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Rubella Cataracts
RUBELLA CATARACTS FURTHER CLINICAL AND VIROLOGIC OBSERVATIONS A. M . M U R P H Y , B . S C , R. R. R E I D , M.B., I R E N E POLLARD, A . I . M . L . T . , A I L S A M . G I L L E S P I E , M . B . , D. C. D O R M A N , P H . D . , MARGARET A . M E N S E R , M.B., J. D. H A R L E Y , M . D . , A N D R. HERTZBERG, M . B . Sydney, Australia
In early 1966, we described the isolation of rubella virus from cataractous material obtained at operation from three infants with the rubella syndrome.1 During that year, other independent reports of this same phenomenon were made.2·3 Subsequently, some of us suggested that exposure to other influences such as drugs may have been a factor in the postnatal development of a cat aract from which rubella virus was later isolated.4 The present report describes the results of a prospective clinical and virologic study of children with cataract formation associated with congenital rubella. MATERIALS AND METHODS PATIENTS
This study has arisen from a survey of the causative factors in childhood cataracts.5 The infants included in the present group are those born since January 1, 1965, who were referred to us with cataract formation which at the time of referral had not been treated surgically, and in whom the clinical and laboratory findings confirmed beyond reasonable doubt a diagnosis of congenital rubella. Of the 23 infants under review, Cases 1, 4 and 14 were noted in a preliminary report of isolation of rubella virus from cataracts at operation,1 Case 10 was described in a report of postnatal formation of rubella cataracts,4 and Cases 16 and 19 were the subjects of reports of renal-artery stenosis in the rubella syndrome."'7 From the Institute of Clinical Pathology and Medical Research, Lidcombe, New South Wales, and the Institute of Pathology and the Children's Medical Research Foundation, Royal Alexandra Hospital for Children, Camperdown, New South Wales, Australia.
The infants were examined physically and ophthalmologically, and appropriate col lections were made for virologic and séro logie studies, including the removal of a sample of venous blood from the mother. In view of the fact that neutralizing antibodies are present in approximately 80% of New South Wales women of child-bearing age,8 it was essential that a distinction be made between passively transferred maternal anti bodies and those produced by the infant. Blood samples were therefore collected from the infants at regular intervals, or as oppor tunity permitted, up to or beyond the age of 12 months. It was assumed on the basis of the observations of Dudgeon and associates8 that the continuing presence of antibody in the infant after the age of six months reflected infection in utero. When possible, at the time of cataract re moval a conjunctival swab, specimen of aqueous humor and specimen of lens tissue were collected in that order. Swabs were placed in 2.0 ml of Hanks balanced salt so lution and lens fragments in 1.0 ml of ster ile physiologic saline before dispatch to the laboratory. All specimens for isolation were kept at 4°C prior to inoculation into RK 13 cell cultures. In two instances specimens of lens tissue were collected at autopsy. These two infants had previous laboratory exam inations during life but died before cataract removal. VIROLOGIC TECHNIQUES
The techniques of virus isolation were as described in the previous paper.1 The RK 13 line of rabbit kidney cells (Glaxo Labo ratories Ltd.) was used exclusively through out this work. Isolates were provisionally classified as rubella virus if a typical cyto-
1109
5/ 5/65
5/ 5/65
5/22/65
6/ 7/65
6/ 7/65
6/12/65
6/27/65
2 (I.P.) Male
3 (A.P.) Female
4 (G.W.) Male
S (J.M.) Female
6 (C.B.) Female
7 (D.G.) Male
g (H.F.) Female
Moderate rubella at 10 wk
Moderate rubella at about six wk
Mild rubella at 2-3 wk
Rubella at about 3wk
Severe rubella at 4 wk
Nil
Nil
Rash at 6 wk gestation
History of Maternal Rubella During Pregnancyt
Classic rubella syndrome
Nil
Classic rubella syndrome
Classic rubella syndrome
Classic rubella syndrome
Microcephaly, retarded develop ment, typical rubella chorioreti nopathy, twin brother (Case 2) affected as above
Microcephaly, retarded develop ment, twin sister (Case 3) simi larly affected plus typical rubella chorioretinopathy
Classic rubella syndrome
Physical Abnormalities in the Infants §
Basis of Clinical Diagnosis of Congenital Rubella
Î
* Abbreviations and symbols: + Rubella virus isolated — Attempted virus isolation unsuccessful LLeft R Right C.S.F. Cerebrospinal fluid P.D.A. Patent ductus arteriosus A11 times were estimated from the presumed time of ovulation. Specimens obtained at autopsy. § For definition of the classical rubella syndrome. See Text.
3 / 9/65
Date of Birth
1 (N.W.) Female
Patient and Sex
TABLE 1
10 17 19
5 7 12
5 g 12
10 12 17
-
—
—
-(L)
+ (R)
+ (L)
+ (R)
- (L)
+ (R)
-
-
-
-
-
Conjunctival Swab
—
-
-
~
—
-
Aqueous Humor
L. iris — C.S.F. -
Other Tissues
128 64
128 128
Child
/Iris — \Vitreous —
256 64
128 64
64
128 64
256 128
32
64
64
64
64
Mother
256
32 32 32
128
128
-(R)
+ (L)
Lens
6 7 g 12
—
Urine
Titer of Neutralizing Antibody
32 64
-
-
Throat Swab
Virus Isolation
9 14
9 12
9 14
Age of Infant when Specimen Collected (mo.)
CLINICAL AND LABORATORY FINDINGS IN INFANTS WITH RUBELLA CATARACTS*
va
o M ω
a w
> o o a K > r S o o
to
c
t—)
*> n > O
M
> S
Rubella at 5 wk
7/27/65
8/25/6S
8/26/65
9/ 8/65
9/ 9/65
9/11/65
11 (G.P.) Female
12 (M.T.) Male
13 (D.W.) Male
14 (R.G.) Male
15 (K.M.) Female
16 (G.H.) Male
Rubella at 1 — 2 wk
Transient rash about time of conception
Rubella in first two wk
Rubella in first mo
No history available
Rubella at 4 wk
7/14/65
10 (D.A.) Female
Rubella during first 4 wk
History of Maternal Rubella During Pregnancyt
7/12/65
Date of Birth
Classic rubella syndrome; renalartery stenosis and deficiency of lymphoid tissue at autopsy.
Microcephaly, mental retardation, ? deafness, bilateral microphthalmos
Classic rubella syndrome
Neonatal to continuing hepatitis; slight microcephaly and mental re tardation
Classic rubella syndrome; agenetic left kidney
Classic rubella syndrome
Classic rubella syndrome
Classic rubella syndrome
Physical Abnormalities in the lnfants§
Basis of Clinical Diagnosis of Congenital Rubella
9 (R.M.) Male
Patient and Sex
7 wk 7 wkî
6 9 11
1 2 9 13
1 wk 2 8 12
4 5 6 8 9 9 9 10 12 15
7 9
8 10 13
3 4 6 8 11
Age of Infant when Specimen Collected (mo.)
+
+
+
—
—
Throat Swab
TABLE 1 (Continued)
—
-
+ + +
Urine
-(L)
-(R)
+ (R) + (L)
+ (R) + (L)
+ (R)
-(L)
Lens
—
—
Conjunctival Swab
Virus Isolation
—
-
Aqueous Humor
Kidney + Bone marrow — Brain — HeartLiver — Vitreous —
Liver —
Other Tissues
64 64 256
64 64
64
512 256
32
512
512 512
256 128
128
256
512
1024
64
64
64
Child
128
64
32
64
256
Mother
Titer of Neutralizing Antibody
P.D.A., deafness, bone lesions
Probable small P . D . A . , slight microcephaly, deafness, bone le sions, syndactyly
Rubella at 8 wk
Rubella at 7 wk
6/25/66
6/28/66
7/ 4/66
7/23/66
20 (A.M.) Male
21 (G.L.) Male
22 (K.W.) Female
23 (D.H.) Male
Nil
P.D.A., thrombocytopenia, haemolytic anemia, bone lesions, death from viral pneumonia; renal-artery stenosis at autopsy
Rubella at about 8 wk
5/15/66
19 (S.C.) Male
P.D.A., ventricular septal defect, bone changes, death from hemorrhagic bronchopneumonia.
Ventricular septal defect, throm bocytopenia, hemolysis, micro cephaly and mental retardation, right microphthalmos
P.D.A. mental retardation, right microphthalmos
Rash at 4 wk
2/24/66
Nil
Physical Abnormalities in the Infants §
18 (A.L.) Female
Nil
History of Maternal Rubella During Pregnancyt
Basis of Clinical Diagnosis of Congenital Rubella
1/21/66
Date of Birth
17 (C.H.) Male
Patient and Sex
1 2
3wk 6
2 4 5 6
8 hrs 8 days 3wk
2 wk 3 4
8 8 14
Age of Infant when Specimen Collected (mo.)
=
+
_
Throat Swab
TABLE 1 (Continued)
-
-
—
(L)
+
-
+Î
+ (R) + (L)
Lens
Conjunctival Swab
Virus Isolation
+
Aqueous Humor
Ad renais+ Brain + Kidneys + Thymus-f Liver — Spleen — Thyroid Lung — Pancreas — Muscle — Rib-
fCord i blood
Lung-f Spleen + HeartLiver — , Thymus -
Other Tissues
64 64Î
64 64
512 512
256
256t
256
64
256
Child
32
128
Mother
Titer of Neutralizing Antibody
Sa
M W
CO
M
w o
Ö
> o to o
H SB
a
o o
>
o a
"—I
H-1
> K w
VOL. 64, NO. 6
RUBELLA CATARACTS
pathic effect was produced. Confirmation was later obtained by neutralization with rabbit rubella antiserum. Isolates differed in their ability to produce a cytopathic effect in cell cultures. Some produced obvious changes on first inoculation but others re quired three or four passages before the majority of cells showed changes. We estimated neutralizing antibodies, using uninactivated sera. Serial twofold dilu tions were made in maintenance medium. To 0.1 ml of each serum dilution was added an equal volume of rubella virus diluted to contain 10 ID 50 . The mixtures were held at 4°C for 18 hours and then added to culture tubes of RK 13 cells which had been seeded six days previously. Cultures were then placed in a roller drum at 36°C. Eight days later, when the virus control tubes showed advanced degeneration, the titrations were read. The end-point was taken as the high est dilution of serum causing 50% or great er reduction in cytopathic effect, compared to the virus control tubes. The virus used in these titrations was the isolate "GW". 10 This virus adapted readily to RK 13 cells causing widespread and reproducible cellu lar degeneration. A positive control serum of known titer was tested with each batch of sera examined. ASSESSMENT OF OPERATIVE RESULTS
For the purpose of this survey, operative results were classified as either good or bad. A good result was one in which a reason ably clear pupil was obtained following sur gery. A bad result was one in which as a re sult of postoperative complications there could be no possibility of effective vision. The fact that subsequent needling of residu al membrane was necessary in Cases 2 and 5 was not regarded as inconsistent with a good surgical result. RESULTS GENERAL CLINICAL AND LABORATORY FEATURES
The general clinical features and labora
1113
tory findings are summarized in Table 1. An infant was regarded as having the clas sic rubella syndrome if in addition to cata ract formation there existed three or more of the following five features : low birth weight ; microcephaly ; retardation of mental or motor development; patent ductus arteriosus or congenital heart disease; deafness. Although mçjit infants suffered from the classic stigmas of congenital rubella, it will be seen that unusual, previously unrecog nized, or recently recognized, manifesta tions of congenital rubella occurred in a substantial number of cases. The diagnosis of congenital rubella was confirmed by re covery of rubella virus from 16 infants, and supported in the remaining cases by the demonstration of appropriate titers of neu tralizing antibody in serum taken from the infant. Brief reference should be made to those infants from whom rubella virus was not isolated. The children in Cases 2 and 3 were twins in whom a diagnosis of congenital rubella was justified by the combination of microcephaly, mental retardation, and cata racts in both ; typical pepper-and-salt rubella chorioretinopathy in Case 3 ; and appropri ate sérologie observations in the mother and both infants. Clinical and sérologie features typical of congenital rubella were observed in Cases 6, 9 and 11. The infant in Case 15 displayed certain clinical features of con genital rubella, plus relatively high titers of rubella neutralizing antibody. Both classic and newly recognized manifestations of con genital rubella occurred in Case 22, again supported by typical sérologie findings. Of the 16 infants from whom rubella virus was isolated, Case 13 was notable for the fact that neonatal, and then continuing, hepatitis constituted the main extraocular finding, and Cases 7 and 17 for the fact that no extraocular abnormality has yet been ob served. Three infants (Cases 16, 19 and 23) with multiple manifestations of congenital rubella died of a fulminating pneumonia; renal-artery stenosis was observed at autop-
1114
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1967
TABLE 2 OCULAR ABNORMALITIES* AND ADDITIONAL CLINICAL FEATURES Patient
Cataract Formation
Micropthalmos
Other Ocular Abnormality
Age when Cataract First Noted
Birth Weight (Kg)
Comment
1 (N.W.)
Bilateral mature
—
—
4 wk
1.68
Ligation of P.D.A.,t neonatal distress, tetracycline, oxygen, digoxin
2 (I.P.)
Bilateral lamellar
—
—
4 mo
2.05
Twin of Case 3, neonatal dis tress, oxygen
3 (A.P.)
Right central opacity, not mature
—
9 mo.
1.90
Twin of Case 2, neonatal dis tress, oxygen
4 (G.W.)
Bilateral dense
—
6 wk
1.93
—
S Ü.M.)
Bilateral dense
—
1.76
—
6 (C.B.)
Bilateral, right more marked than left
—
—
3.10
—
7 (D.G.)
Bilateral
—
—
Soon after birth
2.73
—
8 (H.F.)
Bilateral
—
Soon after birth
2.44
—
9 (R.M.) 10 (D.A.)
Bilateral mature
—
3wk
2.81
—
Bilateral maturing cataracts
Bilateral slight
—
10 wk
2.73
Ligation of P.D.A., oxygen, digoxin, infection prior to first appearance of cataracts
11 (G.P.)
Left mature cataract
Left microphthalmos
4 wk
2.98
—
12 (M.T.)
Bilateral mature cataracts
Soon after birth
3.05
—
13 (D.W.)
Left cataract lamellar at 1 wk, increased at 10 wk, complete at 10 mo.
Soon after birth
2.07
Neonatal hepatitis with jaun dice, treated initially as pos sible bacterial infection with penicillin and kanamycin
14 (R.G.)
Bilateral dense cataracts
Bilateral
—
4 wk
2.36
—
IS (K.M.) 16 (G.H.)
Bilateral mature cataracts
Bilateral and marked
—
Soon after birth
2.58
—
Bilateral, left cen tral dense, right diffuse incomplete
Bilateral
Soon after birth
2.70
17 (C.H.)
Bilateral
12 wk
2.53
—
18 (A.L.)
Right maturing at 1/12, mature at 10/12
4 wk
1.66
Ligation of P.D.A., neonatal distress, oxygen, digoxin
19 (S.C.) 20 (A.M.)
Bilateral complete
—
Soon after birth
2.28
—
Left total
—
11 wk
1.56
Ligation of P.D.A., penicillin, chloramphenicol, oxygen, di goxin, cataract and chorio retinopathy first noted age 11/52, not present previously
Right blocked tear duct
Soon after birth
3.01
—
—
Soon after birth
2.16
—
2.15
Pneumonia at 1 week, convul sion and cyanosis. Treatment with oxygen, erythromycin, kanamycin, penicillin
Bilateral
—
—
— Right
Left marked and diffuse rubella chorioretinopathy
— Bilateral blocked tear ducts
Right chorioreti nopathy
—
— ■ —
21 (G.L.)
Bilateral complete
Bilateral
22 (K.W.)
Right complete
Right
23 (D.H.)
Right central
— Right chorioretinopathy
Soon after birth 6 wk
4 wk
* Unless otherwise indicated, the description was made by the opthalmologist at first examination. t Patent ductus arteriosus.
VOL. 64, NO. 6
RUBELLA CATARACTS
sy in two of these cases, as described previously.6'7 Unusual clinical features noted in the infants who survived include renal agenesis in Case 12, and syndactyly in Case 21.
TABLE 3 AGE OF INFANT WHEN CATARACT FORMATION FIRST NOTED
Age
OCULAR FINDINGS
The ocular findings are summarized in Table 2. Cataract formation was bilateral in 16 of the 23 cases. Typical pepper-and-salt rubella chorioretinopathy was observed in the fellow eye of three of the seven children with unilateral cataract. Microphthalmos was associated with cataract formation in nine of the 23 infants. A striking clinical feature was the rela tively late recognition of cataract formation. The ages at which cataract formation was first recognized are set out in Table 2 and are summarized in Table 3. In only 11 of the 23 cases was the presence of cataracts recognized before the age of four weeks. Postnatal cataract formation was demon strated by repeated ophthalmologic exam ination in two infants (Cases 10 and 20), each of whom sustained an acute illness as sociated with ligation of a patent ductus arteriosus, infection, and administration of ox ygen, digoxin, and multiple antibiotics be fore first evidence of cataract formation. One of these infants (Case 10) has been de scribed in detail previously; 4 the history of the other (Case 20) is outlined later. Although, in the remaining patients, the eyes were not examined by an experienced ophthalmologist during the first month of life, it is perhaps worth noting in Table 2 the pattern observed in Cases 1, 2, 3, 18 and 23, of relatively late recognition of cataract formation in infants of birth weight less than 2.20 kg who suffered from neonatal distress necessitating therapy with oxygen, and drugs such as antibiotics and digoxin. Progressive changes were noted in the cata ract in the left eye of the infant in Case 13. This infant suffered from hepatitis with jaundice and received intensive (but empiri cal) therapy with penicillin and kanamycin during the first week of life.
1115
No. of Infants
Less than Four Weeks 11
Four Six Weeks Three to Six to Nine to Three Months Months Months 10
1
1
ISOLATION OF RUBELLA VIRUS FROM CATARACTS AT OPERATION
Surgical treatment of cataract formation was carried out in 14 infants, all of whom had bilateral cataracts, and 11 of whom had bilateral surgery. The age of the infants at operation, type of operation, frequency of recovery of virus from the lens, and the surgical result are summarized in Table 4. All aspirations were performed by the same surgeon (R. H . ) , whereas the other opera tions were performed by any one of five surgeons (including R. H . ) . An attempt was made to isolate rubella virus from the cataractous material removed at operation from 19 eyes of 13 children. The virus was isolated from 12 eyes of nine children. Their ages at the time of operation ranged from two to 10 months with a mean of 7.3 months in the eyes from which virus was recovered, and from five to 19 months with a mean of 9.9 months in the eyes from which virus could not be recovered; the difference was not statistically significant (P>0.1). Virus was recovered from both eyes in Cases 12, 14 and 17; in Case 4, from the right eye at six months but not from the left eye at eight months of age; and in Case 8, from the right eye at 10 months but not from the left eye at 19 months of age. SURGICAL RESULTS
The results of operation as set out in Table 4 are summarized in Table 5. The surgical result was regarded as good in nine of the 12 eyes from which virus could be isolated, in four of the seven eyes from
1116
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1967
TABLE 4 AGE, TYPE OF OPERATION, RECOVERY OF VIRUS FROM LENS AND SURGICAL RESULT IN INFANTS WHOSE CATARACTS WERE TREATED SURGICALLY Patient 1 (N.W.)
Age a t Operation (mo)
Eye
Type of Operation
Recovery of Virus from Lens
Surgical Result
5 9
Right Left
Aspiration Aspiration
N.T.*
Good Good
9 12 18
Left Right Left
Needled Linear extraction Needled
N.T.
Good Good
4 (G.W.)
6 8
Right Left
Linear extraction Linear extraction
5 (J.M.)
10 12
Right Right
Aspiration Needling
N.T.
6 (C.B.)
5 8
Right Left
Linear extraction Linear extraction
N.T. N.T.
Good Good
7 (D.G.)
5 7
Right Left
Aspiration Aspiration
N.T.
Good Good
8 (H.F.)
10 19
Right Left
Linear extraction Aspiration
9 (R.M.)
3 8
Right Left
Linear extraction Aspiration
10 (D.A.)
8
Right
Discission
Right Left
Aspiration Aspiration
2 (i.p.)
12 (M.T.)
+
N.T. +
Bad Bad
+
Good
+ +
N.T. +
Bad Good Bad Good Good Good Good
14 (R.G.)
2 9
Right Left
Aspiration Aspiration
+ +
Good Bad
15 (K.M.)
6 11
Right Left
Linear extraction Linear extraction
-
Bad Good
17 (C.H.)
8 8
Right Left
Aspiration Aspiration
+ +
Good Good
21 (G.L.)
S
Left
Aspiration
~
Bad
* N.T.—Not tested; no attempt was made to isolate rubella virus from material obtained from the lenses of these eyes. + Rubella virus isolated. ~ Attempted virus isolation unsuccessful. which virus could not be isolated, and in 18 of the total of 25 eyes which were treated surgically. There was thus no evidence from this small group of cases to suggest that the presence of rubella virus in the lens influenced the surgical prognosis. ISOLATION OF RUBELLA VIRUS FROM CATARACTS AT AUTOPSY Rubella virus was isolated from lens re moved at autopsy in Cases 19 and 23, and in
both cases was also obtained at autopsy from other tissues (table 1). Both infants died of a fulminating penumonia. No at tempt was made to isolate rubella virus at autopsy from the lens of the infant in Case 16, who also died of a fulminating pneu monia. The virus had been isolated during life from the infant in Case 19 but not from the infant in Case 23. No surgical treatment of cataract formation was carried out on any of the three infants who died.
VOL. 64, N O . 6 ISOLATION
RUBELLA CATARACTS
OF RUBELLA
SITES OTHER T H A N
VIRUS
1117 TABLE 5
FROM
RELATION OF PRESENCE OF RUBELLA VIRUS TO SURGICAL RESULT
LENS
An interesting feature of the survey was the relative infrequency with which the virus was isolated from sites other than the lens during life. The results of attempted isolation of rubella virus set out in Table 1 are summarized in Table 6. In no case was rubella virus isolated from the conjunctiva, and in only one infant (Case 21) was the virus isolated from the aqueous humor ob tained at operation. The virus was isolated from a pharyngeal swab in five infants, and from urine in two infants. Evidence of per sistence of virus in urine and pharyngeal secretions was obtained in only one infant (Case 12), from whom the virus was ob tained up to the age of 10 months. How ever, the virus was obtained from internal organs at autopsy of the three infants who died : from the kidney in Case 16, from lung and spleen in Case 19, and from adrenals, brain, kidneys and thymus in Case 23. CASE REPORT OF POSTNATAL DEVELOPMENT OF CATARACT FORMATION
Mention has been made above of postna tal development of cataract formation in Cases 10 and 20 of the present group. The infant in Case 10 has already been described in detail.4 The second infant (Case 20) is now considered of sufficient interest to re port as an individual case. This male infant was born on June 25, 1966, at full term, with a birth weight of 1.S6 kg. The mother had suffered from rubella at eight weeks' gestation. Rubella virus was isolated from cord blood obtained from the infant. Physical exam ination revealed a small, dysmature infant with signs of patent ductus arteriosus, and radiologie examination disclosed bony changes consistent with those produced by congenital rubella. Oph-
Number of Lenses Surgical Result
Virus Isolation Attempted Virus isolated
Virus not isolated
Virus Isolation Not Attempted
Good
9
4
5
Bad
3
3
1
thalmologic examination by one of us (R. H.) on June 30, 1966, failed to reveal any evidence of lenticular opacity. Digoxin was commenced on July 25, four days prior to ligation of the ductus arteriosus. The op eration was uneventful but the infant developed a respiratory infection which appeared to respond satisfactorily to a brief period of oxygen therapy and to a short course of penicillin and chloramphenicol. H e was discharged from the hospital on August 19, 1966. The infant was readmitted on August 22 with respiratory distress and was found on radiologie examination to have opacities throughout the right lung. H e was nursed in a humidcrib with up to 50% oxygen for seven days, and received ampicillin from August 22, until September 8, when all treatment was discontinued as he ap peared to have recovered. On September 14, a left cataract was noted in this infant by a medical attendant; when exam ined on September 19 by one of us (R. H . ) , a left total cataract was observed, as well as marked rubella retinopathy, with a clear lens in the right eye. DISCUSSION
The infants with cataracts reviewed here are those in whom a diagnosis of congenital rubella could be established beyond reason able doubt. There thus tended to be a selec tion of those children with multiple mani festations of the rubella syndrome, who could be expected to be severely affected. It
TABLE 6 R E S U L T S OF ATTEMPTED ISOLATIONS OF RUBELLA VIRUS DURING L I F E
(Ratio of number of patients from whom a positive result was obtained/total number of patients examined) Throat Swab
Urine
Lens
5/22
2/18
9/13
Conjunctiva 0/14
Aqueous Humor
Miscellaneous
1/12
1/4
1118
AMERICAN JOURNAL OF OPHTHALMOLOGY
is noteworthy, however, that cataract forma tion was unilateral in no fewer than seven of the 23 infants. A striking feature of the present series was the relative lateness of detection of cat aract formation in 12 infants, six of whom had birthweights in the range 1.50-2.20 kg and sustained stormy episodes in early life requiring therapy with oxygen and drugs. Overall, the mean birthweight of 2.35 kg in the present group was comparable with 2.30 kg found by Gregg in his original series of 78 cases,11 and with that of 2.31 kg calcu lated from a review12 of three recent reports of the congenital rubella syndrome. The possible interaction of low birthweight and chemical agents in the pathogenesis of the inexplicable cataract of childhood has been emphasized previously,5 as has the possible role of chemical factors in the postnatal de velopment of rubella cataracts.4 Although the present series is too small to allow a definitive conclusion, it seems not unreason able to suggest that not only chemical but also nutritional factors may influence the host-virus relationship in such a way as to enhance the cataractogenic effect of rubella virus. Another feature of the present investiga tion was the frequency with which rubella virus was isolated at operation from the cataractous lens, as compared to the frequency of isolation from other tissues. The observa tions are in accord with previous reports of persistent rubella virus in both the cataractous lens1"3'13"15 and in the transparent lens.13 In the present series, the virus was isolated up to 10 months of age, and no significance could be demonstrated between the age at operation in those eyes from which virus was isolated, and the age at op eration in those eyes from which it could not be isolated. The possibility that the virus apparently isolated from the lens was a contaminant from conjunctiva or aqueous virtually has been excluded by the negative cultures almost invariably obtained from these sites.
DECEMBER, 1967
Continued excretion of rubella virus in urine and pharyngeal secretions of congenitally infected infants is well documented. However, the frequency of virus isolation decreases steadily in the first months of life and, in the case of pharyngeal secretions,16 is quite low at six months of age. In our present study the average age at which the first specimens of pharyngeal secretions were obtained was five and a half months, so that the low isolation rate from this source is not unexpected. The majority of isolates from pharyngeal secretions and urine came from Case 9, the only patient whom prolonged, although apparently inter mittent, virus excretion was found. Virus was isolated in this infant up to the age of 10 months. Other congenital rubella syn drome defects, as well as agenesis of the left kidney and possible nephritis," were pres ent. We have suggested previously that the persistence of rubella virus may be a factor in the inexplicably bad results which some times follow surgery of rubella cataracts.1 Contrary to this suggestion, there was no evidence from the present group that the operative results were affected unfavorably by the presence of the virus. It must of course be emphasized that no firm conclu sions can be drawn from this small number of cases, particularly in view of the fact that various surgical techniques were employed by a number of different surgeons. A review of the epidemiology of rubella among nursing staff and patients in contact with these children is proceeding, to deter mine whether infants harboring rubella virus in cataracts may become infectious postoperatively. SUMMARY
1. Ophthalmologic and virologie observa tions of 23 infants with congenital rubella and cataract formation have been reported. 2. In 12 infants cataract formation was detected at or after the age of four weeks. Six of these 12 infants had a birthweight of
VOL. 64, NO. 6
RUBELLA CATARACTS
less than 2.20 kg and sustained episodes of distress, four in the neonatal period and two following ligation of a patent ductus arteriosus. 3. Rubella virus was isolated from cataractous material removed at operation from 12 of 19 eyes. The relative frequency of iso lation was much greater from the lens than from other sites. The possibility of contami nation of lens aspirate from conjunctiva or aqueous humor was virtually excluded. The mean age of the infants for isolation of virus from lens at operation was 7.3 months, with a range of two to 10 months, emphasizing the continuing presence of virus in this tissue. 4. The surgical prognosis did not appear to be affected by the presence of virus in lens. ADDENDUM
Since this paper was submitted for publication rubella virus has been isolated from the cataract ma terial removed at operation from the left eye of a male child aged 2 years and 11 months18 using the same techniques described above. P.O. Box 34 Camperdown, New South Australia
Wales,
2050
ACKNOWLEDGMENTS
We are grateful to Dr. G. Burfitt-Williams, Dr. D. B. Dunlop, Dr. J. W. Hornbrook, Dr. C. J. Housego, and Dr. S. E. L. Stening for referring pa tients; to Dr. K. White and Dr. J. Bishop of the Newcastle Mater Misericordiae Hospital, Dr. N. Rothfield and Dr. J. Müller for providing us with necropsy specimens and other information; to many other colleagues for help with this work; and to Mr. A. G. Baldwin for technical assistance. We would like to thank the DirectorGeneral of Public Health, New South Wales, for permission to publish this paper. REFERENCES
1. Reid, R. R., Murphy, A. M., Gillespie, A. M., Dorman, D. C, Menser, M. A., 'Hertzberg, R. and Harley, J. D. : Isolation of rubella virus from congenital cataracts removed at operation. M. J. Australia 1:540, 1966. 2. Cotlier, E., Fox, J. and Smith, M. : Rubella
1119
virus in the cataractous lens of congenital rubella syndrome. Am. J. Ophth. 62 :233, 1966. 3. Hambidge, K. M., Schaffer, D., Marshall, W. C. and Hayes, K. : Congenital rubella : Report of two cases with generalised infection. Brit. M. J. 5488:650, 1966. 4. Menser, M. A., Harley, J. D., Housego, C. J. and Murphy, A. M. : Possible chemical factors in the postnatal development of rubella cataracts. Lancet, 2 :771, 1966. 5. Harley, J. D. and Hertzberg, R. : Aetiology of cataracts in childhood. Lancet, 1:1084, 1965. 6. Menser, M. A., Dorman, D. C, Reye, R. D. K. and Reid, R. R. : Renal-artery stenosis in the rubella syndrome. Lancet, 1:790, 1966. 7. Menser, M. A., Dorman, D. C, Reye, R. D. K., and Reid, R. R. : Renal-artery stenosis in ru bella. Lancet, 1:571, 1967. 8. Murphy, A. M. : Unpublished observations. 9. Dudgeon, J. A., Butler, N. R. and Plotkin, S. A. : Further serological studies on the rubella syndrome. Brit. M. J. 5402:155, 1964. 10. Murphy, A. M. and Reid, R. R. : A com parison of neutralizing antibodies to rubella virus in gamma globulin and "convalescent" sera M. J. Australia 1:369, 1967. 11. Gregg, N. M. : Congenital cataract follow ing German measles in the mother. Tr. Ophth. Soc. Australia 3 :35, 1941. 12. O'Gorman Hughes, D. W., Parkinson, R., Beveridge, J., Reid, R. R. and Murphy, A. M. : The expanded congenital rubella syndrome : Re port of two cases with neonatal purpura and re view of the recent literature. M. J. Australia 1:420, 1967. 13. Bellanti, J. A., Artenstein, M. S., Olson, L. C, Buescher, E. L., Luhrs, C. E. and Milstead, K. L. : Congenital rubella : Clinicopathologic, virologie, and immunologie studies Am. J. Dis. Child. 110:464,1965. 14. Monif, G. R. G., Avery, G. B., Korones, S. B. and Sever, J. L. : Postmortem isolation of ru bella virus from three children with rubella-syn drome defects. Lancet, 1:723, 1965. 15. Hardy, J. B., Monif, G. R. G., and Sever, J. L. : Studies in congenital rubella, Baltimore 1964-65 : II. Clinical and virologie. Bull. Johns Hopkins Hosp. 118:97, 1966. 16. Lindquist, J. M., Plotkin, S. A., Shaw, L., Gilden, R. V. and Williams, M. L. : Congenital ru bella syndrome as a systemic infection. Studies of affected infants born in Philadelphia, U.S.A. Brit. M. J. 5475:1401, 1965. 17. Menser, M. A., Robertson, S. E. J., Dor man, D. C, Gillespie, A. M. and Murphy, A. M. : Pediatrics (in press). 18. Menser, M. A., Harley, J. D., Hertzberg, R., Dorman, D. C, and Murphy, A. M. : Persistence of Virus in Lens for Three Years After Prenatal Rubella. Lancet, 2:387, 1967.
In early 1966, we described the isolation of rubella virus from cataractous material obtained at operation from three infants with the rubella syndrome.1 During that year, other independent reports of this same phenomenon were made.2·3 Subsequently, some of us suggested that exposure to other influences such as drugs may have been a factor in the postnatal development of a cat aract from which rubella virus was later isolated.4 The present report describes the results of a prospective clinical and virologic study of children with cataract formation associated with congenital rubella. MATERIALS AND METHODS PATIENTS
This study has arisen from a survey of the causative factors in childhood cataracts.5 The infants included in the present group are those born since January 1, 1965, who were referred to us with cataract formation which at the time of referral had not been treated surgically, and in whom the clinical and laboratory findings confirmed beyond reasonable doubt a diagnosis of congenital rubella. Of the 23 infants under review, Cases 1, 4 and 14 were noted in a preliminary report of isolation of rubella virus from cataracts at operation,1 Case 10 was described in a report of postnatal formation of rubella cataracts,4 and Cases 16 and 19 were the subjects of reports of renal-artery stenosis in the rubella syndrome."'7 From the Institute of Clinical Pathology and Medical Research, Lidcombe, New South Wales, and the Institute of Pathology and the Children's Medical Research Foundation, Royal Alexandra Hospital for Children, Camperdown, New South Wales, Australia.
The infants were examined physically and ophthalmologically, and appropriate col lections were made for virologic and séro logie studies, including the removal of a sample of venous blood from the mother. In view of the fact that neutralizing antibodies are present in approximately 80% of New South Wales women of child-bearing age,8 it was essential that a distinction be made between passively transferred maternal anti bodies and those produced by the infant. Blood samples were therefore collected from the infants at regular intervals, or as oppor tunity permitted, up to or beyond the age of 12 months. It was assumed on the basis of the observations of Dudgeon and associates8 that the continuing presence of antibody in the infant after the age of six months reflected infection in utero. When possible, at the time of cataract re moval a conjunctival swab, specimen of aqueous humor and specimen of lens tissue were collected in that order. Swabs were placed in 2.0 ml of Hanks balanced salt so lution and lens fragments in 1.0 ml of ster ile physiologic saline before dispatch to the laboratory. All specimens for isolation were kept at 4°C prior to inoculation into RK 13 cell cultures. In two instances specimens of lens tissue were collected at autopsy. These two infants had previous laboratory exam inations during life but died before cataract removal. VIROLOGIC TECHNIQUES
The techniques of virus isolation were as described in the previous paper.1 The RK 13 line of rabbit kidney cells (Glaxo Labo ratories Ltd.) was used exclusively through out this work. Isolates were provisionally classified as rubella virus if a typical cyto-
1109
5/ 5/65
5/ 5/65
5/22/65
6/ 7/65
6/ 7/65
6/12/65
6/27/65
2 (I.P.) Male
3 (A.P.) Female
4 (G.W.) Male
S (J.M.) Female
6 (C.B.) Female
7 (D.G.) Male
g (H.F.) Female
Moderate rubella at 10 wk
Moderate rubella at about six wk
Mild rubella at 2-3 wk
Rubella at about 3wk
Severe rubella at 4 wk
Nil
Nil
Rash at 6 wk gestation
History of Maternal Rubella During Pregnancyt
Classic rubella syndrome
Nil
Classic rubella syndrome
Classic rubella syndrome
Classic rubella syndrome
Microcephaly, retarded develop ment, typical rubella chorioreti nopathy, twin brother (Case 2) affected as above
Microcephaly, retarded develop ment, twin sister (Case 3) simi larly affected plus typical rubella chorioretinopathy
Classic rubella syndrome
Physical Abnormalities in the Infants §
Basis of Clinical Diagnosis of Congenital Rubella
Î
* Abbreviations and symbols: + Rubella virus isolated — Attempted virus isolation unsuccessful LLeft R Right C.S.F. Cerebrospinal fluid P.D.A. Patent ductus arteriosus A11 times were estimated from the presumed time of ovulation. Specimens obtained at autopsy. § For definition of the classical rubella syndrome. See Text.
3 / 9/65
Date of Birth
1 (N.W.) Female
Patient and Sex
TABLE 1
10 17 19
5 7 12
5 g 12
10 12 17
-
—
—
-(L)
+ (R)
+ (L)
+ (R)
- (L)
+ (R)
-
-
-
-
-
Conjunctival Swab
—
-
-
~
—
-
Aqueous Humor
L. iris — C.S.F. -
Other Tissues
128 64
128 128
Child
/Iris — \Vitreous —
256 64
128 64
64
128 64
256 128
32
64
64
64
64
Mother
256
32 32 32
128
128
-(R)
+ (L)
Lens
6 7 g 12
—
Urine
Titer of Neutralizing Antibody
32 64
-
-
Throat Swab
Virus Isolation
9 14
9 12
9 14
Age of Infant when Specimen Collected (mo.)
CLINICAL AND LABORATORY FINDINGS IN INFANTS WITH RUBELLA CATARACTS*
va
o M ω
a w
> o o a K > r S o o
to
c
t—)
*> n > O
M
> S
Rubella at 5 wk
7/27/65
8/25/6S
8/26/65
9/ 8/65
9/ 9/65
9/11/65
11 (G.P.) Female
12 (M.T.) Male
13 (D.W.) Male
14 (R.G.) Male
15 (K.M.) Female
16 (G.H.) Male
Rubella at 1 — 2 wk
Transient rash about time of conception
Rubella in first two wk
Rubella in first mo
No history available
Rubella at 4 wk
7/14/65
10 (D.A.) Female
Rubella during first 4 wk
History of Maternal Rubella During Pregnancyt
7/12/65
Date of Birth
Classic rubella syndrome; renalartery stenosis and deficiency of lymphoid tissue at autopsy.
Microcephaly, mental retardation, ? deafness, bilateral microphthalmos
Classic rubella syndrome
Neonatal to continuing hepatitis; slight microcephaly and mental re tardation
Classic rubella syndrome; agenetic left kidney
Classic rubella syndrome
Classic rubella syndrome
Classic rubella syndrome
Physical Abnormalities in the lnfants§
Basis of Clinical Diagnosis of Congenital Rubella
9 (R.M.) Male
Patient and Sex
7 wk 7 wkî
6 9 11
1 2 9 13
1 wk 2 8 12
4 5 6 8 9 9 9 10 12 15
7 9
8 10 13
3 4 6 8 11
Age of Infant when Specimen Collected (mo.)
+
+
+
—
—
Throat Swab
TABLE 1 (Continued)
—
-
+ + +
Urine
-(L)
-(R)
+ (R) + (L)
+ (R) + (L)
+ (R)
-(L)
Lens
—
—
Conjunctival Swab
Virus Isolation
—
-
Aqueous Humor
Kidney + Bone marrow — Brain — HeartLiver — Vitreous —
Liver —
Other Tissues
64 64 256
64 64
64
512 256
32
512
512 512
256 128
128
256
512
1024
64
64
64
Child
128
64
32
64
256
Mother
Titer of Neutralizing Antibody
P.D.A., deafness, bone lesions
Probable small P . D . A . , slight microcephaly, deafness, bone le sions, syndactyly
Rubella at 8 wk
Rubella at 7 wk
6/25/66
6/28/66
7/ 4/66
7/23/66
20 (A.M.) Male
21 (G.L.) Male
22 (K.W.) Female
23 (D.H.) Male
Nil
P.D.A., thrombocytopenia, haemolytic anemia, bone lesions, death from viral pneumonia; renal-artery stenosis at autopsy
Rubella at about 8 wk
5/15/66
19 (S.C.) Male
P.D.A., ventricular septal defect, bone changes, death from hemorrhagic bronchopneumonia.
Ventricular septal defect, throm bocytopenia, hemolysis, micro cephaly and mental retardation, right microphthalmos
P.D.A. mental retardation, right microphthalmos
Rash at 4 wk
2/24/66
Nil
Physical Abnormalities in the Infants §
18 (A.L.) Female
Nil
History of Maternal Rubella During Pregnancyt
Basis of Clinical Diagnosis of Congenital Rubella
1/21/66
Date of Birth
17 (C.H.) Male
Patient and Sex
1 2
3wk 6
2 4 5 6
8 hrs 8 days 3wk
2 wk 3 4
8 8 14
Age of Infant when Specimen Collected (mo.)
=
+
_
Throat Swab
TABLE 1 (Continued)
-
-
—
(L)
+
-
+Î
+ (R) + (L)
Lens
Conjunctival Swab
Virus Isolation
+
Aqueous Humor
Ad renais+ Brain + Kidneys + Thymus-f Liver — Spleen — Thyroid Lung — Pancreas — Muscle — Rib-
fCord i blood
Lung-f Spleen + HeartLiver — , Thymus -
Other Tissues
64 64Î
64 64
512 512
256
256t
256
64
256
Child
32
128
Mother
Titer of Neutralizing Antibody
Sa
M W
CO
M
w o
Ö
> o to o
H SB
a
o o
>
o a
"—I
H-1
> K w
VOL. 64, NO. 6
RUBELLA CATARACTS
pathic effect was produced. Confirmation was later obtained by neutralization with rabbit rubella antiserum. Isolates differed in their ability to produce a cytopathic effect in cell cultures. Some produced obvious changes on first inoculation but others re quired three or four passages before the majority of cells showed changes. We estimated neutralizing antibodies, using uninactivated sera. Serial twofold dilu tions were made in maintenance medium. To 0.1 ml of each serum dilution was added an equal volume of rubella virus diluted to contain 10 ID 50 . The mixtures were held at 4°C for 18 hours and then added to culture tubes of RK 13 cells which had been seeded six days previously. Cultures were then placed in a roller drum at 36°C. Eight days later, when the virus control tubes showed advanced degeneration, the titrations were read. The end-point was taken as the high est dilution of serum causing 50% or great er reduction in cytopathic effect, compared to the virus control tubes. The virus used in these titrations was the isolate "GW". 10 This virus adapted readily to RK 13 cells causing widespread and reproducible cellu lar degeneration. A positive control serum of known titer was tested with each batch of sera examined. ASSESSMENT OF OPERATIVE RESULTS
For the purpose of this survey, operative results were classified as either good or bad. A good result was one in which a reason ably clear pupil was obtained following sur gery. A bad result was one in which as a re sult of postoperative complications there could be no possibility of effective vision. The fact that subsequent needling of residu al membrane was necessary in Cases 2 and 5 was not regarded as inconsistent with a good surgical result. RESULTS GENERAL CLINICAL AND LABORATORY FEATURES
The general clinical features and labora
1113
tory findings are summarized in Table 1. An infant was regarded as having the clas sic rubella syndrome if in addition to cata ract formation there existed three or more of the following five features : low birth weight ; microcephaly ; retardation of mental or motor development; patent ductus arteriosus or congenital heart disease; deafness. Although mçjit infants suffered from the classic stigmas of congenital rubella, it will be seen that unusual, previously unrecog nized, or recently recognized, manifesta tions of congenital rubella occurred in a substantial number of cases. The diagnosis of congenital rubella was confirmed by re covery of rubella virus from 16 infants, and supported in the remaining cases by the demonstration of appropriate titers of neu tralizing antibody in serum taken from the infant. Brief reference should be made to those infants from whom rubella virus was not isolated. The children in Cases 2 and 3 were twins in whom a diagnosis of congenital rubella was justified by the combination of microcephaly, mental retardation, and cata racts in both ; typical pepper-and-salt rubella chorioretinopathy in Case 3 ; and appropri ate sérologie observations in the mother and both infants. Clinical and sérologie features typical of congenital rubella were observed in Cases 6, 9 and 11. The infant in Case 15 displayed certain clinical features of con genital rubella, plus relatively high titers of rubella neutralizing antibody. Both classic and newly recognized manifestations of con genital rubella occurred in Case 22, again supported by typical sérologie findings. Of the 16 infants from whom rubella virus was isolated, Case 13 was notable for the fact that neonatal, and then continuing, hepatitis constituted the main extraocular finding, and Cases 7 and 17 for the fact that no extraocular abnormality has yet been ob served. Three infants (Cases 16, 19 and 23) with multiple manifestations of congenital rubella died of a fulminating pneumonia; renal-artery stenosis was observed at autop-
1114
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1967
TABLE 2 OCULAR ABNORMALITIES* AND ADDITIONAL CLINICAL FEATURES Patient
Cataract Formation
Micropthalmos
Other Ocular Abnormality
Age when Cataract First Noted
Birth Weight (Kg)
Comment
1 (N.W.)
Bilateral mature
—
—
4 wk
1.68
Ligation of P.D.A.,t neonatal distress, tetracycline, oxygen, digoxin
2 (I.P.)
Bilateral lamellar
—
—
4 mo
2.05
Twin of Case 3, neonatal dis tress, oxygen
3 (A.P.)
Right central opacity, not mature
—
9 mo.
1.90
Twin of Case 2, neonatal dis tress, oxygen
4 (G.W.)
Bilateral dense
—
6 wk
1.93
—
S Ü.M.)
Bilateral dense
—
1.76
—
6 (C.B.)
Bilateral, right more marked than left
—
—
3.10
—
7 (D.G.)
Bilateral
—
—
Soon after birth
2.73
—
8 (H.F.)
Bilateral
—
Soon after birth
2.44
—
9 (R.M.) 10 (D.A.)
Bilateral mature
—
3wk
2.81
—
Bilateral maturing cataracts
Bilateral slight
—
10 wk
2.73
Ligation of P.D.A., oxygen, digoxin, infection prior to first appearance of cataracts
11 (G.P.)
Left mature cataract
Left microphthalmos
4 wk
2.98
—
12 (M.T.)
Bilateral mature cataracts
Soon after birth
3.05
—
13 (D.W.)
Left cataract lamellar at 1 wk, increased at 10 wk, complete at 10 mo.
Soon after birth
2.07
Neonatal hepatitis with jaun dice, treated initially as pos sible bacterial infection with penicillin and kanamycin
14 (R.G.)
Bilateral dense cataracts
Bilateral
—
4 wk
2.36
—
IS (K.M.) 16 (G.H.)
Bilateral mature cataracts
Bilateral and marked
—
Soon after birth
2.58
—
Bilateral, left cen tral dense, right diffuse incomplete
Bilateral
Soon after birth
2.70
17 (C.H.)
Bilateral
12 wk
2.53
—
18 (A.L.)
Right maturing at 1/12, mature at 10/12
4 wk
1.66
Ligation of P.D.A., neonatal distress, oxygen, digoxin
19 (S.C.) 20 (A.M.)
Bilateral complete
—
Soon after birth
2.28
—
Left total
—
11 wk
1.56
Ligation of P.D.A., penicillin, chloramphenicol, oxygen, di goxin, cataract and chorio retinopathy first noted age 11/52, not present previously
Right blocked tear duct
Soon after birth
3.01
—
—
Soon after birth
2.16
—
2.15
Pneumonia at 1 week, convul sion and cyanosis. Treatment with oxygen, erythromycin, kanamycin, penicillin
Bilateral
—
—
— Right
Left marked and diffuse rubella chorioretinopathy
— Bilateral blocked tear ducts
Right chorioreti nopathy
—
— ■ —
21 (G.L.)
Bilateral complete
Bilateral
22 (K.W.)
Right complete
Right
23 (D.H.)
Right central
— Right chorioretinopathy
Soon after birth 6 wk
4 wk
* Unless otherwise indicated, the description was made by the opthalmologist at first examination. t Patent ductus arteriosus.
VOL. 64, NO. 6
RUBELLA CATARACTS
sy in two of these cases, as described previously.6'7 Unusual clinical features noted in the infants who survived include renal agenesis in Case 12, and syndactyly in Case 21.
TABLE 3 AGE OF INFANT WHEN CATARACT FORMATION FIRST NOTED
Age
OCULAR FINDINGS
The ocular findings are summarized in Table 2. Cataract formation was bilateral in 16 of the 23 cases. Typical pepper-and-salt rubella chorioretinopathy was observed in the fellow eye of three of the seven children with unilateral cataract. Microphthalmos was associated with cataract formation in nine of the 23 infants. A striking clinical feature was the rela tively late recognition of cataract formation. The ages at which cataract formation was first recognized are set out in Table 2 and are summarized in Table 3. In only 11 of the 23 cases was the presence of cataracts recognized before the age of four weeks. Postnatal cataract formation was demon strated by repeated ophthalmologic exam ination in two infants (Cases 10 and 20), each of whom sustained an acute illness as sociated with ligation of a patent ductus arteriosus, infection, and administration of ox ygen, digoxin, and multiple antibiotics be fore first evidence of cataract formation. One of these infants (Case 10) has been de scribed in detail previously; 4 the history of the other (Case 20) is outlined later. Although, in the remaining patients, the eyes were not examined by an experienced ophthalmologist during the first month of life, it is perhaps worth noting in Table 2 the pattern observed in Cases 1, 2, 3, 18 and 23, of relatively late recognition of cataract formation in infants of birth weight less than 2.20 kg who suffered from neonatal distress necessitating therapy with oxygen, and drugs such as antibiotics and digoxin. Progressive changes were noted in the cata ract in the left eye of the infant in Case 13. This infant suffered from hepatitis with jaundice and received intensive (but empiri cal) therapy with penicillin and kanamycin during the first week of life.
1115
No. of Infants
Less than Four Weeks 11
Four Six Weeks Three to Six to Nine to Three Months Months Months 10
1
1
ISOLATION OF RUBELLA VIRUS FROM CATARACTS AT OPERATION
Surgical treatment of cataract formation was carried out in 14 infants, all of whom had bilateral cataracts, and 11 of whom had bilateral surgery. The age of the infants at operation, type of operation, frequency of recovery of virus from the lens, and the surgical result are summarized in Table 4. All aspirations were performed by the same surgeon (R. H . ) , whereas the other opera tions were performed by any one of five surgeons (including R. H . ) . An attempt was made to isolate rubella virus from the cataractous material removed at operation from 19 eyes of 13 children. The virus was isolated from 12 eyes of nine children. Their ages at the time of operation ranged from two to 10 months with a mean of 7.3 months in the eyes from which virus was recovered, and from five to 19 months with a mean of 9.9 months in the eyes from which virus could not be recovered; the difference was not statistically significant (P>0.1). Virus was recovered from both eyes in Cases 12, 14 and 17; in Case 4, from the right eye at six months but not from the left eye at eight months of age; and in Case 8, from the right eye at 10 months but not from the left eye at 19 months of age. SURGICAL RESULTS
The results of operation as set out in Table 4 are summarized in Table 5. The surgical result was regarded as good in nine of the 12 eyes from which virus could be isolated, in four of the seven eyes from
1116
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1967
TABLE 4 AGE, TYPE OF OPERATION, RECOVERY OF VIRUS FROM LENS AND SURGICAL RESULT IN INFANTS WHOSE CATARACTS WERE TREATED SURGICALLY Patient 1 (N.W.)
Age a t Operation (mo)
Eye
Type of Operation
Recovery of Virus from Lens
Surgical Result
5 9
Right Left
Aspiration Aspiration
N.T.*
Good Good
9 12 18
Left Right Left
Needled Linear extraction Needled
N.T.
Good Good
4 (G.W.)
6 8
Right Left
Linear extraction Linear extraction
5 (J.M.)
10 12
Right Right
Aspiration Needling
N.T.
6 (C.B.)
5 8
Right Left
Linear extraction Linear extraction
N.T. N.T.
Good Good
7 (D.G.)
5 7
Right Left
Aspiration Aspiration
N.T.
Good Good
8 (H.F.)
10 19
Right Left
Linear extraction Aspiration
9 (R.M.)
3 8
Right Left
Linear extraction Aspiration
10 (D.A.)
8
Right
Discission
Right Left
Aspiration Aspiration
2 (i.p.)
12 (M.T.)
+
N.T. +
Bad Bad
+
Good
+ +
N.T. +
Bad Good Bad Good Good Good Good
14 (R.G.)
2 9
Right Left
Aspiration Aspiration
+ +
Good Bad
15 (K.M.)
6 11
Right Left
Linear extraction Linear extraction
-
Bad Good
17 (C.H.)
8 8
Right Left
Aspiration Aspiration
+ +
Good Good
21 (G.L.)
S
Left
Aspiration
~
Bad
* N.T.—Not tested; no attempt was made to isolate rubella virus from material obtained from the lenses of these eyes. + Rubella virus isolated. ~ Attempted virus isolation unsuccessful. which virus could not be isolated, and in 18 of the total of 25 eyes which were treated surgically. There was thus no evidence from this small group of cases to suggest that the presence of rubella virus in the lens influenced the surgical prognosis. ISOLATION OF RUBELLA VIRUS FROM CATARACTS AT AUTOPSY Rubella virus was isolated from lens re moved at autopsy in Cases 19 and 23, and in
both cases was also obtained at autopsy from other tissues (table 1). Both infants died of a fulminating penumonia. No at tempt was made to isolate rubella virus at autopsy from the lens of the infant in Case 16, who also died of a fulminating pneu monia. The virus had been isolated during life from the infant in Case 19 but not from the infant in Case 23. No surgical treatment of cataract formation was carried out on any of the three infants who died.
VOL. 64, N O . 6 ISOLATION
RUBELLA CATARACTS
OF RUBELLA
SITES OTHER T H A N
VIRUS
1117 TABLE 5
FROM
RELATION OF PRESENCE OF RUBELLA VIRUS TO SURGICAL RESULT
LENS
An interesting feature of the survey was the relative infrequency with which the virus was isolated from sites other than the lens during life. The results of attempted isolation of rubella virus set out in Table 1 are summarized in Table 6. In no case was rubella virus isolated from the conjunctiva, and in only one infant (Case 21) was the virus isolated from the aqueous humor ob tained at operation. The virus was isolated from a pharyngeal swab in five infants, and from urine in two infants. Evidence of per sistence of virus in urine and pharyngeal secretions was obtained in only one infant (Case 12), from whom the virus was ob tained up to the age of 10 months. How ever, the virus was obtained from internal organs at autopsy of the three infants who died : from the kidney in Case 16, from lung and spleen in Case 19, and from adrenals, brain, kidneys and thymus in Case 23. CASE REPORT OF POSTNATAL DEVELOPMENT OF CATARACT FORMATION
Mention has been made above of postna tal development of cataract formation in Cases 10 and 20 of the present group. The infant in Case 10 has already been described in detail.4 The second infant (Case 20) is now considered of sufficient interest to re port as an individual case. This male infant was born on June 25, 1966, at full term, with a birth weight of 1.S6 kg. The mother had suffered from rubella at eight weeks' gestation. Rubella virus was isolated from cord blood obtained from the infant. Physical exam ination revealed a small, dysmature infant with signs of patent ductus arteriosus, and radiologie examination disclosed bony changes consistent with those produced by congenital rubella. Oph-
Number of Lenses Surgical Result
Virus Isolation Attempted Virus isolated
Virus not isolated
Virus Isolation Not Attempted
Good
9
4
5
Bad
3
3
1
thalmologic examination by one of us (R. H.) on June 30, 1966, failed to reveal any evidence of lenticular opacity. Digoxin was commenced on July 25, four days prior to ligation of the ductus arteriosus. The op eration was uneventful but the infant developed a respiratory infection which appeared to respond satisfactorily to a brief period of oxygen therapy and to a short course of penicillin and chloramphenicol. H e was discharged from the hospital on August 19, 1966. The infant was readmitted on August 22 with respiratory distress and was found on radiologie examination to have opacities throughout the right lung. H e was nursed in a humidcrib with up to 50% oxygen for seven days, and received ampicillin from August 22, until September 8, when all treatment was discontinued as he ap peared to have recovered. On September 14, a left cataract was noted in this infant by a medical attendant; when exam ined on September 19 by one of us (R. H . ) , a left total cataract was observed, as well as marked rubella retinopathy, with a clear lens in the right eye. DISCUSSION
The infants with cataracts reviewed here are those in whom a diagnosis of congenital rubella could be established beyond reason able doubt. There thus tended to be a selec tion of those children with multiple mani festations of the rubella syndrome, who could be expected to be severely affected. It
TABLE 6 R E S U L T S OF ATTEMPTED ISOLATIONS OF RUBELLA VIRUS DURING L I F E
(Ratio of number of patients from whom a positive result was obtained/total number of patients examined) Throat Swab
Urine
Lens
5/22
2/18
9/13
Conjunctiva 0/14
Aqueous Humor
Miscellaneous
1/12
1/4
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AMERICAN JOURNAL OF OPHTHALMOLOGY
is noteworthy, however, that cataract forma tion was unilateral in no fewer than seven of the 23 infants. A striking feature of the present series was the relative lateness of detection of cat aract formation in 12 infants, six of whom had birthweights in the range 1.50-2.20 kg and sustained stormy episodes in early life requiring therapy with oxygen and drugs. Overall, the mean birthweight of 2.35 kg in the present group was comparable with 2.30 kg found by Gregg in his original series of 78 cases,11 and with that of 2.31 kg calcu lated from a review12 of three recent reports of the congenital rubella syndrome. The possible interaction of low birthweight and chemical agents in the pathogenesis of the inexplicable cataract of childhood has been emphasized previously,5 as has the possible role of chemical factors in the postnatal de velopment of rubella cataracts.4 Although the present series is too small to allow a definitive conclusion, it seems not unreason able to suggest that not only chemical but also nutritional factors may influence the host-virus relationship in such a way as to enhance the cataractogenic effect of rubella virus. Another feature of the present investiga tion was the frequency with which rubella virus was isolated at operation from the cataractous lens, as compared to the frequency of isolation from other tissues. The observa tions are in accord with previous reports of persistent rubella virus in both the cataractous lens1"3'13"15 and in the transparent lens.13 In the present series, the virus was isolated up to 10 months of age, and no significance could be demonstrated between the age at operation in those eyes from which virus was isolated, and the age at op eration in those eyes from which it could not be isolated. The possibility that the virus apparently isolated from the lens was a contaminant from conjunctiva or aqueous virtually has been excluded by the negative cultures almost invariably obtained from these sites.
DECEMBER, 1967
Continued excretion of rubella virus in urine and pharyngeal secretions of congenitally infected infants is well documented. However, the frequency of virus isolation decreases steadily in the first months of life and, in the case of pharyngeal secretions,16 is quite low at six months of age. In our present study the average age at which the first specimens of pharyngeal secretions were obtained was five and a half months, so that the low isolation rate from this source is not unexpected. The majority of isolates from pharyngeal secretions and urine came from Case 9, the only patient whom prolonged, although apparently inter mittent, virus excretion was found. Virus was isolated in this infant up to the age of 10 months. Other congenital rubella syn drome defects, as well as agenesis of the left kidney and possible nephritis," were pres ent. We have suggested previously that the persistence of rubella virus may be a factor in the inexplicably bad results which some times follow surgery of rubella cataracts.1 Contrary to this suggestion, there was no evidence from the present group that the operative results were affected unfavorably by the presence of the virus. It must of course be emphasized that no firm conclu sions can be drawn from this small number of cases, particularly in view of the fact that various surgical techniques were employed by a number of different surgeons. A review of the epidemiology of rubella among nursing staff and patients in contact with these children is proceeding, to deter mine whether infants harboring rubella virus in cataracts may become infectious postoperatively. SUMMARY
1. Ophthalmologic and virologie observa tions of 23 infants with congenital rubella and cataract formation have been reported. 2. In 12 infants cataract formation was detected at or after the age of four weeks. Six of these 12 infants had a birthweight of
VOL. 64, NO. 6
RUBELLA CATARACTS
less than 2.20 kg and sustained episodes of distress, four in the neonatal period and two following ligation of a patent ductus arteriosus. 3. Rubella virus was isolated from cataractous material removed at operation from 12 of 19 eyes. The relative frequency of iso lation was much greater from the lens than from other sites. The possibility of contami nation of lens aspirate from conjunctiva or aqueous humor was virtually excluded. The mean age of the infants for isolation of virus from lens at operation was 7.3 months, with a range of two to 10 months, emphasizing the continuing presence of virus in this tissue. 4. The surgical prognosis did not appear to be affected by the presence of virus in lens. ADDENDUM
Since this paper was submitted for publication rubella virus has been isolated from the cataract ma terial removed at operation from the left eye of a male child aged 2 years and 11 months18 using the same techniques described above. P.O. Box 34 Camperdown, New South Australia
Wales,
2050
ACKNOWLEDGMENTS
We are grateful to Dr. G. Burfitt-Williams, Dr. D. B. Dunlop, Dr. J. W. Hornbrook, Dr. C. J. Housego, and Dr. S. E. L. Stening for referring pa tients; to Dr. K. White and Dr. J. Bishop of the Newcastle Mater Misericordiae Hospital, Dr. N. Rothfield and Dr. J. Müller for providing us with necropsy specimens and other information; to many other colleagues for help with this work; and to Mr. A. G. Baldwin for technical assistance. We would like to thank the DirectorGeneral of Public Health, New South Wales, for permission to publish this paper. REFERENCES
1. Reid, R. R., Murphy, A. M., Gillespie, A. M., Dorman, D. C, Menser, M. A., 'Hertzberg, R. and Harley, J. D. : Isolation of rubella virus from congenital cataracts removed at operation. M. J. Australia 1:540, 1966. 2. Cotlier, E., Fox, J. and Smith, M. : Rubella
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virus in the cataractous lens of congenital rubella syndrome. Am. J. Ophth. 62 :233, 1966. 3. Hambidge, K. M., Schaffer, D., Marshall, W. C. and Hayes, K. : Congenital rubella : Report of two cases with generalised infection. Brit. M. J. 5488:650, 1966. 4. Menser, M. A., Harley, J. D., Housego, C. J. and Murphy, A. M. : Possible chemical factors in the postnatal development of rubella cataracts. Lancet, 2 :771, 1966. 5. Harley, J. D. and Hertzberg, R. : Aetiology of cataracts in childhood. Lancet, 1:1084, 1965. 6. Menser, M. A., Dorman, D. C, Reye, R. D. K. and Reid, R. R. : Renal-artery stenosis in the rubella syndrome. Lancet, 1:790, 1966. 7. Menser, M. A., Dorman, D. C, Reye, R. D. K., and Reid, R. R. : Renal-artery stenosis in ru bella. Lancet, 1:571, 1967. 8. Murphy, A. M. : Unpublished observations. 9. Dudgeon, J. A., Butler, N. R. and Plotkin, S. A. : Further serological studies on the rubella syndrome. Brit. M. J. 5402:155, 1964. 10. Murphy, A. M. and Reid, R. R. : A com parison of neutralizing antibodies to rubella virus in gamma globulin and "convalescent" sera M. J. Australia 1:369, 1967. 11. Gregg, N. M. : Congenital cataract follow ing German measles in the mother. Tr. Ophth. Soc. Australia 3 :35, 1941. 12. O'Gorman Hughes, D. W., Parkinson, R., Beveridge, J., Reid, R. R. and Murphy, A. M. : The expanded congenital rubella syndrome : Re port of two cases with neonatal purpura and re view of the recent literature. M. J. Australia 1:420, 1967. 13. Bellanti, J. A., Artenstein, M. S., Olson, L. C, Buescher, E. L., Luhrs, C. E. and Milstead, K. L. : Congenital rubella : Clinicopathologic, virologie, and immunologie studies Am. J. Dis. Child. 110:464,1965. 14. Monif, G. R. G., Avery, G. B., Korones, S. B. and Sever, J. L. : Postmortem isolation of ru bella virus from three children with rubella-syn drome defects. Lancet, 1:723, 1965. 15. Hardy, J. B., Monif, G. R. G., and Sever, J. L. : Studies in congenital rubella, Baltimore 1964-65 : II. Clinical and virologie. Bull. Johns Hopkins Hosp. 118:97, 1966. 16. Lindquist, J. M., Plotkin, S. A., Shaw, L., Gilden, R. V. and Williams, M. L. : Congenital ru bella syndrome as a systemic infection. Studies of affected infants born in Philadelphia, U.S.A. Brit. M. J. 5475:1401, 1965. 17. Menser, M. A., Robertson, S. E. J., Dor man, D. C, Gillespie, A. M. and Murphy, A. M. : Pediatrics (in press). 18. Menser, M. A., Harley, J. D., Hertzberg, R., Dorman, D. C, and Murphy, A. M. : Persistence of Virus in Lens for Three Years After Prenatal Rubella. Lancet, 2:387, 1967.