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Ocular Involvement Associated With an Epidemic
Outbreak of Chikungunya Virus Infection
PRAJNA LALITHA, SIVAKUMAR RATHINAM, KRISHNADAS BANUSHREE, SHANMUGAM MAHESHKUMAR,
RAJENDRAN VIJAYAKUMAR, AND PADMAKAR SATHE
● PURPOSE: To study the range of ocular symptoms in a
cohort of patients with chikungunya infection.
● DESIGN: Retrospective, observational case series.
● METHODS: Patients attending a tertiary eye care hospital
in South India were included in the study. We included
adult patients with serologically confirmed chikungunya
virus infection who received clinical care at the Aravind
Eye Hospital, Madurai, South India. They were assessed for
demographic characteristics, ocular symptoms, laboratory
parameters, and chikungunya virus infection severity. Patients underwent a complete ophthalmologic examination
that included visual acuity, slit-lamp examination, and
indirect funduscopic examination. Visual outcome at the
end of three months was the main outcome measure.
● RESULTS: The charts of 37 patients were analyzed
based on the clinical picture and the serologic results.
Forty patients were included as controls and tested
negative. There were 21 males and 16 females with a
mean age of 44.17 years. The main ocular symptoms
included granulomatous and nongranulomatous anterior
uveitis, optic neuritis retrobulbar neuritis, and dendritic
lesions. Of the 26 patients who were followed up for
three months, the visual acuity improved in 11 patients
(42.3%), remained the same in 12 patients (46.15%),
and worsened in three patients (11.5%).
● CONCLUSIONS: The main ocular manifestation associated with the recent epidemic outbreak of chikungunya
virus infection in South India included granulomatous
and nongranulomatous anterior uveitis, optic neuritis,
retrobulbar neuritis, and dendritic lesions. The visual
prognosis generally was good, with most patients recovering good vision. Further studies are needed to understand the pathogenesis of this disease. (Am J
Ophthalmol 2007;144:552–556. © 2007 by Elsevier
Inc. All rights reserved.)
Accepted for publication Jun 1, 2007.
From the Departments of Ocular Microbiology (P.L., R.V.); Uvea
(S.R.); Medicine (K.B.); and Neuro-ophthalmology (S.M.), Aravind Eye
Hospital, Madurai, India; and the National Institute of Virology, Pune,
India (P.S.).
Inquiries to Prajna Lalitha, Department of Ocular Microbiology,
Aravind Eye Hospital, 1, Anna Nagar, Madurai, Tamil Nadu, Madurai,
India; e-mail: [email protected]
552
©
2007 BY
C
HIKUNGUNYA VIRUS IS AN ALPHAVIRUS INDIGE-
nous to tropical Africa and Asia. It is transmitted
to humans by the bite of infected mosquitoes,
usually of the genus Aedes.1 Chikungunya fever, the disease
caused by chikungunya virus, was recognized first in epidemic form in East Africa in 1952 and 1953.2 The word
chikungunya is thought to derive from description in local
dialect of the contorted posture of patients afflicted with
the severe joint pain associated with this disease. Because
chikungunya fever epidemics are sustained by human–
mosquito– human transmission, the epidemic cycle is similar to those of dengue and urban yellow fever. Large
outbreaks of chikungunya fever have been reported recently on several islands in the Indian Ocean and in
India.3–5 In 2006, chikungunya fever cases also were
reported in travelers returning from known outbreak areas
to Europe, Canada, the Caribbean (Martinique), and
South America (French Guyana). Recent reports of largescale outbreaks of fever caused by chikungunya virus
infection in several parts of Southern India have confirmed
the re-emergence of this virus.5– 8
The main clinical symptom of the disease is a painful and
incapacitating polyarthralgia. Besides the arthralgic form,
other clinical features described include neurological changes
or fulminant hepatitis. In this report, we describe the ocular
manifestations, management, follow-up, and outcome of a set
of patients with seropositive chikungunya virus infection.
METHODS
THIS STUDY WAS A RETROSPECTIVE CHART REVIEW OF
patients with various ocular manifestations who had a positive history of chikungunya virus infection within the previous three months. The period of study was from September 1
through November 30, 2006 and was conducted at Aravind
Eye Hospital, Madurai, South India, during the chikungunya
epidemic. The details that were collected from the record
include the patient demographics, ocular manifestations,
serologic status, follow-up, and outcome. Patients with a
follow-up of at least one month were included. Blood was
collected from these patients and tailored laboratory investigations were performed. All other possible causes of uveitis
were ruled out. Anterior chamber inflammation was graded
using standardized uveitis grading and nomenclature to improve reporting in clinical studies. Laboratory and ancillary
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0002-9394/07/$32.00
doi:10.1016/j.ajo.2007.06.002
TABLE 1. Demographic Details of Patients with Ocular
Symptoms Associated with Chikungunya Virus Infection
Demographic Details
Gender
Male
Female
Age (yrs)
⬍30
31 to 40
41 to 50
51 to 60
61 and older
Residence
Rural
Urban
Treatment follow-up (days)
30
31 to 60
61 to 90
91 to 120
Not followed up
No.
%
21
16
56.76
43.24
9
9
7
7
5
24.32
24.32
18.92
18.92
13.51
11
26
29.73
70.27
13
9
3
1
11
35.14
24.32
8.11
2.70
29.73
TABLE 2. Ocular Diagnosis in 37 Patients with
Chikungunya Infection
OCULAR INVOLVEMENT
No.
%
Nongranulomatous anterior uveitis
Panuveitis
Granulomatous anterior uveitis
Optic neuritis
Lagophthalmos and VIth nerve palsy
Retrobulbar neuritis
Retinitis with vitreitis
Bilateral neuroretinitis
Keratitis
CRAO
Multifocal choroiditis with CME
Exudative retinal detachment
Total
10
5
1
4
3
3
2
1
3
1
2
2
37
27.03
13.51
2.70
10.81
8.11
8.11
5.41
2.70
8.11
2.70
5.41
5.41
100
CME ⫽ cystoid macular edema; CRAO ⫽ central retinal artery
occlusion.
investigations were tailored for each patient as determined by
history and physical findings at presentation. The common
etiologic diagnosis of anterior uveitis included human leukocyte antigen B27-related uveitis, Behçet syndrome, sarcoidosis, syphilis, tuberculosis, and leprosy. These patients
underwent complete systemic examination, radiologic studies, and an internal medicine consultation. Laboratory
work-up included complete blood count, serologic work-up
for syphilis, and a skin test for tuberculosis. Radiologic studies
were carried out in cases of tuberculosis, sarcoidosis, and
ankylosing spondylitis. All patients with a positive purified
protein derivative (PPD) or with clinical suspicion of tuberculosis or leprosy were examined by a physician and dermatologist, respectively. A complete neurologic examination
was carried out for the patients with lagophthalmos, and
other associated cranial nerve palsies were ruled out.
The cases with optic neuritis were diagnosed with the
presence of an afferent pupillary defect and a normal
fundus. Two patients had optic disk edema at presentation.
Retrobulbar neuritis was the most common presentation
that was diagnosed with pain on eye movement, particularly in the elderly patients.
Serum separation and enzyme-linked immunosorbent assay
(ELISA) analysis was carried out on these samples. All
patients were diagnosed to have chikungunya virus infection
based on typical clinical presentation of fever with acute
severe arthralgia and a single positive immunoglobulin M
(IgM) chikungunya serologic test. Age- and gender-matched
controls were selected from patients from same endemic area
who attended the hospital for other reasons such as refractive
error or for cataract surgery. Blood was collected from them
after obtaining informed consent to look for the presence of
chikungunya antibodies and to establish the baseline antiVOL. 144, NO. 4
Ocular Diagnosis
IN
body titer for chikungunya virus. These patients were specifically asked whether they had a history of fever with joint
pain within the previous three months.
The samples were tested for presence of virus-specific
IgM antibodies by MAC ELISA test developed at the
National Institute of Virology, Pune, India. Briefly, solid
support (microwells), which were coated with rabbit antihuman IgM (␮-chain specific) captured IgM antibodies
present in the sample. In the next step, chikungunya
antigen was added that formed a complex only with
chikungunya-specific IgM antibodies. Subsequently, the
reaction was probed with Biotin(Cat No. H-1759, SigmaAldrich, India)-labeled antichikungunya monoclonal antibodies and followed by Avidin-Horseradish Peroxidase
[HRP] (Cat No. A-7419, Sigma-Aldrich, India). Addition
of substrate tetramethyl-benzidine (TMB) led to development of color proportional to the concentration of IgM
antibodies in the sample. Absorbance was monitored at
450 nm. The sample was considered to be positive for
chikungunya virus-specific IgM if the optical density (OD)
value of the sample exceeded the OD value of a negative
control by a factor 2.1 (sample OD/negative OD ⱖ 2.1). If
the OD of the sample was less than the OD of the negative
control by a factor 1.9, it was considered to be negative
(sample OD/negative OD ⱕ 1.9).
RESULTS
WE PRESENT THE OCULAR MANIFESTATIONS ASSOCIATED
with chikungunya virus infection of 37 patients developing
during the convalescent state (Table 1). Forty-eight patients were tested as controls and none tested positive for
chikungunya infection. All patients had classic chikungunya fever with normal platelet counts and without signifCHIKUNGUNYA INFECTION
553
TABLE 3. Comparison of Presenting and Final Visual Outcome of Patients with Chikungunya Infection
Final Visual Acuity
Presenting Visual Acuity
20/20
20/30 to 20/60
20/80 to 20/120
ⱕ20/200
Hand Movements
Light Perception
Total (n ⫽ 26) *
20/20
20/30 to 20/60
20/80 to 20/120
ⱕ20/200
Hand movements
Light perception
Total
4
3
—
—
—
—
7
2
3
3
2
—
—
10
—
—
2
2
—
—
4
—
—
—
2
—
1
3
—
—
—
—
1
—
1
—
—
—
—
1
—
1
6
6
5
6
2
1
26
*The total number of patients was 37; 11 had no follow-up. The results presented are for the remaining 26 patients.
icant general hemodynamic derangement at the time of
presentation with visual symptoms. The average age of our
patients was 44.8 years (range, 22 to 72 years; median, 41
years). There were 16 females and 21 males. There was no
follow-up for 11 patients, and they were excluded for the
final analysis of the clinical and visual outcome. Baseline
data for these patients are included. For the remaining
patients, the mean follow-up was 42.1 days (range, 32 to
135 days). Ocular involvement was unilateral in 30 patients and bilateral in seven patients. The presenting
best-corrected visual acuity ranged from 20/20 to light
perception. The main presenting symptom in our series
was blurring of vision, usually asymmetric. Ocular symptoms occurred after a mean of 33.2 days after the onset of
chikungunya fever symptoms not overlapping with the
febrile episode. The ocular manifestations were varied, and
the main presenting ocular manifestation was acute nongranulomatous uveitis. The various ocular manifestations
are described in Table 2. The most common presentation
was uveitis with anterior granulomatous and nongranulomatous uveitis. Neurologic lesion also was common, along
with optic neuritis and retrobulbar neuritis.
The keratitis was very similar to herpetic keratitis with
dendritic lesions. Two patients had bilateral dendritic
lesions unlikely to be seen in herpetic lesions. The treatment was acyclovir ointment five times daily for seven days
and then tapered according to the clinical response. There
was one patient with central retinal artery occlusion at
presentation who had a poor outcome.
The time to resolution ranged from eight weeks to three
months. All patients received therapy based on the clinical
presentation and not on the suspicion of chikungunya
infection. Treatment was directed mainly at the inflammatory sign and was managed by topical and systemic
steroids.
Presenting visual acuity of 24 (64.9%) patients was
between 20/20 and 20/120, seven (18.9%) patients had
visual acuity of less than 20/200, and six (6.2%) patients
had visual acuity of less than hand movements. Of the 26
patients who had a follow-up of three months, the visual
acuity improved in 11 patients (42.3%), remained the
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same in 12 patients (46.15%), and worsened in three
patients (11.5%; Table 3). The three patients who did
poorly had optic neuritis, which subsequently developed
optic atrophy, and one patient had an underling diabetic
retinopathy along with the granulomatous pan uveitis with
vasculitis, which may have been the reason for the poor
visual recovery.
DISCUSSION
OCULAR MANIFESTATIONS IN CHIKUNGUNYA FEVER ARE
uncommon. A literature search showed that photophobia,
retrobulbar orbital pain, and conjunctivitis may be associated with this infection.9,10 The common clinical manifestations associated with this infection are abrupt onset of
fever, chills, headache, and severe joint pain with or
without swelling (usually the smaller joints). Most often,
chikungunya fever is a self-limiting febrile illness. However, neurologic complications such as meningoencephalitis have been reported in a small proportion of patients
during the first Indian outbreak as well as the recent
French Reunion islands outbreaks.6 Mother-to-child transmission of chikungunya virus was a new observation
recorded during the recent French Reunion islands outbreak. Although chikungunya is a self-limiting febrile
illness, the current outbreak seems to be more severe than
previous outbreaks because many patients experienced
complications and deaths also have been reported.5,6
The ocular manifestations were varied and ranged from
anterior segment involvement with keratitis to posterior
segment involvement. Conjunctivitis was not a noted
feature in this series, as has been reported previously.
There was an outbreak of adenoviral conjunctivitis also
during the same time. It is difficult to distinguish between
the two. Moreover, conjunctivitis resolves within one
week without sequelae. So there is a possibility we might
have missed cases with only conjunctivitis at presentation.
In our series, only three patients did not regain vision, and
most had good visual recovery. None of the ocular symptoms were unique to infection with chikungunya virus
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OCTOBER 2007
infections. Only histories of fever with arthralgia during
the chikungunya epidemic along with positive serologic
results led to a suspicion of association with this virus. In
a retrospective study, it is difficult to establish a cause-andeffect relationship. But similar observations have been
made in outbreaks of dengue virus infections. We did see
an increase in numbers of patients with anterior uveitis,
especially with increased pigmented keratic precipitates
and a history of chikungunya fever.
During this outbreak, Schuffenecker and associates investigated changes in the virus genome leading to its virulence and change in the behavior and morbidity associated
with the disease.11 They surmised that the outbreak began
with a strain related to East African strains of the virus. All
the recent Indian Ocean sequences examined shared certain
areas, which are different from the previously determined
sequences. This may be the reason for the development of
ocular symptoms as well. With limited knowledge available
on the pathogenesis of this disease at the moment, it may not
be possible to speculate on the cause of the severe ocular
involvement. The last outbreak that occurred in India was in
1971. The available literature from that period did not have
information on ocular involvement other than conjunctivitis
and retrobulbar orbital pain. But during this epidemic, other
systemic complications, including an increase in mortality in
elderly patients, have been reported. So in the face of lack of
other evidence, the change in virulence of the virus is a
strong possibility, and there may be a possibility of increased susceptibility of this population, because there was
no previous exposure that would have caused the development of protective antibodies. Because ours is a tertiary
eye care center, the patients with ocular complications
would have sought treatment from us and not from a
general physician.
There is not much evidence to suggest the possible
pathogenic mechanisms of chikungunya virus infections.
The immunopathologic mechanisms involved in chikungunya fever are not completely understood. The ocular
manifestations associated with chikungunya fever observed
in this series may be an immune-mediated process-like
production of autoantibody rather than a direct viral
infection. Because there are no previous reports of this
ocular infection, the mean time for occurrence may not be
established. In this series, it was an average of 33.3 days.
There is no established treatment for ocular manifestations of chikungunya fever. Because the underlying mechanism is likely to be immune mediated, we elected to use
steroids for our patients who did not have any contraindications to the therapy. There are recent molecular biological methods for the diagnosis of chikungunya infections
from the serum. Parida and associates recently standardized
and validated a real-time polymerase chain reaction assay
for this virus and found this to be a valuable tool for rapid,
real-time detection as well as quantification of chikungunya virus in acute-phase serum samples without requiring
any sophisticated equipment; this method has potential
usefulness for clinical diagnosis and surveillance of chikungunya virus in developing countries.12 There are not many
commercial serologic diagnostic kits available for chikungunya virus infection. The National Institute of Virology
in India is the only center that has developed an in-house
ELISA for the diagnosis. Nearly all human arboviral
infections are acute and are terminated by viral clearance.
Thus, recovery of an arbovirus from an ill patient is
virtually diagnostic.
In Asia, chikungunya virus is thought to be transmitted
by the same mosquitoes as dengue, Aedes aegypti, and Aedes
albopictus. Because of similarities in clinical presentation
with dengue, limited awareness, and a lack of laboratory
diagnostic capability, chikungunya virus is probably often
underdiagnosed or misdiagnosed as dengue. Treatment is
supportive. The prognosis is generally good, although some
patients experience chronic arthritis. With no vaccine or
antiviral treatment available, prevention and control depends on surveillance, early identification of outbreaks,
and vector control. Chikungunya virus should be borne in
mind in sporadic cases and in patients epidemiologically
linked to ongoing local or international outbreaks or
endemic areas. Ocular manifestations of chikungunya virus
infection are likely to be encountered during an epidemic.
Ophthalmologists should be aware of the ocular manifestations of chikungunya infection, which can result in
permanent visual impairment.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN AND
conduct of the study (P.L., S.R., K.B., S.M., P.S.); collection, management, analysis, and interpretation of the data (P.L., R.V.); and preparation, review,
or approval of the manuscript (P.L., S.R., P.S.). Institutional review board approval was granted for this study.
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AJO History of Ophthalmology Series
Bilberry and the Royal Air Force
W
inston Churchill’s best remembered quote was
uttered in a speech to the House of Commons on
August 20, 1940 after the French surrender
(“Never in the field of human conflict was so much owed by
so many to so few”). On the same page as the tribute to the
Royal Air Force (RAF), Churchill mentions the penetration
of British bombers deep into Germany in the dark of night.
The Germans did not have the radar that was vital to the
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AMERICAN JOURNAL
British defenses. Some suggest that to hide the existence of
radar the British circulated rumors to be picked up by German
spies that RAF pilots were taking bilberry to improve their
night vision. The idea that bilberry may help retinal problems,
although undocumented, persists even today.
Provided by William S. Tasman, MD, of the Cogan
Ophthalmic History Society.
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