Abstract
Purpose:
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).
Design:
Retrospective cohort study of the Mayo Clinic Study of Aging.
Participants:
The Mayo Clinic Study of Aging is a prospective study evaluating the normal aging population.
Methods:
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.
Main Outcome Measures:
IOP, intracranial pressure, TLCPD, POAG, normal-tension glaucoma (NTG) diagnosis, glaucoma parameters.
Results:
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. non-glaucomatous 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.
Conclusions:
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.
Financial Disclosure(s):
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Keywords: Glaucoma, Normal-tension glaucoma, TLCPD
Glaucoma is one of the leading causes of irreversible vision loss.1 Currently, the only modifiable risk factor in the progression of disease is intraocular pressure (IOP), which can be lowered medically or surgically. Understanding the exact pathophysiologic mechanisms that lead to glaucoma has long been an active area of research, and they are yet to be fully understood.2–8 For instance, it is still unknown why some individuals develop glaucoma despite normal ranges of IOP (normal-tension glaucoma [NTG]), and why most individuals with elevated IOP never develop glaucoma.
A hypothesis for these findings is that glaucomatous changes may not be dependent on IOP alone, but rather the pressure difference between the intraocular and retrobulbar spaces, best represented currently by the difference between IOP and intracranial pressure (ICP), with the latter estimated from cerebrospinal fluid (CSF) pressure measured by lumbar puncture (LP). The intraocular and retrobulbar spaces are separated by the lamina cribrosa, a network of collagen fibers extending from the peripapillary scleral flange. The difference between IOP and ICP has been labeled the translamina cribrosa pressure difference (TLCPD). It is proposed that an increased TLCPD due to either high IOP and/or low ICP may cause a posterior displacement and deformation of the lamina cribrosa, leading to mechanical, vascular, or structural changes that ultimately lead to glaucomatous optic neuropathy.3,7,9–12
The lamina cribrosa pressure gradient hypothesis has been an area of debate within the research literature. Early studies13–15 found that ICP may be lower in open-angle glaucoma patients, but more recent studies16,17 disputed these findings. One reason for the limitation of published data on the TLCPD is the invasive nature of estimating ICP. We had the unique opportunity to explore the lamina cribrosa gradient hypothesis by analyzing data from patients enrolled in the Mayo Clinic Study of Aging (MCSA), a prospective study cohort systematically evaluating the normal aging population, in which many of the participants undergo routine lumbar puncture to measure CSF pressure. Thus, the aim of this study was to examine the IOP, CSF pressure, and TLCPD for glaucoma and nonglaucoma patients within a normal community-based population, and determine whether there is an association between these variables and select diagnostic measurements and biomarkers for glaucoma.
Methods
Patient Selection
A retrospective chart review was performed utilizing the MCSA and the Rochester Epidemiology Project (REP). Comprehensive details regarding the methodology of the MCSA and the REP have previously been published.18,19 Briefly, the MCSA features community-based patients from Olmsted County, Minnesota invited to participate in a prospective cohort study designed to investigate risk factors for cognitive impairment. As part of the study, participants are invited to undergo routine lumbar puncture with measurement of opening ICP. Lumbar punctures were not performed for medical indications such as for diagnostic or therapeutic purposes. The REP meanwhile is a medical record linkage system of the population of Olmsted County, Minnesota used for epidemiologic studies. For this study, patients who had at least 1 CSF measurement as part of the MCSA protocol from October 1, 2004 to November 1, 2018 were identified and utilized the first measurement in patients with multiple CSF measurements. These patients were cross-referenced with the REP database utilizing Current Procedural Terminology codes to identify patients who also met inclusion criteria with at least 1 documented ocular examination including measurement of IOP and estimation of cup-to-disc ratio. Exclusion criteria included glaucoma patients currently on treatment, history of angle-closure glaucoma or secondary open-angle glaucoma (i.e., pseudoexfoliative glaucoma or pigment dispersion syndrome glaucoma), systemic carbonic anhydrase inhibitor use, or a documented medical or surgical history known to affect CSF pressure including CSF leak, intracranial hemorrhage, central nervous system infection such as encephalitis or meningitis, hydrocephalus, hypertensive encephalopathy, or idiopathic intracranial hypertension.
The study was performed with Institutional Review Board approval, complied with the Health Insurance Portability and Accountability Act, and adhered to the tenets of the Declaration of Helsinki. Study protocols were approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards. All participants provided written informed consent to participate in the MCSA and for the LPs.
Data Collection
Patient data abstracted included CSF pressure and ocular information from the eye examination closest in time to the CSF pressure measurement that included IOP, vertical cup-to-disc ratio (highest between the 2 eyes) on clinical examination, mean deviation from Humphrey visual field (HVF) 24–2 or 30–2 (minimum between the 2 eyes), OCT average retinal nerve fiber layer (RNFL) thickness (minimum between the 2 eyes), presence or absence of a primary open-angle glaucoma (POAG) or normal-tension glaucoma (NTG) diagnosis, as documented by an ophthalmologist, and length of time between CSF opening pressure and IOP measurements. Given the variable accuracy of diagnosis codes, all charts were reviewed and reclassified as POAG (> 21 mmHg) and NTG (≤ 21 mmHg) based on pretreatment IOP and testing. For the glaucoma cohort, IOP maximum between both eyes at treatment initiation was recorded. All members in the glaucoma cohort had disease in both eyes that required treatment. Lumbar punctures were performed between L3–L4 early in the morning after fasting, with lateral decubitus positioning according to the MCSA protocol.18
Statistical Analyses
All continuous data were described using descriptive statistics. The estimated TLCPD was calculated for each patient by taking the maximum IOP of the 2 eyes and subtracting the CSF opening pressure. The TLCPD was calculated in 2 ways: (1) using IOP measurements closest in time to the CSF opening pressure measurement (converted from mmH2O to mmHg [closest-in-time TLCPD]); and (2) pretreatment IOP for the glaucoma groups (pretreatment TLCPD). Comparisons were performed for both pretreatment TLCPD for glaucoma cohorts and the closest-in-time TLCPD. The 95% confidence interval (CI) for closest-in-time TLCPD was calculated for a reference value from the patients without glaucoma, along with the proportion of abnormal TLCPD values for each glaucoma cohort (number of abnormal TLCPD values/total number of samples). Continuous variables were compared using the Wilcoxon rank sum test and categorical variables were compared using the Pearson chi-squared test, with 2-sided P values and a significance level of ≤ 0.05. Univariate and multivariate linear regression analyses were performed to identify the association of pretreatment IOP-based TLCPD with cup-to-disc ratio, HVF mean deviation, and OCT average RNFL thickness. Because age and body mass index (BMI) are known to influence ICP, multivariate regression analysis was also performed to identify possible confounders of age and BMI with TLCPD and CSFP.20 Cup-to-disc ratio was corrected for disc diameter for all statistical analyses similar to Jonas et al’s21 methodology. Analyses were performed with SAS version 9.4 (SAS Institute).
Results
Six hundred eighty patients underwent a lumbar puncture as part of the MCSA protocol between October 1, 2004 and November 1, 2018. Of these, 548 patients met inclusion and exclusion criteria, consisting of 38 patients with glaucoma (14 patients with POAG and 24 patients with NTG) and 510 patients without glaucoma. The mean ages for each cohort were as follows: 71.8 ± 11.0 years for the nonglaucomatous cohort, 77.3 ± 5.0 years for the POAG cohort, and 71.9 ± 9.7 years for the NTG cohort.
Closest-in-time TLCPD for the nonglaucomatous cohort was 4.07 ± 4.2 mmHg (Table 1). The closest-in-time TLCPD 95% CI was (–4.20 to 12.34). The mean time difference between LP and IOP measurement was 1.66 ± 2.5 years (range, 0–17.3). The POAG cohort had a significantly higher closest-in-time TLCPD (7.19 ± 3.6 mmHg) than those without glaucoma (4.07 ± 4.2 mmHg, P = 0.005), whereas the NTG cohort had a similar closest-in-time TLCPD (5.79 ± 4.5 mmHg, P = 0.18). 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 < 0.001). In the NTG cohort, 4 of 24 patients (16.7%) had abnormal TLCPD values; whereas in the POAG cohort, 9 of 14 patients (64.2%) had abnormal TLCPD values. The maximum IOP of the 2 eyes at treatment initiation was 26.64 ± 3.7 mmHg for the POAG cohort and 17.42 ± 3.4 mmHg for NTG cohort. Closest-in-time TLCPD for the nonglaucoma cohort (4.07 ± 4.2 mmHg) was significantly lower than pretreatment TLCPDs for both the POAG cohort (16.05 ± 5.2 mmHg; P < 0.001), NTG (7.37 ± 4.1 mmHg; P < 0.001) and the overall glaucoma cohort (10.57 ± 6.1 mmHg; P < 0.001).
Table 1.
Summary Statistics by Cohort
| Metrics | Measure | No Glaucoma (n = 510) | Primary Open-angle Glaucoma (n = 14) | Normal-tension Glaucoma (n = 24) | All Open-angle Glaucoma (n = 38) |
|---|---|---|---|---|---|
| Cerebral spinal fluid opening pressure, mm (H2O) | Mean (SD) | 154.99 (42.20) | 144.00 (33.99) | 136.58 (29.30) | 139.32 (30.87) |
| Median (range) | 152.00 (60.00–360.00) | 147.00 (68.00–200.00) | 137.00 (82.00–200.00) | 142.00 (68.00–200.00) | |
| Cerebral spinal fluid, mmHg | Mean (SD) | 11.40 (3.10) | 10.59 (2.50) | 10.05 (2.16) | 10.25 (2.27) |
| Median (range) | 11.18 (4.41–26.48) | 10.81 (5.00–14.71) | 10.08 (6.03–14.71) | 10.44 (5.00–14.71) | |
| Intraocular pressure (right), mmHg | Mean (SD) | 15.07 (2.99) | 17.36 (4.47) | 14.79 (3.79) | 15.74 (4.18) |
| Median (range) | 15.00 (2.00–25.00) | 17.50 (12.00–25.00) | 15.00 (8.00–26.00) | 15.00 (8.00–26.00) | |
| Missing (n) | 1 | ||||
| Intraocular pressure (left), mmHg | Mean (SD) | 14.97 (2.98) | 15.57 (5.52) | 15.62 (3.98) | 15.61 (4.53) |
| Median (range) | 15.00 (3.00–23.00) | 16.50 (2.00–24.00) | 16.00 (7.00–27.00) | 16.00 (2.00–27.00) | |
| Average intraocular pressure, mmHg | Mean (SD) | 15.02 (2.89) | 16.46 (4.60) | 15.21 (3.75) | 15.67 (4.07) |
| Median (range) | 15.00 (2.50–23.50) | 16.75 (7.00–24.50) | 15.50 (7.50–26.50) | 15.50 (7.00–26.50) | |
| Maximum intraocular pressure between both eyes, mmHg | Mean (SD) | 15.47 (2.99) | 17.79 (4.26) | 15.83 (3.92) | 16.55 (4.10) |
| Median (range) | 16 (3, 25) | 18.00 (12.00–25.00) | 16.00 (8.00–27.00) | 16.50 (8.00–27.00) | |
| Cup to disc, right | Mean (SD) | 0.33 (0.15) | 0.63 (0.23) | 0.70 (0.18) | 0.68 (0.20) |
| Median (range) | 0.30 (0.00–0.80) | 0.65 (0.20–0.90) | 0.70 (0.30–1.00) | 0.70 (0.20–1.00) | |
| Missing (n) | 1 | ||||
| Cup to disc, left | Mean (SD) | 0.33 (0.14) | 0.65 (0.24) | 0.67 (0.17) | 0.66 (0.20) |
| Median (range) | 0.30 (0.00–0.85) | 0.70 (0.20–0.95) | 0.70 (0.40–1.00) | 0.70 (0.20–1.00) | |
| Cup to disc, right (corrected for disc diameter) | Mean (SD) | 0.41 (0.17) | 0.57 (0.13) | 0.58 (0.17) | 0.58 (0.15) |
| Median (range) | 0.39 (0.10–0.72) | 0.59 (0.35–0.77) | 0.57 (0.33–0.96) | 0.58 (0.33–0.96) | |
| Missing (n) | 470 | 1 | 3 | 4 | |
| Cup to disc, left (corrected for disc diameter) | Mean (SD) | 0.37 (0.14) | 0.57 (0.19) | 0.56 (0.16) | 0.57 (0.17) |
| Median (range) | 0.36 (0.09–0.71) | 0.58 (0.35–1.01) | 0.57 (0.31–0.95) | 0.57 (0.31–1.00) | |
| Missing (n) | 470 | 1 | 3 | 4 | |
| Mean deviation, right | Mean (SD) | −0.65 (1.96) | −1.77 (4.09) | −2.43 (3.92) | −2.17 (3.94) |
| Median (range) | −0.16 (−6.90 to 2.64) | −1.16 (−7.30 to 8.16) | −1.85 (−15.03 to 2.85) | −1.81 (−15.03 to 8.16) | |
| Missing (n) | 459 | 1 | 3 | 4 | |
| Mean deviation, left | Mean (SD) | −1.44 (3.12) | −5.05 (6.26) | −2.73 (3.92) | −3.62 (4.99) |
| Median (range) | −0.53 (−15.83 to 2.32) | −3.39 (−21.27 to 1.52) | −1.86 (−13.19 to 2.12) | −2.07 (−21.27 to 2.12) | |
| Missing (n) | 459 | 1 | 3 | 4 | |
| OCT retinal nerve fiber layer, right | Mean (SD) | 84.37 (10.05) | 72.31 (9.26) | 73.55 (11.30) | 73.14 (10.53) |
| Median (range) | 85.00 (67.00–108.00) | 72.00 (56.00–86.00) | 75.00 (47.00–95.00) | 73.00 (47.00–95.00) | |
| Missing (n) | 475 | 3 | 2 | 5 | |
| OCT retinal nerve fiber layer, left | Mean (SD) | 84.97 (9.71) | 73.40 (12.06) | 74.22 (12.37) | 73.95 (12.08) |
| Median (range) | 86.00 (66.00–115.00) | 75.00 (53.00–94.00) | 75.00 (49.00–108.00) | 75.00 (49.00–108.00) | |
| Missing (n) | 475 | 3 | 2 | 5 | |
| Maximum intraocular pressure, right | Mean (SD) | 17.74 (3.36) | 25.07 (3.99) | 19.42 (3.39) | 21.50 (4.51) |
| Median (range) | 18.00 (8.00–49.00) | 24.50 (19.00–34.00) | 19.50 (14.00–28.00) | 21.00 (14.00–34.00) | |
| Missing (n) | 1 | ||||
| Maximum intraocular pressure, left | Mean (SD) | 17.76 (3.49) | 24.29 (2.23) | 19.92 (3.66) | 21.53 (3.83) |
| Median (range) | 18.00 (6.00–42.00) | 24.00 (21.00–28.00) | 19.50 (15.00–29.00) | 21.50 (15.00–29.00) | |
| Closest-in-time trans-lamina cribrosa pressure difference, mmHg | Mean (SD) | 4.07 (4.22) | 7.19 (3.57) | 5.79 (4.48) | 6.31 (4.18) |
| Median (range) | 4.19 (−17.48 to 15.41) | 7.48 (2.44–13.26) | 5.85 (−3.47, 14.50) | 6.98 (−3.47 to 14.50) | |
| Age at lumbar puncture, yrs | Mean (SD) | 71.75 (10.96) | 77.28 (5.04) | 77.88 (9.67) | 77.66 (8.20) |
| Median (range) | 73.41 (33.39–113.02) | 77.75 (67.68–84.44) | 78.11 (59.01–92.03) | 77.75 (59.01–92.03) | |
| Age at closest eye examination, yrs | Mean (SD) | 71.14 (11.75) | 77.20 (4.96) | 77.94 (9.72) | 77.67 (8.22) |
| Median (range) | 72.92 (30.38–112.82) | 77.65 (68.52–84.60) | 79.02 (58.16–91.08) | 78.54 (58.16–91.08) | |
| Time between lumbar puncture and closest eye examination, yrs | Mean (SD) | 1.66 (2.52) | 0.32 (0.35) | 0.44 (0.57) | 0.40 (0.50) |
| Median (range) | 0.70 (0.00–17.31) | 0.23 (0.04–1.25) | 0.24 (0.01–1.92) | 0.24 (0.01–1.92) | |
| Time between lumbar puncture and maximum eye examination, yrs | Mean (SD) | 4.42 (4.08) | 2.40 (2.02) | 4.01 (3.73) | 3.41 (3.27) |
| Median (range) | 3.52 (0.03–27.63) | 1.69 (0.41–8.24) | 3.10 (0.52–17.61) | 2.44 (0.41–17.61) | |
| Right eye pressure at initiation of treatment, mmHg | Mean (SD) | 25.93 (3.15) | 16.62 (3.17) | 20.05 (5.52) | |
| Median (range) | 25.50 (22.00–34.00) | 17.50 (11.00–21.00) | 19.50 (11.00–34.00) | ||
| Left eye pressure at initiation of treatment, mmHg | Mean (SD) | 24.14 (4.61) | 16.79 (3.50) | 19.50 (5.29) | |
| Median (range) | 23.00 (16.00–31.00) | 17.50 (8.00–24.00) | 18.00 (8.00–31.00) | ||
| Maximum intraocular pressure of the 2 eyes at initiation of treatment, mmHg | Mean (SD) | 26.64 (3.67) | 17.42 (3.35) | 20.82 (5.66) | |
| Median (range) | 26.00 (22.00–34.00) | 18.00 (11.00–24.00) | 21.00 (11.00–34.00) | ||
| Pretreatment trans-lamina cribrosa pressure difference, mmHg | Mean (SD) | 16.05 (5.16) | 7.37 (4.07) | 10.57 (6.13) | |
| Median (range) | 14.23 (10.23–29.00) | 6.95 (0.82–14.97) | 10.35 (0.82–29.00) |
SD = standard deviation.
The average CSF pressure for the nonglaucomatous cohort was 155.0 ± v42.2 mmH2O, which trended higher than that of the glaucoma cohort (139.3 ± 30.9 mmH2O; P = 0.11). The NTG cohort had a trend toward lower CSF pressure (136.6 ± 29.3 mmH2O) than that of the high-tension cohort of POAG (144.0 ± 34.0 mmH2O; P = 0.15), and was significantly lower than those without glaucoma (155.0 ± 42.2 mmH2O; P = 0.017).
In linear regression analysis (Tables 2–5), closest-in-time IOP was significantly correlated with HF mean deviation (β = −0.45; 95% CI, −0.83 to −0.07; P = 0.022) for the nonglaucomatous cohort in multivariate models. For CSF opening pressure, the nonglaucomatous cohort was significantly correlated with HVF mean deviation (β = −6.27; 95% CI, −12.19 to −0.34; P = 0.039) and the overall glaucoma cohort was correlated with the corrected cup-to-disc ratio (β = −72.82; 95% CI, −143.09 to −2.57; P = 0.043). Furthermore, closest-in-time TLCPD was correlated with RNFL thickness (β = −0.31; 95% CI, −0.56 to −0.05; P = 0.02). Pretreatment IOP (β = −0.63; 95% CI, −1.07 to −0.18; P = 0.008) and pretreatment TLCPD (β = −0.63; 95% CI, −1.05 to −0.21; P = 0.005) were significantly correlated with HVF mean deviation for the overall glaucoma cohort. For univariate analysis, closest-in-time TLCPD was significantly correlated with cup-to-disc ratio (β = 16.4; 95% CI, 4.61–28.2; ρ = 0.54; P = 0.009) and RNFL thickness (β = −0.26; 95% CI, −0.42 to 0.9; ρ = 0.58; P = 0.004) cohorts (Table 3). In contrast to closest-in-time TLCPD, IOP was only correlated with cup-to-disc ratio in the POAG cohort and was not correlated with any diagnostic glaucoma metrics in the NTG cohort (Table 3). Pretreatment IOP was not correlated with any metric across all cohorts. In the NTG cohort, pretreatment TLCPD was significantly correlated with cup-to-disc ratio (β = 15.59; 95% CI, 5.52–25.67; ρ = 0.59; P = 0.004) and HVF mean deviation (β =−0.43; 95% CI, −0.8 to −0.06; ρ = 0.48; P = 0.02; Table 5). For the overall glaucoma cohort, CSF opening pressure showed a significant correlation to cup-to-disc ratio (β = −103.08; 95% CI, −161.24 to −44.93; ρ = 0.54; P = 0.001), but did not show significant correlation with HVF mean deviation or average RNFL (Table 2). For the POAG cohort, CSF opening pressure was not significantly correlated with cup-to-disc ratio, HVF mean deviation, or average RNFL thickness; however, the NTG cohort was correlated with cup-to-disc ratio (β= −119.2; 95% CI, −188.57 to −47.83; ρ = 0.63; P = 0.002) and RNFL thickness (β = 1.34; 95% CI, 0.16–2.51; ρ = 0.46; P = 0.03). Multivariate regression models adjusting for age and BMI did not identify age or BMI as confounders. The relationships between CSF pressure, closest TLCPD, and pretreatment TLCPD with glaucoma outcomes remained significant after adjusting for age and BMI across all cohorts.
Table 2.
Multivariate Correlations for Glaucoma-Related Metrics Among all Patients
| Closest-in-Time TLCPD | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Metrics | No Glaucoma | Priory Open-Angle Glaucoma | Normal-Tension Glaucoma | All Glaucoma | ||||||||
| (n = 510) | (n = 14) | (n = 24) | (n = 38) | |||||||||
| β (95% CI) | P value | n | β (95% CI) | P value | n | β (95% CI) | P value | n | β (95% CI) | P value | n | |
| Maximum of L or R cup to disc | 0.22 (−8.77 to 9.21) | 0.96 | 28 | −9.72 (−25.11 to 5.67) | 0.179 | 11 | 8.93 (−6.58 to 24.44) | 0.237 | 18 | −2.66 (−13.86 to 8.54) | 0.629 | 29 |
| Minimum of L or R deviation | 0.01 (−0.54 to 0.56) | 0.97 | 28 | −0.25(−0.72 to 0.23) | 0.255 | 11 | 0.12 (−0.48 to 0.72) | 0.682 | 18 | −0.19 (−0.56 to 0.18) | 0.307 | 29 |
| Minimum of L or R OCT RNFL | −0.02 (−0.15 to 0.12) | 0.82 | 28 | 0.07 (−0.22 to 0.37) | 0.577 | 11 | −0.31 (−0.56 to −0.05) | 0.02 | 18 | −0.13 (−0.33 to 0.07) | 0.311 | 29 |
| Maximum Intraocular Pressure at Visit Closest to Lumbar Puncture (mmHg) | ||||||||||||
| Maximum of L or R cup to disc | −1.58 (−4.62 to 7.77) | 0.604 | 28 | −12.91 (−30.29 to 4.47) | 0.122 | 11 | 1.94 (−15.32 to 19.21) | 0.813 | 18 | −8.02 (−19.61 to 3.58) | 0.167 | 29 |
| Minimum of L or R deviation | −0.45 (−0.83 to −0.07) | 0.022 | 28 | −0.19 (−0.718 to 0.347) | 0.438 | 11 | 0.10 (−0.57 to 0.77) | 0.754 | 18 | −0.18 (−0.57 to −0.20) | 0.329 | 29 |
| Minimum of L or R OCT RNFL | 0 (−0.10 to 0.09) | 0.965 | 28 | 0.03 (−0.31 to 0.361) | 0.854 | 11 | −0.26 (−0.55 to 0.02) | 0.065 | 18 | −0.13 (−0.33 to 0.08) | 0.215 | 29 |
| Cerebral Spinal Fluid Opening Pressure (mm H2O) | ||||||||||||
| Maximum of L or R cup to disc | 18.42 (−77.97 to 114.81) | 0.708 | 28 | −43.42 (−140.85 to 54.02) | 0.327 | 11 | −95.01 (−208.32 to 18.30) | 0.094 | 18 | −72.82 (−143.08 to −2.57) | 0.043 | 29 |
| Minimum of L or R deviation | −6.27 (−12.19 to −0.34) | 0.039 | 28 | 0.84 (−2.15 to 3.82) | 0.528 | 11 | −0.24 (−4.61 to 4.14) | 0.909 | 18 | 0.03 (−2.28 to 2.34) | 0.978 | 29 |
| Minimum of L or R OCT RNFL | 0.18 (−1.30 to 1.66) | 0.80 | 28 | −0.63 (−2.50 to 1.24) | 0.452 | 11 | 0.56 (−1.30 to 2.42) | 0.527 | 18 | 0.08 (−1.16 to 1.31) | 0.898 | 29 |
CI = confidence interval; L = left; R = right; RNFL = retinal nerve fiber layer; TLCPD = trans-lamina cribrosa pressure difference.
Table 5.
Univariate Correlations for Glaucoma-Related Metrics Among Glaucoma Patients at Treatment Initiation
| Maximum Intraocular Pressure of the 2 Eyes at Treatment | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Metrics | Primary Open-Angle Glaucoma | Normal-Tension Glaucoma | All Glaucoma | ||||||
| (n = 14) | (n = 24) | (n = 38) | |||||||
| Maximum of L or R to disc | −2.57 (−11.12 to 16.25) | 0.69 | 13 | 6.90 (−2.64 to 16.43) | 0.15 | 21 | 3.87 (−8.25 to 15.99) | 0.52 | 34 |
| Minimum of L or R deviation | 0.05 (−0.40 to 0.51) | 0.800 | 13 | −0.21 (−0.66 to 0.25) | 0.35 | 21 | −0.14 (−0.45 to 0.17) | 0.35 | 34 |
| Minimum of L or R OCT RNFL | 0.09 (−0.21 to 0.40) | 0.51 | 11 | −0.16 (−0.32 to 0.05) | 0.06 | 22 | −0.08 (−0.24 to 0.09) | 0.372 | 33 |
| Pretreatment Trans-Lamina Cribrosa Pressure Difference | |||||||||
| Maximum of L or R cup to disc | 8.70 (−9.86 to 27.25) | 0.33 | 13 | 15.59 (5.52 to 25.67) | 0.004 | 21 | 11.45 (−1.34 to 24.24) | 0.08 | 38 |
| Minimum of L or R deviation | −0.47 (−0.99 to 0.04) | 0.066 | 13 | −0.43 (−0.80 to −0.06) | 0.02 | 21 | −0.53 (−0.88 to −0.18) | 0.004 | 34 |
| Minimum of L or R OCT RNFL | −0.07 (−0.38 to 0.23) | 0.61 | 11 | −0.14 (−0.30 to 0.03) | 0.10 | 22 | −0.09 (−0.30 to 0.12) | 0.38 | 33 |
RNFL = retinal nerve fiber layer.
Table 3.
Univariate Correlations for Glaucoma-Related Metrics Among All Patients
| Closest-in-Time TLCPD | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Metrics | No Glaucoma | Primary Open-Angle Glaucoma | Normal-Tension Glaucoma | All Glaucoma | ||||||||
| (n = 510) | (n = 14) | (n = 24) | (n = 38) | |||||||||
| β (95% CI) | P value | n | β (95% CI) | P value | n | β (95% CI) | P value | n | β (95% CI) | P value | n | |
| Maximum of L or R cup to disc | 2.37 (−4.84 to 9.58) | 0.51 | 40 | −6.72 (−17.61 to 4.17) | 0.20 | 13 | 16.40 (4.61 to 28.20) | 0.009 | 21 | 5.83 (−2.94 to 14.59) | 0.19 | 34 |
| Minimum of L or R deviation | −0.08 (−0.39 to 0.22) | 0.582 | 51 | −0.05 (−0.41 to 0.31) | 0.76 | 13 | −0.39 (−0.86 to 0.07) | 0.09 | 21 | −0.25 (−0.54 to 0.05) | 0.1 | 34 |
| Minimum of L or R OCT RNFL | 0.01 (−0.11 to 0.12) | 0.864 | 35 | 0.10 (−0.17 to 0.37) | 0.409 | 11 | −0.26 (−0.42 to −0.9) | 0.004 | 22 | −0.12 (−0.28 to 0.03) | 0.12 | 33 |
| Maximum Intraocular Pressure at Visit Closest to Lumbar Puncture | ||||||||||||
| Maximum of L or R cup to disc | 1.41 (−3.98 to 6.79) | 0.6 | 40 | −12.85 (−24.73 to −0.97) | 0.036 | 13 | 7.71 (−4.32 to 19.74) | 0.20 | 21 | −1.76 (−10.65 to 7.14) | 0.69 | 34 |
| Minimum of L or R deviation | −0.21 (−0.47 to 0.04) | 0.100 | 51 | 0.05 (−0.40 to 0.51) | 0.800 | 13 | −0.21 (−0.66 to 0.25) | 0.35 | 21 | −0.14 (−0.45 to 0.17) | 0.35 | 34 |
| Minimum of L or R OCT RNFL | 0 (−0.09 to 0.09) | 0.997 | 35 | 0.09 (−0.21 to 0.40) | 0.51 | 11 | −0.16 (−0.32 to 0.05) | 0.06 | 21 | −0.08 (−0.24 to 0.09) | 0.372 | 33 |
| Cerebral Spinal Fluid Opening Pressure | ||||||||||||
| Maximum of L or R cup to disc | −13.06 (−90.9 to 64.79) | 0.736 | 40 | −83.31 (−199.17 to 32.55) | 0.14 | 13 | −119.20 (−188.57 to −47.83) | 0.002 | 21 | −103.08 (−161.24 to −44.93) | 0.001 | 38 |
| Minimum of L or R deviation | −1.77 (−5.2 to 1.66) | 0.304 | 51 | 1.43 (−2.43 to 5.29) | 0.43 | 13 | 2.51 (−0.53 to 5.56) | 0.1 | 21 | 1.39 (−0.60 to 3.39) | 0.164 | 34 |
| Minimum of L or R OCT RNFL | −0.13 (−1.42 to 1.15) | 0.833 | 35 | −0.11 (−1.76 to 1.53) | 0.882 | 11 | 1.34 (0.16 to 2.51) | 0.03 | 22 | 0.62 (−0.42 to 1.67) | 0.233 | 33 |
CI = confidence interval; L = left; R = right; RNFL = retinal nerve fiber layer; TLCPD = trans-lamina cribrosa pressure difference.
Discussion
In this retrospective analysis of a community-based cohort, patients with glaucoma had a significantly lower CSF pressure than the nonglaucomatous cohort. The POAG and NTG cohorts had a significantly higher TLCPD than the nonglaucomatous cohort.
The exact pathophysiology of glaucoma is still not well understood. Early literature in animal studies measured the TLCPD directly using micropipette-based pressure transducers to help formulate the hypothesis that glaucomatous changes may be influenced by both IOP and ICP.22,23 In 2008, Berdahl et al13,14 examined retrospective data from patients who had a lumbar puncture at the Mayo Clinic for pathologic reasons and found significantly lower ICP and higher TLCPD in POAG and NTG patients than controls. Ren et al15 then examined this relationship prospectively in a limited number of patients in 2010, also finding significantly lower ICP in their NTG cohort, and significantly increased TLCPD in the glaucoma cohorts (both high IOP group and normal IOP group) as compared with the controls. This hypothesis gained further momentum when Fleischman et al24 retrospectively found that ICP tended to decrease with age, which could correlate with increased incidence and progression of glaucoma with age. Studies in the 2010s using noninvasive means of estimating ICP, such as MRI,25 mathematical estimation,26,27 and Doppler ultrasound28 seemed to generally support the TLCPD hypothesis, as did select case studies.29–31 However, a retrospective study using lumbar puncture data from Pircher et al16 in 2017 did not find a significant correlation between TLCPD and visual field mean deviation. Most recently, Linden et al17 in 2018 prospectively studied 13 NTG patients and 11 healthy controls and measured ICP and IOP simultaneously in various positions, using MRI data to adjust IOP, ICP, and TLCPD for hydrostatic effects, and did not find any significant differences in ICP, IOP, or TLCPD between the NTG and control group with the exception of lower IOP in the NTG group, adding further doubt to the TLCPD hypothesis as a major explanatory mechanism for NTG pathophysiology.16
This study adds to the literature and fills knowledge gaps in multiple ways. First, by leveraging the MCSA and the REP, this is the largest study to date to measure the TLCPD using CSF pressure from lumbar puncture data in a cohort of normal, community-based patients. Prior studies have either retrospectively examined patients with medical indications for lumbar puncture,13,14,32,33 or a limited number of prospective patients due to the invasive nature of measuring ICP.15,34,35 The ICP data from the MCSA have previously been published,20 and with the addition of the IOP data, the average closest-in-time TLCPD of 4.07 ± 4.22 mmHg is reported in 510 nonglaucomatous patients. These findings can be utilized as the expected TLCPD in normal individuals for future studies.
Next, regression analysis findings suggest improved correlations of TLCPD with diagnostic glaucoma measurements compared with IOP, particularly for the NTG cohort. For both pretreatment TLCPD vs. pretreatment IOP and closest-in-time TLCPD vs. IOP at closest visit, there were significant correlations with diagnostic measurements in the TLCPD groups that were absent in the IOP groups. These finding have also been controversial in the previous literature, with some studies suggesting a correlation between glaucoma diagnostics and the TLCPD15,26–28 that are stronger than IOP alone, and some not finding a consistent correlation.14,16,17,36
It was observed that TLCPD was significantly higher in our NTG group as compared with the control group, a finding in contrast to Linden et al’s17 recently published work, but consistent with prior studies.13–15 Linden et al17 noted that this difference, in comparison to the studies by Berdahl et al13 and Ren et al,15 was primarily due to a difference in the ICP of the control group, with Berdahl et al and Ren et al’s15 control group means being higher (12.7 ± 3.9 mmHg and 12.9 ± 1.9 mmHg respectively) than the Linden et al17 control group (11.3 ± 2.2 mmHg). The present study found a mean of 11.4 ± 3.1 mmHg in 510 controls, which was similar to Linden et al.17 Average age was similar across all control groups. Thus, these findings are consistent with Linden et al17 in that the ICP, and the associated TLCPD, is unlikely to be the primary explanatory driver behind NTG pathophysiology, although it may be contributory in some patients. For the POAG cohort, TLCPD (16.1 ± 5.2 mmHg) was similar to other studies by Ren et al,15 Siaudvytyte et al37 and aggregate analysis of both (12.5 ± 4.1 mmHg, 15.7 ± 7.7 mmHg, and 13.3 ± 1.4 mmHg, respectively). Similar to NTG, ICP differences were the predominant reason, as Siaudvytyte et al37 was different (15.7 ± 7.7 mmHg) than this study’s POAG cohort (10.59 ± 2.5 mmHg). One reason for the differences in the aggregate data and Siaudvytyte et al’s37 data is Siaudvytyte et al37 used Doppler instead of lumbar punctures to measure ICP.
Furthermore, we also calculated the 95% reference interval for TLCPD among our 510 nonglaucomatous individuals, and examined each glaucoma cohort to determine the proportion with abnormal TLCPD values. In the NTG cohort, 4 of 24 patients (16.7%) had abnormal TLCPD values; whereas in the POAG cohort, 9 of 14 patients (64.2%) had abnormal TLCPD values. Comparing TLCPD values to Pang et al’s38 reference ranges, 4 of 24 (16.7%) NTG patients and 13 of 14 (92.9%) PAOG patients had TLCPD values outside the 95% reference interval, all of which were higher. For our nonglaucomatous cohort, 8.4% of patients had TLCPD values outside the reference range.38 Both reference ranges are quite similar, and the proportions reiterate the higher proportions of elevated TLCPD in glaucoma groups compared with controls, which lends credence to the TLCPD hypothesis. It is important to note that the proportion of NTG patients who had TLCPD values compared with the nonglaucomatous cohort shows a ~ 50% difference which further supports the idea TLCPD is contributory in some patients. Given that Pang et al’s38 reference ranges are from individuals who got lumbar punctures for neurologic reasons, the 95% reference interval we provide from this large cohort of community-based patients adds to the current TLCPD literature.
This study does have a number of limitations. Due to the demographics of Olmsted County, Minnesota and the focus on the elderly population as part of the aim of the MCSA, our population is primarily White in race and older in age, so the TLCPD measurements in our control population may not be generalizable to other study populations. Additionally, the relatively low number of NTG and POAG patients limits the power of recognizing any potential small but significant difference in the data. Due to the retrospective nature of the study, IOP was measured at varying lengths from lumbar puncture, which could potentially affect the TLCPD values. Furthermore, IOP was measured in an upright sitting posture and ICP was measured in the lateral decubitus position, resulting in an estimated TLCPD that is in a nonphysiologic posture. Intracranial pressure as measured by lumbar puncture has previously been shown to correlate well with ICP when accounting for differences in hydrostatic forces based on fluid column heights,39 and Qvarlander et al40 in 2013 attempted to fit a mathematical model to ICP data collected at multiple postural angles. Eklund et al41 further examined this in 2016, and was the first known study to measure the ICP and IOP simultaneously at different postures, finding a TLCPD after adjusting ICP based on MRI data for the hydrostatic forces to be approximately 12.3 ± 2.2 mmHg supine and 19.8 ± 4.6 mmHg in the sitting posture41 for 11 healthy subjects. Linden et al17 adopted a similar procedure in their study, measuring IOP, ICP, and TLCPD at supine, sitting, and head down positions with MRI data to account for the hydrostatic forces. Therefore, the TLCPD we report here, due to lack of physiologic positioning with simultaneous measurement of ICP and IOP, and lack of MRI imaging to account for hydrostatic forces, cannot be directly compared with Eklund et al41 or Linden et al,17 but rather should be considered an approximation similar to those from other retrospective13,14,16 or earlier prospective15 studies.
In conclusion, this study is the largest known study to date to examine TLCPD in a community-based population, due to the unique data set of patients undergoing routine lumbar punctures as part of the MCSA and with eye examinations accessible via the REP. This provides references values for normal populations. Differing correlations with diagnostic glaucoma measurements between TLCPD and IOP argue for TLCPD playing a role beyond IOP alone in the NTG cohort, with the significant differences between NTG and control cohorts with regard to TLCPD suggesting that NTG pathophysiology is complex and likely multifactorial.
Table 4.
Multivariate Correlations for Glaucoma-Related Metrics Among Glaucoma Patients at Treatment Initiation
| Maximum Intraocular Pressure of the 2 Eyes at Treatment | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Metrics | Primary Open-Angle Glaucoma | Normal-Tension Glaucoma | All Glaucoma | ||||||
| (n = 14) | (n = 24) | (n = 38) | |||||||
| Maximum of L or R cup to disc | −6.35 (−20.77 to 8.07) | 0.333 | 11 | −0.39 (−12.82 to 12.04) | 0.95 | 18 | −7.65 (−21.19 to 5.90) | 0.256 | 29 |
| Minimum of L or R deviation | −0.33 (−0.77 to 0.12) | 0.124 | 11 | −0.40 (−0.88 to 0.08) | 0.093 | 18 | −0.63 (−1.07 to −0.18) | 0.008 | 29 |
| Minimum of L or R OCT RNFL | −0.07 (−0.34 to 0.21) | 0.592 | 11 | 0.04 (−0.17 to 0.24) | 0.713 | 18 | 0.02 (−0.22 to 0.25) | 0.895 | 29 |
| Pretreatment Trans-Lamina Cribrosa Pressure Difference | |||||||||
| Maximum of L or R cup to disc | −3.15 (−20.58 to 14.26) | 0.682 | 11 | 6.60 (−6.66 to 19.86) | 0.304 | 18 | −2.29 (−15.18 to 10.60) | 0.72 | 29 |
| Minimum of L or R deviation | −0.39 (−0.92 to 0.15) | 0.130 | 11 | −0.39 (−0.90 to 0.13) | 0.129 | 18 | −0.63 (−1.05 to −0.21) | 0.005 | 29 |
| Minimum of L or R OCT RNFL | −0.02 (−0.36 to 0.32) | 0.895 | 11 | −0.01 (−0.22 to 0.21) | 0.957 | 18 | 0.01 (−0.22 to 0.24) | 0.931 | 29 |
L = left; R = right; RNFL = retinal nerve fiber layer.
Acknowledgments
Supported by the Mayo Clinic Department of Ophthalmology, Rochester Epidemiology Project (grant number R01-AG034676; Principal Investigators: Walter A. Rocca, MD, MPH, and Jennifer L. St Sauver, PhD). This study was also supported by grant U01 AG006786 from the Mayo Clinic Study of Aging.
Abbreviations and Acronyms:
- BMI
body mass index
- CSF
cerebral spinal fluid
- HVF
Humphrey visual field
- ICP
intracranial pressure
- IOP
intraocular pressure
- LP
lumbar puncture
- MCSA
Mayo Clinic Study of Aging
- NTG
normal-tension glaucoma
- POAG
primary open-angle glaucoma
- RNFL
retinal nerve fiber layer
- REP
Rochester Epidemiology Project
- TLCPD
trans-lamina cribrosa pressure difference
Footnotes
Disclosure(s):
All authors have completed and submitted the ICMJE disclosures form.
The author(s) have made the following disclosure(s):
J.J.C.: Consulting – UCB, Roche.
The other authors have no proprietary or commercial interest in any materials discussed in this article.
Presented in part at the 2019 Annual Meeting of the American Academy of Ophthalmology, October 12e15, 2019 in San Francisco, California.
HUMAN SUBJECTS: Human subjects were included in this study. Study protocols were approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards.
The study complied with the Health Insurance Portability and Accountability Act and adhered to the tenets of the Declaration of Helsinki. All participants provided written informed consent to participate in the MCSA and for the LPs
No animal subjects were used in this study.
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