Eyes with normal-tension and high-tension glaucoma can have a similar optic nerve head appearance, which differs markedly from the optic disc appearance in vascular optic neuropathies. Factors in addition to intraocular pressure (IOP) may play a role in the pathogenesis of glaucomatous optic neuropathy. Clinical and experimental studies have shown (1) physiologic associations between cerebrospinal fluid pressure (CSFP), systemic arterial blood pressure, IOP, and body mass index; (2) that a low CSFP was associated with the development of glaucomatous optic nerve damage in cats; and (3) that patients with normal-tension glaucoma had significantly lower CSFP and a higher trans-lamina cribrosa pressure difference when compared to normal subjects. Due to anatomic reasons, the orbital CSFP and the optic nerve tissue pressure (and not the atmospheric pressure) form the retro-laminar counter-pressure against the IOP and are thus part of the trans-lamina cribrosa pressure difference and gradient. Assuming that an elevated trans-lamina cribrosa pressure difference and a steeper trans-lamina cribrosa pressure gradient are important for glaucomatous optic nerve damage, a low orbital CSFP would therefore play a role in the pathogenesis of normal-tension glaucoma. Due to the association between CSFP and blood pressure, a low blood pressure would also be indirectly involved.
*Department of Ophthalmology, Medical Faculty Mannheim-Heidelberg, Mannheim, Germany
†Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, Beijing, China
Disclosure: The authors declare no conflict of interest.
Since the lamina cribrosa of the optic nerve head forms the border between the intraocular space with a higher pressure and the retrobulbar space with a lower pressure, a pressure gradient exists across the lamina cribrosa which can be expressed as the difference between intraocular pressure and the pressure in the retrobulbar cerebrospinal fluid and optic nerve tissue space.1,2 This trans-lamina cribrosa pressure gradient is important for ocular diseases in which the pressure on one or on both sides of the lamina cribrosa is either abnormally high and/or abnormally low.3,4 An abnormal pressure gradient influences the physiology and pathophysiology of the optic nerve head,5–9 including the orthograde and retrograde axoplasmic flow.10,11 In that context, it should be kept in mind that the term ‘intraocular pressure (or IOP)’ is a misnomer. What we call ‘IOP’ is just the transcorneal pressure difference.2 The true pressure in an eye with an IOP of 20 mm Hg is 780 mm Hg (760 mm Hg (atmospheric pressure) plus 20 mm Hg). For the optic nerve, however, it is not the transcorneal pressure difference which counts, but the trans-lamina cribrosa pressure difference and the trans-lamina cribrosa pressure gradient.
The trans-lamina cribrosa pressure gradient depends on the pressure difference and the distance between the intraocular compartment and the retrobulbar fluid filled compartment. The distance between both compartments markedly depends on the thickness of the lamina cribrosa.12,13 Consequently, thinning of the lamina in highly myopic eyes may be a reason for their susceptibility to glaucoma.13,14 In addition, histomorphometric studies have shown that in non-highly myopic eyes, the lamina cribrosa gets thinner in advanced stages of the disease.13 This glaucoma-related thinning of the lamina cribrosa may be one of the reasons for the increased risk of progression in eyes with advanced glaucoma.15,16
The trans-lamina cribrosa pressure difference depends on the IOP and the retrobulbar cerebrospinalfluid pressure (CSFP). It is elevated if either the IOP is elevated and/or if the CSFP is reduced. Over 30 years ago, Volkov pointed out that a low CSFP could pathogenetically be associated with glaucomatous optic neuropathy.17 The same idea had earlier been expressed by Szymansky and Wladyczko.18 Yablonski, Ritch and Pokorny postulated that an abnormally low CSFP around the optic nerve may be the reason for a barotraumatically induced optic nerve damage in normal-tension glaucoma.19 In an experimental study, they decreased the intracranial pressure to 5 cm H2O below the atmospheric pressure by cannulation of the cisterna magna. The IOP of one eye was reduced to slightly above atmospheric pressure by cannulation of the anterior chamber. After 3 weeks, the optic nerve heads of the eyes in which the IOP was unaltered showed typical features of glaucomatous optic neuropathy. In contrast, in the eyes in which the IOP was also lowered, no changes occurred. The authors hypothesized that reducing intracranial pressure would have the same effect as increasing the IOP for the development of glaucoma.
Berdahl et al retrospectively reviewed medical records of over 50,000 patients who had undergone lumbar puncture for primarily non-ophthalmological reasons.20,21 The CSFP was significantly (P<0.0001) lower in the subjects with normal-tension glaucoma (8.7±1.16 mm Hg) and in the primary open-angle glaucoma group (9.1±0.77 mm Hg) than in the control group (11.8±0.71 mm Hg). Additionally, the CSFP was higher in the ocular hypertension group than in age-matched controls (12.6±0.85 mm Hg vs. 10.6±0.81 mm Hg; P<0.05). These results were confirmed by a prospective study by Ren et al.22–24 In their study, the lumbar CSFP was significantly (P<0.001) lower in the normal-tension glaucoma group (9.5±2.2 mm Hg) than in the high-IOP glaucoma group (11.7±2.7 mm Hg) or the control group (12.9±1.9 mm Hg). The trans-lamina cribrosa pressure difference was significantly (P<0.001) higher in the normal-IOP glaucoma group (6.6±3.6 mm Hg) and the high-IOP glaucoma group (12.5±4.1 mm Hg) than in the control group (1.4±1.7 mm Hg). In a multivariate analysis, the amount of glaucomatous visual field loss was mainly associated with the trans-lamina cribrosa pressure difference (P=0.005) while IOP and CSFP as single parameters were no longer significantly (P>0.50) associated with the perimetric loss. In a parallel study, the CSFP was significantly (P<0.001) higher in an ocular hypertensive group of 17 patients (16.0±2.5 mm Hg) than in the control group (12.9±1.9 mm Hg).24 In the control group, CSFP was significantly correlated with both systolic blood pressure (P=0.04) and IOP (P<0.001). Since the IOP also showed a tendency toward an association with blood pressure (P=0.09), as was also shown in a population-based study,25 the trans-lamina cribrosa pressure difference was not significantly (P=0.97) related with the blood pressure. In the control group, the pressure in all three fluid compartments was thus correlated with each other, with the systemic blood pressure being the highest, followed by the IOP and finally by the CSFP. In the control group of the study by Ren et al, the CSFP pressure (P=0.01; correlation coefficient r=−0.26), IOP (P=0.001; r=−0.34) and trans-lamina cribrosa pressure difference (P=0.004; r=−0.31) decreased significantly with older age. The CSFP was additionally associated with higher body mass index (P<0.001).26 These findings confirmed the association between an abnormally high body mass index in patients with idiopathic intracranial hypertension.27
In conclusion, taking into account (1) that it is the trans-lamina cribrosa pressure difference (and not the transcorneal pressure difference, i.e. the so-called ‘IOP’) which is most important for the physiology and pathophysiology of the optic nerve; (2) that studies have suggested physiologic associations between the pressure in all three fluid filled compartments, i.e. the systemic arterial blood pressure, the CSFP and the IOP; (3) that an experimental investigation suggested that a low CSFP may play a role in the pathogenesis of normal-tension glaucoma, and (4) that clinical studies have reported that patients with normal-tension glaucoma had significantly lower CSFP and a higher trans-lamina cribrosa pressure difference when compared to normal subjects, one may infer that a low CSFP may be associated with normal-tension glaucoma in some patients. A low systemic blood pressure, particularly at night, could physiologically be associated with a low CSFP, which leads to an abnormally high trans-lamina cribrosa pressure difference (with barotraumatically induced optic nerve damage) which is similar to a situation where the CSFP is normal and the IOP is elevated. This model could explain why patients with normal-tension glaucoma tend to have a low systemic blood pressure, and why eyes with normal- and high-pressure glaucoma, in contrast to eyes with a direct vascular optic neuropathy, can share profound similarities in their optic nerve head appearance.
1. Morgan WH, Yu DY, Alder VA, et al..The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure.Invest Ophthalmol Vis Sci
2. Jonas JB.Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma.Acta Ophthalmol.2011;89:505–514.
3. Hayreh SS.Optic disc edema in raised intracranial pressure. V. Pathogenesis.Arch Ophthalmol.1977;95:1553–1565.
4. Jonas JB, Mardin CY, Schlötzer-Schrehardt U, et al..Morphometry of the human lamina cribrosa surface.Invest Ophthalmol Vis Sci.1991;32:401–405.
5. Morgan WH, Yu DY, Cooper RL, et al..The influence of cerebrospinal fluid pressure on the lamina cribrosa tissue pressure gradient.Invest Ophthalmol Vis Sci.1995;36:1163–1172.
6. Morgan WH, Yu DY, Cooper RL, et al..Retinal artery and vein pressures in the dog and their relationship to aortic, intraocular, and cerebrospinal fluid pressures.Microvasc Res.1997;53:211–221.
7. Morgan WH, Chauhan BC, Yu DY, et al..Optic disc movement with variations in intraocular and cerebrospinal fluid pressure.Invest Ophthalmol Vis Sci.2002;43:3236–3242.
8. 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;17:408–413.
9. Balaratnasingam C, Morgan WH, Johnstone V, et al..Histomorphometric measurements in human and dog optic nerve and an estimation of optic nerve pressure gradients in human.Exp Eye Res.2009;89:618–628.
10. Anderson DR, Hendrickson A.Effect of intraocular pressure on rapid axoplasmatic transport in monkey optic nerve.Invest Ophthalmol Vis Sci.1974;13:771–783.
11. Minckler DS, Tso MOM, Zimmermann LE.A light microscopic, autoradiographic study of axonal transport in the optic nerve head during ocular hypotony, increased intraocular pressure, and papilledema.Am J Ophthalmol.1976;82:741–757.
12. Jonas JB, Berenshtein E, Holbach L.Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes.Invest Ophthalmol Vis Sci.2004;45:2660–2665.
13. Jonas JB, Berenshtein E, Holbach L.Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space.Invest Ophthalmol Vis Sci.2003;44:5189–5195.
14. Xu L, Wang Y, Wang S, et al..High myopia and glaucoma susceptibility. The Beijing Eye Study.Ophthalmology.2007;114:216–220.
15. .The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.Am J Ophthalmol.2000;130:429–440.
16. Jonas JB, Martus P, Budde WM, et al..Small neuroretinal rim and large parapapillary atrophy as predictive factors for progression of glaucomatous optic neuropathy.Ophthalmology.2002;109:1561–1567.
17. Volkov VV.Essential element of the glaucomatous process neglected in clinical practice.Oftalmol Zh.1976;31:500–504.
18. Szymansky J, Wladyczko S.Jaskra prosta doswiadczalna.Klin Oczna.1925;3:145–150.
19. Yablonsky M, Ritch R, Pokorny KS.Effect of decreased intracranial pressure on optic disc.Invest Ophthalmol Vis Sci.1979;18:165.
20. Berdahl JP, Allingham RR, Johnson DH.Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma.Ophthalmology.2008;115:763–768.
21. Berdahl JP, Fautsch MP, Stinnett SS, et al..Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study.Invest Ophthalmol Vis Sci.2008;49:5412–5418.
22. Ren R, Jonas JB, Tian G, et al..Cerebrospinal fluid pressure in glaucoma: a prospective study.Ophthalmology.2010;117:259–266.
23. Ren R, Zhang X, Wang N, et al..Cerebrospinal fluid pressure in ocular hypertension.Acta Ophthalmol.2011;89:142–148.
24. Ren R, Wang NL, Zhang X, et al..Trans-lamina cribrosa pressure difference correlated with neuroretinal rim area in glaucoma.Graefes Arch Clin Exp Ophthalmol.2011;249:1057–1063.
25. Xu L, Wang H, Wang Y, et al..Intraocular pressure correlated with arterial blood pressure: The Beijing Eye Study.Am J Ophthalmol.2007;144:461–462.
26. Ren R, Wang NL, Zhang X, et al..Cerebrospinal fluid pressure correlated with body mass index.Graefes Arch Clin Exp Ophthalmol.2012;250:445–446.
27. Hannerz J, Ericson K.The relationship between idiopathic intracranial hypertension and obesity.Headache.2009;49:178–184.