The new england journal of medicine

review article
MECHANISMS OF DISEASE

Primary Open-Angle Glaucoma

Young H. Kwon, M.D., Ph.D., John H. Fingert, M.D., Ph.D., Markus H. Kuehn, Ph.D., and Wallace L.M. Alward, M.D.

and Visual Sciences, University of Iowa, can be distinguished from most other forms of acquired opt ic neuropat hy Iowa City. Address reprint requests to Dr. Glaucoma by the is ach chronic, ar act erdegenerative ist ic a ppe ar optic a nceneuropathy of the opti that c n er ve. In gl aucom a, th ne ur oKwon at e University of Iowa Health Care, retinal rim of t he optic nerve becomes progressively t hinner, thereb y enlarging200 the Hawkin s Dr., Iowa City, IA 52242. optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause N Engl J Med 2009;360:1113-24. is the loss of retina l ga nglion cell a xons, a long with supportin g glia a nd vasculatu re. C op y r ig ht 2 0 0 9 Ma ssa ch uset t s Med i ca l The remaining neuroretinal rim retains its normal pink color. In other optic neu- ty . ropathies, t he optic-nerve t is sue loses its pink color and cupping do es not develop. A rare exception is arterit ic ant erior ischemic optic neuropathy, in which cupping can occ ur.1 Patien ts with glauc oma ty pic ally lose pe riphe ral vision and may lose all vision if no t treated. Although glaucoma frequently occurs without an elevation of intraocular pressure, t he disease is nonet heless classif ied ac cord ing t o anterior-segment variations that can elevate intraocular pressure. The anterior segment of the eye has its own circulatory system, which nourishes the crystalline lens and cornea, bot h of which lack a blood supply. Aqueous humor, produced by the ciliary body, circulates throughout the anterior chamber and drains through the trabecular meshwork in the iridocorneal angle, which is the angle formed by the iris and cornea (Fig. 1).2 Elevated intraocular pressure does not result from increased aqueous humor production but rather from reduced aqueous outflow. The glaucom as are classif ied by the ap pearanc e of t he iridocorneal angle. There are open-angle, closed-angle, and developmental categories, which are further divided into primary and secondary t ypes. Primary open-angle glaucoma can occur with or wit hout elevated intraocular pressure; the lat ter is sometimes called normal-t ension glaucoma. Primary open-angle glaucoma includes both adult-onset disease (occurring after 40 years of age) and juvenile-onset disease (occurring between t he ages of 3 and 40 years of age). Examples of secondary open-angle glaucomas include those associated with exfoliation or pigment-dispersion syndrome. Closed-angle glaucoma can be primary (e.g., pupillary block) or secondary (e.g., inflammatory or neovascular causes). Development al forms of glaucoma include primary c ongenital glauc oma and glaucoma asso ciated with synd romes (e.g., aniridia or t he AxenfeldRieger syndrome). Primary open-angle glaucoma, the predominant form of glaucoma in Western countries, probably comprises several clinically indistinguishable diseases. In this review, we discuss primary open-angle glaucoma, in which the iridocorneal angle is open (unobstructed) and normal in appearance but aqueous outflow is diminished. We discuss the clinical feat ures of primary open-angle glaucoma and mechanisms of elevated intraocular pressure and opt ic-nerve damage. To illustrate t he mechanisms of elevated intraocular pressure, we focus on mutations in the myocilin (MYOC) gene. Approximately 4% of cases of adult-onset primary open-angle glaucoma and more t han 10% of juvenile-onset cases are n engl j med 360;11 nejm.org march 12, 2009

From the Department of Ophthalmology

So c ie

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The new england journal of medicine

Cornea Iris Sclera Lens

Vitreous body Trabecular meshwork Trabecular meshwork

Aqueous Aqueous humor humor

Anterior chamber Anterior chamber

Schlemms canal Ciliary Schlemms

Ciliary body body

Figure 1. Circulation of the Aqueous Humor. This anterior segment of the eye shows the circulation of the aqueous humor from the ciliary body through the pupil into the anterior chamber. The aqueous humor then passes through the trabecular meshwork into Schlemms canal COL OR F IGUR E and travels from there into the episcleral venous system. A smaller amount of aqueous humor leaves the eye through Draft 02/12/09 the face of2the ciliary body, just below the trabecular meshwork.
A ut h or Fi g # 1 Ti t le associated with M YOC mutations.3,4 These adultpia, and low d iastolic p erfusion pre ssure are risk ME factors for primary open-angle glaucoma.6,7 (TaDE onset cases feat ure an elevated intraocular presble 1). Amon g pa ti ents with a n e le vate d i ntr aoc uSB resultant L A r ti st with sure optic-nerve damage and visual lar pressure, a relatively thin central cornea is anK wo n A UTHO R P LE ASE NOTE: oth er maj or r i sk fac tor for t he di sea se.14 Evi denc e loss, and t hey are clinically indist inguishable F igu r e h as b een r edr awn an d ty p e h as b een r eset P lea se ch eck car efu lly from cases of primary open-angle glaucoma for in other risk factors (diabetes mellitus, elevated systolic blood pressure, and migraine, among Is sue d at e patients without MYOC mut ations.5 To address others) is les s consistent.15

the mechanisms of opt ic-nerve damage, we broaden the discussion t o include primary openangle glaucoma with elevated intraocular presClinical Presentation sure, with or without MYOC mutations. T he m ain clinica l fe atur es of pr ima r y ope n-a ngle CLINICAL FEATURES gl aucoma ar e a n ope n i ri docor nea l angl e a nd c up ping of the optic-nerve head (or optic disk), wit h Epidemiology and Risk Factors corresponding loss of visual field. Elevated intraPr imar y open -an gle glauc oma is the sec ondocular lea d- pressure is not part of the clinical definiing cause of blindness in t he United States and tion because primary open-angle glaucoma can the leading cause of blindness among black o c c u r wh e n int rao c u l ar p r e s s u re i s no r m a l (t y p Americans.6 There is good evidence that black i c al race, older age, elevated intraocular pressu re, famly 10 to 21 mm Hg). Nevertheless, elevated intraily history of primary open-ang le glaucoma, myoocu lar pressu re is a n imp ort an t risk fac tor an d is also considered to be a causat ive factor in glaun engl j med 360;11 nejm.org march 12, 2009

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MECHANISMS OF DISEASE

Table 1. Major Risk Factors Associated with Primary Open-Angle Glaucoma. Risk Factor Race Black White Asian Older age (odds ratio per decade increase) Black White Asian Elevated intraocular pressure <15 mm Hg 1618 mm Hg 1921 mm Hg 2229 mm Hg 3034 mm Hg Diastolic perfusion pressure (adjusted odds ratio) =50 mm Hg 4049 mm Hg 3039 mm Hg <30 mm Hg
Family history in first-degree relative (adjusted odds ratio) 2.9 Tielsch et al.1 1

Prevalence Relative Risk of Glaucoma of Glaucoma* Source of Data %

Rudnicka et al.8

4.2 2.1 1.4

Rudnicka et al.8

1.6 2.1 1.6

Sommer et al.9

1.0 2.0 2.8 12.8 39.0

Tielsch et al.1 0

1.0 1.7 2.1 6.2

1.63.3 Mitchell et al.,1 2 Wong et al.1 3

Myopia (adjusted odds ratio)

Thin central cornea (hazard ratio per 40-m decrease) 1.7 Gordon et al.1 4

* Data are relative risks unless otherwise specified. The category of white race includes Hispanics. Diastolic perfusion pressure is defined as diastolic blood pressure minus intraocular pressure.

coma16; currently, it is the only modifiable causonset form the int raocular pressure is often extremely high (frequent ly >40 mm Hg).21 Large at ive factor. Many randomized clinical t rials have pedig rees with autos omal-dominant inheritance shown t hat reducing intraocular pressure slows of juvenile-onset primary open-angle glaucoma haT vehere be en reported, a nd a na lyse s of ge netic m arkthe onset a nd pr ogre ssi on of g lauc oma.17,18 ers in such pedigrees have mapped a glaucomafore, all curre nt treatme nts of prima ry open-a ngle related gene to a region of chromosome 1q desigglaucoma are aimed at reducing intraocular presnated GLC1A.22 Subsequent linkage st udies of oth er gl aucoma pe di gre es h ave mapp ed t he c hr osure by medical or surgical means.19,20 The Case mosomal locations of 13 additional glaucomaPre sentat ion r ecounts a typ ica l pr esent ation related of prigenes - (GLC1B t hrough GLC1N).23 mary open-angle glaucoma (see box for Case Presentation, and see Fig. 2 f or examination results). The relevant gene at the GLC1A locus is MYOC (Online Mendelian Inheritance in Man number, Genetic Features 601652), wh ich encodes th e protein myocilin. MyoJuvenile-onset primary open-angle glaucoma is cilin is produced in many tissues, including the rare. It has the same clinical features as the ciliary body24 a nd trabe cular meshwork,25 the two adu lt-onse t c ondition, e xcep t th at in t he juven ile - tissues that regulate int raocular presocular Myocilin
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The new england journal of medicine

Case Presentation: Primary Open-Angle Glaucoma History A 71-year-old white woman was refer red to an ophthalmologist because of declining vision. A diagnosis of glaucoma had been made 10 years earlier, with intraocular pressures (mm Hg) in the mid-20s. She underwent laser trabecul oplasty of the left eye before the referral and was treated with topical antiglaucoma medications (timolol and latanoprost) at the time of the referral. She had no other medical problems. Her 49-year-old nephew had glaucoma. Examination On ocular examination, her visual acuity was 20/25 in each eye. She also had mild cataracts in both eyes. Her iridocorneal angles were open, and the intraocular pressure was slightly elevated, at 22 mm Hg, in both eyes, on the two medications. Fundus examination revealed cupped optic disks, with superior notching of the cup in the right eye (Fig. 2A and 2B) and generalized thinning of the neuroretinal rim in the left eye (Fig. 2D and 2E). Automated pe rimetry testing (Humphrey Fiel d Analyzer, Carl Zeiss Meditec) revealed corresponding loss of visual field in both eyes (Fig. 2C and 2F).

The role of MYOC in the pathogenesis of the

common, adult-onset form of primary open-angle glaucoma has been explored by testing large cohorts of patients f or mut ations. A variet y of MYOC mutations have been detected in 3 to 5% of patient s with adult-onset primary open-angle glaucoma in cohorts around the world.3,27-31 Mutations in MYOC are among the most common causes of inherited eye disease wit h a know n molecular basis. Mutations in other genes, including OPTN (encoding optineurin) and WDR36 (encoding a T-cell activation WD repeat-containing protein), have also been studied as potential causes of primary open-angle glaucoma. OPTN, which is in the GLC1E locus, has been associated with a small fract ion of cases of low-pressure glaucoma,32 but less is known about the role of
WDR36, which is in t he GLC1G locus.33 These genes have recent ly been reviewed elsewhere.34

A video showing an optic nerve examination glaucomafor is available at NEJM.org

Diagnosis and Management The diagnosis of primary open-angle glaucoma was confirmed. Given the extent of the opticner ve damage and vision loss, further lowering of the intraocular pressure was recommende d. Follow-up Over the course of the next 7 years, the patient under went additional medical and surgical treatment for glaucoma (laser trabecul oplasty in the right eye and trabeculectomy in the left eye). At the last follow-up visit, her intraocular pressure was 18 mm Hg in the right eye and 12 mm Hg in the left eye, with stable visual fields. With her consent, she was screened for mutations in the gene encoding myocilin (MYOC) as par t of a research study. She was found to have an MYOC Gln368Stop mutation.

Effect on the Trabecular Meshwork Some MYOC mutations have been detected in a suf f icient nu mber of patie nts to allow identification of mut ation-specific glaucoma phenoty pes, including age at onset and maximum intraocular pressure.35,36 A central clinical feature of myocilin-associated glaucoma is elevat ed int raocular pressure, and some mut ations cause higher intr aoc ul ar pr essu re tha n other s. Muta ti ons a ssoci ated with juvenile-onset primary open-ang le glaucoma le ad to th e greate st elevations in intraocular pressure oft en more than 40 mm Hg. Mutations associated with adult-onset primary openangle glaucoma typically cause maximum pressures of 25 to 40 mm Hg.31,35 In patients with

sure.26 In se veral studies of ped igree s, mutation s in MYOC were always coinherited with juvenileonset primary open-ang le g laucoma, a strong indication t hat MYOC is the glaucoma gene in the GLC1A locus.27

MYOC mutations, high intraocular pressure appears to be import ant not only for the onset of glauc oma but a lso for pr ogre ssion of the disea se. These ef fects sug gest that MYOC mut ati ons enc ode a prot ein t hat causes microscopic abnormalities in the struct ures of a n otherwise norma l- appe aring iridocorneal angle, especially the trabecular meshwork. The function of myocilin is unknown. Analysis of its am ino acid s equence has revealed functional domains, including a leucine zipper domain for proteinprotein int eract ions and t wo domains t hat can influence protein localization. The N-terminal of myocilin has a signal sequenc e that targets proteins for secret ion, whereas the last three amino acids at the C-t erminal of myo-

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MECHANISMS OF DISEASE

Right Eye

Left Eye

C
-6 -7 - 7 - 7 -5 -1 -61 - 8 - 6 -8 - 9 -9 -9 -1 0 - 9 -7 -6 - 7 -6 - 6 - -8 5 - -8 5 -5 -1 3 --5 7 -- 10 4 --6 3 -10 - 15 -7 -6 --8 5 - 12 - 14 -8 -5 -9 -18 - 6 - 6 -9

F
- 27 - 15 -8 -17 -2 3- -26 26 - 14 -6 -8 -1 9-2 - 20 3 - 24 -11 -1 0 -1 2 - 22 - 23 -6 -10 -1 1 -6 -4 -6 -8 -9 -2 3 -1 0 -1 1 -7 -1 1 -2 8

-1 5-1 - 29 5- 23 - 33 -31 -2 5 -2 8 -1 7- -32 32 - 29 -32 -3 1 - 21 - 27 - 27 -20 - 32

-9 -5 - 6 - 7 -9

10

10

Total deviation

Total deviation

C RLC <5% <2% <1% <0.5%

LC

CR <5% <2% <1% <0.5%

Figure 2. Optic Disks and Corresponding Visual Fi elds in a Patient with Primary Open-Angle Glaucoma and a MYOC Mutation. AUTHOR: Kwon R ETA KE 1 s t I CM disk, and the accompanying illustration Panel A shows a photograph of the right optic in Panel B shows the superior notching (arrow) of d FIGURE: 2 of 4 rim (R). In addition, the2n REG the cup (C), whi ch represents a focal loss ofF the neuroretinal lamina cribrosa (LC), a dense band of collagen and 3rd glial tissue within the cup that has multipleCA openings for nerve fiber bundles, hasRbecome SE e vi s ed visible because of the loss of overlying neuronal i l Line 4-C tissue. In Panel C, the results of HumphreyEMa visual-field testing show the loss of visual field in total deviati on plots. The upper plot shows SIZE ARTIST: ts H/T H/T the numerical deviation of individual test points, database adjusted for age, and the lower plot 36p6 Enon in decibels, from the values of a normative shows the probability of test points being normal (the darker the Combo square, the lower the probability). There is a substantial loss of visualAUTHOR, PLEASE NOTE: field sensitivity throughout, which is slightly worse inferiorly. The blank space in each plot represents the physiologic blind spot. Panel D Figure has been redrawn and type has been reset. shows a photograph of the left optic disk, with an accompanying illustration Please check carefully.in Panel E, whi ch shows generalized thinning of the rim (R), with enlargement of the cup (C). The results of Humphrey visual-field testing, shown in Panel F, indicate the extensive visual-field loss in the left eye. JOB:36011 ISSUE: 03-12-09

cilin encode a sequence that direct s intracellular proteins to peroxisomes.37 Wild-t ype myocilin protein is secreted, which suggest s that the peroxisomal target ing sequence is not functional under normal circumst ances. The vast majorit y of glaucoma-associated MYOC mutations lie wit hin a large segment of myocilin protein that is homologous to olfactomedin proteins, a family of secreted proteins with unk nown function.31

cilin in aqu eous humor, and myocilin in me diu m from cultured cells can self-associate and form multimers.25,38,43

Decreased Secretion

MYOC mutation s do not app ear t o cause glaucom a as a result of haploinsufficiency or overexpression. Deficiencies in myocilin production resulting from a hemizygous delet ion44 or a presumed Myocilin has been det ected in the t rabecular homozygous null mutation (i.e., Arg46Stop)45 do meshwork, which is the principal structure of not cause glaucoma. Similarly, glaucoma does not th e eye tha t r egu la tes intr aocu lar pr essur e.25,38,39 develop in mice with overexpression of myocilin It has also been found secreted in the growt h or with deficient myocilin production.46,47 These medium of prima ry cultures of hum an tra becular- result s suggest that disease-causing mut at ions meshwork cells and in human and mouse aquealter the myocilin protein in such a way that it ous humor, indicating that myocilin is secreted disrupts t he regulation of intraocular pressure. from trabecular-meshwork cells in vitro and that Indeed, MYOC mut ations associated wit h glaucoin vivo it is secreted from ocular tissues that ma do alter the properties of the protein dismay include the t rabecular meshwork or ciliary ease-associated mut ations reduce t he solubility of body.38,40-42 Re combin ant myocilin pr otein, m yomyocilin in a detergent, whereas benign sequence

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The new england journal of medicine

A
Trabecular-meshwork endothelial cell

Wild-type myocilin protein

Wild-type myocilin protein

Golgi apparatus

Mutant myocilin protein Ribosome Endoplasmic reticulum

DNA mRNA mRNA Nucleus Wild type Wild type mRNA mRNA Wild type

DNA

Mutant

Figure 3. Proposed Pathways for Normal Secretion of Myocilin into the Aqueous Humor and for Secretion Reduced by a MYOC Mutation. In Panel A, wild-type myocilin protein (green symbols) is produced in the endothelial cells of the trabecular meshwork and passes through the secretory pathway to reach the extracellular space. In the first step in this process, messenger RNA (mRNA) is transcribed from the COL OR F IGU RE gene encoding myocilin (MYOC) and is delivered to ribosomes at the endoplasmic reticulum, where the mRNA directs the synthesis of Draft 6 02/19/09 myocilin. Next, transport vesicles convey myocilin to the cell membrane through the Golgi apparatus. These vesicles fuse with the cell membrane A ut and h or release myocilin into the extracellular space and aqueous humor. Along the secretory pathway, molecules of myocilin may Fi with g # each 3 associate other and form multimers (dimers and tetramers are depicted). In Panel B, heterozygous mutations of the MYO C gene Ti t le with an autosomal dominant form of glaucoma. The wild-type copy of MYO C encodes normal myocilin protein (green symare associated MEthe mutant MYOC copy encodes mutant myocilin protein (red symbols). Myocilin protein forms multimers that may be combols), and DE posed of both wild-type and mutant subunits. Secretion of mutant myocilin protein and multimers containing mutant subunits is greatly rer t ist to SB L retention of the mutant protein in the endoplasmic reticulum and intracellular vesicles of trabecular-meshwork cells. duced, A leading the K wo n
A UTHO R P L EASE NOTE : F igu r e h as b een r edr awn a nd ty p e h as bee n r ese t P lea se ch eck car efu lly

Is su e dat e

pol ymor ph ism s ha ve no suc h e ffe ct. 48 Glaucomarect s proteins t o peroxisomes, and there is evia ssociate d mut ations also r educ e t he secr etion dence of that mutant myocilin may be retained myocilin in vitro and in vivo. Secretion of myociwithin the int racellular space by means of an l in i s dra mat i ca ll y reduced i n t r abec ula r-meshw ab normal ork assoc iation wit h prote ins of t he peroxce lls cultur ed fr om pa tients with glaucom a-ass isome-t oargeting system.49 Other studies in mice ciated MYOC mutations.40 Sim ila r ly, MYOC have mut ashown that mutat ions in the murine myotions greatly reduce the quantity of myocilin thatcilin gene (Myoc) can inhibit secretion of myociis se cre ted into t he aque ous h umor,40 supporting lin and cause some signs of glaucoma without the idea t hat failure to secrete myocilin is a cen-a cryptic targeting domain.50 Regardless of the tr a l feat ur e in the pa thoge nesis of myocilin-ass mechanism oof retent ion, decreased secretion and ciated glaucoma (Fig. 3). increased accumulation of int racellular myocilin MYOC mutations may prevent the secretion of appear to be initial steps in t he pathogenesis of myocilin by exposing a cryptic domain that dimyocilin-associated glaucoma.

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MECHANISMS OF DISEASE

Figure 4. The Optic-Nerve Head and Proposed Events A Central Retinal Leading to Retinal Ganglion-Cell Death in Glaucoma. ganglion cell retinal vein Central Mllers cell In the normal optic-nerve head and retina (Panel A), Glial cell retinal artery retinal ganglion-cell axons exit the eye through the lamina cribrosa, becoming myelinated only in the postlaminar region. Glia in the retina (e.g., Mllers cells) and optic-nerve head (e.g., astrocytes and mi croglia) are Sclera Photoreceptor quiescent (green). Increasingly elevated intraocular layer Retinal pigment pressure puts stress on retinal ganglion cells, and glial Lamina epithelium cells become reactive (Panel B, red). Elevated intraocucribrosa lar pressure also leads to the production of a vari ety of Myelinated retinal substances, including tumor necrosis factor a, which ganglion-cell axon in turn damage retinal ganglion-cell axons (dashed lines) at the lamina cribrosa. At this point there is no B clinically detectable change in the cupping of the opticnerve head. Damage to retinal ganglion-cell axons is followed by cell (soma) death throug h apoptosis (Panel C). Loss of retinal ganglion cells and axon fibers results in thinning of the nerve-fiber layer. The lamina cribrosa itself undergoes remodeling , becoming thicker while bowing posteriorly (blue arrows), with increased cupping of the optic-nerve head (black arrows). In the advanced stage of glaucoma (Panel D), apoptosis and neuroinflammatory processes result in cell death and loss of most retinal ganglion cells and axons. The prelaminar tissue is substantially attenuated, and the lamina cribrosa becomes thinner and bowed more posteriorly (blue C Thinning of arrows), resulting in pronounced cupping of the opticnerve fiber layer nerve head (black arrows).

Injury or death of trabecular-meshwork cells

has been implicated in the pathogenesis of openangle glaucoma.51 Endothelial cells of the tra bec-

ular meshwork maintain its structure and facilitate the outflow of aqueous humor from t he eye by remodeling t his porous tissue and preventing D debris from occluding the out flow pathway. A reduction in cellularity and alterations in the architecture of t he t rabecular meshwork have been observed in glaucoma,52 and these changes may increase resistance to aqueous outf low, thereby elevating in traocu lar pressu re and even tually damaging t he optic nerve.51,53 Mutant myocilin that accumulat es in the intracellular space may be toxic to t rabecular-meshwork cells, init iating a cascade of events that begins with loss of function in t hese cells, which damages the outflow pathway and results in elevated intraocular pres- mutations in t he myocilin gene on the structure and sure. The f inding th at aqueou s hu mor outf low is funct ion of t he outflow pat hway at t he t issue, and subcellular levels. In particureduced in pat ients w it h MYOC mutat ions sup- cellular, CO LO R FIG URE lar, the se animal mode ls will fac ilitat e st udies of port s this hypothesis.54 The development of ani- Draft 5 02/23/09 the effect s of MYOC mutat ions on the healt h and m a l m o d e l s o f m yo c il i n- as s o c i at e d l au c o m a50,55,56 A ug t hor F ig # numbers of trabecular-meshwork cells and the 4 provides new tools for exploring the effect s of T it l e
ME DE Ar t is t S BL K12, w OR on n engl j med 360;11 nejm.org march 2009 AUTH PL EASE
NO TE:

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The new england journal of medicine

organization of the ext racellular st ructure of the creased expression of many genes specific to retinal g anglion cells74 ,7 6-79 and increased expression trabecular meshwork.
of markers of hypoxia and glial activation.65,80,81

Damage to the Optic-Nerve Head

It is generally believed that elevated intraocular pressure regardless of it s cause triggers a common set of cellular events. The optic-nerve head consists of axons project ed from retinal ganglion cells, which exit t he eye through the lamina cribrosa, a collagenous structure wit h sievelike openings (Fig. 4A). The lamina cribrosa separates u nm yelinated p relam inar ret inal g anglion-cell axons from myelinated post laminar retina l ga nglion-c ell a xons. The opt ic-n erve hea d also contains ret inal vasculature (the central retinal artery and vein) and such glial elements as microglia, astrocy tes, and oligodendrocytes (the oligodendrocytes are present only in the postlaminar region and are important in postlamin ar a xo n m yel i nat ion).57,5 8 We outl i ne sever a l ke y mechanisms of optic-nerve damage that are ca used by el eva ted i nt ra ocu la r pre ssure , al thoug h damage that is independent of elevated intraocular pressure may also occur in primary openangle glaucoma. We limit t he discussion to recent literature; more comprehensive reviews of the subject can be found els ewhere.59-61

Glial cells in the optic-nerve head (microglia

and astrocy tes) become activated in response to the elevated intraocular pressure in glaucoma82-85 (Fig. 4B). Activat ed ast rocytes synthesize molecu le s that lead to de gradat ion and re modeling of the ext racellular matrix, and these changes can have biomechanical effects on t he opt ic-nerve head that in turn increase stress on retinal ganglion-cell axons.86,87 In a mouse model of glaucoma , activated glia l cells relea sed t umor n ecrosis factor a (TNF-a), a proinf lammatory cyt okine.88 Deletion of the genes encoding TNF-a or it s receptor increased the surv ival of retinal ganglion cells in this model.88,89 Intravitreal injection of TNF-a causes loss of retinal g ang lion-cell axons and subsequent ly loss of entire cells, even in the absence of elevated intraocular pressure. These results suggest that TNF-a can be a mediator of damage of retinal ganglion-cell axons when intraocular pressure is elevated. The presence of TNF-a in human glaucomatous retina90 and optic-nerve head91 h as been detec ted by im munohistochemical analysis. Collect ively, this evidence suggests t hat glial act ivation and TNF-a are important mediators of damage t o ret inal ganglion-cell axons.88,90,91

Cellular Stress Elevated intraocular p ressure h as direc t ef fects on Structural Changes retinal gang lion cells. Axonal transport decreases Cupping of the opt ic-nerve head result s f rom the in the presence of elevated int raocular presloss of prelaminar t issu e and posterior deformasure.62 The reduced retrograde axoplasmic f low tion of the lamina cribrosa. Three-dimensional can stress retinal ganglion cells and cause their histomorphometric studies of primates wit h exdeath from deprivation of neurotrophic factors perimentally induced glaucoma raised the possisuch as brain-derived neurotrophic f actor.62-64 If bilit y that one of t he early changes in t he st rucblood perfusion at the optic-nerve head is persistently reduced,65- 67 tissue hypoxia can induce ture of the optic-nerve head in glaucoma is the th ic kening r athe r tha n thin ning of pr ela mthe formation and accumulation of reactive oxyinar t is sue.87,92 This change is accompanied by gen species in the retina, and t his accumulation microglial proliferation.93 Sub seque ntl y, th e l a mca uses cel l ul ar str ess an d ma l fu ncti on.68 In g la ucoma, proteins and lipids with oxidative modifiina cribrosa bows posteriorly (Fig. 4C). These cations accumulate in t he retina and optic-nerve changes in t he lamina cribrosa, combined wit h he ad, a nd ant iox id an t tr eat ment s ha ve some ben - eventual loss of prelaminar tissue, make the the ef it in animal mod els.69-73 The use of micro array cup larger and deeper. The biomechanical consetechnology in animal models has show n that quences of these changes are believed to strain changes in t he gene-expression profile of the retina occur rapid ly in response to elevated intra- retinal ganglion-cell axons, which f urther comprom ises their function.87 These morphologic ocular pressure.74,75 These changes include de-

findings are accompanied by changes in the composit ion of the ext racellular matrix of the

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MECHANISMS OF DISEASE

opt ic-nerve head, including increased synt hesis of glauco ma. Coupled wit h thinning and f urther of collagen IV, prot eoglycans, adhesion molepost erior bowing of the lamina cribrosa, apopcules, and matrix met alloproteinases and a loss tot ic loss of the retinal ganglion cells result s in of gap-ju nct io n com munication that accompaa large, deep cup, as seen clinically in advanced nies astrocyte acvation.83,86,94,95 ti glaucoma (Fig. 4D). Retinal ganglion-cell deat h is not accompaDamage to Retinal Ganglion-Cell Axons nied by prominent infilt ration of mononuclear cells, alt hough t here is indirect evidence of inClinical observations have indicated that t he opticne rve h ead , an d m ore spe cifically th e lamina c riflammatory processes, as indicated by the presbrosa, is the initial site of glaucomatous damence of autoantibodies against ret inal ant igens age.96 In anim al models, and presum ably also in human glaucoma, damage t o ret inal ganglion-cell in pat ients with glaucoma.81 Instead, glial cells a xon s prece des the de ath of th e c ells9 7,98 (Fig. 4B phagocytose cellular debris and initiate a scar and 4 C). In t he DBA2/J mouse strain, elevated re sp onse after retinal g anglion-ce ll de ath. Inf lamint raocular pressure develops spontaneously at 7 t o 9 mont hs of age, and soon t hereafter, axonal mat ion-like glial activity is frequent ly observed in shrinkage and decreased retrograde transport o cdegenerative disorders of the central nervous syscu r, even thoug h th e soma of th e r eti n al ga ngl i on ce lls appe ars norma l.99 In t hese m ice , the retin al tem and is referred to as neuroinflammat ion, a ganglion-cell axons proxim al to t he point of myprocess distinct from the adapt ive immune reelination survive, suggesting that damage to the sponse and more ak in t o a reaction of t he innat e axons occurs in an area t hat corresponds to the lamina cribrosa in primates.7 7,9 7 Ho we ver, r eti n al immune system.107 In glaucoma, glial expression ga ngl ion ce ll s sur vi ve for on ly ab out 1 to 2 mont hs of major-histocompatibility-complex (MHC) class after axonal degeneration.7 7,97 Thus, the degradation of t he retinal ganglion-cell axon and soma II molecules108 and synthesis of components of may involve separate mechanisms.100 In DBA/2 the complement cascade109,110 occur as retinal mice, damage to retinal ganglion-cell axons ocganglion-cell deat h continues, and t hese procurs despite t he absence of the collagenous lamina cr ibrosa plate s t ypica lly found in p rima tes.101 cesses may further contribute t o t he degeneraThis finding suggest s that a cell-mediated mechtion of retinal ganglion cells. anism underlies the damage, perhaps invo lv ing
excessive synthesis of extracellular matrix material83,86,94,95 or elevation of int ra-axonal calcium levels resulting from overexpression of ephrin-B2 (a receptor tyrosine kinase in glioma ce lls).102,103

Conclusions

In glaucoma, a major cause of blindness, the ganglion-ce ll axons th at m ake up th e op tic ne rve are damaged by a variety of factors, only some of which are underst ood. The most important risk factor for glaucoma is elevated intraocular pressure. Because the optic-nerve damage in glaucoma is not yet amenable to direct treat ment, we provide treat ment for the only k nown risk factor that can be modified, elevated int raocular pressure. As more is understood about the mo lec ular Loss of Retinal Ganglion Cells biology of t he trabecular meshwork and optic Axonal damage and chronic st ress result in thenerve in healt h and disease, our abilit y t o t reat de ath of r eti n al g ang li on cel l s. Most, i f no t al l , ofwill likely improve. glaucoma Supported th e l oss of r eti n al ga ngl i on ce l ls i n the gl aucom a-in part by g rants from the Marlene S. and Leonard A. Hadley Glaucoma Research Fund and Research to Prevent tous re tina o ccurs through apoptosis.104,105 InhiBli ndness. Dr. Kwon received supp ort from the Clifford M. and bition of apoptosis by deletion of t he Bax gene in Ruth M. Altermatt Professorship, and Dr. Alward received sup a mouse model of glaucoma almost completely port from the Frederick C. Blodi Chair. Dr. Fingert reports receiving grant support from Alcon Rer escue s th e r et in a l g an glion- cell soma , but a xon search ands holding several unlicensed patents related to gene a re not pre served .100 By me an s of non inva discovery sive di-in glaucoma, and Dr. Alward reports h oldi ng an unl icensed rect imaging of apoptotic cell death,106 it ha s bee n patent for the diagnosis of MYOC mutations. No other potent ial conflict of interest relevant to this article was reporte d. possible to observe progressive loss of retinal We t hank Patrici a Duffe l, R.Ph., M.A., for her assist ance wit h ganglion-ce ll axons and c ell bodies in a rat model the preparation of the manuscript.

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The new england journal of medicine

References 1. Hayreh SS, Jonas JB. Optic disc mor- Philadelphia: Lippincott Wil liams & Wi l- encoding the evolutionarily conserved olfact om edin-homology domain of T IGR in phology after arteritic anterior ischemic kins, 2005:170-90. optic neuropathy. Ophthalmolog y 2001; 16. Bahrami H. Causal i nference i n pri- fami lial open-angle glaucoma. Hum Mol 108:1586-94. mary open angle glaucoma: speci fic dis- Genet 1997;6:2091-7. cussion on intra ocula r pressure. Opht ha l-31. Fingert JH, Stone EM, Sheffield VC, 2. Alwa rd WL. B iomedici ne: a new a ngle mic Epidemiol 2006;13:283-9. on ocula r deve lopment. Scie nce 2003;299: Alward WL. Myocilin glaucoma. Surv 1527-8. 17. Heijl A, Leske MC, Bengtsson B, Hy- Ophthalmol 2002;47:547-61. 3. Fingert JH, Hon E, Liebmann JM, et man L, Bengtsson B, Hussein M. Reduc- 32. Rezaie T, Child A, Hitchings R, et al. t ion of int ra ocula r pressure and glauc omAdult-onset a a l. Ana lysis of myocil in m ut at ions in 1703 primary open-angle glaucoma progression: results from the Early Mani- ca use d by mut at ions in opt ineurin. Scie nce glaucoma pat ients f rom f ive diff erent pop ulations. Hum Mol Genet 1999;8:899-905. fest Glaucoma Trial. Arch Ophthalmol 2002;295:1077-9. 4. Aldred MA, Bau mber L, Hil l A, et al. 2002;120:1268-79. 33. Monemi S, Spaeth G, DaSilva A, et al. Low pre vale nce of MYOC mut ations in UK 18. Kass MA, Heuer DK, Higgi nbotham Identification of a novel adult-onset priprimary op en-angle glaucoma patients EJ, et al. The Ocular Hypertension Treat- ma ry ope n- angle glaucoma (POAG) gene on limits the uti lity of genetic testing. Hum ment Study: a randomized trial determines 5q22.1. Hum Mol Genet 2005;14:725-33. Genet 2004;115:428-31. that topical ocular hyp otensive medica- 34. Chall a P. Glauc om a genet ics. Int O phtion delays or prevents the onset of pri5. Graul TA, Kwon YH, Zim merma n M B, thalm ol Clin 2008;48(4):73-94. ma ry open-a ngle gla uc om a. Arch Ophtha l- Alward WLM, Fingert JH, Coote MA, et al. A case-control comparison of the 35. cli nical characteristics of glaucoma and mol 2002;120:701-13. et al. Clinical featu res associated with ocular hyper tensive patient s wit h and wit19. h- Alward WL. Medical management of mutations in the chromosome 1 openout the myocilin Gl n368Stop mutation. glaucoma. N Engl J Med 1998;339:1298- angle glaucoma gene (GLC1A). N Engl J Am J Ophthalmol 2002;134:884-90. Med 1998;338:1022-7. 3 07. 6. Kwon YH, Caprioli J. Primary open 20. We inreb RN, Khaw PT. Prima ry ope n36. Allingham RR, Wiggs JL, De La Paz angle glaucoma. In: Tasman W, Jaeger angle glaucoma. Lancet 2004;363:1711-20.MA, et al. Gln368STOP myocilin mutaEA, eds. Duanes clinical ophthalmology. 21. Johnson AT, Ric hards J E, Boehn ke M, tion in fami lies with late-onset primary Philadelphia: J.B. Lippincott, 1999:1-30. et al. Clinic al phenotyp e of juvenile-onset open-angle glaucoma. Invest Ophthalmol Vis Sci 1998;39:2288-95. primary open-angle glaucoma linked to 7. Alwa rd WLM. Open a ngle glaucoma s. In: Alward WLM, ed. Glaucoma: the requi-chromosome 1q. Ophthalmology 1996; 37. Fingert JH, Ying L, Swiderski RE, e t a l. sites in ophthalmology. St. Louis: Mosby, 103:808-14. Ch aracterization and comparison of the 2000:128-40. 22. Sheffield VC, Stone EM, Alward WL, human and mouse G LC 1A g laucoma g enes. Genome Res 1998;8:377-84. 8. Rudnicka AR, Mt-Isa S, Owen CG, et al. Genetic linkage of familial open Cook DG, Ashby D. Variations in primary angle glauc om a to chromos ome 1q21-q31. 38. Nguye n T D, Chen P, Hua ng WD, Chen open-angle gl aucoma prevalence by age, Nat Genet 1993;4:47-50. H, Johnson D, Polansk y JR. Gene strucgender, a nd race: a Bayesia n m eta- ana lysis. 23. Wiggs JL. Genetic etiologies of glau- ture and properties of TIGR, an olfactoInvest Ophthalmol Vis Sci 2006;47:4254- coma. Arch Ophth almol 2007;125:30-7. med in-related glycoprotei n cloned from 61. 24. Ort ego J, Escribano J, Coca-Prados M. glucocorticoid-induced trabecular mesh9. Sommer A, Tielsch JM, Katz J, et al. Cloning and characterization of subtract- work cells. J Biol Chem 1998;273:6341-50. Relationship between intraocul ar pres- ed cDNAs from a human ciliary body l i- 39. Ltjen-Drecoll E, May CA, Polansky sure and pri mary open angle glaucoma brary encoding TIGR, a protei n involved JR, Johnson DH, Bloemend al H, Ng uyen among white and bl ack Americans: the in juvenile open angle glaucoma with TD. Localization of the stress proteins Balti more Eye Sur vey. Arch Ophthalmol alpha B-cr ystallin and trabecular meshhomology to myosin and olfactomedin. work inducible glucocorticoid response 1991;109:1090-5. FEBS Lett 1997;413:349-53. 10. Tie lsch JM, Katz J, Somme r A, Qu igle 25.yPolansky JR, Fauss DJ, Chen P, et al. protein in normal and glaucomatous traHA, Javitt JC. Hypertension, perfusion Cellular pharmacology and molecular bi- becular meshwork. Invest Ophthalmol Vis pressure, and primary open-angle glauco- ology of the trabecular meshwork i nduc- Sci 1998;39:517-25. ma: a population-based as sessment. Arch ible glucocorticoid response gene product. 40. Jac obson N, Andrews M, Shepard AR, Ophthalmol 1995;113:216-21. Ophthalmologica 1997;211:126-39. et al. Non-secret ion of mutant protei ns of 11. Idem. Family history and risk of pri26. Kubota R, Noda S, Wang Y, et al. the glaucoma gene myocili n in cultured t ra ma ry ope n angle glauc om a: the B alt imore A n ovel myosin-l ike prot ein (myoci lin) ex - becul ar m eshwork ce lls and in aqueous humor. Hum Mol Genet 2001;10:117-25. Eye Survey. Arch Ophthalmol 1994;112: pressed in the connecting cilium of the 69-73. photoreceptor: molecul ar cloning, tissue 41. OBrien TE, Metheney CD, Polansky 12. Mitchell P, Hourihan F, Sandbach J, expression, and chromosomal mapping. JR . I mmunof luor esce nce me thod f or qua ntifying the trabecu lar meshwork glucoWang JJ. The rel ationship between glau- Genomics 1997;41:360-9. coma and myopia: the Blue Mountains Eye 27. Stone EM, Fingert JH, Alward WL, et corticoid response (TIGR) protein in trabecular meshwork and Schlemms canal Study. Ophthalmolog y 1999;106:2010-5. al. Identification of a gene that causes primary open angle glaucoma. Science cells. Curr Eye Res 1999;19:517-24. 13. Wong T Y, Klein BE, Klein R, Knudtson M, Lee KE. Refractive errors, i ntraocular 1997;275:668-70. 42. Wordinge r RJ, Cla rk AF. Eff ects of glupressure, and glaucoma in a white popu- 28. Wiggs JL, Allingham RR, Vol lrath D, cocort icoids on the t rabec ular mesh work: lation. Ophthalmology 2003;110:211-7. et al. Prevalence of mutations i n TIGR/ towards a better understanding of glau14. Gordon MO, Beiser JA, Brandt JD, et Myocil in i n patients with adu lt and juve- coma. Prog Retin Eye Res 1999;18:629al. The Ocul ar Hypertension Treatment nile primary op en-angle glaucoma. Am J 67. Study: baseline factors that predict the Hum Genet 1998;63:1549-52. 43. Gobeil S, Rodrigue MA, Moisan S, et onset of primary open-angle glaucoma. 29. Stoilova D, Child A, Brice G, et al. al. Intracellular sequestration of heteroArch Ophthalmol 2002;120:714-20. Novel TIGR/MYOC mutations in families oligomers formed by wild-type and glau15. Clinical epidemiology of glaucoma. with juvenile onset primary open angle coma-causing myocilin mutants. Invest In: Alli ngham RR, Damji KF, Freedman S,glaucom a. J M ed Gen et 1998;35:989-92. Ophthalmol Vis Sci 2004;45:3560-7. Moroi SE, Shafranov G, Shields MB. 30. Adam MF, Belmouden A, Binisti P, et 44. Wiggs JL, Vollrath D. Molecular and Shields textbook of glaucoma. 5th ed. al. Recurrent mutations in a single exon cli nical evaluation of a patient hemizy-

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MECHANISMS MECHANISMS OF DISEASE OF DISEASE

gous for TIGR/MYOC. chanics underlies Arch the Ophthalmol susceptibility 59. Kuehn and MH, bution Fi of ngert connexin JH, Kwon 43 in astrocytes. YH. doxi Glia n 1 andvated thioredoxin intraocular 2 supp pressure. ort retinal Invest Oph2001;119:1674-8. cli nical behavior of the aged optic nerve 2007;55:1085-98. thalm survival ol Visin Sci experimental 2001;42:2303-14. Retinal ganglion cell death in glaucoma: ganglion cell head. J Glaucoma 2008;17:318-28. glaucoma. Gene 2009;16:17-25. and neuroprotective strate45. Lam DS, Leung YF, Chua JK, et al. mechanisms95. Morrison JC, Dorman-Pease ME, Du n104. Ther Kerrigan LA, Zack DJ, Quigley HA, gies. Opht ha lmol Clin Nort h A m 2005;18: Trunca tions 88. in t Nakazawa he TIG R T, gene Nakazawa in in dividuC, M atsubara kelberger GR, Quigley HA. Optic 74. Yang nerve Z, Smith Quigley SD, HA, Pease Pease ME. ME,TUNEL-positive et al. 383-95. mehea als with andA, without open-angle ry opt ic cells in human primary opene t a l.primary Tumor ne crosis f actor-alpha di- d e xt race llular mat rix in prima Changes in ganglion gene expression in experiglaucoma . Iates nve oligodendrocyte st O pht ha lmol Vis Sc i 2000; rophy exThe perime nta l gl ment aucoma . A angle rch glaucoma. Arch Ophthalmol death and a l gla ucoma a nd opt ic nerve tra nsec - 1997; 60.delayed Vrabe c at J P, Leviannd LA. ne urobiology 41:1386-91.retin al ga nglion ce ll loss in a of Opht halmol 1990;108:1020-4. mouse ilibrium between protective cell model death in glaucoma. Ey e 2007;21: tion: the equ115:1031-5. glaucoma. J Neurosci 2006;26:12633-41. and OphSuppl 1:S11-S14. 46. Kim BS,of Savinova OV, Reedy MV, et al. 96. Qui gley HA. Neuronal death in detrimental glau- 105.mechanisms. Quigley HA,Invest Nickells RW, Kerrigan thalm ol VisLA, Sci Pease 2007;48:5539-48. Targeted disruption 89. Kitaoka of the Y,myocilin Kwong JM, gene Ross-Cisneros 61. Wax MB, coma. Tezel Prog G. Retin Neurobiology Eye Res of 1999;18:39ME, Thibault DJ, Zack DJ. Reti(Myoc) suggests human glaucoma- optic ganglion cellStephan death in experimental FN, etthat al. TNF-alpha-induced glaucomatous nerve 57.optic neuropathy: di verse 75. Ahmed nal F, Brown K M, DA, causing mutations are gain of nuclear function. glaucoma and Tomarev after axotomy degeneration and factor-kappaB cellular events neurodegeneration and Jakobs 97. in Howe ll GR, Libby RT, Morrison TC, et JC, a Johnson l. EC, SI. Mi-occurs by Mol Cell Biol 2001;21:7707-13. apoptosis. Invest Oin pht hal mol Vis Sci 1995; p65. Invest Ophthalmol Vis Scineuroprotection. 2006;47: Axons Mol Neurobiol 2002;26: analysis of changes mRNA of retinal ganglion cells croarray are insu lt14 4 Miceli-Libby 8 -5 7. 45-55. levels in the36:774-86. rat retina after experimental ed in t he optic ne rve early in DBA/2J glau47. Gould DB, L, Savi nova elevation of 106. intraocular pressure. Invest coma. J Cell Biol 2007;179:1523-37. OV, et al. Genetically 90. Tez el i G, ncreasing Li LY, Pat Myoc il RV, ex-62. Wa Quigle x MB. y TN HA, F- McKin non SJ, Zack DJ, e t Cordei ro MF, Guo L, Luong V, et al. Ophthalmol Vis Sci 2004;45:1247-58. pression supports necessary pathologic alpha aand TNF-alpha receptor-1 al. Retrograde in the 98.axonal Schlamp transport CL, Liof Y,BDNF Dietz JA, Janssen Real-time imag ing of single nerve cell role of abnormal ns inand glaucoma. retina protei of normal glaucomatous in retinal eyes. ganglion cells RW. is blocked by 76. ap optosis in Clark retinalAF, neurodegeneration. KT, Nickells Progressive ganglion Kim CY, Kuehn MH, Kwon Mol Cell Biol 2004;24:9019-25. Invest Ophthalmol Vis Sci 2001;42:1787acute IOP elevation in rats. Proc Natlprofile Acad of Sci Uadult S A 2004;101: cell loss and opticInvest nerve Ophdegeneration in expression YH. Gene the Sci 2000;41:3460-6. 13352-6. mice is variable and asy mmetric. huma n re tin al gangl ion ce ll laye r. Mol V is 48. Zhou Z, 94. Voll rath D. A cellular assay thalm ol VisDBA/2J BMC Neurosci 2006;7:66. distinguishes 91. normal Yan X, and Tezel mutant G, TIGR/ Wax MB, 63. Edward Pease DP. ME, McKinnon SJ, Quigley HA, 2006;12:1640-8. 10 7. Streit WJ, Mrak RE, Griffi n WS. Mimyoci lin prot ein. Hu m M ol G enet 1999;8: Matrix metalloproteinases and tumor K er r neig an-B 99. au Jakobs mr ind TC, L A, Libby Zack RT, DJ. Ben Ob Y, 77. str John Sot uco tSW, I, Oglesby croglia and E, Buckingha neuroi nflammation: m BP, et al. a patho2221-8. crosis factor alpha in glaucomatous ed axonal optic transport ofRH. BDNF relogical perspective. J Neuroi Ma sland Retand ina its l ga nglion Ret cell inal dege ganglion ncel ls downregul ate ge nflammation ne head. Arch mol ceptor TrkB in experimental glaucoma. 2004;1:14. eration is topological but not expression cell ty pe and lose their axons within 49. Shepard nerve AR, Jacobson N, Ophthal Millar JC, et 2000;118: 666-73. myocili n mutants In vest Ophth almol i Vis Sci 2000;41:764-74. specific n DBA/2J mice. J Cell t Biol he opt 2005; ic nerve he ad in mouse al. Glaucoma-causing 108. Yang J, a Yang P, glauc Tezel om G, aPatil RV, 171:313-25. model. J Neurosci 2008;28:548-61. r equir e the92. perYang oxisom ta rge ting H,alDowns JC, signal-1 Bellezza 64. Balaratnasingam A, C, Morgan WH, Hernandez MR, Wax MB. Induction of receptor (PTS1R) to elevate i ntraocular HLA-DR in human lamina criThompson H, Burgoy ne CF. Bass 3-D L, histoMatich 100. G, Libby Cringle RT,SJ, LiYu Y, DY. Savi Axnova 78. OV, Hua et ng al. W, Filet a expression J, Guo Y, Grosskreut z pressure. Hum Mol Genet 2007;16:609-17. by cytokines morphometry of the normal and onalearly transport and cytoskeletal changes Susceptibility to neurodegeneration CL. Downregulation in a brosa astrocytes of Thy1 in retinaland simulated Invest Ophthalmol Vis Sci glaucomatous monkey opticR, nerve in the head: laminar regions is after elev ated n- gene glaucoma modified by iBax gangldosion cells inischemia. experimental glaucom a. 50. Senatorov V, M alyu kova I, Fariss et 2001;42:365-71. prelaminar tissues andlin tcupping. ra ocula r pressure. I nvest ha lmol Vis age. PLoS GenetOpht 2005;1:17-26. Curr Eye Res 2006;31:265-71. a l. Ex pression of mutaneural ted mouse myoci Invest Ophthalmol 2007;48:5068Sci 2007;48:363244.CA, Lutjen-Drecoll E. induces open-angle glaucoma Vis in Sci trans101. May 79. MorpholSchlamp109. CL, Stasi Johnson K, Nagel EC, Li D, Y, Yang Mor-X, et al. Comgenic mice. 84. J Neurosci 2006;26:11903-14. 65. Rajendram ogyR, ofRao the murine NA. Neuroglobin optic ner ve. rison I nvesJC, t ONickells phplement RW. component Changes 1Q in (C1Q) Thy1 upregulation thalm Vis Sci 2002;43:2206-12. in retina associated of murine, with primate, damaged and human 51. Alvarado 93. J, Murphy JohnsonC, EC, Juste Jia L, r R. Cepurna Trabec inWO, - norm Doser al re tina ol a nd ret ina f rom eye s wgene it h expression retnina l ga nglion glaucomatous c ells. Mol eyes. Vis Invest 2001;7:192Ophthalmol uc Du om J, a. Tran B r JT, O Fu phtC, hal mol 2007; ula r meshwork TA, cellula Morrison rit y JC. in Global primary changes ope adva n- in nced optic gla 102. Sret ava DW. Up 201. at the Vi s Sci 2006;47:1024-9. 91:663-6. angle glaucoma nerve and headnongl geneaucomatous expression after expo- regulation of EphB2 and ephrin-B2 normals. Ophthalmology sure to elevated 1984;91:564-79. intraocular pressure in a G,optic head of DBA/2J glaucomatous 66. Tezel Wax nerve MB. Hypoxia-inducible 80. Steele MR, 110. Inman Kuehn MH, DM, Kim Cal kins CY, Ostojic DJ, J, et al. rat coll glaucoma model. Ophthalmol mice coincides with retina axon loss. Invest Retinal synthesis and analysis deposition of com52. Ltjen-Dre E, Rohe n JW.Invest Morpholfactor 1alpha in the glaucomatous Horner PJ, Vetter ML. M icroarray Vis outflow Sci 2007;48:3161-77. Ophthalmol Vis Ophthalmol Sci 2007;48:5567-81. head. Arch of retinal gene expression in the DBA/2J ogy of aqueous pathways in nor- and optic nerve plement components induced by ocu lar 2004;122:1348-56. of et glaucoma. Invest Ophthalmol mal and gl aucomatous In: H, Ritch R, A, 94. Malone eyes. P, Miao Parker Juarez S, 103. Pena J D, Agapova O, Gamodel belt BT, a l. hypertension. Exp Eye Res 2006;83:620Shields MB,Hernandez Krupin T, MR. eds. The glaucom as. Pressure i nduces 67.loss Moz of af fa Increas rieh M, edG elastin rie shabe expres r MC sion , Flam i Vis n astroc -Sci 2006;47:977-85. ytes 8. 2nd ed. St. Louis: Mosby, 1996:89-123. and gap junction communication redistriof the cribrosa i n response ele-G,CWax mer J. Oxygen andlamina blood flow: p layers in 81. to Tezel immune sysop y rMB. ig ht The 20 0 9 Ma ssa ch uset t s Med i ca l So c ie ty . 53. Rodrigues MM, Spae th GL, Sivali nga the m pathogenesis of glaucoma. Mol Vis tem and glaucoma. Curr Opin Ophthalmol 2004;15:80-4. E, Weinreb S. Histopathology of 150 tra- 2008;14:224-33. beculectomy specimens in glaucoma. Trans 68. Ko ML, Peng PH, Ma MC, Ritch R, 82. Pena JD, Varela HJ, Ricard CS, HerOphthalmol Soc U K 1976;96:245-55. Chen CF. Dy namic changes in reactive nandez MR. Enhanced tenascin expres54. Wilkinson CH, van der Straaten D, oxy gen species and antioxidant levels in sion assoc iat ed with rea ct ive ast roc yt es in Craig JE, et al. Tonog raphy demonstrates retinas in experi mental glaucoma. Free human optic nerve heads with primary Radic Biol Med 2005;39:365-73. open angle glaucoma. Exp Eye Res 1999; reduced facil ity of out flow of aqueous humor in myoc ilin muta tion ca rrie rs . J Gla 69. u- Tezel G, Yang X, Cai J. Proteomic 68:29-40. coma 2003;12:237-42. identi fication of oxidatively modified reti- 83. Agapova OA, Ricard CS, Salvador-Silva ed 55. Zhou Y, Grinchuk O, Tomarev SI. na l pr ote ins i n a chr onic pre ssur e-i nduc M, Hernandez MR. Expression of matri x rat model of glaucoma. Invest Ophthal- metalloproteinases and tissue inhibitors Transgenic m ic e expressi ng the Tyr437His of me ta llopr ot einas es in hum an optic ner ve mutant of human myoci lin protei n devel- mol Vis Sci 2005;46:3177-87. op glaucoma. Invest Ophthalmol Vis Sci 70. Liu Q, Ju WK, Crowston JG, et al. Oxi-head astrocytes. Gl ia 2001;33:205-16. 2008;49:1932-9. dative stress is an early event in hydro- 84. Hernandez MR, Agapova OA, Yang P, 56. Paper W, Kroeber M, Heersink S, et al. static pressure c o l l e c t iinduced o n s o f aretinal r t i c l eganglion s o n t h e j oSalvador-Silva M, Ricard CS, Aoi S. Difu r n a l Invest s w e b Ophthalmol ite cell damage. Vis Sci gene expression in astrocytes Ele vate d a mounts of myoci lin in the aque - The Journals Web ssite (NEJM.org) sortsferential published articles into 2007;48:4580-9. from and glaucomatous ous hu mor of transgenic mice cause sigmore than 50 distinct clinical collections, which can human be usednormal as convenient c nerve by cDNA minificant changes in ocular gene expres-entry71. Moreno MC, Campanelli Sande P, opti points to clinical content. In J, each collection, articles arehead cited analyzed in reverse Glia 2002;38:45-64. sion. Exp Eye Res 2008;87:257-67. Snez DA,chronologic Kel ler Sarmiento MI, Rosenorder, with the most croarray. recent first. 57. Minckler DS, McLean IW, Tso MO. stein RE. Retinal oxidative stress i nduced 85. Yang P, Agapova O, Parker A, et al. Distribution of axonal and gli al elements by high intraocular pressure. Free Radic DNA microarray analysis of gene expresin the rhesus optic nerve head studied by Biol Me d 2004;37:803-12. sion in hum an optic ner ve he ad ast roc yt es electron microscopy. Am J Ophthalmol 72. Tezel G, Luo C, Yang X. Accelerated in response to hydrostatic pressu re . Phys 1 97 6;8 2 :17 9 -8 7. aging in glaucoma: immunohistochemi- iol Genomics 2004;17:157-69. cal assessment of advanced glycation end 86. Hernandez MR. The optic nerve head 58. Zha ng J, Rubi n RM, Rao NA . A na tomy and embryolog y of the optic nerve. In: products in the hu man retina and optic in glaucoma: role of astrocytes in tissue Tasman W, Jaeger EA, eds. Duanes fou n- nerve head. Invest Ophthalmol Vis Sci remodel ing. Prog Reti n Eye Res 2000;19: dations of cl inical ophthalmology. Phila- 2007;48:1201-11. 297-321. delphi a: Lippincott Williams & Wil kins, 73. Munemasa Y, Ahn JH, Kwong JM, 87. Burgoyne CF, Downs JC. Premise and 2005:1-10. Caprioli J, Piri N. Redox proteins thiore- prediction: how optic nerve head biome-

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