**26**

## **Plateau Iris**

#### Yoshiaki Kiuchi, Hideki Mochizuki and Kiyoshi Kusanagi *Hiroshima University Japan*

#### **1. Introduction**

522 Glaucoma - Basic and Clinical Concepts

[59] Hollows F. C, Graham P. A. Intra-ocular pressure, glaucoma, and glaucoma suspects in

[60] Wishart P. K., Atkinson P. L. Extracapsular cataract extraction and posterior chamber

[61] Gunning F. P., Greve E. L. Lens extraction for uncontrolled glaucoma. J Cataract Refract

[62] Ang L. P., Aung T., Chua W. H., et al. Visual field loss from primary angle-closure

[63] Salmon J. F. Long-term intraocular pressure control after Nd:YAG laser iridotomy in

[64] Rosman M., Aung T., Ang L. P., et al. Chronic angle-closure with glaucomatous

chronic angle-closure glaucoma. J Glaucoma. 1993; 2:291-296.

with an Asian population. Ophthalmology. 2002; 109:2227-2231.

lens implantation in patients with primary chronic angle-closure glaucoma: effect

glaucoma: a comparative study of symptomatic and asymptomatic disease.

damage: longterm clinical course in a North American population and comparison

a defined population. Br J Ophthalmol. 1966; 50:570-586.

on intraocular pressure control. Eye. 1989; 3:706-712.

Surg. 1998; 24:1347-1356.

Ophthalmology. 2004; 111:1636-1640.

Primary angle-closure glaucoma (PACG) is a common form of glaucoma in Asia (Foster & Johnson, 2001). It is associated with a high risk of visual loss (Congdon et al., 1992; Foster et al., 1996). PACG was estimated to blind 5 times more people than primary open-angle glaucoma (Quigley et al. 2001). The original concept of primary angle closure glaucoma was a pupil- block angle-closure mechanism occurring in predisposed eyes with shallow anterior chamber angles. Peripheral iridectomy prevents the progression of primary angle closure glaucoma (Lowe, 1964). However, many patients experienced recurrent angle-closure glaucoma attacks after iridectomy (Wand et al., 1977). The occurrence of narrow angle in eyes with relatively normal depth in the anterior chamber and a relatively flat iris plane had been noted as early as 1940 (Gradle & Sugar, 1940). Chandler presented the case of a patient with repeated intermittent angle-closure glaucoma attacks despite a patent iridectomy, who was successfully treated with pilocarpine (Wand et al., 1977). Those cases were considered to be different from ordinary cases of narrow angle glaucoma. They were particularly found

Fig. 1. Plateau iris configuration. Ultrasound biomicroscopy image shows a flat iris plane ( ) accompanied by a narrow or closed anterior chamber angle. Plateau iris configuration is caused by anteriorly located ciliary processes ( ), which close the ciliary sulcus and provide support to the peripheral iris

Plateau Iris 525

over time (Wand et al., 1977). Many people tend to confuse incomplete plateau syndrome

Generally, the diagnosis of a plateau iris configuration is based on typical gonioscopic findings. A plateau iris configuration is defined as a flat iris plane accompanied by a narrow or closed anterior chamber angle. Some patients with a plateau iris configuration show an increased intraocular pressure after the pupils are dilated by angle closure even after laser

Indentation gonioscopy of eyes with a plateau iris configuration following patent iridotomy reveals a sine-shaped curve of the iris surface. Indentation presses the iris surface backward. The deepest point of indentation is not at the iris periphery, but at approximately twothirds of the distance between the center of the pupil and the iris root. The iris rises again from this point to the site of appositional closure. This shape is called a double hump sign.

Right eye Left eye

Fig. 3. Ultrasound biomicroscopy image of Figure 2

Fig. 4. Double hump sign after indentation

with plateau iris configuration.

**3. Diagnosis** 

iridotomy.

**3.1 Gonioscopic findings** 

in younger patients in whom a peripheral iridectomy is often ineffective. These patients had a flat iris and a narrow angle secondary to an abrupt angulation at the root of the iris. This iris shape was called a plateau iris configuration.

The concept of the plateau iris was introduced in a publication by Shaffer (Shaffer, 1960). Primary angle closure includes those that are caused by a pupillary block and plateau iris configuration (Tarongoy et al., 2009).

#### **2. Plateau iris configuration and plateau iris syndrome**

Wand et al. reported that the plateau iris syndrome should be differentiated from the plateau iris configuration, to avoid confusion. Native plateau iris configuration refers to a preoperative (iridectomy or iridotomy) condition, in which angle-closure glaucoma is confirmed by gonioscopy, but the iris is flat and the anterior chamber is not shallow (Wand et al., 1977). One third of all patients demonstrating primary angle closure were estimated to have plateau iris configuration (Kumar et al., 2009, Mochizuki et al., 2010).

Plateau iris syndrome refers to the development of angle closure in an eye with plateau iris configuration. The intraocular pressure (IOP) increases because of angle closure after pupillary dilation. Plateau iris configuration can be diagnosed before iridotomy. However, plateau iris syndrome is normally diagnosed after laser iridotomy. Plateau iris syndrome is rare. Less than 10 % of all patients with primary angle closure are considered to have plateau iris syndrome.

The prevalence of angle closure attack in plateau iris syndrome is not known.

Fig. 2. Slit lamp photograph of an eye with a re-attack of acute closer attack and the patient's opposite eye. Right eye; Pupil is dilated after the second attack. Left eye; The laser iridotomy hole ( ) is observed at 10 o'clock

The right eye developed acute closed-angle attack on December 2005. After successful treatment by laser iridotomy patients had a re-attack on October 2006. This patient underwent cataract surgery for the relief of the angle closure attack. Cataract surgery stabilized the IOP in the right eye.

Plateau iris syndrome is classified into two groups. Complete syndrome has a high plateau and covers the chamber angle after dilation and causes elevation of the IOP. Incomplete Syndrome partially covers the chamber angle after dilation of the pupil. The IOP will not elevate after dilating the pupil. However, the peripheral anterior synechia (PAS) increases

in younger patients in whom a peripheral iridectomy is often ineffective. These patients had a flat iris and a narrow angle secondary to an abrupt angulation at the root of the iris. This

The concept of the plateau iris was introduced in a publication by Shaffer (Shaffer, 1960). Primary angle closure includes those that are caused by a pupillary block and plateau iris

Wand et al. reported that the plateau iris syndrome should be differentiated from the plateau iris configuration, to avoid confusion. Native plateau iris configuration refers to a preoperative (iridectomy or iridotomy) condition, in which angle-closure glaucoma is confirmed by gonioscopy, but the iris is flat and the anterior chamber is not shallow (Wand et al., 1977). One third of all patients demonstrating primary angle closure were estimated to

Plateau iris syndrome refers to the development of angle closure in an eye with plateau iris configuration. The intraocular pressure (IOP) increases because of angle closure after pupillary dilation. Plateau iris configuration can be diagnosed before iridotomy. However, plateau iris syndrome is normally diagnosed after laser iridotomy. Plateau iris syndrome is rare. Less than 10 % of all patients with primary angle closure are considered to have

 Fig. 2. Slit lamp photograph of an eye with a re-attack of acute closer attack and the patient's opposite eye. Right eye; Pupil is dilated after the second attack. Left eye; The laser iridotomy

The right eye developed acute closed-angle attack on December 2005. After successful treatment by laser iridotomy patients had a re-attack on October 2006. This patient underwent cataract surgery for the relief of the angle closure attack. Cataract surgery stabilized the IOP

Plateau iris syndrome is classified into two groups. Complete syndrome has a high plateau and covers the chamber angle after dilation and causes elevation of the IOP. Incomplete Syndrome partially covers the chamber angle after dilation of the pupil. The IOP will not elevate after dilating the pupil. However, the peripheral anterior synechia (PAS) increases

iris shape was called a plateau iris configuration.

**2. Plateau iris configuration and plateau iris syndrome** 

have plateau iris configuration (Kumar et al., 2009, Mochizuki et al., 2010).

The prevalence of angle closure attack in plateau iris syndrome is not known.

configuration (Tarongoy et al., 2009).

plateau iris syndrome.

hole ( ) is observed at 10 o'clock

in the right eye.

over time (Wand et al., 1977). Many people tend to confuse incomplete plateau syndrome with plateau iris configuration.

Right eye Left eye

#### **3. Diagnosis**

#### **3.1 Gonioscopic findings**

Generally, the diagnosis of a plateau iris configuration is based on typical gonioscopic findings. A plateau iris configuration is defined as a flat iris plane accompanied by a narrow or closed anterior chamber angle. Some patients with a plateau iris configuration show an increased intraocular pressure after the pupils are dilated by angle closure even after laser iridotomy.

Indentation gonioscopy of eyes with a plateau iris configuration following patent iridotomy reveals a sine-shaped curve of the iris surface. Indentation presses the iris surface backward. The deepest point of indentation is not at the iris periphery, but at approximately twothirds of the distance between the center of the pupil and the iris root. The iris rises again from this point to the site of appositional closure. This shape is called a double hump sign.

Fig. 4. Double hump sign after indentation

Plateau Iris 527

found in the opposite eyes of 10 (37.0%) of 27 patients with acute angle-closure, 9 (34.6%)of 26 patients with chronic angle-closure glaucoma, and 5 (19.2%) of 26 patients with openangle glaucoma (Mochizuki et al., 2010). Filho also reported that plateau iris configuration in 10.2% of patients with open-angle glaucoma (Diniz Fiho et al., 2010). The clinical significance of plateau iris configurations in open-angle glaucoma eyes is unclear. Openangle glaucoma eyes do not have plateau iris configurations high enough to occlude the trabecular meshwork, which is associated with the elevation of IOP or other clinical events. However, lower plateau iris configuration may become higher over time due to increased thickness and anterior movement of the lens, which would consequently result in angle

Cases of recurrent angle-closure glaucoma after iridectomy, as a result of plateau iris syndrome are relatively rare. Plateau iris syndrome is believed to constitute a small percentage of eyes with plateau iris configuration. A study of eyes that had experienced angle-closure episodes was conducted to determine the relative frequency of plateau iris syndrome. All of the patients had undergone peripheral iridectomy. The IOP increased more than 8 mmHg after topical application of homatropine in 4 (6.2%)of the 65 eyes. Those 4 eyes were classified as the iris plateau type of angle –closure glaucoma (Godel et al., 1968). Saitoh reported that five of 50 iridectomized PACG eyes developed complete closure of the angle with an increase in the IOP exceeding 10 mmHg following the administration of homatropine which acts on the sphincter muscle located at the pupillary margin. However, those 5 subjects did not show IOP elevation after topical application of phenilephrine hydrochloride (alpha adrenergic stimulator) Phenilephrine acts on the iris dilator muscle which is located just above the iris pigment epithelium. Homatropine and phenilephrine act on different muscles in the iris, and the difference in the distribution of the dilator muscle and the sphincter muscle causes the different morphological changes in the iris after application of the midriatic agents. This may explain the difference in IOP response after

Historically, plateau iris configuration is regarded as angle closure with normal anterior chamber depth and flat iris plane. Mandel et al. reported that all plateau iris configuration eyes showed biometric parameters that were completely different for those of normal eyes, except for the peripheral iris thickness at 500 μm from the scleral spur. The eyes with plateau iris configuration showed a shallower anterior chamber depth than normal eyes (Mandell et al., 2003). The mean anterior chamber depth in patients with plateau iris syndrome (2.04 +/- 0.30 mm) was significantly smaller than the hypothesized normal anterior chamber depth (3 mm). The mean anterior chamber depth in patients with pupillary block (2.17 +/- 0.30 mm) was also significantly smaller than the hypothesized normal anterior chamber depth. Although a review of the literature suggested that patients with plateau iris had a normal or deeper axial anterior chamber depth in comparison to those with pupillary block, the mean anterior chamber depth in patients with plateau iris syndrome was significantly smaller than the anterior chamber depth in patients with

There is one more report related to the biometrics of plateau iris configuration. Kiuchi et al. reported that patients with plateau iris configuration had deeper anterior chamber and

closure.

**4.2 Prevalence of plateau iris syndrome** 

dilation of pupil by midriatic agents (Saitoh, 1974).

pupillary block in the report by Mandell et al (Mandell et al., 2003).

**4.3 Biometrics of plateau iris configuration** 

A double hump sign observed on indentation gonioscopy was strongly correlated with the presence of a plateau iris, and is, therefore a useful indicator of a plateau iris configuration. Therefore, a plateau iris configuration can be detected in many cases, without using a UBM (Kiuchi et al., 2009; Ritch, 1992).

#### **3.2 Ultrasound biomicroscopy (UBM) findings**

UBM provides detailed sub surface images of the angle region. This method showed that plateau iris configuration is caused by anteriorly located ciliary processes, which close the ciliary sulcus and provide support to the peripheral iris (Roberts et al., 2008). The ciliary processes were situated anteriorly in all the plateau iris configuration patients in comparison to the position in normal subjects and in patients with angle closure caused by pupillary block. The ciliary processes provide structural support beneath the peripheral iris, preventing the iris root from falling away from the trabecular meshwork after iridotomy (Pavlin et al., 1992).

Observation with a slit lamp causes miosis and thus the iris becomes thinner. An unintentional indentation and/or miosis induced by the slit-lamp light might prevent the identification of appositional angle closure during regular gonioscopic examination (Sakata et al., 2006). The importance of the diagnosis of plateau iris configuration by UBM resides in the fact that the plateau iris configuration can be detected without any interference from the effect of the lighting. Provocative tests were not usually helpful for detecting plateau iris syndrome (Ritch et al., 2009).

#### **4. Gender and age**

Women from Japan, Israel, Finland, and Thailand showed a consistently more frequent occurrence of PACG (Yamamoto et al., 2005). One study found no sexual predisposition for plateau iris configuration (Ritch, 1992). Others report that most patients with plateau iris were female and younger than those with pupillary block. The average age of the patients studied by Diniz et al. was 60.1 years old (Diniz et al., 2010). This is consistent with the results of the study by Mandell et al (Mandell et al., 2003), in which the plateau iris configuration patients averaged 57.5 years old.

Ritch, et al. evaluated the findings in patients 40 years of age or younger with angle closure. Sixty-seven patients (49 females, 18 males) met the entry criteria. Plateau iris configuration was found in 35 patients (52.2%) (Ritch et al., 2003).

On the other hand, the prevalence of PACG significantly increases with age in population based epidemiological studies (Yamamoto et al., 2005). Pupillary block angle closure is a disease of older persons, peaking in incidence between 55 and 70 years of age (Suzuki et al., 2008).

#### **4.1 Prevalence of plateau iris configuration**

Kumar et al. used standardized UBM criteria and found plateau iris in about one third of PACS eyes after laser iridotomy (Kumar et al., 2008, 2009). Mochizuki et al. conducted a study under the same criteria used by Kumar et al. to determine the prevalence of plateau iris configurations in acute angle-closure, chronic angle-closure glaucoma, and open-angle glaucoma eyes using ultrasound biomicroscopy The study included fellow eyes from 27 acute angle-closure patients, 26 open-angle glaucoma patients, and 26 chronic angle-closure glaucoma patients with no history of acute angle-closure. Plateau iris configurations were

A double hump sign observed on indentation gonioscopy was strongly correlated with the presence of a plateau iris, and is, therefore a useful indicator of a plateau iris configuration. Therefore, a plateau iris configuration can be detected in many cases, without using a UBM

UBM provides detailed sub surface images of the angle region. This method showed that plateau iris configuration is caused by anteriorly located ciliary processes, which close the ciliary sulcus and provide support to the peripheral iris (Roberts et al., 2008). The ciliary processes were situated anteriorly in all the plateau iris configuration patients in comparison to the position in normal subjects and in patients with angle closure caused by pupillary block. The ciliary processes provide structural support beneath the peripheral iris, preventing the iris root from falling away from the trabecular meshwork after iridotomy

Observation with a slit lamp causes miosis and thus the iris becomes thinner. An unintentional indentation and/or miosis induced by the slit-lamp light might prevent the identification of appositional angle closure during regular gonioscopic examination (Sakata et al., 2006). The importance of the diagnosis of plateau iris configuration by UBM resides in the fact that the plateau iris configuration can be detected without any interference from the effect of the lighting. Provocative tests were not usually helpful for detecting plateau iris

Women from Japan, Israel, Finland, and Thailand showed a consistently more frequent occurrence of PACG (Yamamoto et al., 2005). One study found no sexual predisposition for plateau iris configuration (Ritch, 1992). Others report that most patients with plateau iris were female and younger than those with pupillary block. The average age of the patients studied by Diniz et al. was 60.1 years old (Diniz et al., 2010). This is consistent with the results of the study by Mandell et al (Mandell et al., 2003), in which the plateau iris

Ritch, et al. evaluated the findings in patients 40 years of age or younger with angle closure. Sixty-seven patients (49 females, 18 males) met the entry criteria. Plateau iris configuration

On the other hand, the prevalence of PACG significantly increases with age in population based epidemiological studies (Yamamoto et al., 2005). Pupillary block angle closure is a disease of older persons, peaking in incidence between 55 and 70 years of age (Suzuki et al.,

Kumar et al. used standardized UBM criteria and found plateau iris in about one third of PACS eyes after laser iridotomy (Kumar et al., 2008, 2009). Mochizuki et al. conducted a study under the same criteria used by Kumar et al. to determine the prevalence of plateau iris configurations in acute angle-closure, chronic angle-closure glaucoma, and open-angle glaucoma eyes using ultrasound biomicroscopy The study included fellow eyes from 27 acute angle-closure patients, 26 open-angle glaucoma patients, and 26 chronic angle-closure glaucoma patients with no history of acute angle-closure. Plateau iris configurations were

(Kiuchi et al., 2009; Ritch, 1992).

(Pavlin et al., 1992).

syndrome (Ritch et al., 2009).

configuration patients averaged 57.5 years old.

**4.1 Prevalence of plateau iris configuration** 

was found in 35 patients (52.2%) (Ritch et al., 2003).

**4. Gender and age** 

2008).

**3.2 Ultrasound biomicroscopy (UBM) findings** 

found in the opposite eyes of 10 (37.0%) of 27 patients with acute angle-closure, 9 (34.6%)of 26 patients with chronic angle-closure glaucoma, and 5 (19.2%) of 26 patients with openangle glaucoma (Mochizuki et al., 2010). Filho also reported that plateau iris configuration in 10.2% of patients with open-angle glaucoma (Diniz Fiho et al., 2010). The clinical significance of plateau iris configurations in open-angle glaucoma eyes is unclear. Openangle glaucoma eyes do not have plateau iris configurations high enough to occlude the trabecular meshwork, which is associated with the elevation of IOP or other clinical events. However, lower plateau iris configuration may become higher over time due to increased thickness and anterior movement of the lens, which would consequently result in angle closure.

#### **4.2 Prevalence of plateau iris syndrome**

Cases of recurrent angle-closure glaucoma after iridectomy, as a result of plateau iris syndrome are relatively rare. Plateau iris syndrome is believed to constitute a small percentage of eyes with plateau iris configuration. A study of eyes that had experienced angle-closure episodes was conducted to determine the relative frequency of plateau iris syndrome. All of the patients had undergone peripheral iridectomy. The IOP increased more than 8 mmHg after topical application of homatropine in 4 (6.2%)of the 65 eyes. Those 4 eyes were classified as the iris plateau type of angle –closure glaucoma (Godel et al., 1968). Saitoh reported that five of 50 iridectomized PACG eyes developed complete closure of the angle with an increase in the IOP exceeding 10 mmHg following the administration of homatropine which acts on the sphincter muscle located at the pupillary margin. However, those 5 subjects did not show IOP elevation after topical application of phenilephrine hydrochloride (alpha adrenergic stimulator) Phenilephrine acts on the iris dilator muscle which is located just above the iris pigment epithelium. Homatropine and phenilephrine act on different muscles in the iris, and the difference in the distribution of the dilator muscle and the sphincter muscle causes the different morphological changes in the iris after application of the midriatic agents. This may explain the difference in IOP response after dilation of pupil by midriatic agents (Saitoh, 1974).

#### **4.3 Biometrics of plateau iris configuration**

Historically, plateau iris configuration is regarded as angle closure with normal anterior chamber depth and flat iris plane. Mandel et al. reported that all plateau iris configuration eyes showed biometric parameters that were completely different for those of normal eyes, except for the peripheral iris thickness at 500 μm from the scleral spur. The eyes with plateau iris configuration showed a shallower anterior chamber depth than normal eyes (Mandell et al., 2003). The mean anterior chamber depth in patients with plateau iris syndrome (2.04 +/- 0.30 mm) was significantly smaller than the hypothesized normal anterior chamber depth (3 mm). The mean anterior chamber depth in patients with pupillary block (2.17 +/- 0.30 mm) was also significantly smaller than the hypothesized normal anterior chamber depth. Although a review of the literature suggested that patients with plateau iris had a normal or deeper axial anterior chamber depth in comparison to those with pupillary block, the mean anterior chamber depth in patients with plateau iris syndrome was significantly smaller than the anterior chamber depth in patients with pupillary block in the report by Mandell et al (Mandell et al., 2003).

There is one more report related to the biometrics of plateau iris configuration. Kiuchi et al. reported that patients with plateau iris configuration had deeper anterior chamber and

Plateau Iris 529

that multiple, bilateral iridociliary cysts causes elevation of the iris structure (Tanihara et al., 1997). This report showed that an iris cyst could cause the pseudo-plateau configuration. The incidence and sector distribution of ciliary body cysts in normal subjects is not low. A UBM study conducted by Kunimatsu et al. showed that cysts were detected in 63 (54.3%) of the 116 subjects. The number and diameter of the cysts decreased with age. Gender and refractive error did not affect the incidence and distribution. A significant bilateral correlation was found in the number, incidence, and distribution of ciliary body cysts (Kunimatsu et al., 1999). There was a high prevalence of iris cysts in young subjects. Younger subjects with a bumpy peripheral iris have a higher likelihood of a diagnosis of

Any disorder that causes swelling of the ciliary body or forward rotation of the ciliary body can create a pseudo-plateau iris configuration. Sulfa based compounds like hydrochlorothiazide, oral acetazolamide, supra ciliary effusions and ciliary body thickening after scleral buckling procedures can cause ciliary swelling and precipitate angle closure

Miotic therapy is one option for plateau iris configuration. One drop of pilocarpine causes significant changes in the anterior eye segment morphology. This decreases the pupillary diameter and the iris thickness (Németh et al., 1996-1997). A single drop of 2% pilocarpine is an effective agent for thinning the iris and opening the angle in plateau iris syndrome. The ability to visualize the degree of angle opening produced by pilocarpine can be helpful in predicting the efficacy of this therapy (Pavlin and Foster, 1999). There are two problems associated with pilocarpine treatment for glaucoma associated with plateau iris configuration. Most patients are relatively young in age in comparison to the usual angleclosure glaucoma patients, and therefore, are unhappy with pilocarpine- induced myopia and miosis. These side effects may decrease the compliance (adherence) to the medical

Yasuda et al. examined the long-term effects of topical pilocarpine on IOP control in primary angle-closure glaucoma without iridectomy. Six (43%) out of 14 eyes with acute PACG under topical pilocarpine therapy had re-attacks while one eye (7%) developed increased IOP. Twelve of 47 fellow eyes of patients with acute PACG (26%) developed acute attacks while 3 eyes (6%) showed increased IOP. They concluded that long-term medical therapy for PACG is unsatisfactory. A single drop of pilocarpine works only for 6 hours. Short acting duration of pilocarpine and poor compliance (adherence) may play some role in this result. They included all types of angle closure glaucoma in their study. Patients with

plateau iris configuration might yield the same results (Yasuda & Kageyama, 1988).

Laser iridotomy (LI) is the appropriate treatment for angle closure glaucoma due to primary pupillary block. UBM studies in patients with pupillary block glaucoma post-LI

glaucoma.(Geason & Perkins, 1995; Palvin et al., 1997; Tripathi et al., 2003)

pseudo-plateau iris (Shukla et al., 2008).

**6.2 Others** 

**7. Management** 

**7.1 Miotics** 

therapy.

**7.2 Laser treatment 7.2.1 Laser iridotomy** 

longer axial length than chronic angle closure patients without plateau iris configuration (Kiuchi et al., 2009). Further study is necessary to clarify this issue.

#### **4.4 Changes in the biometrics of plateau iris configuration after intervention**

Palvin et al. used ultrasound biomicroscopy to image angles in the dark, in the light, and following pilocarpine administration to clarify factors that produce angle opening changes in this syndrome. Changes in angle opening in dark and light were solely related to changes in iris thickness. Their results were consistent with the concept that the space between the ciliary processes and trabecular meshwork constitutes a passageway of fixed dimension. An increase in iris thickness resulted in a decrease in angle opening, and a decrease in iris thickness resulted in an increase in angle opening. Angle closure occured if the iris thickness fills the space between the ciliary processes and the trabecular meshwork (Pavlin & Foster, 1999).

### **5. The cause of plateau iris configuration**

The cause of the plateau iris configuration is not known. The anomaly of the pars plicata position could be developmental or acquired. Ciliary processes develop during the 24th week of embryogenesis and initially overlap the trabecular meshwork but later recede to a position behind the scleral spur. This repositioning is thought to be due to a differential growth rate of the various tissue elements. The specific features of the ciliary processes in the eyes with plateau iris might be due to the failure of the ciliary processes to separate from the posterior iris surface. The displacement of the pars plicata from the peripheral iris to the iris root during embryogenesis may be incomplete in eyes with a shorter axial length. However, incomplete cleavage between the iris and ciliary body is unlikely (Razeghinejad & Kamali-Sarvestani, 2007; Tran et al., 2003).

Tran and associates (Tran et al., 2003) examined the anterior segments of 6 patients with plateau iris syndrome before and after cataract surgery. They found that irido-ciliary apposition persisted after extracapsular cataract extraction, thus indicating that the age related growth of the lens (i.e., acquired changes in the zonular fibers stretched by cataract formation) does not induce a reversible anterior pulling and or rotation of the ciliary body processes.

Etter investigated the prevalence of plateau iris syndrome in the first-degree relatives of patients affected with plateau iris syndrome. They found a high prevalence of plateau iris configuration in family members of patients with plateau iris syndrome. Five of the 10 participating patients (50%) were found to have at least 1 first-degree family member with plateau iris configuration. The presence of plateau iris configuration in successive generations, where there was not consanguineous marriage, therefore suggested that it might be inherited in an autosomal dominant manner with incomplete penetrance (Etter et al., 2006).

#### **6. Differential diagnosis**

#### **6.1 Iris cyst**

Tanihara et al. reported a case of high, broad, peripheral anterior synechiae caused by multiple, bilateral iridociliary cysts. The peripheral anterior synechia extended to the corneal endothelium beyond Schwalbe's line. Ultrasound biomicroscopic imaging showed

longer axial length than chronic angle closure patients without plateau iris configuration

Palvin et al. used ultrasound biomicroscopy to image angles in the dark, in the light, and following pilocarpine administration to clarify factors that produce angle opening changes in this syndrome. Changes in angle opening in dark and light were solely related to changes in iris thickness. Their results were consistent with the concept that the space between the ciliary processes and trabecular meshwork constitutes a passageway of fixed dimension. An increase in iris thickness resulted in a decrease in angle opening, and a decrease in iris thickness resulted in an increase in angle opening. Angle closure occured if the iris thickness fills the space between the ciliary processes and the trabecular meshwork (Pavlin & Foster,

The cause of the plateau iris configuration is not known. The anomaly of the pars plicata position could be developmental or acquired. Ciliary processes develop during the 24th week of embryogenesis and initially overlap the trabecular meshwork but later recede to a position behind the scleral spur. This repositioning is thought to be due to a differential growth rate of the various tissue elements. The specific features of the ciliary processes in the eyes with plateau iris might be due to the failure of the ciliary processes to separate from the posterior iris surface. The displacement of the pars plicata from the peripheral iris to the iris root during embryogenesis may be incomplete in eyes with a shorter axial length. However, incomplete cleavage between the iris and ciliary body is unlikely (Razeghinejad &

Tran and associates (Tran et al., 2003) examined the anterior segments of 6 patients with plateau iris syndrome before and after cataract surgery. They found that irido-ciliary apposition persisted after extracapsular cataract extraction, thus indicating that the age related growth of the lens (i.e., acquired changes in the zonular fibers stretched by cataract formation) does not induce a reversible anterior pulling and or rotation of the ciliary body

Etter investigated the prevalence of plateau iris syndrome in the first-degree relatives of patients affected with plateau iris syndrome. They found a high prevalence of plateau iris configuration in family members of patients with plateau iris syndrome. Five of the 10 participating patients (50%) were found to have at least 1 first-degree family member with plateau iris configuration. The presence of plateau iris configuration in successive generations, where there was not consanguineous marriage, therefore suggested that it might be inherited in an autosomal dominant manner with incomplete penetrance (Etter et

Tanihara et al. reported a case of high, broad, peripheral anterior synechiae caused by multiple, bilateral iridociliary cysts. The peripheral anterior synechia extended to the corneal endothelium beyond Schwalbe's line. Ultrasound biomicroscopic imaging showed

**4.4 Changes in the biometrics of plateau iris configuration after intervention** 

(Kiuchi et al., 2009). Further study is necessary to clarify this issue.

**5. The cause of plateau iris configuration** 

Kamali-Sarvestani, 2007; Tran et al., 2003).

1999).

processes.

al., 2006).

**6.1 Iris cyst** 

**6. Differential diagnosis** 

that multiple, bilateral iridociliary cysts causes elevation of the iris structure (Tanihara et al., 1997). This report showed that an iris cyst could cause the pseudo-plateau configuration. The incidence and sector distribution of ciliary body cysts in normal subjects is not low. A UBM study conducted by Kunimatsu et al. showed that cysts were detected in 63 (54.3%) of the 116 subjects. The number and diameter of the cysts decreased with age. Gender and refractive error did not affect the incidence and distribution. A significant bilateral correlation was found in the number, incidence, and distribution of ciliary body cysts (Kunimatsu et al., 1999). There was a high prevalence of iris cysts in young subjects. Younger subjects with a bumpy peripheral iris have a higher likelihood of a diagnosis of pseudo-plateau iris (Shukla et al., 2008).

#### **6.2 Others**

Any disorder that causes swelling of the ciliary body or forward rotation of the ciliary body can create a pseudo-plateau iris configuration. Sulfa based compounds like hydrochlorothiazide, oral acetazolamide, supra ciliary effusions and ciliary body thickening after scleral buckling procedures can cause ciliary swelling and precipitate angle closure glaucoma.(Geason & Perkins, 1995; Palvin et al., 1997; Tripathi et al., 2003)

#### **7. Management**

#### **7.1 Miotics**

Miotic therapy is one option for plateau iris configuration. One drop of pilocarpine causes significant changes in the anterior eye segment morphology. This decreases the pupillary diameter and the iris thickness (Németh et al., 1996-1997). A single drop of 2% pilocarpine is an effective agent for thinning the iris and opening the angle in plateau iris syndrome. The ability to visualize the degree of angle opening produced by pilocarpine can be helpful in predicting the efficacy of this therapy (Pavlin and Foster, 1999). There are two problems associated with pilocarpine treatment for glaucoma associated with plateau iris configuration. Most patients are relatively young in age in comparison to the usual angleclosure glaucoma patients, and therefore, are unhappy with pilocarpine- induced myopia and miosis. These side effects may decrease the compliance (adherence) to the medical therapy.

Yasuda et al. examined the long-term effects of topical pilocarpine on IOP control in primary angle-closure glaucoma without iridectomy. Six (43%) out of 14 eyes with acute PACG under topical pilocarpine therapy had re-attacks while one eye (7%) developed increased IOP. Twelve of 47 fellow eyes of patients with acute PACG (26%) developed acute attacks while 3 eyes (6%) showed increased IOP. They concluded that long-term medical therapy for PACG is unsatisfactory. A single drop of pilocarpine works only for 6 hours. Short acting duration of pilocarpine and poor compliance (adherence) may play some role in this result. They included all types of angle closure glaucoma in their study. Patients with plateau iris configuration might yield the same results (Yasuda & Kageyama, 1988).

#### **7.2 Laser treatment**

#### **7.2.1 Laser iridotomy**

Laser iridotomy (LI) is the appropriate treatment for angle closure glaucoma due to primary pupillary block. UBM studies in patients with pupillary block glaucoma post-LI

Plateau Iris 531

volume and pupillary block, but also by attenuating the anterior positioning of the ciliary processes in eyes with primary angle closed eyes (Nonaka et al., 2006). There are currently no randomized controlled trials supporting the use of clear lens extraction as the treatment of choice for PACG. However, the potential of obtaining some benefit from this procedure is

Phacoemulsification and goniosynechialysis (PEGS) is also effective in managing acute and subacute primary angle closure including patients plateau iris (Harasymowycz et al., 2005). Topical application of miotic agents, laser peripheral iridoplasty and cataract surgery seem to be effective for glaucoma with plateau iris configuration. There is a lack of well-designed, randomized, controlled trials to assess the effect as a therapeutic modality for glaucoma with plateau iris configuration, because the occurrence of plateau iris is relatively rare.

A plateau iris configuration is defined as a flat iris plane accompanied by a narrow or closed anterior chamber angle. Pathological and physiological data of plateau iris configuration and plateau iris syndrome are increasing. However, we do not have enough information related to plateau iris configuration and syndrome to manage them. The prognosis of this disorder compared to pupillary block angle closure glaucoma also remains to be elucidated. There are no quantitative diagnosis criteria, yet. This condition confuse the interpretation of the data appeared at the journals. The best therapeutic protocol should be established in

Choi, JS. & Kim, YY. (2005). Progression of peripheral anterior synechiae after laser iridotomy., *American Journal of Ophthalmology*, Vol.140, No.6, (2005), pp.1125–1127 Congdon, N., Wang, F., & Tielsch, JM. (1992). Issues in the epidemiology and population-

Crowston, JG., Medeiros, FA. Mosaed, S., & Weinreb, RN. (2005). Argon laser iridoplasty in

cysts, *American Journal of Ophthalmology*, Vol.139, No.2, (2005), pp.381–383 Diniz Filho, A., Cronemberger, S., Ferreira, DM., Mérula, RV., & Calixto, N. (2010). Plateau

Etter, JR., Affel, EL., & Rhee, DJ. (2006). High prevalence of plateau iris configuration in

Foster, PJ., Baasanhu, J., Alsbirk, PH., Munkhbayar, D., Uranchimeg, D., & Johnson, J.

Foster, PJ. & Johnson, GJ. (2001). Glaucoma in China: how big is the problem?, *British Journal* 

Geanon, JD. & Perkins, TW.(1995). Bilateral acute angle-closure glaucoma associated with

*Arquivos brasileiros de oftalmologia*, Vol.73, No.2, (2010), pp.155-160

*of Ophthalmology*, Vol.85, No.11, (2001), pp.1277–1282

based screening of primary angle-closure glaucoma, *Survey of Ophthalmology*,

the treatment of plateau-like iris configuration as result of numerous ciliary body

iris configuration in eyes with narrow-angle: an ultrasound biomicroscopic study,

family members of patients with plateau iris syndrome, *Journal of Glaucoma*, Vol.15,

(1996). Glaucoma in Mongolia: a population-based survey in Hovsgol province, northern Mongolia, *Archives of Ophthalmology*, Vol.114, No.10, (1996), pp.1235–1241

drug sensitivity to hydrochlorothiazide, *Archives of Ophthalmology*, Vol.113, No.10,

future. New imaging technology will help us to obtain the new information.

Vol.36, No.11, (1992), pp.411–423

No.5 (2006), pp.394–398

(1995), pp.1231–1232

considered to be biologically plausible (Thomas et al., 2011).

**8. Conclusions** 

**9. References** 

demonstrated substantial increases in the anterior chamber angle aperture following laser iridotomy. Previous studies have also shown that in eyes with an acute attack, the angle widened in the first 2 weeks after LI, but did not change thereafter over 1 year, and the amount of peripheral anterior synechia (PAS) remained stable throughout. The results indicate the effectiveness of LI in preventing progressive closure of the angle in the first year after the angle closure attack (Porikoff et al., 2005). However, laser iridotomy is insufficient to treat glaucoma associated with plateau iris. Many patients with a patent iridotomy hole experienced acute angle-closed attacks. Polikoff et al. also examined the effect of laser iridotomy on anterior segment anatomy of patients with plateau iris configuration. Iridotomy will remove any contribution from pupillary block in these patients, but the angle will remain narrow because the anteriorly positioned ciliary processes prevent the peripheral iris from moving posteriorly. This report also showed that pupil block and plateau iris configuration coexists in many cases (Polikoff et al., 2005). Approximately one of three of the eyes showed PAS progression during a 3-year follow-up period after LI. The probability of progression was found to be high in the eyes that exhibited plateau iris (Choi & Kim, 2005). These data show that laser iridotomy alone is not an effective treatment for glaucoma with plateau iris configuration.

#### **7.2.2 Argon laser peripheral iridoplasty**

Argon laser peripheral iridoplasty can effectively eliminate residual appositional closure after laser iridotomy caused by plateau iris syndrome, and the effect is maintained for years. Argon laser iridoplasty may also prove valuable in the treatment of plateau-like iris configuration resulting from iridociliary cysts (Crowston et al., 2005). Rich et al. documented the long-term effect of argon laser iridoplasty in patients with plateau iris syndrome. A total of 26 argon laser iridoplasty procedures were performed in 23 eyes of 14 patients. The angle remained open in 20 of 23 (87.0%) eyes after only 1 treatment with Argon laser iridoplasty over a follow-up period of 78.9 ± 8.0 months (range, 72–188 months). They concluded that Argon laser iridoplasty could effectively eliminate residual appositional closure after laser iridotomy caused by plateau iris syndrome (Ritch et al., 2004). However, there are no other reports that indicate the effectiveness of laser peripheral iridoplasty.

#### **7.2.3 Cataract surgery**

Hayashi showed that the anterior chamber depth and angle width in angle closure glaucoma eyes approximates that of POAG eyes and control eyes without glaucoma after phaco-emulsification and posterior chamber intraocular lens implantation (Hayashi et al., 2000). They thought that these changes contribute to the significant IOP reduction seen in the postoperative follow-up period of 12 months. Tran et al. evaluated the ultrasound biomicroscopic appearance of the anterior segment before and after cataract extraction in eyes with plateau iris syndrome. None of the six eyes with plateau iris syndrome in their study showed a change in the configuration of the ciliary body after IOL implantation. However, the anterior chamber depth increased and the angle opened further after cataract surgery. The persistent iridociliary apposition after cataract surgery suggests that the iris and pars plicata appear to move together (Tran et al., 2003). Nonaka et al. reported cataract surgery for angle closure including plateau configuration opened the angle concomitant with attenuation of the anterior positioning of the ciliary processes. Cataract surgery would contribute to postoperative widening of the angle not only by completely removing the lens

demonstrated substantial increases in the anterior chamber angle aperture following laser iridotomy. Previous studies have also shown that in eyes with an acute attack, the angle widened in the first 2 weeks after LI, but did not change thereafter over 1 year, and the amount of peripheral anterior synechia (PAS) remained stable throughout. The results indicate the effectiveness of LI in preventing progressive closure of the angle in the first year after the angle closure attack (Porikoff et al., 2005). However, laser iridotomy is insufficient to treat glaucoma associated with plateau iris. Many patients with a patent iridotomy hole experienced acute angle-closed attacks. Polikoff et al. also examined the effect of laser iridotomy on anterior segment anatomy of patients with plateau iris configuration. Iridotomy will remove any contribution from pupillary block in these patients, but the angle will remain narrow because the anteriorly positioned ciliary processes prevent the peripheral iris from moving posteriorly. This report also showed that pupil block and plateau iris configuration coexists in many cases (Polikoff et al., 2005). Approximately one of three of the eyes showed PAS progression during a 3-year follow-up period after LI. The probability of progression was found to be high in the eyes that exhibited plateau iris (Choi & Kim, 2005). These data show that laser iridotomy alone is not an effective treatment for

Argon laser peripheral iridoplasty can effectively eliminate residual appositional closure after laser iridotomy caused by plateau iris syndrome, and the effect is maintained for years. Argon laser iridoplasty may also prove valuable in the treatment of plateau-like iris configuration resulting from iridociliary cysts (Crowston et al., 2005). Rich et al. documented the long-term effect of argon laser iridoplasty in patients with plateau iris syndrome. A total of 26 argon laser iridoplasty procedures were performed in 23 eyes of 14 patients. The angle remained open in 20 of 23 (87.0%) eyes after only 1 treatment with Argon laser iridoplasty over a follow-up period of 78.9 ± 8.0 months (range, 72–188 months). They concluded that Argon laser iridoplasty could effectively eliminate residual appositional closure after laser iridotomy caused by plateau iris syndrome (Ritch et al., 2004). However, there are no other

Hayashi showed that the anterior chamber depth and angle width in angle closure glaucoma eyes approximates that of POAG eyes and control eyes without glaucoma after phaco-emulsification and posterior chamber intraocular lens implantation (Hayashi et al., 2000). They thought that these changes contribute to the significant IOP reduction seen in the postoperative follow-up period of 12 months. Tran et al. evaluated the ultrasound biomicroscopic appearance of the anterior segment before and after cataract extraction in eyes with plateau iris syndrome. None of the six eyes with plateau iris syndrome in their study showed a change in the configuration of the ciliary body after IOL implantation. However, the anterior chamber depth increased and the angle opened further after cataract surgery. The persistent iridociliary apposition after cataract surgery suggests that the iris and pars plicata appear to move together (Tran et al., 2003). Nonaka et al. reported cataract surgery for angle closure including plateau configuration opened the angle concomitant with attenuation of the anterior positioning of the ciliary processes. Cataract surgery would contribute to postoperative widening of the angle not only by completely removing the lens

reports that indicate the effectiveness of laser peripheral iridoplasty.

glaucoma with plateau iris configuration.

**7.2.2 Argon laser peripheral iridoplasty** 

**7.2.3 Cataract surgery** 

volume and pupillary block, but also by attenuating the anterior positioning of the ciliary processes in eyes with primary angle closed eyes (Nonaka et al., 2006). There are currently no randomized controlled trials supporting the use of clear lens extraction as the treatment of choice for PACG. However, the potential of obtaining some benefit from this procedure is considered to be biologically plausible (Thomas et al., 2011).

Phacoemulsification and goniosynechialysis (PEGS) is also effective in managing acute and subacute primary angle closure including patients plateau iris (Harasymowycz et al., 2005).

Topical application of miotic agents, laser peripheral iridoplasty and cataract surgery seem to be effective for glaucoma with plateau iris configuration. There is a lack of well-designed, randomized, controlled trials to assess the effect as a therapeutic modality for glaucoma with plateau iris configuration, because the occurrence of plateau iris is relatively rare.

#### **8. Conclusions**

A plateau iris configuration is defined as a flat iris plane accompanied by a narrow or closed anterior chamber angle. Pathological and physiological data of plateau iris configuration and plateau iris syndrome are increasing. However, we do not have enough information related to plateau iris configuration and syndrome to manage them. The prognosis of this disorder compared to pupillary block angle closure glaucoma also remains to be elucidated. There are no quantitative diagnosis criteria, yet. This condition confuse the interpretation of the data appeared at the journals. The best therapeutic protocol should be established in future. New imaging technology will help us to obtain the new information.

#### **9. References**


Plateau Iris 533

Pavlin,CJ & Foster, FS.(1999). Plateau iris syndrome: changes in angle opening associated

Pavlin, CJ., Ritch R., & Foster, FS. (1992). Ultrasound biomicroscopy in plateau iris syndrome, *American Journal of Ophthalmology*, Vol.113, No. 4, (1992), pp.390-395 Pavlin, CJ., Rutnin, SS., Deveny R., Wand, M. & Foster, FS.(1997). Supraciliary effusions and

Polikoff, LA., Chanis, RA., Toor, A., Ramos-Esteban, JC., Fahim, MM., Gagliuso, DJ., & Serle,

Quigley, HA., Congdon, NG., & Friedman, DG. (2001). Glaucoma in China (and

Razeghinejad, MR. & Kamali-Sarvestani,E. (2007). The plateau iris component of primary

Ritch, R. (1992). Plateau iris is caused by abnormally positioned ciliary processes, *Journal of* 

Ritch, R., Aung, T., & Lam, DS. (2009). Angle-closure Glaucoma, *Journal of Glaucoma*, Vol.18,

Ritch, R., Chang, BM., & Liebmann, JM. (2003). Angle closure in younger patients,

Ritch, R., Tham, CC., & Lam DS (2004). Long-term success of argon laser peripheral

Roberts, DK., Ayyagari, R., & Moroi, SE. (2008). Possible association between long anterior

Saitoh, S. (1974). Midriasis test in primary angle-closure glaucoma, *Nippon Ganka Gakkai* 

Sakata, LM., Sakata, K.,& Susanna, R Jr. (2006). Long ciliary processes with no ciliary sulcus

Shaffer, RN. (1960). Primary Glaucomas. Gonioscopy, ophthalmoscopy and perimetry,

Shukla, S., Damji, KF., Harasymowycz, P., Chialant, D., Kent, JS., Chevrier, R., Buhrmann,

Suzuki, Y., Yamamoto, T., Araie, M., Iwase, A., Tomidokoro, A., Abe, H., Shirato, S.,

iridoplasty in the management of plateau iris syndrome, *Ophthalmology,* Vol.111,

lens zonules and plateau iris configuration, *Journal of Glaucoma,* Vol.17, No.5, (2008),

and appositional angle closure assessed by ultrasound biomicroscopy, *Journal of* 

*Transactions - American Academy of Ophthalmology and Otolaryngology*, Vol.64, (1960),

R., Marshall, D., Pan, Y., & Hodge, W. (2008). Clinical features distinguishing angle closure from pseudoplateau versus plateau iris, *British Journal of Ophthalmology,*

Kuwayama, Y., Mishima, HK., Shimizu, H., Tomita, G., Inoue, Y., & Kitazawa, Y. (2008). Tajimi Study review, *Nippon Ganka Gakkai Zasshi*, Vol.112, No.12, (2008),

*British Journal of Ophthalmology*; Vol.85, No.11, (2001), pp.1271–1272

Vol.128, No.3, (1999), pp.288–291

No. 3, ( 1997), pp.433-438

No.31, (2007), pp.95–98

No.7, (2009), pp.567–570

No.1, (2004), pp.104–108

pp.393–396

pp.112-127

pp.1039-1058

*Glaucoma,* Vol.1, (1992), pp.23-26

*Ophthalmology,* Vol.110, No.10, (2003), pp.1880–1889

*Zasshi*, Vol.78, No.11, (1974), pp.1179-1185

*Glaucoma*, Vol. 15, No.5, (2006), pp.371–379

Vol. 92, No.3, (2008), pp.340-344

with dark, light, and pilocarpine administration, *American Journal of Ophthalmology*,

ciliary body thickening after scleral buckling procedures, *Ophthalmology*, Vol.104,

JB. (2005). The effect of laser iridotomy on the anterior segment anatomy of patients with plateau iris configuration, *Journal of Glaucoma*, Vol.14, No.2, (2005), pp.109–113

worldwide): changes in established thinkingwill decrease preventable blindness,

angle closure glaucoma: developmental or acquired, *Medical Hypotheses,* Vol. 69,


Godel, V., Stein, R., & Feiler-Ofry, V. (1968). Angle-closure glaucoma: following peripheral

Gradle, HS. & Sugar, HS. (1940). Concerning the chamber angle. III. A clinical method of goniometry, *American Journal of Ophthalmology*, Vol.23, (1940), pp.1135-1139 Harasymowycz, PJ., Papamatheakis, DG., Ahmed, I., Assalian, A., Lesk, M., Al-Zafiri, Y.,

Hayashi, K., Hayashi, H., Nakao, F., & Hayashi, F. (2000). Changes in anterior chamber

Kiuchi, Y., Kanamoto, T., & Nakamura, T. (2009). Double hump sign in indentation

Kumar, RS., Tantisevi, V., Wong, MH., Laohapojanart, K., Chansanti, O., Quek, DT., Koh,

Kunimatsu, S., Araie, M., Ohara, K., & Hamada, C. (1999). Ultrasound biomicroscopy of

Lim, LS., Aung, T., Husain, R., Wu, YJ., Gazzard, G., & Seah, SK. (2004). Acute primary

peripheral iridotomy, *Ophthalmology,* Vol.111, No.8, (2004), pp.1470–1474 Lowe, RF. (1964). Primary angle-closure glaucoma. Investigation after surgery for pupil

Mandell, MA., Pavlin, CJ., Weisbrod, DJ., & Simpson, ER. (2003). Anterior Chamber Depth

Mochizuki, H., Takenaka, J., Sugimoto, Y., Takamatsu, M., & Kiuchi, Y. (2010). Comparison

Németh, J., Csákány, B., & Pregun, T. (1996-1997). Ultrasound biomicroscopic morphometry

Nonaka, A., Kondo, T., Kikuchi, M., Yamashiro, K., Fujihara, M., Iwawaki ,T., Yamamoto,

*Ophthalmoogyl*, Vol.20, No.1-3,(1996-1997), pp.39-42

Vol.113, No.3, (2006), pp.437–441

block, *American Journal of Ophthalmology*, Vol.57, (1964), pp.931-938

patent iridotomy, *Journal of Glaucoma*, Vol.18, No.2, (2009), pp.161–164 Kumar, RS., Baskaran, M., Chew, PT., Friedman, DS., Handa, S., Lavanya, R., Sakata, LM.,

*Ophthalmology*, Vol.107, No.4, (2000), pp.698-703

Vol.127, No.10, (2009), pp.1269-1272

pp.555-560

pp.186–189

pp.430–434

(2010)

iridectomy and mydriasis, *American Journal of Ophthalmology*, Vol.65, No.4, (1968),

Kranemann, C., & Hutnik, C. (2005). Phacoemulsification and goniosynechialysis in the management of unresponsive primary angle closure, *Journal of Glaucoma*, (2005),

angle width and depth after intraocular lens implantation in eyes with glaucoma,

gonioscopy is correlated with presence of plateau iris configuration regardless of

Wong, HT., & Aung ,T.(2008) . Prevalence of plateau iris in primary angle closure suspects an ultrasound biomicroscopy study, *Ophthalmology*, Vol.115, No.3, (2008),

VT., MohanRam, LS., Lee, KY., Rojanapongpun, P., & Aung, T. (2009). Plateau iris in Asian subjects with primary angle closure glaucoma, *Archives of Ophthalmology*,

ciliary body cysts, *American Journal of Ophthalmology*, Vol.127, No.1, (1999), pp.48–55

angle closure: configuration of the drainage angle in the first year after laser

in Plateau Iris Syndrome and Pupillary Block as Measured by Ultrasound Biomicroscopy, *American Journal of Ophthalmology*, Vol.136, No.5, (2003), pp.900–903

of the Prevalence of Plateau Iris Configurations Between Angle-closure Glaucoma and Open-angle Glaucoma Using Ultrasound Biomicroscopy, *Journal of Glaucoma,*

of the anterior eye segment before and after one drop of pilocarpine, *International* 

K., & Kurimoto, Y. (2006). Angle widening and alteration of ciliary process configuration after cataract surgery for primary angle closure. *Ophthalmology,* 


**27** 

*Israel* 

Tsvi Sheleg

**Normal-Tension (Low-Tension) Glaucoma** 

*Department of Ophthalmology, Western Galilee – Nahariya Medical Center, Nahariya,* 

Normal-tension glaucoma, also known as low-tension glaucoma, is defined as glaucomatous damage to the optic nerve and visual fields with normal diurnal values of intraocular pressure (IOP). The term 'low-tension glaucoma' is not often used because in most patients with normal-tension glaucoma, the IOP is within the higher range of normal values and rarely low. The diagnosis is insidious in many cases and requires a complete and thorough work-up to exclude other causes for optic disc and visual field abnormalities. The definition is problematic because the normal limits of IOP have a wide Gaussian curve range and their effect on the development of glaucoma varies. Some patients may retain a high IOP for many years without any glaucomatous damage, while others with low values of IOP may suffer from ongoing progressive glaucomatous disease. IOP is considered as a risk factor for the advancement of glaucoma even in patients with normal values of IOP, and lowering the IOP often protects the optic nerves (Collaborative Normal Tension Glaucoma Study Group [CNTGSG], 1998). Some optic nerves are more vulnerable even to low levels of IOP than others (Drance et al, 1973). Though many factors have been suspected and investigated, it appears that in addition to variability of the structure of the lamina cribrosa, vascular and genetic factors are most likely involved. Most authors consider normal-tension glaucoma to be a variant of primary open angle glaucoma (POAG) (Caprioli & Spaeth, 1984; Chumbley & Brubaker, 1976); others rely on characteristic clinical features of many normal-tension glaucoma patients to consider it a distinct entity (Caprioli & Spaeth, 1984; Shields, 2008). The debate is ongoing and will probably continue to be the subject of research for many years.

The optic nerve damage in normal-tension glaucoma, as in POAG, follows a cascade of pathophysiological events that includes impaired axonal transport, ischemia and free radical formation that leads to apoptosis (Harris et al., 2005). The mechanical theory is based on the assumption that high IOP reduces the axoplasmic axonal flow by causing direct pressure on the axons, resulting in damage to the nerves. Structural differences in the appearance of the optic nerve discs and elastin fibers in glaucoma patients also support the mechanical theory (Dandona et al., 1990; Quigley et al., 1994). The pressure gradient over the optic disc should also be considered, as chronic low intra-cranial pressure may result in a pressure difference that can affect the axoplasmic outflow and lead to glaucomatous progression in normal-

**1. Introduction** 

**2. Pathogenic theories** 

tension glaucoma patients.


### **Normal-Tension (Low-Tension) Glaucoma**

#### Tsvi Sheleg

*Department of Ophthalmology, Western Galilee – Nahariya Medical Center, Nahariya, Israel* 

#### **1. Introduction**

534 Glaucoma - Basic and Clinical Concepts

Tanihara, H., Akita, J., Honjo, M., & Honda, Y. (1997). Angle closure caused by multiple

Tarongoy, P., Ho, CL., & Walton, DS. (2009). Angle-closure glaucoma: the role of the lens in

Tran, HV., Liebmann, JM., & Ritch, R. (2003). Iridociliary apposition in plateau iris

Tripathi, RC., Tripathi, BJ., Haggerty C. (2003). Drug-induced glaucomas: mechanism and

Wand, M., Grant, WM., Simmons, RJ., & Hutchinson, BT. (1977). Plateau iris syndrome,

Yamamoto, T., Iwase, A., Araie, M., Suzuki, Y., Abe, H., & Shirato, S. (2005). The Tajimi

Japanese population, *Ophthalmology*, Vol. 112, No.10,(2005), pp.1661–1669 Yasuda, N. & Kageyama, M. (1988). The long-term effects of local medication on intraocular

management, *Drug safety,* Vol. 26, No.11, (2003), pp.749–767

*Otolaryngology*, Vol. 83, No. 1, (1977), pp.122-130

pp.216–217

(2009), pp.211--225

Vol.135, No.1, (2003), pp.40–43

Vol.92, No.10, (1988), pp.1644-1649

bilateral iridociliary cysts, *Acta ophthalmologica Scandinavica*, Vol. 75, No.2, (1997),

the pathogenesis, prevention, and treatment, *Survey of Ophthalmology*, Vol.54, No. 2,

syndrome persists after cataract extraction, *American Journal of Ophthalmology*,

*Transactions. Section on Ophthalmology. American Academy of Ophthalmology and* 

Study report 2: prevalence of primary angle closure and secondary glaucoma in a

pressure control in primary angle-closure glaucoma, *Nippon Ganka Gakkai Zasshi*,

Normal-tension glaucoma, also known as low-tension glaucoma, is defined as glaucomatous damage to the optic nerve and visual fields with normal diurnal values of intraocular pressure (IOP). The term 'low-tension glaucoma' is not often used because in most patients with normal-tension glaucoma, the IOP is within the higher range of normal values and rarely low. The diagnosis is insidious in many cases and requires a complete and thorough work-up to exclude other causes for optic disc and visual field abnormalities. The definition is problematic because the normal limits of IOP have a wide Gaussian curve range and their effect on the development of glaucoma varies. Some patients may retain a high IOP for many years without any glaucomatous damage, while others with low values of IOP may suffer from ongoing progressive glaucomatous disease. IOP is considered as a risk factor for the advancement of glaucoma even in patients with normal values of IOP, and lowering the IOP often protects the optic nerves (Collaborative Normal Tension Glaucoma Study Group [CNTGSG], 1998). Some optic nerves are more vulnerable even to low levels of IOP than others (Drance et al, 1973). Though many factors have been suspected and investigated, it appears that in addition to variability of the structure of the lamina cribrosa, vascular and genetic factors are most likely involved. Most authors consider normal-tension glaucoma to be a variant of primary open angle glaucoma (POAG) (Caprioli & Spaeth, 1984; Chumbley & Brubaker, 1976); others rely on characteristic clinical features of many normal-tension glaucoma patients to consider it a distinct entity (Caprioli & Spaeth, 1984; Shields, 2008). The debate is ongoing and will probably continue to be the subject of research for many years.

#### **2. Pathogenic theories**

The optic nerve damage in normal-tension glaucoma, as in POAG, follows a cascade of pathophysiological events that includes impaired axonal transport, ischemia and free radical formation that leads to apoptosis (Harris et al., 2005). The mechanical theory is based on the assumption that high IOP reduces the axoplasmic axonal flow by causing direct pressure on the axons, resulting in damage to the nerves. Structural differences in the appearance of the optic nerve discs and elastin fibers in glaucoma patients also support the mechanical theory (Dandona et al., 1990; Quigley et al., 1994). The pressure gradient over the optic disc should also be considered, as chronic low intra-cranial pressure may result in a pressure difference that can affect the axoplasmic outflow and lead to glaucomatous progression in normaltension glaucoma patients.

Normal-Tension (Low-Tension) Glaucoma 537

(Klein et al., 1992). In Japan the prevalence is considerably higher. The Tajimi eye study assessed the prevalence of POAG in patients over 40 years and found it to be 3.9%, in 92% the IOP was 21 mmHg or lower (Iwase et al., 2004). A nationwide survey estimated the normal-tension glaucoma with (IOP under 21mmHg) prevalence to be 3.5 times that of POAG, but these numbers are thought to be biased since normal IOP in Japan is lower than in the western population, averaging 10-18 mmHg. The prevalence of normal tension glaucoma is higher in women than in men, this and other risk factors will be discussed later in this chapter. Whatever the prevalence of normal tension glaucoma is in various populations, it is obvious that the numbers are higher than once assumed, and patients are actually diagnosed only when optic disc and visual field abnormalities are already present.

Family history is a major risk factor in glaucoma ,and genetic mutations related to specific phenotypes of glaucoma are under investigation. Such information can help diagnose and classify subtypes of glaucoma, and perhaps even to clarify the pathogenesis. Research may find ways to repair mutation in utero or early in life, before glaucomatous damage has occurred. Genetic research has found transmission of a NTG phenotype in only a few families, all of them are autosomal dominant (Bennett et al., 1989). Of the seven gene loci that have been linked to POAG, two genes have been identified and named TIGR/ Myocilin and Optineurin (Optic Neuropathy-Inducing Protein - ONTP). A specific mutation GLC1E locus of the ONTP was found in location 10p14-15, with autosomal dominant inheritance as in all POAG locui that were identified (Sarfarazi et al., 1998). ONTP is expressed in the retina and was found to be involved in apoptosis. The Blue Mountains Eye Study in Australia found that the prevalence of mutation in the ONTP gene was higher in POAG than in healthy subjects but the difference was not statistically significant (Baird et al., 2004). Reports found the ONTP mutation associated with high prevalence of POAG and NTG in adult Japanese patients, suggesting it may be involved in the pathogenesis of both entities (Fuse et al., 2004; Umeda et al., 2004). Other reports could not find OPTN mutations in NTG (Toda et al., 2004). Genetic screening for the gene is not an option because of the low incidence of the mutation. Recently another locus GLCA3 was investigated for association

with NTG, but no statistically significant relationship was found (Kamio et al., 2009).

The diagnosis of normal-tension glaucoma is illusive and requires a high degree of suspicion. Since IOP measurements are usually in the high teens in normal-tension glaucoma, routine IOP screening measurement may be deceiving. Often, the first sign is an abnormal optic disc or disk asymmetry suspicious of glaucomatous damage. In up to half of the patients repeated measurements or daily IOP curve discovers high IOP, and the diagnosis of POAG is made (Ito et al., 1991; Perkins, 1973). The significance of a daily IOP curve in the diagnosis of NTG is crucial. Few other factors must be considered. Pachymetry should be performed to adjust the difference between measured IOP by Goldman tonometry and true IOP. Ocular hypertension study (OHTS) highlighted the importance of thin corneas in the diagnosis of glaucoma. Thinner corneas can lead to underestimation of IOP, and misdiagnosis has occurred in many NTG patients compared with POAG patients (Morad et al., 1998). The effect of corneal hysteresis and scleral rigidity should be considered and Ocular Response Analyzer (ORA) can help in estimating the true IOP (Morita et al.,

**4. Genetic considerations**

**5. Diagnosis and differential diagnosis** 

On the other hand, the vascular ischemic theory suggests that low perfusion to the optic nerve is a major factor in the process of glaucomatous damage. This is supported by many articles that emphasize the importance of low ocular perfusion pressure and blood pressure in the development of POAG (Caprioli & Coleman, 2010). Blood supply to the optic nerve is derived through the ophthalmic artery mainly through the pial system and posterior ciliary arteries, but also from the central retinal artery. Several methods have been used to evaluate the blood flow and resistance of the ophthalmic artery and choroidal vessels, and their relationship with glaucomatous disease progression in POAG and in normal-tension glaucoma patients. Ultrasound Doppler has been used to show correlation between low blood flow and high resistance of the ophthalmic artery, to visual field progression in POAG patients (Galassi et al., 2003). Scanning laser ophthalmoscope demonstrated larger fluorescein filling defects, correlated with low blood flow in the central retinal artery and choroidal vessels of normal-tension glaucoma patients compared with controls (Plange et al., 2003). Heidelberg retinal flowmetry has detected a reduction in neuroretinal rim blood flow in conjunction with visual field defects in normal-tension glaucoma patients (Sato et al., 2006). The future of understanding the ischemic aspect in the development of glaucoma may be by optical measurement of retinal vessel oxygenation. Oxygenation of retinal arteries was found to be lower in normal-tension glaucoma patients than in healthy subjects (Michelson et al., 2006). Other factors influence the perfusion of the optic nerve and participate in the development and progression of the disease. Hypertension leads to a greater resistance in small blood vessels and causes atherosclerotic changes. Hypotension, especially in the presence of insufficient vascular autoregulation, may participate in the development of the ischemia (Goldberg et al., 1981). Circadian fluctuation of mean ocular perfusion pressure was found to be an important clinical risk factor for severity of glaucoma in eyes with normal-tension glaucoma (Choi et al., 2007). Nocturnal dips have also been evaluated and are thought to play a role in the development of normal-tension glaucoma (Bechetoille et al., 1995; Graham et al., 1995). Another observation that indirectly supports the vascular theory is that many normal-tension glaucoma patients suffer from vasospastic diseases such as migraine (Corbett et al., 1985; Phelps & Corbett, 1985) and Raynaud disease (Broadway & Drance, 1998). However, other studies found no difference in the prevalence of atherosclerotic vascular disease in NTG and POAG patients (Klein et al., 1993; Leighton & Phillips, 1972). The role of vascular disease in the pathogenesis of NTG is probably related to the reduction of optic nerve resistance to the IOP and this may precedes changes in vasculature that occur also in POAG. Many believe that both theories have a part in the pathogenesis and their importance in the advancement of the disease varies from patient to patient.

#### **3. Epidemiology**

Normal tension glaucoma has been found to be common in many population-based studies, though the numbers vary in different studies and populations. The main reasons for the variation are the difference in normal IOP range in different populations and the difficulty in making the diagnosis. Ruling out high-tension glaucoma by diurnal measurements was not performed in most of these studies. Other causes of "burned out" secondary glaucoma such as steroid-induced or uveitis-related glaucoma were not diagnosed and excluded in some studies. Large epidemiological studies in North America, Europe and Australia estimated the prevalence of normal-tension glaucoma to be up to half that of POAG (Leibowitz et al., 1980; Sommer et al., 1991). The Beaver Dam Eye Study estimated the prevalence of normal-tension glaucoma to be up to 1.6% in patients over 75 years of age

On the other hand, the vascular ischemic theory suggests that low perfusion to the optic nerve is a major factor in the process of glaucomatous damage. This is supported by many articles that emphasize the importance of low ocular perfusion pressure and blood pressure in the development of POAG (Caprioli & Coleman, 2010). Blood supply to the optic nerve is derived through the ophthalmic artery mainly through the pial system and posterior ciliary arteries, but also from the central retinal artery. Several methods have been used to evaluate the blood flow and resistance of the ophthalmic artery and choroidal vessels, and their relationship with glaucomatous disease progression in POAG and in normal-tension glaucoma patients. Ultrasound Doppler has been used to show correlation between low blood flow and high resistance of the ophthalmic artery, to visual field progression in POAG patients (Galassi et al., 2003). Scanning laser ophthalmoscope demonstrated larger fluorescein filling defects, correlated with low blood flow in the central retinal artery and choroidal vessels of normal-tension glaucoma patients compared with controls (Plange et al., 2003). Heidelberg retinal flowmetry has detected a reduction in neuroretinal rim blood flow in conjunction with visual field defects in normal-tension glaucoma patients (Sato et al., 2006). The future of understanding the ischemic aspect in the development of glaucoma may be by optical measurement of retinal vessel oxygenation. Oxygenation of retinal arteries was found to be lower in normal-tension glaucoma patients than in healthy subjects (Michelson et al., 2006). Other factors influence the perfusion of the optic nerve and participate in the development and progression of the disease. Hypertension leads to a greater resistance in small blood vessels and causes atherosclerotic changes. Hypotension, especially in the presence of insufficient vascular autoregulation, may participate in the development of the ischemia (Goldberg et al., 1981). Circadian fluctuation of mean ocular perfusion pressure was found to be an important clinical risk factor for severity of glaucoma in eyes with normal-tension glaucoma (Choi et al., 2007). Nocturnal dips have also been evaluated and are thought to play a role in the development of normal-tension glaucoma (Bechetoille et al., 1995; Graham et al., 1995). Another observation that indirectly supports the vascular theory is that many normal-tension glaucoma patients suffer from vasospastic diseases such as migraine (Corbett et al., 1985; Phelps & Corbett, 1985) and Raynaud disease (Broadway & Drance, 1998). However, other studies found no difference in the prevalence of atherosclerotic vascular disease in NTG and POAG patients (Klein et al., 1993; Leighton & Phillips, 1972). The role of vascular disease in the pathogenesis of NTG is probably related to the reduction of optic nerve resistance to the IOP and this may precedes changes in vasculature that occur also in POAG. Many believe that both theories have a part in the pathogenesis and their

importance in the advancement of the disease varies from patient to patient.

Normal tension glaucoma has been found to be common in many population-based studies, though the numbers vary in different studies and populations. The main reasons for the variation are the difference in normal IOP range in different populations and the difficulty in making the diagnosis. Ruling out high-tension glaucoma by diurnal measurements was not performed in most of these studies. Other causes of "burned out" secondary glaucoma such as steroid-induced or uveitis-related glaucoma were not diagnosed and excluded in some studies. Large epidemiological studies in North America, Europe and Australia estimated the prevalence of normal-tension glaucoma to be up to half that of POAG (Leibowitz et al., 1980; Sommer et al., 1991). The Beaver Dam Eye Study estimated the prevalence of normal-tension glaucoma to be up to 1.6% in patients over 75 years of age

**3. Epidemiology** 

(Klein et al., 1992). In Japan the prevalence is considerably higher. The Tajimi eye study assessed the prevalence of POAG in patients over 40 years and found it to be 3.9%, in 92% the IOP was 21 mmHg or lower (Iwase et al., 2004). A nationwide survey estimated the normal-tension glaucoma with (IOP under 21mmHg) prevalence to be 3.5 times that of POAG, but these numbers are thought to be biased since normal IOP in Japan is lower than in the western population, averaging 10-18 mmHg. The prevalence of normal tension glaucoma is higher in women than in men, this and other risk factors will be discussed later in this chapter. Whatever the prevalence of normal tension glaucoma is in various populations, it is obvious that the numbers are higher than once assumed, and patients are actually diagnosed only when optic disc and visual field abnormalities are already present.

#### **4. Genetic considerations**

Family history is a major risk factor in glaucoma ,and genetic mutations related to specific phenotypes of glaucoma are under investigation. Such information can help diagnose and classify subtypes of glaucoma, and perhaps even to clarify the pathogenesis. Research may find ways to repair mutation in utero or early in life, before glaucomatous damage has occurred. Genetic research has found transmission of a NTG phenotype in only a few families, all of them are autosomal dominant (Bennett et al., 1989). Of the seven gene loci that have been linked to POAG, two genes have been identified and named TIGR/ Myocilin and Optineurin (Optic Neuropathy-Inducing Protein - ONTP). A specific mutation GLC1E locus of the ONTP was found in location 10p14-15, with autosomal dominant inheritance as in all POAG locui that were identified (Sarfarazi et al., 1998). ONTP is expressed in the retina and was found to be involved in apoptosis. The Blue Mountains Eye Study in Australia found that the prevalence of mutation in the ONTP gene was higher in POAG than in healthy subjects but the difference was not statistically significant (Baird et al., 2004). Reports found the ONTP mutation associated with high prevalence of POAG and NTG in adult Japanese patients, suggesting it may be involved in the pathogenesis of both entities (Fuse et al., 2004; Umeda et al., 2004). Other reports could not find OPTN mutations in NTG (Toda et al., 2004). Genetic screening for the gene is not an option because of the low incidence of the mutation. Recently another locus GLCA3 was investigated for association with NTG, but no statistically significant relationship was found (Kamio et al., 2009).

#### **5. Diagnosis and differential diagnosis**

The diagnosis of normal-tension glaucoma is illusive and requires a high degree of suspicion. Since IOP measurements are usually in the high teens in normal-tension glaucoma, routine IOP screening measurement may be deceiving. Often, the first sign is an abnormal optic disc or disk asymmetry suspicious of glaucomatous damage. In up to half of the patients repeated measurements or daily IOP curve discovers high IOP, and the diagnosis of POAG is made (Ito et al., 1991; Perkins, 1973). The significance of a daily IOP curve in the diagnosis of NTG is crucial. Few other factors must be considered. Pachymetry should be performed to adjust the difference between measured IOP by Goldman tonometry and true IOP. Ocular hypertension study (OHTS) highlighted the importance of thin corneas in the diagnosis of glaucoma. Thinner corneas can lead to underestimation of IOP, and misdiagnosis has occurred in many NTG patients compared with POAG patients (Morad et al., 1998). The effect of corneal hysteresis and scleral rigidity should be considered and Ocular Response Analyzer (ORA) can help in estimating the true IOP (Morita et al.,

Normal-Tension (Low-Tension) Glaucoma 539

clinical manifestation. Lesions such as meningiomas, craniopharingiomas, pituitary adenomas, and compressive vascular lesions such as aneurisms can mimic NTG. Some ophthalmic signs are more suggestive of a neurological disease and should prompt a neurological evaluation. Perhaps the most important of them is a rapid progression of the disease despite low IOP with or without treatment. Other signs that should raise suspicion are pale optic disks and poor best corrected visual acuity. Needless to say any neurologic symptoms prompt neurologic workup. Some authors believe that it is important in all cases of NTG to perform a CT scan (Gutman et al., 1993), though others found no value for a routine

Risk factors for the development of NTG in untreated patients that were found in the Collaborative Normal Tension Glaucoma Study (CNTGS) are migraine, female gender and splinter disc hemorrhage at the diagnosis (Drance et al., 2001). Age over 60 years is common (Klein et al., 1992), and a high prevalence was found in Japanese as mentioned earlier (Iwase et al., 2004; Shiose et al., 1991). Other risk factors found to be more prevalent in NTG than in POAG patients were ischemic vascular disease, obstructive sleep apnea, autoimmune diseases, and coagulopathies, but their effect on development of NTG was not consistent. The progression of glaucomatous damage in NTG is usually very slow. Collaborative Normal Tension Glaucoma Study (CNTGS) showed that half of the untreated patients did not progress in 5 years, and in most cases the progression was slow (Anderson, 2003). In some of these patients a previous hypotensive crisis from a massive bleeding or arrhythmia resulted in optic disk cupping. (Drance, 1977). In patients without a subsequent hypotensive crisis the glaucoma is not expected to progress. Other cases such as steroid responders or "burned out" pigmentary or uveitic glaucoma may not progress at all. Despite their effect as risk factors for the development of NTG, neither age nor untreated level of IOP affected the risk for progression in untreated eyes (Anderson, 2003). Disc hemorrhages, as mentioned earlier, where also found to be related to the progression of glaucomatous damage (Ishida et

It is difficult to diagnose NTG if the cup to disc ratio is over 0.5 even if the differences in cupping are 0.2 or higher in the presence of normal IOP. At this stage, the visual fields are usually normal. If the cornea is thin, POAG may be suspected after correction of the IOP according to the corneal thickness. But if the corneal thickness is normal, the diagnosis of NTG cannot be established. Those patients may stay with the diagnosis of glaucoma suspects until new signs of disk abnormalities appear that correlate with the glaucomatous visual field defects. Although these patients may deteriorate slowly, other glaucoma patients may deteriorate rather quickly. Therefore, it is recommended to follow individuals over the age of 40, glaucoma suspects and individuals with family history, at least every 6 months. There have been cases were glaucoma appeared and progressed within less than a year, and this is the reason for a 6 months routine follow-up. Preperimetric normal tension

The diagnosis is made when optic disc cupping and glaucomatous visual field defects are found in conjunction with normal IOP. POAG should be ruled out by corneal pachymetry and adjustment of the IOP to the corneal thickness. Other causes for optic disc cupping and visual field defects should be ruled out by detailed anamnesis (e.g., episodes of major blood loss) and further analysis (e.g., brain computed tomography to rule out tumors as mentioned earlier).

glaucoma should be evaluated using FDT or Swap when available.

neurological examination in NTG patients (Kesler et al., 2010).

al., 2000).

**6. Practical steps for diagnosis** 

2010). Thin corneas following corneal refractive surgery and in patients after penetrating or lamellar keratoplasty can make the task of IOP estimation more challenging (Papastergiou et al., 2010; Sanchez-Naves et al., 2008). Other factors such as refraction and astigmatism should also be considered and ORA may achieve a better estimation of the true IOP in these patients (Hagishima et al., 2010).

The controversy of whether NTG is different from POAG is demonstrated in many articles regarding optic disc appearance. While some studies show no difference in the optic disc appearance between NTG and POAG (Tomita, 2000), others found distinct characteristics such as thin rim that can help distinguish NTG (Caprioli & Spaeth, 1985). OCT plays a major role in the diagnosis and monitoring of glaucoma especially when the diagnosis is not certain. Measuring the RNFL thickness, optic disk cupping and their correlation with visual field abnormalities is a powerful tool. Recently a study comparing the optic discs using optical coherence tomography (OCT) and Heidelberg retina topography (HRT) supports some of the differences (Shin et al., 2008). Disc appearance in NTG is traditionally divided into two sub-groups. The more common is the senile sclerotic group, which is characterized by a pale shallow sloping neuroretinal rim. These patients are often older in age and suffer from vascular diseases. The other group, focal ischemic, is characterized by deep focal notching of the rim. Splinter hemorrhages are a typical finding in NTG and imply in most cases a progressive disease (Drance et al., 2001; Jonas & Xu, 1994). Beta zone peripapillary atrophy has also been suggested related to optic nerve damage in NTG (Xia et al., 2005). The site of the hemorrhage may predict an area of notch development with a correlated visual field loss (Chumbley & Brubaker, 1976; Siegner & Netland, 1996; Tomita, 2000). Visual field patterns in NTG are similar to the ones seen in POAG, still some articles found differences in the distribution and shape of the scotomas. Scotomas observed in NTG visual fields often tend to be deeper, steeper and closer to fixation than in POAG patients (Caprioli & Spaeth, 1984; Harrington, 1960). Some articles mainly from japan found that scotomas in NTG may be more predominant in the lower hemifield (Araie, 1995).

The ophthalmologist should rule out "burned out" secondary glaucoma and other misleading diagnosis. Careful history and meticulous ophthalmic examination should look for previous trauma, uveitis, glaucomatocyclitic crisis, pigmentary glaucoma, previous topical or systemic steroid treatment, previous acute angle closure attack and the use of systemic medication that lowers IOP (e.g., beta-blockers). Compliance should be appreciated to rule out the possibility that the patient takes his anti-glaucoma medications only before the ophthalmologist examination in order to "please" their doctor. Non-glaucomatous optic disc abnormalities such as congenital colobomas, optic nerve pit, anterior ischemic optic neuropathy, traumatic optic neuropathy, optic nerve or chiasm compressing lesion, and various retinal abnormalities should be considered and revoked. The diagnosis and followup of NTG is more challenging with hypoplastic and myopic tilted discs. Systemic evaluation is advised to identify diseases that are more frequent in NTG patients, and when the diagnosis is difficult. Blood pressure, ischemic vascular disease, perfusion pressure, vasospastic disorders (migraine, Raynaud phenomenon) and obstructive sleep apnea should be assessed in selected cases. Some cases may require neurological evaluation and hematological work-up to search for various neurological conditions or coagulopathies. Generally, systemic evaluation is reserved for atypical cases when the optic disc appearance and visual field do not correlate with glaucomatous damage, when glaucomatous damage is found with IOP lower than the high teens before treatment or when other neurological symptoms are present. Neurological examination is vital in all cases of NTG with atypical

2010). Thin corneas following corneal refractive surgery and in patients after penetrating or lamellar keratoplasty can make the task of IOP estimation more challenging (Papastergiou et al., 2010; Sanchez-Naves et al., 2008). Other factors such as refraction and astigmatism should also be considered and ORA may achieve a better estimation of the true IOP in these

The controversy of whether NTG is different from POAG is demonstrated in many articles regarding optic disc appearance. While some studies show no difference in the optic disc appearance between NTG and POAG (Tomita, 2000), others found distinct characteristics such as thin rim that can help distinguish NTG (Caprioli & Spaeth, 1985). OCT plays a major role in the diagnosis and monitoring of glaucoma especially when the diagnosis is not certain. Measuring the RNFL thickness, optic disk cupping and their correlation with visual field abnormalities is a powerful tool. Recently a study comparing the optic discs using optical coherence tomography (OCT) and Heidelberg retina topography (HRT) supports some of the differences (Shin et al., 2008). Disc appearance in NTG is traditionally divided into two sub-groups. The more common is the senile sclerotic group, which is characterized by a pale shallow sloping neuroretinal rim. These patients are often older in age and suffer from vascular diseases. The other group, focal ischemic, is characterized by deep focal notching of the rim. Splinter hemorrhages are a typical finding in NTG and imply in most cases a progressive disease (Drance et al., 2001; Jonas & Xu, 1994). Beta zone peripapillary atrophy has also been suggested related to optic nerve damage in NTG (Xia et al., 2005). The site of the hemorrhage may predict an area of notch development with a correlated visual field loss (Chumbley & Brubaker, 1976; Siegner & Netland, 1996; Tomita, 2000). Visual field patterns in NTG are similar to the ones seen in POAG, still some articles found differences in the distribution and shape of the scotomas. Scotomas observed in NTG visual fields often tend to be deeper, steeper and closer to fixation than in POAG patients (Caprioli & Spaeth, 1984; Harrington, 1960). Some articles mainly from japan found that scotomas in NTG may

The ophthalmologist should rule out "burned out" secondary glaucoma and other misleading diagnosis. Careful history and meticulous ophthalmic examination should look for previous trauma, uveitis, glaucomatocyclitic crisis, pigmentary glaucoma, previous topical or systemic steroid treatment, previous acute angle closure attack and the use of systemic medication that lowers IOP (e.g., beta-blockers). Compliance should be appreciated to rule out the possibility that the patient takes his anti-glaucoma medications only before the ophthalmologist examination in order to "please" their doctor. Non-glaucomatous optic disc abnormalities such as congenital colobomas, optic nerve pit, anterior ischemic optic neuropathy, traumatic optic neuropathy, optic nerve or chiasm compressing lesion, and various retinal abnormalities should be considered and revoked. The diagnosis and followup of NTG is more challenging with hypoplastic and myopic tilted discs. Systemic evaluation is advised to identify diseases that are more frequent in NTG patients, and when the diagnosis is difficult. Blood pressure, ischemic vascular disease, perfusion pressure, vasospastic disorders (migraine, Raynaud phenomenon) and obstructive sleep apnea should be assessed in selected cases. Some cases may require neurological evaluation and hematological work-up to search for various neurological conditions or coagulopathies. Generally, systemic evaluation is reserved for atypical cases when the optic disc appearance and visual field do not correlate with glaucomatous damage, when glaucomatous damage is found with IOP lower than the high teens before treatment or when other neurological symptoms are present. Neurological examination is vital in all cases of NTG with atypical

patients (Hagishima et al., 2010).

be more predominant in the lower hemifield (Araie, 1995).

clinical manifestation. Lesions such as meningiomas, craniopharingiomas, pituitary adenomas, and compressive vascular lesions such as aneurisms can mimic NTG. Some ophthalmic signs are more suggestive of a neurological disease and should prompt a neurological evaluation. Perhaps the most important of them is a rapid progression of the disease despite low IOP with or without treatment. Other signs that should raise suspicion are pale optic disks and poor best corrected visual acuity. Needless to say any neurologic symptoms prompt neurologic workup. Some authors believe that it is important in all cases of NTG to perform a CT scan (Gutman et al., 1993), though others found no value for a routine neurological examination in NTG patients (Kesler et al., 2010).

Risk factors for the development of NTG in untreated patients that were found in the Collaborative Normal Tension Glaucoma Study (CNTGS) are migraine, female gender and splinter disc hemorrhage at the diagnosis (Drance et al., 2001). Age over 60 years is common (Klein et al., 1992), and a high prevalence was found in Japanese as mentioned earlier (Iwase et al., 2004; Shiose et al., 1991). Other risk factors found to be more prevalent in NTG than in POAG patients were ischemic vascular disease, obstructive sleep apnea, autoimmune diseases, and coagulopathies, but their effect on development of NTG was not consistent.

The progression of glaucomatous damage in NTG is usually very slow. Collaborative Normal Tension Glaucoma Study (CNTGS) showed that half of the untreated patients did not progress in 5 years, and in most cases the progression was slow (Anderson, 2003). In some of these patients a previous hypotensive crisis from a massive bleeding or arrhythmia resulted in optic disk cupping. (Drance, 1977). In patients without a subsequent hypotensive crisis the glaucoma is not expected to progress. Other cases such as steroid responders or "burned out" pigmentary or uveitic glaucoma may not progress at all. Despite their effect as risk factors for the development of NTG, neither age nor untreated level of IOP affected the risk for progression in untreated eyes (Anderson, 2003). Disc hemorrhages, as mentioned earlier, where also found to be related to the progression of glaucomatous damage (Ishida et al., 2000).

#### **6. Practical steps for diagnosis**

It is difficult to diagnose NTG if the cup to disc ratio is over 0.5 even if the differences in cupping are 0.2 or higher in the presence of normal IOP. At this stage, the visual fields are usually normal. If the cornea is thin, POAG may be suspected after correction of the IOP according to the corneal thickness. But if the corneal thickness is normal, the diagnosis of NTG cannot be established. Those patients may stay with the diagnosis of glaucoma suspects until new signs of disk abnormalities appear that correlate with the glaucomatous visual field defects. Although these patients may deteriorate slowly, other glaucoma patients may deteriorate rather quickly. Therefore, it is recommended to follow individuals over the age of 40, glaucoma suspects and individuals with family history, at least every 6 months. There have been cases were glaucoma appeared and progressed within less than a year, and this is the reason for a 6 months routine follow-up. Preperimetric normal tension glaucoma should be evaluated using FDT or Swap when available.

The diagnosis is made when optic disc cupping and glaucomatous visual field defects are found in conjunction with normal IOP. POAG should be ruled out by corneal pachymetry and adjustment of the IOP to the corneal thickness. Other causes for optic disc cupping and visual field defects should be ruled out by detailed anamnesis (e.g., episodes of major blood loss) and further analysis (e.g., brain computed tomography to rule out tumors as mentioned earlier).

Normal-Tension (Low-Tension) Glaucoma 541

hypertension, congestive heart failure, arrhythmia and anemia, should be treated (Chumbley

Anderson, D.R. Normal Tension Glaucoma Study. (2003). Collaborative Normal Tension Glaucoma Study. *Current Opinion in Ophthalmology*, Vol.14, No.2, pp. 86-90 Araie, M. (1995). Pattern of Visual Field Defects in Normal-Tension and High-Tension

Baird, P.N., Richardson, A.J., Craig, J.E., Mackey, D.A., Rochtchina, E., & Mitchell, P. (2004).

Bechetoille, A. & Bresson-Dumont, H. (1994). Diurnal and Nocturnal Blood Pressure Drops

Bennett, S.R., Alward, W.L., & Folberg, R. (1989). An Autosomal Dominant Form of Low Tension Glaucoma. *American Journal of Ophthalmology*, Vol.108, pp. 238–244 Bergstrand, I.C., Heijl, A., & Harris, A. (2002). Dorzolamide and Ocular Blood Flow in

Bhandari, A., Crabb, D.P., Poinoosawmy, D., Fitzke, F.W., Hitchings, R.A., & Noureddin,

Broadway, D.C. & Drance, S.M. (1998). Glaucoma and Vasospasm. *British Journal of* 

Caprioli, J. & Spaeth, G.L. (1984). Comparison of Visual Field Defects in the Low-Tension

Caprioli, J. & Spaeth, G.L. (1985). Comparison of the Optic Nerve Head in High- and Low-Tension Glaucoma. *Archives of Ophthalmology*, Vol.103, No.8, pp. 1145-1149 Caprioli, J. & Coleman, A.L. (2010). Blood Pressure, Perfusion Pressure, and Glaucoma.

Choi J, Kim, K.H., Jeong, J., Cho, H.S., Lee, C.H., & Kook, M.S. (2007). Circadian Fluctuation

Glaucoma. *Investigative Ophthalmology & Visual Science*, Vol.48, pp. 104-111 Chumbley, L.C. & Brubaker, R.F. (1976). Low-Tension Glaucoma. *American Journal of* 

Collaborative Normal Tension Glaucoma Study Group. (1998). The Effectiveness of

Corbett, J.J., Phelps, C.D., Eslinger, P., & Montague, P.R. (1985). The Neurologic Evaluation

Analysis of Optineurin (OPTN) Gene Mutations in Subjects With and Without Glaucoma: The Blue Mountains Eye Study. *Clinical and Experimental Ophthalmology*,

in Patients with Focal Ischemic Glaucoma. *Graefes' Archive for Clinical and* 

Previously Untreated Glaucoma Patients: A Controlled Double-Masked Study. *Acta* 

B.N. (1997). Effect of Surgery on Visual Field Progression in Normal-Tension

Glaucomas with Those in the High-Tension Glaucomas. *American Journal of* 

of Mean Ocular Perfusion Pressure is a Consistent Risk Factor for Normal-Tension

Intraocular Pressure Reduction in the Treatment of Normal Tension Glaucoma.

of Patients with Low-Tension Glaucoma. *Investigative Ophthalmology & Visual* 

Glaucoma. *Current Opinion in Ophthalmology,* Vol.6, No.2, pp. 36-45

*Experimental Ophthalmology*, Vol. 232, No. 11, pp. 675-679

*Ophthalmologica Scandinavica,* Vol.80, No.2, pp. 176-182

Glaucoma. *Ophthalmology*, Vol.104, No.7, pp. 1131-1137

*American Journal of Ophthalmology,* Vol.149, No.5, pp.704-712

*American Journal of Ophthalmology*, Vol.126, pp. 498-505

*Ophthalmology*, Vol.82, No.8, pp. 862-870

*Ophthalmology*, Vol.97, No.6, pp. 730-737

*Ophthalmology*, Vol.81, No.6, pp. 761-767

*Sciences*, Vol. 26, No.8, pp. 1101-1104

& Brubaker, 1976).

**8. References** 

Vol.32, No.5, pp. 518-522

#### **7. Treatment**

The decision to treat a patient suspected with NTG must include the patient's age and all aspects of the disease, its extent, pathogenic factors and especially the rate of progression. If the patient's disease seems not to be progressive, monitoring of the disease is advised. When the disease is bilateral and not severe, treatment in one eye may be suitable. Careful followup and comparison of both eyes for progression is essential. Some patients suffer from visual field loss and disc damage and require prompt therapy. As in POAG, it is customary to begin with medical therapy, but laser and even surgical treatment should be considered for advanced cases. The target IOP was recommended to be 30% reduction by CNTGS and this reduces the progression from 35% in untreated patients to 12% in the treated group. Approximately two-thirds of the patients that did not receive any therapy did not progress (Drance et al., 2001). Target IOP was reached with medication and laser trabeculoplasty in half of CNTGS patients. This was achieved without beta-blockers or prostaglandin analogs. Currently the available drugs are thought to produce better effects on lowering the IOP, better compliance and better results in preventing disease progression. Still some patients continue to deteriorate after proper IOP reduction.

Some drops especially brimonidine were found to have neuroprotective effects in animal models (Vidal et al., 2010; Wolde Mussie et al., 2001). The research to achieve better control of glaucoma using a mechanism other than lowering IOP is promising. Unfortunately, neuroprotection by preventing the death of retinal ganglion cells, and vision preservation have not yet been proven in humans (Saylor et al., 2009). Long-term follow-up should determine whether or not neuroprotective agents may be beneficial for glaucoma patients (Sena et al., 2010). A low-tension glaucoma study LoGTS is currently underway comparing timolol and brimonidine treatment in NTG patients. The authors believe the neuroprotective effect of brimonidine will provide better results in preventing the disease progression. Dorzolamide, betaxolol, and latanaprost were considered to increase blood flow around the optic nerve (Harris et al., 1996, 2000), but newer published studies suggest that the effect, if exists at all, is minor (Bergstrand et al., 2002; Harris et al., 2003). Calcium channel blockers treatment was proved to be beneficial (Koseki et al., 2008; Netland et al., 1993). The treatment is recommended especially if a vasospastic disorder is diagnosed. Systemic side effects of calcium channel blockers such as flushing, edema, hypotension, headaches and reflex tachycardia requires careful selection of patients for this therapy.

In patients with low compliance or troubling side effects, laser treatment should be considered. Selective laser trabeculoplasty has promising results on lowering IOP and is considered a safe and reproducible treatment for NTG (El Mallah et al., 2010; Realini, 2008). Argon laser trabeculoplasty was studied as treatment for normal-tension glaucoma patients. The results varied from little to no effect (Schulzer, 1992; Sharpe & Simmons, 1985). SLT is considered a safe and effective treatment for lowering IOP, especially in noncompliant patient and in patients with severe side effects from topical or systemic drug treatment.

Trabeculectomy was found to lower IOP and slow the progression after long term follow-up (Bhandari et al., 1997; Shigeeda et al., 2002). Both medical and surgical treatments increase the risk for cataract formation. Cataract development was more frequent in patients undergoing trabeculectomy than in patients receiving only medical treatment (Drance et al., 2001). Follow-up and cataract extraction is advisable to improve visual acuity and follow-up reliability. Finally any systemic disease that can affect optic nerve perfusion such as systemic hypertension, congestive heart failure, arrhythmia and anemia, should be treated (Chumbley & Brubaker, 1976).

#### **8. References**

540 Glaucoma - Basic and Clinical Concepts

The decision to treat a patient suspected with NTG must include the patient's age and all aspects of the disease, its extent, pathogenic factors and especially the rate of progression. If the patient's disease seems not to be progressive, monitoring of the disease is advised. When the disease is bilateral and not severe, treatment in one eye may be suitable. Careful followup and comparison of both eyes for progression is essential. Some patients suffer from visual field loss and disc damage and require prompt therapy. As in POAG, it is customary to begin with medical therapy, but laser and even surgical treatment should be considered for advanced cases. The target IOP was recommended to be 30% reduction by CNTGS and this reduces the progression from 35% in untreated patients to 12% in the treated group. Approximately two-thirds of the patients that did not receive any therapy did not progress (Drance et al., 2001). Target IOP was reached with medication and laser trabeculoplasty in half of CNTGS patients. This was achieved without beta-blockers or prostaglandin analogs. Currently the available drugs are thought to produce better effects on lowering the IOP, better compliance and better results in preventing disease progression. Still some patients

Some drops especially brimonidine were found to have neuroprotective effects in animal models (Vidal et al., 2010; Wolde Mussie et al., 2001). The research to achieve better control of glaucoma using a mechanism other than lowering IOP is promising. Unfortunately, neuroprotection by preventing the death of retinal ganglion cells, and vision preservation have not yet been proven in humans (Saylor et al., 2009). Long-term follow-up should determine whether or not neuroprotective agents may be beneficial for glaucoma patients (Sena et al., 2010). A low-tension glaucoma study LoGTS is currently underway comparing timolol and brimonidine treatment in NTG patients. The authors believe the neuroprotective effect of brimonidine will provide better results in preventing the disease progression. Dorzolamide, betaxolol, and latanaprost were considered to increase blood flow around the optic nerve (Harris et al., 1996, 2000), but newer published studies suggest that the effect, if exists at all, is minor (Bergstrand et al., 2002; Harris et al., 2003). Calcium channel blockers treatment was proved to be beneficial (Koseki et al., 2008; Netland et al., 1993). The treatment is recommended especially if a vasospastic disorder is diagnosed. Systemic side effects of calcium channel blockers such as flushing, edema, hypotension, headaches and

In patients with low compliance or troubling side effects, laser treatment should be considered. Selective laser trabeculoplasty has promising results on lowering IOP and is considered a safe and reproducible treatment for NTG (El Mallah et al., 2010; Realini, 2008). Argon laser trabeculoplasty was studied as treatment for normal-tension glaucoma patients. The results varied from little to no effect (Schulzer, 1992; Sharpe & Simmons, 1985). SLT is considered a safe and effective treatment for lowering IOP, especially in noncompliant patient and in patients with severe side effects from topical or systemic drug treatment. Trabeculectomy was found to lower IOP and slow the progression after long term follow-up (Bhandari et al., 1997; Shigeeda et al., 2002). Both medical and surgical treatments increase the risk for cataract formation. Cataract development was more frequent in patients undergoing trabeculectomy than in patients receiving only medical treatment (Drance et al., 2001). Follow-up and cataract extraction is advisable to improve visual acuity and follow-up reliability. Finally any systemic disease that can affect optic nerve perfusion such as systemic

reflex tachycardia requires careful selection of patients for this therapy.

**7. Treatment** 

continue to deteriorate after proper IOP reduction.


Normal-Tension (Low-Tension) Glaucoma 543

Harris, A., Migliardi, R., Rechtman, E., Cole, C.N., Yee, A.B., & Garzozi, H.J. (2003).

Harris, A., Rechtman, E., Siesky, B., Jonescu-Cuypers, C., McCranor, L., & Garzozi, H.J.

Ishida, K., Yamamoto, T., Sugiyama, K., & Kitazawa, Y. (2000). Disk Hemorrhage is a

Ito, M., Sugiura, T., & Mizokami, K. (1991). A Comparative Study on Visual Field Defect in Low-Tension Glaucoma. *Nippon Ganka Gakkai Zasshi,* Vol. 95, pp. 790-794 Iwase, A., Suzuki, Y., Araie, M., Yamamoto, T., Abe, H., Shirato, S., Kuwayama, Y.,

Jonas, J.B. & Xu, L. (1994). Optic Disk Hemorrhages in Glaucoma. *American Journal of* 

Kamio, M., Meguro, A., Ota, M., Nomura, N., Kashiwagi, K., Mabuchi, F., Iijima, H.,

Kesler, A., Haber, I., & Kurtz, S. (2010). Neurologic Evaluations in Normal-Tension

Klein, B., Klein, R., Sponsel, W.E., Franke, T., Cantor, L.B., Martone, J., & Menage, M.J.

Klein, B.E., Klein, R., Meuer, S.M., & Goetz, L.A. (1993). Migraine Headache and Its

Koseki, N., Araie, M., Tomidokoro, A., Nagahara, M., Hasegawa, T., Tamaki, Y., &

Leighton, D.A. & Phillips, C.I. (1972). Systemic Blood Pressure in Open-Angle Glaucoma,

Leibowitz, H.M., Krueger, D.E., Maunder, L.R., Milton, R.C., Kini, M.M., Kahn, H.A.,

*Ophthalmology and Visual Sciences,* Vol. 34, No. 10, pp. 3024-3027

*Ophthalmology*, Vol. 115, No. 11, pp. 2049-2057

*Ophthalmology Clinics of North America*, Vol. 18, No. 3, pp. 345-353

*Journal of Ophthalmology,* Vol. 129, No. 6, pp. 707-714

*Ophthalmology*, Vol. 13, No. 1, pp. 24-31

*Ophthalmology*, Vol. 118, pp. 1-8

*Ophthalmology*, Vol.3, pp. 183-188

Vol. 12, No. 5, pp. 287-289

99, No. 10, pp. 1499–1504

56, pp. 447-53

1648

Comparative Analysis of the Effects of Dorzolamide and Latanoprost on Ocular Hemodynamics in Normal Tension Glaucoma Patients. *European Journal of* 

(2005). The Role of Optic Nerve Blood Flow in Pathogenesis of Glaucoma.

Significantly Negative Prognostic Factor in Normal-Tension Glaucoma. *American* 

Mishima, H.K., Shimizu, H., Tomita, G., Inoue, Y., & Kitazawa, Y. Tajimi Study Group, Japan Glaucoma Society. (2004). The Prevalence of Primary Open Angle Glaucoma in Japanese: The Tajimi Study. *Ophthalmology*, Vol. 111, No. 9, pp. 1641-

Kawase, K., Yamamoto, T., Nakamura, M., Negi, A., Sagara, T., Nishida, T., Inatani, M., Tanihara, H., Aihara, M., Araie, M., Fukuchi, T., Abe, H., Higashide, T., Sugiyama, K., Kanamoto, T., Kiuchi, Y., Iwase, A., Ohno, S., Inoko, H., & Mizuki, N. (2009). Investigation of the Association Between the GLC3A Locus and Normal Tension Glaucoma in Japanese Patients by Microsatellite Analysis. *Clinical* 

Glaucoma Workups: Are They Worth the Effort? *Israel Medical Association Journal*,

(1992). Prevalence of Glaucoma: The Beaver Dam Eye Study. *Ophthalmology,* Vol.

Association with Open-Angle Glaucoma. The Beaver Dam Eye Study. *Investigative* 

Yamamoto, S. (2008). A Placebo-Controlled 3-year Study of a Calcium Blocker on Visual Field and ocular Circulation in Glaucoma with Low-Normal Pressure.

Low Tension Glaucoma and the Normal Eye, *British Journal of Ophthalmology*, Vol.

Nickerson, R.J., Pool, J., Colton, T.L., Ganley, J.P., Loewenstein, J.I., & Dawber, T.R. (1980). The Framingham Eye Study Monograph: An Ophthalmological and


Dandona, L., Quigley, H.A., Brown, A.E., & Enger, C. (1990). Quantitative Regional

Drance, S.M., Sweeney, V.P., Morgan, R.W., & Feldman, F. (1973). Studies of Factors

Drance, S.M. (1977). The Visual Field of Low Tension Glaucoma and Shock-Induced Optic Neuropathy. *Archives of Ophthalmology*, Vol. 95, No. 8, pp. 1359-1361 Drance, S., Anderson, D.R., & Schulzer, M. Collaborative Normal-Tension Glaucoma Study

El Mallah, M.K., Walsh, M.M., Stinnett, S.S., & Asrani, S.G. (2010). Selective Laser

Fuse, N., Takahashi, K., Akiyama, H., Nakazawa, T., Seimiya, M., Kuwahara, S., & Tamai,

Galassi, F., Sodi, A., Ucci, F., Renieri, G., Pieri, B., & Baccini, M. (2003). Ocular

Goldberg, I., Hollows, F.C., Kass, M.A., & Becker, B. (1981). Systemic Factors in Patients with Low Tension Glaucoma. *British Journal of Ophthalmology*, Vol. 65, No. 1, pp. 56-62 Graham, S.L., Drance, S.M., Wijsman, K., Douglas, G.R., & Mikelberg, F.S. (1995).

Gutman I, Melamed S, Ashkenazi I, Blumenthal M. Optic nerve compression by carotid

Hagishima, M., Kamiya, K., Fujimura, F., Morita, T., Shoji, N., & Shimizu, K. (2010). Effect of

Harrington, D.O. (1960). Pathogenesis of the Glaucomatous Visual Field Defects: Individual

Harris, A., Arend, O., Arend, S., & Martin, B. (1996). Effects of Topical Dorzolamide on

Harris, A., Arend, O., Chung, H.S., Kagemann, L., Cantor, L., & Martin, B. (2000). A

Glaucoma Patients. *Clinical Ophthalmology,* Vol. 4, pp. 889-893

*in Ophthalmology*, Vol. 121, No. 12, pp. 1711-1715

*Experimental Ophthalmology*, Vol. 248, No. 2, pp. 257-262

*Ophthalmology,* Vol.102, No.1, pp.61-69

*Ophthalmology,* Vol.108, pp. 393-398

Vol. 89, No.6, pp. 457-465

Vol. 13, No. 4, pp. 299-303

231(12):711-7.

Foundation, New York

No. 6, pp. 569-572

434

699-708

Structure of the Normal Human Lamina Cribrosa. A Racial Comparison. *Archives of* 

Involved in the Production of Low Tension Glaucoma. *Archives of Ophthalmology*,

Group. (2001). Risk Factors for Progression of Visual Field Abnormalities in Normal-Tension Glaucoma. *American Journal of Ophthalmology,* Vol.131, No.6, pp.

Trabeculoplasty Reduces Mean IOP and IOP Variation in Normal Tension

M. (2004). Molecular Genetic Analysis of Optineurin Gene for Primary Open-Angle and Normal Tension Glaucoma in the Japanese Population. *Journal of Glaucoma*,

Hemodynamic and Glaucoma Prognosis. A Color Doppler Imaging Study. *Archives* 

Ambulatory Blood Pressure Monitoring in Glaucoma. The Nocturnal Dip.

arteries in low-tension glaucoma. *Graefes Arch Clin Exp Ophthalmol*. 1993 Dec;

Corneal Astigmatism on Intraocular Pressure Measurement Using Ocular Response Analyzer and Goldmann Applanation Tonometer. *Graefes Archive in Clinical and* 

Variations in Pressure Sensitivity, In: Newell FW, editor: *Conference on Glaucoma*. *Transactions of the Fifth Josiah Macy Conference*, F.W. Newell, (ed.), Josiah Macy

Retinal and Retrobulbar Hemodynamics. *Acta Ophthalmologica Scandinavica,* Vol. 74,

Comparative Study of Betaxolol and Dorzolamide Effect on Ocular Circulation in Normal-Tension Glaucoma Patients. , *Ophthalmology,* 2000, Vol. 107, No. 3, pp. 430-


Normal-Tension (Low-Tension) Glaucoma 545

Saylor, M., McLoon, L.K., Harrison, A.R., & Lee, M.S. (2009). Experimental and Clinical

Sena, D.F., Ramchand, K., & Lindsley, K. (2010). Neuroprotection for Treatment of Glaucoma in Adults. *Cochrane Database of Systematic Reviews,* Vol. 17, CD006539 Shields, M.B. (2008). Normal-Tension Glaucoma: Is It Different From Primary Open-Angle Glaucoma? *Current Opinion in Ophthalmology*, Vol. 19, No. 2, p. 85-88 Sharpe, E.D. & Simmons, R.J. (1985). Argon Laser Trabeculoplasty as a Means of Decreasing

Shigeeda, T., Tomidokoro, A., Araie, M., Koseki, N., & Yamamoto, S. (2002). Long-Term

Shiose, Y., Kitazawa, Y., Tsukahara, S., Akamatsu, T., Mizokami, K., Futa, R., Katsushima,

Glaucoma Survey, *Japan Journal of Ophthalmology,* Vol. 35, No. 2, pp. 133-155 Siegner, S.W. & Netland, P.A. (1996). Optic Disc Hemorrhages and Progression of

Sommer, A., Tielsch, J.M., Katz, J., Quigley, H.A., Gottsch, J.D., Javitt, J., & Singh, K. (1991).

Toda, Y., Tang, S., Kashiwagi, K., Mabuchi, F., Iijima, H., Tsukahara, S., & Yamagata, Z.

Tomita, G. (2000). The Optic Nerve Head in Normal-Tension Glaucoma. *Current Opinion in* 

Umeda, T., Matsuo, T., Nagayama, M., Tamura, N., Tanabe, Y., & Ohtsuki, H. (2004).

Vidal, L., Díaz, F., Villena, A., Moreno, M., Campos, J.G., & Pérez de Vargas, I. (2010).

WoldeMussie, E., Ruiz, G., Wijono, M., & Wheeler, L.A. (2001). Neuroprotection of Retinal

Glaucoma. *Ophthalmology,* Vol. 103, No. 7, pp. 1014-1024

*Ophthalmology*, Vol. 109, No. 8, pp. 1090-1095

*Genetics A,* Vol. 125, No. 1, pp. 1-4

Vol. 82, No. 1-2, pp. 18-24

*Ophthalmology,* Vol. 11, No. 2, pp. 116-120

Patients. *Ophthalmic Genetics,* Vol. 25, pp.:91

Normal-Tension Glaucoma. *Ophthalmology,* Vol. 109, No. 4, pp. 766-770 Shin, I.H., Kang, S.Y., Hong, S., Kim, S.K., Seong, G.J., Tak, M.K., & Kim, C.Y. (2008).

*of Ophthalmology,* Vol. 99, No. 6, pp. 704-707

1470

No. 4, pp. 236-241

Evidence for Brimonidine as an Optic Nerve and Retinal Neuroprotective Agent: An Evidence-Based Review. *Archives of Ophthalmology,* Vol. 127, No. 4, pp. 402-406 Schulzer, M. (1992). The Normal-Tension Glaucoma Study Group: Intraocular Pressure

Reduction in Normal-Tension Glaucoma Patients. *Ophthalmology*, Vol. 99, pp. 1468-

Intraocular Pressure from "Normal" Levels in Glaucomatous Eyes. *American Journal* 

Follow-Up of Visual Field Progression After Trabeculectomy in Progressive

Comparison of OCT and HRT Findings Among Normal, Normal Tension Glaucoma, and High Tension Glaucoma. *Korean Journal of Ophthalmology*, Vol. 22,

H., & Kosaki, H. (1991). Epidemiology of Glaucoma in Japan: A Nationwide

Relationship Between Intraocular Pressure and Primary Open Angle Glaucoma among White and Black Americans. The Baltimore Eye Survey. *Archives of* 

(2004). Mutations in the Optineurin Gene in Japanese Patients with Primary Open-Angle Glaucoma and Normal Tension Glaucoma. *American Journal of Medical* 

Clinical Relevance of Optineurin Sequence Alterations in Japanese Glaucoma

Reaction of Müller Cells in an Experimental Rat Model of Increased Intraocular Pressure Following Timolol, Latanoprost and Brimonidine. *Brain Research Bulletin,*

Ganglion Cells by Brimonidine in Rats with Laser-Induced Chronic Ocular

Epidemiological Study of Cataract, Glaucoma, Diabetic Retinopathy, Macular Degeneration, and Visual Acuity in a General Population of 2631 Adults, 1973-1975. *Survey of Ophthalmology*, Vol. 24 (Suppl), pp. 335-610


Michelson, G. & Scibor, M. (2006). Intravascular Oxygen Saturation in Retinal Vessels in

Morad, Y., Sharon, E., Hefetz, L., & Nemet, P. (1998). Corneal Thickness and Curvature in

Morita, T., Shoji, N., Kamiya, K., Hagishima, M., Fujimura, F., & Shimizu, K. (2010).

Netland, P.A., Chaturvedi, N., & Dreyer, E.B. (1993). Calcium Channel Blockers in the

Papastergiou, G.I., Kozobolis, V., & Siganos, D.S. (2010). Effect of Recipient Corneal

Perkins, E.S. (1973). The Bedford Glaucoma Survey. I. Longterm Followup of Borderline

Phelps, C.D. & Corbett, J.J. (1985). Migraine and Low-Tension Glaucoma. A Case-Control Study. *Investigative Ophthalmology and Visual Sciences*, Vol. 26, No. 8, pp. 1105-1108 Plange, N., Remky, A., & Arend, O. (2003). Colour Doppler Imaging and Fluorescein Filling

Quigley, H., Pease, M.E., & Thibault, D. (1994). Change in the Appearance of Elastin in the

Realini, T. (2008). Selective Laser Trabeculoplasty: A Review. *Journal of Glaucoma,* Vol. 17,

Sánchez-Navés, J., Furfaro, L., Piro, O., & Balle, S. (2008). Impact and Permanence of LASIK-

Sarfarazi, M., Child, A., Stoilova, D., Brice, G., Desai, T., Trifan, O.C., Poinoosawmy, D., &

Sato, E.A., Ohtake, Y., Shinoda, K., Mashima, Y., & Kimura, I. (2006). Decreased Blood Flow

Cases. *British Journal of Ophthalmology*, Vol. 57, No. 3, pp. 179-185

*Survey of Ophthalmology*, Vol. 24 (Suppl), pp. 335-610

*Experimental Ophthalmology*, Vol. 248, No. 1, pp. 73-77.

*Ophthalmology*, Vol. 115, No. 5, pp. 608-613

*Ophthalmology*, Vol. 87, No. 6, pp. 731-736.

*Human Genetics*, Vol. 62, No. 3, pp. 641-652

*Ophthalmology*, Vol. 244, No. 7, pp. 795-801

No. 6, pp. 497-502.

No. 8, pp. 611-618

*and Experimental Ophthalmology*, Vol. 232, pp. 257-261

*Scandinavica*, Vol. 84, No. 3, pp. 289-295

164-168

34

Epidemiological Study of Cataract, Glaucoma, Diabetic Retinopathy, Macular Degeneration, and Visual Acuity in a General Population of 2631 Adults, 1973-1975.

Normal Subjects and Open-Angle Glaucoma Subjects. *Acta Ophthalmologica* 

normal-Tension Glaucoma. *American Journal of Ophthalmology*, Vol. 125, No. 2, pp.

Intraocular Pressure Measured by Dynamic Contour Tonometer and Ocular Response Analyzer in Normal Tension Glaucoma. *Graefes Archive of Clinical and* 

Management of Low-Tension and Open-Angle Glaucoma. *American Journal of* 

Pathology on Pascal Tonometer and Goldmann Tonometer Readings in Eyes after Penetrating Keratoplasty. *European Journal of Ophthalmology,* Vol. 20, No. 1, pp. 29-

Defects of the Optic Disc in Normal Tension Glaucoma. *British Journal of* 

Lamina Cribrosa of Glaucomatous Optic Nerve Heads. *Graefes Archive of Clinical* 

Induced Structural Changes in the Cornea on Pneumotonometric Measurements: Contributions of Flap Cutting and Stromal Ablation. *Journal of Glaucoma,* Vol. 17,

Crick, R.P. (1998). Localization of the Fourth Locus (GLC1E) for Adult-Onset Primary Open-Angle Glaucoma to the 10p15-p14 Region. *American Journal of* 

at Neuroretinal Rim of Optic Nerve Head Corresponds with Visual Field Deficit in Eyes with Normal Tension Glaucoma. *Graefes Archive of Clinical and Experimental* 


**28** 

Eitan Z. Rath

*Israel*

**Drug-Induced Glaucoma** 

**(Glaucoma Secondary to Systemic Medications)**

Glaucoma comprises a group of diseases that have in common a characteristic optic nerve and visual field damage and elevated intraocular pressure (IOP) is the main risk factor. The IOP depends on the balance between the formation and drainage of aqueous humor. The glaucoma can be classified into four main groups: open-angle (OAG), acute angle-closure (ACG), secondary and developmental glaucoma. The first two refer to the pathophysiology

Drug-induced glaucoma is a form of secondary glaucoma induced by topical and systemic medications. The most common one is glucorticoid OAG. Several drugs like antidepressants, anticoagulants, adrenergic antagonists, sulpha -based drugs and antiepileptic dugs have been reported to produce an acute ACG and especially in those with predisposed angle closure. Bilateral simultaneous ACG is extremely a rare entity. Drug-induced uveal effusion causing secondary ACG have been reported1-9 involving medications such as topiramate,2,4,6,9 trimethoprin1 and venlafaxine.3 The mechanism of secondary OAG is usually the microscopic obstruction of the trabecular meshwork whereas ACG is induced by uveal effusion. The treatment of these two entities is similar to OAG and, it could be medically as

The differential diagnosis, prognosis and several future directions for research will be

Ophthalmologists should be aware of these types of glaucoma, which to my opinion are

Armaly as shown that within the general population 5 to 6 % of the healthy subjects will develop marked elevation of IOP, 4 to 6 weeks after administration of topical dexamethasone or betamethasone eye drops.12 These studies have also shown that these numbers are directly related to the frequency of the administration and duration of usage of this medication. Increasing usage is related to the increased risk for elevated IOP. At higher risk are patients with primary open-angle glaucoma, their first-degree relatives, diabetic patients, highly myopic individuals, and patients with connective tissue disease, specifically rheumatoid arthritis. In addition, patients with angle recession glaucoma are more

**1. Introduction**

of the disease.

well as surgical.

**2. Epidemiology**

becoming more common in a busy glaucoma clinic.

susceptible to corticosteroid-induced glaucoma.

discussed.

*Department of Ophthalmology, Western Galilee* – *Nahariya Medical Center,* 

Hypertension*. Investigative Ophthalmology and Visual Sciences*, Vol. 42, No. 12, pp. 2849-2855

Xia, C.R., Xu, L., & Yang, Y. (2005). A Comparative Study of Optic Nerve Damage Between Primary Open Angle Glaucoma and Normal Tension Glaucoma. *Zhonghua Yan Ke Za Zhi*, Vol. 41, No. 2, pp. 136-140

### **Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications)**

#### Eitan Z. Rath

*Department of Ophthalmology, Western Galilee* – *Nahariya Medical Center, Israel*

#### **1. Introduction**

546 Glaucoma - Basic and Clinical Concepts

Xia, C.R., Xu, L., & Yang, Y. (2005). A Comparative Study of Optic Nerve Damage Between

2849-2855

*Za Zhi*, Vol. 41, No. 2, pp. 136-140

Hypertension*. Investigative Ophthalmology and Visual Sciences*, Vol. 42, No. 12, pp.

Primary Open Angle Glaucoma and Normal Tension Glaucoma. *Zhonghua Yan Ke* 

Glaucoma comprises a group of diseases that have in common a characteristic optic nerve and visual field damage and elevated intraocular pressure (IOP) is the main risk factor. The IOP depends on the balance between the formation and drainage of aqueous humor. The glaucoma can be classified into four main groups: open-angle (OAG), acute angle-closure (ACG), secondary and developmental glaucoma. The first two refer to the pathophysiology of the disease.

Drug-induced glaucoma is a form of secondary glaucoma induced by topical and systemic medications. The most common one is glucorticoid OAG. Several drugs like antidepressants, anticoagulants, adrenergic antagonists, sulpha -based drugs and antiepileptic dugs have been reported to produce an acute ACG and especially in those with predisposed angle closure.

Bilateral simultaneous ACG is extremely a rare entity. Drug-induced uveal effusion causing secondary ACG have been reported1-9 involving medications such as topiramate,2,4,6,9 trimethoprin1 and venlafaxine.3 The mechanism of secondary OAG is usually the microscopic obstruction of the trabecular meshwork whereas ACG is induced by uveal effusion. The treatment of these two entities is similar to OAG and, it could be medically as well as surgical.

The differential diagnosis, prognosis and several future directions for research will be discussed.

Ophthalmologists should be aware of these types of glaucoma, which to my opinion are becoming more common in a busy glaucoma clinic.

#### **2. Epidemiology**

Armaly as shown that within the general population 5 to 6 % of the healthy subjects will develop marked elevation of IOP, 4 to 6 weeks after administration of topical dexamethasone or betamethasone eye drops.12 These studies have also shown that these numbers are directly related to the frequency of the administration and duration of usage of this medication. Increasing usage is related to the increased risk for elevated IOP. At higher risk are patients with primary open-angle glaucoma, their first-degree relatives, diabetic patients, highly myopic individuals, and patients with connective tissue disease, specifically rheumatoid arthritis. In addition, patients with angle recession glaucoma are more susceptible to corticosteroid-induced glaucoma.

Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications) 549

due to pupillary block, i.e. iris-lens contact at the pupillary border resulting from pupillary

People at risk for Angle Closure Glaucoma (ACG) are those with hypermetropia, microphthalmus and nanophthalmos. Medications have a direct or indirect effect, either in stimulating sympathetic or inhibiting parasympathetic activation causing pupillary dilation, which can precipitate an acute angle-closure in patients with occludable anterior chamber angles. These agents include adrenergic agonists (e.g. β2-specific adrenergic agonists (e.g. salbutamol), non-catecholamine adrenergic agonists (e.g. amphetamine, dextroamphetamine, methamphetamine and phendimetrazine) and anticholinergics (e.g. tropicamide). Histamine H1receptor antagonists (antihistamines) and histamine H2 receptor antagonists (e.g. cimetidine and ranitidine) have weak anticholinergic adverse effects. Antidepressants such as fluoxetine, paroxetine, fluvoxamine and venlafaxine also have been associated with acute angle-closures, which is believed to be induced by either the anticholinergic adverse effects

Sulfa-containing medications may result in acute angle-closures by a different mechanism. This involves the anterior rotation of the ciliary body with or without choroidal effusions, resulting in a shallow anterior chamber and blockage of the trabecular meshwork by the iris. Pupillary dilation and a preexisting shallow anterior chamber angle are not necessary. The exact reason for ciliary body swelling is unknown but it occurs in susceptible individuals. Topiramate is a sulfa-containing anticonvulsant. There were reports about patients on topiramate developing acute angle-closure. However, a pilot study was conducted in the Hong Kong Eye Hospital and the Prince of Wales Hospital recently, which showed that short-term use of topiramate, did not induce an asymptomatic angle narrowing. Therefore, it was suggested that topiramate induced secondary angle-closure glaucoma may be an all-

> Anterior Chamber

Lens Pupil

Carbamazepine is also an anticonvulsive medication and a mood stabilizer and is primarily used in treating of epilepsy, bipolar disorders and trigeminal neuralgia.10 It stabilizes and

Iris

Iris

Angle

Cornea

or the increased level of serotonin that cause mydriasis.

Fluid Forms Here

Fluid Exits Here

Fig. 1. Aqueous humor flow

dilation.

or-none phenomenon.

### **3. Mechanisms of IOP elevation in drug-induced glaucoma**

#### **3.1 Open-angle**

Corticosteroid is a group of drugs that may produce IOP elevation by open-angle mechanism. Not all the patients taking steroid will develop this glaucoma. The risk factors include preexisting primary open-angle glaucoma, a family history of glaucoma, high myopia, diabetes mellitus and young age.13 It has been shown that 18-36% of the general population and 46–92% of patients with primary open-angle glaucoma respond to topical ocular administration of corticosteroids with an elevation of IOP, usually within 2–4 weeks after therapy has been instituted.

Topically applied eye drops and creams to the periorbital area and intravitreal injections are more likely to cause IOP elevation than intravenous, parenteral and inhaled forms. Since IOP elevation can be gradual and asymptomatic, patients on chronic corticosteroid therapy may remain undiagnosed, which can result in glaucomatous optic nerve damage. Steroidinduced IOP elevation typically occurs within a few weeks after commencing steroid therapy. In most cases, IOP returns spontaneously to the baseline within a few weeks to months upon discontinuing the steroid (steroid responders). In rare situations, the IOP remains high (steroid-induced glaucoma) that may require prolonged glaucoma medication or even surgery. This subject is discussed in details in the chapter on steroid-induced glaucoma.

#### **3.2 Closed-angle**

Some drugs have contraindications or adverse effects that are related to acute angle-closure glaucoma. These drugs will incite an attack in individuals with very narrow anterior chamber angles that are prone to occlusion, especially when the pupils are dilated. The classes of medications that have the potential to induce angle-closure are topical anticholinergic or sympathomimetic pupil dilating drops, tricyclic antidepressants, monoamine oxidase inhibitors, antihistamines, anti-Parkinson drugs, antipsychotic medications and antispasmolytic agents.

Sulfonamide-containing medications may induce an ACG by a different mechanism, involving the anterior rotation of the cilliary-body. Typically, the angle-closure is bilateral and occurs within the first few doses. Patients with narrow or wide open angles are potentially susceptible to this rare and idiosyncratic reaction.

#### **4. Pathophysiology of drug-induced glaucoma**

#### **4.1 Open-angle**

The exact pathophysiology of steroid-induced glaucoma is unknown. It is known that steroid-induced IOP elevation is secondary to increased resistance to aqueous outflow. Some evidence shows that there could be an increased accumulation of glycosaminoglycans or increased production of trabecular meshwork-inducible glucocorticoid response (TIGR) protein, which could mechanically at microscopic level obstruct the aqueous outflow. Other evidence suggests that the corticosteroid-induced cytoskeletal changes could inhibit pinocytosis of aqueous humour or inhibit the clearing of glycosaminoglycans, resulting in the accumulation of this substance and blockage of the aqueous outflow.

#### **4.2 Closed-angle**

Aqueous humor is secreted by the ciliary body and circulates through the pupil to reach the anterior chamber angle. (Fig. 1) The pathophysiology of angle-closure glaucoma is usually

Corticosteroid is a group of drugs that may produce IOP elevation by open-angle mechanism. Not all the patients taking steroid will develop this glaucoma. The risk factors include preexisting primary open-angle glaucoma, a family history of glaucoma, high myopia, diabetes mellitus and young age.13 It has been shown that 18-36% of the general population and 46–92% of patients with primary open-angle glaucoma respond to topical ocular administration of corticosteroids with an elevation of IOP, usually within 2–4 weeks

Topically applied eye drops and creams to the periorbital area and intravitreal injections are more likely to cause IOP elevation than intravenous, parenteral and inhaled forms. Since IOP elevation can be gradual and asymptomatic, patients on chronic corticosteroid therapy may remain undiagnosed, which can result in glaucomatous optic nerve damage. Steroidinduced IOP elevation typically occurs within a few weeks after commencing steroid therapy. In most cases, IOP returns spontaneously to the baseline within a few weeks to months upon discontinuing the steroid (steroid responders). In rare situations, the IOP remains high (steroid-induced glaucoma) that may require prolonged glaucoma medication or even surgery. This subject is discussed in details in the chapter on steroid-induced glaucoma.

Some drugs have contraindications or adverse effects that are related to acute angle-closure glaucoma. These drugs will incite an attack in individuals with very narrow anterior chamber angles that are prone to occlusion, especially when the pupils are dilated. The classes of medications that have the potential to induce angle-closure are topical anticholinergic or sympathomimetic pupil dilating drops, tricyclic antidepressants, monoamine oxidase inhibitors, antihistamines, anti-Parkinson drugs, antipsychotic

Sulfonamide-containing medications may induce an ACG by a different mechanism, involving the anterior rotation of the cilliary-body. Typically, the angle-closure is bilateral and occurs within the first few doses. Patients with narrow or wide open angles are

The exact pathophysiology of steroid-induced glaucoma is unknown. It is known that steroid-induced IOP elevation is secondary to increased resistance to aqueous outflow. Some evidence shows that there could be an increased accumulation of glycosaminoglycans or increased production of trabecular meshwork-inducible glucocorticoid response (TIGR) protein, which could mechanically at microscopic level obstruct the aqueous outflow. Other evidence suggests that the corticosteroid-induced cytoskeletal changes could inhibit pinocytosis of aqueous humour or inhibit the clearing of glycosaminoglycans, resulting in

Aqueous humor is secreted by the ciliary body and circulates through the pupil to reach the anterior chamber angle. (Fig. 1) The pathophysiology of angle-closure glaucoma is usually

**3. Mechanisms of IOP elevation in drug-induced glaucoma**

**3.1 Open-angle**

**3.2 Closed-angle**

**4.1 Open-angle**

**4.2 Closed-angle**

after therapy has been instituted.

medications and antispasmolytic agents.

potentially susceptible to this rare and idiosyncratic reaction.

the accumulation of this substance and blockage of the aqueous outflow.

**4. Pathophysiology of drug-induced glaucoma**

due to pupillary block, i.e. iris-lens contact at the pupillary border resulting from pupillary dilation.

People at risk for Angle Closure Glaucoma (ACG) are those with hypermetropia, microphthalmus and nanophthalmos. Medications have a direct or indirect effect, either in stimulating sympathetic or inhibiting parasympathetic activation causing pupillary dilation, which can precipitate an acute angle-closure in patients with occludable anterior chamber angles. These agents include adrenergic agonists (e.g. β2-specific adrenergic agonists (e.g. salbutamol), non-catecholamine adrenergic agonists (e.g. amphetamine, dextroamphetamine, methamphetamine and phendimetrazine) and anticholinergics (e.g. tropicamide). Histamine H1receptor antagonists (antihistamines) and histamine H2 receptor antagonists (e.g. cimetidine and ranitidine) have weak anticholinergic adverse effects. Antidepressants such as fluoxetine, paroxetine, fluvoxamine and venlafaxine also have been associated with acute angle-closures, which is believed to be induced by either the anticholinergic adverse effects or the increased level of serotonin that cause mydriasis.

Sulfa-containing medications may result in acute angle-closures by a different mechanism. This involves the anterior rotation of the ciliary body with or without choroidal effusions, resulting in a shallow anterior chamber and blockage of the trabecular meshwork by the iris. Pupillary dilation and a preexisting shallow anterior chamber angle are not necessary. The exact reason for ciliary body swelling is unknown but it occurs in susceptible individuals. Topiramate is a sulfa-containing anticonvulsant. There were reports about patients on topiramate developing acute angle-closure. However, a pilot study was conducted in the Hong Kong Eye Hospital and the Prince of Wales Hospital recently, which showed that short-term use of topiramate, did not induce an asymptomatic angle narrowing. Therefore, it was suggested that topiramate induced secondary angle-closure glaucoma may be an allor-none phenomenon.

Fig. 1. Aqueous humor flow

Carbamazepine is also an anticonvulsive medication and a mood stabilizer and is primarily used in treating of epilepsy, bipolar disorders and trigeminal neuralgia.10 It stabilizes and

Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications) 551

amount of aqueous production as well as causing culinary body edema. The common denominator to our patients was hypermetropia. Indeed, patients with short axial length, such as nanophthalmos and hyperopia have a tendency to develop thickened uvea, which can be aggravated by intraocular procedures such as cataract surgery resulting in acute

Unlike corticosteroid agents, the list of non-steroidal agents associated with glaucoma is wide and diverse (Table 1). 14 The causes of glaucoma associated with these agents are also varied. The largest single cause of glaucoma in these patients appears to be an atropine-like effect, eliciting pupillary dilatation. This class of agents includes antipsychotropics, antidepressants, monoamine oxidase (MAO) inhibitors, antihistamines, antiparkinsonian agents, antispasmolytic agents, mydriatic agents, sympathetic agents, and botulinum toxin. The pupillary dilatation seen in these cases may be enough to precipitate an attack of angle-

Concerning open-angle glaucoma, the causes of elevated IOP are much more varied, including the release of pigment during the pupillary dilation with subsequent obstruction of the trabecular meshwork, and a possible increase of inflow during papillary dilation. As an alternative, some agents have been documented to produce an idiopathic swelling of the lens, associated with angle closure glaucoma. These agents include the antibiotics sulfa, quinine, and aspirin. Some agents directly obstruct the trabecular meshwork, such as the

Of the antipsychotropic agents on the market today, only perphenazine (Trilafon®) and fluphenazine decanoate (Prolixin®) have been documented to cause glaucoma. In both instances these were attacks of angle-closure glaucoma. These episodes were felt to reflect

Amitryptiline (Elavil® and Amitril®) and imipramine (Tofranil®), which are antidepressant tricyclic agents, have been shown to produce attacks of an angle-closure glaucoma. Of the non-tricyclic drugs, fluoxetine (Prozac®) and mianserin hydrochloride (Bolvidon®) 15 have

**5.3 The role of mood-altering agents, such as minor tranquilizers, sedatives, and** 

This is a rather diverse class of agents including sedatives such as diazepam (Valium®), morphine, barbiturates, and stimulants such as amphetamine and methylxanthines such as caffeine and theophylline. Diazepam has been reported to be taken by some patient having an attack of angle-closure glaucoma, in the literature there it is believed that this drug accentuate the anti cholinergic action on the eye in some rare cases with predisposed ACG . Barbiturates, morphine, para-aldehyde, meperidine, reserpine, and phenytoin have not been reported to produce an elevated IOP. The amphetamines have not been documented to

been documented to be associated with attacks of angle-closure glaucoma.

**5. Non-steroidal agents associated with glaucoma** 

closure glaucoma in patients with narrow angles.

the anticholinergic effect of these agents on the eyes.

viscoelastic agents and silicone oil.

**5.1 The role of psychotropic agents** 

**5.2 The role of antidepressant agents** 

produce an elevated IOP in any patient.

**stimulants** 

ACG.11

inactivates the sodium Chan resulting in fewer active channels and fewer excited brain cells. It was only reported once as causing this disorder.8

We had two cases that developed simultaneously acute angle-closure glaucoma 4-6 weeks after intake of PO carbamazepine.

#### **Case no. 1**

A 58-year-old woman presented with a bilateral acute ACG. Her medical history included epilepsy treated with carbamazepine (Novartis Pharma BU (Novolog), Basel, Switzerland) 200 mg once a day for 4 weeks to stabilize her medical status. Eleven years earlier she underwent thyroidectomy due to hyperthyroidism.

The best-corrected visual acuity (BCVA) was 20/80 (with +3.75D) OD and 20/100 (with +4.25D) OS. The intraocular pressure (IOP) was 54 OD and 46mmHg OS. Both corneas were edematous and the anterior chambers were shallow. Gonioscopy revealed angle closure in both eyes and fixed, mid-dilated pupils. Ultrasound biomicroscopy (UBM) showed an anterior displaced crystalline lens with extensive irido-lenticular contact and peripheral anterior synechiae OU. The axial length was 21.35 mm OD and 21.30 mm OS. B-Scan ultrasound showed normal posterior segment OU.

The patient was treated systemically with PO acetazolamide 250mg, topical timolol maleate – dorzolamide HCl and brimonidine tartrate twice a day and the IOP decreased to 18mmHg OD and 16mmHg OS .Neodymium: Yttrium-Aluminum-Garnet (Nd: YAG) laser iridotomy was successfully performed OU. A week later, the BCVA improved to 20/80 OD and 20/60 OS, on ocular examination, potent iridotomies, mid dilated pupils with sphincter atrophy, mild nuclear sclerosis and normal optic discs were noted. The anterior chamber depth measured by Scheimpflug imaging (Pentacam®, Oculus Optikgerate GmbH, Wetzlar, Germany) was 1.54mm OD and 1.67mm OS and the volume was 90mm3 and 76mm3 respectively. The pachymetry was 572μm OD and 568μm. The visual fields 30-2 (Humphrey II® automatic perimeter, Allergan-Humphrey, San Leandro, CA) performed two months later showed inferior nasal step OU.

#### **Case no. 2**

A 53-year-old female was admitted due to high IOP simultaneously in both eyes. She was hypermetropic since childhood and had amblyopic OS. She suffered from epilepsy and had two attacks four and six weeks before being hospitalized for which she received PO carbamazepine 200mg/d for five weeks. A day before admission, she experienced severe bilateral ocular pain, vomiting and decrease in visual acuity OU.

Her BCVA was 20/40 with +5.50D OD and 20/100 with + 7.50D OS. The IOP was 54 mmHg OD and 49 mmHg OS. Both eyes had edematous cornea, very shallow anterior chamber, iris bombe and mid-dilated pupil that were not reacting to light. The anterior chamber had a narrow angle 360 degrees OU on UBM (Fig. 2). The posterior poles were normal. The patient was treated with topical pilocarpine 2% qid and PO acetazolamide 250mg bid.

The patient underwent Nd: YAG laser iridotomy OU. Three days later, the BCVA improved to 20/25 OD and 20/60 OS. The IOP decreased to 8mmHg OD and 6mmHg OS. The anterior chambers' depth was deepened and patent iridotomies, mild-dilated pupil, clear lens and posterior pole with normal optic discs were observed.

The mechanism of these agents causing bilateral AACG has been attributed to ciliochoroidal effusion, which causes forward rotation of the lens–iris diaphragm resulting in a secondary angle-closure and increased IOP. This medication and others can produce an excessive

inactivates the sodium Chan resulting in fewer active channels and fewer excited brain cells.

We had two cases that developed simultaneously acute angle-closure glaucoma 4-6 weeks

A 58-year-old woman presented with a bilateral acute ACG. Her medical history included epilepsy treated with carbamazepine (Novartis Pharma BU (Novolog), Basel, Switzerland) 200 mg once a day for 4 weeks to stabilize her medical status. Eleven years earlier she

The best-corrected visual acuity (BCVA) was 20/80 (with +3.75D) OD and 20/100 (with +4.25D) OS. The intraocular pressure (IOP) was 54 OD and 46mmHg OS. Both corneas were edematous and the anterior chambers were shallow. Gonioscopy revealed angle closure in both eyes and fixed, mid-dilated pupils. Ultrasound biomicroscopy (UBM) showed an anterior displaced crystalline lens with extensive irido-lenticular contact and peripheral anterior synechiae OU. The axial length was 21.35 mm OD and 21.30 mm OS. B-Scan

The patient was treated systemically with PO acetazolamide 250mg, topical timolol maleate – dorzolamide HCl and brimonidine tartrate twice a day and the IOP decreased to 18mmHg OD and 16mmHg OS .Neodymium: Yttrium-Aluminum-Garnet (Nd: YAG) laser iridotomy was successfully performed OU. A week later, the BCVA improved to 20/80 OD and 20/60 OS, on ocular examination, potent iridotomies, mid dilated pupils with sphincter atrophy, mild nuclear sclerosis and normal optic discs were noted. The anterior chamber depth measured by Scheimpflug imaging (Pentacam®, Oculus Optikgerate GmbH, Wetzlar, Germany) was 1.54mm OD and 1.67mm OS and the volume was 90mm3 and 76mm3 respectively. The pachymetry was 572μm OD and 568μm. The visual fields 30-2 (Humphrey II® automatic perimeter, Allergan-Humphrey, San Leandro, CA) performed two months

A 53-year-old female was admitted due to high IOP simultaneously in both eyes. She was hypermetropic since childhood and had amblyopic OS. She suffered from epilepsy and had two attacks four and six weeks before being hospitalized for which she received PO carbamazepine 200mg/d for five weeks. A day before admission, she experienced severe

Her BCVA was 20/40 with +5.50D OD and 20/100 with + 7.50D OS. The IOP was 54 mmHg OD and 49 mmHg OS. Both eyes had edematous cornea, very shallow anterior chamber, iris bombe and mid-dilated pupil that were not reacting to light. The anterior chamber had a narrow angle 360 degrees OU on UBM (Fig. 2). The posterior poles were normal. The patient

The patient underwent Nd: YAG laser iridotomy OU. Three days later, the BCVA improved to 20/25 OD and 20/60 OS. The IOP decreased to 8mmHg OD and 6mmHg OS. The anterior chambers' depth was deepened and patent iridotomies, mild-dilated pupil, clear lens and

The mechanism of these agents causing bilateral AACG has been attributed to ciliochoroidal effusion, which causes forward rotation of the lens–iris diaphragm resulting in a secondary angle-closure and increased IOP. This medication and others can produce an excessive

was treated with topical pilocarpine 2% qid and PO acetazolamide 250mg bid.

bilateral ocular pain, vomiting and decrease in visual acuity OU.

posterior pole with normal optic discs were observed.

It was only reported once as causing this disorder.8

underwent thyroidectomy due to hyperthyroidism.

ultrasound showed normal posterior segment OU.

later showed inferior nasal step OU.

**Case no. 2** 

after intake of PO carbamazepine.

**Case no. 1** 

amount of aqueous production as well as causing culinary body edema. The common denominator to our patients was hypermetropia. Indeed, patients with short axial length, such as nanophthalmos and hyperopia have a tendency to develop thickened uvea, which can be aggravated by intraocular procedures such as cataract surgery resulting in acute ACG.11

#### **5. Non-steroidal agents associated with glaucoma**

Unlike corticosteroid agents, the list of non-steroidal agents associated with glaucoma is wide and diverse (Table 1). 14 The causes of glaucoma associated with these agents are also varied. The largest single cause of glaucoma in these patients appears to be an atropine-like effect, eliciting pupillary dilatation. This class of agents includes antipsychotropics, antidepressants, monoamine oxidase (MAO) inhibitors, antihistamines, antiparkinsonian agents, antispasmolytic agents, mydriatic agents, sympathetic agents, and botulinum toxin. The pupillary dilatation seen in these cases may be enough to precipitate an attack of angleclosure glaucoma in patients with narrow angles.

Concerning open-angle glaucoma, the causes of elevated IOP are much more varied, including the release of pigment during the pupillary dilation with subsequent obstruction of the trabecular meshwork, and a possible increase of inflow during papillary dilation. As an alternative, some agents have been documented to produce an idiopathic swelling of the lens, associated with angle closure glaucoma. These agents include the antibiotics sulfa, quinine, and aspirin. Some agents directly obstruct the trabecular meshwork, such as the viscoelastic agents and silicone oil.

#### **5.1 The role of psychotropic agents**

Of the antipsychotropic agents on the market today, only perphenazine (Trilafon®) and fluphenazine decanoate (Prolixin®) have been documented to cause glaucoma. In both instances these were attacks of angle-closure glaucoma. These episodes were felt to reflect the anticholinergic effect of these agents on the eyes.

#### **5.2 The role of antidepressant agents**

Amitryptiline (Elavil® and Amitril®) and imipramine (Tofranil®), which are antidepressant tricyclic agents, have been shown to produce attacks of an angle-closure glaucoma. Of the non-tricyclic drugs, fluoxetine (Prozac®) and mianserin hydrochloride (Bolvidon®) 15 have been documented to be associated with attacks of angle-closure glaucoma.

#### **5.3 The role of mood-altering agents, such as minor tranquilizers, sedatives, and stimulants**

This is a rather diverse class of agents including sedatives such as diazepam (Valium®), morphine, barbiturates, and stimulants such as amphetamine and methylxanthines such as caffeine and theophylline. Diazepam has been reported to be taken by some patient having an attack of angle-closure glaucoma, in the literature there it is believed that this drug accentuate the anti cholinergic action on the eye in some rare cases with predisposed ACG . Barbiturates, morphine, para-aldehyde, meperidine, reserpine, and phenytoin have not been reported to produce an elevated IOP. The amphetamines have not been documented to produce an elevated IOP in any patient.

Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications) 553

The anti-Parkinson agents act through two mechanisms: (1) Replenishing diminished stores of dopamine in the corpus striatum, and (2) Acting as a strong anticholinergic. Indeed,

HCl (Artane)17 has been documented to precipitate angle-closure glaucoma. This finding is

These agents act to reduce both the gastrsecretion and the motility of the stomach. Their effect directly reflects their anticholinergic power. Although no attacks of angle-closure glaucoma are documented with these agents, propantheline bromide (Pro-Banthine®) and dicyclomine HCl (Bentyl®) 18 have been documented to raise the IOP in patients with open-

General anesthesia has always entailed an increased risks to the patient, including the risk of elevated IOP and glaucoma. It has always been difficult to separate the various risk factors to the patient undergoing general anesthesia. The induction of general anesthesia itself may be associated with an elevated IOP from laryngeal spasm, coughing, and wheezing associated with endotracheal intubation. Specifically, succinylcholine, ketamine and chloral hydrate have been well documented to raise IOP. This effect is felt to be due to an increased extra-ocular muscle tone from these agents. 19 The preoperative use of atropine, scopalmine, and ephedrine associated with attacks of angle-closure glaucoma following general

The antihistamines are a diverse group of agents that can be divided into two classes the H1 and the H2 antihistamines. The H1 antihistamines block the action of histamine on capillary permeability and vascular, bronchial, and other smooth muscles.20 The H2 antihistamines block the effect of histamine on the smooth muscle in peripheral blood vessels and secretion of gastric acid. This group is important because of their anticholinergic effect of these agents. Although the anticholinergic action is mild, orphenadrine citrate (Norgesic®), an H1 antihistamine, has been documented to precipitate an attack of angle-closure glaucoma. It should also be noted that the H1 antihistamine promethazine HCl (Phenergan®) has been shown to produce an idiopathic swelling of the lens as documented with the sulfa agents. These agents exert only a weak response but should be approached with caution in the

As mentioned above ,a wide variety of agents are found as inhalation products, including sympathomimetic and parasympathomimeric agents. Salbutamol and ipratropium (used in combination for chronic obstructive airway) have also been documented to precipitate attacks of angle-closure glaucoma due to the anticholinergic effect of ipratropium in combination with the effect of salbutamol (a β2 adreno receptor agonist) on increrasing aqueous humor production.21 Therefore, these agents should be used with caution in

**5.5 The role of antiparkinsonian agents** 

**5.6 The role of antispasmolytic agents** 

**5.7 The role of anesthetic agents** 

felt to reflect the anticholinergic effect of this agent.

angle glaucoma probably because of their anticholinergic effect.

**5.8 The role of antihistamines in inducing glaucoma** 

**5.9 The role of inhalation agents in inducing glaucoma** 

patients at risk for such an attack of glaucoma.

trihexyphenidyl

anesthesia.

patient at risk for glaucoma.

#### **5.4 The role of antibiotics**

#### **Sulfa drugs**

Agents that contain sulfa have been well documented to produce an idiosyncratic swelling of the lens associated with shallowing of the anterior chamber, retinal edema, and elevated IOP. These episodes do not involve the pupil and are not responding to cycloplegic agents. This observation has been confirmed by A-scan measurements of the eye during such an attack16.

> **Antipsychotropic agents**  Phenothiazines Perphenazine (Trilafon), fluphenazine decanoate (Prolixin)

**Antidepressants**  Tricyclic agents Amitryptiline (Elavil), imipramine (Tofranil) Nontricyclic agents Fluoxetine (Prozac), mianserin HC1 (Bolvidin)

**Monoamine oxidase (MAO) inhibitors**  Phenylzine sulfate (Nardil) Tranylcypromine sulfate (Parnate)

**Antihistamines**  Ethanolamines Orphenadrine citrate (Norgesic)

**Antiparkinsonian agents**  Trihexyphenidyl HC1 (Artane)

**Antispasmolytic agents** 

Propantheline bromide (Pro-Banthine) Dicydomine HC1 (Bentyl)

**Antibiotics**  Sulfa, quinine

**Sympathomimetic agents**  Epinephrine, ephedrine Phenylephrine Amphetamine Hydroxyamphetamine

**Mydriatic agents**  All agents Surgical agents Viscoelastic agents, silicone oil

**Botulin toxin Cardiac agents**  Disopyramide phosphate (Norpace)

Table 1. Non-steroidal agents

#### **5.5 The role of antiparkinsonian agents**

552 Glaucoma - Basic and Clinical Concepts

Agents that contain sulfa have been well documented to produce an idiosyncratic swelling of the lens associated with shallowing of the anterior chamber, retinal edema, and elevated IOP. These episodes do not involve the pupil and are not responding to cycloplegic agents. This observation has been confirmed by A-scan measurements of the eye during such an

Perphenazine (Trilafon), fluphenazine decanoate (Prolixin)

Amitryptiline (Elavil), imipramine (Tofranil)

Fluoxetine (Prozac), mianserin HC1 (Bolvidin)

**Monoamine oxidase (MAO) inhibitors** 

**Antipsychotropic agents** 

Phenothiazines

**Antidepressants**  Tricyclic agents

Nontricyclic agents

**Antihistamines**  Ethanolamines

**Antibiotics**  Sulfa, quinine

Phenylephrine Amphetamine

**Botulin toxin Cardiac agents** 

Table 1. Non-steroidal agents

Phenylzine sulfate (Nardil) Tranylcypromine sulfate (Parnate)

Orphenadrine citrate (Norgesic)

Propantheline bromide (Pro-Banthine)

**Antiparkinsonian agents**  Trihexyphenidyl HC1 (Artane)

**Antispasmolytic agents** 

Dicydomine HC1 (Bentyl)

**Sympathomimetic agents**  Epinephrine, ephedrine

Hydroxyamphetamine **Mydriatic agents**  All agents Surgical agents

Viscoelastic agents, silicone oil

Disopyramide phosphate (Norpace)

**5.4 The role of antibiotics** 

**Sulfa drugs** 

attack16.

The anti-Parkinson agents act through two mechanisms: (1) Replenishing diminished stores of dopamine in the corpus striatum, and (2) Acting as a strong anticholinergic. Indeed, trihexyphenidyl

HCl (Artane)17 has been documented to precipitate angle-closure glaucoma. This finding is felt to reflect the anticholinergic effect of this agent.

#### **5.6 The role of antispasmolytic agents**

These agents act to reduce both the gastrsecretion and the motility of the stomach. Their effect directly reflects their anticholinergic power. Although no attacks of angle-closure glaucoma are documented with these agents, propantheline bromide (Pro-Banthine®) and dicyclomine HCl (Bentyl®) 18 have been documented to raise the IOP in patients with openangle glaucoma probably because of their anticholinergic effect.

#### **5.7 The role of anesthetic agents**

General anesthesia has always entailed an increased risks to the patient, including the risk of elevated IOP and glaucoma. It has always been difficult to separate the various risk factors to the patient undergoing general anesthesia. The induction of general anesthesia itself may be associated with an elevated IOP from laryngeal spasm, coughing, and wheezing associated with endotracheal intubation. Specifically, succinylcholine, ketamine and chloral hydrate have been well documented to raise IOP. This effect is felt to be due to an increased extra-ocular muscle tone from these agents. 19 The preoperative use of atropine, scopalmine, and ephedrine associated with attacks of angle-closure glaucoma following general anesthesia.

#### **5.8 The role of antihistamines in inducing glaucoma**

The antihistamines are a diverse group of agents that can be divided into two classes the H1 and the H2 antihistamines. The H1 antihistamines block the action of histamine on capillary permeability and vascular, bronchial, and other smooth muscles.20 The H2 antihistamines block the effect of histamine on the smooth muscle in peripheral blood vessels and secretion of gastric acid. This group is important because of their anticholinergic effect of these agents. Although the anticholinergic action is mild, orphenadrine citrate (Norgesic®), an H1 antihistamine, has been documented to precipitate an attack of angle-closure glaucoma. It should also be noted that the H1 antihistamine promethazine HCl (Phenergan®) has been shown to produce an idiopathic swelling of the lens as documented with the sulfa agents. These agents exert only a weak response but should be approached with caution in the patient at risk for glaucoma.

#### **5.9 The role of inhalation agents in inducing glaucoma**

As mentioned above ,a wide variety of agents are found as inhalation products, including sympathomimetic and parasympathomimeric agents. Salbutamol and ipratropium (used in combination for chronic obstructive airway) have also been documented to precipitate attacks of angle-closure glaucoma due to the anticholinergic effect of ipratropium in combination with the effect of salbutamol (a β2 adreno receptor agonist) on increrasing aqueous humor production.21 Therefore, these agents should be used with caution in patients at risk for such an attack of glaucoma.

Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications) 555

anti-inflammatory activity to treat the patient's underlying condition. In the occasional cases in which the patient's IOP does not normalize upon the cessation of the steroid or in those patients who must continue with treatment, topical anti-glaucoma medications are

If the etiology of closed angle glaucoma is sulfa containing medications, the increase in IOP generally will resolve upon discontinuing the agent. However, severe cases of sulfonamideinduced angle-closure (i.e. IOP >45 mm Hg) may not respond to discontinuing the offending agent. They may respond to intravenous mannitol. Other etiologies of drug-induced angleclosure are treated similar to primary acute angle-closure glaucoma with topical betablockers, prostaglandin analogues, cholinergic agonists and often oral acetazolamide.

For open-angle steroid-induced glaucoma, selective laser trabeculoplasty or Argon laser trabeculoplasty (Fig. 3) can be applied in the absence of intraocular inflammation if the IOP

In closed-angle glaucoma, an Argon laser peripheral iridoplasty or YAG laser iridotomy may be performed to widen the angle and deepen the anterior chamber. Laser iridotomy can be performed to reverse pupillary block or to prevent further pupillary block. Laser Irididotomies can be performed as a preventive procedure in hepermetropic naophthalmic and microphthalmic eyes. Fig. 4 shows the effect of Argon laser laser iridotomy. When medical and laser therapy are ineffective in lowering the IOP to target pressure or the patient is intolerant to medical therapy, surgical therapy is indicated. Usually, trabeculectomy, a guarded filtration procedure, with or without intraoperative anti-metabolites, is the primary procedure. In cases of eyes with active neovascularization or inflammation, a

glaucoma drainage implant may be used as the primary procedure.

considered.

**6.2 Medical: Closed-angle** 

**6.3 Laser treatment**

is suboptimal with medication.

Fig. 2. ALT Argon Laser Trabeculoplasy

#### **5.10 The role of cardiac agents in inducing glaucoma**

The traditional cardiac agents including digitalis and quinidine do not appear to have any effect on the IOP. However, disopyramide phosphate (Norpace®) does appear to have some anticholinergic activity and has indeed been documented to produce an attack of angleclosure glaucoma.22

#### **5.11 The role of botulinum toxin (Oculinum)**

Botulinum toxin has become popular for the treatment of essential blepharo-spasm and extraocular muscle palsy; this injectable agent has been documented to produce an acute attack of angle closure glaucoma. The effect of this drug is on the ciliary ganglion, producing pupillarymydriasis.23

#### **5.12 The role of avastin and lucentis**

A series of patients that developed sustained elevation of intraocular pressure (IOP) after intravitreal anti-VEGF injection for the treatment of neovascular age-related macular degeneration (AMD) is presented un numerous of recent publications24 IOP reflects a balance between the rate that fluid flows into the eye and the rate that it exits the eye. If inflow increases or outflow decreases, then IOP will go up. Intravitreal injection of drugs, such as Lucentis (ranibizumab) or Avastin (bevacizumab), increases the amount of fluid within the eye, and hence will increase IOP. Normally, as the excess fluid gradually exits the eye over a period of time, the IOP returns to normal. However, there are a growing number of cases of patients undergoing Lucentis and Avastin therapy that develop elevation of IOP that does not return to normal.

In a recent study four out of 116 patients with AMD (3.45%) developed sustained elevated intraocular pressure (IOP) after multiple intravitreal injections of Avastin (1.5 mg/0.06 mL) and/or Lucentis (0.5 mg/0.05 mL). An analysis of 4 cases revealed: None of the patients had a previous diagnosis or family history of glaucoma/OHT. Two patients had both bevacizumab and ranibizumab injections. Two patients developed OHT after recent intravitreal ranibizumab and 2 patients after recent intravitreal Avastin injection. It appears that anti-VEGF drugs may, in some persons, lead to sustained elevation of IOP and possible glaucoma. It is not clear why this occurs, nor have any risk factors for this adverse effect, such as family history of glaucoma, been identified. Nor is it clear whether the IOP elevation is permanent, or whether IOP may return to normal after cessation of anti-VEGF injections. Glaucoma medications can lower IOP after it has been elevated by anti-VEGF drug use.

There are some publictions25 which describe the decrease of rubeosis iridis in patients with neo-vascular after intra- vitreal Avastin injection and can lead to decrease in IOP within 48 hours.

#### **6. Treatment of drug-induced glaucoma**

#### **6.1 Medical: Open-angle**

If the patient's underlying medical condition can tolerate discontinuation of corticosteroids, then its discontinuation will usually result in normalization of IOP. In case of topical corticosteroid drops, using a lower potency steroid medication, such as the phosphate forms of prednisolone and dexamethasone, loteprednol etabonate or fluorometholone should be considered. These drugs have a lesser chance to increase the IOP, but they are usually not as effective as others. Topical non-steroidal anti-inflammatory medications (e.g., diclofenac, ketorolac) are other alternatives do not cause IOP elevation, but they have only a limited anti-inflammatory activity to treat the patient's underlying condition. In the occasional cases in which the patient's IOP does not normalize upon the cessation of the steroid or in those patients who must continue with treatment, topical anti-glaucoma medications are considered.

#### **6.2 Medical: Closed-angle**

554 Glaucoma - Basic and Clinical Concepts

The traditional cardiac agents including digitalis and quinidine do not appear to have any effect on the IOP. However, disopyramide phosphate (Norpace®) does appear to have some anticholinergic activity and has indeed been documented to produce an attack of angle-

Botulinum toxin has become popular for the treatment of essential blepharo-spasm and extraocular muscle palsy; this injectable agent has been documented to produce an acute attack of angle closure glaucoma. The effect of this drug is on the ciliary ganglion,

A series of patients that developed sustained elevation of intraocular pressure (IOP) after intravitreal anti-VEGF injection for the treatment of neovascular age-related macular degeneration (AMD) is presented un numerous of recent publications24 IOP reflects a balance between the rate that fluid flows into the eye and the rate that it exits the eye. If inflow increases or outflow decreases, then IOP will go up. Intravitreal injection of drugs, such as Lucentis (ranibizumab) or Avastin (bevacizumab), increases the amount of fluid within the eye, and hence will increase IOP. Normally, as the excess fluid gradually exits the eye over a period of time, the IOP returns to normal. However, there are a growing number of cases of patients undergoing Lucentis and Avastin therapy that develop elevation of IOP

In a recent study four out of 116 patients with AMD (3.45%) developed sustained elevated intraocular pressure (IOP) after multiple intravitreal injections of Avastin (1.5 mg/0.06 mL) and/or Lucentis (0.5 mg/0.05 mL). An analysis of 4 cases revealed: None of the patients had a previous diagnosis or family history of glaucoma/OHT. Two patients had both bevacizumab and ranibizumab injections. Two patients developed OHT after recent intravitreal ranibizumab and 2 patients after recent intravitreal Avastin injection. It appears that anti-VEGF drugs may, in some persons, lead to sustained elevation of IOP and possible glaucoma. It is not clear why this occurs, nor have any risk factors for this adverse effect, such as family history of glaucoma, been identified. Nor is it clear whether the IOP elevation is permanent, or whether IOP may return to normal after cessation of anti-VEGF injections. Glaucoma medications can lower IOP after it has been elevated by anti-VEGF drug use. There are some publictions25 which describe the decrease of rubeosis iridis in patients with neo-vascular after intra- vitreal Avastin injection and can lead to decrease in IOP within 48

If the patient's underlying medical condition can tolerate discontinuation of corticosteroids, then its discontinuation will usually result in normalization of IOP. In case of topical corticosteroid drops, using a lower potency steroid medication, such as the phosphate forms of prednisolone and dexamethasone, loteprednol etabonate or fluorometholone should be considered. These drugs have a lesser chance to increase the IOP, but they are usually not as effective as others. Topical non-steroidal anti-inflammatory medications (e.g., diclofenac, ketorolac) are other alternatives do not cause IOP elevation, but they have only a limited

**5.10 The role of cardiac agents in inducing glaucoma** 

**5.11 The role of botulinum toxin (Oculinum)** 

producing pupillarymydriasis.23

that does not return to normal.

**6. Treatment of drug-induced glaucoma**

**6.1 Medical: Open-angle**

hours.

**5.12 The role of avastin and lucentis** 

closure glaucoma.22

If the etiology of closed angle glaucoma is sulfa containing medications, the increase in IOP generally will resolve upon discontinuing the agent. However, severe cases of sulfonamideinduced angle-closure (i.e. IOP >45 mm Hg) may not respond to discontinuing the offending agent. They may respond to intravenous mannitol. Other etiologies of drug-induced angleclosure are treated similar to primary acute angle-closure glaucoma with topical betablockers, prostaglandin analogues, cholinergic agonists and often oral acetazolamide.

#### **6.3 Laser treatment**

For open-angle steroid-induced glaucoma, selective laser trabeculoplasty or Argon laser trabeculoplasty (Fig. 3) can be applied in the absence of intraocular inflammation if the IOP is suboptimal with medication.

In closed-angle glaucoma, an Argon laser peripheral iridoplasty or YAG laser iridotomy may be performed to widen the angle and deepen the anterior chamber. Laser iridotomy can be performed to reverse pupillary block or to prevent further pupillary block. Laser Irididotomies can be performed as a preventive procedure in hepermetropic naophthalmic and microphthalmic eyes. Fig. 4 shows the effect of Argon laser laser iridotomy. When medical and laser therapy are ineffective in lowering the IOP to target pressure or the patient is intolerant to medical therapy, surgical therapy is indicated. Usually, trabeculectomy, a guarded filtration procedure, with or without intraoperative anti-metabolites, is the primary procedure. In cases of eyes with active neovascularization or inflammation, a glaucoma drainage implant may be used as the primary procedure.

Fig. 2. ALT Argon Laser Trabeculoplasy

Drug-Induced Glaucoma (Glaucoma Secondary to Systemic Medications) 557

drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H(1) and H(2) receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber. In some instances, bilateral simultaneous development of acute ACG occurs after carbamazepine and topiramate intake may occur especially in eyes with short axial length such as hypermetropia, microphthalmia and nanophthalmos. Clinicians should be mindful of the possibility of drug-induced glaucoma, whether or not the drug is listed as a contraindication and if in doubt, consult an ophthalmologist. Patients should visit an ophthalmologist routinely twice a year after the

[1] Matz T, Abbott L. Bilateral acute angle-closure glaucoma. *Resident and Staff Physician*

[2] Kakaria V, Chalam, Tillis T, Farhana S, Brar SA. Acute bilateral simultaneous angle

[3] GuMHP, Thiagalingam S, Ong P, Goldberg I. Bilateral acute angle closure caused by supraciliary effusion associated with Velafaxine intake. *MJA* 2005; 182:121-123. [4] Nemet A, Nesher R, Almog Y, Assia E. Bilateral acute angle closure glaucoma following

[5] Ates H.; Kay O., Lu K., Andac K. Bilateral angel closure glaucoma following general

[6] Singh SK, Thapa SS, Badhu BP. Topiramate induced bilateral angle-closure glaucoma.

[7] Lachkar Y, Bouassida W. Drug-induced acute angle closure glaucoma. *Curr Opin* 

[8] Chan KCY, Sachdev N, Wells AP. Bilateral acute angle closure secondary to uveal

[9] Levy J, Yagev R, Petrova A, Lifshitz T. Topiramate – induced bilateral angle-closure

[12] Arnnaly MF. Statistical attributes of the steroid hypertensive response in the clinically

[13] Stewart RH, Kimbrough RL .Intraocular pressure response to topically administered

[14] Mandelkom R. Drug induced Glaucoma, clinical pathway in glaucoma, in :Zimmerman and Kooner, New York: Thieme Medical Publishers inc. 2001 350-333

[10] Sean Sweetman (Ed.). Martindale-the complete drug reference, 36th edition, 471-477. [11] Brockhurst RJ. Nanophthalmos with uveal effusion: A new clinical entity. *Trans Am* 

effusions associated with Flucloxacillin and Carbamazepine. *Br J Ophthalmol* 2008;

normal eye. I. the demonstration of three levels of response. *Invest Ophthalmol* 1965;

closure glaucoma Topiramate administration: a case report. *J Med Case Reports* 2008;

age of 40 and inform him about their different medications.

I acknowledge the support of Tradis Gat Ltd. in publication of this chapter.

Topiramate treatment. *Harefuah* 2002; 141:597-9.

*Kathmandu University Medical Journal* 2007; 5:234-.

glaucoma. *Can J Ophthalmol* 2006; 41:221-5.

fluorometholone. *Arch. Ophthalmol* 1979; 97:2139.

*Ophthalmol* 2007; 18:129-33.

*Ophthalmol Soc* 1974; 72:371-403.

anesthesia: *International Ophthalmology* 1999; 23:129-30.

**9. Acknowledgment** 

2008; 54:3.

92:428-430.

4:187.

**10. References** 

2:1.

Fig. 3. LI Laser Iridotomy

#### **6.4 Surgical: Closed-angle**

Trabeculectomy can also be performed with similar indications as open-angle glaucoma. However, the surgery is more difficult since the anterior chamber is shallower and the cornea is usually hazier due to the acute IOP rise.

#### **7. Prevention of drug induced glaucoma**

#### **7.1 Open-angle**

Unnecessary prolonged use of cortcosteroid should be avoided. Ophthalmic evaluation is recommended for patients treated with long-term steroids especially with risk factors such as family history of primary open-angle glaucoma.

#### **7.2 Closed-angle**

Prophylactic laser iridotomy may be performed in patients requiring frequent mydriasis such as frequent fundus examinations for diabetic retinopathy. Agents causing secondary angle-closure should be avoided in susceptible individuals as far as possible.

#### **8. Conclusion**

Drugs that cause or exacerbate open-angle glaucoma are mostly glucocorticoids. Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H(1) and H(2) receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber. In some instances, bilateral simultaneous development of acute ACG occurs after carbamazepine and topiramate intake may occur especially in eyes with short axial length such as hypermetropia, microphthalmia and nanophthalmos. Clinicians should be mindful of the possibility of drug-induced glaucoma, whether or not the drug is listed as a contraindication and if in doubt, consult an ophthalmologist. Patients should visit an ophthalmologist routinely twice a year after the age of 40 and inform him about their different medications.

#### **9. Acknowledgment**

I acknowledge the support of Tradis Gat Ltd. in publication of this chapter.

#### **10. References**

556 Glaucoma - Basic and Clinical Concepts

Trabeculectomy can also be performed with similar indications as open-angle glaucoma. However, the surgery is more difficult since the anterior chamber is shallower and the

Unnecessary prolonged use of cortcosteroid should be avoided. Ophthalmic evaluation is recommended for patients treated with long-term steroids especially with risk factors such

Prophylactic laser iridotomy may be performed in patients requiring frequent mydriasis such as frequent fundus examinations for diabetic retinopathy. Agents causing secondary

Drugs that cause or exacerbate open-angle glaucoma are mostly glucocorticoids. Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based

angle-closure should be avoided in susceptible individuals as far as possible.

Fig. 3. LI Laser Iridotomy

**6.4 Surgical: Closed-angle**

**7.1 Open-angle**

**7.2 Closed-angle**

**8. Conclusion**

cornea is usually hazier due to the acute IOP rise.

**7. Prevention of drug induced glaucoma** 

as family history of primary open-angle glaucoma.


**1. Introduction** 

**2. Epidemiology** 

of administration: topical, systemic or inhaled.

**29** 

*Israel* 

Avraham Cohen *Western Galilee Hospital, Department Of Ophthalmology* 

**Steroid Induced Glaucoma** 

Increased intraocular pressure and glaucoma following corticosteroid therapy are well known issues for the ophthalmologist for more than 50 years. Corticosteroids use has gained popularity in ophthalmology as anti-inflammatory and anti-allergic agents but can have important consequences and should be used only with judicious monitoring. The therapeutic use of corticosteroids can lead to the development of ocular hypertension and iatrogenic open-angle glaucoma in susceptible individuals. It can occur in any age group, either gender and from steroid therapy for any ocular or systemic disease and by any route

About one in every three people is considered a potential "steroid responder", but only a small percentage will have a clinically significant elevation in intraocular pressure. 5-6% of the normal population develops a marked increase in intraocular pressure of more than 31 mmHg after 4-6 weeks of topical corticosteroids therapy. 33% are moderate responders (elevation of 6-15 mmHg) and the remaining are considered non responreds (less than 6mmHg of elevation in intraocular pressure). Although approximately 30%–40% of the normal population are "steroid responders" (i.e., develop reversible steroid-induced ocular hypertension), most of primary open angle glaucoma patients or with a family history are steroid responders. Normal individuals who are steroid responders are at higher risk for subsequently developing primary open angle glaucoma. In one study, high corticosteroid responders (intraocular pressure greater than 31 mm Hg during dexamethasone administration qid for 6 weeks), 13.0% developed glaucomatous visual field loss during the follow-up period of 5 years. In steroid induced glaucoma patients, glaucoma is triggered by steroid treatment, and intraocular pressure will not decrease after cessation of steroid application. Thus, steroid induced glaucoma patients necessitate anti-glaucoma medications to control intraocular pressure. Steroid responsiveness appears to be heritable, however low concordance of pressure response in monozygotic twins to topical testing may indicate a limited role for a genetic basis. In addition highly myopic patients and diabetic patients

have a higher rate of elevated intraocular pressure response to topical steroids.

Age is also an important factor. In pediatric patients taking oral prednisone for inflammatory bowel disease 32% were steroid responders. When children younger than 10 years of age where treated with topical instillation of dexamethasone, marked elevation in


### **Steroid Induced Glaucoma**

#### Avraham Cohen

*Western Galilee Hospital, Department Of Ophthalmology Israel* 

#### **1. Introduction**

558 Glaucoma - Basic and Clinical Concepts

[15] Kinek M .Glaucoma following the antidepressant mianserin. Harefuah 1990:118-699. [16] Hook SR, Holladay JI, Perager TC, Goosey JD. Transient myopia induced by

[17] Friedman Z, Neuman E. Benzhexalol induced blindness in Parkinson's disease. *Br Med J*

[18] Mody MV, Keeney AH. Propantheline (probanthine) bromide in relation to normal and

[19] Katz RI, Eakins KB. Mode of action of succinylcholine on intraocular pressure.

[20] Bard L.A. Transient myopia associated with promethazine (phenergan) therapy: report

[21] Malawi JT, Rhobinson GM, Seneviratne H. Ipratropium bromide induced angle closure

[22] Monica ML, Hesse RJ, Messerli FH .The effect of a calcium channel blocking agent on

[23] Kupfer C. Selective block of synaptic transmission in ciliary ganglion by type A

[24] Adelman RA, Zheng Q. Mayer HR. Persistent ocular hypertension following intravitreal

[25] Milko E. Iliev, Diego Doming, Ute , Sebastin Wolf, Intravitreal Bevacizumab (Avastin®)

bevacizumab and ranibizumab injections. *J Ocul Pharmacol Ther*. 2010 Feb; 26(1):105-

in the Treatment of Neovascular Glaucoma. *AJO* Volume 142, Pages 1054-56, Dec.

glaucomatous eyes: effects on intraocular tension and pupillary size. *JAMA* 1955;

sulphonamides. *Am J Ophthalmol* 1986; 101:495.

*J Pharmacol Exp Ther* 1968; 162:1.

of a case. *Am J Ophthalmol* 1964; 58:682?

glaucoma (letter). *NZ Med J* 1982; 95:759.

intraocular pressure. *AM J Ophthalmol* 1983; 96:814.

botulinum toxin in Rabbits. *Proc Soc Exp Biol Med* 1958; 99:474.

1972; 1:605.

159:1113.

10.

2006.

Increased intraocular pressure and glaucoma following corticosteroid therapy are well known issues for the ophthalmologist for more than 50 years. Corticosteroids use has gained popularity in ophthalmology as anti-inflammatory and anti-allergic agents but can have important consequences and should be used only with judicious monitoring. The therapeutic use of corticosteroids can lead to the development of ocular hypertension and iatrogenic open-angle glaucoma in susceptible individuals. It can occur in any age group, either gender and from steroid therapy for any ocular or systemic disease and by any route of administration: topical, systemic or inhaled.

#### **2. Epidemiology**

About one in every three people is considered a potential "steroid responder", but only a small percentage will have a clinically significant elevation in intraocular pressure. 5-6% of the normal population develops a marked increase in intraocular pressure of more than 31 mmHg after 4-6 weeks of topical corticosteroids therapy. 33% are moderate responders (elevation of 6-15 mmHg) and the remaining are considered non responreds (less than 6mmHg of elevation in intraocular pressure). Although approximately 30%–40% of the normal population are "steroid responders" (i.e., develop reversible steroid-induced ocular hypertension), most of primary open angle glaucoma patients or with a family history are steroid responders. Normal individuals who are steroid responders are at higher risk for subsequently developing primary open angle glaucoma. In one study, high corticosteroid responders (intraocular pressure greater than 31 mm Hg during dexamethasone administration qid for 6 weeks), 13.0% developed glaucomatous visual field loss during the follow-up period of 5 years. In steroid induced glaucoma patients, glaucoma is triggered by steroid treatment, and intraocular pressure will not decrease after cessation of steroid application. Thus, steroid induced glaucoma patients necessitate anti-glaucoma medications to control intraocular pressure. Steroid responsiveness appears to be heritable, however low concordance of pressure response in monozygotic twins to topical testing may indicate a limited role for a genetic basis. In addition highly myopic patients and diabetic patients have a higher rate of elevated intraocular pressure response to topical steroids.

Age is also an important factor. In pediatric patients taking oral prednisone for inflammatory bowel disease 32% were steroid responders. When children younger than 10 years of age where treated with topical instillation of dexamethasone, marked elevation in

Steroid Induced Glaucoma 561

an abnormal accumulation of dihydrocortisol may potentiate exogenous glucocorticosteroids

Changes in protein synthesis have also been implicated in steroid induced glaucoma. *MYOC* gene, located on chromosome 1, encodes a secretory glycoprotein of 504 amino acids named Myocilin, and is the first gene to be linked to juvenile open-angle glaucoma and some forms of adult-onset primary open-angle glaucoma. The gene was identified as an up regulated molecule in cultured trabecular meshwork cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (*TIGR*). Interestingly, the profile of *MYOC* up regulation by dexamethasone is in a dose- and timedependent manner very similar to the course of development of steroid induced glaucoma. This led many investigators to believe that an increased *MYOC* level is a cause of glaucoma. However, a putative association between *MYOC* induction and primary open angle

Glucocorticosteroids inhibit prostaglandin synthesis by trabecular cells. Prostaglandins E2 and F2a normal function is to lower the intraocular pressure by increasing the outflow facility. Endothelial cells of the trabecular meshwork can act as phagocytes of debris. Glucocorticosteroids can suppress phagocytic activity causing accumulation of debris in the

In a study on rabbit eyes, after topical treatment with dexamethasone, Transmission electron microscopy showed increased abnormality of nucleus of the trabecular meshwork cells, microfilament and microtubules among interstitial cells also increased, cytoplasmic vacuolation, rough endoplasmic reticulum expansion, as well as an increase in intercellular amorphous material. The mechanism of elevated intraocular pressure is thought to be increased aqueous outflow resistance owing to an accumulation of extracellular matrix

Fig. 1. Light microscopic pictures of the trabecular meshwork from steroid-induced glaucoma (SG). a) (Right eye in case 1), b) (Case 2): Schlemm's canal (SC) is open. The intertrabescular spaces in the outer part of the TM are filled with the homogeneous

extracellular matrix (ECM) (asterisks). Azure II staining. Scale bars indicate 50 μm for a) and

Effects of Glucocorticosteroids are mediated by the Glucocorticosteroids receptor, which is a ligand-dependent transcription factor altering the expression of trabecular meshwork genes. Glucocorticosteroids increase the expression of extracellular matrix (collagen, fibronectin, laminin), proteinase inhibitor genes (Serpina3) and decreased expression of proteinase genes (MMP1, TPA). Altered expression of cytoskeletal genes (ACTA2, FLNB, and NEBL) may be associated with Glucocorticosteroids mediated reorganization of trabecular meshwork cell

activity and increased intraocular pressure.

glaucoma has not been firmly established.

material in the trabecular meshwork (fig 1).

20 μm for b)

trabecular meshwork and decrease in outflow facility.

intraocular pressure was noted. A dose-dependent hypertensive pressure response occurs more frequently, more severely and more rapidly in children than in adults.

#### **3. Pathophysiology**

There have been reports suggesting that endogenous cortisol may play a role in the pathogenesis of primary open angle glaucoma. Excess endogenous production of glucocorticosteroids (Cushing's syndrome) can also cause increase in intraocular pressure.

Glucocorticosteroids alter several trabecular meshwork cellular functions including inhibition of cellular proliferation, migration, phagocytosis, and increased cell and nucleus size. Glucocorticosteroids also increase extracellular matrix synthesis and decrease its turnover.

Many mechanisms have been proposed to explain the elevated intraocular pressure in response to glucocorticosteroids. One hypothesis is that glucocorticosteroids protect the lysosomal membrane and thus inhibit release of hydrolases responsible of depolimerization of glycosaminoglycans. Accumulated glycosaminoglycans in the ground substance of the outflow pathways retain water and narrow the trabecular spaces, causing increase in outflow resistance. In steroid-induced glaucoma there is also an increase in fine fibrillar material in the subendothelial region of Schlemm's cannal. These fibrils are deposited underneath the inner wall endothelium. The main finding in steroid-induced glaucoma is an accumulation of basement membrane-like material staining for type IV collagen. These accumulations are found throughout all layers of the trabecular meshwork.

There are multiple isoforms of the glucocorticoid receptor (GR) a ligand-dependent transcriptional factor that activates or represses gene transcription. GRα is the ligand binding form of the receptor that is responsible for the physiologic and pharmacological effects of glucocorticosteroids. Most of the physiological and pharmacological effects of glucocorticosteroids are directly mediated by GRα. GRα resides predominantly in the cytoplasm in the absence of ligand as a multiprotein heterocomplex that contains Hsp 90, Hsp 70 and other proteins. Steroid binding to GRα causes a conformation change and activation of the receptor. Activated GRα can alter gene expression via GRE-dependent (classical) and GRE-independent (nonclassical) mechanisms. In the GRE-dependent pathway activated GRα translocates to the nucleus along microtubules. GRα bind to specific palindromic DNA sequence (GRE) as a homodimer on the promoter region of target genes to induce transcription. In addition, GRα functions as a negative regulator of transcription in a specific subset of genes that contains a negative GRE. The GRE-independent pathway is an additional way to inhibit gene expression. GRα physically interacts with other transcription factors to prevent them from binding to their response elements of genes that encode for proinflammatory cytokines. The anti-inflammatory and immune suppression are mediated via this GRE-independent pathway. GRβ is an alternatively spliced form of the receptor, that resides in the nucleus, which lacks the conventional ligand binding domain, does not bind glucocorticosteroids, and acts as a dominant negative regulator of glucocorticosteroids activity. Increased expression of GRβ appears to be responsible for unresponsiveness to anti-inflammatory therapy for asthma, inflammatory bowel disease rheumatoid arthritis and ulcerative colitis. Recent work has shown that glaucomatous trabecular meshwork cells have lower levels of GRβ compared with normal trabecular meshwork cells, and this appears to be responsible for increased glucocorticosteroids sensitivity in the glaucomatous trabecular meshwork cells. In primary open angle glaucoma

intraocular pressure was noted. A dose-dependent hypertensive pressure response occurs

There have been reports suggesting that endogenous cortisol may play a role in the pathogenesis of primary open angle glaucoma. Excess endogenous production of glucocorticosteroids (Cushing's syndrome) can also cause increase in intraocular pressure. Glucocorticosteroids alter several trabecular meshwork cellular functions including inhibition of cellular proliferation, migration, phagocytosis, and increased cell and nucleus size. Glucocorticosteroids also increase extracellular matrix synthesis and decrease its

Many mechanisms have been proposed to explain the elevated intraocular pressure in response to glucocorticosteroids. One hypothesis is that glucocorticosteroids protect the lysosomal membrane and thus inhibit release of hydrolases responsible of depolimerization of glycosaminoglycans. Accumulated glycosaminoglycans in the ground substance of the outflow pathways retain water and narrow the trabecular spaces, causing increase in outflow resistance. In steroid-induced glaucoma there is also an increase in fine fibrillar material in the subendothelial region of Schlemm's cannal. These fibrils are deposited underneath the inner wall endothelium. The main finding in steroid-induced glaucoma is an accumulation of basement membrane-like material staining for type IV collagen. These

There are multiple isoforms of the glucocorticoid receptor (GR) a ligand-dependent transcriptional factor that activates or represses gene transcription. GRα is the ligand binding form of the receptor that is responsible for the physiologic and pharmacological effects of glucocorticosteroids. Most of the physiological and pharmacological effects of glucocorticosteroids are directly mediated by GRα. GRα resides predominantly in the cytoplasm in the absence of ligand as a multiprotein heterocomplex that contains Hsp 90, Hsp 70 and other proteins. Steroid binding to GRα causes a conformation change and activation of the receptor. Activated GRα can alter gene expression via GRE-dependent (classical) and GRE-independent (nonclassical) mechanisms. In the GRE-dependent pathway activated GRα translocates to the nucleus along microtubules. GRα bind to specific palindromic DNA sequence (GRE) as a homodimer on the promoter region of target genes to induce transcription. In addition, GRα functions as a negative regulator of transcription in a specific subset of genes that contains a negative GRE. The GRE-independent pathway is an additional way to inhibit gene expression. GRα physically interacts with other transcription factors to prevent them from binding to their response elements of genes that encode for proinflammatory cytokines. The anti-inflammatory and immune suppression are mediated via this GRE-independent pathway. GRβ is an alternatively spliced form of the receptor, that resides in the nucleus, which lacks the conventional ligand binding domain, does not bind glucocorticosteroids, and acts as a dominant negative regulator of glucocorticosteroids activity. Increased expression of GRβ appears to be responsible for unresponsiveness to anti-inflammatory therapy for asthma, inflammatory bowel disease rheumatoid arthritis and ulcerative colitis. Recent work has shown that glaucomatous trabecular meshwork cells have lower levels of GRβ compared with normal trabecular meshwork cells, and this appears to be responsible for increased glucocorticosteroids sensitivity in the glaucomatous trabecular meshwork cells. In primary open angle glaucoma

more frequently, more severely and more rapidly in children than in adults.

accumulations are found throughout all layers of the trabecular meshwork.

**3. Pathophysiology** 

turnover.

an abnormal accumulation of dihydrocortisol may potentiate exogenous glucocorticosteroids activity and increased intraocular pressure.

Changes in protein synthesis have also been implicated in steroid induced glaucoma. *MYOC* gene, located on chromosome 1, encodes a secretory glycoprotein of 504 amino acids named Myocilin, and is the first gene to be linked to juvenile open-angle glaucoma and some forms of adult-onset primary open-angle glaucoma. The gene was identified as an up regulated molecule in cultured trabecular meshwork cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (*TIGR*). Interestingly, the profile of *MYOC* up regulation by dexamethasone is in a dose- and timedependent manner very similar to the course of development of steroid induced glaucoma. This led many investigators to believe that an increased *MYOC* level is a cause of glaucoma. However, a putative association between *MYOC* induction and primary open angle glaucoma has not been firmly established.

Glucocorticosteroids inhibit prostaglandin synthesis by trabecular cells. Prostaglandins E2 and F2a normal function is to lower the intraocular pressure by increasing the outflow facility. Endothelial cells of the trabecular meshwork can act as phagocytes of debris. Glucocorticosteroids can suppress phagocytic activity causing accumulation of debris in the trabecular meshwork and decrease in outflow facility.

In a study on rabbit eyes, after topical treatment with dexamethasone, Transmission electron microscopy showed increased abnormality of nucleus of the trabecular meshwork cells, microfilament and microtubules among interstitial cells also increased, cytoplasmic vacuolation, rough endoplasmic reticulum expansion, as well as an increase in intercellular amorphous material. The mechanism of elevated intraocular pressure is thought to be increased aqueous outflow resistance owing to an accumulation of extracellular matrix material in the trabecular meshwork (fig 1).

Fig. 1. Light microscopic pictures of the trabecular meshwork from steroid-induced glaucoma (SG). a) (Right eye in case 1), b) (Case 2): Schlemm's canal (SC) is open. The intertrabescular spaces in the outer part of the TM are filled with the homogeneous extracellular matrix (ECM) (asterisks). Azure II staining. Scale bars indicate 50 μm for a) and 20 μm for b)

Effects of Glucocorticosteroids are mediated by the Glucocorticosteroids receptor, which is a ligand-dependent transcription factor altering the expression of trabecular meshwork genes. Glucocorticosteroids increase the expression of extracellular matrix (collagen, fibronectin, laminin), proteinase inhibitor genes (Serpina3) and decreased expression of proteinase genes (MMP1, TPA). Altered expression of cytoskeletal genes (ACTA2, FLNB, and NEBL) may be associated with Glucocorticosteroids mediated reorganization of trabecular meshwork cell

Steroid Induced Glaucoma 563

intraocular pressure lowering medications during the 12 months study. In patient with central retinal vein occlusion 35% of the patients receiving 4 mg triamcinolone acetonide initiated glaucoma medications. Ozurdex is a slow release intravitreal implant of dexamethasone currently under clinical trials for the treatment of macular edema in retinal vein occlusion disease. It appears that the dexamethasone implant is well tolerated, producing transient, moderate and readily managed increase in intraocular pressure in less

Subconjunctival, sub-Tenon and retrobulbar injections of triamcinolone acetonide may cause dangerous and prolonged elevation of intraocular pressure because of their long duration of action. Surgical excision of sub-Tenon triamcinolone acetonide deposit should be considered if the primary treatment for steroid-induced glaucoma is refractory to medical treatment. The application of topical corticosteroids to the eyelids and periorbital region, in the treatment of atopic dermatitis, even over long periods of time, was not related to the

Systemic administration includes ingestion, inhalation and nasal spray. It is less likely to cause intraocular elevation. However, intraocular pressure may rise weeks to years after treatment. When administrated concurrently with topical steroids it may have an additive

Intranasal corticosteroids have become a gold standard in therapy for allergic rhinoconjunctivitis and recent evidence indicates that may be effective at alleviating ocular symptoms as well. Intranasal corticosteroids are absorbed systemically in small measurable amounts. Some studies suggest a relationship between intranasal steroids and increased

Aerosolized drugs delivered with a facemask may inadvertently deposit in the eyes, raising concerns about ocular side effects. Inhaled corticosteroids have been associated with an increased risk of skin thinning, bruising, cataracts and possibly glaucoma in adults. The risks increase with advanced age, higher doses, and longer duration of use. In children, the risks of cataracts and glaucoma were negligible with inhaled corticosteroids, whether a mouthpiece or a mask interface was used. It is not known whether exposed children will have increased risks from inhaled corticosteroids later in life. Therefore, it is wise to avoid face and eye deposition when possible, to use the minimally effective dose and a regular

Elevated blood levels of corticosteroids of endogenous production, as seen in adrenal hyperplasia or neoplasia (Cushing syndrome) can also cause increase in the intraocular pressure. After adrenalectomy, increased intraocular pressure may retune to normal values

An increase in intraocular pressure may occur days to weeks and even months after the administration of steroids. The increase in intraocular pressure depends on potency, penetration, frequency and route of administration. Individual susceptibility, older age and

than 16% of eyes.

**4.3 Periocular route** 

**4.4 Systemic route** 

intraocular pressure.

follow up of intraocular pressure.

**4.5 Endogenous route** 

**5. Clinical course** 

development of glaucoma or cataracts.

effect and higher intraocular pressure than a single route.

microfibrils and microtubules. Glucocorticosteroids reorganizes the actin cytoskeleton to form cross-linked actin networks (CLANs) in cultured trabecular meshwork cells, and is reversible after Glucocorticosteroids withdrawel. In addition Glucocorticosteroids alters microtubules to form microtubule tangles.

#### **4. Routes of corticosteroid administration**

#### **4.1 Topical route**

Topical route includes ocular drops and ointments. Of various routes of administration, topical therapy most commonly induces elevated intraocular pressure and correlates with the duration and frequency of administration. Dexamethasone and prednisolone increase intraocular pressure more frequently than loteprendol (Lotemax), fluorometholone (FML), rimexolone (Vexol) or hydrocortisone. Fluorometholone (FML) in particular is less likely to increase intraocular pressure but is also a less potent steroid (table 1). Rimexolone has a low intraocular pressure elevating potential comparable to that of fluorometholone in adults. The chemical structure is responsible to the lower propensity to increase intraocular pressure of some steroids. Loteprendol is a site-active steroid that contains an ester rather than a ketone group at the C-20 position, rendering de-esterification to an inactive metabolite. It is highly lipid-soluble, with enhanced penetration into cells. Loteprendol appears to have an improved safety profile compared with ketone corticosteroids. Fluorometholone is deoxygenized at the C-21 position. Rimexolone lacks a hydroxyl substituent at the C-21 position. It has lower aqueous solubility and increased lipophilicity. It appears that the potency of topical steroids is directly correlated with the propensity to elevate intraocular pressure. Intraocular pressure elevation almost never occurs in less than 5 days and rarely in less than 2 weeks of steroid treatment. However, late rise in ocular pressure is not uncommon, even if intraocular pressure has been within normal limits during a treatment course of 6 weeks.

#### **4.2 Intraocular route**

Before the advent of anti VEGF, intravitreal steroid injections have been used largely in the treatment of exudative age related macular degeneration, chronic cystoid macular edema, proliferative diabetic vitreoretinopathy, retinal vascular occlusion and chronic uveitis. Rise in intraocular pressure is dependent on dose, presence of aphakia or pseudophkaia and a history of vitrectomy, facilitating penetration of the drug into the anterior segment. Intraocular pressure may rise in 30-50 % of patients as soon as 1-4 weeks after intravitreal injection of triamcinolone acetonide (Kenalog) and often returns to baseline several months after injection. It is advisable to perform a trial of topical prednisolone acetate before intravitreal triamcinolone acetonide injection is performed.

Fluocinolone acetonide intravitreal implants are an effective therapy for non-infectious posterior uveitis. However, patients receiving this treatment are at high risk for development of vision-threatening increased intraocular pressure. Therefore, patients treated with these implants should have frequent intraocular pressure monitoring. Intractable glaucoma may necessitate removal of the depot by pars plana vitrectomy to lower intraoculare pressure. In the SCORE study grid photocoagulation and repeated injections of triamcinolone acetonide 1 or 4 mg seemed to be equally effective in producing improvements in best corrected visual acuity in patients with macular edema due to branch retinal vein occlusion. 41% of patients treated with triamcinolone acetonide 4 mg initiated

microfibrils and microtubules. Glucocorticosteroids reorganizes the actin cytoskeleton to form cross-linked actin networks (CLANs) in cultured trabecular meshwork cells, and is reversible after Glucocorticosteroids withdrawel. In addition Glucocorticosteroids alters

Topical route includes ocular drops and ointments. Of various routes of administration, topical therapy most commonly induces elevated intraocular pressure and correlates with the duration and frequency of administration. Dexamethasone and prednisolone increase intraocular pressure more frequently than loteprendol (Lotemax), fluorometholone (FML), rimexolone (Vexol) or hydrocortisone. Fluorometholone (FML) in particular is less likely to increase intraocular pressure but is also a less potent steroid (table 1). Rimexolone has a low intraocular pressure elevating potential comparable to that of fluorometholone in adults. The chemical structure is responsible to the lower propensity to increase intraocular pressure of some steroids. Loteprendol is a site-active steroid that contains an ester rather than a ketone group at the C-20 position, rendering de-esterification to an inactive metabolite. It is highly lipid-soluble, with enhanced penetration into cells. Loteprendol appears to have an improved safety profile compared with ketone corticosteroids. Fluorometholone is deoxygenized at the C-21 position. Rimexolone lacks a hydroxyl substituent at the C-21 position. It has lower aqueous solubility and increased lipophilicity. It appears that the potency of topical steroids is directly correlated with the propensity to elevate intraocular pressure. Intraocular pressure elevation almost never occurs in less than 5 days and rarely in less than 2 weeks of steroid treatment. However, late rise in ocular pressure is not uncommon, even if intraocular pressure has been within normal limits

Before the advent of anti VEGF, intravitreal steroid injections have been used largely in the treatment of exudative age related macular degeneration, chronic cystoid macular edema, proliferative diabetic vitreoretinopathy, retinal vascular occlusion and chronic uveitis. Rise in intraocular pressure is dependent on dose, presence of aphakia or pseudophkaia and a history of vitrectomy, facilitating penetration of the drug into the anterior segment. Intraocular pressure may rise in 30-50 % of patients as soon as 1-4 weeks after intravitreal injection of triamcinolone acetonide (Kenalog) and often returns to baseline several months after injection. It is advisable to perform a trial of topical prednisolone acetate before

Fluocinolone acetonide intravitreal implants are an effective therapy for non-infectious posterior uveitis. However, patients receiving this treatment are at high risk for development of vision-threatening increased intraocular pressure. Therefore, patients treated with these implants should have frequent intraocular pressure monitoring. Intractable glaucoma may necessitate removal of the depot by pars plana vitrectomy to lower intraoculare pressure. In the SCORE study grid photocoagulation and repeated injections of triamcinolone acetonide 1 or 4 mg seemed to be equally effective in producing improvements in best corrected visual acuity in patients with macular edema due to branch retinal vein occlusion. 41% of patients treated with triamcinolone acetonide 4 mg initiated

microtubules to form microtubule tangles.

during a treatment course of 6 weeks.

intravitreal triamcinolone acetonide injection is performed.

**4.2 Intraocular route** 

**4.1 Topical route** 

**4. Routes of corticosteroid administration** 

intraocular pressure lowering medications during the 12 months study. In patient with

central retinal vein occlusion 35% of the patients receiving 4 mg triamcinolone acetonide initiated glaucoma medications. Ozurdex is a slow release intravitreal implant of dexamethasone currently under clinical trials for the treatment of macular edema in retinal vein occlusion disease. It appears that the dexamethasone implant is well tolerated, producing transient, moderate and readily managed increase in intraocular pressure in less than 16% of eyes.

#### **4.3 Periocular route**

Subconjunctival, sub-Tenon and retrobulbar injections of triamcinolone acetonide may cause dangerous and prolonged elevation of intraocular pressure because of their long duration of action. Surgical excision of sub-Tenon triamcinolone acetonide deposit should be considered if the primary treatment for steroid-induced glaucoma is refractory to medical treatment.

The application of topical corticosteroids to the eyelids and periorbital region, in the treatment of atopic dermatitis, even over long periods of time, was not related to the development of glaucoma or cataracts.

#### **4.4 Systemic route**

Systemic administration includes ingestion, inhalation and nasal spray. It is less likely to cause intraocular elevation. However, intraocular pressure may rise weeks to years after treatment. When administrated concurrently with topical steroids it may have an additive effect and higher intraocular pressure than a single route.

Intranasal corticosteroids have become a gold standard in therapy for allergic rhinoconjunctivitis and recent evidence indicates that may be effective at alleviating ocular symptoms as well. Intranasal corticosteroids are absorbed systemically in small measurable amounts. Some studies suggest a relationship between intranasal steroids and increased intraocular pressure.

Aerosolized drugs delivered with a facemask may inadvertently deposit in the eyes, raising concerns about ocular side effects. Inhaled corticosteroids have been associated with an increased risk of skin thinning, bruising, cataracts and possibly glaucoma in adults. The risks increase with advanced age, higher doses, and longer duration of use. In children, the risks of cataracts and glaucoma were negligible with inhaled corticosteroids, whether a mouthpiece or a mask interface was used. It is not known whether exposed children will have increased risks from inhaled corticosteroids later in life. Therefore, it is wise to avoid face and eye deposition when possible, to use the minimally effective dose and a regular follow up of intraocular pressure.

#### **4.5 Endogenous route**

Elevated blood levels of corticosteroids of endogenous production, as seen in adrenal hyperplasia or neoplasia (Cushing syndrome) can also cause increase in the intraocular pressure. After adrenalectomy, increased intraocular pressure may retune to normal values

#### **5. Clinical course**

An increase in intraocular pressure may occur days to weeks and even months after the administration of steroids. The increase in intraocular pressure depends on potency, penetration, frequency and route of administration. Individual susceptibility, older age and

Steroid Induced Glaucoma 565

Alternative topical anti-inflammatory agents are the nonsteroidal anti-inflammatory agents (NSAIDs), such as diclofenac (Voltaren), ketorolac tromethamine (Acular LS) and bromfenac (Xibrom). NSAIDs do not induce increase in intraocular pressure but their anti-

When indicated, topical anti-glaucoma medications should be used. Prostaglandins should be used with caution as they may have pro-inflammatory effect. If intraocular pressure remains intractable despite maximal tolerated medical therapy, Argon laser trabeculoplasty and Nd:YAG laser selective trabeculoplasty (SLT) have variable success and patients required additional surgical procedures. Repeat SLT treatments may be necessary. SLT is a

A possible new treatment under investigation is anecortave acetate injection into the anterior sub-Tenon space in eye with uncontrolled steroid-related ocular hypertension following intravitreal or sub-Tenon injections of triamcinolone acetonide. Anecortave acetate is a synthetic molecule derived from cortisol. The resulting molecule is referred to as a cortisene. The modification renders the molecule free of all glucocorticoid and mineralocorticoid activity. Anecortave acetate possesses antiangiogenic activity via inhibition of the proteases necessary for vascular endothelial cell migration and has been evaluated as a potential therapy for neovascular age-related macular degeneration. In one preliminary, uncontrolled study a rapid and sustained reduction of intraocular pressure was noted as soon as 1 week after treatment. The mechanism by which anecortave acetate lowers intraocular pressure in eyes with steroid-related ocular hypertension is unknown. With glucocorticoid treatment, trabecular meshwork cells increases the expression of plasminogen activator inhibitor–1, a protein that inhibits activation of extracellular proteinases and leads to enhanced extracellular matrix deposition. Recent studies have shown that anecortave acetate blocks glucocorticoid induction of plasminogen activator inhibitor–1, which may be partially responsible for anecortave acetate's intraocular pressure

Surgical treatments include filtration surgery, tube shunt, excision of the sub-Tenon steroid depot, explantation of steroid implant and pars plana vitrectomyfor the removal of the

Armaly MF. The heritable nature of dexamethasone-induced ocular hypertension. Arch

Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. Glucocorticoid receptor beta, a

Bartlett JD, Woolley TW, Adams CM. Identification of high intraocular pressure responders to topical ophthalmic corticosteroids. J Ocul Pharmacol. 1993; 9:35–45. Becker B, Chevrette L. Topical corticosteroid testing in glaucoma siblings. Arch Ophthalmol.

Becker B. Diabetes mellitus and and primary open angle glaucoma. Am J Opphthalmol.

Bregmann J, Witmer MT, Slonim CB. The relationship of intranasal steroids to intraocular

pressure. Curr Allergy Asthma Rep. 2009 Jul; 9(4):311-5.

potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest.

temporizing procedure to consider in patients with steroid-induced elevated IOP.

inflammatory potential is lower than that of corticosteroids.

lowering activity.

intravitreal depot.

**7. References** 

Ophthalmol. 1966; 75:32–5.

1995; 95:2435–41.

1966; 76:484–7.

1971; 71:1.

ocular disease are also important factors. An acute presentation may occur after intense systemic steroid therapy. Patient may complain on pain, decreased vision and conjunctival hyperemia. In infants the clinical picture may resemble that of congenital glaucoma. Signs are tearing, Descement's membrane breaks, corneal edema, enlarged corneal diameter, elevated intraocular pressure and optic disc cupping. Unlike congenital glaucoma, the anterior chamber angle is normal.


Table 1. Comparison of anti-inflamatory and intraocular pressure elevating potencies

Additional ocular findings from topical steroids include corneal ulcers, exacerbation of bacterial and viral infections, posterior subcapsular cataracts, mydriasis, delayed wound healing, scleral melting ptosis and skin atrophy and depigmentation of the eyelids. Systemic steroids side effects are suppression of the pituitary-adrenal axis, Cushinoid facies, buffalo hump, truncal obesity, hirsutism, cutaneous striae, easy bruisability, delayed wound healing, osteoporosis, aseptic necrosis of the hip, peptic ulcers, diabetes, hypertension, insomnia and psychiatric disorders.

#### **6. Management**

This secondary glaucoma clinically mimics many features of primary open angle glaucoma. Currently, the propensity to develop steroid-induced ocular hypertension must be determined empirically. Therefore, all patients on protracted steroid therapy should have their intraocular pressure monitored periodically.

Steroid induced glaucoma usually responds to cessation of steroid therapy and to topical anti-glaucoma medication. In steroid responders the intraocular pressure generally returns to normal within few days to weeks after discontinuation of steroids. Rarely, intraocular pressure remains elevated despite steroid cessation and may result from damage to outflow channels. In these cases management is similar to that of open angle glaucoma patients.

If anti-inflammatory therapy is needed in known steroid responders or glaucoma patients, treatment with FML 0.1% or medrisone (MHS) are possible options. Loteprendol (Lotemax) and Rimexolone (Velox) are potent anti-inflammatory corticosteroids with reduced propensity to raise intraocular pressure.

ocular disease are also important factors. An acute presentation may occur after intense systemic steroid therapy. Patient may complain on pain, decreased vision and conjunctival hyperemia. In infants the clinical picture may resemble that of congenital glaucoma. Signs are tearing, Descement's membrane breaks, corneal edema, enlarged corneal diameter, elevated intraocular pressure and optic disc cupping. Unlike congenital glaucoma, the

Potency Steroid Glaucoma risk

Dexamethasone sodium phosphate

Table 1. Comparison of anti-inflamatory and intraocular pressure elevating potencies

Additional ocular findings from topical steroids include corneal ulcers, exacerbation of bacterial and viral infections, posterior subcapsular cataracts, mydriasis, delayed wound healing, scleral melting ptosis and skin atrophy and depigmentation of the eyelids. Systemic steroids side effects are suppression of the pituitary-adrenal axis, Cushinoid facies, buffalo hump, truncal obesity, hirsutism, cutaneous striae, easy bruisability, delayed wound healing, osteoporosis, aseptic necrosis of the hip, peptic ulcers, diabetes, hypertension,

This secondary glaucoma clinically mimics many features of primary open angle glaucoma. Currently, the propensity to develop steroid-induced ocular hypertension must be determined empirically. Therefore, all patients on protracted steroid therapy should have

Steroid induced glaucoma usually responds to cessation of steroid therapy and to topical anti-glaucoma medication. In steroid responders the intraocular pressure generally returns to normal within few days to weeks after discontinuation of steroids. Rarely, intraocular pressure remains elevated despite steroid cessation and may result from damage to outflow channels. In these cases management is similar to that of open angle glaucoma patients. If anti-inflammatory therapy is needed in known steroid responders or glaucoma patients, treatment with FML 0.1% or medrisone (MHS) are possible options. Loteprendol (Lotemax) and Rimexolone (Velox) are potent anti-inflammatory corticosteroids with reduced

Betamethasone Clobetasol propionate Dexamethasone Flucinonide

Fluormethalone

Hydrocortisone Rimexolone Medrisone

Triamcinolone acetonide Loteprendole etabonate

anterior chamber angle is normal.

insomnia and psychiatric disorders.

their intraocular pressure monitored periodically.

propensity to raise intraocular pressure.

**6. Management** 

High

Medium

Low

Alternative topical anti-inflammatory agents are the nonsteroidal anti-inflammatory agents (NSAIDs), such as diclofenac (Voltaren), ketorolac tromethamine (Acular LS) and bromfenac (Xibrom). NSAIDs do not induce increase in intraocular pressure but their antiinflammatory potential is lower than that of corticosteroids.

When indicated, topical anti-glaucoma medications should be used. Prostaglandins should be used with caution as they may have pro-inflammatory effect. If intraocular pressure remains intractable despite maximal tolerated medical therapy, Argon laser trabeculoplasty and Nd:YAG laser selective trabeculoplasty (SLT) have variable success and patients required additional surgical procedures. Repeat SLT treatments may be necessary. SLT is a temporizing procedure to consider in patients with steroid-induced elevated IOP.

A possible new treatment under investigation is anecortave acetate injection into the anterior sub-Tenon space in eye with uncontrolled steroid-related ocular hypertension following intravitreal or sub-Tenon injections of triamcinolone acetonide. Anecortave acetate is a synthetic molecule derived from cortisol. The resulting molecule is referred to as a cortisene. The modification renders the molecule free of all glucocorticoid and mineralocorticoid activity. Anecortave acetate possesses antiangiogenic activity via inhibition of the proteases necessary for vascular endothelial cell migration and has been evaluated as a potential therapy for neovascular age-related macular degeneration. In one preliminary, uncontrolled study a rapid and sustained reduction of intraocular pressure was noted as soon as 1 week after treatment. The mechanism by which anecortave acetate lowers intraocular pressure in eyes with steroid-related ocular hypertension is unknown. With glucocorticoid treatment, trabecular meshwork cells increases the expression of plasminogen activator inhibitor–1, a protein that inhibits activation of extracellular proteinases and leads to enhanced extracellular matrix deposition. Recent studies have shown that anecortave acetate blocks glucocorticoid induction of plasminogen activator inhibitor–1, which may be partially responsible for anecortave acetate's intraocular pressure lowering activity.

Surgical treatments include filtration surgery, tube shunt, excision of the sub-Tenon steroid depot, explantation of steroid implant and pars plana vitrectomyfor the removal of the intravitreal depot.

#### **7. References**


Steroid Induced Glaucoma 567

Nguyen TD, Chen P, Huang WD, et al. Gene structure and properties of TIGR, an

Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform.

Ohji M, Kinoshita S, Ohmi E, Kuwayama Y. marked intraocular response to instillation of

Okka M, Bozkurt B, Kerimoglu H, Ozturk BT, Gunduz K, Ylmaz M, Okudan S. Control of

Robin AL, Suan EP, Sjaarda RN, Callanan DG, Defaller J; Alcon Anecortave Acetate for IOP

Rozsival P, Hampl R, Obenberger J, Starka L, Rehak S. Aqueous humour and plasma cortisol levels in glaucoma and cataract patients. Curr Eye Res. 1981; 1:391–6. Rubin B, Taglienti A, Rothman RF, Marcus CH, Serle JB. The effect of selective laser

Schwartz JT, Reuling FH, Feinleib M et al. Twin study on ocular pressure folloing topically

SCORE Study Research Group. A randomiezed trial compering the efficacy and safety of

SCORE Study Research Group. A randomiezed trial compering the efficacy and safety of

Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and

Southren AL, Gordon GG, Weinstein BI. Genetic defect in cortisol metabolism in primary

Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open

Tawara A, Tou N, Kubota T, Harada Y, Yokota K. Immunohistochemical evaluation of the

extracellular matrix in trabecular meshwork in steroid-induced glaucoma. Graefes

intraocular pressure. Am J Ophthalmol. 2004;138(5):740-743.

open angle glaucoma. Trans Assoc Am Physicians. 1985; 98:361–9.

elevated intraocular pressure. J Glaucoma. 2008 Jun-Jul;17(4):287-92. Schwartz JT, Reuling FH, Feinleib M et al. Twin study on ocular pressure after topical

corticosteroids in children. Am J Ophthalmol 1191; 112:450.

meshwork cells. J Biol Chem 1998; 273:6341–50.

271:9550–9.

Dec; 45(6):621-6.

127(2):173-8.

1973; 76:126.

Ophthalmol 1973; 90:281.

Ophthalmol 2009;127:1101-14.

Ophthalmol 2009;127:1115-28.

angle glaucoma. Science 1997; 275:668–70.

Arch Clin Exp Ophthalmol. 2008 Jul;246(7):1021-8.

olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular

Expression, biochemical properties, and putative function. J Biol Chem. 1996;

steroid-induced glaucoma with surgical excision of sub-Tenon triamcinolone acetonide deposits: a clinical and biochemical approach. Can J Ophthalmol. 2010

Research Team. Reduction of intraocular pressure with anecortave acetate in eyes with ocular steroid injection-related glaucoma. Arch Ophthalmol. 2009 Feb;

trabeculoplasty on intraocular pressure in patients with intravitreal steroid-induced

dexamethasone. I. frequency distribution of pressure response. Am J Ophthalmol

applied dexamethasone. II. Inheritance of variation in pressure response. Arch

intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to central retinal vein occlution: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 5. Arch

intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlution: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 6. Arch


Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and

Fautsch MP, Bahler CK, Jewison DJ, et al. Recombinant TIGR/MYOC increases outflow

Gould DB, Miceli-Libby L, Savinova OV, et al. Genetically increasing MYOC expression

Haeck IM, Rouwen TJ, Timmer-de Mik L, de Bruin-Weller MS, Bruijnzeel-Koomen CA.

Hass JS, NootensRH: Glaucoma secondary to benigne adrenal adenoma. Am J Ophthalmol

Jilani FA, Khan AM, Kesharwani RK: Study of topical corticosteroid response in glaucoma

Jonas JB, Degenring RF, Kreissig I, Akkoyun I, Kamppeter BA. Intraocular pressure

Jonas JB. Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Res.

Jones R 3rd, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief

Julia A. Haller et al for the OZURDEX GENEVA Study Group. Randomized, sham

Kwok AK, Lam DS, Fan DS, et al. Ocular hypertensive response totopical steroids in

Lewis JM, Priddy T, Judd J, Gordon MO, Kass MA, Kolker AE, Becker B. Intraocular

McCarty GR, Schwartz B. Increased plasma noncortisol glucocorticoid activity in open-angle

Mindel JS, Tavitian HO, Smith H, Jr, et al. Comparative ocular pressure elevation by

NG JS, Fan DS, young AL et al,Ocular hypertensive response to topical dexamethasone in children: a dose-dependent phenomenon. Ophthalmol 2000; 107:2097.

primary open-angle glaucoma. Am J Ophthalmol. 1988; 106:607–12. Lutjen-Drecoll E, May CA, Polansky JR, et al. Localization of the stress proteins alpha B-

glaucoma. Invest Ophthalmol Vis Sci. 1991; 32:1600–8.

edema due to retinal vein occlusion. Ophthalmology 2010;117:1134-46. Kitazawa Y, Horie T. The prognosis of corticosteroid-responsive individuals. Arch

102:11–21.

Biol 2004; 24:9019–25.

1974; 78:497.

1987; 35:141.

39:517–25.

1980; 98:1577–8.

2005;112(4):593-598.

2006;38(4):218-245.

Ophthalmol. 1981; 99:819–23.

children. Ophthalmol1997; 104:2112.

Am Acad Dermatol. 2011 Feb; 64(2):275-81.

8.

mechanisms of post-translational modification. J Steroid Biochem Mol Biol. 2006;

resistance in the human anterior segment. Invest Ophthalmol Vis Sci 2000; 41:4163–

supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell

Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts. J

suspects and family members of established glaucoma patients. Indian J Ophthalmol

elevation after intravitreal triamcinolone acetonide injection. Ophthalmology.

review and update of the literature. . Curr Opin Ophthalmol. 2006 Apr; 17(2):163-7.

controlled trial of dexamethasone intravitreal implant in patients with macular

pressure response to topical dexamethasone as a predictor for the development of

crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Invest Ophthalmol Vis Sci 1998;

medrysone, fluorometholone, and dexamethasone phosphate. Arch Ophthalmol


**30** 

*Israel* 

Shimon Rumelt

*Department of Ophthalmology,* 

**Glaucoma in Cases of** 

**Penetrating Keratoplasty, Lamellar** 

**Procedures and Keratoprosthesis** 

The two main issues that concern glaucoma patients before and after penetrating keratoplasty and posterior lamellar procedures and patients that develop glaucoma after surgery are the risks of graft failure and the aggravation of the glaucoma. Failure of the corneal graft may require regrafting, which increases the risk of developing or aggravating glaucoma, while uncontrolled glaucoma may result in graft failure and further damage to the optic disc and visual field. These two problems may lead to each other creating a vicious circle. They should be treated by glaucoma and corneal specialists or by someone who is

Glaucoma was found in 10-42% of the patients with a single corneal transplantation, 0-27% of them had preoperative glaucoma.1-6 Preexisting glaucoma was usually a result of an initial insult such as chemical burn or secondary glaucoma. In repeated corneal transplantation, the incidence of postoperative glaucoma was higher (14-47%) than in primary transplantation.7-12 It increases with increased number of regrafts and in aphakia. Corneal graft failure 3 years after keratoplasty occurred in 29-47% when glaucoma was

Patients requiring penetrating keratoplasty and lamellar procedures (deep lamellar keratoplasty, Descemet's stripping (automated) endothelial keratoplasty, Descemet's membrane endothelial keratoplasty) may suffer from preexisting various types of open and closed angle glaucomas, which may be primary or secondary. Primary open angle and primary closed angle glaucomas may preexist and corneal surgery may be required for unrelated disorders such as Fuchs' corneal dystrophy. Secondary glaucomas may occur due to open and closed globe injuries. In those injuries, the glaucoma may be of open angle and caused by obstruction of the trabecular meshwork by red blood cells (from hyphema), ghost cells (ghost cell glaucoma) or tearing of the meshwork (angle recession). It may also be closed-angle caused by peripheral anterior synechiae. Corneal transplantation may also be required in chemical burns especially alkali. In these cases, the cornea may be opaque because of chronic edema and scarring. Secondary glaucoma may also be associated with corneal abnormalities such as anterior mesenchymal dysgenesis (e.g., Peter's and Axenfeld-Rieger's anomalies). In these disorders, in addition

**1. Introduction** 

expert with both.

present, compared with 9-30% when it was absent.13,14

 *Western Galilee – Nahariya Medical Center, Nahariya,* 


### **Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis**

Shimon Rumelt *Department of Ophthalmology, Western Galilee – Nahariya Medical Center, Nahariya, Israel* 

#### **1. Introduction**

568 Glaucoma - Basic and Clinical Concepts

Tektas OY, Lütjen-Drecoll E. Structural changes of the trabecular meshwork in different

Tripathi RC, Kirschner BS. Kipp M. et al. corticosteroid treatment for inflammatory bowel

Wang RF, Guo BK. Steroid-induced ocular hypertention in high myopia. Chin Med J 1984;

Wang X, Johnson DH. mRNA in situ hybridization of TIGR/MYOC in human trabecular

Zhang X, Clark AF, Yorio T. Regulation of glucocorticoid responsiveness in glaucomatous

Zhang X, Ognibene CM, Clark AF, Yorio T. Dexamethasone inhibition of trabecular

Zhao J, Zhang Q. Ultrastructural changes of the trabecular meshwork in glucocorticoid

Zillig M, Wurm A, Grehn FJ, et al. Overexpression and properties of wild-type and

induced glaucoma. Yan Ke Xue Bao. 2010 Nov; 25(2):119-124.

disease in pediatric patients increases intraocular pressure. Gastroenterology 1992;

trabecular meshwork cells by glucocorticoid receptor-beta. Invest Ophthalmol Vis

meshwork cell phagocytosis and its modulation by glucocorticoid receptor beta.

Tyr437His mutated myocilin in the eyes of transgenic mice. Invest Ophthalmol Vis

kinds of glaucoma. Exp Eye Res. 2009 Apr;88(4):769-75.

meshwork. Invest Ophthalmol Vis Sci 2000; 41:1724–9.

102:1957.

Sci. 2005; 46:4607–16.

Sci 2005; 46:223–34.

Exp Eye Res. 2007;84(2):275-284.

97:24.

The two main issues that concern glaucoma patients before and after penetrating keratoplasty and posterior lamellar procedures and patients that develop glaucoma after surgery are the risks of graft failure and the aggravation of the glaucoma. Failure of the corneal graft may require regrafting, which increases the risk of developing or aggravating glaucoma, while uncontrolled glaucoma may result in graft failure and further damage to the optic disc and visual field. These two problems may lead to each other creating a vicious circle. They should be treated by glaucoma and corneal specialists or by someone who is expert with both.

Glaucoma was found in 10-42% of the patients with a single corneal transplantation, 0-27% of them had preoperative glaucoma.1-6 Preexisting glaucoma was usually a result of an initial insult such as chemical burn or secondary glaucoma. In repeated corneal transplantation, the incidence of postoperative glaucoma was higher (14-47%) than in primary transplantation.7-12 It increases with increased number of regrafts and in aphakia. Corneal graft failure 3 years after keratoplasty occurred in 29-47% when glaucoma was present, compared with 9-30% when it was absent.13,14

Patients requiring penetrating keratoplasty and lamellar procedures (deep lamellar keratoplasty, Descemet's stripping (automated) endothelial keratoplasty, Descemet's membrane endothelial keratoplasty) may suffer from preexisting various types of open and closed angle glaucomas, which may be primary or secondary. Primary open angle and primary closed angle glaucomas may preexist and corneal surgery may be required for unrelated disorders such as Fuchs' corneal dystrophy. Secondary glaucomas may occur due to open and closed globe injuries. In those injuries, the glaucoma may be of open angle and caused by obstruction of the trabecular meshwork by red blood cells (from hyphema), ghost cells (ghost cell glaucoma) or tearing of the meshwork (angle recession). It may also be closed-angle caused by peripheral anterior synechiae. Corneal transplantation may also be required in chemical burns especially alkali. In these cases, the cornea may be opaque because of chronic edema and scarring. Secondary glaucoma may also be associated with corneal abnormalities such as anterior mesenchymal dysgenesis (e.g., Peter's and Axenfeld-Rieger's anomalies). In these disorders, in addition

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 571

than corneal disease exist, such as glaucoma and retinal disorders, they should be evaluated for their contribution to visual acuity. The evaluation includes potential acuity meter (PAM), Lambda and laser interferometry. With these instruments, if the visual acuity is improved, the eye has a potential for visual recovery and a corneal surgery should be attempted. In non-verbal patients as children or in patients with mental retardation, a less accurate method to evaluate the potential for visual recovery is electroretinography (ERG). When anamnesis cannot be obtained, poor prognostic factors for visual improvement are nystagmus, which develops in the first 3 postnatal months, and esotropia that develop in the first 6 postnatal months and indicate severe irreversible amblyopia. Exotropia on the other hand may be acquired at older age and therefore, with poor anamnesis is not a poor

The preoperative evaluation should include a complete ocular examination including examining the anterior chamber angle, especially following ocular trauma, burns, preexisting glaucoma and candidates for large diameter grafts. If the cornea is opaque, ultrasound biomicroscopy (UBM) is a good alternative for gonioscopy. In presence of shallow anterior chamber, peripheral anterior synechiae or partially closed angle even with normal IOP, placement of anterior chamber IOL is contraindicated in triple procedures,

Consider alternative treatment options for penetrating keratoplasty, especially if glaucoma exists. If the corneal opacity is central and localized (e.g., in Peter's anomaly), optical iridectomy may be a better surgical alternative. Rotational autokeratoplasty is an alternative for eccentric. If the corneal opacity is minimal, surgery may not be warranted. It is always imperative to consider whether the expected visual acuity will be better than the

It is important to perform complicated surgical procedures such as filtration surgery in uncontrolled and controlled glaucoma patients before corneal transplantation or posterior lamellar procedures. The IOP should be controlled at time of the penetrating keratoplasty or posterior lamellar procedures. Otherwise, the graft may become edematous and lost. In patients with glaucoma, any procedure should spare the limbus and conjunctiva as much as

**4. Surgical steps of penetrating keratoplasty to increase the success rate** 

Oversized donor corneal button is always required to decrease the risk for development of secondary glaucoma and aggravating a preexisting one. The details for oversizing are

Specular microscopy of the donor button to ensure an endothelial cell count of more than 2,000 mm2 without endothelial polymegatism or pleomorphism will at least guarantee that the corneal graft has safety margins and that the risk of endothelial decompensation will be

Pretreatment of preexisting glaucoma is a crucial step in successful penetrating and posterior lamellar procedures. Therefore, it is important recognizing the type and the etiology of preexisting glaucoma. Surgical pretreatment should be considered even in medically controlled glaucoma, because these patients may become uncontrolled after

because it may result in the development of secondary glaucoma.

preoperative visual acuity. If not, it is better to avoid surgery.

possible to allow glaucoma filtration surgery.

prognostic factor for visual recovery.

**3. Preoperative tips** 

described below.

decreased.

to corneal opacity due to scarring, the angle may be poorly formed. The common features for all these conditions are persistent corneal edema and scarring due to endothelial decompensation. The decompensation is a result of a combination of damaged or compromised endothelium (whether by trauma or other corneal disorders) and increased intraocular pressure (IOP) that contributes to egress of aqueous humor into the corneal layers. Corneal opacity due to persistent edema and scarring is more common in these conditions than in normal population.

Repeated or even primary corneal transplantation may also result in secondary glaucoma. The attributing factors for secondary glaucoma include 1. Donors button undersizing, which results in corneal graft over-stretching, causing corneal flattening and angle closure. 2. Trauma to the angle by the inadvertent touch by surgical instruments. The damage might be micro or macroscopic. 3. Corticosteroid-induced glaucoma, since topical and sometimes systemic corticosteroids are being frequently use after transplantation to decrease the risk for corneal graft rejection or to treat it. 4. Posterior synechiae that may develop due to postoperative intraocular inflammation especially if the angle is traumatized or becomes shallow. The most common forms of post-keratoplasty glaucoma in single and repeated corneal transplantation are chronic angle closure followed by steroid-induced glaucoma.

#### **2. Assessment of patients requiring penetrating keratoplasty**

The preoperative office evaluation of patients requiring penetrating keratoplasty or lamellar procedure whether or not having glaucoma includes defining the primary indication for surgery. Certain indications may require certain precautions or additional treatment to prevent loss of the graft clarity. For example, corneal transplantation for infectious diseases such as herpetic, fungal or acanthamebic keratitis require prolonged postoperative antiherpetic, fungal or acanthamebic treatment to prevent reactivation. Defining the associated ocular disorders of the recipient and donor is paramount.12 Corneal vascularization increases the risk of corneal graft rejection especially if involves three or more quadrants and requires prolonged use of corticosteroids as well as immuno-suppressants. Ocular surface disorders such as entropion and trichiasis also increase the likelihood of graft loss due to persistent rubbing of the ocular surface that results in corneal epithelial defects and ulcers that may lead to perforation.15 Limbal cell deficiency in corneal cicatricial disorders such as ocular cicatricial pemphigoid and erythema multiforme (Steven Johnson disease) provides poor supporting environment to the graft, while dry eyes do both (poor supporting and increased friction upon blinking). Poor blinking and lagophthalmos may also cause dryness of the ocular surface resulting in persistent epithelial defects, ulcers and even perforation. These findings should be pretreated.

Cataract, glaucoma and retinal disorders may be associated with poor visual prognosis despite of clear corneal graft and should be evaluated before any corneal procedure. Defining the associated systemic disorders in recipient and donor are also essential. Diabetes mellitus is also manifested as fragile epithelium and slow epithelial healing, which could endanger the corneal graft.

Before any corneal surgery, best-corrected visual acuity of each eye should be obtained and recorded. This will assist in surgery decision making. Ultrasound is part of the evaluation if the cornea is severely opaque and fundus cannot be evaluated. It is used to rule out retinal detachment and intraocular masses (e.g., choroidal melanoma). When ocular disorders other than corneal disease exist, such as glaucoma and retinal disorders, they should be evaluated for their contribution to visual acuity. The evaluation includes potential acuity meter (PAM), Lambda and laser interferometry. With these instruments, if the visual acuity is improved, the eye has a potential for visual recovery and a corneal surgery should be attempted. In non-verbal patients as children or in patients with mental retardation, a less accurate method to evaluate the potential for visual recovery is electroretinography (ERG). When anamnesis cannot be obtained, poor prognostic factors for visual improvement are nystagmus, which develops in the first 3 postnatal months, and esotropia that develop in the first 6 postnatal months and indicate severe irreversible amblyopia. Exotropia on the other hand may be acquired at older age and therefore, with poor anamnesis is not a poor prognostic factor for visual recovery.

The preoperative evaluation should include a complete ocular examination including examining the anterior chamber angle, especially following ocular trauma, burns, preexisting glaucoma and candidates for large diameter grafts. If the cornea is opaque, ultrasound biomicroscopy (UBM) is a good alternative for gonioscopy. In presence of shallow anterior chamber, peripheral anterior synechiae or partially closed angle even with normal IOP, placement of anterior chamber IOL is contraindicated in triple procedures, because it may result in the development of secondary glaucoma.

#### **3. Preoperative tips**

570 Glaucoma - Basic and Clinical Concepts

to corneal opacity due to scarring, the angle may be poorly formed. The common features for all these conditions are persistent corneal edema and scarring due to endothelial decompensation. The decompensation is a result of a combination of damaged or compromised endothelium (whether by trauma or other corneal disorders) and increased intraocular pressure (IOP) that contributes to egress of aqueous humor into the corneal layers. Corneal opacity due to persistent edema and scarring is more common in these

Repeated or even primary corneal transplantation may also result in secondary glaucoma. The attributing factors for secondary glaucoma include 1. Donors button undersizing, which results in corneal graft over-stretching, causing corneal flattening and angle closure. 2. Trauma to the angle by the inadvertent touch by surgical instruments. The damage might be micro or macroscopic. 3. Corticosteroid-induced glaucoma, since topical and sometimes systemic corticosteroids are being frequently use after transplantation to decrease the risk for corneal graft rejection or to treat it. 4. Posterior synechiae that may develop due to postoperative intraocular inflammation especially if the angle is traumatized or becomes shallow. The most common forms of post-keratoplasty glaucoma in single and repeated corneal transplantation are chronic angle closure followed by

The preoperative office evaluation of patients requiring penetrating keratoplasty or lamellar procedure whether or not having glaucoma includes defining the primary indication for surgery. Certain indications may require certain precautions or additional treatment to prevent loss of the graft clarity. For example, corneal transplantation for infectious diseases such as herpetic, fungal or acanthamebic keratitis require prolonged postoperative antiherpetic, fungal or acanthamebic treatment to prevent reactivation. Defining the associated ocular disorders of the recipient and donor is paramount.12 Corneal vascularization increases the risk of corneal graft rejection especially if involves three or more quadrants and requires prolonged use of corticosteroids as well as immuno-suppressants. Ocular surface disorders such as entropion and trichiasis also increase the likelihood of graft loss due to persistent rubbing of the ocular surface that results in corneal epithelial defects and ulcers that may lead to perforation.15 Limbal cell deficiency in corneal cicatricial disorders such as ocular cicatricial pemphigoid and erythema multiforme (Steven Johnson disease) provides poor supporting environment to the graft, while dry eyes do both (poor supporting and increased friction upon blinking). Poor blinking and lagophthalmos may also cause dryness of the ocular surface resulting in persistent epithelial defects, ulcers and

Cataract, glaucoma and retinal disorders may be associated with poor visual prognosis despite of clear corneal graft and should be evaluated before any corneal procedure. Defining the associated systemic disorders in recipient and donor are also essential. Diabetes mellitus is also manifested as fragile epithelium and slow epithelial healing, which

Before any corneal surgery, best-corrected visual acuity of each eye should be obtained and recorded. This will assist in surgery decision making. Ultrasound is part of the evaluation if the cornea is severely opaque and fundus cannot be evaluated. It is used to rule out retinal detachment and intraocular masses (e.g., choroidal melanoma). When ocular disorders other

**2. Assessment of patients requiring penetrating keratoplasty** 

even perforation. These findings should be pretreated.

could endanger the corneal graft.

conditions than in normal population.

steroid-induced glaucoma.

Consider alternative treatment options for penetrating keratoplasty, especially if glaucoma exists. If the corneal opacity is central and localized (e.g., in Peter's anomaly), optical iridectomy may be a better surgical alternative. Rotational autokeratoplasty is an alternative for eccentric. If the corneal opacity is minimal, surgery may not be warranted. It is always imperative to consider whether the expected visual acuity will be better than the preoperative visual acuity. If not, it is better to avoid surgery.

It is important to perform complicated surgical procedures such as filtration surgery in uncontrolled and controlled glaucoma patients before corneal transplantation or posterior lamellar procedures. The IOP should be controlled at time of the penetrating keratoplasty or posterior lamellar procedures. Otherwise, the graft may become edematous and lost. In patients with glaucoma, any procedure should spare the limbus and conjunctiva as much as possible to allow glaucoma filtration surgery.

#### **4. Surgical steps of penetrating keratoplasty to increase the success rate**

Oversized donor corneal button is always required to decrease the risk for development of secondary glaucoma and aggravating a preexisting one. The details for oversizing are described below.

Specular microscopy of the donor button to ensure an endothelial cell count of more than 2,000 mm2 without endothelial polymegatism or pleomorphism will at least guarantee that the corneal graft has safety margins and that the risk of endothelial decompensation will be decreased.

Pretreatment of preexisting glaucoma is a crucial step in successful penetrating and posterior lamellar procedures. Therefore, it is important recognizing the type and the etiology of preexisting glaucoma. Surgical pretreatment should be considered even in medically controlled glaucoma, because these patients may become uncontrolled after

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 573

If glaucoma develops after corneal surgery, a distinction between immediate postoperative and late postoperative glaucoma should be made. Immediate postoperative glaucoma develops within a week after surgery in 42-55% of the primary keratoplasties. The causes for its development include viscoelastic agent left in the anterior chamber and blocking the drainage of the aqueous humor through the angle and corticosteroid-induced glaucoma. The later develops after the initiation of corticosteroid treatment and occurs at least in 20- 30% of the patients. It can occur with any form of corticosteroid although it occurs more often after topical use. The increase in IOP in these cases is usually reversible if diagnosed early and if corticosteroids are discontinued. Therefore, topical and if necessary systemic corticosteroids should be replaced immediately with non-steroidal anti-inflammatory (NSAID) medications. Corticosteroid-induced glaucoma may be avoided by employment of topical NSAID such as ketorolac tromethamine 0.5% (Acular® or Tradol®), diclofenac sodium (Voltaren® (0.1%), Solaraze® (3%)) or indomethacin 1% (Indoptic®). Its incidence is also lowered with IOP sparing corticosteroids such as loteprednol etabonate 0.5% (Lotemax®) or rimexolone 1% (Vexol®) but because of their low potency, they may be more

Late postoperative glaucoma may develop weeks or months after surgery. The incidence of this complication is 10-42% after primary keratoplasty. The risk factors for its development include preexisting glaucoma in 27-80% of the cases, aphakia in 20-39%, semi-flexible, closed-loop anterior chamber IOL in 23-50%, regrafting in 43% and wound dehiscence in 50%. Anterior mesenchymal disorders are risk factors for glaucoma in 50-90% of the patients, while open or closed globe injury in 31-77%. Glaucoma may be encountered in up to 47% of the patients with pseudophakic or aphakic bullous keratopathy, and the corneal edema may be a result of it. Certain old types of IOLs have also been associated with late postoperative glaucoma including iris-fixed anterior chamber IOL due to uveitis-glaucomahyphema (UGH) syndrome, caused by rubbing of the IOL against the iris. Large corneal grafts and posterior lamellar grafts may also increase the risk for glaucoma development because they may interfere with the angle. The same may occur from the sutures if they are long, tight and full thickness The causes for late postoperative glaucoma include synechial angle closure, changes in angle ultrastructure, direct mechanical damage to angle by surgical instruments, chronic postoperative inflammation causing toxic effects and presence of vitreous in the angle. Immune graft rejection was found to be more common in patients developing postoperative glaucoma than in those who did not develop it.16,17 The glaucoma

also increases with the number of corneal transplantation procedures.17

**7. Post-keratoplasty evaluation of preexisting and secondary glaucoma** 

The evaluation of the anterior chamber is important not only before corneal transplantation and other posterior lamellar procedures but also after surgery, because if there is a progressive closure of the angle or formation of peripheral anterior synechiae, they may be treated before the development of glaucoma or to prevent its worsening. Periodic gonioscopy for development of anterior chamber angle closure is performed with gonioscopic lens when the peripheral cornea is clear. A 4 mirror hand-held lens has the advantages of avoiding viscoelastic material and of short diameter that allow indentation of the cornea. This allows distinguishing between apposition of the iris against the angle

**6. Post-keratoplasty glaucoma** 

frequently required.

surgery and this may endanger the transparency of the corneal graft. Trabeculectomy is the treatment of choice for primary open angle glaucoma. Antimetabolites such as mitomycin-C (MMC) are indicated for all patients under the age of 55 even in primary surgery, for repeated surgery and for combined procedures. Trabeculectomy should be preferred over glaucoma drainage devices in triple procedures and in the presence of corneal graft. MMC should be applied in all cases of secondary glaucomas, triple procedure or in the presence of corneal graft although potential diffusion of the drug may endanger the endothelium. MMC 0.04% is soaked by a small piece of sponge and is placed under the scleral flap before penetrating into the anterior chamber or under the conjunctival flap for 2min avoiding its edges. It should not be placed over corneal button–recipient bed interface. Such a low concentration and short exposure minimize the risks for complications such as poor healing, scleral melting, anterior chamber reaction and increased IOP.

In angle closure glaucoma, laser iridotomy and laser iridoplasty or synechiolysis are warranted. Laser iridotomy may facilitate aqueous flow from the posterior into the anterior chamber and deepen the anterior chamber. Laser iridoplasty causes shrinkage of the peripheral iris and retracts the base of the iris to open the angle, while, synechiolysis has a similar effect by breaking peripheral anterior synechiae and opening the angle. The last two procedures are beneficial if peripheral anterior synechiae have been present for less than 6 months. Peripheral iridectomy may replace laser iridotomy only if iridotomy cannot be performed due to corneal opacity, thick iris or when laser in unavailable. The procedures are described below.

Penetrating keratoplasty should be delayed until the intraocular inflammation subsides and the IOP is stable within the target pressure range. This should be at least 3 months after any intraocular surgery.

#### **5. Prevention of secondary glaucoma**

Several precautions should be employed to prevent a secondary glaucoma. As mentioned, preoperative evaluation of the anterior chamber angle is essential especially in patients with preexisting glaucoma. If the angle is already compromised (close, narrow or has peripheral anterior synechiae), the risks of development of glaucoma or aggravation of preexisting one increase. It is important to oversize corneal donor button by 0.5-0.75 mm. In keratoconus or keratoglobus, an over-sizing of 0.25 mm is sufficient to decrease the risk of postoperative angle closure, while preventing too steep postoperative graft. For large graft diameter (8.0- 9.5 mm) that is required sometimes for corneal perforations, large descematocele or widespread disease, an over-sizing of 0.75-1.0 mm is advocated. Avoiding manipulations near the angle with surgical instruments is important. The only exception is when synechiolysis is performed. The angle may also be filled with viscoelastic agent to protect it during the procedure, but the viscoelastic material should be aspirated at the conclusion of the surgery to prevent postoperative high IOP. To decrease damage to the trabecular meshwork, preoperative and postoperative intraocular inflammation should be controlled. This may be done by topical corticosteroids with high corneal penetrance such as prednisolone acetate (Pred Forte®). The frequency of drop instillation depends on the degree of inflammation and it is tapered gradually according to the response. Additional systemic corticosteroids may be employed for severe or recurrent sterile uveitis. Usually, 1 gr/kg/day of prednisone is sufficient.

#### **6. Post-keratoplasty glaucoma**

572 Glaucoma - Basic and Clinical Concepts

surgery and this may endanger the transparency of the corneal graft. Trabeculectomy is the treatment of choice for primary open angle glaucoma. Antimetabolites such as mitomycin-C (MMC) are indicated for all patients under the age of 55 even in primary surgery, for repeated surgery and for combined procedures. Trabeculectomy should be preferred over glaucoma drainage devices in triple procedures and in the presence of corneal graft. MMC should be applied in all cases of secondary glaucomas, triple procedure or in the presence of corneal graft although potential diffusion of the drug may endanger the endothelium. MMC 0.04% is soaked by a small piece of sponge and is placed under the scleral flap before penetrating into the anterior chamber or under the conjunctival flap for 2min avoiding its edges. It should not be placed over corneal button–recipient bed interface. Such a low concentration and short exposure minimize the risks for complications such as poor healing,

In angle closure glaucoma, laser iridotomy and laser iridoplasty or synechiolysis are warranted. Laser iridotomy may facilitate aqueous flow from the posterior into the anterior chamber and deepen the anterior chamber. Laser iridoplasty causes shrinkage of the peripheral iris and retracts the base of the iris to open the angle, while, synechiolysis has a similar effect by breaking peripheral anterior synechiae and opening the angle. The last two procedures are beneficial if peripheral anterior synechiae have been present for less than 6 months. Peripheral iridectomy may replace laser iridotomy only if iridotomy cannot be performed due to corneal opacity, thick iris or when laser in unavailable. The procedures are

Penetrating keratoplasty should be delayed until the intraocular inflammation subsides and the IOP is stable within the target pressure range. This should be at least 3 months after any

Several precautions should be employed to prevent a secondary glaucoma. As mentioned, preoperative evaluation of the anterior chamber angle is essential especially in patients with preexisting glaucoma. If the angle is already compromised (close, narrow or has peripheral anterior synechiae), the risks of development of glaucoma or aggravation of preexisting one increase. It is important to oversize corneal donor button by 0.5-0.75 mm. In keratoconus or keratoglobus, an over-sizing of 0.25 mm is sufficient to decrease the risk of postoperative angle closure, while preventing too steep postoperative graft. For large graft diameter (8.0- 9.5 mm) that is required sometimes for corneal perforations, large descematocele or widespread disease, an over-sizing of 0.75-1.0 mm is advocated. Avoiding manipulations near the angle with surgical instruments is important. The only exception is when synechiolysis is performed. The angle may also be filled with viscoelastic agent to protect it during the procedure, but the viscoelastic material should be aspirated at the conclusion of the surgery to prevent postoperative high IOP. To decrease damage to the trabecular meshwork, preoperative and postoperative intraocular inflammation should be controlled. This may be done by topical corticosteroids with high corneal penetrance such as prednisolone acetate (Pred Forte®). The frequency of drop instillation depends on the degree of inflammation and it is tapered gradually according to the response. Additional systemic corticosteroids may be employed for severe or recurrent sterile uveitis. Usually, 1

scleral melting, anterior chamber reaction and increased IOP.

described below.

intraocular surgery.

**5. Prevention of secondary glaucoma** 

gr/kg/day of prednisone is sufficient.

If glaucoma develops after corneal surgery, a distinction between immediate postoperative and late postoperative glaucoma should be made. Immediate postoperative glaucoma develops within a week after surgery in 42-55% of the primary keratoplasties. The causes for its development include viscoelastic agent left in the anterior chamber and blocking the drainage of the aqueous humor through the angle and corticosteroid-induced glaucoma. The later develops after the initiation of corticosteroid treatment and occurs at least in 20- 30% of the patients. It can occur with any form of corticosteroid although it occurs more often after topical use. The increase in IOP in these cases is usually reversible if diagnosed early and if corticosteroids are discontinued. Therefore, topical and if necessary systemic corticosteroids should be replaced immediately with non-steroidal anti-inflammatory (NSAID) medications. Corticosteroid-induced glaucoma may be avoided by employment of topical NSAID such as ketorolac tromethamine 0.5% (Acular® or Tradol®), diclofenac sodium (Voltaren® (0.1%), Solaraze® (3%)) or indomethacin 1% (Indoptic®). Its incidence is also lowered with IOP sparing corticosteroids such as loteprednol etabonate 0.5% (Lotemax®) or rimexolone 1% (Vexol®) but because of their low potency, they may be more frequently required.

Late postoperative glaucoma may develop weeks or months after surgery. The incidence of this complication is 10-42% after primary keratoplasty. The risk factors for its development include preexisting glaucoma in 27-80% of the cases, aphakia in 20-39%, semi-flexible, closed-loop anterior chamber IOL in 23-50%, regrafting in 43% and wound dehiscence in 50%. Anterior mesenchymal disorders are risk factors for glaucoma in 50-90% of the patients, while open or closed globe injury in 31-77%. Glaucoma may be encountered in up to 47% of the patients with pseudophakic or aphakic bullous keratopathy, and the corneal edema may be a result of it. Certain old types of IOLs have also been associated with late postoperative glaucoma including iris-fixed anterior chamber IOL due to uveitis-glaucomahyphema (UGH) syndrome, caused by rubbing of the IOL against the iris. Large corneal grafts and posterior lamellar grafts may also increase the risk for glaucoma development because they may interfere with the angle. The same may occur from the sutures if they are long, tight and full thickness The causes for late postoperative glaucoma include synechial angle closure, changes in angle ultrastructure, direct mechanical damage to angle by surgical instruments, chronic postoperative inflammation causing toxic effects and presence of vitreous in the angle. Immune graft rejection was found to be more common in patients developing postoperative glaucoma than in those who did not develop it.16,17 The glaucoma also increases with the number of corneal transplantation procedures.17

#### **7. Post-keratoplasty evaluation of preexisting and secondary glaucoma**

The evaluation of the anterior chamber is important not only before corneal transplantation and other posterior lamellar procedures but also after surgery, because if there is a progressive closure of the angle or formation of peripheral anterior synechiae, they may be treated before the development of glaucoma or to prevent its worsening. Periodic gonioscopy for development of anterior chamber angle closure is performed with gonioscopic lens when the peripheral cornea is clear. A 4 mirror hand-held lens has the advantages of avoiding viscoelastic material and of short diameter that allow indentation of the cornea. This allows distinguishing between apposition of the iris against the angle

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 575

The treatment of postoperative progressive angle closure even with normal IOP includes peripheral laser iridotomy and topical corticosteroids to control anterior chamber

Open angle glaucoma is treated in the following order. The first line of treatment is medical with alpha-agonists (brimonidine tartrate) and beta-blockers (timolol maleate, betaxolol). In phakic eyes, prostaglandin analogs (latanoprost) and adrenergic agents (dipivefrin, epinephrine) may be added. In aphakic and pseudophakic eyes, prostaglandin analogs and adrenergic agents may induce cystoid macular edema (CME), which may result in a decrease in visual acuity, and therefore should be avoided. Topical carbonic anhydrase inhibitors (dorzolamide, brinzolamide) may cause graft failure due to toxicity to endothelial cells. Miotics may initiate intraocular inflammation by breaking the blood-aqueous barrier and may increase the likelihood of corneal graft rejection. In aphakic eyes, the risk of retinal

The adverse effects of beta-blockers include superficial punctate keratopathy, corneal anesthesia and dry eyes. Alpha-adrenergic agents may also cause superficial punctate

If medical treatment fails, trabeculectomy with MMC (option for two such procedures) should be considered (Figure 1). However, some authors suggested that the prognosis might be poorer than for placement of a glaucoma drainage implant. If a trabeculectomy is performed, a soaked sponge (WekCel) of MMC 0.2-0.4 mg/ml under the scleral flap before penetrating the anterior chamber (or under the conjunctiva avoiding its edge) for 2-3 min should be added. The MMC should not be placed over corneal button–recipient bed interface. Then the area should be copiously irrigated with balanced salt solution or saline. This procedure may be repeated if it failed once. In some cases, the filtration procedure may be functioning well causing a decrease in IOP, but to insufficient level (above the target pressure). In such a case, an additional trabeculectomy rather than anti-glaucoma medications may be successful decreasing further the IOP to the desired level because they may diminish the filtration through the trabeculectomy resulting in its failure for long term. Also, with a successful second trabeculectomy, the patient may not need long-term topical medications, which are a burden. An alternative for MMC is 5-fluorouracil (5FU). Five-mg may be injected subconjunctivally before or at intervals after surgery, but is less potent. Another option is to place 50mg/ml of 5-FU over or under the scleral flap intraoperatively. It inhibits epithelial proliferation, while MMC is better against fibrous proliferation. Both drugs may

The complications of trabeculectomy with MMC in the presence of corneal graft are similar to those without a graft, but in addition, damage to the endothelium may be caused by the MMC, if it penetrates into anterior chamber. The same precautions that apply for placing

If one or two trabeculectomies with MMC have been failed or as a first surgical option, glaucoma shunt tube may be performed. Anterior or posterior drainage devices are available. Anterior drainage devices connect the anterior chamber with the subconjunctival space. Schlemm's canal or suprachoroidal space are easier to implant and require only limited healthy conjunctiva to function. Among the anterior drainage devices are Ex-Press,

MMC during surgery for primary open angle glaucoma should be applied here.

inflammation. If the IOP increases, a prompt surgical synechiolysis is warranted.

detachment also increases. Therefore, these agents should be spared if possible.

**8. Treatment of progressive angle closure** 

**9. Treatment of secondary glaucoma** 

keratopathy and dry eyes.

be injected in conjunction.

and true closure. It also allows breaking of fresh anterior synechiae if present. Indentation should be performed cautiously immediately after surgery, because it can result in wound dehiscence. Other gonioscopic lenses include the Goldman three and four mirror lenses, which have a broader base (diameter) and cannot indent only the cornea. They also require viscoelastic agent. Newer imaging modalities of the anterior chamber angle include the anterior segment optical coherence tomography (OCT) using 1310nm wavelength, which has a resolution of 10µm and Scheimpflug camera (Pentacam®) that has UV-free blue light source of 475nm with a similar resolution. Scheimpflug camera requires a clear cornea and direct visualization of the angle is still a better choice. When the peripheral cornea is opaque, ultrasound biomicroscopy (UBM) is the imaging of choice. It may also assists in evaluation of the ciliary body for congestion as part of uveal effusion syndrome and for aqueous misdirection. Thus, it may elucidate the mechanism of closed angle glaucomas.

Periodic IOP measurements are essential to disclose the development of glaucoma or aggravation of preexisting one. They should be performed in scheduled meetings during different hours of the day to reveal high IOP spikes in patients with high diurnal variations. In cases of doubt, a diurnal IOP curve is indicated and is usually performed every 4 hours between 8:00 and 20:00, but may be performed more frequently (i.e., every 2 hours) and during nighttime as well. IOP measurements should be especially performed when a patient is treated with topical and/or systemic corticosteroids or receives corticosteroid in other forms (e.g., inhalations). If newly IOP elevation is disclosed, recognizing the type of secondary glaucoma is important in treatment decision making (see above). IOP measurements of with Goldmann applanation tonometry may be challenging, because of corneal graft edema, which underestimate the real IOP and corneal graft astigmatism that distorts the image. When measured with Goldmann, the prism may be rotated to aim the red mark on it to the least curved corneal meridian (the negative axis). To overcome the astigmatism, the IOP may be measured twice, one in 90 degrees from the other, and the mean IOP may be calculated from these two measurements. IOP measurements may be performed by pneumatic tonometer, Tono-Pen or Mackay-Marg tonometer if they are impossible to be obtained with Goldmann. Alternatively, the IOP may be qualitatively estimated with a glass rod or by digital palpation. In eyes with corneal scarring, the IOP is overestimated.

When the diagnosis of postoperative or secondary glaucoma is established and the patient is being treated, it is important to avoid discontinuation of the anti-glaucoma medications, unless the patient is closely being followed-up. The course of postoperative glaucoma may be unpredictable and unstable. There might be high long-term fluctuations; i.e. cycles of normal IOP may alternate with increased IOP and the ophthalmologist may mislead to think that the glaucoma has resolved.

Actually, when a diagnosis of secondary glaucoma is made, the patient should always be on anti-glaucoma medications, unless he/ she develops excessive low IOP or intermittent ocular hypotony. In such cases, the anti-glaucoma medications should be discontinued while the patient is followed- up closely. These cases may represent a transition to phthisis bulbi. In cases of ocular hypotony, corticosteroids either topically or systemically may induce some IOP elevation, but if this does not result, pars plana vitrectomy with silicone oil injection into the vitreous might prevent phthisis. Pars plana vitrectomy with silicone oil injection is indicated for chronic ocular hypotony even if the visual acuity is no light perception, because it may prevent phthisis bulbi.

### **8. Treatment of progressive angle closure**

574 Glaucoma - Basic and Clinical Concepts

and true closure. It also allows breaking of fresh anterior synechiae if present. Indentation should be performed cautiously immediately after surgery, because it can result in wound dehiscence. Other gonioscopic lenses include the Goldman three and four mirror lenses, which have a broader base (diameter) and cannot indent only the cornea. They also require viscoelastic agent. Newer imaging modalities of the anterior chamber angle include the anterior segment optical coherence tomography (OCT) using 1310nm wavelength, which has a resolution of 10µm and Scheimpflug camera (Pentacam®) that has UV-free blue light source of 475nm with a similar resolution. Scheimpflug camera requires a clear cornea and direct visualization of the angle is still a better choice. When the peripheral cornea is opaque, ultrasound biomicroscopy (UBM) is the imaging of choice. It may also assists in evaluation of the ciliary body for congestion as part of uveal effusion syndrome and for aqueous misdirection. Thus, it may elucidate the mechanism of

Periodic IOP measurements are essential to disclose the development of glaucoma or aggravation of preexisting one. They should be performed in scheduled meetings during different hours of the day to reveal high IOP spikes in patients with high diurnal variations. In cases of doubt, a diurnal IOP curve is indicated and is usually performed every 4 hours between 8:00 and 20:00, but may be performed more frequently (i.e., every 2 hours) and during nighttime as well. IOP measurements should be especially performed when a patient is treated with topical and/or systemic corticosteroids or receives corticosteroid in other forms (e.g., inhalations). If newly IOP elevation is disclosed, recognizing the type of secondary glaucoma is important in treatment decision making (see above). IOP measurements of with Goldmann applanation tonometry may be challenging, because of corneal graft edema, which underestimate the real IOP and corneal graft astigmatism that distorts the image. When measured with Goldmann, the prism may be rotated to aim the red mark on it to the least curved corneal meridian (the negative axis). To overcome the astigmatism, the IOP may be measured twice, one in 90 degrees from the other, and the mean IOP may be calculated from these two measurements. IOP measurements may be performed by pneumatic tonometer, Tono-Pen or Mackay-Marg tonometer if they are impossible to be obtained with Goldmann. Alternatively, the IOP may be qualitatively estimated with a glass rod or by digital palpation. In eyes with corneal scarring, the IOP is

When the diagnosis of postoperative or secondary glaucoma is established and the patient is being treated, it is important to avoid discontinuation of the anti-glaucoma medications, unless the patient is closely being followed-up. The course of postoperative glaucoma may be unpredictable and unstable. There might be high long-term fluctuations; i.e. cycles of normal IOP may alternate with increased IOP and the ophthalmologist may mislead to

Actually, when a diagnosis of secondary glaucoma is made, the patient should always be on anti-glaucoma medications, unless he/ she develops excessive low IOP or intermittent ocular hypotony. In such cases, the anti-glaucoma medications should be discontinued while the patient is followed- up closely. These cases may represent a transition to phthisis bulbi. In cases of ocular hypotony, corticosteroids either topically or systemically may induce some IOP elevation, but if this does not result, pars plana vitrectomy with silicone oil injection into the vitreous might prevent phthisis. Pars plana vitrectomy with silicone oil injection is indicated for chronic ocular hypotony even if the visual acuity is no light

closed angle glaucomas.

overestimated.

think that the glaucoma has resolved.

perception, because it may prevent phthisis bulbi.

The treatment of postoperative progressive angle closure even with normal IOP includes peripheral laser iridotomy and topical corticosteroids to control anterior chamber inflammation. If the IOP increases, a prompt surgical synechiolysis is warranted.

#### **9. Treatment of secondary glaucoma**

Open angle glaucoma is treated in the following order. The first line of treatment is medical with alpha-agonists (brimonidine tartrate) and beta-blockers (timolol maleate, betaxolol). In phakic eyes, prostaglandin analogs (latanoprost) and adrenergic agents (dipivefrin, epinephrine) may be added. In aphakic and pseudophakic eyes, prostaglandin analogs and adrenergic agents may induce cystoid macular edema (CME), which may result in a decrease in visual acuity, and therefore should be avoided. Topical carbonic anhydrase inhibitors (dorzolamide, brinzolamide) may cause graft failure due to toxicity to endothelial cells. Miotics may initiate intraocular inflammation by breaking the blood-aqueous barrier and may increase the likelihood of corneal graft rejection. In aphakic eyes, the risk of retinal detachment also increases. Therefore, these agents should be spared if possible.

The adverse effects of beta-blockers include superficial punctate keratopathy, corneal anesthesia and dry eyes. Alpha-adrenergic agents may also cause superficial punctate keratopathy and dry eyes.

If medical treatment fails, trabeculectomy with MMC (option for two such procedures) should be considered (Figure 1). However, some authors suggested that the prognosis might be poorer than for placement of a glaucoma drainage implant. If a trabeculectomy is performed, a soaked sponge (WekCel) of MMC 0.2-0.4 mg/ml under the scleral flap before penetrating the anterior chamber (or under the conjunctiva avoiding its edge) for 2-3 min should be added. The MMC should not be placed over corneal button–recipient bed interface. Then the area should be copiously irrigated with balanced salt solution or saline. This procedure may be repeated if it failed once. In some cases, the filtration procedure may be functioning well causing a decrease in IOP, but to insufficient level (above the target pressure). In such a case, an additional trabeculectomy rather than anti-glaucoma medications may be successful decreasing further the IOP to the desired level because they may diminish the filtration through the trabeculectomy resulting in its failure for long term. Also, with a successful second trabeculectomy, the patient may not need long-term topical medications, which are a burden. An alternative for MMC is 5-fluorouracil (5FU). Five-mg may be injected subconjunctivally before or at intervals after surgery, but is less potent. Another option is to place 50mg/ml of 5-FU over or under the scleral flap intraoperatively. It inhibits epithelial proliferation, while MMC is better against fibrous proliferation. Both drugs may be injected in conjunction.

The complications of trabeculectomy with MMC in the presence of corneal graft are similar to those without a graft, but in addition, damage to the endothelium may be caused by the MMC, if it penetrates into anterior chamber. The same precautions that apply for placing MMC during surgery for primary open angle glaucoma should be applied here.

If one or two trabeculectomies with MMC have been failed or as a first surgical option, glaucoma shunt tube may be performed. Anterior or posterior drainage devices are available. Anterior drainage devices connect the anterior chamber with the subconjunctival space. Schlemm's canal or suprachoroidal space are easier to implant and require only limited healthy conjunctiva to function. Among the anterior drainage devices are Ex-Press,

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 577

follow-up of 12 months, but a longer follow-up is required. The implantation is performed under 5x5mm partial thickness scleral flap similar to limbal-based trabeculectomy and MMC 0.05% is applied for 3min and rinsed after it. No data exist yet concerning the other anterior devices. In cases of corneal transplantation or posterior lamellar procedure, the position of the shunt tube may play a critical role in preservation of clear graft. In phakic eyes, the tube is usually placed through the anterior chamber angle. This results in control of the glaucoma in 68-96%.19-25 However, placement of the tube into the anterior chamber may endanger the transparency of the graft due to tube-endothelial touch or turbulent flow of aqueous through the tip even in the absence of touch. Additional causes include eye rubbing and pressure on the cornea on sleeping. This complication is unique for corneal grafts and for compromised corneas (e.g., in Fuchs' endothelial dystrophy), since it has been demonstrated that progressive endothelial cell lost is observed after placement of glaucoma drainage tube into the anterior chamber angle, and this may occur even in the absence of endothelial-tube touch. Forty-two percent of the eyes with corneal transplants develop

It is possible to redirect the tube placed into the anterior chamber angle through an existing iridectomy to the posterior chamber in aphakic or pseudophakic eyes as long as the iris would not block it. Another alternative in pseudophakic or aphakic eyes, is to place the tube into the posterior chamber through the ciliary sulcus, by an incision made 1mm posterior to the limbus.26 This procedure is especially advantageous in eyes with corneal transplants or which are candidates for corneal transplantation or posterior lamellar grafts, Fuchs' corneal dystrophy, shallow anterior chamber and extensive synechial angle closure. A meticulous

For placement of glaucoma shunt tube into the ciliary sulcus, limbal peritomy is performed in the upper temporal (or if not feasible, inferonasal) quadrant and dissection is carried posteriorly over the sclera. The drainage plate is secured to the sclera with 6-0 polyester sutures 8 to 10mm posterior to the limbus between the superior and the horizontal recti muscles. A 2 to 5mm-long scleral tunnel is fashioned with angled crescent knife and the drainage tube is passed beneath it. Alternatively, the tube may be covered with scleral, corneal, pericardial or dural patch adjacent to the external sclerostomy. The tube is passed into the ciliary sulcus through a sclerostomy performed 1mm posterior to the limbus at 11 or 1 o'clock position under a half-thickness, limbal based scleral flap of 3x3mm. The sclerostomy is performed with a myringotomy blade that is inserted with its shaft perpendicular to the limbus and beveled parallel to the iris plane (as performed for scleral-fixated intraocular lens). The position of the tip of the blade is observed through the dilated pupil to confirm its position and avoid ciliary body separation. The edge of the tube is protruding 3mm into the posterior chamber. It should not exceed the dilated pupil margin to avoid glare and should not be too short to avoid blockage by ciliary processes. The fornix-based conjunctival flap is secured to the limbus with 7-0 polygalactin sutures (Figures 2,3). At the conclusion of the surgery betamethasone acetate 3mg and gentamicin sulfate 20mg are injected subconjunctivally 180° away from the implant plate. Topical corticosteroid, antibiotic and cycloplegic are prescribed and tapered gradually. The main potential complications include ciliary body separation and suprachoroidal hemorrhage. These were not observed in a series of patients that underwent this procedure.26-28 The corneal grafts remained clear for years of follow-up and the glaucoma was controlled following this procedure. Placement of the shunt tube into the posterior chamber through the ciliary sulcus is contraindicated in phakic

corneal decompensation.23

anterior vitrectomy is required if cases of vitreous loss.

eyes because it may endanger the integrity of the crystalline lens.

Solx Gold shunt and iStent. Posterior drainage devices also drain the anterior chamber through a silastic tube, but the tube is connected to a plate that is placed under the conjunctiva posteriorly. This is the reason that they are called posterior devices. Two types of posterior shunt tubes exist. The first type is with control of the flow (with a "valve" or flow resistance) includes Ahmed (New World Medical, Rancho Cucamonga, CA) and Krupin-Denver (Hood Laboratories, Pembroke, MA) drainage implants. The second type is without pressure control and includes Molteno single or double plate (IOP, Inc., Costa Mesa, CA, USA, and Molteno Ophthalmic Limited, Dunedin, New Zealand), Baerveldt (Advanced Medical Optics, Santa Ana, California, USA), Shocket (self-assembled) and Eagle Vision (Eagle Vision, Inc. Memphis, TN, USA) implants. The later require blocking the aqueous flow for a few days externally by temporary suture or internally by passing a suture through the lumen of the tube or injecting viscoelastic agent. The implantation may also be performed as a two-stage implantation, to decrease the risk for postoperative hypotony. Ahmed and Krupin implants should be preferred over the implants without a valve, because the risk for postoperative overflow and hypotony that may result in endothelial-iris and lens touch is decreased. Ahmed has a convenient plate to implant and suture in variable sizes including for pediatric population.

Fig. 1. Trabeculectomy in presence of clear corneal graft in a pseudophakic eye. Note the two patent peripheral iridectomies

The experience with anterior drainage devises is limited to a short follow-up, since they are relatively new. Results with Ex-press are promising.18 The success rate defined as IOP below 21mmHG in 15 corneal transplanted eyes with closed angle glaucoma was 87% over a mean

Solx Gold shunt and iStent. Posterior drainage devices also drain the anterior chamber through a silastic tube, but the tube is connected to a plate that is placed under the conjunctiva posteriorly. This is the reason that they are called posterior devices. Two types of posterior shunt tubes exist. The first type is with control of the flow (with a "valve" or flow resistance) includes Ahmed (New World Medical, Rancho Cucamonga, CA) and Krupin-Denver (Hood Laboratories, Pembroke, MA) drainage implants. The second type is without pressure control and includes Molteno single or double plate (IOP, Inc., Costa Mesa, CA, USA, and Molteno Ophthalmic Limited, Dunedin, New Zealand), Baerveldt (Advanced Medical Optics, Santa Ana, California, USA), Shocket (self-assembled) and Eagle Vision (Eagle Vision, Inc. Memphis, TN, USA) implants. The later require blocking the aqueous flow for a few days externally by temporary suture or internally by passing a suture through the lumen of the tube or injecting viscoelastic agent. The implantation may also be performed as a two-stage implantation, to decrease the risk for postoperative hypotony. Ahmed and Krupin implants should be preferred over the implants without a valve, because the risk for postoperative overflow and hypotony that may result in endothelial-iris and lens touch is decreased. Ahmed has a convenient plate to implant and suture in variable

Fig. 1. Trabeculectomy in presence of clear corneal graft in a pseudophakic eye. Note the

The experience with anterior drainage devises is limited to a short follow-up, since they are relatively new. Results with Ex-press are promising.18 The success rate defined as IOP below 21mmHG in 15 corneal transplanted eyes with closed angle glaucoma was 87% over a mean

sizes including for pediatric population.

two patent peripheral iridectomies

follow-up of 12 months, but a longer follow-up is required. The implantation is performed under 5x5mm partial thickness scleral flap similar to limbal-based trabeculectomy and MMC 0.05% is applied for 3min and rinsed after it. No data exist yet concerning the other anterior devices. In cases of corneal transplantation or posterior lamellar procedure, the position of the shunt tube may play a critical role in preservation of clear graft. In phakic eyes, the tube is usually placed through the anterior chamber angle. This results in control of the glaucoma in 68-96%.19-25 However, placement of the tube into the anterior chamber may endanger the transparency of the graft due to tube-endothelial touch or turbulent flow of aqueous through the tip even in the absence of touch. Additional causes include eye rubbing and pressure on the cornea on sleeping. This complication is unique for corneal grafts and for compromised corneas (e.g., in Fuchs' endothelial dystrophy), since it has been demonstrated that progressive endothelial cell lost is observed after placement of glaucoma drainage tube into the anterior chamber angle, and this may occur even in the absence of endothelial-tube touch. Forty-two percent of the eyes with corneal transplants develop corneal decompensation.23

It is possible to redirect the tube placed into the anterior chamber angle through an existing iridectomy to the posterior chamber in aphakic or pseudophakic eyes as long as the iris would not block it. Another alternative in pseudophakic or aphakic eyes, is to place the tube into the posterior chamber through the ciliary sulcus, by an incision made 1mm posterior to the limbus.26 This procedure is especially advantageous in eyes with corneal transplants or which are candidates for corneal transplantation or posterior lamellar grafts, Fuchs' corneal dystrophy, shallow anterior chamber and extensive synechial angle closure. A meticulous anterior vitrectomy is required if cases of vitreous loss.

For placement of glaucoma shunt tube into the ciliary sulcus, limbal peritomy is performed in the upper temporal (or if not feasible, inferonasal) quadrant and dissection is carried posteriorly over the sclera. The drainage plate is secured to the sclera with 6-0 polyester sutures 8 to 10mm posterior to the limbus between the superior and the horizontal recti muscles. A 2 to 5mm-long scleral tunnel is fashioned with angled crescent knife and the drainage tube is passed beneath it. Alternatively, the tube may be covered with scleral, corneal, pericardial or dural patch adjacent to the external sclerostomy. The tube is passed into the ciliary sulcus through a sclerostomy performed 1mm posterior to the limbus at 11 or 1 o'clock position under a half-thickness, limbal based scleral flap of 3x3mm. The sclerostomy is performed with a myringotomy blade that is inserted with its shaft perpendicular to the limbus and beveled parallel to the iris plane (as performed for scleral-fixated intraocular lens). The position of the tip of the blade is observed through the dilated pupil to confirm its position and avoid ciliary body separation. The edge of the tube is protruding 3mm into the posterior chamber. It should not exceed the dilated pupil margin to avoid glare and should not be too short to avoid blockage by ciliary processes. The fornix-based conjunctival flap is secured to the limbus with 7-0 polygalactin sutures (Figures 2,3). At the conclusion of the surgery betamethasone acetate 3mg and gentamicin sulfate 20mg are injected subconjunctivally 180° away from the implant plate. Topical corticosteroid, antibiotic and cycloplegic are prescribed and tapered gradually. The main potential complications include ciliary body separation and suprachoroidal hemorrhage. These were not observed in a series of patients that underwent this procedure.26-28 The corneal grafts remained clear for years of follow-up and the glaucoma was controlled following this procedure. Placement of the shunt tube into the posterior chamber through the ciliary sulcus is contraindicated in phakic eyes because it may endanger the integrity of the crystalline lens.

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 579

In cases of posterior segment disorders, when pars plana vitrectomy is required, the tube may be placed into the vitreous cavity through it.30,31 A meticulous vitrectomy is a prerequisite so vitreous strands will not block the tube. The common feature for placement of the shunt tube into the posterior chamber through the ciliary sulcus or into the vitreous cavity through the pars plana is placing the tip of the tube away from the corneal graft, which decreases the risk of endothelial cell loss and corneal graft

For pars plana placement of glaucoma drainage device, a limbal peritomy is performed and the lateral and superior rectus muscles are engaged by 4-0 silk traction sutures. The sclera is exposed further back by elevating the conjunctiva and Tenon's capsule with blunt dissection. The plate is secured to the superotemporal sclera with 6-0 polyester sutures. Then a threeport pars plana vitrectomy is performed through sclerostomies 3.5mm from the limbus. The tube is introduced 5mm into the vitreous through the superotemporal sclerostomy. A sclera, corneal, dural or pericardial patch may be used to cover the tube and the conjunctival-Tenon flap is sutured to the limbus with 7-0 polygalactin sutures. A Pars Plana Clip (Model PC,New World M, Inc., Rancho Cucamonga, CA, USA), which can be used with any drainage device, or Hoffman elbow, which is mounted on a Baerveldt 350-mm2 implant (Advanced Medical Optics, Inc., Santa Ana, CA, USA) may be used. New pars plana Ahmed and Baeverdlt implants are also available and the procedure may be performed using even the regular glaucoma setones, preferably those with a "valve". Fluid-gas exchange provides a temporary tamponade and prevents postoperative hypotony. Pars plana vitrectomy and placement of glaucoma shunt device may be performed endoscopically in eyes with media opacity such as corneal opacity.32 This procedure allows controlling the glaucoma first and then performing corneal surgery later to improve visual acuity. Possible unique complications for this procedure include vitreous hemorrhage, retinal detachment and choroidal detachment. Although corneal graft failure is reduced if the glaucoma drainage device is placed through the ciliary sulcus or pars plana and if the glaucoma is controlled, it should

be remembered that there are other causes that may result in graft failure.

the eye is quiet, if the edema has not been resolved.

In posterior lamellar grafts, if a glaucoma shunt tube is introduced into the anterior chamber, the graft may block the tip of the tube resulting in increased IOP. It can be avoided by trimming the tip of the tube, so it will not be blocked. It is also possible to pre-plane the corneal surgery and to prepare a thin lamellar graft or perform a DMEK rather than DSAEK (Figures 4,5).29 Tube-endothelial touch without blockage may also occur and is manifested as corneal edema. It may increase the risk for corneal graft rejection. If tube-endothelial touch or tube blockage is suspected, the diagnosis may be confirmed by direct visualization with slit lamp biomicroscopy or indirectly with UBM, Scheimpflug camera (Pentacam) or anterior segment OCT. When tube-endothelial touch or tube blockage is confirmed, the tube should be trimmed. The trimming should be performed so that the opening of the tip would not face the corneal graft, because turbulence at the tip may cause progressive loss of endothelial cells and corneal decompensation that will require a new transplant. The opening should not face the iris as well because it may be blocked. The tip may also be redirected if long and mobile enough. This can be done by retrieving the tube from the anterior chamber, creating a new passage into the chamber and suturing the old route. Just moving the tube in the existing route is usually unhelpful. If the graft is edematous at the time of managing the tube, regrafting may be performed later when the IOP is stable and

decompensation.

Fig. 2. A diagram showing a side view of placement of a glaucoma drainage device in the ciliary sulcus. c – cornea, a/c – anterior chamber, I – iris, p – pupil, s/f – scleral flap, c/b – ciliary body, s/t in c/s – shunt tube in the ciliary sulcus, s/t in sl/tl – shunt tube in scleral tunnel, d/i – implant disc

Fig. 3. The tip of ciliary sulcus glaucoma shunt tube behind the iris during surgery before placing a corneal graft

**s/f**

**s/t in sl/tl**

Fig. 2. A diagram showing a side view of placement of a glaucoma drainage device in the ciliary sulcus. c – cornea, a/c – anterior chamber, I – iris, p – pupil, s/f – scleral flap, c/b – ciliary body, s/t in c/s – shunt tube in the ciliary sulcus, s/t in sl/tl – shunt tube in scleral

Fig. 3. The tip of ciliary sulcus glaucoma shunt tube behind the iris during surgery before

**a/c**

**p**

**c**

**s/t in s/c**

**d/i**

tunnel, d/i – implant disc

placing a corneal graft

In cases of posterior segment disorders, when pars plana vitrectomy is required, the tube may be placed into the vitreous cavity through it.30,31 A meticulous vitrectomy is a prerequisite so vitreous strands will not block the tube. The common feature for placement of the shunt tube into the posterior chamber through the ciliary sulcus or into the vitreous cavity through the pars plana is placing the tip of the tube away from the corneal graft, which decreases the risk of endothelial cell loss and corneal graft decompensation.

For pars plana placement of glaucoma drainage device, a limbal peritomy is performed and the lateral and superior rectus muscles are engaged by 4-0 silk traction sutures. The sclera is exposed further back by elevating the conjunctiva and Tenon's capsule with blunt dissection. The plate is secured to the superotemporal sclera with 6-0 polyester sutures. Then a threeport pars plana vitrectomy is performed through sclerostomies 3.5mm from the limbus. The tube is introduced 5mm into the vitreous through the superotemporal sclerostomy. A sclera, corneal, dural or pericardial patch may be used to cover the tube and the conjunctival-Tenon flap is sutured to the limbus with 7-0 polygalactin sutures. A Pars Plana Clip (Model PC,New World M, Inc., Rancho Cucamonga, CA, USA), which can be used with any drainage device, or Hoffman elbow, which is mounted on a Baerveldt 350-mm2 implant (Advanced Medical Optics, Inc., Santa Ana, CA, USA) may be used. New pars plana Ahmed and Baeverdlt implants are also available and the procedure may be performed using even the regular glaucoma setones, preferably those with a "valve". Fluid-gas exchange provides a temporary tamponade and prevents postoperative hypotony. Pars plana vitrectomy and placement of glaucoma shunt device may be performed endoscopically in eyes with media opacity such as corneal opacity.32 This procedure allows controlling the glaucoma first and then performing corneal surgery later to improve visual acuity. Possible unique complications for this procedure include vitreous hemorrhage, retinal detachment and choroidal detachment. Although corneal graft failure is reduced if the glaucoma drainage device is placed through the ciliary sulcus or pars plana and if the glaucoma is controlled, it should be remembered that there are other causes that may result in graft failure.

In posterior lamellar grafts, if a glaucoma shunt tube is introduced into the anterior chamber, the graft may block the tip of the tube resulting in increased IOP. It can be avoided by trimming the tip of the tube, so it will not be blocked. It is also possible to pre-plane the corneal surgery and to prepare a thin lamellar graft or perform a DMEK rather than DSAEK (Figures 4,5).29 Tube-endothelial touch without blockage may also occur and is manifested as corneal edema. It may increase the risk for corneal graft rejection. If tube-endothelial touch or tube blockage is suspected, the diagnosis may be confirmed by direct visualization with slit lamp biomicroscopy or indirectly with UBM, Scheimpflug camera (Pentacam) or anterior segment OCT. When tube-endothelial touch or tube blockage is confirmed, the tube should be trimmed. The trimming should be performed so that the opening of the tip would not face the corneal graft, because turbulence at the tip may cause progressive loss of endothelial cells and corneal decompensation that will require a new transplant. The opening should not face the iris as well because it may be blocked. The tip may also be redirected if long and mobile enough. This can be done by retrieving the tube from the anterior chamber, creating a new passage into the chamber and suturing the old route. Just moving the tube in the existing route is usually unhelpful. If the graft is edematous at the time of managing the tube, regrafting may be performed later when the IOP is stable and the eye is quiet, if the edema has not been resolved.

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 581

Laser procedures for the angle such as selective trabeculoplasty have a limited value in the long-term treatment of secondary open angle glaucomas and therefore, were not included in the sequence of treatment. The main reason is their limited effect in this type of glaucoma. Even in primary open angle glaucoma, where it is more effective, the success rate is only

Closed angle glaucoma should be confirmed by gonioscopy or UBM or with other imaging techniques (anterior segment OCT or Scheimpflug camera). The first treatment modality, which is usually simplest, if the cornea is clear, is peripheral laser iridotomy. This is usually performed with Neodymium: Yttrium-Aluminum-Garnet (Nd:YAG) laser. After instillation of topical pilocarpine 2% or 4% and topical analgesic (e.g., oxybuprocaine HCl 0.4% or proparacaine HCl 0.5%) eye drop, a spot of 10mJ is placed over the peripheral iris. Two pulses may be used simultaneously. The size of the spot is constant depending on the instrument (50-70μm). The spot is placed at the periphery of the iris in the superior half to avoid glare and over a thin part of the iris (usually a crypt) avoiding blood vessels. If bleeding occurs, the cornea is pressed by a contact lens until bleeding ceases. The procedure may be performed with contact lens such as Abraham (+66D), Wise (+103D), CGI or without it. The advantages of a contact lens are additional magnification, focusing the beam, absorbing part of the heat, stabilizing the eye and maintaining the eyelids open. Topical glycerin may be placed over the cornea before the procedure if it is edematous. Topical apraclonidine (Iopidine®) 0.5%-1.0% or other alpha 2 agonist (e.g., brimonidine tartrate) is administered following the procedure to decrease IOP spikes and corticosteroids such as prednisolone acetate 1% qid are prescribed of a week to decrease intraocular inflammation and risk for synechiae formation. Additional anti-glaucoma medications may be added. This procedure facilitates aqueous flow from the posterior into the anterior chamber and may result in deepening of the anterior chamber and lowering the IOP. The major complication is acceleration of cataract. If Nd:YAG laser is unavailable, Argon laser iridotomy may be performed. The parameters for this procedure depend on the iris pigmentation. For brighter iris, the power is lower than for darker ones. The preparatory stretch burns are of 200- 600mW, 0.2-0.6 sec, 200-500μm. The penetration burns are of 800-1000mW, 0.2 sec, 50μm. The iridotomy size should be increased to 150-500μm. The position of the Argon iridotomy in this case is preferably supero-nasal to prevent injury to the macula. The treatment before and after the procedure is identical to Nd:YAG laser iridotomy. Perforation of the iris is obtained when aqueous mixed with pigment is flowing from the posterior to the anterior chamber through the iridotomy. The lens should be visible through the iridotomy, since positive transillumination is not reliable. When laser iridotomy is not feasible, surgical peripheral iridectomy should be performed. Complications include visual disturbances such as halo and glare, development and progression of cataract, corneal burns that are usually transient, temporary increase in IOP, intraocular inflammation and rarely retinal injury,

If laser iridotomy does not result in decrease in IOP, surgical peripheral goniosynechiolysis or laser peripheral iridoplasty may be performed. This should be performed as earlier as possible and preferably if the angle closure is of less than 6 months. Otherwise, it is usually useless, because of scarring. Peripheral goniosynechiolysis is performed through a paracentesis. It may be performed under viscoelastic material or with anterior chamber maintainer. A spatula is transferred along the peripheral iris to withdraw it from the angle.

50% 5 years after the procedure.

**10. Closed angle glaucoma** 

CME and malignant glaucoma.

Fig. 4. Glaucoma shunt tube (arrow) in an eye after Descemet's membrane - endothelial keratoplasty (DMEK). Note the clear lamellar graft

Fig. 5. Pentacam image of the same eye as in figure 4 showing the position of the tube in the anterior chamber (arrow)

Laser procedures for the angle such as selective trabeculoplasty have a limited value in the long-term treatment of secondary open angle glaucomas and therefore, were not included in the sequence of treatment. The main reason is their limited effect in this type of glaucoma. Even in primary open angle glaucoma, where it is more effective, the success rate is only 50% 5 years after the procedure.

#### **10. Closed angle glaucoma**

580 Glaucoma - Basic and Clinical Concepts

Fig. 4. Glaucoma shunt tube (arrow) in an eye after Descemet's membrane - endothelial

Fig. 5. Pentacam image of the same eye as in figure 4 showing the position of the tube in the

keratoplasty (DMEK). Note the clear lamellar graft

anterior chamber (arrow)

Closed angle glaucoma should be confirmed by gonioscopy or UBM or with other imaging techniques (anterior segment OCT or Scheimpflug camera). The first treatment modality, which is usually simplest, if the cornea is clear, is peripheral laser iridotomy. This is usually performed with Neodymium: Yttrium-Aluminum-Garnet (Nd:YAG) laser. After instillation of topical pilocarpine 2% or 4% and topical analgesic (e.g., oxybuprocaine HCl 0.4% or proparacaine HCl 0.5%) eye drop, a spot of 10mJ is placed over the peripheral iris. Two pulses may be used simultaneously. The size of the spot is constant depending on the instrument (50-70μm). The spot is placed at the periphery of the iris in the superior half to avoid glare and over a thin part of the iris (usually a crypt) avoiding blood vessels. If bleeding occurs, the cornea is pressed by a contact lens until bleeding ceases. The procedure may be performed with contact lens such as Abraham (+66D), Wise (+103D), CGI or without it. The advantages of a contact lens are additional magnification, focusing the beam, absorbing part of the heat, stabilizing the eye and maintaining the eyelids open. Topical glycerin may be placed over the cornea before the procedure if it is edematous. Topical apraclonidine (Iopidine®) 0.5%-1.0% or other alpha 2 agonist (e.g., brimonidine tartrate) is administered following the procedure to decrease IOP spikes and corticosteroids such as prednisolone acetate 1% qid are prescribed of a week to decrease intraocular inflammation and risk for synechiae formation. Additional anti-glaucoma medications may be added. This procedure facilitates aqueous flow from the posterior into the anterior chamber and may result in deepening of the anterior chamber and lowering the IOP. The major complication is acceleration of cataract. If Nd:YAG laser is unavailable, Argon laser iridotomy may be performed. The parameters for this procedure depend on the iris pigmentation. For brighter iris, the power is lower than for darker ones. The preparatory stretch burns are of 200- 600mW, 0.2-0.6 sec, 200-500μm. The penetration burns are of 800-1000mW, 0.2 sec, 50μm. The iridotomy size should be increased to 150-500μm. The position of the Argon iridotomy in this case is preferably supero-nasal to prevent injury to the macula. The treatment before and after the procedure is identical to Nd:YAG laser iridotomy. Perforation of the iris is obtained when aqueous mixed with pigment is flowing from the posterior to the anterior chamber through the iridotomy. The lens should be visible through the iridotomy, since positive transillumination is not reliable. When laser iridotomy is not feasible, surgical peripheral iridectomy should be performed. Complications include visual disturbances such as halo and glare, development and progression of cataract, corneal burns that are usually transient, temporary increase in IOP, intraocular inflammation and rarely retinal injury, CME and malignant glaucoma.

If laser iridotomy does not result in decrease in IOP, surgical peripheral goniosynechiolysis or laser peripheral iridoplasty may be performed. This should be performed as earlier as possible and preferably if the angle closure is of less than 6 months. Otherwise, it is usually useless, because of scarring. Peripheral goniosynechiolysis is performed through a paracentesis. It may be performed under viscoelastic material or with anterior chamber maintainer. A spatula is transferred along the peripheral iris to withdraw it from the angle.

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 583

The treatment of steroid-induced glaucoma follows the same principles applied for primary

Glaucoma in cases of posterior segment disorders (e.g. proliferative diabetic retinopathy, neovascular glaucoma, uveitic glaucoma) along with corneal disorders are more challenging to treat. Pars plana vitrectomy may require a temporary keratoprosthesis for visualization of the posterior segment. Following which, a corneal transplantation is being performed. Otherwise, pars plana vitrectomy may be performed endoscopically. In both instances, if the glaucoma is refractory to medical treatment, a pars plana implantation of glaucoma

Cyclodestructive procedures should be avoided if possible, because the degree of IOP reduction and intraocular inflammation are unpredictable. Excessive intraocular inflammation may cause intense pain, CME and hypotony that may result in phthisis bulbi. External inflammation may cause excessive scarring of the conjunctiva, preventing other procedures such as trabeculectomy to be performed. The corneal graft may also fail. Cyclodestructive procedures should be reserved only for painful eyes with no potential for visual rehabilitation. If cyclodestructive procedures are employed, transscleral cyclophotocoagulation (contact or non-contact, Nd:YAG or diode laser) or transcorneal ciliary processes photocoagulation should be preferred over cyclocryoablation. The former causes less postoperative pain, postoperative inflammatory reaction and phthisis bulbi than cyclocryoablation. Even when transscleral cyclophotocoagulation (contact or non-contact, Nd:YAG or diode laser) or transcorneal ciliary processes photocoagulation is being performed, it may be applied to half to two thirds of the ciliary body to prevent these complications. This book contains a chapter on controlled cyclophotocoagulation to decrease

For cyclodestructive procedures, sub-Tenon, peribulbar or retrobulbar anesthesia with 2% lidocaine (or a 1:1 mixture with 0.75% bupivicaine) is used. Transscleral Nd:YAG (1064nm) may be contact or non-contact, continuous or pulsed. Eight to 25 applications of 1.5-10J are placed 2-3mm beyond the limbus over 180°. This position corresponds to the location of the ciliary body and is confirmed by transillumination. Trans scleral Diode (810nm), 10-20 applications of 5-6mJ over 180-270° is performed 2mm posterior to the limbus. Following the procedure, topical corticosteroids such as prednisolone acetate 1% qid or more and atropine sulfate 1% tid for a few weeks are warranted. Analgesia may also be required. The antiglaucoma medications are tapered gradually according to the decrease in IOP. The success of the procedure is usually assessed 4 weeks after treatment. The complications include hyphema, corneal decompensation, chronic intraocular inflammation, CME, epiretinal membranes, chronic hypotony and even phthisis bulbi. They may be fewer with Diode laser

The prognosis of preexisting glaucoma depends on its type.17 It is usually more favorable for primary open angle glaucoma as long as precautions have been taken during the penetrating keratoplasty or the lamellar grafting. The prognosis for graft survival is also

**12. Glaucoma in patients with corneal and posterior segment disorders**

open-angle glaucoma (see above).

drainage implant is advised.

complications.

with G-probe.33

**13. Prognosis** 

Goniosynechiolysis may be performed in a similar way with viscoelastic agent injected toward the angle to open it. However, the viscoelastic material should be removed at the conclusion of the procedure to prevent postoperative high IOP. Laser iridoplasty is performed after instillation of topical anesthetic eye drop with Argon laser, 200-400mW, 0.3- 0.6 sec, 500 μm, 20-40 burns in a row with 2-beam diameter space between each spot over 360 peripheral iris avoiding blood vessels. The procedure is performed with a contact lens such as the Abraham (+66D), Wise (+103D), CGI or Goldmann three-mirror lens (through the center, non-mirror part) or without it. The preparations before and the management following the procedure are similar to this described above for Nd:YAG laser iridotomy. The procedure is aimed to contract the peripheral iris away from the angle. The contraindications for the procedure include extensive synechial closure and flat anterior chamber. The complications of the procedure include corneal burns, increased IOP, iritis, new synechiae formation and mydriasis.

If the IOP did not decrease substantially to the target level following these two procedures, medical treatment with anti-glaucoma medications including pilocarpine 2% four times a day may be added. If pilocarpine is added, it is worthwhile to have two consecutive days off this medication every month. This decreases the probability to have fixed small pupil, which may be an obstacle if cataract extraction is required.

If the IOP remained high or becoming high despite of medical treatment, other surgical procedures may be performed. The usual approach is to have trabeculectomy first. Trabeculectomy in this case may require a long tunnel (or sclerostomy) that will penetrate the peripheral cornea anterior to the peripheral anterior synechiae.

When a trabeculectomy is failed, a glaucoma shunt tube may be placed as mentioned earlier. In aphakic and pseudophakic eyes it may be placed into the ciliary sulcus.

#### **11. Steroid-induced glaucoma**

Steroid-induced glaucoma is defined as elevation of IOP following administration of topical and/or systemic corticosteroids that remains high after their discontinuation. Steroid responder is a patient in whom the IOP returns to normal after discontinuation of the steroids. These medications are often used after corneal transplantation to prevent or treat corneal graft rejection. They are also used to treat postoperative intraocular inflammation. Differentiation between steroid-induced glaucoma and inflammatory (uveitic) glaucoma may be performed by increasing the topical corticosteroid dosage for several days. If IOP remains high despite decreased intraocular inflammation, a corticosteroid-induced glaucoma is most reasonable.

In cases of steroid responders or steroid-induced glaucoma, discontinuation of the corticosteroids is mandatory. Patients, who are steroid responders, should be aware that they are "allergic" to steroid in the specific form that causes their IOP to increase. This should be written in their medical chart and added to a note (or a card) for the patient, specify that he should not receive this type of drug. For episodes of graft immune rejection, a combination of topical NSAID (sodium diclofenac 0.1% or ketorolac tromethamine 0.5%) and topical cyclosporine-A may be employed. Systemic cyclosporine-A or other drugs such as PO tacrolimus 0.1mg/kg/day may be added. Another option is to use IOP-sparing corticosteroids such as loteprednol etabonate 0.5% (Lotemax®) or rimexolone 1% (Vexol®). Judicious use of systemic corticosteroids instead of topical corticosteroids may be adopted if they do not cause an increase in IOP.

The treatment of steroid-induced glaucoma follows the same principles applied for primary open-angle glaucoma (see above).

#### **12. Glaucoma in patients with corneal and posterior segment disorders**

Glaucoma in cases of posterior segment disorders (e.g. proliferative diabetic retinopathy, neovascular glaucoma, uveitic glaucoma) along with corneal disorders are more challenging to treat. Pars plana vitrectomy may require a temporary keratoprosthesis for visualization of the posterior segment. Following which, a corneal transplantation is being performed. Otherwise, pars plana vitrectomy may be performed endoscopically. In both instances, if the glaucoma is refractory to medical treatment, a pars plana implantation of glaucoma drainage implant is advised.

Cyclodestructive procedures should be avoided if possible, because the degree of IOP reduction and intraocular inflammation are unpredictable. Excessive intraocular inflammation may cause intense pain, CME and hypotony that may result in phthisis bulbi. External inflammation may cause excessive scarring of the conjunctiva, preventing other procedures such as trabeculectomy to be performed. The corneal graft may also fail. Cyclodestructive procedures should be reserved only for painful eyes with no potential for visual rehabilitation. If cyclodestructive procedures are employed, transscleral cyclophotocoagulation (contact or non-contact, Nd:YAG or diode laser) or transcorneal ciliary processes photocoagulation should be preferred over cyclocryoablation. The former causes less postoperative pain, postoperative inflammatory reaction and phthisis bulbi than cyclocryoablation. Even when transscleral cyclophotocoagulation (contact or non-contact, Nd:YAG or diode laser) or transcorneal ciliary processes photocoagulation is being performed, it may be applied to half to two thirds of the ciliary body to prevent these complications. This book contains a chapter on controlled cyclophotocoagulation to decrease complications.

For cyclodestructive procedures, sub-Tenon, peribulbar or retrobulbar anesthesia with 2% lidocaine (or a 1:1 mixture with 0.75% bupivicaine) is used. Transscleral Nd:YAG (1064nm) may be contact or non-contact, continuous or pulsed. Eight to 25 applications of 1.5-10J are placed 2-3mm beyond the limbus over 180°. This position corresponds to the location of the ciliary body and is confirmed by transillumination. Trans scleral Diode (810nm), 10-20 applications of 5-6mJ over 180-270° is performed 2mm posterior to the limbus. Following the procedure, topical corticosteroids such as prednisolone acetate 1% qid or more and atropine sulfate 1% tid for a few weeks are warranted. Analgesia may also be required. The antiglaucoma medications are tapered gradually according to the decrease in IOP. The success of the procedure is usually assessed 4 weeks after treatment. The complications include hyphema, corneal decompensation, chronic intraocular inflammation, CME, epiretinal membranes, chronic hypotony and even phthisis bulbi. They may be fewer with Diode laser with G-probe.33

#### **13. Prognosis**

582 Glaucoma - Basic and Clinical Concepts

Goniosynechiolysis may be performed in a similar way with viscoelastic agent injected toward the angle to open it. However, the viscoelastic material should be removed at the conclusion of the procedure to prevent postoperative high IOP. Laser iridoplasty is performed after instillation of topical anesthetic eye drop with Argon laser, 200-400mW, 0.3- 0.6 sec, 500 μm, 20-40 burns in a row with 2-beam diameter space between each spot over 360 peripheral iris avoiding blood vessels. The procedure is performed with a contact lens such as the Abraham (+66D), Wise (+103D), CGI or Goldmann three-mirror lens (through the center, non-mirror part) or without it. The preparations before and the management following the procedure are similar to this described above for Nd:YAG laser iridotomy. The procedure is aimed to contract the peripheral iris away from the angle. The contraindications for the procedure include extensive synechial closure and flat anterior chamber. The complications of the procedure include corneal burns, increased IOP, iritis,

If the IOP did not decrease substantially to the target level following these two procedures, medical treatment with anti-glaucoma medications including pilocarpine 2% four times a day may be added. If pilocarpine is added, it is worthwhile to have two consecutive days off this medication every month. This decreases the probability to have fixed small pupil, which

If the IOP remained high or becoming high despite of medical treatment, other surgical procedures may be performed. The usual approach is to have trabeculectomy first. Trabeculectomy in this case may require a long tunnel (or sclerostomy) that will penetrate

When a trabeculectomy is failed, a glaucoma shunt tube may be placed as mentioned earlier.

Steroid-induced glaucoma is defined as elevation of IOP following administration of topical and/or systemic corticosteroids that remains high after their discontinuation. Steroid responder is a patient in whom the IOP returns to normal after discontinuation of the steroids. These medications are often used after corneal transplantation to prevent or treat corneal graft rejection. They are also used to treat postoperative intraocular inflammation. Differentiation between steroid-induced glaucoma and inflammatory (uveitic) glaucoma may be performed by increasing the topical corticosteroid dosage for several days. If IOP remains high despite decreased intraocular inflammation, a corticosteroid-induced

In cases of steroid responders or steroid-induced glaucoma, discontinuation of the corticosteroids is mandatory. Patients, who are steroid responders, should be aware that they are "allergic" to steroid in the specific form that causes their IOP to increase. This should be written in their medical chart and added to a note (or a card) for the patient, specify that he should not receive this type of drug. For episodes of graft immune rejection, a combination of topical NSAID (sodium diclofenac 0.1% or ketorolac tromethamine 0.5%) and topical cyclosporine-A may be employed. Systemic cyclosporine-A or other drugs such as PO tacrolimus 0.1mg/kg/day may be added. Another option is to use IOP-sparing corticosteroids such as loteprednol etabonate 0.5% (Lotemax®) or rimexolone 1% (Vexol®). Judicious use of systemic corticosteroids instead of topical corticosteroids may be adopted if

new synechiae formation and mydriasis.

**11. Steroid-induced glaucoma** 

glaucoma is most reasonable.

they do not cause an increase in IOP.

may be an obstacle if cataract extraction is required.

the peripheral cornea anterior to the peripheral anterior synechiae.

In aphakic and pseudophakic eyes it may be placed into the ciliary sulcus.

The prognosis of preexisting glaucoma depends on its type.17 It is usually more favorable for primary open angle glaucoma as long as precautions have been taken during the penetrating keratoplasty or the lamellar grafting. The prognosis for graft survival is also

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 585

Many of the patients undergoing keratoprosthesis have multiple ocular pathologies and glaucoma is one of them. Between 36-76% of the eyes with keratoprosthesis have glaucoma.34-39 Of these, about 2-28% develop glaucoma after the implantation of keratoprosthesis, usually because of progressive angle closure. This may be caused because of inadvertent injury to the angle and postoperative intraocular inflammation. A peripheral iridectomy may decrease the risk of postoperative angle closure. The prosthesis may also serve as a scaffold for retoprosthetic membrane that may cover the angle. The use of corticosteroids for prolonged period may also cause corticosteroid-induced glaucoma in

Glaucoma is more frequent in keratopsrosthetic patients than in repeated corneal transplantation. One of the most challenging situations in the presence of keratoprosthesis is to detect and follow-up glaucoma, because it is impossible to check the IOP using the standard methods such as Goldmann applanation tonometry or Schiotz indentation tonometry. These instruments are employed through normal cornea and not through a keratoprosthesis, which cannot be indent. In many cases, visualization of the optic disc may be difficult and therefore, changes in cupping are difficult to observe or document directly, or indirectly using Heidelberg Retinal Tomography (HRT), scanning laser polarimeter (GDx) or OCT. Reliable visual fields may also be difficult to obtain and the maximal field

It is paramount to obtain the history of glaucoma in patients with keratoprosthesis and to document it. In presence of keratoprosthesis, IOP qualitative estimation may be performed by digital palpation over the sclera. It should not be performed over the keratoprosthesis or the glaucoma shunt plate. Qualitative estimation with glass rod over the conjunctiva is

Fig. 6. Type I keratoprosthesis (courtesy of Peter Rubin, MD)

Fig. 7. Type II keratoprosthesis (courtesy of Peter Rubin, MD)

that may be obtained is 60° with type I and 40° with type II.

susceptible patients.

better than with other types of preexisting glaucoma, as long as the IOP is well controlled and the corneal graft has a healthy endothelium.

The prognosis for secondary open angle glaucoma is similar. If the IOP is poorly controlled, there are increased risks for corneal decompensation and development of bullous keratopathy that may require additional grafting. However, performing corneal transplantation in an eye with uncontrolled glaucoma is inadvisable. Resolution of postkeratoplasty glaucoma has been observed in chronic angle closure glaucoma after an additional corneal transplantation probably due to changes in the angle configuration by applying the above advises. In steroid responders, the IOP returns to normal following discontinuation of the corticosteroids.

With the approaches described in this chapter, it would be possible to improve the outcomes of patients with corneal transplants and coexisting glaucoma.

#### **13.1 Follow-up**

Patients undergoing corneal surgery and having or developing glaucoma usually have concurrent disorders and are more challenging to treat. These patients should be followedup regularly at least every 3 months for their lifetime. If they experience ocular pain, decrease in vision or redness of the eye, they should immediately report to their ophthalmologist. It is essential not to postpone the next step in treatment if the current one is not sufficient to abolish the risk of further deterioration.

#### **14. Controversies in management of glaucoma in patients with corneal grafts**

Whether trabeculectomy with MMC or glaucoma drainage implant is the surgical treatment of choice for glaucoma in patients with corneal grafts is still controversial. Different authors have reported comparable results with both. At present, it is up to the decision of the surgeon according to his experience. Comparative studies are required for a definite answer. Such studies will be required also to decide whether simultaneous procedures have the same success rate as separate procedures and whether the new anterior glaucoma devices such as Solx gold shunt or iStent, will have a benefit over the posterior ones.

#### **15. Glaucoma in cases of permanent keratoprosthesis**

Several types of keratoprosthesis are available including one that pass through the cornea and fused eyelids (type II) and the more common ones through the cornea only (type I, e.g., Boston and osteo-odonto-keratoprosthesis) (Figures 6,7). Keratoprosthesis is usually reserved for eyes in which other corneal procedures have failed and the prognosis for additional ones is poor. A publication on repeated corneal transplantation demonstrated that as the number of repeated corneal grafts is increased, the prognosis for long-term survival of the regraft decreases.12 Most of the regrafts do fail due to graft rejection, glaucoma and other complications. These findings have led keratoprosthesis specialists to advocate keratoprosthesis. However, the publication was intended to elaborate the importance of proper preventive measures and early and correct treatment of corneal transplantation complications of rather than to advocate the use of keratoprosthesis. With better preventive measures and treatments, it will be possible to decrease the necessity for repeated transplantation and of course to avoid keratoprosthesis.

Fig. 6. Type I keratoprosthesis (courtesy of Peter Rubin, MD)

better than with other types of preexisting glaucoma, as long as the IOP is well controlled

The prognosis for secondary open angle glaucoma is similar. If the IOP is poorly controlled, there are increased risks for corneal decompensation and development of bullous keratopathy that may require additional grafting. However, performing corneal transplantation in an eye with uncontrolled glaucoma is inadvisable. Resolution of postkeratoplasty glaucoma has been observed in chronic angle closure glaucoma after an additional corneal transplantation probably due to changes in the angle configuration by applying the above advises. In steroid responders, the IOP returns to normal following

With the approaches described in this chapter, it would be possible to improve the outcomes

Patients undergoing corneal surgery and having or developing glaucoma usually have concurrent disorders and are more challenging to treat. These patients should be followedup regularly at least every 3 months for their lifetime. If they experience ocular pain, decrease in vision or redness of the eye, they should immediately report to their ophthalmologist. It is essential not to postpone the next step in treatment if the current one

**14. Controversies in management of glaucoma in patients with corneal grafts**  Whether trabeculectomy with MMC or glaucoma drainage implant is the surgical treatment of choice for glaucoma in patients with corneal grafts is still controversial. Different authors have reported comparable results with both. At present, it is up to the decision of the surgeon according to his experience. Comparative studies are required for a definite answer. Such studies will be required also to decide whether simultaneous procedures have the same success rate as separate procedures and whether the new anterior glaucoma devices

Several types of keratoprosthesis are available including one that pass through the cornea and fused eyelids (type II) and the more common ones through the cornea only (type I, e.g., Boston and osteo-odonto-keratoprosthesis) (Figures 6,7). Keratoprosthesis is usually reserved for eyes in which other corneal procedures have failed and the prognosis for additional ones is poor. A publication on repeated corneal transplantation demonstrated that as the number of repeated corneal grafts is increased, the prognosis for long-term survival of the regraft decreases.12 Most of the regrafts do fail due to graft rejection, glaucoma and other complications. These findings have led keratoprosthesis specialists to advocate keratoprosthesis. However, the publication was intended to elaborate the importance of proper preventive measures and early and correct treatment of corneal transplantation complications of rather than to advocate the use of keratoprosthesis. With better preventive measures and treatments, it will be possible to decrease the necessity for repeated

such as Solx gold shunt or iStent, will have a benefit over the posterior ones.

**15. Glaucoma in cases of permanent keratoprosthesis** 

transplantation and of course to avoid keratoprosthesis.

and the corneal graft has a healthy endothelium.

of patients with corneal transplants and coexisting glaucoma.

is not sufficient to abolish the risk of further deterioration.

discontinuation of the corticosteroids.

**13.1 Follow-up** 

Fig. 7. Type II keratoprosthesis (courtesy of Peter Rubin, MD)

Many of the patients undergoing keratoprosthesis have multiple ocular pathologies and glaucoma is one of them. Between 36-76% of the eyes with keratoprosthesis have glaucoma.34-39 Of these, about 2-28% develop glaucoma after the implantation of keratoprosthesis, usually because of progressive angle closure. This may be caused because of inadvertent injury to the angle and postoperative intraocular inflammation. A peripheral iridectomy may decrease the risk of postoperative angle closure. The prosthesis may also serve as a scaffold for retoprosthetic membrane that may cover the angle. The use of corticosteroids for prolonged period may also cause corticosteroid-induced glaucoma in susceptible patients.

Glaucoma is more frequent in keratopsrosthetic patients than in repeated corneal transplantation. One of the most challenging situations in the presence of keratoprosthesis is to detect and follow-up glaucoma, because it is impossible to check the IOP using the standard methods such as Goldmann applanation tonometry or Schiotz indentation tonometry. These instruments are employed through normal cornea and not through a keratoprosthesis, which cannot be indent. In many cases, visualization of the optic disc may be difficult and therefore, changes in cupping are difficult to observe or document directly, or indirectly using Heidelberg Retinal Tomography (HRT), scanning laser polarimeter (GDx) or OCT. Reliable visual fields may also be difficult to obtain and the maximal field that may be obtained is 60° with type I and 40° with type II.

It is paramount to obtain the history of glaucoma in patients with keratoprosthesis and to document it. In presence of keratoprosthesis, IOP qualitative estimation may be performed by digital palpation over the sclera. It should not be performed over the keratoprosthesis or the glaucoma shunt plate. Qualitative estimation with glass rod over the conjunctiva is

Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 587

more challenging as quantitative estimation of the IOP by Tonopen or Schiotz indentation tonometry through the limbal area. If the IOP cannot be estimated in follow-up visits, it is also possible to follow patients by observing the optic disc and visual fields for deterioration as is done with some patients without keratoprosthesis who do not allow checking their IOP. New transducers are being developed to allow IOP measurements in patients with

In patients who are candidate for keratoprosthesis, it is preferable to implant glaucoma drainage device and to wait for 3-6 months before placing the keratoprosthesis especially when the IOP is refractory to medical treatment or the damage to the optic disc is advanced. This period would allow the postoperative intraocular inflammation to subside and to the

The respond to medical treatment in patients with keratoprosthesis is limited because there is no absorption area in patients with type II and limited absorption area with type I keratoprosthesis and the glaucoma is usually more severe compared with glaucoma in penetrating keratoplasty. The next step is introducing a glaucoma drainage device (Figure 8). A placement of glaucoma shunt tube into the vitreous through the pars plana may be better than into the anterior chamber that is already crowded because of the backplate of the prosthesis. In aphakic eyes, it is mandatory to ascertain that no vitreous remains in the anterior chamber, by meticulous anterior vitrectomy. Since the patients are either aphakic or pseudophakic, the tube may be inserted through the ciliary sulcus. Recently, it was suggested to place the valved drainage tube such as Ahmed valve in the lacrimal sac, ethmoid or maxillary sinuses and to avoid the subconjunctival plate.38,39 The shunt tube was modified for this purpose (Figure 9) and was placed into the lacrimal sac or the ethmoid sinus through an external dacryocystorhinostomy incision although it may be placed in a similar manner as a Pyrex tube in conjunctivo-dacryo-cystorhinostomy. Placement into the maxillary sinus was performed through a lower eyelid crease or subciliary incision but it is also possible to go through the inferior fornix. Penetration may be performed with intravenous catheter and the tube may be passed through it after removing the catheter hub. These procedures may decrease the failure of glaucoma shunt tube from fibrosis around the subconjunctival plate. The main risk in these cases is endophthalmitis. Therefore, I would not advocate these procedures if the lacrimal sac or the sinus is not sterile. Therefore, such a procedure should be avoided in patients with active sinusitis or history of this disorder. In one series of 37 patients, one (3%) developed endophthalmitis.38 Cyclophotocoagulation may be employed as an adjunct treatment to glaucoma drainage implants for painful eyes

[1] Thoft RA, Gardon JM, Dohlman CH. Glaucoma following penetrating keratoplasty. *Trans* 

[2] Polack FM. Keratoplasty in aphakic eyes with corneal edema: results in 100 cases with

[3] Goldberg DB, Schanzlin DJ, Brown SI. Incidence of increased intraocular pressure after

[4] Foulks GN. Glaucoma associated with penetrating keratoplasty. *Ophthalmology* 1987;

keratoprosthesis.

IOP to stabilized.

with no potential for visual rehabilitation.42,43

*Am Acad Ophthalmol Otolaryngol* 1974;78:352-64.

10-year follow-up. *Ophthalmic Surg* 1980;11:701-7.

keratoplasty. *Am J Ophthalmol* 1981;92:372-7.

**16. References** 

94:871-4.

Fig. 8. The tip of Ahmed shunt tube seen through type I keratoprosthesis. It was placed into the vitreous though the pars plana (courtesy of Peter Rubin, MD)

Fig. 9. A modified Ahmed closed shunt (courtesy of Peter Rubin, MD)

more challenging as quantitative estimation of the IOP by Tonopen or Schiotz indentation tonometry through the limbal area. If the IOP cannot be estimated in follow-up visits, it is also possible to follow patients by observing the optic disc and visual fields for deterioration as is done with some patients without keratoprosthesis who do not allow checking their IOP. New transducers are being developed to allow IOP measurements in patients with keratoprosthesis.

In patients who are candidate for keratoprosthesis, it is preferable to implant glaucoma drainage device and to wait for 3-6 months before placing the keratoprosthesis especially when the IOP is refractory to medical treatment or the damage to the optic disc is advanced. This period would allow the postoperative intraocular inflammation to subside and to the IOP to stabilized.

The respond to medical treatment in patients with keratoprosthesis is limited because there is no absorption area in patients with type II and limited absorption area with type I keratoprosthesis and the glaucoma is usually more severe compared with glaucoma in penetrating keratoplasty. The next step is introducing a glaucoma drainage device (Figure 8). A placement of glaucoma shunt tube into the vitreous through the pars plana may be better than into the anterior chamber that is already crowded because of the backplate of the prosthesis. In aphakic eyes, it is mandatory to ascertain that no vitreous remains in the anterior chamber, by meticulous anterior vitrectomy. Since the patients are either aphakic or pseudophakic, the tube may be inserted through the ciliary sulcus. Recently, it was suggested to place the valved drainage tube such as Ahmed valve in the lacrimal sac, ethmoid or maxillary sinuses and to avoid the subconjunctival plate.38,39 The shunt tube was modified for this purpose (Figure 9) and was placed into the lacrimal sac or the ethmoid sinus through an external dacryocystorhinostomy incision although it may be placed in a similar manner as a Pyrex tube in conjunctivo-dacryo-cystorhinostomy. Placement into the maxillary sinus was performed through a lower eyelid crease or subciliary incision but it is also possible to go through the inferior fornix. Penetration may be performed with intravenous catheter and the tube may be passed through it after removing the catheter hub. These procedures may decrease the failure of glaucoma shunt tube from fibrosis around the subconjunctival plate. The main risk in these cases is endophthalmitis. Therefore, I would not advocate these procedures if the lacrimal sac or the sinus is not sterile. Therefore, such a procedure should be avoided in patients with active sinusitis or history of this disorder. In one series of 37 patients, one (3%) developed endophthalmitis.38 Cyclophotocoagulation may be employed as an adjunct treatment to glaucoma drainage implants for painful eyes with no potential for visual rehabilitation.42,43

#### **16. References**

586 Glaucoma - Basic and Clinical Concepts

Fig. 8. The tip of Ahmed shunt tube seen through type I keratoprosthesis. It was placed into

the vitreous though the pars plana (courtesy of Peter Rubin, MD)

Fig. 9. A modified Ahmed closed shunt (courtesy of Peter Rubin, MD)


Glaucoma in Cases of Penetrating Keratoplasty, Lamellar Procedures and Keratoprosthesis 589

[26] Rumelt S. Rehany U. Implantation of glaucoma drainage implant tuinto the ciliary sulcuin patients with corneal transplants. *Arch Ophthalmol* 1998;116:685-7. [27] Tello C, Espana EM, Mora R, et al. Baerveldt glaucoma implant insertion in the

[28] Weiner A, Cohn AD, Balasubramaniam M, Weiner AJ. Glaucoma tube shunt

[29] Bersudsky V, Trevin o A, Rumelt S. Management of endothelial decompensation

[30] Gandham SB, Costa VP, Katz LJ, Wilson RP, SA, Belmont J, Smith M. Aqueous tube-

[31] Ritterband DC, Shapiro D, Trubnik V, et al. Cornea Glaucoma Implant Study Group

[32] Tarantola RM, Agarwal A, Lu P, Joos KM. Long-term results of combined endoscope-

[33] Fishbaugh G. Overview and new technology in cyclodestructive procedures. *Insight* 

[34] Netland PA, Terada H, Dohlman CH. Glaucoma associated with keratoprosthesis.

[35] Zerbe BL, Belin MW, Ciolino JB. Boston Type 1 Keratoprosthesis Study Group. Results

[36] Aldave AJ, Kamal KM, Vo RC, Yu F. The Boston type I keratoprosthesis: improving outcomes and expanding indications. *Ophthalmology* 2009;116:640-51. [37] Bradley JC, Hernandez EG, Schwab IR, Mannis MJ. Boston type 1 keratoprosthesis: the

[38] Chew HF, Ayres BD, Hammersmith KM, et al. Boston keratoprosthesis outcomes and

[39] Rivier D, Paula JS, Kim E, Dohlman CH, Grosskreutz CL. Glaucoma and

[40] Rubin PA, Chang E, Bernardino CR, Hatton MP, Dohlman CH. Oculoplastic technique

[41] Dohlman CH, Grosskreutz CL, Chen TC, et al. Shunts to divert aqueous humor to

[42] Rivier D, Paula JS, Kim E, Dohlman CH, Grosskreutz CL. Glaucoma and

keratoprosthesis surgery: role of adjunctive cyclophotocoagulation. *J Glaucoma*

of connecting a glaucoma valve shunt to extraorbital locations in cases of severe

distant epithelialized cavities after keratoprosthesis surgery. *J Glaucoma* 2010;

keratoprosthesis surgery: role of adjunctive cyclophotocoagulation. *J Glaucoma*

university of California Davis experience. *Cornea* 2009;28:321-7.

glaucoma. *Ophthal Plast Reconstr Surg* 2004;20:362-7.

implantation through the ciliary sulcus in pseudophakic eyes with high risk of

because of glaucoma shunt tube touch by Descemet membrane endothelial

shunt implantation and pars plana vitrectomy in eyes with refractory glaucoma.

(COGIS). Penetrating keratoplasty with pars plana glaucoma drainage devices.

assisted pars plana vitrectomy and glaucoma tube shunt surgery. *Retina* 2011;

from the multicenter Boston Type 1 Keratoprosthesis Study. *Ophthalmology* 2006;

posterior chamber sulcus. *Br J Ophthalmol* 2007;91:739-42.

corneal decompensation. *J Glaucoma* 2010;19:405-11.

keratoplasty and tube revision. *Cornea* 2011;30:709-11.

*Am J Ophthalmol* 1993;116:189-95.

*Ophthalmology* 1998;105:751-7.

complications. *Cornea* 2009;28:989-96.

*Cornea* 2007;26:1060-6.

31:275-83.

113:1779.

2009;18:321-4.

19:111-5.

2009;18:321-4.

1999;19:26-9.


[6] Simmons RB, Stern RA, Teekhasaenee C, Kenyon KR. Elevated intraocular pressure following penetrating keratoplasty. *Trans Am Ophthalmol Soc* 1989;87:79-91. [7] Cowden J, Kaufman HE, Polack FM. The prognosis of keratoplasty after previous graft

[8] Robinson CH. Indications, complications and prognosis for repeated penetrating

[9] Insler MS, Pechous B. Visual results in repeat penetrating keratoplasty. *Am J Ophthalmol*

[10] MacEwen CJ, Khan ZUH, Anderson E, MacEwen CG. Corneal re-graft: indications and

[11] Rapuano CJ, Cohen EJ, Brady SE et al. Indications and outcomes of repeat penetrating

[12] Bersudsky V, Blum-Hareuveni T, Rehany U, Rumelt S. The profile of repeated corneal

[13] Sugar A. An analysis of corneal endothelial and graft survival in pseudophakic bullous

[14] Byrd S, Tayeri T. Glaucoma associated with penetrating keratoplasty. *Clin Ophthalmol*

[15] Rumelt S, Blum-Hareuveni T, Bersudsky V, Rehany U. Persistent epithelial defects and

[17] Rumelt S, Bersudsky V, Blum-Hereuveni T, Rehany U. Preexisting and postoperative glaucoma in repeated corneal transplantation. *Cornea*, 2002;21:759-765. [18] Kirkness CM. Penetrating keratoplasty, glaucoma, and silicone drainage tubing. *Dev* 

[19] Ates H, Palamar M, Yagci A, Egrilmez S. Evaluation of mini Ex-Press glaucoma shunt implantation in refractory penetrating glaucoma. *J Glaucoma* 2010;19:556-60. [20] McDonnell PJ, Robin JB, Schanzlin DJ et al. Molteno implant for control of glaucoma in

[21] Kirkness CM, Ling Y, Rice NSC. The use of silicone drainage tubing to control

[22] Beebe WE, Starita RJ, Fellman RL, Lynn JR, Gelender H. The use of Molteno implant

[25] Coleman AL, Mondino BJ, Wilson MR, Casey R. Clinical experience with the Ahmed

glaucoma in penetrating keratoplasty. *Ophthalmology* 1990;97:1414-22. [23] Sherwood MB, Smith MF, Driebe WT Jr et al. Drainage tube implants in the treatment of glaucoma following penetrating keratoplasty. *Ophthalmic Surg* 1993:24:185-9. [24] Rapuano CJ, Schmidt CM, Cohen EJ, et al. Results of alloplastic tube shunt procedures

before, during, oafter penetratikeratoplasty. *Cornea* 1995;14:26-32.

and anterior chamber tube shunt to encycling band (ACTSEB) for treatment of

glaucoma valve implant in eyes with prior or concurrent penetrating keratoplasties.

eyes after penetrating keratoplasty. *Ophthalmology* 1988;95:364-9.

predisposing factors and treatment outcomes. *Eye*, 2008;246:1139-1145. [16] Aldave AJ, Rudd JC, Cohen EJ et al. The role of glaucoma therapy in the need for repeat

ulcers in repeated corneal transplantation: incidence, causative agents,

[5] Polack FM. Glaucoma in keratoplasty. *Cornea* 1988;7:67-9.

failures. *Am J Ophthalmol* 1974;78:523-5.

1986;102:371-5.

1999;39:17-28.

*Ophthalmol* 1987;14:161-5.

*Am J Ophthalmol* 1997;123:54-61.

keratoplasty. *Ophthalmic Surg* 1979;10:27-34.

outcome. *Ophthalmic Surg* 1988;19:706-12.

keratoplasty. *Am J Ophthalmol* 1990;109:689-95.

transplantation. *Ophthalmology* 2001;108:461-9.

penetrating keratoplasty. *Cornea* 2000, 19:772-6.

postkeratoplasty glaucoma. *Eye* 1988;2:583-90.

keratopathy. *Trans Am Ophthalmol Soc* 1989;87:762-801.


[43] Parthasarathy A, Aung T, Oen FT, Tan DT. Endoscopic cyclophotocoagulation for the management of advanced glaucoma after osteo-odonto-keratoprosthesis surgery. *Clin Experiment Ophthalmol* 2008;36:93-4.

[43] Parthasarathy A, Aung T, Oen FT, Tan DT. Endoscopic cyclophotocoagulation for the

*Clin Experiment Ophthalmol* 2008;36:93-4.

management of advanced glaucoma after osteo-odonto-keratoprosthesis surgery.

### *Edited by Shimon Rumelt*

This book addresses the basic and clinical science of glaucomas, a group of diseases that affect the optic nerve and visual fields and is usually accompanied by increased intraocular pressure. The book incorporates the latest development as well as future perspectives in glaucoma, since it has expedited publication. It is aimed for specialists in glaucoma, researchers, general ophthalmologists and trainees to increase knowledge and encourage further progress in understanding and managing these complicated diseases.

Glaucoma - Basic and Clinical Concepts

Glaucoma

Basic and Clinical Concepts

*Edited by Shimon Rumelt*

Photo by OPHfoto / iStock