Acta Ophthalmologica 2016
Review Article Primary angle-closure glaucoma: an update Carrie Wright, Mohammed A. Tawfik, Michael Waisbourd and Leslie J. Katz Wills Eye Hospital, Philadelphia, PA, USA
ABSTRACT. Primary angle-closure glaucoma is potentially a devastating disease, responsible for half of glaucoma-related blindness worldwide. Angle closure is characterized by appositional approximation or contact between the iris and trabecular meshwork. It tends to develop in eyes with shallow anterior chambers, anteriorly positioned or pushed lenses, and angle crowding. Risk of primary angle-closure glaucoma is high among women, the elderly and the hyperopic, and it is most prevalent in Asia. Investigation into genetic mechanisms of glaucoma inheritance is underway. Diagnosis relies on gonioscopy and may be aided by anterior segment optical coherence tomography and ultrasound biomicroscopy. Treatment is designed to control intraocular pressure while monitoring changes to the angle and optic nerve head. Treatment typically begins with medical management through pressurereducing topical medications. Peripheral iridotomy is often performed to alleviate pupillary block, while laser iridoplasty has been found effective for mechanisms of closure other than pupillary block, such as plateau iris syndrome. Phacoemulsification, with or without goniosynechialysis, both in eyes with existing cataracts and in those with clear lenses, is thus far a viable treatment alternative. Long-term research currently underway will examine its efficacy in cases of angle closure in early stages of the disease. Endoscopic cyclophotocoagulation is another treatment option, which can be combined with cataract surgery. Trabeculectomy remains effective therapy for more advanced cases. Key words: angle-closure glaucoma – argon laser iridoplasty – lensectomy – peripheral iridotomy – phacoemulsification – plateau iris – primary angle closure – pupillary block – review
Acta Ophthalmol. 2016: 94: 217–225 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12784
Introduction Glaucoma is currently the second leading cause of blindness worldwide. It affects over 60 million people, a number expected to increase to nearly 80 million by 2020 (Quigley & Broman 2006). Primary angle-closure glaucoma (PACG) is a type of glaucoma estimated to affect approximately 26% of the glaucoma population; however, PACG is responsible for nearly half the cases of glaucoma-related blindness in the world (Quigley 1996; Quigley & Broman 2006).
As the name implies, primary chronic angle-closure glaucoma is a type of chronic angle-closure glaucoma (CACG), a gradual, often clinically silent, closure of the angle resulting in increased intraocular pressure (IOP) and eventual glaucomatous optic nerve damage. CACG is a broader term that includes secondary causes for angleclosure glaucoma, for example anterior traction of the peripheral iris due to neovascular membrane formation (Tarongoy et al. 2009), which are not the focus of this review.
The classification of PACG is often considered confusing, due to early inconsistencies in terminology and nomenclature. These were addressed in a study by Foster et al. (2002) who standardized the definitions based on progression of the disease. Current American Academy of Ophthalmology (AAO) classifications follow a similar framework, as follows (2010) (Table 1).
Classification PACG exists in a spectrum of angleclosure disorders that includes primary angle-closure suspect (PACS), primary angle closure (PAC) and PACG itself. PACS is diagnosed by the presence of iridotrabecular contact (ITC) on gonioscopy. The degree of ITC necessary for a PACS diagnosis has often been contested, but most ophthalmologists consider the presence of 180° or more of ITC sufficient. According to the AAO Preferred Practice Guidelines, 1 in 4 patients with PACS goes on to develop IOP elevation or peripheral anterior synechiae (PAS) over 5 years (2010). The criteria for PAC include 180° or more of ITC in conjunction with an elevated IOP or the presence of PAS. These may not be secondary to any other known cause or ocular disease. A diagnosis of PAC becomes PACG in the presence of glaucomatous optic neuropathy. For classification purposes, glaucomatous nerve damage is defined as an abnormality in the optic disc or retinal nerve fibre layer, or a reliably reproducible abnormality of the visual field.
Pathogenesis In early cases of angle closure, the angle may be only appositionally
217
Acta Ophthalmologica 2016
Table 1. Classification of angle-closure disorders.
Primary Angle-closure Suspect (PACS) Primary Angle-closure (PAC) Primary Angle-closure Glaucoma (PACG)
≥180° of ITC
Elevated IOP or Presence of PAS
Glaucomatous optic neuropathy
+ + +
+ +
+
ITC, iridotrabecular contact; IOP, intraocular pressure; PAS, peripheral anterior synechiae.
Fig. 1. Double-hump sign as seen on gonioscopy. Figure reproduced with permission of Bryn Mawr Communications LLC. Nagori S, Laroche D. Treating plateau iris. Glaucoma Today. September/October 2012;10(5):38–40.
closed. With time, broad synechiae form, and the angle closes superiorly to inferiorly, accompanied by an increasing intraocular pressure that is difficult to control. There are several mechanisms by which PACG can develop. The appositional obstruction of the trabecular meshwork by the peripheral iris can be a consequence of an abnormal relationship between the size and position of the structures of the anterior segment or of the relative pressure differential between the anterior and posterior chambers of the eye (Lowe & Ritch 1989). Pupillary block and anterior lens movement
The most common aetiology of PAC is pupillary block, in which inhibition of aqueous flow causes an increased pressure differential between the anterior and posterior compartments of the eye, leading to iris bowing and appositional closure of the angle. At baseline, a pressure differential of approximately 0.23 mmHg exists between the anterior and posterior chambers (Heys et al. 2001). This accounts for the normal outflow of aqueous humour from posterior to anterior chamber between the posterior iris and anterior lens. When this pressure differential increases, it causes anterior bowing of the iris into a
218
convex form. The convex shape of the iris brings it into appositional contact with the trabecular meshwork, obstructing drainage and potentially allowing for the formation of PAS and progression down the path to PACG. Shallow anterior chambers are predisposed to pupillary block due to apposition of the pupil and anterior lens capsule. Of note, studies demonstrate that iris thickness can influence the pressure differential between anterior and posterior chambers (Wyatt & Ghosh 1970; Tarongoy et al. 2009), suggesting that darker irides may predispose to pupillary block (Quigley et al. 2003). The lens plays a crucial part in the pathogenesis of PAC, with more anteriorly positioned lenses causing greater degrees of iris convexity (Wyatt & Ghosh 1970). Movement of the lens forward, as observed with increasing age, in phacomorphic glaucoma with advanced cataract, and in instances of choroidal expansion, can narrow the anterior chamber and cause appositional contact between iris and trabecular meshwork. Choroidal expansion, seen in malignant glaucoma and secondary to a wide range of ocular diseases, is also suspected to occur to some degree in healthy eyes (Quigley et al. 2003). A certain degree of physiological expansion of the choroid occurs in response to changes in arterial and venous pressure, blood volume, colloid osmotic pressures and transient variations in IOP. Increasing choroidal volume may hypothetically exert pressure on the vitreous and be conducted forward to the lens, shifting it more anteriorly in the eye. Loose zonules, as seen in exfoliation syndrome, may also contribute to the development of PAC via anterior lens shift. Angle crowding
Angle crowding refers to the phenomenon of angle closure in response to the compression of the iris between the
trabecular meshwork and another anatomical structure (Tarongoy et al. 2009). This is most frequently seen with plateau iris configuration, a condition most common among women aged 30–50 years, particularly those with hyperopic refractive error. Kumar et al. estimated that 30% of primary angle-closure suspect eyes were diagnosed with plateau iris on UBM after laser iridotomy (2008). Plateau iris configuration occurs in patients with a large and/or anteriorly positioned ciliary body that compresses the iris root forward against the trabecular meshwork (Pavlin et al. 1992). Clinically, irides appear flat or slightly convex from pupil to periphery, and the central anterior chamber depth is relatively normal. However, gonioscopy reveals that the peripheral iris takes a sharp turn posteriorly before inserting into the ciliary body. This sharp turn can facilitate angle closure when the pupil is dilated. The ciliary body’s positioning also prevents easy movement of the peripheral iris during indentation gonioscopy. This causes the iris to assume a sine-shaped curve, known as the double-hump sign (Fig. 1), as it curves first over the ciliary body and then over the anterior capsule. The term plateau iris syndrome refers to the clinical picture of angle closure despite a patent iridectomy. This condition may lead to widespread peripheral anterior synechiae and, with persistent elevations in IOP, may progress to PACG.
Epidemiology Risk factors
Numerous risk factors play a role in the development of PACG, including increasing age, female gender, shallow anterior chamber, short axial length of the eye in hyperopia, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and thick, anteriorly positioned lenses. Age
The prevalence of relative pupillary block and PAC, and thus PACG, has been shown to increase with age. A recent study of European-derived populations reported an age-specific prevalence of PACG of 0.02% for those aged 40–49, increasing to 0.95% for those 70 years and older (Day et al. 2012). Anterior chamber depth and
Acta Ophthalmologica 2016
volume gradually decrease throughout life. A 1996 analysis of anterior chamber changes demonstrated a depth decrease of 0.21 mm and volume decrease of 19 ll over 10 years (Sakai et al. 1996); in concert, these changes contribute to angle narrowing and increase the likelihood of PAS among the elderly. Lens thickness also contributes to anterior chamber shallowing (Lee et al. 1984). In younger populations, PACG is rare and is generally associated with other ocular abnormalities or plateau iris syndrome (Chang et al. 2002). Gender
Risk of PACG among women is approximately 3 times higher than in men (Foster et al. 1996, 2000; Quigley & Broman 2006). This, too, is likely the result of anatomical and mechanical differences between male and female eyes. Okabe studied 1169 eyes of participants diagnosed with PACG and found that certain measurements, including anterior chamber depth and axial length, were much lower in women, while angle width in women was significantly narrower than in men across all age groups (1991). Prevalence among women is also a function of relative life spans, as PACG is primarily a disease of the elderly, and women tend to outlive men. Ethnicity
Worldwide, the prevalence of PACG is highest in China. Of the 15 million people estimated to have ACG in 2010, 47.5% were located in China, and projections suggest that 20 million Chinese will have ACG by the year 2020 (Quigley & Broman 2006). An estimated 1.7 million Chinese persons are bilaterally blind from glaucoma, and the majority (91%) of that blindness is attributable to PACG (Foster & Johnson 2001). Numbers are similarly high – 86.5% – throughout Asia (Quigley & Broman 2006). Prevalence differs among Asian groups, with Mongolians demonstrating the highest prevalence of PAGC at 1.4% (Foster et al. 1996). Asians have a notably higher prevalence of PACG (0.6–1%) (Dandona et al. 2000; Foster et al. 2000; Yamamoto et al. 2005) than either Caucasians (0.09–0.4%) (Bonomi et al. 1998; Day et al. 2012) or Africans (0.5%) (Rotchford & Johnson 2002). Within individual ethnic groups, prevalence of
PACG was highest by far among the Inuit population, at 2.65% (Arkell et al. 1987). Refractive error
Small, hyperopic eyes are most at risk for developing PACG; the condition is rare in myopes, although it has been noted more frequently in those with a spherical equivalent of -6 dioptres (Mitchell et al. 1999; Barkana et al. 2006; He et al. 2006). As mentioned above, patients with PACG have a shorter axial length, shallower anterior chamber depth and diameter, and a thicker, more anteriorly positioned lens (Fontana & Brubaker 1980; Lee et al. 1984; Marchini et al. 1998). Family history and genetic predisposition
Although most cases of PACG are sporadic, recent research among Asian populations has indicated a hereditary element to the disease. In a 2014 study of prevalence of angle closure among siblings, 57.9% of siblings with one family member affected by PACG were categorized along the angle-closure spectrum themselves, with 14.7% demonstrating full PACG (Yazdani et al. 2014). A broader study of first-degree relatives of PAC and PACG patients conducted in Singapore found that 32.1% had narrow angles, with overall heritability of narrow angles calculated at 57.95. Siblings of PACG and PAC patients, in particular, were more than 7 times more likely to have narrow angles than the general population (Amerasinghe et al. 2011). A similar study in India examined the risk of narrow angles in siblings of PACS and/ or PACG patients. The study found that odds of developing narrow angles were nearly 14 times greater among these siblings than in the general population, with a greater than 1 in 3 risk of angle closure (Kavitha et al. 2014). Though imperfectly understood, the familial connection is clear, and siblings may benefit from PACG screening. The genetic causes that underlie angle-closure glaucoma are still being elucidated. An extensive genomewide association study published in 2012 identified three genomic loci that predispose patients to PACG: rs11024102 on PLEKHA7, rs3753841 on COL11A1 and rs1015213 on chromosome 8q (Vithana et al. 2012). The precise mechanism of pathology arising
from aberrant gene loci is still unknown. PLEKHA7 is known to regulate tight junctions; it is theorized that a deficiency at this locus might disrupt fluid dynamics in the eye. COL11A1 generally encodes collagen; the study’s authors proposed that this might manifest in scleral matrix anomalies or alteration of trabecular meshwork cells that could contribute to PACG development. Additional analysis determined that these polymorphisms did not impact axial length or anterior chamber depth (Nongpiur et al. 2013); further research may yet clarify the functional insult contributing to the development of acute disease. The clinical implications of the presence of these polymorphisms were recently investigated in a paper by Wei et al., who found no significant association between the alleles and the clinical features of glaucoma in the patients whose genotype contained them. No particular allele was found to be associated with phenotypically higher IOP, disease severity or disease progression; the presence of these loci appeared to increase susceptibility only (2014). Numerous other studies have examined genetic determinants for the risk factors referenced above. Nair et al. demonstrated an association between alterations in serine protease PRSS56 and a decreased axial length in the mouse model, contributing to the development of increased IOP, angle closure and choroidal expansion, presumably secondary to alterations in extracellular matrix processing during development (2011). Mutations of this protease also contributed to decreased axial length in humans with posterior microphthalmia. Other avenues of enquiry include research into the membrane-type frizzled-related protein (MFRP), another factor responsible for determining axial length and depth of the anterior chamber, observed in eyes with nanophthalmos (Liu & Allingham 2011) and into single nucleotide polymorphisms (SNPs) in metalloproteinases responsible for extracellular matrix formation (Shastry 2013). Still more genetic studies have shown an association between PACG and endothelial nitric oxide synthase polymorphisms in Australian, Nepalese and Pakistani populations (Ayub et al. 2010; Awadalla et al. 2013). Further research will hopefully clarify the
219
Acta Ophthalmologica 2016
Using the four-mirror lens, the clinician gently indents the central cornea; this displaces the aqueous from the centre to the periphery of the anterior chamber, mechanically deepening the angle and enabling better visualization of angle structures (Fig. 2) (Shields 1998). Dynamic indentation gonioscopy also aides in determining the extent of PAS (Fig. 3A) and may differentiate plateau iris configuration from pupillary block. Corneal indentation during gonioscopy results in posterior movement of the mid-peripheral iris in eyes with pupillary block, whereas in plateau iris configuration, the ciliary process prevents movement and a sine-shaped curve of the iris surface can be seen at the slit lamp (Shields 1998). Clinical estimation
Fig. 2. Anatomically narrow angle. Top panel: Prior to indentation gonioscopy, most angle structures are not visible, apart from the anterior portion of Schwalbe’s line (barely seen). The iris curvature is anteriorly bowed. Bottom panel: Following indentation gonioscopy, the iris flattens and angle structures are revealed. (From top to bottom: Schwalbe’s line, non-pigmented trabecular meshwork, pigmented trabecular meshwork and scleral spur. The ciliary body band is barely seen).
(A)
(B)
Fig. 3. Peripheral anterior synechiae as seen on gonioscopic (A) and OCT (B) imaging. Figure adapted with permission of Elsevier (Lai et al. 2013).
link between known genetic loci and phenotypic expression of narrowed angles.
Diagnosis Gonioscopy
Gonioscopy remains the most important diagnostic method for assessing angle closure. Indentation gonioscopy
220
in particular is an essential technique for assessing PAS and appositional angle closure. The technique relies on the use of a four-mirror Zeiss, Sussman or Posner lens rather than the standard Goldmann lens. These lenses have an area of contact smaller than the cornea to enable the ease of indentation, and unlike the Goldmann lens, they require no coupling medium for a clear view.
Several techniques exist for the evaluation of anterior chamber depth at the slit lamp to identify patients at risk of angle closure. One traditional assessment method is Van Herick’s technique, which measures limbal chamber depth. This technique is performed by offsetting the light beam of the slit lamp by 60° from its central axis to create a thin column of light which is then directed at the temporal limbus. The observer compares the corneal thickness to the depth of the anterior chamber, which is visualized as a black space between the light reflexes on the cornea and iris (Fig. 4). Based on the ratio of limbal depth to corneal thickness, the observer grades the likelihood of angle closure on a scale from 1 to 4 (Table 2), with 1 indicating complete closure and 4 indicating completely open angles (Van Herick et al. 1969; Gispets et al. 2014). Gonioscopy is recommended at grade 1 and below. A second means of assessment is Smith’s method. In this technique, the angle between the slit beam and microscope is set to 60°, and the light beam is oriented horizontally. The physician directs a horizontal beam of light from the slit lamp across the cornea, forming two images of the slit beam upon the patient’s eye: one image is in focus on the cornea, and the second is out of focus across the lens and iris. The physician then adjusts the slit length control knob until these two images appear to touch end-to-end (Smith 1979). The length of the slit beam with the two images in contact is multiplied
Acta Ophthalmologica 2016
Fig. 4. Semi-objective measurement, through image analysis, of the width of the peripheral corneal thickness (PCT, solid line rectangle) and the peripheral anterior angle depth (PACD, broken line rectangle). This image was awarded a grade 3. Figure reproduced with permission of John Wiley & Sons, Inc. (Gispets et al. 2014), © 2013 The Authors and Optometrists Association Australia.
Table 2. Van Herick grading scale.
Grade
Limbal depth relative to corneal thickness
4 3 2 1 Narrow
≥ corneal thickness ¼–½ corneal thickness ¼ corneal thickness
Review Article Primary angle-closure glaucoma: an update Carrie Wright, Mohammed A. Tawfik, Michael Waisbourd and Leslie J. Katz Wills Eye Hospital, Philadelphia, PA, USA
ABSTRACT. Primary angle-closure glaucoma is potentially a devastating disease, responsible for half of glaucoma-related blindness worldwide. Angle closure is characterized by appositional approximation or contact between the iris and trabecular meshwork. It tends to develop in eyes with shallow anterior chambers, anteriorly positioned or pushed lenses, and angle crowding. Risk of primary angle-closure glaucoma is high among women, the elderly and the hyperopic, and it is most prevalent in Asia. Investigation into genetic mechanisms of glaucoma inheritance is underway. Diagnosis relies on gonioscopy and may be aided by anterior segment optical coherence tomography and ultrasound biomicroscopy. Treatment is designed to control intraocular pressure while monitoring changes to the angle and optic nerve head. Treatment typically begins with medical management through pressurereducing topical medications. Peripheral iridotomy is often performed to alleviate pupillary block, while laser iridoplasty has been found effective for mechanisms of closure other than pupillary block, such as plateau iris syndrome. Phacoemulsification, with or without goniosynechialysis, both in eyes with existing cataracts and in those with clear lenses, is thus far a viable treatment alternative. Long-term research currently underway will examine its efficacy in cases of angle closure in early stages of the disease. Endoscopic cyclophotocoagulation is another treatment option, which can be combined with cataract surgery. Trabeculectomy remains effective therapy for more advanced cases. Key words: angle-closure glaucoma – argon laser iridoplasty – lensectomy – peripheral iridotomy – phacoemulsification – plateau iris – primary angle closure – pupillary block – review
Acta Ophthalmol. 2016: 94: 217–225 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12784
Introduction Glaucoma is currently the second leading cause of blindness worldwide. It affects over 60 million people, a number expected to increase to nearly 80 million by 2020 (Quigley & Broman 2006). Primary angle-closure glaucoma (PACG) is a type of glaucoma estimated to affect approximately 26% of the glaucoma population; however, PACG is responsible for nearly half the cases of glaucoma-related blindness in the world (Quigley 1996; Quigley & Broman 2006).
As the name implies, primary chronic angle-closure glaucoma is a type of chronic angle-closure glaucoma (CACG), a gradual, often clinically silent, closure of the angle resulting in increased intraocular pressure (IOP) and eventual glaucomatous optic nerve damage. CACG is a broader term that includes secondary causes for angleclosure glaucoma, for example anterior traction of the peripheral iris due to neovascular membrane formation (Tarongoy et al. 2009), which are not the focus of this review.
The classification of PACG is often considered confusing, due to early inconsistencies in terminology and nomenclature. These were addressed in a study by Foster et al. (2002) who standardized the definitions based on progression of the disease. Current American Academy of Ophthalmology (AAO) classifications follow a similar framework, as follows (2010) (Table 1).
Classification PACG exists in a spectrum of angleclosure disorders that includes primary angle-closure suspect (PACS), primary angle closure (PAC) and PACG itself. PACS is diagnosed by the presence of iridotrabecular contact (ITC) on gonioscopy. The degree of ITC necessary for a PACS diagnosis has often been contested, but most ophthalmologists consider the presence of 180° or more of ITC sufficient. According to the AAO Preferred Practice Guidelines, 1 in 4 patients with PACS goes on to develop IOP elevation or peripheral anterior synechiae (PAS) over 5 years (2010). The criteria for PAC include 180° or more of ITC in conjunction with an elevated IOP or the presence of PAS. These may not be secondary to any other known cause or ocular disease. A diagnosis of PAC becomes PACG in the presence of glaucomatous optic neuropathy. For classification purposes, glaucomatous nerve damage is defined as an abnormality in the optic disc or retinal nerve fibre layer, or a reliably reproducible abnormality of the visual field.
Pathogenesis In early cases of angle closure, the angle may be only appositionally
217
Acta Ophthalmologica 2016
Table 1. Classification of angle-closure disorders.
Primary Angle-closure Suspect (PACS) Primary Angle-closure (PAC) Primary Angle-closure Glaucoma (PACG)
≥180° of ITC
Elevated IOP or Presence of PAS
Glaucomatous optic neuropathy
+ + +
+ +
+
ITC, iridotrabecular contact; IOP, intraocular pressure; PAS, peripheral anterior synechiae.
Fig. 1. Double-hump sign as seen on gonioscopy. Figure reproduced with permission of Bryn Mawr Communications LLC. Nagori S, Laroche D. Treating plateau iris. Glaucoma Today. September/October 2012;10(5):38–40.
closed. With time, broad synechiae form, and the angle closes superiorly to inferiorly, accompanied by an increasing intraocular pressure that is difficult to control. There are several mechanisms by which PACG can develop. The appositional obstruction of the trabecular meshwork by the peripheral iris can be a consequence of an abnormal relationship between the size and position of the structures of the anterior segment or of the relative pressure differential between the anterior and posterior chambers of the eye (Lowe & Ritch 1989). Pupillary block and anterior lens movement
The most common aetiology of PAC is pupillary block, in which inhibition of aqueous flow causes an increased pressure differential between the anterior and posterior compartments of the eye, leading to iris bowing and appositional closure of the angle. At baseline, a pressure differential of approximately 0.23 mmHg exists between the anterior and posterior chambers (Heys et al. 2001). This accounts for the normal outflow of aqueous humour from posterior to anterior chamber between the posterior iris and anterior lens. When this pressure differential increases, it causes anterior bowing of the iris into a
218
convex form. The convex shape of the iris brings it into appositional contact with the trabecular meshwork, obstructing drainage and potentially allowing for the formation of PAS and progression down the path to PACG. Shallow anterior chambers are predisposed to pupillary block due to apposition of the pupil and anterior lens capsule. Of note, studies demonstrate that iris thickness can influence the pressure differential between anterior and posterior chambers (Wyatt & Ghosh 1970; Tarongoy et al. 2009), suggesting that darker irides may predispose to pupillary block (Quigley et al. 2003). The lens plays a crucial part in the pathogenesis of PAC, with more anteriorly positioned lenses causing greater degrees of iris convexity (Wyatt & Ghosh 1970). Movement of the lens forward, as observed with increasing age, in phacomorphic glaucoma with advanced cataract, and in instances of choroidal expansion, can narrow the anterior chamber and cause appositional contact between iris and trabecular meshwork. Choroidal expansion, seen in malignant glaucoma and secondary to a wide range of ocular diseases, is also suspected to occur to some degree in healthy eyes (Quigley et al. 2003). A certain degree of physiological expansion of the choroid occurs in response to changes in arterial and venous pressure, blood volume, colloid osmotic pressures and transient variations in IOP. Increasing choroidal volume may hypothetically exert pressure on the vitreous and be conducted forward to the lens, shifting it more anteriorly in the eye. Loose zonules, as seen in exfoliation syndrome, may also contribute to the development of PAC via anterior lens shift. Angle crowding
Angle crowding refers to the phenomenon of angle closure in response to the compression of the iris between the
trabecular meshwork and another anatomical structure (Tarongoy et al. 2009). This is most frequently seen with plateau iris configuration, a condition most common among women aged 30–50 years, particularly those with hyperopic refractive error. Kumar et al. estimated that 30% of primary angle-closure suspect eyes were diagnosed with plateau iris on UBM after laser iridotomy (2008). Plateau iris configuration occurs in patients with a large and/or anteriorly positioned ciliary body that compresses the iris root forward against the trabecular meshwork (Pavlin et al. 1992). Clinically, irides appear flat or slightly convex from pupil to periphery, and the central anterior chamber depth is relatively normal. However, gonioscopy reveals that the peripheral iris takes a sharp turn posteriorly before inserting into the ciliary body. This sharp turn can facilitate angle closure when the pupil is dilated. The ciliary body’s positioning also prevents easy movement of the peripheral iris during indentation gonioscopy. This causes the iris to assume a sine-shaped curve, known as the double-hump sign (Fig. 1), as it curves first over the ciliary body and then over the anterior capsule. The term plateau iris syndrome refers to the clinical picture of angle closure despite a patent iridectomy. This condition may lead to widespread peripheral anterior synechiae and, with persistent elevations in IOP, may progress to PACG.
Epidemiology Risk factors
Numerous risk factors play a role in the development of PACG, including increasing age, female gender, shallow anterior chamber, short axial length of the eye in hyperopia, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and thick, anteriorly positioned lenses. Age
The prevalence of relative pupillary block and PAC, and thus PACG, has been shown to increase with age. A recent study of European-derived populations reported an age-specific prevalence of PACG of 0.02% for those aged 40–49, increasing to 0.95% for those 70 years and older (Day et al. 2012). Anterior chamber depth and
Acta Ophthalmologica 2016
volume gradually decrease throughout life. A 1996 analysis of anterior chamber changes demonstrated a depth decrease of 0.21 mm and volume decrease of 19 ll over 10 years (Sakai et al. 1996); in concert, these changes contribute to angle narrowing and increase the likelihood of PAS among the elderly. Lens thickness also contributes to anterior chamber shallowing (Lee et al. 1984). In younger populations, PACG is rare and is generally associated with other ocular abnormalities or plateau iris syndrome (Chang et al. 2002). Gender
Risk of PACG among women is approximately 3 times higher than in men (Foster et al. 1996, 2000; Quigley & Broman 2006). This, too, is likely the result of anatomical and mechanical differences between male and female eyes. Okabe studied 1169 eyes of participants diagnosed with PACG and found that certain measurements, including anterior chamber depth and axial length, were much lower in women, while angle width in women was significantly narrower than in men across all age groups (1991). Prevalence among women is also a function of relative life spans, as PACG is primarily a disease of the elderly, and women tend to outlive men. Ethnicity
Worldwide, the prevalence of PACG is highest in China. Of the 15 million people estimated to have ACG in 2010, 47.5% were located in China, and projections suggest that 20 million Chinese will have ACG by the year 2020 (Quigley & Broman 2006). An estimated 1.7 million Chinese persons are bilaterally blind from glaucoma, and the majority (91%) of that blindness is attributable to PACG (Foster & Johnson 2001). Numbers are similarly high – 86.5% – throughout Asia (Quigley & Broman 2006). Prevalence differs among Asian groups, with Mongolians demonstrating the highest prevalence of PAGC at 1.4% (Foster et al. 1996). Asians have a notably higher prevalence of PACG (0.6–1%) (Dandona et al. 2000; Foster et al. 2000; Yamamoto et al. 2005) than either Caucasians (0.09–0.4%) (Bonomi et al. 1998; Day et al. 2012) or Africans (0.5%) (Rotchford & Johnson 2002). Within individual ethnic groups, prevalence of
PACG was highest by far among the Inuit population, at 2.65% (Arkell et al. 1987). Refractive error
Small, hyperopic eyes are most at risk for developing PACG; the condition is rare in myopes, although it has been noted more frequently in those with a spherical equivalent of -6 dioptres (Mitchell et al. 1999; Barkana et al. 2006; He et al. 2006). As mentioned above, patients with PACG have a shorter axial length, shallower anterior chamber depth and diameter, and a thicker, more anteriorly positioned lens (Fontana & Brubaker 1980; Lee et al. 1984; Marchini et al. 1998). Family history and genetic predisposition
Although most cases of PACG are sporadic, recent research among Asian populations has indicated a hereditary element to the disease. In a 2014 study of prevalence of angle closure among siblings, 57.9% of siblings with one family member affected by PACG were categorized along the angle-closure spectrum themselves, with 14.7% demonstrating full PACG (Yazdani et al. 2014). A broader study of first-degree relatives of PAC and PACG patients conducted in Singapore found that 32.1% had narrow angles, with overall heritability of narrow angles calculated at 57.95. Siblings of PACG and PAC patients, in particular, were more than 7 times more likely to have narrow angles than the general population (Amerasinghe et al. 2011). A similar study in India examined the risk of narrow angles in siblings of PACS and/ or PACG patients. The study found that odds of developing narrow angles were nearly 14 times greater among these siblings than in the general population, with a greater than 1 in 3 risk of angle closure (Kavitha et al. 2014). Though imperfectly understood, the familial connection is clear, and siblings may benefit from PACG screening. The genetic causes that underlie angle-closure glaucoma are still being elucidated. An extensive genomewide association study published in 2012 identified three genomic loci that predispose patients to PACG: rs11024102 on PLEKHA7, rs3753841 on COL11A1 and rs1015213 on chromosome 8q (Vithana et al. 2012). The precise mechanism of pathology arising
from aberrant gene loci is still unknown. PLEKHA7 is known to regulate tight junctions; it is theorized that a deficiency at this locus might disrupt fluid dynamics in the eye. COL11A1 generally encodes collagen; the study’s authors proposed that this might manifest in scleral matrix anomalies or alteration of trabecular meshwork cells that could contribute to PACG development. Additional analysis determined that these polymorphisms did not impact axial length or anterior chamber depth (Nongpiur et al. 2013); further research may yet clarify the functional insult contributing to the development of acute disease. The clinical implications of the presence of these polymorphisms were recently investigated in a paper by Wei et al., who found no significant association between the alleles and the clinical features of glaucoma in the patients whose genotype contained them. No particular allele was found to be associated with phenotypically higher IOP, disease severity or disease progression; the presence of these loci appeared to increase susceptibility only (2014). Numerous other studies have examined genetic determinants for the risk factors referenced above. Nair et al. demonstrated an association between alterations in serine protease PRSS56 and a decreased axial length in the mouse model, contributing to the development of increased IOP, angle closure and choroidal expansion, presumably secondary to alterations in extracellular matrix processing during development (2011). Mutations of this protease also contributed to decreased axial length in humans with posterior microphthalmia. Other avenues of enquiry include research into the membrane-type frizzled-related protein (MFRP), another factor responsible for determining axial length and depth of the anterior chamber, observed in eyes with nanophthalmos (Liu & Allingham 2011) and into single nucleotide polymorphisms (SNPs) in metalloproteinases responsible for extracellular matrix formation (Shastry 2013). Still more genetic studies have shown an association between PACG and endothelial nitric oxide synthase polymorphisms in Australian, Nepalese and Pakistani populations (Ayub et al. 2010; Awadalla et al. 2013). Further research will hopefully clarify the
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Using the four-mirror lens, the clinician gently indents the central cornea; this displaces the aqueous from the centre to the periphery of the anterior chamber, mechanically deepening the angle and enabling better visualization of angle structures (Fig. 2) (Shields 1998). Dynamic indentation gonioscopy also aides in determining the extent of PAS (Fig. 3A) and may differentiate plateau iris configuration from pupillary block. Corneal indentation during gonioscopy results in posterior movement of the mid-peripheral iris in eyes with pupillary block, whereas in plateau iris configuration, the ciliary process prevents movement and a sine-shaped curve of the iris surface can be seen at the slit lamp (Shields 1998). Clinical estimation
Fig. 2. Anatomically narrow angle. Top panel: Prior to indentation gonioscopy, most angle structures are not visible, apart from the anterior portion of Schwalbe’s line (barely seen). The iris curvature is anteriorly bowed. Bottom panel: Following indentation gonioscopy, the iris flattens and angle structures are revealed. (From top to bottom: Schwalbe’s line, non-pigmented trabecular meshwork, pigmented trabecular meshwork and scleral spur. The ciliary body band is barely seen).
(A)
(B)
Fig. 3. Peripheral anterior synechiae as seen on gonioscopic (A) and OCT (B) imaging. Figure adapted with permission of Elsevier (Lai et al. 2013).
link between known genetic loci and phenotypic expression of narrowed angles.
Diagnosis Gonioscopy
Gonioscopy remains the most important diagnostic method for assessing angle closure. Indentation gonioscopy
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in particular is an essential technique for assessing PAS and appositional angle closure. The technique relies on the use of a four-mirror Zeiss, Sussman or Posner lens rather than the standard Goldmann lens. These lenses have an area of contact smaller than the cornea to enable the ease of indentation, and unlike the Goldmann lens, they require no coupling medium for a clear view.
Several techniques exist for the evaluation of anterior chamber depth at the slit lamp to identify patients at risk of angle closure. One traditional assessment method is Van Herick’s technique, which measures limbal chamber depth. This technique is performed by offsetting the light beam of the slit lamp by 60° from its central axis to create a thin column of light which is then directed at the temporal limbus. The observer compares the corneal thickness to the depth of the anterior chamber, which is visualized as a black space between the light reflexes on the cornea and iris (Fig. 4). Based on the ratio of limbal depth to corneal thickness, the observer grades the likelihood of angle closure on a scale from 1 to 4 (Table 2), with 1 indicating complete closure and 4 indicating completely open angles (Van Herick et al. 1969; Gispets et al. 2014). Gonioscopy is recommended at grade 1 and below. A second means of assessment is Smith’s method. In this technique, the angle between the slit beam and microscope is set to 60°, and the light beam is oriented horizontally. The physician directs a horizontal beam of light from the slit lamp across the cornea, forming two images of the slit beam upon the patient’s eye: one image is in focus on the cornea, and the second is out of focus across the lens and iris. The physician then adjusts the slit length control knob until these two images appear to touch end-to-end (Smith 1979). The length of the slit beam with the two images in contact is multiplied
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Fig. 4. Semi-objective measurement, through image analysis, of the width of the peripheral corneal thickness (PCT, solid line rectangle) and the peripheral anterior angle depth (PACD, broken line rectangle). This image was awarded a grade 3. Figure reproduced with permission of John Wiley & Sons, Inc. (Gispets et al. 2014), © 2013 The Authors and Optometrists Association Australia.
Table 2. Van Herick grading scale.
Grade
Limbal depth relative to corneal thickness
4 3 2 1 Narrow
≥ corneal thickness ¼–½ corneal thickness ¼ corneal thickness
