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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 ELSEVIER INC. ALL RIGHTS RESERVED. 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 554 AMERICAN JOURNAL 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 OF OPHTHALMOLOGY 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. REFERENCES 1. Calisher CH, Shope RE, Brandt W, et al. Proposed antigenic classification of registered arboviruses I. Togaviridae, Alphavirus. Intervirology 1980;14:229 –232. 2. Ross RW. The Newala epidemic. III. The virus: isolation, pathogenic properties and relationship to the epidemic. J Hyg (London) 1956;54:177–191. VOL. 144, NO. 4 OCULAR INVOLVEMENT IN 3. Enserink M. Infectious diseases. Massive outbreak draws fresh attention to little-known virus. Science 2006; 311:1085. 4. Centers for Disease Control and Prevention. Chikungunya fever in India. Travelers Health Outbreak Notice. Available at: http://www.cdc.gov/travel/other/2006/chikungunya_india.htm. Accessed Date: April 21, 2006. 5. Chikungunya and Dengue in the South West Indian Ocean. Epidemic and Pandemic Alert and Response (EPR). Available CHIKUNGUNYA INFECTION 555 6. 7. 8. 9. Philadelphia, Pennsylvania: Churchill Livingstone, 2000: 1703–708. 10. Centres for Disease Control and Prevention. Chikungunya fever diagnosed among international travelers—United States, 2006. MMWR Morb Mortal Wkly Rep 2007;56:276 – 277. 11. Schuffenecker I, Iteman I, Michault A, Murri S, Frangeul L, Vaney MC, et al. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med 2006;3:e263. 12. Parida MM, Santhosh SR, Dash PK, et al. Rapid and real-time detection of chikungunya virus by reverse transcription loop mediated isothermal amplification assay. J Clin Microbiol 2007;45:351–357. at: http://www.who.int/csr/don/2006_03_17/en/. Accessed Date: February 17, 2007. Quatresous I. The Investigation Group, E-alert 27 January: Chikungunya outbreak in Réunion, a French ‘overseas département.’ Euro Surveill 2006;11:E060202. Available at: http://www.eurosurveillance.org/ew/2006/060202.asp. Accessed Date: February 17, 2007. Ravi V. Re-emergence of chikungunya virus in India. Indian J Med Microbiol 2006;24:83– 84. Yergolkar PN, Tandale BV, Arankalle VA, et al. Chikungunya outbreaks caused by African genotype, India. Emerg Infect Dis 2006;12:1580 –1583. Markoff L. Togaviridae. In: Mandell GL, Bennet JE, Dolin R, eds. Principles and practice of infectious disease. 5th ed. 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 556 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. OF OPHTHALMOLOGY OCTOBER 2007