Markers for neurocognitive impairment in congenitally CMV infected infants: MARVELYS study

Rationale: Congenital cytomegalovirus (cCMV) infection is the leading cause of
congenital viral infection worldwide and can cause serious disease to the
newborn. In 15%-23% of CMV infected neonates signs of symptomatic disease are
present at birth, such as intrauterine growth restriction, hepatosplenomegaly
or microcephaly. Of these symptomatic children, 90% will develop additional
complications within the first two years of life. The most important long-term
complications are due to central nervous system (CNS) damage, of which hearing
and visual impairment and mental retardation are the most common. In case of
cCMV infection without symptoms at birth, 10- 15% of the affected children
will develop one or more long-term neurological sequelae.
The exact prevalence of congenital CMV infection in the Netherlands is not
known, but recent estimates calculated a prevalence rate at 0.54% (de Vries,
2011), leading to annual incidence of 1000 children are born with cCMV
infection in the Netherlands, of whom at least 180 children (0.1% of all
newborns) will be affected by long term neurologic sequelae.
Currently there is no prenatal intervention to prevent CMV transmission from
mother to child and thus prevent or reduce neonatal neurologic damage.
Postnatal antiviral treatment with (val)ganciclovir is the state-of-the art
treatment of symptomatic cCMV disease. The outcome of cCMV infected children
varies significantly and prognostic predictors of outcome in CMV infected
children are missing. To understand the pathogenesis of neurological and
neurocognitive deficits in cCMV infected patients, long term evaluation
starting at the earliest age possible is necessary. Immunological and
neurological host factors, as well as virological and pharmacological factors
most likely play a role in the outcomes of cCMV infected children. We
hypothesize that the several immunological, neurological host factors and
virological and pharmacological factors may influence long term outcomes of
cCMV infected children.

1. To characterize long-term neurologic- and cognitive disorders, audiological
and ophthalmological alterations in cCMV-infected children.
2. To identify immunological, neurological host factors and virological factors
that are predictive of neurological and neurocognitive impairments in cCMV
infected infants.
3. To evaluate the added value of advanced Magnetic Resonance Imaging (MRI)
techniques, including Diffusion Tensor Imaging (DTI), Magnetic Resonance
Spectroscopy (MRS) and Arterial Spin Labelling (ASL) to predict neurological
outcome within this pediatric population.

prospective longitudinal observational study

This study is classified as an observational study in subjects incompetent to
give informed consent. CCMV infected infants will undergo as part of their
standard treatment plan neuropsychological assessments (NPA), MRI neuroimaging,
audiological and ophthalmological examination. As part of their standard
treatment plan, cCMV infected children will undergo venous blood sampling at
various time points in the follow up period according to international and AMC
guidelines. Extra blood samples to evaluate immunological and neurological host
factors will be collected during routine vena punctures (VP) that are performed
as standard patient care (6,5 ml of blood taken at 7 time point during 8
years). For this study, the study participant will undergo a novel
neuro-imaging using novel MRI technique (3Tesla) instead of the conventional
1,5 Tesla MRI imaging. For this study, the study participant will undergo an
NPA, MRI neuroimaging, audiological and ophthalmological examination at the age
of eight years. At the age of eight year, the study participants will undergo a
venous blood draw and sampling. Children younger than three months of age and
older than eight years of age can undergo MRI imaging without general
anesthesia.
All parents and/or caregivers of the study participants will be given
extensive information on all the tests that need to be taken as part of
routine patient care as well as part of this study. Patients will be included
on voluntary basis. During all procedures we will guarantee guidance from
research staff for all participants. Parents/guardians can join their child at
all times.
CCMV infants may later develop sequelae. To understand the pathogenesis of
neurological and neurocognitive deficits in these patients long term evaluation
starting at the earliest age possible is necessary. Therefore we aim to
include neonates with a cCMV infection as early as possible in life to be able
to tailor medical treatment and initiate supportive care if needed as soon as
possible.
We expect to find various prognostic (host) factors of poor neurological and
cognitive outcome in our study group. Former comparable pediatric neuro-imaging
and NPA studies have obtained medical ethical approval and have produced
satisfying results (Cohen CID 2015, Cohen Neurology 2015, Aukema,2009).