Ocular Perfusion Pressure and Severity of Glaucoma: Is There a Link?

INTRODUCTION

Intraocular pressure (IOP) is a known modifiable risk factor for glaucoma. Thus, the objective of glaucoma management is to lower the IOP to achieve a safe target pressure. However, glaucomatous damage still occurs in some patients despite a significant reduction of IOP. This implies that other factors may be responsible. About 20% of normal-tension glaucoma (NTG) patients in The Collaborative Normal-Tension Glaucoma (CNTG) study progressed despite achieving 30% IOP reduction from baseline.¹

Low ocular perfusion pressure (OPP) is also identified as a potential risk factor for the progression of glaucoma. The Egna-Neumarkt study, Proyecto VER, and the Baltimore Eye Survey reported that low diastolic OPP (dOPP) was associated with three-, four-, and six-folds increase risk of open-angle glaucoma (OAG), respectively.^2–4 The Barbados Eye Study and the Los Angeles Latino Eye Study also showed that mean OPP (mOPP) and systolic OPP (sOPP) were associated with glaucoma.^5,6 Ocular perfusion pressure affects ocular blood flow to the optic nerve head (ONH).^7–9

Circulatory abnormalities by occlusion of small vessels produce infarction of the ONH.¹⁰ Persistently high IOP mechanically causes stretching of the laminar beams, which subsequently damages the retinal ganglion cell axons.^11,12 Ocular blood flow reduces with decreasing perfusion pressure, especially when vascular autoregulation is impaired.^7–9 Autoregulatory mechanism maintains the blood flow to the ONH to a certain extent. Thus, theoretically, the combination of high IOP and low BP may lead to the progression of glaucoma.

In addition, diurnal OPP fluctuation is also a risk factor for the progression of glaucoma.¹³ Long-standing instability of OPP may also be responsible for chronic optic disk circulation insufficiency that ultimately causes further deterioration and progression of glaucoma.¹⁴ Asrani et al. found that diurnal IOP and short-term IOP fluctuations over the days are important predictors for the progression of glaucoma.¹⁵

However, 24-hour monitoring of OPP is impractical for most patients and ophthalmologists. It is usually conducted in the sleep lab or requires hospital admission that disturbs the patient’s daily routine. The hospital setting and sleep lab create an artificial environment. The 24-hour blood pressure (BP) measurement performed may not truly reflect a patient’s daily rhythm.¹⁶ Inter-visit OPP is, therefore, more practical in clinical practice with less disruption to the patient’s routine and cost-effective. The inter-visit OPP is best conducted according to the patient’s routine clinic appointment. The relationship between OPP and the severity of glaucoma has not been studied thoroughly. This study aimed to study the association between 12 months inter-visits OPP with different types of primary glaucoma. The inter-relationship between OPP, BP, IOP, and primary glaucoma was also explored.

MATERIALS AND METHODS

A prospective cohort study was conducted involving patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and primary angle-closure glaucoma (PACG), who were seen in the eye clinics of Hospital Raja Permaisuri Bainun (HRPB), Perak and Hospital Universiti Sains Malaysia (HUSM), Kelantan, Malaysia, between September 2010 and September 2012 to establish the association between 12-month inter-visits OPP and severity of glaucoma. This study received ethical approval from the Research Ethics Committee, Ministry of Health Malaysia (NMRR-10-1244-7957) and the Research Ethics Committee, Universiti Sains Malaysia (reference no. USMKK/PPP/JEPeM[234.3(12)]). This study was conducted in accordance with the Declaration of Helsinki for human research.

RESULTS

DISCUSSION

The elusive role of OPP in glaucoma remains the interest of many researchers till now. Ocular perfusion pressure is calculated mathematical according to the assumption that IOP represents the venous pressure and BP as the arterial pressure. The association between inter-visit mOPPs and the severity of glaucoma was statistically significant. Our end-stage glaucoma patients were found to have the lowest mOPP of <50 mm Hg (47.8 mm Hg). This group of patients was also noted to have the highest mean IOP (16.7 mm Hg) and lowest mean sBP (132.7 mm Hg), both of which mathematically translated into a low OPP. In advanced glaucoma eyes which are already compromised structurally and functionally, low OPP may exert a significant effect in hastening the process of retinal fiber layer damage.²¹ The relationship between mOPP and different severity of glaucoma has not been explored. But OPP as a risk factor for glaucoma was previously reported with variable results. In Los Angeles Latino Eye Study, up to 3.6-folds increase risk of OAG were identified among individuals with mOPP ≤50 mm Hg.⁵ The Barbados Eye Study also found a 3.1-folds increase risk of developing glaucoma at 4 years with mOPP <42 mm Hg.⁶

In the present study, patients with end-stage glaucoma shown the widest mOPP fluctuation (4 mm Hg) compared with patients with early (2.5 mm Hg) and mild (2 mm Hg) glaucoma. Choi et al. reported that fluctuation of circadian OPP is a consistent risk factor for progression to more severe disease.¹³ In their study, patients with NTG have wider circadian fluctuation and are associated with worse structural and functional outcome.¹³ It is believed that vascular dysregulation within the retrobulbar hemodynamic in patients with NTG may be responsible for OPP fluctuation causing unstable ONH perfusion leading to retinal nerve fiber layer damage.²²

On the other hand, the Early Manifest Glaucoma Trial (EMGT) identified that sOPP of ≤125 mm Hg was associated with a higher risk of progression, and a mean sBP of %3E;160 mm Hg protects against progression.²³ Interestingly, in our patients, the mean sOPP was <125 mm Hg in all patients except for severe glaucoma at baseline. Mean sOPP was highest in patients with early glaucoma, followed by mild and lowest in patients with end-stage (121.2, 119.6, and 116.2 mm Hg, respectively). Mean sBP of <137 mm Hg (early 136.3 mm Hg, mild 134.1 mm Hg, and end-stage 132.7 mm Hg) were recorded in all patients. Our findings are almost similar to the Singapore Epidemiology of Eye Diseases (SEED) study.²³ The SEED study concluded that low (%3C;110 mm Hg) and high (%3E;137 mm Hg) sOPP was significantly associated with POAG, after being adjusted to IOP.²³

In our study, patients with early glaucoma, demonstrated low mean IOP (15.6 mm Hg), higher mean dBP (80 mm Hg), and sBP (136.5 mm Hg) compared with patients with end-stage glaucoma (78.7 and 132.7 mm Hg, respectively). Relatively higher BP in early glaucoma may have a protective effect on the optic nerve due to potentially high hydrostatic pressure within the small vessels providing more resistance to compression caused by IOP.²⁴ However, as the disease progresses from early to mild or moderate glaucoma, the small vessels may start to lose their compensating ability and possibly upset the autoregulatory functions.

Based on 24-hour BP monitoring, Kaiser et al. found lower day and night time sBP at the day in patients with OAG who continued to progress despite well-controlled IOP.²⁵ Cardiovascular disease and hypotension was found to increase the risk of rapid progression of glaucoma 2.33 times despite lower mean IOP.²⁶ Nocturnal BP dipping and fluctuations have also been linked to the progression of glaucoma.²⁷ Progression of glaucoma leads to a more severe stage of the disease. The AGIS reported that long-term IOP fluctuations were one of the important predictors for progression of glaucoma, even in patients with low mean IOP.^28,29 Wide fluctuations could possibly cause repetitive ischemia and reperfusion insult which may have more damaging effects on the retinal nerve fiber layer compared with eyes with constant pressure.

There were limitations in our study. It was not adjusted for IOP and patients on systemic treatment for hypertension were not excluded. As we assume that BP and IOP are part of the equation in OPP, any factors affecting these two variables will theoretically affect the OPP. All patients with glaucoma were on at least one topical pressure-lowering drug. Patients with end-stage glaucoma mostly achieved their target IOP with multiple topical pressure-lowering drugs. However, we excluded those who have undergone filtering surgery. Topical pressure-lowering drugs cause reduction of IOP mathematically elevates OPP measurement.³⁰ However, the effect of IOP on OPP is not as simple as mathematical calculation.²⁷ Quaranta et al. reported that in their patients with glaucoma who were not on any BP-lowering medications, dOPP was significantly increased by dorzolamide 2% and latanoprost 0.005%.³¹ Brimonidine 0.2%, on the other hand, induced a significant decreased in dOPP but there was no significant difference with timolol 0.5%.³¹ Both timolol and brimonidine were also found to significantly reduce sBP and dBP.^30,31 Topical pressure-lowering drugs could therefore induce changes to OPP by affecting IOP, BP, or both.

More than half of our study population were also treated for systemic hypertension. The manipulation of BP by oral anti-hypertensive agents can have effects not only on the mean OPP but possibly indirectly on the retinal nerve fiber layer integrity through the pressure effect. American College of Cardiology and American Heart Association in their latest report on hypertension has redefined normal BP to 120/80 or below.³² Ocular perfusion pressure can be expected to be lower with the more aggressive BP treatment depending on target BP. Aggressive BP treatment could also contribute to a more frequent occurrence of hemodynamic instability (e.g., greater nocturnal BP dips) and hence ONH insult. In susceptible individuals, failure of ONH reperfusion to compensate for the overly pharmacologically induced low BP may occur.^9,27

Hayreh found that patients on both topical and systemic beta-blocker medications had more occurrence of nocturnal BP drops.⁹ Interestingly, our patients demonstrated a downward trend of BP with each visit in all stages of glaucoma. This may be due to better compliance of patients on oral anti-hypertensive medication once they were enrolled in the study. However, office measurement of BP and IOP may not be the true reflection of the patient’s BP and IOP. Blood pressure and IOP follow the physiological circadian rhythm and are affected by habitual position. Moreover, it is not uncommon for some patients to have “white coat hypertension” or even “reverse white coat” effect (masked hypertension), which may give rise to inaccurate BP interpretation.³³ There is also a possibility of “regression towards the mean” that normally occurs in the study involving repeated measurements such as BP and IOP.³⁴

In this study, three types of primary glaucoma were included; POAG, NTG, and PACG. Primary angle-closure glaucoma patients tend to have wider 24-hour IOP fluctuation and higher mean IOP than the other types. Subdividing them according to severity without looking into types of glaucoma may not reflect the actual condition as the IOP results were presented as an average mean of IOP readings. There were only seven patients with end-stage glaucoma due to the high drop-out rate in this group. This happened due to their inability to provide a reliable visual field, and also, in the course of the study, there were inevitable changes in the management, e.g., needs for filtering surgery. The AGIS score adopted in this study may also not be ideal in determining the severity of the disease as it is based on the total deviation plot of Humphrey’s visual field analysis. The effect of media opacity especially cataracts was not eliminated in this plot.

Nevertheless, balancing BP and IOP as well as minimizing inter-visit OPP fluctuation is important in the management of glaucoma particularly at the early stage of glaucoma. Arresting further progression is crucial at the early stage of the disease. However, balancing BP and IOP is not as easy as mathematical calculation.

CONCLUSION

Our study demonstrated the importance of monitoring OPP rather than just IOP alone in the management of glaucoma especially at the early stage of the disease to prevent further progression. However, many factors are affecting OPP calculation. Balancing BP in glaucoma patients is crucial especially in those who achieved target IOP and on systemic antihypertensive treatment.

REFERENCES

1. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998;126(4):498–505. DOI: 10.1016/S0002-9394(98)00272-4.

2. Bonomi L, Marchini G, Maraffa M, et al. Vascular risk factors for primary open angle glaucoma. The egna-neumarkt study. Ophthalmology 2000;107(7):1287–1293. DOI: 10.1016/s0161-6420(00)00138-x.

3. Quigley HA, West SK, Rodriguez J, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects: proyecto VER. Arch Opthalmol 2001;119(12):1819–1826. DOI: 10.1001/archopht.119.12.1819.

4. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma: a population-based assessment. Archives Ophthalmol 1995;113(2):216. DOI: 10.1001/archopht.1995.01100020100038.

5. Memarzadeh F, Ying-Lai M, Chung J, et al. Los Angeles Latino Eye Study Group Blood pressure, perfusion pressure, and open-angle glaucoma: the Los Angeles Latino eye study. Invest Opthalmol Vis Sci 2010;51(6):2872–2877. DOI: 10.1167/iovs.08-2956.

6. Leske MC, Wu SY, Hennis A, et al. Risk factors for incident open-angle glaucoma: the barbados eye studies. Ophthalmology 2008;115(10):85–93. DOI: 10.1016/j.ophtha.2007.03.017.

7. Harris A, Werne A, Cantor LB. Vascular abnormalities in glaucoma: from population-based studies to the clinic. Ophthalmol Clin North America 2008;145(4):595–597. DOI: 10.1016/j.ajo.2007.12.019.

8. Werne A, Harris A, Moore D, et al. The circadian variations in systemic blood pressure, ocular perfusion pressure, and ocular blood flow: risk factors for glaucoma? Surv Ophthalmol 2008;53(6):559–567. DOI: 10.1016/j.survophthal.2008.08.021.

9. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog Retinal Eye Res 2001;20(5):595–624. DOI: 10.1016/s1350-9462(01)00005-2.

10. Drance SM. Disc hemorrhages in the glaucomas. Surv Ophthalmol 1989;33(5):331–337. DOI: 10.1016/0039-6257(89)90010-6.

11. Yan DB, Coloma FM, Metheetrairut A, et al. Deformation of the lamina cribrosa by elevated intraocular pressure. Br J Ophthalmol 1994;78(8):643–648. DOI: 10.1136/bjo.78.8.643.

12. Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol 1994;39(1):23–42. DOI: 10.1016/s0039-6257(05)80042-6.

13. Choi J, Kim KH, Jeong J, et al. Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma. Invest Ophthalmol Vis Sci 2007;48(1):104–111. DOI: 10.1167/iovs.06-0615.

14. Nicolela MT, Walman BE, Buckley AR, et al. Various glaucomatous optic nerve appearances. A color Doppler imaging study of retrobulbar circulation. Ophthalmology 1996;103(10):1670. DOI: 10.1016/s0161-6420(96)30448-x.

15. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 2000;9(2):134. DOI: 10.1097/00061198-200004000-00002.

16. Pikilidou MI, Tsirou E, Stergiou GS, et al. Effect of hospitalization on 24-h ambulatory blood pressure of hypertensive patients. Hypertens Res 2010;33(10):995–999. DOI: 10.1038/hr.2010.127.

17. Foster PJ, Buhrmann R, Quigley HA, et al. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86(2):238–242. DOI: 10.1136/bjo.86.2.238.

18. Anderson DR. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol 2003;14(2):86. DOI: 10.1097/00055735-200304000-00006.

19. Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002;156(9):871–881. DOI: 10.1093/aje/kwf113.

20. Sehi M, Flanagan JG, Zeng L, et al. Relative change in diurnal mean ocular perfusion pressure: a risk factor for the diagnosis of primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2005;46(2):561–567. DOI: 10.1167/iovs.04-1033.

21. Renard E, Palombi K, Gronfier C, et al. Twenty-four hour (nyctohemeral) rhythm of intraocular pressure and ocular perfusion pressure in normal-tension glaucoma. Invest Ophthalmol Vis Sci 2010;51(2):882–889. DOI: 10.1167/iovs.09-3668.

22. Galassi F, Giambene B, Varriale R. Systemic dysregulation and retrobulbar hemodynamics in normal-tension glaucoma. Invest Ophthalmol Vis Sci 2011;5(7):4467–4471. DOI: 10.1167/iovs.10-6710.

23. Tham YC, Lim SH, Gupta P, et al. Inter-relationship between ocular perfusion pressure, blood pressure, intraocular pressure profiles and primary open-angle glaucoma: the Singapore epidemiology of eye diseases study. Br J Ophthalmol 2018;102(10):1402–1406. DOI: 10.1136/bjophthalmol-2017-311359.

24. Riva CE, Hero M, Titze P, et al. Autoregulation of human optic nerve head blood flow in response to acute changes in ocular perfusion pressure. Graefe’s Arch Clin Exp Ophthalmol 1997;235(10):618–626. DOI: 10.1007/BF00946937.

25. Kaiser HJ, Flammer J, Graf T, et al. Systemic blood pressure in glaucoma patients. Graefes Arch Clin Exp Ophthalmol 1993;231(12):677–680. DOI: 10.1007/BF00919280.

26. Wai Chan TC, Bala C, Siu A, et al. Risk factors for rapid glaucoma disease progression. Am J Ophthalmol 2017;180:151–157. DOI: 10.1016/j.ajo.2017.06.003.

27. Costa VP, Harris A, Anderson D, et al. Ocular perfusion pressure in glaucoma. Acta Ophthalmol 2014;92(4):e252–e266. DOI: 10.1111/aos.12298.

28. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. predictive factors for glaucomatous visual field progression in the advanced glaucoma intervention study. Ophthalmology 2004;111(9):1627–1635. DOI: 10.1016/j.ophtha.2004.02.017.

29. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressure in the advanced glaucoma intervention study. Ophthalmology 2008;115(7):1123–1129. DOI: 10.1016/j.ophtha.2007.10.031.

30. Harris A, Jonescu-Cuypers CP. The impact of glaucoma medication on parameters of ocular perfusion. Curr Opin Ophthalmol 2001;12(2):131–137. DOI: 10.1097/00055735-200104000-00009.

31. Quaranta L, Gandolfo F, Turano R, et al. Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated ocular perfusion pressure in patients with glaucoma. Invest Ophthalmol Vis Sci 2006;47(7):2917–2923. DOI: 10.1167/iovs.05-1253.

32. Whelton PK, Carey RM, Aronow WS, et al. 2017ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 2017.[Epub ahead of print].

33. Larkin KT, Schauss SL, Elnicki DM. Isolated clinic hypertension and normotension: false positives and false negatives in the assessment of hypertension. Blood Press Monit 1998;3:247–254.

34. Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol 2005;34(1):215–220. DOI: 10.1093/ije/dyh299.