Epileptogenic Tubers Research Articles

F162. Lesion-Constrained Electrical Source Imaging (LC-ESI) in epilepsy surgery for tuberous sclerosis complex: A pilot study

Tuberous Sclerosis Complex (TSC) is a genetic neurocutaneous disorder associated with multiple dysplastic lesions called tubers. Neurologically, up to 60% of children with TSC have refractory epilepsy, and are at risk for poor neurological outcome. In these patients epilepsy surgery should be explored, the success of which hinges on the identification of the epileptogenic tuber. Electrical source imaging (ESI) models the cerebral origin of scalp EEG data. In TSC, ESI can yield ambiguous results as the distributed source solution is typically constrained to the cortex, whereas the epileptogenic zone is in subcortical tubers. We tested the clinical utility of lesion-constrained electrical source imaging (LC-ESI) in epilepsy surgery in six children with TSC. LC-ESI is based on a proposed head model in which the source solution is constrained to multiple lesions, rather than to the cortical ribbon. We performed LC-ESI on the ictal and interictal EEG data from the presurgical workup of six patients with TSC. In addition, tubers were expanded in 3 directions to include an 8 mm perituber rim as a potential seizure onset zone. We used a goodness of fit analysis to quantify the ability of individual tubers to approximate the measured EEG data. Tubers were rank-ordered, and color-coded to determine the overlap of the LC-ESI solution maximum with the surgical resection cavity, in the context of surgical outcome. Comparison was made to Low Resolution Brain Electromagnetic Tomography (LORETA). Patients were grouped according to good outcome (Engel Class I or II, n = 3), and poor outcome (Engel Class III or IV, n = 3). LORETA predicted the surgical cavity in 1 patient with good outcome (true positive), and had a positive predictive value of 50% and 100% for interictal and ictal data, respectively. Due to a high number of false negatives (source outside of the cavity in patients with a good outcome), the negative predictive value was only 40% and 60% for interictal and ictal data, respectively. LC-ESI identified individual tubers concordant with the resection cavity in 2 (interictal, PPV 66%), and 3 (ictal, PPV 100%) out of 3 patients with a good outcome. Epileptogenic tubers were identified correctly outside of the resection cavity in 2 (interictal, NPV 66%) and 3 (ictal, NPV 100%) out of 3 patients with a poor outcome, where the resection did not include the epileptogenic tubers. There was no difference between solutions constrained to tubers only as compared to those also incorporating a perituber rim. This pilot study supports clinical utility of LC-ESI in the presurgical workup for patients with TSC. Ictal data was more accurate than interictal data in all models. The epileptogenic tuber identified by LC-ESI was concordant with the resection zone in patients with a good surgical outcome, and appropriately discordant in patients with a poor outcome. LC-ESI outperformed conventional LORETA, but further validation is required.

Ictal and interictal MEG in pediatric patients with tuberous sclerosis and drug resistant epilepsy

PurposeDrug resistant epilepsy (DRE) is common in patients with tuberous sclerosis (TS). Interictal MEG has been shown as a valuable instrument in the presurgical workup. The goal of our study was to evaluate the role of ictal MEG in epileptogenic tuber selection, especially in patients with multiple irritative zones. MethodsThe clinical and MEG data of 23 patients with TS and DRE from two medical/research centers were reviewed. Seven pediatric patients, who had seizures during MEG recording and underwent resection or disconnection surgery, were included into the study. Cortical sources of ictal and interictal epileptiform MEG discharges were compared with epileptogenic zone location in six patients with favorable surgery outcome. ResultsIn patients who improved substantially after surgery all resected and several other tubers demonstrated epileptiform activity on interictal MEG. Ictal MEG provided crucial information about lobar location of the seizure onset zone (SOZ) in two cases, and in the other four it confirmed the SOZ location derived from the interictal data. In one case, ictal MEG findings were unreliable. In one patient, who did not benefit from surgical treatment, the resected tubers did not overlap with interictal and ictal MEG sources. ConclusionThe combination of interictal and ictal MEG is a valuable tool for identification of the epileptogenic tuber/tubers in presurgical work-up in patients with TS.

A distinct microRNA expression profile is associated with α[11C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[11C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.

Targeting tubers in paediatric epilepsy surgery candidates.

This scientific commentary refers to ‘Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis’, by Kannan et al. (doi:10.1093/brain/aww192) . First described clinically at the end of the 19th century, tuberous sclerosis complex is a multi-organ system disorder displaying characteristic skin involvement, benign tumours, and hamartomatous and cystic lesions. Affected children often experience debilitating focal epilepsy that typically begins in very early life and remains medically resistant. For this reason, surgical therapy was advocated as far back as 1966 (Perot et al. , 1966) based on the hypothesis that a single tuber might well be responsible for the epileptogenesis. This conceptual approach has been well validated, and yet the precise anatomical and physiological substrates of focal epilepsy in affected individuals remain a matter of debate. Do the seizures in tuberous sclerosis complex begin directly within the cortical tuber itself or does onset occur in surrounding tissue? And do seizures propagate from the seizure onset zone to distant non-tuberal sites? In this issue of Brain , Kannan and co-workers provide elegant support for a central role of the tuberal core in seizure initiation and propagation (Kannan et al. , 2016). Building on previous analyses (Mohamed et al. , 2012), Kannan et al. investigated the spatio-temporal patterns of seizure onset and propagation in children with tuberous sclerosis complex by analysing intracranial EEG recordings in 10 patients with focal epilepsy. Multiple depth and surface electrodes sampled tubers and perituberal cortex both during seizures and interictally. In many cases, depth electrodes were positioned directly into the centre of the tuber. Analyses of 10 electro-clinically distinct seizure types revealed that nine originated in the centre of the tuber; one began in the tuberal rim, and most importantly, none originated in perituberal tissue alone. In all cases, electrical seizure activity preceded …

Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis.

SEE DUCHOWNY DOI101093/AWW216 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Multiple seizure foci, seizure propagation and epileptic spasms complicate presurgical seizure localization in tuberous sclerosis. Furthermore, controversy exists about the contribution of tubers, perituberal cortex and the underlying genetic abnormality to epileptogenesis. We aimed to determine the epileptogenic substrate in tuberous sclerosis by studying spatio-temporal patterns of seizure onset and propagation on intracranial EEG recordings in which multiple depth and surface electrodes sampled multiple tubers and perituberal cortex. Ten intracranial EEG recordings (seven extraoperative, three intraoperative) from 10 children with tuberous sclerosis were analysed. Notable thickening and signal abnormality in the centre of many tubers on magnetic resonance imaging led to tuber centres being recorded with depth electrodes. Spatially-meaningful bipolar montages were reformatted incorporating channels recording only from the tuber centre, tuber rim and perituberal cortex. Interictal epileptiform discharges and ictal rhythms were analysed visually for location, field, morphology, frequency, latency and temporal dispersion. Fifteen electroclinically distinct seizures were recorded in the 10 patients. Seizure onset was recorded in tubers in all 15 electroclinically distinct seizures; in 9/10 electroclinically distinct seizures recorded with optimal spatial sampling, seizure onset was recorded in the tuber centre, with or without involvement of the tuber rim but not perituberal cortex. Quantitative electroencephalography analysis by pairwise cross-correlation confirmed that the tuber centre led the tuber rim and perituberal cortex during interictal, preictal and ictal spike trains. Seizure propagation was observed in 10/15 electroclinically distinct seizures, being tuber-to-tuber in all. Seven of the 17 tubers showing seizure propagation activated an independent ictal rhythm, morphologically distinct from that seen in seizure onset region (intra-ictal activation). Of the total 48 tubers sampled, 16 exhibited seizure onset, 17 were involved in seizure propagation and 40 exhibited interictal epileptiform discharges, 33 independent and seven propagated. Seizure onsets were recorded in 16/33 tubers with independent interictal epileptiform discharges, but 0/7 tubers with only propagated epileptiform discharges or 0/8 tubers with no epileptiform discharges (P = 0.003). Seizure onsets were recorded from 4/7 tubers with and 0/10 tubers without intra-ictal activation (P = 0.015). Thus, focal seizures and interictal epileptiform discharges in tuberous sclerosis arise in the centre of epileptogenic tubers and propagate to the tuber rim, perituberal cortex and other epileptogenic tubers. Rhythmic interictal epileptiform discharges and intra-ictal activation of propagated ictal rhythms are potential biomarkers of epileptogenic tubers. Interictal and ictal EEG features of epileptogenic tubers have similarities to focal cortical dysplasia type II, consistent with the reported imaging, histological and molecular similarities.

Diffusion Tensor Imaging of Epileptogenic Lesions in TSC.

Investigators from University of California Los Angeles, studied whether epileptogenic tubers in Tuberous Sclerosis Complex (TSC) can be identified by diffusion tensor imaging (DTI).

Evolution of Surgical Management for Intractable Epileptic Spasms

The understanding and management of epileptic spasms has considerably evolved since the mid 19th century. The realization that epileptic spasms can be generated from a focal brain lesion played a pivotal role in the development of neurosurgical management for intractable forms of this epilepsy. During pre-surgical planning, the addition of functional FDG PET imaging has further refined the electroencephalographic localization of epileptogenic lesions. In some cases, neurosurgical resection of a focus that is co-localized by the FDG PET scan and electroencephalography can lead to partial or complete reversal of developmental delay along with reduced seizure frequency or seizure freedom. In cases where near-complete hemispheric cortex is implicated in spasm generation, subtotal hemispherectomy has shown encouraging results. Moreover, palliative resection of the major perpetrating focus in carefully chosen patients with bilateral multifocal spasms has also led to favorable outcomes. However, in patients with tuberous sclerosis with high tuber burden, the localizing value of FDG PET imaging may be limited. In such cases, employment of AMT PET technology has become a valuable tool for localization of actively epileptogenic tubers. This article highlights the historic steps in the successful advancements of neurosurgical interventions for the treatment of intractable epileptic spasms.

DTI of tuber and perituberal tissue can predict epileptogenicity in tuberous sclerosis complex.

To evaluate whether diffusion tensor imaging (DTI) can predict epileptogenic tubers by measuring apparent diffusion coefficient (ADC), fractional anisotropy, axial diffusivity, and radial diffusivity in both tubers and perituberal tissue in pediatric patients with tuberous sclerosis complex (TSC) undergoing epilepsy surgery. We retrospectively selected 23 consecutive patients (aged 0.4-19.6 years, mean age of 5.2; 13 female, 10 male) who underwent presurgical DTI and subsequent surgical resection between 2004 and 2013 from the University of California-Los Angeles TSC Clinic. We evaluated presurgical examinations including video-EEG, brain MRI, (18)F-fluorodeoxyglucose-PET, magnetic source imaging, and intraoperative electrocorticography for determining epileptogenic tubers. A total of 545 tubers, 33 epileptogenic and 512 nonepileptogenic, were identified. Two observers generated the regions of interest (ROIs) of tubers (ROI(tuber)), the 4-mm-thick ring-shaped ROIs surrounding the tubers (ROI(perituber)), and the combined ROIs (ROI(tuber+perituber)) in consensus and calculated maximum, minimum, mean, and median values of each DTI measure in each ROI for all tubers. The Mann-Whitney U test demonstrated that the epileptogenic group showed higher maximum ADC and radial diffusivity values in all ROIs, and that maximum ADC in ROI(tuber+perituber) showed the strongest difference (p = 0.001). Receiver operating characteristic analysis demonstrated that maximum ADC measurements in ROI(tuber+perituber) (area under curve = 0.68 ± 0.05, p < 0.001) had 81% sensitivity and 44% specificity for correctly identifying epileptogenic tubers with a cutoff value of 1.32 μm(2)/ms. DTI analysis of tubers and perituberal tissue may help to identify epileptogenic tubers in presurgical patients with TSC more easily and effectively than current invasive methods.

Topographical Distribution of Epileptogenic Tubers in Patients With Tuberous Sclerosis Complex.

Tuberous sclerosis complex is a multisystem genetic syndrome often affecting the central nervous system. The purpose of the current study was to identify topographical patterns in the distribution specific to epileptogenic (n = 37) and nonepileptogenic (n = 544) tubers throughout the brain for a cohort of 23 tuberous sclerosis complex patients with a history of seizures. Tubers localized to the inferior parietal lobes, middle frontal lobes, middle temporal lobes, or central sulcus regions were associated with a high frequency of epileptogenic tubers. Epileptogenic tubers occurred statistically more frequently within the inferior parietal lobe and within the central sulcus region in children younger than 1 or between 1 and 3 years old, respectively. Results imply seizure activity in tuberous sclerosis complex patients can be associated with the location of cortical tubers.

Cortical Tubers: Windows into Dysregulation of Epilepsy Risk and Synaptic Signaling Genes by MicroRNAs.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a.

Resecting the epileptogenic tuber: What happens in the long term?

Tuberous sclerosis complex (TSC) is an autosomal dominant, neurocutaneous disorder causing benign noninvasive lesions in multiple organ systems. Cognitive delays and neuropsychiatric disorders such as autism are common. Epilepsy is very common and is associated with single or multiple epileptogenic cortical tubers. More than half of these individuals will become medically refractory over time. For these patients, epilepsy surgery with resection of the epileptogenic tuber or tubers not only can render a select patient population seizure-free, but also improves IQ and cognitive behaviors over time.

Localization of the epileptogenic tuber with electric source imaging in patients with tuberous sclerosis

Patients with tuberous sclerosis complex (TSC) often suffer from medically refractory epilepsy. Despite the multifocality of the disease, resection of the most epileptogenic tuber can lead to major improvement of seizure control. Therefore, non-invasive imaging methods are needed for detecting epileptogenic sources. We assessed the utility of electric source imaging (ESI) in the presurgical work-up of TSC patients and its combination with Positron Emission Tomography (PET) and ictal/interictal Single Photon Emission Computed Tomography (SISCOM). Thirteen patients underwent high density ESI (8/13) and/or low density ESI (13/13). We investigated the concordance between ESI, PET, SISCOM and the resection area in the 11 operated patients (nine seizure-free). High resolution ESI was partially or completely concordant with the resected area in 5/5 seizure free patients. Low resolution ESI was partially or completely concordant in 7/9 seizure free patients. PET and SPECT were concordant (partially or completely) in 8/9 and 6/9 cases, respectively. We found multifocal ESI sources in 2/9 seizure free patients, marked multifocal PET hypometabolism in 3/9 and multifocal SISCOM in 4/9. The region of concordant ESI and PET accurately predicted the dominant epileptogenic source in 6/9 patients. The same was true for concordant ESI and SISCOM in 4/9 patients, whereas the coregistration of only PET and SISCOM was insufficient in 3/9 successfully operated cases. The combination of all three imaging modalities could successfully identify the resection area in all but one patient with a favorable post-operation outcome. ESI is an important tool for the pre-surgical evaluation of TSC patients. It complements PET and SPECT results and can improve the management of candidates for surgery when integrated with electro-clinical information.

Positron emission tomography with α‐[11C]methyl‐l‐tryptophan in tuberous sclerosis complex–related epilepsy

Tuberous sclerosis complex (TSC) is often associated with cerebral tubers and medically intractable epilepsy. We reevaluated whether increased uptake of α-[(11) C]methyl-l-tryptophan (AMT) in cerebral tubers is associated with tuber epileptogenicity. We included 12 patients (six male, 4-53years old) with TSC and refractory seizures who were evaluated for epilepsy surgery in our center, including video-electroencephalographic (EEG) monitoring, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI), and positron emission tomography (PET) with α-[(11) C]methyl-l-tryptophan (AMT-PET). Nine of these 12 patients also underwent intracerebral EEG recording. AMT uptake in each tuber was visually evaluated on PET coregistered with MRI. An AMT uptake index based on lesional/healthy cortex ratio was also calculated. Sensitivity and specificity values of AMT-PET in the detection of epileptogenic lesions were obtained, using the available electroclinical and neuroimaging evidence as the gold standard for epileptogenicity. A total of 126 tubers were identified. Two of 12 patients demonstrated a tuber with clearly increased AMT uptake, one of whom also showed a subtle increased AMT uptake in another contralateral tuber. Four other patients showed only subtle increased AMT uptake. The only two tubers with clearly increased AMT uptake proved to be epileptogenic based on intracerebral EEG data, whereas none of the tubers associated with subtle increased AMT uptake were involved at ictal onset. In a per-patient approach, this yielded a sensitivity of clearly increased AMT uptake in detecting tuber epileptogenicity of 17% (2/12 patients), whereas the per-lesion sensitivity and specificity were 12% (95% confidence interval [CI]: 3-34%) and 100% (95% CI: 97-100%), respectively. AMT-PET is a specific neuroimaging technique in the identification of epileptogenic tubers in TSC. Despite its low sensitivity, the clinical usefulness of AMT-PET still deserves to be considered according to the challenging complexity of epilepsy surgery in tuberous sclerosis.

Diffusion Tensor Imaging and Related Techniques In Tuberous Sclerosis Complex: Review and Future Directions

In this article, the authors aim to introduce the nonradiologist to diffusion tensor imaging (DTI) and its applications to both clinical and research aspects of tuberous sclerosis complex. Tuberous sclerosis complex is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes refractory epilepsy, intellectual disability, behavioral abnormalities and autism spectrum disorder. DTI is a method for modeling water diffusion in tissue and can noninvasively characterize microstructural properties of the brain. In tuberous sclerosis complex, DTI measures reflect well-known pathological changes. Clinically, DTI can assist with detecting the epileptogenic tuber. For research, DTI has a putative role in identifying potential disease biomarkers, as DTI abnormalities of the white matter are associated with neurocognitive morbidity including autism. If indeed DTI changes parallel phenotypical changes related to the investigational treatment of epilepsy, cognition and behavior with mTOR inhibitors, it will facilitate future clinical trials.

Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring

We sought to identify intracranial EEG patterns characteristic of epileptogenic tubers and to understand the contribution of perituberal cortex. Twenty-three intracranial EEG monitoring studies were reviewed from 17 children aged 1.3-7.7 years with tuberous sclerosis complex and intractable multifocal epilepsy, 14 with a history of epileptic spasms. Interictal epileptiform discharges and ictal rhythms for 60 electroclinically distinct seizures (EDS) were analyzed in relation to 162 sampled tubers. Localized, tuber-related, ictal rhythms were seen in 49/60 EDS, most commonly as low-voltage fast activity recruiting to rhythmic spiking, then diffuse slowing or bursts of ripple range activity. Ictal onset in localized EDS involved only tubers in 57% and tubers with perituberal cortex in 31%. Ictal fast ripples (FR) noted at seizure onset in 15/38 localized EDS were confined to tubers in 73% and involved tuber with perituberal cortex in 27%. Intraictal activation occurred during seizure propagation in 19 localized EDS, being to tubers in 63% and to tubers with perituberal cortex in 37%; 63% of activated tubers generated independent EDS. Trains of periodic sharp waves on an attenuated background were seen interictally at 36/162 tubers, with 67% of those tubers generating EDS (p = 0.0001). Interictal FR, when present, involved tubers more commonly than perituberal cortex but were not associated with EDS. The study demonstrates interictal and ictal intracranial EEG findings characteristic of epileptogenic tubers, suggests that tubers play a greater role in seizure genesis than perituberal cortex, and suggests tuberectomy may be a sufficient surgical approach in a number of patients.

Epilepsy surgery in tuberous sclerosis: a review

Seizures are the initial manifestation of tuberous sclerosis complex (TSC) in 90% of individuals. The prevalence of epilepsy in TSC is 80%-90% with a large proportion refractory to antiepileptic drugs. A review of the literature of epilepsy surgery in TSC demonstrates impressive success rates for seizure-free outcomes. These studies describe a number of novel noninvasive methods for seizure localization including PET, SPECT, and magnetoencephalography. Additionally, there is a subset of patients with TSC with bilateral, multifocal, or generalized epileptiform discharges that would have previously been excluded from resection. New developments in neuroimaging and invasive monitoring with intracranial electrodes are useful methods in identifying an epileptogenic tuber in these individuals with refractory epilepsy. The authors offer a survey of the literature and description of these methods. Additionally they present an illustrative case of ictal SPECT and intracranial electroencephalography used in the preoperative evaluation of a 10-year-old girl with intractable seizures and TSC. This patient ultimately underwent resection of an epileptogenic region within the occipital lobe.

Can Diffusion Tensor Imaging (DTI) Identify Epileptogenic Tubers in Tuberous Sclerosis Complex? Correlation With α-[11C]methyl-l-tryptophan ([11C] AMT) Positron Emission Tomography (PET)

In this study, we determined whether diffusion tensor imaging (DTI), a more widely available imaging modality, is as effective as α-[(11)C]methyl-l-tryptophan (AMT)-positron emission tomography (PET) in localizing epileptogenic tubers in tuberous sclerosis complex. Following that, coregistration of AMT-PET and diffusion tensor imaging scans apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in all tubers using a region-of-interest approach and were compared with AMT-PET tuber/cortex uptake ratios, which were used to differentiate between epileptogenic and nonepileptogenic tubers. Forty-three tubers, out of a total of 320 tubers, had AMT-PET uptake ratios greater than 1 and hence were classified as potentially epileptogenic. FA in epileptogenic tubers was reduced compared with the other tubers (P = .03). A significant negative correlation was observed between AMT-PET uptake ratio of epileptogenic tubers and FA values (r = -.45; P = .003). Tubers with higher AMT-PET uptake ratios corresponded well with lower FA values in tuberous sclerosis complex patients.

Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex

PurposeTo elucidate the functional characteristics of cortical tubers that might be responsible for epilepsy in tuberous sclerosis complex (TSC), proton magnetic resonance spectroscopy (1H-MRS) and [123I] iomazenil (123I-IMZ) single photon emission computed tomography (SPECT) were performed. Methods1H-MRS using a clinical 3-tesla magnetic resonance imager was performed in four children with TSC and 10 age-and sex-matched healthy control subjects. A single voxel was set on the right parietal lobe in control subjects. In patients with TSC, a single voxel was set on the epileptogenic tuber in the parietal or temporal lobe, and another voxel was set on the contralateral normal-appearing brain region. N-Acetylaspartate (NAA), myo-Inositol (mIns) and Glutamate (Glu) were analyzed using a conventional STEAM (Stimulated Echo Acquisition Mode) method. The concentration of gamma-aminobutyric acid (GABA) was quantified using MEGA-Point Resolved Spectroscopy (PRESS). Interictal 123I-IMZ SPECT was examined in all four patients with TSC. ResultsA significant decrease in the NAA concentration and significant increases in the mIns and GABA concentrations were detected in the cortical tubers of all 4 patients. No significant difference was observed in Glu concentrations. In all of the cortical tubers detected by magnetic resonance imaging, 123I-IMZ binding was significantly decreased. ConclusionEpileptogenesis in TSC might be caused by decreased inhibition secondary to the decrease in GABA receptors in dysplastic neurons of cortical tubers. An increase in the GABA concentration may compensate for decreased inhibition.

Surgery of infantile spasms with tuberous sclerosis

Objective To investigate the surgical indications, methods and outcomes of infantile spasms with tuberous sclerosis(TS). Method Surgical treatment of 17 infantile spasms patients with TS was reviewed. Single epileptogenic tuber or lobe was resected when a focal epileptic discharge was indicated according to preoperative evaluation and EcoG, and multiple lobes or tubers resection were chosen to deal with hemisphere limited multiple epileptic foci. Anterior corpus callosotomy was added when contralateral hemisphere showed epileptic discharges. Results Acording to follow - up of 3 years in average after surgery, 11 patients had an Engel Class Ⅰ outcome, 4 patients had rare seizure ( Engel Class Ⅱ ), and 2 patients had a reduction in seizure frequency (Engel Class Ⅲ ). The mean IQ of patients was improved from 52.6 to 61. 8. Conclusions Epilepsy surgery in tuberous sclerosis with infantile spasms showes a favourable outcome,and surgical intervention should be considered in some intractable infantile spasms after corresponding tuber is derermined. Key words: Intractable epilepsy; Tuberous sclerosis; Spasms, infantile; Surgical procedures, operative

Clinical and histopathologic correlates of 11C-alpha-methyl-l-tryptophan (AMT) PET abnormalities in children with intractable epilepsy

Interictal increase of (11) C-alpha-methyl-l-tryptophan (AMT) on positron emission tomography (PET) can be seen in cortical epileptic foci, and is particularly common in cortical developmental malformations. Therefore, in the present study, we evaluated the clinical and histopathologic correlates of AMT-PET abnormalities in children with intractable epilepsy undergoing resective surgery. Thirty children (mean age: 6.7 ± 3.2 years) were included in this study. All patients received AMT-PET as part of their presurgical evaluation and subsequently underwent epilepsy surgery. Magnetic resonance imaging (MRI) scans were normal in 15, showed nonspecific changes in 8, and suggested malformations of cortical development (MCDs) in nine children. Asymmetry indices (AIs) were calculated to determine increased AMT uptake. Histopathology revealed MCDs in 16 (53%) children, including 12 with cortical dysplasia (CD) [mild MCD = 3; CD type IA = 2; CD type IIA = 2 and CD type IIB (severe CD with balloon cells) = 5]. Polymicrogyria and heterotopias (P&Hs) were seen in three cases and subependymal heterotopias (SEHs) in one child. The remaining 14 cases showed normal histopathology with varying degrees of gliosis. Increased AMT uptake was found in all five with CD type IIB, and all three with P&H, but in none with mild MCD and types IA-IIA CD or SEH. Whereas all five children with CD IIB and two with P&H had excellent surgical outcome (class I); children with milder CD or SEH had variable surgical outcome. The 14 patients with normal histopathology included seven patients with focally increased and seven with normal AMT uptake. Although patients with normal pathology and normal AMT-PET had better surgical outcome (class I = 5; II = 2), those with normal pathology, normal MRI, but abnormal AMT-PET had poor surgical outcome (class III = 4; IV = 3). Increased AMT uptake in children with CD may predict type IIB dysplasia (with balloon cells) and good surgical outcome. Histopathologic similarities between CD type IIB and epileptogenic cortical tubers may imply a common role of the inflammatory kynurenine pathway of tryptophan metabolism in these lesions. In children with normal histopathology, there is a subgroup with increased AMT uptake and poor surgical outcome.