Asymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord

doi:10.1016/j.braindev.2016.03.006

Brain and Development

Volume 38, Issue 9, October 2016, Pages 819-826

https://doi.org/10.1016/j.braindev.2016.03.006 Get rights and content

Abstract

Background

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.

Objective

This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Congenital cytomegalovirus (CMV) infection represents a common cause of intrauterine infection [1], [2], [3] and is a major cause of neurological sequelae [4], [5]. There are two categories of congenital CMV infection—symptomatic and asymptomatic—that are generally based on the presence of clinical findings that suggest congenital infection at birth. Common physical and laboratory findings of symptomatic infants include petechial rash, jaundice, hepatosplenomegaly, microcephaly, elevated aspartate aminotransferase, hyperbilirubinemia and thrombocytopenia [6]. Approximately 90% of infants with congenital CMV infection are asymptomatic [7]. This categorization is clinically useful because infants with symptomatic infection are at a much higher risk for neurological sequelae than asymptomatic infants. Most (60–90%) symptomatic and 10–15% of asymptomatic congenital CMV infection patients develop one or more long-term neurological sequelae, such as intellectual disability [8] and sensorineural hearing loss [2], [9]. Several prospective screening studies have shown that symptomatic infants generally show mild symptoms during the neonatal period [5], [10]. Therefore, congenital CMV infection could easily be overlooked during the early infantile period.

More than two-thirds of patients with symptomatic congenital CMV infection exhibit various neuroimaging abnormalities, such as intracranial (especially periventricular) calcifications, cortical dysplasia, periventricular cysts (especially anterior temporal) and a parietal dominant white matter (WM) abnormality [11]. However, few previous studies have assessed brain imaging abnormalities in asymptomatic cases with neurological sequelae because retrospective diagnosis is difficult beyond the neonatal period.

A recent study reported that intellectual disability in 5 of 20 patients was caused by congenital CMV infections, which were retrospectively diagnosed using umbilical cords [12]. To determine the clinical characteristics of asymptomatic congenital CMV infection associated with neurological sequelae, we performed retrospective diagnoses of congenital CMV infections using preserved dried umbilical cord tissues and investigated the associated clinical and neuroimaging findings.

Section snippets

Data collection

This study was performed retrospectively between January 2005 and December 2013. Samples and data were collected from patients from all regions of Japan with possible congenital CMV infection who showed neurological symptoms such as intellectual disability, hearing impairment, cerebral palsy, microcephaly, and epilepsy. The lead author (MU) announced the enrollment of patients through the website of The Japanese Society of Child Neurology and the mailing list of the Annual Zao Conference on

Clinical characteristics of enrolled patients

We enrolled 191 patients who exhibited neurological symptoms (including intellectual disability, hearing impairment, cerebral palsy, epilepsy, and microcephaly) and/or brain imaging abnormalities (e.g., intracranial calcification and white matter abnormalities detected by CT and/or cortical dysplasia detected by MRI). A total of nine patients with symptomatic CMV infection (clinical symptoms such as petechiae, hepatosplenomegaly, and thrombocytopenia along with CMV identification near the

Discussion

In this study, we aimed to retrospectively investigate aspects of asymptomatic congenital CMV infection. Most enrolled congenital CMV patients with neurological sequelae had intellectual disabilities, which occurred more frequently than indicated in previous reports of low incidences (symptomatic: >50%, asymptomatic: 5–25%) [6], [10], [12], [19], [20]. From another point of view, 51 of 127 (40.2%) patients with intellectual disabilities were CMV-positive. Our result is more frequent but not

Acknowledgements

We are grateful to Ms. Yoko Chiba and Ms. Kumi Ito for their technical assistance of quantitative PCR analysis. We are also grateful for support of our research by the Japanese Society of Child Neurology.

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Brain Magnetic Resonance Imaging in Congenital Cytomegalovirus With Failed Newborn Hearing Screen
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Citation Excerpt :
The explanations for such phenomena include the presence of subtle signs of CMV infection, such as mild petechiae, intrauterine growth retardation, jaundice, or small head circumference, that were unrecognized in the newborn period or intracranial abnormalities that were not clinically apparent in early infancy. The latter explanation is supported by a recent, retrospective study suggesting that a substantial number of children with asymptomatic congenital CMV infections have intracranial abnormalities when studied by MRI.4 There may also be brain damage that is not apparent on imaging, as one study of fetuses with congenital CMV examined at gestational age 21 week showed that a little less than 43% of those with histologic brain damage had abnormalities visualized on ultrasound.21
In 2013, Utah enacted legislation requiring that infants failing newborn hearing screening be tested for cytomegalovirus infection. As a result, cytomegalovirus-infected infants are being identified because of hearing deficits. The neuroimaging findings in this population have not been characterized.
Retrospective medical record review was used to identify patients seen at the University of Utah and Primary Children’s Hospitals in Salt Lake City, Utah, who failed newborn hearing screening. A cohort of patients with congenital cytomegalovirus infection, brain magnetic resonance imaging (MRI), and sedated auditory brainstem response testing was studied.
Seventeen patients were identified; 11 (65%) were female. Confirmatory auditory brainstem response testing, performed at a median age 29 days, showed profound hearing loss in 8 (47%) subjects, severe loss in two (12%), moderate loss in two (12%), and mild loss in three (18%); two (12%) subjects had normal hearing. The diagnosis of cytomegalovirus infection was made at a median age 23 days. Brain imaging was performed at a median age 65 days. Ten (59%) subjects had one or more neuroimaging abnormality. White matter lesions were found in eight (47%) subjects, cysts in three (18%), and stroke in two (12%). Polymicrogyria was identified in two (12%) subjects. Seven (41%) subjects had normal brain MRIs.
These results indicate that most infants whose cytomegalovirus infections were identified after failing newborn hearing screening had abnormal brain MRIs. Our results suggest that brain MRIs should be considered in infants with congenital cytomegalovirus infections who are identified through hearing screening programs.
Feasible alternatives to DBS in the retrospective diagnosis of congenital cytomegalovirus infection
2020, Journal of Clinical Virology
Citation Excerpt :
Assuming that viral loads are higher in body fluids than in peripheral blood whether symptoms are present or not, some authors have proposed the use of dried urine [10] or dried saliva [11] spots for CMV retrospective diagnosis. In the absence of DBS, molecular detection of CMV using preserved DUC samples has been proposed as a feasible method by several Japanese authors [12,13]. In Japan, DBS is usually stored for one year by institutions, whereas umbilical cord is stored by parents, clean and dry, as a symbol of the traditional mother-to-child bond [14,12].
Retrospective diagnosis of congenital cytomegalovirus (cCMV) infection may be challenging mainly because of the high variable sensitivity of PCR on dried blood spots (DBS) samples.
To compare cytomegalovirus (CMV) viral load (VL) values in different samples obtained at birth from infants with cCMV infection. To evaluate dried umbilical cord (DUC) samples as an alternative to DBS.
Saliva and/or urine, peripheral blood (PB), and DBS from 16 infants with confirmed cCMV infection were collected at birth. CMV VL were determined by DNA extraction and real-time polymerase chain reaction (rt-PCR). In two cases, VL was determined from DUC samples.
Six (37.5 %) of the 16 infants were symptomatic, and 10 (62.5 %) were asymptomatic. The CMV VL found in saliva (median: 1,958,525 [IQR: 597,683−3,483,843] IU/mL) and in urine (median: 691,865 [IQR: 188,489.5−3,175,696] UI/mL) were both higher than those found in PB (median: 1115 [IQR: 364−4,002] IU/mL), p: 0.0001). Symptomatic infants presented 100 % of detectable VL in PB and 50 % in DBS. Asymptomatic infants showed 75 % of detectable VL in PB and 30 % in DBS. The VL in DUC were 22,341, 9754 IU/mL and 994 IU/mL.
When VL was detectable in PB, the values were lower than in saliva or urine, in both symptomatic and asymptomatic cases of cCMV. The low sensitivity in DBS samples could be due to low blood volume content, making CMV VL undetectable even when using optimised extraction and PCR protocols. In our limited experience, DUC could play a complementary diagnostic role when DBS VL is undetectable.
Basal ganglia calcification
2020, Revue de Medecine Interne
Des calcifications des noyaux gris centraux sont fréquemment visibles sur les scanners cérébraux et particulièrement au niveau des globes pâles. Leurs fréquences augmentent de manière physiologique avec l’âge après 50 ans. Cependant des processus pathologiques peuvent aussi être associés à des dépôts de calcium au niveau des noyaux gris, de la fosse postérieure ou de la substance blanche. Des calcifications unilatérales orienteront le plus souvent vers une origine acquise. En revanche devant une atteinte bilatérale, une origine acquise mais aussi génétique sera recherchée après avoir éliminé une perturbation du métabolisme phosphocalcique. Dans ces contextes pathologiques, ces calcifications peuvent être accompagnées de symptômes neurologiques liés à la maladie sous-jacente : syndrome parkinsonien, troubles psychiatriques et cognitifs, épilepsie ou céphalées. L’objectif de cette mise au point est d’apporter une aide diagnostique, outre la clinique et la biologie, grâce à l’analyse de la topographie des calcifications et à l’étude des différentes séquences IRM.
Calcifications of the basal ganglia are frequently seen on the cerebral CT scans and particularly in the globus pallidus. Their frequency increases physiologically with age after 50 years old. However, pathological processes can also be associated with calcium deposits in the gray nuclei, posterior fossa or white matter. Unilateral calcification is often related to an acquired origin whereas bilateral ones are mostly linked to an acquired or genetic origin that will be sought after eliminating a perturbation of phosphocalcic metabolism. In pathological contexts, these calcifications may be accompanied by neurological symptoms related to the underlying disease: Parkinson's syndrome, psychiatric and cognitive disorders, epilepsy or headache. The purpose of this article is to provide a diagnostic aid, in addition to clinical and biology, through the analysis of calcification topography and the study of different MRI sequences.
Apparent diffusion coefficient values of the white matter in magnetic resonance imaging of the neonatal brain may help predict outcome in congenital cytomegalovirus infection
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Estimates of congenital cytomegalovirus-attributable infant mortality in high-income countries: A review
2024, Reviews in Medical Virology
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Original articleAsymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Data collection

Clinical characteristics of enrolled patients

Discussion

Acknowledgements

J Clin Virol

J Clin Virol

J Clin Virol

J Clin Virol

J Pediatr

Lancet Neurol

J Clin Virol

Brain Dev

J Pediatr

J Clin Virol

J Clin Virol

Brain Dev

J Clin Virol

Detection of congenital cytomegalovirus infection using umbilical cord blood samples in a screening survey

J Med Virol

New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection

Rev Med Virol

Congenital cytomegalovirus infection: clinical outcome

Clin Infect Dis

Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection

Rev Med Virol

Original article
Asymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord