Glaucoma

Definition

A variety of conditions with a common feature of glaucomatous optic neuropathy (GON) characterized by loss of retinal nerve fibers and changes in the optic disc. Permanent damage ensues if left untreated and results in progressive loss of vision and irreversible blindness.

Increased intraocular pressure (IOP) is the most common causative risk factor but is not necessary for diagnosis.

Open and closed-angle glaucoma can be primary or secondary.

• Primary glaucoma: Refers to conditions in which there are no other associated ocular or systemic cause
• Secondary glaucoma: Refers to those conditions in which there is an associated ocular or systemic condition
• Congenital or developmental glaucoma: Represent only a small percentage of the overall cases of glaucoma and are usually identified prior to 3-5 years of age

Note: Open-angle glaucoma makes up ~90% of all primary glaucoma cases, while angle closure glaucoma makes up the other 10%, and its incidence increases with age.

Classification flowchart:

1) Open-angle    2) Angel closure    3) Developmental

Etiology

Primary and secondary glaucoma may be associated with increased intraocular pressure (IOP).

Putative mechanisms of elevated IOP include:

Obstruction to aqueous outflow from:

1. Closure of iridocorneal drainage due to apposition of the trabecular meshwork and iris root (closed-angle) or obstruction to outflow through the drainage pathways of an open angle
2. Obstruction to the venous drainage of the eye

Other potential causes of increased IOP include:

• Trauma to outflow pathways
• Metabolic factors related to aqueous production
• Anatomic or physiologic features of the trabecular meshwork
• Mutations in the myocilin gene (MYOC) have been identified. Myocilin is produced in the ciliary body and in the trabecular meshwork

Closed-angle glaucoma develops if the high IOP causes glaucomatous damage to the optic disc.

Open-angle glaucoma occurs if damage to the disc is present in the face of an open angle.

Secondary causes that may lead to glaucoma include:

• Pseudo-exfoliation syndrome
• Pigment dispersion syndrome (pigmentary glaucoma)
• Lens-induced glaucoma
• Ocular inflammatory diseases
• Intraocular tumours
• Raised episcleral venous pressure (e.g. Sturge Weber syndrome, orbit tumor, carotid cavernous fistula)
• Neovascularization of trabecular meshwork (diabetes mellitus, vascular occlusions etc.)

Risk factors for glaucoma include

• Age
• Family history of glaucoma
• Elevated eye pressure (IOP)
• Nearsightedness (POAG)
• Farsightedness (angle closure)
• African, Hispanic or Asian ancestry
• Diabetes mellitus
• Previous eye injury
• Thin cornea
• Prolonged use of topical, periocular, inhaled, or systemic corticosteroids

Epidemiology

Canadian:

• Glaucoma is the leading cause of irreversible blindness
• Approximately affects 300,000 Canadians, ~80% are >40 years of age, while ~50% of these are unaware of there diagnosis

USA:

• Prevalence for primary open angle glaucoma (POAG)
  • In the adult US population over age 40 is 1.86%
  • In whites is 1.69%
  • Age-adjusted prevalence in blacks is three times higher than in whites

Worldwide:

Approximately 3 million people are bilaterally blind from POAG.

Prevalence:

• Primary open angle glaucoma is 1.96%
• Angle-closure glaucoma is 0.69%

The incidence increases with age and is more prevalent among men.

Pathophysiology

Pathogenesis of open-angle glaucoma:

Although the exact mechanism is unknown, elevated IOP is often associated with the development of glaucoma.

The putative mechanism by which IOP initiates glaucomatous damage includes:

• Mechanical Hypothesis: Elevated IOP causes backward bowing of the lamina cribrosa, compressing the axons as they exit through the luminal pores, interfering with the axoplasmic flow of trophic factors, triggering cell death
• Vascular Hypothesis: Chronic hypoxia and ischemia leads to glaucomatous damage

Other potential mechanisms include:

• Excitotoxic injury from excessive retinal glutamate
• Deprivation of neuronal growth factors
• Peroxynitrite toxicity from increased nitric oxide synthetase activity
• Immune-mediated nerve damage, and oxidative stress

The above mentioned conditions lead to apoptotic cell death.

Pathogenesis of acute angle closure glaucoma (AACG):

Apposition of the iris to the trabecular meshwork at the angle of the anterior chamber, obstructs aqueous outflow from the eye leading to increased IOP.

In primary angle closure glaucoma, this apposition is due to a mechanism called Pupil Block.

• The normal flow of aqueous humour is from the posterior chamber, around the lens, through the pupil, into the anterior chamber, and out through the trabecular meshwork. In predisposed patients, the pupil margin touches the lens and can cause resistance to the normal flow through the pupil. Pressure builds in the posterior chamber causing the peripheral iris to bulge forward (iris bombe). If the peripheral iris covers the trabecular meshwork, outflow is obstructed

Note: Immediate treatment is required to prevent nerve damage and vision loss; symptoms are severe in sudden closure.

Pathogenesis of chronic angle closure glaucoma (CACG):

• May occur when portions of the anterior chamber angle are closed permanently by peripheral anterior synechiae (PAS)

Note: Eyes with progressive peripheral anterior synechiae (PAS) formation eventually may develop AACG when pupillary block results in closure of the remaining portions of the angle unaffected by PAS.

Combined mechanism glaucoma:

• Carry both components of open and closed angle glaucoma

Clinical Presentation

Open-Angle Glaucoma:

History is crucial in the evaluation of open-angle glaucoma as this condition is often asymptomatic until most of the vision is lost.

Acute Angle-Closure Glaucoma:

Triggered by rapid elevation in IOP resulting in:

• Decreased vision
• Halos around lights
• Headache
• Severe eye pain
• Nausea and vomiting

Chronic Angle-Closure Glaucoma:

• Patients remain asymptomatic for a long time due to slow elevation in IOP

Differential Diagnosis

Other optic neuropathies

a) Vascular Causes:

• Stroke
• Central retinal artery occlusion or branch occlusion
• Anterior ischemic optic neuropathy (AION)
  • Arteritic AION (AAION) – e.g. secondary to temporal arteritis
  • Non-arteritic AION (NAAION) – e.g. secondary to small vessel arteriopathy
• Venous engorgement and ensuing hemorrhage

b) Optic neuritis

c) Multiple sclerosis/neuromyelitis optica

d) Retinal detachment

e) Cataracts

f) Tumors:

• Causing compression of visual pathways e.g. pituitary tumour

g) Congenital anomalies:

• Mitochondrial disorders
  • Lebers hereditary optic neuropathy
• Optic nerve pit
• Optic nerve drusen
• Coloboma
• Tilted disc
• Physiological cupping

h) Acquired anomalies:

• Toxic optic neuropathy
• Traumatic optic neuropathy

Investigation and Workup

History should include:

• Birth and developmental history
• Family history
• Episodes of eye pain/headache/nausea/blurred vision (acute glaucoma)
• Halos around lights (acute glaucoma)
• Cataract
• Uveitis
• Previous eye surgery/trauma
• Systemic illnesses
  • Diabetes
  • Hypertension
  • Cardiovascular disease
  • Migraines
  • Raynaud’s disease
• Use of medicines affecting intraocular pressure (steroids-systemic, ocular, inhaled)

Physical examination should include assessment of:

• Pupil
• Anterior segment
• Central corneal thickness (CCT)
• Gonioscopy
• Optic nerve head and retinal nerve layer evaluation
• Visual field sensitivities
• Intraocular pressure (IOP)

Normal intraocular pressure

• Adult: 10-21 mmHg (16 mmHg ±2.5); tends to increase with age
• Children: Increases ~1 mmHg every 2 years till 12 years
  • At birth 6-8 mmHg
  • At 12 years 12 ±3 mmHg
• Diurnal variation: IOP often follows circadian rhythm
  • Maximum: Between 8 a.m. and 11 a.m.
  • Minimum: Between midnight and 2 a.m.
  • Variation: Between 3 and 5 mmHg

Tonometry: To measure IOP in millimeters of mercury(mmHg)

• Multiple readings from hour to hour are taken
• IOP in both eyes are measured
• Comparison with previous readings are done
• Difference of 3 mmHg in both eyes is an indication for further investigation for glaucoma
• Factors that need to be taken into account when measuring IOP include:
  • Age, gender, race
  • Refraction
  • Posture, holding breath, tight collar/tie
  • Exercise
  • Blood pressure
  • Corneal thickness
  • Ocular movement
  • Variety of drugs

Corneal Pachymetry:

• Used to check central corneal thickness(CCT)
• Independent risk factor for development of glaucoma
• Average cornea is about 560 microns thick
• Generally, patients with thin cornea (less than 555 µm) show artificially low IOP readings
• Patients with thicker CCT (589 microns or more) show a higher reading of IOP than actually exists

Gonioscopy:

• Used to determine if the angle is open, closed or abnormal

Fundoscopy:

• Direct ophthalmoscopy: Produces an upright, or unreversed, image of approximately 15 times magnification
• Indirect ophthalmoscopy: Produces an inverted, or reversed, direct image of 2 to 5 times magnification
• Findings:
  • Evidence of glaucomatous optic nerve damage
  • Thinning or notching of the disc rim
  • Retinal nerve fiber layer defects

Slit lamp examination:

Focus on cornea, anterior chamber, lens, optic nerve fibers, and fundus.

• Narrow-angle or shallow anterior chamber
  • Von Herrick’s sign: If peripheral anterior chamber depth is ¼ or less of the thickness of peripheral cornea, angle-closure possible
• Corneal edema
• Large optic cup
  • Cup to Disc Ratio: Disc >0.5 or asymmetry between eyes of >0.1 are risk factors
• Narrowing, notching, or pallor of the neuroretinal rim
• Splinter hemorrhage at disk
• Nerve fiber layer defects
• Beta peri-papillary atrophy (pigment changes directly adjacent to optic disc)

Perimetry (visual fields):

• It is the systematic measurement of visual field function, that is central and peripheral (side) vision
• It is a crucial component of glaucoma diagnosis, and more importantly, for follow up

Laboratory:

Routine labs are not routinely done, unless considering normal tension glaucoma or other optic neuropathies.

• CBC, ESR, electrolytes
• Serology for syphilis

Imaging:

Methods of measuring the optic disc and the nerve fiber layer:

• Laser scanning polarimetry (e.g. GDx Nerve Fiber Analysis System)
  • Measures the thickness of the nerve fiber layer
• Confocal laser ophthalmoscopy – (e.g. Heidelberg Retinal Tomography or HRT)
  • Scans layers of the retina to make quantitative measurements of the surface features of the optic nerve head and fundus
• Optical coherence tomography (OCT)
  • OCT can create a contour map of the optic nerve, optic cup and measure the retinal nerve fiber thickness
  • New anterior segment OCT machines are helpful in the evaluation of angle closure
• Stereo photographs
  • Used to determine the three-dimensional characteristics of the optic nerve head, and for following glaucomatous change of the optic nerve head over time
• Ultrasound biomicroscopy (UBM) – (High-resolution ultrasound technique)
  • Helpful to obtain a better view of the angle, iris, and ciliary body structures to rule out anatomical pathology and secondary causes of elevated IOP

Treatment

Clinical Trials

• Canadian Glaucoma Study: 2. Risk factors for the progression of open-angle glaucoma
• Ocular Hypertension Treatment Study (OHTS)
• Early Manifest Glaucoma Trial (EMGT)

Pipeline Agents

NOTHING NEW AT THE MOMENT.

Physician Resources

1. Tips for Patient Care

• Early detection and treatment of glaucoma is always important to control the disease progress
• Most primary angle closure glaucoma’s are bilateral
• Ensure patient is well informed about the disease and its treatment
• Encourage compliance – this is one of the most significant barriers to control of the disease

Medications:

• Inform patients of the proper administration techniques as follows
  • Tip of the eye drop bottle should not touch the eyelashes
  • Administration should be conducted one drop at a time
  • After administration, gently close the eye and compress the lacrimal sac
  • Allow at least 5 minutes interval between multiple eyes drops use
• Drugs with Anticholinergic activity can precipitate angle-closure glaucoma
• Compliance issues must be verified before changing medications
• Appropriate therapeutic modality must be selected based on the individual patient and the disease stage and type
• In Angle-closure glaucoma, risk of permanent vision loss is minimized if the patient is treated promptly

Social and stress factors:

• Inadequate or incomplete information about the disease and its treatment is one of the most distressing factors for the patient and family
• Optic nerve damage and visual field damage caused by glaucoma is essentially progressive and irreversible, which are typical stressors
• Provide social and psychological support, and discuss in detail

Physical activity:

• Maintain regular activity but avoid overwork and fatigue
• Advise patient to rest during periods of acute relapse

Expected outcome

• Optic nerve damage and visual field damage caused by glaucoma is essentially progressive and irreversible
• Once visual function has been lost in glaucoma, there is no way to regain it
• Risk of permanent vision loss is minimized if the patient is treated promptly
• Outcome depends on risk factors for progression and includes:
  • Pre-diagnosis high mean intraocular pressure
  • Higher anticardiolipin antibodies ( ACA) levels
  • Older age at the time of diagnosis and female gender
  • Time to treatment
  • Underlying eye disease
  • Ethnicity

Ref: Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline Expert Committee. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of glaucoma in the adult eye. Can J Ophthalmol 2009; 44:S7-S93.

2. Scales and Tables

• Open-angle glaucoma
• Angle-closure glaucoma
• Developmental glaucoma

References

Core Resources:

• Allingham RR, Damji KF, Freedman S, et al (2005) Shields’ Textbook of Glaucoma (5thed.) Philadelphia: Lippincott Williams & Wilkins
• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
• Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
• European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition – Chapter 2: Classification and terminology Supported by the EGS Foundation: Part 1: Foreword; Introduction; Glossary; Chapter 2 Classification and Terminology. Br J Ophthalmol. 2017;101(5):73‐127. doi:10.1136/bjophthalmol-2016-EGSguideline.002
• Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
• Hoy SM. Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension [published correction appears in Drugs. 2018;78:857]. Drugs. 2018;78(7):773‐780. doi:10.1007/s40265-018-0914-6
• Kopczynski CC, Heah T; Netarsudil ophthalmic solution 0.02% for the treatment of patients with open-angle glaucoma or ocular hypertension; drugs Today (Barc). 2018;54(8):467-478. doi: 10.1358/dot.2018.54.8.2849627
• Leary, KA, Lin, K‐T, Steibel, JP, Harman, CD, Komáromy, AM. Safety and efficacy of topically administered netarsudil (Rhopressa™) in normal and glaucomatous dogs with ADAMTS10‐open‐angle glaucoma (ADAMTS10‐OAG). Vet Ophthalmol. 2019; 00: 1– 12. https://doi.org/10.1111/vop.12734
• Liu Y, Mao W. Tafluprost once daily for treatment of elevated intraocular pressure in patients with open-angle glaucoma. Clin Ophthalmol. 2013;7:7‐14. doi:10.2147/OPTH.S30951
• Longo D, Fauci A, Kasper D, et al (eds). Harrison’s Principles of Internal Medicine. 18thed. New York: McGraw-Hill; 2011
• McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
• Pagana KD, Pagana TJ eds. Mosby’s Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
• Rafuse PE, Buys YM,Damji KF et al. Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline Expert Committee. Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline for the management of glaucoma in the adult eye. Can J Ophthalmol 2009;44:S7-93
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
• Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011
• Yanoff M and Duker J S (2009) Yanoff and Duker: Ophthalmology (3rd ed.) Edinburgh: Elsevier

Online Pharmacological Resources:

• e-therapeutics
• Lexicomp
• RxList
• Epocrates Online

Journals/Clinical Trials:

• Chauhan BC, Mikelberg FS, Balaszi AG, et al; Canadian Glaucoma Study Group. Canadian Glaucoma Study: 2. Risk factors for the progression of open-angle glaucoma Arch Ophthalmol. 2008 Aug; 126(8):1030-6
• Francis BA, Singh K, Lin SC, et al. Novelglaucoma procedures: a report by the American Academy of Ophthalmology. Ophthalmology 2011; 118: 1466-80
• Heijl A, Peters D, Leske MC, et al. Am J Ophthalmol.2011; 152: 842-8
• Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002; 120:701-13
• Van Buskirk EM, Weinreb RN, Berry DP, et al. Betaxolol in patients with glaucoma and asthma. Am J Ophthalmol. 1986 May 15;101:531-4