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Summary: Purpose: We compared epileptiform activity recorded with EEG and magnetoencephalography (MEG) in 19 patients with tuberous sclerosis complex (TSC) and epilepsy.
Methods: High-resolution (HR) EEG, HR-MEG, and 1.5-T MRI scans were performed. Epileptiform spikes were identified in EEG and MEG recordings offline by three observers. Spikes for which the interobserver agreement (spike consensus) was >0.40 were used for source localization with CURRYV 3.0 software. MUSIC analysis was performed. The distance between the source determined from EEG and MEG recordings and the border of the closest tuber was calculated and compared.
Results: Consensus spikes (kappa >0.4) were identified in 12 patients in the EEG recording and in 14 patients in the MEG recording. MEG sources were closer to tubers in all but one patient. Three patients underwent epilepsy surgery, two of whom are seizure free after complete resection of the tuber.
Conclusions: In patients with TSC, epileptogenic sources identified on MEG are closer to the presumed epileptogenic tuber than are similar sources identified on EEG. Moreover, spike consensus is greater with MEG. Clear identification of the epileptogenic zone may offer opportunities for surgery in patients with TSC with intractable epilepsy.
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome, involving multiple organs. The characteristic hamartomas are most commonly found in the skin, retina, heart, kidney, and brain. TSC is an autosomal dominant disorder with linkage to chromosome 9q34 (TSC1) (1) and chromosome 16p13 (TSC2) (2). Hamartin and tuberin, the protein products of TSC1 and TSC2, respectively, are tumor-suppressor genes.
In the CNS, the disordered proliferation, migration, and differentiation of neurons as a result of TSC give rise to noduli, subependymal giant-cell astrocytomas, and cortical tubers (3). Cortical tubers are associated with neurologic symptoms, such as epilepsy, mental retardation, and focal neurologic deficit. Although the phenotypic expression of TSC is extremely variable, seizures are common, occurring in 80–90% of cases, and are often the presenting symptom. Furthermore, they are often intractable (50%). Surgery should be considered in patients with TSC and drug-resistant epilepsy, but it may be difficult to identify the epileptogenic tuber if several tubers are distributed throughout the cerebral cortex. To date, the outcome of surgery has been variable in children with TSC (4–10).
Although structural and functional imaging techniques [MRI, functional MRI (fMRI), single-photon emission computed tomography (SPECT), positron emission tomography (PET)] are being increasingly used in patient workup, epileptiform activity can be recorded only with neurophysiologic techniques. With standard EEG, it is often impossible to delineate the irritative zone and establish its relation to the tuber(s) with sufficient precision, and for this reason, high-resolution (HR) EEG and HR-magnetoencephalography (MEG) are used to increase the accuracy of functional localization (11). Source localization with EEG requires modeling of the skin, skull, and brain, which in turn requires knowledge of their shape and their conductivity. Conductivity values in particular can only be approximated. Because MEG records the magnetic field around the head, and magnetic fields are not attenuated by volume conductors, MEG is more accurate than EEG for source localization. Results from the literature based on realistic phantom models, using the same methods (MUSIC) as described in this article and for comparable numbers of measurement channels, indicate that localization errors for true dipolar sources on average are 7–8 mm for EEG and 3 mm for MEG (12). However, because a radial dipole does not generate a magnetic field outside the head, MEG selectively detects tangential sources (e.g., sources on a sulcus). Moreover, measurements are affected by movement of the head, which means that patient cooperation is essential. The shortcomings of EEG and MEG can largely be overcome by combining the two techniques, by recording MEG and EEG simultaneously. The sources computed on the basis of HR-EEG and HR-MEG findings can be visualized by plotting the equivalent current dipole representation on the MRI of the patient's brain with volume reconstruction. This technique, termed magnetic source imaging (MSI), has been successfully applied to reduce the need for invasive monitoring in candidates for surgery (11,13,14). Only limited experience has been gained in the use of MEG in patients with TSC and epilepsy (11,15,16).
In this study, we determined the correspondence between epileptiform activity recorded with EEG and MEG in patients with TSC and epilepsy and to what extent the sources differed after mapping of the relevant dipoles on MRI images.
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We found that epileptiform activity detected with MEG is closer to a presumed epileptogenic tuber than is epileptiform activity detected with EEG. Although the value of MEG in the preoperative workup of candidates for epilepsy surgery has been acknowledged worldwide (23,24), experience with MEG in TSC patients is limited. Spike detection with MEG may be difficult and is subjective (19). For this reason, we analyzed only sources for which at least moderate interobserver agreement existed. Interobserver agreement tended to be worse when only a few spikes were detected.
MEG detected a single localization of epileptiform activity more often than EEG did. However, we cannot exclude the possibility that MEG was unable to detect radial sources, whereas EEG did. Although most of the analyzed traces were not recorded at the same time in all patients, only two patients had significantly more spikes in the MEG recording than in the EEG recording. Although interictal EEG recordings (sometimes HR-EEG) are used routinely in the preoperative workup of patients, our results show that spike detection is better with MEG recordings.
The characteristics of TSC lesions (e.g., multiple tubers) make it difficult to assess the association between the functional and the structural abnormalities. Tubers are often not far apart, and it is not surprising that EEG and MEG sources were not associated with the same tuber in two patients. We found that the distance from MEG source to EEG-associated tuber was smaller than the distance from EEG source to MEG-associated tuber. The difference between EEG and MEG recordings may not be as marked as one would expect from data in the literature. However, studies comparing EEG and MEG data often involved standard EEG recording, whereas HR-EEG, as used in our study, probably allows more accurate source localization. This would mean that a better agreement would be found between HR-EEG and MEG data.
It could be argued that the tuber closest to the epileptogenic source is not necessarily the epileptogenic tuber. Obviously immediate electrocorticography during epilepsy surgery or prolonged electrocorticography (ECoG) is the gold standard. MEG and video-EEG results have been proven to be equivalent in most patients considered for epilepsy surgery, with MEG providing additional information in a significant number of patients (25). The localization of interictal epileptiform activity has to be confirmed by ictal recordings before epilepsy surgery is performed. We are currently investigating the agreement between interictal and ictal source localization. If reproducible spikes are not detected during interictal EEG recording, or integration of the EEG source in the MRI does not identify a single tuber, simultaneous MEG recording is helpful to identify the tuber that should be resected. However, during and after resection of the presumed epileptogenic tuber, ECoG recordings should be performed for more accurate delineation of the irritative zone. Other techniques that can be used to identify the epileptogenic tuber include [11C]methyl-l-tryptophan ([11C] AMT) PET (26) and diffusion-weighted MRI (27). Both techniques can distinguish between epileptogenic and nonepileptogenic tubers.
Three of the patients underwent epilepsy surgery. In these patients, we found a found good agreement between interictal EEG, interictal MEG, and ictal recordings. Complete tuber resection took place in two patients, who remained seizure free postoperatively. In the third patient, only partial resection was possible because of the localization of the tuber in the eloquent cortex and the size of the tuber; unfortunately in this patient, seizure frequency was not changed in a clinically relevant way.
In conclusion, our results show that the epileptogenic source identified on MEG recordings was closer to the presumed epileptogenic tuber than was the source identified on EEG recordings from the same patients with TSC. In addition, interobserver agreement on source localization was greater with MEG recordings than with EEG recordings. Especially in patients with numerous tubers in whom interictal and ictal EEG recordings are taken for source localization, MEG source localization can help to delineate the source of the epileptiform activity and define the relation to the closest tubers. Hence, MEG is a useful technique and should be used to evaluate TSC patients considered for epilepsy surgery.