This brief article summarizes the influence of cerebrospinal fluid pressure (CSFP) on the retrolaminar tissue pressure, translaminar pressure gradient (TLPG), and central retinal vein. We also discuss the influence of CSFP upon central retinal vein flow and how it may be associated with glaucoma.
The typical dog TLPG with intraocular pressure (IOP) 15 mm Hg and CSFP 0 mm Hg is 25 mm Hg/mm with a retrolaminar tissue pressure of 4 mm Hg.1 The TLPG is largely influenced by the difference between IOP and CSFP, but modulated by a buffering effect thought to be due to orbital tissue and pia mater, which limits the reduction in retrolaminar tissue pressure as intracranial CSFP falls below 0 mm Hg (Fig. 1). The magnitude of the TLPG is set by the IOP and retrolaminar tissue pressure with the laminar thickness determining the distance across which the pressure drop falls and hence affects the gradient also. The normal human CSFP is from −10 to 0 mm Hg in the sitting or standing posture, so these effects are likely to be relevant to normal human physiology.2 Using measurements of normal human lamina and pia mater thickness, we have calculated the likely retrolaminar tissue pressure to be 4.5 mm Hg and the TLPG to be 20 mm Hg/mm if it occurs evenly across the glial and collagenous lamina cribrosa or 33 mm Hg/mm if it occurs across the collagenous lamina only. Rapid axonal transport is inhibited at gradients of 45 mm Hg3 and the central retinal vein central retinal vein (CRV) passes through this region and is subject to the same gradients.
Accordingly, the CRV experiences the greatest pressure gradient of any vein in the body, with capillary gradients of 6 mm Hg/mm and venular gradients of 1.5 mm Hg/mm elsewhere being reported.4 The CRV pressure gradient is thought to spread beyond the lamina confines and into the intraocular region, where sub-zero transmural pressures promote intermittent collapse and pulsation.2 A minimum gradient of 5 to 10 mm Hg is required for retinal vein pulsations to occur at normal IOP.5,6 When CSFP rises, the minimum IOP required to induce venous pulsation pressure (VPP) rises with CSFP (r=0.95, slope=0.90).7,8
We thought that if glaucoma patients tended to have a lower CSFP, then they would tend to have a lower VPP. However our early results demonstrated that the opposite was true (normal=11.4±0.7, n=10, vs. glaucoma=14.4±1.0 mm Hg, n=16, P=0.03).7 We explored this conundrum further using ophthalmodynamometry to add pressure to IOP until VPP was reached. We found that absent spontaneous venous pulsation, and hence elevated VPP, was found in 46% of glaucoma patients compared to 2% of normals. Additionally, VPP was associated with glaucoma severity (mean deviation, r=0.48, P=0.003),7,9 and that elevated VPP was strongly associated with future glaucomatous disc progression over 7 years (P=0.004, Fig. 2).10,11 The same work demonstrated that patients with spontaneous venous pulsations had 14% risk of progression compared to those without spontaneous pulsation (28%). Modeling work indicates that the glaucomatous effect upon the retinal veins is likely due to increased flow resistance along the vein in the lamina region.12 This acts to limit the pressure gradient to the higher resistance region requiring a greater gradient to induce negative transmural pressures and collapse. The gradient can be increased by increasing IOP or lowering CSFP, allowing for the above-mentioned buffering effects.
The normal human CRV endothelial cells in the scleral lamina region resemble typical arterial endothelial cells and are quite unlike other venous cells. Their length to width ratios average 12.3, compared to 6.6 (P=0.0002) for the other venous segments and were insignificantly different to the central retinal arterial endothelia ratios of 11.1.13 It is likely that the TLPG increases retinal vein shear stresses within the scleral lamina region and in glaucoma this effect is likely to be increased with possible venous wall effects. This data suggests that the calculation of 33 mm Hg/mm TLPG down the scleral lamina cribrosa is probably closer to the true situation than 20 mm Hg/mm. Therefore, we suspect that with time, in glaucoma, a venous wall thickening in response to the higher shear occur and that this may be a marker of increased disease activity or nerve vulnerability. Another possible explanation to account for the venous resistance is that lamina cribrosa expansion in early glaucomatous monkeys is seen.14 Such laminar swelling may occur in active glaucoma and represent an extrinsic cause of venous compression.
Hence, glaucoma induces non-CSFP effects upon VPP most likely due to a gradual increase in CRV resistance. This may be implicated in CRV occlusions, shunt vessels and disc hemorrhages, which all occur in glaucoma. Our knowledge regarding CRV flow is limited. Recently we found in a number of glaucoma and normal subjects that CRV pulsation occurs with the collapse part of the phase in time with IOP diastole, not systole as had widely been assumed.15 This raises the possibility that CSFP diastole is driving the collapse part of the venous pulsation cycle.
At present the target IOP required to minimize glaucoma progression varies between individuals and its appropriate selection is only found in retrospect after disease progression or stability has been noted several years later. VPP is the first quantifiable test that indicates likelihood of glaucoma progression. These results also strongly suggest that glaucoma has fundamental effects upon venous flow and resistance. Further work to increase our understanding of the vascular etiology of glaucoma may lead to new treatment methods. Our understanding and capacity to measure CSFP needs to be improved.
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