The review is restricted to original publications on the field of neuroimaging for epilepsy in the last year, focusing on areas of ongoing research, development and application.
For further background reading, there have been recent reviews of aspects of neuroimaging applied to epilepsy [1–6].
Scanning patients with refractory focal epilepsies, who have had unremarkable MRI scans previously, using a modern 3T MRI scanner and sequences, will identify focal abnormalities, commonly malformations of cortical development, or provide useful clarification of uncertain findings in 20% [7•]. The use of surface coils could provide further clarification of identified lesions, but did not usefully increase the detection rate. The important practice point is that patients who could be candidates for surgical treatment, and who have had previously unremarkable MRI scans, should be rescanned when more advanced equipment and methods become available.
Voxel-based analysis of MRI gives insight into subtle structural changes that may not be evident to visual inspection in individual patients and can be used to probe associations in groups of patients. Analysis of diffusion tensor imaging (DTI) in patients with hippocampal sclerosis showed widespread abnormalities, particularly in the ipsilateral temporal lobe and limbic system, and also in the arcuate fasciculus . Bilateral abnormalities of DTI parameters have also been shown in the thalamus of those with hippocampal sclerosis, but not in those without hippocampal sclerosis . A voxel-based analysis of FLAIR signal intensity detected malformations of cortical development in individual patients, suggesting that this method may be a useful adjunct to the visual reading of MRI scans [10•]. The next step is to evaluate the sensitivity and specificity of the method in individuals in whom visual reading of scans has not identified any abnormality.
The clinical utility of voxel-based analysis of individual patients is constrained by the need to balance sensitivity and specificity, and the optimal balance will differ for various MRI contrasts . Overall, the yield of positive and helpful findings in individuals with unremarkable conventional MRI is in the range of 10–30%.
Voxel-based morphometry (VBM) is based on the distribution of grey matter in the brain and, in a group, may reveal areas of grey matter loss. In a series of patients with hippocampal sclerosis, cognitive performance correlated with global grey matter volume but there were no specific anatomical correlations, suggesting that the cognitive impairment seen in association with hippocampal sclerosis is on the basis of involvement of widespread networks . Further evidence for temporal lobe epilepsy (TLE) being part of an affected network comes from a VBM study that showed widespread distributed grey matter loss in patients with TLE, and which was more extensive in those with left TLE. In those with mesial TLE, loss of grey matter was noted in the thalamus, limbic system and cerebellum. In contrast, cryptogenic TLE was associated with grey matter loss in the temporal, frontal and orbitofrontal cortex . Corroborating previous work using VBM, increased grey matter concentration in the medial frontal lobe and relative atrophy of the thalamus have been reported in a cohort with juvenile myoclonic epilepsy (JME), supporting the contention of an abnormal thalamo-frontal circuit in this syndrome .
In accord with earlier studies, voxel-based assessments of parametric maps of mean diffusivity and fractional anisotropy have shown abnormalities in a proportion of patients with refractory focal epilepsy and unremarkable standard MRI. The lobar concordance with clinical and electroencephalogram (EEG) data was 50%, highlighting the need to balance sensitivity and specificity and to interpret images cautiously .
The correlation of in-vivo imaging with histopathological findings is crucial for the interpretation and understanding of the significance of brain imaging data. These correlations were made in the hippocampus a decade ago and the neocortex is an order of magnitude more complicated in terms of structure and interindividual variations. Recent advances in MRI acquisition, such as the PROPELLER sequence, give improved spatial resolution and definition of hippocampal substructures in vivo, and precise alignment of imaging and histological slices allows correlation with histological findings that are highlighted with a variety of stains, for example, the increased staining with glial fibrillary acidic protein (GFAP) correlated with increased T2 signal in the hilus .
In temporal neocortex, there was a significant inverse correlation between the T2 in grey matter and the neuronal field fraction, implicating that neurone loss is a feature that gives rise to elevation of T2 in in-vivo MRI . T2 measures have been established at 3T with a dual echo sequence that also is used for qualitative imaging, so no extra acquisition is required .
The co-registration of in-vivo MRI with anatomy is important for making MRI–histological correlations and also for determining the precise location of intracranial electrodes prior to resection. A recent study describes techniques for aligning surface-rendered MRI with digital photographs of the brain surface taken after a craniotomy, which are useful for determining the coordinates of subdural grids .
Automated hippocampal volumetry
Manual hippocampal volumetry has been used for over a decade in both clinical and research work to identify unilateral and bilateral hippocampal damage, and to localize this within a hippocampus. This needs a skilled operator and requires at least 30 min of interactive time. Accordingly, attempts have been made to automate hippocampal volume estimations. A voxel-based approach using estimations of grey matter content has given promising results [19•]. The next crucial stage will be evaluation of a less well selected prospective series of patients in whom the scans may be suboptimal.
Analysis of the surface structure of the hippocampus has been used recently to identify abnormalities of hippocampal morphology, and may do so when conventional analysis concludes that a hippocampus is unremarkable [20•]. These approaches will need careful evaluation and assurance of their sensitivity and specificity before they are brought into clinical practice.
Animal model imaging
An interesting recent development, so far only used in a proof of principle study in a rodent model of TLE, has been to combine alpha-methyl tryptophan with magneto nanoparticles that include dextran and iron oxide. The compound crossed the blood–brain barrier, was visible on a 19-min acquisition at 7T and appeared to be taken up into the hippocampi [21••]. Much more work needs to be done to validate or refute these findings, and if confirmed, the method could be useful for visualizing the uptake of specific ligands into the brain in vivo, without recourse to radiation emitting isotopes.
Tractography is a derivative of DTI that visualizes the white matter connections in the brain, allowing inferences to be drawn regarding structural connectivity. In patients with left TLE, there were reduced connections on that side from the parahippocampal gyrus and the extent of the connections correlated with verbal memory performance, with the implication that the reduced function was associated with structural impairment in this part of the brain . In a study using different methods, diffusion abnormalities were found in the uncinate fasciculus ipsilateral to the epileptic focus and were related to impairments of memory .
Using functional MRI (fMRI) activation maxima as a seed point of tractography, the white matter connectivity of Broca's area has been demonstrated, with relative enhancement of the connectivity of the homologous area in the right inferior frontal lobe in those with left TLE [24••]. The asymmetry of these connections was a predictor of naming difficulties following anterior temporal lobe resection, with greater lateralization of tracts to the dominant hemisphere being associated with greater decline in naming function [24••].
Tractography is user-dependent and very time-consuming. Attempts are being made to automate parts of the process and hence reduce the input needed and the potential bias; prior anatomical knowledge continues to be necessary .
Electroencephalogram–functional magnetic resonance imaging
Studies of fMRI with simultaneous EEG recordings are revealing more about the spatial distribution of interictal epileptic discharges, and the relation of these sites to the seizure onset zone, as determined with fortuitous ictal EEG–fMRI or intracranial EEG recording and subsequent resective surgery. Paired analyses of cerebral blood-oxygen-level-dependent (BOLD) signal and perfusion during generalized spike-wave activity have shown that the BOLD signal change is on the basis of alterations in cerebral perfusion, indicating preservation of normal neurovascular coupling .
Work is in progress to evaluate the feasibility of fMRI studies in patients with intracranial EEGs, which will be an important validation of fMRI. To date, work with deep brain stimulation electrodes suggests that fMRI studies at 3T look achievable .
The poor temporal resolution of fMRI precludes a precise dissection of the nature of spread of epileptic activity but this may be inferred with studies of functional connectivity [28•]. Simultaneous electrical source imaging of epileptic activity can provide the temporal resolution necessary to resolve the patterns of propagation. Comparative studies have shown that whereas some fMRI activations may co-localize with electrical source localization, others are discordant , the implication being that the latter represent downstream effects on cerebral activity.
Cognitive functional magnetic resonance imaging
Impairment of language and memory function after anterior temporal lobe resection is a concern – particularly impairment of verbal memory and language after left-sided surgery. fMRI studies are now being introduced to determine the extent to which they may give useful prediction of the likely change following surgery, over and above that obtained from consideration of demographic and clinical variables.
Language dominance, determined using fMRI, explained an additional 10% of the variance in postoperative verbal memory outcome, over and above the 50% explained by clinical and baseline neuropsychological variables. This indicated clinical utility to identify those at high risk of impairment of verbal memory after surgery. It was also of note that the intracarotid amytal test did not give further useful data [30••].
Patients with relatively greater ipsilateral than contralateral medial temporal lobe activation on fMRI memory activation studies had greater memory decline following temporal lobe resection for both verbal memory decline following dominant temporal lobe resection and for nonverbal memory decline following nondominant temporal lobe resection. For verbal memory decline, activation within the dominant hippocampus was predictive of postoperative memory change, whereas activation in the nondominant hippocampus was not. This investigation suggests that preoperative memory fMRI may be a useful noninvasive predictor of postoperative memory change following temporal lobe resection .
Viewing fearful faces causes amygdala activation, and in patients going for right anterior temporal lobe resection the degree of activation was predictive of postoperative anxiety [32•].
The evidence base supporting the use of fMRI as a predictor of memory decline after anterior temporal lobe resection continues to accumulate, in a recent series with an object location memory task .
Studies of functional connectivity with cognitive tasks such as working memory are being used to infer the neuronal networks that subserve these tasks . It remains to be seen whether these studies have any clinical utility that advances the treatment of patients with epilepsy.
Single photon emission computed tomography
Although ictal–interictal subtraction single photon emission computed tomography (SPECT) has been in use for many years as a method of inferring the location of epileptogenic zone, important caveats are still being documented, such as the study of patients with supplementary area seizures in whom ictal SPECT did not localize to the supplementary motor area, but to the anterior cingulate bilaterally .
Fluorodeoxyglucose (FDG) PET has been a workhorse of presurgical evaluation since the 1970s, and its role has now been largely superseded by high-quality MRI. In the presence of a concordant lesion shown on MRI and clinical and neurophysiological data, an FDG PET study is redundant. In the 20–25% of patients with refractory focal epilepsy who have unremarkable MRI scans, however, the finding of focal hypometabolism can provide useful data towards a decision to carry out an invasive intracranial EEG recording. A recent meta-analysis showed that in TLE, ipsilateral focal hypometabolism was a predictor of good surgical outcome .
Further, a decision tree analysis has concluded that FDG PET provides useful information that is cost-effective, particularly if its use is restricted to the evaluation of patients in whom MRI and scalp video-EEG telemetry do not provide a definitive answer [37•].
The hope that PET with specific ligands would reveal the in-vivo neurochemistry of epilepsies and seizures and the functional anatomy of abnormalities has been an aspiration for many years. In particular, it was suggested that increased uptake of 11C-alpha-methyl tryptophan (AMT) might indicate the epileptic focus, when then there was more than one contender, as in tuberous sclerosis. The goal is that this method might be useful to localize the focus in those with MRI-negative refractory focal epilepsy, particularly when this is on the basis of an occult malformation. In 25% of children with normal MRI, there was a focal increase of AMT binding, and positive findings had a high specificity , suggesting that this may be a useful investigation in patients with occult malformations and refractory focal epilepsies.
In children who had had failed cortical resections, there was increased AMT uptake in the ipsilateral lentiform nucleus, and the increase was less with greater intervals between surgery and scanning . In the absence of preoperative scans, these data are difficult to interpret, and the problem would be well suited to rigorous prospective study using an animal model.
Uptake of AMT has been assessed in four patients with periventricular heterotopia . In this condition, it is controversial whether seizure onset will be within the nodules or in the neocortex. Increased binding was not found in the nodules themselves, but their small size and partial volume effects would militate against this. Areas of increased AMT uptake were found in the neocortex, consistent with the possibility that this is the site of seizure onset, but there was not a precise correlation with intracranial EEG data.
Depression is a common accompaniment of refractory epilepsy, and understanding the mechanism of this is an important goal. Increased binding of a 5HT-1A receptor antagonist, 18F-MPPF, was found in central serotoninergic networks, particularly the raphe and contralateral insula, ipsilateral hippocampus and bilateral frontal cortex, and there was a correlation with symptoms of depression . The most likely explanation was felt to be reduced serotonin concentrations. Longitudinal studies before and after cognitive behaviour therapy, and pharmacological treatment would be of great interest.
Previous PET studies of 5HT1A receptor binding in those with epilepsy and depression, however, have given conflicting results. Reduced binding of the antagonist [18F]FCWAY was reported in the hippocampus in TLE and with the relationship that lower binding was found in those with higher depression scores . It would help to resolve these differences by undertaking studies with more than one tracer in the same population, but there would be grave logistic difficulties with such a study.
The role of the dopaminergic system in aspects of the pathophysiology of the epilepsies has received attention in recent years. Impulsive behaviour and working memory impairments are sometimes associated with JME. Given the role of dopamine in behaviour, it is of interest, therefore, that impaired dopamine transporter binding was found in the midbrain and substantia nigra, with normal values in the putamen and caudate in those with JME. There was some correlation of tracer uptake with psychological function, raising the possibility of a causal relationship between the neurochemical abnormality and the psychological traits [43••]. This is clearly an area that merits further evaluation in larger cohorts of well characterized and stratified patients.
In patients with autosomal dominant nocturnal frontal lobe epilepsy, the seizures are characterized by vigorous paroxysmal motor activity. In a group of homogenous patients with mutations of the acetylcholine receptor, reduced D1-receptor binding was found in the striatum . How this finding contributes to the clinical picture is uncertain – a possibility is that increased dopamine levels in the striatum gives rise to lessening of the normal inhibition of excitatory thalamo-cortical projections.
Small animal PET scanners have been refined in recent years and may be used for serial studies in living animals, to follow changes in ligand distribution in relation to seizures, and the evolution of epilepsy . Despite many attempts, no satisfactory PET tracers have been identified that visualize the N-methyl-D-aspartic acid (NMDA) or other excitatory receptors in vivo, and this remains an important goal in developing a biomarker for epileptogenesis.
Integration of multimodal data
It is the nature of the evaluation of patients for epilepsy surgery that a consensus is built using a variety of data. The current gold standards for localization of an epileptic focus are ictal intracranial EEG and a good outcome following resection. Both are constrained by the fact that many individuals may not proceed to invasive studies or surgery if noninvasive data do not implicate a single area. The utility of surgical follow-up as a gold standard is also constrained by the long follow-up needed to be clear about the quality of the outcome.
Also, by their nature intracranial EEG samples a limited part of the brain and the conclusion of a study may be that the seizures start from an area of the brain that is not being sampled. In this context it may not be possible to determine whether noninvasive imaging study has, or has not, identified the focus. Further, in a straightforward case, there is the inclination to carry out less tests than if a case is very complex, and when designing an intracranial sampling strategy, it may not be possible or ethical to ignore the results of functional imaging.
With these caveats, an important recent study assessed the relative predictive value of FDG PET, ictal SPECT and magnetic source imaging (MSI) against the gold standards of intracranial EEG  and outcome of epilepsy surgery [47••]. MSI had a high correlation with the findings of intracranial EEG, and both PET and ictal SPECT were of additional localizing value. All three modalities were of benefit in predicting seizure freedom following surgery.
A further difficulty for such correlative studies is that many years are needed to enrol a sufficient number of patients and obtain adequate postoperative follow-up, and imaging technology continues to evolve rapidly such that it may be impossible to fix protocols for the necessary time.
There continue to be rapid advances in structural and functional brain imaging that are being applied clinically. Although this is excellent and is undoubtedly helping patient care and our understanding of the causes and consequences of the epilepsies, a consequence is that the field does not stand still for long enough to carry out large-scale randomized controlled trials with adequate follow-up that generate classical type 1 evidence.
I am very grateful to the Wellcome Trust, Medical Research Council, European Union, National Society for Epilepsy and UCLH/UCL CBRC for support. I am indebted to Jane de Tisi for assistance with the bibliography and formatting this paper.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).
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The first study of the use of functional connectivity and tractography
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A useful study that indicates the additional predictive use of language
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A study that shows that FDG PET is a cost-effective investigation, particularly if its use is restricted to those patients in whom MRI and scalp video-EEG telemetry do not provide a definitive answer.
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44 Fedi M, Berkovic SF, Scheffer IE, et al
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47•• Knowlton RC, Elgavish RA, Bartolucci A, et al
. Functional imaging: II. Prediction of epilepsy
surgery outcome. Ann Neurol 2008; 64:35–41. This reference and the previous Knowlton 2008 reference is an important pair of studies that consider the predictive value of functional imaging methods of PET, SPECT and MRI against the gold standards of intracranial EEG and outcome of epilepsy