IMAGINE-study (imaging study in epilepsy).
Is there a neuronal correlate for cognitive impairment and response to antiepileptic drugs in children with frontal lobe epilepsy?

Frontal lobe epilepsy (FLE), i.e. epilepsy with a frontal epileptic focus,
represents a substantial proportion of all partial epilepsies. The average age
at onset of FLE is between 6 and 12 years. After the diagnosis FLE is made, the
prognosis is still uncertain. Part of the children responds well to
antiepileptic drug (AED) treatment, while others will become refractory and
have frequent and disabling seizures. A second problem is that part of the
children with FLE will suffer from cognitive impairment. The nature and
severity of this impairment is highly variable, but it may seriously affect
their development. Up to now, no clear patient or epilepsy-related factors
responsible for refractoriness and/or cognitive decline have been identified,
and structural MRI scans commonly reveal no abnormalities that may explain
this, even after years of ongoing seizures. Therefore, there are no markers to
recognise this patient category. Hence, a diagnostic tool for the recognition
of patients at risk for refractory epilepsy and cognitive impairment is needed
to increase our understanding of the neuronal substrate and thus aetiology of
refractoriness as well as cognitive impairment. Such a diagnostic tool may help
clinical practice (define those that need more aggressive treatment
strategies), and open new possibilities for pro-active therapy, including drug
development and a more accurate determination of prognosis.
Magnetic resonance imaging (MRI) is a sensitive, safe, available and well-known
technique to visualize brain structure. However, as mentioned, macrostructural
brain abnormalities are commonly not found and are not expected in the early
phase of epilepsy, hence in paediatric patients. Based on the type of cognitive
impairments frequently observed in these children, functional networks in the
frontal and/or temporal lobe are expected to be disrupted. Therefore we expect
neuronal reorganisation especially in this early phase of the epilepsy, as this
is the phase in which refractoriness and cognitive impairment develop.
Recently, more advanced MRI-techniques, including diffusion tensor imaging
(DTI) and functional magnetic resonance imaging (fMRI) became available. These
techniques are capable of visualizing and assessing the level and integrity of
functional networks. Such techniques may reveal the neuronal correlates of
cognitive impairment and refractoriness on the level of microstructural and
functional abnormalities. Such functional network changes have recently been
observed by Vlooswijk et al (CODICE study) in adult frontal lobe epilepsy
patients with cognitive impairment (Janssen & Vlooswijk, ISMRM 2008). This is
in fact the long-term outcome of FLE and shows that once refractoriness and
cognitive comorbidity have been developed, these functional network changes
appear to be irreversible. The emergence of cognitive impairment and
refractoriness are both observed early in the course of FLE thus in childhood.
They develop slowly over the course of two or three years after the onset of
the epilepsy, between the age of 8 to 12 years. Our study forms the third phase
of investigations. First, Reijs & van Mil evaluated both the clinical course
and the impact on cognitive development in children with frontal epilepsy,
resulting in two PhD studies. These studies confirmed that a subset of patients
develop refractoriness in a period of about two years after the onset of the
epilepsy. Cognitive comorbidity developed in this same period, again in some
children. Second, Janssen & Vlooswijk investigated whether neuronal correlates
could be found in adults with FLE as this represents the long-term outcome of
this process, again leading to two PhD studies. These studies demonstrated
microstructural MRI changes and disruption of functional networks in those
adults with FLE who suffer from cognitive impairment. Moreover, these changes
seem to be irreversible as they are also seen in adult patients with low
seizure frequency or those who are in remission. Therefore, any intervention
must be at an early phase. Therfore, we now focus on the phase in which the
neuronal changes develop to evaluate which changes are correlated with the
resistance to treatment and which changes may explain the developmental arrest
of cognitive functions. This can only be observed in children with FLE, i.e. in
the first years after the onset of the epilepsy

In this study we investigate correlations between cognitive impairment as well
as response to AED treatment in children with FLE and brain microstructure,
function and neuronal connectivity, by using DTI, task related fMRI, and
resting state fMRI.

Cohort study

This study involves minors who are unable to give informed consent. Following
the WHO guidelines, the *not unless* principle applies to granting permission
for this study. The MRI-techniques and neuropsychological assessments that are
applied in this study are non-invasive. The risks of a MRI-scan are negligible
because it is a magnetic field, does not involve ionizing radiation and does
not require contrast agents or anaesthetics. To minimize the burden, we will
start with good education, including an information folder. Children can get
used to the sound of the MRI-scan from a computer program. Children will be
constantly guided by their parents and a specialized trial nurse. The scanning
environment will be made as comfortable and cosy as possible. A Walt Disney
movie will be displayed between the scanning sessions. In preparation, the
children will be familiarized with the MRI system. The scanning time is 2 times
30 minutes with a half hour break in between (if necessary longer) and consists
of individual programs with an average duration of 7 minutes. These sessions
can be interrupted at any time. The neuropsychological assessment will take one
hour in total. Recruitment of children in
the age of 8-12 years is essential as FLE is basically a disease of childhood
and often disappears during adolescence (commonly with persistence of the
cognitive impairments). Young adults are therefore not representative to
unravel the development of neuronal correlates of refractoriness and cognitive
comorbidity in FLE. The study of possible neuronal correlates of cognitive
impairment and refractoriness in FLE requires the inclusion of an age-matched
control group. There are three reasons for doing so. Firstly, all effects will
be relative effects and not absolute effects that require a comparison with
normal development to be able to understand. Secondly, apart from the secondary
changes due to the seizures, brain development in children with FLE may as well
differ from healthy subjects. Thirdly, MRI derived cerebral properties such as
oxygenation changes due to brain activation and diffusion properties of white
matter depends on age, and changes most strongly in the age category that makes
up our study population. The imaging of the normally developing brain provides
a necessary baseline for comparisons, both with FLE and FLE complicated by
cognitive impairment or refractoriness. To minimize the burden in the control
group, we will perform the neuropsychological assessment and scanning during
their holiday period and on the same day. Moreover, we will apply short scan
protocols to minimize the magnet time of all the children.