Original Contribution
Risk of Acute Ischemic Stroke in Patients With
Monocular Vision Loss of Vascular Etiology
Lucy Y. Zhang, MD, MEng, Jason Zhang, MD, Richard K. Kim, MD, Jared L. Matthews, MD,
Danielle S. Rudich, MD, David M. Greer, MD, Robert L. Lesser, MD, Hardik Amin, MD
Background: To evaluate the risk of concurrent acute
ischemic stroke and monocular vision loss (MVL) of
vascular etiology.
Design: Retrospective, cross-sectional study.
Subjects: Patients aged 18 or older diagnosed with MVL of
suspected or confirmed vascular etiology who had no other
neurologic deficits and who received brain MRI within 7 days
of onset of visual symptoms were included.
Methods: A medical record review was performed from
2013 to 2016 at Yale New Haven Hospital. Patients were
included if vision loss was unilateral and due to transient
monocular vision loss (TMVL), central retinal artery occlu-
sion (CRAO), or branch retinal artery occlusion (BRAO). Any
patients with neurologic deficits other than vision loss were
excluded. Other exclusion criteria were positive visual
phenomena, nonvascular intraocular pathology, and intra-
cranial pathology other than ischemic stroke.
Main Outcome Measures: The presence or absence of
acute stroke on diffusion-weighted imaging (DWI) on brain
MRI.
Results: A total of 641 records were reviewed, with 293
patients found to have MVL. After excluding those with focal
neurologic deficits, there were 41 patients who met the
inclusion criteria and received a brain MRI. Eight of the 41
subjects (19.5%) were found to have findings on brain MRI
positive for acute cortical strokes. The proportion of lesion
positive MRI was 1/23 (4.3%) in TMVL subjects, 4/12
(33.3%) in CRAO subjects, and 2/5 (40%) in BRAO subjects.
Department of Ophthalmology and Visual Sciences (LYZ, JZ, JLM,
DSR, RLL), Yale University School of Medicine, New Haven, Con-
necticut; Yale University School of Medicine (RKK), New Haven,
Connecticut; The Eye Care Group (DSR, RLL), New Haven, Con-
necticut; and Department of Neurology (DMG, HA), Yale University
School of Medicine, New Haven, Connecticut.
Presented at the American Academy of Ophthalmology Annual
Meeting, November 14–17, 2015, Las Vegas, NV.
The authors report no conflicts of interest.
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text and are provided in the full text
and PDF versions of this article on the journal’s Web site (www.
jneuro-ophthalmology.com).
Address correspondence to Jason Zhang, MD, Department of
Ophthalmology and Visual Sciences, Yale University School of
Medicine, 40 Temple Street, Suite 3D, New Haven, CT 06510;
E-mail: jason.zhang@yale.edu
Zhang et al: J Neuro-Ophthalmol 2018; 0: 1-6
Copyright Ó North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Brain computed tomography (CT) scans were not able to
identify the majority of acute stroke lesions in this study.
Conclusions: Patients with MVL of vascular etiology such
as TMVL, CRAO, or BRAO may have up to 19.5% risk of
concurrent ischemic stroke, even when there are no other
neurologic deficits. These strokes were detected acutely
with brain MRI using DWI but were missed on CT.
Journal of Neuro-Ophthalmology 2018;0:1–6
doi: 10.1097/WNO.0000000000000613
© 2018 by North American Neuro-Ophthalmology Society
T
he pathogenesis of monocular vision loss (MVL) of
ischemic origin, categorized as transient monocular
vision loss (TMVL), central retinal artery occlusion
(CRAO), or branch retinal artery occlusion (BRAO), is
considered to be analogous to that of a transient ischemic
attack (TIA) or ischemic cerebral stroke (1). The 2009
revised definition of a TIA by the American Heart Asso-
ciation and the American Stroke Association (AHA/ASA)
is “a transient episode of neurological dysfunction caused
by focal brain, spinal cord, or retinal ischemia, without
acute infarction” (2). Similarly, the updated 2013 defini-
tion of stroke by AHA/ASA is “brain, spinal cord, or
retinal cell death attributable to ischemia, based on neu-
ropathological, neuroimaging, and/or clinical evidence of
permanent injury” (3). The ophthalmic artery is the first
major branch off of the internal carotid artery. Therefore,
it is reasonable to expect that emboli from a proximal
source such as the heart, aorta, or carotid artery that
affects the retinal vasculature could also cause brain
ischemia by occluding the more distal anterior and mid-
dle cerebral arteries (4).
The evidence for stroke after ischemic retinal events has
been steadily increasing. A European prospective study of
77 CRAO patients enrolled in the European Assessment
Group for Lysis in the Eye (EAGLE) study found that 5
patients (6%) had a newly diagnosed stroke within 1
month, of which only 1 was silent (5). Interestingly, 2 of
1
 Original Contribution
the stroke patients in this study experienced their strokes
immediately after local intra-arterial fibrinolysis. A Taiwa-
nese population-based study showed that 19.6% of retinal
artery occlusion patients had a stroke within a 3-year follow-
up period, compared with 10.1% of matched controls. The
highest incidence of stroke was within the first month after
the retinal artery occlusion. The overall adjusted hazard
ratio for having a stroke in these patients was 2.07 times
higher than that of controls and 3.34 times higher in the
#60-year-old subgroup (6). A Korean study of CRAO pa-
tients showed that the incidence rate ratio of ischemic stroke
is significantly increased in the period just before and just
after a CRAO, with the highest risk in the first 7 days after
a CRAO (7).
Two recent retrospective studies have shown that
patients with MVL of ischemic origin are also more likely
to have concurrent acute brain infarcts with a frequency of
approximately 1 in 4 patients (8,9). Helenius et al (8) ana-
lyzed 129 patients with MVL of presumed ischemic origin
and found that 31 (24.0%) of these patients had concurrent
infarcts demonstrated on MRI imaging. Helenius et al did
do a subgroup analysis of patients with isolated MVL (i.e.,
without other focal neurological signs at the time of pre-
sentation) and found that approximately 20% of these pa-
tients had a concurrent acute cerebral infarct. Lee et al (9)
studied 33 patients with funduscopic evidence of acute ret-
inal artery occlusion and found that 8 (24.2%) had concur-
rent acute brain infarctions of which only 3 (9.1%) had
isolated MVL. The studies by Helenius et al and Lee et al
had a disproportionate number of patients with additional
focal neurological deficits (29% and 62.5%, respectively).
Although patients with focal neurological symptoms are
very likely to undergo brain imaging, those with isolated
MVL may not. It is, therefore, important to characterize the
true risk of an otherwise “clinically silent” stroke in patients
with isolated MVL as the presenting symptom.
Lauda et al (10) studied a cohort of patients with
TMVL, CRAO, and BRAO seen at a single ophthalmic
emergency department. The authors suggested that there
is likely a high incidence of concurrent acute cerebral infarc-
tion in patients with isolated MVL but did not exclude
patients with other focal neurological deficits from their
study and subgroup analyses.
The purpose of our study was to evaluate the risk of
concurrent stroke as identified by MRI with diffusion-
weighted imaging (DWI) within 1 week of the onset of
MVL (either transient of permanent) due to a vascular
cause. We wanted to determine the true risk of a “silent
stroke” in which the only presenting symptom was the
MVL.
METHODS
The study protocol was approved by the Human Inves-
tigations Committee of the Yale University School of
2 Zhang et al: J Neuro-Ophthalmol 2018; 0: 1-6
Copyright Ó North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Medicine. A retrospective cross-sectional study was con-
ducted through a chart review of all patients presenting to
Yale New Haven Hospital with either transient or perma-
nent MVL of vascular etiology (TMVL, CRAO, BRAO,
and ophthalmic artery occlusion) between February 2013
and June 2016. Charts were selected through a review of
ICD-9 codes. The inclusion criteria were age greater than
18 years; MVL with presumed or confirmed vascular etiol-
ogy; and acquisition of a brain MRI within 7 days of onset
of visual symptoms that included DWI. The exclusion cri-
teria were bilateral vision loss, the presence of concurrent
neurological symptoms not involving the visual pathways
detected within 48 hours of presentation, the presence of
concurrent higher order visual phenomenon including pho-
topsias and aura, and the presence of intracranial pathology
on MRI other than stroke. The diagnosis of vascular etiol-
ogies of MVL was made based on a combination of patient
history, examination and findings, fundus photography, and
fluorescein angiography. All patients included in the study
were evaluated by both an ophthalmologist and a neurologist
at Yale New Haven Hospital, and all patients with a cerebral
infarct were managed accordingly. MRI scans were reviewed
in all cases by an experienced neuroradiologist at Yale New
Haven Hospital, and the images were re-reviewed to con-
firm the radiologist report for the purposes of this study. A
total of 641 charts that included the previously mentioned
ICD-9 codes were reviewed; of which 41 patients met the
inclusion criteria for the study.
These charts were analyzed with respect to various
patient characteristics including age, sex, ethnicity, vascular
risk factors (i.e., hypertension, diabetes, hyperlipidemia,
atrial fibrillation, coronary artery disease), smoking status,
history stroke/TIA, and cancer. One-way analysis of
variance (ANOVA) was used to compare baseline demo-
graphics and risk factors and Fisher exact tests were used to
assess associations of etiologies between patients with and
without infarcts. Statistical analyses were performed using
SAS 9.3 (SAS Institute, Inc, Glastonbury, CT).
The primary outcome of this study was to assess the rate
of co-occurrence of neurologically silent acute ischemic
stroke and MVL of vascular etiology (TMVL, CRAO,
BRAO ophthalmic artery occlusion) as diagnosed by MRI
with DWI protocol. A secondary outcome was to evaluate
the association between neurologically silent acute ischemic
stroke in this setting and patient characteristics and
comorbid medical conditions.
RESULTS
A total of 641 records were reviewed with 327 patients
found to have MVL between February 2013 and June
2016. After excluding those with focal neurologic deficits
(155), those without MRI imaging within 7 days of
presentation (104), and those with intracranial pathology
other than stroke (27), the inclusion criteria were met by 41
 Original Contribution

FIG. 1. Flowchart of selection of patients with transient or permanent visual loss due to a vascular cause. MVL, monocular
vision loss.

patients and 41 eyes with either transient or permanent found in a statistically significant higher proportion of pa-
MVL of vascular etiology (Fig. 1). Patient demographics tients with CRAO than in patients with TMVL and BRAO
and characteristics are listed in Table 1. The average patient with P values , 0.05. Likewise, atrial fibrillation was found
age was 64.8 years (SD, 13.5 years; range, 43–98 years), and in a statistically significant higher proportion of patients with
the majority were men (68.2%). Most of the patients were BRAO than in patients with TMVL and CRAO with a P
Caucasian (70.7%) Nearly, all patients had comorbid risk value , 0.05. No other statistically significant association
factors at the time of presentation. The characteristics of the was found.
patients with available visual data (38 eyes) are listed in A Fisher exact test was also conducted for the
Table 2. Most patients presented with a visual acuity of at same comorbid risk factors used in the ANOVA analysis
least 20/40 or better (58.5%), and 11 patients (30.6%)
presented with a visual acuity of count fingers or worse. TABLE 1. Patients with transient or permanent visual
Among the 41 patients who met the inclusion criteria, 8 loss of vascular etiology
(19.5%) were found to have a MRI positive for acute
cortical stroke (Fig. 2). Of these, 4 patients had CRAO, 2 Demographics Eyes (N = 41)
had BRAO, 1 had TMVL (14.3%), and 1 had an ophthal-
mic artery occlusion. Brain computed tomography (CT) Male 28 (68.2%)
was able to identify acute infarction in only 2 patients. Of Female 13 (21.8%)
Average age, yr 64.5 (SD 13.5; range 43–98)
the 8 patients, 2 were found to have carotid stenosis of at Caucasian 29 (70.7%)
least 70%. The proportion of patients with positive MRI Hypertension 31 (75.6%)
findings was 1/23 for TMVL, 3/12 for CRAO, 2/5 for Diabetes Mellitus 6 (14.6%)
BRAO, and 1/1 for ophthalmic artery occlusion. Prior stroke or transient 7 (17.1%)
A 1-way ANOVA analysis was conducted for each ischemic attack
comorbid risk factor among our patient cohort patients Coronary artery disease 13 (31.7%)
with TMVL, CRAO, and BRAO to see if there was Atrial fibrillation 8 (19.5%)
Hyperlipidemia 21 (51.2%)
a statistically significant association between risk factor and Tobacco use 14 (34.1%)
MVL etiology (See Supplemental Digital Content, Table Hypercoagulable 5 (12.2%)
E1, http://links.lww.com/WNO/A289). Coronary artery risk factors
disease, a history of stroke or TIA, and hypertension were

Zhang et al: J Neuro-Ophthalmol 2018; 0: 1-6 3

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 Original Contribution
TABLE 2. Visual function parameters of patients with
transient or permanent visual loss due to a vascular
cause
Characteristics Eyes (N = 38)*
Right sided visual symptoms 23 (56.0%)
Visual acuity better than or 23 (62.1%)
equal to 20/40 at presentation
Visual acuity worse than or 12 (32.4%)
equal to count fingers at presentation
Permanent visual deficits (.24 h) 18 (43.9%)
*Visual data were not available for 3 eyes.
between patients with positive MRI findings and those
with normal MRI findings (See Supplemental Digital
Content, Table E2, http://links.lww.com/WNO/A290).
A statistically higher proportion of patients with positive
MRI findings also had concurrent hypercoagulability risk
factors. No other statistically significant risk factor was
identified.
DISCUSSION
The management of transient and permanent MVL without
other neurologic symptoms or signs typically is for giant cell
arteritis and embolic causes. This includes hematologic
studies for acute phase reactants and carotid ultrasound and
echocardiography. Most patients are not urgently evaluated
nor do they frequently receive a full stroke work-up. A
population-based study in the United Kingdom found that
average time to referral and time to carotid ultrasound for
patients with TMVL were 16 and 46 days, respectively
(11). The North American Symptomatic Carotid Endarter-
ectomy Trial (NASCET) found that patients with transient
ischemic events of the retina had a longer average time of
delay to medical treatment compared with patients with
hemispheric TIAs, 48.5 vs 15.2 days, respectively (12).
The American Heart Association/American Stroke Associa-
tion recommends that patients with TIA be evaluated as
soon as possible and undergo MRI with DWI within 24
hours of the symptom onset (2).
In our study, we found that the rate of concurrent silent
brain infarcts detected on MRI with DWI sequence was
19.5%. This finding is in contrast to the rate of incidental acute
infarcts identified on DWI imaging in patients without clinical
symptoms, which was reported to be 0.37% in a study of
16,206 individuals at a university hospital in Japan (13). An
interesting finding of our study was that the strokes identified
varied from singular to multifocal, and varied in size. Many of
these infarcts were only seen on DWI sequence and not iden-
tified on CT. Multifocal infarcts suggest an embolic cause.
Although the NASCET study found that the risk of subse-
quent ipsilateral stroke was lower after TMVL compared with
hemispheric TIA in patients with carotid stenosis, there are
4 Zhang et al: J Neuro-Ophthalmol 2018; 0: 1-6
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certain features that may identify higher risk patients for whom
carotid revascularization should be considered (advanced age,
male gender, lack of collateral flow, peripheral vascular disease,
and carotid stenosis .80%) (14,15). Carotid revascularization
in patients with 2 or 3 of these risk factors led to a 3-year stroke
absolute risk reduction of 4.9% and 14.3%, respectively.
Silent brain infarcts are associated with adverse neuro-
logical and cognitive consequences, including impaired
mobility, physical decline, depression, cognitive dysfunc-
tion, dementia, and clinical stroke (16). The risk of a sub-
sequent stroke after a TIA or a minor stroke (defined as
having no symptoms or no disability) has been reported
to be 1.5%–3.9% within 2 days, increasing to 3.7%–
14.6% within 90 days (17,18). The Rotterdam Scan Study
found that patients with silent brain infarcts experienced
a 5 times higher incidence of follow-up stroke over an
average 4.2 years than those without (19). When adjusted
for other stroke risk factors, the adjusted hazard ratio for
stroke was still 3.9 in patients with silent brain infarcts seen
on MRI.
Given this evidence, patients with MVL due to
a vascular cause need to be evaluated urgently for stroke
and given appropriate medical or surgical treatment.
Unfortunately, this is not the practice pattern of most
ophthalmologists. A survey of providers in the United
States showed that only 35% of ophthalmologists would
refer a patient with CRAO to the emergency department
for immediate evaluation, whereas more neurologists
(73%) and neuro-ophthalmologists (86%) would send
patients with CRAO to the emergency department (20).
A study in the United Kingdom demonstrated that even
3 years after introducing a daily TIA clinic at Leicester
Royal Infirmary offering single-visit imaging (MRI and
carotid ultrasound) and implementation of best medical
therapy, almost none of the providers in the ophthalmol-
ogy department reported referring a patient with TMVL
to this clinic (21). Instead, 95% of the survey respond-
ents reported a preference for sending patients for out-
patient carotid ultrasound with a follow-up referral for
carotid endarterectomy as needed. Interestingly, 90% of
the respondents were aware of the TIA clinic and the
services it provided. This study underscores the impor-
tance of increasing generalized awareness that MVL is
a risk factor for concurrent and subsequent stroke.
Limitations of our study included a small patient sample
size. The requirement of TMVL, CRAO, or BRAO with
a brain MRI done within 7 days, and excluding all patients
with other neurologic deficits left a limited number of
qualifying subjects for analysis. However, our strict
inclusion and exclusion criteria provided a realistic assess-
ment of the risk of concurrent acute stroke in patients with
isolated MVL without other neurologic symptoms that
would otherwise prompt brain imaging. Longer patient
follow-up would also help determine the rate of subsequent
TIA or stroke in these patients. Another limitation was the
 Original Contribution

inclusion of some patients based on subjective negative study lends itself to possible bias in terms of why certain
visual phenomena without a dilated funduscopic examina- providers decided to obtain a brain MRI on some patients
tion by an ophthalmologist. The retrospective nature of the and not others. This bias would be eliminated with

FIG. 2. Acute ischemic stroke in patients with monocular vision loss of vascular etiology.

Zhang et al: J Neuro-Ophthalmol 2018; 0: 1-6 5

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 Original Contribution
a prospective study in which all patients with MVL due to
a vascular case underwent brain MRI.
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