elevated IOP. Black traces indicate baseline waveforms and coloured traces indicate waveforms when IOP was 70 mmHg. The response is more affected when ICP was normal (C, orange trace) and less affected when ICP was high (E. blue trace). Adapted from Zhao and colleagues5
Interestingly, our study shows that small changes to intracranial pressure can produce more substantial effects on the optic nerve structure and function than do equivalent changes in intraocular pressure. For example, the total complete loss of retinal ganglion cell function caused by IOP elevation of 80 mmHg (from 10 to 90 mmHg) could be entirely ameliorated by elevating ICP by 25 mmHg (from 5 to 30 mmHg, normal ICP ~ 5 mmHg). While the findings of our study need to be interpreted with caution, they highlight the potential that small changes in ICP might significantly influence glaucoma risk.
There are both laboratory and clinical studies that support a potential role for ICP in glaucoma. Yang and colleagues4 placed lumbar-peritoneal shunts into non-human primates to chronically drain a small amount of CSF and lower ICP. After 12 months, the authors reported reductions in retinal nerve fibre layer thickness, neuroretinal rim area and volume, as well as increased cup/disc ratio.
These results suggest that even with normal IOP, one can get ganglion cell loss, as low ICP produces a higher trans-laminar pressure gradient. These findings raise the possibility that injury in both normal tension glaucoma and primary open angle glaucoma arises from a higher trans-laminar pressure. Similarly, the absence of injury with apparent ocular hypertension is due to a lower trans-laminar pressure. These concepts are shown in Figure 2.
Figure 2. Pressures that can influence the health of the optic nerve include IOP, which is opposed by both intracranial pressure and blood pressure. Growing evidence suggests that combinations of these pressures and the subsequent translaminar pressure gradient may help in our understanding of glaucoma.
Consistent with this above contention, several studies report that ICP is lower in those with NTG and POAG compared to age-matched controls.9,10,11 These authors found that the lower ICP was, the more severe the visual field loss tended to be. Also consistent with a critical role for trans-laminar pressure is the finding that those with ocular hypertension (without visual field loss) tended to have higher ICP.12
Interestingly, it has been found that ICP decreases by about 3 mmHg between the fourth and ninth decades of life.13 A 3 mmHg higher trans-laminar pressure gradient may be enough to increase the risk of glaucoma.
While it is not clear how the findings of studies such as ours will impact clinical practice, it is critical that we first attempt to fully understand the risk factors for glaucoma. If simple non-invasive approaches for ICP measurement become available, perhaps we will have a much clearer picture of an individual’s risk for glaucoma development and progression.
In this regard, it is worth noting that formulae are available that allow us to estimate ICP, based on age, blood pressure and body mass index.14 Further studies are needed to allow us to fully understand how to implement these ideas in clinical practice.
1. Nguyen CT, Vingrys AJ, Bui BV. Dietary omega-3 fatty acids and ganglion cell function. Invest Ophthalmol Vis Sci 2008; 49: 3586-3594.
2. Wong VH, Bui BV, Vingrys AJ. Clinical and experimental links between diabetes and glaucoma. Clin Exp Optom 2011; 94: 4-23.
3. He Z, Vingrys AJ, Armitage JA, Bui BV. The role of blood pressure in glaucoma. Clin Exp Optom 2011; 94: 133-149.
4. Yang D, Fu J, Hou R, Liu K et al. Optic neuropathy induced by experimentally reduced cerebrospinal fluid pressure in monkeys. Invest Ophthalmol Vis Sci 2014; 55: 3067-3073.
5. Zhao D, He Z, Vingrys A, Bui B, Nguyen C. The effect of intraocular and intracranial pressure on retinal structure and function in rats. PHY2 2015; 3: 8: e12507.
6. Morgan W, Balaratnasingam C, Lind C, Colley S, Kang M, House P et al. Cerebrospinal fluid pressure and the eye. Brit J Ophthalmol 2015; 100: 1: 71-77.
7. Fortune B, Choe TE, Reynaud J, Hardin C, Cull GA, Burgoyne CF, Wang L. Deformation of the rodent optic nerve head and peripapillary structures during acute intraocular pressure elevation. Invest Ophthalmol Vis Sci 2011; 52: 6651-6661.
8. Morgan WH, Chauhan BC, Yu DY, Cringle SJ, Alder VA, House PH. Optic disc movement with variations in intraocular and cerebrospinal fluid pressure. Invest Ophthalmol Vis Sci 2002; 43: 3236-3242.
9. Berdahl J, Allingham R, Johnson D. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology 2008; 115: 5: 763-768.
10. Berdahl J, Fautsch M, Stinnett S, Allingham R. 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.
11. Ren R, Zhang X, Wang N, Li B, Tian G, Jonas JB. Cerebrospinal fluid pressure in ocular hypertension. Acta Ophthalmologica 2011; 89: e142-148.
12. Ren R, Jonas JB, Tian G, Zhen Y et al. Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology 2010; 117: 259-266.
13. Fleischman D, Berdahl J, Zaydlarova J, Stinnett S, Fautsch M, Allingham R. Cerebrospinal fluid pressure decreases with older age. PLoS ONE 2012; 7: 12: e52664.
14. Berdahl JP, Yu DY, Morgan WH. The translaminar pressure gradient in sustained zero gravity, idiopathic intracranial hypertension, and glaucoma. Medical Hypotheses 2012; 79: 719-724.
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