Britishgournal ofOphthalmology 1993; 77: 358-363

Congenital rubella syndrome: ophthalmicmanifestations and associated systemic disorders

Kerry T Givens, David A Lee, Thomas Jones, Duane M Ilstrup

Department ofOphthalmology,Geisinger MedicalCenter, Danville, PA,USAK T Givens

Jules Stein Eye Institute,UCLA School ofMedicine, 100 SteinPlaza, Los Angeles, CA,USAD A Lee

5017 23rd Avenue West,Everett, WA, USAT Jones

Department of Statistics,Mayo Clinic, Rochester,MN, USAD M IlstrupCorrespondence to:David A Lee, MD, Jules SteinEye Institute, UCLA School ofMedicine, 100 Stein Plaza, LosAngeles, CA 90024-7004,USA.

Accepted for publication2 February 1993

AbstractCongenital rubella syndrome has a widevariety of severe ophthalmic and systemiccomplications. A worldwide rubella epidemicfrom 1%3 to 1965 affected thousands ofinfants. This is a 20 year follow up study ofpatients with congenital rubella syndromeanalysing the prevalence of ophthalmic dis-orders, associated systemic problems, andcorrelations among these defects. The authorsstatistically analysed 125 cases of congenitalrubella seen in the Mayo clinic ophthalmologydepartment over a 32 year interval. Mostpatients were young adults. Ocular disease wasthe most commonly noted disorder (78%),followed by sensorineural hearing deficits(66%), psychomotor retardation (62%),cardiac abnormalities (58%), and mentalretardation (42%). Multiorgan disease wastypical (88%). Ocular disease and hearing losswere frequently associated (53% had both) butnot significantly correlated. A similar associa-tion existed between ocular and cardiacdisease. Cataracts and microphthalmia weresignificantly correlated with poor visual acuity(each p<00001). Glaucoma was significantlycorrelated with cataracts (p=00002) andmicrophthalmia (p=00024) but not poor visualacuity. Four patients with microphthalmiadeveloped late onset glaucoma. No significantassociation was found between gestational ageat time of maternal infection and the incidenceof individual ocular conditions. However,several cardiac disorders were significantlyassociated with gestational age. Although newcases of congenital rubella are rare, survivingvictims continue to challenge the ophthalmicand medical communities with a wide range ofocular and systemic disorders.(BrJ7 Ophthalmol 1993; 77: 358-363)

Veale, a Scottish physician, characterised rubellaas a benign contagious disease in 1866.' Acentury later, Sir Norman Gregg described thetriad of congenital cataracts, deafness, and heartdefects in children ofwomen who had contractedthe infection during the first trimester.23 Thetremendous morbidity associated with the con-genital rubella syndrome is now well known tothe medical community.

Before perfection of an effective vaccine in1969, a worldwide rubella epidemic lasting from1963 to 1965 affected an estimated 10% ofpregnant women; approximately 30% of infantsfrom infected mothers ultimately manifestedcongenital disease.4 One recent estimate suggeststhat, in the United States alone, at least 10000infants were born with moderate to severe mani-festations during that epidemic.5 Over the course

of the ensuing 20 years, many of those infantshave matured into young adults who pose anenormous challenge to the medical community.The complexity and multiplicity of their defectsdemand the combined disciplines of medicine,special education, and rehabilitation. Becauseserious ocular abnormalities are commonlyassociated with congenital rubella, ophthalmolo-gists share the responsibility of managing thesepatients.

Epidemiological assessment of ocular diseasein large populations of congenital rubellapatients are few; 17 years have passed sinceWolff, following a cohort of victims from the1963-65 epidemic, published the last indepthreport.6 Many of the earlier studies employ onlydescriptive statistics, commenting on apparentassociations without actually testing theirvalidity. The subject is worthy of continuingattention, especially because additional oculardisorders associated with congenital rubella havebeen characterised since Wolff s paper, andbecause some defects may continue to evolvemany years after birth,7-9. We reviewed retro-spectively 125 congenital rubella cases to discernthe prevalence of specific ocular defects, identifyassociated systemic abnormalities, and discernstatistical correlations (if any) among thesedefects.

Materials and methodsCharts of all patients with a diagnosis of congeni-tal rubella seen in the Mayo clinic's departmentof ophthalmology from 1950 to 1982 werereviewed. Criteria for diagnosis of congenitalrubella syndrome included classic stigmas(cardiac anomalies, hearing defects, cataracts),plus a history of maternal exposure coupled withrash or positive immunoglobulin M serologyand/or isolation of the virus.

Primary demographic data included sex, race,date of birth, date of diagnosis, estimated gesta-tional age at the time of maternal infection,residence (Olmstead County, MN, versus allother locations), and the data and patient statusat last follow up examination. Records werescreened for many clinical variables, tallied inTable 1 (ophthalmic involvement) and Table 2(involvement of non-ocular systems).To elucidate correlations among the most

prevalent ocular findings (pigmentary retino-pathy, cataract, microphthalmia, glaucoma), abattery of statistical tests was applied to the data,examining the coincidence of these conditionswith all other ocular findings. In a separateanalysis gestational age at time of maternalrubella infection was compared with the incid-ence of the most common ocular and systemicdisorders. All testing was performed using SAS

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Table I Manifestations ofocular disease among 125 patientswith the congenital rubellasyndrome

Unilateral BilateralI

Symptom No % No % C

Retinopathy 4 3 71 57 6Cataracts 13 10 21 17 2Strabismus - - 30 24 2Nystagmus 5 4 26 21 2Microphthalmia 19 15 10 8 2Amblyopia 12 10 8 6 1Glaucoma 6 5 5 4Iris coloboma 4 3 2 2Optic atrophy 2 2 2 2Cornealhaze 3 2 1 1Dacryostenosis 3 2 - -

Anyeyedisease - - - - 7

*Figures published by other authors.

Table 2 Systemic manifestations ofcongenit

Symptom

OtologicalSensorineural defects

UnilateralBilateral

Degree of hearing lossMildModerateSevere

CardiacPatent ductus arteriosusPulmonary stenosisVentricular septal defectTetralogy of FallotCoarctation of aortaMitral stenosisAtrial septal defect

DevelopmentalFailure to thrive

MildModerateSevere

Psychomotor retardationMildModerateSevere

Mental retardationMildModerateSevere

Low birth weight (<2500 grams)Prematurity (<36 weeks)

NeurologicalMicrocephalyHyperactivitySpastic diplegiaSeizure disorderSpastic quadriplegiaHydrocephalusHemiparesisOther diagnoses

GenitourinaryInguinal hernia

UnilateralBilateral

Recurrent urinary tract infectionsUndescended testes

UnilateralBilateral

HydroceleUnilateralBilateral

HypospadiaMeatal stenosisHydronephrosisUrinary reflux

OrthopaedicSyndactylyScoliosisDislocated hipLegg-Perthes diseasePeroneal palsyCalcaneovalgus deformity

DentalMicrognathiaHypoplastic teethCleft lip

EndocrineDiabetes mellitusGraves' diseaseHashimoto's thyroiditis

*Audiometric data available for

percentages reflect that total.only 103pa

'otal Others%l) (%)*

0 9-6i1526,7 l6-85621!4 9q 21 24

software (SAS InstituteInc, SAS Campus Drive,Cary, NC 27513, USA) on a VAX mainframecomputer. Analyses includedx2, Wilcoxon twosample, and Fisher's exact tests. Probabilityvalues of p<005 were considered statisticallysignificant.

!5 13-38~6'1 Results3 "3l06321i6 16 One hundred and twenty five patients fulfilled9 2-25'1 the diagnostic criteria for the congenital rubella4 96 syndrome.Sex distribution was approximately3 1-86 15 equal, with 71 men and 54 women affected (5728 346812 14 and 43%, respectively). One hundred and four-

teen patients (93%) were still alive at the last dateof follow up. All but three of the patients werewhite; no black patients were among the studypopulation. The median gestational age at thetime of maternal infection was 8 weeks (range,

al rubella 0 to 29 weeks). The majority of patients (51%)No % were born during the worldwide rubella

epidemic from 1963 to 1965 (Fig 1).82 66 Age at diagnosis for patients residing in1 1 Olmstead County ranged from 0 to 270 days, 45

81 65 days being the mean. In contrast, the mean age at3 3* diagnosis of all 125 patients was 4-6 years. This

23 19* delay reflects thehigh proportion of patients whowere tertiary referrals. Only eight of the 125

32 26 patients were residents of Olmstead County; of21 17 those eight, 50% had ocular disease, compared3 2 with 80% of the non-residents (difference not2 2 statistically significant: p=0 074, Fisher exact6 5 test; power of test to detect significant difference

=51%). The mean duration of follow up was 4 534 27 years with ages ranging from less than 1 year to

1 1 65 years (Fig2).27 22 Ocular disorders in the study group are listed38 30 in Table 1. Overall, 78% of the group (9712 10 patients) had some form of ocular disease. The23 18 most common finding was pigmentary retino-154 12 pathy, seen in 75 patients (60%) and usually58 46 present in both eyes (71 out of 75). Cataracts32 26 followed retinopathy in frequency (34 patients or53 42 27%). Sixty per cent of the latter group (2122 18h18 14 patients) had bilateral involvement. Glaucoma9 7 was noted in 11 patients (9%). No cases of2 2 subretinal neovascular membranes, chronic2 21 1 inflammation, progressive cataracts, spontane-6 5 ous resorption of cataracts, or congenital aphakia

were detected.27 103 No significant relationships were detected7 10 between pigmentary retinopathy and any other14 20 defect, including visual acuity; however,3 4 because of limited subgroup sample sizes, the2 3 power of our analyses to detect a statistically1 1 significant relationship was typically very low for2 3 most of the comparisons. For instance, the3 41 1 power to discern a relationship between poor2 3 visual acuity (defined as worse than 20/200) for3 4 data collected from right and left eyes was only23 4' 5% and 15%, respectively. However, statistically2 32 3 significant associations involving other ocular

1 diseases were identified (Table 3). Notably, theincidence of cataracts in microphthalmic eyes

6 9 was almost 90% (p<0-0001), and both of the3 42 3 latter conditions were significantly correlated

with poor visual acuity, regardless of prior2 3 ophthalmic surgeries (p<0-0001). Among2 3 aphakic patients, acuity ranged from 20/70 to no

atients; these light perception, mean acuity at last follow upvisit being 10/200.

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_ l- l . . ............. . l ll L :l .......50-535S5657-59 604263 65 66 6 6>71 72-77.77 78 8Year of birth

Figure I Breakdown ofstudy population byyear ofbirth.

Figure 2 Distribution ofthe ages ofthe studypopulation at the time oflastfollow up visit.

Glaucoma was significantly correlated withmicrophthalmia (p<00024, Fisher's exact test).Ten of the 11 patients with glaucoma also hadcataracts. Four patients developed glaucoma intheir late teens. Two of the latter cases involvedpreviously unoperated microphthalmic eyes,and two involved aphakic, microphthalmic eyes.Patients requiring glaucoma surgery typicallyrequired repeat glaucoma operations as well. Inmost cases, the primary surgical procedure wasgoniotomy.

Involvement of non-ocular systems is detailedin Table 2. Hearing loss was common in thispatient population. Moreover, the prevalence ofhearing loss in the entire study group (66%) wassimilar to the prevalence ofhearing loss in the eyedisease subgroup (53%). Similarly, the occur-rence of eye disease in the entire study group(78%) was comparable to that among hearing-impaired patients (80%). Although the frequentassociation between ocular disease and hearingdeficits was not statistically significant (p=028,x2 test), the power of the test to detect such adifference was only 18%.

Cardiac defects and ocular disease were alsofrequently associated in this population (60patients, or 48%, had both). The prevalence ofcardiac disease among patients with eye diseasewas 62%, compared to 58% for the entire studygroup. Conversely, the prevalence of eye diseaseamong patients with heart disease (82%) wassimilar to that for the entire population (78%).This relationship was not statistically significant

(p=0 145, X2 test); the power of the test to detectsuch a difference was 31%.The preponderance of defects in the study

population occurred in infants exposed to rubelladuring the first trimester of gestation. While theprevalence of hearing deficits tended to increasewith time of maternal rubella infection duringthe first trimester, the prevalence of ocular andcardiac disease went down (Fig 3); however, onlythe cardiac trend was statistically significant(p=0 009, Wilcoxon rank sum test); the trendfor hearing defects was of borderline significance(p=0086, Wilcoxon rank sum test). Althoughthe correlation between gestational age and anysingle ocular condition was statistically notsignificant, significant associations were foundbetween gestational age and the followingspecific cardiac diseases: patent ductus arterio-sus, pulmonary stenosis, ventricular septaldefect, and failure to thrive (Table 3).A large proportion of the patients demon-

strated some degree ofdevelopmental or intellec-tual deficiency. Sixty two per cent of the patientshad a history of psychomotor retardation, and42% had microcephaly. Table 2 lists the pre-valence of other systemic manifestations ofcongenital rubella, including genitourinary,orthopaedic, dental, and endocrine problems.

Overall, multiorgan disease was the rule: 88%of the patients suffered involvement of at leasttwo systems, and nearly two thirds (64%) hadabnormalities in four or more systems. Only onepatient with the diagnosis of congenital rubellahad no detectable defects on last examination.

DiscussionThe classic rubella syndrome is characterised bythe combination of cardiac, ocular, and hearingdefects, although infection and damage canoccur in every organ system. As many as twothirds of infants with congenital rubella will befree of any abnormality at birth. Most patientswho are symptomatic at birth and many of thosewho lack signs of infections eventually will havesome degree of hearing loss or psychomotordamage. Congenital rubella should be viewed asa chronic infection capable ofproducing progres-sive damage. Clinical follow up and testing haveshown that ultimately central nervous systemdamage (hearing loss, intellectual and motordeficiencies) is the most frequent and significantclinical problem associated with congenitalrubella. The diagnosis should be suspected whenmaternal seroconversion or a compatible illnessoccurs during pregnancy, when a neonate hasclinical signs of congenital rubella, and in anyinfant with hearing loss, retinitis, or encephal-opathy of unknown aetiology. Even with a highindex of suspicion, many cases will be missed,since many mothers and infected newborns alsolack clinical signs of rubella.'0Both the rate of in utero transmission of

rubella and the consequences of fetal infectionare related to the stage of gestation at the time ofmaternal infection. Infection during the first 8weeks of pregnancy results in a fetal infectionrate of about 50%; subsequently, the rate of inutero transmission drops sharply to less than10% by the 16th week. The proportion of

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Congenital rubella syndrome: ophthalmic manifestations and associated systemic disorders

Table 3 Significant correlations among 125 patients unth thecongenital rubella syndrome

Poor visual GCorrelative symptom acuity Cataracts Glaucoma ag

Cataracts p<O0OOo1* - - -Microphthalmia p<O0OOOl* p<0.OOOl* p<00024tGlaucoma - p<O00002* -

Patent ductus arteriosus - - - pPulmonary stenosis - - - p.Ventricular septal defect - - - p<Failure to thrive - - - p.

*XI test; tFisher exact test; tWilcoxon two sample test.

infected fetuses with damage caused by rubellafollows a similar pattern. These gestationalinfluences probably are due to a number offactors, including timing in relation to organo-genesis, maturation of fetal host mechanisms,and maturation of the placental barrier.Developing fetal organs are damaged by infec-tion of cells in blood vessels in both the placentaand fetus. These vascular lesions are character-ised by endothelial necrosis and are often accom-panied by petechiae and haemosiderin ladenmacrophages in fetal organs. In addition, rubellacan produce cytolytic infection of host cells;cellular damage caused by virus has been identi-fied in a number of tissues, including myo-cardium, central nervous system, skeletalmuscle, and epithelial cells of the developinginner ear, lens, and teeth."'

In the 1960s and '70s, publications concerningcongenital rubella were legion. Since the adventofeffective vaccination, the number ofnew cases

of congenital rubella has plummeted and with itthe number of reports addressing this devastat-ing disease. Nonetheless, congenital rubella con-

tinues to have a sizeable impact on the medicaland social community: conservative estimatesplace society's cost for the long term rehabilita-tion of patients from the 1963-65 epidemic at$US1-3 billion." Because eye disease accountsfor much of this burden, congenital rubellamerits continued attention from the ophthalmiccommunity.Most papers from the ophthalmic literature

regarding this disease report the incidence andcoincidence of various eye findings without test-

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Figure 3 Prevalence ofselected organ defects relativeto gestational age at the timeofmaternal rubellainfection.

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ing the data statistically. Arguably, in manyearlier reports such analysis was problematic,owing to very small samples, uncontrolled vari-ables, and non-random patient populations.While the current study suffers from the usuallimitations of a retrospective approach, we nonethe less feel that prudent application of selectedstatistics may help clarify important relation-ships and stimulate directions for further study.The present study has certain advantages over

previous reports: a larger sample size than most,a broader range of patient ages, longer follow up,and more complete assessment of concomitantocular and systemic variables. On the otherhand, our population is heavily skewed towardspatients with ocular disease. Because the Mayoclinic is a tertiary referral centre situated in arelatively small city, the majority of patients inthis study were probably screened elsewhere andreferred specifically because of known eye prob-lems. Not surprisingly, the overall prevalence ofocular disease in this population, 78%, is higherthan the 43% prevalence of eye disease describedby Wolffin his prospective review ofinfants withcongenital rubella (of the I1 different eye condi-tions that Wolff documented in his study, all buttwo were more frequent among our patients).6Notably, the present study documented a higheroverall frequency of ocular disorders, evenwhen compared with other retrospective series (aliterature search showed a high of 68%). 12Longer follow up and larger sample size areprobable factors, as both favour discovery ofrarer, overlooked, or delayed eye conditions (forexample, delayed glaucoma).

Several authors have commented on the fre-quent association of hearing deficits and oculardisease in congenital rubella patients. Woodruff,in her study ofchildren attending a school for thedeaf, noted that 82% of congenital rubellapatients with ocular findings were hearingimpaired.13 This figure parallels the 80% preva-lence of ocular disease among hearing impairedpatients in our study. Some authors have impliedthat the association between these two defects isnon-random.'4 x2 analysis of our data suggeststhe association of these common findings is onlycoincidental. An alternative explanation is thatthis test had insufficient power (only 18%) touncover a significant relationship, given thelimitations of our data. If the ocular and oticsystems share some embryological feature result-ing in similar vulnerability to rubella dysgenesis,the current evidence remains circumstantial.

Cardiac anomalies are one component ofGregg's archetypal rubella syndrome. Subse-quent authors have commented on the specificassociation between ocular and cardiac defects inthese patients.'5 16 Seltzer et al reported, forinstance, that of a population of 100 congenitalrubella patients, 95% of the subgroup with eyedisease had associated cardiac defects, comparedwith only 56% of the group without eye disease.'5Our data show a much lower prevalence ofcardiac defects (62% in patients with eye find-ings) and approximately the same frequency ofcardiac defects among patients with ocular dis-orders as among the entire study population. Aswith the analysis of hearing deficits and oculardisease, however, the power of the x2 test to

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identify a significant relationship was signific-antly lessened by sample size.

Several previous studies have described theapparent rarity ofcombined glaucoma and catar-acts in congenital rubella patients,'4 17-1 implyingthat these conditions are mutually exclusive.Wolff" questioned this conclusion, and with XIanalysis of prospective patient data showed thatthe infrequency of the association was due to theoverall rarity of glaucoma in all rubella patients,including those with cataracts; glaucoma andcataracts behaved like independent events, andthe chance of a patient having both conditionswas correspondingly much less than that ofhaving only one. In contrast, our analysis sug-gests that the two conditions occur togethersignificantly more often than by chance alone.Because glaucoma among congenital rubellapatients is not a homogeneous disease, however,*such analysis is complicated. The delayed glau-coma following cataract surgery (seen in two ofour patients) is felt to have a pathophysiologydifferent from the infantile glaucoma more com-monly associated with the rubella syndrome.20

Microphthalmia is another variable that mayinfluence rubella related glaucoma. Wolff'observed that glaucoma in congenital rubellapatients 'may have a special predilection formicrophthalmic eyes that have undergone catar-act surgery, sometimes years earlier'. In ourpatient population, microphthalmos was highlycorrelated with glaucoma, irrespective of pre-vious surgery. Cataracts also showed a verystatistically significant relationship with bothmicrophthalmia and glaucoma in our popula-tion. While proteins leaking from hypermaturecataracts may promote elevated intraocular pres-sure (for example, as in phacolytic glaucoma),our data do not clarify whether the glaucoma inmicrophthalmic eyes is secondary to lens medi-ated effects, angle abnormalities, or both.The association between microphthalmos and

cataracts, though frequent, is not well under-stood. In our study, almost 90% of the micro-phthalmic eyes had cataracts; similarly, O'Neillreported that 100% of 12 culture proved congeni-tal rubella patients with microphthalmia hadcataracts.2' In contrast, other researchers havereported microphthalmos as 'usually, but notnecessarily' linked with cataract.22Some authors feel that microphthalmos is a

non-specific consequence ofcongenital rubella, asort of ocular failure to thrive,5 perhaps due tothe generalised slowing of replication commonlyseen in rubella infected cells.23 Microphthalmosmay, therefore, signify diffuse ocular involve-ment with virus, although this has not beensubstantiated in vitro. That an eye with morerubella damaged cells might have several simul-taneous defects - that is, glaucoma and cataracts,seems plausible.While most published reports agree that

defects from congenital rubella are more pro-found and numerous when maternal infectionoccurs in the first trimester, even third trimesterinfection may result in significant disease. Theliterature disagrees, however, as to the exacttiming of specific embryological insults. Forinstance, one author felt the risk of cataractsharply declined after week 5 of gestation, when

the embryologic lens capsule was complete'7;Wolff,' however, wrote that the period ofvulnerability extends to week 11. Cooper andKrugman'6 felt that hearing deficits resultedprimarily from material infection occurring afterthe eighth week of gestation; Boniuk,24 however,attributed hearing deficits to infections preced-ing the eighth week. Our data did not demon-strate any statistically significant trends betweenindividual ocular diseases and gestational age.Determining precise gestational age at the timeof maternal infection is inherently difficult,however, and this factor may have weakened theanalysis. Conversely, several cardiac defectsdemonstrated strong associations with gesta-tional age at time of maternal infection, perhapsreflecting a more sharply defined period ofembryonal vulnerability for this organ system.

Delayed ocular disease is an increasinglyimportant consideration in patients withcongenital rubella. The characteristic 'salt-and-pepper' pigmentary retinopathy shows progres-sive tendencies in some patients,25 although earlyreports implied the condition was stationary.26Patients with retinopathy may enjoy relativelygood visual acuity into adulthood, then experi-ence sudden loss of vision secondary to sub-retinal neovascularisation.72728 Even withoutidentifiable neovascularisation, visual acuitymay occasionally reach no more than 20/60 inpatients whose only ocular finding is pigmentaryretinopathy.5 Of 27 patients in our series withisolated retinopathy, one had vision in the20/100-20/200 range in one eye; interestingly,the vision in the fellow eye was in the 20/20-20/30 range.

Diabetic retinopathy is considered an increas-ing threat in congenital rubella patients, sincemany develop diabetes mellitus with age.Twenty per cent of Gregg's 1941 study cohorthad developed clinical diabetes at last follow up;diabetic retinopathy appeared in one patient bythe age of 18 months.`9 Although three patientsin the present study had documented diabetes,no diabetic retinopathy was observed.

Like the studies before it, the present reviewunderlines the multiplicity and severity ofdefects in the congenital rubella syndrome.However uncommon the disease has become, itremains a serious and sometimes treatable threatto vision in thousands of patients.This paper was presented in part at the annual meeting of theAssociation for Research in Vision and Ophthalmology, Sarasota,May 1990. Supported in part by NIH Grants EY07701 andEY00331, and the Lucille Ellis Simon Glaucoma Research Fund,Los Angeles, CA, USA.

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2 Gregg NM. Congenital cataract following German measles inthe mother. Trans Ophthalmol Soc Aust 1941; 3: 35-46.

3 Gregg NM. Further observations on congenital defects ininfants following maternal rubella. Trans Ophthalmol SocAust 1944; 4:119-25.

4 Krugman S. Rubella symposium. Am J Dis Child 1965; 110:345.

5 Wolff SM. Rubella syndrome. In: Darrell RW, ed. Viraldiseases of the eye. Philadelphia: Lea & Febiger, 1985: 199-207.

6 Wolff SM. The ocular manifestations of congenital rubella: aprospective study of 328 cases of congenital rubella.J Pediatr Ophthalmol Strabismus 1973; 10:101-4 1.

7 Frank KE, Purnell EW. Subretinal neovascularization follow-ing rubella retinopathy. AmJ7 Ophthalmol 1978; 86: 462-6.

8 Boger WP III. Late ocular complications in congenital rubellasyndrome. Ophthalmology 1980; 87: 1244-52.

9 Sever JL, South MA, Shaver KA. Delayed manifestations ofcongenital rubella. Rev Infect Dis 1985; 7 (suppl): S164-9.

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11 Calvert DR. The rubella epidemic of 1964: problems andresponse. Am Optom Assoc 1%9; 40: 794-8.

12 Harley RD. Discussion comments in: Boniuk V, Boniuk M.The prevalence ofphthisis bulbi as a complication ofcataractsurgery in the congenital rubella syndrome. Trans Am AcadOphthalmol Otol 1970; 74: 360-8.

13 Woodruff ME. Differential effects of the various causes ofdeafnesss on the eyes, refractive errors, and vision ofchildren. AmJ Optom Phys Opt 1986; 63: 668-75.

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18 Zimmerman LE. Histopathologic basis for ocular manifesta-tions of congenital rubella syndrome. Am J Ophthalmol1968; 65: 837-62.

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22 Alfano JE. Ocular aspects of the maternal rubella syndrome.TransAmAcad Ophthalmol Otol 1966; 70: 235-66.

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24 Boniuk V. Systemic and ocular manifestations of the rubellasyndrome. Int Ophthalmol Clin 1972; 12: 67-76.

25 Colfis WJ, Cohen DN. Rubella retinopathy: a progressivedisorder. Arch Ophthalmol 1970; 84: 33-5.

26 Krill AE. Retinopathy secondary to rubella. Int OphthalmolClin 1972; 12: 89-103.

27 Deutman AF, Grizzard WS. Rubella retinopathy and sub-retinal neovascularization. Am Ophthalmol 1978; 85:82-7.

28 Slusher MM, Tyler ME. Rubella retinopathy and subretinalneovascularization. Ann Ophthalmol 1'982; 14: 292-4.

29 Menser MA, Dods L, Harley JD. A twenty-five year follow-upof congenital rubella. Lancet 1967; ii: 1347-50.

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