Revisao-bjo-completa-atual

Vital P. Costa, MD1,2; Enyr S. Arcieri, MD1,3; Alon Harris, PhD, MS4. 1. Department of Ophthalmology, University of Campinas, Brazil. 2. Department of Ophthalmology, University of São Paulo, Brazil. 3. Department of Ophthalmology, Federal University of Uberlândia, Brazil. 4. Department of Ophthalmology, Indiana University, Indianapolis, USA. Address for correspondence: Vital P. Costa, MD Director, Glaucoma Service, University of Campinas, Brazil Rua Pará 269 apto 142. São Paulo SP 01243-020 Brazil Email: vp.costa@uol.com.br Abstract Although intraocular pressure (IOP) is considered the main risk factor for the development of glaucoma and the only parameter subject to treatment, there is sufficient evidence to suggest that glaucoma may continue to progress despite lowering patients’ IOP to targeted levels. Several studies have implicated vascular risk factors in the pathogenesis of glaucoma. Among them, blood pressure (BP) and ocular perfusion pressure have become increasingly important. Although clinicians cannot currently visualize ocular blood flow directly, they can easily measure glaucoma patients’ BP and IOP to calculate their ocular perfusion pressure and quantify the vascular changes. The purpose of this review article is to discuss the relationship between BP and IOP, BP and glaucoma, and perfusion pressure and glaucoma. We discuss the importance of autoregulation to maintain the adequate perfusion of the optic nerve head, and suggest that ocular perfusion pressure and its fluctuation may be parameters that need to be measured in glaucoma patients. Glaucoma is a multifactorial disease characterized by loss of retinal ganglion cells that leads to typical damage of the optic nerve and visual field. Glaucoma is the second leading cause of blindness worldwide, and affects more than 50 million people1. Although intraocular pressure (IOP) is considered the main risk factor for the development of glaucoma and the only parameter subject to treatment, there is sufficient evidence to suggest that glaucoma may continue to progress despite lowering patients’ IOP to targeted levels2-4. Several studies have implicated vascular risk factors in the pathogenesis of primary open-angle glaucoma (POAG)5-29. Among them, blood pressure (BP) and ocular perfusion pressure (OPP) have become increasingly important. Perfusion pressure is defined as the difference between arterial and venous pressure. In the eye, venous pressure is equal to or slightly higher than IOP. OPP can therefore be defined as the difference between arterial BP and IOP. OPP can be further broken down into diastolic perfusion pressure (diastolic BP minus IOP) and systolic perfusion pressure (systolic BP minus IOP)30. The purpose of this review article is to discuss the relationship between BP, perfusion pressure and glaucoma. 1. BLOOD PRESSURE AND INTRAOCULAR PRESSURE Several epidemiological studies have shown that elevated systemic BP is associated with a slight increase in IOP11-13,16. In the Blue Mountains Eye Study14,21, mean IOPs of the two eyes increased from 14.3 mmHg for systolic BP levels < 110 mmHg to 17.7 mmHg for systolic BP levels ≥ 200 mmHg. Mean IOPs of the two eyes increased from 15.2 mmHg for diastolic BP levels < 70 mmHg to 18.6 mmHg for diastolic BP levels of ≥120 mmHg. Mean IOP in right eyes increased by 0.28 mmHg for each 10-mm Hg increase in systolic BP, or by 0.52 mmHg for each 10-mmHg increase in diastolic BP. In the Beijing Eye Study28,31,32, multivariate regression analysis revealed significant associations between IOP and both systolic (P<0.001) and diastolic BP (P<0.001). Hennis et al19 examined the longitudinal relationship between systemic hypertension and a 4-year IOP change in residents of Barbados aged ≥ 40 years. Overall, mean IOP increased by 2.5 ± 3.9 mmHg in black participants during the 4-year period of follow-up. Participants with elevated systolic and diastolic BP at baseline, or those receiving antihypertensive therapy had greater increases in IOP than did others. Klein et al23 investigated the association between change in systemic BP and change in IOP in Beaver Dam. Five years after baseline, the authors performed a follow-up examination of 3684 participants. In cross sectional analyses at baseline and follow up, it was found that a 10 mmHg increase in systolic BP was associated with a 0.3 mmHg increase in IOP, whereas a 10 mmHg increase in diastolic BP was associated with a 0.6 mmHg increase in IOP. Over the 5 year interval, an increase of 10 mmHg in systolic BP was associated with an increase of about 0.2 mmHg in IOP, and an increase of 10 mmHg in diastolic BP was associated with a 0.4 mmHg increase in IOP. The Egna-Neumarkt Glaucoma Study16 evaluated the association between systemic BP and age-adjusted IOP. The correlation between BP and IOP was statistically significant (r>0.94; P<0.001) for both systolic and diastolic BP. A 10-mmHg increase in systolic BP was associated with a 0.24 mmHg increase in IOP, whereas the same 10-mmHg increase in diastolic BP was associated with a 0.4 mmHg increase in IOP. In summary, increases in IOP in response to a 10-mmHg increase in systolic and diastolic BP vary from 0.20 to 0.44 mmHg and 0.40 to 0.85 mmHg, respectively. Therefore, although real, the IOP increase in association with systemic hypertension is of modest proportion, which indicates that the clinical importance of BP increase in the pathogenesis of glaucoma may be limited. 2. PHYSIOLOGY BEHIND THE RELATIONSHIP BETWEEN IOP AND BP The physiological meaning of the correlation between BP and IOP remains speculative. Bill33 demonstrated that variations in systolic BP resulted in small changes in aqueous humor formation, possibly related to increased capillary pressure in the ciliary body. In fact, when monkeys are rapidly bled to a femoral arterial BP of about 60mmHg, the rate of aqueous formation is reduced about 20%. Blood pressure may also affect the episcleral venous pressure, modifying aqueous humor outflow28. There are two theories that speculate on the specific mechanism which controls the relationship between BP and IOP. The first suggests the role of the autonomic nervous system, which could control IOP by changing the balance between aqueous humor formation and outflow34. The second proposes that the renin-angiotensin system may regulate both IOP and BP, which is supported by a number of studies where olmesartan and ACE inhibitors have been reported to lower IOP in rabbits, monkeys and humans35-40. Tissue or local renin-angiotensin system has been found in the eye by a number of investigators41-44. This evidence is further supported by a recent finding that intravitreally administered angiotensin (1-7) reduces IOP in normotensive rabbit eyes48. Since both of these systems are involved in the control of BP and there is evidence of these actions in the control of IOP, further investigation is necessary to elucidate if the two systems are connected in some way. While it is not clear by what mechanism IOP might be influenced by systemic BP, it is reasonable to speculate how the effect of elevated BP can raise IOP. Hvidberg et al45 investigated the effect of PCO2 changes and body positions on IOP during general anesthesia. This study found that when CO2 administration was removed, a rapid simultaneous reduction in IOP occurred, which had therefore to be of vascular origin, presumably due to change in choroidal volume. Gupta46 described how coughing raises intracranial pressure, which produces an instantaneous effect on choroidal volume and IOP due to mechanical deformation of ocular structures. These two reports, while not explaining how BP and IOP are directly related, support the hypothesis that elevated systemic BP might produce increased choroidal volume, which in turn increases IOP. 3. BLOOD PRESSURE AND GLAUCOMA The relationship between BP and the prevalence and progression of glaucoma remains controversial. While some studies indicated systemic hypertension as a significant risk factor for glaucoma8,16,47-56, others have identified BP reductions as an important risk factor for the development and progression of glaucoma57-63. 3.1 SYSTEMIC HYPERTENSION AND GLAUCOMA Several studies found correlation between arterial hypertension and glaucoma (Table 1). In the Blue Mountains Eye Study21, systemic hypertension was found to be significantly associated with an increased risk of POAG, independently of the effect of BP on IOP. Interestingly, systemic hypertension accounted for the greatest attributable risk for POAG than any other risk factors found in the study. In the Egna-Neumarkt Study16, when risk factors for POAG were evaluated, the use of antihypertensive medication, and the presence of systemic hypertension led to age- and sex-adjusted odds ratios greater than 1, although the confidence limits were broad. Overall, this may suggest a correlation between POAG and systemic hypertension regardless of age. To assess the importance of vascular risk factors in glaucoma, data from the medical history of 2,879 POAG patients and 973 age-matched controls were collected and analyzed by Orzalesi et al26 in an observational survey. Mean systolic BPs were 139.2 mmHg in POAG patients vs. 137.1 mmHg in controls (P=0.001), while mean diastolic BPs were 82.4 mmHg in POAG patients vs. 81.5 mmHg in controls (P=0.001). The small magnitude of the between-groups difference for systolic and diastolic BP persisted after adjustment for confounding variables such as age, gender, and history of systemic hypertension. 3.2 SYSTEMIC HYPOTENSION AND GLAUCOMA On the other hand, a number of studies have found a higher risk for development and progression of glaucoma in people with low BP, especially in normal tension glaucoma (NTG) (Table 1). In a series of 4 glaucoma patients with rapid glaucoma progression despite normal or well controlled IOP, low systemic BP in tandem with sustained BP drop during sleep was observed64. Kaiser et al65 monitored 24-hour BP in 78 POAG patients, 39 NTG patients, and 32 controls, and found that both POAG patients with progression despite well controlled IOP and patients with NTG had a markedly reduced systolic BP during day and night. Leske et al29 evaluated the risk factors for POAG in 3222 participants of the Barbados Eye Studies over 9 years of follow-up and found a high POAG incidence of 4.4%. Evaluations of systolic BP, diastolic BP, pulse pressure, and arterial pressure consistently indicated a trend toward a negative relationship with POAG risk. The relative risks (RR) per mmHg were decreased for these four variables (0.89–0.92 per 10 mmHg higher). When BP measurements were grouped as high, medium, and low, the lowest categories of systolic BP and diastolic BP had RR > 1, indicating an increased risk for glaucoma. Recently, the Thessaloniki Eye Study25 evaluated the association between BP and optic disk structure as measured with the Heidelberg Retina Tomograph (HRT) in 462 eyes. The authors found that subjects with diastolic BP < 90 mmHg as a result of antihypertensive therapy presented with increased cup area, greater C/D ratio, and decreased rim area compared with subjects with diastolic BP≥ 90 mmHg or with subjects with normal diastolic BP (< 90 mmHg without antihypertensive treatment). Similarly, low perfusion pressure was also associated with decreased rim area, increased cup area, and greater C/D ratio. Additional evidence suggesting the influence of low BP on the pathogenesis of glaucoma comes from reports of glaucomatous-like optic nerve and visual field damage secondary to a spontaneous fall in BP as a result of transient shocklike state6,66-72. In individuals with glaucoma and repeated hemodynamic crises, it becomes difficult to differentiate between real glaucoma progression and progressive ischemic damage. Patients who experience large fluctuations in BP at night may have a higher risk of glaucomatous progression compared with individuals whose BP fluctuates within normal limits60,63,73-76. Previous reports have indicated that a nocturnal BP reduction (dip) of 10-20% can be considered physiologic77,78. Ambulatory BP monitoring studies in NTG, POAG, and anterior ischemic optic neuropathy (AION) disclosed a significantly (P=0.0028) lower nighttime mean diastolic BP and significantly (P=0.0044) greater mean percentage drop in diastolic BP in NTG than in AION patients. Furthermore, arterial hypertensive patients on oral hypotensive therapy showed a significant association between progressive visual field deterioration and nocturnal hypotension70. Graham et al61 found that, in 37 patients with progressive visual field defects, compared with 15 patients with stable visual fields, there was a significantly greater drop in the systolic (P=0.001), diastolic (P=0.060), and mean (P=0.016) BP during the night in those with visual field deterioration. On the other hand, others have observed that small nocturnal BP dips or lack of dips were associated with glaucoma progression79-81. Tokunaga et al81 assessed prospectively the relationship between nocturnal BP reduction and progression of the visual field in 38 patients with NTG or POAG who had been followed for at least 4 years. Glaucoma patients with a dip of < 10% were assigned to the nondipper group, those with a dip of 10%–20% to the physiologic dipper group, and those with a dip of > 20% to the extreme dipper group. The nondipper and the extreme dipper groups were defined as nonphysiologic dippers. The nonphysiologic dippers had a significantly higher incidence of progression compared with the physiologic dippers (P=0.05). Among the glaucoma patients in the nondipper and dipper categories only, those who progressed had significantly smaller dips (P=0.02). Since there were only four extreme dippers, it was not possible to evaluate this group separately. PHYSIOLOGY BEHIND THE RELATIONSHIP BETWEEN BP AND GLAUCOMA The vascular or ischemic hypothesis postulates that glaucomatous damage may be caused or facilitated by inadequate perfusion of the proximal portion of the optic nerve. In order to elucidate the relationship between BP and glaucoma, it is fundamental to understand the concept of autoregulation. Autoregulation is a term applied to the physiologic phenomenon in which the resistance changes dynamically to keep flow at whatever constant level is required by the local and metabolic activity despite changes in perfusion pressure, e.g., when arterial pressure changes or when venous pressure is affected by IOP82-87. According to Anderson87, when venous pressure at the exit point from the eye is elevated by IOP, the arteriovenous pressure difference is reduced, and nutrition is maintained only because of blood flow autoregulation. IOP–induced ischemia can result if autoregulation is impaired, either because of an innate deficiency, or as a result of vasospastic disease. Autoregulation can also be impaired if another disease has caused much of the autoregulatory capacity to be already utilized, so that little is left to respond to the additional challenge of IOP. In glaucoma, any increase in IOP above orbital venous pressure will reduce perfusion pressure of intraocular beds, which represents a challenge to the circulation. Hence, microcirculatory disturbances in both POAG and NTG is simply a matter of how much the IOP exceeds the orbital venous pressure and whether the autoregulatory mechanisms can compensate for that degree of challenge. When the ability to regulate is adequate, an IOP somewhat above the normal range will not produce inadequate vascular perfusion. However, if the regulatory mechanisms are compromised, blood flow may not be adequate beyond some critical level of IOP, but can be restored by lowering the IOP. Several pathophysiological mechanisms have been proposed to explain the association between hypertension and glaucoma20,60,61,74,88-94. Direct microvascular damage from systemic hypertension could impair blood flow to the optic disk74,90. This notion is supported by studies linking glaucoma to abnormal ocular blood flow20,91 and narrowing of the retinal vasculature89,93. Hayreh et al studied the effects of systemic cardiovascular disease in monkey eyes with chronic, experimentally increased IOP 95,96. The authors induced atherosclerosis97 and chronic arterial hypertension98 in 24 of 38 monkeys for several years before experimentally increasing the IOP. Their morphologic study suggested that vascular disease may influence glaucomatous damage, with damage being greater in those with atherosclerosis-hypertension. Hypertension could also compromise the autoregulation of the posterior ciliary artery circulation, which is already impaired in glaucoma88. On the other hand, systemic hypotension and antihypertensive treatment could induce hypotensive episodes, especially at night60,61, which could reduce blood flow to the optic disk, resulting in glaucomatous damage69. Similarly, this deleterious effect would be enhanced by an impaired autoregulation. As mentioned above, the lack of nocturnal BP dips may also be harmful to glaucoma patients. It has been suggested that an insufficient nocturnal BP decrease may cause impaired microcirculation, possibly due to excessive production of free radicals or other harmful molecules that are toxic to neurons or glial cells81. A similar finding has been reported to cause glomerular damage to the kidney99. In summary, both systemic hypertension and hypotension, as well as the diurnal fluctuation of BP, could, through different mechanisms, be risk factors for glaucoma. In any case, the balance between IOP and BP, and the ability to deal with an eventual unbalance, are determinant to the development of glaucoma. For this reason, the concept of perfusion pressure may be highly important, as discussed below. 4. PERFUSION PRESSURE AND GLAUCOMA Reduced OPP in POAG patients has been reported in a number of studies, including large epidemiologic surveys12,16,17,21,26. Population-based studies have identified low perfusion pressure as a risk factor for the development of glaucoma (Table 2). The Baltimore Eye Survey indicated that individuals with diastolic perfusion pressures lower than 30 mmHg had a six-fold higher risk of developing the disease than individuals with diastolic perfusion pressures greater than 50 mmHg12. In the Barbados Study, subjects with the lowest 20% of diastolic perfusion pressures were 3.3 times more likely to develop glaucoma13. In this study, all lower OPPs were positively related to OAG risk, with RR at least doubling in the lowest perfusion pressure categories. In a subsequent study among participants of the Barbados Eye Study, risk factors for the incidence of glaucoma over 9 years of follow-up were evaluated. Again, lower systolic BP, and lower OPPs were identified as risk factors29. Similarly, the Egna-Neumarkt study reported a 4.5% increase in the prevalence of the disease in patients with diastolic perfusion pressures < 50 mmHg compared with those whose diastolic perfusion pressures were 65 mmHg16. In the Proyecto Ver Study100 patients who presented with a diastolic perfusion pressure of 45 mmHg had a three times greater risk of developing glaucoma than those with measurements of 65 mmHg. Although these population-based studies examined individuals from different geographic locations and various ethnic origins, they all found that low diastolic perfusion pressure is an important risk factor for the prevalence of glaucoma. Furthermore, recently published data from the Early Manifest Glaucoma Trial (EMGT) established lower systolic perfusion pressure as a new predictor for disease progression, suggesting a 50% increase in risk101. According to the EMGT, exfoliation, worse baseline mean defect on perimetry, bilateral disease, disc hemorrhages and lower systolic perfusion pressure (< 125 mmHg) increased the risk of glaucoma progression in all individuals. When assessing the role of systolic blood pressure on progression, the authors found that it was not a risk factor in those with higher baseline IOP (defined as IOP > 21 mmHg), but was a risk factor in those with lower IOP (< 21 mmHg). These findings indicate that vascular factors may be an important determinant of glaucoma progression. Additionally, cardiovascular disease was found to be a risk factor for glaucoma progression in patients with higher baseline IOP. 5. PERSPECTIVES The measurement of ocular blood flow is complicated by the fact that the posterior pole of the eye is nourished by two different vascular beds, the retina and the choroid102. These two vascular systems significantly differ in terms of physiological and pathological properties103. The utility of several instruments developed to measure blood flow in various ocular beds is limited. Each technology only assesses a small portion of the ocular vasculature. Abnormal ocular blood flow in glaucoma has been documented in the optic disk, choroid, retina, and retrobulbar circulation104. At present, because no single blood-flow device can assess all the relevant vascular beds, a comprehensive analysis using several modalities is needed to fully evaluate a patient’s ocular blood flow. Moreover, due to the complexity of the various datasets and the analysis necessary to interpret these outcomes, it is essentially only possible for scientists who are highly trained in imaging and who have a background in vascular physiology to complete a comprehensive examination of ocular blood flow. Although clinicians cannot currently visualize ocular blood flow directly, they can easily measure glaucoma patients’ BP and IOP to calculate their OPP and quantify the vascular changes. Diurnal fluctuations in IOP have been identified as a possible risk factor for glaucomatous progression105-108. We hypothesize that investigating patients’ OPP, and measuring perfusion pressure throughout a 24-hour period may allow physicians to be more comprehensive when determining patients’ risk for progression. Recently, Choi et al75 performed a retrospective chart review of 113 eyes with NTG to investigate systemic and ocular hemodynamic risk factors for glaucomatous damage. Systolic BP and diastolic BP fluctuations were defined as the difference between the highest and lowest SBP and DBP recorded during the 24-hour period. Of the functional and anatomic outcome variables, circadian mean OPP fluctuation was the most consistent clinical risk factor for glaucoma severity in eyes with NTG. Some patients may benefit from an assessment of their 24-hour perfusion pressures. Measuring uncontrolled elevations in IOP and undesirable reductions in blood pressure during a 24-hour period may identify a risk for changes in the optic disc. In the first case, patients would require further reduction in IOP. When their BP is low and they are on antihypertensive therapy, as illustrated in Figures 1, 2, and 3, modifications in patients’ medical regimens are warranted. CONCLUSION
For years, fierce discussions have occurred between supporters of the
mechanical and vascular theories for the pathogenesis of glaucoma. The concept of OPP and the identification of this as an important risk factor for the development and progression of glaucoma brought together the vascular and mechanical components of glaucoma. We believe that it is the balance between IOP and BP, influenced by the autoregulatory capacity of the eye, that determines whether an individual will develop optic nerve damage. However, further research is required to evaluate the importance of OPP and its fluctuation as parameters to be measured in glaucoma patients. Acknowledgments: The participation of Alon Harris is supported in part by an unrestricted research grant from Research to Prevent Blindness, New York, NY. The authors would also like to thank Lynne McCranor for her assistance in the Table 1 – Studies showing a relationship between glaucoma and blood pressure. Author(s) CCS – case control series; CSS – cross-sectional study; CR – case report; ES – epidemiological study; RCA – retrospective chart analysis. Table 2 – Studies investigating the association between perfusion pressure and glaucoma. had a 6-fold higher risk of developing POAG increased 4-fold at lower diastolic PP (OR = 0.96) Diastolic PP < 55 mmHg – RR = 3.2 Mean PP < 42 mmHg – RR = 3.1 10 mmHg increase in systolic PP (OR = 1.09) associations in a mmHg) inversely population- = 0.25) and positively associated with POAG (OR = 4.68) Diastolic PP < 55 mmHg – RR = 2.2 Mean PP < 42 mmHg – RR = 2.2 PP = perfusion pressure; POAG = primary open angle glaucoma; OR = odds ratio; RR = relative risk; OH = ocular hypertension; EMGT = early manifest glaucoma trial; NTG = normal tension glaucoma. 20
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12
06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 1 – 24-hour IOP measurements of a treated patient with progressive glaucoma despite normal IOPs. The IOP fluctuates between 9 and 12 mmHg in both eyes.
120
110
100

Systolic
Diastolic
06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 2 – The same patient’s systolic and diastolic blood pressures showing a drop at 6:00 am (circle). Diastolic
06:00 09:00 12:00 15:00 18:00 21:00 00:00
Figure 3 – The same patient´s diastolic perfusion pressure throughout the 24 hours. Clinicians can use the cutoff value of 30 mm Hg, as suggested by the Baltimore Eye Survey4, as an indicator of low diastolic perfusion pressure. REFERENCES: 1. Congdon N, Friedman DS, Lietman T. Important causes of visual impairment in the world today. JAMA 2003;290:2057-60.
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