Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Glaucoma_Grehn, Stamper_2008

age, PACG occurred at a rate of 2.65%, but women were affected almost four times as often as men, and there was a high prevalence of occludable angles (17%) [1].

The prevalence of PACG in European-derived people appears to be much lower compared to Asians, and has been reported to be 0.04% in the Beaver Dam study, 0.06% in Melbourne, 0.09% in Wales, 0.4% in Baltimore, 0.6% in North Italy [21].

Summary for the Clinician

■Glaucoma is the second leading cause of preventable blindness and is the leading cause of irreversible visual loss. By the year 2020 it is estimated that there will be almost 80 million people in the world with glaucoma. The majority of these individuals will have OAG. Of those with ACG, 70% will be women and 87% will be Asian. Bilateral blindness from glaucoma is projected to affect 11 million individuals worldwide by 2020.

■Risk factors for open-angle glaucoma include increased age, African or Latino ethnicity, family history, increased IOP, myopia, and decreased corneal thickness. Possible risk factors for OAG include diurnal intraocular pressure variation, long-term intraocular pressure variation, sleep apnea, Hispanic or Indian ethnicity, and migraine.

■Risk factors for angle-closure glaucoma include increased age, female gender, Asian ethnicity, shallow anterior chamber, short axial length, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and a thick or anteriorly positioned lens.

■Because 50% or more of those individuals with glaucoma are unaware of their diagnosis; more effort is needed to effectively screen high-risk groups and to educate society about the preventability and consequences of glaucoma.

References

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7.Coleman AL, Gordon MO, Beiser JA et al. (2004) Baseline risk factors for the development of primary open-angle glaucoma in the Ocular Hypertension Treatment Study. Ophthalmology 138:684–685

8.Congdon NC, Qi Y, Quigley HA et al. (1997) Biometry and primary angle-closure glaucoma among Chinese, white and black populations. Ophthalmology 104:1489–1495

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13.European Glaucoma Prevention Study Group (2007) Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology 113:3–9

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17.Foster PJ, Johnson GJ (2001) Glaucoma in China: how big is the problem? Br J Ophthalmol 85:1277–1282

18.Friedman DS, Gazzard G, Foster P et al. (2003) Ultrasonographic biomicroscopy, Scheimpflug photography, and novel provocative tests in contralateral eyes of Chinese patients initially seen with acute angle closure. Arch Ophthalmol 121:633–642

19.Gordon MO, Beiser JA, Bandt JD et al. (2002) The ocular hypertension treatment study. Baseline factors that predict

20 2 The Epidemiology of Glaucoma

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20. He M, Foster PJ, Ge J et al. (2006) Prevalence and clinical characteristics of glaucoma in adult Chinese: a populationbased study in Liwan District, Guangzhou. Invest Oph-

2 thalmol Vis Sci 47:2782–2788

21. He M, Foster PJ, Johnson GJ et al. (2006) Angle-closure in East Asian and European people. Different diseases? Eye 20:3–12

22. He M, Foster PJ, Ge J et al. (2006) Gonioscopy in adult Chinese: the Liwan Eye Study. Invest Ophthalmol Vis Sci 47:4772–4779

23. Hulsman CA, Vingerling JR, Hofman A et al. (2007) Blood pressure, arterial stiffness, and open-angle glaucoma. The Rotterdam Study. Arch Ophthalmol 125:805–812

24. Klein BE, Klein R, Sponsel WE et al. (1992) Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 99:1499–1504

25. Klein BE, Klein R, Meuer SM et al. (1993) Migraine headache and its association with open-angle glaucoma: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 34:3024–3027

26. Klein BD, Klein R, Jensen SC (1994) Open-angle glaucoma and older-onset diabetes. The Beaver Dam Eye Study. Ophthalmology 101:1173–1177

27. Klein BE, Klein R, Lee KE (2004) Heritability of risk factors for primary open-angle glaucoma: the Beaver Dam Eye study. Invest Ophthalmol Vis Sci 45:59–62

28. Klein BE, Klein R, Knudtson MD (2005) Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study. Br J Ophthalmol 89:284–287

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■Intraocular pressure (IOP) follows a circadian rhythm

■While the suprachiasmatic nucleus controls these rhythms, an intrinsic oscillator may be present within the eye

■Dysregulation of 24-hour IOP may be responsible for some cases of glaucomatous optic neuropathy

■IOP is highest in the habitual positions during the nocturnal period

■Prostaglandin analogs and carbonic anhydrase inhibitors more effectively lower IOP during the nocturnal period than beta-adrenergic antagonists

3.1Introduction

Circadian rhythms explain a variety of physiologic processes, including sleep, body temperature, hormone secretion, and cell regeneration. These rhythms maintain a periodicity of approximately 24 hours (24H) in light or dark, are relatively independent of external temperature, and can be reset by external stimuli. The patterns of a number of processes undergoing circadian rhythm have been linked to melatonin secretion, which peaks in the early morning, and body temperature, which is at its trough at 5 a.m.

Extensive clinical evidence indicates that intraocular pressure (IOP) follows a 24H pattern of peaks (in the morning) and troughs (in the evening). The sinusoidal 24H IOP curve suggests a dynamic regulation of the variables in the Goldmann equation (aqueous production, outflow facility, and episcleral venous pressure). Indeed, it has been well recognized that aqueous production follows a circadian cycle [1–3], peaking during the diurnal period and with sleep deprivation [4, 5]. The stimulus for these rhythms likely comes from the hypothalamus and the photic-sensitive suprachiasmatic nucleus (SCN). Neuroendocrine signaling molecules such as norepinephrine and dopamine may regulate these rhythms. Still, the persistence of these rhythms in patients with Horner syndrome may indicate an additional source of biochemical regulation of aqueous flow.

The importance of 24H IOP, particularly the nocturnal (sleep) values, has not yet been elucidated. Nevertheless, IOP remains the only clinically modifiable risk factor for glaucoma. Moreover, a number of patients with statistically average or low IOPs show progression of glaucomatous optic neuropathy. Twenty-four-hour IOP studies have demonstrated a distinct difference in IOP curves in glaucoma relative to normal subjects [5, 6]. These studies suggest the possibility that a dysregulation of circadian rhythms that may control 24H IOP contribute to the development and worsening of glaucomatous optic neuropathy. Further, peak values of IOP achieved during the nocturnal period may have to be lowered to optimally prevent worsening glaucoma.

3.2Normal IOP Curve

IOP is typically determined in an office setting using Goldmann applanation tonometry (GAT). The limitations of GAT, including the underestimation of IOP in patients with thin or less rigid corneas, have long been recognized. Only recently, however, has the importance of habitual positioning on the clinical measurement of IOP been quantified [7]. GAT is measured in a seated position. However, up to one-third of the day is spent in a recumbent position. Episcleral venous pressure (EVP) rises when recumbent, though autoregulatory

24 3 Circadian Changes in Intraocular Pressure

mechanisms may modify IOP changes related to body position. In a study of normal patients conducted at the Hamilton Glaucoma Center, University of California, San Diego, a sustained rise in IOP was noted during the

3nocturnal period (an 8 h period during sleep), which was partially explained by the change in body posi-

tion from seated to supine (Fig. 3.1) [5, 7]. When IOPs were measured while subjects were in a supine position throughout the 24H study, the nocturnal rise in IOP, though present, fitted within a biphasic IOP curve with two peaks within 24H.

The relationship of aqueous flow dynamics to 24H IOP remains unclear. Aqueous production is known to decrease by 50–60% at night [8]. However, IOP rises during the nocturnal period, partly due to positional changes [5, 7]. An increase in EVP may contribute to this rise [9]. However, when data is collected in a supine position over 24H, fluctuations in IOP are still present [5]. This underlying fluctuation in IOP suggests circadian control of IOP. This control is independent of ambient lighting and changes in corneal biomechanical properties [10, 11]. Animal studies also suggest that the nocturnal rise in IOP can be entrained by using light and dark stimuli [12].

One possible explanation for the 24H IOP measurements is that an IOP rise during the diurnal period is

related to an increase in aqueous production, while a rise in the nocturnal period is due to a decrease in outflow facility. Yet, the biochemical basis of a circadian rhythm in normal subjects remains unclear. In a rabbit study, aqueous norepinephrine (but not plasma melatonin) concentrations were correlated to rises in IOP during the nocturnal period [13]. Central control of circadian changes in IOP, however, can be altered. Lesions in the SCN significantly blunt the nocturnal IOP rise, suggesting that the hypothalamus regulates daily fluctuations in IOP [14]. Furthermore, mice that lack the expression of circadian clock genes no longer show circadian changes in IOP [15]. Yet, while the SCN may modulate 24H IOP fluctuation, animals recover a circadian pattern of IOP several weeks after SCN lesions, which may indicate compensatory sources of circadian control.

3.3Sources of Circadian Control

The primary regulator of circadian rhythms is the SCN, a paired nucleus located above the optic chiasm in the anterior hypothalamus. The SCN is entrained by photic stimuli detected by photoreceptors and transmitted as neural signals via the retinohypothalamic tract (Fig. 3.2).

These neural signals activate the expression of clock-con- trolled genes that regulate the release of endocrine and paracrine factors.

Recent evidence suggests that circadian clocks also exist in several peripheral tissues and cells [16, 17]. These peripheral oscillators are kept in phase by the SCN. Circadian control of IOP, however, can continue after superior cervical ganglionectomy [18] and ablation of the SCN [14], suggesting an additional source of circadian control of aqueous flow. Aqueous secretion is primarily controlled by the nonpigmented ciliary body epithelium, which shows some neuroendocrine activity. This has led some to believe that the ciliary body is a peripheral oscillator with endocrine and paracrine secretions that may produce circadian variations in aqueous production as well as changes in trabecular outflow facility [16]. According to this hypothesis, the function of trabecular meshwork cells is regulated in part by factors secreted by ciliary processes into the aqueous humor.

If ciliary body epithelial cells release hormones and neuropeptides under circadian control, the aqueous concentrations of specific biomolecules would vary based on time of day. Indeed, overall protein concentration in

12H light/12H dark entrained rabbits increases during the entrained diurnal period, even when kept in constant darkness [19]. Aqueous concentrations of melatonin and norepinephrine, however, increase with IOP at night [13]. In rabbits, the IOP increase at the onset of dark is due to the activity of ocular sympathetic nerves [20]. This IOP elevation can be modulated by short-wavelength light [21]. Laboratory evidence thereby indicates that at least a component of IOP is under central control, oscillates over approximately 24H, can be entrained with light stimuli, and is correlated with changes in aqueous concentration of neuroendocrine products. Sources of circadian control of outflow facility, however, are yet to be determined.

3.4Glaucoma and 24-Hour IOP

Several changes occur in the 24H IOP curve in normal relative to untreated glaucoma (OAG) patients [6]. Nocturnal IOP remains higher than diurnal IOP, as in normal subjects, but the magnitude of this change is diminished. A peak IOP delay is present in the OAG group as well,

26 3 Circadian Changes in Intraocular Pressure

with peak supine IOP at 7:30 a.m. in OAG. Normal subjects experience a peak approximately 2 h earlier, followed by a net IOP decline (Fig. 3.1). The net effect is a 4-h phase delay in the 24H IOP curve in OAG relative

3to normal. While the cause of this phase delay remains unclear, alterations in 24H IOP regulation may be related

to early pathogenesis of glaucoma.

The prevailing explanations for differences in early morning IOP curves in normal versus OAG patients involve either a decrease in outflow facility or an increase in aqueous production in the latter group [22]. Aqueous flow dynamics are altered in OAG, with a relatively higher flow rate at night versus normal based on fluorophotometry studies [23]. While this relative increased flow rate alone probably does not account for an increase in IOP, a decrease in outflow facility in conjunction with this change may account for experimental 24H IOP data. Several pathophysiologic responses may account for changes in outflow facility and trabecular function [24]. Trabecular meshwork cells are known to be steroid-sensitive [25] and therefore susceptible to increases in plasma glucocorticoid activity prior to awakening. The MYOC gene, which accounts for 3–4% of OAG cases, is particularly steroid-sensitive [26]. Circadian control of specific genes and cell products that may affect outflow facility is actively being investigated. Targeted modification of trabecular function based on these findings may be a promising area of future therapy [27]. Still, a recent study suggests that nocturnal changes in EVP or uveoscleral flow may also have to be altered to account for absolute changes in IOP [28].

3.5Medical Management of 24-Hour IOP

Current treatment standards may need to be re-evaluated based on 24H IOP studies. Despite clear evidence for a nocturnal elevation in IOP in many individuals, it is not clear how such short-term fluctuations in IOP (changes over a 24H period) may impact the pathogenesis of glaucoma. While mean IOP and peak IOP are known risk factors for glaucoma progression, short-term fluctuation of IOP plays an unclear role [29, 30].

Several physiologic parameters apart from IOP change during the 24H period, including ocular blood flow. As optic nerve perfusion pressure is directly correlated with blood flow (which decreases at night) and IOP (which increases at night), glaucoma pathogenesis may be related to a dysregulation of one or both of these variables [31]. The correlation of short-term fluctuation in IOP and disease progression in patients with statistically low IOPs may be coincident to changes in ocular blood flow.

Loss of autoregulatory mechanisms that maintain optic nerve perfusion pressure may also account for worsening of glaucoma. Further study is needed to determine the exact role of elevated nocturnal IOP in glaucoma pathogenesis.

The 24H efficacies of several different topical medications have now been evaluated prospectively. 24H data indicate that beta-adrenergic antagonists have a minimal nocturnal effect, while prostaglandin analogs such as latanoprost and travoprost have both a nocturnal and a diurnal effect in habitual positions (Fig. 3.3) [32–34]. The limited nocturnal effect of beta-blockers is related to the low aqueous humor flow rate at night. Prostaglandin analogs may be effective over 24H because uveoscleral outflow is IOP-independent. The IOP-reducing effect of prostaglandin analogs is also sustained over 48 h [34]. Carbonic anhydrase inhibitors are also effective during the nocturnal period [35], though the basis of a 24H effect is unclear. These medication studies suggest that nocturnal IOP reduction may require a change in outflow facility. Indeed, the ability of laser trabeculoplasty to lower nocturnal IOP is consistent with the hypothesis that nocturnal IOP increases due to an increase in outflow resistance [36].

Optimal dosing of medications as well as the choice of IOP-lowering therapy may in the future account for their 24H effect. Nighttime dosing of beta-blockers, for example, may be unnecessary, while a carbonic anhydrase inhibitor may be a reasonable second-line treatment to improve 24H IOP control. Prostaglandin analogs, when tolerated, have the strongest evidence for a 24H IOPlowering effect.

Until routine clinical measurement of 24H IOP is practical, the importance of 24H IOP reduction remains unclear for each individual patient. A clinician should, however, understand how well clinical measurements of IOP correlate with IOP in habitual positions. It recently has been suggested that peak nocturnal IOP can be estimated using office measurements [37]. This calculation requires measurement of a diurnal IOP curve, which can be time-consuming. Interestingly, single IOP measurements alone correlate only moderately well with peak nocturnal IOP in the same eye and poorly with between-eye IOP. Accurate monocular drug trials may therefore require calculation of, at the minimum, a diurnal IOP curve [38]. A recent study has also shown that the transient elevation of IOP during the waterdrinking test [39] may correlate with peak 24H IOP and may serve as a more practical method of estimating peak IOP [40]. Further study is needed to determine the true value of the water-drinking test in predicting circadian variability in IOP.

Summary for the Clinician

■Circadian rhythms control aqueous production and may control outflow resistance.

■Aqueous production peaks in the diurnal period, while IOP rises at night. This rise in IOP during the nocturnal period may be associated with a decrease in trabecular outflow facility, though the predominant cause of a rise in nocturnal IOP is supine positioning.

■Certain IOP-lowering therapies, such as prostaglandin analogs, carbonic anhydrase inhibitors and laser trabeculoplasty, may be more effective at lowering 24H IOP than beta-adrenergic antagonists.

■Diurnal IOP curves allow for an estimation of peak IOP at night. However, as short-term fluctuations in 24H IOP as well as peak IOP have not been clearly correlated to worsening of disease, the importance of 24H IOP in glaucoma progression remains unclear.

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■Measuring disease progression is vital in the management of patients with glaucoma and ocular hypertension.

■Progression may be assessed by structure (optic disc photography or semi-automated imaging devices) and function (perimetry).

■Progression strategies may be subdivided into “event analyses” (progression requires a predetermined threshold to be exceeded) and “trend analyses” (the behaviour of the parameter over time is monitored).

■Stereophotographic examination is prone to high inter-observer variability.

■Amongst imaging devices, the HRT has the most published longitudinal data, as it has been commercially available for the longest time and its software is “backward compatible”.

■Two progression algorithms are currently available in the HRT software: “trend analysis” and “topographical change analysis”.

■To date there are no statistically supported progression algorithms in the OCT or GDx-VCC operational software.

■There is poor concordance between HRT and visual field progression. The reasons for this remain unclear.

4.1Introduction

4.1.1 The Principles of Progression

The ability to monitor disease progression is central to the management of the patient with established glaucoma or who is perceived to be at risk of glaucoma, particularly the ocular hypertensive. Such monitoring affords the clinician the potential to assess the patient’s immediate and long-term risk of functionally significant visual loss, as well as the effectiveness of any treatment intervention.

As glaucoma is an optic neuropathy associated with characteristic visual field deficits, one can monitor disease progression according to both functional changes and structural changes at the optic nerve head and retinal nerve fibre layer. In current clinical practice, functional progression is monitored by static automated perimetry. The characteristic features of glaucomatous optic neuropathy are discernible by careful examination using indirect ophthalmoscopy, as are nerve fibre layer changes, assisted by red-free illumination. However, clinical examination is prone to wide inter-observer variation, even amongst experienced observers, and does not allow quantitative

comparison [20]. Such a subjective method is suboptimal for longitudinal disease assessment. A degree of objectivity and the potential to quantify change are possible by using optic nerve head photography and, more recently, automated optic nerve head imaging devices. As yet, no consensus exists regarding the best method of assessing structural changes in glaucoma (as is the case for visual field changes). The ideal method will utilise a technology that can reliably discriminate true change secondary to disease progression from observer and measurement variability.

As with measuring visual field progression, there are two broad strategies for monitoring change over time— event analyses and trend analyses. Event analyses classify change as occurring when the measurement exceeds a predetermined threshold. Visual field strategies of this type have been utilised in a number of clinical trials of glaucoma [1, 15, 23]; they are particularly useful for clinical trials as they give a binary outcome—either “change” or “no change”. A major disadvantage of event analyses is that they do not allow a measurement of “rate of change”, which is possible using trend analyses. Trend analyses monitor the behaviour of a test parameter over time; the