Outcome in Children With
Symptomatic Congenital Cytomegalovirus Infection James F. Bale, Jr, MD; James A. Blackman, MD, MPH; Yutaka Sato, MD
Abstract To determine factors that
are associated with adverse developmental outcome after congenital cytomegalovirus infection, reviewed the clinical, laboratory, and radiographic findings in 18 children with symptomatic congenital cytomegalovirus infections. When children with adverse outcomes (intelligence or developmental quotients of 50 or less, n 10) were with no with children mild or of 70 or n we found 8), compared sequelae (intelligence developmental quotients higher, relationship between developmental outcome and neonatal clinical features (birth weight, jaundice, hepatomegaly, splenomegaly, or petechiae). With the possible exception of intracranial calcifications, no single clinical or radiographic feature was associated with a specific developmental outcome. However, children who had postnatal microcephaly, postnatal seizures, and an abnormal central nervous system imaging study were more likely to have severe developmental sequelae. ( JChild Neurol 1989;4:131-136). we
=
=
and 2.0% of all newborn infants Bin the United States and other developed countries excrete cytomegalovirus in their urine. 1-4 The majority of these virus-excreting infants, approximately 80% to 90%, have no signs at birth attributable to cytomegalovirus. Although some silently infected infants will later exhibit sensorineural hearing loss, these infants are not at risk for other
etween 0.5%
neurodevelopmental disabilities.5-’ The remaining infants, approximately 10% of
cytomegalovirus-excreting newborns, exhibit signs of infection at birth consisting of petechiae, jaundice, hepatosplenomegaly, microcephaly, or chorioretinitis.8 Previous longitudinal studies indicate that the majority of these symptomatic infants will have per-
or intellectual disabilities.9-12 further the clinical, laboratory, or To identify that are associated with adverse features radiographic in infants with outcome symptomatic congenital
manent
visual, motor,
Received Jan 26, 1989. Received revised April 24, 1989. for publication May 3, 1989. From the Departments of Pediatrics, Neurology, and Radiology, The University of Iowa College of Medicine, Iowa City, IA. Presented in part at the 17th Annual Meeting of the Child Neurology Society, Halifax, Nova Scotia, September 1988. Address correspondence to Dr James F. Bale, Jr, Division of Pediatric Neurology, Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242.
Accepted
cytomegalovirus infections, we reviewed the records of 18 such children seen during a 13-year period at the University of Iowa. Methods Patient Population Eighteen children with symptomatic congenital cytomegalovirus infection were identified by a computer-assisted search of the medical records of the University of Iowa Hospitals and Clinics between January 1, 1975, and December 31, 1987. Six patients were seen in the interval from 1975 through 1980, whereas 12 patients were seen after January 1, 1981. The children ranged in age from 1 day to 23 years at the time of their initial evaluation. Twelve children were evaluated here during the neonatal period (within the first month of life). Ten children (56%) were female, and 17 (94%) were white. Medical records were directly reviewed by us to retrieve clinical data. Cytomegalovirus infection was confirmed by culture of virus from urine (15 children), identification of urinary inclusion bodies (2 children), or serologic responses (1 child). All children had one or more of the following signs of cytomegalovirus infection at birth: jaundice, hepatomegaly, spleno-
megaly, petechiae, thrombocytopenia, microcephaly, 131
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TABLE 1
Summary of Clinical and Radiographic Features in Children with IQ or DQ of 50 or Less
IQ
=
intelligence quotient; DQ developmental quotient; + tomography; ND = no data; MRI =
sonogram; CT computed * At follow-up evaluation. =
and chorioretinitis. Sixteen children had one of these clinical features.
more
=
=
feature present; -
magnetic
than
were
Seventeen children
were
studied
using
various
neuroimaging methods, including plain skull radiography (8 children), head sonography (8 children), computed tomography (11 children), and magnetic resonance imaging (2 children). Eleven were studied
during the neonatal period. Computed tomographic results from five children and magnetic resonance from two children were described imaging results 13,14 but no outcome data were available at previously, the time of those reports. Imaging studies were reviewed by one radiologist (Y.S.) who was unaware of the clinical or laboratory features and developmental outcome of the children.
feature absent; SR
=
skull
radiograph;
US
=
head
imaging.
outcome of the two other children
was
obtained
interview. Where standardized test
phone
Imaging Studies
=
resonance
unavailable,
a
by
scores
developmental quotient
was
derived by dividing the child’s performance age by the chronological age or age adjusted for prematurity. In addition, all children have been evaluated and served by Iowa’s Area Education Agencies, a statewide comprehensive program for disabled children. Audiometric evaluation was obtained on 13 children using behavioral audiometry or measuring brain stem auditory evoked responses. Statistical Analysis Frequency data were compared using Fisher’s exact test, and continuous variables were analyzed by a two-tailed Student’s t test. P values less than .05 were considered significant.
Results
Assessment of Outcome
Neurodevelopmental children during routine follow-up outcome
was
assessed in 16
examinations. In-
struments administered to the children included the
Bayley Scales of Infant Development, Stanford-Binet, Wechsler Intelligence Scales for Children, and the Hiskey-Nebraska Test of Learning Aptitude for hearing-impaired children. Information regarding the
Neurodevelopmental 37 months (range 10
assessment at
months to 23
median age of years) indicated broad range of 10) consisted of a
that the 18 children exhibited a neurologic sequelae. One group (n children who had adverse developmental outcomes (intelligence or developmental quotients of 50 or less) (Table 1). Eight of these children (80%) do not walk,
132
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on May 27, 2015
=
TABLE 2
Summary of Clinical and Radiographic Features in Children with IQ or DQ of 70 or Higher
IQ
=
US * At
intelligence quotient; DQ developmental quotient; + feature present; - feature absent; SR head sonogram; CT computed tomography; MRI magnetic resonance imaging. follow-up evaluation.
=
=
=
=
=
=
skull
radiograph; ND
=
no
data;
=
and
seven (70%) have not developed recognizable speech. Eight (80%) have postnatal microcephaly (occipitofrontal head circumference lower than 2 standard deviations below the mean for age). Nine (90%) of the adversely affected children have had postnatal seizures, reported at a median
age of 12 months. The seizure types consisted of generalized tonic-clonic or tonic (4 children), focal (3 children), and infantile spasms or minor motor seizures (2 children). Seizure frequency varied from a single, generalized tonic-clonic episode (case 6) to multiple, daily myoclonic seizures. Eight children were treated with anticonvulsant medications. The second group (n = 8) consisted of children who were normal or had mild intellectual or developmental sequelae (Table 2). Intelligence quotients and/ or developmental quotients among these children were 70 or higher. Four of these children (50%) have postnatal microcephaly (P .20 when compared with children with severe developmental sequelae), but only one (13%) has a seizure disorder (P = .002 when compared with children with severe sequelae). Table 3 compares the relationship of outcome to the presence of various clinical signs during the neonatal period. We observed a trend toward a longer mean gestational age in children with intelligence or developmental quotients of 50 or less (P .065). Otherwise, we found no differences between the two outcome groups with regard to birth weight =
=
TABLE 3
Proportion of Cytomegalovirus-Infected Infants with Abnormal Physical Signs in the Neonatal Period
*P
=
.065
by
t test; P values in all other
categories were
>
.10.
the
frequency of neonatal jaundice, hepatomegaly, petechiae, retinitis, microcephaly at birth, or neonatal seizures. The proportion of infants whose birth weights were appropriate for gestational age was also similar in the two groups (4/8 [50%] for children with intelligence or developmental quotients of 70 or higher versus 7/10 [70%] for children with severe developmental sequelae, P .35). Although laboratory studies were not available for all children, severe thrombocytopenia (platelet count < 25,000/mm3) was somewhat more frequent or
=
133
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Discussion In this report, we retrospectively examined the relationship between developmental outcome and the clinical and radiographic features in children with symptomatic congenital cytomegalovirus infections. Such children have varying degrees of neurologic sequelae and can be segregated into two groups with respect to outcome, those who have mild neuro-
TABLE 4
Proportion of Cytomegalovirus-Infected Infants with Abnormal Neuroimaging Studies
* P
tP P
=
=
=
.074, Fisher .278, Fisher .145, Fisher
exact test. exact test. exact test. z
children with intelligence or developmental quotients of 70 or higher (6 of 8 [75% ] children versus only 1 of 6 [17%] severely affected children, P .051). Otherwise, we found no differences in the frequency of mild thrombocytopenia, elevated aspartate aminotransferase (> 100 IU), or hyperbilirubinemia (> 10 mg/dL). Seventeen children were studied using one or more neuroimaging techniques (Tables 1 and 2). The average number of imaging studies was 1.6/child for children with an intelligence or developmental quotients of 50 or less and 1.6/child for those with 70 or above. Abnormalities identified in association with symptomatic cytomegalovirus infections included intracranial calcifications, periventricular cysts, ventricular dilation, hydrocephalus, hemorrhage, infarc-
in
=
tion,
or
porencephaly.
When the results of imaging studies were compared with developmental outcome (Table 4), a higher proportion of children with adverse outcomes had abnormal skull radiographs or head sonograms. Overall, a somewhat higher but not statistically significant proportion of children with adverse outcomes had abnormal imaging studies. Eight of the 10 children with intelligence or developmental scores of 50 or less had at least one abnormal imaging study versus 3 of 7 children with more favorable outcomes (P = .14). However, normal imaging studies were not uniformly associated with favorable developmental outcomes, as illustrated by cases 6 and 10. Specific developmental outcomes did not relate to a single clinical, laboratory, or radiographic feature. However, with one exception (case 6), the combination of postnatal microcephaly, postnatal seizures, and an abnormal imaging study was associated with severe
developmental sequelae.
developmental sequelae (intelligence or developmental quotients of 70 or higher) and those who are severely affected (intelligence or developmental quotients of 50 or less). When outcome groups are compared according to the frequency of various neonatal clinical features, we observed, as did Conboy and coworkers,11 that the presence or severity of the reticuloendothelial involvement, as assessed by physical and laboratory findings, does not have a strong relationship with subsequent neurologic outcome. Although we did not find that the frequency of neonatal seizures or microcephaly at birth differed statistically between the two groups of children, microcephaly or seizures were more likely to be identified subsequently in children with severe developmental sequelae. This finding supports prior observations indicating that the appearance of neurologic abnormalities during the first year of life heralds long-term neurodevelopmental disabilities.11,12 Nine of the 10 children with adverse developmental outcomes in this series had postnatal seizures, first reported at a median age of 12 months. In contrast to a prior report that found a strong correlation between chorioretinitis and low intelligence,11 we did not observe that the frequency of chorioretinitis differed between children in the two outcome groups. Selection bias could account for our failure to identify this relationship, because relatively fewer children in the present study were functioning in the average or above-average intellectual range. However, cases 14 and 16 in this study and an intellectually normal child with chorioretinitis reported previously by Berenberg and Nankervis 12 suggest that the presence of chorioretinitis may not preclude a favorable intellectual outcome in infants with symptomatic congenital cytomegalovirus infections. Several different modalities-ultrasonography, computed tomography, and magnetic resonancecan be used to image infants with proven or suspected congenital cytomegalovirus infections. However, prospective studies comparing the sensitivity of these techniques in cytomegalovirus-infected children have not, to our knowledge, been published. Cranial ultrasonography effectively detects periventricular lesions, including calcifications, and can be performed at the
134
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bedside in unstable infants. 15 Although magnetic resonance generally has superior sensitivity, unenhanced computed tomography 13 detects intracranial calcifications more effectively than magnetic resonance and provides sufficient information regarding cerebral and cerebellar pathology. Plain skull radiography, an insensitive technique,16 should be abandoned as an imaging method for children with suspected cytomegalovirus-induced central nervous system lesions. When outcome in this case series was compared with the results of imaging studies (Table 4), a higher proportion of children with adverse outcomes had abnormal skull radiographs or head sonograms. In addition, a somewhat higher proportion of children with adverse outcomes had at least one abnormal imaging study (8 of 10 [80%] versus 3 of 7 [42%], P .14), but not all children were studied by equivalent modalities. We emphasize that symptomatic cytomegalovirus-infected infants can have adverse developmental outcomes despite normal imaging studies. We believe that the character of the imaging abnormalities may have an important relationship with subsequent outcome. For example, only 1 of the 4 children with identified calcifications has progressed beyond the 5-month performance level. This contrasts with the mild delays experienced by one child with an occipital infarct (case 18) and another with a small occipital white-matter lesion (case 16), abnormalities that might be attributed to other pathogenic factors, such as vasculitis, 17 rather than to direct virus-induced destruction of brain parenchyma.l3 The relationship between outcome and the presence of periventricular cysts, as identified by ultrasonography, is less clear because one child in each outcome group had this abnormality. The host or virus factors that contribute to the variability in outcome of congenitally infected infants have not been fully defined for cytomegalovirus. Thus far, analysis of virus isolates from symptomatic congenitally infected children has not revealed virusrelated features that determine neurovirulence.’8 Timing of maternal infection likely has a critical role in the pathogenesis of cytomegalovirus-induced central nervous system lesions.’9 Infection before the 25th week of gestation, when the cellular mass of the subependymal germinal matrix zone is largest,2o could destroy glial precursors and cause microcephaly, intracranial calcifications, migrational abnormalities,21,22 and severe neurodevelopmental =
sequelae. In
conclusion, this review further indicates that
there may not be
a strong relationship between developmental outcome and the neonatal systemic signs of cytomegalovirus infection. With the possible exception of intracranial calcifications, no single clinical or radiographic finding was invariably associated with a specific developmental outcome. However, the combination of postnatal seizures, postnatal microcephaly, and an abnormal central nervous system imaging study may portend, with few exceptions, severe developmental sequelae following symptomatic cytomegalovirus infection.
References 1. Weller TH: The
cytomegaloviruses: Ubiquitous agents with protean clinical manifestations. N Engl J Med 1971;285:203-214,
267-274. 2. Krech V, Jung M, Jung F: S Karger AG, Basel, 1971. 3. Alford CA, Stagno S, Pass
Cytomegalovirus Infections of Man.
RF, Huang ES: Epidemiology of in Nahmias AJ, Dowdle WR, Schinazi R (eds): The Human Herpes Viruses. New York, Elsevier, 1981, pp 159-171. Ho M: Cytomegalovirus: Biology and Infection. New York, Plenum, 1982, pp 79-104. Kumar M, Nankervis GA, Gold E: Inapparent congenital cytomegalovirus infection: A follow-up study. N Engl J Med 1973;
cytomegalovirus infection,
4. 5.
288:1370-1372. 6.
7.
8.
Saigal S, Lunyk O, Larke RPB, Chernesky MA: The outcome in children with congenital cytomegalovirus infection: A longitudinal follow-up study. Am J Dis Child 1982;136:896-901. Conboy TJ, Pass RF, Stagno S, et al: Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics 1986;77:801-806. Bale JF Jr: Human cytomegalovirus infection and disorders of
the nervous system. Arch Neurol 1984;41:310-320. 9. McCracken GH Jr, Shinefield HR, Cobb K, et al: Congenital cytomegalic inclusion disease. A longitudinal study of 20
patients. AmJ Dis Child 1969;117:522-539. 10. Williamson WD, Desmond MM, LaFevers N, et al: Symptomatic congenital cytomegalovirus: Disorders of language, learning, and hearing. AmJ Dis Child 1982;136:902-905. 11. Conboy TJ, Pass RF, Stagno S, et al: Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 1987;111: 343-348. 12. Berenberg W, Nankervis G: Long-term follow-up of cytomegalic inclusion disease of infancy. Pediatrics 1970;46:403-410. 13. Bale JF Jr, Bray PF, Bell WE: Neuroradiographic abnormalities in congenital cytomegalovirus infection. Pediatr Neurol 1985;1: 42-47. 14. Bale JF Jr, Andersen RD, Grose C: Magnetic resonance imaging of the brain in childhood herpesvirus infections. Pediatr Infect
DisJ 1987;6:644-647. Ahmann PA, Lazzara A: Cranial ultrasound in the detection of intracranial calcifications. J Pediatr 1982;100: 406-408. 16. Norman D, Diamond C, Boyd D: Relative detectability of intracranial calcifications on computed tomography and skull radiography. J Comput Assist Tomogr 1978;2:61-64. 17. Koeppen AH, Lansing LS, Peng SK, Smith RS: Central
15.
Dykes FD,
135
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nervous system vasculitis in cytomegalovirus infection. J Neurol Sci 1981;51:395-410. 18. Grillner L, Ahlfors K, Ivarsson SA, et al: Endonuclease cleavage pattern of cytomegalovirus DNA of strains isolated from congenitally infected infants with neurologic sequelae. Pediatrics 1988;81:27-30. 19. Stagno S, Pass RF, Cloud G, et al: Primary cytomegalovirus infection in pregnancy: Incidence, transmission to fetus, and clinical outcome. JAMA 1986;256:1904-1908. 20. Gilles FH, Dooling EC: Cerebral developmental changes at the
end of the second trimester. J Neuropathol Exp Neurol 1977;36: 602. 21. Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA: Lissencephaly-pachygyria associated with congenital cytomegalovirus infection, abstr. Ann Neurol 1988;24:345. 22. Dias MJM, Harmant-van Rijckevorsel G, Landrieu P, Lyon G: Prenatal cytomegalovirus disease and cerebral microgyria: Evidence for perfusion failure, not disturbance of histogenesis, as the major cause of fetal cytomegalovirus encephalopathy.
Neuropediatrics 1983;15:18-24.
Vignette A
Psychic Analysis of the American Neurological Association by Milt Gross
This is a series of 16 cartoons depicting prominent early members of the American Neurological Association. The original is in the archives of the American Neurological Association, housed in the Coy C. Carpenter Library of the Bowman Gray School of Medicine of Wake Forest University, and is reproduced with the kind assistance of Ms Sarah-Patsy Knight, Archivist, and Dr James F. Toole, Historian of the American Neurological Association.
136
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Symptomatic Congenital Cytomegalovirus Infection James F. Bale, Jr, MD; James A. Blackman, MD, MPH; Yutaka Sato, MD
Abstract To determine factors that
are associated with adverse developmental outcome after congenital cytomegalovirus infection, reviewed the clinical, laboratory, and radiographic findings in 18 children with symptomatic congenital cytomegalovirus infections. When children with adverse outcomes (intelligence or developmental quotients of 50 or less, n 10) were with no with children mild or of 70 or n we found 8), compared sequelae (intelligence developmental quotients higher, relationship between developmental outcome and neonatal clinical features (birth weight, jaundice, hepatomegaly, splenomegaly, or petechiae). With the possible exception of intracranial calcifications, no single clinical or radiographic feature was associated with a specific developmental outcome. However, children who had postnatal microcephaly, postnatal seizures, and an abnormal central nervous system imaging study were more likely to have severe developmental sequelae. ( JChild Neurol 1989;4:131-136). we
=
=
and 2.0% of all newborn infants Bin the United States and other developed countries excrete cytomegalovirus in their urine. 1-4 The majority of these virus-excreting infants, approximately 80% to 90%, have no signs at birth attributable to cytomegalovirus. Although some silently infected infants will later exhibit sensorineural hearing loss, these infants are not at risk for other
etween 0.5%
neurodevelopmental disabilities.5-’ The remaining infants, approximately 10% of
cytomegalovirus-excreting newborns, exhibit signs of infection at birth consisting of petechiae, jaundice, hepatosplenomegaly, microcephaly, or chorioretinitis.8 Previous longitudinal studies indicate that the majority of these symptomatic infants will have per-
or intellectual disabilities.9-12 further the clinical, laboratory, or To identify that are associated with adverse features radiographic in infants with outcome symptomatic congenital
manent
visual, motor,
Received Jan 26, 1989. Received revised April 24, 1989. for publication May 3, 1989. From the Departments of Pediatrics, Neurology, and Radiology, The University of Iowa College of Medicine, Iowa City, IA. Presented in part at the 17th Annual Meeting of the Child Neurology Society, Halifax, Nova Scotia, September 1988. Address correspondence to Dr James F. Bale, Jr, Division of Pediatric Neurology, Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242.
Accepted
cytomegalovirus infections, we reviewed the records of 18 such children seen during a 13-year period at the University of Iowa. Methods Patient Population Eighteen children with symptomatic congenital cytomegalovirus infection were identified by a computer-assisted search of the medical records of the University of Iowa Hospitals and Clinics between January 1, 1975, and December 31, 1987. Six patients were seen in the interval from 1975 through 1980, whereas 12 patients were seen after January 1, 1981. The children ranged in age from 1 day to 23 years at the time of their initial evaluation. Twelve children were evaluated here during the neonatal period (within the first month of life). Ten children (56%) were female, and 17 (94%) were white. Medical records were directly reviewed by us to retrieve clinical data. Cytomegalovirus infection was confirmed by culture of virus from urine (15 children), identification of urinary inclusion bodies (2 children), or serologic responses (1 child). All children had one or more of the following signs of cytomegalovirus infection at birth: jaundice, hepatomegaly, spleno-
megaly, petechiae, thrombocytopenia, microcephaly, 131
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TABLE 1
Summary of Clinical and Radiographic Features in Children with IQ or DQ of 50 or Less
IQ
=
intelligence quotient; DQ developmental quotient; + tomography; ND = no data; MRI =
sonogram; CT computed * At follow-up evaluation. =
and chorioretinitis. Sixteen children had one of these clinical features.
more
=
=
feature present; -
magnetic
than
were
Seventeen children
were
studied
using
various
neuroimaging methods, including plain skull radiography (8 children), head sonography (8 children), computed tomography (11 children), and magnetic resonance imaging (2 children). Eleven were studied
during the neonatal period. Computed tomographic results from five children and magnetic resonance from two children were described imaging results 13,14 but no outcome data were available at previously, the time of those reports. Imaging studies were reviewed by one radiologist (Y.S.) who was unaware of the clinical or laboratory features and developmental outcome of the children.
feature absent; SR
=
skull
radiograph;
US
=
head
imaging.
outcome of the two other children
was
obtained
interview. Where standardized test
phone
Imaging Studies
=
resonance
unavailable,
a
by
scores
developmental quotient
was
derived by dividing the child’s performance age by the chronological age or age adjusted for prematurity. In addition, all children have been evaluated and served by Iowa’s Area Education Agencies, a statewide comprehensive program for disabled children. Audiometric evaluation was obtained on 13 children using behavioral audiometry or measuring brain stem auditory evoked responses. Statistical Analysis Frequency data were compared using Fisher’s exact test, and continuous variables were analyzed by a two-tailed Student’s t test. P values less than .05 were considered significant.
Results
Assessment of Outcome
Neurodevelopmental children during routine follow-up outcome
was
assessed in 16
examinations. In-
struments administered to the children included the
Bayley Scales of Infant Development, Stanford-Binet, Wechsler Intelligence Scales for Children, and the Hiskey-Nebraska Test of Learning Aptitude for hearing-impaired children. Information regarding the
Neurodevelopmental 37 months (range 10
assessment at
months to 23
median age of years) indicated broad range of 10) consisted of a
that the 18 children exhibited a neurologic sequelae. One group (n children who had adverse developmental outcomes (intelligence or developmental quotients of 50 or less) (Table 1). Eight of these children (80%) do not walk,
132
Downloaded from jcn.sagepub.com at The University of Iowa Libraries on May 27, 2015
=
TABLE 2
Summary of Clinical and Radiographic Features in Children with IQ or DQ of 70 or Higher
IQ
=
US * At
intelligence quotient; DQ developmental quotient; + feature present; - feature absent; SR head sonogram; CT computed tomography; MRI magnetic resonance imaging. follow-up evaluation.
=
=
=
=
=
=
skull
radiograph; ND
=
no
data;
=
and
seven (70%) have not developed recognizable speech. Eight (80%) have postnatal microcephaly (occipitofrontal head circumference lower than 2 standard deviations below the mean for age). Nine (90%) of the adversely affected children have had postnatal seizures, reported at a median
age of 12 months. The seizure types consisted of generalized tonic-clonic or tonic (4 children), focal (3 children), and infantile spasms or minor motor seizures (2 children). Seizure frequency varied from a single, generalized tonic-clonic episode (case 6) to multiple, daily myoclonic seizures. Eight children were treated with anticonvulsant medications. The second group (n = 8) consisted of children who were normal or had mild intellectual or developmental sequelae (Table 2). Intelligence quotients and/ or developmental quotients among these children were 70 or higher. Four of these children (50%) have postnatal microcephaly (P .20 when compared with children with severe developmental sequelae), but only one (13%) has a seizure disorder (P = .002 when compared with children with severe sequelae). Table 3 compares the relationship of outcome to the presence of various clinical signs during the neonatal period. We observed a trend toward a longer mean gestational age in children with intelligence or developmental quotients of 50 or less (P .065). Otherwise, we found no differences between the two outcome groups with regard to birth weight =
=
TABLE 3
Proportion of Cytomegalovirus-Infected Infants with Abnormal Physical Signs in the Neonatal Period
*P
=
.065
by
t test; P values in all other
categories were
>
.10.
the
frequency of neonatal jaundice, hepatomegaly, petechiae, retinitis, microcephaly at birth, or neonatal seizures. The proportion of infants whose birth weights were appropriate for gestational age was also similar in the two groups (4/8 [50%] for children with intelligence or developmental quotients of 70 or higher versus 7/10 [70%] for children with severe developmental sequelae, P .35). Although laboratory studies were not available for all children, severe thrombocytopenia (platelet count < 25,000/mm3) was somewhat more frequent or
=
133
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Discussion In this report, we retrospectively examined the relationship between developmental outcome and the clinical and radiographic features in children with symptomatic congenital cytomegalovirus infections. Such children have varying degrees of neurologic sequelae and can be segregated into two groups with respect to outcome, those who have mild neuro-
TABLE 4
Proportion of Cytomegalovirus-Infected Infants with Abnormal Neuroimaging Studies
* P
tP P
=
=
=
.074, Fisher .278, Fisher .145, Fisher
exact test. exact test. exact test. z
children with intelligence or developmental quotients of 70 or higher (6 of 8 [75% ] children versus only 1 of 6 [17%] severely affected children, P .051). Otherwise, we found no differences in the frequency of mild thrombocytopenia, elevated aspartate aminotransferase (> 100 IU), or hyperbilirubinemia (> 10 mg/dL). Seventeen children were studied using one or more neuroimaging techniques (Tables 1 and 2). The average number of imaging studies was 1.6/child for children with an intelligence or developmental quotients of 50 or less and 1.6/child for those with 70 or above. Abnormalities identified in association with symptomatic cytomegalovirus infections included intracranial calcifications, periventricular cysts, ventricular dilation, hydrocephalus, hemorrhage, infarc-
in
=
tion,
or
porencephaly.
When the results of imaging studies were compared with developmental outcome (Table 4), a higher proportion of children with adverse outcomes had abnormal skull radiographs or head sonograms. Overall, a somewhat higher but not statistically significant proportion of children with adverse outcomes had abnormal imaging studies. Eight of the 10 children with intelligence or developmental scores of 50 or less had at least one abnormal imaging study versus 3 of 7 children with more favorable outcomes (P = .14). However, normal imaging studies were not uniformly associated with favorable developmental outcomes, as illustrated by cases 6 and 10. Specific developmental outcomes did not relate to a single clinical, laboratory, or radiographic feature. However, with one exception (case 6), the combination of postnatal microcephaly, postnatal seizures, and an abnormal imaging study was associated with severe
developmental sequelae.
developmental sequelae (intelligence or developmental quotients of 70 or higher) and those who are severely affected (intelligence or developmental quotients of 50 or less). When outcome groups are compared according to the frequency of various neonatal clinical features, we observed, as did Conboy and coworkers,11 that the presence or severity of the reticuloendothelial involvement, as assessed by physical and laboratory findings, does not have a strong relationship with subsequent neurologic outcome. Although we did not find that the frequency of neonatal seizures or microcephaly at birth differed statistically between the two groups of children, microcephaly or seizures were more likely to be identified subsequently in children with severe developmental sequelae. This finding supports prior observations indicating that the appearance of neurologic abnormalities during the first year of life heralds long-term neurodevelopmental disabilities.11,12 Nine of the 10 children with adverse developmental outcomes in this series had postnatal seizures, first reported at a median age of 12 months. In contrast to a prior report that found a strong correlation between chorioretinitis and low intelligence,11 we did not observe that the frequency of chorioretinitis differed between children in the two outcome groups. Selection bias could account for our failure to identify this relationship, because relatively fewer children in the present study were functioning in the average or above-average intellectual range. However, cases 14 and 16 in this study and an intellectually normal child with chorioretinitis reported previously by Berenberg and Nankervis 12 suggest that the presence of chorioretinitis may not preclude a favorable intellectual outcome in infants with symptomatic congenital cytomegalovirus infections. Several different modalities-ultrasonography, computed tomography, and magnetic resonancecan be used to image infants with proven or suspected congenital cytomegalovirus infections. However, prospective studies comparing the sensitivity of these techniques in cytomegalovirus-infected children have not, to our knowledge, been published. Cranial ultrasonography effectively detects periventricular lesions, including calcifications, and can be performed at the
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bedside in unstable infants. 15 Although magnetic resonance generally has superior sensitivity, unenhanced computed tomography 13 detects intracranial calcifications more effectively than magnetic resonance and provides sufficient information regarding cerebral and cerebellar pathology. Plain skull radiography, an insensitive technique,16 should be abandoned as an imaging method for children with suspected cytomegalovirus-induced central nervous system lesions. When outcome in this case series was compared with the results of imaging studies (Table 4), a higher proportion of children with adverse outcomes had abnormal skull radiographs or head sonograms. In addition, a somewhat higher proportion of children with adverse outcomes had at least one abnormal imaging study (8 of 10 [80%] versus 3 of 7 [42%], P .14), but not all children were studied by equivalent modalities. We emphasize that symptomatic cytomegalovirus-infected infants can have adverse developmental outcomes despite normal imaging studies. We believe that the character of the imaging abnormalities may have an important relationship with subsequent outcome. For example, only 1 of the 4 children with identified calcifications has progressed beyond the 5-month performance level. This contrasts with the mild delays experienced by one child with an occipital infarct (case 18) and another with a small occipital white-matter lesion (case 16), abnormalities that might be attributed to other pathogenic factors, such as vasculitis, 17 rather than to direct virus-induced destruction of brain parenchyma.l3 The relationship between outcome and the presence of periventricular cysts, as identified by ultrasonography, is less clear because one child in each outcome group had this abnormality. The host or virus factors that contribute to the variability in outcome of congenitally infected infants have not been fully defined for cytomegalovirus. Thus far, analysis of virus isolates from symptomatic congenitally infected children has not revealed virusrelated features that determine neurovirulence.’8 Timing of maternal infection likely has a critical role in the pathogenesis of cytomegalovirus-induced central nervous system lesions.’9 Infection before the 25th week of gestation, when the cellular mass of the subependymal germinal matrix zone is largest,2o could destroy glial precursors and cause microcephaly, intracranial calcifications, migrational abnormalities,21,22 and severe neurodevelopmental =
sequelae. In
conclusion, this review further indicates that
there may not be
a strong relationship between developmental outcome and the neonatal systemic signs of cytomegalovirus infection. With the possible exception of intracranial calcifications, no single clinical or radiographic finding was invariably associated with a specific developmental outcome. However, the combination of postnatal seizures, postnatal microcephaly, and an abnormal central nervous system imaging study may portend, with few exceptions, severe developmental sequelae following symptomatic cytomegalovirus infection.
References 1. Weller TH: The
cytomegaloviruses: Ubiquitous agents with protean clinical manifestations. N Engl J Med 1971;285:203-214,
267-274. 2. Krech V, Jung M, Jung F: S Karger AG, Basel, 1971. 3. Alford CA, Stagno S, Pass
Cytomegalovirus Infections of Man.
RF, Huang ES: Epidemiology of in Nahmias AJ, Dowdle WR, Schinazi R (eds): The Human Herpes Viruses. New York, Elsevier, 1981, pp 159-171. Ho M: Cytomegalovirus: Biology and Infection. New York, Plenum, 1982, pp 79-104. Kumar M, Nankervis GA, Gold E: Inapparent congenital cytomegalovirus infection: A follow-up study. N Engl J Med 1973;
cytomegalovirus infection,
4. 5.
288:1370-1372. 6.
7.
8.
Saigal S, Lunyk O, Larke RPB, Chernesky MA: The outcome in children with congenital cytomegalovirus infection: A longitudinal follow-up study. Am J Dis Child 1982;136:896-901. Conboy TJ, Pass RF, Stagno S, et al: Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics 1986;77:801-806. Bale JF Jr: Human cytomegalovirus infection and disorders of
the nervous system. Arch Neurol 1984;41:310-320. 9. McCracken GH Jr, Shinefield HR, Cobb K, et al: Congenital cytomegalic inclusion disease. A longitudinal study of 20
patients. AmJ Dis Child 1969;117:522-539. 10. Williamson WD, Desmond MM, LaFevers N, et al: Symptomatic congenital cytomegalovirus: Disorders of language, learning, and hearing. AmJ Dis Child 1982;136:902-905. 11. Conboy TJ, Pass RF, Stagno S, et al: Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 1987;111: 343-348. 12. Berenberg W, Nankervis G: Long-term follow-up of cytomegalic inclusion disease of infancy. Pediatrics 1970;46:403-410. 13. Bale JF Jr, Bray PF, Bell WE: Neuroradiographic abnormalities in congenital cytomegalovirus infection. Pediatr Neurol 1985;1: 42-47. 14. Bale JF Jr, Andersen RD, Grose C: Magnetic resonance imaging of the brain in childhood herpesvirus infections. Pediatr Infect
DisJ 1987;6:644-647. Ahmann PA, Lazzara A: Cranial ultrasound in the detection of intracranial calcifications. J Pediatr 1982;100: 406-408. 16. Norman D, Diamond C, Boyd D: Relative detectability of intracranial calcifications on computed tomography and skull radiography. J Comput Assist Tomogr 1978;2:61-64. 17. Koeppen AH, Lansing LS, Peng SK, Smith RS: Central
15.
Dykes FD,
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nervous system vasculitis in cytomegalovirus infection. J Neurol Sci 1981;51:395-410. 18. Grillner L, Ahlfors K, Ivarsson SA, et al: Endonuclease cleavage pattern of cytomegalovirus DNA of strains isolated from congenitally infected infants with neurologic sequelae. Pediatrics 1988;81:27-30. 19. Stagno S, Pass RF, Cloud G, et al: Primary cytomegalovirus infection in pregnancy: Incidence, transmission to fetus, and clinical outcome. JAMA 1986;256:1904-1908. 20. Gilles FH, Dooling EC: Cerebral developmental changes at the
end of the second trimester. J Neuropathol Exp Neurol 1977;36: 602. 21. Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA: Lissencephaly-pachygyria associated with congenital cytomegalovirus infection, abstr. Ann Neurol 1988;24:345. 22. Dias MJM, Harmant-van Rijckevorsel G, Landrieu P, Lyon G: Prenatal cytomegalovirus disease and cerebral microgyria: Evidence for perfusion failure, not disturbance of histogenesis, as the major cause of fetal cytomegalovirus encephalopathy.
Neuropediatrics 1983;15:18-24.
Vignette A
Psychic Analysis of the American Neurological Association by Milt Gross
This is a series of 16 cartoons depicting prominent early members of the American Neurological Association. The original is in the archives of the American Neurological Association, housed in the Coy C. Carpenter Library of the Bowman Gray School of Medicine of Wake Forest University, and is reproduced with the kind assistance of Ms Sarah-Patsy Knight, Archivist, and Dr James F. Toole, Historian of the American Neurological Association.
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