Low Vision Management in Glaucoma Patient

I. Definition
Glaucoma is a multifactorial optical neuropathy with the characteristic loss
of optic nerve fibers (Olver and Cassidy, 2005). In glaucoma there will be a weakness
of the function of the eye with the occurrence of field defect of view and anatomical
damage in the form of excavation and optic nerve degeneration of the optic nerve,
which can end with blindness. Glaucoma may be due to increased production of eye
fluids by the ciliary body or by decreasing expenditure of eye fluids in the corner of
the eye chamber or in the pupil gap.
Angle closure is defined as the apposition of iris to the trabecular meshwork,
which results in increased intraocular pressure (IOP). In acute angle closure (AAC),
the process occurs suddenly with a dramatic onset of symptoms, including blurred
vision, red eye, pain, headache, and nausea and vomiting. The sudden and severe IOP
elevation can quickly damage the optic nerve, resulting in acute angle-closure
glaucoma (AACG).
AAC is a true ophthalmic emergency, and a delay in treatment can result in
blindness. While immediate treatment can sometimes minimize the amount of visual
loss, the best treatment is to stop its occurrence in susceptible individuals. (1,2,3,4)

II. Patofisiolghy
The exact cause of glaucomatous optic neuropathy is not known, although
many risk factors have been identified, to include the following: elevated IOP, family
history, race, age older than 40 years, and myopia.
Elevated IOP is the most studied of these risk factors because it is the main
clinically treatable risk factor for glaucoma. Multiple theories exist concerning how
IOP can be one of the factors that initiates glaucomatous damage in a patient. Two of
the major theories include the following: (1) onset of vascular dysfunction causing
ischemia to the optic nerve, and (2) mechanical dysfunction via cribriform plate
compression of the axons.
In addition to vascular compromise and mechanically impaired axoplasmic
flow, contemporary hypotheses of possible pathogenic mechanisms that underlie
glaucomatous optic neuropathy include excitotoxic damage from excessive retinal
glutamate, deprivation of neuronal growth factors, peroxynitrite toxicity from
increased nitric oxide synthase activity, immune-mediated nerve damage, and
oxidative stress. The exact role that IOP plays in combination with these other factors
and their significance to the initiation and progression of subsequent glaucomatous
neuronal damage and cell death over time is still under debate; the precise mechanism
is still a hot topic of discussion.
However, IOP is the only clinical risk factor that has been able to be
successfully manipulated to date. Categorizing and managing patients based on their
IOP and determining when IOP should be treated to prevent optic nerve damage
became the forefront issue of glaucoma management for most of the last half of the
20th century.
Several studies over the years have shown that as IOP rises above 21 mm
Hg, the percentage of patients developing visual field loss increases rapidly, most
notably at pressures higher than 26-30 mm Hg. A patient with an IOP of 28 mm Hg is
about 15 times more likely to develop field loss than a patient with a pressure of 22
mm Hg. Therefore, a patient population of those with elevated IOP should not be
thought of as homogeneous. Furthermore, before initiating treatment of a patient
based on a specific IOP measurement, the following factors should be considered
regarding that IOP level obtained:
 Variability of tonometry measurements per examiner (usually found to be about
10%, or 1-2 mm Hg)
 Effect corneal thickness has on accuracy of IOP measurements (see Other Tests)
 Diurnal variation of IOP (often highest in the early morning hours, but
maximum IOP can be at any time of day in some patients)
 In addition, remember that while normal eyes have a diurnal variation of
approximately 3-4 mm Hg, glaucomatous eyes have even higher variation (>10
mm Hg). Note: Multiple readings should be taken over time and should be
considered with correlative evidence of visual field and optic nerve examination
before any diagnosis or therapy is rendered.
A study by Costa et al supports the need to more accurately assess the
relationship of 24-hour IOP to 24-hour diastolic perfusion pressure in patients with
glaucoma. Future methodology that performs noninvasive, real-time IOP
measurements throughout the 24 hours of the day may enable a more complete
understanding of the roles that IOP and blood pressure have to the etiology of
glaucomatous damage and progression of the disease. (5)
Other points of importance when considering a diagnosis of POAG are
described below.
Disc cupping and nerve fiber layer loss of up to 40% have been shown to
occur before actual visual field loss has been detected. Therefore, visual field
examination cannot be the sole tool used to determine when a patient has begun to
sustain undeniable glaucomatous damage, and it should not be used in isolation as the
benchmark for treatment.
In cases where POAG is associated with increased IOP, the cause for the
elevated IOP generally is accepted to be decreased facility of aqueous outflow
through the trabecular meshwork. Occurrence of this increase in resistance to flow has
been suggested by multiple theories, to include the following:
 An obstruction of the trabecular meshwork by accumulated material
 A loss of trabecular endothelial cells
 A reduction in trabecular pore density and size in the inner wall endothelium of
the Schlemm canal
 A loss of giant vacuoles in the inner wall endothelium of the Schlemm canal
 A loss of normal phagocytic activity
 Disturbance of neurologic feedback mechanisms
Other processes thought to play a role in resistance to outflow include altered
corticosteroid metabolism, dysfunctional adrenergic control, abnormal immunologic
processes, and oxidative damage to the meshwork.
Numerous other undetermined factors are considered to be at work in the
pathogenesis of glaucoma. Basic and clinical science research continues to play a role
in the search for such factors that contribute to the development and prognosis of the
patient with POAG.

III. Epidemiology

United State
Multiple population studies (eg, Framingham, Beaver Dam, Baltimore,
Rotterdam, Barbados, Egna-Neumarkt) have been performed to estimate the
prevalence of eye disease, including that of POAG and those individuals with ocular
hypertension (OHT) who are at risk for POAG.
Estimates of the prevalence of glaucoma in studies involving only the United
States suggest the following: glaucoma is a leading cause of irreversible blindness,
second only to macular degeneration; only one half of the people who have glaucoma
may be aware that they have the disease; and more than 2.25 million Americans aged
40 years and older have POAG.
More than 1.6 million have significant visual impairment, with 84,000-
116,000 bilaterally blind in the United States alone. These statistics emphasize the
need to identify and closely monitor those at risk of glaucomatous damage.
In a white population at risk for glaucoma, visual field loss can be expected to
develop in about 3% of subjects over 10 years of follow up without treatment. Risk
increases with age and IOP. (6)
In the United States, 3-6 million people, including 4-10% of the population
older than 40 years, are currently without detectable signs of glaucomatous damage
using present-day clinical testing, but they are at risk due to IOP of 21 mm Hg or
higher. Roughly 0.5-1% per year of those individuals with elevated IOP will develop
glaucoma over a period of 5-10 years. The risk may be declining to less than 1% per
year, now that ophthalmoscopic and perimetric techniques for detecting glaucomatous
damage have improved significantly.

International
Glaucoma is the second leading cause of blindness in the world (surpassed
only by cataracts, a reversible condition). More than 3 million people are bilaterally
blind from POAG worldwide, and more than 2 million people will develop POAG
each year.

Mortality/Morbidity
Over a 5-year period, several studies have shown the incidence of new onset
of glaucomatous damage in previously unaffected patients to be about 2.6-3% for
IOPs 21-25 mm Hg, 12-26% incidence for IOPs 26-30 mm Hg, and approximately
42% for those higher than 30 mm Hg.
The Ocular Hypertension Treatment Study (OHTS) found that the overall
risk for patients with IOPs ranging from 24-31 mm Hg but with no clinical signs of
glaucoma have an average risk of 10% of developing glaucoma over 5 years, with that
risk being cut in half if patients are preemptively started on IOP-lowering therapy.
Significant subsets of higher and lower risk exist when pachymetry (central corneal
thickness [CCT]) is taken into account (see the image below).
Some patients' first sign of morbidity from elevated IOP can be presentation
with sudden loss of vision due to a central retinal vein occlusion (CRVO), the second most
common risk factor for CRVO behind systemic hypertension.

Race
Prevalence of POAG is 3-4 times higher in blacks than in Caucasians; in
addition, blacks are up to 6 times more susceptible to optic disc nerve damage than
Caucasians. A higher prevalence of larger cup-to-disc ratios exists in the normal black
population as compared with white controls.
Glaucoma is the most common cause of blindness among people of African
descent. They are more likely to develop glaucoma early in life, and they tend to have
a more aggressive form of the disease.
 The Barbados Eye Study over 4 years showed a 5 times higher incidence of
developing glaucoma in a group of black ocular hypertensives as compared with a
predominantly white population.
Some population studies have found the mean IOP in blacks to be higher
than Caucasian controls. Other studies (eg, Baltimore) found no difference.
Consequently, further study needs to be conducted to clarify this issue.
Furthermore, the OHTS has suggested that black patients overall may have a thinner
average central corneal thickness, thereby leading to underdiagnosis of elevated
pressure, and consequently, exposure to higher risk of developing glaucoma.
Therefore, pachymetry measurement is particularly important in establishing a
baseline for African-American patients who are glaucoma suspects.

Sex
Reports on sex predilection also differ. Although some age-controlled studies
have reported significantly higher mean IOP values in women than in men, others
have failed to find such a difference, while others have even shown males to have a
higher prevalence of glaucoma.

Age
Age older than 40 years is a risk factor for the development of POAG, with
up to 15% of people affected by the seventh decade of life.
Consequently, glaucoma is found to be more prevalent in the aging
population, even after compensating for the fact that mean IOP slowly rises with
increasing age.
However, the disease itself is not limited to only middle-aged and elderly
individuals.

IV. Sign and Symptomps

Because of the silent nature of glaucoma, patients usually don’t present with
any symptoms or visual complaints until late in the disease course, particularly with
primary open-angle glaucoma. However, narrow/closed-angle glaucoma and
secondary glaucomas can cause a rapid rise in intraocular pressure, which is usually
symptomatic, particularly when intraocular pressure is 35 mm Hg or more.
Significant attention should be given to the following in the patient’s clinical
history:
 Past ocular history
 Previous ocular surgery, including photocoagulation or refractive procedures
 Ocular/head trauma
 Past medical history
 Current medications
 Risk factors for glaucomatous optic neuropathy

V. Diagnosis
Screening the general population for primary open-angle glaucoma is most
effective if targeted toward those at high risk, such as African Americans and elderly
individuals, especially if the screening consists of intraocular pressure measurements
combined with assessment of optic nerve status.
Examination of patients with suspected primary open-angle glaucoma
includes the following:
 Slit lamp examination of the anterior segment
  Funduscopy
 Tonometry
 Gonioscopy
 Pachymetry

Lab Tests
Laboratory tests that may be used to rule other causes for optic neuropathy in
patients suspected of having normal-tension glaucoma include the following:
 CBC count
 Erythrocyte sedimentation rate
 Serology for syphilis (micro-hemagglutination- Treponema pallidum[MHA-
TP], not Venereal Disease Research Laboratory [VDRL] test)
 Rarely, serum protein electrophoresis: For individuals with potential
autoimmune etiology for some glaucomatous optic neuropathies

Imaging studies
The following imaging studies may be used to evaluate patients with
suspected primary open-angle glaucoma:
 Fundus photography
 Retinal nerve fiber layer imaging on high-contrast black and white film using
red-free techniques
 Confocal scanning laser ophthalmoscopy
 Scanning laser polarimetry
 Optical coherence tomography
 Neuroimaging, if suggested by the patient’s pattern of visual field loss
Investigational imaging modalities in the evaluation and management of
patients with primary open-angle glaucoma include the following:
 Fluorescein angiography
 Ocular blood flow analysis via laser Doppler flowmetry
 Color vision measurements
 Contrast sensitivity testing
 Electrophysiologic tests
 Ultrasound biomicroscopy

VI. Treatment
In low-tension glaucoma (LTG), the aim of IOP-lowering medications is for
a reduction of at least 30%.
Surgical Care
Argon laser trabeculoplasty (ALT): This procedure may have minimal effect
because the intraocular pressure (IOP) is already in the reference range.
Selective laser trabeculoplasty (SLT): SLT targets pigment-producing cells in the
trabecular meshwork with less tissue destruction and scarring compared with ALT.
Trabeculectomy: If medical therapy is ineffective, adjunctive antimetabolite
therapy likely is needed for postoperative IOP to be in the single digits. A higher risk
of hypotony and endophthalmitis exists when targeting extremely low pressures that
may be needed to retard or prevent progression of field loss.
Diet
An increase in salt intake may be recommended if the patient's diastolic
blood pressure is significantly lower than the systolic blood pressure (ie, >70 mm
Hg). However, controversy exists regarding this recommendation. Exercise caution in
those patients with vascular or cardiac disease.

VII. Medication
The goals of pharmacotherapy are to reduce IOP and morbidity and to
prevent complications. The goal of therapy with IOP-lowering medications is for a
reduction of at least 30%. Nonselective beta-blockers (eg, timolol maleate,
levobunolol) are controversial because as visual-field progression is possibly due to
secondary aggravated nocturnal arterial hypotension. (7,8) A systematic review and
meta-analysis of 15 randomized clinical trials studying IOP-lowering agents for
treatment of normal-tension glaucoma determined that latanoprost, bimatoprost, and
timolol were most effective. (9)
Medications for neuroprotection are as follows:
 Calcium channel blockers - Less progression [21]
 Betaxolol - Improved choroidal flow, better visual-field preservation
 Dorzolamide - Increased retinal blood flow velocity in humans
 Brimonidine - Increased retinal ganglion cell survival in rat optic nerve crush
injury
Future medications include the following:
 N -methyl-D-aspartate (NMDA) receptor antagonist (Memantine) - Prevents
binding of glutamate and resultant calcium influx; blocks rat ganglion cells from
glutamate toxicity in rats and blocks toxic level of glutamate in vitreous
 Serotonin S2 receptor antagonist (Naftidrofuryl) - Arteriolar vasodilation,
improved blood flow in Raynaud Syndrome
 Glutamate antagonists
 Monoamine oxidase inhibitors (Deprenyl) - Neuroprotection in rat crush model
 Neurotrophic factors (Neurotrophins) - Retard apoptosis in cell culture
 Free radical scavengers - Ginkgo biloba extract scavenges free radicals and
nitric oxide, improves blood flow (60-120 mg bid)
 Cannabinoids (marijuana) - Reduces IOP with NMDA antagonist and
antioxidant activity

 Alpha2-adrenergic agonists
Selective alpha2-receptor that reduces aqueous humor formation and may
increase uveoscleral outflow or inhibit inflow

 Carbonic anhydrase inhibitors

Class Summary
By slowing the formation of bicarbonate ions with subsequent reduction in
sodium and fluid transport, may inhibit carbonic anhydrase in the ciliary processes of
the eye. This effect may decrease aqueous humor secretion, reducing IOP.
Dorzolamide (Trusopt)
Used concomitantly with other topical ophthalmic drug products to lower
IOP. If more than 1 ophthalmic drug is being used, administer the drugs at least 10
min apart. Reversibly inhibits carbonic anhydrase, reducing hydrogen ion secretion at
renal tubule and increasing renal excretion of sodium, potassium bicarbonate, and
water to decrease production of aqueous humor.
  Beta-adrenergic blockers
Class Summary
The exact mechanism of ocular antihypertensive action is not established, but
it appears to be a reduction of aqueous humor production or inhibition of inflow.
Timolol Opthalmic (Timoptic XE, Timoptic, Blocadren)
May reduce elevated and normal IOP with or without glaucoma by inhibiting
inflow.
Levobunolol (AKBeta, Betagan)
Non selective beta-adrenergic blocking agent that lowers IOP by reducing
aqueous humor production and possibly increasing outflow of aqueous humor.
Betaxolol ophthalmic (Betoptic)
Indicated for glaucoma. Selectively blocks beta1-adrenergic receptors with
little or no effect on beta2-receptors. Reduces IOP by reducing production of aqueous
humor.

 Prostaglandin agonists
Class Summary
For reduction of IOP in patients intolerant to other IOP - lowering medications or who
do not respond optimally to other IOP - lowering medications.
Travoprost ophthalmic solution (Travatan)
Prostaglandin F2-alpha analog. Selective FP prostanoid receptor agonist believed to
reduce IOP by increasing uveoscleral outflow. Used to treat open-angle glaucoma or
ocular hypertension.
Unoprostone ophthalmic solution (Rescula)
Prostaglandin F2-alpha analog. Selective FP prostanoid receptor agonist believed to
reduce IOP by increasing uveoscleral outflow. Used to treat open-angle glaucoma or
ocular hypertension.
Bimatoprost ophthalmic solution (Lumigan)
A prostamide analogue with ocular hypotensive activity. Mimics the IOP-lowering
activity of prostamides via the prostamide pathway. Used to reduce IOP in open-angle
glaucoma or ocular hypertension.

VIII. References
1. Kim M, Kim TW, Park KH, Kim JM. Risk factors for primary open-angle
glaucoma in South Korea: the Namil study. Jpn J Ophthalmol. 2012 Jul.
56(4):324-9.
2. Kim KCY, Ahn AMD, Seong SGJ. Does redefining of high intraocular
pressure (IOP) according to IOP distribution change prevalence of normal
tension glaucoma in Korea? [abstract]. World Glaucoma Congress, 2009.
Available at http://www.worldglaucoma.org/WGC/WGC2009/index.php.
Accessed: July 24, 2009
3. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for
visual field progression at low intraocular pressures in the advanced glaucoma
intervention study. Ophthalmology. 2008 Jul. 115(7):1123-1129.e3.
4. Paul T, Radcliffe N, Shimmio M. Reclassification of normal and high tension
glaucoma eyes using corneal compensated IOP [abstract]. World Glaucoma
Congress, 2009. Available at http://www.worldglaucoma.org/WGC2009/.
Accessed: July 28, 2009.
5. Akopov E, Astakhov Y, Nefedova D. Retinal vessels calibrometry in normal
pressure glaucoma evaluation [abstract]. World Glaucoma Congress, 2009.
Available at http://www.worldglaucoma.org/WGC/WGC2009/index.php.
Accessed: July 28, 2009.
6. Furlanetto RL, De Moraes CG, Teng CC, Liebmann JM, Greenfield DS,
Gardiner SK, et al. Risk factors for optic disc hemorrhage in the low-pressure
glaucoma treatment study. Am J Ophthalmol. 2014 May. 157(5):945-52.
7. Orgul S, Zawinka C, Gugleta K, Flammer J. Therapeutic strategies for normal-
tension glaucoma. Ophthalmologica. 2005 Nov-Dec. 219(6):317-23.
8. Tarkkanen AH, Kivelä TT. Vascular comorbidity in patients with low-tension
glaucoma. Eur J Ophthalmol. 2014 Jul 21.
9. Cheng JW, Cai JP, Wei RL. Meta-analysis of medical intervention for normal
tension glaucoma. Ophthalmology. 2009 Jul. 116(7):1243-9.
10. Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the
management of low-tension and open-angle glaucoma. Am J Ophthalmol.
1993 May 15. 115(5):608-13.