The main structural feature of optic neuropathy in primary open-angle glaucoma (POAG) is cupping of the optic nerve head due to thinning of the neuroretinal rim and retinal nerve fiber layer.1 Elevated intraocular pressure (IOP) has long being considered to be the major risk factor for the development and progression of glaucomatous damage.2 However, because many patients have normal IOP measurements at all times,3 additional factors in the pathogenesis of optic nerve damage have been postulated. One of these is vascular insufficiency at the optic nerve head,4 but this, however, does not explain why patients with a typical vascular optic neuropathy, such as after central vein occlusion or non-arteritic anterior ischemic optic neuropathy, do not develop typical glaucomatous optic nerve head features, such as cupping and enlargement of parapapillary atrophy.5,6
In the 1970s, Volkov pointed out that cerebrospinal fluid pressure (CSFP) could pathogenically be associated with glaucomatous optic neuropathy.7 Similarly, Yablonski, Ritch and Pokorny showed that in cats with decreased CSFP, eyes with normal IOP developed signs of glaucomatous optic nerve damage, while eyes with additionally lowered IOP showed a normal optic nerve at study end.8 Thirty years after that experimental study, Berdahl et al found in a retrospective chart analysis study9,10 and Ren et al reported in a prospective study11–13 that the CSFP as measured by lumbar puncture was significantly lower in patients with normal-tension glaucoma (NTG) than in control subjects. In an independent third study, Jaggi et al confirmed these findings.14
To further corroborate the results of these studies, we performed a meta-analysis of the data published in Jaggi’s study and of the data obtained in Ren’s study, which included 14 patients with NTG. Jaggi’s study contained single CSFP measurement values of 11 of 18 patients with NTG (Table 1). The study population was stratified into 4 groups according to the CSFP values. In none of the patients was CSFP more than 14.7 mm Hg (200 mm H2O), while the majority of the patients in both studies had a CSFP from 5.9 mm Hg to 11.0 mm Hg (Table 1). Although the mean CSFP was significantly (P<0.001) lower in the study group than in the control group (in Ren’s study: 9.5±2.2 mm Hg vs. 12.9±1.9 mm Hg), there was a marked overlap between both groups, with the values in the control group ranging from 7.0 to 16.9 mm Hg.11 The question therefore arises, whether all subjects with low CSFP are at risk of developing glaucomatous optic neuropathy, or whether the CSFP may just be a concomitant parameter in POAG. In that context, one may consider that the optic nerve subarachnoid space CSFP (or orbital CSFP) is one component of the equation that describes the trans-lamina cribrosa pressure difference and gradient, which may be important for glaucomatous optic nerve damage. Other parts of the equation are the IOP and the distance between the intraocular compartment and the retrobulbar compartment (including the thickness of the lamina cribrosa). Additional parameters which may also play a role in the pathogenesis of glaucomatous optic nerve damage are the biomechanical properties of the optic nerve head tissues,15 the thickness and anatomy of the peripapillary region,16 compartmentalization of the orbital CSF space,17 and others.18
From the mechanical point of view, increased trans-lamina cribrosa pressure (TLCP) difference may be important in the process of glaucomatous optic disc deformation. Ren et al found that the TLCP difference was significantly correlated with neuroretinal rim area (P=0.006; correlation coefficient r=−0.38) and mean visual field defect (P=0.008; r=0.38); moreover, the correlation coefficients were higher for the associations between rim area/visual field defect with TLCP than for the associations between rim area/visual field defect and IOP or lumbar CSFP alone.13 Berdahl et al also described that TLCP difference was significantly correlated with cup-to-disk (C/D) ratio (P<0.0001; r=0.34).9 These results suggest that TLCP difference may play a stronger role in the pathogenesis of POAG than IOP or CSFP alone.
In a second study, we addressed the question whether the lumbar measurements of the CSFP correlated with the orbital CSFP, and whether there was a relationship between the lumbar CSFP, CSFP in the cerebral ventricles, and the orbital CSFP. In dogs, the orbital CSFP was lower than the lumbar CSFP. If the TLCP difference was calculated as difference of IOP minus orbital CSFP (instead of lumbar CSFP as in the previous studies), the TLCP difference was about 2 mm Hg higher than previously thought. These results suggest that the TLCP difference is underestimated if the lumbar CSFP values are used instead of orbital CSFP.
Since direct measurement of the orbital CSFP is invasive and not feasible in practice, we explored the possibility of using a surrogate for the orbital CSFP. We measured the optic nerve subarachnoid space width by magnetic resonance imaging (by 3.0 T MRI) and compared POAG patients with normal IOP or with elevated IOP and healthy subjects. We found that the optic nerve subarachnoid space width was significantly smaller in POAG patients with normal IOP. Since the width of the optic nerve subarachnoid space correlates with the CSFP,19 the results suggested that indeed the TLCP difference was higher in POAG patients with normal IOP than in healthy subjects.
Many questions remain. These include: (1) the physiologic production, turn-over and resorption of the CSF; (2) the physiologic variation in the CSFP and the factors associated with it; (3) how to measure the CSFP (including techniques though the inner ear using stapedius reflex or tympanometry, including ophthalmodynamometry, and including a continuous monitoring of the CSFP through an indwelling intrathecal pressure sensitive catheter) and more specifically, how to measure orbital CSFP (using optic nerve subarachnoid space width as a surrogate for example); (4) the dynamics of the CSFP and its relationship with the ocular pulse; (5) the potential involvement of the CSFP in non-glaucomatous ocular disorders, such as retinal vein occlusion, hypertensive retinopathy, diabetic retinopathy and others; (6) the medical treatment of elevated or decreased CSFP (e.g. carbonic anhydrase inhibitors); (7) surgical techniques to increase an abnormally low CSFP; (8) treatment algorithms to elevate blood pressure and CSFP; (9) whether glaucoma is a dysregulation between IOP, blood pressure, and CSFP; and (10) whether diseases other than NTG may be connected with abnormally low or high CSFP.
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