Glaucoma

Mechanisms of Glaucoma

The primary causes of glaucomatous optic neuropathy are unknown. The disorder affects the individual axons of the optic nerve, which may die by apoptosis. Various theories to explain the possible role of elevated IOP in glaucomatous optic neuropathy include:
Mechanical compression theory suggesting that elevated IOP causes a rearward curving or 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.

Various vascular theories proposing that cell death is triggered by ischemia – whether induced by elevated IOP or other primary cause.

Genetic theories suggest that cell death is triggered by genetic predisposition. Substances may be released into the eye, after the death of individual axons, that cause a secondary reaction of apoptosis in neighboring cells, including glutamate (a neurotransmitter that may cause excitotoxicity), calcium, nitric oxide, and free radicals.

Factors that may play a role in the development of primary open-angle glaucoma, the most common form of glaucoma, include a history of vasospasm and vascular disorders ranging from migraine headaches, cardiovascular disease, diabetes, systemic hypertension and arteriosclerosis, to systemic hypotension associated with decreased perfusion.

Secondary Causes of Glaucoma:

• Exfoliation syndrome
• Pigment dispersion syndrome (pigmentary glaucoma) occurs when pigment from the iris flakes off and blocks the meshwork. This slows fluid drainage and increases IOP.
• Lens-induced glaucoma
• Uveitis and other ocular inflammatory diseases
• Intraocular tumors
• Raised episcleral venous pressure
• Prolonged or excessive use of topical or systemic corticosteroids
• Axenfeld-Rieger and other syndromes
• Complications of eye surgery or advanced cataracts and traumatic eye injuries

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Types of Glaucoma

Glaucomatous disorders are classified into different types. The most frequently diagnosed types are primary open-angle, angle-closure and normal-tension, or low-tension, glaucoma.

People who maintain elevated pressures in the absence of nerve damage or visual field loss exist as well. They are considered at risk for glaucoma and have been termed glaucoma suspects or ocular hypertensives.

Early diagnosis is the key to successful management of all types of glaucoma. Treatment strategies generally entail IOP-lowering drops, but may include trabeculectomy or other surgery as well as newer, neuroprotective approaches.

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Primary Open-Angle Glaucoma

Primary open-angle glaucoma (POAG) is a major worldwide health problem. It is usually non-symptomatic and progressive in nature, and is one of the leading preventable causes of blindness in the world. With early screening and treatment, POAG can usually be diagnosed and its progress stopped before significant vision loss occurs.

POAG is distinctly a multifactorial optic neuropathy that is chronic and progressive with a characteristic loss of optic nerve fibers and cupping and atrophy of the optic disc. The loss of optic nerve fibers is associated with open anterior chamber angles, visual field abnormalities, and IOP that is too high for the continued health of the eye.

Elevated IOP is a risk factor associated with the development of POAG but it is not the disease itself. As with other forms of glaucomatous neuropathies, the exact cause of POAG is not known. Many risk factors have been identified, including elevated IOP, family history, race, age older than 40 years, and myopia. Elevated IOP is the most studied because it is the most clinically treatable risk factor for glaucoma.

Theories explaining how IOP may initiate glaucomatous damage fall into two major camps divided between the possible causative factors of vascular compromise and mechanical dysfunction. One possible explanation is the onset of vascular dysfunction causing ischemia to the optic nerve. Another theory is that mechanical dysfunction via the cribriform plate compresses the axons and impairs flow. Other contemporary hypotheses of possible pathogenic mechanisms include:

• Excitotoxic damage from excessive retinal glutamate
• Deprivation of neuronal growth factors
• Peroxynitrite toxicity from increased nitric oxide synthase activity
• Immune-mediated nerve damage
• Oxidative stress

The exact role of IOP 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 hotly debated in the clinical literature.

IOP is the only clinical risk factor that has been successfully managed to date. Several studies have shown the incidence of new onset of glaucomatous damage in previously unaffected patients to be about:

• 2.6-3% for IOPs in the range of 21-25 mm Hg
• 12-26% incidence for IOPs 26-30 mm Hg
• 42% for those higher than 30 mm Hg

The Ocular Hypertension Treatment Study (OHTS) found that 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. The study found that IOP-lowering therapy reduced the incidence of POAG in trial participants by more than 50% after 5 years, from 9.5% incidence in the observation group to 4.4% in the treatment group

Patients with elevated IOP should not, however, be thought of as homogeneous. Several studies have shown that as IOP rises above 21 mm Hg, the number 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, for example. Before initiating treatment based on a specific IOP measurement, the following factors may be considered:

• Disc cupping and nerve fiber layer losses of up to 40% have been shown to occur before actual visual field loss has been detected. Visual field examinations, therefore, cannot be the sole tool used to determine when a patient has begun to sustain glaucomatous damage.
• Effect of corneal thickness has on accuracy of IOP measurements
• Variability of tonometry measurements between different examiners (found to be about 10% in studies)
• Diurnal variation of IOP (often highest in the early morning hours)

In cases where POAG is associated with increased IOP, the cause for the elevated IOP is generally accepted to be decreased outflow of aqueous humor through the trabecular meshwork. Increased resistance to flow may be caused by:

• Obstruction of the trabecular meshwork by foreign material
• Loss of trabecular endothelial cells
• Reduction in trabecular pore density and size in the inner wall endothelium of the Schlemm canal
• Loss of giant vacuoles in the inner wall endothelium of the Schlemm canal
• 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
• Oxidative damage to the meshwork

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Angle-Closure Glaucoma

Angle-closure glaucoma (ACG) is a condition in which the iris is apposed to the trabecular meshwork at the angle of the anterior chamber of the eye. Angle-closure relates to anatomic factors in the anterior segment (shallow anterior chamber, crowded drainage angle, pupil block) compounded by pathophysiologic events. The iris may be pushed forward into contact with the trabecular meshwork, as in pupillary block or plateau iris, or it may be pulled anteriorly, as occurs with other inflammatory conditions. The position of the iris in either case causes the normally open chamber angle to close. Aqueous humor that should drain out of the anterior chamber is trapped inside the eye. Pain, blurred vision, and nausea may occur if the ensuing rise in pressure is sudden.Damage occurs potentially both to outflow pathways and to the optic nerve head. This causes a dramatic and painful rise in IOP. If closure of the angle occurs suddenly, symptoms are severe and dramatic. Acute ACG is an emergency and immediate treatment is essential to prevent damage to the optic nerve and loss of vision. If closure occurs intermittently or gradually, ACG may be confused with chronic open-angle glaucoma. Intermittent episodes of ACG over a long period of time will cause glaucomatous damage to the optic nerve.

The most common cause of ACG is pupillary block. Normally, aqueous humor is made by the ciliary epithelial cells in the posterior chamber and flows through the pupil to the anterior segment. Here it drains out of the eye through the trabecular meshwork and Schlemm canal. If contact happens between the lens and the iris, aqueous accumulates behind the pupil, increasing posterior chamber pressure and forcing the peripheral iris to shift forward and block the anterior chamber angle. The anterior surface of the iris may be apposed to the posterior surface of the cornea or to the trabecular meshwork. This blockage causes accumulation of aqueous in the anterior chamber and an acute rise in IOP.

Plateau iris is a condition in which anterior insertion of the iris to the ciliary body causes the anterior chamber angle to become occluded on dilation of the pupil. The iris may insert on the anterior edge of the ciliary body, close to the trabecular meshwork. This may cause the patient to have genetically narrow angles despite a normal anterior chamber depth. The iris also may appear unusually flat, not bowed as might be expected in ACG. A diagnosis of plateau iris can be confirmed with ultrasound biomicroscopy.

Patients with hyperopic eyes showing shallow anterior chambers and narrow angles are predisposed to develop ACG. Dilation of the eye may precipitate an attack of acute ACG because the peripheral iris relaxes when dilated to mid-position. When the iris is relaxed, it may bow anteriorly and maximize iris-lens apposition, possibly causing pupillary block.

Some medicines have been implicated in causing acute ACG. These include sulfa-derivative medications such as acetazolamide, sulfamethoxazole, and hydrochlorothiazide. A newer sulfa-derivative medication, topiramate, which blocks glutamate receptors and is labeled for use in treating seizures, has also been associated with ACG. The presumed mechanism of angle closure involves swelling of the ciliary body with anterior displacement of the lens-iris diaphragm. Stopping the medication is effective in treating this condition and requires a high index of suspicion by the treating physician.

Other mechanisms that can cause the iris-lens diaphragm to be pushed forward may cause ACG. A space-occupying lesion such as a tumor or swelling associated with ciliary body inflammation may cause the iris to block the trabecular meshwork, is one example. Other causative factors include central retinal vein occlusion, placement of a scleral buckle, history of panretinal photocoagulation, and nanophthalmos.

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Normal-Tension & Low-Tension Glaucoma

People can develop optic neuropathy of glaucoma in the absence of documented elevated IOP. Patients who do not have elevated IOP but glaucomatous optic discs or visual fields may have normal-tension glaucoma (NTG), or low-tension glaucoma (LTG). This is a diagnosis of exclusion (after other causes for optic neuropathy, such as temporal arteritis, have been investigated and ruled out).NTG is a chronic optic neuropathy that affects adults. Its clinical characteristics are similar to POAG, including optic disc cupping and visual field loss, with the exception of a consistently normal IOP of less than 22 mm Hg. Patients with NTG experience a chronic loss of retinal ganglion cells (RGC) due to a genetic hypersensitivity to IOP.

Research studies show that NTG is associated with a variety of vasospasm and ischemic disorders and conditions including migraine, peripheral vasospasm and Raynaud syndrome, systemic vascular disease including atherosclerotic disease, systemic nocturnal hypotension, autoimmune disorders, and sleep apnea.

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Epidemiology & Cost of Glaucoma

Glaucoma afflicts between 5 and 6 million Americans, or 4 to 10% of the total population older than 40 years in the United States. Without detectable signs using present-day clinical testing, only one half of the people who have glaucomatous damage may be aware that they have the disease. It is a leading cause of irreversible blindness, second only to macular degeneration. Approximately 120,000 people in the U.S. are blind from glaucoma, accounting for 9% to 12% of all cases of blindness in the U.S. Glaucoma accounts for over 7 million visits to physicians each year.

In the United States, POAG afflicts more than 2.3 million people aged 40 years and older.

Up to 15-25% of patients with POAG experience LTG. According to the Baltimore Eye Study, 50% of individuals with glaucomatous disc and visual field changes had an IOP of less than 21 mm Hg on a single visit, and 33% had an IOP of less than 21 mm Hg on 2 measurements.

Fewer than 10% of total U.S. glaucoma cases, or about 500,000 persons, are due to ACG.

The total number of suspected cases of glaucoma worldwide is estimated to be around 65 million people. Of these cases, about 85% are undiagnosed, but when it is diagnosed, it is primarily POAG. Recent studies estimate that between 40% and 68% of glaucoma cases diagnosed worldwide are POAG. The remaining cases have ACG or some level of ocular hypertension.

Glaucoma is the second leading cause of blindness worldwide. Glaucoma accounts for 10 million, or about 12%, of the estimated 83 million bilaterally blind people worldwide. Blindness is 10 times higher in the developing than in the developed world. POAG is responsible for almost half (46%) of the irreversible blindness from glaucoma worldwide.

The incidence POAG and ACG are different in diverse geographic areas of the world. Asia, for example, has much higher rates and accounts for a disproportionate amount of the worldwide glaucoma burden: 60% of all cases overall and 80% of angle-closure.

The risk of blindness is much greater for patients with ACG than POAG even though there are fewer cases. About 10% of POAG patients are bilaterally blind, but the figure for ACG is about 25%. More people are blind from ACG, even though it is far less common.

Cost of Glaucoma

A number of recent studies have measured the larger costs of the disease to society. In the U.S., a study utilizing Medicare data estimated the lifetime cost of glaucoma-related vision impairment at $9,200 per person. Interestingly, about 80% of this figure relates to costs not directly related to visual impairment itself but to the increased rates of depression, hip fractures, and home health care associated with glaucoma vision loss.

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Risk Factors

Age

Age is a major risk factor in the development of glaucoma. Everyone older than 40 is at increased risk of the disorder. About 2% of the population age 40-50 and 8% over age 70 have elevated IOP. POAG is found to be more prevalent in the aging population, even after compensating for the fact that mean IOP slowly rises with increasing age. The incidence of primary ACG also increases as the lens enlarges, and the depth and volume of the anterior chamber decrease. In fact, people over age 60 are six times more likely to develop glaucoma, and 15% of all United States residents are affected by the seventh decade of life. For African-Americans, the increase in risk becomes apparent earlier, soon after age 40. LTG patients tend to be older than POAG patients.

Genetics

The most common type of glaucoma, primary open-angle glaucoma, may be hereditary. Glaucoma may have a genetic link, meaning a defect in one or more genes may cause certain individuals to be more susceptible to the disease. There are currently studies underway evaluating whether there are genes that are associated with primary angle-closure suspect, primary angle-closure, and primary angle-closure glaucoma. Once such genes are identified, it may be possible to predict more accurately the future clinical course of patients with primary angle-closure suspect, primary angle-closure, and primary angle-closure glaucoma, and it may be possible to prevent patients from going blind secondary to primary angle-closure glaucoma.

Race

People of African descent are more likely to develop glaucoma. African-Americans are six to eight times more likely to develop glaucoma than Caucasians, and they are more likely to suffer permanent blindness as a result. 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. The Baltimore study, and others, 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 under-diagnosis 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.

Prevalence of POAG is 3 to 4 times higher in people of African descent than in Caucasians. Studies show that, in addition, people of African descent 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 population of people of African descent as compared with Caucasian controls.

Asians, and Eskimos, have a higher incidence of ACG than Caucasian populations. The reasons for this are not clear, but Dr. Harry Quigley and other experts argue that physiologic factors such as shallow anterior chamber, narrow angle, smaller eyes (hence more females than males) and older age (larger crystalline lens increasing anterior segment crowding) may be involved.

Medical Conditions

Vascular risk factors and the role of optic nerve perfusion may be of importance. The blood supply to the optic nerve, the axonal or ganglion cell metabolism, and the lamina cribrosa extracellular matrix may play a role. This is especially important in a subgroup of individuals with low-tension glaucoma who have progressive disease despite IOP of less than 21 mm Hg.

Diabetes increases the risk of developing glaucoma.

Structural changes and abnormalities of the eye can lead to secondary glaucoma. For example, pigmentary glaucoma is a form of secondary glaucoma caused by pigment granules being released from the back of the iris. These granules can block the trabecular meshwork. Retinal detachment, eye tumors, eye inflammations such as chronic uveitis and iritis, and certain types of eye surgery also may trigger secondary glaucoma.

Myopia also is a risk factor for glaucoma.

Hyperopes are at increased risk for acute ACG because their anterior chamber angles are relatively shallow.

Other anecdotal medical condition risk factors include obesity, excessive smoking or alcohol use, routine use of coffee and a history of stress and anxiety.

Physical Injuries

Severe trauma, such as being hit in the eye, may cause secondary open angle glaucoma. Injury can also dislocate the lens, closing the drainage angle. This type of glaucoma can occur immediately after the injury or years later. Blunt traumas that “bruise” the eye or injuries that penetrate the eye can damage the eye’s drainage system, leading to glaucoma. The most common cause is sports-related injuries such as baseball or boxing.

Corticosteroid Use

Some evidence links prolonged use of corticosteroids to the risk of getting secondary glaucoma. A study demonstrated a 40% increase in the incidence of ocular hypertension and open-angle glaucoma in adults who require approximately 14 to 35 puffs of steroid inhaler to control asthma. This is a very high dose, only required in cases of severe asthma.

Gender

Research findings on the link between gender and incidence of glaucoma 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. Among Caucasian patients, the incidence of ACG is reported to be 3 times higher in women than in men. In persons of African descent patients, men and women are affected equally. NTG seems to be more prevalent in women than men according to some studies.

Clinical Glaucoma Bibliography

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