An Epidemiological and Clinical Study of Ocular Manifestations of Congenitalrubella Syndrome in Omani Children

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EPIDEMIOLOGY An Epidemiological and Clinical Study of Ocular Manifestations of Congenital Rubella Syndrome in Omani Children

Rajiv Khandekar, MS (Ophth) PGDip Epi; Salah Al Awaidy, PGDip Epi; Anuradha Ganesh, MRCOphth; Shyam Bawikar, MD, MPH

Objective: To conduct a follow-up study in patients with testing was possible in 16 children; 4 were bilaterally blind. congenital rubella syndrome (CRS) in Oman and ana- Patients who had undergone eye surgery had signifi- lyze the prevalence of ophthalmic disorders and associ- cantly lower visual acuity, as compared with those who ated systemic problems. had not undergone surgery (relative risk 2.53; 95% con- fidence interval, 1.07-6.13). Among the 11 patients with Methods: This historical prospective cohort study in- CRS with cataract, we found hearing loss, cardiac anoma- cluded review of 32 surviving patients with CRS re- lies, and neuropsychologic anomalies in 7, 4, and 6 chil- ported by the surveillance system in Oman from 1987 dren, respectively. through 2002. All patients underwent a complete ophthalmic examination that included visual acuity estima- Conclusions: Congenital rubella syndrome has a wide va- tion, refraction and anterior and posterior segment evalu- riety of severe ophthalmic and systemic complications. High ation, and intraocular pressure measurement. Pediatric clinical vigilance for signs of CRS and regular observation and otorhinolaryngologic consultations were also per- of surviving patients with CRS is desirable. In patients with formed. cataract, the functional results of surgery, despite state-of- the-art ophthalmic care, continue to be poor. Because of a Results: The age-adjusted prevalence of CRS in Oman high prevalence of visual, audiologic, and neurologic dis- was 73.2 per million in the Omani population younger abilities, surviving patients with CRS pose a burden on the than 20 years, and the incidence was 0.6 per 1000 live medical and social communities. Emphasis in manage- births. Cataract, retinitis, microphthalmos, and glau- ment ought to be prevention of CRS through effective im- coma were observed in 11, 16, 6, and 4 patients, respec- munization programs. tively. Keratoconus, corneal hydrops, and spontaneous resorption of lens were found in 1 patient each. Vision Arch Ophthalmol. 2004;122:541-545

ONGENITAL RUBELLA SYN- later, and patients with little or no hear- drome (CRS) was first de- ing loss initially may later become deaf. scribed by an ophthal- Therefore, all reported and surviving pa- mologist who linked tients with CRS need to be carefully ob- congenital cataract to served for early detection and manage- German measles infection in mothers dur- ment of new disease manifestations.4 C1 ing pregnancy. Although rubella is a mild The World Health Organization en- disease in adults, when a woman con- courages its member countries to From the Eye and Ear Health Care Programme, Ministry of tracts rubella during pregnancy, there is strengthen their surveillance system for Health (Dr Khandekar); a risk for transplacental transmission of the CRS to achieve global elimination of CRS 5 Department of Disease virus and development of serious compli- by 2010. New cases of CRS have been rare Surveillance and Disease cations in the fetus. The consequences of since the development of an attenuated Control, Ministry of Health rubella infection in utero are the manifes- vaccine in 1969 and the effective imple- (Dr Al Awaidy); Department of tations of CRS.2 Congenital cataract, glau- mentation of immunization programs.6 Ophthalmology, Sultan Qaboos coma, and pigmentary retinopathy are con- However, epidemics of rubella continue to University Hospital sidered cardinal features of the syndrome, occur. De Owens et al7 reported the birth (Dr Ganesh); and Department and a diagnosis of CRS can be made in their of 54 neonates with CRS in Panama in of Disease Surveillance and presence despite lack of laboratory evi- 1986. Lee et al8 reported a resurgence of Disease Control, Ministry of 3 Health (Dr Bawikar), Muscat, dence. CRS in the United States in the 1990s. Oman. The authors have no Patients with CRS exhibit progres- The Sultanate of Oman is a member relevant financial interest in sive disease; patients without cataract or country in the Eastern Mediterranean Re- this article. glaucoma in infancy might manifest them gion of the World Health Organization,

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 cally suspected CRS. The child is immediately referred to a pe- Table 1. Profile of the 32 Patients diatrician for detailed examination and laboratory confirmation. With Congenital Rubella Syndrome in Oman The patient is examined by a senior ophthalmologist, otorhinolaryngologic surgeon, cardiologist, neurologist, and en- Patient Characteristic No. of Patients (%) docrinologist. All physicians and staff in the specialist clinic Sex are aware of mandatory notification of a clinically suspected Male 22 (69) CRS case in Oman. The cases that fulfill the CRS definition are Female 10 (31) evaluated annually for the presence of newer manifestations. Age group, y Patients with CRS who cannot be offered treatment at facili- Ͻ5 2 (6) ties available within Oman are sent abroad for treatment at the 5-9 4 (12) government’s expense. The tertiary child health care units main- 10-14 20 (62) tain details of such cases. The information of all CRS cases re- 15-19 6 (19) ported through the surveillance system and case records at sec- Region ondary and tertiary hospitals were reviewed to ensure complete Muscat 5 (16) enlisting of all CRS cases. Dhofar 9 (28) For the present study, so we could determine their pres- Dhakhiliya 2 (6) ent status, all children with CRS underwent a detailed oph- North Sharqiya 6 (19) thalmic examination that included evaluation of best- South Sharqiya 0 (0) corrected visual acuity, slitlamp examination of the anterior North Batinah 3 (9) segment, measurement of intraocular pressure, and examina- South Batinah 3 (9) tion of the posterior segment by means of indirect ophthal- Dhahira 2 (6) moscopy through dilated pupils. B-scan ultrasonography was Musundam 0 (0) performed for posterior segment evaluation in cases of media Al Wousta 2 (6) opacities. Axial length was evaluated by means of A-scan ultrasonography. Presence of strabismus was established by per- forming the Hirschberg test. Children older than 6 years were with a high-quality surveillance and disease control sys- tested by means of the Snellen chart. Younger children were tem for communicable diseases9 and aims to eliminate evaluated by means of the Snellen chart and Kolt test. When CRS by 2005.10 In Oman, there was an outbreak of ru- formal visual acuity testing was not possible, counting fingers bella in 1992 and 1993, and many infants born in that or identification of items used on a daily basis was tested at a year exhibited features of CRS. Since 1994, important distance of 1 m. milestones in the control of rubella in Oman have been achieved, notably mass vaccination of children; intro- QUALITY ENSURANCE PROCEDURES duction of measles, mumps, and rubella vaccination in A national seminar was conducted by the Department of Dis- an immunization schedule; and rubella immunization for ease Surveillance and Disease Control to explain the revised all mothers after childbirth. A high-quality surveillance surveillance and reporting system for CRS. Uniform pretested and disease control system for communicable diseases data collection forms were used. Multiple sources were used has been established, and strategies have been reorga- to ensure enrollment of all CRS cases. nized to make surveillance of CRS more sensitive.10 The ocular profile pertaining to congenital cataract DATA MANAGEMENT SYSTEM during the 1992 epidemic of rubella in Oman has been reported.11 However, limited information is available about Data were collected from regional hospitals and computed by the entire spectrum of ocular manifestations of CRS in using a pretested format (Epi Info 6.0; Centers for Disease Con- this cohort. We reviewed the magnitude of CRS and the trol and Prevention, Atlanta, Ga). Predetermined checks ensured a high standard of data entry. The frequencies, percent- ocular profile in children with CRS in Oman. age, and proportion of different ocular manifestations were METHODS calculated (SPSS 9.0; SPSS Inc, Chicago, Ill), and a univariate method of analysis was adopted for the study. The prevalence This was a historical prospective cohort study. All patients with of CRS in the Omani population younger than 20 years was CRS reported through the national surveillance system from adjusted by using an indirect standardization method, for which 14 January 1, 1987, through December 31, 2002, formed the study the proportion of the global population was used. population. Patients had CRS diagnosed on the basis of criteria provided by the World Health Organization.12,13 ETHICAL ISSUES At nearly 165 primary health institutions, physicians ex- amine the newly born and children at the time of their vacci- The permission of national and regional health administrators nation visits to assess the presence of white pupil, nystagmus, was obtained to conduct this study. Patient identity was kept and abnormal eyeball size. Clinically suspected CRS cases are confidential. The results of the study were shared with the re- referred to ophthalmologists for confirmation. A newborn with gional health administrators, and recommendations to further any congenital anomaly is screened by a pediatrician to rule improve the care of patients with CRS were discussed. out toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex infection in the mother and the possibility of RESULTS CRS in the child. On the basis of the criteria set by the World Health Organization, all health institutions (governmental and private clinics) notify the Department of Disease Surveillance Thirty-two patients had clinical manifestations compat- and Disease Control, Muscat, Oman, by fax of any child with ible with CRS; 28 (88%) had ocular manifestations. Their CRS. This information includes the parents’ telephone num- sex, age group, and regional distribution are shown in ber and health institution and the criteria observed for clini- Table 1. The distribution of cases of CRS in Oman ac-

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10 No. of Patients

5 4 4

2 2

1 1 1 1 1 1

00 0 00 0 1986 198719881989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 Year of Birth

Number of patients with congenital rubella syndrome (CRS) in Oman according to year of birth. In view of the limited study sample, nearly half of the patients were born in 1992. From 1994, after introduction of the vaccine against rubella in Oman, the number of patients with CRS decreased, so our cohort has only3 patients born after 1995.

cording to year of birth is shown in the Figure. More than 50% of children with CRS were born during the epi- Table 2. Systemic Manifestations of Congenital Rubella Syndrome demic of 1992 and 1993. The number of boys was greater than the number of girls, with 22 boys (69%) and 10 girls Manifestation Unilateral Bilateral Total (31%) affected. The mean age of patients with CRS was 10.4 years (range, 3.2 to 16.4 years; SD, 3.3 years). More Ocular than one fourth of the patients resided in the mountain- Cataract 5 6 11 Microphthalmos 2 4 6 ous southern region of Dhofar, Oman. Retinitis 2 14 16 The prevalence of CRS was estimated to be 37.3 per Glaucoma 1 3 4 million in the Omani population younger than 20 years, Corneal hydrops 0 1 1 and the age-specific prevalence was 73.2 per million in Keratoconus 0 1 1 this population. The incidence of CRS in 2002 was esti- Absorbed lens 0 1 1 mated to be 0.6 per 1000 live births. Disciform maculopathy 0 0 0 Other in eye* 314 Systemic manifestations of CRS in Omani children No ocular anomaly NA NA 4 are shown in Table 2. Ocular complications (28 of 32), Hearing loss hearing loss (23 of 32), and neurologic deficits (24 of 32) Sensorineural NA NA 21 were the chief manifestations. Of 30 children who could Conductive NA NA 1 be tested, 12 (38%) had cardiac anomalies. All except 1 Mixed NA NA 1 child had undergone cardiac surgery to treat the con- Cardiac Patent ductus arteriosus NA NA 9 genital anomalies. Ventricular septal defect NA NA 2 The most common ocular finding was retinitis, seen Pulmonary atresia and left NA NA 1 in 16 patients (50%) and present in most patients in both ventricular failure eyes (14 of 16). Cataracts followed retinopathy in fre- Neurologic quency (11 patients [34%]). Fifty-five percent of chil- Microcephaly NA NA 19 dren with cataracts had bilateral involvement. Microph- Cerebral palsy NA NA 7 Ͻ Mental retardation NA NA 14 thalmos (axial length 17 mm) was noted in 6 patients Behavioral changes NA NA 6 (19%), and glaucoma was noted in 4 patients (12%). One Diabetes NA NA 1 case each of keratoconus, corneal hydrops, and sponta- Hypospadias NA NA 1 neous lens resorption (aphakia in the absence of surgery) were detected. No case of disciform maculopathy Abbreviation: NA, not applicable. was found. Because of limited subgroup sample sizes, the *Included children with nystagmus (n = 1), strabismus (n = 2), and chronic uveitis (n = 1). statistical significance of each ocular manifestation in terms of sex and other variables was not calculated. Systemic complications among patients with Of the 64 eyes in the 32 patients with CRS, 18 eyes congenital cataract and retinitis are shown in Table 3. (28.1%) had undergone surgery; their visual acuity was Sensory hearing loss was common among those with compared with that in the eyes that had not undergone retinitis. surgery (Table 4). In 30 eyes, vision testing was not pos-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 lance system. Hospitals with easy and affordable access Table 3. Ocular Manifestations and Systemic to child health care in Oman also ensured reporting of Complications in Congenital Rubella Syndrome all cases of CRS. The prevalence of CRS in our study is much lower Complication No. (%) of Patients than that reported in the past in Oman and in other de- Congenital cataract (n = 11) veloping countries. During the rubella epidemic of 1992 Hearing loss 7 (64) and 1993, the incidence of clinical CRS was 0.7 per 1000 Cardiac anomalies 4 (36) 11,12 Neuropsychologic anomalies 6 (54) live births. The serologically confirmed CRS rate in Diabetes 1 (9) Saudi Arabia was 2.2% among children aged 1 to 14 Retinitis (n = 16) years.18,19 The rate of CRS was 1.7 per 1000 births in Ja- Hearing loss 11 (69) maica and Israel, 0.9 in Sri Lanka, and 1.5 in Sin- Cardiac anomalies 6 (38) gapore.2 The absence of new CRS cases in Oman in the Neuropsychologic anomalies 12 (75) past 3 years and the deaths of some patients with CRS Diabetes 0 (0) during the epidemic in 1992 could be responsible for this observation. A high rate of immunization of children aged 15 months, the mass vaccination campaign in 1994 for Table 4. Visual Acuity in Surviving Patients children aged 15 months to 18 years, and the vaccina- With Congenital Rubella Syndrome tion of mothers postpartum has resulted in a marked de- crease in CRS cases in Oman. No. of Eyes (%) Ocular disease accounts for much of the effect that CRS has on the medical and social communities,2 Total a finding also observed in our cohort. Among the Visual Acuity Right Eye Left Eye (N = 64) Omani population with CRS, retinitis was the most No impairment 6 (19) 4 (12) 10 (16) common ocular complication; however, congenital Ͼ6/18 3 (9) 4 (12) 7 (11) 6/60 to 6/18 2 (6) 3 (9) 5 (8) cataract and glaucoma accounted for the most cases of Ͻ6/60 but Ͼ3/60 3 (9) 3 (9) 6 (9) visual disability. Inability to obtain fundus details in a Ͻ3/60 3 (9) 2 (6) 5 (8) number of patients may have resulted in underestima- Testing not possible 15 (47) 16 (50) 31 (48) tion of this complication. Congenital cataract and glaucoma were also the main reported ocular manifestations in the past in Omani children.11 In comparison sible because of poor cooperation or the child being men- with the high prevalence (85%-95%) of cataract due to tally challenged. Among those undergoing routine vi- CRS reported in other studies,19,20 only 11 cases (34%) sion tests, visual acuity was normal in 10 eyes (16%). Five were detected in our cohort, which is difficult to eyes (8%) had visual acuity less than 3/60, and 18 eyes explain. Isolation of virus from lens material might (28%) had visual acuity less than 6/18 but greater than enable us to determine the strain of virus and its affin- or equal to 3/60. The eyes that had undergone surgery ity for retinal tissue rather than lens tissue. We had a significantly higher risk of visual impairment than detected 1 case each of spontaneous lens resorption, did those that had not (relative risk, 2.53; 95% confi- keratoconus, and corneal hydrops. These changes are dence interval, 1.07-6.13). Observation of children who reported as rare and delayed ones.19 Long-term did not cooperate for vision testing revealed that 20 eyes follow-up of CRS cases is thus justified. had some residual vision: light perception, identifica- The 8% (5 of 64 eyes) bilateral blindness in pa- tion of familiar objects, counting fingers close to the face. tients with CRS in our study is much higher than the childhood blindness rate of 0.07% reported in 1997.21 This find- COMMENT ing supports the need for special care and periodic evaluation in this high-risk population. Acquired rubella is mild and self-limiting, and infection Visual impairment was significantly greater in eyes usually produces lifelong immunity.15 Mass vaccination that had undergone ocular surgery, mainly for cataract, of children induces immunity in 80% to 90% of the popu- as compared with those that had not undergone sur- lation. In countries with effective immunization pro- gery. Poor outcomes after cataract surgery in patients with grams, new cases of CRS are therefore rare.9 Unfortu- rubella are documented in the literature.22,23 Inflamma- nately, outbreaks continue to occur, and investigation tion and incidence of pupillary membrane, posterior syn- results suggest that failure to vaccinate susceptible indi- echiae, and secondary glaucoma are increased in pa- viduals, rather than failure of the vaccine, is the major tients with CRS. These findings have been attributed to factor underlying resurgence.16 To eliminate CRS, it is release of virus from the lens at the time of surgery and crucial to monitor the magnitude of the disease and to initiation of an immune reaction after cataract surgery.5 observe surviving cases to manage newer complications The level of visual impairment in our patients, despite and offer rehabilitative services. A study in Oman is cru- quality care free of cost, favors the argument that even cial because it aims to achieve this goal by 2005. though surgical and medical treatment of complica- Loss of the sample in a cohort study is always a mat- tions of CRS are available, the emphasis ought to be on ter of concern.17 However, the present study is unlikely prevention.12 to be affected by this bias because a historical cohort was Most patients with CRS with congenital cataract had studied by using data from a highly sensitive surveil- additional nonocular disabilities, such as hearing loss and

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 cardiac and mental or behavioral anomalies, that com- genital rubella syndrome (CRS) in developing countries, part 1: burden of dis- pounded visual disability. Many patients with retinitis ease from CRS. Bull World Health Organ. 1997;75:55-68. 3. Armstrong NT. The ocular manifestations of congenital rubella syndrome.In- had associated sensorineural hearing loss. Further stud- sight. 1992;17:14-16. ies are needed to confirm this association. 4. Sever JL, South MA, Shaver KA. Delayed manifestations of congenital rubella. Few patients with CRS died during follow-up, which Rev Infect Dis. 1985;7(suppl 1):S164-169. could be because of prompt management of cardiac 5. Robertson SE, Featherstone DA, Marta GD, Hersh BD. Rubella and congenital rubella syndrome: global update. Pan Am J Public Health. 2003;14:306-315. anomalies in our cohort. Late ocular manifestations of 6. Resnikoff S, Parajasegaram R. Blindness prevention programmes: past, pres- CRS thus can be observed, provided cardiac complica- ent and future. Bull World Health Organ. 2001;79:222-226. tion in a CRS case is managed effectively to increase the 7. De Owens CS, De Espino RT. Rubella in Panama: still a problem. Pediatr Infect patient’s chances of survival. Dis J. 1989;8:110-115. In conclusion, the prevalence of CRS is lower in 8. Lee SH, Ewert DP, Fredrick PD, Mascola L. Resurgence of congenital rubella syndrome in the 1990s: report on missed opportunities and failed prevention poli- Oman since 1994. Although ocular complications were cies among women of childbearing age. JAMA. 1992;267:2616-2620. a major complication of CRS, congenital cataract was less 9. World Health Report Health Systems: Improving Performance. Geneva, Swit- common than that observed in other studies. A high pro- zerland: World Health Organization; 2000:200. portion of visual disability in eyes that underwent sur- 10. World Health Organization. Expanded programme on immunization: rubella out- gery, as compared with those that did not, needs further break, Oman. Wkly Epidemiol Rec. 1994;69:333-336. 11. Ministry of Health, Oman. Elimination of rubella and CRS in Oman by 2005. Com- investigation. Effective immunization programs can pre- munity Health Dis Surveill Newsl. 2000;9:1-3. vent CRS and childhood blindness from its ocular mani- 12. Juma AH. Infantile rubella cataract in Oman. Med Newslett (Oman). 1989;6:27-28. festations. 13. Cutts FT, Best J, Siqueira MM, Robertson SE. Guidelines for surveillance of congenital rubella syndrome and rubella. Surveillance of CRS. Available at: http://www.who .int/vaccines-documents/DocsPDF99/www9934.pdf. Accessed February 4, 2004. Submitted for publication June 19, 2003; final revision re- 14. The Sex and Age Distribution of the World Populations: The 1994 Revision.New ceived January 6, 2004; accepted January 15, 2004. York, NY: United Nations; 1994. We thank the staff of the Department of Disease Sur- 15. Chin J. Control of Communicable Diseases Manual. 17th ed. Washington, DC: veillance and Disease Control, Muscat, Oman, for provid- American Public Health Association Rubella; 2000:435-440. ing CRS case data. We also appreciate the efforts of the pe- 16. Lindegren ML, Fehrs LJ, Hadler SC, Hinman AR. Update: rubella and congenital rubella syndrome, 1980-1990. Epidemiol Rev. 1991;13:341-348. diatricians, ophthalmologists, and otorhinolaryngologists 17. Mayrent S, Doll S, eds. Epidemiology in Medicine. Boston, Mass: Little Brown & who helped in evaluating these cases. We thank the authori- Co; 1987:170-171. ties in the Ministry of Health, Muscat, Oman, for their sup- 18. Abdulla MA, Jamjoom G, Karrar ZA, Badreldine A, Al Jishi N, Taha SA. Sero- port of this study. A. 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