Multimodal neuroimaging in presurgical evaluation of childhood epilepsy

1. Positron-emission tomography (PET)

Hypometabolism identified by FDG-PET has been ascribed to factors such as neuronal loss, diaschisis, inhibitory processes, reduction in synaptic density, or decreased blood-brain barrier glucose transporter activity10-12). Interictal ¹⁸F-FDG-PET is routinely used to detect brain areas of hypometabolism, which usually encompass the seizure onset zone and can also extend beyond this zone13). Thus, ¹⁸F-FDG PET has lateralizing rather than localizing value in temporal lobe epilepsy (TLE). However, because of the poor resolution of this imaging modality, the focus may in fact be at the margin of the area of hypometabolism. A recent report14) has demonstrated that co-registering or fusing the PET data with the structural MRI can improve the ability to identify subtle cortical dysplasias. Such studies have demonstrated that in patients with previously MR-negative test results, the fusion information helped to identify lesions, guide surgical planning, and improve overall surgical outcomes. The presence of contralateral cortical hypometabolism predicts a low chance of seizure freedom after temporal lobectomy15) and the extent of resection of brain areas with hypometabolism on FDG-PET is correlated with improved seizure outcome16). The localizing value of FDG-PET in neocortical epilepsy was significantly worse in patients with extratemporal epilepsy, relative to patients with TLE17). Also, for assessment of FDG-PET, it is advisable to use an automated technique to compare the patient's images to normal data images in a database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. A semi-automated method for assessment of asymmetries in the brain cortex was developed which compares activity concentrations in homotopic cortical areas18). When these differences exceed a predefined threshold, the areas with lower activity are marked and 3-dimensional surface rendered images are created to guide placement of intracranial electrodes (ECoG). This step is followed by surgical resection. The sensitivity-specificity pairs for correct localization of epileptogenic lobes based on the ECoG results were found to be best for the 15% threshold (80/94%, accuracy 0.90)18). This objective PET method enables accurate determination of cortical asymmetries, and it has proven to be highly efficient in guiding epilepsy surgery.

Although ¹⁸FDG, a glucose analog, has been the most common radiotracer nuclide used in PET imaging, it is possible to perform PET imaging with other radiotracers. For example, flumazenil, a benzodiazepine antagonist that acts as a competitive inhibitor against the γ-aminobutyric acid (GABA)_A receptor, can be labeled with a ¹¹carbon (¹¹C) radiotracer which has a considerably shorter half-life. Because GABA_A is the principal inhibitory neurotransmitter in the brain, its role in epilepsy is of ongoing interest. Reports have suggested that, relative to ¹⁸FDG-PET, flumazenil provides improved localization and better correlation with the epileptogenic focus19, 20). Another ligand of interest is ¹¹C-alpha-methyl-l-tryptophan (¹¹C-AMT), an analog of tryptophan and a precursor to serotonin. This ligand has also been reported to be specific for differentiating epileptogenic from nonepileptogenic foci in patients with intractable epilepsy with or without tuberous sclerosis complex21). Resection of tubers with increased AMT uptake is highly desirable to achieve a seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery22). The combination of some of these or other novel radioligands with PET-MRI technology may increase the rate of detection of FCD. However, these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven. Their use in clinical practice is currently limited23).

2. Single Photon Emission Computed Tomography (SPECT)

Ictal SPECT typically indicates areas of regional hyperperfusion, which reflects relative hypermetabolism in parts of the brain involved in onset or propagation of seizure24). Subtraction of the interictal images from the ictal images and co-registration to the patient's MRI (SISCOM) improves the interpretation of the study25). SISCOM has proven to be more sensitive and more specific compared with visual assessment. The importance of early tracer injection after the beginning of the seizure cannot be overemphasized. It has been shown that an injection delay of less than 20 seconds is significantly correlated with a correct localization. With early injections, the largest and most intense cluster is more likely to represent the seizure onset zone and not propagation of the seizure26). The interpretation of automatically-generated SISCOM data is generally straightforward. The result of the SISCOM analysis must be concordant with the result of the visual comparison of the ictal and interictal images, and other data related to the presurgical evaluation. Furthermore, SISCOM may provide a false negative test result because of subclinical seizure activity at the moment of tracer injection for interictal SPECT imaging26). Therefore, EEG monitoring during the interictal injection should be routinely performed. PET results were similarly reliable in lateralizing the temporal epileptic area, while its efficacy was lower for extratemporal cases. SISCOM was found to effectively localize lesions in extratemporal cases, but its efficacy is lower in temporal lesions27).

3. Magnetic resonance spectroscopy (MRS)

Reduced 1H-MRS N-acetyl aspartate over choline (NAA/Cho) and N-acetyl aspartate over creatine (NAA/Cr) have been demonstrated in FCD. Large increases in GABA, alanine, tyrosine, acetate, inositol, glucose, and lactate, as well as decreased NAA were found in a group of four patients with "mild" cortical dysplasia28). These findings may reflect underlying regional structural abnormalities under the resolution of conventional MRI. Alternatively, decreases in N-acetyl aspartate may reflect neuronal or glial cell dysfunction29). The clinical utility of MRS in the evaluation of FCD is not known because MRS is limited by spatial sampling and the above findings are non-specific for FCD. Reduced NAA/Cho ratios outside the epileptogenic region have been reported in temporal lobe epilepsy, and correlate with reductions in seizure-free outcomes after surgery30). However, there are no data supporting this observation in an FCD setting. The sensitivity and specificity of MRS for detecting FCD has not been systematically studied. In another study, preoperative reductions in the NAA/Cr ratio in the non-operated temporal lobe or the presence of higher metabolic ratios contralateral to the proposed surgery are associated with surgical failure. The predictive value of 1H MRSI absolute metabolite concentrations for outcome in mesial temporal lobe epilepsy requires further investigation.

4. Diffusion tensor imaging (DTI)

DTI measures the molecular motion of water within brain tissue. The diffusivity (a measurement of the amplitude of the diffusional motion) and anisotropy (a measurement of the directionality of the motion) can be calculated from the DTI sequence. In the physiologic state, the diffusion of water is restricted by cell membranes. In the white matter, water diffusion is typically highly anisotropic. This characteristic is used in the reconstruction of white matter tracts using tractography31) . The principal diffusion direction of the brain structure to be examined can be color-coded, resulting in color-coded maps or directionally encoded fractional anisotropy (FA) maps. In these maps, the fibers have been given different colors (blue for superior-inferior, green for anterior-posterior and red for left to right) depending on their direction of diffusion. DTI has also been investigated in terms of its use in differentiating pathologic tissue from normal tissue based on differences in the anisotropic diffusion of water32). Several investigations using DTI have revealed higher diffusivity and lower anisotropy in the zones of FCD33), and in surrounding brain tissue that appeared normal in conventional MRI34). Although clinical experience with DTI in the presurgical evaluation of epilepsy is limited, two cases have been published so far where surgery was aided by DTI abnormalities35, 36). DTI may prove valuable for identifying epileptogenic foci as well as more optimally defining the extent of the lesion for surgical resection. In addition, the molecular diffusion of water is typically highly anisotropic in white matter tracts. This characteristic is being explored for reconstruction of fiber tracts using tractography37). The first data set of patients with FCD suggests that there are decreased fiber bundle densities adjacent to an area of FCD38). Fiber tractography will improve our understanding of brain pathology, especially that of white-matter abnormalities. Fiber tracking can be used in conjunction with functional MRI to analyze the anatomical connections and functional pathways for diagnostic purposes and presurgical planning39). The usefulness for DTI and tractography in various pathologies, including FCD, will be in the detection and full delineation of structural abnormalities, and in determining both the functional connectivity of a given area of the cortex and the spatial relationship between the lesion and important white matter tracts. This information may provide critical information for the planning of resective surgery in order to reduce functional morbidity. However, further improvements in techniques and stable post-processing analyses are needed to increase the utility of DTI in clinical applications.

5. Functional MRI (fMRI)

Identification of eloquent areas of cortex responsible for speech, motor, and visual function, to assist in the surgical resection plan, can be obtained non-invasively through the use of fMRI. Functional MRI identifies changes in cerebral blood flow by measuring MRI contrast differences between oxygenated and deoxygenated hemoglobin. Increased cerebral blood flow is thought to represent functional activation of the surrounding cortex. Primary sensorimotor areas can be readily identified non-invasively by fMRI, and the results correlate well, but not perfectly, with those of cortical stimulation and evoked potentials40-43) .A major role of fMRI in epilepsy surgery work-up is in lateralizing language functions as a means to supplement or replace the intracarotid amobarbital test. A panel of tasks, including verbal fluency and language comprehension, has been advocated to increase the reliability of fMRI44). This modality also predicted language deficits following epilepsy surgery45) and could influence surgical planning. The correlation between fMRI with various neuropsychological tests and the intracarotid amybarbital procedure (IAP, Wada-test) to predict memory decline after temporal lobectomy46) and to determine the language dominant hemisphere has been studied47).

The main limitation of fMRI is its suboptimal specificity. A significant percentage of the cortical areas that are "activated" during an fMRI paradigm are dispensable for that specific function. Further work is therefore needed to clarify the role of fMRI in localizing eloquent cortex. At present, this method must be considered a research tool rather than part of the routine diagnostic workup of patients undergoing epilepsy surgery.