Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma

PURPOSE: To investigate systemic and ocular hemodynamic risk factors for glaucomatous damage in eyes with normal tension glaucoma (NTG). METHODS: Each patient with diagnosed NTG underwent 24-hour monitoring of intraocular pressure (IOP) and blood pressure (BP), scanning laser polarimetry (GDx-VCC), and a Humphrey visual field (HVF) examination. Multivariate regression models were used to evaluate potential risk factors: age, spherical equivalent, central corneal thickness (CCT), mean/peak in-hospital IOP, circadian IOP fluctuation, average mean arterial pressure (MAP), circadian MAP fluctuation, and circadian fluctuation of mean ocular perfusion pressure (MOPP). Functional outcome variables for glaucomatous damage were mean deviation (MD), pattern SD (PSD), and Advanced Glaucoma Intervention Study (AGIS) score. Anatomic outcome variables were TSNIT (temporal, superior, nasal, inferior, and temporal) average, superior average, inferior average, and nerve fiber indicator (NFI) on GDx-VCC. RESULTS: One hundred thirteen eyes of 113 patients met the inclusion criteria. In the multivariate regression models, larger circadian MOPP fluctuation was significantly associated with decreased MD, increased PSD, and increased AGIS score among functional outcome variables and with reduced TSNIT average, reduced inferior average, and increased NFI among anatomic outcome variables. Larger MAP fluctuation was associated with decreased MD, increased PSD, reduced TSNIT average, reduced inferior average, and increased NFI. CCT was not associated with any outcome variable. CONCLUSIONS: Of the functional and anatomic outcome variables, circadian MOPP fluctuation was the most consistent clinical risk factor for glaucoma severity in eyes with NTG. This finding may suggest an etiology of NTG as a chronic ischemic end organ disease.     

Relative change in diurnal mean ocular perfusion pressure: a risk factor for the diagnosis of primary open-angle glaucoma

PURPOSE: To investigate diurnal change and pattern of variation in intraocular pressure (IOP) and systolic (SBP) and diastolic (DSP) blood pressures in a group with untreated primary open-angle glaucoma (uPOAG) and compare it with an age-matched, normal group. METHODS: IOP, SBP, and DBP were measured in 14 patients with uPOAG and in 14 normal subjects, every hour between 7 AM and 10 PM and the mean ocular perfusion pressure (MOPP) was calculated. Mixed-effect linear models were used to analyze the repeated-measures data in which both fixed and random effects were included. The relative diurnal change was calculated as the percentage decrease from maximum. RESULTS: The uPOAG group had the higher IOP (P < 0.001) and lower MOPP (P = 0.025). There was a significant diurnal change in IOP, SBP, DBP, and MOPP in both groups (P < 0.001). The pattern of diurnal variation in IOP (P = 0.137), SBP (P = 0.569), and DBP (P = 0.937) was not significantly different between groups but was significantly different for MOPP (P = 0.040). MOPP and IOP were most similar at 7 AM and 1 PM. Postprandial hypotension was significant for SBP, DBP, and MOPP (P < 0.001), but not IOP (P = 0.388) in both groups. The relative change in MOPP was larger in the uPOAG group (38% vs. 26%, P < 0.001), but the change in IOP was similar (42% vs. 41%, P = 0.786). There was a significant effect of DBP on IOP over the course of the day in the uPOAG group (P = 0.011) but not in the normal group (P = 0.733). CONCLUSIONS: The relative diurnal change in IOP was similar in both uPOAG and normal subjects but MOPP showed a significant difference. MOPP significantly decreased after lunch, and was at its lowest in uPOAG at 7 AM, when IOP was at its highest. A significant association was found between diurnal DBP and IOP in uPOAG.     

Effect of latanoprost on the diurnal variations in the intraocular and ocular perfusion pressure in normal tension glaucoma

PURPOSE: To evaluate the effects of latanoprost on the diurnal variations in the intraocular pressure (IOP) combined with the ocular perfusion pressure (OPP) in patients with normal tension glaucoma (NTG). PATIENTS AND METHODS: Twenty-two eyes from 22 patients with NTG were used for the study. The diurnal variations in the IOP and blood pressure (BP) were measured every 3 hours without therapy, and then the patients were treated with latanoprost (0.005%) once daily for more than 12 weeks. The diurnal variations in the IOP and BP under medication were again measured every 6 hours. The diurnal variation of IOP for 24 hours, mean diurnal IOP, maximum IOP, minimum IOP, range of variation in IOP, OPP, and BP were compared between the baseline and after treatment by means of a paired t test. RESULTS: At 3 months after the start of the latanoprost treatment regimen, the IOP showed a statistically significant decrease at every assessed time point over 24 hours (P<0.001). Latanoprost significantly reduced the mean diurnal IOP, maximum IOP, minimum IOP, and mean range of variation in the IOP values from baseline (P<0.001, <0.001, <0.001, and 0.009, respectively). OPP after treatment showed no significant difference at any assessed time points from the baseline (P>0.1). Latanoprost did not significantly alter the mean diurnal OPP (P>0.1), and BP (P>0.5) from the baseline. CONCLUSIONS: Latanoprost was thus found to significantly reduce IOP over 24 hours, whereas it does not affect OPP and BP in NTG patients. Therefore, it may be a useful medication for NTG.     

原发性开角型青光眼患者不同体位眼灌注压昼夜波动趋势分析

Objective To characterize the circadian fluctuation of ocular perfusion pressure (OPP) in different position  in patients with newly diagnosed, untreatedprimary open-angle glaucoma（POAG）. Design Cohort study. Participants Nineteen patients with POAG (19 eyes) and eighteen healthy controls (18 eyes) were included in the Peking University Shenzhen Hospital. Methods POAG patients and healthy controls were included and underwent 24-hour monitoring of IOP and blood pressure. On 10:00, 14:00, 18:00 and 22:00 o’clock in the daytime, all the subjects were monitored in sitting position, then POAG patients were monitored again after lying down for 5 minutes. On 2:00, 5:00 and 7:00 o’clock at night all the subjects were monitored in supine position, then POAG patients were monitored again after sitting for 5 minutes. Calculating the mean ocular perfusion pressure (MOPP), the systolic ocular perfusion pressure (SOPP) and diastolic perfusion pressure (DOPP) by the formula and analyzing the data. Main Outcome Measures  MOPP, SOPP, DOPP. Results In both groups of habitual position (sitting position in day and supine position in night), the nocturnal MOPP, SOPP and DOPP were lower than diurnal. In both groups, the nocturnal MOPP was lower than diurnal in habitual position (POAG group t=4.092, P=0.000; healthy group t=4.513, P=0.000). However, there was no obvious difference between those two groups (t=-0.973, P=0.350). POAG group had higher 24-hour fluctuation of MOPP (t=2.204, P=0.039), higher nocturnal fluctuation of SOPP (t=3.097, P=0.018), higher nocturnal and 24-hour fluctuation of DOPP than healthy group, all the differences had statistical significance (all P<0.05).  In POAG group , there was no statistical difference between the nocturnal MOPP and the diurnal MOPP in sitting position or in supine position of 24 h (all P>0.05). POAG group had higher 24-hour mean MOPP in sitting position than in supine position, the difference had statistical significance (t=4.306, P=0.001).  Comparing the MOPP of  POAG group  in habitual position with in sitting position of 24 h, there was no statistical difference(t=-2.101, P=0.080). However, POAG group had higher 24-hour mean MOPP in habitual position than in supine position of 24 h, the difference had statistical significance (t=2.707, P=0.035). Conclusions There circadian fluctuation of  OPP in different position in POAG pations can not be treated as the same. The nocturnal MOPP  was lower than diurnal in habitual position, but there was no obvious difference in the 24h-sitting position and 24h-supine position.  (Ophthalmol CHN, 2017, 26: 20-25）     

Prolonged retinal arteriovenous passage time is correlated to ocular perfusion pressure in normal tension glaucoma

BACKGROUND: The pathogenesis of normal tension glaucoma (NTG) might be related to impaired autoregulation of ocular blood flow. The purpose of the study is to evaluate retinal haemodynamics by fluorescein angiography and to correlate arteriovenous passage times (AVP) with ocular perfusion pressure in patients with NTG and controls. METHODS: Thirty-five patients with NTG without any topical treatment (mean age 53 +/- 11 years) and 35 age-matched controls (mean age 53 +/- 11 years) were included in this study. Retinal AVP was assessed by video fluorescein angiography using a scanning laser ophthalmoscope (Rodenstock, Germany). Dye dilution curves of temporal superior and inferior arterioles and venules were evaluated by digital image analysis. AVP was correlated to mean arterial blood pressure and ocular perfusion pressure. RESULTS: The AVP was significantly prolonged in patients with NTG compared to controls (1.82 +/- 0.57 versus 1.42 +/- 0.46, p = 0.002). Patients with NTG and controls showed no significant differences in intraocular pressure, mean arterial pressure and mean and diastolic ocular perfusion pressure. The AVP was significantly correlated to mean arterial pressure and mean and diastolic ocular perfusion pressure in patients with NTG (r = -0.54; p = 0.0006, r = -0.51; p = 0.002, r = -0.49, p = 0.002), but not in controls (r = -0.21; p = 0.23, r = -0.19; p = 0.27, r = 0.02, p = 0.93). CONCLUSIONS: Patients with NTG exhibit prolonged retinal AVP compared to controls. A significant correlation of retinal haemodynamics to mean arterial blood pressure and ocular perfusion pressure might reflect impaired autoregulation in NTG.     

Long axial length as risk factor for normal tension glaucoma

Background  The high prevalence of normal tension glaucoma (NTG) in the Japanese requires special screening tests other than measurements of only the intraocular pressure (IOP). This study was carried out to determine whether there is a significant association between the axial length of the eye and the presence of NTG. Methods  We reviewed the medical records of all patients who were scheduled to undergo cataract surgery alone or combined with glaucoma surgery at the same time. There were 87 patients with NTG, 137 with POAG, and 978 non-glaucomatous control cases. The axial length, IOP, curvature of the anterior corneal surface, age, and gender were determined at the time of the operation. If both eyes had surgery, data from only the right eyes were analyzed. An association of these parameters with NTG and POAG was analyzed by logistic regression analysis. The three groups were analyzed for differences in the axial length using the Kruskal-Wallis test followed by the Mann-Whitney U test. Results  The axial length was significantly associated with NTG (odds = 1.24, P = 0.002) and POAG (odds = 1.28, P = 0.001). The incidence of either POAG or NTG was significantly higher in patients with axial lengths ≥25.0 mm (odds = 2.29, P < 0.001, Fisher’s exact test). The age at the time of cataract surgery was weakly but significantly correlated negatively with the axial length (r = −0.24, P < 0.001, Pearson’s correlation coefficient test). Men had significantly longer axial lengths than women. Conclusions  Long axial lengths can be considered a risk factor for NTG and POAG, and patients with long axial lengths need to be carefully examined for glaucoma.     

Diurnal fluctuation and concordance of intraocular pressure in glaucoma suspects and normal tension glaucoma patients

PURPOSE: The study objective was to determine the concordance of intraocular pressure (IOP) in glaucoma suspects (GS) and normal tension glaucoma (NTG) patients. METHODS: This was a retrospective review of diurnal curves of untreated GS and NTG patients. No subject had IOP greater than 21 mm Hg. We defined GS patients as having suspicious optic nerves with normal visual fields, and NTG patients as having glaucomatous optic nerves with associated visual field loss. Goldmann applanation tonometry was performed at 10:00, 13:00, 16:00, 19:00, 22:00, and 07:00. Linear association of OD and OS IOP was estimated using Pearson correlation coefficient (r). The diurnal period was divided into 7 time intervals of 3, 6, 9, 12, 15, 18, and 21 hours, and the absolute difference in change in IOP between fellow eyes and probability that it was within 3 mm Hg were calculated. RESULTS: The study included 68 GS and 95 NTG subjects. The diurnal curves of the OD and OS showed a parallel course in both groups. The average correlations (r) of OD and OS IOP over the 6 time points were 0.78 and 0.81 for GS and NTG, respectively. The mean absolute difference in IOP change between OD and OS over the 6 time intervals ranged between 1.4 and 1.9 mm Hg for GS, and 1.3 and 1.5 mm Hg for NTG subjects. The probability that this difference was within 3 mm Hg ranged between 87% and 94% for GS, and 86% and 93% for NTG subjects. CONCLUSIONS: The diurnal variation in IOP between the 2 eyes in GS and NTG is largely concordant in approximately 90% of the time.     

Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma

PURPOSE: To compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on intraocular pressure (IOP), blood pressure (BP), and diastolic ocular perfusion pressure (DOPP), calculated as the difference between the diastolic blood pressure (DBP) and IOP. METHODS: According to a 4 x 4 Latin squares design for repeated measures, 27 untreated patients and patients with newly diagnosed primary open-angle glaucoma (POAG) were treated with timolol 0.5% at 8 AM and 8 PM; brimonidine 0.2% at 8 AM and 8 PM; dorzolamide 2% at 8 AM, 2 PM, and 8 PM; and latanoprost 0.005% at 8 PM. The duration of each treatment course was 6-weeks, with a 4-week washout between each treatment. IOP and BP were measured at baseline and at the end of each treatment period. IOP was measured every 2 hours throughout a 24-hour period. Sitting IOP was measured from 8 AM to 10 PM by Goldmann applanation tonometry. Supine IOP was assessed from 12 to 6 AM by means of a handheld electronic tonometer (TonoPen XL; Mentor, Norwell, MA). BP monitoring was performed by means of an automated portable device (TM-2430; A & D Co., Saitama, Japan). RESULTS: All the drugs tested decreased the IOP significantly at all time points in comparison with baseline pressure. The mean 24-hour IOP after latanoprost administration (16.62+/-0.98 mm Hg) was significantly lower than that after timolol, brimonidine, or dorzolamide (P=0.0001). During the 24-hour period, brimonidine induced a significant decrease in systolic BP (SBP) and DBP at all time points when compared with baseline measurements and with those after administration of the other drugs (P<0.0001). Timolol caused a significant decrease in DBP and SBP at all the 24-hour time points when compared with the baseline and with the dorzolamide- and latanoprost-induced changes (P<0.0001). The mean 24-hour DOPPs were 50.7+/-5.9 mm Hg at baseline, 53+/-5.5 mm Hg with timolol, 46.2+/-5.4 mm Hg with brimonidine, 55.9+/-4.6 mm Hg with dorzolamide, and 56.4+/-4.9 mm Hg with latanoprost. Brimonidine induced a significant decrease in the mean 24-hour DOPP compared with that at baseline (P<0.0001), whereas dorzolamide and latanoprost induced a significant increase (P<0.0001). CONCLUSIONS: Latanoprost seemed to induce a uniform reduction in IOP during the 24-hour period, although timolol was as effective as latanoprost during the daytime, and dorzolamide are as effective as latanoprost at night. SBP and DBP were significantly decreased by either timolol or brimonidine. In this study of patients with newly diagnosed POAG, only dorzolamide and latanoprost significantly increased mean 24-hour DOPP.     

Association of ocular blood flow and contrast sensitivity in normal tension glaucoma

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate the relationship of ocular blood flow (via arteriovenous passage time, AVP) and contrast sensitivity (CS) in...     

Effect of nimodipine on ocular blood flow and colour contrast sensitivity in patients with normal tension glaucoma

AIM: To investigate the effects of oral nimodipine on ocular haemodynamic parameters and colour contrast sensitivity in patients with normal tension glaucoma (NTG). DESIGN: The study was performed in a randomised, placebo controlled, double masked, crossover design. PARTICIPANTS: Nimodipine (60 mg) or placebo was administered to 14 consecutive NTG patients. METHODS: The effects or oral nimodipine or placebo on ocular and systemic haemodynamic parameters and colour contrast sensitivity along the tritan axis were studied two hours after administration. Optic nerve head blood flow (ONHBF) and choroidal blood flow (CHBF) were assessed with laser Doppler flowmetry. Ocular fundus pulsation amplitude (FPA) was measured with laser interferometry. Colour contrast sensitivity (CCS) was determined along the tritan colour axis. MAIN OUTCOME MEASURES: ONHBF, CHBF, FPA, intraocular pressure and CCS were assessed in patients with NTG. RESULTS: Mean ocular FPA increased by 14% (SD 14%) (p = 0.0008), ONHBF by 18% (SD 16%) (p = 0.0031), and CHBF by 12% (SD 14%) (p<0.001) after administration of nimodipine. Nimodipine also decreased the threshold of colour contrast sensitivity along the tritan colour axis (-14% (SD 12%); p = 0.048). However, individual changes in FPA, ONHBF, or CHBF were not correlated with changes in threshold of CCS along the tritan colour axis. CONCLUSIONS: The results indicate that nimodipine increases ONH and choroidal blood flow in NTG patients and improves CCS. The latter effect does not, however, seem to be a direct consequence of the blood flow improvement.     

The complex interaction between ocular perfusion pressure and ocular blood flow – Relevance for glaucoma

Glaucoma is an optic neuropathy of unknown origin. The most important risk factor for the disease is an increased intraocular pressure (IOP). Reducing IOP is associated with reduced progression in glaucoma. Several recent large scale trials have indicated that low ocular perfusion pressure (OPP) is a risk factor for the incidence, prevalence and progression of the disease. This is a strong indicator that vascular factors are involved in the pathogenesis of the disease, a hypothesis that was formulated 150 years ago. The relation between OPP and blood flow to the posterior pole of the eye is, however, complex, because of a phenomenon called autoregulation. Autoregulatory processes attempt to keep blood flow constant despite changes in OPP. Although autoregulation has been observed in many experiments in the ocular vasculature the mechanisms underlying the vasodilator and vasoconstrictor responses in face of changes in OPP remain largely unknown. There is, however, recent evidence that the human choroid regulates its blood flow better during changes in blood pressure induced by isometric exercise than during changes in IOP induced by a suction cup. This may have consequences for our understanding of glaucoma, because it indicates that blood flow regulation is strongly dependent not only on OPP, but also on the level of IOP itself. Indeed there is data indicating that reduction of IOP by pharmacological intervention improves optic nerve head blood flow regulation independently of an ocular vasodilator effect.     

Therapy of normal tension glaucoma: effect of brinzolamide on ocular haemodynamics

BACKGROUND: Altered ocular perfusion plays a role in the pathophysiology of normal tension glaucoma. Dorzolamide, a locally applied inhibitor of carbonic anhydrase, is thought to increase ocular blood flow. Less data are available regarding the influence exercised on ocular perfusion by brinzolamide, another and different, locally administered, inhibitor of carbonic anhydrase. PATIENTS AND METHODS: n = 15 eyes of 8 normal tension glaucoma patients were subjected to colour Doppler imaging and Langham-OBF (LOBF) before and during a therapy for 3 - 5 weeks with brinzolamide. RESULTS: Brinzolamide reduces intraocular pressure from 15.8 +/- 0.9 to 12.6 +/- 0.9 mm Hg (n = 15; P < 0.05). Systolic as well as diastolic blood flow velocities, resistive (RI) and pulsatility index (PI), measured by CDI, remained unchanged in the presence of brinzolamide. LOBF values are also not influenced by brinzolamide (1014 + 115 before vs. 1113 +/- 178 microl under therapy; n = 15; n. s.). DISCUSSION: Brinzolamide does not exercise any impact on ocular haemodynamics. This is different from the properties of dorzolamide that had been reported previously.     

Effect of hospitalization on intraocular pressure in patients with high tension and normal tension glaucoma

PURPOSE: To determine the effect of hospitalization on intraocular pressure (IOP) in glaucoma patients. DESIGN: Prospective case series. METHODS: IOP was measured on three consecutive days in 26 high-tension (HTG) and 13 normal-tension (NTGwm) glaucoma patients under IOP-lowering treatment, and in 28 normal-tension glaucoma patients without IOP-lowering treatment (NTGnm), and change was compared by analysis of variance. RESULTS: IOP decreased significantly, but comparably, in the three groups and between right and left eyes, although, the relative change to IOP on day 1 was significantly less pronounced in the group without treatment on day 2 and 3 compared with the treated groups. CONCLUSIONS: Glaucoma patients showed a significant decrease in IOP during hospitalization. Although this decrease was more pronounced among the treated patients, it was also present in nontreated patients. Consequently, other factors than improved compliance during hospitalization must play a role in this phenomenon.     

Effect of latanoprost 0.005% and brimonidine tartrate 0.2% on pulsatile ocular blood flow in normal tension glaucoma

AIM: To determine the effect of brimonidine tartrate 0.2% and latanoprost 0.005% on pulsatile ocular blood flow (POBF) in patients with normal tension glaucoma (NTG). METHOD: NTG patients with progressive optic neuropathy, new disc haemorrhage, or field defects that threatened fixation were enrolled into a randomised, investigator masked, crossover study. Group I patients received 4 weeks each of latanoprost, lubricant, and brimonidine, while group II patients received 4 weeks each of brimonidine, lubricant, and latanoprost. Diurnal POBF was measured at baseline and after each 4 week treatment. RESULTS: 25 patients completed the study and had reliable POBF measurement at each visit. There was no significant diurnal change in baseline POBF (p = 0.768). Latanoprost increased POBF by 213 (SD 257) micro l/min (22.8%, p <0.001) while brimonidine increased it by 97 (183) micro l/min (10.4%, p = 0.014). POBF increased at 8 am (p = 0.004), 12 noon (p = 0.002), and 4 pm (p <0.001) with latanoprost, while it increased only at 8 am (p = 0.016) with brimonidine. After adjusting for the factor of IOP, neither latanoprost nor brimonidine increased POBF significantly. CONCLUSIONS: Latanoprost increases the mean POBF that is related to its IOP lowering effect. The increase in POBF noted after brimonidine is within the range of long term variation and may not be attributable to the drug effect.     

Anterior optic nerve capillary blood flow response to diurnal variation of mean ocular perfusion pressure in early untreated primary open-angle glaucoma

PURPOSE: To examine the impact of diurnal variation in intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) on the variation in anterior optic nerve capillary blood flow (BF) in patients with untreated early primary open-angle glaucoma (uPOAG) and healthy volunteers. METHODS: Fourteen patients with uPOAG (age, 56.3 +/- 12 years [SD]; seven men) and 14 normal subjects (age, 57.6 +/- 9.9 years; five men) were examined. Diurnal IOP, systolic (SBP) and diastolic (DBP) blood pressures, and optic nerve head (ONH) topography were measured every hour; and diurnal BF was measured by flowmeter every 2 hours between 0700 and 2200 hours. A perfusion image analyzer was used to calculate the mean BF within the rim (mean rim flow, MRF). The local flow (LF) was calculated using the median and mean flow rates within a 10 x 10-pixel window placed on the rim in the area of maximum topography fluctuation (MTF). The MOPP was then calculated. Mixed-effect linear models were used to analyze the repeated measures data in which both fixed and random effects were included. RESULTS: IOP, BP, and MOPP had significant diurnal variation (P < 0.040). LF measured at the sector of MTF significantly changed in patients with uPOAG (P = 0.006) but not in normal subjects (P = 0.660). MRF did not show significant diurnal change in either group (P = 0.130, P = 0.770). LF increased significantly after lunch in the uPOAG group (P = 0.001). SBP had a significant effect on LF over the course of the day in the uPOAG group (P = 0.043). The diurnal change in IOP, BP, and MOPP did not have a significant effect on MTF in either group. In uPOAG, the local flow, in areas of greatest topographical change, correlated inversely with IOP at 0700 hours (P < or = 0.002). CONCLUSIONS: The mean rim flow did not change during the day, implying that the anterior optic nerve capillary blood flow was autoregulated in both normal subjects and in patients with uPOAG, despite significant changes in IOP and MOPP. However, the regions of greatest diurnal change in rim topography (MTF) had significant diurnal change in capillary blood flow in patients with uPOAG but not in normal subjects.