Primary Angle-Closure Glaucoma

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Practice Essentials

Overview

Background

Variable and sometimes conflicting terminology was used to describe different forms of angle-closure glaucoma before the advent of indentation gonioscopy and laser iridotomy, when the mechanisms of angle-closure glaucoma were poorly understood.[1, 2]

In the era of surgical iridectomy, an attack of acute angle-closure glaucoma (AACG) could arise in an eye that had developed peripheral anterior synechiae (PAS) as a result of gradual angle closure before the attack. Apposition in prolonged acute attacks or a series of subacute attacks could also lead to progressive PAS formation. Even in the presence of patent surgical iridectomy, AACG eyes with shallow anterior chambers that were dilated postoperatively were not infrequently found to have PAS.[3, 4] These usually form as pinpoint synechiae reaching to the mid-trabecular meshwork and they gradually expand in width, beginning in the superior angle which is narrower than the inferior angle.[5]

Primary angle-closure suspect (PACS) was defined as non-visibility of the filtering trabecular meshwork for 180° or more in the absence of PAS with normal intraocular pressure (IOP).[6, 7] Primary angle closure (PAC) can be further classified as synechial or appositional. Appositional primary angle closure refers to an eye with raised IOP (>21 mm Hg) associated with obstructed filtering trabecular meshwork of more than 180° in the absence of PAS, disc damage, or field changes. On the other hand, synechial PAC refers to an eye in which portions of the anterior chamber angle are closed permanently by PAS with more than 180° of iridotrabecular contact, with or without raised IOP. The term primary angle-closure glaucoma (PACG) is used to denote PAC eyes with glaucomatous optic nerve damage or visual field loss.[8]

Pathophysiology

Combined mechanism glaucoma refers to eyes in which both open-angle and angle-closure components are present.

The term mixed mechanism glaucoma has often been used interchangeably with combined mechanism glaucoma. However, to reduce confusion, the term mixed mechanism glaucoma is better reserved to describe eyes with angle closure due to more than one contributory mechanisms. 

Plateau iris refers to an anatomic configuration in which the iris root angulates forward and then centrally. Two subtypes have been differentiated. In the complete syndrome, which is rare, IOP rises when the angle closes with pupillary dilation. In the incomplete syndrome, IOP does not rise. 

Miotic-induced angle-closure glaucoma may result from prolonged miotic treatment, which may occur in eyes with open-angle glaucoma or narrow angles.

Epidemiology

The global prevalence of PACG is 0.6%. The prevalence is highest in Asia (12.30 million), and risk factors include Asian race, female sex, and advancing age.[9]  

Mortality/Morbidity

If IOP is not controlled, glaucomatous optic neuropathy and visual field loss may progress.

Race

The prevalence of PACG is highest among Chinese (1.26% among those ≥40 years), 0.25% among Whites of European ancestry, and 0.16% among those of African and Middle Eastern ancestry, according to a review of worldwide statistics.[9]  

Creeping angle closure is uncommon in Whites, but it is much more prevalent in Asians, in whom it ranks high as a cause of blindness.[9] Black patients with angle closure are also associated with this feature.

Sex

Patients with PACG and plateau iris tend to be female.

Age

Those with PACG tend to be elderly and often have coexisting cataract or at least lens thickening. 

Patients with plateau iris tend to be in their fourth to sixth decade of age.

Prognosis 

The prognosis is favorable with the control of IOP.[10]

Factors associated with disease progression in PACG eyes include large IOP fluctuations[11]  and thin central corneal thickness.[12]

Presentation

History 

Primary angle-closure glaucoma (PACG) is usually asymptomatic because of its slow onset, as opposed to acute angle-closure glaucoma (AACG), which presents with pain and nausea due to the rapid intraocular pressure (IOP) increase. However, patients with PACG may report transient eye pain, headache, and/or halo visualization.

Physical

Insertion of the iris at or anterior to the scleral spur is rare in young individuals. In eyes with angle-closure glaucoma, creeping angle closure is often the underlying cause for such atypical insertion. The IOP in eyes with primary angle closure (PAC) may be normal or elevated while PACG eyes have higher baseline IOP and glaucoma medication requirements, and greater IOP fluctuations than PAC or PACS eyes. Previous trabeculectomy and current smoking status are associated with larger IOP fluctuations,[13]  which is a significant and independent predictor for subsequent VF deterioration in eyes with PACD.[14]

Blotches of pigment on the meshwork, particularly in the superior angle, or deposits of black pigment in the angle of a lightly pigmented iris are highly suggestive of previous appositional closure. This deposited line of pigment shows the extent of previous angle closure and sometimes can be a helpful diagnostic feature.

The anterior chamber in PACG is quiet and usually deeper than in eyes with AACG.

The pupil is normal but can be atonic for those with prior history of angle closure attacks.

The gradual elevation of IOP in PACG does not result in corneal endothelial decompensation, and corneal edema is rare. The IOP is usually less than 40 mmHg and does not reach the levels found in AACG. Symptoms are absent until the pressure rises high enough to affect the cornea or until extensive visual field damage has occurred. Although iridotomy will eliminate the risk of pupillary block, IOP often remains elevated, and further medical treatment or surgery may be required.

Causes

Causes of PACG include PAS formation, plateau iris, combined mechanism glaucoma, mixed mechanism glaucoma, and miotic-induced glaucoma.

Workup

Imaging studies

In patients with glaucoma, analysis of serial retinal nerve fiber layer thickness (RNFL) maps generated with spectral-domain optical coherence tomography (OCT) can aid in the detection of RNFL progression.[15]  

Other tests

Goldmann applanation tonometry remains the gold standard for IOP assessment.

Static and dynamic (indentation) gonioscopy are used to evaluate and document the extent, nature (appositional versus synechial), and causes of angle closure.

Slit-lamp biomicroscopy examination using noncontact lenses (e.g. 90-D lens) or contact lenses (e.g. central lens in Goldmann 3-mirror lens) may utilize green filter (red-free light) to aid in the identification of RNFL thinning. Fundus photography can be used for documentation (stereoscopic or non-stereoscopic) of the disc appearance.

A GDx VCC nerve fiber analyzer, Heidelberg retinal tomography (HRT), and OCT can be used for quantitative assessments of the optic nerve head and retinal nerve fiber layer thickness. 

Visual field assessment can include threshold testing by automated perimetry. Special programs, such as SWAP, may help identify early visual field losses.

Further investigations to delineate the mechanism of angle closure can include ultrasound biomicroscopy examination and anterior segment OCT (AS-OCT).

Treatment

Medical care

It is important to recognize early stages of appositional angle closure in the absence of peripheral anterior synechiae (PAS) and deep circumferential angle closure.

Laser iridotomy involves the creation of a hole in the peripheral iris by laser and is indicated for primary angle closure (PAC) and primary angle-closure glaucoma (PACG).

Miotic treatment may enhance the development of PACG in the absence of an iridotomy. When miotic-induced angle closure occurs, regimen should be reviewed and adjusted to control the glaucoma.

Selective laser trabeculoplasty (SLT) delivers laser energy to pigmented cells in the trabecular meshwork without thermal damage to adjacent cells. Outcomes of Argon laser trabeculoplasty (ALT) in the treatment of combined-mechanism glaucoma after iridotomy were controversial; however, overall it has been found to be reasonably successful.[16, 17]  

Surgical care

The two main goals in the management of PACG are, firstly, to prevent progression of angle closure and, secondly, to prevent glaucomatous optic neuropathy progression by controlling the IOP. Various surgical procedures have different roles in meeting these challenges.

To prevent progression of angle closure, all eyes with closed or narrow drainage angles should undergo iridectomy or iridotomy to eliminate pupillary block. Nowadays, laser iridotomy has largely replaced surgical iridectomy, unless in exceptional circumstances.[18, 19]

Trabeculectomy is effective for PACG.[20, 21, 22, 23, 24]  with an overall success rate of 68% in controlling IOP. However, compared to primary open-angle glaucoma (POAG), like any aqueous-draining procedures, trabeculectomy in eyes with shallow anterior chamber and chronically closed angle poses higher risks of filtration failure, further anterior chamber shallowing and malignant glaucoma/aqueous misdirection. 

Lens position and thickness both play important roles in the etiology of angle-closure glaucoma. Angle narrowing may be more marked in cataractous lenses due to anterior displacement of the peripheral iris. Lens extraction has been actively studied and reported in recent years in the treatment of PACG. Both traditional extracapsular cataract extraction and phacoemulsification alone have been reported to increase anterior chamber depth and lower IOP in PACG.

Goniosynechialysis (GSL) is a surgical technique performed to strip PAS from the trabecular surface in the angle and provide renewed aqueous access to the trabecular meshwork.[25, 26, 27]  In eyes with minimal PAS, trabeculectomy is preferred because trabecular function in these eyes is expected to be poor and a fistula procedure would be more appropriate. On the other hand, IOP spikes during and after GSL may lead to loss of vision. GSL is more suitable for eyes with a minimal to moderate degree of neuronal damage.

Consultations

Consult a glaucoma specialist.

Complications

Cataract can occur with steroid and laser treatment.

Medication

The first step in the management of primary angle-closure glaucoma (PACG) often involves surgical procedures that open, as far as possible, the segments of the drainage angle that are appositionally closed or narrow. Options may include laser peripheral iridotomy, argon laser peripheral iridoplasty, and lens extraction, depending on the mechanism(s) of angle closure. Intraocular pressure (IOP) may, however, remain elevated after these procedures, possibly as a result of extensive residual synechial angle closure. IOP-lowering medications are indicated if a safe IOP level cannot be reached after angle-opening procedures.

In the past, timolol and pilocarpine were extensively used in PACG. Recent studies have demonstrated the superior IOP-lowering efficacy of prostaglandin analogue monotherapy over these conventional drugs, as well as some combination therapies, in PACG. The IOP-lowering effect of prostaglandin analogues does not appear to be related to the degree of angle closure or the extent of peripheral anterior synechiae (PAS). Once-daily prostaglandin analogue regimes are generally well tolerated, and they have become an important member in the medical arsenal against PACG.

Miotic agents

These agents directly stimulate cholinergic receptors in the eye, decreasing resistance to aqueous humor outflow.

Beta-adrenergic Blocker

Thought to decrease IOP by reducing aqueous formation; however, some studies observed increased outflow.

Prostaglandin, ophthalmic

Reduces IOP by increasing uveoscleral outflow.

Carbonic anhydrase inhibitor

Inhibits aqueous humor formation by inhibiting carbonic anhydrase 2 (CA-II).

Alpha2-adrenergic agonist agent, ophthalmic

Reduces aqueous humor production and increases uveoscleral outflow.

Brimonidine (Alphagan P)

Rho kinase inhibitors

Increase trabecular aqueous outflow by reducing trabecular meshwork resistance.

Riparsudil

Netarsudil  

Diuretic, Osmotic

These agents elevate glomerular filtrate osmolarity, resulting in decreased tubular reabsorption of water, thereby inducing diuresis.

Mannitol (Osmitrol)

Background

In the past, variable and sometimes conflicting terminology was used to describe different forms of angle-closure glaucoma. The problem arose from the fact that terminology was developed before the advent of indentation gonioscopy and laser iridotomy, when the mechanisms of angle-closure glaucoma were poorly understood.[1, 2]

In the era of surgical iridectomy, an attack of acute angle-closure glaucoma (AACG) could arise in an eye that had developed peripheral anterior synechiae (PAS) because of gradual angle closure before the attack. Conversely, a prolonged acute attack or a series of subacute attacks could lead to progressive PAS formation. Patients undergoing surgical iridectomy were dilated routinely after surgery, and shallow anterior chambers were not uncommon. Patients undergoing surgical iridectomy for AACG who were dilated postoperatively and had shallow anterior chambers not infrequently formed PAS.[3, 4] Prolonged apposition or repeated subacute attacks lead to gradual PAS formation. These usually begin in the superior angle, which is narrower than the inferior angle, as pinpoint synechiae, reaching to the midtrabecular meshwork and gradually expanding in width.[5]

Primary angle-closure suspect (PACS) was defined as non-visibility of the filtering trabecular meshwork for 180° or more in the absence of PAS with normal intraocular pressure (IOP). Primary angle closure (PAC) can be further classified as synechial or appositional. Appositional primary angle closure refers to an eye with raised IOP (>21 mm Hg) associated with obstructed filtering trabecular meshwork of more than 180° in the absence of PAS, disc damage, or field changes. On the other hand, synechial primary angle closure (PAC) refers to an eye in which portions of the anterior chamber angle are closed permanently by PAS with more than 180° of iridotrabecular contact with or without raised IOP. The term primary angle-closure glaucoma (PACG) is used to denote PAC eyes with glaucomatous optic nerve damage or visual field loss.[8]

Pathophysiology

Eyes with progressive PAS formation eventually may develop AACG when pupillary block results in closure of the remaining portions of the angle unaffected by PAS. However, many patients develop gradual angle closure, elevated IOP, and glaucomatous damage in the absence of symptoms. The presentation is similar to that of PACG, with progression of glaucomatous cupping and visual field loss.[28]

PAS also may form during an acute attack, remaining after iridotomy has opened the unaffected portions of the angle. These PAS are usually high and broad. When first observed at this stage, it is impossible to determine whether the PAS formed before or during the attack, or at both times.

In eyes with darker irides, a second mechanism of progressive angle closure is more common. The closure is circumferential and begins in the deepest portion of the angle. Closure occurs more evenly in all quadrants, so that the angle progressively becomes shallower. The appearance over time is of a progressively more anterior iris insertion. Lowe has termed this creeping angle closure,[29] where PAS gradually creeps up the ciliary face to the scleral spur and then to the trabecular meshwork.

Combined mechanism glaucoma

Combined mechanism glaucoma refers to situations in which both open-angle and angle-closure components are present. Angle-closure component in this type of glaucoma can be treated with iridotomy, which eliminates the appositional closure. However, IOP may remain elevated, with or without the presence of PAS of any extent.

Conversely, an eye with open-angle glaucoma may later develop angle closure, either because of the natural development of pupillary block or because of exacerbation by miotic therapy.

Exfoliation syndrome commonly predisposes to combined mechanism glaucoma.[30] In this case, open-angle glaucoma can develop independently years after iridotomy for angle closure, with progressive blockage of the trabecular network. In all of these cases, the residual open-angle component is treated as open-angle glaucoma.

Mixed mechanism glaucoma

This term often is used interchangeably with combined mechanism glaucoma, but it is better to reserve this description for eyes with angle closure due to more than one contributory mechanism. When pupillary block is eliminated and the angle opens to a greater degree by iridotomy, appositional closure may remain due to mixed mechanisms such as plateau iris, phacomorphic glaucoma, or malignant glaucoma.

Plateau iris

Plateau iris refers to an anatomic configuration in which the iris root angulates forward and then centrally[31, 32, 33] due to large and/or anteriorly positioned ciliary processes that hold the peripheral iris up against the trabecular meshwork.[34, 35]  Iris root in this entity often is short and inserts anteriorly on the ciliary face, leading to angle that is shallow and narrow with a sharp drop-off of the peripheral iris at the inner aspect of the angle. The iris surface is relatively flat and the anterior chamber is not unusually shallow.

When appositional angle closure develops either spontaneously or after pupillary dilation in an eye with this anatomic configuration despite a patent iridotomy or iridectomy, plateau iris syndrome is present.[36] Such appositional angle closure may lead to AACG.

Until recently, plateau iris syndrome was considered rare. Two subtypes have been differentiated. In the complete syndrome, which is rare, IOP rises when the angle closes with pupillary dilation. In the incomplete syndrome, IOP does not rise. The differentiating factor is the height of the plateau with respect to the angle structures. If the angle closes to the upper meshwork or Schwalbe line, IOP rises because aqueous outflow is blocked completely; whereas, if the angle closes partially, leaving the upper portion of the filtering meshwork open, aqueous humor can still exit the eye. This condition is far more common than once thought, and its detection is important. These patients can develop PAS years after successful iridotomy even when the angle appears well-formed.

Iris cysts also may cause anatomical changes equivalent to plateau iris and on dynamic gonioscopy, a sinuous configuration of the iris, named double hump sign, may be seen. When pressure is applied on the eye through a goniolens, the ciliary processes prevent posterior movement of the peripheral iris, forcing the iris to follow the curvature of the lens, reaches its deepest point at the lens equator, and then rises again over the ciliary processes before dropping peripherally. Much more force is needed during gonioscopy to open the angle than in pupillary block because the ciliary processes must be displaced, and the angle does not open as widely. In a morphometric study of the ciliary sulcus, Orgul et al proposed that the displacement of the pars plicata from the peripheral iris to the iris root during embryogenesis may be incomplete in eyes of shorter axial length.[37]

Patients with plateau iris tend to be female, younger (30-50s), and less hyperopic than those with relative pupillary block. They often have a family history of angle-closure glaucoma. Except in the rare younger patients (20-30s), some element of pupillary block also is present. If plateau iris was not diagnosed before iridotomy and IOP is elevated post-laser, careful gonioscopy should be performed. If the angle is open, secondary damage to the trabecular meshwork or pigment liberation with dilation are the most likely causes. If the angle is closed, the differential diagnoses, besides plateau iris, should include malignant glaucoma, in which the anterior chamber is extremely shallow; PAS, which can be ruled out by dynamic gonioscopy; or incomplete iridectomy.

Miotic-induced angle-closure glaucoma

Prolonged miotic treatment in eyes with open-angle glaucoma and narrow angles may lead to pupillary block and angle-closure glaucoma.[38] PACG has developed after several years of miotic therapy in eyes that initially had wide-open angles. In some eyes, zonular relaxation occurs more readily than in other eyes, so that anterior lens movement and an increase in axial lens thickness may facilitate pupillary block and angle closure.

In some eyes, little change in the lens occurs, but progressively increasing pressure in the posterior chamber gradually pushes the peripheral iris against the trabecular meshwork. It is believed that eyes with exfoliation syndrome are particularly prone to develop miotic-induced angle closure. In these eyes, the iris is thicker and stiffer than normal because of deposition of exfoliation material within the stroma. In addition, zonular weakness allows the lens to move forward, leading to pupillary block.

Less commonly, miotic therapy can have a pronounced effect on lens position and trigger malignant glaucoma.[39, 40, 41] Unequal anterior chamber depths, a progressive increase in myopia, or progressive shallowing of the anterior chamber are clues to the correct diagnosis.

Epidemiology

Frequency

Worldwide

The worldwide prevalence of PACG was 0.6% in a meta-analysis of 20 years of data from 144,354 participants. The risk for PACG increases with age; the disease is estimated to affect approximately 17.14 million individuals older than 40 years, 20.73 million in 2030, 23.73 million in 2040, and 26.26 million in 2050.

The prevalence is highest in Asia (12.30 million), and risk factors include Asian race, female sex, and advancing age.[9]  

Europe and United States

Based on data captured from European-derived populations published in 2012, an estimated 130,000 people in the United Kingdom had PACG, compared with 1.60 million people in Europe, and 581,000 people in the United States. Accounting for aging population structures, cases were predicted to increase by 19% in the United Kingdom, 9% in Europe, and 18% in the United States in 10 years.[42]

Asia

The overall pooled prevalence of PACG among adult Asians was 0.75%. Ethnicity-specific pooled prevalence estimates were 0.97% in the Middle East group, 0.66% in the Southeast Asia group, 0.46% in the India group, 1.10% in the China group, and 1.19% in the Japan group.[43]

Mortality/Morbidity

If IOP is not controlled, glaucomatous optic neuropathy and visual field loss may progress.

Race

The prevalence of PACG appears to be highest among Chinese (1.26% among those ≥40 years), according to a review of worldwide statistics. The prevalence of PACG in whites of European ancestry is around 0.25%. The prevalence of PACG appears to be lowest among Africans and people of Middle Eastern ancestry (0.16%).[44]

Among the subtypes of angle closure, creeping angle closure is uncommon in whites, but it is much more prevalent in Asians, in whom it ranks high as a cause of blindness.[7, 45] Black patients with angle closure also tend to have this form.

Sex

Patients with PACG and plateau iris tend to be female.

Age

Patients with PACG tend to be elderly, often with coexisting cataract or at least lens thickening.

Patients with plateau iris tend to be in their fourth to sixth decade of age.

Prognosis

The prognosis is favorable with the control of IOP.[10]

Factors associated with disease progression in PACG eyes include large IOP fluctuations[11]  and thin central corneal thickness.[12]

History

Primary angle-closure glaucoma (PACG) is usually asymptomatic because of its slow onset, as opposed to acute angle-closure glaucoma (AACG), which presents with pain and nausea due to the rapid intraocular pressure (IOP) increase. However, patients with PACG may report transient eye pain, headache, and/or halo visualization.

Physical

Insertion of the iris at or anterior to the scleral spur is rare in young individuals, and, in many eyes with angle-closure glaucoma with such insertion, creeping angle closure is the underlying reason. It occurs in eyes with slightly deeper anterior chambers than that in AACG. Gradual shortening of the angle in the presence of iris bombé brings the peripheral iris close to the anterior external angle wall, narrowing the gap between the iris and the trabecular meshwork. Eventually, AACG may supervene, or PAS may permanently occlude the trabecular meshwork and lead to elevated IOP and glaucomatous damage.

The IOP in eyes with primary angle closure (PAC) may be normal or elevated. As peripheral anterior synechiae (PAS) formation progresses in the absence of intermittent attacks, IOP rises gradually as less and less functional meshwork becomes available. In eyes with intermittent attacks, IOP rises more rapidly relative to the extent of PAS formation caused by recurrent trabecular meshwork damage from transient angle closure.

Higher baseline IOP, glaucoma medication requirements, previous trabeculectomy and current smoking status are associated with larger IOP fluctuations in PACG eyes compared to PAC or PACS eyes.[13]  IOP fluctuation is a significant and independent predictor for subsequent VF deterioration in eyes with PACD.[14]

Other signs 

Blotches of pigment on the meshwork, particularly in the superior angle, or deposits of black pigment in the angle of a lightly pigmented iris are highly suggestive of previous appositional closure. If the angle opens, this deposited line of pigment shows the extent of previous angle closure and sometimes can be a helpful diagnostic feature.

The anterior chamber of PACG is quiet and usually deeper than in eyes with AACG.

The pupil is normal but can be atonic for those with prior history of angle closure attacks.

The gradual elevation of IOP does not result in corneal endothelial decompensation, and corneal edema is rare. The IOP is usually less than 40 mm Hg and does not reach the levels found in AACG. Symptoms are absent until the pressure rises high enough to affect the cornea or until extensive visual field damage has occurred. Although iridotomy will eliminate the pupillary block, IOP often remains elevated, and further medical treatment or surgery is required.

 

Causes

Causes of PACG include PAS formation, plateau iris, combined mechanism glaucoma, mixed mechanism glaucoma, and miotic-induced glaucoma.

Approach Considerations

The comprehensive initial evaluation for glaucoma, particularly primary open-angle glaucoma (POAG), involves a thorough history and physical examination, incorporating all aspects of a comprehensive adult medical eye evaluation.[6, 7] This process may require multiple visits, as a patient suspected of having glaucoma may need to return for further assessments to confirm the diagnosis. These assessments can include additional intraocular pressure (IOP) measurements, gonioscopy, central corneal thickness (CCT) determination, visual field testing, and imaging evaluations of the optic nerve head (ONH), retinal nerve fiber layer (RNFL) and macula.

Imaging Studies

Spectral-domain optical coherence tomography

In patients with glaucoma, analysis of serial retinal nerve fiber layer thickness (RNFL) maps generated with spectral-domain optical coherence tomography (OCT) can aid in the detection of RNFL progression.[15]  

Other Tests

Intraocular pressure (IOP) assessment

Goldmann applanation tonometry remains the gold standard for IOP assessment.[6, 7]

The accuracy of the measurement may be affected by the central corneal thickness, so the measurement of the corneal thickness (usually via ultrasound pachymetry) is important.

Gonioscopy

Static and dynamic (indentation) gonioscopy is used to evaluate and document the extent, the nature (appositional versus synechial), and the cause of the angle closure.[6, 7]

Optic nerve head and RNFL assessments

Qualitative: Slit-lamp biomicroscopy examination using noncontact lenses (eg, 90-D lens) or contact lenses (eg, central lens in Goldmann 3-mirror lens); green filter (red-free light) may aid in the identification of RNFL thinning; fundus photography for documentation (stereoscopic or nonstereoscopic) of the disc appearance.[6, 7]

Quantitative: GDx VCC nerve fiber analyzer; Heidelberg retinal tomography (HRT); OCT

Visual fields [46]

Threshold testing by automated perimetry

Special programs, such as SWAP, may help identify early visual field losses.

Further investigations to delineate the mechanism of angle closure

Ultrasound biomicroscopy examination[47, 48]

Anterior segment OCT (AS-OCT)[49]

Histologic Findings

Peripheral anterior synechiae (PAS) across chamber angle, pigment deposition in trabecular meshwork

Staging

There is no formal staging for primary angle-closure glaucoma (PACG), but grading systems (eg, Shaffer, Spaeth) exist to allow more objective documentation of the openness of the drainage angle.

Medical Care

It is important to recognize early stages of appositional angle closure in the absence of peripheral anterior synechiae (PAS) and to recognize deep, circumferential angle closure.

Laser iridotomy is indicated for primary angle closure (PAC) and primary angle-closure glaucoma (PACG). Laser iridotomy involves the creation of a hole in the peripheral iris by laser.[6, 7, 50, 51] The hole provides an alternative pathway for aqueous to flow from the posterior chamber into the anterior chamber, bypassing the pupil. Therefore, iridotomy eliminates pupillary block and prevents forward bowing of the iris as a result of pressure difference between the two chambers. Iridotomy opens those areas of the angle not involved by PAS and prevents further synechial closure.

Miotic treatment may enhance the development of PACG in the absence of an iridotomy. When miotic-induced angle closure occurs, the approach to treatment should be determined by assessing the medications necessary to control the glaucoma. If a patient is taking dipivefrin, discontinuation may be enough to open the angle and allow the patient to remain on miotics, assuming that intraocular pressure (IOP) remains under control. If the patient has been treated with miotics alone, substitution with aqueous suppressants may suffice. If the patient requires miotics for IOP control, laser iridotomy is warranted.

If the angle remains appositionally closed or spontaneously occludable after laser iridotomy, argon laser peripheral iridoplasty (ALPI) is indicated to prevent progressive damage to the angle or further appositional and/or synechial closure of the angle.[52, 53, 54, 55] If, after iridoplasty, some of the angle still remains appositionally closed, low-dose pilocarpine, such as pilocarpine 2% at bedtime, often suffices to maintain the patency of the angle.

The level of IOP and the extent of glaucomatous damage determine the need for continued medical treatment after iridotomy. Treatment is similar to that of open-angle glaucoma. Repeated gonioscopy is necessary. The need for further surgery cannot be predicted from the level of initial IOP or gonioscopic changes.

Argon laser trabeculoplasty (ALT) has been reported to be both successful and unsuccessful after iridotomy in combined-mechanism glaucoma; however, overall, it has been found to be reasonably successful.[16, 17] Selective laser trabeculoplasty (SLT) delivers laser energy to pigmented cells in the trabecular meshwork while avoiding thermal damage to adjacent cells. In a multicenter prospective study on PACG eyes with high IOP despite iridotomy but with at least 90° of gonioscopically visible pigmented trabecular meshwork, it has shown 20% or more IOP reduction in 54% of eyes at 6 months. The authors suggested selective laser trabeculoplasty to be a safe and effective method of reducing IOP in PACG in which there is a sufficient extent of visible trabecular meshwork.[56] However, long-term therapeutic effectiveness of selective laser trabeculoplasty in PACG eyes will have to be determined. Possible side effects include reduced endothelial cell count, IOP spike, and persistent uveitis.[57]

If the pressure remains uncontrolled and glaucomatous damage develops, filtration surgery is indicated. An increased chance of developing malignant glaucoma is present after filtration surgery in patients who have had angle-closure glaucoma.

Surgical Care

The two main challenges in the management of PACG are, firstly, to prevent progression of the angle closure and, secondly, to prevent progression of the glaucomatous optic neuropathy by controlling IOP. Various surgical procedures have different roles in meeting these challenges.[6, 7]

The diminishing role of surgical iridectomy

To prevent progression of the angle closure, all eyes with angle closure or very narrow drainage angles should undergo iridectomy or iridotomy to eliminate pupillary block. Laser iridotomy has largely succeeded surgical iridectomy, other than in exceptional circumstances.[18, 19]

Laser iridotomy has many advantages over surgical iridectomy. Laser iridotomy is non-invasive, so there is no inherent risk for endophthalmitis and wound complications such as wound leak. With sequential laser techniques, the wound edge of the iridotomy is well coagulated and the risk for hemorrhage from iris tissue is much reduced. The movement of fluid when the iris is penetrated is a good sign of iridotomy patency, and the chance of an incomplete iridotomy is minimal. Furthermore, as no ocular incision is required, there is no risk of further shallowing of the anterior chamber causing iridocorneal adhesion and damage, PAS, permanently closed angle or precipitating malignant glaucoma. Laser iridotomy can also be conveniently performed in an outpatient basis, and it does not require operating room facilities.

As laser equipment and expertise have become widely available, the role of surgical iridectomy in the management of angle-closure glaucoma is now limited to situations in which laser iridotomy is not possible or effective, for example, in patients with significant corneal opacity. The inability of patients to cooperate may also be a relative indication for surgical iridectomy, which can be performed under sedation or even general anesthesia. Severe anterior chamber inflammation may repeatedly occlude a laser iridotomy, whereas the relatively larger iridectomy created by surgery is much more likely to remain open under such circumstances.

Trabeculectomy

Trabeculectomy is effective for PACG.[20, 21, 22, 23, 24] Trabeculectomy has an overall success rate of 68% in controlling IOP. However, compared with primary open-angle glaucoma (POAG), any aqueous-draining procedure in an eye with a shallow anterior chamber and chronically closed angle poses the risk of further shallowing of the anterior chamber or precipitating malignant glaucoma. Trabeculectomy in PACG is associated with a higher risk of filtration failure, shallow anterior chamber, and malignant glaucoma/aqueous misdirection. As the incidence of PACG increases with age, many patients with PACG have coexisting cataract. Trabeculectomy increases the rate of cataract progression, and a significant proportion of patients will soon need cataract extraction after trabeculectomy.

Furthermore, future cataract extraction may result in loss of the functioning filter. It has been reported that 30% to 100% of previously functioning blebs required antiglaucoma medications to control IOP after extracapsular cataract extraction (ECCE). Therefore, trabeculectomy alone is not the ideal surgical option in medically uncontrolled PACG.

In theory, adjunctive antimetabolite should be used with trabeculectomy when performed in eyes with a high risk for filtration failure or when a very low target pressure needs to be attained. However, the risk factors for filtration failure and target pressure specific to angle-closure glaucoma are not clearly defined. Trabeculectomy is associated with various complications, both early and late, including bleb leaks and bleb-related infections. These risks are further increased by adjunctive antimetabolite.

Lens extraction—alone or in combination with trabeculectomy

Lens position and thickness both play important roles in the etiology of angle-closure glaucoma.[58] Lens extraction significantly increases anterior chamber depth and width of the drainage angle. Lens extraction has been actively studied and reported in recent years in the treatment of PACG. The lens may narrow the angle by pushing the peripheral iris anteriorly, and this effect will be more marked if the lens is cataractous. Both traditional extracapsular cataract extraction and phacoemulsification have been reported to lower IOP in PACG. Compared to phacotrabeculectomy, phacoemulsification alone leads to more opening of the drainage angle and greater deepening of the anterior chamber.[59]  Phacoemulsification alone has also been shown to normalize IOP and reduce IOP fluctuations in PACG.[60, 61]  Lens extraction eliminates the chance of cataract progression after an initial glaucoma procedure, and the need of cataract surgery which may jeopardize the filtering function of previous drainage procedures.

Hayashi has shown that the depth of the anterior chamber and the width of the drainage angle in eyes with angle-closure glaucoma increased significantly after cataract extraction and intraocular lens implantation, which may lead to the decrease in IOP seen in the postoperative period. It has been postulated that removal of a large cataractous lens from an eye with crowded anterior segment may improve aqueous outflow. It has also been postulated that during phacoemulsification, the irrigating fluid flushes cellular debris from the trabecular meshwork and leads to extracellular matrix remodelling, decreasing resistance to aqueous outflow.

A multicenter, randomized controlled clinical trial comparing lens extraction versus laser iridotomy in patients with newly diagnosed PAC or PACG was conducted by The Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) Study Group.[62] Results published in 2016 demonstrated a high efficacy of clear lens extraction (CLE) as compared with laser peripheral iridotomy with regards to IOP reduction, quality of life, and cost in angle-closure glaucoma at 3 years. There was also a significant difference in the number of subsequent glaucoma surgeries performed between the two groups (one in CLE group versus 24 in LPI group). Nevertheless, CLE for treating PACG remains controversial to this date as a high proportion of patients were noted to be ineligible or refused to join the EAGLE study (386 patients) and the results only apply to a specific group of patients with mild to moderate PACG aged 50 years or older to lessen the effect of loss of accommodation from CLE. The financial advantage specific to the UK may not be applicable to other countries.[63]

Randomized controlled surgical trials by Tham et al in Hong Kong directly compared cataract extraction alone by phacoemulsification against combined phaco-trabeculectomy in PACG eyes with coexisting cataract. Their first study focused on PACG eyes that were adequately controlled by glaucoma drugs before surgery,[64] whereas their second study focused on PACG eyes that were medically uncontrolled.[65] In both clinical scenarios, phacoemulsification alone significantly reduced IOP, as well as the requirement for glaucoma drugs, for at least 2 years after surgery. Combined phacotrabeculectomy resulted in even greater IOP and drug reductions, but was associated with more complications and additional surgery to manage the complications.[66]  On the basis of these initial results, the authors concluded that in medically controlled PACG with cataract, phacoemulsification alone may be considered as an initial treatment. Similar results were noted up to 5 years after surgery.[67]  In PACG eyes with cataract, higher preoperative IOP and increased requirement for glaucoma drugs correlate with failure to control IOP after phacoemulsification or phacotrabeculectomy.[68] In medically uncontrolled PACG with cataract, either phacoemulsification alone or combined phacotrabeculectomy may be considered depending on patient factors.[64, 65, 66, 69]   Although combined phacotrabeculectomy may be a more cost-effective option for IOP reduction in PACG eyes,[70]  the potential additional surgical risk has to be thoroughly discussed with patients. 

In situations where medically uncontrolled PACG coexisted with an optically clear lens, a third randomized controlled trial by Tham et al compared the outcomes of clear lens extraction by phacoemulsification with trabeculectomy alone.[71] In this study, both phacoemulsification and trabeculectomy reduced IOP by more than 30% at 24 months after surgery. Phacoemulsification reduced the requirement for glaucoma drugs by 60% and for trabeculectomy by 89% at 24 months after surgery. Trabeculectomy was associated with more complications. Compared with trabeculectomy, clear lens extraction resulted in a significant reduction in synechial angle closure and an increase in anterior chamber angle width and anterior chamber depth in PACG eyes without cataract.[72] The authors concluded that, with available data, either surgery could be considered for medically uncontrolled PACG eyes without cataract depending on patient factors.

One study suggested that the IOP-lowering effect of lens extraction may be less pronounced in PACG cases with PAS covering three fourths or more of the angle. Therefore, lens extraction alone may have a role in improving IOP control especially in PACG with less extensive PAS and better preoperative IOP control. Good long-term IOP control has been found following lens extraction for PACG, and lens extraction should be considered in patients with PACG, especially those with hyperopia or thick and anteriorly vaulted lens.[73]

A recently published Cochrane review found moderate-quality evidence that lens extraction is preferable to standard care in treating patients with chronic PACG and clear crystalline lens. There was low-certainty evidence that combined phacoemulsification with trabeculectomy does not confer additional benefit over phacoemulsification alone, and may be associated with more complications. The authors, however, also emphasized that the conclusions only apply to short- to medium-term outcomes and highlighted the importance of a shared decision-making process between clinicians and patients, taking into account their preferences, health status, and visual prognosis.[74]

Goniosynechialysis with/without lens extraction

Goniosynechialysis (GSL) is a surgical technique performed to strip the PAS from the trabecular surface in the angle and provide renewed aqueous access to the trabecular meshwork.[25, 26, 27] In eyes with minimal PAS, trabeculectomy is preferred because trabecular function in these eyes is expected to be poor and a fistula procedure would be more appropriate. On the other hand, there may be IOP spikes during and after the GSL procedure leading to loss of vision. GSL is more suitable for eyes with minimal to moderate degree of neuronal damage.

In the past, ophthalmologists have tried to sweep open a closed angle without direct visualization. This often failed because accurate instrument placement could not be achieved. In 1984, Campbell and Vela introduced a technique using direct intraoperative visualization of the angle and anterior chamber deepening with viscoelastic agents.[75] Visualization has been further improved with the use of the Swan-Jacob lens. This specially-designed lens has a handle attached to a small diameter prism so that it will not obstruct the spatula from entering the anterior chamber at the limbus. When PAS has been present for less than 1 year, the reported overall success rate in terms of IOP control is approximately 80%. Irreversible damage to the meshwork may occur in areas of synechial closure, with proliferation of iris or fibrous tissue into the intertrabecular space. This may explain why GSL appeared to be less effective in closed angle of longer duration.

In order for GSL to be effective, it must be performed before there is irreversible histological change in the meshwork. The mechanisms causing the angle closure should also be eliminated by performing peripheral iridotomy, laser peripheral iridoplasty, or lens extraction, either alone or in combination, to minimize the possibility of recurrent closure. Tanihara et al reported success in using GSL followed by argon laser peripheral iridoplasty.[76]

The most common complication of GSL is intraoperative hemorrhage. Other complications include iridodialysis, cyclodialysis, and lens damage.

Evidence for the IOP-lowering effect of GSL with or without lens extraction has been inconsistent. Teekhasaenee and Ritch have reported success with phacoemulsification combined with GSL, and Lai et al were successful with combined phacoemulsification and limited GSL, followed by diode laser peripheral iridoplasty, for PACG.[77] The authors demonstrated with ultrasound biomicroscopy that lens removal in PACG would only deepen the peripheral anterior chamber, without actually opening up the angle, while GSL opened up the angle and allowed aqueous access to the trabeculum.

Nevertheless, both lens extraction and GSL performed alone have been shown to lower the IOP, although the mechanisms are uncertain and may or may not be common to both procedures. Combining GSL with lens extraction has the advantages of noticeable visual improvement after surgery, and the combined IOP-lowering effect of the two procedures. Furthermore, removal of the lens may decrease the possibility of recurrent angle closure. It has been shown that eyes undergoing combined phacoemulsification with GSL have a greater reduction in circumferential iridotrabecular contact area than eyes undergoing phacoemulsification alone.[78] A 2015 prospective study, however, demonstrated that IOP-lowering effects of phacoemulsification and GSL do not differ significantly from those of phacoemulsification alone in medically well-controlled PACG with cataract.[79]  Cochrane systemic review revealed low certainty evidence for GSL, suggesting that combined phacoemulfication with either goniosynechialysis or viscogonioplasty does not confer additional benefit over phacoemulsification alone in patients with chronic PACG and visually significant cataract.[74]

Cyclodestructive procedures

In 1950, Bietti introduced cyclocryotherapy. A temperature of -80°C was applied with a cryoprobe to destroy the ciliary body epithelium, stroma, and vasculature. The clinical usefulness of cyclocryodestruction is limited by its complications, which include hypotony, phthisis, hyphema, choroidal detachment, and retinal detachment.

In the past 10 years, transscleral diode laser cyclophotocoagulation (TSCPC) employing either the continuous or micropulse wave settings have become more popular in the treatment of different types of glaucoma.[80, 81] The semiconductor diode laser emits light of wavelength 810 nm, near the infrared spectrum. It is transmitted through the sclera and absorbed by melanin. The success rates of cyclodestruction vary among the different procedures and the types of glaucoma. Diode TSCPC was reported effective in controlling IOP to less than 21 mm Hg in 70% to 81% of pediatric and adult refractory glaucoma. However, there has been no large-scale study on its efficacy in the treatment of PACG. Since it decreases IOP through the reduction of aqueous production by destroying the ciliary epithelium, it should, theoretically, be effective even in eyes with complete synechial closed angle closure.

In a recent study, adjunctive diode TSCPC was effective in lowering IOP in four cases of PACG that were uncontrolled despite a glaucoma aqueous tube shunt and multiple medications. In another study, diode TSCPC appeared to be an effective and safe primary surgical treatment of medically-uncontrolled PACG, with IOP-lowering effect persisting up to 2 years.

The efficacy, relative safety, portability of the equipment, short learning curve, and short procedure time make diode TSCPC a potential primary or secondary surgical procedure in the treatment of PACG. However, TSCPC is associated with some rare but potentially serious complications, and these should be balanced against its many advantages. Potential complications include uveitis, pupillary distortion, conjunctival burns, hyphema, chronic hypotony, cystoid macular edema, retinal detachment, phthisis bulbi, and scleral perforations.

An alternative to TSCPC is endoscopic cyclophotocoagulation (ECP), which involves laser treatment of the ciliary processes under direct visualization and is most commonly performed in combination with lens extraction. Endoscopic laser allows a more precise application of laser to the targeted ciliary tissue. An animal study showed that TSCPC is associated with a more persistent poor perfusion of the ciliary processes and therefore a higher risk for hypotony and phthisis.[82] In an earlier retrospective study, it achieved an IOP of less than 21 mm Hg in 90% of refractory glaucoma, including PACG eyes.[83] Although hypotony and phthisical change were not seen in this series, reported complications of ECP included uveitis, hyphema, cystoid macular edema, visual loss, choroidal detachment and malignant glaucoma.

A randomized prospective study compared the safety profile of phacotrabeculectomy and cataract surgery combined with ECP.[84]  With a mean follow up period of 2 years, 30% of ECP eyes achieved IOP of less than 19 mm Hg without medication and 52% with medication. The two procedures were reported to have similar rate of additional surgical intervention. The authors suggested that combined cataract surgery with ECP is a reasonably safe and effective alternative to phacotrabeculectomy.

Compared to phacoemsulfication alone, combined phacoemulsification with ECP has not been shown to increase the rate of serious complications.[85]  However, myopic refractive shift was more commonly reported after combined phacoemulsification and ECP due to an altered expected lens position. A more recent randomized controlled trial compared phacoemulsification alone with combined cataract extraction and ECP in PACG eyes with cataract specifically. Lai et al showed that combining cataract extraction with ECP resulted in lower mean IOP at 24 months despite lower or similar glaucoma drug requirements. Both groups had comparable visual improvement and safety profile. This pilot study demonstrated potential additional benefit of additional ECP during cataract extraction in the management of PACG patients. However, further studies are required to evaluate the long term outcomes and cost-effectiveness of adjunctive ECP.[86]

Glaucoma implants in primary angle-closure glaucoma

The use of a glaucoma implant for difficult-to-treat glaucoma is not new. There is a wide variety of such glaucoma drainage devices, from the early Molteno implant to the currently popular valve-equipped variety, such as the Ahmed implant. Overall, the success rates for controlling IOP for complicated cases range from 70% to 90%. However, because it is technically more difficult than trabeculectomy, and potentially serious complications can occur, the use of glaucoma implant for PACG has been mainly confined to those patients in whom one or more previous filtering procedures have failed.

The safety and efficacy of glaucoma implant in PACG remains controversial as published studies only included a small proportion of patients with PACG ranging from 1.7% to 9%. Among these studies, only two published the results of the PACG subgroup. One of these two studies had only a single non-Asian patient with angle-closure glaucoma, who ended up with no light perception at 6 months; while the other included 10 patients of unspecified race, seven of whom had successful surgery.

A subsequent randomized study evaluated non-valved tube shunt surgery against trabeculectomy in patients with glaucoma who had previously failed trabeculectomy and/or cataract extraction with intraocular lens implantation. In this study, there were 18 eyes with PACG, with seven randomly assigned to the implant group and 11 to the trabeculectomy group. In the former study, there were 15 eyes (23%) with the diagnosis of PACG, iridocorneal endotheliopathy, and juvenile open-angle glaucoma treated with the 350 mm2 Baerveldt glaucoma implant. The immediate-term failure rate in this subgroup was 47%, compared with 19% in the group with POAG. Although this study did not provide a subgroup analysis for patients with PACG, the 1-year results found a higher success rate in the tube group compared to the trabeculectomy group. These results suggest a possibly expanded role for the use of implants in eyes with previous ocular surgery.

Consultations

Consult a glaucoma specialist.

Complications

Cataract can occur with steroid, laser and surgical treatment.

Prevention

The risk factors for the development of angle-closure glaucoma are listed below. Individuals with such risk factors may consider ophthalmological screening.

An eye with previous acute primary angle closure (PAC) has over 50% chance of developing primary angle-closure glaucoma (PACG), despite laser peripheral iridotomy. These patients should be regularly monitored. Preventive measures, such as laser peripheral iridoplasty or lens extraction, may be indicated to lower this risk.

The fellow eye in a patient with previous episodes of acute PAC (acute glaucoma) has a 50% chance of developing acute PAC in 5 years and should be screened for narrow angle by gonioscopy. Prophylactic laser peripheral iridotomy is often indicated in the fellow eye to prevent acute or progressive angle closure.

Medication Summary

The first step in the management of primary angle-closure glaucoma (PACG) is often a surgical procedure to open, as far as possible, those segments of the drainage angle that are appositionally closed or narrow. Options may include laser peripheral iridotomy, argon laser peripheral iridoplasty, and lens extraction, depending on the mechanism(s) of angle closure. Intraocular pressure (IOP) may, however, remain elevated after these procedures, which may be the result of extensive residual synechial angle closure and pre-existing trabecular meshwork damage. IOP-lowering medications are indicated if a safe IOP level cannot be reached after angle-opening procedures.[87]

In the past, timolol and pilocarpine were extensively used in PACG. Subsequent studies have demonstrated the superior IOP-lowering efficacy of prostaglandin analogue monotherapy over these conventional drugs, and even some combination therapies, in PACG. The IOP-lowering effect of prostaglandin analogues does not appear to be related to the degree of angle closure or the extent of peripheral anterior synechiae (PAS). Once-daily prostaglandin analogue regimes are generally well tolerated by patients with PACG. Prostaglandin analogues have become an important member in the medical arsenal against PACG.[88]

Pilocarpine ophthalmic (Isopto Carpine, Pilopine HS Gel)

Clinical Context:  Instillation frequency and concentration are determined by response. Individuals with heavily pigmented irides may require higher strengths.

If other glaucoma medication also is being used, at bedtime, use gtt at least 5 min before gel.

Patients may be maintained on pilocarpine as long as IOP is controlled and no deterioration in visual fields occurs.

Class Summary

These agents directly stimulate cholinergic receptors in the eye, decreasing resistance to aqueous humor outflow.

Timolol ophthalmic (Betimol, Istalol, Timoptic, Timoptic-XE, Tiimoptic Ocudose)

Clinical Context:  May reduce elevated and normal intraocular pressure (IOP), with or without glaucoma by inhibiting inflow. Available in various solutions and gels with varying recommended application frequency.

The brands Timoptic XE and Istalol are both administered once daily. However, Timoptic XE is a gel-forming solution while Istalol is an aqueous solution.

Class Summary

Thought to decrease IOP by reducing aqueous formation; however, some studies observed increased outflow.

Travoprost ophthalmic solution (Travatan Z)

Clinical Context:  Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

Latanoprost (Xalatan, Xelpros)

Clinical Context:  May decrease IOP by increasing outflow of aqueous humor.

Bimatoprost (Lumigan, Latisse)

Clinical Context:  Prostaglandin agonist that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes. Used to reduce IOP in open-angle glaucoma or ocular hypertension.

Tafluprost (Zioptan)

Clinical Context:  Prostaglandin agonist that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes. Used to reduce IOP in open-angle glaucoma or ocular hypertension.

Class Summary

Reduces IOP by increasing uveoscleral outflow.

Brinzolamide (Azopt)

Clinical Context:  Catalyzes reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. May use concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, administer drugs at least 10 min apart.

Dorzolamide (Trusopt)

Clinical Context:  Reversible carbonic anhydrase inhibitor that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably, it slows bicarbonate ion formation with subsequent reduction in sodium and fluid transport.

Systemic absorption can affect carbonic anhydrase in the kidney, reducing hydrogen ion secretion at renal tubule, and increasing renal excretion of sodium, potassium bicarbonate, and water.

Used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one ophthalmic drug is being used, administer the drugs at least 10 min apart.

Acetazolamide (Diamox Sequels)

Clinical Context:  Reduces rate of aqueous humor formation by direct inhibition of enzyme carbonic anhydrase (CA) on secretory ciliary epithelium, causing in turn a reduction in intraocular pressure (IOP). More than 90% of CA must be inhibited before IOP reduction can occur. May reduce IOP by 40-60%. Effects are seen in about an hour, they peak in 4 h, and trough in about 12 h. Derived chemically from sulfa drugs. If one form is not well tolerated, another form may be better or lower dose of the drug may be better tolerated.

Used for adjunctive treatment of chronic simple (open-angle) glaucoma and secondary glaucoma and preoperatively in acute angle-closure glaucoma when delay of surgery desired to lower IOP

Class Summary

Inhibits aqueous humor formation by inhibiting carbonic anhydrase 2 (CA-II).

Brimonidine (Alphagan P)

Clinical Context:  Relatively selective alpha2-adrenergic receptor agonist, decreases IOP by dual mechanisms. Reduces aqueous humor production and increases uveoscleral outflow. Has minimal effect on cardiovascular and pulmonary parameters. A moderate risk of allergic response to this drug exists. Caution should be used in individuals who have developed an allergy to Iopidine.

The brand Alphagan-P contains the preservative Purite and has been shown to be much better tolerated than its counterpart Alphagan.

Class Summary

Reduces aqueous humor production and increases uveoscleral outflow.

Ripasudil

Clinical Context:  Increases aqueous outflow through the trabecular meshwork by reducing trabecular outflow resistance. Clinically useful concentration is 0.4%, which is applied twice a day for the treatment of glaucoma and ocular hypertension. Associated conjunctival hyperaemia usually peaks at 15 minutes after instillation and gradually returns to baseline at 120 minutes. Other common side effects include blepharitis and allergic conjunctivitis (most commonly occurs after 12 weeks of use).

Netarsudil

Clinical Context:  A amino-isoquinolone amide Rho kinase inhibitor and norepinephrine transport inhibitor for the treatment of glaucoma and ocular hypertension. Mechanisms proposed include the reduction of trabecular outflow resistance and therefore increase in trabecular aqueous outflow, decrease in aqueous humour production and lowering of episcleral venous pressure. Studies suggested that netarsudil may be relatively more effective in patients with lower baseline IOP due to its mechanism to lower episcleral venous pressure. Conjunctival hyperaemia, increased lacrimation, small perilimbal subconjunctival haemorrhage and corneal verticillate are some of the common side effects.

Class Summary

Reduces trabecular outflow resistance by modifying Schlemm’s canal cell cytoskeleton and relaxing smooth muscle cells in the trabecular meshwork

Mannitol (Osmitrol)

Clinical Context:  Reduces elevated intraocular pressure when the pressure cannot be lowered by other means.

Initially assess for adequate renal function in adults by administering a test dose of 200 mg/kg, given IV over 3-5 min. Should produce a urine flow of at least 30-50 mL/h of urine over 2-3 h.

In children, assess for adequate renal function by administering a test dose of 200 mg/kg, given IV over 3-5 min. Should produce a urine flow of at least 1 mL/kg over 1-3 h.

Class Summary

These agents elevate glomerular filtrate osmolarity, resulting in decreased tubular reabsorption of water, thereby inducing diuresis.

Author

Clement Chee-yung Tham, MBBCh, MA, FRCS(Glasg), SH Ho Professor of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong; Honorary Chief-of-Service, Hong Kong Eye Hospital; Secretary General, Asia-Pacific Academy of Ophthalmology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Consultancy: Alcon Laboratories Inc; Allergan, Inc; Bausch & Lomb; IOPtima Ltd.; Merck & Co Inc; Pfrizer Inc; Santen Pharmaceutical Co Ltd; Sensimed;C-MER Eye Care Holdings Ltd<br/>Serve(d) as a speaker or a member of a speakers bureau for: Lectures Fees: Alcon Laboratories Inc; Merck & Co Inc, Pfizer Inc; Santen Pharmaceutical Co, Ltd.<br/>Received research grant from: Aeon Astron Corporation; Alcon Laboratories Inc; AMO Asia Ltd; Icare Finland; Pfizer Inc; Santen Pharmaceutical Co Ltd; Sensimed; <br/>Travel Support for: Alcon Laboratories Inc; Allergan Inc; Merck & Co Inc; Pfizer Inc; Santen Pharmaceutical Co Ltd.

Coauthor(s)

,

Disclosure: Nothing to disclose.

Noel C Y Chan, MBChB, FRCSEd, FCOphth(HK), FHKAM(Ophth), Consultant Ophthalmologist, Prince of Wales Hospital and Alice Ho Miu Ling Nethersole Hospital; Honorary Clinical Assistant Professor, Department of Ophthalmology and Visual Sciences, Honorary Clinical Assistant Professor, Clinical Skills Learning Center, The Chinese University of Hong Kong, China

Disclosure: Nothing to disclose.

Specialty Editors

Martin B Wax, MD, Professor, Department of Ophthalmology, University of Texas Southwestern Medical School; Vice President, Research and Development, Head, Ophthalmology Discovery Research and Preclinical Sciences, Alcon Laboratories, Inc

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy, Sr, MD, † Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Andrew I Rabinowitz, MD, Director of Glaucoma Service, Barnet Dulaney Perkins Eye Center

Disclosure: Nothing to disclose.

Robert Ritch, MD, FACS, FARVO, Shelley and Steven Einhorn Distinguished Chair in Ophthalmology, Professor of Ophthalmology, Surgeon Director Emeritus, New York Eye and Ear Infirmary of Mount Sinai

Disclosure: Received none from Sensimed for board membership; Received none from iSonic Medical for board membership; Received consulting fee from Aeon Astron for consulting; Received honoraria from Pfizer for speaking and teaching; Received honoraria from Allergan for speaking and teaching; Received honoraria from Ministry of Health of Kuwait for speaking and teaching; Received honoraria from Aeon Astron for speaking and teaching; Received royalty from Ocular Instruments for other.

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