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Glaucoma: Changing Concepts and Future Directions

      Important concepts about glaucoma have evolved during the past few decades. Glaucoma is a family of diseases not defined by a specific intraocular pressure but rather as an optic neuropathy that can occur at any intraocular pressure depending on the optic nerve susceptibility of the individual person. Increased risk factors for idiopathic open-angle glaucoma include advancing age, black race, a family history of glaucoma, and increased intraocular pressure. The primary-care physician is in the prominent position of recognizing patients with increased risk factors or suspicious eye findings who should be referred to an ophthalmologist. Topically applied ophthalmic medications have systemic side effects that must be recognized and monitored by the primary-care physician. In the United States, glaucoma is usually treated with topically applied medications; laser or surgical therapy is done if medical treatment fails. The National Eye Institute is conducting multicenter studies to confirm whether this is still the most appropriate strategy for this common disease.
      IOP (intraocular pressure)
      Glaucoma is the second most common cause of blindness in the United States and the most common cause of blindness among blacks. Almost 2 million people in the United States have glaucoma, and only half of them are aware that they have the disease. The risk factors for the development of glaucoma include increased intraocular pressure (IOP), advancing age, black race, and family history of glaucoma; possible risk factors include severe myopia, cardiovascular disease, diabetes, migraine, hypertension, and vasospasm (Table 1).
      • Leske MC
      The epidemiology of open-angle glaucoma: a review.
      Table 1Risk Factors for Glaucoma
      • Advancing age
      • Black race
      • Increased intraocular pressure
      • Large optic cup-disk ratio
      • Family history of glaucoma
      • Severe myopia
      • Diabetes
      • Cardiovascular disease
      • Migraine
      • Hypertension
      • Vasospasm
      Important concepts of the disease process that have evolved during the past several years have given the primary-care physician a central role in recognizing patients with glaucoma who should be referred to an ophthalmologist. Potent drugs now available for treatment require the primary-care physician to interact with the ophthalmologist in order to monitor for systemic side effects.

      Definition of Glaucoma

      Glaucoma is best defined as an optic neuropathy with characteristic optic nerve head and associated visual field changes. The healthy optic nerve has approximately 1.2 million nerve fibers that originate in the ganglion cells of the retina and traverse as retinal nerve fibers in an arcuate pattern to enter the optic nerve head. Most optic nerves have a central depression (a cup), and the tissue between the border of the cup and the disk is the neuroretinal rim. On examination of a patient for glaucoma, both eyes should be assessed because healthy optic nerves are usually symmetric; asymmetric cups may be a sign of glaucoma.
      The characteristic nerve head findings in glaucoma are visible with the direct ophthalmoscope and include increased size of the optic cup with an increased cup-to-disk ratio, thinning of the neuroretinal rim, progressive loss of neural rim tissue, occasional disk hemorrhage, increased pallor of the remaining neural tissue, increased visibility of the pores of the lamina cribrosa, and displacement of retinal vessels to the margin of the disk. The most telling feature is the progression of neural damage over time, which is best determined by comparative disk photographs or drawings on successive visits. Characteristic changes in the visual field correspond to the optic nerve changes because of the strict anatomic nerve pattern in the eye (Fig. 1).
      Figure thumbnail gr1
      Fig. 1A, Optic disk and nerve fiber layer defect in patient with early glaucoma. Optic cup extends toward optic rim, with thinning of neuroretinal tissue. B, Superior arcuate defect in visual field corresponding to optic disk damage in A.
      Although increased IOP was synonymous with glaucoma in prior decades, this is no longer tenable. Only about 10% of the 5 to 10 million patients with increased IOP (22 mm Hg or higher) have glaucoma. Increased IOP alone has poor sensitivity, poor specificity, and poor predictability for glaucoma damage. About one-sixth of patients with glaucoma have “normal” IOP (less than 22 mm Hg).
      Two mechanisms of optic nerve damage in glaucoma have been proposed: a mechanical theory and a vascular theory. The mechanical theory suggests that distortion and displacement of the lamina cribrosa in the optic nerve cause damage to the axons, resulting in blockade of axonal transport and later axonal death. The vascular theory proposes that ischemia causes loss of and the later characteristic appearance of glaucomatous optic neuropathy. These theories are not necessarily mutually exclusive. A third theory, with suggested mechanisms of retinal ganglion cell death, has also been proposed.
      • Fechtner RD
      • Weinreb RN
      Mechanisms of optic nerve damage in primary open angle glaucoma.

      Classification of Glaucoma

      Glaucoma is not one disease but rather a large family of diseases (Table 2). Primary (idiopathic) open-angle glaucoma is the most common type; it accounts for 60 to 70% of all cases and is the focus of this review. It is generally bilateral, but not necessarily symmetric, with a characteristic glaucomatous optic neuropathy and visual field damage. Onset is usually during adulthood. The anterior chamber has normal depth and appearance. Specific secondary causes of open-angle glaucoma are occasionally identified and include pigment dispersion syndrome, exfoliation syndrome, and corticosteroid responsiveness. As the mechanisms of disease are better defined, most cases of glaucoma will be more accurately classified.
      Table 2Classification of Glaucoma
      Open-angle glaucoma
      • Primary (idiopathic)
        • Cause of trabecular obstruction unknown
      • Secondary
        • Trabecular obstruction due to pigment, exfoliation material, trauma, corticosteroids, and other entities
      • “Glaucoma suspect”
        • Increased intraocular pressure or disk or visual field suggestive of glaucoma
      • Normal-tension glaucoma
        • “Normal” intraocular pressure
      • Angle-closure glaucoma
        • Primary
          • With relative pupillary block (for example, narrow-angle closure)
          • Without pupillary block (for example, plateau iris)
        • Secondary
          • With pupillary block (for example, swollen lens, secluded pupil)
          • Without pupillary block (for example, lens iris diaphragm pushed forward or anterior segment processes pulled forward)
      • Childhood glaucoma
        • Primary congenital glaucoma
          • Poorly formed or incomplete regression of trabecular meshwork
        • Secondary glaucoma associated with congenital ocular or systemic abnormalities
      Although the exact cause of open-angle glaucoma is unknown, there is a demonstrated increased resistance to outflow of the normal aqueous humor out of the eye through the trabecular meshwork. This progressive resistance to outflow results in a gradual increase in IOP, higher than the person's baseline, and causes glaucomatous optic nerve damage in susceptible patients. Because the early stages of the disease cause minimal loss of visual field, patients are unaware of the disease. The pace of progressive damage varies with the individual patient, but most patients do not notice visual loss until it is far advanced. The visual loss and optic nerve damage are generally irreversible.
      A “glaucoma suspect” is an adult who has a normal visual field but either an increased IOP or an optic disk appearance suggestive of glaucoma. Such persons have an increased risk for the development of glaucoma and must be reexamined at regular intervals. A family history of visual loss due to glaucoma increases the person's risk for nerve damage.
      A person with normal-tension (or low-tension) glaucoma has characteristic optic nerve changes of glaucoma and accompanying visual field damage but has a “normal” IOP (less than 22 mm Hg). These persons represent about one-sixth of patients with glaucoma. They may have an inherent weakness of their optic nerve or some vascular process that causes optic neuropathy. Whether these patients respond to any therapy is debatable; however, their treatment is similar to that of other patients with glaucoma, but the aim is toward a very low target IOP.
      Angle-closure glaucoma is the second most common type of glaucoma in the United States, and approximately 10% of patients with glaucoma have this variant. It is characterized by an appositional closure of the drainage angle of the eye and usually occurs suddenly when the pupil is dilated, as in a darkened room or with drugs. Because the fluid cannot leave the eye, the IOP may increase quickly and cause damage to the optic nerve. This type of glaucoma is characterized by variable and severe pain and nausea that cause the patient to seek medical care, and, occasionally, it is mistaken for an acute abdomen. Ironically, most patients are unaware that they have the narrow anterior chamber angles that predispose them to angle closure. These persons should not take the prescribed and over-the-counter medications that have the warning “avoid with glaucoma.” Such medications cause pharmacologic dilatation of the pupil. With age, most patients have progressive narrowing of the anterior chamber because of the increased size of the lens in the eye. Angle-closure glaucoma is most common in patients with hyperopia (farsightedness) and in middle-aged or elderly women, and laser iridotomy is necessary. Multiple other entities cause secondary angle-closure glaucoma. These secondary glaucomas require management of the underlying condition and the IOP.
      Childhood glaucoma manifests usually within days after birth; characteristics are watering, photophobia, hazy corneas, and an enlarged eye. It is more common in male than in female infants and can be unilateral or bilateral. The drainage angle usually has a structural defect. A later onset occasionally occurs in children or adolescents, and then it follows a course similar to idiopathic open-angle glaucoma.

      Idiopathic (Primary) Open-Angle Glaucoma

      The prevalence of elevated lOP and open-angle glaucoma increases dramatically with advancing age in all races. Two to 7% of persons older than 70 years of age have open-angle glaucoma. In black persons in comparison with white persons, glaucoma is more prevalent, occurs at an earlier age, is more advanced when diagnosed, and causes blindness 3 to 4 times more often. Moreover, black persons seem to have more susceptibility to damage of the optic nerves, a higher prevalence and earlier onset of increased lOP, lower utilization of resources for detection and treatment, as well as poorer compliance with therapy and less successful response to treatment.
      American Academy of Ophthalmology Quality of Care Committee Glaucoma Panel
      • Sommer A
      • Tielsch JM
      • Katz J
      • Quigley HA
      • Gottsch JD
      • Javitt J
      • et al.
      Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Study.

      Diagnosis

      Although increased IOP is a major risk factor for the development of glaucoma, such a finding alone does not successfully determine, per se, the diagnosis of glaucoma.
      • Shields MB
      The challenge of screening for glaucoma [editorial].
      • Sommer A
      Intraocular pressure and glaucoma.
      Nonetheless, persons with elevated IOP have an increased risk for the development of glaucomatous optic nerve damage. Current screening programs for glaucoma are educational and increase awareness, but little scientific or economic evidence supports their usefulness.
      • Tielsch JM
      • Katz J
      • Singh K
      • Quigley HA
      • Gottsch JD
      • Javitt J
      • et al.
      A population-based evaluation of glaucoma screening: the Baltimore Eye Survey.
      For a person who has not previously undergone screening, the possibility of identifying a new case of glaucoma based on one screening test for lOP is approximately 0.15% (by using 21 mm Hg or higher as abnormal). In addition, a single lOP reading would overlook 30 to 50% of patients with actual glaucoma.
      • Le Blanc R
      Value of intraocular pressure measurement as a screening tool for glaucoma.
      Screening for glaucoma on the basis of lOP alone may be counterproductive because of the overlap of IOP distribution in patients with and without glaucoma and the false assurance a person may have after a single reading. Glaucoma screening is best accomplished by an assessment of the optic disk and by visual field testing, and these tests are difficult for population screening.
      Studies have shown that 50% of patients with undiagnosed glaucoma are being assessed regularly by primarycare physicians.
      • Sommer A
      • Tielsch JM
      • Katz J
      • Quigley HA
      • Gottsch JD
      • Javitt J
      • et al.
      Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Study.
      • Tielsch JM
      • Katz J
      • Singh K
      • Quigley HA
      • Gottsch JD
      • Javitt J
      • et al.
      A population-based evaluation of glaucoma screening: the Baltimore Eye Survey.
      Routine eye examinations in high-risk persons may be the most cost-effective approach. Factors to consider when referring a patient to an ophthalmologist include age, race, family history of glaucoma, and no recent eye examination.
      The best approach for evaluating the optic disk is by having the patient's pupil dilated, as in a darkened room or with pharmacologic agents (for example, 2 ½% phenylephrine). The dioptric power of the direct ophthalmoscope is set at zero, and the patient fixates at a distant target while the examiner uses his thumb to lift the patient's upper lid. The examiner should be at a 15° angle nasal to the patient's line of sight. The optic nerve can be drawn or photographed for future comparison.
      The best measure of optic nerve function is an assessment of the visual field performed with a manual or automated perimeter. The normal visual field of each eye spans up to 160° horizontally and up to 135° vertically. Characteristic changes of glaucoma include loss of the nasal field (nasal scotoma), loss of the central field (paracentral scotoma), and loss of the midperipheral visual fields (arcuate scotoma).
      In monitoring a patient with glaucoma, the ophthalmologist repeats the optic nerve and visual field assessments at regular intervals because any progression in either the optic disk or the visual field indicates the need for additional therapy. Unfortunately, optic nerve damage has already occurred by the time early visual field abnormalities are detected. Although glaucoma is best detected on the basis of the optic disk appearance, it is best followed up by periodic visual field testing; however, this type of testing is tedious for many patients and occasionally unreliable.

      Treatment

      Glaucoma is a chronic disease that lacks a cure. The disease itself continues to progress. The treatment goal in idiopathic open-angle glaucoma is to stabilize the visual field loss and the optic nerve damage once the diagnosis has been made. Currently, the only modifiable risk factor is the lOP. Past visual field damage predicts future damage unless the lOP is lowered. On the basis of the initial lOP, the ophthalmologist chooses a “target pressure,” which will vary among patients and may change in the same patient during the course of follow-up examination based on reassessment of progression of optic disk or visual field changes. Medical, laser, or surgical therapy is used to achieve this target pressure. Currently, no a priori method is available to determine a target pressure precisely, although most ophthalmologists aim for a 20 to 30% reduction in the initial pressure.
      Most topically applied glaucoma medications affect the autonomic nervous system and influence aqueous production or the resistance to outflow in various ways. Medications, proposed mechanisms of actions, and some of the local and systemic side effects are summarized in Table 3. After instillation of the drops, eyelid closure and nasolacrimal occlusion with a finger may help to reduce the systemic side effects of topically applied medications. The responsiveness of the individual patient to therapy varies. Compliance is a major problem; one-third of patients fail to comply completely with therapy.
      Table 3Drug Therapy for Glaucoma
      • Topically applied β-adrenergic antagonists
        • Nonselective: timolol, levobunolol, carteolol, metipranolol
        • Selective: betaxolol
        • Mechanism of action: decrease in aqueous secretion during waking hours by blocking β-receptors
        • Side effects: congestive heart failure, bronchospasm, bradycardia, confusion, depression, impotence, worsening of myasthenia gravis
      • Topically applied adrenergic agonists
        • Adrenergic agonists: epinephrine, dipivefrin
        • Mechanism of action: increased aqueous uveoscleral outflow and possible trabecular meshwork outflow
        • Side effects: increased blood pressure, tachyarrhythmias, tremor, headache, anxiety, burning on instillation, conjunctival infection, allergic conjunctivitis, pupillary dilatation
        • Selective α2-agonist: apraclonidine
        • Mechanism of action: decrease in aqueous secretion
        • Side effects: allergic reactions, dry mouth
      • Topically applied cholinergic agonists (miotics)
        • Direct acting: pilocarpine (Pilopine-HS Gel, Ocusert-Pilo), carbachol
        • Indirect acting: echothiophate, demecarium
        • Mechanism of action: enhanced aqueous outflow through trabecular meshwork by contracting ciliary muscles
        • Side effects: miosis, increased myopia, eye or brow pain, decreased vision, bronchial secretions, nausea, diarrhea, apnea
      • Topically applied carbonic anhydrase inhibitors
        • Dorzolamide
        • Mechanism of action: decreased aqueous humor formation
        • Side effects: stinging, burning, blurred vision, conjunctivitis, bitter taste
      • Systemic carbonic anhydrase inhibitors
        • Acetazolamide, methazolamide, dichlorphenamide
        • Mechanism of action: decreased aqueous production by inhibiting ion transport in the pigmented ciliary epithelium
        • Side effects: malaise, anorexia, depression, paresthesias, electrolyte abnormalities, renal calculi, blood dyscrasias
      • Prostaglandins (in the future)
        • Latanoprost
        • Mechanism of action: increased uveoscleral flow by dilating blood vessels
        • Side effects: change in iris color (20%), conjunctival vasodilatation, bronchoconstriction
      Laser trabecular surgical treatment substantially reduces lOP in about 75% of patients; however, 50% will experience a loss of effect over 5 years. With laser therapy, there is a low risk of causing an increase in the lOP, necessitating an emergent glaucoma filtration operation. Laser therapy is applied to the trabecular meshwork for 180° or 360°. The mechanism of effect remains elusive, although such therapy increases aqueous outflow. Glaucoma filtering surgical treatment can have a high rate of success but also has associated risks of infection, hemorrhage, cataract formation, persistent low pressure (hypotony), or failure.
      In the United States, therapy for glaucoma is usually instituted with a topically applied β-blocker drop initially, and then dorzolamide or pilocarpine is added if necessary. Epinephrine preparations rarely increase benefit. The recently introduced topical dorzolamide therapy has circumvented the multiple metabolic problems of oral carbonic anhydrase inhibitors. Laser therapy is done, if needed, and glaucoma filtration surgical treatment may be necessary in a small percentage of patients. Progression of the visual field damage is usually a combination of failure of therapy, non-compliance with therapy, and the inexorable progression of the disease. Many patients have continual damage despite compliance with therapy.
      More recently, the target lOP control has been reassessed, and the suggestion is that a lower lOP must be obtained sooner for a better long-term prognosis. Compliance with medication, side effects of medications, and limitations of laser trabeculoplasty are recognized problems, and evidence shows improved stabilization of nerve damage with a very low lOP. The long-term cost-to-benefit analysis is tending to suggest glaucoma filtering surgical treatment as initial therapy for glaucoma, at least in select patients.
      • Migdal C
      • Gregory W
      • Hitchings R
      Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma.
      • Diggory P
      • Franks W
      Medical treatment of glaucoma—a reappraisal of the risks.
      Substantial evidence shows that long-term topically applied glaucoma medications damage the conjunctiva to the degree that glaucoma surgical treatment is less likely to be effective.
      • Sherwood MB
      • Grierson I
      • Miller L
      • Hitchings RA
      Longterm morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients.
      There is a trend among European surgeons to consider glaucoma filtration surgery as the initial treatment of idiopathic open-angle glaucoma, but currently in the United States, this surgical approach is rarely used as the initial treatment. This is a current focus of debate among ophthalmologists.

      Changing Concepts of Glaucoma

      Most types of glaucoma have a heritable component.
      • Lichter PR
      Genetic clues to glaucoma's secrets: the L. Edward Jackson Memorial Lecture; part 2.
      In tense study of chromosomes and genes with three commonly used strategies (candidate gene approach, chromosomal abnormalities, and linkage analysis) has yielded several diseases with a genetic linkage as a possible cause for glaucoma. Unfortunately, idiopathic open-angle glaucoma is much more difficult to analyze because of its characteristic late onset and multifactorial components. In the future, gene therapy may have a role in glaucoma.
      Because the definition and treatment of glaucoma are shifting, the treatment administered to an individual patient may be determined by the era of training or bias of the ophthalmologist. The concept is not as simple as an increased IOP equals glaucoma or a normal lOP rules out glaucoma. Ninety percent of patients with increased lOP on a single screening test do not have glaucoma, and 10 to 50% of patients with actual glaucoma will have normal IOP on a screening test.
      • Shields MB
      The challenge of screening for glaucoma [editorial].
      • Le Blanc R
      Value of intraocular pressure measurement as a screening tool for glaucoma.
      One-sixth of patients with glaucoma will not have an lOP greater than 21 mm Hg.
      • Sommer A
      • Tielsch JM
      • Katz J
      • Quigley HA
      • Gottsch JD
      • Javitt J
      • et al.
      Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Study.
      The most cost-effective approach is to examine high-risk populations, including elderly persons, black persons, persons who have first-degree relatives with glaucoma, and those with severe myopia or vascular disease. The examination should include tonometry, optic disk evaluation, and screening visual field testing.
      • Shields MB
      The challenge of screening for glaucoma [editorial].
      Recent studies necessitate reevaluation of the traditional concept of glaucoma as a disorder of aqueous outflow with secondary damage to the optic nerve. Intrinsic optic nerve abnormalities, especially vascular (for example, peripheral vasospasm or intrinsic vascular disease), could be the underlying cause of many cases of glaucoma;
      • Van Buskirk EM
      • Cioffi GA
      Glaucomatous optic neuropathy.
      in this situation, the IOP is higher than the particular optic nerve can tolerate.
      Currently, lOP is the only feature that can be modified. Many patients have progressive optic neuropathy despite lowering of their IOP with therapy. Their lOP may need to be even lower. Others will have a healthy optic nerve despite years of increased IOP. This multifactorial perspective should encourage physicians to determine other means of treating this optic neuropathy.
      • Van Buskirk EM
      • Cioffi GA
      Glaucomatous optic neuropathy.
      Newer concepts and approaches to treating glaucoma include attempts to improve blood flow to the optic nerve. Therapy may be directed at the retinal ganglion cell bodies or axons themselves with neural protective mechanisms, rescue of damaged neural tissue, or regeneration of damaged neurons. Research continues in these areas.

      Clinical Trials in Glaucoma

      The usual recommendations for the treatment of glaucoma are based on short-term studies. Long-term data are important in assessing quality-of-life issues. Proven long-term clinical effectiveness and outcome of therapy for glaucoma are lacking. Even in the absence of disk or visual field change, most ophthalmologists conclude that therapy is indicated if the lOP is higher than 30 mm Hg. Four prospective randomized clinical studies are currently being sponsored by the National Eye Institute to address these issues.
      The Glaucoma Laser Trial reported that argon laser trabeculoplasty is safe and effective in treating glaucoma.
      Glaucoma Laser Trial Research Group
      The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-Up Study. 7. Results.
      The interpretation of the role of argon laser trabeculoplasty as the initial treatment of glaucoma is still controversial among glaucoma specialists.
      The Advanced Glaucoma Intervention Study is determining whether patients with advanced, progressive glaucoma will benefit more from argon laser trabeculoplasty or glaucoma filtering surgical treatment as the next step after medical therapy alone has failed.
      The Ocular Hypertension Treatment Study is determining whether patients with a high lOP without optic disk or visual field damage might receive long-term benefit if their IOP is lowered in comparison with no treatment.
      The Collaborative Initial Glaucoma Treatment Study is recruiting patients with newly diagnosed glaucoma. Patients are randomized to undergo either initial filtering surgical treatment or standard medical therapy.
      The Early Manifest Glaucoma Trial is sponsored in Sweden. It is attempting to determine how current standard therapy (that is, β-blockers and argon laser trabeculoplasty) compares with no therapy in influencing the long-term course of glaucoma. This most fundamental of studies is extremely important in demonstrating, definitively, the long-term effectiveness of therapy for glaucoma.

      References

        • Leske MC
        The epidemiology of open-angle glaucoma: a review.
        Am J Epidemiol. 1983; 118: 166-191
        • Fechtner RD
        • Weinreb RN
        Mechanisms of optic nerve damage in primary open angle glaucoma.
        Surv Ophthalmol. 1994; 39: 23-42
        • American Academy of Ophthalmology Quality of Care Committee Glaucoma Panel
        Preferred Practice Patterns: Primary Open-Angle Glaucoma. American Academy of Ophthalmology, San Francisco1992
        • Sommer A
        • Tielsch JM
        • Katz J
        • Quigley HA
        • Gottsch JD
        • Javitt J
        • et al.
        Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Study.
        Arch Ophthalmol. 1991; 109: 1090-1095
        • Shields MB
        The challenge of screening for glaucoma [editorial].
        Am J Ophthalmol. 1995; 120: 793-795
        • Sommer A
        Intraocular pressure and glaucoma.
        Am J Ophthalmol. 1989; 107: 186-188
        • Tielsch JM
        • Katz J
        • Singh K
        • Quigley HA
        • Gottsch JD
        • Javitt J
        • et al.
        A population-based evaluation of glaucoma screening: the Baltimore Eye Survey.
        Am J Epidemiol. 1991; 134: 1102-1110
        • Le Blanc R
        Value of intraocular pressure measurement as a screening tool for glaucoma.
        Surv Ophthalmol. 1989; 33: 445-446
        • Migdal C
        • Gregory W
        • Hitchings R
        Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma.
        Ophthalmology. 1994; 101: 1651-1656
        • Diggory P
        • Franks W
        Medical treatment of glaucoma—a reappraisal of the risks.
        Br J Ophthalmol. 1996; 80: 85-89
        • Sherwood MB
        • Grierson I
        • Miller L
        • Hitchings RA
        Longterm morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients.
        Ophthalmology. 1989; 96: 327-335
        • Lichter PR
        Genetic clues to glaucoma's secrets: the L. Edward Jackson Memorial Lecture; part 2.
        Am J Ophthalmol. 1994; 117: 706-727
        • Van Buskirk EM
        • Cioffi GA
        Glaucomatous optic neuropathy.
        Am J Ophthalmol. 1992; 113: 447-452
        • Glaucoma Laser Trial Research Group
        The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-Up Study. 7. Results.
        Am J Ophthalmol. 1995; 120: 718-731