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Introduction
[Figure]: "Schematic of the Eye"

  1. Definition
    1. Group of progressive optic neuropathies with slow progression of retinal ganglion cells
    2. Raised intraocular pressure (IOP) leading to optic nerve damage
    3. IOP elevations due to overproduction and/or (usually) obstruction of aqueous outflow
    4. Will progress to visual field loss and irreversible blindness if untreated
  2. Epidemiology
    1. Second leading cause of blindness worldwide and in USA
    2. Prevalence is 66.8 million worldwide
    3. About 6.8 million, or10%, of these people are blind due to glaucoma
    4. About 2 million persons have glaucoma in USA
    5. About 80,000 persons legally blind from glaucoma (more blacks than whites) in USA
    6. About 900,000 persons are visually impaired from glaucoma in USA
  3. Open Angle
    1. Primary Open Angle (POAG) - cause of decreased aqueous outflow unknown
    2. Secondary - trabecular meshwork resistance increased by pigment, inflammatory debris, increased episcleral venous pressure, etc.
    3. POAG is the most common form of glaucoma in USA
  4. Angle Closure
    1. Primary Angle Closure (PACG) - papillary block due to anatomically shallow angle
    2. Secondary - angle closed by scar, neovascularization, others.
    3. PACG is the most common form among Asian persons
  5. Congenital defects blocking ocular aqueous outflow also occur
  6. Screening for glaucoma (both types) by measuring pressure in eye (tonometry)
  7. Gonioscopy is used to differentiate between the two main types of glaucoma
    1. Gonioscopy involves examination of anterior chamber
    2. The gonioscope lens visualizes the angle between cornea-sclera and the iris

A. Characteristicsnavigator

  1. Trabecular meshwork is open and unobstructed by the iris
  2. Etiology of decreased aqueous outflow (and/or elevated inflow) in POAG is unclear
  3. Epidemiology
    1. Age-adjusted prevalence of 1.55% in USA
    2. Present in 2% of USA population >65 years old, 15% over age 80
    3. 90% of patients are asymptomatic for long periods
  4. Definition
    1. Previously defined as a disease of increased IOP in chambers of eye
    2. Now defined as a set of ocular diseases that cause characteristic, progressive changes in the optic nerve head, visual-field loss, or both
    3. Normal (population mean) IOP is 15.5 mm Hg
    4. POAG IOP is typically >18mm (though not required for diagnosis)
    5. Although unusual, damage to optic nerve can occur with IOP <15.5 mm Hg
    6. Bilateral disease is present in most cases
    7. In general, elevated IOP causes cumulative damage to optic nerve
    8. Result is slow deterioration of vision which may lead to blindness
    9. Visual loss generally asymmetric when it occurs
  5. Patients with raised IOP but no characteristic changes to optic nerve are called glaucoma suspects or ocular hypertensives
  6. Familial disease - relatives of glaucoma patients have 5-6X increased risk of glaucoma
  7. Genes Associated with Glaucoma
    1. About 3% of patients with POAG have mutations in GLC1A gene (myocilin)
    2. GLC1A is a trabecular meshwork induced glucocorticoid response protein myocilin
    3. GLC1A is on chromosome 1
    4. Mutations in GLC1A cause glaucoma through an unclear mechanism
    5. GLC1B is located on chromsome 2 and is associated with elevated ICP
    6. GLC1C on chrom 3 associated with increase ICP
    7. GLC1D and 1E found on chrom 8 and 10 associated with moderately raised ICP
    8. GLC1F found on chrom 7 associated with increased ICP

B. Risk Factorsnavigator

  1. Elevated IOP is most important risk factor
  2. Myopia (near sightedness)
  3. Black race
  4. Sytemic Hypertension
  5. Diabetes
  6. Smoking
  7. Increasing Age
  8. Family history of glaucoma
  9. Other Contributing Factors
    1. Glucocorticoids [11]
    2. Non-Clearing Vitreous Hemorrhage
    3. Ghost cell glaucoma
    4. Hemolytic and hemosiderotic glaucoma

C. Screeningnavigator

  1. Depends on demonstration of increased pressure and/or visual changes
  2. Detection of optic nerve cupping on ophthalmalogic exam
  3. Tonometry screen only ~50% true positives
    1. Overall, ~50% of patients with disease will have pressures <21 mmHg
    2. 5-10% of persons over age 40 have IOP >21 mmHg with normal optic nerves
    3. In general, elevated IOP causes damage to optic nerve
    4. Challenge is in selecting appropriate population to treat
  4. Visual field exam - single eye at a time, either automated or manual
  5. Nerve fiber layer exam (green light with ophthalmascope)
  6. Newer screening exams are being developed

D. Symptoms navigator

  1. Usually only occur late in the course or with acute disease
  2. Night vision initially decreased (may not be noticed)
  3. Depth perception is also lost
  4. Loss of visual fields, nasal before temporal, finally left only with central vision
  5. Blindness
  6. Acute angle closure glaucoma will lead to painful, red eye but open angle will not

E. Signsnavigator

  1. Night vision loss detectable on highly quantitative meters
  2. Nasal visual fields usually affected before temporal (contrast with pituitary adenoma)
  3. Elevated IOP (usually detected on screening with tonometry)
    1. Normal adult intraocular pressure is 15-16mm Hg
    2. Range ±2 standard deviations is 10-21mm Hg, skewed to higher levels
    3. High pressures without optic nerve damage is called ocular hypertension
  4. Changes in Optic Nerve
    1. Increased cupping or excavation
    2. Increased notching
    3. Thinning of neuroretinal (optic nerve) rim
    4. Disc hemorrhages
    5. Loss of retinal nerve fiber layer
    6. Asymmetry of amount of optic nerve cupping between two eyes
    7. Optic nerve pallor is not considered characteristic of glaucoma
  5. Cup to Disk Ratios
    1. Differences in two eyes' cup to disk ratios of 0.2 or greater
    2. Increased cup/disk ratio to >0.5 (only 6% of normal population have elevated ratio)
  6. Slit lamp exam with binocular view is best way to examine optic nerve head

F. Treatment Overview [1,3]navigator

  1. Goal is reduction of ICP
    1. Reduce aqueous humor produciton by ciliary body OR
    2. Increase outflow of aqueous humor through trabecular meshwork or uveoscleral pathway
    3. Create synthetic outflow route surgically
  2. Initiate treatment with new or worsening optic nerve damage or visual field loss
    1. In patients with optic nerve damage, goal ICP is <12 mm Hg
    2. For patients with early or minimal damage, goal ICP is probably <15 mm Hg
  3. Consider treatment in persons without optic nerve damage if:
    1. Elevated ICP
    2. Other risk factors for glaucoma
  4. Medical
    1. Topical agents are generally first line
    2. These agents are concentrated due to brief contact time with eye
    3. Excess drug drains into nasolacrimal duct to systemic circulation
    4. ß-adrenergic blockers are usually given first; reduce aqueous inflow
    5. Prostaglandins are probably the most effective agents; increase aqueous outflow
    6. alpha2-agonists, or topical carbonic anhydrase inhibitor may be added
    7. Oral carbonic anhydrase inhibitors can be added as well
  5. Argon laser trabeculoplasty - 5 year success rate ~50%
  6. Surgical trabeculectomy - most widely used
  7. In USA, above modalities are used in the order listed
  8. Trials ongoing to assess whether initial laser or surgical methods are more appropriate
  9. Once target ICP is achieved, monitor every 3-12 months

G. Medical Therapy [4] navigator

  1. ß-Adrenergic Blocking Agents (see below)
    1. Topical agents are usually used
    2. In some patients, ß1-selective blockers may be preferred (such as betaxolol)
    3. Systemic absorption may be problematic
    4. Concern in chronic obstructive pulmonary disease, asthma, some heart failure patients
    5. Timolol 0.25% or 0.5% (Betimol®) - 1 drop bid 0.25% initially, up to 1 drop bid 0.5%
    6. Levobunolol 0.25% or 0.5% (betagan®) - 1 drop bid 0.25% initially, up to 1 drop bid 0.5%
    7. betaxolol 0.25% (Betoptic®) - 1-2 drops bid
    8. Carteolol 1% (Ocupress®) - 1 drop bid
    9. Metipranolol 0.3% (Optipranolol®) - 1 drop bid
    10. Timolol + Dorzolamide (Cosopt®) - ß-blocker + carbonic anhydrase inhibitor; 1 drop bid
  2. Prostaglandin analogs
    1. Latanoprost (see below)
    2. Travoprost 0.004% (Travatan®) - 1 drop daily each eye in PM
    3. Unaprostone 0.15% (Rescula®) - 1 drop twice daily each eye
    4. Bimatoprost 0.03% (Luigan®) - 1 drop qpm each eye
  3. Latanoprost (Xalatan®) [6]
    1. Prostaglandin F2a analog, increases uveoscleral outflow and thereby decreases IOP
    2. Latanoprost 0.005% solution reduces in IOP 6-8mmHg
    3. Efficacy is at least as good as, or more than, timolol
    4. Can be used with other agents
    5. Up to 15% of patients developed brown pigment in iris after 1 year
    6. Otherwise well tolerated with minimal systemic effects
    7. A few patients have muscle and joint pains
  4. Carbonic Anhydrase Inhibitors
    1. Decrease aqueous humor production
    2. Synergistic activity with ß-blockers
    3. Dorzolamide (Trusopt®) 2% tid - as effective as ß-blockers, reduced side effects [7]
    4. Dorzolamide combined with timolol maleate (Cosept®)
    5. Brinzolamide 1% (Azopt®) drops - better tolerated (less stinging) than dorzolamide [10]
    6. Acetazolamide (Diamox®) - oral, increased renal stones, lethargy, low K+, paresthesia
    7. Methazolamide (Neptazane®) - oral
  5. alpha-2 Adrenergic Agonists
    1. Reduce aqueous production, synergistic with ß-blockers
    2. Useful in preventing acute IOP increaser after laser procedures
    3. Topical sensitivity may limit effectiveness as long term agent
    4. Apraclonidine (Iopidine®) 0.5-1% solutions, tid
    5. Overall, ~20% of patients discontinued use of apraclonidine due to adverse effects
    6. Brimonidine 0.15% (alphagan®) alpha-2 adrenergic selective agonist, 1 drop q8 hours [9]
    7. Brimonidine very well tolerated
    8. Useful in patients who do not tolerate ß-blockers and as add-on therapy
  6. Parasympathomimetics
    1. Pilocarpine (Akarpine®, Adsorbocarpine®, Isopto Carpine®, Piloptic®, Pilagan®)
    2. Direct acting parasympathomimetic with myopic activities
    3. Improves outflow of aqueous by ciliary body contraction
    4. Side Effects: brow ache, decreased night vision, induced myopia, bradycardia, gastrointestinal upset
  7. Adrenergic Agonists
    1. Usually second line agents
    2. Mechanism: works primarily through alpha stimulated increase in fluid uptake
    3. Side Effects:Tachycardia, Hypertension (unusual)
    4. Epinephrine hydrochloride (Epifrin®, Glaucon®) - 0.1%, 0.5%, 1%, 2% bid
    5. Epinephrine borate (Epinal®) - 0.5-1% bid
    6. Dipivefrin (Propine®) - 0.1% bid (nonselective prodrug)
    7. alpha2-agonsists: apraclonidine (Iodpidine®) 0.5-1%) tid
  8. Investigational topical calcium channel blockers - may be of use in low tension glaucoma

H. ß-Adrenergic Blockers [4] navigator

  1. Topical ß-adrenergic blockers are usual first line therapy for open angle glaucoma
  2. Non-selective ß-blockers
    1. Carteolol (Ocupress®) - 1% bid
    2. Levobundolol (AKbeta®, betagan®) - 0.25-0.5% bid
    3. Metipranolol (OptiPranolol®) - 0.3% bid
    4. Timolol maleate (Timoptic®) - 0.25-0.5% solution bid
    5. Timolol maleate Gel (Timoptic XE®) - 0.25-0.5% gel once daily only
  3. ß1-selective ß-blockers
    1. betaxolol (Betoptic®) - 0.5% solution bid
    2. betaxolol (Betopic Sß) - 0.25% suspension bid
  4. Mechanism of Action
    1. Aqueous production is stimulating by sympathetic output
    2. ß-adrenergic receptor blockade reduces aqueous production by ciliary body
    3. This leads to reduced optic pressures by 20-30%
    4. Reduction in intraocular pressue is additive with other agents
  5. Cardiac Side Effects
    1. Mainly due to ß1-blocking effects
    2. Bradycardia, hypotension, and heart failure exacerbation can occur
    3. ß1-blocking effects can reduce exercise tolerance
  6. Pulmonary Side Effects
    1. Exacerbates bronchospasm mainly due to ß2-blocking effects
    2. betaxolol is ß1-selective and may be helpful in patients with history of bronchospasm
    3. However, caution must be used when giving ß-blockers to any patient with bronchospasm
  7. Central Nervous System (CNS) Side Effects
    1. Fatigue
    2. Weakness
    3. Confusion
    4. Memory loss
    5. Headaches
    6. Anxiety
    7. Depression has been reported, though unclear association with ß-blockers
    8. Overall, ~5% of patients discontinue topical ß-blockers due to CNS side effects
  8. ß-blockade may reduce symptoms of hypoglycemia in diabetics, which can increase risks
  9. Drug Interactions
    1. Timolol side effects may be worsened by poor P450 enzyme CYP2D6 metabolism [5]
    2. Quinidine also blocks CYP2D6 function
    3. Therefore, quinidine and timolol should not be given concurrently

I. Laser Therapynavigator

  1. Argon laser burns applied to trabecular network in angle of eye
  2. Result is increased aqueous flow
  3. 80% of patients have reduced IOP at 1year, 50% at 3-5 years, and 30% at 10 years
  4. Treat 180° of angle initially, may treat other 180° if needed
  5. Gonioscopy lens at slip lamp used to view angle
  6. Glaucoma Laser Trial [8]
    1. Found laser therapy as effective as initial medical therapy at two years
    2. More than half of eyes required addition of medicine for IOP control over time
  7. Overall, several trials have suggested that early laser treatment leads to less optic nerve damage over time compared with early medication [2]

J. Surgerynavigator

  1. Employed in US after patient has failed medical and laser treatment
  2. Trabeculectomy
    1. Partial thickness filter - block of tissue removed at limbus, scleral flap over opening into anterior chamber limits flow to prevent excessive fluid loss
    2. Conjunctival filtering "bleb" formed as aqueous collects underneath
    3. May be combined with cataract surgery
    4. Antimetabolites such as mitomycin C and 5-fluorouracil useful to prevent scarring of filter and hence failure
    5. Laser used to cut sutures to loosten scleral flap if filtration rate too low
  3. Incidence of complications considerably higher than Laser therapy
    1. Bleb leakage with flat anterior chamber
    2. Choroidal effusion
    3. Increased incidence of cataract formation
    4. Infection

ACUTE CLOSED ANGLE GLAUCOMA

A. Characteristics
[Figure]: "Schematic of the Eye" navigator
  1. Iris obstructs the trabecular meshwork in the angle of the eye
    1. Increased intraocular pressure due to pupillary block
    2. Pupillary block limits ability of fluid to move from posterior to anterior chamber
    3. This causes iris to balloon into the angle covering the trabecular meshwork
  2. Pressure will increase in eye to mean arterial of ~75mm and then leads to Ischemia
  3. Epidemiology
    1. Less common than open-angle glaucoma in USA
    2. In USA, most commonly affects far-sighted women in their 50s
    3. Eskimo, Chinese, or Asian Indian persons at increased risk
    4. Prevalence of PACG in UK in persons >40 years is 0.09% (versus 0.05% for POAG)
    5. Prevalence of PACG in Chinese is 1.37% versus 0.11% for POAG
  4. Can occur without pupillary block - neovascularization, scarring which blocks meshwork
  5. Prior to pharmacologic pupillary dilatation, patient's angle should be evaluated
    1. Narrow angled persons are at risk for acute glaucoma if dilated
    2. Shine a temporal light source tangential to the cornea
    3. If the light extends over more than 1/3 of the iris, refer to ophthalmologist
    4. Do not dilate eyes where there is a question of narrow angle

B. Symptomsnavigator

  1. Sudden Onset of Pain
  2. Red eye with blurred vision, halos around lights
  3. Headache
  4. Nausea and vomiting may occur

C. Signs navigator

  1. Fixed, mid-dilated pupil
  2. Foggy iris which is difficult to visualize
  3. Intraocular pressure elevated

D. Etiologynavigator

  1. Closure of ciliary body/iris angle juxtaposing angle against lens
  2. Inability of fluid to escape from posterior chamber
  3. Buildup of pressure in posterior chamber (vitreous)
  4. Creeping angle closure occurs by different mechanism
    1. Involves development of peripheral anterior synechiae
    2. Peripheral iridotomy is usually patent

E. Treatmentnavigator

  1. Medications are similar to those used for POAG
  2. Acute Symptomatic Management (Pupillary Block Form)
    1. Decrease intraocular pressure medically - ß-blockers and carbonic anhydrase inhibitors
    2. Pilocarpine 1-2% - nly effective if IOP below 40-50 mmHg
    3. IV mannitol
    4. Paracentesis to release aqueous directly
    5. This is an ophthalmological emergency
    6. Attempt to confirm diagnosis when cornea clears by gonioscopic visualization of angle
  3. Laser Iridectomy - definitive treatment; treat other eye as if angle narrowed
  4. Surgical Iridectomy - rarely used primarily, needed for hazy conrea at times
  5. Scarring can lead to chronic angle closure with glaucoma (iridocorneal adhesions)

References navigator

  1. Alward WLM. 1998. NEJM. 339(18):1298 abstract
  2. Coleman AL. 1999. Lancet. 354(9192):1803 abstract
  3. Weinreb RN and Khaw PT. 2004. Lancet. 363(9422):1711 abstract
  4. Stewart WC and Garrison PM. 1998. Arch Intern Med. 158(3):221 abstract
  5. Edeki TI, He H, Wood AJJ. 1995. JAMA. 274(20):1611 abstract
  6. Latanoprost. 1996. Med Let. 38(987):100 abstract
  7. Dorzolamide. 1995. Med Let. 37(956):76 abstract
  8. Glaucoma Laser Trial Research Group. 1990. Ophthalmology. 97:1403 abstract
  9. Brimonodine. 1997. Med Let. 39(1002):54 abstract
  10. Brinzolamide. 1998. Med Let. 40(1036):95 abstract
  11. 2. Garbe E, LeLorier J, Boivin JF, Suissa S. 1997. Lancet. 350(9083):979 abstract