Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma

The pathogenesis of normal (intraocular) pressure glaucoma has remained unclear so far. As hospital-based studies showed an association of normal-pressure glaucoma with low systemic blood pressure, particularly at night, and with vasospastic symptoms, it has been hypothesized that a vascular factor may play a primary role in the pathogenesis of normal-pressure glaucoma. That assumption may, however, be contradicted by the morphology of the optic nerve head. Eyes with normal-pressure glaucoma and glaucomatous eyes with high-intraocular pressure can show a strikingly similar appearance of the optic nerve head, including a loss of neuroretinal rim, a deepening of the optic cup, and an enlargement of parapapillary atrophy. These features, however, are not found in any (other) vascular optic neuropathy, with the exception of an enlargement and deepening of the optic cup in arteritic anterior ischaemic optic neuropathy. One may additionally take into account (i) that it is the trans-lamina cribrosa pressure difference (and not the trans-corneal pressure difference, i.e. the so-called intraocular pressure) which is of importance for the physiology and pathophysiology of the optic nerve head; (ii) that studies have shown that the anatomy of the optic nerve head including the intraocular pressure, the anatomy and biomechanics of the lamina cribrosa and peripapillary sclera, retrobulbar orbital cerebrospinal fluid pressure and the retrobulbar optic nerve tissue pressure may be of importance for the pathogenesis of the highly myopic type of chronic open-angle glaucoma; (iii) that studies have suggested a physiological association between the pressure in all three fluid filled compartments, i.e. the systemic arterial blood pressure, the cerebrospinal fluid pressure and the intraocular pressure; (iv) that an experimental investigation suggested that a low cerebrospinal fluid pressure may play a role in the pathogenesis of normal (intraocular) pressure glaucoma; and (v) that recent clinical studies reported that patients with normal (intraocular) pressure glaucoma had significantly lower cerebrospinal fluid pressure and a higher trans-lamina cribrosa pressure difference when compared to normal subjects. One may, therefore, postulate that a low cerebrospinal fluid pressure may be associated with normal (intraocular) pressure glaucoma. A low systemic blood pressure, particularly at night, could physiologically be associated with a low cerebrospinal fluid pressure, which leads to an abnormally high trans-lamina cribrosa pressure difference and as such to a similar situation as if the cerebrospinal fluid pressure is normal and the intraocular pressure is elevated. This model could explain why patients with normal (intraocular) pressure glaucoma tend to have a low systemic blood pressure, and why eyes with normal (intraocular) pressure glaucoma and eyes with high-pressure glaucoma, in contrast to eyes with a direct vascular optic neuropathy, show profound similarities in the appearance of the optic nerve head. Numerous studies have shown that the intraocular pressure in the group of patients with open-angle glaucoma ranges between low normal values to highly elevated values, leading to the (artificial) differentiation into a subtype of high-pressure glaucoma with intraocular pressure readings higher than 21 mmHg and a subtype of normal-pressure glaucoma with a normal intraocular pressure (Quigley 1993; Dielemans et al. 1994; Leske et al. 1994; Mitchell et al. 1996; Drance 1999; Graham & Drance 1999; Anderson et al. 2001; Iwase et al. 2004). Hospital-based studies have shown that patients with normal-pressure glaucoma have a normal intraocular pressure in day-and-night intraocular pressure curves and often show additionally low systemic blood pressure in combination with vasospastic symptoms. It was the reason that a vascular component was considered to be present in the pathogenesis of normal-pressure glaucoma (Drance 1972; Drance et al. 1973; Hayreh et al. 1994; Broadway & Drance 1998; Emre et al. 2004). The optic disc appearance in eyes with normal-pressure glaucoma, however, contradicted a purely vasogenic pathogenesis of optic nerve damage. Studies have shown that the optic disc size, as any quantitative biological parameters, shows a marked interindividual variability (Jonas et al. 1988a). In addition, the ethnic background influences the optic disc size, according to the rule of thumb, that the closer the equator, the larger the optic disc is (Jonas et al. 1999). Furthermore, the optic disc size is related with the myopic refractive error, in the sense that beyond a myopic refractive error of about-eight dioptres, the optic disc enlarges, resulting in a secondary or acquired macrodisc (Jonas 2005; Xu et al. 2007a, 2009a). Despite the pronounced variability in optic disc size, studies have revealed that in nonhighly myopic eyes, the susceptibility for glaucomatous optic neuropathy nor the risk for progression of glaucomatous optic neuropathy is associated with the optic disc size (Jonas et al. 2002a). In highly myopic eyes, however, hospital-based studies and population-based investigations such as the Beijing Eye Study have revealed that glaucoma susceptibility is increased according to a higher prevalence of glaucomatous optic neuropathy in highly myopic subjects compared with nonhighly myopic subjects (Xu et al. 2007b). The reason for the increased glaucoma susceptibility in the highly myopic macrodiscs may be because of the stretching and secondary thinning of the lamina cribrosa and a marked thinning of the peripapillary sclera as shown in several histomorphometric studies (Jonas et al. 2004; Ren et al. 2009a). The thinning of the lamina cribrosa leads to a decreased distance between the intraocular and the of the retrobulbar cerebrospinal fluid so that at a trans-lamina cribrosa pressure difference between the pressure because of the distance between In addition, in the of the lamina cribrosa tissue may to the stretching of the lamina cribrosa as and of recent in the biomechanics of the optic nerve head et al. & et al. et al. et al. 2005; et al. & et al. et al. & et al. et al. The thinning of the peripapillary sclera may be an factor which by an increased in the lamina cribrosa may to increased glaucoma was that in the highly myopic glaucoma eyes compared with highly myopic eyes, the of the lamina cribrosa was significantly often to the and by to the cerebrospinal fluid The of the lamina cribrosa was to the optic for the of the of the lamina cribrosa to the (and to the cerebrospinal fluid is that because of the myopic stretching of the optic nerve head, the optic disc the of the optic nerve of the not show In highly myopic glaucoma eyes, the optic nerve additionally because of the loss of optic nerve the between the optic nerve and the of the optic disc and lamina One has that the of the of the lamina cribrosa to the cerebrospinal fluid in eyes with glaucomatous optic nerve may be the reason for acquired of the optic nerve head which can in the of the optic disc as has been for nonhighly myopic eyes by and et al. et al. et al. In contrast to nonhighly myopic eyes, highly myopic eyes with glaucoma not show acquired optic disc The reason may be that because of the myopic stretching of the lamina cribrosa in highly myopic eyes, the lamina cribrosa may be however, so that a of the lamina cribrosa into the cerebrospinal fluid may not The of the optic nerve head was the with the distance between the intraocular and the cerebrospinal fluid pressure that a distance between the cerebrospinal fluid and the intraocular the pressure and that a pressure the glaucoma susceptibility of optic nerve may that optic nerve in the optic disc be glaucoma than the optic disc In nonhighly myopic eyes, the glaucomatous are often found to the with a loss of to the (Drance et al. et al. The of in the of the nerve and are to the optic disc & & Anderson It with the that the pressure may be at the of the optic disc leading to an increased glaucoma susceptibility of the optic nerve in that studies have not been to the for highly myopic eyes than for nonhighly myopic eyes, may that because of the anatomy of the lamina for highly myopic eyes the optic nerve in the of the optic nerve head may be to glaucoma than closer to the of the optic nerve head. the optic nerve head in highly myopic eyes, may that highly myopic glaucomatous eyes with normal-pressure glaucoma may present a of primary open-angle glaucoma, the so-called highly myopic type of normal-pressure glaucoma of the group of the chronic open-angle (Jonas & It may show that for type of normal-pressure glaucoma, a component when compared with a vasogenic component may be to play a role in the In all normal eyes with a physiologically optic cup, the neuroretinal the in that the is than by the disc and the disc (Jonas et al. 1988a). the can the of glaucomatous optic nerve (Jonas et al. In a glaucoma the is or in the disc when compared with the disc In a glaucoma the shows in the disc often than in the disc The are not at the or however, are to the disc In the loss in the disc is that the are In are present in the with larger in the than in the In all are This of the glaucomatous neuroretinal loss at the disc and disc by the disc in the glaucoma are present larger than may be because of the anatomy of the lamina with the larger and tissue in the and disc when compared with the and disc (Jonas et al. factor may be the distance to the in the lamina the larger the distance the higher the glaucoma susceptibility (Jonas et al. into account the disc and that the is into the disc the disc with the distance to the is the the glaucomatous loss The disc with the distance to the is the disc to the glaucoma can be The of the disc with to the glaucomatous loss of neuroretinal can be found in all of glaucoma including normal-pressure glaucoma. the exception of arteritic anterior ischaemic optic neuropathy, all vascular optic not show a loss of neuroretinal rim, which physiological (Jonas & Xu reported for an experimental (Jonas & Hayreh In such as anterior ischaemic optic neuropathy, or optic nerve because of the of the neuroretinal may to a of the nerve It leads to a decreased contrast between the of the and the of the optic In addition, the neuroretinal rim, in difference to glaucomatous optic neuropathy, in which the is not 1972; et al. The in the loss of neuroretinal in all of glaucoma including normal-pressure glaucoma in contrast to the in the vascular optic the normal of the in glaucoma in contrast to the of the in eyes with a vascular optic nerve the that the loss in neuroretinal in normal-pressure glaucoma is related to the of the intraocular pressure (Jonas et the that the of the of the optic cup in normal-pressure glaucoma with the of the marked loss (Jonas & and the that of intraocular pressure is in normal-pressure glaucoma Study may a vascular pathogenesis in normal-pressure glaucoma. can be into a with and and a at the of the peripapillary of and by and sclera (Jonas & et al. Hospital-based studies and population-based investigation have shown that is significantly often present and that it is significantly larger in glaucomatous eyes than in normal eyes (Jonas et al. Xu et al. studies in and in revealed that to a loss of an loss of and a of the and that to in the of the and to a of the (Jonas et al. studies showed that to a and to an & can be found in all of the chronic open-angle including normal-pressure glaucoma. In of the vascular optic including arteritic anterior ischaemic optic neuropathy shows an enlargement of or an increased of (Jonas et al. Hayreh & The that is for all of chronic glaucoma and that it is not associated with any vascular optic neuropathy may a vascular pathogenesis of normal-pressure glaucoma. studies such as the Eye Study and the Beijing Eye Study have shown that optic disc can be found in of all eyes of subjects et al. 1998; et al. In of eyes, glaucomatous optic neuropathy could be leading to a highly association between glaucomatous optic neuropathy and disc In addition, hospital-based studies and population-based studies revealed that a disc in a glaucomatous a high of a progression of the & 1996; Xu et al. Hospital-based studies have additionally revealed that eyes with normal-pressure glaucoma have significantly often and disc than eyes with high-pressure glaucoma et al. Drance showed that the size of the is larger in eyes with normal-pressure glaucoma than in eyes with high-pressure glaucoma (Jonas & Xu have been that the significantly higher prevalence of disc in normal-pressure glaucoma a difference in the pathogenesis of normal-pressure glaucoma high-pressure glaucoma. however, that the difference in the of disc is because of the difference in intraocular pressure between high-pressure glaucoma and normal-pressure glaucoma. that the size of the in the is similar in glaucoma the of blood of the into the tissue the pressure The is the difference between the blood pressure in the and the pressure in the i.e. the intraocular into account the lower intraocular pressure in the normal-pressure glaucoma eyes than in the high-pressure glaucoma eyes, the difference in intraocular pressure between glaucoma may be reason for larger disc which take a to be and have a higher to be by In the in the of disc between normal-pressure glaucoma and high-pressure glaucoma may be by the difference in intraocular pressure and may not be for a pathogenesis between high-pressure glaucoma and normal-pressure glaucoma. In addition, a disc is not by a which that may be ischaemic the disc of the in a and in a have been to in eyes with glaucoma, and that the and of the in the with the and of glaucomatous optic nerve (Jonas & et al. The has been found in eyes with normal-pressure as as in eyes in high-pressure glaucoma. however, the and thinning of the can be found in any type of optic nerve & et al. the in the is not for glaucoma in nor for normal-pressure glaucoma in may at be a secondary because of the loss of tissue and the for blood the morphology of the optic nerve for between of chronic open-angle glaucoma may to The optic nerve head is found in the highly myopic type of (Jonas & & A secondary or acquired an disc that the myopic stretching of the disc in the a disc leading to low contrast in to a low contrast between the neuroretinal and the optic a myopic which in of parapapillary in nonhighly myopic The highly myopic of a sclera and nerve or between the nerve and the the sclera is and the cerebrospinal fluid with the as can into the parapapillary et al. The high-pressure glaucoma type is by a of the patients at the of the with a and a parapapillary and an loss of nerve (Jonas & 1996; & a however, are nerve which can a The so-called type of normal-pressure glaucoma may be be found in than in with an of the patients tend to have a low arterial blood pressure and to vasospastic may have higher are and are The optic disc can show a and disc marked nerve and parapapillary (Jonas & The of the of the optic cup in normal-pressure glaucoma with the of the marked loss (Jonas & 1999). In is a strikingly similar appearance in the appearance of the optic nerve head between eyes with glaucoma and high-intraocular pressure and eyes with normal intraocular pressure (Jonas & by Hayreh have shown that with experimental high-pressure glaucoma nerve was to be for normal-pressure glaucoma (Jonas & Hayreh The why marked in intraocular pressure between eyes with high-pressure glaucoma and eyes with normal-pressure glaucoma, glaucoma could have strikingly similar optic nerve head and may explain the marked in the optic nerve head appearance between eyes with normal-pressure glaucoma and eyes with any (other) vascular optic neuropathy, if normal-pressure glaucoma was to have a vascular In of the may beyond the lamina cribrosa into the of the The of the optic cup the of the optic nerve head is by the lamina the lamina cribrosa the anterior of the optic The of the lamina cribrosa are to the and the to the to the to the intraocular and to the intraocular pressure by a between the intraocular and the of the the lamina cribrosa a of the into the retrobulbar cerebrospinal fluid the retrobulbar of the optic As the lamina cribrosa the between the intraocular with a higher pressure and the retrobulbar with a lower pressure, a pressure the lamina cribrosa as difference of intraocular pressure pressure in the retrobulbar cerebrospinal fluid This trans-lamina cribrosa pressure is of importance for in which the pressure or of the lamina cribrosa is abnormally high abnormally low et al. et al. et al. pressure influences the physiology of the optic nerve with and & et al. & Anderson The importance of the trans-lamina cribrosa pressure difference may be shown in eyes with an intraocular pressure of and the pressure in the with an intraocular pressure of mmHg is higher than in the with the intraocular pressure of The reason is that the is a is the trans-corneal pressure The pressure in the with an intraocular pressure of mmHg is mmHg mmHg pressure) and the pressure in eyes with an intraocular pressure of mmHg is As a into a of the pressure in the eyes glaucoma however, not as the trans-corneal difference In a similar of or in high is not a of glaucoma as the trans-corneal pressure difference a pronounced in the pressure in the because of the lower the optic however, it is not the trans-corneal pressure difference which the trans-lamina cribrosa pressure difference is intraocular pressure orbital cerebrospinal fluid pressure) and the trans-lamina cribrosa pressure which is the pressure difference in to the distance between the intraocular intraocular pressure) and the retrobulbar the orbital cerebrospinal fluid It may show that in the orbital cerebrospinal fluid pressure because of a in the or in the pressure may have to be into account if an in intraocular pressure because of a or (Jonas It has remained the tissue pressure in the optic nerve additionally to the trans-lamina cribrosa the intraocular pressure et al. The trans-lamina cribrosa pressure the pressure difference and the distance between the intraocular and the retrobulbar fluid filled The distance between the of the lamina the thinning of the lamina cribrosa in highly myopic eyes may be of the why the glaucoma susceptibility is increased in highly myopic eyes (Jonas et al. 2004; Xu et al. 2007b). In addition, histomorphometric studies have shown that in nonhighly myopic eyes the lamina cribrosa in an of the This thinning of the lamina cribrosa may be of the why the risk for glaucoma progression in eyes with glaucoma is increased et al. 1994; et al. et al. 2001; The Study The trans-lamina cribrosa pressure difference the intraocular pressure and the retrobulbar cerebrospinal fluid It is elevated if the intraocular pressure is elevated if the cerebrospinal fluid pressure is than that a low cerebrospinal fluid pressure could be associated with glaucomatous optic neuropathy The had been by and & In a similar and that an abnormally low cerebrospinal fluid pressure the optic nerve may be the reason for a optic nerve in normal-pressure glaucoma et al. In an experimental decreased the pressure to the pressure by of the The intraocular pressure of was to pressure by of the anterior the optic nerve of the eyes in which intraocular pressure was showed of glaucomatous optic neuropathy. In in the eyes in which the intraocular pressure was The hypothesized that pressure have the as the intraocular pressure for the of glaucoma. and a of of a group of patients in a of for et al. patients with open-angle glaucoma and a group of found that the cerebrospinal fluid pressure was significantly higher in the patients than in patients with open-angle glaucoma In an larger of a similar and the of patients had a between and et al. subjects with primary open-angle glaucoma, subjects with glaucoma a of primary open-angle glaucoma, subjects with and subjects The cerebrospinal fluid pressure was significantly lower in the primary open-angle glaucoma than in the group that had glaucoma the subjects with glaucoma had a lower cerebrospinal fluid pressure than the subjects Furthermore, the cerebrospinal fluid pressure was higher in the group than in subjects In a recent the cerebrospinal fluid pressure was in patients with open-angle glaucoma with a normal intraocular pressure, and with an elevated intraocular pressure) and subjects of a group glaucoma et al. The cerebrospinal fluid pressure was significantly lower in the pressure glaucoma group than in the high-intraocular pressure glaucoma group or the group The trans-lamina cribrosa pressure difference was significantly higher in the pressure glaucoma group and the high-intraocular pressure glaucoma group than in the group In the of glaucomatous loss was with the cerebrospinal fluid pressure and with the trans-lamina cribrosa pressure In a the of glaucomatous loss was associated with the trans-lamina cribrosa pressure difference intraocular pressure and cerebrospinal fluid pressure as (and not as of the cribrosa pressure significantly associated with the In the cerebrospinal fluid pressure was significantly with blood pressure and intraocular pressure As the intraocular pressure showed a an association with blood pressure the trans-lamina cribrosa pressure difference was not significantly related with the blood The cerebrospinal fluid pressure intraocular pressure and trans-lamina cribrosa pressure difference decreased significantly with The cerebrospinal fluid pressure was significantly associated with the intraocular pressure In a the cerebrospinal fluid pressure was significantly higher in an group of patients than in the group The that in the the of glaucomatous loss was associated with the trans-lamina cribrosa pressure difference the intraocular pressure as was significantly associated with the the importance of a high trans-lamina cribrosa pressure difference for the and for the of glaucoma. a high trans-lamina cribrosa pressure difference is associated with glaucoma, may cerebrospinal fluid pressure, such as systemic may that such of a mmHg in the trans-lamina cribrosa pressure difference between the normal-pressure glaucoma group and the group may have a pronounced it with In the population-based Eye the prevalence of glaucoma was related to a in intraocular pressure of mmHg et al. In a similar the Study progression in subjects with all intraocular pressure subjects with an intraocular pressure a mmHg higher had a significantly higher risk for progression of glaucoma The Study revealed a when the intraocular pressure was a mmHg the to mmHg Study One may that the between the risk of glaucoma and intraocular pressure and the risk of glaucoma progression and intraocular pressure is so that a in intraocular pressure at higher a risk than a in intraocular pressure at lower One may that the Study and the Study with intraocular pressure and glaucoma progression which was not the of The may however, that in pressure can be In the the intraocular pressure showed a an association with the blood It several population-based studies in which the intraocular pressure was highly significantly with the arterial blood pressure et al. 2005; Xu et al. the cerebrospinal fluid pressure and the intraocular pressure with have been a between cerebrospinal fluid pressure and intraocular pressure in patients with an elevated cerebrospinal fluid pressure et al. 2004; et al. et al. It is however, the situation of an elevated pressure can a physiological between cerebrospinal fluid pressure and intraocular pressure normal The between all three pressure parameters, cerebrospinal fluid pressure, blood pressure and intraocular pressure may a systemic all three of It may explain why arterial associated with elevated intraocular pressure, was not associated with glaucoma in population-based One may that the in intraocular pressure was by the in cerebrospinal fluid pressure, so that the trans-lamina cribrosa pressure difference remained This assumption was by the of Ren and et al. in which the trans-lamina cribrosa pressure difference was not significantly related to blood The between the cerebrospinal fluid pressure and arterial blood pressure clinical that patients with normal-pressure glaucoma tend to have low blood pressure (Drance 1972; Drance et al. 1973; Hayreh et al. 1994; Broadway & Drance 1998; et al. Emre et al. 2004). It was the reason to postulate a vasogenic pathogenesis of normal-pressure glaucoma. however, a low blood pressure is associated with a low cerebrospinal fluid pressure, a in normal-pressure glaucoma with an elevated trans-lamina cribrosa pressure may In a the trans-lamina cribrosa pressure difference was not significantly associated with the arterial blood the trans-lamina cribrosa pressure difference the for optic nerve in glaucoma, the of an association between the trans-lamina cribrosa pressure difference and the systemic arterial blood pressure may that a vascular in the optic nerve head may play a primary role in the pathogenesis of glaucomatous optic nerve loss (Drance 1972; Drance et al. 1973; Hayreh et al. 1994; Broadway & Drance 1998; et al. Emre et al. 2004). are of the studies cerebrospinal fluid pressure in glaucoma. it has remained unclear the cerebrospinal fluid pressure is related to the cerebrospinal fluid pressure in the the optic One has to in that it is the difference between the tissue pressure and the intraocular pressure which the pressure difference the lamina In a recent patients with and that cerebrospinal fluid pressure to cerebrospinal fluid pressure in patients with cerebrospinal fluid with a of et al. A by and showed that the cerebrospinal fluid pressure at is at the as the when or was between and mmHg The patients had cerebrospinal fluid of mmHg in the The suggested that the cerebrospinal fluid pressure at by an of mmHg as a the to the or may have to take into account the difference between the pressure and the optic nerve pressure, which is to be by orbital may have to the difference between the optic nerve pressure and the tissue pressure which may be by the These have been in a recent by and et al. as for any hospital-based is a risk of by including patients may not be of the group of patients by the of the studies is the of the including patients in the for associated with an increased cerebrospinal fluid pressure the that of patients had had an abnormally high cerebrospinal fluid the of a low orbital cerebrospinal fluid pressure in the pathogenesis of pressure glaucoma may be that at a low cerebrospinal fluid pressure a low pressure in the fluid the retrobulbar optic the tissue pressure the optic nerve may be be so that a low cerebrospinal fluid pressure the tissue of the optic nerve may as a of the lamina cribrosa the intraocular in that are the studies by et al. found that the difference between the tissue pressure and the optic nerve was at mmHg and that the difference between the tissue pressure and the fluid pressure in the cerebrospinal fluid decreased with cerebrospinal fluid an optic nerve pressure of the tissue pressure was to the fluid pressure in the cerebrospinal fluid the cerebrospinal fluid to the optic nerve pressure may be to the tissue pressure in the optic nerve when in the or the cerebrospinal fluid pressure at (and the optic nerve pressure) may to so that the pressure difference the may that are similarities between the anatomy and physiology of and In addition, the may as as with or to factor may be the orbital tissue has to that the studies by and by Ren have to be considered to be primary In of the of a low cerebrospinal fluid pressure as of several for glaucomatous optic neuropathy, as and by Hayreh and et al. 1996; Hayreh and in of of a cerebrospinal fluid the optic nerve as by and et al. has to In into account (i) that it is the trans-lamina cribrosa pressure difference (and not the trans-corneal pressure difference, i.e. the so-called intraocular pressure) which is of importance for the physiology and pathophysiology of the optic (ii) that studies have shown that the anatomy of the optic nerve head the intraocular pressure, the anatomy and biomechanics of the lamina cribrosa and peripapillary sclera, the retrobulbar orbital cerebrospinal fluid pressure and the retrobulbar optic nerve tissue pressure) may be of importance for the pathogenesis of the highly myopic type of chronic open-angle glaucoma; (iii) that studies have suggested physiological between the pressure in all three fluid filled compartments, i.e. the systemic arterial blood pressure, the cerebrospinal fluid pressure and the intraocular pressure; (iv) that an experimental investigation suggested that a low cerebrospinal fluid pressure may play a role in the pathogenesis of normal (intraocular) pressure glaucoma, and (v) that clinical studies have reported that patients with normal (intraocular) pressure glaucoma had significantly lower cerebrospinal fluid pressure and a higher trans-lamina cribrosa pressure difference when compared to normal may that a low cerebrospinal fluid pressure may be associated with normal (intraocular) pressure glaucoma. A low systemic blood pressure, particularly at night, could physiologically be associated with a low cerebrospinal fluid pressure, which leads to an abnormally high trans-lamina cribrosa pressure difference and as such to a similar situation as if the cerebrospinal fluid pressure is normal and the intraocular pressure is elevated. This model could explain why patients with normal (intraocular) pressure glaucoma tend to have a low systemic blood pressure, and why eyes with normal (intraocular) pressure glaucoma and eyes with high-pressure glaucoma, in contrast to eyes with a direct vascular optic neuropathy, show profound similarities in the appearance of the optic nerve head.