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 can be distinguished from most other forms of acquired opt ic neuropat hy Visual Sciences, University of Iowa, Iowa reprint requests to Dr. Glaucoma the ach ar act erdegenerativear a nceneuropathy thater ve. In gl aucom a, City. Address o- Iowa Health Care, by is chronic, ist ic a ppe optic of the opti c n Kwon th e ne ur of at University retinal rim of t he optic nerve becomes progressively t hinner, thereb y enlarging200 Hawkin s Dr., Iowa City, IA 52242. the optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause N Engl J Med is the loss of retina l ga nglion cell a xons, a long with supportin g glia a nd vasculatuigre. 2009;360:1113-24. t s Med i ca l C op y r ht 2 0 0 9 Ma ssa ch uset 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 adult-and low d iastolic p erfusion pre ssure are risk pia, 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 uL A r ti st with resultant optic-nerve damage and visual sure SBwo n lar pressure, a relatively thin central cornea is anK A UTHO R P LE oth loss, rand b eenhey ASE an d clinically r indist inguishable er maj or r i sk fac tor for t he di sea se.14 Evi denc e t r edr awn NOTE: p e h as b een eset are ty F igu e h as risk elevated P lea ch car efu lly from cases seofeckprimary open-angle glaucoma for otherbloodfactors (diabetes mellitus,among in systolic pressure, and migraine, Is sue d at e patients without MYOC mut ations.5 To address is les s consistent.15 others)

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 pressure is not part of the clinical definilea ding cause of blindness in t he United States and because primary open-angle glaucoma can tion 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, fam- 10 to 21 mm Hg). Nevertheless, elevated intraly ily history of primary open-ang le glaucoma, myo- lar pressu re is a n imp ort an t risk fac tor an d is ocu 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 caus- form the int raocular pressure is often exonset tremely at ive factor. Many randomized clinical t rials have high (frequent ly >40 mm Hg).21 Large pedig rees with autos omal-dominant inheritance shown t hat reducing intraocular pressure slows juvenile-onset primary open-angle glaucoma of ha ve 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 T here ers in mapped a glaucomafore, all curre nt treatme nts of prima ry open-a ngle such pedigrees havechromosome 1q desigrelated gene to a region of glaucoma are aimed at reducing intraocular pres- GLC1A.22 Subsequent linkage st udies of nated oth sure by medical or surgical means.19,20 The Case er gl aucoma pe di gre es h ave mapp ed t he c hr omosomal locations of 13 additional glaucomaPre sentat ion r ecounts a typ ica l pr esent ation related genes (GLC1B t hrough GLC1N).23 of pri 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 for glaucoma 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 1 - 8 - 6 -8 -6 - 9 -9 -1 0 - 9 -7 -6 -9 - 7 -66 - -8 - -8-5 5 5 -1 3 --5 -- 10--6 -10 7 4 3 - 15 -7 --8 - 12 - 14 -8 -6 5 -5 -9 - 6 - 6 -9 -18

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

-1 5-1 29 2333 -31 -2 5 -2 8 - 5- -1 7- -32 - 29 -32 -3 1 32 - 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 I CM Panel A shows a photograph of the right optic disk, and the accompanying illustration in1 sdt Panel B shows the superior notching (arrow) of 2n FIGURE: of 4 2 REG the cup (C), whi ch represents a focal loss ofF the neuroretinal rim (R). In addition, the3rd lamina cribrosa (LC), a dense band of collagen and glial tissue within the cup that has multipleCA SE openings for nerve fiber bundles, hasRbecome visible because of the loss of overlying neuronal e vi s ed 4-C tissue. In Panel C, the results of HumphreyEMa i l Line testing show the loss of visual field in total deviati on plots. The upper plot shows visual-field SIZE ARTIST: ts H/T the numerical deviation of individual test points, in decibels, fromH/T values of a normative database adjusted for age, and the lower plot the 36p6 Enon shows the probability of test points being normal (the darker the Combo the lower the probability). There is a substantial loss of visualsquare, AUTHOR, 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 in Panel E, whi ch shows generalized thinning of the rim (R), Please check carefully. 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 IGU RE the extracellular space. In the first step in this process, messenger RNA (mRNA) is transcribed from the reach COL OR F 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 and release myocilin into the extracellular space and aqueous humor. Along the secretory pathway, molecules of myocilin may A ut h or Fi g # 3 associate with each other and form multimers (dimers and tetramers are depicted). In Panel B, heterozygous mutations of the MYO C gene Ti t le are associated with an autosomal dominant form of glaucoma. The wild-type copy of MYO C encodes normal myocilin protein (green symME bols), and the mutant MYOC copy encodes mutant myocilin protein (red symbols). Myocilin protein forms multimers that may be comDE posed of both wild-type and mutant subunits. Secretion of mutant myocilin protein and multimers containing mutant subunits is greatly reL duced, A r t ist toSBthenretention of the mutant protein in the endoplasmic reticulum and intracellular vesicles of trabecular-meshwork cells. leading K wo
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 of that mutant myocilin may be retained dence 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 ork ab normal assoc iation wit h prote ins of t he peroxce lls cultur ed fr om pa tients with glaucom a-ass oisome-t argeting system.49 Other studies in mice ciated MYOC mutations.40 Sim ila r ly, MYOC mut ahave shown 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 cause some signs of glaucoma without lin and 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 omechanism of 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, CO LO R and reduced in pat ients w it h MYOC mutat ions sup- cellular, FIG URE subcellular levels. In particular, mode ls port s this hypothesis.54 The development of ani- the se5animal 02/23/09 will fac ilitat e st udies of Draft the horau c o m a50,55,56 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 ug l A t F ig # 4 provides new tools for exploring the effect snumbers of trabecular-meshwork cells and the of T it l e
ME DE Ar t is t S BL K w 2009 n engl j med 360;11 nejm.org march 12,OR PL EASE AUTH on
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 glauco ma. Coupled wit h thinning and f urther of of collagen IV, prot eoglycans, adhesion mole- erior bowing of the lamina cribrosa, apoppost cules, 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 M. Altermatt Professorship, and Dr. Alward received sup Ruth 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 sholding several unlicensed patents related to gene search and a re not pre served .100 By me an s of non inva discovery in glaucoma, and Dr. Alward reports h oldi ng an unl isive dicensed patent for mutations. No other rect imaging of apoptotic cell death,106 it ha s bee n ial conflict the diagnosis of MYOCthis article was reporte d. potent of interest relevant to 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 modelpreparation of the manuscript. the

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The new england journal of medicine

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