Abnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards

doi:10.1016/S0387-7604(02)00088-8

Brain and Development

Volume 24, Issue 7, October 2002, Pages 710-714

https://doi.org/10.1016/S0387-7604(02)00088-8 Get rights and content

Abstract

We report on two patients with congenital cytomegalovirus (CMV) infection asymptomatic at birth that was diagnosed retrospectively by polymerase chain reaction (PCR) of CMV DNA using blood stored on Guthrie cards. Neuroimaging studies showed abnormal myelination without any gray matter abnormalities. In the differential diagnosis of patients with abnormal white matter lesions and sensorineural hearing loss, one should consider congenital CMV infection. When investigating the etiology of patients with behavioral problems, migrational disorder, or white matter disease, PCR analysis of CMV DNA using blood stored on Guthrie cards might be helpful.

Introduction

Cytomegalovirus (CMV) is the most common cause of congenital and perinatal viral infections worldwide. Congenital infection occurs in 1% of all live births in developed countries and in an even higher percentage in developing nations [1]. Only 10% of infected infants have symptoms at birth. The manifestations of congenital infection seen most frequently at birth are petechiae, hepatosplenomegaly, jaundice, and microcephaly. Intrauterine growth retardation, cerebral calcifications, prematurity, inguinal hernia and chorioretinitis are less common [2]. In contrast, 90% of infected infants are asymptomatic at birth, although about 15% of these infants suffer from hearing loss [2]. Although neuroimaging studies of patients with symptomatic congenital CMV infection have been reported [3], [4], [5], [6], [7], there are few reports on patients with congenital CMV infection asymptomatic at birth [8], [9]. Recently, the retrospective diagnosis of congenital CMV infection has become possible using polymerase chain reaction (PCR) of CMV DNA in blood stored on Guthrie cards [9], [10]. Here, we report on two children who were asymptomatic at birth, but who had abnormal white matter lesions detected by magnetic resonance imaging (MRI), with sensorineural hearing loss, and were diagnosed as congenital CMV infection by PCR of CMV DNA in blood stored on Guthrie cards.

Section snippets

Case 1

A 9-year-old girl had a birth history of normal gestation by vacuum delivery from healthy, non-consanguineous parents. Her birth weight was 2432 g, which is less for a term baby. She did not have birth asphyxia. Her early development was normal (head control: 4 m, sit alone: 8 m, walk alone: 12 m). However, she visited our hospital at the age of 16 months because her father noticed that she had difficulty in hearing. A computed tomographic (CT) scan of the head taken at that time showed multiple

Discussion

Neuroimaging studies of patients with symptomatic congenital CMV infection have revealed multiple abnormalities, such as lissencephaly, pachygyria, micropolygyria, dysmyelination, paraventricular cysts, cerebellar hypoplasia, and intracranial calcification [3], [4], [5], [6], [7]. The heterogeneity of CNS abnormalities likely depends on the developmental stage at which the fetus is infected by CMV [5]. Infection before the 18th week of gestation leads to lissencephaly, while infection between

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Cytomegalovirus infection is also associated with white matter lesions, in addition to being associated with prematurity. Accordingly, previous studies indicated the association between cytomegalovirus infection and congenital deafness [25,26]. Sufang et al. [20] showed that white matter lesions in their population were due to maternal infections during pregnancy, premature birth, intrauterine growth retardation, hypoxia, and perinatal ischemia.
To estimate the incidence of brain abnormalities in a cohort of prelingually deaf children and whether these abnormalities can impact the hearing outcomes of patients eligible for cochlear implantation (CI).
We performed a retrospective review of consecutive medical charts of prelingually deaf children under 12 years of age who underwent brain magnetic resonance imaging (MRI) during their preoperative workup for CI surgery. We used the category of auditory performance (CAP) test and the speech intelligibility rating (SIR) test to assess the hearing and speech performance of the children, respectively.
The MRIs of 285 patients, 174 boys and 111 girls with a mean age of 36.4 (±16) months, were evaluated for this study. We identified 31 patients with abnormal findings (10.88%): (17/31) (54.8%) had MRI brain abnormalities, (9/31) (29%) had inner ear anomalies, and (5/31) (16.1%) had both inner ear and brain abnormalities. The most frequent inner ear anomaly was an enlarged vestibular aqueduct, while white matter lesions were the most common brain abnormality. The CAP and SIR mean score of patients with inner ear anomalies was slightly, but not significantly, higher than those of patients with brain abnormalities.
CAP and SIR scores were not significantly different in children with brain abnormalities than inner ear anomalies. These patients can still benefit from CI to improve their overall hearing and speech performance.
Is it not time for international guidelines to combat congenital cytomegalovirus infection? A review of central nervous system manifestations
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Imaging findings of inner ear structures are almost entirely normal on MRI.67 Until recently, this was thought to be due to imaging resolution limitations; however, multiple studies have now demonstrated the relationship between white matter lesions and SNHL.46,50 MRI, however, remains a necessity to exclude other structural causes of hearing loss.49
Cytomegalovirus (CMV) is the most commonly transmitted virus in utero with a prevalence of up to 1.5%. The infection has potentially debilitating and devastating consequences for the infected fetus, being a leading cause for neurological disability worldwide. Once acquired, it often goes undetected with only an assumed 10% of infected neonates displaying the classic clinical or imaging features. Viral DNA polymerase chain reaction (PCR) of saliva or urine obtained within the first 21 days of life is required to make the diagnosis. As the majority of infected neonates are initially asymptomatic, diagnosis is often delayed. An abnormal routine neonatal hearing test and characteristic antenatal cranial ultrasound imaging findings may raise the suspicion of congenital CMV (cCMV) in the asymptomatic group. Ultimately, the aim is to facilitate early diagnosis and timely treatment. In this article, we highlight diagnostic and treatment challenges of the commonest congenital infection, we present the current available central nervous system imaging severity grading systems, and highlight the need for an internationally agreed diagnostic grading system that can aid treatment decision-making.
Fetal Infections
2019, Fetal Medicine: Basic Science and Clinical Practice
Asymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord
2016, Brain and Development
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The diagnosis of congenital CMV infection with virological and serological evidence is nearly impossible beyond the neonatal period. Neonatal blood that is collected on filter paper within the first week of life (dried blood spots) has been shown to be useful for retrospective diagnoses [33,34]. Unfortunately, these are normally only kept for up to several years in Japanese neonatal screening centers.
Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period.
This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection.
We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA.
Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n = 51, 94.4%), hearing impairment (n = 36, 66.7%) and cerebral palsy (n = 21, 38.9%), while microcephaly (n = 16, 29.6%) and epilepsy (n = 14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability.
Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection.
Hereditary Hearing Impairment
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
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La infección intrauterina por citomegalovirus es la más frecuente de las viriasis/parasitosis intrauterinas que afectan al sistema nervioso central y causan lesiones permanentes tanto en el córtex como en la sustancia blanca subcortical. Son escasos los estudios de resonancia magnética (RM) cerebral.
Seis pacientes (4 M y 2 V) fueron estudiados desde los primeros meses de vida para hacer el diagnóstico de citomegalia congénita e identificar la presencia de lesiones corticales y subcorticales, utilizando las necesarias secuencias de RM.
Los 6 pacientes mostraban malformaciones del desarrollo cortical (MDC) (esquisencefalia, polimicrogiria o lisencefalia-paquigiria) desde la época neonatal y alteraciones difusas de la sustancia blanca, que se mantuvieron con pocos cambios durante los dos primeros años y después se iban reduciendo de tamaño en forma de zonas de hiperseñal en T2, circunscritas a determinadas áreas y permanecían con pocos cambios durante algunos años más.
La infección intrauterina por citomegalovirus causa lesiones en sustancia gris cortical, que consisten en MDC y en sustancia blanca subcortical. Estas últimas muestran aspecto cambiante, ya que aparecen como áreas difusas y amplias de hiperseñal, que se suelen interpretar como retraso en la mielinización, pero que también pueden ser causadas directamente por el virus de la citomegalia. Estas alteraciones de la sustancia blanca sufren cambios morfológicos a lo largo de los primeros años de vida, dejando atrofia cerebral. Las secuelas neurológicas que dejan estas alteraciones son severas y crónicas.
Intrauterine infection due to cytomegalovirus is the most common of the intrauterine viral/parasitic infections that affect the central nervous system and cause permanent lesions in the cortex as well as the subcortical white matter. Studies using brain magnetic resonance imaging (MRI) are limited.
Six patients (4 females and 2 males) were studied in the first months of life in order to make a diagnosis of congenital cytomegalovirus, and identify the cortical and subcortical lesions using the necessary MRI sequences.
The six patients showed malformations of cortical development (MDC) (schizencephaly, polymicrogyria or lissencephaly-pachygyria) from the neonatal period, and diffuse changes of the white matter, which remained with few changes during the first two years. They then began reducing in size in the form of high signal areas in T2, restricted to certain areas, and were evident for a few years more with little change.
Intrauterine infection due to cytomegalovirus causes changes in the cortical grey matter, which consists of MDC, and in the subcortical white matter. The latter show a changing aspect as they appear as diffuse and wide areas of high signal intensity, which is usually due to delay in myelinisation, but could also be caused directly by the cytomegalovirus. These changes in the white matter are subjected to morphological changes throughout the first years of life, leading to brain atrophy. The neurological sequelae of these lesions left by these alterations are severe and chronic.

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Original articleAbnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards

Abstract

Introduction

Section snippets

Case 1

Discussion

Brain Dev

Pediatr Neurol

Pediatr Neurol

Congenital and perinatal cytomegalovirus infections

Rev Infect Dis

Cytomegalovirus infection in pregnancy

Semin Perinatol

Magnetic resonance imaging of the brain in congenital cytomegalovirus infection

Pediatr Radiol

Magnetic resonance imaging of the brain in congenital rubella virus and cytomegalovirus infections

Neuroradiology

Original article
Abnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards