AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The definition of glaucoma has changed drastically since its introduction around the time of Hippocrates (approximately 400 BC). The word glaucoma came from ancient Greek, meaning clouded or blue-green hue, most likely describing a patient having corneal edema or rapid evolution of a cataract precipitated by chronic elevated pressure. Over the years, extensive refinement of the concept of glaucoma has continued, accelerating, especially in the last 100 years, to the present date.

Currently, glaucoma is defined as a disturbance of the structural or functional integrity of the optic nerve that causes characteristic atrophic changes in the optic nerve, which may also lead to specific visual field defects over time. This disturbance usually can be arrested or diminished by adequate lowering of intraocular pressure (IOP). Nevertheless, some controversy still exists as to whether IOP should be included in the definition, as some subsets of patients can exhibit the characteristic optic nerve damage and visual field defects while having an IOP within the normal range. The generic term glaucoma should only be used in reference to the entire group of glaucomatous disorders as a whole, because multiple subsets of glaucomatous disease exist. A more precise term should be used to describe the glaucoma, if the specific diagnosis is known.

Primary open-angle glaucoma (POAG) is described distinctly as a multifactorial optic neuropathy that is chronic and progressive with a characteristic acquired loss of optic nerve fibers. Such loss develops in the presence of open anterior chamber angles, characteristic visual field abnormalities, and IOP that is too high for the continued health of the eye. It manifests by cupping and atrophy of the optic disc, in the absence of other known causes of glaucomatous disease. Note that the definition of POAG is not synonymous or solely defined by the presence of elevated IOP, but that increased IOP is a risk factor associated with the development of the disease, and is not the disease itself. Patients could develop optic neuropathy of glaucoma in the absence of documented elevated IOP. This condition has been termed normal-tension or low-tension glaucoma.

People who maintain elevated pressures in the absence of nerve damage or visual field loss exist. They are considered at risk for glaucoma and have been termed glaucoma suspects or ocular hypertensives (see Ocular Hypertension). POAG is a major worldwide health concern, because of its usually silent, progressive nature, and because it is one of the leading preventable causes of blindness in the world. With appropriate screening and treatment, glaucoma usually can be identified and its progress arrested before significant effects on vision occur.

Pathophysiology

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 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%)
• Effect corneal thickness has on accuracy of IOP measurements (see Other Tests)
• Diurnal variation of IOP (often highest in the early morning hours)
• 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.

Other points of importance when considering a diagnosis of POAG are as follows:

Disc cupping and nerve fiber layer losses 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 foreign 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.

Frequency

United States

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 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

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 Image 11).
• 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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The initial patient interview is extremely important in the evaluation for POAG or other ocular diseases secondarily causing elevated IOP. Because of the silent nature of the disease, patients usually will not present with any visual complaints until late in the course. Therefore, attention should be given to the following:

• Past ocular history
• • History of eye pain or redness
  • Multicolored halos
  • Headache
  • Previous ocular disease, including cataracts
  • Uveitis
  • Diabetic retinopathy
  • Vascular occlusions
  • Previous ocular surgery, including photocoagulation or refractive procedures
  • Ocular/head trauma
• Past medical history - Any surgeries or pertinent vasculopathic systemic illnesses
• Current medications, including any hypertensive medications (which may indirectly cause fluctuation of IOP) or topical/systemic corticosteroids
• Risk factors for glaucomatous optic neuropathy
• • Strong implications are as follows:
  • • History of elevated IOP; advanced age, particularly after 50 years; African American descent; positive family history of glaucoma (first-degree relative, especially correlative if present in a sibling; relative risk 3.7-fold higher than if no family history of glaucoma); myopia
    • Be specific when asking family history (Which family members? Was there actual visual loss from glaucoma or other causes of visual field loss? Are they under control on one or more medications? Did they require surgery for adequate control?)
  • Possible implications are as follows:
  • • Systemic cardiovascular disease
    • Diabetes mellitus
    • Migraine headache
    • Systemic hypertension
    • Vasospasm
• Anecdotal risk factors
• • Obesity
  • Smoking
  • Alcohol
  • History of stress
  • Anxiety

Physical

• Screening the general population for POAG is most effective if targeted toward those at high risk, such as African Americans and elderly individuals, especially if the screening consists of IOP measurements combined with assessment of optic nerve status.
• Perform screening at least every 3-5 years in asymptomatic patients aged 40 years or younger and more often if the person is African American or older than 40 years. For those with multiple risk factors, evaluate and monitor on a more frequent basis, as appropriate.
• Perform a standard comprehensive eye examination, such as that outlined in the American Academy of Ophthalmology (AAO) Preferred Practice Patterns, on the initial visit. If any visual field or optic nerve changes consistent with early glaucoma are present, then diagnose the patient as having such.
• Emphasize the following points during the examination to distinguish POAG from either secondary causes of glaucoma or from OHT in patients with only elevated IOP and no damage.
• • Compare visual acuity with previous known acuities. If declining, rule out secondary causes of vision loss, whether it is from cataracts, age-related macular degeneration (ARMD), ocular surface disorders (eg, dry eye), or adverse effects from topical medications (especially if using miotics).
  • Pupils - Test for presence/absence of afferent pupillary defect (Marcus Gunn pupil).
  • Slit lamp examination of the anterior segment
  • • Cornea - Signs of microcystic edema (found only with acute elevation of IOP); keratic precipitates, pigment on endothelium (Krukenberg spindle); congenital anomalies
    • Anterior chamber - Cell or flare, uveitis, hyphema, angle closure
    • Iris - Transillumination defects, iris atrophy, synechiae, rubeosis, ectropion uveae, iris bombe, difference in iris coloration bilaterally (eg, Fuchs heterochromic iridocyclitis), pseudoexfoliation (PXF) material
    • Lens - Cataract progression (ie, signs of phacomorphic glaucoma, pseudoexfoliation, phacolytic glaucoma with a Morgagnian cataract)
    • Optic nerve/nerve fiber layer - Stereoscopically examine for evidence of glaucomatous damage, including the following: cup-to-disc ratio in horizontal and vertical meridians (describe by color and slope, and diagram, if needed); appearance of disc; progressive enlargement of the cup; evidence of nerve fiber layer damage with red-free filter; notching or thinning of disc rim, particularly at superior and inferior poles (because nerve fibers at the superior and inferior poles of the disc can often be affected first); pallor; presence of hemorrhage (most common inferotemporally); asymmetry between discs; parapapillary atrophy (possible association with development of glaucoma); or congenital nerve abnormalities.
    • Fundus - Other abnormalities that could account for any nonglaucomatous visual field defects or vision loss present (eg, disc drusen, optic pits, retinal disease), vitreous hemorrhage, or proliferative retinopathy.
  • Baseline stereo fundus photographs for future reference/comparison; if unavailable, record representative drawings.
  • Tonometry
  • • IOP varies from hour-to-hour in any individual. The circadian rhythm of IOP usually causes it to rise most in the early hours of the morning; IOP also rises with a supine posture.
    • When checking IOP, measurements for both eyes, the method used (Goldmann applanation is the criterion standard), and the time of the measurement should all be recorded.
    • Previous tonometry readings, if available, should be reviewed (eg, Is the reading reproducible? What method was used to obtain the reading? What time of the day was it? Where does it fall on the diurnal pressure curve? Do both eyes have similar measurements?).
    • In obese patients, the possibility of a Valsalva movement causing an increased IOP should be considered when measured in the slit lamp by Goldman applanation. Measurement should be tried via Tono-Pen, Perkins, or pneumotonometer with the patient resting back in the examination chair.
    • A difference between the 2 eyes of 3 mm Hg or more indicates greater suspicion of glaucoma. An average of 10% difference between individual measurements should be expected. The measurements should be repeated on at least 2-3 occasions before deciding on a treatment plan. The measurement should be completed in the morning and at night to check the diurnal variation, if possible. (A diurnal variation of more than 5-6 mm Hg may be suggestive of increased risk for POAG.) Early POAG is suspected strongly when a steadily increasing IOP is present.
  • Perform gonioscopy to rule out angle-closure or secondary causes of IOP elevation, such as angle recession, pigmentary glaucoma, and PXF.
  • • Check the peripheral contour of the iris for plateau iris, and examine the trabecular meshwork for peripheral anterior synechiae, as well as neovascular or inflammatory membranes.
    • The Schlemm canal may be seen with blood refluxing through the canal into the posterior trabecular meshwork. This possibly could indicate elevated episcleral venous pressure, with such conditions as carotid-cavernous fistula, Graves orbitopathy, or Sturge-Weber syndrome needing to be ruled out.
  • Pachymetry: Pachymetry is used to measure CCT. According to the OHTS, pachymetry is now the criterion standard for every baseline examination in patients who are at risk for or suspected of having glaucoma (see Image 11).
  • Visual field testing
  • • Perform automated threshold testing (eg, Humphrey 24-2) to rule out any glaucomatous visual field defects.
    • If the patient is unable to perform automated testing, Goldmann testing may be substituted.
  • Caveats about visual field analysis are outlined below. (See Other Tests.)
  • • New-onset glaucomatous defects are found most commonly as an early nasal step, temporal wedge, or paracentral scotoma (more frequent superiorly); generalized depression related to IOP level also can be found.
    • Swedish interactive thresholding algorithm (SITA)-based software algorithms may decrease testing time and boost reliability, especially in older patients.
    • SWAP (short wavelength automated perimetry or blue-yellow perimetry) may provide a more sensitive method of detecting visual field deficits, especially in those previously labeled as ocular hypertensive. If the Humphrey visual field testing results are normal, SWAP should be considered to help detect visual field loss earlier. Recent studies suggest SWAP may detect visual loss/progression up to 3-5 years earlier than conventional perimetry, as well as in 12-42% of patients previously diagnosed with only OHT. Because the testing time may be lengthened, it may be tiring for some patients. However, new SITA-SWAP algorithm software may speed up the testing time and thus improve reliability.
    • Examination results must take into account that visual field defects may not be apparent until over 40% loss of the nerve fiber layer has occurred. Therefore, the therapy should be based on the overall clinical picture and not on visual field testing alone (see Treatment).
    • The pupil size should be documented at each testing session, as constriction can reduce retinal sensitivity and mimic progressive field loss.
    • Risk factors, specifically for the development of glaucomatous field loss in OHT, have recently been studied, and it was found that several presumed risk factors (ie, presence of hypertension, diabetes, refractive error, race, family history of glaucoma, gender, smoking or ethanol use, disc area) were not significant for prediction of eventual field loss.
    • Significant positive predictive factors of field loss included higher IOP, older age, presence of a disc crescent, larger cup-to-disc ratio, smaller rim-disc area ratio, and cup asymmetry. Consequently, the relationship of risk factors for OHT and POAG compared with that of actual field loss development is much more complex than has been previously presumed.
    • The initial visual field baseline may need to be repeated at least twice on successive visits, especially if initial testing shows low reliability indices. Newer glaucoma progression analysis (GPA) software can help identify reliable perimetric baselines, and probability-based analyses of subsequent fields can assist in determining if there is true progression over time versus artifact. In follow-up, if a low risk of onset of glaucomatous damage is present, then repeat testing may be performed once a year. If a high risk of impending glaucomatous damage is present, then testing may be adjusted (as frequent as every 2 mo).

Causes

• In general, the cause of glaucomatous optic neuropathy is unknown.
• The disease affects the individual axons of the optic nerve, which may die by apoptosis, also known as programmed cell death.
• Various theories (see Pathophysiology) have been advanced to explain the possible etiologic role of elevated IOP in glaucomatous optic neuropathy.
• • The mechanical compression theory suggests that elevated IOP causes a backward bowing of the lamina cribrosa, kinking the axons as they exit through the lamina pores. This may lead to focal ischemia, deprive the axons of neurotrophins, or interfere with axoplasmic flow, triggering cell death.
  • The vascular theories propose that cell death is triggered by ischemia, whether induced by elevated IOP or as a primary insult.
  • Other risk factors may play a role in the development of POAG, including a history of migraine headaches (a condition associated with vasospasm), cardiovascular disease, diabetes, systemic hypertension (leading to arteriosclerosis), and systemic hypotension (leading to decreased perfusion).
  • Genetic theories propose that cell death is triggered by genetic predisposition. Following the death of individual axons, substances may be released into the environment that causes a secondary triggering of apoptosis in neighboring cells, including glutamate (a neurotransmitter that may cause excitotoxicity), calcium, nitric oxide, and free radicals.
• Glaucoma is not just a disease of IOP but rather a multifactorial optic neuropathy. However, patients with OHT who have IOP outside of the statistically normal range should continue to have periodic follow-up examinations, because they are always at risk for development of glaucoma.
• • Other causes for optic neuropathy should be considered in all patients with apparent normal-tension glaucoma, and appropriate lab or radiologic testing should be initiated if history and/or physical findings are suggestive.
  • Patients who do not have elevated IOP but glaucomatous optic discs or visual fields may have normal-tension glaucoma. It is a diagnosis of exclusion (after other causes for optic neuropathy, such as temporal arteritis, have been investigated and ruled out).
• Several secondary causes of glaucoma must be considered before diagnosing POAG. These causes include the following (see Differentials):
• • Exfoliation syndrome
  • Pigment dispersion syndrome (pigmentary glaucoma)
  • Lens-induced glaucoma
  • Ocular inflammatory diseases
  • Intraocular tumors
  • Raised episcleral venous pressure
  • Topical or systemic corticosteroid use
  • Syndromes (eg, Axenfeld-Rieger syndrome)

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Patients suspected of having normal-tension glaucoma may need workup to rule out other causes for optic neuropathy, including, but not limited to, CBC, erythrocyte sedimentation rate (ESR), serology for syphilis (micro-hemagglutination-Treponema pallidum [MHA-TP], not Venereal Disease Research Laboratory [VDRL] test), and if suggested by the pattern of visual field loss, neuroimaging.
• Some researchers have suggested an autoimmune etiology for some glaucomatous optic neuropathies and have identified monoclonal gammopathies. Serum protein electrophoresis can identify these rare individuals.

Imaging Studies

• Fundus photography provides a permanent record of the appearance of the optic disc. Photographs taken over a period of time may be compared to track the progression of glaucoma.
• The retinal nerve fiber layer sometimes can be imaged on high-contrast black and white film using red-free techniques. This can allow identification of nerve fiber layer defects that are characteristic of glaucomatous damage.
• New techniques that use optical analysis of different physical properties of light can document the status of the optic nerve and the nerve fiber layer, and they can be used to detect changes over time. The value of these technologies for diagnosing and following glaucoma over time is currently under active investigation.
• • Confocal scanning laser ophthalmoscopy can examine the optic disc and peripapillary retina in 3 dimensions and provide quantitative information about the cup, neuroretinal rim, and contour of the nerve fiber layer.
  • Scanning laser polarimetry measures the change in the polarization state of an incident laser light passing through the naturally birefringent nerve fiber layer to provide indirect estimates of peripapillary nerve fiber layer thickness.
  • Optical coherence tomography (OCT) uses reflected light in a manner analogous to the use of sound waves in ultrasonography to create computerized cross-sectional images of the retina and optic disc, and also gives quantitative information about the peripapillary retinal nerve fiber layer thickness.

Other Tests

• Other tonometric methods
• • Goldmann applanation tonometry is considered the criterion standard. However, in cases of increased corneal or scleral rigidity (ie, S/P keratoplasty, scleral buckle), pneumotonometry or a Tono-Pen measurement can be used, which may be more accurate.
  • Recent studies suggest that applanation pressures may vary significantly depending on the corneal thickness.
  • • Some patients diagnosed with OHT actually may be normotensive when corrected for increased corneal thickness.
    • Some supposed glaucoma suspects or patients with apparent low-tension glaucoma (with normal range IOPs on applanation) can have abnormally thin corneas on pachymetry (central corneal thickness measurements); therefore, their IOP measurements are underestimated by applanation.
    • Pachymetry may play a role in determining a "fudge factor" by which to adjust each patient's IOP measurement.
• Frequency doubling perimetry (also termed frequency doubling technology or FDT, which is now also enhanced with new MATRIX software), scanning laser polarimetry (GDx), scanning retinal tomography (HRT), and OCT are all relatively new technologies that may be able to detect nerve fiber layer loss at an earlier stage in the glaucomatous disease process, thereby screening out more people who currently are misdiagnosed as having OHT instead of early POAG. Current sensitivities and specificities are continuing to improve, but more baseline data is needed to determine in what setting these new techniques will prove to be most useful.
• Fluorescein angiography, ocular blood flow analysis via laser Doppler flowmetry, color vision measurements, contrast sensitivity testing, and electrophysiological tests (eg, pattern electroretinograms) are used currently as research tools in the evaluation and management of POAG patients. Routine clinical use is not advocated at this time.
• Ultrasound biomicroscopy (UBM) may prove to be helpful in the future for obtaining a better view of the angle, iris, and ciliary body structures to rule out anatomical pathology and secondary causes of elevated IOP.
• Other tests of historical and research interest include the following:
• • Tonography, which has been used to help determine trabecular outflow facility, is primarily a research tool used in testing pharmacologic agents.
  • Provocative testing (eg, water-drinking test) was used in the past to try to differentiate who would develop early open-angle glaucoma. This test was of no aid in distinguishing those patients who would develop visual field defects from those who would not develop them.
• Patients whose visual field defects seem to progress in a manner uncharacteristic of glaucoma should have a workup for other causes of visual loss.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Major drug classes for medical treatment of POAG include the following:
• • Alpha-agonists
  • Beta-blockers
  • Carbonic anhydrase inhibitors
  • Miotic agents
  • Prostaglandin analogs
• Currently, some physicians treat all elevated IOPs over 21 mm Hg with the above topical medications. Some physicians do not treat unless evidence of optic nerve damage exists although nerve fiber layer loss of up to 40% may occur before visual field defects occur, so do not treat based on visual field testing alone). Most physicians select and treat only those patients thought to be at greatest risk for POAG (most common approach). See History and Visual field testing for a list of risk factors for glaucomatous field loss.
• In any case, the goal of treatment is reduction of the pressure before it causes progressive loss of vision. However, the average monthly cost of glaucoma medication in 1986 alone was $51.65. Considering these costs, along with the possible risks of adverse effects or toxic reactions from drugs, inconvenience of use, and incidence of noncompliance, a strong reason not to treat indiscriminately exists.
• Several questions should be asked when considering treatment, to include the following: Is the elevated pressure significant? Will this patient develop visual loss if left untreated? Is the treatment worth the risk of adverse effects of the medications?
• One should consider treatment more strongly if the patient reliability or the consequences of missing field loss is an issue (eg, poor reliability on visual field examination, 1-eyed patient, poor availability for follow-up care, younger patient, patient whose optic nerve is difficult to visualize, history of vascular occlusion).
• Treatment is obligatory if signs of damage (eg, disc hemorrhage; visible nerve fiber layer defects; notching or vertical ovalization of the cup; asymmetric cupping, especially if >0.7) are observed. Progressive cupping, even in the absence of visual field loss, is glaucoma and should be treated as such. Otherwise, it depends on the assessment of risk factors and benefit of therapy to the patient.
• Discussion with the patient about the pros and cons of treatment versus observation should be completed. Individualization of therapy is the key; an ideal pressure in one patient may cause glaucomatous damage in another patient. Risk factors, systemic conditions, life expectancy of the patient, quality of life issues, and the patient's desire for therapy should be weighed when considering treatment.
• Due to the high risk of optic nerve damage, most ophthalmologists treat if pressures are consistently above 28-30 mm Hg. If treatment is based on a high IOP only, then it should be ensured that the risks of treatment do not exceed the risk of the disease.
• Other reasons to treat include such symptoms as halos, blurred vision, or pain, or recent elevation of IOP, with continuing elevation on successive visits.
• Initiation of a monocular trial (see Medication) may be useful in helping to decide whether or not to treat (ie, if the medication is effective in achieving good pressure reduction without adverse effects, which may argue in favor of treatment, instead of just observation).
• Considering all of the above, no consensus exists on what is the appropriate medical treatment for preventing or delaying the damage due to POAG when a patient has only elevated IOP and no other signs of POAG. To date, no one has been able to define conclusively which subgroups will develop damage if left untreated, as opposed to those who will not sustain damage even if not treated.
• The question of medical therapy versus observation in patients with solely elevated IOP is being addressed in the OHTS, an ongoing multicenter randomized clinical trial.
• • The OHTS is a multicenter, prospective, randomized, controlled, clinical trial studying over 1600 subjects to evaluate the safety and efficacy of medical treatment in preventing or delaying onset of visual field loss and/or optic nerve damage in patients with OHT who are at moderate risk for developing POAG.
  • Their medical therapy goal for the treated group is stepped therapy to reduce IOP by at least 20% from the average baseline IOP with its treated absolute value of 24 mm Hg or less.
  • So far, their results show a 10% risk over 5 years of developing glaucoma in those patients with baseline IOP of 24-31 mm Hg. This risk was reduced to 5% with medical therapy.
  • The OHTS has also revealed the importance of pachymetry as a diagnostic tool as well as in the workup.
• Several sources agree on this initial goal of 20-25% reduction, while some specialists feel that more absolute numbers of less than 15 should be the goal of treatment. Keep in mind that the IOP goal must be set independently for each patient, depending on the risk factors, as an IOP level for one person with minimal risk factors may be far too high for a patient with multiple risk factors for sustaining glaucomatous damage.
• Other regimens have been suggested, as follows: for minimal risk factors, consider lowering IOP by 20-30%; if moderate number of risk factors are present, lower by 30-40%; and in cases of numerous risk factors with markedly elevated pressures, reduction in the 40-60% range may need to be achieved to prevent neuronal loss.
• If the patient is older than 65 years, consider treatment to keep IOP 25 mm Hg or less, secondary to 3% risk of vascular occlusion in OHT patients.
• In any case, the target IOP should be reevaluated periodically, and regular review of IOP trends should be performed to determine whether the patient is consistently maintaining that goal.
• Below is a suggested time guideline for therapy and follow-up based on initial IOP level. Adjust frequency of follow-up testing as needed based on the number of risk factors and clinical picture.
• • IOP 28 mm Hg or greater: Patients should be treated (see Medication), with follow-up care in 1 month to assess if treatment is effective and no adverse effects are present. If the goal is reached, then follow-up care should be performed every 3-4 months.
  • IOP 26-27 mm Hg: Follow-up care should be performed in 2-3 weeks to recheck pressure. If IOP is still within 3 mm Hg of the initial reading, then follow-up should be continued every 3-4 months with visual field and dilated optic nerve evaluation at least once a year. If IOP is lower, then a longer time should be considered between the pressure checks, making sure to recheck IOP at different times of the day on subsequent appointments.
  • IOP 22-25 mm Hg: Follow-up care should be performed 2-3 months later for recheck of IOP at different times of the day (ie, 8 am, 11 am, 1 pm, 4 pm). If it is still within 3 mm Hg of the initial reading at the second visit, then follow-up at 6 months with Humphrey visual field testing and dilated optic nerve evaluation, repeating it at least yearly.
• Other caveats concerning follow-up care are as follows:
• • If a new visual field defect becomes apparent on testing, confirmation with repeat (possibly multiple) examinations during future office visits should be performed, before using it as a basis for the treatment of presumed progression of POAG.
  • Gonioscopy should be performed at least once every 1-2 years if a significant increase in IOP occurs, or if miotic therapy is instituted.
  • Optic disc photos should be repeated after the initial examination if a change in disc appearance is noted.
  • Retinal tomography, ocular coherence tomography, and/or laser polarimetry should be measured at baseline and then every 1-2 years. Results should be correlated with visual field results, IOP measurements, and examination findings.

Surgical Care

Surgery is indicated when glaucomatous optic neuropathy worsens (or is expected to worsen) at any given level of IOP and the patient is on maximum tolerated medical therapy (MTMT).

MTMT varies considerably between individuals, and it may consist of medicines from 1 or several classes (including a beta-adrenergic antagonist, a prostaglandin agent, an alpha-agonist, and a topical carbonic anhydrase inhibitor). Some patients are observed to progress simply because compliance with the medical regimen becomes too difficult because of the following: high drug costs, inability to remember the schedule of multiple medications, inability to instill them in the eyes properly secondary to arthritis or other incapacitation (especially common among elderly patients or those with other chronic systemic conditions), or intolerable ocular and systemic adverse effects.

A brief mention of surgical options is listed below. Detailed information on surgical procedures, indications, and postoperative care is beyond the scope of this chapter.

• Argon laser trabeculoplasty
• • Argon laser trabeculoplasty (ALT) uses a laser beam focused through a goniolens to treat at the border between anterior and posterior trabecular meshwork. A full treatment consists of 100 spots placed over the entire 360° of the trabecular meshwork. This may be divided between 2 sessions consisting of 50 spots over 180°.
  • Aqueous outflow improves after the procedure.
  • The specific mechanism of this improved outflow is unknown, but one hypothesis is up-regulation of trabecular endothelial cells.
  • IOP reduction obtained is usually in the 7-10 mm Hg range, and it may last up to 3-5 years following ALT.
  • Unfortunately, the decrease in IOP is not usually permanent. Approximately 10% of treated patients will return to pretreatment IOP for each year following treatment.
  • Complications include a brief, but potentially significant, increase in IOP after the procedure (therefore, alpha-agonists often are used either preoperatively or postoperatively for prophylaxis of this occurrence); transient iritis or corneal opacities; peripheral anterior synechiae; and hyphema.
  • ALT usually is pursued after MTMT has been reached, but it may be performed sooner in the treatment algorithm if pseudoexfoliation or pigmentary glaucoma is present, or if the patient is of black ethnicity, because laser therapy may be most effective in these individuals.
• Selective laser trabeculoplasty
• • Selective laser trabeculoplasty (SLT) uses a Q-switched 532 Nd:YAG laser to selectively target pigmented cells of the trabecular meshwork in a nonthermal manner, increasing fluid outflow and thereby lowering IOP.
  • The 3-nanosecond high-energy specific wavelength of light used induces the same cell replacement mechanism as traditional ALT but without the destructive burning and obliteration of structural support tissue in the meshwork. The short pulse of the laser does not allow time for heat to spread to other cells. SLT delivers just enough energy to the trabecular meshwork to target specific melanin-rich cells, without incurring collateral thermal damage and scarring to adjacent nonpigmented trabecular meshwork cells and underlying trabecular beams. When treated with SLT, a primarily biologic response is induced in the trabecular meshwork that involves the release of cytokines that trigger macrophage recruitment as well as other changes leading to IOP reduction.
  • The laser beam bypasses surrounding tissue leaving it undamaged by light. Unlike ALT, SLT can be repeated several times. Whereas patients treated with ALT can receive only 2 treatments in their lifetime, patients treated with SLT can receive 2 treatments a year.
• • SLT requires a specially designed laser, as follows:
  • • A short pulse to allow for thermal relaxation
    • Precise wavelength for optimal melanin absorption
    • Sufficient energy to heat melanin to the point that it releases cytokines
    • Sufficient spot size to ensure full coverage at the trabecular meshwork
• Trabeculectomy
• • Trabeculectomy surgery usually is performed after MTMT and ALT have failed to control IOP adequately.
  • A superficial flap of sclera is dissected anteriorly to the trabecular meshwork, and a section of trabecular meshwork is removed underneath the flap.
  • This alternate outflow pathway is created to increase passage of aqueous from the anterior chamber to the subconjunctival space, creating a filtering bleb and, thereby, lowering IOP.
  • Either releasable sutures or laser suture-lysis may be used to control aqueous drainage and corresponding IOP postoperative. Alternatively, to maximize surgical success, antimetabolites (eg, 5-fluorouracil, mitomycin C) may be applied during or after surgery to decrease fibroblast proliferation and scar formation.
  • Risks and complications of filtering surgery include the following: hypotony, blebitis/endophthalmitis, hyphema, suprachoroidal hemorrhage or effusions, encapsulation of the bleb with resultant transient IOP elevation, loss of 1 or more lines of visual acuity, and increased risk of cataract formation.
• Drainage implant (ie, seton/tube/shunt) surgery
• • Generally, this procedure is performed after multiple attempts at successful trabeculectomy have failed.
  • A tube is placed in the anterior chamber to shunt aqueous to an equatorial reservoir, and then posteriorly to be absorbed in the subconjunctival space.
  • Types of implants include Molteno, Baerveldt, Ahmed, and Krupin.
  • • Most shunts function by allowing passive drainage of aqueous from the anterior chamber.
    • The Molteno implant consists of a silicone drainage tube, which is connected to 1 or 2 acrylic plates that are sutured to the sclera.
    • The Baerveldt implant is available with larger plates with increased reservoir size. The seton (tube) connected to the reservoir usually is tied off with an absorbable suture, allowing flow to initiate 4-6 weeks postoperative once some conjunctival wound remodeling has taken place, thereby reducing the risk of immediate postoperative hypotony.
    • The Krupin and Ahmed implants have 1-way valves, which are designed to maintain pressure above 8 mm Hg. These implants may reduce the risk of hypotony, a complication of nonvalved shunts in the early postoperative period.
• Ciliary body ablation
• • Postoperative pain and inflammation are common complaints. Loss of 1 or more lines of visual acuity has been reported. Phthisis is a concern after this procedure, although it has not been reported as of yet after the diode laser method of cycloablation.
  • This procedure is a last resort for patients who have failed medical management and other surgeries.
  • By destroying a portion of the nonpigmented ciliary epithelium, aqueous humor production is limited.
  • The ciliary body epithelium can be destroyed by cyclocryotherapy, diathermy, ultrasound, transscleral Nd:YAG or diode laser, or endolaser.

Consultations

Neuro-ophthalmology consultation may have a role in those patients who are experiencing progressive visual loss that does not appear to follow a typical glaucomatous pattern.

Activity

Some studies show that a moderate amount of exercise can decrease IOP in both POAG patients and normal individuals. Whether it results in actual long-term IOP control and prevention of visual loss has yet to be determined.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Current medical therapy is limited toward lowering IOP. A rational approach to choosing antiglaucoma medications should minimize the number of medications and the probability of significant adverse effects. The ideal drug for treatment of POAG should have the following characteristics: (1) effectively lower IOP, (2) no adverse effects or systemic exacerbation of disease, and (3) inexpensive with once-a-day dosing. However, because no medicine possesses all of the above, these qualities must be prioritized based on the patient's individual needs and risks; then, therapy should be chosen accordingly.

Once a medicine has been initiated, close follow-up care should be performed to assess its effect. Initial follow-up care should be performed 3-4 weeks after the beginning of therapy. IOP should be rechecked at the drug's peak and trough times to see if the target IOP has been reached and is maintained throughout the day. Look for signs of allergy (eg, hyperemia, skin rash, follicular reaction). Inform the patient of systemic adverse effects and symptoms that may occur. Treatment should be continued if a therapeutic trial has shown effective lowering of IOP without adverse effects. Reevaluation should be performed 2-4 months later depending on the clinical picture.

A monocular therapeutic trial should be considered when first initiating the medical therapy, as the other eye's IOP can be used as a baseline control to gauge effect of a medication (particularly useful in patients with a widely fluctuating diurnal curve). A difference of more than 4 mm Hg between the 2 eyes posttreatment is strongly suggestive of a clinical effect. However, some agents (especially beta-blockers) may have crossover effects on the other eye even with monocular treatment, so clinical correlation must be kept in mind. If monocular therapy is found to be effective, then initiation of binocular therapy may be considered.

Some medications (eg, latanoprost, brimonidine) may have an effect that plateaus at 6-8 weeks in certain patients; keep this effect in mind when scheduling further follow-up examinations. Other patients will be nonresponders to some therapies. If this occurs, the medication should be discontinued and a new drug initiated. While discontinuing or changing therapies, keep in mind that many drugs have a wash-out period of up to 2-4 weeks (especially beta-blockers), during which they may still have some IOP-lowering effect or residual systemic response.

If one medication is not adequate in reaching the target pressure, a second medication should be chosen that has a different mechanism of action, so that the 2 drug therapies will have an additive effect. (Usually, no additive effect is seen if 2 medications from the same drug class are used.)

A specific plan of pharmacotherapy should be administered only after the possible effects of the systemic medications that a patient is taking (eg, beta-blockers, calcium channel blockers, ACE inhibitors) have been taken into consideration.

Before mention of particular medications currently used in most practices, note that as the mechanisms of axonal death by apoptosis are becoming better understood, therapies are being developed to protect nerve fibers from undergoing injury and death by several possible theoretical mechanisms. This halting of processes that is believed to contribute to ganglion cell death in glaucoma has been termed neuroprotection, and several new pharmaceuticals are being developed that hopefully will work in this manner. Agents currently under investigation as neuroprotective include glutamate receptor blockers, calcium channel blockers, inhibitors of nitric oxide synthase, free radical scavengers, and drugs to increase blood flow to the optic nerve.

See Ocular Hypertension and AAO monograph #13 for further in-depth descriptions of particular drugs.

Newly approved drugs

Bimatoprost (Lumigan), travoprost (Travatan), and unoprostone (Rescula) are new ophthalmic prostaglandin analogs recently approved in the United States. Bimatoprost is a prostamide analog with ocular hypotensive activity. It mimics the IOP-lowering activity of prostamides via the prostamide pathway. Travoprost and unoprostone are prostaglandin F2-alpha (ie, dinoprost) analogs similar to latanoprost. They are selective FP prostanoid receptor agonists believed to reduce IOP by increasing uveoscleral outflow. They are indicated for the lowering of IOP in patients with open-angle glaucoma or OHT who are intolerant of other IOP-lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another IOP-lowering medication.

Bimatoprost and travoprost are each administered once daily at bedtime (ie, 1 gtt in affected eye[s] hs); whereas, unoprostone must be administered bid. They have not been studied in pediatric patients.

These medications are contraindicated if hypersensitivity has been documented. No drug interactions have been reported. All are classified as pregnancy category C (ie, safety for use during pregnancy has not been established).

Like latanoprost, all of these agents can demonstrate the unusual adverse effect of permanent increase in pigment of the iris (ie, increases brown pigment) and eyelid, and they may increase eyelash growth. Bacterial or herpes viral keratitis may occur. Use is cautioned in uveitis or macular edema. They should not be used if inflammation is present.

Drug Category: Beta-adrenergic blockers

Topical beta-adrenergic receptor antagonists decrease aqueous humor production by the ciliary body. Adverse effects are due to systemic absorption of the drug, decreased cardiac output, and bronchoconstriction. In susceptible patients, this may cause bronchospasm, bradycardia, heart block, or hypotension. The patient's pulse rate and blood pressure also should be monitored if symptoms emerge after initiation of treatment. Patients may be instructed to perform punctal occlusion after administering the drops to reduce systemic absorption. Depression or anxiety may be experienced in some patients, and sexual dysfunction may be initiated or exacerbated. Ocular adverse effects may include blurred vision, eye ache, and corneal anesthesia.

Drug Category: Adrenergic agonists

Alpha2-adrenergic agonists work by decreasing aqueous production. Systemic adverse effects include dry mouth, fatigue, and drowsiness. Ocular adverse effects include allergic (follicular) conjunctivitis and contact dermatitis.

Of this class, the alpha2-selective agonist, brimonidine, is used most commonly to treat POAG. Apraclonidine also is alpha2-selective but is believed to have more of an allergic potential; therefore, it is used less commonly as a long-term medication.

Drug Category: Less-selective sympathomimetics

These less-selective adrenergic drugs increase outflow of aqueous humor through the trabecular meshwork and possibly through the uveoscleral outflow pathway, probably by a beta2-agonist action. Up to one third of patients will not respond to these drugs.

Less-selective adrenergics, such as epinephrine and dipivefrin, also can have a significantly higher allergic component and other substantial adverse effects, such as exacerbation of hypertension, angina, palpitations, or cystoid macular edema (CME). These less-selective agents are used infrequently.

Drug Category: Carbonic anhydrase inhibitors

Reduce secretion of aqueous humor by inhibiting carbonic anhydrase (CA) in the ciliary body. In acute angle-closure glaucoma, administer systemically; apply topically in patients with open-angle glaucoma. These drugs are less effective, and their duration of action is shorter than many other classes of drugs. Adverse effects are relatively rare but include superficial punctate keratitis, acidosis, paresthesias, anorexia, nausea, depression, dysgeusia, and lassitude.

Oral agents, such as acetazolamide and methazolamide, primarily are used only for the treatment of refractory POAG and secondary glaucomas because they have increased systemic adverse effects. However, oral CAIs can have a slightly greater effect than topical CAI medications and are appropriate to use in certain clinical situations. The mechanism of IOP reduction is similar to other CAIs, being accomplished by reduction of bicarbonate accumulation in the posterior chamber, with a resultant decrease in sodium and associated fluid movement linked to the bicarbonate ion. An additional IOP-lowering effect exists by the creation of a relative metabolic acidosis.

Drug Category: Beta-blocker/carbonic anhydrase inhibitor combination

Combination solution may further decrease aqueous humor secretion compared to each solution used as monotherapy.

Drug Category: Prostaglandin analogs

Increase uveoscleral outflow of aqueous. One mechanism of action may be through induction of metalloproteinases in the ciliary body, which breakdown the extracellular matrix, thereby reducing resistance to outflow through the uveoscleral pathway. Can be used in conjunction with beta-blockers, alpha-agonists, or topical CAIs. Many patients respond well to these agents; other patients do not respond at all. Adverse effects include conjunctival hyperemia, iris pigmentation, CME, and uveitis.

Drug Category: Miotic agents (parasympathomimetics)

Miotics work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of aqueous through traditional pathways. Miosis results from action of these drugs on the pupillary sphincter. Adverse effects include brow ache, induced myopia, and decreased vision in low light. These agents are used less commonly today since the advent of newer drugs with fewer adverse effects.

Pilocarpine is one of the more commonly used agents in this class. Less frequently used miotics include phospholine iodide (0.03%, 0.06%, 0.125%, 0.25% qd/bid) and carbachol (0.75%, 1.5%, 3% tid/qid).

Drug Category: Hyperosmotic agents

These agents are used infrequently, most commonly to reduce extremely elevated IOP in acute situations of angle-closure or certain secondary glaucomas, or selectively as a preoperative measure before intraocular surgery.

Osmotics lower IOP by increasing the osmotic gradient between the blood and ocular fluids, resulting in loss of water from the eye (especially the vitreous) into the hyperosmotic blood plasma, with concomitant lowering of IOP, but an increase in intravascular volume. Therefore, care should be used in any patient with cardiac, renal, or hepatic abnormalities.

Systemic adverse effects include nausea, vomiting, headache, increased thirst, chills, fever, confusion or disorientation, electrolyte imbalances, and urinary retention.