Imaging Markers of Epileptogenesis: New Research Directions

NINDS Neurodegeneration Group Event Series

This workshop primarily focused on technological advances in neuroimaging that could be applied to understanding the neurobiology of epilepsy. Epilepsy basic scientists and clinicians met with experts on imaging to have an in-depth discussion on the potential role of imaging modalities in elucidating the microstructural and physiologic development of epilepsy. The presented topics included epileptogenesis at the cellular and microsystem or macrosystem levels, current technological developments in imaging and electrophysiology, specific application of neuroimaging on physiologic dysfunction, and general new approaches for anatomical, functional and molecular imaging of the brain. Issues that arose from these presentations included development of imaging measures of in vivo neuritic sprouting, as well as multi-modal measures of both resting and/or challenged (pharmacological, cognitive, hypercapnic, etc.) functional viability of in vivo neural structures. The need is to identify in vivo neuroimaging approaches that are predictive of the eventual development of epilepsy so that longitudinal measures of these parameters may be predictive or reflect epileptogenicity at earlier of later stages of the disease. Following the presentations, the participants separated into three smaller groups for the purposes of discussing how imaging can help address the issues presented. Each discussant group was asked to propose study design for targeting epileptogenesis in humans. Newly generated ideas from the participants in these two separate fields lead to specific research strategies that might be developed into research proposals. Specific recommendations that resulted from this workshop include:

1. A need for preclinical imaging studies to develop and evaluate methods in animal models which might facilitate determining the sequence of events leading to habitual epilepsy. For example, data for frequent seizures, rare seizures, and no seizures could be compared in groups of animals with stimulus evoked status epilepticus. These would include methods that cannot be readily applied in humans, for example, invasive studies investigating neurovascular coupling at the single-cell level, or multi-modal experiments for understanding relationships between energy metabolism, neurotransmission, and glial interactions.
2. Emphasis was also placed on the need to use animal models to develop imaging markers that could be linked to electrophysiological abnormalities. Specific suggestions included markers of ionic flux, very high resolution quantitative morphometric analysis, measures of neuronal functional viability, or ion channel activation. Animal models should be used to develop surrogate markers of epileptogenesis and to predict epileptogenicity for human studies.
3. In both animals and man, new methods for ictal mapping might be able to help detect structures participating in seizure spread. A need for prospective collaborative clinical investigations that could have event-related (such as first febrile or afebrile seizure or traumatic brain injury) or genetic susceptibility entry points became apparent. For these studies, participants emphasized integration of multi-modal imaging markers of epilepsy (EEG, MR technologies, PET, MEG, optical imaging) whose combined information may better define at-risk individuals or specific targets of intervention.
4. A need for clinical trialsto include long-term clinical follow-up to differentiate individuals who progress to develop seizures and/or other neurological, neuropsychological or neuropsychiatric disorders in later life. In the context of long-term multicenter collaborative studies, the issues discussed included effective and ethical recruitment and study of pediatric, at risk, and underserved populations.
5. There was clear agreement on the need for technical and infrastructure development, potentially including epilepsy-dedicated animal and human imaging centers, as well as, in the context of multicenter studies, development of standard probabilistic pediatric atlas sequences to enable statistically based analyses of early structural or metabolic changes in patients at risk for epilepsy. Targeted development of PET ligands for specific receptors such as NMDA was suggested. A major theme of the conclusions was the vital importance of collaboration between basic and clinical epileptologists and imaging researchers.

Recommendations from this workshop are relevant to the epilepsy benchmark related to neuroimaging from the March 2000 "Curing Epilepsy" Conference. The overall goal of this benchmark is to "discover the range of anatomical, physiological, and molecular substrates associated with the epilepsies; define unambiguous markers of epileptogenicity." Specific sub-benchmarks seek ways to: develop a non-invasive imaging or physiological monitoring system capable of detecting an epileptic region; generate large-scale imaging databases; and establish a collaborative network of investigators.