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Purpose: Mutations in the ATP1A2 gene have been described in families with familial hemiplegic migraine (FHM). FHM is a variant of migraine with aura characterized by the occurrence of hemiplegia during the aura. Within several FHM families, some patients also had epileptic seizures. In this study we tested the hypothesis that mutations in ATP1A2 may be common in patients presenting with epilepsy and migraine., Methods: We selected 20 families with epilepsy and migraine and performed mutation analysis of ATP1A2 in the probands by direct sequencing of all exons and splice-site junctions., Results: Novel ATP1A2 mutations were found in two of the 20 families (10%). The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation occurred in a family with occipitotemporal epilepsy and migraine with and without visual aura. In the two families together, six mutation carriers had the combination of epilepsy and migraine, two had only epilepsy, and six had only migraine., Discussion: This study shows that a history of migraine and a family history of both epilepsy and migraine should be obtained in all patients presenting with epilepsy in the epilepsy clinic. It may be worthwhile to screen patients with a combination of epilepsy and migraine and a positive family history of either migraine or epilepsy for mutations in the ATP1A2 gene.

We describe a young woman with progressive cognitive and neurological deficits during a parietal lobe status epilepticus (SE). Ictal FDG-PET showed left parietal lobe hypermetabolism and frontal lobe hypometabolism with concomitant EEG slowing. Cognitive and neurological deficits fully reversed more than 1 year after seizure remission, and were associated with normalization of FDG-PET and EEG. Our findings suggest that ictal hypometabolism and EEG delta activity at a distance from the epileptic focus were seizure-related phenomena, possibly representing inhibition in seizure propagation pathways, which could be responsible for the epileptic encephalopathy.

Long-term electroencephalographic (EEG) recordings are important in the presurgical evaluation of refractory partial epilepsy for the delineation of the irritative and ictal onset zones. In this paper we introduce a new algorithm for an automatic, fast and objective localizing of the ictal onset zone in ictal EEG recordings. We extracted the potential distribution of the ictal activity from EEG using the higher order canonical decomposition method, also referred to as the CP model. The CP model decomposes in a unique way a higher order tensor in a minimal sum of rank-1 'atoms'. We showed that only one atom is related to the seizure activity. Simulation experiments demonstrated that the method correctly extracted the potential distribution of the ictal activity even with low signal-to-noise ratios. In 37 ictal EEGs, the CP method correctly localized the seizure onset zone in 34 (92%) and visual assessment in 21 cases (57%) (p=0.00024). The CP method is a fast method to delineate the ictal onset zone in ictal EEGs and is more sensitive than visual interpretation of the ictal EEGs.

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.

Background: Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients., Objective: To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity., Methods: A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing proconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated., Results: Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%. The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring. The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients., Conclusions: The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients' possible neurologic deterioration, meropenem and valproate should not be administered together.

Objective: To map the disease-causing locus in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura and to describe the clinical, electrophysiologic, and imaging characteristics., Methods: DNA samples from 21 family members were obtained and an 8 cM density genome-wide scan was performed. The authors interviewed 21 individuals and performed interictal EEG in 14 and brain MRI in 13 individuals., Results: Nine at risk family members and one deceased individual had epilepsy with occipital and temporal lobe symptomatology, variable age at onset, usually good prognosis, no epileptic EEG features, and normal brain MRI. Five of the 10 patients had a history of migraine with aura (p = 0.0026). Seizures and migraine attacks occurred as separate episodes in all but one patient. Three patients described light flashes both as epileptic and migraine aura. Epilepsy and migraine started at the same age in three patients and remitted simultaneously in two. The epileptic phenotype had a dominant mode of inheritance with a reduced penetrance of 75%. A conclusive two-point lod score of 3.3 was obtained for marker D9S257 at recombination fraction zero. Haplotype analysis defined a candidate region of 9.95 cM (5.96 Mb) between markers GATA152H04 and D9S253 located at chromosome 9q21-q22 based upon recombinations in affected individuals., Conclusions: The clinical association in this family of occipitotemporal lobe epilepsy and migraine with visual aura and the conclusive linkage of the occipitotemporal lobe epilepsy/migraine with aura trait to a single locus suggests a common monogenic gene defect.

Purpose: To investigate the potential clinical relevance of a new algorithm to remove muscle artifacts in ictal scalp EEG., Methods: Thirty-seven patients with refractory partial epilepsy with a well-defined seizure onset zone based on full presurgical evaluation, including SISCOM but excluding ictal EEG findings, were included. One ictal EEG of each patient was presented to a clinical neurophysiologist who was blinded to all other data. Ictal EEGs were first rated after band-pass filtering, then after elimination of muscle artifacts using a blind source separation-canonical correlation analysis technique (BSS-CCA). Degree of muscle artifact contamination, lateralization, localization, time and pattern of ictal EEG onset were compared between the two readings and validated against the other localizing information., Results: Muscle artifacts contaminated 97% of ictal EEGs, and interfered with the interpretation in 76%, more often in extratemporal than temporal lobe seizures. BSS-CCA significantly improved the sensitivity to localize the seizure onset from 62% to 81%, and performed best in ictal EEGs with moderate to severe muscle artifact contamination. In a significant number of the contaminated EEGs, BSS-CCA also led to an earlier identification of ictal EEG changes, and recognition of ictal EEG patterns that were hidden by muscle artifact., Conclusions: Muscle artifacts interfered with the interpretation in a majority of ictal EEGs. BSS-CCA reliably removed these muscle artifacts in a user-friendly manner. BSS-CCA may have an important place in the interpretation of ictal EEGs during presurgical evaluation of patients with refractory partial epilepsy.

Purpose of Review: The aim of this article is to give a subjective review of the usefulness of single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging in clinical practice in epilepsy for 2007., Recent Findings: Both ictal perfusion SPECT and interictal fluorodeoxyglucose PET can provide new information in the presurgical evaluation of intractable partial epilepsy. These functional imaging modalities reflect dynamic seizure-related changes in cerebral cellular functions. Although asymmetry of fluorodeoxyglucose PET metabolism has been useful to localize the epileptic temporal lobe, which tends to be more hypometabolic than the contralateral one, both frontal lobes are more hypometabolic than the epileptic temporal lobe, and may represent a region of 'surround inhibition'. Due to its low temporal resolution, ictal perfusion SPECT hyperperfusion patterns often contain both the ictal onset zone and propagation pathways. These patterns often have a multilobulated 'hourglass' appearance. The largest and most intense hyperperfusion cluster often represents ictal propagation, and does not always need to be resected in order to render a patient seizure free., Summary: Optimized interictal FDG-PET and ictal perfusion SPECT as part of a multimodality imaging platform will be important tools to better understand the neurobiology of epilepsy and to better define the epileptogenic, ictal onset, functional deficit and surround inhibition zones in refractory partial epilepsy.

Only hundreds of milliseconds after an incoming stimulus is perceived, we make an evaluation of whether it is good or bad. This evaluation seems to occur automatically and can significantly influence behavior. According to several functional imaging studies, the amygdala, which is localized in the temporal lobes of the brain, is an important structure for the automatic processing of affective stimuli. To investigate how critical a role the amygdala plays in this process, we had 20 participants with unilateral resection of the temporal lobe and 20 controls perform an affective priming task. Both controls and patients demonstrated shorter response latencies on trials where prime and target had the same valence than on trials where prime and target had the opposite valence. This finding is generally known as the affective priming effect and is considered to reflect automatic stimulus evaluation. More specifically, it is assumed that the valence of the prime stimulus is activated automatically and exerts an influence on the speed by which the target stimulus is evaluated. Given that the affective priming effect is equally large in both groups, our results suggest that the automatic processing of stimulus valence is intact in participants who sustained unilateral resection of the temporal lobe.

Long-term electroencephalographic (EEG) recordings are important in the presurgical evaluation of refractory partial epilepsy for the delineation of the ictal onset zones. In this paper, we introduce a new concept for an automatic, fast, and objective localisation of the ictal onset zone in ictal EEG recordings. Canonical decomposition of ictal EEG decomposes the EEG in atoms. One or more atoms are related to the seizure activity. A single dipole was then fitted to model the potential distribution of each epileptic atom. In this study, we performed a simulation study in order to estimate the dipole localisation error. Ictal dipole localisation was very accurate, even at low signal-to-noise ratios, was not affected by seizure activity frequency or frequency changes, and was minimally affected by the waveform and depth of the ictal onset zone location. Ictal dipole localisation error using 21 electrodes was around 10.0 mm and improved more than tenfold in the range of 0.5-1.0 mm using 148 channels. In conclusion, our simulation study of canonical decomposition of ictal scalp EEG allowed a robust and accurate localisation of the ictal onset zone.

The electroencephalogram (EEG) is often contaminated by muscle artifacts. In this paper, a new method for muscle artifact removal in EEG is presented, based on canonical correlation analysis (CCA) as a blind source separation (BSS) technique. This method is demonstrated on a synthetic data set. The method outperformed a low-pass filter with different cutoff frequencies and an independent component analysis (ICA)-based technique for muscle artifact removal. In addition, the method is applied on a real ictal EEG recording contaminated with muscle artifacts. The proposed method removed successfully the muscle artifact without altering the recorded underlying ictal activity.

Accurate analysis of EEG sleep spindle frequency is challenging. The frequency content of true sleep spindles is not known. Therefore, simulated spindle activity was studied in the present work. Five types of simulated test signals were designed, all containing a dominant spindle represented by a 13-Hz sine wave as such or with a waxing and waning pattern accompanied by a secondary spindle activity in three test signals. Background EEG was included in four test signals, modeled either as small additional sinusoids across the spindle frequency range or as filtered Gaussian noise segments. The purpose of this study was to investigate how accurately the dominant spindle frequency of 13 Hz could be resolved with different methods in the presence of the interfering waveforms. A matching pursuit (MP) based approach, discrete Fourier transform (DFT) with Hanning windowing with and without zero padding, Hankel total least squares (HTLS) and wavelet methods were compared in the analyses. MP method provided best overall performance, followed closely by DFT with zero padding. Comparative studies like this are important to decide the method of choice in clinical sleep EEG analysis.

Objective: Aim of the study was to assess the efficacy and safety of levetiracetam as add-on treatment in patients with partial-onset epilepsy in clinical practice., Methods: In this observational, multi-centre study patients were treated with levetiracetam for 16 weeks. From a starting dose of 1000 mg/day, dose levels were adjusted at 2-weekly intervals in 1000-mg steps, to a maximum of 3000 mg/day, based on seizure control and tolerance. Analysis of efficacy was based on reduction in seizure frequency relative to baseline, 50% and 100% responder rates (for partial seizures and all seizure types combined) and percentage of patients using levetiracetam at the end of the study. Analysis of safety was based on occurrence of adverse events., Results: The present analysis concerns the results of patients recruited in Belgium and The Netherlands. Of the 251 patients included in the study, 86.9% completed 16 weeks of treatment. Reduction in frequency of partial-onset seizures was 62.2%, with 19.3% of the patients becoming seizure free and 56.6% having a reduction in seizure frequency of > or = 50%. These percentages were more or less the same when calculated for all seizure types combined. Tolerance of levetiracetam treatment was good, with most adverse events being only mild to moderate in severity, and only 10.0% of the adverse events leading to discontinuation from the study. Asthenia, somnolence, dizziness and headache were the most frequently reported adverse events., Conclusion: Levetiracetam is effective and safe as add-on treatment for partial-onset seizures in clinical practice.

Background: Invasive electroencephalogram (EEG) studies are often considered necessary to localize the epileptogenic zone in partial epilepsies associated with focal dysplastic lesions (FDL). Our aim was to evaluate the relationships between subtraction ictal SPECT coregistered with magnetic resonance imaging (MRI) (SISCOM) hyperperfusion clusters and MRI-visible FDL, and to establish a preliminary algorithm for a noninvasive presurgical evaluation protocol for MRI-visible FDLs in patients with refractory epilepsy., Methods: Fifteen consecutive patients with refractory partial epilepsy and a single MRI-visible FDL underwent a noninvasive presurgical evaluation including SISCOM. Each hyperperfusion cluster was visually analyzed, automatically quantitated, and its distance form the lesion as outlined on the MRI was measured. In patients who underwent surgery, the volumes of resected brain tissue containing the FDL, the SISCOM hyperperfusion cluster, and surrounding regions were assessed on postoperative MRI and correlated with surgical outcome., Results: Fourteen of the 15 patients (93%) showed SISCOM hyperperfusion overlapping with the FDL. The FDL was detected only after reevaluation of the MRI guided by the ictal SPECT in 7 of the 15 patients (47%). Four distinct hyperperfusion patterns were observed, representing different degrees of seizure propagation. Nine patients have been operated on. Five have been seizure-free since surgery and one since a reoperation. The degree of resection of the MRI-visible FDL was the major determinant of surgical outcome. Full resection of the SISCOM hyperperfusion cluster was not required to render a patient seizure-free., Conclusion: Detailed analysis of SISCOM hyperperfusion patterns is a promising tool to detect subtle FDL on MRI and to establish the epileptic nature of these lesions noninvasively. Overlap between the SISCOM hyperperfusion cluster and MRI-visible FDL in a noninvasive presurgical evaluation with concordant data may suffice to proceed to epilepsy surgery aimed at removing the MRI-visible FDL and the part of the hyperperfusion cluster within and immediately surrounding the FDL.

Background: The pathophysiological role of the extensive interictal cerebral hypometabolism in complex partial seizures (CPS) in refractory mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) is poorly understood. Our aim was to study ictal-interictal SPECT perfusion versus interictal fluorodeoxyglucose (FDG)-PET metabolic patterns., Methods: Eleven adults with refractory unilateral mTLE-HS, who were rendered seizure free after epilepsy surgery, were included. All had an interictal FDG-PET and an interictal and ictal perfusion SPECT scan. FDG-PET data were reconstructed using an anatomy-based reconstruction algorithm, which corrected for partial volume effects, and analyzed semi-quantitatively after normalization to white matter activity. Using Statistical Parametric Mapping (SPM), we compared interictal metabolism of the patient group with a control group. We correlated metabolic with ictal perfusion changes in the patient group., Results: Global cerebral grey matter glucose metabolism in patients was decreased 10-25% compared with control subjects. Interictal PET hypometabolism and ictal SPECT hypoperfusion were maximal in the ipsilateral frontal lobe. Ictal frontal lobe hypoperfusion was associated with crossed cerebellar diaschisis. The ipsilateral temporal lobe showed maximal ictal hyperperfusion and interictal hypometabolism, which was relatively mild compared with the degree of hypometabolism affecting the frontal lobes., Conclusion: Interictal hypometabolism in mTLE-HS was greatest in the ipsilateral frontal lobe and represented a seizure-related dynamic process in view of further ictal decreases. Crossed cerebellar diaschisis suggested that there is a strong ipsilateral frontal lobe inhibition during CPS. We speculate that surround inhibition in the frontal lobe is a dynamic defense mechanism against seizure propagation, and may be responsible for functional deficits observed in mTLE.

Objective: To prospectively assess the safety and efficacy of levetiracetam in patients with uncontrolled focal epilepsy, in a common practice-based setting., Patients and Methods: In this phase IV, open-label, 16-week community-based study, adult patients with focal seizures initially received levetiracetam 1,000 mg/day. Throughout the study, the dose was adjusted in increments of 1,000 mg (maximum 3,000 mg/day) to achieve seizure control and maintain tolerability. The outcome parameters were the percentage reduction in partial and total seizure frequency per week from historical baseline, global evaluation scale (GES), and adverse events (AE)., Results: Seven hundred and thirty-one patients were included in this analysis and 84.4% completed the study. The median percent reduction in all seizures was 47.8%, and 49.3% for all partial seizures. The 50% responder rate was 49%, and the seizure-free rate was 17.2% for all partial seizures. Approximately 60% of patients showed moderate to marked improvement on the GES. The majority of AE were of mild to moderate severity; the most commonly reported being asthenia, somnolence, headache, and dizziness., Conclusion: Levetiracetam is both efficacious and safe as an add-on therapy in patients with refractory epilepsy treated by clinicians in their daily practice.

Several lesion and functional imaging studies conducted in animals and humans suggest that structures within the amygdaloid nuclear complex (ANC) are important for the occurrence of fear conditioning. Whether this brain structure is also critical for evaluative conditioning, has been investigated less frequently. In the current experiment, a group of participants with unilateral resection of the anterior temporal lobe and a control group received a differential evaluative flavor-taste conditioning task. In the pre-acquisition phase, two fruit flavors (the conditioned stimuli (CSs)) were presented and participants were instructed to evaluate both. In the subsequent acquisition phase, one of these fruit flavors (CS+) was presented together with a bad tasting substance Tween20 (polysorbate 20, the US), while the other flavor (CS-) was never paired with Tween20. Finally, in the post-acquisition phase, the two flavors were presented again without Tween20 and participants were asked to evaluate both of them for a last time. The control group as well as the lesion group rated the CS+ in the post-acquisition phase less favorable than in the pre-acquisition phase, while the ratings of the CS- remained the same in both phases. We clearly demonstrated evaluative conditioning in both test groups. Because the lesion group had still one intact ANC it would be premature, however, to conclude that the ANC is not involved in evaluative conditioning. We conclude that despite evidence for impaired fear conditioning, unilateral damage to the ANC does not impair evaluative conditioning.

Muscle and eye movement artifacts are very prominent in the ictal EEG of patients suffering from epilepsy, thus making the dipole localization of ictal activity very unreliable. Recently, two techniques (BSS-CCA and pSVD) were developed to remove those artifacts. The purpose of this study is to assess whether the removal of muscle and eye movement artifacts improves the EEG dipole source localization. We used a total of 8 EEG fragments, each from another patient, first unfiltered, then filtered by the BSS-CCA and pSVD. In both the filtered and unfiltered EEG fragments we estimated multiple dipoles using RAP-MUSIC. The resulting dipoles were subjected to a K-means clustering algorithm, to extract the most prominent cluster. We found that the removal of muscle and eye artifact results to tighter and more clear dipole clusters. Furthermore, we found that localization of the filtered EEG corresponded with the localization derived from the ictal SPECT in 7 of the 8 patients. Therefore, we can conclude that the BSS-CCA and pSVD improve localization of ictal activity, thus making the localization more reliable for the presurgical evaluation of the patient.

Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.

Generalised epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous epilepsy syndrome. Using positional cloning strategies, mutations in SCN1B, SCN1A, and GABRG2 have been identified as genetic causes of GEFS+. In the present study, we describe a large four generation family with GEFS+ in which we performed a 10 cM density genome-wide scan. We obtained conclusive evidence for a novel GEFS+ locus on chromosome 2p24 with a maximum two point logarithm of the odds (LOD) score of 4.22 for marker D2S305 at zero recombination. Fine mapping and haplotype segregation analysis in this family delineated a candidate region of 3.24 cM, corresponding to a physical distance of 4.2 Mb. Linkage to 2p24 was confirmed (p = 0.007) in a collection of 50 nuclear and multiplex families with febrile seizures and epilepsy. Transmission disequilibrium testing and association studies provided further evidence (p < 0.05) that 2p24 is a susceptibility locus for febrile seizures and epilepsy. Furthermore, we could reduce the candidate region to a 2.14 cM interval, localised between D2S1360 and D2S2342, based upon an ancestral haplotype. Identification of the disease gene at this locus will contribute to a better understanding of the complex genetic aetiology of febrile seizures and epilepsy.

Removing artifacts and background electroencephaloraphy (EEG) from multichannel interictal and ictal EEG has become a major research topic in EEG signal processing in recent years. We applied for this purpose a recently developed subspace-based method for modeling the common dynamics in multichannel signals. When the epileptiform activity is common in the majority of channels and the artifacts appear only in a few channels the proposed method can be used to remove the latter. The performance of the method was tested on simulated data for different noise levels. For high noise levels the method was still able to identify the common dynamics. In addition, the method was applied to real life EEG recordings containing interictal and ictal activity contaminated with muscle artifact. The muscle artifacts were removed successfully. For both the synthetic data and the analyzed real life data the results were compared with the results obtained with principal component analysis (PCA). In both cases, the proposed method performed better than PCA.

This paper presents a method for fully automated detection and localization of Focal Cortical Dysplastic (FCD) lesions from anatomical magnetic resonance (MR) images of the human brain. Model-based tissue classification of the image under study was applied first such that a gray matter (GM) segmentation map is obtained of which we demonstrate that it also includes possible FCD lesions. Cortical thickness was estimated at each voxel using an appropriate distance transform applied to the binarized GM object and an FCD specific feature map was constructed by computing the ratio of cortical thickness over absolute image intensity gradient at each voxel. In absence of any prior anatomical hypothesis on the spatial location of the lesion, a statistical parameter map was constructed by evaluating the evidence for each gray matter voxel against the null hypothesis of no difference in the feature map of the patient versus similar maps obtained for a group of normal controls. Voxel clusters for which the null hypothesis was found to be improbable at optimally selected thresholds for cluster height and extent were reported as lesions. The method was applied to a surgical series of 17 FCD patient images that were compared against a group of 64 neurologically normal controls. The method correctly detected and located the FCD lesion in 9 out of 17 FCD cases (53%) using a threshold that minimized false positives and 12 of 17 (71%) using a threshold that allowed more false positive results. The detected lesions had a median volume of 7.2 cm(3) versus 2.9 cm(3) for the non-detected lesions. The detected lesions more often had an increased cortical thickness on T1 than the non-detected lesions (P=0.015, Fisher's exact test). Due to a high variance of the feature maps in the temporal lobes and insula, detection of FCD lesions in these regions appeared more difficult than in other brain regions with lower variance.

Purpose: To present the first ictal fluorodeoxyglucose-positron emission tomography (FDG-PET) evidence of the hypothalamic origin of gelastic seizures in a patient with a hypothalamic hamartoma (HH) and to raise the issue of true dual pathology related to this entity., Methods: Ictal FDG-PET was acquired during an episode of status gelasticus with preserved consciousness, in a patient previously operated on for complex partial seizures (CPSs) due to a temporal lobe epileptogenic cyst., Results: Ictal hypermetabolism was localized to the region of the HH during the status gelasticus. CPSs had been completely eliminated after temporal lobe surgery., Conclusions: Ictal FDG-PET independently confirmed that gelastic seizures in patients with HH do originate in the diencephalic lesion. An HH may coexist with another epileptogenic lesion, in a context of dual pathology.

In this paper a new method for muscle artifact removal in EEG is presented, based on Canonical Correlation Analysis (CCA) as a Blind Source Separation technique (BSS). This method is demonstrated on a synthetic data set. The method out-performed a low pass filter with different cutoff frequencies and an Independent Component Analysis (ICA) based technique for muscle artifact removal. The first preliminary results of a clinical study on 26 ictal EEGs of patients with refractory epilepsy illustrated that the removal of muscle artifact results in a better interpretation of the ictal EEG, leading to an earlier detection of the seizure onset and a better localization of the seizures onset zone. These findings make the current method indispensable for every Epilepsy Monitoring Unit.

Removing artifacts and background EEG from multichannel interictal and ictal EEG has become a major research topic in EEG signal processing in recent years. We applied for this purpose a recently developed subspace-based method for modelling the common dynamics in multichannel signals. When the epileptiform activity is common in the majority of channels and the artifacts appear only in a few channels the proposed method can be used to remove the latter. The performance of the method was tested on simulated data for different noise levels. For high noise levels the method was still able to identify the common dynamics. In addition, the method was applied to a real life EEG recording. Also in this case the muscle artifacts were removed successfully. For both the synthetic data and the analyzed real life data the results were compared with the results obtained with principal component analysis (PCA). In both cases the proposed method performed better than PCA.

Unlabelled: FDG-PET contributes to the diagnosis and management of neurological diseases. In some of these diseases, pathological gray matter (GM) areas may have a reduced FDG uptake. Detection of these regions can be difficult and some remain undiscovered using visual assessment. The main reason for this detection problem is the relatively small thickness of GM compared to the spatial resolution of PET, known as the partial volume effect. We have developed an anatomy-based maximum-a-posteriori reconstruction algorithm (A-MAP) which corrects for this effect during the reconstruction using segmented magnetic resonance (MR) data. Monte-Carlo based 3-D brain software phantom simulations were used to investigate the influence of the strength of anatomy-based smoothing in GM, the influence of misaligned MR data, and the effect of local segmentation errors. A human observer study was designed to assess the detection performance of A-MAP versus post-smoothed maximum-likelihood (ML) reconstruction. We demonstrated the applicability of A-MAP using real patient data. The results for A-MAP showed improved recovery values and robustness for local segmentation errors. Misaligned MR data reduced the recovery values towards those obtained by post-smoothed ML, for small registration errors. In the human observer study, detection accuracy of hypometabolic regions was significantly improved using A-MAP, compared to post-smoothed ML (P < 0.004). The patient study confirmed the applicability of A-MAP in clinical practice., Conclusion: A-MAP is a promising technique for voxel-based partial volume correction of FDG-PET of the human brain.

MR imaging allows the in vivo detection of hippocampal sclerosis (HS) and has been instrumental in the delineation of the syndrome of mesial temporal lobe epilepsy with HS (mTLE-HS). MR features of HS include hippocampal atrophy with an increased T2 signal. Quantitative MR imaging accurately reflects the degree of hippocampal damage.Ictal single photon emission computed tomography (SPECT) in mTLE-HS shows typical perfusion patterns of ipsilateral temporal lobe hyperperfusion, and ipsilateral frontoparietal and contralateral cerebellar hypoperfusion. Interictal 18fluoro-2-deoxyglucose positron emission tomography (PET) shows multiregional hypometabolism, involving predominantly the ipsilateral temporal lobe. 11C-flumazenil PET shows hippocampal decreases in central benzodiazepine receptor density. Future strategies to study the etiology and pathogenesis of HS should include longitudinal MR imaging studies,MR studies in families with epilepsy and febrile seizures, stratification for genetic background, coregistration with SPECT and PET, partial volume correction and statistical parametric mapping analysis of SPECT and PET images.

Positron emission tomography (PET) of the cerebral glucose metabolism has shown to be useful in the presurgical evaluation of patients with epilepsy. Between seizures, PET images using fluorodeoxyglucose (FDG) show a decreased glucose metabolism in areas of the gray matter (GM) tissue that are associated with the epileptogenic region. However, detection of subtle hypo-metabolic regions is limited by noise in the projection data and the relatively small thickness of the GM tissue compared to the spatial resolution of the PET system. Therefore, we present an iterative maximum-a-posteriori based reconstruction algorithm, dedicated to the detection of hypo-metabolic regions in FDG-PET images of the brain of epilepsy patients. Anatomical information, derived from magnetic resonance imaging data, and pathophysiological knowledge was included in the reconstruction algorithm. Two Monte Carlo based brain software phantom experiments were used to examine the performance of the algorithm. In the first experiment, we used perfect, and in the second, imperfect anatomical knowledge during the reconstruction process. In both experiments, we measured signal-to-noise ratio (SNR), root mean squared (rms) bias and rms standard deviation. For both experiments, bias was reduced at matched noise levels, when compared to post-smoothed maximum-likelihood expectation-maximization (ML-EM) and maximum a posteriori reconstruction without anatomical priors. The SNR was similar to that of ML-EM with optimal post-smoothing, although the parameters of the prior distributions were not optimized. We can conclude that the use of anatomical information combined with prior information about the underlying pathology is very promising for the detection of subtle hypo-metabolic regions in the brain of patients with epilepsy.

The localizing value of ictal single-photon emission computed tomography (SPECT) performed with cerebral blood flow agents in patients with epilepsy is based on cerebral metabolic and perfusion coupling. Ictal hyperperfusion is used to localize the epileptogenic zone noninvasively, and is particularly useful in magnetic resonance (MR)-negative partial epilepsy and focal cortical dysplasias. Subtraction ictal SPECT coregistered with MRI (SISCOM) improves the localization of the area of hyperperfusion. Ictal SPECT should always be interpreted in the context of a full presurgical evaluation. Early ictal SPECT injections minimize the problem of seizure propagation and of nonlocalization due to an early switch from ictal hyperperfusion to postictal hypoperfusion during brief extratemporal seizures. The degree of thresholding of SISCOM images affects the sensitivity and specificity of ictal SPECT. Ictal hypoperfusion may reflect ictal inhibition or deactivation. Postictal and interictal SPECT studies are less useful to localize the ictal-onset zone. Statistical parametric mapping analysis of groups of selected ictal-interictal difference images has the potential to demonstrate the evolution of cortical, subcortical, and cerebellar perfusion changes during a particular seizure type, to study seizure-gating mechanisms, and to provide new insights into the pathophysiology of seizures.

Background: Status epilepticus (SE) is a common neurological emergency. In around 10 percent, the etiology of SE is not clear, i.e. cryptogenic SE., Aim: To describe six young adult patients with de novo cryptogenic multifocal febrile SE with poor outcome., Methods: Retrospective chart review., Results: We describe six patients who presented with de novo SE. All were young adults with an unremarkable previous medical history. In all except one, the family history for epilepsy was negative. All had a febrile illness in the week preceding SE. Investigations were unable to reveal the underlying etiology. SE proved refractory to conventional antiepileptic drug treatment (AED) and anesthesia was required to control seizures. Seizures during SE or ensuing epilepsy were multifocal. Brain pathology in four patients was normal in two and showed changes secondary to seizures in two. Outcome was poor in all cases: one patient died during the course of SE, another patient remained with severe mental and physical disability as well as refractory epileptic seizures, the other four developed refractory multifocal epilepsy. One of these patients died a sudden unexpected death in epilepsy (SUDEP) and one drowned during a seizure., Conclusions: Six patients were reviewed who presented with de novo cryptogenic multifocal refractory febrile SE. The possible etiologies are discussed. Based on the similarities in these cases, a distinct refractory SE syndrome might be assumed. Further prospective studies will, however, be required to validate this hypothesis as well as to elucidate its etiology and optimize treatment.

Cerebral perfusion changes reliably reflect changes in neuronal activity. Our aim was to obtain new insights into the pathophysiology of complex partial seizures (CPS) in patients with hippocampal sclerosis (HS) using interictal and ictal single photon emission computed tomography (SPECT). We studied 24 patients with refractory temporal lobe epilepsy (TLE) associated with HS. All had an interictal and ictal SPECT with early injection during a CPS. Images were normalized and co-registered. Using statistical parametric mapping (SPM99), brain regions with significant ictal perfusion changes were determined. To assess possible interrelationships between these regions, Pearson correlation coefficients were calculated. The temporal lobe ipsilateral to the seizure focus, the border of the ipsilateral middle frontal and precentral gyrus, both occipital lobes and two small regions in the contralateral postcentral gyrus showed ictal hyperperfusion. The frontal lobes, contralateral posterior cerebellum and ipsilateral precuneus showed hypoperfusion. Further exploratory analysis suggested an association between ipsilateral temporal lobe hyperperfusion and ipsilateral frontal lobe hypoperfusion, and an inverse association between seizure duration and hyperperfusion in the ipsilateral anterior cerebellum and contralateral postcentral gyrus. We conclude that there is a network of perfusion changes during CPS in patients with HS. Studying a particular seizure type in patients with HS with peri-ictal SPECT performed during a defined time window will allow further analysis of the cerebral network activities, and excitatory, inhibitory and gating mechanisms during seizures associated with HS.

We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated families and one sporadic case with episodic ataxia type 2 (EA-2). In two of the families and the sporadic patient, novel truncating mutations, which disrupt the reading frame and result in a premature stop of the CACNA1A protein, were identified in exons 14, 16 and 26. In the remaining family, a novel missense mutation (H253Y) was found. Of the twenty two EA-2 mutations identified thus far, including those of the present study, seventeen are truncating mutations and five are missense mutations, all resulting in an EA-2 clinical phenotype.

Described are the clinical, EEG, MR, and genetic characteristics of 106 members of a family with autosomal dominant temporal lobe epilepsy (TLE) and febrile seizures (FS), with 22 affected individuals. Eleven patients had a history of FS, and 10 patients had TLE. EEG showed epileptic activity in five. None had hippocampal sclerosis. There was no evidence for linkage to 13 candidate loci. This large family with autosomal dominant TLE has a distinct phenotype and shows no linkage to known candidate regions for familial partial epilepsy and FS.

Purpose: To determine whether specific temporal lobe simple partial seizures (SPSs) are associated with an abnormal amygdala T2 (AT2) ipsilateral to the seizure focus in patients with intractable unilateral temporal lobe epilepsy (TLE). AT2 relaxation time mapping is a sensitive method for the detection of abnormal tissue in the amygdala in patients with refractory TLE. The relation between an abnormal AT2 in the epileptic temporal lobe and amygdala seizure onset has not been established., Methods: Fifty patients with intractable unilateral TLE and concordant data during presurgical evaluation were included. Patients with a foreign-tissue lesion on standard magnetic resonance imaging (MRI) were excluded. All had AT2 mapping. Fifteen types of SPSs were ascertained prospectively, systematically, and blinded to the results of AT2 mapping. The SPSs of patients with a normal AT2 (n = 25) were compared with those of patients with an abnormal AT2 ipsilateral to the seizure focus (n = 25)., Results: The group of patients with an abnormal AT2 reported a median of six types of SPSs (range 1-11), in comparison with a median of three types of SPSs (range, 0-7) for the group with a normal AT2 (p<0.01). Déjà vu, a warm sensation, an indescribable strange sensation, a cephalic sensation, and fear were associated with an abnormal AT2. The combination of déjà vu, a cephalic sensation, a warm sensation, a gustatory hallucination, and an indescribable strange sensation discriminated best between the 25 patients with a normal and the 25 patients with an abnormal AT2., Conclusions: A high number and the types of different SPSs provide clinical evidence for early involvement of the amygdala during seizures in patients with refractory unilateral TLE and an abnormal AT2 in the epileptic temporal lobe

The authors compared ictal SPECT injection performed by medical personnel with self-injection ictal SPECT in six patients with refractory temporal lobe epilepsy. Self-injection was safe and started faster. Self-injection subtraction ictal SPECT coregistered to MRI (SISCOM) was localizing in three patients who had a complex partial seizure, but only one of three patients who had a simple partial seizure, which may limit its usefulness in clinical practice. The localizing information of self-injection was better in three patients, and obviated the need for depth-EEG studies in one patient.

Objective: To determine the 1H MRS findings in patients with intractable temporal lobe epilepsy (TLE) who had no detectable abnormality on either qualitative or quantitative MRI., Background: Previous work has indicated that approximately 20% of patients with TLE remain MRI negative after extensive qualitative and quantitative investigation. Single-voxel 1H MRS provides a means of identifying potentially diffuse disease., Methods: Seven patients with intractable TLE, normal routine MRI, normal hippocampal volumes, and normal hippocampal and amygdala quantitative T2 values underwent single-voxel 1H MRS of the medial temporal lobes. The results are compared with those from 13 control subjects and 15 patients with evidence of hippocampal sclerosis (HS)., Results: The ratio N-acetylaspartate/(choline-creatine + phosphocreatine) was abnormally low in five of the seven MRI-negative patients. In two of these patients, the ratios were low bilaterally. The observed MRS ratios in the MRI-negative group with abnormal EEG were similar to those from temporal lobes ipsilateral to HS, suggesting the presence of widespread or diffuse disease of a similar degree in both groups., Conclusions: These results demonstrate that MRS can provide evidence of temporal lobe abnormalities in TLE patients who show no abnormality on extensive MRI investigation.

Deficits in memory for figurative detail, spatial composition and the spatial location of objects in a scene have been reported postoperatively in right temporal lobectomy patients. The aim of this study was to examine whether these deficits can be used as a sign of lateralised dysfunction in pre-surgical temporal lobe epilepsy (TLE) patients. Sixty-nine patients with lateralised TLE (27 right, 42 left) were assessed on a battery of neuropsychological tests, including tests of general intellectual functioning and psychomotor speed and standardised memory tests involving the learning and recall of verbal and non-verbal material. A new task, the "Aspects of Spatial Memory Test" (AoSMT), based on the experimental tasks developed by Pigott and Milner [39] was also administered. The RTLE and LTLE groups did not differ in their overall level of intellectual function or on measures of cognitive and motor speed. On the AoSMT the LTLE group recognised significantly more figurative detail changes than the RTLE group. In addition, the RTLE group took significantly longer than the LTLE group to identify changes in orientation, figurative detail and filled/unfilled spaces. Poor scores on the AoSMT were significantly correlated with quantitative MRI measures of right hippocampal pathology. The clinical and theoretical implications of these findings are discussed.

Purpose: We wished to establish whether hippocampal changes occur in 1 year in adults with newly diagnosed partial seizures and, if so, to identify possible causes and mechanisms., Methods: Thirty-six adult patients with newly diagnosed partial seizures underwent a magnetic resonance imaging (MRI) scan of the brain including hippocampal volume and T2 relaxation time (HCT2) measurement and had a follow-up quantitative MRI scan approximately 1 year after the baseline MRI scan., Results: At baseline, 4 patients (11%) had hippocampal sclerosis (HS), 4 (11%) had abnormalities other than HS, and 28 had a normal MRI scan (78%). Twenty-three patients (64%) had recurrent seizures in the period between the two MRI scans. One of the 4 patients with HS, who had daily seizures, had significantly increased HCT2 values on follow-up, possibly reflecting progressive hippocampal damage. None of the 32 patients with MRI findings other than HS at baseline progressed to HS on follow-up. However, 2 of the 32 patients had significant hippocampal changes, probably related to resolution of inflammatory swelling or edema after seizures were controlled., Conclusions: Subtle changes in hippocampi can occur in 1 year in adults with newly diagnosed partial seizures, which could be due to resolution of edema after seizure control or to hippocampal changes associated with frequent and daily seizures. Follow-up of the studied cohort for several years will be required to settle the question of whether progressive hippocampal damage occurs in temporal lobe epilepsy (TLE).

By using [11C]flumazenil-positron emission tomography ([11C]FMZ-PET), we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [11C]FMZ-PET and ex vivo binding using [3H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [11C]FMZ volume of distribution ([11C]FMZ Vd) obtained in 10 patients with refractory mTLE due to unilateral, histologically verified HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([3H]FMZ Bmax). After correction for partial volume effect, [11C]FMZ Vd in the body of the epileptogenic hippocampus was reduced by a mean of 42.1% compared with normal controls. [3H]FMZ Bmax, determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neurons in HS can be reliably detected in vivo by using [11C]FMZ-PET after correction for partial volume effect.