Translaminar Pressure Gradient Research Articles

The Upright Body Position Increases Translaminar Pressure Gradient in Normotensive and Hypertensive Rats

ABSTRACTAim: Several lines of evidence suggest that the pathogenesis of glaucoma may depend on an increased translaminar pressure gradient (TPG), the difference between intraocular and intracranial pressure (ICP), rather than on intraocular pressure (IOP) itself. It has also been suggested that high blood pressure might correlate with the incidence of glaucoma; however, the data are contradictory. Here, we studied the effect of arterial blood pressure and changes in body position on TPG in rats.Methods: Experiments were performed on anesthetized 15- to 16-week-old, male, spontaneously hypertensive rats (hypertensive rats, n = 10) and Wistar–Kyoto rats (normotensive rats, n = 10). Continuous recordings of intracranial and IOPs were performed before, during, and after changing the body position from horizontal to vertical.Results: At baseline, hypertensive rats had a significantly higher arterial blood pressure than normotensive rats, while intraocular and intracerebroventricular pressures and TPG did not differ between the groups. Changing the body position from horizontal to vertical produced a significant decrease in ICP, a nonsignificant decrease in IOP, and a significant increase in the TPG. There was no significant difference between normotensive and hypertensive rats in the pattern of changes in intraocular and intracerebroventricular pressures and TPG.Conclusions: Change in the body position from horizontal to vertical, but not hypertension, causes a significant increase in TPG in rats. If further studies confirm that TPG plays a role in the etiology of glaucoma, a vertical position and changes in the body position might be considered as debilitating factors.

Current aspects on the management of normal tension glaucoma

In a considerable proportion of glaucoma patients (25-50 %) the intraocular pressure (IOP) is not elevated higher than 22 mmHg at first diagnosis and during subsequent follow-up controls. Although the IOP level remains in the low range < 22 mmHg, progression of glaucoma can still occur. A multitude of different factors are assumed to be involved in glaucoma progression, such as very low nocturnal diastolic blood pressure values, a low mean ocular perfusion pressure, extensive fluctuations in perfusion (e.g. in cases of vascular dysregulation), an increased vulnerability of the optic nerve support structures, an increased translaminar pressure gradient and various underlying systemic diseases. The most important evidence-based aspect of treatment in normal tension glaucoma is pharmaceutical or surgical reduction of the IOP by 30 % or more in comparison to the initial pressure level. Vascular and neuroprotective concepts of treatment for normal tension glaucoma have been strongly advocated and the object of experimental and clinical studies. As yet a clear clinical benefit has not been proven by large prospective randomized studies.

Influence of translaminar pressure dynamics on the position of the anterior lamina cribrosa surface.

To determine how the translaminar pressure difference (TLPD) and gradient (TLPG) influence the position of anterior lamina cribrosa (LC) surface. Twenty-six eyes of 26 healthy subjects were subjected to enhanced-depth imaging volume scanning of the optic nerve using spectral-domain optical coherence tomography (SD-OCT). The anterior LC surface depth (LCD) relative to the Bruch's membrane (BM) opening was measured at 11 equidistant planes, and the LC thickness (LCT) was measured at three locations (superior midperipheral, midhorizontal, and inferior midperipheral). Intraocular pressure and lumbar cerebrospinal fluid pressure (CSFP) were measured on the same day as the SD-OCT examination. The TLPD was defined as the difference between IOP and CSFP (i.e., IOP-CSFP), and the TLPG as the TLPD divided by LCT (i.e., TLPD/LCT). Subjects were aged 63.4 ± 8.0 years and comprised 12 males and 14 females. Regression analyses revealed a significant association between a larger mean LCD and male sex (P = 0.002), and between a larger central LCD and male sex (P ≤ 0.012), larger TLPD (P = 0.048), and higher TLPG (P = 0.029). There was no significant association between IOP, CSFP, and LCT, and either the mean LCD (P = 0.438, 0.368, and 0.416, respectively) or central LCD (P = 0.284, 0.085, and 0.144, respectively). A larger central LCD was associated with larger TLPD and higher TLPG in healthy eyes, which indicates that the translaminar pressure dynamics may play a role in the position of the anterior LC surface relative to BM opening in healthy human eyes.

Discussion of possible interaction mechanisms between high myopia and glaucoma

Myopia is known to be one of risk factors of glaucoma, but the possible interaction mechanism between high myopia and glaucoma is below understood.High myopia is found to have some similar pathological changes to glaucoma, such as peripapillary detachment in pathologic myopia (PDPM), pit-like structure, peripapillary atrophy (PPA), thin lamina cribrosa, etc.In addition, high myopic eyes have higher intraocular pressure.According to trans-laminar pressure gradient hypothesis, high myopic eyes have higher trans-laminar pressure gradients than emmetropic eyes, which may be one of possible interaction mechanisms.In the study on genetics, the relationship between myopia and glaucoma has not been clearly elucidated.Recent researches of possible interaction mechanisms between high myopia and glaucoma were summarized in this paper. Key words: Myopia; Glaucoma; Risk factors; Optic disc

Senile dementia and glaucoma: Evidence for a common link

Dementia and glaucoma are both neurodegenerative conditions characterized by neuronal loss leading to cognitive and visual dysfunction, respectively. A variety of evidence exists linking the two diseases including structural signs, specifically degenerative changes within ganglion cells. Both diseases become more prevalent with increased age, but that alone is unlikely to account for the increased co-prevalence of the diseases found in various studies. Neurotoxic substances including abnormal hyperphosphorylated tau and amyloid-β have been found in both disease processes suggesting possible pathophysiologic links between the diseases. The exact mechanism of apoptosis, whether by direct toxicity or potentiation, still needs to be established, but could prove important for both diseases. Another potential link relates to low intracranial pressure in patients with both diseases causing a high translaminar pressure gradient and optic nerve damage in certain patients. While this alone may not account for direct optic nerve damage, it could lead to cerebrospinal fluid (CSF) circulatory failure causing increased neurotoxins along the optic nerves with resultant damage. All of this evidence suggests the need to further study links between the two diseases, as this could prove instrumental in understanding their overlapping pathophysiology and developing directed therapies for both diseases. While this is more thoroughly investigated, it may be prudent to have a lower threshold for a glaucoma work-up in patients with pre-existing dementia.

Update in intracranial pressure evaluation methods and translaminar pressure gradient role in glaucoma.

Glaucoma is one of the leading causes of blindness worldwide. Historically, it has been considered an ocular disease primary caused by pathological intraocular pressure (IOP). Recently, researchers have emphasized intracranial pressure (ICP), as translaminar counter pressure against IOP may play a role in glaucoma development and progression. It remains controversial what is the best way to measure ICP in glaucoma. Currently, the 'gold standard' for ICP measurement is invasive measurement of the pressure in the cerebrospinal fluid via lumbar puncture or via implantation of the pressure sensor into the brains ventricle. However, the direct measurements of ICP are not without risk due to its invasiveness and potential risk of intracranial haemorrhage and infection. Therefore, invasive ICP measurements are prohibitive due to safety needs, especially in glaucoma patients. Several approaches have been proposed to estimate ICP non-invasively, including transcranial Doppler ultrasonography, tympanic membrane displacement, ophthalmodynamometry, measurement of optic nerve sheath diameter and two-depth transcranial Doppler technology. Special emphasis is put on the two-depth transcranial Doppler technology, which uses an ophthalmic artery as a natural ICP sensor. It is the only method which accurately and precisely measures absolute ICP values and may provide valuable information in glaucoma.

Pathogenesis and Treatment of Maculopathy Associated With Cavitary Optic Disc Anomalies

To propose a unifying theory regarding the pathogenesis of maculopathy associated with cavitary optic disc anomalies and to describe a rational approach to achieving a permanent cure in affected eyes. Interpretive essay. Review and synthesis of selected literature, with interpretation and perspective in relating pathoanatomic features to pathogenesis and treatment. Congenital cavitary anomalies of the optic disc, including typical coloboma, optic pit (and other atypical colobomas), morning glory anomaly, and extrapapillary cavitation, are associated with an enigmatic maculopathy characterized by schisis-like thickening and serous detachment. The unifying anatomic theme of these anomalies is the presence of a scleral (or lamina cribrosa) defect permitting anomalous communications between intraocular and extraocular spaces. These communications enable the critical pathogenic mechanism responsible for the maculopathy, namely, dynamic fluctuations in the gradient between intraocular and intracranial pressures that direct the movement of fluid (vitreous humor or cerebrospinal fluid) into and under the retina. Vitreous traction does not seem to play a significant pathogenic role. Permanent cure of the maculopathy requires either elimination of the translaminar pressure gradient or closure of the pathway for fluid flow into the retina. We advocate carefully titrated juxtapapillary laser photocoagulation followed by vitrectomy with gas tamponade for creation of a permanent intraretinal and subretinal fluid barrier. The peculiar features of cavitary optic disc maculopathy can be explained only by considering the pressure gradients that develop along anomalous communications between intraocular and extraocular spaces. A permanent cure for this condition can be achieved by closing the pathway for fluid migration from the cavitary lesion into and under the retina.

The difference in translaminar pressure gradient and neuroretinal rim area in glaucoma and healthy subjects.

Purpose. To assess differences in translaminar pressure gradient (TPG) and neuroretinal rim area (NRA) in patients with normal tension glaucoma (NTG), high tension glaucoma (HTG), and healthy controls. Methods. 27 patients with NTG, HTG, and healthy controls were included in the prospective pilot study (each group consisted of 9 patients). Intraocular pressure (IOP), intracranial pressure (ICP), and confocal laser scanning tomography were assessed. TPG was calculated as the difference of IOP minus ICP. ICP was measured using noninvasive two-depth transcranial Doppler device. The level of significance P < 0.05 was considered significant. Results. NTG patients had significantly lower IOP (13.7(1.6) mmHg), NRA (0.97(0.36) mm2), comparing with HTG and healthy subjects, P < 0.05. ICP was lower in NTG (7.4(2.7) mmHg), compared with HTG (8.9(1.9) mmHg) and healthy subjects (10.5(3.0) mmHg); however, the difference between groups was not statistically significant (P > 0.05). The difference between TPG for healthy (5.4(7.7) mmHg) and glaucomatous eyes (NTG 6.3(3.1) mmHg, HTG 15.7(7.7) mmHg) was statistically significant (P < 0.001). Higher TPG was correlated with decreased NRA (r = −0.83; P = 0.01) in the NTG group. Conclusion. Translaminar pressure gradient was higher in glaucoma patients. Reduction of NRA was related to higher TPG in NTG patients. Further prospective studies are warranted to investigate the involvement of TPG in glaucoma management.

Central Venous Pulsations

The translaminar pressure gradient (TLPG) is largely influenced by the difference between intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFP), but modulated by the buffering effect of orbital tissue and pia mater, which limits the reduction in retrolaminar tissue pressure as intracranial CSFP falls below 0 mm Hg. Across the lamina cribrosa, the central retinal vein experiences the greatest pressure gradient (TLPG) of any vein in the body. When CSFP rises, the minimum IOP required to induce venous pulsation pressure (VPP) rises with CSFP (r=0.95, slope=0.90). Lowering IOP in glaucoma patients leads to a reduction in VPP (P=0.0003). The normal human central retinal vein endothelial cells in the lamina region resemble typical arterial endothelia and are quite unlike other venous cells. It is likely that the TLPG is increasing retinal vein shear and in glaucoma this effect is likely to be increased with possible wall effects.

The translaminar pressure gradient in sustained zero gravity, idiopathic intracranial hypertension, and glaucoma

Papilledema has long been associated with elevated intracranial pressure. Classically, tumors, idiopathic intracranial hypertension, and obstructive hydrocephalus have led to an increase in intracranial pressure causing optic nerve head edema and observable optic nerve swelling. Recent reports describe astronauts returning from prolonged space flight on the International Space Station with papilledema (Mader et al., 2011) [1]. Papilledema has not been observed in shorter duration space flight. Other recent work has shown that the difference in intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFp) may be very important in the pathogenesis of diseases of the optic nerve, especially glaucoma (Berdahl and Allingham, 2009; Berdahl, Allingham, et al., 2008; Berdahl et al., 2008; Ren et al., 2009; Ren et al., 2011) [2–6]. The difference in IOP and CSFp across the lamina cribrosa is known as the translaminar pressure difference (TLPD).We hypothesize that in zero gravity, CSF no longer pools in the caudal spinal column as it does in the upright position on earth. Instead, CSF diffuses throughout the subarachnoid space resulting in a moderate but persistently elevated cranial CSF pressure, including the region just posterior to the lamina cribrosa known as the optic nerve subarachnoid space (ONSAS). This small but chronically elevated CSFp could lead to papilledema when CSFp is greater than the IOP. If the TLPD is the cause of optic nerve head edema in astronauts subjected to prolonged zero gravity, raising IOP and/or orbital pressure may treat this condition and protect astronauts in future space travels from the effect of zero gravity on the optic nerve head. Additionally, the same TLPD concept may offer a deeper understanding of the pathogenesis and treatment options of idiopathic intracranial hypertension (IIH), glaucoma and other diseases of the optic nerve head.

Intraocular pressure correlates with optic nerve sheath diameter in patients with normal tension glaucoma

1. Identify differences in optic nerve sheath diameter (ONSD) as an indirect measure of intracranial pressure (ICP) in glaucoma patients and a healthy population. 2. Identify variables that may correlate with ONSD in primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) patients. Patients with NTG (n = 46) and POAG (n = 61), and healthy controls (n = 42) underwent B-scan ultrasound measurement of ONSD by an observer masked to the patient diagnosis. Intraocular pressure (IOP) was measured in all groups, with additional central corneal thickness (CCT) and visual field defect measurements in glaucomatous patients. Only one eye per patient was selected. Kruskal-Wallis or Mann-Whitney were used to compare the different variables between the diagnostic groups. Spearman correlations were used to explore relationships among these variables. ONSD was not significantly different between healthy, NTG and POAG patients (6.09 ± 0.78, 6.03 ± 0.69, and 5.71 ± 0.83 respectively; p = 0.08). Visual field damage and CCT were not correlated with ONSD in either of the glaucoma groups (POAG, p = 0.31 and 0.44; NTG, p = 0.48 and 0.90 respectively). However, ONSD did correlate with IOP in NTG patients (r = 0.53, p < 0.001), while it did not in POAG patients and healthy controls (p = 0.86, p = 0.46 respectively). Patient's age did not relate to ONSD in any of the groups (p > 0.25 in all groups). Indirect measurements of ICP by ultrasound assessment of the ONSD may provide further insights into the retrolaminar pressure component in glaucoma. The correlation of ONSD with IOP solely in NTG patients suggests that the translaminar pressure gradient may be of particular importance in this type of glaucoma.

Shape Analysis of the Peripapillary RPE Layer in Papilledema and Ischemic Optic Neuropathy

Geometric morphometrics (GM) was used to analyze the shape of the peripapillary retinal pigment epithelium-Bruch's membrane (RPE/BM) layer imaged on the SD-OCT 5-line raster in normal subjects and in patients with papilledema and ischemic optic neuropathy. Three groups of subjects were compared: 30 normals, 20 with anterior ischemic optic neuropathy (AION), and 25 with papilledema and intracranial hypertension. Twenty equidistant semilandmarks were digitized on OCT images of the RPE/BM layer spanning 2500 μm on each side of the neural canal opening (NCO). The data were analyzed using standard GM techniques, including a generalized least-squares Procrustes superimposition, principal component analysis, thin-plate spline (to visualize deformations), and permutation statistical analysis to evaluate differences in shape variables. The RPE/BM layer in normals and AION have a characteristic V shape pointing away from the vitreous; the RPE/BM layer in papilledema has an inverted U shape, skewed nasally inward toward the vitreous. The differences were statistically significant. There was no significant difference in shapes between normals and AION. Pre- and posttreatment OCTs, in select cases of papilledema, showed that the inverted U-shaped RPE/BM moved posteriorly into a normal V shape as the papilledema resolved with weight loss or shunting. The shape difference in papilledema, absent in AION, cannot be explained by disc edema alone. The difference is a consequence of both the translaminar pressure gradient and the material properties of the peripapillary sclera. GM offers a novel way of statistically assessing shape differences of the peripapillary optic nerve head.

A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma

This article is dedicated to Rosario Hernandez for her warm support of my own work and her genuine enthusiasm for the work of her colleagues throughout her career. I first met Rosario as a research fellow in Harry Quigley’s laboratory between 1991 and 1993. Along with Harry, John Morrison, Elaine Johnson, Abe Clark, Colm O’Brien and many others, Rosario’s work has provided lamina cribrosa astrocyte cellular mechanisms that are biomechanically plausible and in so doing provided credibility to early notions of the optic nerve head (ONH) as a biomechanical structure. We owe a large intellectual debt to Rosario for her dogged persistence in the characterization of the ONH astrocyte and lamina cribrosacyte in age and disease. Two questions run through her work and remain of central importance today. First, how do astrocytes respond to and alter the biomechanical environment of the ONH and the physiologic stresses created therein? Second, how do these physiologic demands on the astrocyte influence their ability to deliver the support to retinal ganglion cell axon transport and flow against the translaminar pressure gradient? The purpose of this article is to summarize what is known about the biomechanical determinants of retinal ganglion cell axon physiology within the ONH in the optic neuropathy of aging and Glaucoma. My goal is to provide a biomechanical framework for this discussion. This framework assumes that the ONH astrocytes and glia fundamentally support and influence both the lamina cribrosa extracellular matrix and retinal ganglion cell axon physiology. Rosario Hernandez was one of the first investigators to recognize the implications of this unique circumstance. Many of the ideas contained herein have been initially presented within or derived from her work (Hernandez, M.R., 2000. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 19, 297–321.; Hernandez, M.R., Pena, J.D., 1997. The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 115, 389–395.).

Histomorphometric measurements in human and dog optic nerve and an estimation of optic nerve pressure gradients in human

Intraocular pressure and cerebrospinal fluid (CSF) pressure are important determinants of the trans-laminar pressure gradient which is believed to be important in the pathogenesis of glaucomatous optic nerve degeneration. Computational models and finite element calculations of optic nerve head biomechanics have been previously used to predict pressures and stresses in the human optic nerve. The purpose of this report is to morphometrically compare the optic nerve laminar and pia mater structure between humans and dogs, and to use previously reported tissue pressure measurements in the dog optic nerve to estimate individual-specific human optic nerve pressures and pressure gradients. High resolution light microscopy was used to acquire quantitative histological measurements from sagittal sections taken from the middle of the optic nerve in 34 human cadaveric eyes and 10 dog eyes. Parameters measured included the pre-laminar and lamina cribrosa thickness, distance from posterior boundary of lamina cribrosa to inner limiting membrane (ILM), shortest distance between anterior lamina cribrosa surface and subarachnoid space, shortest distance between ILM and inner surface of pia mater in contact with the subarachnoid space and optic nerve diameter. Pia mater thickness in the proximal 4 mm of post-laminar nerve was also determined. There was no significant difference in lamina cribrosa thickness between dog and human eyes (P = 0.356). The distance between the intraocular and subarachnoid space was greater in dogs (P < 0.001). Pia mater thickness was greatest at the termination of subarachnoid space in both species. In humans, pia mater thickness decreased over the proximal 500 μm to reach a constant value of approximately 60 μm. In dogs this decrease occurred over 1000 μm to reach a constant diameter of approximately 30 μm. Using previous measurements of optic nerve pressures and pressure gradients in dogs we estimate that at an IOP of 15 mmHg and a CSF pressure of 0 mmHg the mean pressure difference across the human pia mater will be 4.8 ± 2.2 mmHg. If we assume that the pressure difference between the intraocular space and post-laminar tissue falls across the entire thickness of the human lamina cribrosa then an estimate of the trans-laminar pressure gradient is 2.0 ± 0.8 mmHg/100 μm. If we assume that this pressure difference only occurs across the dense collagenous plates of the posterior lamina cribrosa then a trans-laminar pressure gradient high estimate of 3.3 ± 1.4 mmHg/100 μm is calculated. Changes in tissue pressure gradients in the optic nerve may be an important factor in the pathogenesis of glaucomatous optic neuropathy.

The Role of Cerebrospinal Fluid Pressure in Glaucoma Pathophysiology: The Dark Side of the Optic Disc

It is generally accepted that glaucoma occurs when intraocular pressure (IOP) is raised above atmospheric pressure beyond tolerable limits for the optic disc. However, the other, unseen side of the optic disc is not air but a set of pressure compartments dominated by the cerebrospinal fluid (CSF) within the subarachnoid space. This invisibility has made investigation difficult; however, in recent decades there has been increased interest in this corollary to IOP. We briefly review the anatomy of the optic nerve subarachnoid space and its pressure relationships to intracranial, retrolaminar, and orbital tissue pressures. The CSF pressure is equivalent to IOP in its influence on translaminar pressure gradient and optic disk surface movement. At low CSF pressure, its influence on retrolaminar tissue pressure is reduced tending to minimize an increase in translaminar pressure gradient. The available evidence suggests that orbital tissue pressure provides this moderating influence. CSF pressure affects axonal transport, which is known to be important in glaucoma etiology and retinal venous outflow and pressures. Recent attempts to develop noninvasive measurement of CSF pressure have increased our knowledge of retinal venous changes in glaucoma. Further work in this area is likely to greatly increase our understanding of glaucoma.

Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes.

To evaluate the spatial relationships of the intraocular space, the cerebrospinal fluid space, and the lamina cribrosa in highly myopic eyes. The study included 36 human globes with an axial length of more than 26.5 mm that showed marked glaucomatous optic nerve damage (n = 29; highly myopic glaucomatous group) or in which the optic nerve was affected by neither glaucoma nor any other disease (n = 7; highly myopic normal group). Two non-highly myopic control groups included 53 globes enucleated because of malignant choroidal melanoma (n = 42; non-highly myopic normal group) or because of painful absolute secondary angle-closure glaucoma (n = 11; non-highly myopic glaucomatous group). Anterior-posterior histologic sections through the pupil and the optic disc were morphometrically evaluated. In both highly myopic groups compared with both non-highly myopic groups and in the highly myopic glaucomatous group compared with the highly myopic normal group, the lamina cribrosa was significantly (P < 0.001) thinner. Correspondingly, the distance between the intraocular space and the cerebrospinal fluid space was significantly (P < 0.05) shorter in the highly myopic normal group than in the non-highly myopic normal group and in the highly myopic glaucomatous group than in the highly myopic normal group. In highly myopic eyes, the lamina cribrosa is significantly thinner than in non-highly myopic eyes, which decreases the distance between the intraocular space and the cerebrospinal fluid space and steepens the translaminar pressure gradient at a given intraocular pressure, which may explain the increased susceptibility to glaucoma in highly myopic eyes. As in non-highly myopic eyes, thinning of the lamina cribrosa gets more pronounced in highly myopic eyes if glaucoma is also present.