Trans-lamina Cribrosa Pressure Difference Research Articles

“Dual‐pressure theory” in pathogenesis of glaucomatous optic neuropathy from the Beijing intracranial and intraocular pressure study

AbstractThe mechanical theory of glaucoma indicates that high intraocular pressure (IOP) leads to glaucomatous optic nerve damage. However, nearly half of primary open‐angle glaucoma patients with normal intraocular pressure also exhibit progression of what appears to be glaucomatous optic nerve damage. Our earlier prospective study identified for the first time that the relatively low intracranial pressure (ICP) is also an important risk factor for progressive glaucomatous injury of normal‐tension glaucoma. When considering the results of studies in nonhuman primates, clinical research, large‐scale natural‐population studies, and basic laboratory investigations, a new understanding of the pathophysiology of glaucoma, the “Dual‐Pressure Theory”, has been proposed. This theory states that “either high IOP or low ICP contributes to increasing the translaminar cribrosa pressure difference; it is the pressure difference rather than the IOP alone that results in the glaucomatous optic neuropathy”. Here, we provide a systematic introduction to Dual‐Pressure Theory relating to glaucoma, the form of a research map, an outline of basic laboratory investigations, the main methodology, and research updates.

Determination of the Trans-Lamina Cribrosa Pressure Difference in a Community-Based Population and its Association with Open-Angle Glaucoma

To determine the trans-lamina cribrosa pressure difference (TLCPD) in a cohort of normal community-based patients and the relationship to primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). Retrospective cohort study of the Mayo Clinic Study of Aging. The Mayo Clinic Study of Aging is a prospective study evaluating the normal aging population. Mayo Clinic Study of Aging patients who underwent routine lumbar puncture (LP) studies with eye examinations were reviewed. The trans-lamina cribrosa pressure difference was calculated in 2 contexts of intraocular pressure (IOP): (1) maximum IOP at eye visit closest in time to the LP (closest-in-time TLCPD); and (2) IOP before IOP-lowering treatment (pretreatment IOP and pretreatment TLCPD) in POAG and NTG patients. Glaucoma patients without POAG or NTG were excluded. Regression analyses were performed to determine the relationship with glaucoma. IOP, intracranial pressure, TLCPD, POAG, normal-tension glaucoma (NTG) diagnosis, glaucoma parameters. Five hundred forty-eight patients were analyzed. Of these, there were 38 treated glaucoma patients (14 POAG and 24 NTG) and 510 nonglaucomatous patients. Cerebral spinal fluid (CSF) opening pressure was 155.0 ± 42.2 mmH2O in nonglaucomatous patients, 144.0 ± 34.0 mmH2O in POAG (P= 0.15 vs. nonglaucomatous patients), and 136.6 ± 29.3 mmH2O in NTG (P= 0.017 vs. nonglaucomatous patients). Intraocular pressure was 15.47 ± 2.9 mmHg in nonglaucomatous patients, 26.6 ± 3.7 mmHg in POAG, and 17.4 ± 3.4 mmHg in NTG. The closest-in-time TLCPD in the nonglaucomatous cohort was 4.07 ± 4.22 mmHg, which was lower than both the POAG cohort (7.19 ± 3.6 mmHg) and the NTG cohort (5.79 ± 4.5 mmHg, P= 0.04). Pretreatment TLCPD for the overall glaucoma cohort was 10.57 ± 6.1 mmHg. The POAG cohort had a higher pretreatment TLCPD (16.05 ± 5.2 mmHg) than the NTG cohort (7.37 ± 4.1 mmHg; P < 0.0001). Closest-in-time TLCPD for the nonglaucoma cohort (4.07± 4.2 mmHg) was significantly lower than pretreatment TLCPDs for both POAG (16.05 ± 5.2 mmHg; P < 0.0001) and NTG (7.37 ± 4.1 mmHg; P < 0.0001) cohorts. This study establishes the baseline TLCPD in a large cohort of normal, community-based patients. The differences in regression analysis between TLCPD and IOP suggests NTG pathophysiology is partially driven by TLCPD, but is also likely multifactorial. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cerebrospinal Fluid Pressure Reduction Induces Glia-Mediated Retinal Inflammation and Leads to Retinal Ganglion Cell Injury in Rats.

Low intracranial pressure (LICP)-induced translaminar cribrosa pressure difference (TLCPD) elevation has been proven as a risk factor in glaucomatous neurodegeneration, whereas the underlying retinal immune features of LICP-induced retinal ganglion cells (RGC) injury remain elusive. Here, we identified the retinal immune characteristics of LICP rats, and minocycline (Mino) treatment was utilized to analyze its inhibitory role in glia-mediated retinal inflammation of LICP rats. The results showed that retrograde axonal transport was decreased in LICP rats without significant RGC loss, indicating the RGC injury was at an early stage before the morphological loss. The activation of retinal microglia and astrocytes with morphologic and M1 or A1-marker alternations was detected in TLCPD elevation rats, the activation level is more dramatic in HIOP rats than in the LICP rats (P<0.05). Besides, we detected reduced retinal tight junction protein expressions, accompanied by specific imbalance patterns of T lymphocytes in the retina of both LICP and HIOP rats (P<0.05). Further Mino treatment showed an effective inhibitory role in glia-driven inflammatory responses in LICP rats, including improving retrograde axonal transport, inhibiting retinal glial activation and proinflammatory subtype polarization, and alleviating the blood-retina barrier compromise. This study identified the glia-mediated retinal inflammation features triggered by LICP stimulus, and Mino application exhibited an effective role in the inhibition of retinal glia-mediated inflammation in LICP-induced TLCPD elevation rats.

Reference values for trans-laminar cribrosa pressure difference and its association with systemic biometric factors.

To provide reference values of trans-laminar cribrosa pressure difference (TLCPD) and reveal the association of TLCPD with systemic biometric factors. In this cross-sectional study, 526 quasi-healthy subjects (including 776 eyes) who required lumbar puncture for medical reasons were selected from 4915 neurology inpatients from 2019 to 2022. Patients with any diseases affecting intraocular pressure (IOP) or intracranial pressure (ICP) were excluded. The ICPs of all subjects were obtained by lumbar puncture in the left lateral decubitus position. IOP was measured in the seated position by a handheld iCare tonometer prior to lumbar puncture. TLCPD was calculated by subtracting ICP from IOP. Systemic biometric factors were assessed within 1 h prior to TLCPD measurement. The TLCPD (mean ± standard deviation) was 4.4 ± 3.6 mmHg, and the 95% reference interval (defined as the 2.5th-97.5th percentiles) of TLCPD was -2.27 to 11.94 mmHg. The 95% reference intervals for IOP and ICP were 10-21 and 6.25-15.44 mmHg, respectively. IOP was correlated with ICP (r = 0.126, p < 0.001). TLCPD was significantly negatively correlated with body mass index (r = -0.086, p = 0.049), whereas it was not associated with age, gender, height, weight, blood pressure, pulse, or waist and hip circumference. This study provides reference values of TLCPD and establishes clinically applicable reference intervals for normal TLCPD. Based on association analysis, TLCPD is higher in people with lower BMI.

Approach to glaucoma diagnosis and prediction based on multiparameter neural network.

To investigate the effect of comprehensive factor analysis on the relationship between glaucoma assessment and combined parameters including trans-laminar cribrosa pressure difference (TLCPD) and fractional pressure reserve (FPR). The clinical data of 1029 patients with 15 indicators from the medical records of Beijing Tongren Hospital and 600 cases with 1322 indicators from Beijing Eye Research were collected. The doc2vec method was used to vectorize. The multivariate imputation by chained equations (MICE) method was used to interpolate. The original data combined with TLCPD, combined with FPR, and not combined parameters were respectively applied to train the neural network based on VGG16 and autoencoder to predict glaucoma and to evaluate the effect of combined parameters. The accuracy rates used to classify the glaucoma of the two sets reach over 0.90, and the precision rates reach 0.70 and 0.80 respectively. After using TLCPD and FPR for the autoencoder method, the accuracy rates are both close to 1.0, and the precision rates are 0.90 and 0.70 respectively. Using the combined parameters of FPR and TLCPD can effectively improve the diagnosis and prediction of glaucoma. Compared with TLCPD, FPR is more suitable for improving the effect of neural network for glaucoma classification.

Pressure Related Ocular Parameters in Caucasian Patients with Primary Open-Angle Glaucoma

Objectives: To investigate pressure related ocular parameters (intraocular pressure (IOP), estimated trans-lamina cribrosa pressure difference (TLPD) and ocular perfusion pressure (OPP) in Caucasian patients with primary open angle glaucoma (POAG) and control subjects. Methods: This is an observational cross-section study that included 57 subjects (27 patients with open-angle glaucoma and 30 healthy control subjects). All subjects underwent ophthalmic and systemic measurements in order to evaluate pressure related ocular parameters – IOP (mmHg), OPP (mmHg), and TLPD (mmHg) based on established formulas. The differences in the IOP, OPP and TLPD values between patients with POAG and control subjects were evaluated. Results: Intraocular pressure and TLPD were significantly higher in patients with glaucoma (mean IOP= 18.93 ± 4.53 mmHg; TLPD= 9.47 ± 5.02 mmHg), than in control subjects (IOP= 16.47 ± 2.60 mmHg; TLPD= 6.82 ± 3.60 mmHg) (p=0.017 and p=0.025 respectively). In univariate logistic progression, IOP and TLPD were significant predictors for POAG. Conclusion: Our results suggest that in addition to IOP, TLPD is also significantly higher in Caucasian patients with POAG than in control subjects and both parameters are significant predictors of POAG. This suggests that TLPD may have a role in the pathogenesis of POAG.

Correlation between ocular perfusion pressure and estimated translamina cribrosa pressure difference in healthy young adults

Introduction and Aim: Glaucoma is a chronic optic neuropathy which is the leading cause of irreversible blindness across the globe. It is known that Intraocular pressure is responsible for these altered changes but recent experimental and clinical studies have reported that cerebrospinal fluid pressure (CSFP) and trans-lamina cribrosa pressure difference (TLCPD), may be an important cause of glaucomatous optic nerve damage, especially in subjects with normal-tension glaucoma. To assess the correlation between ocular perfusion pressure (OPP) and TLCPD in healthy young adults.&#x0D; Materials and Methods: One hundred healthy young adult volunteers comprising of 50 obese (25 males and 25 females) and 50 non-obese (25 males and 25 females) in the age group of 18-19 years among MBBS Phase I students of JSS Medical College, JSSU, Mysore were the subjects for the study. Blood Pressure and Intra Ocular Pressure were recorded. Mean arterial pressure (MAP), OPP, CSFPand TLCPD were calculated.&#x0D; Results: There exists a positive correlation (0.50) between OPP and TLCPD. There was a statistically significant difference in OPP, CSFP and TLCPD between obese and non-obese groups.&#x0D; Conclusion: The present study provides information on the relationship of TLCPD with CSFP and OPP that are higher in obese individuals.&#x0D;

Finite element analysis of trans-lamina cribrosa pressure difference on optic nerve head biomechanics: the Beijing Intracranial and Intraocular Pressure Study.

The present study aims to assess the potential difference of biomechanical response of the optic nerve head to the same level of trans-lamina cribrosa pressure difference (TLCPD) induced by a reduced cerebrospinal fluid pressure (CSFP) or an elevated intraocular pressure (IOP). A finite element model of optic nerve head tissue (pre- and post-laminar neural tissue, lamina cribrosa, sclera, and pia mater) was constructed. Computed stresses, deformations, and strains were compared at each TLCPD step caused by reduced CSFP or elevated IOP. The results showed that elevating TLCPD increased the strain in optic nerve head, with the largest strains occurring in the neural tissue around the sclera ring. Relative to a baseline TLCPD of 10 mmHg, at a same TLCPD of 18 mmHg, the pre-laminar neural tissue experienced 11.10% first principal strain by reduced CSFP and 13.66% by elevated IOP, respectively. The corresponding values for lamina cribrosa were 6.09% and 6.91%. In conclusion, TLCPD has a significant biomechanical impact on optic nerve head tissue and, more prominently, within the pre-laminar neural tissue and lamina cribrosa. Comparatively, reducing CSFP showed smaller strain than elevating IOP even at a same level of TLCPD on ONH tissue, indicating a different potential role of low CSFP in the pathogenesis of glaucoma.

Postural Changes and the Trans–Lamina Cribrosa Pressure Difference: A Pilot Study in Neurosurgical Patients without Glaucoma

To evaluate the effect of changes in position in the trans-lamina cribrosa pressure difference (TLCPD) by simultaneously measuring and comparing intracranial pressure (ICP) with intraocular pressure (IOP) in seated and supine positions. Prospective cohort study. Patients admitted to the neurosurgery unit at Toronto Western Hospital with an external ventricular drain placed for ICP monitoring. Exclusion criteria were any ophthalmic surgical procedures within the preceding 6 months, history of glaucoma, and corneal abnormalities affecting IOP measurement. Intraocular pressure and ICP were recorded simultaneously in both the supine and seated positions with the order of positions randomized. Measurements were made 10 minutes after assuming each position. The TLCPD (IOP minus ICP) was calculated for the sitting and supine positions. The paired t test was used to assess significance of differences. The TLCPD. Twenty patients were included in the study. The average age was 54±17 years. Results were similar for left and right eyes. Data are shown for right eyes only. Mean sitting and supine IOPs were 15.3±3.5 mmHg and 15.9±3.7 mmHg, respectively (P= 0.32). Mean sitting and supine ICPs were 12.5±6.8 mmHg and 12.8±5.1 mmHg, respectively (P= 0.66). Mean TLCPD was 3.1±6.0 mmHg in the sitting position and 3.1±7.0 mmHg in the supine position (P= 1.00). Supine TLCPD increased in 10 patients (50%), decreased in 8 patients (40%), and was unchanged in 2 patients (10%). In this pilot study of 20 neurosurgical patients without glaucoma, posture-induced TLCPD changes were variable.

Latest Developments in Normal-Pressure Glaucoma: Diagnosis, Epidemiology, Genetics, Etiology, Causes and Mechanisms to Management.

Normal-pressure glaucoma (NPG) is part of the spectrum of the open-angle glaucomas and morphologically characterized, as any glaucoma, by a loss of neuroretinal rim parallel to an enlargement and deepening of the optic cup, and development or enlargement of parapapillary beta zone. These morphological characteristics, in addition to the therapeutic benefit of lowering the intraocular pressure (IOP), make NPG differ from vascular-induced optic neuropathy. Based on the anatomy of the optic nerve as a cerebral fascicle, the physiological counter-pressure against the IOP is the orbital cerebrospinal fluid pressure (CSFP), with both pressures forming the trans-lamina cribrosa pressure difference (TLCPD). In contrast to the IOP, the TLCPD is the true pressure exerting force on the optic nerve fibers when passing through the lamina cribrosa. As a theoretical notion, an abnormally high TLCPD due to a low CSFP, in association with a low arterial blood pressure, could therefore be involved in the pathogenesis of NPG. It fits with the finding that the reduction of the IOP (and thus indirectly of the TLCPD) is (the only proven) procedure for NPG therapy. This review additionally highlights the genetic background, diagnostic methods, and therapeutic modalities of NPG.

Mechanism study of trans-lamina cribrosa pressure difference correlated to optic neuropathy in individuals with glaucoma.

Mechanism study of trans-lamina cribrosa pressure difference correlated to optic neuropathy in individuals with glaucoma.

Selective Early Glial Reactivity in the Visual Pathway Precedes Axonal Loss, Following Short-Term Cerebrospinal Fluid Pressure Reduction.

To examine the early glial reactivity and neuron damage in response to short-term cerebrospinal fluid pressure (CSFp) reduction, as compared with intraocular pressure (IOP) elevation. The experiment included 54 male Sprague-Dawley rats with elevated translaminar cribrosa pressure difference (TLPD), defined as IOP minus CSFp. These rats underwent either continuous CSF drainage for 6 hours (n = 18), or unilateral IOP elevation to 40 mm Hg for 6 hours (n = 18). For control, 18 normal rats were anesthetized for 6 hours. Orthograde axonal transport was examined by intravitreal injection of 3% rhodamine-β-isothiocyanate. We also used transmission electron microscopy to display the ultrastructural features of retinal ganglion cell axons in the optic nerve head. Early glial reactivity in the retina, lateral geniculate nucleus (LGN), and superior colliculus (SC) was detected by immunostaining and Western blot for the glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). We also observed the glial reactivity in the inferior colliculus and hippocampus to rule out possible influences of CSF dynamics and composition. Anterograde staining with 3% rhodamine-β-isothiocyanate revealed decreased fluorescence intensity of the SC and LGN projected from both lower CSFp and higher IOP eyes. Transmission electron microscopy showed loss of axons from the optic nerve head in the high-IOP group, but not in the low-CSFp group. Compared with the anesthesia control group, GFAP expression was significantly increased in the retina, LGN, and SC, whereas GS expression was only increased in the retina following CSFp reduction. However, their expressions were not significantly elevated in the inferior colliculus and hippocampus. In the high-IOP group, expressions of GFAP and GS were significantly increased in the retina, LGN, and SC. Visual system neurons may be much more sensitive than other nervous tissues. Following short-term CSFp reduction, early glial reactivity may precede axonal loss. Changes of translaminar cribrosa pressure difference in both experimental low-CSFp and high-IOP groups induce selective early glial reactivity. The neuron damage from abnormally low CSFp may be pathogenetically similar to high IOP.

Intracranial pressure and glaucoma: Is there a new therapeutic perspective on the horizon?

Primary open-angle glaucoma is one of the leading causes of irreversible blindness worldwide. Raised intraocular pressure is the most important modifiable risk factor and lowering it remains the mainstay therapeutic approach for slowing optic nerve damage and visual field progression in glaucoma patients. An intriguing finding of clinical retrospective and prospective studies is that intracranial pressure is lower in patients with glaucoma. Furthermore, in a recent study on monkeys subjected to an implantation of a lumboperitoneal cerebrospinal fluid shunt to lower intracranial pressure, chronic reduction in intracranial pressure was associated with the development of glaucoma-like pathology in half of the monkeys. In addition, a very recent study demonstrated that patients whose intracranial pressure has been lowered following ventriculoperitoneal shunt placement, as treatment for normal pressure hydrocephalus, have a significantly increased risk of developing normal-tension glaucoma. These findings suggest that a reduced intracranial pressure may play an important role in the pathogenesis of glaucoma. This may be due to an abnormally high pressure difference across the lamina cribrosa resulting in biomechanical changes of the optic nerve head and/or to a deficient clearance of toxic substances, particularly in the subarachnoid space of the optic nerve and/or in the ‘ocular glymphatic system’. The search for drugs or medical devices useful to ameliorate glaucoma by lowering the trans-lamina cribrosa pressure difference and/or by facilitating cerebrospinal fluid circulation may therefore be an important area for future research. In this article, we propose that infusion of artificial cerebrospinal fluid through an implantable pump into the intrathecal space surrounding the spinal cord could be a new promising strategy for the treatment of glaucoma. Although the implantation of such a cerebrospinal fluid pump is a relatively invasive intervention, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given the significant number of patients for whom non-invasive treatment options are ineffective.

Noninvasive evaluation of cerebrospinal fluid pressure in ocular hypertension: a preliminary study

To compare the orbital cerebral spinal fluid pressure (CSFP) and trans-lamina cribrosa pressure difference (TLCPD) determined noninvasively in ocular hypertensive (OH) subjects and controls. Cross-sectional observational study. Magnetic resonance imaging was used to measure orbital subarachnoid space width (OSASW). The CSFP (mmHg) was estimated from a published formula as 17.54×MRI derived OSASW at 15mm behind the globe+0.47×body mass index+0.13×mean arterial blood pressure -21.52. Estimated TLCPD was calculated as IOP- CSFP. The orbital subarachnoid space width was significantly wider (p=0.01) in the OH group than in the control group at all three measurement locations. The MRI derived CSFP value in OH (14.9±2.9mmHg) was significantly higher than in the normal group (12.0±2.8mmHg; p<0.01). The estimated TLCPD value in OH (9.0±4.2mmHg) was significantly higher than in controls (3.6±3.0mmHg; p<0.01). The wider OSASW and higher estimated CSFP in OH subjects suggest a higher orbital CSFP. Despite a higher orbital CSFP that could be protective, the higher TLCPD in OH may play a significant role in the risk of developing glaucoma.

The effect of increased intra-abdominal pressure on orbital subarachnoid space width and intraocular pressure.

In accordance with the trans-lamina cribrosa pressure difference theory, decreasing the trans-lamina cribrosa pressure difference can relieve glaucomatous optic neuropathy. Increased intracranial pressure can also reduce optic nerve damage in glaucoma patients, and a safe, effective and noninvasive way to achieve this is by increasing the intra-abdominal pressure. The purpose of this study was to observe the changes in orbital subarachnoid space width and intraocular pressure at elevated intra-abdominal pressure. An inflatable abdominal belt was tied to each of 15 healthy volunteers, aged 22-30 years (12 females and 3 males), at the navel level, without applying pressure to the abdomen, before they laid in the magnetic resonance imaging machine. The baseline orbital subarachnoid space width around the optic nerve was measured by magnetic resonance imaging at 1, 3, 9, and 15 mm behind the globe. The abdominal belt was inflated to increase the pressure to 40 mmHg (1 mmHg = 0.133 kPa), then the orbital subarachnoid space width was measured every 10 minutes for 2 hours. After removal of the pressure, the measurement was repeated 10 and 20 minutes later. In a separate trial, the intraocular pressure was measured for all the subjects at the same time points, before, during and after elevated intra-abdominal pressure. Results showed that the baseline mean orbital subarachnoid space width was 0.88 ± 0.1 mm (range: 0.77-1.05 mm), 0.77 ± 0.11 mm (range: 0.60-0.94 mm), 0.70 ± 0.08 mm (range: 0.62-0.80 mm), and 0.68 ± 0.08 mm (range: 0.57-0.77 mm) at 1, 3, 9, and 15 mm behind the globe, respectively. During the elevated intra-abdominal pressure, the orbital subarachnoid space width increased from the baseline and dilation of the optic nerve sheath was significant at 1, 3 and 9 mm behind the globe. After decompression of the abdominal pressure, the orbital subarachnoid space width normalized and returned to the baseline value. There was no significant difference in the intraocular pressure before, during and after the intra-abdominal pressure elevation. These results verified that the increased intra-abdominal pressure widens the orbital subarachnoid space in this acute trial, but does not alter the intraocular pressure, indicating that intraocular pressure is not affected by rapid increased intra-abdominal pressure. This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-ONRC-14004947).

Measurement and Associations of the Optic Nerve Subarachnoid Space in Normal Tension and Primary Open-Angle Glaucoma

To measure the area of the optic nerve subarachnoid space (ONSASA) in patients with normal tension glaucoma (NTG), primary open-angle glaucoma (POAG), and controls and examine its association with relevant ocular and systemic parameters. Cross-sectional study. The study included 40 patients with NTG, 42 with POAG, and 45 healthy controls. B-scan ultrasound was performed binocularly, using a 12.5-MHz linear array probe. The measurement of the optic nerve subarachnoid space (ONSAS) and calculation of the ONSASA using ImageJ 1.51e analysis software was done by 2 experienced observers in a masked manner. The ONSASA between 3 and 7mm behind the globe in NTG (5.15 ± 0.81mm2) was significantly smaller than that in the POAG (6.24 ± 1.62mm2, P= .0008) or control (6.40 ± 2.20mm2; P= .0007) groups. ONSASA in the POAG and control groups were not significantly different (P= .13). ONSASA was significantly associated with mean IOP (P= .0004) and highest IOP (P= .0007). The optic nerve sheath diameter in NTG compared to POAG was significantly different at 3mm (4.46 ± 0.43mm vs 4.79 ± 0.40mm, P= .0007), 5mm (4.40 ± 0.39mm vs 4.65 ± 0.47mm, P= .003), and 7mm (4.36 ± 0.35mm vs 4.61 ± 0.30mm, P= .004) behind the globe. The ONSASA is smaller in NTG as compared to normal control. This is compatible with a lower cerebrospinal fluid pressure in the optic nerve in NTG, implying that trans-lamina cribrosa pressure difference might be abnormally higher in the NTG group than in normal controls.

Normal-Tension Glaucoma Has Normal Intracranial Pressure: A Prospective Study of Intracranial Pressure and Intraocular Pressure in Different Body Positions

To test the hypothesis that normal-tension glaucoma (NTG) is caused by an increased pressure difference across the lamina cribrosa (LC) related to a low intracranial pressure (ICP). Prospective case-control study. Thirteen NTG patients (9 women; median 71 [range: 56-83] years) were recruited for investigation with the same protocol as 11 healthy volunteers (8 women; 47 [30-59] years). A larger control group (n=51; 30 women; 68 [30-81] years) was used only for ICP comparison in supine position. ICP and intraocular pressure (IOP) were simultaneously measured in supine, sitting, and 9° head-down tilt (HDT) positions. Trans-lamina cribrosa pressure difference (TLCPD) was calculated using ICP and IOP together with geometric distances estimated from magnetic resonance imaging to adjust for hydrostatic effects. ICP, IOP, and TLCPD in different body positions. Between NTG patients and healthy volunteers, there were no differences in ICP, IOP, or TLCPD in supine, sitting, or HDT (P ≥ 0.11), except for IOP in HDT (P= 0.04). There was no correlation between visual field defect and TLCPD, IOP, or ICP and in any body position (P ≥ 0.39). Mean ICP in supine was 10.3 mmHg (SD=2.7) in the NTG group (n= 13) and 11.3 (2.2) mmHg in the larger control group (n= 51) (P= 0.24). There was no evidence of reduced ICP in NTG patients as compared with healthy controls, either in supine or in upright position. Consequently, the hypothesis that NTG is caused by an elevated TLCPD from low ICP was not supported.

Association of intraocular pressure-related factors and retinal vessel diameter with optic disc rim area in subjects with and without primary open angle glaucoma.

The data may support the notion that the intra-ocular pressure (IOP)-related factors and vascular factors were implicated concurrently in glaucomatous optic nerve damage. To study the association of intraocular pressure (IOP)-related factors, IOP, trans-lamina cribrosa pressure difference (TLCPD), cerebrospinal fluid pressure (CSFP) and retinal vessel diameters (RVD), central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE) with neuro-retinal rim area (RA). A population-based, cross-sectional study. A total of 6830 people aged 30 years and over. All participants underwent a comprehensive eye examination, fundus photograph-based measurements of RVD and Heidelberg retinal tomogram (HRT) measurement of optic disc. RA, CRAE, CRVE, IOP, body mass index (BMI), CSFP and TLCPD. Primary open-angle glaucoma (POAG) was diagnosed using two separate methods: 67 from expert consensus, and 125 from the International Society of Geographical and Epidemiologic Ophthalmology (ISGEO) classification. After excluding of those with high myopia or without gradable HRT images, 4194 non-glaucoma and 40 POAG were analysed for determinants of RA. On multivariable analysis determinants of reduced RA were POAG (P < 0.001), higher IOP (P = 0.03), higher refractive error (P < 0.01), longer axial length (P = 0.01), CRVE (P < 0.001), lower BMI (P = 0.015), older age (P < 0.001) smaller disc area (P < 0.001) and higher TLCPD (P = 0.03). When age and/or BMI were omitted from the model, reduced RA was also associated with lower CSFP (P < 0.001). Reduced RA is associated with narrow CRVE and higher IOP or lower CSFP. The data supports the concurrent role of IOP-related and vascular factors in glaucomatous optic nerve damage.

Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma.

The underlying pathophysiology of primary open-angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered 'glymphatic system' in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including β-amyloid, from the brain along paravascular channels. Given that β-amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open-angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open-angle glaucoma, present supporting preliminary data from our own post-mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans-lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.

Non-invasive Evaluation of Cerebrospinal Fluid Pressure in Ocular Hypertension: The Beijing Intracranial and Intraocular Pressure Study

Objective: To compare the orbital CSFP and trans-lamina cribrosa pressure difference (TLCPD) determined noninvasively in Ocular Hypertension (OH) and controls, and study its association with the estimated risk of conversion to glaucoma. Design: Cross-sectional observational study. Participants: 19 subjects with OH recruited from the Tongren Eye Center and 23 controls enrolled in the Beijing Intracranial and Intraocular Pressure Study between June 2010 to December 2013. Methods: Magnetic resonance imaging was used to measure orbital subarachnoid space width (OSASW) at 3, 9 and 15 mm posterior to the globe. The CSFP (mmHg) was estimated from a published formula as 17.54 × MRI derived OSASW at 15 mm behind the globe +0.47 × body mass index +0.13 × mean arterial blood pressure -21.52. Estimated TLCPD was calculated as IOP- CSFP. The values of CSFP and TLCPD were compared between OH and controls. The estimated risk of progression to glaucoma in OH was calculated and its correlation with CSFP determined. Main outcome measures: Orbital subarachnoid space width; MRI derived CSFP value; TLCPD value. Association of risk of progression with CSFP. Results: The orbital subarachnoid space width was significantly wider (P=0.01) in the OH group than in the control groups at all three measurement locations. The MRI derived CSFP value in OH (14.9 ± 2.9 mmHg) was significantly higher than in the normal group (12.0 ± 2.8 mmHg; P<0.01). The estimated TLCPD value in OH (9.0 ± 4.2 mmHg) was significantly higher than in controls (3.6 ± 3.0 mmHg; P<0.01). The estimated risk of conversion to glaucoma in OH (15.2 ± 8.7%) was negatively correlated with the MRI derived CSFP value (r=-0.51, r2=-0.26, P<0.01). Conclusions: The wider OSASW and higher estimated CSFP in OH subjects suggest a higher orbital CSFP. Despite a higher orbital CSFP that could be protective, the higher TLCPD in OH may play a significant role in the risk of developing glaucoma.