AMERICAN
JOURNAL
OF
NUMBER 1
VOLUME 109
OPHTHALMOLOGY® JANUARY, 1990
Late Ophthalmologic Manifestations of Neonatal Herpes Simplex Virus Infection Mildred el Azazi, M.D., Gunilla MaIm, M.D., and Marianne Forsgren, M.D. We examined 32 children one to 15 years after virologically verified neonatal herpes simplex virus infection. Sixteen of 17 (94%) neurologically impaired children had ocular abnormalities compared to three of 15 (20%) neurologically healthy children. Disturbed oculomotor control occurred in 14 children (44%), most of whom were among those with severe handicap. Ocular morbidity was present in 13 (40%) of 32 children: one had cataracts, two had corneal scars, seven had optic atrophy, and nine had chorioretinal scars. The clinically silent chorioretinal lesions were manifest as coarse hyperpigmented areas between the equator and ora serrata. One child had suffered from acute fulminant retinitis. Twelve of 13 (93%) severely handicapped children had impaired vision, mainly because of cortical blindness. Less affected children had normal vision unless corneal scars were present. Long-term observation of patients with neonatal herpes infections is essential because ocular manifestations are not rare, and recurrences may be more common than previously reported.
T HE HERPES SIMPLEX VIRUS is an infectious agent that results in manifestations ranging from blis-
Accepted for publication Oct. 20, 1989. From the Departments of Ophthalmology (Dr. el Azazi) and Pediatrics (Dr. Maim), Huddinge University Hospital, Huddinge, and Department of Virology (Dr. Forsgren), Central Microbiological Laboratory, Stockholm County Council, Sweden, This study was supported in part by grants from the Samaritan Foundation and Erco Lakemedel AB. Reprint requests to M. eI Azazi, M.D., Department of Ophthalmology, Danderyds Hospital, S-182 88 Danderyd, Sweden.
©AME!uCAN JOURNAL OF OPHTHALMOLOGY
109:1-7,
JANUARY,
ters to fatal encephalitis. Rare but devastating infections occur in the neonate, in whom 80% of infections are caused by type 2 herpes simplex virus.' Because the frequency of the genital herpes infections is increasing, the incidence of herpes simplex virus infections in the newborn may also be expected to rise.! Because genital herpes in the mother at term is often subclinical or not recognized, prevention is difficult. The clinical manifestations of neonatal herpes include the following"; skin, eye, and mouth disease; central nervous system disease; and the disseminated form of the disease when visceral organs are affected. The latter two forms may also be accompanied by skin, eye, or mouth involvement. Despite antiviral therapy, the disseminated form and localized central nervous system disease have a mortality of approximately 57% and 10%, respectively.' and sequelae occur in survivors. In the acute stage of the neonatal herpes infection, the most frequent ocular symptom is conjunctivitis, often coexisting with keratitis, which is the next most common symptom. After the acute phase, serious complications such as necrotizing retinochoroiditis, cataracts, optic neuritis, and phthisis have been reported! Because few long-term studies's? have been carried out on late ophthalmologic manifestations of neonatal herpes simplex disease, a follow-up study was performed on patients one to 15 years after the infection. We found a much higher incidence of herpetic ocular manifestations than previously reported.v"
Subjects and Methods The records of 45 patients with virologically confirmed neonatal herpes were obtained from 1990
1
2
January, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
the registers of four diagnostic virologic laboratories in Sweden (31 consecutive cases from the Central Microbiological Laboratory of Stockholm and National Bacteriological Laboratory in Stockholm, 1971 to 1986; 14 consecutive cases from the Departments of Virology in Malmo (General Hospital) and Gothenburg (University of Gothenburg), 1981 to 1986. Twelve children died, and the parents of one child refused ophthalmologic examination of their child. The 32 remaining children were examined by one of us (M.A.), except for two patients about whom information was obtained from the primary ophthalmologist. The distribution of type 1 and type 2 herpes simplex infections among the examined children is shown in Table 1, and mean age at examination is shown in the footnote. The medical treatment of the children between 1971 and 1986 had depended on the availability of antiviral drugs (vidarabine, cytosine arabinoside, and acyclovir) and had also included blood exchange, herpes hyperimmune globulin, and interferon. In some patients, no treatment had been given. Visual acuity was assessed with Snellen charts, letter matching tests, preferential looking charts, or simpler tests, such as the ability to follow a penlight. The anterior segment and optical media were examined with a slit lamp when possible, and a magnifying lens was used in other patients. The fundus was examined by indirect ophthalmoscopy with the pupils dilated. The examined children were divided into three groups according to the neurologic sequelae of the neonatal herpes simplex infection as follows: 1, no apparent disease; II, mild neurologic disability or mental disability or both; and
III, severe handicap." A summary of the ophthalmologic findings in the three groups of children is shown in Table 2. Group I consisted of 15 apparently healthy children of both sexes. Two of the patients had not been treated. Fourteen children had normal vision, and 12 had normal eyes. One 13-yearold girl had a unilateral reduction of visual acuity to 20/30 because of a central corneal scar, as well as posterior synechiae and sectorshaped iris atrophy from unilateral recurrent keratitis at the age of 3 years. This patient, treated systemically with 10 rng Zday of cytosine arabinoside for a week, was diagnosed to have a strictured esophagus at the age of 1 year. One 2-year-old boy showed small, circumscribed areas of retinal atrophy with pigmented borders in the temporal equatorial regions of both fundi. Another 13-year-old girl had a small, circumscribed hyperpigmented spot in the nasal periphery of one eye. These three children had suffered from type 1 herpes simplex infections of the disseminated form. Group II included four children with mild neurologic disability or mental retardation. One child had, at the age of 9 years, a reduction of visual acuity to 20/40 in the right eye and 20/30 in the left eye and residual corneal scars because of severe bilateral keratoconjunctivitis as part of a disseminated type 1 infection at the age of 8 days. Other sequelae in this child were exotropia, dissociated vertical deviation, and slight mental retardation. The other children had normal visual acuity. One boy, with a slight spastic hemiparesis after a type 2 meningoencephalitis, showed at the age of 10 years heavily hyperpigmented scars in the peripheral fundi (Figure). None of these children had any iris
TABLE
1
MORBIDITY DATA DISEASE (STATE OF HEALTH)' CENTRAL NERVOUS
SKIN. EYES,
SYSTEM (I
Herpes simplex virus type 2 Herpes simplex virus type 1 Total
7 1 8
3 0 3
DISSEMINATED
MOUTH
III)
(I
III)
(I
10 1 11
0
1
1
3 3
0 1
0 1
3 1 4
0 0 0
III)
TOTAL
%
1 0 1
26 6 32
81 19 100
*1 indicates apparently healthy (mean age, 6 ± 5 years); II, mild neurologic or mental disability or both (mean age, 9 ± 3 years); III, severe neurologic and mental disability (mean age, 5 ± 4 years).
Vol. 109, No.1
Neonatal Herpes Simplex Virus Infection
3
TABLE 2 OPHTHALMOLOGIC DATA DISEASE (STATE OF HEALTH)" CENTRAL NERVOUS
SKIN, EYES,
SYSTEM (I
DISSEMINATED
MOUTH
III)
(I
Corneal scars Cataract Chorioretinal scars
0
0
0
1
1
0 0
0 1
0 5
0 1
Optic atrophy Exotropia Esotropia
0 0
0
0
0
0
0
0 0
1
0
5 8 1
0 0 0 0
0
0
Skew deviation
0
1
7
0
1
0
Tonic deviation
0 0
0 0
6 10
0
0
0
0
0 0 1
Visual acuity < 20/200
1
'I indicates apparently healthy (mean age, 6
1:
III)
(I
0 1 1 1
0
0 1
0
0 0
III)
0 0 0
0 0 0
0 0 0 1 1
0
0 0
1 1
0
1
TOTAL
2 1
6 3 28 22
9 7 11 1
34 3 31 22
10 7 12
5 years); II, mild neurologic or mental disability or both (mean age, 9
%
37 1:
3 years); III,
severe neurologic and mental disability (mean age, 5 ± 4 years).
atrophy or posterior synechiae, One 4-year-old girl with normal fundi had an alternating exotropia and dissociated vertical deviation of her eyes, Only one patient in group II was ophthalmologically normal. Two children had received antiviral treatment. Group III consisted of 13 children who had developed severe neurologic handicaps after neonatal herpes simplex encephalitis, which in
all cases but one were type 2-associated, Three children had not received treatment. All but one of the children were tetraplegic, and all were severely mentally impaired. None of the children was ophthalmologically normal. One girl with mental retardation had, at the age of 15 years, heavily pigmented chorioretinal scars inferiorly in both fundi and in the nasal upper periphery of the right eye, One 5-year-old boy
Figure (el Azazi, MaIm, and Forsgren). Fundus of a 10-year-old boy with mild neurologic disability with clinically silent, pigmented, chorioretinal lesions in the nasal equatorial regions of both eyes and, as shown, in the upper temporal quadrant of the left eye.
4
AMERICAN JOURNAL OF OPHTHALMOLOGY
was blind because of a bilateral necrotizing vitreoretinitis. He had cataracts, optic atrophy, and large retrolenticular calcifications. The visual acuity of the remaining children ranged from 20/400 to total blindness (usually of the cortical type) as tested with the preferential looking method. Six children had pale optic disks. Four of these children also showed pigmentary epithelial disturbances in their peripheral fundi. None of the children had macular lesions. All but one of the children in group III demonstrated overt disturbances of ocular alignment and displayed various kinds of nystagmus. The eye movements of the amaurotic child were not assessed, except for the presence of nystagmus. Seven children demonstrated an intermittent conjugated tonic deviation in the horizontal plane. One child had additional convergent spastic movements. Nine children exhibited an intermittent large angle exotropia, and three of them had earlier been described as esotropic. Only one child showed an esotropia. Seven of these children demonstrated alternating skew deviation, that is, a reproducible vertical dissociation of their eyes during horizontal gaze movements, manifested as an upward torsion of the abducted eye and a simultaneous depression of the adducted eye when looking right or left. Ductions and versions did not suggest any ocular muscle palsy. Responses to oculocephalie maneuvers were not tested. Ophthalmologic data could be extracted from the medical records of an additional three children with the encephalitic form of the neonatal disease. They had died between the ages of 8 months and 6 years. All had severe visual impairment, optic atrophy, as well as peripheral coarse retinal hyperpigmentation with some retinal atrophy; in one eye of one patient, the macula was affected. Two children had tonic gaze deviations. None had a history of uveitis or opacities of the media. The ocular manifestations of neonatal herpes simplex virus disease have been well described by Nahmias and assoctates.F'-" who concluded that ophthalmologic findings occurred in 51 (17%) of the 297 patients examined. They reported an incidence of conjunctivitis in 30 patients (10%), keratitis in 19 (7%), chorioretinitis or chorioretinal scarring in 13 (4.4 %), cataract in three (1 %), and optic atrophy in two (less than 1 %). Their observations referred to the acute and immediate convalescent period, whereas this study addresses the late ophthalmologic sequelae. Even though the most com-
January, 1990
mon ocular herpetic manifestation, conjunctivitis, is not included in this study, the general ocular morbidity was found to be 40% (13 of 32 cases), which may be related to the increased findings of chorioretinal scarring in nine children (28%) and optic atrophy in seven children (22 %). The incidence of phthisis, cataract, and corneal scarring after earlier keratitis did not differ from previous investigations. Our findings, which are in accordance with a recent study," may partly reflect a decreased mortality of the disease with the advance of antiviral therapy, as well as a progression of the disease in the retina. The incidence of corneal scars after previous keratitis in two children (6%) in our relatively small study agrees with that described in previous reports'" on the acute corneal manifestation of the disease. This finding is unexpected because residual scars after acute keratitis are less common than the acute manifestation itself, and recurrent keratitis is rare. Recurrences may, however, occur years later, as in one of our patients. It is evident that useful vision may develop despite the sometimes dramatic appearance of an acute keratitis with totally opaque cornea because of diffuse epithelial and stromal involvement. The lowest visual acuity because of corneal scars was 20/40 in the patients in this study. One patient in this study developed bilateral cataracts as a late complication of fulminant uveitis. The five cases of neonatal herpetic cataracts reported up to 19886,9,11-13 were all associated with previous chorioretinitis, and these cataracts developed several months after the acute phase, as in our patient. The incidence of chorioretinal scars in nine children (28%) is similar to the observations in a recent study" and much higher than the previously reported incidence of acute retinitis." In half of these earlier reported cases,6,9,1I.12,14-18 clinically inactive chorioretinal lesions were documented. The lesions were described as prominent hyperpigmented areas with discrete spots of retinal atrophy located between the equator and ora serrata, often bilaterally. This description is compatible with the retinal scars found in the patients in this study. Because there were no signs or history of antecedent uveitis in our patients or in those reported in the literature, it seems reasonable to assume that the initial herpetic retinal lesion was confined to the retinal pigment epithelium. Immunologic mechanisms and a restricted amount of the intraocular virus may confine the infection
Vol. 109, No.1
Neonatal Herpes Simplex Virus Infection
to a mild involvement of the retinal pigment epithelium and prevent immediate development of acute fulminant retinitis. This ophthalmologic complication of neonatal herpes infection seems to be infrequent. Less than ten cases of active fulminant retinitis have been reported since 1952.6.9.13.14.19-22 In our study, only one patient suffered from the sequelae of necrotizing retinitis. The chorioretinal scars found at a higher rate than previously reported may indicate a long latency of the herpes virus infection within the retina. This may indicate that the patient is at risk for the later development of the acute retinal necrosis syndrome, as was recently observed in a 30-year-old woman (unpublished data). The late appearance of the fundus lesions, usually found in children with encephalitis, may suggest that the virus gains access to the eye from the central nervous system. The obvious route would be the optic nerve or its sheaths. Animal studies of herpes simplex retinitis, however, have shown that viral spread from the brain to the eye may also occur despite transected optic nerves." It is, therefore, tempting to suggest that the virus spreads intraaxonally in the ciliary nerves or by immune complexes by means of ciliary vessels, which could explain the peripheral location of the fundus lesions. In animal studies, herpes simplex virus retinopathies can be induced by both types of the herpes simplex virus, whereas in human neonates the retinopathies have been considered to be exclusively type 2-associated. s In this study, however, we found two cases of chorioretinal scarring among the healthy children infected with type 1 herpes simplex virus, and one case of necrotizing type 1 retinitis has been reported earlier." The most severe visual impairment was found among the children with extensive brain damage, presumably caused by cortical blindness. In more than half of these children, who also had various degrees of optic atrophy, it was not possible to distinguish cortical blindness from visual deterioration caused solely by optic atrophy. Limited attention has been focused on the presence and pathogenesis of optic atrophy in neonatal herpes virus encephalitis.v'
JOURNAL
OF
NUMBER 1
VOLUME 109
OPHTHALMOLOGY® JANUARY, 1990
Late Ophthalmologic Manifestations of Neonatal Herpes Simplex Virus Infection Mildred el Azazi, M.D., Gunilla MaIm, M.D., and Marianne Forsgren, M.D. We examined 32 children one to 15 years after virologically verified neonatal herpes simplex virus infection. Sixteen of 17 (94%) neurologically impaired children had ocular abnormalities compared to three of 15 (20%) neurologically healthy children. Disturbed oculomotor control occurred in 14 children (44%), most of whom were among those with severe handicap. Ocular morbidity was present in 13 (40%) of 32 children: one had cataracts, two had corneal scars, seven had optic atrophy, and nine had chorioretinal scars. The clinically silent chorioretinal lesions were manifest as coarse hyperpigmented areas between the equator and ora serrata. One child had suffered from acute fulminant retinitis. Twelve of 13 (93%) severely handicapped children had impaired vision, mainly because of cortical blindness. Less affected children had normal vision unless corneal scars were present. Long-term observation of patients with neonatal herpes infections is essential because ocular manifestations are not rare, and recurrences may be more common than previously reported.
T HE HERPES SIMPLEX VIRUS is an infectious agent that results in manifestations ranging from blis-
Accepted for publication Oct. 20, 1989. From the Departments of Ophthalmology (Dr. el Azazi) and Pediatrics (Dr. Maim), Huddinge University Hospital, Huddinge, and Department of Virology (Dr. Forsgren), Central Microbiological Laboratory, Stockholm County Council, Sweden, This study was supported in part by grants from the Samaritan Foundation and Erco Lakemedel AB. Reprint requests to M. eI Azazi, M.D., Department of Ophthalmology, Danderyds Hospital, S-182 88 Danderyd, Sweden.
©AME!uCAN JOURNAL OF OPHTHALMOLOGY
109:1-7,
JANUARY,
ters to fatal encephalitis. Rare but devastating infections occur in the neonate, in whom 80% of infections are caused by type 2 herpes simplex virus.' Because the frequency of the genital herpes infections is increasing, the incidence of herpes simplex virus infections in the newborn may also be expected to rise.! Because genital herpes in the mother at term is often subclinical or not recognized, prevention is difficult. The clinical manifestations of neonatal herpes include the following"; skin, eye, and mouth disease; central nervous system disease; and the disseminated form of the disease when visceral organs are affected. The latter two forms may also be accompanied by skin, eye, or mouth involvement. Despite antiviral therapy, the disseminated form and localized central nervous system disease have a mortality of approximately 57% and 10%, respectively.' and sequelae occur in survivors. In the acute stage of the neonatal herpes infection, the most frequent ocular symptom is conjunctivitis, often coexisting with keratitis, which is the next most common symptom. After the acute phase, serious complications such as necrotizing retinochoroiditis, cataracts, optic neuritis, and phthisis have been reported! Because few long-term studies's? have been carried out on late ophthalmologic manifestations of neonatal herpes simplex disease, a follow-up study was performed on patients one to 15 years after the infection. We found a much higher incidence of herpetic ocular manifestations than previously reported.v"
Subjects and Methods The records of 45 patients with virologically confirmed neonatal herpes were obtained from 1990
1
2
January, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
the registers of four diagnostic virologic laboratories in Sweden (31 consecutive cases from the Central Microbiological Laboratory of Stockholm and National Bacteriological Laboratory in Stockholm, 1971 to 1986; 14 consecutive cases from the Departments of Virology in Malmo (General Hospital) and Gothenburg (University of Gothenburg), 1981 to 1986. Twelve children died, and the parents of one child refused ophthalmologic examination of their child. The 32 remaining children were examined by one of us (M.A.), except for two patients about whom information was obtained from the primary ophthalmologist. The distribution of type 1 and type 2 herpes simplex infections among the examined children is shown in Table 1, and mean age at examination is shown in the footnote. The medical treatment of the children between 1971 and 1986 had depended on the availability of antiviral drugs (vidarabine, cytosine arabinoside, and acyclovir) and had also included blood exchange, herpes hyperimmune globulin, and interferon. In some patients, no treatment had been given. Visual acuity was assessed with Snellen charts, letter matching tests, preferential looking charts, or simpler tests, such as the ability to follow a penlight. The anterior segment and optical media were examined with a slit lamp when possible, and a magnifying lens was used in other patients. The fundus was examined by indirect ophthalmoscopy with the pupils dilated. The examined children were divided into three groups according to the neurologic sequelae of the neonatal herpes simplex infection as follows: 1, no apparent disease; II, mild neurologic disability or mental disability or both; and
III, severe handicap." A summary of the ophthalmologic findings in the three groups of children is shown in Table 2. Group I consisted of 15 apparently healthy children of both sexes. Two of the patients had not been treated. Fourteen children had normal vision, and 12 had normal eyes. One 13-yearold girl had a unilateral reduction of visual acuity to 20/30 because of a central corneal scar, as well as posterior synechiae and sectorshaped iris atrophy from unilateral recurrent keratitis at the age of 3 years. This patient, treated systemically with 10 rng Zday of cytosine arabinoside for a week, was diagnosed to have a strictured esophagus at the age of 1 year. One 2-year-old boy showed small, circumscribed areas of retinal atrophy with pigmented borders in the temporal equatorial regions of both fundi. Another 13-year-old girl had a small, circumscribed hyperpigmented spot in the nasal periphery of one eye. These three children had suffered from type 1 herpes simplex infections of the disseminated form. Group II included four children with mild neurologic disability or mental retardation. One child had, at the age of 9 years, a reduction of visual acuity to 20/40 in the right eye and 20/30 in the left eye and residual corneal scars because of severe bilateral keratoconjunctivitis as part of a disseminated type 1 infection at the age of 8 days. Other sequelae in this child were exotropia, dissociated vertical deviation, and slight mental retardation. The other children had normal visual acuity. One boy, with a slight spastic hemiparesis after a type 2 meningoencephalitis, showed at the age of 10 years heavily hyperpigmented scars in the peripheral fundi (Figure). None of these children had any iris
TABLE
1
MORBIDITY DATA DISEASE (STATE OF HEALTH)' CENTRAL NERVOUS
SKIN. EYES,
SYSTEM (I
Herpes simplex virus type 2 Herpes simplex virus type 1 Total
7 1 8
3 0 3
DISSEMINATED
MOUTH
III)
(I
III)
(I
10 1 11
0
1
1
3 3
0 1
0 1
3 1 4
0 0 0
III)
TOTAL
%
1 0 1
26 6 32
81 19 100
*1 indicates apparently healthy (mean age, 6 ± 5 years); II, mild neurologic or mental disability or both (mean age, 9 ± 3 years); III, severe neurologic and mental disability (mean age, 5 ± 4 years).
Vol. 109, No.1
Neonatal Herpes Simplex Virus Infection
3
TABLE 2 OPHTHALMOLOGIC DATA DISEASE (STATE OF HEALTH)" CENTRAL NERVOUS
SKIN, EYES,
SYSTEM (I
DISSEMINATED
MOUTH
III)
(I
Corneal scars Cataract Chorioretinal scars
0
0
0
1
1
0 0
0 1
0 5
0 1
Optic atrophy Exotropia Esotropia
0 0
0
0
0
0
0
0 0
1
0
5 8 1
0 0 0 0
0
0
Skew deviation
0
1
7
0
1
0
Tonic deviation
0 0
0 0
6 10
0
0
0
0
0 0 1
Visual acuity < 20/200
1
'I indicates apparently healthy (mean age, 6
1:
III)
(I
0 1 1 1
0
0 1
0
0 0
III)
0 0 0
0 0 0
0 0 0 1 1
0
0 0
1 1
0
1
TOTAL
2 1
6 3 28 22
9 7 11 1
34 3 31 22
10 7 12
5 years); II, mild neurologic or mental disability or both (mean age, 9
%
37 1:
3 years); III,
severe neurologic and mental disability (mean age, 5 ± 4 years).
atrophy or posterior synechiae, One 4-year-old girl with normal fundi had an alternating exotropia and dissociated vertical deviation of her eyes, Only one patient in group II was ophthalmologically normal. Two children had received antiviral treatment. Group III consisted of 13 children who had developed severe neurologic handicaps after neonatal herpes simplex encephalitis, which in
all cases but one were type 2-associated, Three children had not received treatment. All but one of the children were tetraplegic, and all were severely mentally impaired. None of the children was ophthalmologically normal. One girl with mental retardation had, at the age of 15 years, heavily pigmented chorioretinal scars inferiorly in both fundi and in the nasal upper periphery of the right eye, One 5-year-old boy
Figure (el Azazi, MaIm, and Forsgren). Fundus of a 10-year-old boy with mild neurologic disability with clinically silent, pigmented, chorioretinal lesions in the nasal equatorial regions of both eyes and, as shown, in the upper temporal quadrant of the left eye.
4
AMERICAN JOURNAL OF OPHTHALMOLOGY
was blind because of a bilateral necrotizing vitreoretinitis. He had cataracts, optic atrophy, and large retrolenticular calcifications. The visual acuity of the remaining children ranged from 20/400 to total blindness (usually of the cortical type) as tested with the preferential looking method. Six children had pale optic disks. Four of these children also showed pigmentary epithelial disturbances in their peripheral fundi. None of the children had macular lesions. All but one of the children in group III demonstrated overt disturbances of ocular alignment and displayed various kinds of nystagmus. The eye movements of the amaurotic child were not assessed, except for the presence of nystagmus. Seven children demonstrated an intermittent conjugated tonic deviation in the horizontal plane. One child had additional convergent spastic movements. Nine children exhibited an intermittent large angle exotropia, and three of them had earlier been described as esotropic. Only one child showed an esotropia. Seven of these children demonstrated alternating skew deviation, that is, a reproducible vertical dissociation of their eyes during horizontal gaze movements, manifested as an upward torsion of the abducted eye and a simultaneous depression of the adducted eye when looking right or left. Ductions and versions did not suggest any ocular muscle palsy. Responses to oculocephalie maneuvers were not tested. Ophthalmologic data could be extracted from the medical records of an additional three children with the encephalitic form of the neonatal disease. They had died between the ages of 8 months and 6 years. All had severe visual impairment, optic atrophy, as well as peripheral coarse retinal hyperpigmentation with some retinal atrophy; in one eye of one patient, the macula was affected. Two children had tonic gaze deviations. None had a history of uveitis or opacities of the media. The ocular manifestations of neonatal herpes simplex virus disease have been well described by Nahmias and assoctates.F'-" who concluded that ophthalmologic findings occurred in 51 (17%) of the 297 patients examined. They reported an incidence of conjunctivitis in 30 patients (10%), keratitis in 19 (7%), chorioretinitis or chorioretinal scarring in 13 (4.4 %), cataract in three (1 %), and optic atrophy in two (less than 1 %). Their observations referred to the acute and immediate convalescent period, whereas this study addresses the late ophthalmologic sequelae. Even though the most com-
January, 1990
mon ocular herpetic manifestation, conjunctivitis, is not included in this study, the general ocular morbidity was found to be 40% (13 of 32 cases), which may be related to the increased findings of chorioretinal scarring in nine children (28%) and optic atrophy in seven children (22 %). The incidence of phthisis, cataract, and corneal scarring after earlier keratitis did not differ from previous investigations. Our findings, which are in accordance with a recent study," may partly reflect a decreased mortality of the disease with the advance of antiviral therapy, as well as a progression of the disease in the retina. The incidence of corneal scars after previous keratitis in two children (6%) in our relatively small study agrees with that described in previous reports'" on the acute corneal manifestation of the disease. This finding is unexpected because residual scars after acute keratitis are less common than the acute manifestation itself, and recurrent keratitis is rare. Recurrences may, however, occur years later, as in one of our patients. It is evident that useful vision may develop despite the sometimes dramatic appearance of an acute keratitis with totally opaque cornea because of diffuse epithelial and stromal involvement. The lowest visual acuity because of corneal scars was 20/40 in the patients in this study. One patient in this study developed bilateral cataracts as a late complication of fulminant uveitis. The five cases of neonatal herpetic cataracts reported up to 19886,9,11-13 were all associated with previous chorioretinitis, and these cataracts developed several months after the acute phase, as in our patient. The incidence of chorioretinal scars in nine children (28%) is similar to the observations in a recent study" and much higher than the previously reported incidence of acute retinitis." In half of these earlier reported cases,6,9,1I.12,14-18 clinically inactive chorioretinal lesions were documented. The lesions were described as prominent hyperpigmented areas with discrete spots of retinal atrophy located between the equator and ora serrata, often bilaterally. This description is compatible with the retinal scars found in the patients in this study. Because there were no signs or history of antecedent uveitis in our patients or in those reported in the literature, it seems reasonable to assume that the initial herpetic retinal lesion was confined to the retinal pigment epithelium. Immunologic mechanisms and a restricted amount of the intraocular virus may confine the infection
Vol. 109, No.1
Neonatal Herpes Simplex Virus Infection
to a mild involvement of the retinal pigment epithelium and prevent immediate development of acute fulminant retinitis. This ophthalmologic complication of neonatal herpes infection seems to be infrequent. Less than ten cases of active fulminant retinitis have been reported since 1952.6.9.13.14.19-22 In our study, only one patient suffered from the sequelae of necrotizing retinitis. The chorioretinal scars found at a higher rate than previously reported may indicate a long latency of the herpes virus infection within the retina. This may indicate that the patient is at risk for the later development of the acute retinal necrosis syndrome, as was recently observed in a 30-year-old woman (unpublished data). The late appearance of the fundus lesions, usually found in children with encephalitis, may suggest that the virus gains access to the eye from the central nervous system. The obvious route would be the optic nerve or its sheaths. Animal studies of herpes simplex retinitis, however, have shown that viral spread from the brain to the eye may also occur despite transected optic nerves." It is, therefore, tempting to suggest that the virus spreads intraaxonally in the ciliary nerves or by immune complexes by means of ciliary vessels, which could explain the peripheral location of the fundus lesions. In animal studies, herpes simplex virus retinopathies can be induced by both types of the herpes simplex virus, whereas in human neonates the retinopathies have been considered to be exclusively type 2-associated. s In this study, however, we found two cases of chorioretinal scarring among the healthy children infected with type 1 herpes simplex virus, and one case of necrotizing type 1 retinitis has been reported earlier." The most severe visual impairment was found among the children with extensive brain damage, presumably caused by cortical blindness. In more than half of these children, who also had various degrees of optic atrophy, it was not possible to distinguish cortical blindness from visual deterioration caused solely by optic atrophy. Limited attention has been focused on the presence and pathogenesis of optic atrophy in neonatal herpes virus encephalitis.v'
