Brain & Development 30 (2008) 420424 www.elsevier.

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Original article

Epilepsy in patients with congenital cytomegalovirus infection

Yasuhiro Suzuki
a

a,*

, Yasuhisa Toribe a, Yukiko Mogami a, Keiko Yanagihara a, Masanori Nishikawa b

Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan b Department of Radiology, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan Received 25 September 2007; received in revised form 6 December 2007; accepted 8 December 2007

Abstract Patients with congenital cytomegalovirus (CMV) infection were at high risk for postnatal seizures, but little is known about epilepsy associated with congenital CMV infection. To dene the features of epilepsy, we retrospectively reviewed the clinical, laboratory and neuroradiographic ndings in 19 children (male 9) with congenital CMV infection. Seven (37%) patients had developed epilepsy (partial seizure 5 and epileptic spasms 2) at a mean age of 20 months (range 237 months). During the clinical course, West syndrome occurred in only three patients. The most common seizure type in our series was partial seizure. At the time of last followup (mean 96 months), seizures remained uncontrolled in six patients. Neonatal clinical manifestations (gestational age, gender distribution, birth asphyxia or symptoms at birth) were not predictive of the development of epilepsy. On the contrary, some neuroradiographic ndings (ventricular dilatation and migration disorder) were signicantly associated with the development of epilepsy. 2007 Elsevier B.V. All rights reserved.
Keywords: Congenital cytomegalovirus infection; Epilepsy; West syndrome; Children; TORCH syndrome

1. Introduction Congenital cytomegalovirus (CMV) infection is the most common intrauterine infection, aecting 0.22.2% of all newborns [1]. The majority of these infants are, however, subclinical at birth (asymptomatic congenital CMV infection) [1]. Only 1015% of infected infants exhibit clinical symptoms or signs of congenital infection at birth (symptomatic congenital CMV infection); these include smallness for gestational age, petechiae (purpura) or thrombocytopenia, hepatomegaly, splenomegaly, jaundice at birth, microcephaly, chorioretinitis, unexplained neurologic abnormality, hearing impairment, and intracranial calcications [2]. Nearly 90% of
Corresponding author. Tel.: +81 725 56 1220; fax: +81 725 56 5682. E-mail address: yasuzuki@mch.pref.osaka.jp (Y. Suzuki). 0387-7604/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2007.12.004
*

patients with symptomatic congenital CMV infection and 1015% of patients with asymptomatic congenital CMV infection subsequently develop neurodevelopmental sequelae [1]. These sequelae consist of sensorineural hearing loss, mental retardation, cerebral palsy, visual defects and seizures [1]. However, little is known about epilepsy associated with congenital CMV infection because previous reports have only indicated the word seizures or provided extremely limited descriptions of epilepsy [36]. This retrospective study investigated the features of epilepsy associated with congenital CMV infection, and determined risk factors predictive of epilepsy. 2. Methods Between October 1981 and February 2007, 19 children (male 9, female 10) with congenital CMV infection were i-

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dentied at Osaka Medical Center and Research Institute for Maternal and Child Health, a 363-bed tertiary referral center for the high risk pregnant women and sick children; nine patients were born at our medical center, and ten children were referred to us for neurodevelopmental assessment (eight patients) or elevated GOT/GPT (two patients) at the ages of two weeks to three years (mean 10.6 months). Of 19 patients, 16 patients were classied as symptomatic because they had one or more characteristic clinical symptoms of congenital CMV infection at birth, such as intrauterine growth retardation, hepatomegaly, splenomegaly, petechiae, microcephaly and chorioretinitis. The remaining three patients were categorized as having asymptomatic congenital CMV infection because they had no clinically apparent ndings at birth. In 17 patients, including one asymptomatic infant whose mother had CMV IgM antibody in the routine serologic screening during pregnancy, denitive diagnosis of congenital CMV infection was ascertained within the rst three weeks of life by positive CMV DNA by polymerase chain reaction (PCR) in urine, blood or placenta (15 patients), or isolation of virus from urine (two patients). In two asymptomatic patients who were referred to us for developmental delay, the diagnosis of congenital CMV infection was suspected based on neuroradiological ndings suggestive of congenital infection, and conrmed by CMV DNA which was demonstrated in preserved dried umbilical cord by PCR. We retrospectively reviewed all medical records of patients to obtain the clinical data at birth, development of epilepsy (age at onset, seizure evolution and seizure frequency at the last follow-up), sequelae at follow-up (cerebral palsy, mental retardation, hearing loss, and microcephaly), and electroencephalograph (EEG) ndings. Neuroimagings (CT and MRI) were reviewed by one of the authors (M.N.) who was unaware of the clinical features. Birth asphyxia was dened as Apgar score <7 at 1 min. Microcephaly was dened as a head circumference of less than the fth percentile. Patients were diagnosed as having mental retardation when they had DQ score (the revised Kyoto Child Guidance Clinic Developmental Scale for Children) of less than 70.
Table 1 Patients with epilepsy Patient No./Sex Symptoms at birth + + + + + + Migration Disorder At onset Age Schizen Poly+Schizen None Poly+Schizen Poly Poly Poly 8M 10M 2M 23M 37M 34M 31M

Using the stastical software package Dr. SPSSII for Windows (SPSS Japan Inc., Tokyo), clinical manifestations and neuroradiological ndings were compared between children with epilepsy and those without epilepsy. Frequency data were compared using Fisher exact test, and continuous variables were analyzed by Wilcoxon rank sum test. p < 0.05 was considered signicant. 3. Results Overall, seven (37%) of 19 patients with congenital CMV infection developed epilepsy; six (38%) of 16 children with symptomatic congenital CMV infection developed epilepsy, whereas epileptic seizures occurred in one (33%) of three patients with asymptomatic congenital CMV infection. Clinical data of patients with epilepsy are shown in Table 1. The mean age at onset was 20 months; seizure onset occurred at age <1 year in three children, and between 1 and 4 years in four. Seizure types at onset consisted of epileptic spasms in two children, and partial seizure alone in three, and partial seizure with secondary generalized tonicclonic seizure in two. During the course of disease, three patients developed other types of seizures. In a patient with West syndrome (patient 1), epileptic spasms was replaced by myoclonic seizure at the age of 2 years, subsequently followed by both myoclonic seizure and tonic seizure at the age of 5 years. The other child with West syndrome (patient 2) developed partial seizure at the age of 3 years after a 5-month seizure-free period. One infant with partial seizure (patient 3) developed epileptic spasms at 18 months, which then evolved to partial seizure at 20 months. The mean follow-up period was 86 months, ranging from 12 to 140 months. At the time of last follow-up (age 312 years, mean 96 months), only one patient had remained free of seizures for more than one year, while the other six children had uncontrolled seizures (partial seizures 5, and myoclonic seizure plus tonic seizure 1). Seizure frequency varied from daily seizure to yearly seizure (Table 1).

Seizure Evolution EEG Hyps Multi Multi Multi Multi Multi Multi MYO GT+MYO PS+sGTC ES PS+sGTC

At last follow-up Age 12Y4M 7Y 0M 6Y 9M 10Y 11M 7Y 4M 7Y10M 3Y 7M Seizure Frequency Daily Yearly Daily Yearly Monthly Controlled Yearly

Seizure type ES ES PS PS PS, sGTC PS PS, sGTC

1/M 2/F 3/M 4/M 5/F 6/M 7/F

M, male; F, female; Schizen, schizencephaly; Poly, polymicrogyria; ES, epileptic spasms; PS, partial seizure; sGTC, secondary generalized tonic clonic seizure; GT, generalized tonic seizure; MYO, myoclonic seizure; Hyps, hypsarrhythmia; Multi, multifocal spikes.

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Sixteen patients had undergone one or more EEG examinations, using the international 1020 system. In all patients with epilepsy, EEG at the time of seizure onset showed epileptic activity (1 with hypsarrhythmia, and 6 with multifocal spikes) (Table 1). On the other hand, EEGs were performed in nine of 12 patients without epilepsy at the mean age of 21 months (range 8 months to 3 years 10 months). EEG showed multifocal spikes in two children and absence of paroxysmal discharges in seven. Clinical manifestations were compared between children with epilepsy and those without epilepsy (Table 2). The age at the last follow-up did not dier between the two groups. Six of seven patients with epilepsy were delivered at term (gestational age =37 weeks), whereas four of 12 patients without epilepsy were born before 37 weeks of gestation. However, the gestational age was not signicantly dierent between the group with epilepsy (38.6 1.7 weeks) and the group without epilepsy (35.1 6.1 weeks). There were also no signicant dierences between the two groups with respect to gender, or birth asphyxia. A comparison of various newborn clinical symptoms demonstrated that none of the symptoms at birth, including intrauterine growth retardation, hepatomegaly, splenomegaly, petechiae, chriorentitis, microcephaly or neonatal seizure were associated with the development of epilepsy.
Table 2 Clinical manifestations and neuroimaging ndings Characteristics Age at last follow-up (months) Sex (male/female) Birth asphyxia Gestational age (weeks) =37 weeks 3037 weeks <30 weeks Symptoms at birth IUGR Hepatomegaly Splenomegaly Petechiae Chorioretinitis Microcephaly Neonatal seizure CT/MRI ndings Migration disorder Ventricular dilatation Calcication WM low density on CT WM high intensity on T2-weighted MRI Hemorrhage Cerebellar hypoplasia Hydrocephalus

The incidence of sequelae at follow-up was compared between the group of children with epilepsy and group without epilepsy. All seven children with epilepsy developed cerebral palsy, in contrast to three (25%) of 12 children without epilepsy (p = 0.003). Although not signicant, a higher proportion of the children with epilepsy demonstrated microcephaly at follow-up compared with that in those without epilepsy (epileptic group 5/7 vs. non-epileptic group 3/12, p = 0.074). However, there were no signicant dierences in the incidence of mental retardation (epileptic group 6/7 vs. non-epileptic group 7/12, p = 0.333) or hearing loss (epileptic group 3/7 vs. non-epileptic group 5/12, p = 1.000) between the two groups. Neuroimaging (CT 18 and MRI 16) was performed in all patients, including 15 who underwent both CT and MRI. Neuroradiological ndings were also compared between children with epilepsy and those without epilepsy (Table 2). Two patients without epilepsy had normal neuroradiological ndings. The remaining 17 patients showed one or more imaging abnormalities, including intracranial calcications in 13, ventricular dilatation in 12, white matter low density on CT in 11, white matter high intensity on T2-weighted MRI in 10, hemorrhage in two, cerebellar hypoplasia in one, hydrocephalus in one and migration disorders in 9 (polymicrogyria 6, polymicrogyria + schizencephaly 2, and schizencephaly 1).

Patients with epilepsy (N = 7) 95.6 34.6 (median 88.0, range 43148) 4/3 0/7 38.6 1.7 (median 38.5, range 3641) 6 1 0 1/7 3/7 2/7 4/7 2/7 3/7 0/7 6/7 7/7 7/7 5/7 6/7 0/7 0/7 0/7

Patients without epilepsy (N = 12) 82.1 56.8 (median 81.5, range 14160) 5/7 5/12 35.1 6.1 (median 38.0, range 2341) 8 2 2 7/12 7/12 5/12 5/12 2/12 5/12 1/12 3/12 5/12 6/11 6/11 4/9 2/12 1/12 1/12

p Value 0.582 0.650 0.106 0.287

0.147 0.650 0.656 0.650 0.603 1.000 1.000 0.020 0.017 0.101 0.637 0.145 0.509 1.000 1.000

IUGR, intrauterine growth retardation; WM, white matter.

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There were signicant dierences between children with epilepsy and those without epilepsy regarding the presence of migration disorder and ventricular dilatation. Patients with epilepsy were more likely to show intracranial calcication. Other neuroradiological ndings, including white matter low density on CT, white matter high intensity on T2-weighted MRI, cerebral hemorrhage, cerebellar hypoplasia or hydrocephalus, did not signicantly dier between the two groups. 4. Discussion Diagnosis of intrauterine CMV infection is dicult after the neonatal period, because serologic or virologic examination will not discriminate between prenatal and postnatal infection. In Japan, obstetric hospitals customarily give the dried umbilical cord to the parents of newborns as a symbol of the mother-to-child bond. Recently, these preserved dried umbilical cord specimens can be used for the retrospective diagnosis of congenital CMV infection [7]. Our study included 19 patients with conrmed congenital CMV infection. In 17 children, the diagnosis of congenital CMV infection was made within the rst three weeks of life by positive CMV DNA by PCR in urine, blood or placenta, or isolation of virus from urine. The remaining two patients who had no symptoms at birth were diagnosed with congenital CMV infection after the neonatal period by detecting CMV DNA from their dried umbilical cord. Patients with congenital CMV infection are more likely to experience postnatal seizures. The reported frequency of postnatal seizure ranged from 10 to 56% in children with symptomatic congenital CMV infection [1,35], whereas the rate was 0.9% in patients with asymptomatic congenital CMV infection [1]. In the present study, seven (37%) of 19 children with congenital CMV infection developed epilepsy (partial seizure 5 and epileptic spasms 2) before four years (mean 20 months). Our data did not show that patients (38%) with symptomatic congenital CMV infection were more likely to developed epilepsy compared to children (33%) with asymptomatic congenital CMV infection. Selection bias could account for this high frequency of epilepsy associated with asymptomatic congenital CMV infection, because asymptomatic patients were referred for evaluation of developmental delay, which may have automatically selected a group of individuals with neurological damage. There are limited data on epilepsy occurring after congenital CMV infection. Bale et al reported that postnatal seizures, including generalized tonicclonic or tonic seizure, focal seizure, infantile spasms and minor motor seizure, occurred at a median age of 12 months in children with symptomatic congenital CMV infection [5]. In a European report (Spanish language), a diversity of epileptic seizures, including spasms, tonic seizure,

partial seizure, epilepsia partial continua, hemiconvulsion, and atypical absence with focal atonic phenomena, was described in 10 children with various neuronal migration disorders associated with congenital CMV infection [6]. Although it has been widely recognized that congenital CMV infection has been linked to West syndrome [8], West syndrome was found in only three (43%) of seven patients in our series. The most common seizure type that was observed during the clinical course was partial seizure. At the last follow-up, seizures remained uncontrolled in most (6/7) of the epileptic patients. Our data also demonstrated that all patients with epilepsy developed cerebral palsy in contrast to one-quarter of children without epilepsy. However, the development of epilepsy was not signicantly associated with the development of mental retardation, microcephaly at follow-up or hearing loss. The clinical predictors of neurodevelopmental problems in children with symptomatic congenital CMV infection have been studied with conicting results. Of clinical symptoms at birth, the presence of microcephaly or chorioretinitis has been reported to be signicantly associated with low intelligence [9,10]. On the contrary, Bale et al reported that there was no relationship between developmental outcome and neonatal clinical features [5]. Recently, the risk factors for audiologic problems have also been studied. Evidence of disseminated infection at birth, including intrauterine growth retardation, petechiae, hepatitis, or thrombocytopenia, was considered predictive of hearing loss, while clinical evidence of central nervous system involvement at birth, such as microcephaly or seizures, was not associated with the development of hearing loss [11]. Previous studies demonstrated that newborn CT abnormalities were also associated with adverse neurodevelopmental outcome and hearing loss on follow-up [3]. However, risk factors for the development of epilepsy have not been identied. The present study showed that clinical features at birth such as gestational age, intrauterine growth retardation, hepatomegaly, splenomegaly, petechiae, chorioretinitis, microcephaly, and neonatal seizure were not associated with the development of epilepsy. In our series, a variety of neuroradiological ndings, including intracranial calcication, ventricular dilatation, migration disorder, and white matter abnormalities, were detected by CT and/or MRI. Of these ndings, the presence of ventricular dilatation and the presence of migration disorder were signicantly associated with the development of epilepsy. Our ndings suggested that neuroradiographic ndings, rather than clinical symptoms at birth, might be more helpful in the identication of infected children who are at a risk for the development of epilepsy. However, further studies with a large sample size are necessary to determine the odds ratios for the development of epilepsy.

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Y. Suzuki et al. / Brain & Development 30 (2008) 420424 development in children with congenital cytomegalovirus infection (in Spanish). Rev Neurol 1998;26:429. Ogawa H, Baba Y, Suzutani T, Inoue N, Fukushima E, Omori K. Congenital cytomegalovirus infection diagnosed by polymerase chain reaction with the use of preserved umbilical cord in sensorineural hearing loss children. Laryngoscope 2006;116:19914. Riikonen R. Cytomegalovirus infection and infantile spasms. Dev Med Child Neurol 1978;20:5709. Conboy TJ, Pass RF, Stagno S, Alford CA, Myers GJ, Britt WJ, et al. Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 1987;111:3438. Noyola DE, Demmler GJ, Nelson CT, Griesser C, Williamson WD, Atkins JT, et al. Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J Pediatr 2001;138:32531. Rivera LB, Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics 2002;110: 7627.

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