Epilepsy Clinical Trial
Official title:
The Biomarkers of Neurological Disease in Utero Study
Anti-epileptic drugs (AEDs) are potent teratogens associated with a spectrum of physical and
neurodevelopmental anomalies to the exposed fetus. Particular risks include congenital
malformations, impaired motor and cognitive functioning, autism and poorer educational
attainment. Fetal exposure to drugs that bind to central nervous system targets as part of
their therapeutic effect (e.g. neurotransmitter receptors and neuronal channels) appear to
alter brain structure and function in both animal models and humans.
Fetal magnetic resonance imaging offers an approach to investigate these effects in vivo,
identifying biomarkers, defining the onset of abnormalities and dose response. Fetal MRI may
offer risk stratification and identify patients that may benefit from intervention early in
development. The overall aim of this study is to contribute to improving developmental
outcomes following the inevitable exposure during treatment of maternal epilepsy.
This novel study aims to explore the central nervous system with state-of-the-art
non-invasive multimodal magnetic resonance imaging consistent with the University of
Nottingham Precision Imaging Beacon, so as to improve outcomes in patients at risk of long
term complex neuropsychiatric conditions.
BACKGROUND There are approximately 50 million people with epilepsy worldwide, with
approximately 3-5 births per thousand to women with epilepsy; in the United Kingdom (UK)
there are 2500 births per year to women with epilepsy. The teratogenic effects of
anti-epileptic drugs (AEDs) on the fetus is a major public health concern. In 2016 UK
national prescribing data showed around 18,000 women of child-bearing age were taking Sodium
Valproate. for which current evidence suggests has the most potent teratogenic effects of all
AEDs. The Medicines and Healthcare Products Regulatory Agency (MHRA) has formulated a
specific prevention programme aimed at reducing the rates of valproate-associated
teratogenicity. Longitudinal studies of fetal AED exposure show increased rates of congenital
malformations, abnormal motor development, lower intelligence quotient, and poorer
educational attainment. However, to date there is a major lack of research on the underlying
neuroanatomical basis for such alterations in cognitive function, whether pre or post-natal.
Early exposure to neuromodulatory drugs likely induces abnormalities in structural brain
development, neuromotor behaviour, and functional networks. Fetal MRI presents a novel
multimodal approach for interrogating the effects of pathological exposures, identify
biomarkers, define onset of abnormalities, and the dose response. This may aiding risk
stratification, identify candidates for earlier intervention, and improve neurodevelopmental
outcomes.
There are limited strategies available to the clinician to assess the risk to the fetus'
brain health. Current guidance recommends Ultrasound Scan (USS) to screen for physical
defects. However, USS is limited in its ability to comprehensively understand brain
development. Fetal MRI presents an advance that is of clinical utility to neurologists,
psychiatrists and obstetricians who routinely prescribe AEDs for a range of neurobiological
conditions. Advances in fetal MRI have identified biomarkers for disease that may guide
clinical management, and offers the potential of a multi-dimensional characterisation of the
developing nervous system by analysing brain structure, neuronal networks, expression of
metabolites and behavioural analysis, which may also provide the basis for long-term adverse
outcomes. A small unpublished case series from the Chief Investigator's doctoral study
elucidated several promising features of fetal MRI : (i) MRI confirms USS findings and can
improve the characterisation of brain structure; (ii) longitudinal in utero imaging is
feasible and sometimes necessary; (iii) brain anomalies are present and may be attributable
to exposure to AEDs; (iv) clinical management of pregnancies and the postnatal period is
directly impacted by fetal MRI.
This study will undertake a pilot study using fetal MRI on 20 pregnant women with the aim of
developing a tool to further characterise in utero brain development. This is a pilot study
which will include 2 cohorts: women with epilepsy taking AEDs (WWE) (N=10), and age-matched
healthy pregnant controls (HC) with no known neurological disorder (N=10).
RESEARCH QUESTIONS The aim of this study is to investigate the adverse neurological effects
on a fetus exposed to Anti-Epileptic Drugs.
STUDY DESIGN This case control observational study aims to characterise fetal brain
development in the context of exposure to Anti-Epileptic Drugs. Participants will attend a
single session at the SPMIC, University of Nottingham, in addition to their clinical
antenatal care. Pregnancy outcome will be collated from clinical records. At their SPMIC
session, they will complete a simple demographics data collection questionnaire on their
personal medical history, followed by a 3 Tesla MRI Fetal MRI scan. There is no requirement
for randomization or blinding. Each participant will be assigned a study identity code
number, allocated at randomisation for use on study documents and the electronic database.
The documents and database will also use their initials.
The Chief Investigator has overall responsibility for the study and shall oversee all study
management. The data custodian will be the Chief Investigator. The Chief Investigator and
co-investigators will meet regularly for the duration of the study to discuss the project
implementation and overall progress.
The study is planned to be implemented over over 5 years from 2019. This will allow for
recruitment and scanning of participants, and then a period of allowing participants to
deliver the fetus, and post-partum outcome information to be collected. The end of the study
will be marked by the final outcome from the last participant to deliver.
The imaging will all take place at the Sir Peter Mansfield Imaging Centre (SPMIC; University
Park, University of Nottingham). Before commencing the scan the pregnant woman will be asked
to fill in the SPMIC safety form to screen for any contraindications of MRI. The MRI will
take up to one hour to perform and women will be in the centre for about 1-2 hours.
Demographic and outcome data from the pregnancy will be collected by the research staff
during the study. Women will be asked if they wish to be informed of the results of the study
and asked to leave contact information for this purpose (Email or address).
MRI data will acquired using sequences including, but not limited to, T2-weighted structural,
functional MRI (fMRI), Diffusion Tensor Imaging (DTI), and Cine (for motor analysis).
Structural data will be acquired in 3 orthogonal planes, registered and reconstructed for
further automated tissue segmentation. Segmented tissues will be used for volumetric analysis
and the development of shape analysis methods. The fMRI data will analysed for resting state
network differences between cohorts, and differences in Blood-Oxygen Level Dependent response
during motor activity. DTI data will be analysed according to an analysis pipeline described
recently, and will allow comparison of differences in tract formation between cohorts. Motor
behaviour will be analysed according to principles of General Movement analysis between
cohorts.
MRI is a safe, non-invasive and non-ionizing clinical imaging modality. Concerns naturally
arise when using any imaging modality in the fetus, both in terms of immediate teratogenicity
and long term development effects. In this regard, UK guidelines do not recommend MRI prior
to 18 weeks gestation, unless there are exceptional clinical concerns. The magnitude of the
primary magnetic field does not occur in natural phenomena, however there are no known
adverse biological effects due to such interactions. However repeated radiofrequency pulses
result in energy deposition in tissues and can lead to heating effects. This is measured by
the specific absorption rate and the distribution of thermal energy deposition has been
investigated in pregnancy. Animal models have demonstrated that thermal energy generated by
metabolic processes in the fetus dissipate through two routes: thermal energy transfer from
fetal to maternal blood in the placenta and directly from the fetal tissues into the
surrounding amniotic fluid. Clinical studies into the long term effects of MRI exposure to
fetuses have also shown no adverse outcomes in terms of growth deficits, or changes in
physiological parameters.
Descriptive statistics will be produced of the variables collected. Graphical displays will
be generated as appropriate. Data summaries for continuous variables will be expressed as
median and interquartile ranges and for categorical variables will be expressed as n (%).
Further statistical testing will depend on the distribution of the data. Parametric (e.g. t
tests) and non-parametric statistics (e.g. Mann-Whitney U-test) will be used to compare
differences in the continuous and non-continuous variables respectively, between groups.
Chi-square test or Fisher's exact test will be used to examine associations between
categorical variables. Limits of agreement and Bland-Altman plots will be used to examine
intra- and inter-observer reliability of measurements.
STUDY SETTING Demographic and medical history will be collected from two sources: hospital
records, and directly from a patient administered questionnaire on the day of the SPMIC
visit. MRI data will be acquired using the 3 Tesla wide-bore MRI scanner at SPMIC, University
of Nottingham. The choice of scanner permits greater participant comfort particularly later
in gestation where changes in body habitus would benefit from a larger circumference scanner.
There is also a substantial amount of experience for scanning pregnant women on this scanner.
Patients will be recruited from a single site at the Joint Obstetrics-Epilepsy Service at
Nottingham University Hospitals, which has specifically designed to manage women with
epilepsy that are both considering or are currently pregnant. The clinical team consists of
Consultant Obstetricians, Consultant Neurologists/Epileptologists, Obstetrician Specialist
Trainees, Physician Specialist Trainees, and Specialist Nurses.
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