Award:

Study Cohort

The study will recruit 65 epilepsy subjects and healthy controls (HC) each, aged 5–18 years at enrollment. Subjects will come in for 1 baseline visit at enrollment. Following informed consent, baseline imaging and neurobehavioral testing will be completed. The 1-year follow up will consist of 1 visit with a similar format for follow up imaging and behavioral testing. Standardized clinical data will be collected using the Epilepsy CDE domains categorized into: (1) Patient characteristics, (2) Disease Related Events, (3) Assessments and Examinations and (4) Treatment and intervention. Neuropsychological assessment will focus on 3 domains (neurocognition, adaptive behavior and social adjustment) through direct assessment of children and proxy-based measures to be completed by parents. Imaging protocols are designed in parallel with the Epilepsy Connectome Project to include a structural MRI, resting state fMRI and high angular resolution diffusion images to assess white matter tracts.

Inclusion Criteria

Epilepsy subjects are children with newly diagnosed FCD epilepsy following standard clinical, neurophysiological and imaging diagnostic criteria. Subjects will be followed for a minimum of 1 year. Data will be acquired at enrollment and at 1-year follow-up to establish a patient and normative (HC) longitudinal database. Patients with coexistent neurological conditions like cerebral palsy or developmental delays due to secondary causes will be excluded. Presence of any radiographic lesions other than non-specific white matter abnormalities on 3 Tesla MRI will also preclude inclusion. 65 healthy control subjects to establish a normative and longitudinal database. Volunteers will be screened using a medical history questionnaire, followed by neurologic and psychometric evaluations. Exclusion criteria include: coexistent neurological conditions, metabolic diseases or primary developmental delays; intracranial structural abnormality on T1-weighted MRI scans.

Primary and secondary outcomes

Primary outcomes are functional and structural characteristics of neural networks between FCD subjects and age matched healthy controls at clinical diagnosis and at 1 year follow up. This dataset will serve as a normative baseline for longitudinal evaluation of network changes in relation to the cognitive and clinical trajectories for subjects. Seizure burden (medication response, treatment refractory state, seizure frequency) and neurocognitive function (domain specific indices) will be used as secondary outcome measures at 1-year follow-up. Multivariable regression models will be used to determine the correlations between seizure burden, connectivity changes and behavioral change correlations.

Estimated sample size and number of centers needed

Sample size estimates were computed to detect effect sizes of 0.5 (moderate) with 90% power. Assuming a type I error rate of 0.05 with a 2-sided independent t-test, a total sample size of 120 with 60 subjects each in FCD and control group is needed. To account for ~10-15% data loss due to subject drop out, data loss due to head motion and other factors, we propose to recruit a total of 65 participants in each group. Up to 10-12 subjects will be enrolled from up to 6 participating sites for a total of 65 epilepsy subjects.

Study Funding

Grant


Authors: Raheel Ahmed, MD (Madison, WI)

Background Focal cortical dysplasia (FCD), the most common cause of treatment refractory epilepsy in children, involves a focal radiographic lesion, but is associated with widespread seizure networks. Current treatment approaches directed at the focal lesion or seizure onset zone are often insufficient to effectively eliminate the long-term seizure burden. There is an evolving recognition that alterations in distributed cortical networks in epilepsy that extend from the seizure onset zone and involve distant brain regions. How neural network activity patterns in FCD epilepsy are responsible for progression to a treatment refractory state remains largely unknown. These tenets of neural network properties could address current limitations in understanding disease heterogeneity between patients, medication responsiveness, cognitive morbidity, and predict efficacy of surgical treatment. Resting state functional neuroimaging (rs-FMRI) and Diffusion Tensor Imaging (DTI) assess dynamic neural activity and structural connectivity respectively and can provide important insights into altered functional and structural connectivity in epilepsy. They are well suited for children with epilepsy that also have concurrent intellectual disability and neurobehavioral impairments since they do not require subject participation. Cross-sectional studies to date, exploring the nexus between neural networks and epilepsy have reported changes in neural connectivity in epileptic networks. Whether these changes reflect underling structural brain pathology or neurocognitive alteration or reflect the electrophysiological networks that underlie epilepsy remains to be determined. These studies are limited by heterogeneity in case populations, underlying etiology, extent of epilepsy, ongoing pharmacotherapy and lack concurrent assessment of neurobehavioral functions. This goal of this collaborative proposal is to determine neural network changes in FCD epilepsy and generate an updated framework for clinical decision-making and therapeutic management based on neural connectivity patterns. A multi-center patient cohort will be recruited to acquire longitudinal imaging and clinical data on FCD pediatric patients from disease onset through progression, focused on determining neural substrates for seizure burden and neurocognitive dysfunction, the principal morbidities of epilepsy networks in FCD. A longitudinal assessment allows us to account for age dependent re organization within brain networks and removes a significant source of heterogeneity. Network properties will be assessed with respect to healthy subjects (inter-individual variation) and differences over time (intra individual variability). Hypothesis A dynamic understanding of neural network organization in epilepsy from clinical onset through its natural history is currently lacking. It is also unclear as to how network dysfunction can give rise to disparate outcomes of neurological (seizures) and neurobehavioral manifestations. The study hypothesis is that specific patterns of intrinsic neural oscillatory activity and structural connectivity have a critical role in development and maintenance of functional and structural properties of the FCD epileptogenic network. Study aims are to determine (1) baseline connectivity patterns in new onset FCD epilepsy, and (2) whether changes in neural networks correlate with temporal patterns of seizure burden and cognitive morbidity.