Section 10
`
`Glaucoma
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`Petitioner - New World Medical
`Ex. 1012, p. 1 of 53
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`Basic and Clinical Science Course
`
`Glaucoma
`Section 10
`
`2000-2001
`
`t::I[� THE FOUNDATION
`\!!J OF THE AMERICAN ACADEMY
`OF OPHTHALMOLOCiV
`
`LIFELONG
`
`EDUCATION FORTHE
`
`0PHTHALMOLOGISi--
`
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`LEO,..
`
`The Basic and Clinical Science Course is one component
`of the Lifelong Education for the Ophthalmologist (LEO)
`framework, which assists members in planning their con-
`tinuing medical education. LEO includes an array of clin-
`ical education products that members may select to form
`individualized, self-directed learning plans for updating
`their clinical knowledge. Active members or fellows who use LEO
`components may accumulate sufficient CME credits to earn the LEO
`Award. Contact the Academy's Clinical Education Division for further
`information on LEO.
`
`This CME activity was planned and produced in accordance
`with the ACCME Essentials.
`
`The Academy provides this material for educational purposes only. It is
`not intended to represent the only or best method or procedure in every
`case, nor to replace a physician's own judgment or give specific advice
`for case management. Including all indications, contraindications, side
`effects, and alternative agents for each drug or treatment is beyond the
`scope of this material. All information and recommendations should be
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`Copyright © 2000
`The Foundation of the American Academy of Ophthalmology
`All rights reserved
`Printed in the United States of America
`
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`HISTORICAL INTRODUCTION
`Development of Our Concept of
`Glaucoma and Its Treatment
`The word glaucoma derives from the Greek word glauk6s, meaning a watery or
`diluted blue. Hippocrates mentioned the condition of glaukosis among the infirmi-
`ties suffered by old people. Hippocrates meant by the term a bluish discoloration of
`the pupil. The condition was later called ypochyma and corresponded to a cataract.
`In antiquity glaukosis and hypochyma were considered identical. Later, during
`the Alexandrian time, glaucoma was thought to be a disease of the crystalline body
`(or fluid), which changed its normal color to light blue; hypochyma, in contrast, was
`regarded as the exudation of a fluid that later congealed and lay between the iris and
`the lens. All glaucomas were considered incurable, while it was believed that some
`hypochymata could be improved.
`The authors of antiquity and Arab physicians interpreted glaucoma as an incur-
`able cataract with desiccation of the lens. During the Middle Ages, the School of
`Salerno introduced the concept of "gutta serena," which was supposed to be one
`type of incurable cataract in which the pupil was dilated and clear; the condition
`was considered to be possibly congenital. According to this school, another type of
`incurable cataract existed in which the pupil would dilate suddenly and appear
`green. Pierre Brisseau, with his little book on cataract and glaucoma published in
`1709, was the first to consider glaucoma as a vitreous opacification. He correctly
`interpreted cataract as an opaque crystalline lens. The first reasonably satisfactory
`description of glaucoma was written by Charles St: Yves (1722): "Glaucoma is one
`of the spurious cataracts. First the patients see smoke and fog; then they lose vision
`while the pupil becomes dilated; finally, only a remnant of vision remains tempo-
`rally. The disease may begin with severe pain. The prognosis is poor. There is danger
`that the other eye will also be affected." Quite likely he was describing angle-
`closure glaucoma.
`Johann Zacharias Platner (1745) was the first to state that the glaucomatous eye
`was hard, resisting the pressure exerted by the fingers. The pressure theory was then
`emphasized and clarified by William Mackenzie (1830). Jakob Wenzel (1808)
`thought that glaucoma was primarily a disease of the retina, while S. Canstatt (1831 ),
`Julius Sichel (1841 ), and followers declared glaucoma a form of choroiditis. All of
`them considered glaucoma incurable. Georg Josef Beer (1817) thought that glau-
`coma was an opacification of the vitreous and the sequel of an arthritic ophthalmia
`that would only develop in patients with gout who had had no preceding ocular
`inflammation.
`A few futile attempts were made to treat glaucoma in the early nineteenth cen-
`tury. Mackenzie suggested a sclerotomy or lensectomy. Georg Stromeyer recom-
`mended tenotomy of the superior oblique and myotomy of the inferior oblique.
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`St. Yves wanted to enucleate the affected eye to prevent involvement of the second
`eye. The first real breakthrough in treatment was the discovery in 1856 by Albrecht
`von Graefe that iridectomy could be a curative procedure for certain types ·of glau-
`coma. He had first tried without success the instillation of atropine and repeated
`paracenteses to lower intraocular pressure (IOP).
`Only with the invention of the ophthalmoscope by Hermann von Helmholtz in
`1851 was it possible to observe the changes in the optic nerve head associated with
`glaucoma. The term pressure excavation had been coined by von Graefe. This oph-
`thalmoscopic concept was corroborated by careful pathologic examinations initiat-
`ed by Heinrich Muller. Edward Jaeger and Isidor Schnabel defended the hypothesis
`that glaucoma was characterized by specific optic nerve disease.
`It soon became obvious that an iridectomy could not cure all types of glauco-
`ma. Albrecht von Graefe had already noted that a "cystoid scar," meaning a filtering
`bleb in today's jargon, would offer certain advantages for normalizing IOP. Sclerot-
`omy was first proposed by Louis de Wecker in 1869. Surgeons then tried to keep
`the wound open on purpose, either by infolding of the conjunctiva (H. Herbert, 1903)
`or by incarceration of the iris (George Critchett of London in 1858 and Soren Holth
`of Oslo in 1904). Finally, the iridosclerectomy was devised by Pierre Lagrange in
`Paris (1905), and the trephining operation was introduced by Robert H. Elliot of
`Madras, India. Thermosclerotomy was first described by Luigi Preziosi of Malta in
`1924, and it was later modified and popularized by Harold Scheie of Philadelphia
`in 1958. Trabeculectomy was subsequently described by Watson and Cairns in the
`1950s in England.
`The medical treatment of glaucoma was initiated with eserine, which is derived
`from the Calabar bean of West Africa. This drug was first recognized as a miotic and
`used for treating iris prolapse. In 1876 Ludwig Laqueur of Strasbourg and Adolf
`Weber of Darmstadt were the first to use eserine to treat glaucoma. The alkaloid pilo-
`carpine was isolated in 1875, and it was first topically applied to the eye by John
`Tweedy of London (1875) and by Weber (1876) in an effort to lower IOP.
`
`Frederick C. Blodi, MD
`
`4
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`llntroduction to Glaucoma:
`
`:Terminology, Epidemiology,
`
`and Heredity
`
`l Definitions
`
`
`: The term glaucoma refers to a group of diseases that have in common a characteris-
`'
`tic optic neuropathy with associated visual field loss for which elevated intraocular
`pressure (IOP) is one of the primary risk factors. The commonly accepted range for
`normal IOP in the general population is 10—22 mm Hg. Three factors determine the
`
`IOP (Fig H):
`u The rate of aqueous humor production by the ciliary body
`in Resistance to aqueous outflow across the trabecular meshworkaSchIemm's canal
`system
`
`
`i: The level of episcleral venous pressure
`In most cases increased IOP is caused by increased resistance to aqueous humor
`outflow.
`
`Clllary body .1
`
`Aqueous vein
`Schlemm‘s canal
`
`FIG l-1—-Diagrammatic cross section of the anterior segment of the normal
`eye, showing the site of aqueous production (ciliary body} and sites of resis-
`tance to aqueous outflow (trabecular meshwork—Schlemm’s canal system
`and episcleral venous plexus).
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`Several risk factors, many of which remain unknown, increase the likelihood
`of the development of glaucoma. Those factors known to be associated with an
`increased risk for the development of glaucoma besides increased IOP include
`and a positive famlly history -..._
`ac;lyanced ag racia nd,
`In most indivwuals the optic nerve and visual field changes seen in glaucoma
`are determined by both the level of the IOP and the resistance of the optic nerve
`axons to pressure damage. Other factors, which at present are poorly defined, also
`seem to predispose the optic nerve axons to damage. Although progressive changes
`in the visual field and optic nerve are usually related to increased IOP, in cases of
`normal-tension glaucoma the IOP remains within the normal range (see chapter IV).
`In most cases of glaucoma the IOP is too high for proper functioning of the optic
`nerve axons, and lowering the IOP will stabilize the damage. In cases involving
`other pathophysiologic mechanisms that may affect the optic nerve, however, pro-
`gression of optic nerve damage may continue despite lowering of IOP.
`The terms primary and secondary have been helpful in current definitions of
`glaucoma, and they are still in widespread use. However, as discussed below under
`Classification, new concepts are emerging that may change this common usage. By
`definition, the primary glaucomas are not associated with known ocular or systemic
`disorders that cause increased resistance to aqueous outflow. The primary glaucomas
`usually affect both eyes and may be inherited. Conversely, the secondary glaucomas
`are associated with ocular or systemic disorders responsible for decreased aqueous
`outflow. The diseases that cause secondary glaucoma are often unilateral, and famil-
`ial occurrence is less common.
`
`Classification
`Open-Angle, Angle-Closure, Primary, and Secondary Glaucomas
`Traditionally, glaucoma has been classified as open angle or closed angle and as pri-
`mary or secondary (Table 1-1 ). Differentiation of open-angle glaucoma from closed-
`angle glaucoma is essential from a therapeutic standpoint (see chapters IV and V).
`The concept of primary and secondary glaucomas is also useful, but it reflects our
`lack of understanding of the pathophysiologic mechanisms underlying the glauco-
`matous process. Open-angle glaucoma is classified as primary when no identifiable
`underlying cause of the events that led to outflow obstruction and elevation of IOP
`can be found. It is classified as secondary when an abnormality is identified and a
`putative role in the pathogenesis can be ascribed to this abnormality.
`However, it is now recognized that all glaucomas are secondary to some abnor-
`mality, whether currently identified or not. As our knowledge of the mechanisms
`underlying the causes of glaucoma continues to expand, the primary/secondary clas-
`sification has become increasingly artificial. This scheme is particularly inadequate
`for classifying the angle-closure glaucomas.
`Other schemes for classifying glaucoma have been proposed. Classification of
`the glaucomas based on initial events and on mechanisms of outflow obstruction are
`two schemes that have gained increasing popularity (Table 1-2).
`Ritch R, Shields MB, Krupin T, eds. The Glaucomas. 2nd ed. St Louis: Mosby; 1996:722.
`
`6
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`TABLE 1-1
`
`CLASSIFICATION OF GLAUCOMA
`
`TYPE
`
`CHARACTERISTICS
`
`Normal-tension
`glaucoma
`Juvenile open-angle
`glaucoma
`Glaucoma suspect
`
`Secondary open-angle
`glaucoma
`
`Open-angle glaucoma (Fig 1-2, seep 9)
`Not associated with known ocular or systemic disorders that
`Primary open-angle
`glaucoma (POAG)
`cause increased resistance to aqueous outflow or damage to
`optic nerve; usually associated with elevated IOP
`Considered in continuum of POAG; terminology often used
`when IOP is not elevated
`Terminology often used when open-angle glaucoma diagnosed
`at young age (typically 10-30 years of age)
`Normal optic disc and visual field associated with elevated IOP
`Suspicious optic disc and/or visual field with normal IOP
`Increased resistance to trabecular meshwork outflow associated
`with other conditions (e.g., pigmentary glaucoma, phacolytic
`glaucoma, steroid-induced glaucoma)
`Increased posttrabecular resistance to outflow secondary to
`elevated episcleral venous pressure (e.g., carotid cavernous
`sinus fistula)
`Angle-closure glaucoma (Fig 1-3, seep 9)
`Primary angle-closure
`Movement of aqueous humor from posterior chamber to anteri-
`or chamber restricted; peripheral iris in contact with trabecular
`glaucoma with relative
`meshwork
`pupillary block
`Occurs when IOP rises rapidly as a result of relatively sudden
`Acute angle closure
`blockage of the trabecular meshwork
`Repeated, brief episodes of angle closure with mild symptoms
`and elevated IOP, often a prelude to acute angle closure
`IOP elevation caused by variable portions of anterior chamber
`angle being permanently closed by peripheral anterior synechiae
`(E.g., swollen lens, secluded pupil)
`
`Subacute angle closure
`(intermittent angle closure)
`Chronic angle closure
`
`Secondary angle-closure
`glaucoma with pupillary
`block
`Secondary angle-closure
`glaucoma without
`pupillary block
`
`Plateau iris syndrome
`
`Childhood glaucoma
`Primary congenital/
`infantile glaucoma
`Glaucoma associated with
`congenital anomalies
`
`Secondary glaucoma in
`infants and children
`
`Posterior pushing mechanism: lens-iris diaphragm pushed for-
`ward (e.g., posterior segment tumor, scleral buckling procedure,
`uveal effusion)
`Anterior pulling mechanism: anterior segment process pulling iris
`forward to form peripheral anterior synechiae (e.g., iridocorneal
`endothelial syndrome, neovascular glaucoma, inflammation)
`Primary angle closure with or without component of pupillary
`block, but pupillary block is not predominant mechanism of
`angle closure
`
`Primary glaucoma present from birth to first few years of life
`
`Associated with ocular disorders (e.g., anterior segment dysgen-
`esis, aniridia)
`Associated with systemic disorders (e.g., rubella, Lowe syndrome)
`(E.g., glaucoma secondary to retinoblastoma or trauma)
`
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`*Clinical examples cited in this table do not represent an inclusive list of the glaucomas.
`Modified with permission from Ritch R, Shields MB, Krupin T, eds. The Glaucomas. 2nd ed. St Louis; Mosby; 1996:722.
`
`PLATEAU IRIS SYNDROME
`
`PRETRABECULAR
`(MEMBRANE OVERGROWTH)
`
`Fibrovascular membrane
`(neovascular glaucoma)
`Endothelial layer, often
`with Descemet-like
`membrane
`lridocorneal endothelial
`syndrome
`Posterior polymorphous
`dystrophy
`Penetrating and non-
`penetrating trauma
`Epithelial downgrowth
`Fibrous ingrowth
`Inflammatory membrane
`Fuchs heterochromic
`iridocyclitis
`Luetic interstitial
`keratitis
`
`TRABECULAR
`
`Obstruction of
`Schlemm's canal, e.g.,
`collapse at canal
`Elevated episcleral
`venous pressure
`Carotid cavernous
`fistula
`Cavernous sinus
`thrombosis
`Retrobulbar tumors
`Thyroid ophthal-
`mopathy
`Superior vena cava
`obstruction
`Mediastinal tumors
`Sturge-Weber
`syndrome
`Familial episcleral
`venous pressure
`elevation
`
`POSTTRABECULAR
`
`Idiopathic
`Chronic open-angle glaucoma
`Juvenile open-angle glaucoma
`"Clogging" of trabecular meshwork
`Red blood cells
`Hemorrhagic glaucoma
`Ghost cell glaucoma
`Sickled red blood cells
`Macrophages
`Hemolytic glaucoma
`Phacolytic glaucoma
`Melanomalytic glaucoma
`Neoplastic cells
`Primary ocular tumors
`Neoplastic tumors
`Juvenile xanthogranuloma
`Pigment particles
`Pigmentary glaucoma
`Exfoliation syndrome (glaucoma
`capsulare)
`Malignant melanoma
`Protein
`Uveitis
`Lens-induced glaucoma
`Viscoelastic agents
`o:-chymotrypsin-induced glaucoma
`Vitreous
`Alterations of the trabecular meshwork
`Steroid-induced glaucoma
`Edema Uveitis (trabeculitis)
`Scleritis and episcleritis
`Alkali burns
`Trauma (angle recession)
`lntraocular foreign bodies
`(hemosiderosis, chalcosis)
`
`OPEN-ANGLE GLAUCOMA MECHANISMS
`
`ANGLE-CLOSURE GLAUCOMA MECHANISMS
`
`CLASSIFICATION OF THE GLAUCOMAS BASED ON MECHANISMS OF OUTFLOW OBSTRUCTION*
`With pupillary block
`Pupillary-block glaucoma
`Lens-induced mechanisms
`Phacomorphic lens
`Ectopia lentis
`Posterior synechiae
`Iris-vitreous block
`Pseudophakia
`Uveitis
`Without pupillary block
`Ciliary block (malignant)
`glaucoma
`Lens-induced mechanisms
`Phacomorphic lens
`Ectopia lentis
`Following lens extraction
`(forward vitreous shift)
`Anterior rotation of ci I iary body
`Following scleral buckling
`Following panretinal
`photocoagulation
`Central retinal vein occlusion
`lntraocular tumors
`Malignant melanoma
`Reti noblastoma
`Cysts of the iris and ciliary body
`Retrolenticular tissue contracture
`Retinopathy of prematurity
`(retrolental fibroplasia)
`Persistent hyperplastic
`primary vitreous
`
`TABLE 1-2
`Contracture of
`membranes
`Neovascular
`glaucoma
`Iridocorneal
`endothelial
`syndrome
`Posterior polymor-
`phous dystrophy
`Penetrating and non-
`penetrating trauma
`Consolidation of
`inflammatory products
`
`ANTERIOR ("PULLING")
`
`POSTERIOR ("PUSHING'')
`
`DEVELOPMENTAL ANOMALIES OF
`ANTERIOR CHAMBER ANGLE
`
`Incomplete development
`of trabecular meshwork/
`Schlemm's canal
`Congenital (infantile)
`glaucoma
`Axenfeld-Rieger syndrome
`Peters anomaly
`Glaucomas associated with
`other developmental
`anomalies
`lridocorneal adhesions
`Broad strands (Axenfeld-
`Rieger syndrome)
`Fine strands that contract to
`close angle (aniridia)
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`
`Aqueous
`flow
`
`
`
`FIG l-Z—Schematic of open-angle glaucoma with resistance to aqueous
`outflow through the trabecular meshwork—Schlemm’s canal system in the
`absence of gross anatomic obstruction. Small white arrow shows normal
`path of outflow and indicates that resistance in this illustration is relative,
`not total.
`
`flow
`
`Aqueous
`
`FIG l~3—Schematic of angle-closure glaucoma with pupillary block leading
`to peripheral iris obstruction of the trabecular meshwork.
`
`
`
`
`
`ModifiedwithpermissionfromRitchR,ShieldsMB,KrupinT,eds.TheGlaucomas.2nded.StLouis;Mosby;19962722.
`
`
`
`
`
`
`
`
`
`
`
`pun-carenemy-c:ulcuIII(III:taunt:uullUlrepresentallInUUSlVeIISIOImeglaucomas,
`
`
`
`
`
`
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`Combined-Mechanism Glaucoma
`
`When a combination of two or more forms of glaucoma present either sequentially
`or simultaneously, the term combined-mechanism glaucoma is sometimes used. This
`situation may occur following a primary acute angle-closure glaucoma attack, when
`IOP remains elevated after a peripheral iridectomy in spite of an open and normal-
`appearing anterior chamber angle. Combined-mechanism glaucoma can also ap-
`pear in a patient with open-angle glaucoma who develops secondary angle closure
`from other causes. Examples include a patient with open-angle glaucoma who
`develops angle closure as a result of miotic therapy or a patient with pseudophakic
`open-angle glaucoma who develops peripheral anterior synechiae after an episode
`of pupillary block.
`IOP elevation in these cases can occur as a result of either or both of the
`following:
`□ The intrinsic resistance of the trabecular meshwork to aqueous outflow in open-
`angle glaucoma
`□ The direct anatomic obstruction of the filtering meshwork by synechiae in angle-
`closure glaucoma
`Treatment is modified based on the proportion of open angle to closed angle and the
`etiology of the angle-closure component.
`
`Epidemiologic Aspects of Glaucoma
`Primary Open-Angle Glaucoma �
`Magnitude of the problem Primary open-angle glaucoma represents a significant
`public health problem. At least2.25 million individuals in the United States 45 year-s
`of age or older are estimated to have this disease. Estimates based on the available
`data indicate that between 84,000 and 116,000 of them have become bilaterally
`blind (best-corrected visual acuity less than or equal to 20/200 or visual field <20 °).
`,POAG is thus an important cause of blindness in the United States and the most fre-
`-
`. u
`cause of nonreversible blindness in blac mericans.
`The World Health Organiza I
`HO) has undertaken an extensive analysis of
`the literature to estimate the prevalence, incidence, and severity of the different
`types of glaucoma on a worldwide basis. Using data collected predominantly in the
`late 1980s and early 1990s, WHO estimated the global population of people with
`high IOP (>21 mm Hg) at 104.5 million. The incidence of primary open-angle glau-
`coma was estimated at 2.4 million people per year. Blindness prevalence for all
`types of glaucoma was estimated at 5.2 million people, with 3 million cases caused
`by POAG. The different types of glaucoma were theoretically calculated to be
`responsible for 15% of blindness, placing glaucoma as the third leading cause of
`blindness worldwide, f o l l o w i n g � -
`Despite these staggering statistics, the impact of glaucoma from a public health
`perspective has not been fully appreciated. Relatively little information is currently
`available regarding the individual burden associated with the psychologic effects of
`having a potentially blinding chronic disease, the debilitating side effects of treat-
`ment, and the qualitative functional loss associated with diminished visual fields.
`Nor does reliable information exist on the societal costs associated with the detec-
`tion, treatment, and rehabilitation of this disease.
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`./
`
`·
`
`l
`
`Prevalence Prevalence of POAG shows a strong racial disparity. Among whites 40
`years of age and older, a prevalence of between 1 .1 % and 2 .1 % has been consis-
`tently obtained by population-based studies performed throughout the world. The
`prevalence among blacks is three to four times higher. The prevalence of POAG in-
`\ h t ;·iv
`creases with age, and estimates among persons in. their seventies have generally
`. \
`been three to eight times higher compared with persons in t ir
`fo;cti s.
`; JL#-'> 0 � 1
`·N,u_, l r r: L J2
`Risk factors/identi gYrrs lfactors
`is importa t bec se
` i
`info
`Un may lead
`J
`to development of strategies for disease screening and prevention and may be use-
`ful in identifying persons for whom close medical supervision is indicated. Strictly
`defined, a factor can be considered a risk factor only if it predates disease occur-
`rence. From a clinical perspective, it is often difficult to differentiate very early dis-
`ease from normal. In fact, this determination is often dependent on how the disease
`is defined.
`Glaucoma is usually defined by the presence of characteristic visual field de-
`fects and sometimes, in the absence of visual field defects, by the appearance of
`optic nerve damage. How often this diagnosis is made in marginal cases is influ-
`enced by the sensitivity of available diagnostic tests. Thus, it may be difficult to deter-
`mine whether abnormalities in certain parameters-e.g., optic nerve parameters
`such as nerve fiber layer loss-are indicative of increased susceptibility to develop-
`ing glaucoma or are signs of early disease. From a practical standpoint, the distinc-
`tion is unimportant. Individuals manifesting such abnormalities must be closely
`monitored for signs of clinically significant disease development in either situation.
`The quality of available data regarding potential risk factors for the development
`of POAG varies greatly. Evidence that IOP, age, race, and positive family history are
`risk factors for POAG is considerable and reliable. Data also support ru,abetes and
`myopia_a.5 risk factors, but these data are generally less convincing. The relevance of
`s x and of various systemic factors, such as systemic hypertension and arterioscle-
`rotic and ischemic vascular disease, to glaucoma risk has been widely debated, and
`currently available data do not permit the drawing of definitive conclusions.
`Compared with primary open-angle glaucoma, the epidemiology of primary angle-
`closure glaucoma (PACG) has received much less attention. Most of the available
`information is derived fromi:os. ital-based surveys or from population screeni2fs.
`of small high-risk115_ubpopulati ns.1'
`·+)
`.
`'J' 17 /8;c t (
`?' 1 trS,o"'
`Race The prevalence of p mary an'gle-closure glaucoma varies in different racial
`and ethnic groups. Among white populations in the United States and Europe, it is
`estimated at approximately 0.1 %. Inuit o ulations from Arctic re ions have the
`highest kno
`of ri · ar an le-closure
`laucoma, 20-40 times higher
`t an whites. The relative prevalences of PACG and POAG among Inuits are a sot e
`reverse of what is noted in white populations, with POAG being uncommon.
`Estimates of the prevalence of primary angle-closure glaucoma in Asian popu-
`lations have varied considerably. Some of this variability may be the result of differ-
`ences in quality and design of the studies from which the estimates were derived.
`Another factor, however, is that Asian populations are not one homogeneous group,
`and substantial differences in PACG prevalence between many Asian groups are
`11
`
`Primary Angle-Closure Glaucoma
`
`I ·1'-
`
`1'r--v1
`
`J
`
`f,l
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`Ex. 1012, p. 12 of 53
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`

`I\ t J D ,-...J-r
`
`r r+ r f
`
`likely. The available data suggest that most of the Asian population groups have a
`prevalence of primary angle-closure glaucoma between that of whites and Inuits.
`Acute angle-closure glaucoma is relatively uncommon in blacks. However,
`chronic angle-closure glaucoma is much more common than initially believed.
`Some studies have suggested that the prevalence of primary angle-closure glaucoma
`in blacks is similar to that in whites, with most of the cases in blacks being of the
`chronic variety.
`0 Sex Women of all races develop a a
`three to four times
`more often than do men. Studies of normal eyes have shown that women have shal-
`lower anterior chambers than men.
`Age The anterior chamber decreases in depth and volume with age. These changes
`predispose to pupillary block, and the prevalence of pupillary-block angle-closure
`glaucoma thus increases with age. Acute angle-closure glaucoma is most common
`between the ages of 55 and 65 years, but it can occur in young adults and the elder-
`ly and has been reported jn children.
`Refraction ' The interior chamber depth and volume are smaller in hyperopic eyes.
`Although primary angle-closure glaucoma may occur in eyes with any type of refrac-
`tive error, it is thus typically associated with hyperopia.
`Inheritance Some of the anatomic features of the eye that predispose to pupillary
`block, such as more forward position of the lens and greater than average lens thick-
`ness, are inherited. Thus relatives of subjects with angle-closure glaucoma are at
`greater risk of developing angle-closure than the general population. However, esti-
`mates of the exact risk vary greatly.
`
`Epstein DL, Allingham RR, Schuman JS, eds. Chandler and Grant's Glaucoma. 4th ed.
`Baltimore: Williams & Wilkins; 1997:641-646.
`Ritch R, Shields MB, Krupin T, eds. The Glaucomas. 2nd ed. St Louis: Mosby; 1996:
`753-765.
`
`Hereditary and Genetic Factors
`
`The prevalences of glaucoma, enlarged cup-disc ratio, and elevated IOP are all
`much higher in siblings and offspring of patients with glaucoma than in the general
`population. A positive family history is a major risk factor for the development of
`POAG. The prevalence of glaucoma among siblings of patients is approximately
`10%, and the lifetime absolute risk of glaucoma at age 89 years is 10 times higher
`for relatives of glaucoma patients compared with relatives of unaffected persons.
`The precise mechanism of inheritance is not clear, and a single underlying sus-
`ceptibility gene cannot be assumed. Inheritance may involve more that one gene
`(polygenic), have a late or variable age of onset, demonstrate incomplete penetrance
`(the disease may not develop even when the causative gene has been inherited), and
`may have substantial environmental influences. See also BCSC Section 2, Funda-
`mentals and Principles of Ophthalmology, Part 3, Genetics.
`Genetic studies have been successful in identifying the location of genes for
`juvenile open-angle glaucoma (chromosome 1 q21-q31) and for disorders associat-
`
`12
`
`Petitioner - New World Medical
`Ex. 1012, p. 13 of 53
`
`

`

`TABLE 1-3
`CLONED GENES KNOWN TO BE ASSOCIATED WITH GLAUCOMA
`
`GENE
`
`TIGR/Myocilin
`CYP1B1
`PITX2
`FKHL7
`LMX1B
`PAX6
`
`Table courtesy of Janey L. Wiggs, MD, PhD.
`
`LOCUS
`
`1q23 (GLC1A)
`2p21 (GLC3A)
`4q25 (RIEG1)
`6p25 (IDYS1)
`9q34 (NPS1)
`11p13 (AN1)
`
`PHENOTYPE
`
`Juvenile and adult open-angle glaucoma
`Congenital glaucoma
`Rieger syndrome
`lridodysgenesis
`Glaucoma associated with nail-patella syndrome
`Aniridia
`
`ed with glaucoma such as Axenfeld-Rieger syndrome (4q25 or 4q27) (Table 1-3).
`Identifying the gene(s) responsible for POAG will revolutionize our understanding of
`this disorder and will lead to major new therapeutic interventions.
`
`Wolfs RC, Klaver CC, Ramrattan RS, et al. Genetic risk of primary open-angle glau-
`coma: population-based familial aggregation study. Arch Ophtha/mol. 1998;116:
`1640-1645.
`
`13
`
`Petitioner - New World Medical
`Ex. 1012, p. 14 of 53
`
`

`

`C H A P T E R
`
`II
`
`lntraocular Pressure and
`Aqueous Humor Dynamics
`
`The clinical approach to glaucoma begins with an understanding of aqueous humor,
`which flows from the posterior chamber through the pupil into the anterior chamber
`and exits the eye by passing through the trabecular meshwork into Schlemm's canal
`and then draining into the venous system through a plexus of collector channels, as
`shown in Figure 1-1. The formation and outflow of aqueous humor are discussed in
`detail below. The Goldmann equation summarizes the relationship between these
`factors and the IOP in the undisturbed eye:
`P0 = (F/C) + Pv
`in which P0 is the IOP in millimeters of mercury (mm Hg), Fis the rate of aqueous
`formation in microliters per minute (µI/min), C is the facility of outflow in microliters
`per minute per millimeter of mercury (µI/min/mm Hg), and P v is the episcleral
`venous pressure in millimeters of mercury. Resistance to outflow (R) is the inverse of
`facility (C) and may replace C in rearrangements of the Goldmann equation.
`
`Aqueous Humor Formation
`Aqueous humor is formed by the ciliary processes, each of which is composed of a
`double layer of epithelium over a core of stroma and a rich supply of fenestrated
`capillaries (Fig 11-1 ). The apical surfaces of both the outer pigmented and the inner
`nonpigmented layers of epithelium face each other and are joined by tight junctions,
`which are probably an important part of the blood-aqueous barrier. The inner non-
`pigmented epithelial cells contain numerous mitochondria and microvilli, and these
`cells are thought to be the site of aqueous production. The ciliary processes provide
`a large surface area for secretion. BCSC Section 2, Fundamentals and Principles
`of Ophthalmology, discusses aqueous humor composition in detail in Part 4, Bio-
`chemistry and Metabolism.
`Aqueous humor formation is not precisely understood, but it involves the com-
`bination of several processes:
`□ Active transport (secretion)
`□ U ltrafiltration
`□ Sim