Chronic Closed Angle Glaucoma

Etiology

PAC glaucoma is characterized by synechial or appositional closure of the anterior iridocorneal angle, leading to elevations in intraocular pressure. In the acute form, the increased intraocular pressure is sudden and not self-limiting.[8] Repeated, intermittent, and prolonged iridotrabecular contact can result in the formation of PAS between the peripheral iris and trabecular meshwork, serving as the primary underlying cause of chronic angle-closure glaucoma.

The categorization of primary closure disease, characterized by the presence of at least 180° of iridotrabecular contact, is outlined below. 

Primary angle-closure suspects: Eyes exhibiting an occludable angle without elevated intraocular pressures or PAS.

Primary angle-closure: Eyes displaying elevated intraocular pressures or the presence of PAS without indications of glaucomatous optic neuropathy and visual field damage.

Primary angle-closure glaucoma: Eyes exhibiting signs of chronic angle damage, PAS, elevated intraocular pressures, along with typical signs of glaucomatous functional or morphological damage.[9]

Mechanisms and forces within the eye that cause PAC glaucoma are mentioned below. 

Pupillary block: The peripheral iris bows forward, forming a bombè, and closes the angle due to a pressure gradient that develops from the posterior chamber when the flow of aqueous humor through the pupil is obstructed. Pupillary block is responsible for more than two-thirds of cases of acute PAC.[10]

Plateau iris: In these eyes, the ciliary body tends to be more anterior, resulting in a narrow angle due to the anteriorly positioned peripheral iris insertion. The iris plane typically appears flat, and the anterior chamber can have a normal depth, making diagnosis challenging without the use of ultrasound biomicroscopy (UBM).[11] 

Increased lens vault: As individuals age, the crystalline lens may undergo anterior anatomical displacement, often associated with cataract formation. The bulking effect behind the iris can play a crucial role in PAC.[12]

Malignant glaucoma: Elevated forces behind the lens can occur as a result of diverting aqueous humor into the posterior segment, potentially caused by the anterior displacement of the ciliary body. While the exact mechanism of this condition is unknown, it may manifest as a complication following surgery.[13][14]

Physiological features that elevate the risk of PAC glaucoma include shallow anterior chamber depth, short axial length, increased lens thickness, increased anterior curvature of the lens, small corneal radius of curvature, increased lens vaulting and anterior positioned crystalline lens, increased iris volume, expansion of choroidal thickness, forward positioning or rotation of the ciliary body, choroidal effusion, refractive error hyperopia with eyes having short axial lengths, recurrent intraocular inflammation, cataract with an intumescent lens, and plateau iris.[15][16]

Other secondary causes include uveitis, trauma, iris neovascularization, surgery, iridociliary cysts or tumors, retinal gas or silicone oil tamponade, massive vitreous hemorrhage, iridocorneal endothelial syndrome, epithelial or fibrous ingrowth after surgery or trauma, uveal effusion, retinopathy of prematurity, and congenital anomalies.[17]

In susceptible individuals, certain systemic medications can induce angle closure, including nebulized bronchodilators such as salbutamol and ipratropium bromide, selective serotonin reuptake inhibitors, tricyclic antidepressants, sulfa drugs, glucocorticoids, cold and flu medications that contain phenylephrine or pseudoephedrine, muscle relaxants, topiramate, benzodiazepines, parasympatholytics, and sympathomimetics.[18][19]

Epidemiology

Glaucoma is a leading cause of irreversible blindness worldwide, ranking second only to cataracts. Studies project that the global count of individuals with glaucoma will exceed 110 million by the year 2040.[20] The prevalence of PAC glaucoma exhibits considerable variation among different populations. A recent meta-analysis published in 2021 indicates a global prevalence of 0.6% for PAC glaucoma, a rate that rises with age. The highest prevalence is observed in Asian populations, with a reported rate of 1.1%.[20][21] Studies based on individuals residing in China suggest that most PAC glaucoma cases are multifactorial, resulting from a plateau iris, a thicker peripheral iris, forward lens shifting, and anterior insertion of the iris root.[22]

Primary open-angle glaucoma is 3 times more prevalent than angle-closure glaucoma, yet angle closure accounts for 50% of glaucoma-related blindness.[23] 

The frequency of occurrence of angle-closure glaucoma is 2 to 3 times higher in females than males, higher in individuals older than 40, highest in Asian, African, and Inuit populations, and increased in individuals with a family history of angle closure.[7][24] 

The prevalence of PAC glaucoma and relative pupillary block tends to increase after the age of 40. Studies on European individuals indicates that the age-specific prevalence of PAC glaucoma is 0.02% for those aged 40 to 49, progressively increasing to 0.95% in patients older than 70.[23] This increase is likely attributed to a gradual reduction in anterior chamber volume and depth, in addition to lens thickening due to cataract formation and a progressive shallowing of the anterior chamber throughout life. PAC glaucoma is less prevalent in younger individuals and, when encountered, is often associated with plateau iris syndrome and other ocular abnormalities.[25]

Pathophysiology

Irreversible iridotrabecular adhesions typically cause chronic PAC glaucoma due to intermittent angle closure and PAS.[26] The ciliary body produces aqueous humor, which flows through the pupil to the anterior chamber and exits the eye. The balance between aqueous fluid production and drainage determines the intraocular pressure. Obstruction, damage, or destruction of the trabecular network leads to increased intraocular pressure and subsequent glaucomatous optic nerve damage. Normal intraocular pressure ranges from 8 to 21 mmHg. Acute episodes of angle-closure glaucoma can lead to intraocular pressure exceeding 30 mmHg.

Iridotrabecular contact characterizes PAC, which may lead to chronic angle closure due to PAS formation. Chronic angle-closure glaucoma results when optic neuropathy develops due to increased intraocular pressure. The major mechanisms leading to angle closure include:

• Pupillary block: It is the most common mechanism for PAC, representing about 75% of cases, especially in acute cases.[10]
• Anomalies at the level of the iris and/or ciliary body: These anomalies may result in a plateau iris configuration and include the factors below.[27]
  • Thicker iris 
  • Anterior iris insertion
  • Anterior ciliary body position
  • Anteriorly positioned ciliary processes 
• Anomalies at the level of the lens: These include the factors mentioned below.
  • Cataract or lens intumescence
  • Lens subluxation
  • Microspherophakias [28]
• Anomalies posterior to the lens include aqueous misdirection [29]
• Other secondary causes include:
  • Uveitis
  • Trauma
  • Iris neovascularization
  • Surgery
  • Iridociliary cysts or tumors
  • Retinal gas or silicone oil tamponade
  • Massive vitreous hemorrhage
  • Iridocorneal endothelial syndrome
  • Epithelial and/or fibrous ingrowth after surgery or trauma
  • Uveal effusion
  • Retinopathy of prematurity
  • Congenital anomalies [17][7]

History and Physical

The majority of patients with chronic angle-closure glaucoma do not exhibit symptoms.[30] Some may present with symptoms resulting from episodes of intermittent angle-closure that spontaneously resolve.[7]

Medical History

A patient's medical history may indicate a background of ophthalmic surgery, trauma, recurrent inflammation, acute angle-closure glaucoma, hyperopia, or a long-standing cataract. Furthermore, individuals may present with a medical history that includes a family history of angle closure, diabetes, and connective tissue diseases associated with uveitis, such as rheumatoid arthritis and spondylitis. Paying careful attention to the medication history of patients is necessary to identify any potential medications that may precipitate acute angle closure in susceptible patients. 

Symptoms

Acute angle-closure glaucoma is characterized by symptoms such as halos around lights, decreased visual acuity, headache, severe eye pain, and episodic nausea and vomiting.[31]

Conjunctival redness, corneal edema or cloudiness, a shallow anterior chamber, and a mid-dilated pupil of 4 to 6 mm that reacts poorly to light all indicate that the rise in intraocular pressure is acute.

Clinical Signs

The clinical signs observed in angle-closure glaucoma are as follows:

• Visual acuity may appear normal
• Elevated intraocular pressure, usually exceeding 21 mmHg
• Varying degrees of PAS observed on gonioscopy
• Damage to the head of the optic nerve
• Visual field loss
• Thinning of the layers of the retinal nerve observed on optical coherence tomography [32]

Evaluation

The assessment of angle-closure glaucoma involves the following steps:

• Visual acuity
• Evaluation of the pupils
• Intraocular pressure 
• Slit-lamp examination of the anterior segments
• Visual field testing, either by confrontation with finger testing or by formal methods
• Gonioscopy 
• Undilated fundus examination

Patients may present with unilateral symptoms, but both eyes require examination. Evidence of prior episodes of increased intraocular pressure is:

• Iris irregularity due to ischemia during the attack
• Glaucomflecken or scattered opacities in the anterior lens
• Normal or increased intraocular pressure
• Cupping of the optic disc if narrow-angle glaucoma is present

Gonioscopy

Goinoscopy involves using a special lens during a slit lamp examination and is considered the gold standard for diagnosing angle-closure glaucoma. During indentation gonioscopy, posterior pressure is applied to the eyeball using the gonioscopy lens. If scarring has not led to complete closure, the angle should widen.[33] Gonioscopy is instrumental in determining the severity and chronicity of angle-closure glaucoma.

Slit-Lamp Biomicroscope Examination

The anterior segment examination assesses the anterior chamber depth and angle, with a quick evaluation possible using the Van Herick score. Clinicians calculate the anterior drainage angle by determining the ratio between the peripheral anterior chamber depth and corneal thickness after directing a narrow beam of light at around 60° at the limbus.[34] 

The Van Herick technique is a quick screening and does not replace goinoscopy. Van Herick's estimation of angle widths is listed below.

Grade 4: The distance between the posterior surface of the cornea and the iris (CA) is at least the same width as the slit projected onto the cornea (SC). The angle is wide open, and the risk of closure is low. The angle width is likely 35° to 45°.

Grade 3: Closure is unlikely if CA is one-half of SC and the chamber angle is open. The angle width is likely 20° to 35°.

Grade 2: Closure is possible if the CA is one-fourth of the SC. The angle width is approximately 20°.

Grade 1: If the width of CA is smaller than one-fourth of the SC, closure of the angle is likely. The angle is approximately 10°.

Grade 0: If no space exists between the corneal slit image and the slit image on the iris, the chamber angle is closed, and an angle closure already exists.

Tonometry

The measurement of intraocular pressure is crucial for diagnosing and managing all types of glaucoma, and it is performed by the tonometry method.[35] The gold standard for this measurement is Goldmann applanation tonometry.[36]

Pachymetry

Tonometer readings may be underestimated in patients with thin corneas and overestimated in individuals with thick corneas.[37] A pachymeter measures central corneal thickness to provide this helpful information.

Indirect ophthalmoscope

The clinical examination of the head of the optic nerve is mandatory.[38] Therefore, avoiding a dilated eye examination is advisable, as it can exacerbate the condition. Cupping, characterized by a hollowed-out appearance of the optic nerve during fundus examination, is a distinctive finding in glaucoma. A cup with a diameter exceeding 50% of the vertical disc diameter raises suspicion for glaucoma. In addition, observations of thinning or notching of the disc rim, progressive changes in the size or shape of the cup, and asymmetry of the cup-to-disc ratio between the eyes also suggest glaucoma.

Perimetry

Visual field analysis is crucial for identifying and evaluating progressive functional damage caused by glaucoma. Testing can be conducted either by confrontation with finger testing or by formal methods, depending on the acuity of the clinical situation. Generally, confrontational testing is ineffective in detecting glaucoma; automated perimetry is significantly more reliable.[39] Manual perimetry testing is helpful in patients with dementia, advanced visual field loss, or with limitations that preclude automated testing.

Optical Coherence Tomography [40]

Optical coherence tomography analyzes light reflected off the fundus. Clinicians generate a digital image and evaluate the anterior segment, including PAS and quantification of the drainage angle. The evaluation also encompasses specific features such as retinal nerve fiber layer thickness and the structure of the optic nerve head. Furthermore, structural parameters of the macula, including the macular retinal nerve fiber layer, the ganglion cell layer with the inner plexiform layer, and the ganglion cell complex, are examined.[41][42][43]

Ultrasound Biomicroscopy

UBM uses a specialized ultrasound to visualize the anterior chamber. This technique may assist in evaluating the position of the ciliary body, lens position, and the presence of an iridociliary cyst or mass.[44] UBM, however, is relatively expensive and not widely available.

A darkroom-prone provocation test has been described but does not assist in discriminating PAC glaucoma suspects from those with open angles.[45]

Pharmacological provocation tests involving the use of phenylephrine to dilate the pupil, followed by pilocarpine to induce an episode of acute angle-closure glaucoma, pose unnecessary risks to the patient. Furthermore, a negative result from such tests does not rule out the diagnosis of glaucoma. 

Treatment / Management

The initial treatment for chronic angle-closure glaucoma is laser peripheral iridotomy using an Nd-Yag laser with or without argon laser pre-treatment to relieve any component of pupillary block.[46][47] The argon laser helps reduce appositional angle closure caused by non-pupillary block mechanisms, such as plateau iris syndrome.[46] If intraocular pressure persists at an elevated level, clinicians initiate medical therapy. (B2)

Medical Treatment

Aqueous production reduction: Aqueous production can be reduced by the below-mentioned factors.

• Topical or oral carbonic anhydrase inhibitors such as dorzolamide, brinzolamide, acetazolamide, or methazolamide
• Topical alpha-adrenergic agonists such as brimonidine tartrate and apraclonidine
• Topical beta blockers such as timolol and levobunolol

Aqueous outflow elevation: Aqueous outflow can be increased by the below-mentioned factors.

• Topical prostaglandins such as latanoprost, travoprost, and bimatoprost
• Alpha-adrenergic and cholinergic agonists
• Rho kinase inhibitors [48]
(A1)

The effectiveness of medications that increase aqueous outflow may be reduced as the trabecular meshwork is obstructed due to PAS.

With once-daily administration, superior efficacy compared to timolol, and the lack of systemic adverse effects associated with topical beta blockers, topical prostaglandins are frequently the preferred medical therapy. Adverse effects of topical prostaglandins include hyperemia, eye irritation, orbital fat atrophy, increased number and length of eyelashes, and changes in iris and lash pigmentation. Beta blockers serve as a viable alternative. Possible adverse effects of topical beta blockers encompass worsening heart failure, bradycardia, heart block, increased airway resistance, exercise intolerance, depression, and sexual dysfunction. 

Topical carbonic anhydrase inhibitors are not as effective as beta blockers and prostaglandins. However, multiple topical medications may be necessary to control intraocular pressure in many patients, and combination products are available.

Rho kinase regulates various aspects of cell morphology. Inhibition of this pathway induces a change in cell shape and actin cytoskeleton structure. Netarsudil blocks the rho kinase pathway, leading to rounded cell bodies and disrupted actin production. This alteration facilitates increased outflow of aqueous humor through the trabecular meshwork. In addition, netarsudil is a norepinephrine transport inhibitor, contributing to a reduction in episcleral venous pressure and aqueous humor production.

Surgical Treatment

Trabeculectomy is beneficial in angle-closure glaucoma but poses an elevated risk of further shallowing the anterior chamber or triggering malignant glaucoma.[49][50] Trabeculectomy also increases the risk of cataract progression, precipitating the need for cataract removal shortly after surgery. Subsequently, cataract surgery increases the likelihood of patients requiring medications to control intraocular pressure 30% to 100% of the time.(A1)

For these reasons, trabeculectomy alone is not the ideal surgical intervention for patients with cataracts. Lens extraction through traditional methods or phacoemulsification increases the diameter of the anterior chamber and widens the drainage angle.[51] Lens extraction alone, whether in a patient with or without a cataract, can be an effective treatment strategy for PAC glaucoma. However, combining lens extraction with trabeculectomy leads to a further decrease in intraocular pressure but significantly elevates the complication rate and the necessity for additional surgery to manage these complications.(A1)

Goniosynechialysis (GSL) involves stripping PAS from the trabecular surface in the angle, restoring renewed access of aqueous humor to the trabecular meshwork. This method is preferred over trabeculectomy in eyes with minimal to moderate neuronal damage. Goniosynechialysis is often performed with a peripheral iridotomy, laser peripheral iridoplasty, or lens extraction to help prevent recurrent angle closure.[52] (B2)

Cyclocryotherapy techniques previously used extreme cold to destroy the ciliary body epithelium, stroma, and vasculature. More recent techniques use a transscleral diode laser, which emits light at a wavelength of 810 nm, or endoscopic cyclophotocoagulation (ECP), which involves laser treatment of the ciliary processes under direct visualization. Endoscopic cyclophotocoagulation is typically performed in conjunction with lens extraction in refractory cases.[48] (A1)

Glaucoma drainage devices and valves have success rates ranging from 70% to 90% in controlling intraocular pressure for complicated cases. This technique is more intricate than trabeculectomy, and the adverse effects can be severe. Clinicians contemplate the use of glaucoma implants for PAC glaucoma in cases where one or more previous procedures have failed.[53][52](B2)

Differential Diagnosis

Clinicians must differentiate chronic angle-closure glaucoma from open-angle glaucoma and causes of nonglaucomatous optic neuropathy, such as ischemic, compressive, and hereditary optic neuropathies.[54] 

Other differential diagnoses include iritis, traumatic hyphema, conjunctivitis, episcleritis, subconjunctival hemorrhage, corneal abrasion, and infectious keratitis.

Prognosis

The prognosis of chronic angle-closure glaucoma is favorable when there is effective control of intraocular pressure. However, factors such as advanced disease at presentation, significant intraocular pressure fluctuations, and a thin central corneal thickness can influence disease progression. Furthermore, more extensive PAS and a narrower drainage angle are associated with higher intraocular pressures and a larger vertical cup-to-disc ratio.[55] 

A study involving Chinese patients indicates poorer visual field and acuity outcomes, with 7% progressing to blindness while on treatment over 10 years.[56] Notably, performing a prophylactic peripheral iridotomy does not guarantee the prevention of angle-closure glaucoma. In fact, 50% of the eyes receiving a prophylactic iridotomy at the time of acute-angle closure in the contralateral eye develop chronic angle-closure glaucoma.[57] 

Complications

Glaucomatous damage to the optic nerve is irreversible. Complications include visual field loss, decreased visual acuity, complete blindness, damage to the corneal endothelium leading to corneal decompensation, and aqueous misdirection syndrome.

Surgical complications encompass further shallowing of the anterior chamber, malignant glaucoma, progression of cataracts, irreversible damage to the meshwork, and proliferation of iris or fibrous tissue into the intertrabecular space.