Baseline and Early Natural History Report

The Central Vein Occlusion Study

Central Vein Occlusion Study Group

Objectives: To evaluate panretinal photocoagulation for
grid-pattern
ischemic central vein occlusion and macular
photocoagulation for macular edema with reduced visual
acuity due to central vein occlusion and to further define
the natural history of central vein occlusion.
Design: A multicenter randomized controlled clinical trial
supported by the National Eye Institute, Bethesda, Md.
Patients: A total of 728 eyes from 725 patients were
entered into one or more of four study groups: per-
fused, nonperfused, indeterminate perfusion, and mac-
ular edema.
Results: Follow-up of study patients is still in
progress and no results are available for the random-
ized groups (nonperfused and macular edema). Thirty-
eight (83%) of 46 evaluable eyes in the indeterminate
group eventually demonstrated at least 10 disc areas of
nonperfusion (28 eyes) or developed iris and/or angle
neovascularization before retinal status could be deter-
mined (10 eyes). Four-month follow-up information is
available for 522 of the 547 eyes in the perfused
group. Thirty of these 522 eyes demonstrated iris
and/or angle neovascularization at or before the
4-month follow-up visit. An additional 51 eyes had de-
veloped evidence of at least 10 disc areas of nonperfu-
sion by the time of the 4-month visit.
Conclusions: These findings confirm the importance of
frequent follow-up examinations, including undilated slit-
lamp examination of the iris, and gonioscopy in the man-
agement of all patients with recent onset of central vein
occlusion.
(Arch Ophthalmol. 1993;111:1087-1095)

From Central Vein Occlusion
Study Coordinating Center,
Texas A & M University Health
Science Center, Temple.
The
Central Vein Occlu¬
sion Study (CVOS) is a
multicenter, randomized,
controlled clinical trial
supported by the Na¬
tional Eye Institute, Bethesda, Md. In
this article, we summarize the study de¬
sign and baseline results. In addition,
we report and discuss two early natural
history findings that led us to change
our management of the study patients.
The study design and baseline character¬
istics of the population will be in more
detail in a separate article.
The CVOS is an ongoing study de¬
signed to answer the following three
questions about central vein occlusion
(CVO):
1. Does early panretinal photocoag¬
ulation (PRP) prevent iris neovasculariza¬
tion (INV) in eyes with ischemie CVO?
2. Does macular grid-pattern laser pho-
tocoagulation improve visual acuity in eyes
with reduced vision due to macular edema
from CVO?
3. What is the natural history of eyes
with CVO that have little or no evidence
of ischemia (less than 10 disc areas of non¬
perfusion)?
Before patient recruitment began, the
Data and Safety Monitoring Board re¬
viewed the study design and recom¬
mended that the study address, insofar as
possible, one additional question:
4. Is early PRP more effective than PRP
at first identification of INV in preventing
further ocular morbidity due to progres-
See Materials and Methods
next
on page

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 MATERIALS AND METHODS
RECRUITMENT, ELIGIBILITY, AND STUDY ENTRY
Between August 1, 1988, and July 31, 1992, patients seen in
the nine clinics with signs of CVO were considered for the
study. Eligibility and exclusion criteria for each group are shown
in Table 1. For the purpose of the study, CVO was defined
as demonstrated retinal hemorrhage in all four quadrants with
a dilated venous system. Patients with evidence of any in¬
tercurrent retinal disease in the study eye or any diabetic re¬
tinopathy in either eye were excluded. Random treatment as¬
signments in groups and M were made using computer-
generated random allocation. Group eyes were stratified
by clinic and group M eyes by both clinic and duration of the
CVO (less than 1 year or greater than or equal to 1 year).
Both eyes of a patient could be considered for the study only
if they were eligible simultaneously. If both eyes of the pa¬
tient were eligible for a randomized group, one eye was ran¬
domly assigned to treatment and the other to observation.
On the assumption that the need to evaluate grid-pattern treat¬
ment for macular edema is independent ofthe treatment sta¬
tus of the periphery of the eye, the protocol allowed eyes in
other CVOS groups to be entered into group M as well. Group
eyes were entered into group I or and closed out of group
if sufficiently increased retinal hemorrhage and/or retinal
capillary nonperfusion occurred and the eye met the eligi¬
bility criteria for the new group.
Following an orientation session regarding the CVOS,
a detailed initial visit was undertaken for each patient that
sive neovascular glaucoma in eyes with ischemie CVO?
The nine clinics listed at the end of this article en¬
rolled a total of 728 eyes from 725 patients in the study.
Eligibility was determined on the basis of clinical exam¬
ination and photographic documentation evaluated at a
Central Reading Center (Miami, Fla).
The following four groups of eyes were defined in
the original protocol and are discussed in this report:
Group (perfused): defined angiographically as eyes
with less than 10 disc areas of nonperfusion (retinal cap¬
illary dropout); these eyes served as a pool for possible
later entry into group M and are being followed up for
natural history.
Group (nonperfused): defined angiographically as
eyes with at least 10 disc areas of retinal capillary non¬
perfusion; these eyes were randomly assigned to either
PRP observation; the outcome variables for group
or
eyes INV and progressive neovascular glaucoma.
are
Group I (indeterminate perfusion): eyes with suffi¬
cient intraretinal hemorrhage to prevent determination of
perfusion status by fluorescein angiography; the study de¬
sign was to follow up eyes in group I on a monthly basis
until they became eligible for either group or group P.
Group M (macular edema): reduced visual acuity (20/50
Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015
included a medical and ophthalmologic history, blood pres¬
sure measurement, protocol visual acuity examination, in¬
traocular pressure measurement, and slit-lamp examination
that included gonioscopy and color slit-lamp iris photogra¬
phy with the pupils undilated. Examination of the iris with
undilated pupils was found to be particularly important. Early
in the study, several patients were ineligible owing to INV
undetected during a dilated slit-lamp examination performed
only 1 or 2 days prior to the eligibility examination. A dilated
slit-lamp and fundus examination was followed by color ste¬
reo fundus photography of both eyes and fundus fluorescein
angiography of the affected eye. The investigator discussed
the study protocol with each patient, and each patient read
and signed a written consent form. Photographs were sent to
the Reading Center and forms were sent to the Coordinating
Center (Temple, Tex) for determination of eligibility.
Patients eligible for group or group I were entered
into the study at the time the clinic was notified of eligi¬
bility. Patients eligible for one of the randomized groups
(groups and M) returned to the clinic within 4 weeks of
the date of the eligibility angiogram for a second visit; at the
second visit, eligibility was confirmed and the random as¬
signment was obtained from the Coordinating Center by
telephone. If the patient was assigned to treatment, the treat¬
ment was generally performed that day. Recruitment was
completed on August 12, 1992.
PATIENT FOLLOW-UP
Patients in the CVOS are followed up at regular intervals
for 3 years according to the schedule in Table 2. Re-
or worse) due to angiographically proven macular edema;
group M eyes were randomly assigned to grid-pattern pho¬
tocoagulation or observation without treatment; the pri¬
mary outcome variable for group M eyes is visual acuity.
In this report we describe the patient population and
ocular findings at baseline; we also report the natural his¬
tory of group I eyes and the early natural history ob¬
served in group eyes because of their importance to the
early management of these eyes.
RESULTS
BASELINE FINDINGS
Description of Study Patients
A total of 725 patients were enrolled in the CVOS. Of
these patients, 546 were at some time in group P, 180
were in group N, 52 in group I, and 155 in group M.
Nine patients recruited after a change in the protocol on
August 16,1991, were enrolled in a new randomized group
of indeterminate eyes; two of these patients transferred
from group P. The baseline characteristics for the four
original groups defined above and for the whole study
 fraction isperformed and visual acuity is measured by
a study-certified visual acuity examiner at baseline and
every 4 months during follow-up. A back-lighted chart
developed for the Early Treatment Diabetic Retinopathy
Study is used and visual acuity and refraction proto¬
cols are similar to those used in that study. At eight
of the nine centers, the visual acuity examiner is
masked regarding the patient's treatment status. For logistic
reasons, masking was not attempted at the remaining
center. Color fundus photographs and fundus fluorescein
angiography are taken at baseline and at regular inter¬
vals thereafter. At every follow-up visit, slit-lamp examina¬
tion of the undilated iris, gonioscopy, and slit-lamp pho¬
tography are performed. Panretinal photocoagulation is
mandated following appropriate photographic docu¬
mentation for any eye that develops 2 clock hours of INV
or any angle neovascularization (ANV) at any time during
the study, regardless of the patient's treatment assignment
or group.
Determinations of nonperfusion are made at
the Reading Center. The area of nonperfusion is mea¬
sured angiographically in the standard photographic
fields shown in Figures 1 and 2 using a disc area
template. Iris neovascularization is quantified at the
Reading Center on the basis of slit-lamp color iris
photography.
The accumulating data are examined every 6 months
by the Data and Safety Monitoring Board. The voting mem¬
bers, recruited from outside the study, include retina spe¬
cialists, statisticians with experience in ophthalmologic stud¬
ies, and a patient advocate.
population are summarized in Table 3 and given in more
detail in the companion electronic article.
Seventy-two percent of the patients were 60 years of
age or older, and 25% were between 75 and 92 years of
age. The mean and median ages were 65 and 68 years,
respectively. There were slightly more men in the study
than women; the ratio of men to women was 2:1 for the
97 patients under 50 years of age and decreased with in¬
creased age. Ninety-four percent ofthe patients were white
and 12% were current smokers. Seven percent ofthe pa¬
tients reported having diabetes, but the patients with di¬
abetic retinopathy were excluded. Sixty-one percent of
patients had some evidence of hypertension, either dias¬
tolic blood pressure of 90 mm Hg or higher or systolic
blood pressure of 160 mm Hg or higher, or they received
medication for hypertension.
Description of Study Eyes
The major baseline characteristics for the eyes in each group
are shown in Tables 4 and 5. A total of 547 eyes of 546
patients were entered into group and 181 eyes of 180
patients in group N. Only three patients had both eyes in
the study. One patient had both eyes in group N, one
Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015
PHOTOGRAPHY PROTOCOL
Fundus photographs are taken using the wide-angle fundus
camera (Canon 60° [Canon USA Ine, Lake Success, NY] or
Topcon 45° [Topcon America Corporation, Paramus, NY])
with the five standard views shown in Figure 1. Eyes that
do not dilate adequately for wide-angle fundus photogra¬
phy are photographed using the 30° Zeiss (Carl Zeiss,
Oberkochern, Germany) fundus camera for the eight stan¬
dard views shown in Figure 2. For group M eyes, stereo
Zeiss photographs of the macula are required. A timed fun¬
dus fluorescein angiogram is obtained with the same type
of camera as used for the color fundus photographs. After
30 seconds, a sweep that includes all of the protocol fields
in the midperiphery is obtained.
STATISTICAL METHODOLOGY
Standard descriptive statistics were used to characterize the
population of patients enrolled in the CVOS and the study
eyes at baseline. Contingency tables were evaluated using
the 2 test. Factors relating to the early development of non¬
perfusion in eyes determined to be perfused at baseline were
examined using the SAS program for logistic regression.1
All potential risk factors were coded as binary variables so
that odds ratios (ORs) represented the odds of patients with
that factor having an event vs patients without that factor
having the same event, adjusted for all other variables in
the analysis. A backward stepwise elimination procedure
was also used with elimination based on a value of greater
than .05. values less than .05 are considered significant.
patient had both eyes in group P, and one patient had the
left eye in group I and the right eye in group N. Most of
the eyes in group M were simultaneously in another group,
120 in group and 22 in group N.
All eyes in group had at least 10 disc areas of non¬
perfusion. Thirty-five percent of group eyes had some
measurable nonperfusion (less than 10 disc areas) at base¬
line. At the time of the initial evaluation, nonperfusion
could not be evaluated by fluorescein angiography in some
eyes because retinal capillary detail was obscured by in-
traretinal hemorrhage. These eyes were entered into group
I, anticipating that they would be transferred into either
group or group within 6 months as the hemorrhage
cleared and the retinal capillary detail could be evaluated
by fluorescein angiography. Fifty-two eyes were entered
in group i.
Randomization for group M eyes was stratified by
duration of the CVO. Eighty-five (55%) of the 155 eyes
in group M were entered within 1 year of onset of the
CVO; 70 eyes (45%) had duration of CVO of at least 1
year at entry. Duration of more than 1 year was an ex¬
clusion criterion for all other groups.
The Reading Center found angiographie evidence of
macular edema involving the fovea at baseline in 84% of
 Table 1. Central Vein Occlusion Study Eligibility and Exclusion Criteria
Eligibility Criteria
All groups: Confirmed presence of central vein occlusion (CVO); intraocular pressure of <30 mm Hg; ability to obtain good quality fundus photographs
and fluorescein angiography; willingness to sign consent form; visual acuity light perception or better
Group P: Duration of CVO of <1 y with intraretinal hemorrhage present in all four quadrants; retinal capillary nonperfusion, if any, <10 disc areas;
study eye iris and angle free of any neovascularization
Group N: Duration of CVO of <1 y with intraretinal hemorrhage present in all four quadrants; at least 10 disc areas of retinal nonperfusion in study
eye as judged by Reading Center on basis of fundus fluorescein angiography; study eye iris and angle free of any neovascularization
Group I: Duration of CVO of <1 y; retinal hemorrhage that prevents measurement of retinal capillary nonperfusion; study eye iris and angle free of
any neovascularization
Group M: Duration of CVO of >3 mo; macular edema that involves fovea confirmed by Reading Center based on fundus fluorescein angiography;
visual acuity between 5/200 and 20/50 with no explanation apparent for decreased acuity except for CVO; phakic with clear media; no
improvement in visual acuity on consecutive visits prior to entry
Exclusion Criteria
All groups: Previous photocoagulation for retinal vascular disease of study eye; intercurrent eye disease that is likely to affect visual acuity over study
period; presence of any diabetic retinopathy in either eye, new or old branch arterial and/or vein occlusion in study eye, retinal neovascular¬
ization in study eye, other retinal vascular disease in study eye, or vitreous hemorrhage other than breakthrough in study eye; presence of
peripheral anterior synechia in the study eye; patient cannot stop receiving heparin sodium and/or warfarin sodium (Coumadin) for duration
of study

the 547 eyes in group P, although most of these eyes had
characteristics that excluded them from group M, such as
visual acuity of better than 20/50, pseudophakia, or blood
in the fovea.
As shown in Table 5, median visual acuity at base¬
line was 20/63 for group eyes, 20/400 for group and
I eyes, and 20/125 for group M eyes. Best corrected visual
acuity was 20/40 or better for 36% of group eyes, 7%
of group eyes, and 2% of group I eyes. Visual acuity
was less than 20/200 in 15% of group eyes, in 69% of
Description of Fellow Eyes
Sixty-five (9%) of the 722 patients with one eye in the
study had a history or evidence of prior vascular occlu¬
sion in the fellow eye at the time of study entry: either
branch vein occlusion (17 eyes), old CVO (46 eyes), or
branch artery occlusion (two eyes). Prospective data on
the incidence of vascular occlusion in the fellow eye will
be reported when follow-up is completed. Visual acuity
was 20/50 or worse for 16% of fellow eyes.

group eyes, and in 73% of group I eyes.

Because of eligibility restrictions all eyes in group M NATURAL HISTORY
had visual acuities between 20/50 and 5/200.
Four-Month Natural History for Eyes in Group
Table 2.Summary of Follow-up and Group was designed to obtain natural history and to serve
Photography Schedules* as apool for recruitment into group M. Group eyes were
Follow-up Visits
expected to be at low risk for the development of INV and
neovascular glaucoma. For this reason, the initial protocol
Group P: Every 4 mo for 3 yf
N:
included the first follow-up examination at 4 months, and
Group Every month for first 6 mo; every 4 mo for 3 y no fundus fluorescein angiography was required between
Group I: Every month until perfusion status of eye can be
determined baseline and 12 months. However, at the 4-month visit,
Group M: Every 4 mo for 3 y some group eyes demonstrated ischemia (areas of cap¬
All groups: Any eye with iris or angle neovascularization followed illary nonperfusion not evident at baseline) or markedly
up monthly until stabilized increased hemorrhage, and in some cases these changes
Photography were accompanied by INV and/or ANV. On the basis of
All groups: this experience, the investigators were advised to examine
Every visit: Slit-lamp photographs of iris (study eye) patients in group at 2 months following entry.
Every 4 mo: Color stereophotographs of fundus (study eye) Ofthe 547 eyes entered into group P, 522 were éval¬
Every 12 mo: Iris and fundus color photographs of both eyes, plus uable for early natural history (506 completed the 4-month
fundus fluorescein angiogram
visit and an additional 16 transferred to group I or be¬
Group M only: Fundus fluorescein angiogram at 4 mo
fore 4 months). Five group patients died before the
Group I only: Fundus fluorescein angiogram every 2 mo
4-month visit could be completed and 20 missed the visit.
*See the text, introductory section, and Table 1 for explanation of the An angiogram (optional at this visit) was obtained at 165
groups.
fSee the "Results" section of the text for modification adopted during of the 506 4-month visits.
the study. In all, 81 (16%) of the 522 évaluable group eyes

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 Superior (4)

Temporal (2) Macula (1) Nasal (3)

Inferior (5)

Figure 1. Standard photographie views for Canon (Canon USA Ine, Lake
Success, NY) or Topcon (Topcon America Corporation, Paramus, NY)
wide-angle camera.

demonstrated at least 10 disc areas of nonperfusion and/or

INV and/or ANV or were transferred to group I at or before
the 4-month visit. Thirty of these 81 eyes showed INV and/or
ANV and required PRP at or before the 4-month visit: f 4
with at least 2 clock hours of INV only, three with ANV
only, and 13 with both. Ten eyes developed at least 10 disc
areas of nonperfusion but were ineligible for transfer to
group for other reasons. At or before the 4-month visit,
41 eligible eyes were transferred to group or group I (31
Figure 2. Standard photographie views tor Zeiss (Carl Zeiss, Oberkochern,
Germany) fundus camera.
and 10 eyes, respectively); outcome for eyes in group
will be reported later when follow-up is complete, as will
the complete natural history of the eyes that remained in
group P. None of the 10 eyes that went from group to
group I returned to the perfused state; one patient who was

Total No. of patientsf

Age, y
Mean 64 71 67 65
Median 67 70 72 69 68
Range 20-89 38-92 24-89 27-87 20-92
Specified characteristics, %
Age, y
<60 31 20 10 25 28
60-74 47 49 54 50 47
>75 23 31 37 25 25
M 55 47 40 59 53
White 93 94 94 94 94
Smoker
Present 13 16 12 12 12
Past 40 36 46 47 39
Diabetes present 7 6 7 7
Blood pressure
Diastolic blood pressure >90 mm Hg 37 34 37 29 37
Elevated blood pressure|| or receiving
medication for hypertension 59 62 73 57 61

*See the text introductory section, and Table 1 for explanation of the groups.
'[Number of patients in each group do not add up to the total, since patients may be in more than one group.
\Not included are nine eyes entered in a new randomized group I late in study.
§Status at time ol initial study entry.
\\Elevated blood pressure is defined as diastolic pressure >90 mm Hg and/or systolic pressure a 160 mm Hg.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 Total No. of eyesf
Specified characteristics, %
Right eye 49 51 48 43 50
Duration of central vein occlusion of <1 mo 27 16 23 0 26
Glaucoma 10 10 13 7 11
Foveal hemorrhage 29 52 83 1 36
Cotton-wool spots 52 71 46 35 54
Venous collaterals 25 29 13 64 25
Macular exudates 5 8 8 15 6
Cilioretinal artery 7 4 6 6 7
Blunting and staining of venules 46 68 69 34 51
Venous tortuosity (moderate or severe) 39 54 71 37 43
Fluorescein evidence of macular edema in fovea 84 54 63 100 76
Fluorescein not évaluable for macular edema 3 36 35 0 12

*See the text, introductory paragraphs, and Table 1 for explanation of the groups.
j Number of eyes in each group do not add up to the total, since eyes may be in more than one group.
i-Not included are nine eyes entered in a new randomized group I late in the study.
§Status at time of initial study entry.

transferred to group I died shortly after transfer and the
remainder were determined to be nonperfused.
The proportion of group eyes that progressed to at
least 10 disc areas of nonperfusion, transferred to group I,
or developed INV and/or ANV by 4 months is shown in
Table 6 for each of several subgroups. Some of the factors
of interest were significantly correlated with each other as
well as with the development of ischemia. The adjusted
ORs shown in Table 6 are based on a logistic regression
the presence of five to nine disc areas of nonperfusion based
on fundus fluorescein angiography. When a backward step-
wise elimination procedure was performed starting with
the 18 variables listed in Table 6, no additional variables
became significant, and the same three variables remained
in the final analysis. This reduced model produced only
small changes in the adjusted ORs compared with the an¬
alysis summarized in Table 6, but all three variables be¬
came even more statistically significant. The adjusted ORs

considering all of the listed factors together. Three base¬ in the reduced model were 2.9 for duration of CVO of less
line variables were statistically significant predictors of pro¬ than 1 month (P-C0001), 3.8 for baseline visual acuity of
gression in the multivariate analysis: duration of CVO of less than 20/200 (P<.0001), and 3.1 for five to nine disc
less than 1 month, visual acuity of less than 20/200, and areas of nonperfusion (P=.001). Current smoking was

Total No. of eyesf 181 52 155 728

Median baseline visual acuity 20/400 20/400 20/125 20/80
Specified visual acuity, %
20/20 12 2 0 0 10
20/25 to 20/40 24 5 2 0 19
20/50 to 20/100 34 14 10 43 29
20/125 to 20/200 14 9 15 35 14
20/250 to 5/200 14 49 58 22 22
<5/200 1 20 15 0 6
Total, % 99 99 100 100 100

'"See the text, introductory section, and Table 1 for explanation of the groups.
\Number of eyes in each group do not add up to the total, since eyes may be in more than one group.
%Not included are nine eyes entered in a new randomized group I late in study.
^Status at time ol initial study entry.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 Table 6. Proportion of Group P Eyes Progressing by Selected Baseline Characteristics With Adjusted Odds Ratios (ORs)*
No. in Proportion Progressing 95% Confidence
Subgroup Subgroup In Subgroup Adjusted OR Interval for OR
All eyes 522 0.16
Age>50y 444 0.17 2.1 (0.8,5.1)
M 292 0.14 0.8 (0.5,1.3)
Current smoker 61 0.25 2.0 (1.0,4.1)
Diastolic blood pressure >90 mm Hg 183 0.19 1.2 (0.7,2.1)
Diabetes 38 0.08 0.4 (0.1,1.7)
Duration of central vein occlusion <1 mo 146 0.24 2.5 (1.4,4.5)f
Baseline visual acuity worse than 20/200 79 0.33 3.0 (1.6,5.7)
Baseline intraocular pressure of <13 mm Hg 80 0.20 1.6 (0.8,3.1)
Between five and nine disc areas of nonperfusion 50 0.34 3.2 (1.5,6.6)f
Cotton-wool spots 269 0.19 1.2 (0.7,2.0)
Venous collaterals on the disc 124 0.09 0.5 (0.3,1.1)
Moderate or severe venous tortuosity 204 0.20 1.4 (0.8,2.4)
Superior and/or inferior asymmetry 26 0.08 0.5 (0.1,2.2)
Macular exudates 25 0.12 0.8 (0.2,3.2)
Cilioretinal artery 32 0.16 1.2 (0.4,3.5)
Intraretinal microvascular changes 75 0.15 1.0 (0.4,2.3)
Blunting or staining of venules 236 0.19 1.2 (0.7,2.1)
Presence or history of vascular occlusion in the fellow eye 55 0.20 1.2 (0.5,2.5)
*See the text, introductory section, and Table 1 for explanation of the groups. Progression is defined as the presence of any of the following by the
4-month visit: 10 disc areas ol nonperfusion, transfer to group I, 2 clock hours of iris neovascularization, or angle neovascularization.
fP<.07.
\P<.001.

the last variable to be eliminated (P=.06; adjusted OR, 1.9).
Progression by the number of significant risk factors present
is shown in Figure 3. Only 22 (8%) of the 284 eyes with
none ofthe three significant risk factors progressed. Forty-
three (21%) of the 204 eyes with one of the risk factors
progressed; the three factors were not significantly differ¬
ent in rate of progression (P=.74). Thirteen (42%) of the
3f eyes with two risk factors showed progression. There
was no significant difference between combinations of two
factors (P=.33). Only three group eyes had all three risk
factors at baseline; all three of these had progressed by the
4-month visit.
As shown in Table 7, while eyes with duration of
CVO of less than 1 month were at greater risk than eyes
with longer duration, there were no significant differ¬
ences in duration after the first month.
Natural history for group eyes beyond the 4-month
visit will be reported when follow-up is complete.
Complete Natural History for Eyes in Group
Following study entry, the 52 eyes enrolled in group I were
followed up at least monthly with iris photographs taken
at each visit for review by the Reading Center. Fundus flu¬
orescein angiograms were required every 2 months; as soon
as the hemorrhage cleared sufficiently for the eye to be re-
classified, it was transferred to group if perfused or group
if nonperfused. Classification status changed quickly for
group I eyes. Four (8%) ofthe 52 eyes developed INV and/or
ANV in less than 1 month after study entry. As shown in
Table 8, most eyes (30/52 [58%]) were eligible for trans¬
fer or had developed INV and/or ANV by the 2-month visit,
which included the first scheduled follow-up fundus flu¬
orescein angiogram. In all, eight ofthe 52 group I eyes were
determined to be perfused and transferred to group P, 22
demonstrated enough nonperfusion to qualify for group
N, and f 6 developed INV and/or ANV while still in group
I, which made them ineligible for transfer. Outcome was
not determined for six of the 52 patients; three died while
still in group I (at 1, 3, and 9 months), two were lost to
follow-up before the status of the eye resolved, and one
developed a dense cataract within a few months of entry
that prohibited evaluation of retinal capillary detail. Three
ofthe nonperfused eyes were not entered into group be¬
cause of eligibility criteria unrelated to nonperfusion. Long-
term outcome for the eight eyes transferred to group and
the 19 transferred to group will be reported when follow-up
for those groups is complete.
I
COMMENT
The clinics of this collaborative multicenter clinical trial
on CVO have completed recruitment. Follow-up of the
725 patients with 728 eligible eyes is continuing.
Sixteen percent (81/522) of perfused eyes developed
evidence of ischemia (10 or more disc areas of nonperfu¬
sion or intraretinal hemorrhage with transfer to group I)
by the time of the first 4-month follow-up visit; over one

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 1.0- Table 7. Proportion of Group P Eyes Progressing by
Duration of Central Vein Occlusion*
0.8-
Proportion
No. Progressing
0.6- Duration Progressing by 4-Mo Visit
< 1 mo 146 0.24
1 moto < 3 mo 182 0.14

ill
0.4-
3 mo to <1 y 194 0.11
Total group 522 0.16

*See the text, introductory section, and Table 1 for explanation ol the
groups. Progression is defined as the presence of any of the following by
=204 N=31 the 4-month visit: 10 disc areas of nonperfusion, transfer to group I, 2
1 2 clock hours of iris neovascularization, or angle neovascularization.
No. of Risk Factors

Figure 3. Group P progression (INV and/or ANV, group I, or nonperfusion)
by number of risk factors present at entry. Risk factors are duration of
central vein occlusion of less than 1 month, visual acuity of worse than
20/200, and five to nine disc areas of nonperfusion. Error bars represent
95% confidence intervals. See the text, introductory section, and Table 1
for explanation of groups.
third (30 of 81) of these had already developed INV and/or
ANV. The three significant risk factors for ischemia were
duration of less than 1 month, visual acuity of worse than
20/200, and five to nine disc areas of nonperfusion.
Although the OR for progression in group for pa¬
tients 50 years of age or older was relatively large (ap¬
proximately 2), the sample size for patients less than 50
years of age (N=78) was inadequate to provide a clear
understanding of the interactions between age, outcome,
and other factors affecting prognosis. Similarly, the study
population did not contain enough current smokers to
make a firm conclusion about smoking, but the OR was
close to 2 for current smokers.
For the early months following entry into group P,
fundus fluorescein angiograms were taken only at the dis¬
cretion of the ophthalmologist. Progression of the CVO
was documented in 16% of group patients but may have
occurred undetected in additional patients for whom no
angiogram was ordered. All patients with CVO, espe-
daily those who present with one or more of the three
significant risk factors, should be followed closely for pos¬
sible development of INV and/or ANV.
The finding that 83% of group Î eyes developed ev¬
idence of ischemie CVO led us to change the protocol
and consider these eyes nonperfused. The clinical appli¬
cation of this information is that eyes with a large amount
of intraretinal hemorrhage obscuring capillary detail on
fluorescein angiography need to be watched closely for
INV and/or ANV. In this study, no group eye pro¬
gressed to group I and then returned to a perfused status.
We urge caution in interpreting the baseline data as
representing all patients with CVO. Patients with serious
intercurrent illness were excluded, as were those with other
ocular conditions such as diabetic retinopathy and un¬
controlled glaucoma. Unknown selection factors may have
been operative as well.
The advanced age of the CVOS population confirms
earlier studies.2-3 Even though over half of the CVOS pa¬
tients are over 65 years of age, an age group in which a
predominance of females might be expected, slightly over
half the patients in the study are male.
The results presented herein confirm our assumption
in the study design that detection of early INV and ANV
are both important features of the follow-up examination

Table 8. Outcome and Reclassification of Eyes Initially in Group I by Length of Time Required for Determination*
No. of Eyes
I I
Baseline to 2-mo to After
2-mo Visit 6-mo Visit 6-mo Visit Total
INV/ANVf before retinal status could be determined 9 1 0 10
INV/ANV present at same visit at which
eye was determined to be nonperfused 5 1 0 6
Nonperfusion seen without INV/ANV 9 10 3 22
Perfused 7 1 0 8
Total 30 13 3 46$
*See the text, introductory section, and Table 1 for explanation ol the groups.
\INV/ANV indicates iris neovascularization and/or angle neovascularization.
\Of the 52 patients entered into group I, three died, two were lost to lollow-up, and one developed a dense cataract before outcome or retinal status could
e determined.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015

 in the early months after the onset of CVO. It is our clinical Accepted for publication May 12, 1993.
impression that in the management of patients with CVO, ÏhTTÎTÏTTÏ Supported by grants EY06752, EY07525,
an undilated slit-lamp examination that uses high magni¬ EY06749, EY06751, EY06750, EY07813,
fication and carefully scrutinizes the pupillary border as well VIS EY06797, EY06777, EY06730, EY07788,
as careful gonioscopy are an essential part of every exam¬ ION EY06753, EY06815from the National Eye In¬
ination. Pupillary dilatation may obscure early INV. There¬ m stitute, National Institutes of Health.
fore, eyes being followed up for the development of INV and/or Reprint requests to Central Vein Occlu¬
ANV should be examined prior to dilating the pupils. sion Study Coordinating Center, Texas A & M University
The question of whether early PRP might prevent Health Science Center, 2401 S 31st St, Temple, TX 76508
the development of ÍNV and possibly lead to an im¬ (Argye Hillis, PhD).
proved prognosis has not yet been answered. Group
treatment results will be reported when the planned REFERENCES
follow-up is complete. Follow-up in group M also con¬
tinues to evaluate whether macular grid-pattern laser 1. SAS Institute Inc. SAS/STAT(r) User's Guide, Version 6. 4th ed. Cary, NC: SAS
photocoagulatlon improves the visual prognosis in pa¬ Institute Inc; 1989;2:1071-1134.
2. Zegarra H, Gutman FA, Conforto J. The natural course of central retinal vein
tients with CVO that involves reduced vision due to occlusion. Ophthalmology. 1979;86:1931-1939.
macular edema. Treatment results for group M eyes 3. Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovas-
will also be reported when the planned follow-up is cularization with retinal vascular occlusion, III: incidence of ocular neovascu-
larization with retinal vein occlusion. Ophthalmology. 1983;90:488-506.
complete.

Members of the Central Vein Occlusion Study Group

Bascom Palmer Eye Institute, University of Miami, Fla: John G. Clarkson, MD; Elaine Chuang, MD; Donald Gass, MD;
Maria Pedroso; Tony Cubillas; Erlinda S. Duria; Ditte J. Hess; Isabel Rams; Marguerite Ball, OD; Alex Gutierrez; Philip Kies,
OD; Nayla Muniz; Michele Pall; Charles Pappas, OD (Protocol Monitor). The Wilmer Ophthalmological Institute, Thejohns
Hopkins University, Baltimore, Md: Daniel Finkelstein, MD; Arnall Patz, MD; Dolores Rytel; Judy Belt; Dennis Cain; Terri
Cain; David Emmert; Terry George; Mark Herring; Pete Sotirakos. Illinois Retina Associates, Harvey and Chicago, 111: David
H. Orth, MD; Timothy P. Flood, MD; Toni Larsen, RN; Nancy Perez; Doug Bryant; Don Doherty; Jay Fitzgerald; Martha
Gordon; Cynthia Holod, RN; Kathy Kwiatkowski; Celeste MacLeod; Chris Morrison; Charlotte Westcott, RN. Oregon Health
Sciences University, Casey Eye Institute, Portland: Michael L. Klein, MD; David Wilson, MD; Richard G. Weleber, MD;
Susan Nolte; Nancy Hurlburt (1988-1992); Mark Evans; Patrick Wallace; Peter Steinkamp; Debora Funkner; Cathy Gordon.
Retina Associates of Boston (Mass): Clement Trempe, MD; Alex Jalkh, MD; John Weiter, MD; Sherry Anderson; Dennis
Donovan; Tom O'Day; Gerald Friedman; Rodney Immerman. Clinique Ophthalmologique, Creteil, France: Gabriel Coscas,
MD; Gisèle Soubrane, MD; Rose Marie Haran; Christophe Debibie; Jean Gizelsky. University of Wisconsin, Madison: Ingolf
H. L. Wallow, MD; Guillermo de Venecia, MD; George Bresnick, MD (1988-1992); Sandra Larson; Sandy Fuller; Bob Harrison;
Gene Knutson; Michael Neider; Greg Weber; Ruth Bahr; Bonnie Grosnick; Bob Harrison; Robert Lazorik; Helen Lyngaas; Diane
Quackenboss; Guy Somers. Cleveland (Ohio) Clinic: Froncie A. Gutman, MD; Sanford Myers, MD; Tina Kiss; Vivian Tanner;
Deborah Ross; Pamela Vargo; Janet Edgarton; Sue Hanson; Janet Nader; Nancy Tomsak. Retina Associates of Cleveland
(Ohio): Lawrence J. Singerman, MD; Hernando Zegarra, MD; Susan Lichterman, RN; Adrienne Fowler Kramer; Sheila Smith-
Brewer; Pam Brown Rowe; Géraldine Daley; Anne Pinter; Kathy Coreno; Lori Cooper; Marty Delisio; Donna Cross; Wendy
Lord. Scott and White Memorial Hospital, Texas A & M Health Science Center, Temple (Coordinating Center): Argye
Hillis, PhD; Mark W. Riggs, PhD; Cheryl Kasberg, MS; Krista Carlson Giniewicz (1988-1991); Carol Zimmerman; Kimberly
Christie Burke, MS; Kevin Gilmore. McKnight Vision Research Center, University of Miami (Ffa) (Reading Center): John
G. Clarkson, MD; Mary Lou Lewis, MD; Elaine Chuang, MD; Maria Cristina Wells; Julie Lord Forbes; Kathleen C. Fetzer
(1988-1992); Heather McNish. University of Wisconsin, Madison (Electroretinogram Reading Center): George H. Bresnick,
MD; Sandy Fuller; Lissa McNulty (1988-1989); Jim Baliker; Linda Allanen (1991-1992); Laura Gentry. National Eye Institute,
Bethesda, Md: Richard L. Mowery, PhD (1988-1990); Donald F. Everett, MA.
Executive Committee Members
John G. Clarkson, MD (Study Chairman); George H. Bresnick, MD; Gabriel Coscas, MD; Daniel Finkelstein, MD; Froncie A.
Gutman, MD; Argye Hillis, PhD; Michael L. Klein, MD; Richard L. Mowery, PhD (1988-1990); Donald F. Everett, MA; David
H. Onh, MD; Lawrence J. Singerman, MD; Clement Trempe, MD.
Data and Safety Monitoring Committee
Voting members: Robert J. Hardy, PhD (Chairman), Houston, Tex; Gary Abrams, MD, Rochester, Mich; Robert N. Frank, MD,
Detroit, Mich; Maureen G. Maguire, PhD, Baltimore, Md; Abner V. McCall, JD, Waco, Tex.
Nonvoting members: John G. Clarkson, MD; Donald F. Everett, MA; Argye Hillis, PhD.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Iowa User on 05/25/2015