West Nile Virus Retinopathy and Associations with Long Term Neurological and Neurocognitive Sequelae
West Nile Virus Retinopathy and Associations with Long Term Neurological and Neurocognitive Sequelae
Rodrigo Hasbun 0 1 2
Melissa N. Garcia 0 1 2
Judianne Kellaway 0 1 2
Laura Baker 0 1 2
Lucrecia Salazar 0 1 2
Steven Paul Woods 0 1 2
Kristy O. Murray 0 1 2
0 1 University of Texas Health Science Center at Houston, Medical School, Section of Infectious Diseases , Houston , Texas, United States of America, 2 Baylor College of Medicine, Department of Pediatrics, Section of Pediatric Tropical Medicine, National School of Tropical Medicine , Houston , Texas, United States of America, 3 University of Texas Health Science Center at Houston, Medical School, Ruiz Department of Ophthalmology and Visual Science , Houston , Texas, United States of America, 4 Robert Cizik Eye Clinic , Houston , Texas, United States of America, 5 Department of Psychology, University of Houston , Houston, Texas , United States of America
1 Funding: This work was supported by the Gillson Longenbaugh Foundation and the National Institutes of Health/National Institute for Allergy and Infectious Diseases (NIH/NIAID 1R01AI091816-01), National Eye Institute Vision Core Grant (P30EY010608), a Challenge Grant to The University of Texas Medical School from Research to Prevent Blindness , and the
2 Editor: Tian Wang, University of Texas Medical Branch , UNITED STATES
West Nile virus (WNV) has emerged as an important vector-borne pathogen in North America, with more than 3 million estimated to have been infected. Retinopathy from WNV infection has been previously reported in acute cases, though those prior reports did not evaluate the risk of retinopathy based on clinical severity of neurologic disease. The purpose of this cross-sectional study was to perform comprehensive ophthalmological and neurological examinations on 111 patients with a history of West Nile virus infection and describe the ocular manifestations. Out of 111 patients, 27 (24%) had evidence for West Nile virus associated retinopathy (WNVR); this observation was higher (49%) in those patients who initially presented with encephalitis. Individuals with WNVR had more frequent involvement of the macula and peripheral involvement compared to those patients without WNVR (p<0.05). WNVR was also associated with a greater likelihood of abnormal reflexes on neurological exam, poorer learning, greater dependence in activities of daily living, and lower quality of life (p<0.05). WNVR was seen more frequently in elderly patients (age > 60 years), and was associated with higher rates of diabetes mellitus and a history of encephalitis (p<0.05). A multivariable logistic regression revealed that only a history of encephalitis was independently associated with WNVR [Adjusted Odds Ratio = 4.9 (1.8-13.2); p = 0.001]. Our study found that WNVR occurs in one fourth of patients with a history of WNV infection and is more frequently observed in those with apparent severe neurological sequelae (e.g., encephalitis). The clinical relevance of WNVR was supported by its associations with dependence in activities of daily living and lower quality of life. This unique evaluation of WNV patients included fundoscopic examinations and their associations with neurologic impairment. Our findings can be used during ophthalmological consultation for the evaluation, treatment and rehabilitation phases of care for WNV patients.
Hermann Eye Fund, and National Center for
Research Resources (NIH-1 K23 RR018929-01A2).
The funders had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
West Nile virus (WNV) has infected approximately 3 million adults across the United States
since it was first identified in New York City in 1999.[
] WNV is transmitted to humans
through the bite of an infected mosquito. Approximately 1% of infected individuals will
develop neuroinvasive disease characterized by either meningitis, encephalitis, and/or acute
flaccid paralysis. West Nile virus-associated retinopathy (WNVR) has been documented in
patients presenting with acute neuroinvasive disease and has been characterized by a multifocal
chorioretinitis with or without vitreous inflammatory changes.[
] Linear clustering of
chorioretinal scars, sometimes following the course of retinal nerve fibers, is a typical characteristic
of WNVR. Other findings described in WNV infections include uveitis, retinitis, retinal
hemorrhages, vascular sheathing and leakage, macular edema, vasculitis, optic disc swelling,
and retinal pigment epithelium (RPE) changes.[
] The objective of our study was to
characterize the prevalence of WNVR among a large cohort of patients with a history of WNV
infection and explore the association of WNVR to neurological and everyday living implications.
A cohort of WNV-positive patients was established in 2002 in Houston, Texas and followed
prospectively from the time of acute infection to time of evaluation with a median of 6.8 years
(0.1–11 years) post-infection. Study patients were originally identified through local health
department surveillance or routine screening of the blood supply at local blood donation
centers during 2002–2012. Detailed procedures for diagnosis and confirmation of WNV-positive
status were previously described.[
] The University of Texas Health Science Center and the
Baylor College of Medicine institutional review boards approved our study protocol and
procedures. To date, 220 patients have been consented and enrolled into the cohort. From the
original cohort, 61 were excluded from this study based on the following criteria: 24 being deceased,
11 determined a false positive case for WNV, 24 were lost-to-follow-up, and/or 6 refusing to
continue long-term participation. Of the 159 patients eligible for both ophthalmic and
neurologic examinations, 111 (70%) consented and were available to participate. Our final study
population included: 26 asymptomatic cases, 36 uncomplicated fever cases, 14 aseptic
meningitis cases, and 35 encephalitis cases.
The patients underwent a thorough eye examination which included a history, present and
past ocular health, medical and surgical history, and review of systems. Historical information
collected from these patients included hospitalization for encephalitis and meningitis, febrile
illness, and for some asymptomatic patients, notification by the blood donor agency of their
positive result for WNV viremia. Visual acuity with present correction or pinhole was
performed using a Snellen chart. Intraocular pressures were performed in those patients who
agreed to have it done. The anterior segment was examined with biomicroscopy, and a dilated
fundus examination was performed. Fundus photography with a Topcon camera was
performed to document abnormal findings. The main outcome of the study was the presence of
WNVR that was defined as a characteristic multifocal chorioretinitis with linear clustering of
chorioretinal scars that was easily differentiated from diabetic or hypertensive retinopathy, or
other ophthalmic disease (see Fig 1).[
1, 3, 4
] Any clinical finding that could not be definitively
characterized as WNVR as previously reported in the literature was not included.
A complete neurological exam was performed and included testing of cranial nerves,
strengths of all muscle groups, tone, sensory examination, deep tendon reflexes, assessment for
tremors and cerebellar examination. The presence of any abnormality in the neurological exam
was categorized as an abnormal neuro examination. The Barthel Index assessed the ability to
perform activities of daily living,[
] the SF-36 was used to measure quality of life,[
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Fig 1. Severe retinopathy seen in four patients with history of West Nile virus infection.
Beck Depression Inventory was used to assess recent mood,[
] and the Modified Fatigue
Impact Scale (MFIS) measured the impact of fatigue on physical, cognitive and psychosocial
] The Repeatable Battery for Assessment of Neuropsychological Status
(RBANS) test was administered to provide a comprehensive screening of relevant
] including attention, language, visuospatial construction abilities, and
immediate and delayed memory.
The t-test was used to analyze differences in baseline clinical characteristics, neurological
exam and ophthalmological exam findings between patients with and without WNVR. To
assess differences in the RBANS, Barthel index, SF-36, Modified Impact Fatigue Scale and Beck
Depression Inventory, test scores were reported as mean and standard deviation, and an F
value and p value were calculated by the a one-way analysis of variance. A p value <0.05 was
considered significantly different between both groups. Bivariate analysis were then conducted
by using the Pearson’s X2 test or Fisher’s exact test to identify factors that were significantly
associated with WNVR (P < 0.05). Only clinically cogent baseline variables showing a bivariate
association (P<0.05) were entered into a step-wise logistic regression model to verify
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independent associations with an adverse clinical outcome. Bootstrap analysis was performed
to validate the model internally. All analyses were performed by IBM1 SPSS1 version 21.
Among a cohort of patients with a history of WNV infection, 24% (27/111) had evidence of
WNVR. Of the 35 patients with an encephalitis presentation, 17 (49%) had evidence of
WNVR, compared to none of the 14 meningitis cases, 9 (25%) of the 36 uncomplicated fever
cases, and 1 (4%) of the 26 asymptomatic cases.
In the 27 patients with ocular findings of WNVR, the visual acuity ranged from 20/20 to 20/
70. The anterior segment was carefully examined for evidence of previous or current
inflammation such as the presence of cell and/or flare, posterior synechiae, fibrin, iris atrophy and
pigment on the anterior lens capsule. One patient showed iris synechiae indicative of previous
anterior uveitic disease, which may have been related to WNV. No other patients had anterior
segment evidence of old (or current) inflammatory or infectious disease. Incidental findings
considered not to be related to WNV in the anterior segment which are consistent with the age
of this population included dermatochalasis, ptosis, corneal scars, guttata, cataracts and
pseudophakia. A few patients had significant anatomical narrowing of the anterior chamber angle.
These patients were not dilated, and were referred to the appropriate specialist for evaluation
of angle closure glaucoma.
The fundoscopic examination in these patients revealed a variety of clinical findings, some
considered to be related to previous WNVR infections, and other findings considered
incidental or unrelated to previous WNVR. Findings included the classic curvilinear pattern of
chorioretinal scarring, other chorioretinal scarring occurring in clusters, optic nerve pallor,
peripapillary sheathing, and vascular sheathing. In one patient an epiretinal membrane in the
macula was consistent with other findings of previous WNV infection (optic nerve pallor and
multiple chorioretinal scars).
Patients with WNVR were older, had higher prevalence of coexisting diabetes mellitus, and
were more likely to have had an encephalitis presentation (p<0.05) (see Table 1). There were
a P value comparing patients with and without West Nile virus retinopathy, P <0.05 considered significant
b initial presentation with altered mental status, focal neurological signs or seizures
c any abnormality on a comprehensive neurological exam
57 years (18–89)
no significant differences seen regarding race, gender, or education level. An abnormal
neurological exam was present in 17 (62%) of the patients with WNVR. Abnormal deep tendon
reflexes were seen more commonly in the WNVR group (7/27 (25.9%) vs. 7/84 (8.3%);
P = 0.039). Patients with WNVR also had other neurological abnormalities of the spinal cord
identified on exam such as motor weakness (29.6%), and sensory deficits (7.4%) but their
incidence was not significantly different from those WNV patients without retinopathy.
Patients with evidence of previous WNVR were also more likely to have other abnormalities
in the macula, iris, and in the periphery of the retina (P<0.01) (see Table 2). Macular and
peripheral abnormalities seen on exam included retinal pigment epithelium (RPE) mottling in
the papillomacular bundle as well as other areas of the macula, drusen, cotton wool spots,
microaneurysms, hemorrhages, epiretinal membrane macular degeneration, geographic
atrophy, cystic retinal tuft, peripheral RPE mottling, pigmented and hypopigmented chorioretinal
scars of varying sizes, choroidal nevus, paving stone degeneration, and pigmented lattice.
Clinical findings in the iris recorded in this WNVR group included iris nevi, and ectropion
uvea. Abnormalities in the optic disc and eyelid were seen more frequently in WNVR but in
only one eye (OS) (P<0.05). The abnormalities of the optic disc included a cup to disc ratio
>0.5, scleral crescents, sheathing, peripapillary atrophy, spontaneous venous pulsation, pallor.
Eyelid findings in this group included blepharitis, dermatochalasis, dermatitis, tattoo, lid laxity,
ptosis, hyperemia, trichiasis. There were no significant differences between those with and
without WNVR regarding visual fields, visual acuity, conjunctiva, pupils, lens, cornea, anterior
chamber, vitreous fluid, and vessels. It should be noted that many of these clinical findings are
not specifically related to previous WNVR and simply demonstrate a detailed characterization
of the eye exam of these patients
WNVR was associated with significantly lower RBANS scores in the domain of immediate
memory (F = 5.1, p = 0.02) (see Table 3). There were no statistically significant differences in
visuospatial construction abilities, language, attention, or delayed memory (p > 0.1). WNVR
were more likely to report lower quality of life on the SF-36 (F = 9.5, p = .003) and experience
difficulties in the performance on activities of daily living as assessed by the Barthel index
(F = 6.7, P = 0.01). There were no significant differences observed in chronic fatigue or
depression between those with and without WNVR (p>0.2).
On bivariate analyses, baseline clinical factors associated with WNVR included age >60
years, diabetes mellitus, and encephalitis presentation (P<0.05). (See Table 4). An abnormal
neurological exam was not statistically associated with WNVR. All significant variables on bivariate
analyses were entered into a multivariable logistic regression analyses, and only an encephalitis
presentation remained associated with WNVR [Adjusted OR 4.9 (1.8–13.2) P = 0.001].
Our study of retinopathy among patients with a history of WNV infection has many important
and unique findings. To our knowledge, this is the largest study to assess evidence of
retinopathy in a WNV cohort that included asymptomatic, febrile, and neuroinvasive disease patients.
Additionally, this is the first study correlating WNVR with neurological exam abnormalities,
neurocognition, depression, fatigue, and with activities of daily living. We found that 24% of
the cohort had evidence of WNV-related retinopathy. This retinopathy was seen in 49% of
patients with WNV infection that presented with encephalitis and had a distinctive multifocal
chorioretinitis characterized by linear clustering of hypopigmented scars. Interestingly, we also
observed some subtle retinal pigment epithelium (RPE) mottling in several patients, which has
not been reported in WNVR. It is possible that this RPE mottling represents an abnormality
from previous WNVR, and these findings should be studied further in the future. (See Fig 1)
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a P value <0.05 considered significant; Fisher Exact used when cell count was less than 5.
b abnormal visual acuity defined as >20:40
c eye lid abnormalities included blepharitis, dermatitis, lid laxity, ptosis, hyperemia, scurf, trichiasis, injection, dermatochalasis
d conjunctival abnormalities included hyperemia, injection, dilated vessels, pinguecula, cysts, subconjuctival hemorrhage, follicular response, scarring,
e pupillary abnormalities included persistent pupillary membrane, abnormal dilation and reactivity, tonic pupil and irregularity due to synechia
f cataracts, pigmentation of anterior capsule, nuclear sclerosis, vacuoles, posterior capsule intraocular lens
g radial keratotomy and astigmatic keratotomy scars, arcus, pigmentation, LASIK(Laser-Assisted in situ Keratomileusis) flap scars, dry eye, pannus,
keratopathy, guttata, microcysts, pterygium, keratoconus,
h persistent pupillary membrane, cells, flare, shallow peripherally or temporally, narrow peripherally, posterior embryotoxin, shallow angles.
i nevi, synechia, wrinkles, brown, bowed peripherally, ectropion,
j cup to disc ratio >0.5, scleral crescent, pigmented crescent, sheathing, peripapillary atrophy, spontaneous venous pulsation, pallor.
k posterior vitreous detachment, floaters, Weiss ring, syneresis, asteroid hyalosis
l disc area mottling, drusen, blond fundus, cotton wool spots, microaneurysms, hemorrhages, cystic retinal tuft, dull fovea reflex, epiretinal membrane,
mottling, hypopigmented areas, hypopigmented scars, chorioretinal scars, macular degeneration, microaneurysm, fovea, pigment mottling, retinal pigment
epithelium, geographic atrophy, nevus
m arteriovenous nicking, venous enlargement, nevus across superior arcades, tortous vessels, blockages, attenuation, scars
n paving stone degeneration, punched out lesion, pigmented spot, cotton wool spots, microaneurysms, chorioretinal scars, dot blot hemorrhages, drusen,
nevus, pigmented lattice, chorioretinal degeneration, mottling, retinal pigment epithelium changes, hypertensive retinopathy
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Barthel index d
Modified fatigue impact scale (MFIS) e
Beck’s depression inventory f
a test scores are reported as mean and standard deviation (in parentheses).
b F value and p value as calculated by the analysis of variance. A p value <0.05 was considered significantly different between both groups.
c Repeatable Battery for the assessment of neuropsychological status. RBANS scores are age- and education-corrected standardized score to a median
d Barthel index is an ordinal scale that measures activities of daily living.
e MFIS is an instrument that provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning.
f 21-question multiple-choice self-report inventory to assess presence and severity of depression
As to be expected, we observed other posterior segment findings that were clearly unrelated
to WNV infection. Some patients exhibited macular or peripheral drusen, one patient had a
retinal hemorrhage related to macular degeneration, and one patient had diabetic retinopathy.
All of these disease entities are distinctly different in their appearance, well known to a general
ophthalmologist, and unrelated to WNV infection. No active vitritis was found in any of our
patients, and no vitreous cells were found in any of the patients, which would indicate prior
inflammatory disease. Occasionally a small, isolated darkly pigmented lesion or atrophic spot
were seen and could not definitively be attributed to WNV, but rather could be an incidental
finding unrelated to the WNV infection. Possibilities include old chorioretinal scars due to
reactive hyperplasia of the RPE, presumed ocular histoplasmosis, or other injuries, infections
or inflammatory entities; however, the association with WNV cannot be excluded. These
patients were not included in the WNVR group for analysis of the data.
a 95% confidence intervals,
b clinical presentation with altered mental status, seizures or focal neurological abnormalities,
c validated by bootstrap analysis (p = 0.001)
dany abnormality on a comprehensive neurological exam
WNV is a positive-sense RNA virus from the Flaviviridae family that has a distinctive
] Following infection, WNV patients continue to experience chronic neurological
abnormalities including cognitive impairment, depression and fatigue.[
14, 17, 18
] In our
cohort study, 55 (48%) had an abnormal neurological examination. Abnormal deep tendon
reflexes were the only neurological abnormality seen more commonly in the WNVR group (7/
27 (26%) vs. 7/84 (8.3%) (p = 0.039). WNV can cause acute flaccid paralysis due to
involvement of the anterior horn cells, and motor polyneuropathies [
] that could explain some of
the abnormal deep tendon reflexes found in our study population.
Patients with WNVR were more likely to have abnormalities in the macula (e.g., epiretinal
membrane, scars) and in the periphery of the retina (p<0.01) (see Table 2). WNV is known to
cause a multifocal chorioretinitis that involves both the macula and the periphery of the retina
and can be associated with vitreous inflammation.[
1, 3, 4, 20
] Macular involvement is
important to recognize early as it can lead to central visual impairment. Intravitreal bevacizumab has
been used successfully to treat macular edema in a patient with acute WNV infection.
Multifocal chorioretinitis was present in 27 out of 36 (75%) of patients with WNV and was the
only predictor in logistic regression analyses to be association with WNVR.[
] In our study,
we also observed a similar rate of multifocal chorioretinitis in 20 out of 27 (74%) with WNVR.
A prospective study of 38 patients with WNV infection identified diabetes mellitus as an
independent predictor of having WNVR.[
] Within our cohort that included a much larger
sample size, WNVR was associated with encephalitis, diabetes mellitus, and age greater than 60
years of age in bivariate analysis, but only encephalitis was associated with WNVR on logistic
Patients with WNVR were more likely to have lower scores on a well-validated measure of
immediate memory (i.e., story and complex figure learning). At the clinical level, WNVR was
associated with notable problems in everyday functioning, including dependence activities of
daily living as documented by the Barthel index and lower general quality of life. Patients with
WNVR and neurological sequelae show significant changes in their activities of daily living.
Our finding of neurological impairment in those with WNVR is most likely due to the high
prevalence of WNVR in those who had an acute clinical presentation of encephalitis. Almost
half (49%) of our patients who experienced encephalitis had evidence of WNVR, and this was
found to be highly statistically significant (p<0.001) when compared to less severe clinical
presentations. We recently conducted a study to examine recovery over time from WNV infection
and found those with encephalitis were significantly more likely to have poorer recovery, with
70% reporting continued disability more than 5.5 years following infection (MURRAY PLoS
ONE ref). Interestingly, in that study we also found those with a presentation of uncomplicated
fever had poorer recovery when compared to meningitis cases, with 60% still reporting
symptoms more than 5.5 years following infection. In this current study, one quarter of
uncomplicated fever cases had evidence of WNVR compared to 0 meningitis cases and 1 (4%)
asymptomatic case. As we speculated in the prior study, it is possible that these presumed
uncomplicated fever cases are misclassified since most were hospitalized for their infection but
did not have a lumbar puncture procedure to confirm neuroinvasive disease. These findings
warrant further investigation.
The ocular findings due to WNV in our cohort are similar to what has been reported in
] Our study though has several advantages over previous work. First, this
is the largest prospective cohort study of WNV infected patients that have undergone a
thorough dilated fundoscopic examination documenting the largest series of WNVR. Second, our
assessment of the WNV infected patients include a comprehensive neurological assessment
that included a complete neurological exam, neurocognitive evaluation and assessment for
depression, fatigue and impact in activities of daily living. Third, in order to reduce the hazards
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of multiple statistical contrasts, bivariate analysis emphasized only clinically plausible variables
and the inclusion of limited number of variables allowed us to avoid hazards of overfitting in
Despite its methodological advances, our study had limitations. First, our study lacked
agematched controls to compare patients without WNV infection in order to assess other causes
of eye abnormalities. Second, we did not have a baseline examination before the onset of the
WNV infection for comparison. Third, there is the possibility of misclassification of some of
the West Nile encephalitis cases as not all patients with WNV infection underwent a lumbar
puncture at time of diagnosis. Finally, we had a large number of deaths (n = 24) among our
patient population, and deaths occurred mostly in individuals who had neuroinvasive disease.
Unfortunately, we were unable to perform ophthalmic exams prior to their death, and
excluding their findings could create some bias to our analysis.
In summary, WNVR is seen in almost half of patients with WNV encephalitis and is
associated with neurological abnormalities, impaired memory and has an impact of activities of daily
living. Routine ophthalmological consultation should be considered in patients presenting with
WNV encephalitis as retinopathy can be associated with visual loss. It is feasible, for example,
that steroid or anti-VEGF therapies for inflammation or edema in the acute care setting might
help decrease vision loss in these patients. Many of these patients who present with severe
neuroinvasive disease are initially managed in intensive care settings, where the ophthalmological
exam might be considered secondary, when in fact, it might identify disease that could be
amenable to treatment. Future studies should aim to try to identify the specific mechanisms of
ocular involvement and potential therapies during acute WNV disease.
We would like to thank the West Nile virus cohort study participants for their invaluable
Conceived and designed the experiments: KOM RH JK SPW. Performed the experiments: LS
MNG LB JK. Analyzed the data: RH KOM MNG. Contributed reagents/materials/analysis
tools: SPW RH KOM JK. Wrote the paper: RH KOM MNG.
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