Clinical Review & Education

JAMA | Review

Glaucoma in Adults—Screening, Diagnosis, and Management

A Review
Joshua D. Stein, MD, MS; Anthony P. Khawaja, MBBS, PhD; Jennifer S. Weizer, MD

Multimedia
IMPORTANCE Glaucoma is the most common cause of irreversible blindness worldwide. Many Related article page 177
patients with glaucoma are asymptomatic early in the disease course. Primary care clinicians
should know which patients to refer to an eye care professional for a complete eye CME Quiz at
jamacmelookup.com
examination to check for signs of glaucoma and to determine what systemic conditions or
medications can increase a patient’s risk of glaucoma. Open-angle and narrow-angle forms of
glaucoma are reviewed, including a description of the pathophysiology, risk factors,
screening, disease monitoring, and treatment options.

OBSERVATIONS Glaucoma is a chronic progressive optic neuropathy, characterized by damage Author Affiliations: W.K. Kellogg
to the optic nerve and retinal nerve fiber layer, that can lead to permanent loss of peripheral Eye Center, Department of
Ophthalmology and Visual Sciences,
or central vision. Intraocular pressure is the only known modifiable risk factor. Other University of Michigan, Ann Arbor
important risk factors include older age, nonwhite race, and a family history of glaucoma. (Stein, Weizer); Center for Eye Policy
Several systemic medical conditions and medications including corticosteroids, and Innovation, University of
Michigan, Ann Arbor (Stein);
anticholinergics, certain antidepressants, and topiramate may predispose patients to
Department of Health Management
glaucoma. There are 2 broad categories of glaucoma, open-angle and angle-closure and Policy, University of Michigan
glaucoma. Diagnostic testing to assess for glaucoma and to monitor for disease progression School of Public Health, Ann Arbor
includes measurement of intraocular pressure, perimetry, and optical coherence tomography. (Stein); NIHR Biomedical Research
Centre, Moorfields Eye Hospital NHS
Treatment of glaucoma involves lowering intraocular pressure. This can be achieved with Foundation Trust and UCL Institute of
various classes of glaucoma medications as well as laser and incisional surgical procedures. Ophthalmology, London, United
Kingdom (Khawaja).
CONCLUSIONS AND RELEVANCE Vision loss from glaucoma can be minimized by recognizing
Corresponding Author: Joshua D.
systemic conditions and medications that increase a patient’s risk of glaucoma and referring Stein, MD, MS, Kellogg Eye Center,
high-risk patients for a complete ophthalmologic examination. Clinicians should ensure that Department of Ophthalmology and
patients remain adherent with taking glaucoma medications and should monitor for adverse Visual Sciences, University of
Michigan, 1000 Wall St, Ann Arbor,
events from medical or surgical interventions used to treat glaucoma.
MI 48105 (jdstein@med.umich.edu).
Section Editors: Edward Livingston,
JAMA. 2021;325(2):164-174. doi:10.1001/jama.2020.21899 MD, Deputy Editor, and Mary McGrae
McDermott, MD, Deputy Editor.

G
laucoma, a chronic progressive optic neuropathy charac-
terized by damage to the optic nerve head (ONH) and reti-
nal nerve fiber layer (RNFL), leads to peripheral and occa-
sionally central vision loss. If untreated, this condition can cause
irreversible blindness. An estimated 3 million people in the US have
glaucoma, a number expected to increase to 6.3 million by 2050.1
Worldwide, it is estimated that more than 76 million persons have
the condition, with projections increasing to 112 million by 2040.2
Glaucoma is the leading cause of irreversible blindness worldwide
and the second leading cause of irreversible blindness in the US.3
Glaucoma is also the most common cause of blindness among Black
persons (6.1%), who have a risk of greater than 2 times higher than
White persons (2.8%).2,4,5 Glaucoma also has higher prevalence
among Latinx (4.1%) and Asian American persons (3.5%) than among
those who are non-Hispanic White.2,6 Risk factors for glaucoma in-
clude older age, nonwhite race, family history of glaucoma, and el-
evated intraocular pressure (IOP).7 Elevated IOP is the only known
modifiable risk factor for glaucoma, and all existing interventions
work by lowering IOP.
Glaucoma can be classified into 2 broad categories, open-
angle glaucoma (OAG) and angle-closure glaucoma (ACG), based on
the configuration of the anterior chamber drainage angle and the
location where aqueous humor is obstructed from exiting the eye
(Figure 1).8 Adult-onset OAG is frequently asymptomatic early in the
disease course; 50% of patients do not know they have the
disease.9-14 As OAG progresses, patients experience difficulty with
peripheral vision and sometimes central vision, resulting in limita-
tions in driving, mobility, and reading (Figure 2; modeled after Crabb
and colleagues15).16 If OAG remains untreated, ultimately central vi-
sion can be lost, resulting in irreversible blindness. In contrast, acute
ACG involves abrupt IOP elevation, which leads to blurry vision, ha-
los around lights, eye pain, nausea and vomiting, and can rapidly
cause blindness. Patients at greatest risk for ACG are those whose
drainage angle is narrow (the portion of the eye between the iris and
cornea where the aqueous humor exits the eye), as visualized using
gonioscopy or anterior-segment imaging with spectral-domain op-
tical coherence tomography or ultrasound biomicroscopy.
Primary ACG usually has a chronic coarse. While patients may
experience intermittent symptoms, such as haloes around lights,
chronic primary ACG is often asymptomatic,17 and ophthalmic ex-
amination is required for diagnosis. Primary OAG is the most com-
mon form of glaucoma, but various secondary forms of glaucoma

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 Glaucoma in Adults—Screening, Diagnosis, and Management Review Clinical Review & Education

Figure 1. Key Ocular Structures in Glaucoma

A Anatomy of healthy eye and aqueous humor drainage pathways

Iridocorneal angle
Aqueous humor exits through Trabecular meshwork
the trabecular meshwork
and uveoscleral route
IRIS

Cornea
Canal of
Schlemm

ANTERIOR Iris
CHAMBER
Drainage through
trabecular meshwork
Posterior Episcleral vein
chamber
Uveoscleral
drainage route
Pupil
Sclera
LENS
Ciliary body

VITREOUS HUMOR

B Primary open-angle glaucoma C Primary angle-closure glaucoma

Increased resistance to aqueous Obstruction of drainage

humor drainage through the pathways by the iris
trabecular meshwork
Narrowed or closed
Open drainage angle drainage angle

Region of
pupillary block

exist, including exfoliative glaucoma, pigmentary glaucoma, trau- systematic reviews or meta-analyses, and 6 clinical practice guide-
matic glaucoma, uveitic glaucoma (associated with inflammation), lines or position papers.
and neovascular glaucoma (resulting from ocular ischemia due to
conditions such as proliferative diabetic retinopathy).

Methods
MEDLINE was searched using the MeSH term glaucoma for articles
published in English between January 2010 and August 2020, and
manuscript references also were examined. Additionally, the
Cochrane Library was searched from January 2010 to August 2020
using the keyword glaucoma. Seventy articles were selected that
were considered of primary relevance to general physicians. These
70 articles included 14 clinical trials, 9 population-based studies, 19
Pathophysiology
Glaucoma is characterized by degeneration of retinal ganglion cells.
The pathophysiological mechanisms underlying this degeneration
remain uncertain, but several theories exist. The biomechanical
theory proposes that IOP mechanically induces glaucomatous
changes in the ONH.18 Retinal ganglion cell axons pass through pores
in the lamina cribrosa at the ONH, and axons here may be suscep-
tible to IOP-related mechanical forces. In the vascular theory, insuf-
ficient blood supply to the ONH is thought to play a major role in the
pathogenesis of retinal ganglion cell loss.19 This reduced blood supply

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 Clinical Review & Education Review
Figure 2. Examples of Vision Loss From Glaucoma
A Common perceptions of visual field loss
Full unaltered image Blurred details in affected areas
B Uncommon perceptions of visual field loss
Tunnel vision, peripheral blurring Black patches in affected areas
may be caused by systemic hypotension, vasospasm, atheroscle-
rosis, or compression of vasculature secondary to elevated IOP.
A third theory posits a primary neurodegenerative component to
glaucoma that may be particularly evident in primary OAG that oc-
curs without evidence of raised IOP (normal-tension glaucoma). Sup-
porting this theory are reports of an association between primary
OAG and Alzheimer disease20 and studies associating optic nerve
measures with cognitive function and future cognitive decline.21
Genetics
Glaucoma, a highly heritable complex human disease, has an esti-
mated heritability of 70%.22 First-degree relatives of persons with
glaucoma have a 22% lifetime risk for glaucoma, compared with 2.3%
among other persons.23 Approximately 5% of primary OAG is
Mendelian, with autosomal-dominant inheritance. Myocilin gene
sequence variations give rise to the most common form of Mende-
lian glaucoma, characterized by elevated IOP.24 Cascade genetic
testing of unaffected relatives of patients with known myocilin se-
quence variations can guide screening strategies. Relatives carrying
the sequence variation require close monitoring, whereas noncar-
rier relatives have a glaucoma risk similar to the general population.25
Precision treatment of patients with myocilin sequence variation may
be possible in the future; glaucoma was cured in a mouse model of
myocilin glaucoma using CRISPR-Cas9 genome editing.26
Most primary OAG, however, is not Mendelian inherited and
is caused instead by the cumulative contributions of many genetic
and environmental factors, each of small effect; this is known as
complex glaucoma. Discovery of the genetic factors underlying com-
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Glaucoma in Adults—Screening, Diagnosis, and Management
Missing details in affected areas
Tunnel vision, peripheral blackening
plex glaucoma has advanced considerably in recent years. Very large
studies (eg, UK Biobank)27 and consortia of many smaller studies
(eg, the International Glaucoma Genetics Consortium)28 have yielded
adequate power for hypothesis-generating genome-wide association
studies. Now, more than 70 genetic loci have been associated with
primary OAG.29 Even more successful have been genome-wide as-
sociation studies for IOP, identifying at least 100 associated genetic
loci. Combining these IOP-associated genetic factors into a regression-
based model predicted primary OAG in an independent study with
an area under the curve of 0.76.27 These sorts of studies raise the pos-
sibility of targeted genotype-based population screening. Potential
personalization of patient care using genetic prediction models also
holds promise. The genetic variant most strongly associated with IOP
and primary OAG (in the gene transmembrane and coiled-coil
domains 1 [TMCO1] [HGNC accession ID 18188]) strongly predicts
which patients with elevated IOP will develop glaucoma (partici-
pants homozygous for the risk allele were at a 3-fold increased risk
compared with participants who do not have the risk allele).30
Associations With Systemic Conditions and
Medications
Several medical conditions predispose to glaucoma,31 including im-
mune system disorders (eg, sarcoidosis, human leukocyte antigen
(HLA) B27 diseases, rheumatoid arthritis, systemic lupus erythema-
tosus), selected infectious diseases (eg, herpes simplex virus, vari-
cella zoster virus, syphilis, toxoplasmosis), some endocrine disorders
(eg,diabetes,Cushingsyndrome),andconditionsthatmightaffectocu-
lar perfusion (eg, obstructive sleep apnea, migraine) (Box 1).32
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 Glaucoma in Adults—Screening, Diagnosis, and Management Review Clinical Review & Education

inhaled, injections, skin creams) can induce glaucoma, the greater

Box 1. Some Systemic Conditions and Medications Associated the strength, the longer the exposure, and the closer the proximity
With Glaucoma of administration to the eye, the greater the risk. Referring patients
receiving long-term corticosteroid therapy to an eye care profes-
Medical Conditions Associated With Glaucoma sional is advisable for periodic IOP monitoring and checking for
Infectious or Inflammatory Conditions
signs of glaucoma. Lower blood pressure (especially diastolic blood
Behçet disease
pressure) may be associated with an increased glaucoma preva-
Congenital rubella
lence (eg, 1.9-fold [95% CI, 1.1-3.0] as was found in the the
Cytomegalovirus retinitis Los Angeles Latino Eye Study, which compared participants with
Herpetic disease diastolic blood pressure ⱕ60 mm Hg with participants with dia-
Human leukocyte antigen (HLA) B27–related disease stolic blood pressure 71-80 mm Hg).34 Some studies suggest these
Juvenile idiopathic arthritis associations are particularly evident in patients using antihyperten-
Lyme disease sive medications, suggesting that aggressive blood pressure lower-
Rheumatoid arthritis
ing may be relatively contraindicated in persons at high risk for
glaucoma-related blindness.35 However, no randomized clinical
Sarcoidosis
trial evidence exists to support a causal role of blood pressure in
Syphilis
glaucoma or to support modification of antihypertensive medica-
Systemic lupus erythematosus tions for patients with glaucoma. Systemic medications with anti-
Toxocariasis cholinergic properties (eg, tricyclic antidepressants, certain selec-
Toxoplasmosis tive serotonin reuptake inhibitors, antihistamines, Botulinum toxin)
and sulfa derivatives (eg, topiramate)36 can predispose patients to
Other Conditions
Cushing disease ACG. Anticholinergics dilate the pupil, which can lead to pupillary
block in susceptible patients; the aqueous humor therefore builds
Diabetes
up in the posterior chamber, pushing the iris forward and closing
Ehlers-Danlos syndrome
the anterior chamber drainage angle (Figure 1). Sulfonamides pre-
Marfan syndrome cipitate supraciliary effusions with forward rotation of the iris-lens
Migraine diaphragm, closing the angle. Likewise, clinicians should educate
Obstructive sleep apnea patients starting any of these agents about ACG symptoms and the
Sickle cell syndrome importance of seeking immediate care by an eye-care professional
Systemic hypotension or overaggressive management if symptoms arise.
of systemic hypertension Treating certain systemic conditions can reduce the risk for glau-
coma or aid in its control. For instance, controlling blood glucose lev-
Systemic Medications Associated With Glaucoma
Open-Angle Glaucoma
els and blood pressure levels in patients with diabetes reduces the
Corticosteroids (any formulation or route of administration) risk for neovascular glaucoma. Treating sleep apnea with continu-
ous positive airway pressure may affect IOP and ocular perfusion,
Angle-Closure Glaucoma
although whether this intervention is helpful in glaucoma is unclear.37
Antihistamines
Likewise, studies are conflicting about a possible association be-
Antiparkinsonian medications
tween statin drugs and glaucoma, with some studies suggesting
Antipsychotics with anticholinergic properties statin use lowers glaucoma risk.38,39 Randomized clinical trials are
Benzodiazepines needed to better substantiate these associations.
Botulinum toxin
Cocaine
Disopyramide Screening and Monitoring
Epinephrine
In 2013, the US Preventive Services Task Force did not recommend
H2 blocker agents
population-based screening of asymptomatic adults for glaucoma,
Mefenamic acid
citing relatively low disease prevalence, low accuracy of screening
3,4-Methylenedioxymethamphetamine tests performed in primary care settings, and potential adverse ef-
Promethazine fects of treatment of false positives40; these recommendations are
Selective serotonin reuptake inhibitors being revisited. However, glaucoma screening has demonstrated
Sulfa drugs usefulness and cost effectiveness for high-risk populations, includ-
Topiramate ing persons with a positive family history or nonwhite race.41 Since
2002, the Centers for Medicare & Medicaid Services has covered
Tricyclic antidepressants
glaucoma examinations by eye care professionals for persons with
diabetes, a family history of glaucoma, Black race and age of 50 years
Some disease treatments may contribute to glaucoma or older, and Latinx heritage plus age of 65 years or older. Patients
(Box 1).33 Corticosteroids can elevate IOP and predispose patients with glaucoma diagnoses should be monitored regularly (at least
to glaucoma. While all steroid formulations (eg, eye drops, oral, once yearly) by an eye care professional to monitor for signs of

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 Clinical Review & Education Review
Box 2. Frequently Asked Questions
Why do so many medications have warnings on the package insert
about glaucoma, and what should I do if I need to prescribe one
of these medications?
Several common medication classes (eg, adrenergics, drugs with
anticholinergic properties, certain antidepressants and anxiolytics,
topiramate) can induce acute angle-closure crisis in susceptible
individuals. If a patient is going to start one of these medications,
the patient should be assessed by an eye care professional to
determine if they have a high risk for glaucoma. If they are high
risk, there are prophylactic procedures such as laser iridotomy or
cataract surgery that can be performed to greatly reduce the risk
of developing glaucoma.
Can exposure to corticosteroids cause glaucoma?
Any formulation of corticosteroids, including oral, inhaled,
intravenous, topical, and eye drop formulations can elevate the
intraocular pressure and increase the risk of glaucoma. The
corticosteroid strength, length of exposure, and proximity of
administration to the eye can affect the risk of increased intraocu-
lar pressure that can lead to glaucoma. Patients receiving chronic
corticosteroids should be evaluated by an eye care professional for
intraocular pressure monitoring and for signs of glaucoma such as
loss of peripheral vision or progressive glaucomatous damage to
the optic nerve.
Since many patients with glaucoma are asymptomatic early on,
how do I know who is a high-risk patient?
Risk factors for glaucoma include older age, nonwhite race,
and a family history of glaucoma. While screening guidelines
vary by country, in the US, patients who have a high risk for
glaucoma should be evaluated by an eye care professional for a
comprehensive ocular examination to check for signs of glaucoma.
Is it normal for patients who have glaucoma to have red inflamed
eyes, and is there anything that can be done about this?
Conjunctival injection and inflammation is a common adverse
effect of many classes of glaucoma medications such as α-agonists
or prostaglandin analogues. Switching glaucoma medication
classes or to a preservative-free formulation of the medication
may alleviate the problem. Laser trabeculoplasty or other intraocu-
lar pressure–reducing procedures are good alternatives for
patients who cannot tolerate glaucoma medications.
What is the first-line treatment for glaucoma?
Most patients who are newly diagnosed with glaucoma are initially
treated with topical glaucoma medications or laser trabeculoplasty.
There are several classes of glaucoma medications, such as topical
prostaglandin analogues, β-blockers, and carbonic anhydrase
inhibitors. Prostaglandin analogues are the most commonly used
first-line medication class.
Do many patients with glaucoma become blind?
The rate of blindness from glaucoma in one or both eyes over 20
years of follow-up is approximately 13%. Regular monitoring by an
eye care professional to check for disease progression and prompt
intervenion to lower intraocular pressure when progression is
detected can reduce the risk of blindness. Earlier disease detection
helps prevent blindness from glaucoma.
disease progression. Some patients require more frequent moni-
toring, especially those with unstable or advanced disease (Box 2).
Diagnostic tests to assess glaucoma include perimetry (visual
field testing), gonioscopy, IOP measurement, corneal thickness mea-
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Glaucoma in Adults—Screening, Diagnosis, and Management
surement (helping to estimate the true IOP from the measured IOP,
which can be influenced by corneal properties), and ONH and RNFL
evaluation using optical coherence tomography (OCT) and fundus
photography. Visual field loss typically initially occurs in the periph-
ery and advances toward central fixation as the disease pro-
gresses, although some patients experience central loss earlier in the
disease course. By comparing sequential perimetry results, clini-
cians can assess for expansion of visual field loss and possibly indi-
cate the need for further IOP lowering to achieve disease stabiliza-
tion. Likewise, increased thinning of RNFL tissue on sequential OCT
tests or expansion of ONH cupping may indicate disease progres-
sion and a need for additional IOP reduction. Often when struc-
tural damage affects a certain portion of the ONH or RNFL, func-
tional loss is seen in the corresponding location on perimetry
(Figure 3). Researchers have been using machine-learning model-
ing techniques to help identify patients who have glaucoma that will
likely progress over time, predict future visual field loss, and deter-
mine an appropriate target IOP level that will stabilize the
disease.42-45
Disease Management
Decisions regarding which patients to treat and how aggressively to
lower their IOP to reduce the risk for progression should be indi-
vidualized. Considerations include the amount of existing glauco-
matous damage, overall health, and patient preferences. In gen-
eral, IOP should be lowered more aggressively if the existing
glaucoma damage is more severe. If a patient continues to prog-
ress at a certain target IOP, the target should be lowered further.
Therefore, target IOP is individualized, and no set level will apply uni-
versally. The Ocular Hypertension Treatment Study46,47 evaluated
1636 patients with ocular hypertension (OHTN; elevated IOP with-
out glaucoma-related structural or functional damage) who were ran-
domized to observation (n = 819) or treatment (n = 817) and found
that treatment reduced the risk for OAG by 50% (cumulative prob-
ability for OAG at 60 months, 4.4% for treated vs 9.5% for un-
treated patients), yet more than 90% of patients without treat-
ment never measurably progressed to glaucoma over the
60-month follow-up. Therefore, treatment of all persons with OHTN
is not recommended, and risk calculators48 can help determine risk
and need for treatment in individuals (analogous to cardiovascular
risk predictors that help to determine the need for preventive
therapy). In contrast, treatment is generally indicated for all pa-
tients with established glaucoma; the Early Manifest Glaucoma
Trial,49 Collaborative Initial Glaucoma Treatment Study,50 Collab-
orative Normal-Tension Glaucoma Treatment Study,51 and United
Kingdom Glaucoma Treatment Study52 all clearly demonstrated that
IOP lowering can prevent disease progression (Table). Therapies in-
clude medications, laser procedures, and incisional surgery.
Open-Angle Glaucoma Treatment
Medications
Glaucoma medications lower IOP by reducing aqueous humor pro-
duction or increasing aqueous humor outflow from the eye (see From
the Medical Letter in this issue of JAMA).64 Prostaglandin ana-
logues are the most common first-line medication because of their
effectiveness at lowering IOP, once-daily dosing, and relatively benign
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 Glaucoma in Adults—Screening, Diagnosis, and Management Review Clinical Review & Education

Figure 3. Glaucoma Structure Function Relationship

A Optic nerve photograph B Red-free photograph C Visual field

D Optical coherence tomography

IR 30˚ ART [HS] Sector thickness measurements and comparison to normative database

NS TS
S 44 93
69 (102) (134)

N G T
N T 29 50 50
29 50
−13.1˚ (72) (97) (74)

NI TI
I 67 74
71 (106) (142)

400 μm Within normal limits (P >.05) Borderline (P <.05) Outside normal limits (P <.01)

OCT ART (100) Q: 33 [HS] Continuous circle thickness profile and comparison to normative database
300
RNFL thickness, μm

240
ILM
180 Nerve fiber layer
measurement
RNFL 26
120
Classification
60
Outside normal limits
0
0 45 90 135 180 225 270 315 360
T S N I T
200 μm
Position, ˚

A, Photograph of the optic nerve demonstrating glaucomatous cupping and
thinning of the inferior rim tissue. B, Corresponding red-free photograph
revealing a wedge-like focal loss of nerve fiber layer tissue at the 4 o’clock to
5 o’clock clock hour around the optic nerve. C, Corresponding visual field with a
focal superior paracentral scotoma just above central fixation. D, Corresponding
optical coherence tomography reveals diffuse loss of retinal nerve fiber layer
tissue. G indicates global mean retinal nerve fiber layer thickness; I, inferior;
N, nasal; NI, inferonasal; NS, superonasal; S, superior; T, temporal;
TI, inferotemporal; TS, superotemporal.
Photo credits: Timothy S. Costello, CRA, COA, and Robert Prusak, CRA.

adverse effect profile. Other medication classes include β-blockers,
α-agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors, and
parasympathomimetics. Topical β-blockers are the least expensive
therapy, although their potential adverse effects include bradycar-
dia, hypotension, depression, and asthma exacerbation. Systemic
absorption of topical β-blockers is considerable. Drops are ab-
sorbed by the nasal mucosa, passed through the nasolacrimal ca-
nal, and inhaled in the lungs, bypassing hepatic first-pass metabo-
lism. Primary care clinicians should not underestimate the adverse
effects of topical β-blockers and their potential to cause falls or con-
tribute to reduced exercise tolerance or impotence.65 A careful medi-
cation history is required to determine what sort of eye drops a pa-
tient uses. The names of some branded combination drop therapies
do not allude to the products’ inclusion of a β-blocker (Xalacom
[latanoprost/timolol], DuoTrav [travaprost/timolol], Ganfort
[bimatoprost/timolol], Cosopt [dorzolamide/timolol], and Combigan
[brimonidine/timolol]). Topical β-blocker eye drops are less effec-
tive at lowering IOP and have more adverse effects for patients con-
comitantly receiving oral β-blockers; in these patients, another topi-
cal medication class is often advisable. IOP can be effectively lowered
with α-agonists, but they frequently cause conjunctival hyperemia
and irritation. Uncommon but potentially serious adverse effects in-
clude compromised mentation in older adults, dysrhythmias, head-
aches, and apnea in children. Oral carbonic anhydrase inhibitors ef-
fectively reduce IOP, but their adverse effects (eg, paresthesias,
gastrointestinal upset, nephrolithiasis, electrolyte disturbances, leth-
argy) may be intolerable; thus, when possible, long-term use should
be avoided. Cannabinoids can decrease IOP, but because of their re-
quired frequent dosing and adverse effect profile, and given the avail-
ability of safer more effective interventions, guidelines from the

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 Clinical Review & Education Review Glaucoma in Adults—Screening, Diagnosis, and Management

Table. Summary of Randomized Clinical Trials Evaluating Glaucoma Treatment

Clinical trial Purpose Population Design Significant outcomes

Collaborative To determine if intraocular 140 Eyes of 140 patients with One eye of each participant Twenty-eight (35%) of the control eyes
Normal Tension pressure plays a role in the normal tension glaucoma were was randomized to be and 7 (12%) of the treated eyes
Glaucoma Study,53 pathogenesis of normal tension defined as the median of untreated as a control or to (P < .001) had glaucoma progression
1998 glaucoma baseline untreated intraocular have intraocular pressure during follow-up
pressure ≤20 mm Hg, with no lowered by 30% from baseline
measurement >24 mm Hg
Advanced To compare the clinical outcomes 789 Eyes of 591 patients with Multicenter RCT comparing Lower intraocular pressure was associated
Glaucoma of 2 treatment sequences in medically uncontrolled procedure sequences with less visual field loss during
Intervention glaucoma: trabeculoplasty- open-angle glaucoma follow-up; eyes that had 100% of visits
Study,54 2000 trabeculectomy-trabeculectomy with intraocular pressure <18 mm Hg
vs trabeculectomy- (average intraocular pressure during
trabeculoplasty- follow-up of 12.3 mm Hg) had
trabeculectomy significantly less visual field progression
during follow-up
Collaborative To compare medical vs surgical 607 Patients with open-angle Multicenter RCT Although intraocular pressure was lower
Initial Glaucoma therapy as initial treatment glaucoma in the surgical group, initial medical
Treatment therapy resulted in similar visual field
Study,55 2001 outcomes to the surgery group for up to
9 y of follow-up
Ocular To evaluate the safety and 1637 Patients with ocular Multicenter RCT comparing Topical ocular hypotensive medication
Hypertension efficacy of ocular hypotensive hypertension observation with medical was effective in delaying or preventing
Treatment treatment in preventing or therapy the onset of primary open-angle
Study,56 2002 delaying the onset of visual field glaucoma; the incidence of open-angle
or optic nerve damage glaucoma after 60 mo of follow-up was
9.5% in the observation group vs 4.4% in
the treated group
Early Manifest To evaluate the efficacy of 255 Newly diagnosed patients Multicenter RCT comparing At 6 y of follow-up, 62% of untreated
Glaucoma Trial,57 intraocular pressure reduction in with open-angle glaucoma observation with betaxolol and eyes vs 45% of treated eyes showed
2002 preventing progression of argon laser trabeculoplasty progression; in multivariate analysis,
glaucoma progression risk was halved in the
treatment group
Tube vs To determine the efficacy and 212 Patients with medically Multicenter RCT of 350-mm2 At 5 y, the mean (SD) intraocular pressure
Trabeculectomy safety of trabeculectomy and uncontrolled glaucoma Baerveldt glaucoma implant was 12.6 (5.9) mm Hg in patients
(TVT) Study,58,59 glaucoma drainage device surgery and trabeculectomy receiving trabeculectomy vs 14.4 (6.9)
2006 mm Hg in those with the glaucoma
drainage device. Probability of failure
(29.8% vs 46.9%) and reoperation rates
(9% vs 29%) were higher with
trabeculectomy
United Kingdom To assess the efficacy of 516 Participants with newly Multicenter RCT comparing Visual field was preserved for longer in
Glaucoma latanoprost for vision diagnosed primary open-angle latanoprost therapy with the latanoprost group than in the placebo
Treatment Study preservation in glaucoma or exfoliation glaucoma placebo group (HR, 0.44 [95% CI, 0.28 to 0.69];
(UKGTS),52 2015 patients. P = .0003)
Effectiveness in To assess the efficacy, safety, and 419 Participants with primary Multicenter RCT comparing Quality of life (EQ-5D) was better and
Angle-closure cost effectiveness of clear-lens angle-closure glaucoma or clear-lens extraction with mean intraocular pressure lower (1 · 2
Glaucoma of Lens extraction compared with the primary angle closure and laser peripheral iridotomy as mm Hg [95% CI, –2.0 to –0.4]; P = .004)
Extraction (EAGLE) standard care of laser peripheral intraocular pressure initial treatment after clear-lens extraction compared with
Study,60 2016 iridotomy for primary ≥30 mm Hg standard care
angle-closure disease
Laser in Glaucoma To assess the effectiveness of eye 718 Participants with newly Multicenter RCT comparing There was no significant difference in
and ocular drops vs selective laser diagnosed open-angle quality of life and quality of life between the groups; 74%
HyperTension trabeculoplasty as first-line glaucoma or ocular cost-effectiveness at 3 y of of patients in the selective laser
(LiGHT) Study,61 treatment for open-angle hypertension initial selective laser trabeculoplasty group required no drops
2019 glaucoma or ocular hypertension trabeculoplasty with initial to maintain intraocular pressure at target;
drop therapy there was a 97% probability of initial
selective laser trabeculoplasty being more
cost effective than initial eye drops at a
willingness to pay of £20 000 per
quality-adjusted life-year gained
Zhongshan Angle To assess the efficacy and safety 889 Chinese participants with Single-center RCT in which While incidence of angle-closure disease
Closure Prevention of laser peripheral iridotomy anatomically narrow angles one randomly selected eye was lower in treated eyes (HR, 0.53 [95%
(ZAP) Trial,62 prophylaxis against primary but no signs of raised received laser peripheral CI, 0.30 to 0.92]; P = .02), the overall
2019 angle-closure glaucoma intraocular pressure or iridotomy and the other eye incidence of disease was low, suggesting
glaucoma (primary served as control in each that the benefit of laser peripheral
angle-closure suspect) participant iridotomy is limited
Primary Tube vs To compare the safety and 242 Participants with Multicenter RCT comparing Primary outcome was at 1 year; failure
Trabeculectomy efficacy of tube shunt medically uncontrolled tube shunt (350-mm2 was more likely in the tube group (HR,
(PTVT) Study,63 implantation and trabeculectomy glaucoma and no prior Baerveldt glaucoma implant) 2.59 [95% CI, 1.20 to 5.60]; P = .01);
2020 in eyes without prior ocular incisional ocular surgery or trabeculectomy with serious complications were less common
surgery mitomycin C in the tube group (1% vs 7%; P = .03)

Abbreviations: HR, hazard ratio; RCT, randomized clinical trial.

American Glaucoma Society and the American Academy of Oph- These medication classes have various mechanisms of action,
thalmology currently preclude recommending this drug in any form and some patients require several different drugs to sufficiently lower
for glaucoma treatment.66,67 IOP. While medication use is the least invasive therapeutic option,

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© 2021 American Medical Association. All rights reserved.

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 Glaucoma in Adults—Screening, Diagnosis, and Management
adherence to glaucoma medication regimens is a major problem for
many patients; fewer than 50% of recipients of glaucoma-
medication prescriptions persist with use beyond 1 year.68 Other chal-
lenges patients have with long-term glaucoma medication use in-
clude difficulty with eye drop administration, intolerable adverse
effects, and difficulty affording expensive medications.69 Research-
ers are exploring novel drug delivery systems to help overcome some
of the challenges patients face with eye drop administration and ad-
herence. Ongoing trials of sustained-release implants have demon-
strated promising results.70 Behavioral aids such as counseling and
smart phone reminders also show promise to improve adherence.71
Laser
An alternative to medication is laser trabeculoplasty (LT), which re-
duces IOP by enhancing aqueous outflow through the trabecular
meshwork.72,73 Laser types include argon, micropulse, and selec-
tive laser trabeculoplasty and excimer trabeculostomy. The Laser in
Glaucoma and ocular HyperTension (LiGHT) study, a pragmatic clini-
cal trial involving 718 patients randomized to selective laser trabecu-
loplasty (n = 356) or medication (n = 362) as initial therapy, dem-
onstrated that selective laser trabeculoplasty is a reasonable initial
treatment.61 Laser trabeculoplasty tends to be as effective as medi-
cations at decreasing IOP without the adverse effects and costs of
long-term medication use, and its adverse effect profile is rela-
tively favorable with mild risks for short-term IOP spikes and inflam-
mation. In the LiGHT study, selective laser trabeculoplasty had no
sight-threatening complications, and participants randomized to se-
lective laser trabeculoplasty first experienced fewer medication-
related adverse events than participants treated initially with medi-
cations (6% vs 20%). According to LiGHT and other studies,74 laser
trabeculoplasty is more cost effective than medications. However,
approximately 15% of LiGHT patients required additional IOP-
lowering interventions within 1 year of selective laser trabeculo-
plasty. Laser trabeculoplasty is not advisable for patients with cer-
tain glaucoma types such as ACG, and some patients require
retreatment to maintain IOP lowering. In the LiGHT study, after 3
years, nearly 75% of patients randomized to selective laser trabecu-
loplasty first required no ancillary medications to maintain IOP con-
trol. Laser trabeculoplasty can be particularly helpful in patients with
difficulty adhering to medications or tolerating them.61
Incisional Surgery
In the Advanced Glaucoma Intervention Study, which randomly as-
signed 591 patients with advanced glaucoma to laser or incisional
surgery, preserving sight and preventing further deterioration re-
quired aggressive IOP control.75 Traditional incisional surgeries with
established long-term efficacy data include trabeculectomy and glau-
coma drainage device (tube/GDD) implantation. These surgeries,
which remain the most effective IOP-lowering procedures, create
a new pathway for aqueous humor to exit the eye. In the Tube
Vs Trabeculectomy study, a randomized clinical trial of 212 eyes un-
dergoing one of these surgeries, outcomes were similar between
both groups at 5 years for the mean (SD) IOP of 14.4 (6.9) mm Hg in
patients who received trabeculectomy vs 12.6 (5.9) mm Hg in pa-
tients with the glaucoma drainage device, and for the number of
ancillary glaucoma medications, 1.4 (1.3) in patients who received tra-
beculectomy vs 1.2 (1.5) for those with a glaucoma drainage device.
Patients who received a glaucoma drainage device had a lower prob-
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Review Clinical Review & Education
Figure 4. Description of Glaucoma Therapies
GLAUCOMA THERAPY OPTIONS
Open-angle glaucoma Angle-closure glaucoma
Medical therapy Medical therapy for acute lowering
of intraocular pressure
• Prostaglandin analogues
• β-blockers (topical) • Topical and oral carbonic
• α-agonists (topical) anhydrase inhibitors
• Carbonic anhydrase inhibitors • α-agonists (topical)
• β-blockers (topical)
(topical and oral)
• Rho kinase inhibitors (topical) • Anterior chamber paracentesis
• Parasympathomimetics (topical)
Definitive therapy after lowering
Laser trabeculoplasty of intraocular pressure
• Argon, selective, micropulse • Laser iridotomy, surgical iridotomy, or
clear lens extraction
Incisional surgery If patient has no or minimal cataract
• Microinvasive glaucoma surgery • Cataract surgery
If patient has visually significant cataract
• Cataract surgery
• Trabeculectomy or
• Trabeculectomy
glaucoma drainage device surgery
• Glaucoma drainage device surgery May be required if iridotomy and/or
• Cyclodestructive procedures cataract surgery do not stabilize disease
ability of failure (29.8% vs 46.9%) and reoperation rate (9% vs 29%)
than trabeculectomy recipients.58 Risks of trabeculectomy and GDD
implantation include bleeding, inflammation, infection, cataract for-
mation, corneal swelling, hypotony (IOP that is too low), and per-
sistent IOP elevation resulting from scar tissue that limits outflow,
necessitating additional intervention.59 The risk for infection is life-
long as the conjunctiva of the aqueous drainage bleb is susceptible
to thinning, reducing a bacterial barrier. Because of these risks, tra-
ditional glaucoma surgery is generally reserved for patients with ad-
vanced glaucoma and progression despite medical or laser treat-
ment. Cyclodestructive procedures, which lower IOP by destroying
the tissue that produces aqueous humor, are often reserved for pa-
tients whose eyes have poor visual potential or extensive scarring
due to prior surgery or trauma, making them poor candidates for the
aforementioned surgeries.76 However, endoscopic cyclophotoco-
agulation, a version of cyclodestruction that specifically targets the
ciliary body where aqueous humor is produced, may provide more
selective, albeit less powerful, IOP reduction with lower risk for se-
vere adverse effects than traditional cyclodestruction.77
Microinvasive glaucoma surgeries (MIGS), relatively new treat-
ment options, are potentially safer than traditional glaucoma sur-
gery. Most MIGS work by dilating, cleaving open, or bypassing abnor-
mally resistant tissue obstructing aqueous outflow, or by inserting a
device into an outflow structure or space to enhance aqueous
drainage.78 MIGS can be performed with concomitant cataract sur-
gery. Some patients require more than 1 MIGS to achieve sufficient low-
ering of IOP. Although the longer-term effectiveness and safety of
MIGS are unknown, several short-term studies have reported prom-
isingresults.79-81 WhilethecommonlyusedMIGSdevicesandthemore
conventional GDDs are safe for patients requiring magnetic reso-
nance imaging with static magnetic fields of 3 Tesla or less, manufac-
turer recommendations should be checked for each device.
Angle-Closure Glaucoma Treatment
Acute angle closure is an ophthalmologic emergency and can lead
to irreversible blindness if not promptly identified and treated. Pa-
tients with suspected acute ACG should be urgently referred to an
(Reprinted) JAMA January 12, 2021 Volume 325, Number 2 171
 Clinical Review & Education Review Glaucoma in Adults—Screening, Diagnosis, and Management

ophthalmologist or sent to the emergency department. For pa-
tients in acute ACG crisis, an initial attempt to immediately lower the
IOP typically involves oral or intravenous carbonic anhydrase inhibi-
tors and topical α-agonists and β-blocker eye drops. In addition, an-
tiemetic and pain medications can help make the patient more com-
fortable while the IOP is being stabilized. Another way to quickly
lower the IOP is by performing an anterior chamber paracentesis (in-
serting a needle into the eye and releasing accumulated fluid). Since
there are risks associated with damaging ocular structures, this pro-
cedure should only be attempted by an ophthalmologist and re-
quires patient cooperation. After IOP lowering such that the pa-
tient is more comfortable and corneal swelling has subsided, the
patient should promptly undergo definitive ACG therapy (ie, laser
peripheral iridotomy)82 unless a concomitant, visually significant
cataract is present, in which case cataract extraction (replacing the
human crystalline lens with a thin artificial lens, opening the drain-
age angle) is a viable alternative (Figure 4).60 Performing prophy-
lactic iridotomy or cataract surgery in the contralateral eye is advis-
able to reduce the risk for second eye involvement. Guidelines, such
as those from the American Academy of Ophthalmology,41 recom-
mend prophylactic laser peripheral iridotomy in eyes with narrow
angles to prevent acute ACG crisis, although recent evidence from
the ZAP trial (Table) questions this approach.62
ACG also exists in a chronic form in which the IOP increases more
slowly but still can cause severe vision loss because the patient may
be asymptomatic in the early or moderate disease stages. Treat-
ment of chronic ACG involves a combination of modalities used to
treat OAG and acute ACG. Evidence from the EAGLE Study (Table)
suggests that clear-lens extraction (surgically identical to cataract
extraction but the crystalline lens is removed in the absence of cata-
ract) is a superior treatment option to laser peripheral iridotomy in
patients with primary ACG and very high IOP or manifest glaucoma.60
patients are often asymptomatic until late in the disease course, they
must have regular follow-up (interval individualized according to risk,
usually 1-4 times yearly if stable) by an eye care professional to moni-
tor for signs of progression and need for additional therapy.
The Future of Glaucoma Care
Future research may use techniques such as machine learning84 and
incorporate information on genetic risk factors to personalize rec-
ommendations for safe IOP levels in individual patients and to help
guide treatment decisions.85 Researchers are also studying novel
drugs, drug-delivery systems, and surgical procedures to enhance
the care of patients with glaucoma.
Limitations
Our study has several limitations. First, while we tried to perform a
comprehensive search of the literature on glaucoma, there may be
some important articles we inadvertently overlooked. Second, some
of the studies we cited in this review, such as studies describing the
epidemiology of glaucoma, are several years old. Additional re-
search is needed in these areas to determine whether the findings
from those studies are still valid today. Third, the diagnostic testing
and treatment options described in this review are relevant op-
tions for patients residing in higher-income countries. Providing care
for patients with glaucoma in lower-resourced countries, where ac-
cess to eye care professionals, diagnostic testing, and therapeutic
interventions can be quite limited, was beyond the scope of this re-
view. Fourth, the quality of the evidence for the long-term effec-
tiveness of some of the newer therapeutic interventions for glau-
coma is lacking.

Prognosis
For many patients, glaucomatous disease progresses slowly. In a ret-
rospective population-based cohort study, Malihi and colleagues83
estimated the probability of glaucoma-related blindness in 1 or both
eyes over 20-year follow-up at 13.5% (95% CI, 8.8%-17.9%). Diag-
nosing and treating the disease relatively early in its course can help
slow the progression rate and minimize functional impairment. Since
Conclusions
Vision loss from glaucoma can be minimized by recognizing sys-
temic conditions and medications that increase a patient’s risk of
glaucoma and referring high-risk patients for a complete ophthal-
mologic examination. Clinicians should ensure that patients re-
main adherent with taking glaucoma medications and should moni-
tor for adverse events from medical or surgical interventions used
to treat glaucoma.

ARTICLE INFORMATION
Accepted for Publication: October 19, 2020.
Author Contributions: Dr Stein had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Weizer.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Khawaja, Weizer.
Administrative, technical, or material support:
Khawaja, Weizer.
Supervision: Weizer.
Conflict of Interest Disclosures: Dr Stein reported
receipt of grants from the National Eye Institute,
the Lighthouse Guild, and Research to Prevent
Blindness during the conduct of the study.
Dr Khawaja reported receipt of personal fees
from Allergan, Novartis, Thea, Aerie, Santen,
and from Google Health outside the submitted
work. No other disclosures were reported.
Funding/Support: The Lighthouse Guild, National
Eye Institute (1R01EY026641-01A1), and
Dr Beverley and Gerson Geltner Fund (Dr Stein);
Research to Prevent Blindness (Drs Stein and
Weizer); Moorfields Eye Charity Career
Development Fellowship (Dr Khawaja).
Role of the Funder/Sponsor: None of the funders
or sponsors had any role in the design and conduct
of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Edward Livingston, MD, at Edward.
livingston@jamanetwork.org or Mary McGrae
McDermott, MD, at mdm608@northwestern.edu.
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