**2005 Report submitted by Benchmark Steward(s):**

William Theodore, M.D. (National Institute of Neurological Disorders and
Stroke)

Ruben Kuzniecky, M.D. (New York University)

**Background of the benchmark goal:**

**Current status of field:**

*PET as a surrogate marker*

-   Likely to be more useful to study long-term epileptogenesis than
    varying epileptogenicity, due to 'physiologic time frame' (hours) of
    studies, and limits on replicability due to radiation exposure.

-   5HT1A decreases confirmed by several studies (1-3). Decreases are
    not due to cell loss (4), raises issue of relation of increased
    precursor (AMT) and decreased receptors, potential role in onset of
    MTS---seizure-related HF neurogenesis .

-   BZP receptor studies---studies of clinical role continue

-   Other receptors---some groups working on several potential
    EAA-related tracers; Radioactivity uptake of intravenously
    administered reduced (S)-\[N-methyl-11C\]ketamine activity in TLE
    may reflect reduced NMDA-receptor density, focal atrophy, or other
    factors (5).

*MEG*

Most studies directed toward comparing clinical value of MEG and EEG,
and role of the former in epilepsy surgery (6-11). Analysis of MEG
dipoles may reveal participation of additional structures in
epileptogenicity, and varying modes of spread of cortical excitation. In
some cases it may be possible to obtain ictal MEG (12). It is uncertain
how much MEG adds to multichannel EEG electrical activity modeling.

*MR Spectroscopy*:

Recent studies suggest that proton MRS measurements reflect neuro/glial
dysfunction rather than neuronal cell loss. MRS is more sensitive than
MRI to detect early changes in the epileptogenic area and thus, it may
be a suitable tool to study progression in epilepsy.

MRS studies in humans have shifted to 1) High resolution combined
Phosphorus/Proton studies of the temporal lobes and adjacent structures
2) editing techniques to quantify absolute neurotransmitters (Glutamate,
GABA) in cortical structures. Studies demonstrate absolute reductions in
Glutamate in the epileptogenic temporal lobe.

*MRI Techniques*

Several studies under way to evaluate sensitivity of higher field
Magnets (3T Vs 1.5T) in epilepsy. DTI studies have not yielded
significant findings to-date.

*MRI in animal models*

There has been increasing use of MRI in rodent models of epilepsy,
including excitatory amino acids, febrile seizures, and other approaches
( 13-19 ). So far, most studies have used structural imaging, although
both BOLD signal and arterial spin tagging CBF measurements, and
diffusion weighted imaging have been performed as well. The short 'time
window' of MRI allows study of fluctuating physiologic states. EEG and
MRI have been combined in animal models by some investigators, although
not all the technical details have been worked out (20-1).

*Imaging cognitive / psychological / structural consequences of
epilepsy*

Both MEG and fMRI are being used for both preoperative cognitive
mapping, and studies of functional reorganization due to epilepsy,
generally confirming older data showing early onset of seizures is
strongly associated with atypical language lateralization, and that
Lesions in the dominant hemisphere tend to result in an intrahemispheric
reorganization of linguistic function (21-27). Studies using structural
MRI or PET to follow long-term structural consequences of 'new-onset'
epilepsy have found much less evidence of initial injury, or
progression, than reported previously in populations of patients with
established intractable epilepsy, due possibly to subject heterogeneity,
relatively short follow-up, or the higher chance of a benign course in
some patient samples (28-30).

**Activities update:**

A conference on Imaging Markers of Epileptogenesis: New Research
Directions was held April 10-11, 2003
(<http://www.ninds.nih.gov/news_and_events/proceedings/Epileptogenesis_2003.htm>
)

The conclusions / recommendations were:

-   A need for preclinical imaging studies to develop and evaluate
    methods in animal models

-   need to use animal models to develop imaging markers that could be
    linked to electrophysiological abnormalities

-   new ictal mapping methods to detect structures participating in
    seizure spread

-   Prospective collaborative clinical investigations with event-related
    (such as first febrile or afebrile seizure or traumatic brain
    injury) entry

-   need for technical and infrastructure development

**Top priorities for next 5-10 years:**

-   Establish validity of imaging markers of both epileptogenicity and
    epileptogenesis, followed by intervention trials in animal models.

-   Refinement of fMRI-EEG techniques for both animal and human studies.

-   Additional human collaborative imaging studies such as current
    consequences of prolonged febrile seizures

-   Develop additional PET ligands, and refine techniques to allow more
    studies in children with new onset epilepsy.

-   Validation of new MRS editing techniques to quantify
    neurotransmitters in humans

-   Encourage / support more widespread use of ICBM database
    (http://www.loni.ucla.edu/ICBM/).

**Roadblocks to progress:**

-   Lack of knowledge of complementary techniques

-   Insufficient interaction of 'imagers' and 'epileptologists'.

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