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Drug Therapy

A

LASTAI R

J . J . W

OOD

, M.D.,

Editor

DRUG THERAPY

A

GE

-R

ELATED

M

ACULAR

D

EGENERATION

S

TUART

L. F

INE

, M.D., J

EFFREY

W. B

ERGER

, M.D., P

H

.D.,

M

AUREEN

G. M

AGUIRE

, P

H

.D., AND

A

LLEN

C. H

O

, M.D.

From the Department of Ophthalmology, Scheie Eye Institute, Univer-sity of Pennsylvania Health System (S.L.F., J.W.B., M.G.M.), and the De-partment of Ophthalmology, Wills Eye Hospital, Thomas Jefferson Uni-

versity (A.C.H.) — both in Philadelphia. Address reprint requests to Dr.Fine at the Scheie Eye Institute, University of Pennsylvania Health System,51 N. 39th St., Philadelphia, PA 19104-2689.

©2000, Massachusetts Medical Society.

GE-RELATED macular degeneration, a de-terioration of the central portion of the retina,is the chief cause of severe and irreversible

loss of vision in developed countries.

1,2

There is noeffective treatment for most patients with age-relatedmacular degeneration, and many patients thereforeresort to experimental treatments. Physicians must

know how to counsel their patients about the limita-tions and risks of these experimental therapies. For-tunately, several clinical trials sponsored by both theNational Eye Institute and the private sector are eval-uating novel prophylactic and therapeutic interven-tions. In addition, there is much exciting, ongoingbasic research, some of which may lead to major ther-apeutic advances.

CLINICAL FEATURES

AND CLASSIFICATION

The macula is the posterior aspect of the retinaand has the highest concentration of photoreceptors,

which facilitate central vision and permit high-reso-lution visual acuity (Fig. 1). The macula is a circulararea 5 to 6 mm in diameter with the fovea at its centerthat lies within the vascular arcades of the retina. His-tologically, the macula is the region of the retina withtwo or more layers of ganglion cells.

3

Age-relatedmacular degeneration is associated with typical oph-thalmoscopic features and usually affects people 60

years of age or older. Because the macula is in the cen-tral portion of the retina, advanced age-related mac-ular degeneration often leads to irreversible loss of the ability to read, recognize faces, and drive. Howev-er, most patients, even those with extensive macularinvolvement in both eyes, maintain enough periph-eral vision to walk unaided.

Age-related macular degeneration can be classifiedinto early and late stages. The early stage is associat-

ed with minimal visual impairment and is character-ized by large drusen and pigmentary abnormalitiesin the macula (Fig. 2).

4

Drusen are accumulations of acellular, amorphous debris subjacent to the basementmembrane of the retinal pigment epithelium (Fig.3).

5

Nearly all people over the age of 50 years haveat least one small druse («63 µm) in one or botheyes.

6

Only eyes with large drusen (>63 µm) are atrisk for late age-related macular degeneration.

7

There are two forms of late age-related maculardegeneration: the atrophic form and the neovascular,exudative form. The atrophic form typically involvesthe choriocapillaris, retinal pigment epithelium, and

Figure 1.

Normal Macula and Optic Nerve (Arrow).

The avascular zone of the fovea (inner circle) is at the center of the macula. By clinical definition the macula is a circular area,centered on the fovea, 5 to 6 mm in diameter within the vascu-

lar arcades (outer circle).

Figure 2.

Early Age-Related Macular Degeneration, Character-ized by Large Drusen (Arrows) and Clumps of Pigment (Arrow-

heads) in the Macula.

This eye has normal visual acuity but is at risk for late age-related macular degeneration and loss of vision.

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The New England Journal of Medicine

photoreceptor elements (rods and cones) and does notinvolve leakage of blood or serum; hence, it is calleddry age-related macular degeneration. The neovas-cular, exudative form includes serous or hemorrhagicdetachment of retinal pigment epithelium and cho-roidal neovascularization, which lead to leakage and

fibrovascular scarring; hence, it is called wet age-relat-ed macular degeneration.

Loss of vision can occur in either the atrophic orthe neovascular form of the disorder. Patients with theatrophic form may have good central vision (20/40or better) but substantial functional limitations, in-cluding fluctuating vision, difficulty reading becauseof their limited area of good central vision, and lim-ited vision at night or under conditions of reducedillumination.

8,9

The ophthalmoscopic appearance of progressive,or “geographic,” atrophy involving the center of themacula is shown in Figure 4. The histopathologicalfindings of atrophic age-related macular degenerationreflect the loss of the photoreceptor layer, the retinalpigment epithelium, and the choriocapillaris. As the

atrophy progresses, reading vision decreases and textmust be magnified to be perceived.

Figure 5 shows the ophthalmoscopic appearanceof a central fibrovascular scar with exudation in themacula, which is a typical feature of late, untreatedchoroidal neovascularization. The retina surroundingthe scar appears normal. Fibrovascular tissue has re-placed the normal anatomical structures in the macula,including photoreceptors, so there is profound lossof central vision. Choroidal neovascularization can beidentified before scarring and extensive leakage causeirreversible loss of vision (Fig. 6 and 7). Among pa-tients with severe loss of visual acuity (20/200 or

worse), choroidal neovascularization is the cause in

at least 80 percent.

11

EPIDEMIOLOGY

The prevalence of age-related macular degenerationincreases dramatically with age. In the population-based Beaver Dam Eye Study in the United States,the prevalence of late age-related macular degenera-tion increased from 0.1 percent among people 43 to54 years of age to 7.1 percent among those 75 yearsof age or older.

6

The respective prevalences of early age-related macular degeneration were 8 percent and30 percent.

Case–control, cross-sectional, and prospective co-hort studies have identified several risk factors for age-

related macular degeneration.

7,11-17

In addition to old-er age, they include a family history of the disorder,

13,18

cigarette smoking,

19-21

low dietary intake or plasmaconcentrations of antioxidant vitamins and zinc,

15,22,23

and white race (in the case of wet age-related macu-lar degeneration).

24,25

Female sex,

7

light-colored iris-es,

13

cardiovascular disease,

13,14

and increased expo-sure to sunlight

26

have been identified as risk factorsin some studies, but not consistently (Table 1). Amongthese factors, diet and smoking are potentially mod-ifiable. The association with cigarette smoking pro-

vides another compelling reason to counsel patientsregarding the dangers of smoking. An ongoing clini-cal trial involving more than 4000 subjects is assessingthe effect of taking antioxidant and zinc supplementson the development and progression of age-relatedmacular degeneration.

27

COURSE AND VISUAL PROGNOSIS

Patients with only drusen (in one or both eyes)typically do not have much loss of vision, but they may require additional magnification of the text andmore intense lighting to read small print. However,the presence of large drusen, even though not nec-

Figure 3.

Cross Section of Normal Retina (Panel A) and Retinawith Drusen (Panel B) (Hematoxylin and Eosin).

The asterisks in Panel A identify photoreceptors, and the arrow-heads point to retinal pigment epithelium (¬100). The asterisksin Panel B identify drusen, or accumulations of eosinophilic

acellular debris subjacent to the basement membrane of retinalpigment epithelium (¬400). Panel B was provided by J.D.M.Gass, Vanderbilt University.

A

B

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Eyes with choroidal neovascularization can have widely varying degrees of visual loss, distortion, andscotomata (blind spots) depending on the type, lo-cation, size, and duration of neovascularization. Muchof the information about the natural course of cho-roidal neovascularization has been derived from stud-ies of the untreated eyes of patients enrolled in clin-ical evaluations of laser photocoagulation or othertreatments. Some patients have a rapid decline in vi-sion in the affected eye, with visual acuity changingfrom normal to 20/200 or worse within weeks. More

frequently, visual acuity deteriorates more slowly andstabilizes within three years. At this time, the average

visual acuity of eyes with the more aggressive, “clas-sic” form of choroidal neovascularization is usually between 20/250 and 20/400, but it may be worsethan 20/800. For eyes with the “occult” form of choroidal neovascularization, the average visual acuity is somewhat better, between 20/80 and 20/200.

30

Once choroidal neovascularization has developedin one eye, with or without visual loss, the other eyeis at relatively high risk for the same change. In pro-spective studies of patients with choroidal neovascu-larization in one eye, the risk to the second eye can

be predicted by evaluating both systemic and oph-thalmoscopic risk factors (Table 2 and Fig. 9). Whenall four risk factors — more than five drusen, largedrusen, pigmental clumping, and systemic hyperten-sion — are present, the five-year risk of choroidalneovascularization in the second eye is 87 percent,

whereas if none of these risk factors are present, therisk is 7 percent.

31

TREATMENTS EVALUATED

IN CLINICAL TRIALS

Choroidal neovascularization may progress rapid-ly, and therefore, any sudden change in central vi-sion in a patient with drusen in one or both eyes re-quires a prompt ophthalmoscopic examination afterdilation of the eyes. The purpose of this evaluationis to determine whether this sudden loss of vision isdue to leakage from new blood vessels that might beamenable to treatment with laser photocoagulationor photodynamic therapy.

Laser Photocoagulation Therapy

Between 1979 and 1994, the Macular Photocoag-ulation Study Group conducted a number of clinical

Figure 6.

Choroidal Neovascularization.

Panel A shows choroidal neovascularization (asterisks) tempo-ral to the fovea, surrounded by subretinal blood. In Panel B,

fluorescein dye fills the new blood vessels (asterisks) above theavascular zone of the fovea.

A

B

Figure 7.

Choroidal Neovascularization in Cross Section.

Reprinted from Bressler et al.

10

with the permission of the pub-lisher.

Choroidal neovascularization

Sensory retina

Subretinalfluid

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trials supported by the National Eye Institute that en-rolled patients with neovascular lesions of one or botheyes. Each affected eye was randomly assigned to eitherlaser treatment or observation. For eligible eyes withneovascularization in extrafoveal locations (200 µmor more from the center of the macula), juxtafoveallocations (more than 1 µm but less than 200 µmfrom the foveal center), and subfoveal locations, la-ser treatment reduced the risk of severe visual loss.

32-34

Laser photocoagulation, as performed in the Mac-ular Photocoagulation Study, is the only treatment forage-related macular degeneration with proven long-term benefit. To identify patients eligible for lasertreatment, intravenous fluorescein angiography is per-formed. Well-circumscribed new blood vessels iden-tified on the fluorescein angiogram (Fig. 6B) aretreated with laser photocoagulation after topical orlocal (retrobulbar or peribulbar) anesthesia. Figure10 shows the effects of laser photocoagulation im-mediately after treatment and six months later.

There are three major limitations of laser photo-coagulation treatment. First, not more than 10 to 15percent of all neovascular lesions are small enoughand sufficiently delineated by fluorescein angiography to be eligible for laser treatment. Second, even if lasertreatment is initially successful — that is, the new blood vessels appear closed on fluorescein angiogra-phy — there is at least a 50 percent chance that leak-age will recur during the next two years. Fortunate-ly, many recurrences are amenable to additional lasertreatment if detected early, thus mandating carefulmonitoring after laser treatment. Third, at least half the patients with sufficiently well-circumscribed neo-

vascular lesions have some initial leakage beneath thecenter of the fovea. Laser treatment leads to an im-mediate reduction in central vision. Even so, with suf-

T

ABLE

1.

E

STABLISHED

AND

P

OSSIBLE

R

ISK

F

ACTORS

FOR

A

GE

-R

ELATED

M

ACULAR

D

EGENERATION

I

DENTIFIED

BY

E

PIDEMIOLOGIC

S

TUDIES

.

E

STABLISHED

R

ISK

F

ACTORS

P

OSSIBLE

R

ISK

F

ACTORS

Older age (>60 years) Female sex

Family history Light-colored iris

Cigarette smoking Cardiovascular disease

Low dietary intake or plasma con-centrations of antioxidant vita-mins and zinc

Increased exposure tosunlight

White race (in the case of wet age-related macular degeneration)

Figure 8.

Amsler’s Grid.

Amsler’s grid is used to detect subtle abnormalities in centralvision caused by fluid in the subretinal space. Macular abnor-

malities may be manifested as distortions in the lines of the grid.

T

ABLE

2.

R

ISK

F

ACTORS

FOR

C

HOROIDAL

N

EOVASCULARIZATION

IN

THE

O

THER

E

YE

OF

A

P

ATIENT

WITH

THE

D

ISORDER

IN

O

NE

E

YE

.

More than 5 drusen

Large drusen (>63 µm)

Focal hyperpigmentation of the retinal pig-ment epithelium

Systemic hypertension

Figure 9.

Five-Year Risk of Choroidal Neovascularization in theContralateral Eye, According to the Number of Risk FactorsPresent.

Adapted from the Macular Photocoagulation Study Group.

31

0

100

0 4

10

20

30

40

50

60

70

80

90

1 2 3

7

87

25

44

53

No. of Risk Factors

P e r c e n t a g

e

o f P a t i e n t s

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ficient follow-up, the extent of visual loss is less inlaser-treated eyes than in untreated eyes.

34,35

Photodynamic Therapy

Photodynamic therapy is a nonthermal process lead-ing to the localized production of reactive oxygenspecies, including singlet oxygen, superoxide anions,and hydroxyl radicals, which may mediate local cel-lular, vascular, and immunologic injury, and ultimate-ly result in the partially selective destruction of new

blood vessels.

36

The process of destruction can beconfined to the area of choroidal neovascularizationby the intravenous administration of a photosensitiz-er and irradiation of this region. Typically, the new blood vessels will remain closed for a few weeks, andthen treatment should be repeated on the basis of theappearance of the region on fluorescein angiography.

In a recent, large clinical trial, photodynamic ther-apy with verteporfin as the photosensitizer delayedor prevented loss of vision during at least one year

Figure 10.

Choroidal Neovascularization in the Absence of and after Laser Treatment.

In Panel A, choroidal neovascularization (asterisks) has caused new blood vessels to penetrate Bruch’s membrane (arrowheads).The arrows identify the retinal pigment epithelium (periodic acid–Schiff, ¬775). In Panel B, immediately after laser treatment, thereis opacification of the normally clear retina over the treated area. In Panel C, six months after treatment, there is a circumscribed

laser scar with no accompanying blood or subretinal fluid. In Panel D, a fluorescein angiogram obtained six months after treatmentshows no leakage from the treated blood vessels. Panel A was provided by W.R. Green, Wilmer Eye Institute, Johns Hopkins MedicalInstitution. Panel B was reprinted from Bressler et al.10 with the permission of the publisher.

A

B

C D

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of follow-up in patients with predominantly classicneovascular lesions.37 This type of lesion is typically

well delineated on fluorescein angiography. Patientsassigned to treatment with verteporfin photodynamictherapy received an average of 3.4 treatments in thefirst year. Treatment was beneficial only in the group

of patients with predominantly classic choroidal neovascularization. Within that subgroup, only 33 per-cent of the patients who received verteporfin had sub-stantial loss of vision, as compared with 61 percentof those given a placebo photosensitizer.

Photodynamic therapy extends the group of eyesthat can benefit from some type of treatment. Thelong-term benefit of this promising therapy, as wellas the refinement of the treatment regimen, awaitsfurther study. Clinical trials of verteporfin in patients

with poorly defined areas of choroidal neovascular-ization and of other photosensitizing agents in allsorts of lesions are currently under way.

Interferon Alfa-2a Although preliminary data in animals and anec-

dotal reports in humans had suggested that interfer-on alfa-2a was beneficial in patients with choroidalneovascularization, the results of a large, multicenter,international trial of interferon alfa-2a were nega-tive.38 Indeed, patients treated with high-dose inter-feron alfa-2a had more rapid loss of vision than didthose given placebo.

INVESTIGATIONAL TREATMENTS

Submacular Surgery

Advances in microsurgical techniques have permit-

ted the development and refinement of surgical meth-ods for the treatment of age-related macular degen-eration. Areas of choroidal neovascularization can beexcised and blood extracted from the subretinal spaceby means of vitreous surgery. The efficacy of this pro-cedure is now being evaluated in a trial supported by the National Eye Institute.39

External-Beam Radiation Therapy

External-beam radiation therapy is being consid-ered as a treatment for the neovascular lesions in pa-tients with age-related macular degeneration becauseof the radiosensitivity of vascular endothelial cells,especially proliferating vascular endothelial cells. Since

1993, when the results of the first series were pub-lished,40 many large studies have been conducted, butnone included a control group. A recent small, ran-domized clinical trial in the Netherlands found thatpatients who received external-beam radiation ther-apy had a smaller decrease in visual acuity than diduntreated patients one year after enrollment.41

Thalidomide

Thalidomide is being evaluated as a treatment forage-related macular degeneration because of its effi-

cacy in controlling growth factor–induced cornealangiogenesis in rabbits and mice.42 Accordingly, asmall clinical trial (

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Retinal Prosthesis

Efforts to transplant or regenerate retinal neuraland supportive elements have not been successful.Therefore, stimulated by advances in microelectron-ics and biomaterials science and buoyed by the suc-cess of cochlear implants, several groups are develop-ing and evaluating an electronic retinal prosthesis.49,50

The challenges are formidable and include the needfor biocompatible materials that will not be rejectedby the host, the need to devise microsurgical meth-ods and materials that will allow stable fixation of thedevice, the establishment of a successful interface be-tween neural elements and electronic materials, andthe design and implementation of appropriate strat-egies to stimulate neurons with signals that allow

visual perception. There is tempered optimism withrespect to the use of this treatment for degenerativeconditions such as retinitis pigmentosa. In such con-ditions a treatment may be deemed successful if vis-ual acuity improves from light perception to 20/400

vision, restoring a patient’s ability to walk unaided.Since peripheral vision is usually preserved in patients

with age-related macular degeneration, an implantmust do far more to be deemed effective.

Gene Therapy

Advances in molecular genetics, in concert withepidemiologic studies and analyses of blood samplesfrom patients and families with age-related macular de-generation, are beginning to increase our understand-ing of the molecular basis of this disorder.51,52 Puta-tive genes responsible for some forms of the disorderare being identified,53 and several groups are explor-ing the potential of gene therapy to reverse or slow theprogression of the disorder.54 Better characterizationof the genetic aspects of age-related macular degen-eration may lead to the identification of some formsof the disorder that are amenable to gene therapy.

VISUAL REHABILITATION

AND COUNSELING

Most patients with even moderate loss of vision asa result of age-related macular degeneration, regard-less of the stage, can benefit from the use of low-visionaids. Patients with even mild degrees of vision lossshould be encouraged to see a low-vision specialist forevaluation and a prescription for various types of magnifying devices, lighting intensifiers, or computer-assisted reading devices. Such early intervention islikely to improve the quality of life and to lead tomore effective use of these devices should visual lossprogress.55

In addition, all physicians should be alert for clin-ical depression in patients with recent loss of visionfrom age-related macular degeneration. Losing one’sability to read or drive a car often results in a depres-sion similar to that experienced with the loss of aloved one, and treatment for depression may be more

effective than the treatment for macular degeneration.Patients who are thought to be depressed should beencouraged to see their primary care physician or apsychiatrist so that their depression can be diag-nosed accurately and treated effectively. Often treat-ment for depression can be discontinued once the

patients have adjusted to their visual loss.

PROPHYLAXIS

Laser Treatment

Perhaps the most promising approach for the fu-ture is prophylactic treatment. Even if the rate of ef-ficacy of prophylaxis were only 30 percent, such a re-sponse would still reduce by half the rate of legalblindness from age-related macular degeneration.56

On the basis of the encouraging results of pilot stud-ies in the United States and elsewhere,57-61 the Na-tional Eye Institute recently funded a clinical trial toevaluate the effect of low-intensity laser applicationas prophylaxis in high-risk patients with numerous

large drusen in both eyes — the Complications of Age-Related Macular Degeneration Prevention Trial.In each patient in this study, one eye will be randomly assigned to receive laser photocoagulation of the mac-ula in a grid pattern and the other eye to observa-tion. Patients will be followed for at least five years.In addition, an industry-sponsored, clinical trial of prophylaxis with the infrared diode laser is being con-ducted in patients with bilateral drusen and patients

who already have choroidal neovascularization in oneeye and in whom the other eye is at risk.

Although prophylactic laser treatment can pro-mote the resolution of drusen and, in some patients,improve visual function moderately, it is not clear

whether the ophthalmoscopic resolution of drusen isaccompanied by a reduction in the risk of severe vis-ual loss from atrophy or neovascularization.56 In fact,in a pilot study of moderate-intensity laser treatment(the Choroidal Neovascularization Prevention Tri-al), which was conducted from 1994 to 1999 to pre-pare for the large-scale study, the risk of choroidalneovascularization in prophylactically treated fellow eyes was increased.57

Nutrition and Dietary Supplements

Nutritional factors have been a subject of great in-terest among patients with age-related macular de-generation and their physicians. In case–control stud-ies, subjects who habitually consumed large quantitiesof leafy green vegetables and other foods containingantioxidant vitamins had a decreased risk of age-relat-ed macular degeneration.62 Can people who begin toconsume antioxidant vitamins in their 60s and 70salter their risk of age-related macular degeneration?For the past decade, the National Eye Institute hassupported the Age-Related Eye Disease Study, whichis assessing whether supplementation with antioxi-dant vitamins alone or in combination with zinc can

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neovascularization in age-related macular degeneration with verteporfin:one-year results of 2 randomized clinical trials — TAP report. Arch Oph-thalmol 1999;117:1329-45.38. Pharmacological Therapy for Macular Degeneration Study Group. In-terferon alfa-2a is ineffective for patients with choroidal neovascularizationsecondary to age-related macular degeneration: results of a prospective ran-domized clinical trial. Arch Ophthalmol 1997;115:865-72.39. Bressler NM. Submacular surgery: are randomized trials necessary?

Arch Ophthalmol 1995;113:1557-60.40. Chakravarthy U, Houston RF, Archer DB. Treatment of age-relatedsubfoveal neovascular membranes by teletherapy: a pilot study. Br J Oph-thalmol 1993;77:265-73.41. Bergink GJ, Hoyng CB, van der Maazen RWM, Vingerling JR, vanDaal WAJ, Deutman AF. A randomized controlled clinical trial of the effi-cacy of radiation therapy in the control of subfoveal choroidal neovascular-ization in age-related macular degeneration: radiation versus observation.Graefes Arch Clin Exp Ophthalmol 1998;236:321-5.42. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide isan inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91:4082-5.43. Bischoff PM, Flower RW. Ten years experience with choroidal angiog-raphy using indocyanine green dye: a new routine examination or an epi-logue? Doc Ophthalmol 1985;60:235-91.44. Regillo CD, Benson WE, Maguire JI, Annesley WH Jr. Indocyaninegreen angiography and occult choroidal neovascularization. Ophthalmolo-gy 1994;101:280-8.45. Slakter JS, Yannuzzi LA, Sorenson JA, Guyer DR, Ho AC, Orlock

DA. A pilot study of indocyanine green videoangiography-guided laserphotocoagulation of occult choroidal neovascularization in age-relatedmacular degeneration. Arch Ophthalmol 1994;112:465-72.46. Kaplan HJ, Tezel TH, Berger AS, Wolf ML, Del Priore LV. Humanphotoreceptor transplantation in retinitis pigmentosa: a safety study. ArchOphthalmol 1997;115:1168-72.47. Machemer R, Steinhorst UH. Retinal separation, retinotomy, andmacular relocation. I. Experimental studies in the rabbit eye. Graefes ArchClin Exp Ophthalmol 1993;231:629-34.48. de Juan E Jr, Lowenstein A , Bressler NM, Alexander J. Translocationof the retina for management of subfoveal choroidal neovascularization.II. A preliminary report in humans. Am J Ophthalmol 1998;125:635-46.49. Rizzo JR III, Wyatt J. Prospects for a visual prosthesis. Neuroscientist1997;3:251-62.

50. Humayun MS, de Juan E Jr, Dagnelie G, Greenberg RJ, Propst RH,Phillips DH. Visual perception elicited by electrical stimulation of retina inblind humans. Arch Ophthalmol 1996;114:40-6.51. Allikments R, Shroyer NF, Singh N, et al. Mutation of the Stargardtdisease gene (ABCR) in age-related macular degeneration. Science 1997;277:1805-7.52. ABCR gene and age-related macular degeneration. Science 1998;279:1107.

53. Stone EM, Lotery JA, Munier FL, et al. A single EFEMP1 mutationassociated with both Malattia Leventinese and Doyne honeycomb retinaldystrophy. Nat Genet 1999;22:199-202.54. Bennett J, Maguire AM. Gene therapy. In: Berger JW, Fine SL, Ma-guire MG, eds. Age-related macular degeneration. St. Louis: Mosby, 1999:395-412.55. Steinberg JD. Principles of low-vision rehabilitation. In: Berger JW,Fine SL, Maguire MG, eds. Age-related macular degeneration. St. Louis:Mosby, 1999:433-42.56. Lanchoney DM, Maguire MG, Fine SL. A model of the incidence andconsequences of choroidal neovascularization secondary to age-relatedmacular degeneration: comparative effects of current treatment and poten-tial prophylaxis on visual outcomes in high-risk patients. Arch Ophthalmol1998;116:1045-52.57. Choroidal Neovascularization Prevention Trial Research Group. Lasertreatment in eyes with large drusen: short-term effects seen in a pilot ran-domized clinical trial. Ophthalmology 1998;105:11-23.58. Little HL, Showman JM, Brown BW. A pilot randomized controlledstudy on the effect of laser photocoagulation of confluent soft macular

drusen. Ophthalmology 1997;104:623-31.59. Figueroa MS, Regueras A, Bertrand J. Laser photocoagulation to treatmacular soft drusen in age-related macular degeneration. Retina 1994;14:391-6.60. Frennesson C, Nilsson SEG. Prophylactic laser treatment in early agerelated maculopathy reduced the incidence of exudative complications. BrJ Ophthalmol 1998;82:1169-74.61. Ho AC, Maguire MG, Yoken J, et al. Laser-induced drusen reductionimproves visual function at 1 year. Ophthalmology 1999;106:1367-74.62. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vita-mins A, C, and E, and advanced age-related macular degeneration. JAMA1994;272:1413-20. [Erratum, JAMA 1995;273:622.]63. Sperduto RD, Ferris FL III, Kurinij N. Do we have a nutritional treat-ment for age-related cataract or macular degeneration? Arch Ophthalmol1990;108:1403-5.

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