Central retinal vein occlusion in young adults

SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 37 * NUMBER 6. MAY-JUNE 1993

REVIEW

Central Retinal Vein Occlusion in Young Adults ANDREW C. 0. FONG, M.D., AND HOWARD SCHATZ, M.D.

St. Mary’s Hospital and Medical Center, San Francisco, California

Abstract. Central retinal vein occlusion (CRVO) is usually seen in older adults and is often associated with systemic vascular disease. CRVO can be seen in young adults, and although it is occasionally associated with a systemic disease, in the majority of cases it occurs in an otherwise healthy patient with no known systemic disease or ocular problem. Inflammation ofthe central retinal vein has been proposed as a cause of the occlusion in young adults and for that reason it has been called papillophlebitis. The appearance of unilateral optic disc edema, dilatation, and tortuosity of the major retinal veins with a variable amount of retinal hemorrhage in young, healthy adults with complaints of blurred vision or photopsias has been called, in addition to papillophlebitis, benign retinal vasculitis, optic disc vasculitis, nonischemic CRVO, big blind spot syndrome, and presumed phlebitis of the optic disc. An approach to the diagnostic evaluation of the young adult with CRVO is presented. Although most eyes recover vision to better than 20/40, about one-fifth have significant visual loss, and many suffer ocular sequelae. Many treatment modalities have been tried for this entity, but no conclusive evidence exists that any treatment alters its natural history. (SW-V Ophthalmol 37:393-417, 1993)

glaucoma central retinal vein occlusion Key words. big blind spot syndrome hypercoagulability neovascularization optic disc edema papillophlebitis . retinal detachment retinal hemorrhage retinal vasculitis vascular disorders l

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Central retinal vein occlusion (CRVO) in young adults has been difficult to characterize because the cause is unknown. It has been thought that, in young adults, CRVO is a different entity from CRVO in older patients. Hence, a number of different terms have been used for this entity, including papillophlebitis, benign retinal vasculitis, optic disc vasculitis, nonischemic CRVO, big blind spot syndrome, and presumed phlebitis of the optic disc. :4,27.4.i.4fi.47.49..55.74.HO.XY.’)1.104 Most authors describe the fundus findings as identical to those seen in CRVO in older adults: disc edema, dilated retinal veins, tortuosity of the major retinal veins, and a variable degree of retinal hemorrhages. l:i.l6,‘LI.:i4.:i7.:~x.4~,4~~47.4c.),55.5F CRVO in young adults is probably a general

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(nonspecific) change that results from a number of individual causes or a combination of causes. In unusual cases the cause is known, but in the vast majority the specific cause or even the contributing causes are unknown, mostly because the literature is limited by a paucity of-histopathologic material. This review is a compilation of all previously reported cases, and it attempts to clarify the clinical course of CRVO in young adults, to recommend the proper work-up through a discussion of the various possible causes, and to guide the practitioner to the useful therapeutic alternatives. Table 1 summarizes information from reports on 488’ cases of CRVO in young adults. Table 2 provides a guide for performing the 393

# 01. Cascr

Age

Sex M:F

I

44

0: I

I I

42 29

T ype

Laterality

Ocular CondiCons

0

0

1

0

0

I :n I :o

I 0

0 0

0 0

0 I

I 0

,I 0

I I I

47 28 32

0: 1 0:I I :o

I 0 o

0 0 0

0 0 0

0 0 I

I I II

,I 0 0

7

2%35

:4: 4

3

0

0

2

5

0

I H-48

5’6

0

0

0

II

0

0

SyswnC

3

Z-42

2:1

2

I

0

0

0

3

MVP-I

HRAO-3

5

24-46

1:4

3

2

0

0

0

5

MVP-I

Opllc neurilw5

3 IO2

25-34 I S-49

1:2 65 : 57

3 47

0 54

0 I

0 0

n 29

3 75

4Y

I :n

I

0

0

0

0

n

I

6:s

6

5

,I

0

7

4

0

I

4H

0: I

I

0000

I

n

I 15

39 22-46

n:i 5:10

0 6

I Y

0 0

0 0

0 0

I 0

n 15

5

HII+

4:1

3

I

I

0

5

,I

I

9

21-37

$:I

8

I

0

0

0

0

9

8

0

0

0

9

o

15-45

II

NI

Medncal Conditwns

0

I

I

Awxialed

NS

I

I.

NS

B

II

R

Smoking hisloryllype

IV lipoproteinemia-I

_ Amblyopia ew

ill other

Sr&lda,-y$w,n1a

AMYW

All had high diurnal pressure vasculids-I;

lupu-I:

NOW? Hypertension-26: diabelics-excluded: heart disease-8; hyperlipldemia-6; arlhrilis-5; migl-aim-4; AIDS-2 Migraine-l Hypertensrow:4; DM-2; O(;P-2/5 ~crmen; pregnancy- I polycyslic kidney- I mirwr arrhythmia- I ; I;ype;ch;lester,,emi.-I Hyperlension/mitral valve pn~lapseioral sympathomimetic-l N<,IK Platelet abnormalities-I I; mtwal valve prolapse-7; nasal sympathomimaics-2; Type IV hyperlipide. miaAMlJthrombucylopenia-I; Reye’s syndrome-I; hyperlension It chronic renal failure-l Malignant hyprrtemion-I

;

_

skm rash-l

_ Glauc-uma 7% prior CRVO 2% _

:

_

I

8

2Ft55

5::s

0

0

0x0

Y

23-49

6 : :3

fi

2

I

I Y--lY

6: 5

6

5

0

0

,I

,I

23

27.4?6

Y: I4

0

0

0

~‘3 _

in

I3

0

Hypea-lension-I; diahrler-I; OCP-I; UTI-I; elevated &globulin-I Not noted

0:2

0

2

0

0

2

0

0

None

Iron deficiency anemid-I NWle

II

II

2

2630

I I

44 40

n:I I :o

0 0

I I

0 0

0 0

0 II

I I

0 0

I

22

I :o

I

0

0

n

0

I

0

P(:N allergy and $kin depigmentarion-I; prrgnan‘y-1; hiscory ot ‘I‘H-I: sinusms-I Pregnancy-I (others nrn specified hetwcen <,ldrr patients and younger pariems)

I

22

n:l

0

0

0

0

I

Lupus-l

2&25 25-49

o

:2 p:2

2 2

0 II

o II

0 0

2 4

None None

7

14-49

5:2

I

inn

7

Tuberculosis-I

69

15-50

41:2I(

x

25-9.5

4:4

42

I 4-4n

27: I5

15

42

12-64

24: IX

I* 40

I3 I5-40

n:l 22: IX

I

27

I I I

Id 45 40

I :o I :o 0: I 0: 1 I :o

I:

3ti 14-39

I I

30 34

2

I S-26

27

5

5

3

II

0

0

27

*

0

21

PO

13

9

0

0

II

42

0 ,I

I 0

0 0

0 40

I 0

0 40

0 0

i 0

0

0

4

0

0

0 I o

0 0

0 ,I 017

0 0

I 0

I 0

0 0

0 I

I 0

0

I

0: I l:n ]:I

:PO4

14

inno 1001

in:7

272

0

IXY

0 0

5H

2

x

0

?I

0

pregnam-I;

Hypertension-22; diabetes-68; hyperlipidemia-$ migraine-6; rheumaric heal-2; M\‘P-7; vawaclive-h; sarcoidoris-I; OCP-I: renal dysfunction-S; l’lx- I

Death-!?; hyprrtrnswtl&$; diahetrr-2; panel eatitir- I: polycysGc kidneys- I; us~eopwwis-I: ulcerauve wlilis-I NOI specified

0 0

LUpUS-I AIDS/high Ikabrrcs

I

II

0

2

0

0

IY

YY

YB

277

I22

HR.40.I

Ncmr listed

None Hypertension-4: hype, lipidrmia-2: oral c~mwaceplives-2; hyperuricemia-I; mimal valve prolapse-7; abnormal platrlel funaion-W2:i Abnormal cloumg and fihrinralytic tesung-I

Systemic thromb~~phlebi~is-I Asthma-l; diabetes-2; wwker-5; OCP-2: migraine2; Raynaud’s-I; myopathy-l; AS-I; anemia-l

I61

_

F.xial ,r.ruma- I

2 4*

37

COAC 2; IOFH-I

IriGs- I; par- I

_ glaucoma sus_

ESR-I mellitus, hypolhywtid-

‘txludrd cases rrporwd wer age 50 that WCBPincluded in the series. **l‘ype uf CRVO (uchemic, nomschrnw. no, specified) l**Laer-alhy (right, left, hilalrral. ~1 specified). Total number of eyes may nor add up because wme t,f Ihe hilateral ases did not include data from b&

I

Mild diabetic reunr,pathy

eyes.

TAHLE

I:

Summarv nj ~:hamrlrnrla~

oJ -188 Lkw~

In&al

Vlwal

Pigment

Final Visual

Follow-up

Acuity

Duration

Acully

N1.P

20/200

NVC

4 yews

?0/200 ti/:i 6 20/:400

201100 Iii9 LP

5 years

“O/20. 2o/:io. 201300. <:F (2). HM,

_

Average follow-up

I.P. NLP

“Months

CF, 20/70. 20120

20/:w,

20125. ?0/40.

20120.20/:40-4.

_

2012.5. 20120

to years”

2/l

_ _

m 7m. 2111,

I

2n1-2 year,

POI’LOO. CF 20/:40 (2). 20/70 (I)

‘Lo/20 (3)

-“O/40

-2w40

(37);

-20/100 (20)

Duration

(56):

-20/l00

6m-I

HM

lnonths

I years

I/3

Medical comrol

Yrednisolone (for AMPPE) PRP, cyclocryothcrapy, cyclophotocoa-

NV{..2

HRVO

gulalionPRP in 2 cases

Retinal awry _

_

_

17/10:4

NVCX%

201100

3 months

No bllow-up we6/30; 20/:40 or bet-

Average follow-up

?0/30 1,1 5

20120 (2): 2WO

ter-II/19

Sub-tenons NV%

1%:

NVE-I%

PO/20 (8); a140 20/20

W/l

age group 2Oi’LO-20150

5-20/50

(8); ?O/XO (I 20/40 1” Iwttrr

, f IX)

l/Y 2/Y 2/H 2/x

IX

months I)urauon “few weeks”

(I)

Not specified Ii” younger vs. older

No pauen,

NV<;-1

HRAO-I;

(I I )

NVV-2

fovea1

l/Y _ _

(:hronic

(I);‘?0/x0 (1); rc:l; (5)

PRWgrid-2:

cyrlcb

vilrecwmy-3:

mu

o1 migraine

I; PRP- I

tnucleaion-

Slopped

l’aalh. studies ofenucleaed eyes, CME-2

oral sympathomimeu<

4SA sulfapyraronr

(antipll)

Systemic steroids-l;

enucleatinns-:4;

post-mortem-2 Systemic steroids-3 acelazolamide-I; hypenensionSystemic sleroidr-6

treat

(:ME-I

I

2/H Syslemic steroids-5; a&lion(,hronic

aspwin-I:

an”co-

I

Systemac steroids-4; steroids + amcoagulalion-3; anlicoagulanr only-l

CME-3

Systemic steroids-9

?I)/40

hollow-up

_

2 namths

Cihorelinal clusion-l

20/50

20/70

H nmntha

‘1:

2 yrarr

_

20/20 (2)

‘1.otal rr‘““ery

I

20/400

)

I

20/I.%20/20 (I): 20/120 N,

= =

(5):2wio (I)

>20,200-85%. > 201200.2 I%

‘Lo/ I5-2l/2~1

I

(8)

18);

PO/al-20/40 ( 20/5~2O/I 00 (41: < 20/200 ( I 5) “O/20-20/40 (47): 20/50-20/100 (2);

1.1’

1.1’ 20170.(:F

20/200 2wnoo

20/40 (:44): 20/50-20/

IO0(:I):

(:‘I 20140

20~0;

(6); (:F 10 1.1’ (:I)

= f*lH

_

2ol2o W-Ii/Y (7). ti/ I H-ti/liO (9,; <:I; (I ): “<>L k”own (6)

3-25

_ re-

+ antiwagulalion-

I.

steroads only-l

Grid Aceuarolamide-

I

A”ucoagolai~m None Steroid

Ciliorelmal ar[ery occlusion-2: HRAO-3; CRA0.2

NW)-4;

NW;-3;

NVE-I

+ ,yrtrnlic

and rmicoagulanl-

slcroidr-

I, ryrlrmr

steroid only- I Anlicoagolanl-I , anlicoagulalion steroid-l; ryslemir rceroids-I Not specified (m?jor”y divid”&ed

I

&

on aspirin.

“I”-

therapy”)

Macular hole-l; op”c awophy-I; TRV-I; hilateral follow-up-2

Y/42

9 weeks LO

I

Amrrwr chamher dclion- I NVI-X:

1,342

years

I:4years

It351 II/51

(I 2..4 months)

_

Follow-up 9 months Only 9%. decrrdse ill vision

n/40 1%

after milial

‘,‘l _ _

improving 4 months Follow-up months NV<; 4 months sIta ““se1 Rcrolulion 90 day,

2IN400

o (:4+Y years 4 n;onth\ (average :49.5 months) 4 months I’rogressed 10 ix hcmic

N,.,‘.

‘YPC l-9 yrn,>

20,XlO

214 217 I17 -

systenuc

of internal

swn-

Systemic steroids

Now

Duration = 4-X months

I5

(variable)

2012.5

214 L’i4 917 Ii7

= up Lo 9

artery oc-

Grid performed for chronic CME (:hronic CMUwrinkline linlieng mernbranc Retinal anery occlu-

_

_

No1 sperdicd

Recurred

~.“u&aled-l

20/m 6/5-6/Y lx): I3 IX-fwO

_

NV&9

!!0/2(-‘?11/40 (I HI: 20/5l&20/ IO0 (:!): <2lv!!OO (21) ??0/2%20/40 (361; “0/50-“0!100 (H): <20/“00 (7) W20 > 20/40 (‘ail2O/BO-2O/iOO (0): < 20/200 (5) w/25: 20/w

<2lu200

_ _

I months

Duralion monlhr Duration years

?0/20 in all LUCY

WI 5-20/w (4): 2O/HO (I); 20/200 (I). (:F >20,200-X2’%.

NW;-3;

swrold-2

grid+

cryotherapy-4:

I

411 I _

No follow-up

= >201s00.43%

(ML-

Chronic CME-4. hemorrhage-l

_

Dul-ation = 6 wks-Y months

(:RAo No follow-up 20/:40

(1) =

optic aww

2 IY‘Y

20~20-( ItxY.6%):

PRP-21;

cleation-

VH-I

type

2OlliO 20/x0

NI

_

progressed

LO lschrrnw

2011.5 (!!)-r”“lll x0loma m one will1

‘?a/ 15. 20125

20/20 (21 ‘%/20 (3). 2o/:w (I

macular

.Treatme”l VH-I.

_

5

Recovery I” 6 wks 11)

(I )

(6); 2w40

artery oc-

elusion-5%:

months

ZMJO or belleI -76%; 20/40 01 brtlrr-YO%

(I ); 2w‘oo

(:ilioretinal

I -

_

(4);

Steroids-5

C:hronic CME-I

,rport

20/120(2);(:F(1) 20/2(~20/30 (7)

occlu-

sion-8 Optic disc pallor-2

phy-2;

2nl20 20/20-(X;

I

occlusion Steroids-.4

_

Xi/IO:1

_ _

<:I;

H,swpathologic

in fellow eye-l;

I” fellow eye-l

14/I 0:4

2-I :4 years

of 10P

Fibrotic vitreal strands

1

2/l

2z IO3

6 months

with

(no response). enuclealion

NV&I

C:F <,I WOl’K

hater-6/l

Started on anucoagulants _


hole-l%

(:F

WI I presented

2-6

(14); -20/400(17): (:I;-NLP (16)

CF. HM or 1.I’ (18)

Mature

arteriolar

Resolution

(:F-l

Steroids

_

_

I ‘/z

Treatment

Optic awophy-I

_

_

and 31”

- 20/400

NV<;

yea,-s

No1 specdird

(28);

_

_

7 months

HM.

20/60.

_

Retinal

Findings

NV<;

X months

20/20 (2). 201800. CF.

NLP

NV?

after

_

NLP

rrt thr l_tl~ratu,r

Other

Exudate

7 monrhs

No li~llow-up

HZ F#ung AdulL? Hrporled

Collalerals:

““St3

20/30 HM

of CHVO

:

Sheathed

4/51 2215 I

2151 NVK

(:ME-2

None

_ 4140 _ _

(Chronic (:ME-Y; BRAW I

Not specified

C:hronic CMW preretinal Shrosis-I

Steroids, digoxin.

_

_

_

_

(&orelinal artery ocelusion-2; arteriole occlusion-l; (:ME-3

_

_

lAn\Cl

NV<;. NVV.

aspirin.

acelwola-

mide, laser grid- I Systemic stcroida-I None Enucleated after BV(;

VH NV<;-1

l/l

No1 specified

a”d

rcuohulhar

alcohol Systemic steroids- I Not spatied

Asp”,“.I PRP-I Uilc-

L:xudativc retinal druchmrm-2

laser

(rc;lller)-”


mat alar edena;

HRVO

= branch

retinal vein occlusion:

HRAO

=

branch

retinal artery

crcluno”.

396

Surv Ophthalmol

37 (6) May-June

FONG, SCHATZ

1993 TABLE

2

Work-up for CRVO in Young Adults Basic Eualuation *History Age Sex Race Medical conditions *Hypertension *Diabetes melhtus *Hyperlipidemia Coagulopathy Migraine Mitral valve prolapse/cardiac problems Collagen vascular disease *Acquired immunodeficiency syndrome Carotid artery disease Medications *Contraceptives/hormone therapy Diuretics Sympathomimetics Ocular conditions *Glaucoma Optic nerve disease Previous vascular occlusions Other *Ocular examination Symptoms Refractive error Visual acuity Pupillary examination Funduscopic examination Fluorescein angiography Visual field examination *Intraocular pressure General physical Carotid (bruit) Heart (murmur) *Blood pressure *Denotes necessary components

for CRVO

work-up

I.

Laboratory *Fasting blood sugar *Lipid profile *Complete blood count with platelet (CBC)

*Human immunodefrciency virus Syphilis serology Erythrocyte sedimentation rate (ESR) SecondaryEvaluation (as indicated)

History (see Table 1) Ocular examination Diurnal pressure curve Electrophysiology Physical examination Additional testing as indicated from general physical Laboratory Coagulation studies Neuro-imaging Chest X-ray Anti-nuclear antibodies Rheumatoid factor Skin testing for anergy and tuberculosis Angiotensin converting enzyme/lysozyme Uric acid Anticardiolipin Lupus anticoagulant Carotid Doppler Echocardiogram Creatinine Cryofibrinogen Blood viscosity Pregnancy test

of work-up.

in young adults.

Clinical Characteristics

to be referred to a retinal specialist because of the rarity of the condition and such cases are more likely to be reported.

A. AGE CRVO in young adults is considered uncommon and is probably rare. Previous reviews have shown that 7.5-19.8% of CRVOs are found in patients under 50 years of age [Zegarra et al,‘“’ five of 67 patients (7.5%) under age 50; Ellis et alz8 18 of 146 (12.3%); Brown et al: four of 35 (11.4%); Dodson et al, I9five of 40 (12.5%); Quinlan et al”? 24 of 160 (15%); Kohner and Cappin,6” 23 of 116 (19.8%); McGrath et al,” nine of 79 (11.4%) under 401. The actual prevalence is probably less than these numbers suggest; i.e., a young adult who develops a CRVO is more likely

B. SEX In most series3”,“4.X0.8’.““,“” there is a male predominance in the incidence of CRVO in young adults, but some series have shown no difference in sex ratios.‘“‘“5,86 Of the reported 478 patients under 50 for whom sex was specified, 272 (57%) were men and 206 (43%) were women. McGrath et alXYfound that in patients under 50, there was a twofold greater male ratio; however, there was an equal number of males and females in patients older than 50. The reason for the apparently greater incidence in males is not clear, but

CRVO IN
397 TABLE

real.

S

Medical Conditions Known to he Associatrd with CRIW

C. LATERALITY Earlier reports suggested that the right eye was involved more frequently than the left (Ellenberger and Messner,” 3 OD: 0 OS; Hart et a1,4” 8 : 1; Hayreh,4Y 6: 2; Lyle and Wybar,= 5 : 1), but more recently, larger series have shown that the involvement of right and left eyes is approximately equal.“‘.‘“’ Although CRVO is typically unilateral, it has been reported to be bilateral in l-14% of patients. Hayreh4’ reported bilaterality in one of nine patients (1 I%), Lyle and Wybarx’ in one of seven (14%), and Magargal et al’” in five of 69 (‘7%). Priluck et al”” reported that two of their 42 cases (5%) became bilateral on longterm followUP. Fong et aI”2 reported one bilateral case in a series of 102 patients that excluded patients with diabetes. Dodson et al” suggest that hypertension and hyperlipidemia may be more common in patients with recurrent retinal vein occlusions. Bilaterality in CRVO in young nondiabetic adults is extremely rare and probably indicates a systemic cause in combination with an anatomic susceptibility.

I ‘,!I. I :w. I-10 Hypertension IO. I!l.L’0.:~‘i.4’1.4~,.~.~.‘;!l,“l.~’~,~!~~l!l, Acquired immune deficient syndrome’“~‘:” Diabetes meliitus”!‘,“!‘.H”, l:I!l.I4Y) pregnancyl:‘.47.4!J.“” IO!,. I4’I Hyperlipidemla. ‘1,10.1!l.:‘4.:~x.4~i.‘il~.70.x!~. Preeclampsia”’ ‘W :I’.:l~.J’i,H!,.!lN. I I,!,. I x. IS’I. I :I I Platelet abnormalities I”-_-’ “‘I.:i4..59.‘Y!l,I01,. I!!,, Oral contraceptives I‘,*Hyperviscosity:‘.N”.i

I!).I2li

Sympthomimetics”,:‘~,~ Cryofibrinogenemia”!’ Diuretics”” Hyper~ricemia”!‘,X!I.

Systemic

Renal

lupus

I II!)

ery~~em~~osusl~~.~~~.il.7.~.i!~.l

Ili

disease:‘4,x’.l40

SarcoidosisK’ Carotid disease7.:‘4,77.7x.l40 Tuberculosis’~” Leukemia”’ Malignancy”!’ Blood dys,-rasia’sl2s”!

Keye’s syndrome’ I5 Head

in~Ury”,I”,“X.X!’

Epidemic dropsy’“’ Migrai,le”I.:i:‘,XI’

D. RACE Of the young CRVO patients reported in the literature, 86-90% have been white.2”~“‘~X”~‘09 We cannot know whether this is a true racial predilection, or a reflection of the practice populations of the authors. Nevertheless, Dodson and Kritzinger”’ suggest that whites may be more likely to be affected because of genetic differences. Appiah and Greenridge’ found that associated medical conditions among Hispanics with CRVO were similar to those among white patients. E. ASSOCIATED In

older

have

been

MEDICAL

adults,

CONDITIONS

medical conditions CRVOs. The most common is systemic vascular disease, found in 74% of patients over 50 with CRVO.“‘.‘“’ Similarly, hypertension (32-60%), hyperlipidemia (32-60%), and diabetes (15-340/o) are strongly associated with CRVO in older patients.‘,“‘~~“,“‘. “x”‘.“‘!’ Associated systemic disease is much less frequent in CRVO patients under 50 years old (,,_,,%)~!?‘,.:~?.I’~n Moreover, the prevalence of the diseases reported in these CRVO patients is similar to that found in the general population of this age group. However, hypertension and diabetes associated

several

with

are certainly important factors, when present. Medical conditions reported to be associated with CRVO

are listed in Table

3.

1. Hypertension Of young adults who develop CRVO, 23-42s’ have hypertension.“‘.“‘*Xfi,“” Dodson and Kritzinge? found that 23% of their patients with CRVO under 50 years of age were hypertensive, significantly less than older adults with CRVO (62%) (Pc.001). 2. Diabetes Studies by Zegarra et al,‘“” McGrath et al,‘” Kohner et al,fi” Dodson and Kritzinger,“’ and Elman et al’” have reported an occurrence rate of diabetes mellitus in patients with CRVO to be 13-34%. In the series involving patients under fifty years of age, Quinlan et al,“” Magargal et al,‘” and Dodson and Kritzinger”” have shown that 3-9% of these patients have diabetes. This is less prevalent than their older counterparts with CRVO, but in excess of the National Center for Health Statistics rates for diabetes in their age group (9.1 per lOOO).“” 3. Hyperlipidemia Unlike series of patients over 50, a low incidence of hyperlipidemia has been reported in

398

Surv Ophthalmol

FONG, SCHATZ

37 (6) May-June 1993

other series of young adults with CRVO, including Walters and Spalton (none of 17),“’ Sanborn and Magargal (two of 40),‘“9 Gonder et al (one of 15),“” Frucht et al (one of 1 1),34 Fong et al (six of 102),“’ and Magargal et al (three of 69).86 In contrast, McGrath et al*’ and Dodson and Kritzinger to found an association between hyperlipidemia and CRVO in young adults. The source of this discrepancy is not clear; it may be related to the fact that these latter investigators placed an emphasis on detection of hyperlipidemia and used different testing methods or assigned less rigid criteria in defining hyperlipidemia. An estimated 12.4-20.5% of men and 13.2-17.6% of women under age 50 have serum cholesterol levels that put them at high risk of developing coronary artery disease.‘27 From current studies, hyperlipidemia is probably not any more prevalent in young patients with CRVO than the normal population of that same age. However, given the possibility that hyperlipidemia may somehow play a role, it is probably worth investigating blood lipids on any young patient who develops CRVO. 4. Hypercoagulability Other conditions that produce intrinsic changes in vessel walls or alterations in blood constituents, such as hyperviscosity”~xg~“g~‘2”or hypercoagulable states, have been linked to CRVO. These include smoking,3 abnormal platelet function”7.~6.96~‘O”.’ 19.126~13~~19’ or platelet fat_ tor concentration,” decreased antithrombin III, y8,‘56cryofibrinogenemia,*” and beta-thromboglobulin abnormalities.= Blood dyscrasias such as anemia, polycythemia, leukemia, sickle cell disease, macroglobulinemia, multiple myeloma, and paraproteinemia are also associated with central retina1 vascular occ1usions.40x7”.“‘.‘“’ Lupus anticoagulant has been associated with thrombosis from a hypercoagulable state.7” A case of systemic thrombophlebitis associated with papillophlebitis was reported in a 36-yearold white man by Vandervleit.lZ8 Savir et al”” presented a 27-year-old man with bilateral retinal vasculitis who demonstrated clotting abnormalities. Furthermore, Magargal et al”” found that 11 of 15 (73%) of patients with no other medical etiology for CRVO were found to have a platelet-coagulant abnormality on extensive testing. A cyclic variation in the onset of CRVO was demonstrated by Lavin and Dhillon,7” with patients most frequently being seen in the months of September through February. They speculate

that this seasonal variation may reflect seasonal changes in hemostasis and retinal perfusion; this remains to be proven. Hyperviscosity does cause the picture of bilateral venous stasis or nonischemic (rarely ischemic) CRVO and should be the major diagnostic consideration (in addition to diabetes and hypertension) for any young patient with the findings of bilateral CRVO. 5. Migraine Migraine has been associated with CRVO in young adults.32,““*X6Friedman”” reported a 49year-old woman who developed an occlusion of the central retinal vein coincident with atypical migraine. Magargal et ala6 found that 9% of their patients suffered from migraine headaches and speculate that migraine may be related to platelet abnormalities, which may be instrumental in causing of CRVO. The series of Fong et al”* included four of 102 (4%) patients with migraine headaches, and Walters and Spalton”’ reported that two of 17 (12%) of their patients had migraine. Because migraine headaches affect as many as 25% of late adolescents and adults, the association of migraine and CRVO seems weak.“‘7 6. Mitral Valve Prolapse

Gonder et al’” reported seven of 11 patients with CRVO who showed evidence of mitral valve prolapse (MVP) on echocardiography. Four of these seven patients had abnormal platelet function. These authors suggested that mitral valve prolapse contributes to platelet hyperactivity and, ultimately, to CRVO. Seven of 40 (17.5%) patients studied by Sanborn and Magargal”” had MVP. The incidence of MVP in the genera1 population has been reported to be 0.5% for men and up to 10% for young women, however.‘.‘“’ MVP is more likely to cause arterial occlusion and its association with CRVO is probably very unlikely. 7. Collagen Vascular Disease Collagen vascular disease has been reported in association with retinal vascular occluSystemic lupus erythemato_ sions. ‘6.:~4.7’.75~79~‘0?.“6 sus is known to incite an inflammatory process in blood vessels, including those of the retina.“”

8. Acquired (AIDS)

Immunodeficiency

Teich and Sonnabend””

CRVO

in a patient

Syndrome

reported

with AIDS.

They

a case of

hypoth-

CRVO IN YOUNG

ADULTS

399

esized either a link with high anticardiolipin antibody levels (which can be associated with a hypercoagulative state), immune complex deposition, or a direct toxic effect of the human immunodeficiency virus on the endothelium as possible causes of the CRVO in their patient. Perivasculitis has been reported in children and adult patients”” as part of a noninfectious AIDS retinopathy. Optic disc edema from a myriad of causes has also been reported in these patients.“’ Others have also reported the association of AIDS and CRVO.“” The association ofAIDS and CRVO is almost certainly real, although the specific causative pathway from AIDS to CRVO is unknown to this date. 9. Carotid Artery Disease

Brown et al7 showed an association with carotid artery atherosclerosis, demonstrated by digital subtraction angiography, and ischemic CRVO in three patients, one ofwhom was younger than 50 years of age. They suggest that ischemic CRVO may be more likely to occur in a patient with systemic atherosclerosis for which carotid disease may serve as an index. Lazzaro7’ found that six of his twelve patients who had been initially diagnosed with retinal venous disease were subsequently diagnosed as having carotid artery disease. He did not report the age of these patients. We have seen two patients with CRVO, both of whom were in their 30s who showed sponateous central retinal arterial pulsations with only a moderate elevation of intraocular pressure (under 40 mm Hg). The cause of the arterial pulsation was puzzling; one possible explanation (speculation) may be that a developmental abnormality of the carotid-ophthalmic-central retinal artery existed, causing reduced arterial perfusion pressure to the fundus, leading to venous stasis and eventual CRVO (in the face of elevated Further investigation is intraocular pressure). needed in this area; the results of ophthalmodynamometry on cases of CRVO in young patients would be interesting. 10. Elevated Sedimentation

Rate (ESR)

Appiah and Trempe’ found an association between ESR and CRVO. They hypothesized that the elevated ESR reflects changes in shear forces and viscosity of plasma that may lead to hemodynamic changes at the lamina cribrosa and result in CRVO. F. MEDICATIONS

Various

medications

have

been

linked

to

CRVO, including oral contraceptives,‘“.2”.““.j”.X”. ‘09.“” diuretics,‘” and sympathomimetics.““~“‘~” 1. Oral Contraceptives

Many reports have shown a trend toward hypercoagulability with the use of oral contraceptives. ‘-1.‘“6.12’Kulvin et a17’ performed experimental studies using owl monkeys given various doses of oral contraceptives and observed dilatation of retinal veins in these animals. Stowe et histopathologic findings of intimal al IL’”reported proliferation with occlusion and thrombosis of the central retinal vessels in a patient who had taken oral contraceptives for four years and who developed neovascular glaucoma from a CRVO. Thus, the development of CRVOs associated with oral contraceptives has been linked to changes in coagulation and vessel wall changes leading to secondary thrombosis. However, CRVO caused by oral contraceptives is a very rare occurrence and is probably related to other contributing factors. 2. Diuretics Cutman”’ has suggested that patients receiving diuretics may be more at risk for CRVO because of a secondary hemoconcentration effect which could lead to hyperviscosity. However, patients on diuretics usually have systemic vascular disease, so the role of diuretics in the development of CRVO is speculative. 3. Sympathomimetics Gilmer et al’“reported a case of CRVO in a 48year-old patient taking an over-the-counter sympathomimetic, phenylpropanolamine (PPA), for nasal congestion. They suggest a similar role of PPA in a number of case reports linking cerebrovascular accidents following the ingestion of PPA. As vasoactive medications, sympathomimetics theoretically could cause vascular occlusion from vascular spasm and subsequent thrombotic occlusion. Magargal et al”” reported that six of 69 (9%) of their young adults used vasoactive medications prior to the development of CRVO. They also suggested that sympathomimetics are related to the development of vascular occlusive disease. The association of CRVO in patients under 50 and the ingestion of oral sympathomimetics is anecdotal at best. G. OCULAR

CONDITIONS

Magargal et al’” reported that 16/69 (23%) of their patients had associated ocular abnormalities, However, most of the large series of CRVO

400

Surv Ophthalmol

37 (6) May-June

in young adults do not report lar a~norma~iti~s.‘6~27~“4’38’““‘56.9”.’0’

any associated

ocu-

1. Glaucoma Glaucoma is well known to predispose to CRVO in elderly patients.‘3B”8 The incidence of chronic open-angle glaucoma (COAG) in patients with CRVO has been reported to range from 25-66%.2”,““,8’1”8 The incidence appears to be much lower in younger adults (O-7%).‘6,s7,se. 54.98*J5,56.gg~‘0’ Conversely, CRVO has been reported in 2-5% of patients with primary open-angle glaucoma. Mansour et als7 and Strahlman et al”’ found no relationship between the cup-to-disc ratio and the development of CRVO. Chew et alI3 reported a series of seven patients with CRVO, 22-35 years of age (mean 29. l), who were monitored for diurnal intraocular pressure (IOP) abnormalities. All seven had a peak IOP of 24 or greater in either the involved or fellow eye. Elevated intraocular pressure may deform the vessel wall and can also contribute to increased resistance to blood flow.“” Cole et alI7 recently suggested that glaucoma may have a less prominent etiological role in the development of a retinal vein occlusion, as they found a strikingly high prevalence of systemic hypertension and hyperlipidemia in patients with glaucoma who also had CRVO. They suggested that the systemic disease was more etiologically important. Elevated intraocular pressure is probably a very important factor contributing to the development of CRVO. We have seen three young patients who developed CRVO and were treated with periocular steroids who subsequently developed extreme intraocular pressure elevation unresponsive to medication and required filtering surgery. These patients may well have had a tendency toward spontaneous elevation of intraocular pressure prior to their development of CRVO. 2. Optic

Nerve

FONG, SCHATZ

1993

Disease

Other ocular conditions known to influence the development of CRVO include pressure on the orbital portion of the optic nerve from an increase in orbital volume (e.g., orbital tumor or abscess or thyroid ophthalmopathy).4” Optic nerve disease (e.g., drusen or papilledema) has also been associated with CRVO.‘“~“~““~*” Duker et al’” reported five cases of optic neuritis accompanied by the clinical appearance of a nonischemic CRVO, although the reverse association is also possible.

3. Retinal Artery

Occlusion

Magargal et al” found a retinal artery obstruction in the presence of CRVO, including branch retinal artery occlusion (three of 69 patients), central retinal artery occlusion (two of 69 patients), and cilioretinal artery occlusion (two of 69 patients). They suggest that a diffuse intravascular abnormality is responsible for this association. However, McLeod” and Schatz et al”’ suggest that cilioretinal artery obstruction occurs secondary to the high intravascular pressure head caused by a patent central retinal artery that is pumping up against the occluded central retinal vein (see Section IV. E). 4. Retinal

Arteriovenous

Malformation

(AVM)

two cases and reviewed Schatz et al”’ reported the literature on the occurrence of a CRVO in association with a retinal AVM. They propose that two factors contributed to the development of the CRVO: (1) changes in the venous wall as a result of the arterial pressure in the AVM; and (2) the mass effect of an optic nerve AVM which is often present when a retinal AVM is present. 5. Other

Ocular

Conditions

CRVO has also been reported in association with ocular syphilis,“7 acute posterior multifocal placoid pigment epitheliopathy,” tuberculosis,8’ and uveitis.“*‘J’ H. TRAUMA McGrath et alx” suggest that head injury is an important association with retinal vein occlusions in patients younger than 50 years of age. They suggest that sudden eyeball compression or sudden change in intraocular pressure may result in damage to the vein wall by shearing or compressing the central retinal vein against the lamina cribrosa. Kline et al@’ reported that the central retinal vein may undergo thrombosis from indirect trauma. They suggest that congenital anomalies of the central retinal vein, such as increased tortuosity of the orbital veins or an anomalous anatomic configuration, may result in an insult to the hemodynamics of venous outflow and cause thrombosis of the central retinal vein. Pollock and Millerg and Brunette and Boghen’ also report that trauma leading to a carotid-cavernous fistula may result in CRVO and suggest that elevation in intraocular pressure from the fistula plays an important role in the pathogenesis of CRVO in this setting. Retrobulbar injections have been associated

CRVO IN YOUNG ADULTS with both retinal artery and retinal vein occlusions.“” The mechanism is thought to be compression of the vessels from intraneural sheath hemorrhage.

II. Ocular Manifestations of CRVO A. SYMPTOMS Patients usually notice a mild or severe blurring of vision, mainly in the central field, that in some cases improves during the day. They may report metamorphopsia as well. Some patients complain of multiple small black spots, or floaters, and a “shimmering” sensation. In up to 18%, (five of 28) of patients, CRVO has been discovered on routine examination.“” B. REFRACTION Gutman reported a high incidence of hyperopia in young patients with CRVO.‘“’ Hyperopia has also been reported as a risk factor for branch retinal vein occlusion (BRVO).“,‘” Why hyperopia is more prevalent in retinal venous occlusive disease opia

is unknown. the

therefore

eye

may

One

theory

be smaller

is that than

in hyper-

normal

the venous outflow channels

and

are com-

promised. C. VISUAL ACUITY When first seen, most CRVO patients have visual acuity that is not severely reduced, but this can vary considerably, ranging from 20115 to light perception.“” Vision may be decreased due to macular edema, detachment or hemorrhage, capillary nonperfusion, vitreous hemorrhage or, rarely, arteriolar occlusion. As in older adults, patients with a nonischemic CRVO have better initial and final visual acuities than those with significant ischemia. Magargal et al’” found that 82% (47 of 58) of patients with good capillary perfusion had an initial acuity of 201200 or better, and 34% (20 of 58) had 20140 or better vision. In contrast, 43% (six of 14) patients with ischemic CRVO had initial acuities of 20/200 or better, and only 14% (two of 14) had 20/40 or better. Fong et al”’ reported that 47% (35 of 74) of patients with nonischemic CRVOs had 20140 or better vision, and only 28% (21 of 74) were worse than 20/200. In their report, patients with ischemia had much worse initial acuity - only 7% (two of 29) had 20/40 or better, and 45% (13 of 29) had vision worse than 201400. Initial visual acuity appears to be reasonably correlated with the type of CRVO (degree of capillary perfusion).

Fig. 1. CKVO in a young patient, right fundus. Note the marked flame-shaped hemorrhages, blurred disc margins, and venous dilation and tortuosity.

D. PUPILLABY

EXAMINATION

In nonischemic CRVO, it is uncommon to find a relative afferent pupillary defect,‘” and Servais et al”” report that an afferent pupillary defect is often seen in an ischemic CRVO. Duker et al” suggest that, although a relatively afferent pupillary defect can be seen with a nonischemic CRVO, it is atypical, and if present, is not marked. When a dramatic relative afferent pupillary defect is present and significant retinal ischemia is not, it would indicate concomitant optic nerve disease. E. FUNDUSCOPIC APPEARANCE FLUORESCEIN ANGIOGBAPHY

AND

Funduscopic examination of young patients with CRVO shows one or more of the following in various degrees: retinal hemorrhages throughout the fundus, often along the nerve fiber layer; disc edema; cystoid macular edema; venous dilation and tortuosity; vitreous hemorrhage; focal areas of secondary exudative retinal detachment; cotton-wool spots; and areas of white (ischemic) retina. Most patients have some degree of hemorrhage, macular edema, and venous dilation and tortuosity (Fig. 1). Fluorescein angiography reveals: (1) normal retinal arterial and choroidal filling; (2) delayed retinal venous filling; (3) a black retinal venous pattern (nonhllseen in silhouette ing, i.e., hypofluorescence) against the normal bright choroidal fluorescence in the arterial phase of a positive print or film of the angiogram; (4) variable staining of the large walls of the retinal veins; and (5) variable retinal vascular leakage resulting in retinal and macular

402

Surv Ophthalmol

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1993

FONG, SCHATZ

Fig. 2. CRVO in right eye of a Y9-year-old white male. Vision is X/40. A: Red-free fundus photograph shows dilated and tortuous retinal veins and retinal hemorrhages. Hemorrhages appear to be more numerous inferiorly than superiorly. The macula is mildly edematous. B: Early arteriovenous-phase fluorescein angiogram shows filling of the retinal arteries and delayed filling of the retinal veins. The retinal veins and venules are dilated and tortuous. C: Midphase fluorescein angiogram shows the markedly hyperfluorescent veins displaying delayed emptying. D: Late-phase fluorescein angiogram shows leakage from the large retinal veins. Note the retinal vascular leakage and mild macular edema. E: Two-and-one-half years later vision is 20/25. Red-free photograph, shows that the disc, macula, and retinal vessels appear normal. There is a small venous collateral on the disc, superiorly.

CRVO IN YOUNG ADULTS edema (Figs. 2 and 3). In some cases there may be a greater amount of hemorrhage in one section of the fundus than elsewhere (Fig. 2A). Two different types of CRVO have been described: (1) a milder form called nonischemic, incomplete, partial, hyperpermeable, perfused or venous stasis retinopathy (Fig. 2), and (2) a severe form called ischemic, complete, nonperfused, or hemorrhagic retinopathy (Figs. 4 and 5). The milder variant is characterized by none to a minimal degree of capillary nonperfusion (nonischemic), whereas the more severe variant exhibits widespread capillary nonperfusion (ischemic) and has a more guarded visual prognosis. There is almost certainly a continuum between a very mild, fully perfused CRVO and one in which the retinal vascular occlusion and nonperfusion is severe, and in some cases, it is difficult to determine which type is present. Additionally, a large amount of hemorrhage may so significantly block retinal capillary fluorescence on angiography that it may be impossible to determine if any ischemia is present when, in fact, it may be severe. Hayreh et al”“,“’ have suggested that four functional tests [visual acuity, visual fields, relative afferent pupillary defect (RAPD), and electroretinography (ERG)] and two morphologic tests (ophthalmoscopy and fundus fluorescein angiography) are useful to distinguish ischemic from

Fig.

Ischemic

-#.

ous-phase rhage,

CKVO

fluorescein

and tortuous

capillaries Late-phase extremely

in left eye ofa Y5-year-old

angiogram, veins. The

fluorescein

angiogram

male.

retina

is extremely

shows marked

Focal

Vision

temporal veins. The

phlebitis in left eye of 29-year-old

is 20/25.

area,

shows

arteries

Fluorescein

angiogram,

focal leakage

along

white infero-

the retinal

do not leak.

nonischemic central retinal vein occlusion during the early acute phase (Table 4). Magargal’” reported that 73% of his cases of CRVO in young adults were hyperpermeable presentations (nonischemic), 8% were “indeterminate,” and only 19% were ischemic. Fong et al’” found that 7 1% of 103 eyes (102 pts) were nonischemic, 28% were ischemic; 1% progressed

white male. Vision is finger-counting

left disc and inferior

retina.

edematous

on the disc. Note the diffuse retinal vascular edematous.

k‘ig. 3.

dilation.

leakage

Note

at two feet. .4: Arterioven-

the markedly

blurred

disc margins,

and shows marked

dilation

and leakage

The retinal veins show a marked

from the disc and retinal

vessels;

hemorfrom

the

delay in filling. B:

the disc and retina

are

404

Surv Ophthalmol

37 (6) May-June

1993

FONG, SCHATZ

Fig. 5. A: Red-free photograph of same eye shoMbn in Fig. 4 five months later. The media are very unclear. The disc margins are indistinct and the retina is extrem ely e dematous. B: Arteriovenous-phase fluorescein angiogram. The retina1 vessels around the disc are extremely tdilate :d. Note the capillary nonperfusion inferonasally. C: Latephase fluorescein angiogram. There is almost tot-al nc,nperfusion of the entire inferonasal retina. D: Note the hyperfluorescence and irregularity of the left iris indic zating marked ruheosis.

from nonischemic to ischemic. In older patients, 50-78% of CRVOs have been reported to be nonischemic.” The progression of nonischemic to ischemic CRVOs can occur in 5-20% of older patients;“‘.y’ however, this progression appears to occur less frequently in younger patients.“’ Ichioka et aIs reported that in his series ofyoung patients with CRVO, patients with ischemic CRVO were older than those who had nonischemic CRVO. On the other hand, Fong et al”” found no difference in the percentage of ischemic and nonischemic CRVO between young and older patients. F. VISUAL

FIELD

EXAMINATION

Visual field examinations may be normal, or exhibit enlargement of the blind spot (due to disc edema) with or without a central scotoma reflecting macular involvement.“’ Examination of the

peripheral visual fields may be used to help classify the CRVO; in patients with nonischemic CRVO, the peripheral fields are usually normal, whereas ischemic eyes tend to exhibit a constriction of the peripheral field.‘” G. ELECTROPHYSIOLOGIC

TESTING

Because of a lack of agreement among “expert” observers concerning the extent of nonperfusion in a given angiogram’“” and the difftculty of performing fluorescein angiography when there has been significant intraretinal hemorrhage,“” electroretinography (ERG) has been used to distinguish which eyes with CRVO are at risk for developing rubeosis.” ERG was first used in central retinal vein occlusion by Karpe in 1946.“’ Since then several studies have been published. Johnson et al”’ showed that by measuring of “retinal sensitivity” or “log K” (the amount

405

CRVO IN YOUNG ADULTS light needed to achieve half of the maximum scotopic amplitude response) electrophysiologitally, they could accurately classify CRVOs. Kay and Harding”’ reported that the scotoptic bwave implicit time was the best ERG predictor of iris new vessel growth. Sabates et allo used the b/a wave ratio to help classify CRVO. Hayreh et al”’ suggest that combined ERG and relative afferent pupillary defect (RAPD) tests could differentiate 97-100% of ischemic from nonischemic CRVO cases, with a specificity of about 70%.

TABLE

Differentiation of Ischemic Vs. Non-I.schtvnir Central Retinal Vein Occfuion

Ischemic Visual acuity

Relative afferent pupillary defect Visual fields

III. Differential Diagnoses The differential diagnoses of CRVO include other diseases that cause disc swelling and retinal hemorrhages. Conditions sometimes mistaken for CRVO in young adults include diabetic or radiation retinal vasculopathy or optic neuropathy, valsalva retinopathy, venous stasis retinopathy from carotid disease,““,“” malignant hypertensive retinopathy, isolated papillitis,” neuroretinitis,‘)’ papilledema,““,“” optic disc vasculitis in epidemic dropsy,‘“X ocular or generalized trauma, blood dyscrasias and hyperviscosity, sickle cell disease or Eales’ disease, and disc neovascularization or cystoid macular eclema from uveitis. However, the diagnosis of<:KVO is usually not difficult to make. Miller reported eight cases of unilateral optic disc edema without visual loss or increased intraand coined the descriptive cranial pressure name, “the Big Blind Spot Syndrome” (BBSS).!” Others have reported similar cases.“.“” There is a BBSS without disc edema”’ as well and it has been suggested by Hoyt that the BBSS with clisc edema be called “Miller’s BBSS.” This diagnosis can only be made if all other causes of unilateral disc swelling have been excluded. Kosenberg that this may repreand colleagues’04 suggested sent the least severe form of papillophlebitis. Hayrehq7 suggests that the etiology of such cases is “optic disc vasculitis” and divided this entity into two groups: Type I (optic disc edema alone), and Type II (CRVO).

IV. Natural History and Prognosis A slow, spontaneous resolution over a 3-6month period is found to be typical by some authat vision is usuthors. 27.“.xn.84They emphasize ally only minimally affected.‘“.“.Hn,XY Other investigators, however, have shown poorer visual results: Chew’” noted that five of seven consecutive patients had visual acuity 20/300 or worse; Frucht et als4 found six of 11 patients with finger counting or worse vision;

4

Funduscopy (acute)

Non-Ischemic

Usually Mild impairment May be present

Usually Marked impairment Absent

Peripheral normal Central * relative scotoma Milder degree of hemor-

Peripheral abnormal (;entral scotoma

rhages, venous tortuosity, and disc CChll2l

More striking

amount ot hemorrhages, \‘cIlous

tar-

tuosity, cotton wool spots, and disc ede111a

Fluorescein giogl-aph!

an-

N~o\,;~scul~ll~i/~~tion Electrot-ctinogKlph\

No or minimal capillary nonpcl-fiision Not SCCI~

Extensive capillary non-per-

Normal b wave aniplitudc NOI-ma1 b/a wave ratio

Reduced b wave amplitude Reduced b/a wave ratio

fusion Ma) he seen

Sanborn and Magargal’“” reported 12%. of‘ patients with 201200 or worse vision). Final visual acuity is highly correlated with the amount of capillary perfusion; nonischemic eyes resolve with better visual acuities than ischemic eyes. Magargal et al”” found that 85% of nonischemic eyes had a final visual acuity of 20/200 or better vision, and 61% were better than 20140. Conversely, follow-up on the ischemic eyes showed that only 2 1% (three of 14) had vision of 20/200 or better. Similarly Fong et al:<’ found that 85% (62 of 73) of nonischemic eyes had vision of 2O/2OO or better, including 73% (53 of 73) that were 20/40 or better. In eyes with an ischemic type of CRVO, only 10% saw 20/40 or better, and 83% (22 of 30) were 201200 or worse, including 20% (six of 30) of the ischemic eyes that had no light perception. (One ischemic eye had become nonischemic since initial visual acuities were recorded.) Ocular sequelae of CRVO include chronic cystoid macular edema, pigment or exudate in the macula, sheathed vessels, retinal artery occlusion, venous-venous collaterals of the disc, macu-

406

Surv

Ophthalmol

37 (6) May-June

FONG, SCHATZ

1993

Fig. ci. Nonischemic CRVO with cystoid macular edema in the right eye of a Y4-year-old white male. Vision is 20/50. A: Dilated, tortuous retinal veins on collaterals. the disc with a few small venous-venous

Note the marked macular edema with a central fovea1 cyst, retinal hemorrhages and dilated and tortuous retinal veins. B: Fluorescein angiogram shows dilated and tortuous retinal veins and macular capillaries. C: Late-phase fluorescein angiogram shows marked cystoid macular edema.

lar hole, retinal or disc neovascularization, rubeosis iridis, neovascular glaucoma, and traction or exudative retina1 detachment. A. CHRONIC

CYSTOID

MACULAR

worse (including two eyes with no light perception). Two of the five were in young adults (ages 18 and 26).

EDEMA

&ME)

B. MACULAR

PIGMENTARY

CHANGES

Chronic CME was reported to occur in three of 15 (20%) of Gonder’s cases,” one of three (33.3%) of Hayreh’s,” and three of 15 (20%~) of Hunter’s”” and to be a frequent cause of decrease in vision. Damage to the capillary endothelium is widespread, causing dilation and tortuosity of the perifoveal capillary network with multiple points of leakage (Fig. 6).4’ Macular edema may be seen as diffuse thickening of the retina, as large cystic spaces, or may be seen in association with a sensory retinal detachment. Weinberg et al’“” reported five eyes (of five patients) who developed an exudative retina1 detachment following a CRVO. This developed from seven to 36 weeks after the onset of symptoms. All five patients exhibited severe damage to the retinal capillary bed with nonperfusion, and all five had final visual acuities of 20/200 or

A common finding is a pigmented or depigmented scar in the central macula (Fig. 7). This is thought to be caused by chronic CME. Chronic CME usually is associated with some degree of subretinal fluid; chronic subretinal fluid in the macula predisposes to retinal pigment epithelial atrophy (causing a depigmented scar) as well as hyperplasia (resulting in a pigmented scar). Subretinal hemorrhage (rare) may also cause fovea1 pigment epithelial hyperplasia. In very rare cases, the hyperpigmentation may be caused by laser photocoagulation. Pigmentary changes occur in 1 l-38% of patients [Hart et al,“” one of 9 (11%); Lyle and Wybar,” one of seven (14%); Priluck et al,“!’ 16 of 42 (38%); Fong et al,“’ 38 of 102 (38%)]. Although vision can be good, it is usually impaired significantly.

CRVO IN YOUNG ADULTS

Fig. 7.

white male. Depigmented scar from chronic cystoid macular edema in the right eye of a 45-year-old Vision is 20160. A: Note the retinal hemorrhages in right fundus. ‘rhe central macula is very edematous. H: Latephase fluorescein angiogram. Marked retinal vascular leakage results in cystoid macular edema. C: Five-and-onehalf years later: Vision is 201400. The CRVO has resolved. The disc margins are no longer blurred. There are disc area of collaterals present. The retinal veins are no longer tortuous or dilated. The macula shows a well-demarcated pigment epithelial atrophy (arrows). D: Early arteriovenous-phase fluorescein angiogram shows marked hyperfluorescence in the macula. This is a large area of pigment epithelial window defect indicating marked atrophy of the pigment epithelium in the macula. The surrounding retinal capillaries are dilated.

C. MACULAR EXUDATE Sanborn and Magargal’“” reported that five of 40 (13%) of their patients under age 40 with CRVO had macular exudate; one eye had the appearance of a partial macular star. When exudate is present, it may be in a circinate form, in clumps, or in the form of a macular star, either complete or partial (Fig. 8). A macular star exudate is usually the result of vascular leakage from the optic disc. Circinate exudate or clumps of exudate in the macula in the presence of a CRVO usually result from retinal vascular leakage of capillaries in the macular area. An occasional

case will exhibit round exudate in the central macula corresponding to a sensory retinal detachment.“” Brown reported a “marked amount of hard exudate” in four of 250 patients with CRVO, including a 29-year-old. Brown found that patients with large amounts of hard exudate had a higher triglyceride level, poorer visual acuity, and an increased degree of retinal ischemia.” D. VASCULAR

SHEATHING

Sheathed vessels have been reported associated with CRVO in young adults [Ellenberger,”

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Fig. 8. CRVO and macular edema in the right eye of a 4%year-old white woman with hypertension. Vision is finger counting at five feet. Note rhe marked exudate in the macula. Note also the retinal hemorrhages, dilated and tortuous retinal veins, and marked retinal edema.

one one of three; Hart,‘” one of nine; Hayreh,” of eight; Lonn and Hoyt,‘” two of five (Fig. 9)]. The presence of sheathed vessels had no correlation with final visual acuity.‘“’ E. RETINAL

ARTERY OCCLUSION

Katz and Smith”’ presented a single case report of cilioretinal artery occlusion in papillophlebitis, and Kremer” presented a case with a “combined” retinal artery and vein occlusion in a young adult with lupus, which appeared to represent a cilioretinal artery occlusion in CKVO. McLeod”” and Schatz et al’” proposed that the mechanism of cilioretinal artery occlusion following a CRVO is as follows: the occlusion of the central retinal vein produces an elevation of intraluminal capillary pressure because the central retinal artery continues to pump blood into the retina. Because the perfusion pressure of the cilioretinal artery is lower than the central retinal artery, it becomes relatively occluded. Because such relative cilioretinal artery occlusions that occur secondary to CRVO are frequently transient, they may be missed. Duker et al’” observed seven patients with a combined branch retinal artery and central retinal vein obstruction, including three young patients without systemic disease. They suggested that in young patients an underlying inflammatory condition of the optic nerve seemed the most likely etiology. In older patients they suggested this reflected generalized atherosclerosis.

Fig.

Y. CRVO with venous sheathing in the left eye 42-year-old white male. Vision is 20140. A: Redfree photograph of inferotemporal area shows focal sheathing of the retinal vein and diffuse sheathing throughout the fundus. B: Midphase fluorescein angiogram. Note the hyperfluorescence where the retinal vein is sheathed.

of a

When retinal artery occlusions occur in association with CRVO, the arterial component is, in most cases, probably secondary to the CRVO and is simply a manifestation of severe ischemia. F. VENOUS-VENOUS DISC

COLLATERALS

OF THE

In Priluck’s series,“” nine of 42 (21%) cases formed collaterals (opticiliary shunts) after a mean follow-up of 14 years. Other investigators have found similar incidences [Hunter,“” one of 15 (7%); Lyle and Wybar,” one of seven, (14%); Sanborn,“” eight of 40 (20%); Hart et al,“’ two of nine (22%); Quinlan et al,lO” 80 of 168 (48%); Hayreh,‘” two of four (50%)]. The incidence of collaterals may be hard to quantify because in a

CRVO IN YOUNG ADULTS few cases collaterals formed and disappeared after the central retinal vein had reopened. Priluck et al”” have suggested that eyes that develop venous-venous collaterals of the disc have better visual acuity results. Quinlan et al’” found no relation between the presence of collaterals and the improvement in visual acuity. Schatz et al”” confirmed that venous-venous collaterals on the optic nerve head were, in fact, retinal venous to choroidal venous collaterals (bypass channels) based on a pathologic study of 500 serial sections in a case of optic nerve meningioma that developed collaterals and was studied at autopsy. Four of the six collaterals in this case extended around the end of Bruch’s membrane at the optic nerve head. G. MACULAR

HOLE

Fong et al”” and Priluck”” reported young adults with CKVO who developed a macular hole. Boniuk’ estimated that the incidence of macular holes in vein occlusions is about 4% and hypothesized that the mechanism is the unroofing of a cyst after long-standing <:ME. H. NEOVASCULARIZATION The risk of neovascular complications in venous occlusive disease is related to the extent of capillary nonperfusion (Fig. 10). The incidence of neovascularization of the disc or retina in CRVO appears to be low. It occurred in 5% of Priluck’s”” cases of ischemic type CRVO and in none of his nonischemic type. Similarly, Magargal”’ and Zegarra”i” showed no neovascularization of the disc or retina. Vitreous hemorrhage is also relatively rare (O-6%) of ischemic type CRVO);“‘.‘S” it appears more likely to occur when the patient is anticoagulated.‘E Neovascular glaucoma (NVG) following central retinal vein obstruction is a devastating complication that occurs in approximately 20% of young patients with CRVO.“,““,“’ The risk of developing NVG is approximately 60%) in those eyes with extensive retinal ischemia.“‘,x’ Panretinal photocoagulation has been reported to be beneficial in reducing the incidence of NVG in these cases. I”” I. SYSTEMIC

PROGNOSIS

Priluck et al”” reviewed the longterm follow-up of CRVO in young adults aged 40 years or younger to delineate the course. They found that of 42 patients followed for an average of 14 years, five had died (12% mortality). All five patients died of vascular causes (four cardiovascular, one

409

cerebrovascular). Similarly, Cassady’” found a lo-year mortality in older patients with CRVO of 33.3%, and Moore”” found a 5%year life expectancy after CRVO in older patients. These findings support the role of generalized vascular disease as an associated finding in some young adult patients with CRVO.

V. Pathogenesis The eye of a 44-year-old woman was enucleated two months after she developed CRVO followed by neovascular glaucoma and was studied histopathologically by Appen et al.” They reported that “the central retinal vein showed mild cuffing by a mononuclear infiltrate, and the central retinal artery was patent. The optic nerve pial vessels showed extensive phlebitis and obliteration of the lumens of several arterioles. .. The central retinal vein in the retrolaminar optic nerve was practically obliterated by a marked mononuclear inflammatory infiltrate.” Appen argued that the initial lesion was a diffuse phlebitis that caused obstruction and stagnation of blood flow. Green et al”’ studied 29 eyes in 28 cases of CRVO from patients of all ages, including five patients under fifty years of age, and showed that all cases had either a fresh or recanalized thrombus in the area of the lamina cribrosa. He also showed chronic inflammation around the vessels in 48.3% of these cases, but it can be argued that the inflammation was a result of the thrombosis and not the cause.‘“’ Many authors have suggested that inflammation of the retinal or papillary vessels, or both, is the major cause of CRVO in young adults. Lonn occlusion ocand Hoyt”’ suggest that venous curred after initiation by a phlebitis in and about the optic nerve head. Lyle and Wyba? hypothesize that CRVO in young adults is a form of Kales’ disease; they reported a patient with retinal vasculitis in one eye and peripheral Eales’ disease in the other. Cogan’” suggests that this is the mild degree of a spectrum of retinal vasculitis aflecting veins preferentially; retinal arteries become involved in more severe cases. Hayreh”’ proposes that a mild, nonspecific vasculitis of the ciliary vessels in the loose prelaminar region leads to optic disc edema (optic disc vasculitis type 1” or the big blind spot syndrome”‘). If the disc edema progresses to compress the venous channels in the prelaminar region, the classic picture of CRVO may develop (optic disc vasculitis type II). Hoyt”’ suggests that this syndrome may not be caused by inflammation, as he had originally

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Fig. IO. Ischemic CRVO leading to neovascularization of the retina in the right eye ofa 4 1-year-old white woman. Vision is finger counting at one foot. A: Redfree photograph shows many cotton-wool spots, hemorrhages, retinal edema, and dilated tortuous retinal veins. B: Early arteriovenous-phase fluorescein angiogram shows dilated retinal vessels and hypofluorescent areas of capillary nonperfusion around the disc. C: Fluorescein angiogram, temporal area, shows dilated tortuous retinal veins and venules. Note the areas of capillary nonperfusion (arrows). D: Two months

CRVO IN YOUNG ADULTS proposed, but may be due to vitreous traction. Miller”’ observed that in several of his patients, the papillophlebitis resolved when the vitreous became totally detached. However, it appears that for these later cases Hoyt and Miller were describing the vitreoretinal traction syndrome in which disc edema (but not CRVO) can occur secondary to vitreous traction, which occurs with a partial posterior vitreous detachment. Thus, the etiology of CRVO is usually unknown and is probably multifactorial in the majority of cases. It appears, however, that in at least some, inflammation does play a role. Focal phlebitis, optic disc swelling, and vitreous cells are present in a significant number of patients,“‘.“‘” and suggest an inflammatory process. Some patients experience prompt resolution with the use of periocular steroids, further indicating that inflammation plays a role. Walters and Spalton”? suggest that in some patients a congenital abnormality may be present at the level of the lamina cribrosa, causing turbulent flow and predisposing to thrombus formation. Similarly, Kline et al” hypothesize that congenital anomalies of the central retinal vein, such as increased tortuosity of the orbital veins or anomalous anatomic configurations, may result in insults to the hemodynamics of the venous outflow and subsequent thrombosis of the central retinal vein. CRVO can occur in association with a retinal arteriovenous malformation.“4

VI. Treatment The best treatment for CRVO in young adults is unknown because its cause is usually unknown. Many eyes with a nonischemic CRVO recover spontaneously, requiring no treatment. Since many of these patients (who, if left untreated, would have recovered spontaneously) were variously treated, many treatments have been reported to be beneficial. No treatment has been

later, vision is 201400. Red-free photograph, shows retinal hemorrhages, cotton-wool spots, and cystoid macular edema. E: Fluorescein angiogram, nasal to right disc, shows tine. dilated retinal capillaries and many areas of capillary nonperfusion. F: Seven years later, vision is 20170. The retina is no longer edematous. The retinal vessels appear normal. Far temporally, there is a small patch of retinal neovascularization. C: Arteriovenous-phase fluorescein angiogram appears normal except for the patch of neovascularization temporally.

411

studied in a controlled fashion and, therefore, the appropriate treatment of CRVO in young patients, if any, is unknown. A. STEROIDS The use of systemic or periocular steroids has been advocated by those proposing an inflammatory mechanism for the pathogenesis of CRVO. The presence of vitreous cells or the laboratory finding of an elevated ESR may implicate an inflammatory origin.‘” Although there have been no controlled studies to test the effectiveness of steroid therapy, some feel that any therapy that appears to clear the macular edema and prevents the development of permanent cystoid degeneration is indicated.4”“’ Some have found steroids to be effective,47.4”.x’ while others have not. “‘+.” Appen et al” felt that because of the evidence of inflammation in their case of CRVO studied histopathologically, steroids may be useful in the treatment. In a group of cases treated with steroids by Hayreh,“” it appeared that steroids did have a beneficial effect on the vision, although he found that on tapering or removing steroids, some patients had a recurrence of the visual reduction. Steroids are probably useful in some cases of CRVO in adults under 50. Steroids may help to reduce inflammatory cell infiltrates around the optic nerve and therefore improve blood flow through the CRVO. This, in turn, may reduce cystoid macular edema and improve visual acuity. The major problem with the use of steroids (oral or periocular) is that some eyes tend to undergo an elevation in intraocular pressure. If an elevation of the intraocular pressure was an initial inciting factor in the development of CRVO, then the occlusion could conceivably be made worse by steroid treatment. B. ANTICOAGULATION Anticoagulation therapy has been suggested by some clinicians”7~xx~“” to decrease the incidence of neovascular glaucoma and promote the formation of retinal venous to ciliary venous anastamoses (collaterals) at the optic nerve head.“” Others have questioned the effectiveness of anticoagulation medication and have even suggested that it may be harmful because of the hemorrhagic complications.““~4”~8’~‘2” Fong et al”’ found that of six patients who received anticoagulation therapy, two suffered severe vitreous hemorrhage; both required vitrectomy, and both deteriorated to no light perception. Of their remaining 97 cases, none had received anticoagulation and

sllo\vs Fig. II. CKVO with CME in right eye of 30-year-old \\‘oman. Vision is “O/lOO. ,-I: Kcd-fiiec pllotoglTlph tortuous retinal veins, blurred disc margins, and venous-venous collaterals on the disc. .I‘hcre is evidence of’cystoid macular edema. B: Early al-tel-io~enoLls-phase fluowsccin angiogl-am shows dilated capillaries in the macula. (:: Late-phase fluorescein angiogram sholvs marked cystic edema in the macula. ‘I‘he fovea Ilas a large wntral cyst. II. Fifteen months following grid laser photocoagul~~tion, vision is ‘10/100. Red-ficc photogi~aph shob3 niultiple, fine angiosmall grid laser photocoagLtlatiot1 spots throughout the nlacula~~ arca. I:‘: ,-\l.tcl-io\enoL~~-l~~~~ls~ fluorcsccin gram shows multiple, fine small grid laser photocoagulation spots in the maculate area. P; Late-phase fluorcstciu the cystoid macula edema has I-esol\xxl. C:ot//~/v~/: i\lthough grid Iascr angiogram shows no leakage in the mac~~la treatment may have contributed to some of the clearing of the c),stoitl macular- edema, it appears that this C?C underwent a general improvement spontaneously and this alone IIGI>’have caused the c-lcal.ing of the cystoltl macular edema. A randomized treatment trial is necessary to ;I~SCSSthe efficacy of’pitl lasc‘r trwtnlctlt for c.!.stoid macular edema in CXVO.

CRVO IN YOUNG ADULTS none suffered vitreous hemorrhage. Thrombolytic agents have been tried by Kohner et al”’ to remove the clot and relieve the central retinal vein occlusion. They found streptokinase to be effective in reducing the neovascular complications, but there was a much greater risk of vitreous hemorrhage. In addition, a more activator selective agent, tissue plasminogen (TPA), is currently being investigated for use in improving visual results and reducing complications,70.“” but to date has not been proven beneficial for vein occlusions. Because of the association with platelet and coagulation disorders, antiplatelet medications, such as aspirin and persantine, have been suggested for therapeutic use.“‘,” Fong et al”” showed in a retrospective series that there was no difference in visual acuity in those treated with antiplatelet medication compared with those not so treated. Gonde? reported finding that only one in 15 patients under 50 years of age with CRVO had a systemic disease (hyperlipoproteinemia). When tested for platelet function, however, 11 (73%) of these patients were found to have platelet abnormalities. Because platelet studies are not routinely performed on these patients, platelet abnormalities may be grossly underestimated. Because of the low morbidity associated with aspirin therapy, many retinal specialists recommend aspirin therapy for those patients who have no condition that would preclude its use;“’ it is not known, however, that aspirin has any substantive effect on CRVO. Hemodilution and plasma exchange have been used to reduce morbidity in CRV0.7” Ring et al”” have shown that patients with ischemic CRVO have higher blood viscosity than patients with nonischemic CRVO. In addition, Kohner et al”’ reported in pig studies that hemodilution reduces whole blood viscosity and increases retinal blood flow. Hansen et a14’-‘” have found that isovolemic hemodilution is effective in improving visual prognosis in both ischemic and nonischemic CRVO. C. OTHER MEDICATIONS Gutman and Zegarra” suggested that lowering the intraocular pressure medically resulted in a coincident improvement in visual acuity associated with improved circulation and a transient remission in macular edema. Since elevated intraocular pressure probably plays some role in the development of some CRVOs, control of it may help aid the tendency toward resolution.

413 Recently, the use of acetalozamide’” for chronic cystoid macular edema has been suggested to be effective for certain disorders (although not for primary vascular diseases). Other treatments, such as digoxinq7 low molecular weight dextran,” surgical decompression,“” carbon dioxide inhalationicarbenogen,“” potassium iodide and pilocarpine, ‘* irradiation,“” and hyperbaric oxygen”‘” have been tried with only limited success. D. PHOTOCOAGULATION The usefulness of panretinal photocoagulation (in the technique similar to that for proliferative diabetic retinopathy for prevention and treatment of neovascular complications) has been I:l.4ti,7:~.H’).1M1. I”4.13:~ supported by many investigators. Cryotherapy has also been suggested.xg Panretinal photocoagulation does seem to halt the progression of rubeosis iridis to neovascular glaucoma in those CRVOs with a great deal ofischemia. Others have used grid laser photocoagulation of the macula for macular edema in older patients with CRVO (Fig. 1 1).‘“,‘“‘.4’~4F.“” Grid laser may help reduce macular edema in CRVO but there is no proof that it makes any difference in final visual acuity. Those cases where it does seem to be beneficial are those mild cases of CRVO that show spontaneous resolution but have residual retinal vascular leakage and cystoid macular edema. A prospective, randomized, multicentered study funded by the National Eye Institute to determine whether photocoagulation therapy can help prevent iris neovascularization in ischemic CRVO and assess grid-pattern photocoagulation is currently in the recruitment stages. Its purpose is to give more insight in the role of laser photocoagulation for CRVO in adults.‘” E. VITRECTOMY Yeshaya and Treister reported a poorer prognosis for eyes undergoing vitrectomy for CRVO compared with eyes undergoing vitrectomy for branch retinal vein occlusion.“” However, when vitreous hemorrhage is present following CRVO, vitrectomy may be quite helpful not only in restoring clarity to the media, but in then allowing panretinal laser photocoagulation to the ischemic areas which can result in regression of the neovascularization and prevention of recurrent vitreous hemorrhage.‘“’

V. Summary In this review, we have compiled the information from all scientifically published reports of

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central retinal vein occIusion in young adults. We attempt to clarify its clinical characteristics and course (indicating the broad range of ocular manifestations), discuss the differential diagnosis and the various possible causes and pathogenesis, list the appropriate medical work-up, and recommend therapeutic alternatives. Most patients under 50 who develop central retinal vein occlusion are healthy and recover vision for the most part. Few have related systemic disease or other ocular problems. About one out of five suffers significant, permanent visual loss.

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Outline I. Clinical

characteristics

A.

Age

B. C. D. E.

Sex Lateralit); Race Associated medical conditions I. Hypertension 2. Diabetes 3. Hyperlipidemia 4. Hypercoagulability 5. Migraine 6. Mitral valve prolapse 7. Collagen vascular disease 8. Acquired immunodeficiency syndrotne 9. Carotid artery disease 10. Elevated sedimentation rate (ESR)

F.

Medications 1. Oral contraceptives 2. Diuretics

CRVO

IN YOUNG

417

ADULTS

3. Sympathomimetics Ocular conditions I. Glaucoma 2. Optic nerve disease 3. Retinal artery occlusion 4. Retinal arteriwenous malformation (AVM) 5. Other ocular conditions H. ‘Trauma 11. Ocular manifestations A. Symptoms B. Kefraction (1. Visual acuity D. Pupillary examination appearance and fluorescein E. Funduscopic angiography F. Visual field examination C;. Electrophysiologic testing II I. Difbential diawmsis A. Diabetic rebpathy B. bdiation retinopathy C. Valsalva retinopathy 1). Venous stasis retinopathy from carotid disease IC Malignant hypertensive retinopathy I-. Papillitis (.i. Neuroretinitis H. Papilledema 1. Optic disc vasculitis (;.

.I. Ii. L. M.

Trauma Hyperviscosity Sickle cell disease Eales’ disease Disc

neovascularization

from

uveitis

Big blind spot syndrome :: IV. Natural history and prognosis A. Chronic cvstoid macular edema

(CME)

B. Macular pigmentary changes C. Macular exudate D. Vascular sheathing E. Retinal artery occlusion F. Venous-venous collaterals of the disc G. Macular hole H. Neovascularization I. Systemic prognosis V. Pathogenesis VI. Treatment A. Steroids B. Anticoagulation <:. Other medications D. Photocoagulation E. Vitrectomy

\Yr would like to thank the following physicians who loaned us cases for our ot-iginal paper cm this subject? l‘homas C. Burton. A.L. Maberley, Leonard J&e. Hernando Zegarra, Alfred .J. Nadel, Paul Holmwood, Terr) Ann Scriven, Gary C. Brown, Lawrence J. Singerman. Randy V. Campo. Richard C;. Chcnoweth, Lawrence A. YannuLLi, Kussell Sobel, Robert-r. Wendel, Charles P. Wilkinson. R. Joseph Olk, 1.1. De Lacy, Everett Ai, Bernard H. Doft, Steven V. Guiak, Howard D. Gilbert. Gary E. Fish, Hsushi Yeh, Michael A. Bloome. Frederick H. Davidorf, Louis V. Xnxiolelti, Richard A. Lewis, and Steven -1‘. Charles. We also thank Drs. H. Richard McDonald and Robert N. Johnson for their help. Supported by the Retina Research Fund of St. Mary’s Hospital and MedIcal Center-, San Francisco,