Eye infections with herpes simplex viruses in neonates

SURVEY OF OPHTHALMOLOGY

VOLUME 21

l

NUMBER 2 *SEPTEMBER-OCTOBER

1976

Eye Infections with Herpes Simplex Viruses in Neonates

A. J. NAHMIAS, M.D., A. M. VISINTINE, L. A. WILSON, M.D.

M.D., D. R. CALDWELL, M.D. AND

Department of Pediatrics and Ophthalmology, Emory University School of Meditine, Atlanta, Georgia, and the Division of Ophthalmology, University of Mississippi Medical Center, Jackson, ibfissksippi A newborn with severe ocular herpes simplex virus (HSV) type 2 infection acquired in utero is presented to exemplify problems in diagnosis and management. A review of 297 newborns with HSV type 1 or type 2 infection reveals that about one-fifth demonstrate ocular involvement including one or more of the following: microphthalmia, conjunctivitis, keratitis, chorioretinitis, optic neuritis and cataracts. (SW Ophthaimol 21:100-105, 1976)

Abstract.

;

heroes simDlex virus viral ocular infections Kev words:

l

keratitis

T

he first case of herpes simplex virus (HSV) infection in a neonate was reported by an Italian ophthalmologist, Batignani, in 1934.’ In this infant with conjunctivitis and keratitis, the virus was demonstrated by inducing keratitis in the rabbit eye with specimens obtained from human herpetic lesions, a technique developed 20 years earlier by Griiter.’ As cases of neonatal HSV infections have been reported in larger numbers over the past decade,e*11~12 so have the number of cases of ocular involvement microphthalmia, conjunctivitis, keratitits, chorioretinitis, and complicating optic neuritis and cataracts. In order to put this subject into perspective, particularly regarding diagnosis and treatment, we are presenting first the case of a newborn with severe ocular involvement, and updating our earlier reviewlo to present current information on this important aspect of neonatal HSV infection.

Case Report A 4 lb. 12 oz. (2150 grams) female was born on September 14, 1974, at 36 weeks 100

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neonatal infections

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gestation to a 33-year-old primiparous woman. Her last menstrual period had been January 14, 1974; the expected date of confinement was October 11, 1974. The father, age 40 years, had had recurrent genital herpetic lesions for approximately 2 years, with recurrences occurring about every 4 to 6 weeks. In June of 1974, he had a recurrence of his lesions and the mother, who was in her 5th month of pregnancy, developed a primary genital herpetic infection with ulcerations on the labia and dysuria. Her genital lesions were present for about 4 weeks; she was treated with proflavine photoinactivation. There was no history of previous oral or genital herpetic infection in the mother. No definite history of recurrence of the maternal genital lesions during the remainder of pregnancy was elicited. On August 31, the mother experienced mild labor pains and was examined by her physician. A diagnosis of false labor was made, and the membranes were said to be intact. Slight vaginal bleeding noted at this time persisted until September 12 when mild labor pains began again. The labor was described

101

EYE INFECTIONS WITH HSV IN NEONATES

FIG.1. Skin vesicles age 3 days. by the mother as long and difficult. She was admitted to the Mississippi Baptist Hospital, Jackson, Mississippi, at noon on September 14, and was delivered of a viable female infant by forceps at 8:OOPM. The membranes were ruptured artificially at the time of delivery; the amniotic fluid was bloody and the placenta was described as friable. The infant appeared mature, but was small for the gestational age; the Apgar scores were 8 and 9. Bilateral cornea1 clouding was noted on the initial physical examination; the tentative diagnosis was bilateral congenital cataracts. The remainder of the physical examination, performed shortly after birth, was within normal limits. At one day of age, a blister developed on the right middle finger. Over the next 48 hours, additional vesicular lesions appeared on the right hand and arm, extending to the shoulder, and on the perineum (Fig. 1). At 3 days of age, detailed ophthalmological examination revealed a membranous conjunctivitis, ulceration, opacification and vascularization of both corneas, and extensive ecchymosis and edema of the upper and lower eyelids (Figs. 2A and B). There were no palpable preauricular lymph nodes. Conjunctival scrapings revealed only occasional Gram positive cocci on Gram stain; on Giemsa stain, a mixed cellular response and eosinophilic intranuclear inclusions were observed. A presumptive diagnosis of neonatal herpes infection was made. Viral cultures of the cor-

nea and conjunctiva taken on September 17 were negative for herpes simplex virus; however, HSV (later typed as HSV-2) was isolated from a vesicle on the arm. The mother had no known active lesions and viral cultures of the breast milk were negative. Therapy with topical IDU ointment 5 times a day, mydriatics and gentamicin (Garamycin@) ointment was begun. Serum immunoglobulins were obtained when the infant was 4 days old; the IgM was 290 mgm%, IgG, 670 mgm% and IgA, 6 mgm%. Cerebrospinal fluid examination at age 6 days showed 7 lymphocytes, the protein was 123 mgm%, and the CSF sugar was reported as normal. Radiologic examinations of the chest and skull were normal.

Hospital Course The infant was afebrile, had good cry, muscle tone and activity. Neurological examination was within normal limits. At six days of age, there had been no improvement in the ocular findings and IDU was changed to 3% adenine arabinoside [(Ara-A), vidarabine (Vira-A)] ointment; within 24 hours clearing of the membranous conjunctivitis had occurred and filling in of the corneal ulcerations had begun. The infant was transferred at 8 days of age to the Henrietta Egleston Hospital for Children in Atlanta, Georgia, for evaluation and possible systemic antiviral therapy.

102

Surv Ophthalmol 21 (2) September-October 1976

Physical examination at the time of transfer was within normal limits, except as follows: there was evidence of old vesicular lesions in various stages of healing with minimal scarring on the right hand and arm, left cheek, and the right side of the back. Small ulcerations were noted along the right anterior edge of the tongue. The spleen tip was palpable 1 cm below the left costal margin; the liver was not enlarged. The eyelids were erythematous with ecchymosis, but no vesicles or ulcerations were present on the eyelids. There was mild injection of the bulbar and palpebral conjunctiva in the left eye (OS), and moderate conjunctival infection in the right (OD) (Figs. 3A and B). The corneas showed opacification bilaterally with 2+ circumcorneal flush. Under magnification, diffuse epithelial and stromal edema was present bilaterally, with a central epithelial defect (ulcer) on the left cor-

NAHMIAS

ET AL

nea. There was a 360° vascular ingrowth bilaterally, more marked in the left cornea. The fundus could not be visualized in either eye. The findings in the right eye were compatible with a postinfectious inflammatory syndrome. The left eye was still involved by active ulceration. Treatment to both eyes included Ara-A ointment q4H, Polymixin B-Bacitracin (Polysporin”) ointment q6H and atropine 1% ointment BID. In addition, dexamethasone (Decadron*) 0.01% solution was instilled in the right eye q6H. After 48 hours, both eyes were much less injected; the cornea OD showed some clearing. By 72 hours, signiticant clearing of the right cornea was apparent, and a red fundal reflex was present. The central scarring OD still precluded funduscopic examination. Resolution of the cornea1 ulcer OS was complete by 72 hours. At this time Poly-

FIG.2. Left, Ocular lesions O.D. age 3 days. Right, Ocular lesions OS. age 3 days.

FIG.3. Left, Ocular lesions O.D. age 8 days. Right, Ocular lesions OS. age 8 days.

103

EYE INFECTIONS WITH HSV IN NEONATES

sporin” was discontinued OU, instillation of DecadrorP 0.01% drops was begun in the left eye (and continued in the right eye). Both Ara-A and atropine 1% ointments were continued OU. On the seventh day after admission, when the infant was 15 days old, vascularization of the periphery of the corneas OU was much decreased. A central cornea1 haze persisted bilaterally, but was greater on the right. No cornea1 ulcerations were seen. Neurological consultation, as well as repeated examination of the cerebrospinal fluid and liver function studies during the hospital stay, showed no evidence of central nervous system or visceral involvement. The infant was active and gained weight. She was discharged from the hospital at 3 weeks of age, on 0.01% Decadron eye drops OU and on Ara-A. On return to Jackson, topical Decadron” q.i.d. and Ara-A q.i.d. were continued for 4 more weeks. At that time, there was marked clearing of the vascularization and cornea1 haze. The latest examination at age 22 months revealed persistent cornea1 scars bilaterally, more prominent on the right. Under indirect ophthalmoscopy, the lens and fundi were clear. The child appeared to have no gross visual defect. Although no recurrences of the keratitis have been noted, the infant has experienced multiple skin recurrences. The child has developed normally with no evidence of neurological sequelae.

Laboratory Studies

time the ophthalmological consdtation was obtained, vesicular skin lesions had appeared. The diagnosis was confirmed by the finding of intranuclear inclusions of cornea1 scrapings and the recovery of HSV from the skin lesions. We cannot explain the inability to isolate the virus from eye cultures obtained at the same time (3rd day). The diagnosis of neonatal HSV should be suspected if a history of genital herpes is obtained in the mother, particularly if it occurs during pregnancy. In this case, the mother experienced a primary genital herpetic infection 16 weeks before premature delivery. The infant therefore must have acquired transplacental IgG HSV antibodies, as demonstrated by laboratory testing (Table 1). The presence of the severe cornea1 lesions at birth, the marked elevation of serum IgM at 4 days and the high titers of serum IgM HSV antibodies by the 8th day (when these were first tested) suggested strongly an intrauterine infection, probably acquired 2 or more weeks prior to birth, perhaps at the time of a false labor episode 2 weeks before delivery. It is not possible to state whether the intrauterine infection was acquired transplacentally or via an ascending infection. However, wc would have expected to note signs of disseminated disease if viral transmission had occurred transplacentally at the time the mother experienced her genital infection. These clinical and laboratory findings influenced greatly our decision regarding possiTABLE1 Indirect

Fluorescent Antibody Antibodies

Herpes simplex virus type 2 was cultured from the infant’s skin lesions at 8 days of age. Cultures of the right and left eyes and mouth Infant at 8 and I1 days of age were negative for HSV. Cultures of a rectal swab, as well as Age 9 days urine at 12 and 15 days of age, and of cerebro12 days spinal fluid at 8, 12, 17 and 20 days of age, 3 mos. were also negative for HSV. 4 mos. Vaginal cultures obtained on the mother 8 and 20 days postpartum did not grow HSV. CSF 9 days Results of serologic studies on mother and 20 days infant are presented in Table 1.

Discussion HSV ocular involvement in newborns is often misdiagnosed, particularly if only conjunctivitis is present and if skin or oral lesions are absent. In this case, the initial impression was congenital cataracts, although by the

Mother Days post-partum 8 days

3 mos. 4 mos. *QNS for titration N.T. = not tested

IgM

Tests for

Serum L@

HSV

LiG!

? 1:32 1:4 1:4 1:16

>1:128 >1:1024 >I:64 > 1:64

<1:4 <1:4 <1:4 <1:4

0

+*

0

+*

N.T. 0

<1:4 1:8 1:4

I:128 154 I:32

<1:4
104

SurvOphthalmol 21 (2) September-October 1976

NAHMIAS

ET AL

TABLE2 Ocular Manifestations

Category

No. cases neonatal HSV infections

According

No. with one or more ocular manifestaConjunctions tivitis

to Type of Neonatal

Keratitis

Chorioretinitis

HSV Infection

Cataracts

Optic atrophy

Microphthalmia

I. Disseminated A. B. Without With CNS* CNS* I I. Localized

98 96

17 2

A. CNS*

51 43 3 6

12

14 0 6

297

51

30

B. Skin C. Mouth D. Eye TOTAL

11 2

04

04

:,

:,

0

8

5

4

0

0

1

6 0 3

7 0 3

3 0 2

1 0 1

1 0 0

0 0 0

19

13

3

2

2

*may also have associated skin or oral lesions.

ble systemic therapy with adenine arabinoside.g We postulated that in the absence of clinical or laboratory signs of disseminated herpetic involvement (liver, adrenals, shock, etc.,&ll+l2) the child was not likely to develop that condition, which has an average incubation period of 6 days, ranging up to 21 days.O There was still a possibility of CNS involvement, since the average incubation period is 12 days, ranging up to 28 days? It was therefore decided to treat initially with topical eye therapy only, and reserve systemic therapy in case neurological manifestations appeared. In a recently reported case of congenital herpetic keratitist topical IDU and systemic administration of Ara-A for 10 days were not sufficient to cause healing of the cornea1 lesions; only after topical Ara-A was used did the cornea1 lesions clear. It is not possible to ascertain whether topical Ara-A was indeed superior to IDU in our case. However, there was rapid clearing of the membranous conjunctivitis after the Ara-A was administered. Although the use of topical corticosteroids under cover of an antiviral drug is still controversial, because of the inability to recover the virus from the eyes on the 8th day and the deep inflammatory reactions, DecadrorP was instilled at low concentrations first in the right eye, which had no further ulcers, and then in both eyes when the ulcer in the left eye resolved. The sequelae of ocular involvement in newborns (Table 2) have included chorioretinitis, cataracts and optic neuritis.@JO Fortunately, this infant did not demonstrate any of these sequelae. In addition, no subclinical CNS in-

volvement has been revealed on neurological follow-up. Table 2 presents the ocular manifestations noted among 297 cases of neonatal HSV infections according to the type of infection; thus 5 1 newborns (17%) demonstrated ocular involvement. Combined involvement, e.g. keratitis and conjunctivitis, occurred bilaterally or unilaterally in several of the cases. In addition, some infants manifested cataracts, chorioretinitis or optic atrophy late after birth. Such ocular involvement, as well as cornea1 scars or recurrent keratitis represent important ocular sequelae. Microphthalmia, keratitis or conjunctivitis were noted within the first day of life in a few instances. In general, the ocular manifestations were noted from 2 days to 2 weeks after birth and occurred as either the first manifestation of the herpetic infection or after skin, disseminated or CNS disease had been noted. The clinicopathological descriptions of each of the types of neonatal ocular manifestations and their pathogenesis are outlined in our earlier review. lo (Newer cases are listed in the references.) Several observations are of particular interest. (1) Although the conjunctivitis and keratitis observed in newborns are not much different from those found in older children or adults, cataracts and chorioretinitis (except for one case’*) have not been recorded in older individuals. (2) The cases of neonatal chorioretinitis in which viral cultures were typed were all HSV-2. An untyped HSV was recovered from the lens of an infant with cataracts since the age of 6 months.’ It should be stressed that about 30%

105

EYE INFECTIONS WITH HSV IN NEONATES

TABLE3 HSV

Type in Neonatal Cases Associated Ocular involvement

HSV-2HSV-I Disseminated with or without encephalitis + chorioretinitis CNS + chorioretinitis

4 2

; 0

3 0 1 0 4 0 2 0

16

10

2

2 4

Skin + chorioretinitis Eye + chorioretinitis

with HSV untyped

5 2 2

0 2 2 2

1 16

of neonatal HSV infections are HSV-l;‘* of the cases with ocular involvement, in which the virus was typed, 39% were HSV-1 (Table 3). (3) Silver nitrate used for gonococcal prophylaxis in newborns has been found in the laboratory to be more effective for HSV-1 than HSV-2.1B In view of this observation and the likelihood that the eye is the portal of entry of HSV in a few cases, we have recommended prophylactic antiviral therapy to both eyes in cases of newborns born to women with genital herpes at delivery.

References 1. Batignani A: Conjunctivite da virus erpetico in neonato. Boll Ocul (Bologna) 13:1217-1220, 1934 2. Bobo CB, Antine B, Manos JP: Neonatal herpes simplex infection limited to the cornea. Arch Ophthahnol 84:697-698, 1970 3. Chien LT, Whitley RJ, Nahmias AJ, et al: Antiviral chemotherapy and neonatal herpes simplex virus infection: a pilot study - experience with adenine arabinoside (Ara-A). Pediatrics 55(5): 678-685, 1975 4. Cibis A, Burde R: Herpes simplex virusinduced congenital cataracts. Arch Ophthalmol 85:220-223, 1971 5. Gershon A, Fish I, Brunell P: Herpes simplex infection of the newborn. Am J Dis Child 124:739-741, 1972 6. Golden B, Bell WE, McKee AP: Disseminated herpes simplex with encephalitis in a neonate: treatment with idoxuridine. JAMA 209:1219-1221, 1969 7. Griiter W: Das Herpesvirus, seine atiologische

Munch Med und klinische Bedeutung. Wochenschr 71:1058, 1924 8. Hutchinson DS, Smith RE, Haughton PB: Congenital herpetic keratitis. Arch Ophthalmol, 93:70-73, 1975 9. Nahmias A, Alford C, Korones S: Infection of the newborn with Herpesvirus hominis. In Advances in Pediatrics I Schulman (ed), 1970, pp 185-226 10. Nahmias A, Hagler W: Ocular manifestations of herpes simplex in the newborn. Int Ophthalmol Clin 12:191-213, 1972 11. Nahmias AJ, Visintine AM: Perinatal herpes simplex virus infection, in Remington J, Klein, JO (eds): infections of the Fetus and Newborn Infant, Philadelphia, Saunders, 1976 (in press) 12. Nahmias AJ, Visintine AM, Reimer CB, et al: Herpes simplex virus infection of the fetus and newborn, in Krugman S, Gershon A (eds): Infections of the Fetus and Newborn Infant, Progress in Clinical and Biological Research, Vol3, New York, Alan R Liss Inc, 1975, pp 63-77 D, Brockhurst RJ: Herpes 13. Pavan-Langston simplex panuveitis. Arch Ophthalmol 81: 783-787, 1969 14. Pettay 0, Leinikki P, Donner M, Lapinleimu K: Herpes simplex virus infection in the newborn. Arch Dis Child 47:97-103, 1972 15. Pierson RB, Kirkham TH: Neonatal keratitis due to herpesvirus hominis type 1 infection. Can J Ophthalmol 9:429-431, 1974 M, Coleman V, 16. Wilkie JS, Easterbrook Stevens T: Crede prophylaxis and neonatal cornea1 infection with herpesvirus. Arch Ophtbalmol 91:386-388, 1974 17. Winkler K: Herpes simplex encephalitis bei einem Bruhgeborenen mit bolligem Fehlen des Immunglobulins IgA. Bd Heft 3:87, 1969 New references of neonatal herpes with ocular involvement since our earlier review in 1972 (10) include references 2, 3, 5, 6, 8, 14, 15, 17 and unpublished observations by several investigators and our group.

Supported by a grant from the National Foundation, March of Dimes and by the Cricket Fund for the Study of Perinatal Infections. Reprint requests should be addressed to: Dr. A. Nahmias, Division of Infectious Diseases and Immunology, Department of Pediatrics, Emory University School of Medicine, 69 Butler Street S.E., Atlanta, Ga. 30303