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Ocular complications of Rift Valley fever outbreak in Saudi Arabia
Ocular Complications of Rift Valley Fever Outbreak in Saudi Arabia Ali Al-Hazmi, MD,1 Ali A. Al-Rajhi, MD, FRCOphth,2 Emad B. Abboud, MD,2 Ephraim A. Ayoola, MD, FACP,3 Mohammed Al-Hazmi, MD,3 Rukban Saadi, MD,1 Nasser Ahmed, MS1 Objective: To report ocular complications of Rift Valley fever (RVF) during its first reported outbreak in southwest Saudi Arabia in autumn 2000. Design: Cross-sectional study of patients in a referral hospital. Participants: One hundred forty-three consecutive patients with confirmed RVF serologic test results and ocular lesions were enrolled in the study. Methods: Hospitalized patients (n ⫽ 30) and outpatients (n ⫽ 113) with clinical symptoms consistent with RVF, positive RVF serologic test results, and ocular abnormalities were studied. Ophthalmologic examinations, including fundus photography and fluorescein angiography, were performed. Patients were followed up at regular intervals to determine the prognosis and outcome of identified ocular abnormalities. Main Outcome Measures: Visual acuity at initial presentation and course of anterior and posterior segment complications. Results: Among 143 patients (78% males; mean age, 53.2 years), 212 eyes were affected, comprising 47 eyes in 30 inpatients and 165 eyes in 113 outpatients. The mean interval between the onset of RVF and visual symptoms ranged from 4 to 15 days (mean, 8.8 days). Macular or paramacular retinitis was identified in all the affected eyes (n ⫽ 212) at the time of initial assessment. Lesions included retinal hemorrhages (40%), vitreous reactions (26%), optic disc edema (15%), and retinal vasculitis (7%). Anterior uveitis was present in 31% of outpatients. Fluorescein angiography of the retinitis showed early hypofluorescence with late staining of retinal lesions and blood vessels. Initial visual acuity was less than 20/200 in 80% of eyes in the outpatient group; their vision improved, deteriorated, or remained the same in 13%, 15%, or 72%, respectively. Evaluation at the last follow-up showed macular (60%) or paramacular (9%) scarring, vascular occlusion (23%), and optic atrophy (20%) in the outpatient group. Conclusions: Rift Valley fever was associated with major ocular morbidity. Ocular manifestations of RVF occurred with a relatively higher frequency than reported up to now and were not limited to severe infections. Rift Valley fever affects the uvea and posterior chorioretinal area and is associated with permanent visual loss resulting from macular and paramacular scarring, vascular occlusion, and optic atrophy. The study demonstrated for the first time that transient nongranulomatous anterior uveitis is associated with RVF. Ophthalmology 2005; 112:313–318 © 2005 by the American Academy of Ophthalmology.
Rift Valley fever (RVF) is an arthropod-borne viral disease caused by Bunyaviridae, an RNA virus with a diameter of 94 to 100 nm that is transmitted to humans through a bite by infected mosquitoes or through direct contact with infected animals.1 Since the first report of an epizootic outbreak of RVF in Kenya in 1930,2 several Originally received: April 9, 2004. Accepted: September 3, 2004. Manuscript no. 240267. 1 Department of Ophthalmology, King Fahad Central Hospital, Jizan, Saudi Arabia. 2 Department of Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. 3 Department of Medicine, King Fahad Central Hospital, Jizan, Saudi Arabia. Presented at: American Academy of Ophthalmology Annual Meeting, November, 2001; New Orleans, Louisiana. The authors have no conflict of interest or proprietary interest in any of the instruments or topics mentioned. Correspondence to Ali Al-Hazmi, MD, PO Box 902 Jizan, Saudi Arabia. E-mail: [email protected]. © 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
epidemics have been described in Africa. These included the largest outbreak in Egypt in 1977, involving an estimated 18,000 cases of human illness and 598 fatalities,3 and a smaller one in Kenya and Somalia from 1997 through 1998.4 Observations in these epidemics indicated that most human illness caused by the RVF virus was mild and was characterized by influenzalike symptoms, with major complications such as hepatic syndromes, hemorrhagic manifestations, meningoencephalitis, and retinitis occurring in a minor proportion of patients with severe illness.5 Ophthalmic abnormalities with loss of central lesion resulting from retinitis and macular changes were reported previously.6 –12 The occurrence of a major outbreak of RVF in the southwestern region of Saudi Arabia from September through November 2000 has been well described.13–15 During the epidemic, we carried out a cross-sectional study to determine the clinical pattern of ocular manifestations of RVF and to determine the outcome of ocular lesions during the follow-up period. ISSN 0161-6420/05/$–see front matter doi:10.1016/j.ophtha.2004.09.018
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Ophthalmology Volume 112, Number 2, February 2005 Table 1. Case Definition of Rift Valley Fever 1. Unexplained illness, 48 hours in duration, in association with any of the following: a. ⱖ3 folds elevation in the alanine transferase, aspirate transferase, or ␥-glutamytransferase level or clinical jaundice. b. Abortion or bleeding manifestations (e.g., from puncture sites, ecchymosis, petechiae, purpura, epistaxis, gastrointestinal bleeding, or menorrhagia). c. Neurological manifestations (e.g., vertigo, confusion, disorientation, convulsions, lethargy, ataxia, or coma). d. Unexplained acute visual loss or scotoma. e. Fever, diarrhea, nausea, vomiting, or abdominal pain with any of these laboratory values: hemoglobin ⬍8 g/dl; platelets ⬍100,000 mm3; creatinine ⬎150 mol/l; lactate dehydrogenase or creatine kinase enzyme level of ⬎2 times the upper limit of normal. 2. Unexplained death with recent fever within preceding 2 weeks. 3. Positive Rift Valley fever serology test. From Outbreak of Rift Valley fever: Saudi Arabia, August–October, 2000. MMWR Morb Mortal Wkly Rep 2000; 49:905– 8. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4940a1.htm.
disc edema were classified as having posterior segment inflammation. Ocular complications were defined as irreversible structural changes caused by intraocular inflammation.
Laboratory Evaluation Blood specimens were obtained at admission or in the outpatient clinic from all suspected RVF patients who sought treatment at the hospital. Serum samples were tested by enzyme-linked immunosorbent assay for RVF antigen, and for immunoglobulin M and immunoglobulin G antibody to RVF virus. Other laboratory tests performed included complete blood counts, prothrombin time, blood sugar, serum electrolytes, and liver and renal function tests.
Treatment Patients in group 1 received supportive care with intravenous fluid and, when indicated, antimicrobial therapy, blood transfusion hemodialysis, or mechanical ventilation. None of the patients was treated with antiviral medications or steroids. Group 2 patients were not treated with any medication.
Statistical Analysis
Patients and Methods The study was carried out in a special RVF unit of the King Fahad Central Hospital, Jizan, located in southwestern Saudi Arabia. The study protocol was approved by the Research Council and Human Ethics Committee of the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
Patients Patients suspected of having RVF were identified through an elaborate preexisting system of primary health centers that refer acutely ill persons to district hospitals for assessment of criteria for admission as RVF case patients (Table 1). Only those patients who had symptoms and signs consistent with RVF and who were serologically positive for RVF were diagnosed as RVF cases and were included in this study. The patients were studied in 2 groups. The patients in group 1 (n ⫽ 206 inpatients) were consecutively seen patients who were admitted to the RVF unit of the King Fahad Central Hospital from September through November 2000 for the management of moderately severe illness. Group 2 consisted of ambulant patients (outpatients) who were referred to the ophthalmology outpatient department for an assessment of visual symptoms. They had mild symptoms consistent with RVF and were serologically positive for RVF but did not require admission into the hospital. They were followed up in the clinics at regular intervals. Information such as medical history and demographic data, risk factors of RVF virus infection, clinical manifestations, and laboratory results were obtained from each patient, as well as the onset of ocular and systemic symptoms. Complete ophthalmologic examination, laterality, localization of uveitis, and ocular finding were undertaken. It included baseline and final best-corrected visual acuity on a Snellen scale, slit-lamp biomicroscopy, tonometry, and detailed funduscopy by indirect ophthalmoscopy with a 20-diopter (D) or 90-D lens, or both. Color fundus photography and fluorescein angiography were performed in selected patients when media opacities allowed visualization of the fundus. Outpatients were reexamined at 3-, 6-, and 9-month intervals. Patients who experienced only anterior inflammatory reactions were classified as having anterior uveitis. Those who had vitreitis, sheathing of retinal vessels, retinitis, retinal hemorrhage, or optic
314
Descriptive statistics were used to summarize the demographic data at baseline. Continuous variables were presented as mean ⫾ standard deviation. Discrete or categorical variables were expressed as percentage. Comparison of data in proportions was performed using chi-square analysis, Fisher exact test, or analysis of variance. Groups of continuous data were compared using Student’s t test for parametric data and nonparametric data. P values less than 0.05 were statistically significant.
Results Five hundred sixteen case patients (407 males) were identified during the epidemic; 424 (82%) were Saudi citizens, and 92 (18%) had other nationalities. The largest number of cases, 365 (71%), were reported from the southwestern province of Jizan, and 151 cases (29%) were reported from the contiguous regions.13,14
Group 1: Inpatients Serologic test results were available for 216 of 246 severe case patients who were admitted to the King Fahad Central Hospital for suspected RVF during the period of the study; results were positive in 206 patients. No ocular lesions were found in the 10 patients with negative serologic results. Of the 206 admitted patients with severe RVF, 30 (15%; 47 affected eyes) had ocular lesions. All had multiple serious systemic complications including hepatic (18/30) and renal (15/30) involvement, hemorrhagic syndrome (7/30), and meningoencephalitis (4/30). Only indirect ophthalmoscopy was possible in this group and only 5 of 30 attended follow-up clinics. The mortality rate was 23% (7 of 30 patients) within the study period.
Group 2: Outpatients Outpatients (n ⫽ 113) were referred for evaluation of visual symptoms in addition to the presence of symptoms consistent with mild RVF (e.g., myalgia and fever), positive serologic results, and absence of comorbid diseases, such as diabetes and hypertension, known to be associated with ocular complications.
Overall Pattern of Ocular Lesions A total of 143 cases with ocular lesions and confirmed RVF serologic test results were identified during the study period. Males
Al-Hazmi et al 䡠 Rift Valley Fever Outbreak Table 2. Demographic Data of 143 Patients with Ocular Rift Valley Fever Disease Characteristics
Inpatients
Outpatients
All
No. of patients Age (yrs) Range Mean ⫾ standard deviation Gender Male Female Nationality Saudi Arabia Yemen Affected eyes Bilateral Unilateral Total no. of affected eyes
30
113
143
15–77 49.1 ⫾ 18
14–80 54.3 ⫾ 14.8
14–80 53.2 ⫾ 15.64
22 (73%) 8 (27%)
89 (79%) 24 (21%)
111 (78%) 32 (22%)
23 7
104 9
127 16
17 (57%) 13 (43%) 47
52 (46%) 61 (54%) 165
69 (48%) 74 (52%) 212
comprised 78% of the study (male-to-female ratio, 3.5:1). Patient demographic characteristic data are summarized in Table 2. The outpatient group had sudden deterioration of vision at presentation and sought treatment within a range of 4 to 15 days (mean, 8.8⫾3.02 days) after the onset of RVF with no reports of ocular pain. All male and most female patients were farmers, herders, or both. All patients reported having had exposure to repeated mosquito bites, direct contact with infected animals, or both. None of these patients were butchers or veterinary workers. Table 3 lists the ophthalmic findings at initial examination for the total population group. Posterior uveitis occurred in both study groups. The retinal lesions were located in the posterior pole as a single well-demarcated focus of retinal necroses, and usually were circular or oval with widths of 1 to 3 disc diameters in size with features of ill-defined creamy-white patchy lesions as macular retinitis (71% of affected eyes; Fig 1), and paramacular retinitis (29% of affected eyes; Fig 2). The retinitis lesions usually associated with retinal vasculitis (7%) were mostly phlebitis, and occasionally arteritis, which can lead to vascular occlusion, retinal hemorrhages, or both (35%; Fig 3); vitreous reactions (26%; the minimal to mild amount of vitreous cells ranged from 1⫹ to 2⫹); and optic disc edema (15%). Anterior uveitis was observed in 51 of 165 of the affected eyes in the outpatient group (31%) and was always accompanied by posterior uveitis (panuveitis). Anterior uveitis was characterized by the presence of 1⫹, 2⫹, or 3⫹ cells. None of these patients had keratic precipitates or iris nodules, and they did not seem to be severe, recurrent, or chronic, which is suggestive of nongranulomatous inflammation. Symptoms resolved spontaneTable 3. Ocular Lesions in Affected Eyes (n ⫽ 212) at Initial Assessment Condition No. of affected eyes Retinitis Macular Paramacular Retinal hemorrhage Vitreous reactions Optic disc edema Retinal vasculitis Anterior uveitis
Inpatients (n ⴝ 30)
Outpatients (n ⴝ 113)
Total (n ⴝ 143)
47
165
212
35 (75%) 12 (25%) 25 (53%) 10 (21%) 7 (15%) 3 (6%) Unavailable
116 (70%) 49 (30%) 60 (36%) 45 (27%) 25 (15%) 12 (7%) 51 (31%)
151 (71%) 61 (29%) 85 (40%) 55 (26%) 32 (15%) 15 (7%) —
ously within 2 to 3 weeks from the onset of systemic symptoms and did not result in complications such as glaucoma, posterior synechiae, or cataract. Intraocular pressure and gonioscopy remained normal in all cases. Fluorescein angiography of the retinitis areas revealed early hypofluorescence with late staining of retinal lesions and blood vessels (Fig 4). After initial testing, 28 outpatients (55 affected eyes) were lost to follow-up. The visual acuities at the initial evaluation in 85 patients (110 affected eyes) ranged from 20/80 to light perception and were arbitrarily classified into 4 subgroups as follows. Subgroup 1 consisted of eyes with light perception to hand motion (15 eyes). Among these, 3 eyes deteriorated to complete loss of vision, whereas 12 eyes remained the same. Subgroup 2 consisted of all 24 eyes with visual acuities of counting fingers that remained the same by the end of follow-up. Subgroup 3 consisted of 58 eyes with visual acuities ranging from 20/200 to 20/1200; visual acuities improved, decreased, or remained the same in 36, 12, or 10 eyes, respectively. Subgroup 4 consisted of the remaining 13 eyes that had visual acuities of 20/80 to 20/120, which decreased in 2 eyes, improved in 4 eyes, and remained the same in 7 eyes by the end of the follow-up period. Overall, the visual acuities showed improvement by at least 1 line in 14 eyes (13%), deteriorated by 1 or 2 lines in 17 eyes (15%), and remained the same in 79 eyes (72%) by the end of the follow-up period. Most active lesions spontaneously healed within the 9-month follow-up period in the outpatient group. Chorioretinal scarring— macular (65 eyes; 60%) and paramacular (10 eyes; 9%)—was the most frequent complication (Figs 5, 6), along with vascular occlusion (25 eyes; 23%) and optic atrophy (22 eyes; 20%; Fig 7).
Discussion This epidemic of RVF in Saudi Arabia represents the largest reported in medical literature and the first documented evidence of the RVF virus outside Africa. In our study, we evaluated the clinical characteristics and compared the major outcome parameters of 2 groups of patients: inpatients (severe systemic cases) and outpatients (mild disease). Demographic characteristics, including age and gender, were similarly represented in both groups. The observation that our male-to-female ratio was 3.5:1 could be related to the higher likelihood of male patients being involved in farming fieldwork and care of animals, and hence being more exposed to infected mosquitoes or animals. Ocular lesions occurred mainly in adults, with no children involved for the same reason. A high prevalence in females reported in a previous study can be attributed to their being more exposed to infected mosquitoes or animals in their societies.12 Before 1977, survey studies in Africa showed ocular complications of RVF were less frequent and the disease was only known to cause mild illness in humans.2,16 Conversely, a higher frequency of ocular complications was reported during epidemics in Egypt, which have been estimated to occur in approximately 1% of all RVF infections.5,9,12,17 The current study could not estimate the overall prevalence of ocular complications of RVF, because the total number of RVF patients is still unknown. Thirty of the 206 patients (15%) admitted with severe RVF were found to have ocular lesions. This is probably an overestimation of the prevalence of RVF-related ocular complications.
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Al-Hazmi et al 䡠 Rift Valley Fever Outbreak Figure 1. Fundus photograph of the right eye shows active retinitis in the foveal region. Figure 2. Fundus photograph of the left eye shows parafoveal active retinitis. Figure 3. A, Active retinitis in the macular region. B, Four months later, scarring of the lesions is clearly seen. Figure 4. A, Early-phase fluorescein angiogram of the right eye demonstrating abnormal foveal hypofluorescence and small vessel occlusion. B, Late-phase fluorescein angiogram demonstrating staining of the retinal lesion and small vessels. Figure 5. A, Fundus photograph of the left eye shows a large area of retinitis. B, Three months later, the same eye with a large macular scar.
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Our patients reported blurred or decreased vision or seeing floaters. They also reported scotomatous areas. Of note was the absence of associated pain. This is different from several reports of RVF in which patients had periocular pain at presentation.9,10,12,18 Previous studies showed that 40% to 50% of patients have permanent loss of vision after the resolution of the retinal lesions.9,12 In the present study, 80% of the involved eyes had an initial visual acuity of less than 20/200. Final visual acuity of affected eyes remained the same in 72% of patients throughout the follow-up and deteriorated in 15% of patients, and 78 of 110 eyes (71%) were legally blind. To the best of our knowledge, anterior uveitis has not been reported with RVF. This could be because patients had not been examined by slit-lamp biomicroscopy, sought treatment from the ophthalmologist late in the course of the disease, or were treated early with topical steroids.12 In this study, transient anterior uveitis, all cases of which were associated with posterior uveitis (panuveitis), was detected in 31% of the outpatient group (Table 3). All cases of
anterior uveitis were mild or moderate, were not accompanied by keratic precipitates or iris nodules suggestive of nongranulomatous type, resolved spontaneously without treatment within 2 to 3 weeks, and were not complicated by cataract, glaucoma, or posterior synechiae. Our findings are consistent and comparable with previous observations regarding posterior uveitis,9,10,12,18 which is the most common clinical feature of ocular RVF leading to partial or total loss of vision. Schrire,6 Freed,7 and Deutman and Klomp18 reported the occurrence of retinitis and retinal detachment in RVF leading to central visual loss. However, none of our cases were complicated by retinal detachment. In the present series, the major insult occurred in the posterior segment of the eye. The most striking ocular manifestation of the disease was posterior retinitis in both severe (inpatients) and mild (outpatients) forms. The most common ocular finding consisted of a focal area of retinitis involving the macular (71%) and paramacular (29%) areas. Retinitis may occur with or without other ocular manifestations. Patients with RVF infection usually experience sudden, progressive
Figure 6. A, Fundus photograph of the left eye demonstrating macular hemorrhagic retinitis. B, Four months later, the same eye shows a macular scar.
Figure 7. A, Fundus photograph of the right eye with large geographic retinitis. Note the healthy disc. B, Midphase of the fluorescein angiogram showing persistent hypofluroescence and vasculitic multiple arteriolar occlusion. C, Six months later, severe sheathing and vascular occlusion are easily seen. D, Obvious atrophy of the optic disc.
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Ophthalmology Volume 112, Number 2, February 2005 retinitis. The lesion may be associated with 1 of 4 major clinical features: (1) hemorrhages (40%), which frequently accompany retinal vasculitis and presumably are related to the retinal ischemia produced by the inflammation; (2) vasculitis (7%), which may affect small or large vessels with both arteritis and phlebitis occurring usually in association with retinal hemorrhages and vascular sheathing in the posterior pole (sheathing often is accompanied by vessels narrowing and sometimes by vascular occlusions); (3) vitreous reaction (26%; the vitreous has cells, particularly overlying the active lesion, and haze, but usually not severe enough to markedly hamper an examination of the posterior segment); (4) optic disc edema, presented in mild form sometimes associated with hyperemia, which occurred in 15% of patients with posterior uveitis. Spontaneous resolution of the RVF retinitis occurs within 10 to 12 weeks. As the retinitis becomes less acute, the area of bright-yellow appearance becomes dull white to become atrophic (scar) finally, which is the most frequent complication. The associated changes, such as retinal hemorrhage and vitreous reaction, also begin to clear. Attenuation or occlusion of retinal vessels also may occur, leading to retinal ischemia and optic atrophy. Vision decreased in our patients for several reasons. The most important one is the direct involvement of the fovea. By the end of the study, 3 patients were blind with no light perception, 60% had macular scarring, and another 9% had paramacular scarring. The fluorescein angiographic changes that were observed among our patients were similar to those observed in earlier studies.9,12,18 During the active period of the disease, the angiographic sequence revealed early hypofluorescence of the area of retinitis with delayed filling of arterioles and venules, with late staining of the retinal lesion and blood vessels. Follow-up angiography months after initial symptoms may reveal severe vascular occlusions, obliterated macular vessels, sheathing, and window defects corresponding to an area of retinitis. It has been suggested that retinal lesions are the result of primary occlusion of retinal circulation,9 although other authors argue the pathologic features are of an inflammatory rather than of an ischemic nature.10 We agree with Elwan et al,12 who suggested that the primary pathologic features are retinitis and retinal vasculitis, resulting in arteriolar occlusion. Retinal vasculitis is another manifestation of RVF disease and includes sheathing and angiospasm as well as vascular occlusion.12 In patients with RVF, vascular occlusion resulting from inflammation, as was found in 23% of our patients, may lead to retinal ischemia and optic atrophy, with subsequent permanent visual loss. The exact pathogenesis, histopathologic features, and possible treatment are still unknown and need to be investigated further. In conclusion, the epidemic of RVF in Saudi Arabia was characterized by the frequent occurrence of retinitis. Mac-
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ular retinitis, paramacular retinitis, and optic atrophy are the most frequent causes of visual loss in RVF. This is the first report of RVF associated with transient mild to moderate nongranulomatous anterior uveitis, which can be resolved completely without complications. At present, there is no effective treatment for RVF infection.
References 1. Ellis DS, Simpson DI, Stamford S, Abdel Wahab KS. Rift Valley fever virus: some ultrastructural observations on material from outbreak in Egypt 1977. J Gen Virol 1979;42:329 –37. 2. Daubney R, Hudson JR, Garnham PC. Enzootic hepatitis or Rift Valley fever: an undescribed virus disease of sheep, cattle and man from East Africa. J Pathol Bacteriol 1931;34:545–79. 3. El-Akkad AM. Rift Valley fever outbreak in Egypt, October– December 1977. J Egypt Public Health Assoc 1978;53:123– 8. 4. Rift Valley fever, East Africa, 1997–1998. MMWR Morb Mortal Wkly Rep 1998;47:261– 4. Available at: http://www. cdc.gov/mmwr/PDF/wk/mm4713.pdf. Accessed February 1, 2004. 5. Meegan JM, Watten RH, Laughlin LW. Clinical experience with Rift Valley fever in humans during the 1977 Egyptian epizootic. Contrib Epidemiol Biostatics 1981;3:114 –23. 6. Schrire L. Macular changes in Rift Valley fever. S Afr Med J 1951;25:926 –30. 7. Freed I. Rift Valley fever in man, complicated by retinal changes and loss of vision. S Afr Med J 1951;25:930 –2. 8. Cohen C, Luntz MH. Rift Valley fever and rickettsial retinitis including fluorescein angiography [in German]. Klin Monatsbl Augenheilkd 1976;169:685–99. 9. Siam AL, Meegan JM, Gharbawi KF. Rift Valley fever ocular manifestations: observations during the 1977 epidemic in Egypt. Br J Ophthalmol 1980;64:366 –74. 10. Ayoub M, Barhoma G, Zaghlol I. Ocular manifestations of Rift Valley fever. Bull Ophthalmol Soc Egypt 1978;71:125–33. 11. Arthur RR, el-Sharkawy MS, Cope SE, et al. Recurrence of Rift Valley fever in Egypt. Lancet 1993;342:1149 –50. 12. Elwan MS, Sharaf MH, Gameel K, et al. Rift Valley fever retinopathy: observations in a new outbreak. Ann Saudi Med 1997;17:377– 80. 13. Outbreak of Rift Valley fever. Saudi Arabia, August–October, 2000. MMWR Morb Mortal Wkly Rep 2000;49:905– 8. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm4940a1.htm. Accessed February 1, 2004. 14. Al-Hazmi M, Ayoola EA, Abdurahman M, et al. Epidemic Rift Valley fever in Saudi Arabia: a clinical study of severe illness in humans. Clin Infect Dis 2003;36:245–52. 15. Madani TA, Al-Mazrou YY, Al-Jefri MH, et al. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical and laboratory characteristics. Clin Infect Dis 2003;37:1084 –92. 16. Mundel B, Gear J. Rift Valley fever: the occurrence of human cases in Johannesburg. S Afr Med J 1951;25:797– 800. 17. Laughlin LW, Meegan JM, Strausbaugh LJ, et al. Epidemic Rift Valley fever in Egypt: observations of the spectrum of human illness. Trans R Soc Trop Med Hyg 1979;73:630 –3. 18. Deutman AF, Klomp HJ. Rift Valley fever retinitis. Am J Ophthalmol 1981;92:38 – 42.
Rift Valley fever (RVF) is an arthropod-borne viral disease caused by Bunyaviridae, an RNA virus with a diameter of 94 to 100 nm that is transmitted to humans through a bite by infected mosquitoes or through direct contact with infected animals.1 Since the first report of an epizootic outbreak of RVF in Kenya in 1930,2 several Originally received: April 9, 2004. Accepted: September 3, 2004. Manuscript no. 240267. 1 Department of Ophthalmology, King Fahad Central Hospital, Jizan, Saudi Arabia. 2 Department of Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. 3 Department of Medicine, King Fahad Central Hospital, Jizan, Saudi Arabia. Presented at: American Academy of Ophthalmology Annual Meeting, November, 2001; New Orleans, Louisiana. The authors have no conflict of interest or proprietary interest in any of the instruments or topics mentioned. Correspondence to Ali Al-Hazmi, MD, PO Box 902 Jizan, Saudi Arabia. E-mail: [email protected]. © 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
epidemics have been described in Africa. These included the largest outbreak in Egypt in 1977, involving an estimated 18,000 cases of human illness and 598 fatalities,3 and a smaller one in Kenya and Somalia from 1997 through 1998.4 Observations in these epidemics indicated that most human illness caused by the RVF virus was mild and was characterized by influenzalike symptoms, with major complications such as hepatic syndromes, hemorrhagic manifestations, meningoencephalitis, and retinitis occurring in a minor proportion of patients with severe illness.5 Ophthalmic abnormalities with loss of central lesion resulting from retinitis and macular changes were reported previously.6 –12 The occurrence of a major outbreak of RVF in the southwestern region of Saudi Arabia from September through November 2000 has been well described.13–15 During the epidemic, we carried out a cross-sectional study to determine the clinical pattern of ocular manifestations of RVF and to determine the outcome of ocular lesions during the follow-up period. ISSN 0161-6420/05/$–see front matter doi:10.1016/j.ophtha.2004.09.018
313
Ophthalmology Volume 112, Number 2, February 2005 Table 1. Case Definition of Rift Valley Fever 1. Unexplained illness, 48 hours in duration, in association with any of the following: a. ⱖ3 folds elevation in the alanine transferase, aspirate transferase, or ␥-glutamytransferase level or clinical jaundice. b. Abortion or bleeding manifestations (e.g., from puncture sites, ecchymosis, petechiae, purpura, epistaxis, gastrointestinal bleeding, or menorrhagia). c. Neurological manifestations (e.g., vertigo, confusion, disorientation, convulsions, lethargy, ataxia, or coma). d. Unexplained acute visual loss or scotoma. e. Fever, diarrhea, nausea, vomiting, or abdominal pain with any of these laboratory values: hemoglobin ⬍8 g/dl; platelets ⬍100,000 mm3; creatinine ⬎150 mol/l; lactate dehydrogenase or creatine kinase enzyme level of ⬎2 times the upper limit of normal. 2. Unexplained death with recent fever within preceding 2 weeks. 3. Positive Rift Valley fever serology test. From Outbreak of Rift Valley fever: Saudi Arabia, August–October, 2000. MMWR Morb Mortal Wkly Rep 2000; 49:905– 8. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4940a1.htm.
disc edema were classified as having posterior segment inflammation. Ocular complications were defined as irreversible structural changes caused by intraocular inflammation.
Laboratory Evaluation Blood specimens were obtained at admission or in the outpatient clinic from all suspected RVF patients who sought treatment at the hospital. Serum samples were tested by enzyme-linked immunosorbent assay for RVF antigen, and for immunoglobulin M and immunoglobulin G antibody to RVF virus. Other laboratory tests performed included complete blood counts, prothrombin time, blood sugar, serum electrolytes, and liver and renal function tests.
Treatment Patients in group 1 received supportive care with intravenous fluid and, when indicated, antimicrobial therapy, blood transfusion hemodialysis, or mechanical ventilation. None of the patients was treated with antiviral medications or steroids. Group 2 patients were not treated with any medication.
Statistical Analysis
Patients and Methods The study was carried out in a special RVF unit of the King Fahad Central Hospital, Jizan, located in southwestern Saudi Arabia. The study protocol was approved by the Research Council and Human Ethics Committee of the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
Patients Patients suspected of having RVF were identified through an elaborate preexisting system of primary health centers that refer acutely ill persons to district hospitals for assessment of criteria for admission as RVF case patients (Table 1). Only those patients who had symptoms and signs consistent with RVF and who were serologically positive for RVF were diagnosed as RVF cases and were included in this study. The patients were studied in 2 groups. The patients in group 1 (n ⫽ 206 inpatients) were consecutively seen patients who were admitted to the RVF unit of the King Fahad Central Hospital from September through November 2000 for the management of moderately severe illness. Group 2 consisted of ambulant patients (outpatients) who were referred to the ophthalmology outpatient department for an assessment of visual symptoms. They had mild symptoms consistent with RVF and were serologically positive for RVF but did not require admission into the hospital. They were followed up in the clinics at regular intervals. Information such as medical history and demographic data, risk factors of RVF virus infection, clinical manifestations, and laboratory results were obtained from each patient, as well as the onset of ocular and systemic symptoms. Complete ophthalmologic examination, laterality, localization of uveitis, and ocular finding were undertaken. It included baseline and final best-corrected visual acuity on a Snellen scale, slit-lamp biomicroscopy, tonometry, and detailed funduscopy by indirect ophthalmoscopy with a 20-diopter (D) or 90-D lens, or both. Color fundus photography and fluorescein angiography were performed in selected patients when media opacities allowed visualization of the fundus. Outpatients were reexamined at 3-, 6-, and 9-month intervals. Patients who experienced only anterior inflammatory reactions were classified as having anterior uveitis. Those who had vitreitis, sheathing of retinal vessels, retinitis, retinal hemorrhage, or optic
314
Descriptive statistics were used to summarize the demographic data at baseline. Continuous variables were presented as mean ⫾ standard deviation. Discrete or categorical variables were expressed as percentage. Comparison of data in proportions was performed using chi-square analysis, Fisher exact test, or analysis of variance. Groups of continuous data were compared using Student’s t test for parametric data and nonparametric data. P values less than 0.05 were statistically significant.
Results Five hundred sixteen case patients (407 males) were identified during the epidemic; 424 (82%) were Saudi citizens, and 92 (18%) had other nationalities. The largest number of cases, 365 (71%), were reported from the southwestern province of Jizan, and 151 cases (29%) were reported from the contiguous regions.13,14
Group 1: Inpatients Serologic test results were available for 216 of 246 severe case patients who were admitted to the King Fahad Central Hospital for suspected RVF during the period of the study; results were positive in 206 patients. No ocular lesions were found in the 10 patients with negative serologic results. Of the 206 admitted patients with severe RVF, 30 (15%; 47 affected eyes) had ocular lesions. All had multiple serious systemic complications including hepatic (18/30) and renal (15/30) involvement, hemorrhagic syndrome (7/30), and meningoencephalitis (4/30). Only indirect ophthalmoscopy was possible in this group and only 5 of 30 attended follow-up clinics. The mortality rate was 23% (7 of 30 patients) within the study period.
Group 2: Outpatients Outpatients (n ⫽ 113) were referred for evaluation of visual symptoms in addition to the presence of symptoms consistent with mild RVF (e.g., myalgia and fever), positive serologic results, and absence of comorbid diseases, such as diabetes and hypertension, known to be associated with ocular complications.
Overall Pattern of Ocular Lesions A total of 143 cases with ocular lesions and confirmed RVF serologic test results were identified during the study period. Males
Al-Hazmi et al 䡠 Rift Valley Fever Outbreak Table 2. Demographic Data of 143 Patients with Ocular Rift Valley Fever Disease Characteristics
Inpatients
Outpatients
All
No. of patients Age (yrs) Range Mean ⫾ standard deviation Gender Male Female Nationality Saudi Arabia Yemen Affected eyes Bilateral Unilateral Total no. of affected eyes
30
113
143
15–77 49.1 ⫾ 18
14–80 54.3 ⫾ 14.8
14–80 53.2 ⫾ 15.64
22 (73%) 8 (27%)
89 (79%) 24 (21%)
111 (78%) 32 (22%)
23 7
104 9
127 16
17 (57%) 13 (43%) 47
52 (46%) 61 (54%) 165
69 (48%) 74 (52%) 212
comprised 78% of the study (male-to-female ratio, 3.5:1). Patient demographic characteristic data are summarized in Table 2. The outpatient group had sudden deterioration of vision at presentation and sought treatment within a range of 4 to 15 days (mean, 8.8⫾3.02 days) after the onset of RVF with no reports of ocular pain. All male and most female patients were farmers, herders, or both. All patients reported having had exposure to repeated mosquito bites, direct contact with infected animals, or both. None of these patients were butchers or veterinary workers. Table 3 lists the ophthalmic findings at initial examination for the total population group. Posterior uveitis occurred in both study groups. The retinal lesions were located in the posterior pole as a single well-demarcated focus of retinal necroses, and usually were circular or oval with widths of 1 to 3 disc diameters in size with features of ill-defined creamy-white patchy lesions as macular retinitis (71% of affected eyes; Fig 1), and paramacular retinitis (29% of affected eyes; Fig 2). The retinitis lesions usually associated with retinal vasculitis (7%) were mostly phlebitis, and occasionally arteritis, which can lead to vascular occlusion, retinal hemorrhages, or both (35%; Fig 3); vitreous reactions (26%; the minimal to mild amount of vitreous cells ranged from 1⫹ to 2⫹); and optic disc edema (15%). Anterior uveitis was observed in 51 of 165 of the affected eyes in the outpatient group (31%) and was always accompanied by posterior uveitis (panuveitis). Anterior uveitis was characterized by the presence of 1⫹, 2⫹, or 3⫹ cells. None of these patients had keratic precipitates or iris nodules, and they did not seem to be severe, recurrent, or chronic, which is suggestive of nongranulomatous inflammation. Symptoms resolved spontaneTable 3. Ocular Lesions in Affected Eyes (n ⫽ 212) at Initial Assessment Condition No. of affected eyes Retinitis Macular Paramacular Retinal hemorrhage Vitreous reactions Optic disc edema Retinal vasculitis Anterior uveitis
Inpatients (n ⴝ 30)
Outpatients (n ⴝ 113)
Total (n ⴝ 143)
47
165
212
35 (75%) 12 (25%) 25 (53%) 10 (21%) 7 (15%) 3 (6%) Unavailable
116 (70%) 49 (30%) 60 (36%) 45 (27%) 25 (15%) 12 (7%) 51 (31%)
151 (71%) 61 (29%) 85 (40%) 55 (26%) 32 (15%) 15 (7%) —
ously within 2 to 3 weeks from the onset of systemic symptoms and did not result in complications such as glaucoma, posterior synechiae, or cataract. Intraocular pressure and gonioscopy remained normal in all cases. Fluorescein angiography of the retinitis areas revealed early hypofluorescence with late staining of retinal lesions and blood vessels (Fig 4). After initial testing, 28 outpatients (55 affected eyes) were lost to follow-up. The visual acuities at the initial evaluation in 85 patients (110 affected eyes) ranged from 20/80 to light perception and were arbitrarily classified into 4 subgroups as follows. Subgroup 1 consisted of eyes with light perception to hand motion (15 eyes). Among these, 3 eyes deteriorated to complete loss of vision, whereas 12 eyes remained the same. Subgroup 2 consisted of all 24 eyes with visual acuities of counting fingers that remained the same by the end of follow-up. Subgroup 3 consisted of 58 eyes with visual acuities ranging from 20/200 to 20/1200; visual acuities improved, decreased, or remained the same in 36, 12, or 10 eyes, respectively. Subgroup 4 consisted of the remaining 13 eyes that had visual acuities of 20/80 to 20/120, which decreased in 2 eyes, improved in 4 eyes, and remained the same in 7 eyes by the end of the follow-up period. Overall, the visual acuities showed improvement by at least 1 line in 14 eyes (13%), deteriorated by 1 or 2 lines in 17 eyes (15%), and remained the same in 79 eyes (72%) by the end of the follow-up period. Most active lesions spontaneously healed within the 9-month follow-up period in the outpatient group. Chorioretinal scarring— macular (65 eyes; 60%) and paramacular (10 eyes; 9%)—was the most frequent complication (Figs 5, 6), along with vascular occlusion (25 eyes; 23%) and optic atrophy (22 eyes; 20%; Fig 7).
Discussion This epidemic of RVF in Saudi Arabia represents the largest reported in medical literature and the first documented evidence of the RVF virus outside Africa. In our study, we evaluated the clinical characteristics and compared the major outcome parameters of 2 groups of patients: inpatients (severe systemic cases) and outpatients (mild disease). Demographic characteristics, including age and gender, were similarly represented in both groups. The observation that our male-to-female ratio was 3.5:1 could be related to the higher likelihood of male patients being involved in farming fieldwork and care of animals, and hence being more exposed to infected mosquitoes or animals. Ocular lesions occurred mainly in adults, with no children involved for the same reason. A high prevalence in females reported in a previous study can be attributed to their being more exposed to infected mosquitoes or animals in their societies.12 Before 1977, survey studies in Africa showed ocular complications of RVF were less frequent and the disease was only known to cause mild illness in humans.2,16 Conversely, a higher frequency of ocular complications was reported during epidemics in Egypt, which have been estimated to occur in approximately 1% of all RVF infections.5,9,12,17 The current study could not estimate the overall prevalence of ocular complications of RVF, because the total number of RVF patients is still unknown. Thirty of the 206 patients (15%) admitted with severe RVF were found to have ocular lesions. This is probably an overestimation of the prevalence of RVF-related ocular complications.
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Al-Hazmi et al 䡠 Rift Valley Fever Outbreak Figure 1. Fundus photograph of the right eye shows active retinitis in the foveal region. Figure 2. Fundus photograph of the left eye shows parafoveal active retinitis. Figure 3. A, Active retinitis in the macular region. B, Four months later, scarring of the lesions is clearly seen. Figure 4. A, Early-phase fluorescein angiogram of the right eye demonstrating abnormal foveal hypofluorescence and small vessel occlusion. B, Late-phase fluorescein angiogram demonstrating staining of the retinal lesion and small vessels. Figure 5. A, Fundus photograph of the left eye shows a large area of retinitis. B, Three months later, the same eye with a large macular scar.
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Our patients reported blurred or decreased vision or seeing floaters. They also reported scotomatous areas. Of note was the absence of associated pain. This is different from several reports of RVF in which patients had periocular pain at presentation.9,10,12,18 Previous studies showed that 40% to 50% of patients have permanent loss of vision after the resolution of the retinal lesions.9,12 In the present study, 80% of the involved eyes had an initial visual acuity of less than 20/200. Final visual acuity of affected eyes remained the same in 72% of patients throughout the follow-up and deteriorated in 15% of patients, and 78 of 110 eyes (71%) were legally blind. To the best of our knowledge, anterior uveitis has not been reported with RVF. This could be because patients had not been examined by slit-lamp biomicroscopy, sought treatment from the ophthalmologist late in the course of the disease, or were treated early with topical steroids.12 In this study, transient anterior uveitis, all cases of which were associated with posterior uveitis (panuveitis), was detected in 31% of the outpatient group (Table 3). All cases of
anterior uveitis were mild or moderate, were not accompanied by keratic precipitates or iris nodules suggestive of nongranulomatous type, resolved spontaneously without treatment within 2 to 3 weeks, and were not complicated by cataract, glaucoma, or posterior synechiae. Our findings are consistent and comparable with previous observations regarding posterior uveitis,9,10,12,18 which is the most common clinical feature of ocular RVF leading to partial or total loss of vision. Schrire,6 Freed,7 and Deutman and Klomp18 reported the occurrence of retinitis and retinal detachment in RVF leading to central visual loss. However, none of our cases were complicated by retinal detachment. In the present series, the major insult occurred in the posterior segment of the eye. The most striking ocular manifestation of the disease was posterior retinitis in both severe (inpatients) and mild (outpatients) forms. The most common ocular finding consisted of a focal area of retinitis involving the macular (71%) and paramacular (29%) areas. Retinitis may occur with or without other ocular manifestations. Patients with RVF infection usually experience sudden, progressive
Figure 6. A, Fundus photograph of the left eye demonstrating macular hemorrhagic retinitis. B, Four months later, the same eye shows a macular scar.
Figure 7. A, Fundus photograph of the right eye with large geographic retinitis. Note the healthy disc. B, Midphase of the fluorescein angiogram showing persistent hypofluroescence and vasculitic multiple arteriolar occlusion. C, Six months later, severe sheathing and vascular occlusion are easily seen. D, Obvious atrophy of the optic disc.
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Ophthalmology Volume 112, Number 2, February 2005 retinitis. The lesion may be associated with 1 of 4 major clinical features: (1) hemorrhages (40%), which frequently accompany retinal vasculitis and presumably are related to the retinal ischemia produced by the inflammation; (2) vasculitis (7%), which may affect small or large vessels with both arteritis and phlebitis occurring usually in association with retinal hemorrhages and vascular sheathing in the posterior pole (sheathing often is accompanied by vessels narrowing and sometimes by vascular occlusions); (3) vitreous reaction (26%; the vitreous has cells, particularly overlying the active lesion, and haze, but usually not severe enough to markedly hamper an examination of the posterior segment); (4) optic disc edema, presented in mild form sometimes associated with hyperemia, which occurred in 15% of patients with posterior uveitis. Spontaneous resolution of the RVF retinitis occurs within 10 to 12 weeks. As the retinitis becomes less acute, the area of bright-yellow appearance becomes dull white to become atrophic (scar) finally, which is the most frequent complication. The associated changes, such as retinal hemorrhage and vitreous reaction, also begin to clear. Attenuation or occlusion of retinal vessels also may occur, leading to retinal ischemia and optic atrophy. Vision decreased in our patients for several reasons. The most important one is the direct involvement of the fovea. By the end of the study, 3 patients were blind with no light perception, 60% had macular scarring, and another 9% had paramacular scarring. The fluorescein angiographic changes that were observed among our patients were similar to those observed in earlier studies.9,12,18 During the active period of the disease, the angiographic sequence revealed early hypofluorescence of the area of retinitis with delayed filling of arterioles and venules, with late staining of the retinal lesion and blood vessels. Follow-up angiography months after initial symptoms may reveal severe vascular occlusions, obliterated macular vessels, sheathing, and window defects corresponding to an area of retinitis. It has been suggested that retinal lesions are the result of primary occlusion of retinal circulation,9 although other authors argue the pathologic features are of an inflammatory rather than of an ischemic nature.10 We agree with Elwan et al,12 who suggested that the primary pathologic features are retinitis and retinal vasculitis, resulting in arteriolar occlusion. Retinal vasculitis is another manifestation of RVF disease and includes sheathing and angiospasm as well as vascular occlusion.12 In patients with RVF, vascular occlusion resulting from inflammation, as was found in 23% of our patients, may lead to retinal ischemia and optic atrophy, with subsequent permanent visual loss. The exact pathogenesis, histopathologic features, and possible treatment are still unknown and need to be investigated further. In conclusion, the epidemic of RVF in Saudi Arabia was characterized by the frequent occurrence of retinitis. Mac-
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ular retinitis, paramacular retinitis, and optic atrophy are the most frequent causes of visual loss in RVF. This is the first report of RVF associated with transient mild to moderate nongranulomatous anterior uveitis, which can be resolved completely without complications. At present, there is no effective treatment for RVF infection.
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