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Focal cortical dysplasias type II (FCD II) are highly epileptogenic lesions frequently causing pharmacoresistant epilepsy. Detection of these lesions on MRI is still challenging as FCDs may be very subtle in appearance and might escape conventional visual analysis. Morphometric MRI analysis is a voxel-based post-processing method based on algorithms of the statistical parametric mapping software (SPM5). It creates three dimensional feature maps highlighting brain areas with blurred grey-white matter junction and abnormal gyration, and thereby may help to detect FCD. In this study, we evaluated the potential diagnostic value of morphometric analysis as implemented in a morphometric analysis programme, compared with conventional visual analysis by an experienced neuroradiologist in 91 patients with histologically proven FCD II operated on at the University Hospital of Bonn between 2000 and 2010 (FCD IIa, n = 17; IIb, n = 74). All preoperative MRI scans were evaluated independently (i) based on conventional visual analysis by an experienced neuroradiologist and (ii) using morphometric analysis. Both evaluators had the same clinical information (electroencephalography and semiology), but were blinded to each other's results. The detection rate of FCD using morphometric analysis was superior to conventional visual analysis in the FCD IIa subgroup (82% versus 65%), while no difference was found in the FCD IIb subgroup (92% versus 91%). However, the combination of conventional visual analysis and morphometric analysis provided complementary information and detected 89 out of all 91 FCDs (98%). The combination was significantly superior to conventional visual analysis alone in both subgroups resulting in a higher diagnostic sensitivity (94% versus 65%, P = 0.031 for FCD IIa; 99% versus 91%, P = 0.016 for FCD IIb). In conclusion, the additional application of morphometric MRI analysis increases the diagnostic sensitivity for FCD II in comparison with conventional visual analysis alone. Since detection of FCDs on MRI during the presurgical evaluation markedly improves the chance of becoming seizure free postoperatively, we apply morphometric analysis in all patients who are MRI-negative after conventional visual analysis at our centre.

Purpose: Several small patient studies and case reports raise concerns that the reliability of functional magnetic resonance imaging (fMRI) may be impaired in the vicinity of cerebral lesions. This could affect the clinical validity of fMRI for presurgical language lateralization. The current study sets out to identify if a systematic effect of lesion type and localization on fMRI exists., Methods: We classify lesions typically occurring in epilepsy patients according to (1) their potential to disturb blood oxygenation level dependent (BOLD)-effect generation or detection or to disturb spatial brain normalization, and (2) the proximity of lesions to protocol-specific volumes of interest (VOIs). The effect of lesions is evaluated through the examination of 238 epilepsy patients and a subgroup of 37 patients with suspected unilateral left-language dominance according to the Wada test., Results: Patients with fMRI-critical lesions such as cavernomas, gliomas, and mass defects close to VOIs, or with severe atrophy, show lower lateralization indices (LIs) and more often discordant language lateralization with the Wada test than do patients without such lesions., Discussion: This study points seriously toward fMRI-language lateralization being sensitive to cerebral lesions. Some lesion types and locations are more critical than others. Our results question the noncritical application of fMRI in patients with cerebral lesions.

Balloon cells of distinct focal cortical dysplasias type IIb (FCD(IIb)) and giant cells of cortical tubers in tuberous sclerosis (TSC) constitute neuropathological hallmarks and cytological similarities. In TSC, frequent mutations in the TSC1 or TSC2 genes result in mTOR-signaling activity. Here, we addressed whether Pi3K-pathway activation differentiates balloon cells from giant cells. We used immunohistochemistry with antibodies against p-PDK1 (S241), p-Akt (S473), p-tuberin (T1462), p-p70(S6K) (T389), p-p70(S6K) (T229) and phalloidin-staining to analyze stress fiber formation in balloon cells of FCD(IIb) (n = 23) compared with cortical tuber giant cells (n = 5) and adjacent normal CNS tissue as control. We have further established an in vitro assay to assess potential phosphorylation between Akt and S6. We observed phosphorylated (p-)PDK1, p-Akt, p-tuberin, and p-p70-kDa S6-kinase (p-p70(S6K); residue T229) in balloon cells, whereas giant cells showed only equivalent levels of p-tuberin, p-p70(S6K) and stress fibers. Furthermore, Pi3K-cascade activity in balloon cells may reflect pathway "cross-talk". An in vitro assay revealed S6, a major target of p70(S6K), to increase phosphorylation of Akt. Our data suggest recruitment of different Pi3K-cascade factors in the molecular pathogenesis of giant cells in cortical tubers vs. balloon cells in FCD(IIb) and provides new implications for the development of treatment strategies for these cortical malformations.

Focal cortical dysplasias (FCD) with Taylor-type balloon cells (FCD(IIb)) are frequently observed in biopsy specimens of patients with pharmacoresistant focal epilepsies. The molecular pathogenesis of FCD(IIb), which lack familial inheritance, is only poorly understood. Due to their highly differentiated, malformative nature and glioneuronal phenotype, FCD(IIb) share neuropathological characteristics with lesions observed in familial disorders such as cortical tubers present in patients with autosomal dominant tuberous sclerosis complex (TSC), related to mutations in the TSC1 or TSC2 genes, and dysplastic gangliocytomas of the cerebellum found in Cowden disease. Current data have indicated distinct allelic variants of TSC1 to accumulate in FCD(IIb). TSC1 represents a tumor suppressor operating in the phosphatidylinositol 3-kinase (PI3K)/insulin pathway. The tumor-suppressor gene PTEN is mutated in Cowden disease. Like PTEN, also carboxyl-terminal modulator protein (CTMP) modulates PI3K-pathway signaling, both via inhibition of Akt/PKB, a kinase inactivating the TSC1/TSC2 complex. Here, we have analyzed alterations of Akt, PTEN and CTMP relevant for insulin signaling upstream of TSC1/TSC2 in FCD(IIb). Immunohistochemistry with antibodies against phosphorylated Akt (phospho-Akt; Ser 473) in FCD(IIb) (n=23) showed strong phospho-Akt expression in dysplastic FCD(IIb) components. We have further studied sequence alterations of PTEN (n=34 FCD(IIb)) and CTMP (n=20 FCD(IIb)) by laser microdissection/single-strand conformation polymorphism analysis. We observed a somatic mutation in an FCD(IIb), i.e., amino-acid exchange at nucleotide position 834 (PTEN cDNA, GenBank AH007803.1) in exon 8 with replacement of phenylalanine by leucine (F278L). We also found several silent polymorphisms of PTEN in exon 2 and exon 8 as well as silent and coding polymorphisms but no mutations in CTMP. No loss of heterozygosity in FCD(IIb) (n=6) at 10q23 was observed. To our knowledge, we here report on the first somatic mutation of a tumor-suppressor gene, i.e., PTEN, in FCD(IIb). However, our study also demonstrates that mutational alterations of PTEN and CTMP do not play major pathogenetic roles for activation of Akt in FCD(IIb). Future studies need to determine the origin of insulin pathway activation upstream of TSC1/TSC2 in FCD(IIb).

Glioneuronal lesions are frequently observed in biopsy specimens obtained from patients with pharmacoresistant epilepsies, comprising focal cortical dysplasias (FCD) and gangliogliomas. Recent findings point to the phosphoinositide 3-kinase (PI3K) pathway and tuberin/hamartin signaling cascade as being compromised in these lesions. Ezrin, radixin and moesin (ERM-/band-4.1 proteins) genes represent downstream effectors of the PI3K pathway, are involved in cytoskeleton-membrane interference, cell growth, migration and differentiation, and harbor tumor suppressor motifs. Accumulation of band-4.1 proteins has been identified in cortical tubers of tuberous sclerosis patients, which share neuropathological similarities with FCD and gangliogliomas. Here, we have studied the immunohistochemical distribution pattern of ERMs, as well as allelic variants, occurring in gangliogliomas (n=20) and FCDs (FCD(IIa), n=7; FCD(IIb), n=37). Aberrant accumulation of ERMs was observed in dysplastic neurons of FCDs and gangliogliomas as well as in balloon cells. Adjacent brain tissue without structural abnormalities was used as control and showed only faint neuropil staining. Mutational screening revealed silent polymorphisms in the ezrin gene in two individuals suffering from FCD(IIb). A transition from G to A in radixin exon 2 resulted in an exchange of valine by isoleucine at codon 50 in an additional FCD(IIb) specimen. Such sequence alterations were not found in controls. The present data suggest accumulation of ERM expression in dysplastic cellular components but do not favor mutational events of ERM in the pathogenesis of FCDs or gangliogliomas. Aberrant expression of ERMs is, however, compatible with compromised PI3K-pathway signaling in glioneuronal lesions characterized by abnormal cellular differentiation and aberrant network formation.

Focal brain lesions such as cortical dysplasia and glioneural tumors generate epileptic activity and thus may be synaptically connected with normal cortex. To test this hypothesis, we compared event-related potentials recorded directly from the medial temporal lobe (MTL) and a dysplastic lesion in eight patients with intractable temporal lobe epilepsy. The P3 component, related to visual target detection, showed different peak latencies in four patients and a larger intralesional amplitude compared to established anterior-MTL-generators in two patients. Semantic processing was identified by the N400 component and showed a different latency in four patients and larger intralesional amplitudes in two patients. These results are compatible with the hypothesis that cortical lesions interact with synaptic pathways related to cognitive functions such as visual target detection, and verbal processing.

Summary: Rasmussen encephalitis (RE) is an immune‐mediated brain disease with progressive unihemispheric atrophy. Although it is regarded as a strictly one‐sided pathology, volumetric magnetic resonance imaging (MRI) studies have revealed atrophy in the so‐called unaffected hemisphere. In contrast to previous studies, we hypothesized that the contralesional hemisphere would show increased gray matter volume in response to the ipsilesional atrophy. We assessed the gray matter volume differences among 21 patients with chronic, late‐stage RE and 89 age‐ and gender‐matched healthy controls using voxel‐based morphometry. In addition, 11 patients with more than one scan were tested longitudinally. Compared to controls, the contralesional hemisphere of the patients revealed a higher cortical volume but a lower subcortical gray matter volume (all P < 0.001, unpaired t test). Progressive gray matter volume losses in bilateral subcortical gray matter structures were observed (P < 0.05, paired t test). The comparatively higher cortical volume in the contralesional hemisphere can be interpreted as a result of compensatory structural remodeling in response to atrophy of the ipsilesional hemisphere. Contralesional subcortical gray matter volume loss may be due to the pathology or its treatment. Because MRI provides the best marker for determining the progression of RE, an accurate description of its MRI features is clinically relevant. [ABSTRACT FROM AUTHOR]

Background: Generalized tonic-clonic seizures (GTCS) frequently lead to emergency inpatient referrals. Laboratory blood values are routinely performed on admission to detect underlying causes and metabolic or cardiac complications. Our goal was to assess the nature and frequency of complications occurring in association with GTCS.Methods: We retrospectively extracted data from emergency protocols and discharge letters of adult patients admitted to the Department of Epileptology between 01/2010 and 06/2015. Inclusion criteria were diagnosis of GTCS and admission via emergency services. Exclusion criteria were status epilepticus prior to admission to hospital and non-generalized seizures.Results: A total of 223 patients (of 986 screened cases) were included. Overall, 1.8% required intubation while 1.3% had less severe respiratory problems. In 5.6% of patients, a transient hypoxemia was measured. Hypertensive urgencies affected 7.8% of the patients, sinus tachycardia occurred in 41.2%. Troponin I (cTNI) was determined in 75 patients and was increased in 12% of these cases. Occurrence of elevated cTNI levels was significantly correlated with patient's age. Four patients were diagnosed with NSTEMI and one patient with STEMI. Creatine kinase (CK) was increased in 59.4% of the patients, with <5-fold increases in 47%, <10-fold in 5.8% and >10-fold increases in 4.3%. Rhabdomyolysis with an >50 fold increase in CK was detected in 1.9% of patients. Prolonged disturbances of consciousness affected 5% of cases while agitation, delirium, and psychotic episodes occurred in 6.3%. Minor traumatic injuries affected 45.7% of patients.Conclusions: Troponin elevations in association with GTCS are one of the more common complications after emergency admissions especially in older patients. In our selected patient population, serious complications such as intracranial hemorrhage, myocardial infarction and acute renal failure occurred in <1% of GTCS only. [ABSTRACT FROM AUTHOR]

Objective Autoantibodies against glutamic acid decarboxylase ( GAD) and the voltage-gated potassium channel ( VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). Methods Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. Results We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC-complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. Significance The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex-associated limbic encephalitis, primarily affecting mesiotemporal gray matter. [ABSTRACT FROM AUTHOR]

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes. [ABSTRACT FROM AUTHOR]

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy ( ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. 'Resolved' is not necessarily identical to the conventional view of 'remission or 'cure.' Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Recent findings indicate that the hippocampus is not only crucial for long-term memory (LTM) encoding, but plays a role for working memory (WM) as well. In particular, it has been shown that the hippocampus is important for WM maintenance of multiple items or associations between item features. Previous studies using intracranial electroencephalography recordings from the hippocampus of patients with epilepsy revealed slow positive potentials during maintenance of a single item and during LTM encoding, but slow negative potentials during maintenance of multiple items. These findings predict that WM maintenance of multiple items interferes with LTM encoding, because these two processes are associated with slow potentials of opposing polarities in the hippocampus. Here, we tested this idea in a dual-task paradigm involving a LTM encoding task nested into a WM Sternberg task with either a low (one item) or a high (three items) memory load. In the high WM load condition, LTM encoding was significantly impoverished, and slow hippocampal potentials were more negative than in the low WM load condition. Time-frequency analysis revealed that a reduction of slow hippocampal activity in the delta frequency range supported LTM formation in the low load condition, but not during high WM load. Together, these findings indicate that multi-item WM and LTM encoding interfere within the hippocampus. [ABSTRACT FROM AUTHOR]

Electrical stimulation mapping (ESM) is the gold standard for identifying language-relevant cortex prior to neurosurgical resections near the eloquent cortex. However, its application mode is not standardized, as some procedures rely on a single task, whereas others depend on task batteries. In this study, we examine whether multitask ESM is necessary, quantify the information loss that occurs from restricting the number of applied tasks, and search for a procedure that allows for time-efficient, multitask ESM. Thirty-eight epilepsy and 11 brain tumor patients with subdural grid electrodes receive extraoperative ESM for language cortex at 1,890 stimulation sites. The applied test battery includes counting, naming, repeating, reading, Token Test, and body commands. Correlation analysis and principal component analysis are used to identify the functional overlap between tasks. Sensitivity analysis is the basis for determining the optimal task order, which requires a minimum number of stimulations for identifying language loci. Correlation coefficients between tasks are −0.17 to 0.63; frontal and temporoparietal language cortex are organized differently. Naming is the most sensitive task, but 31% (temporoparietal) to 43% (frontal) of language sites remained undetected after naming alone. The optimal procedure starts with naming and the Token Test and differs thereafter between frontal and temporoparietal cortex. Omitting the Token Test and body commands from the battery results in up to 26% information loss. Despite considerable overlap between different tasks, multitask ESM appears necessary to avoid missing language relevant cortex. Applying the tasks in an optimal order allows economizing the procedure. [ABSTRACT FROM AUTHOR]

Abstract: Gray matter heterotopia are a common cause of pharmacoresistant epilepsy. Recently, several case studies have addressed the question of whether heterotopia can contribute to physiological cerebral functions. We describe two cases that demonstrate a functional role for periventricular heterotopia in higher cognitive processes. During presurgical diagnostics, two patients underwent electric stimulation of both the periventricular heterotopia and the overlying cortex. This revealed a functional role of periventricular heterotopia in higher cerebral functions such as language and complex visual and acoustic processing. Furthermore, stimulation of the overlying cortex led to unusually intense positive phenomena, including complex acoustic and gustatory hallucinations and language production. These cases illustrate that periventricular heterotopic neurons can contribute to higher cerebral functions. Interestingly, the anterior-to-posterior representation of these functions is comparable to the normal anterior-to-posterior representation in a normal neocortex (similar to a periventricular “minicortex” in early developmental stages). [Copyright &y& Elsevier]

The human hippocampus is essential for both encoding and recollection, but it remains controversial whether there is a functionally different involvement of anterior versus posterior parts of the hippocampus in these memory processes. In the present study, we examined encoding and retrieval processes via intrahippocampal recordings in 27 patients with unilateral temporal lobe epilepsy. Multicontact depth electrodes were implanted along the longitudinal axis of the hippocampus as part of the presurgical evaluation. In a continuous word recognition test, subjects had to indicate whether words were new or already presented. Recognized old words, as compared to new words, resulted in a larger P600 component, as well as in a larger late negative component (LNC, 600-900 msec). In addition, subsequently remembered words elicited a larger positivity (400 to 900 msec) than later forgotten words. We found differences concerning the distribution along the hippocampus for the LNC old-new effect, reflecting successful retrieval, as well as for the subsequent memory effect, reflecting successful encoding. Both effects were larger the further posterior an electrode was located in the hippocampus. Findings are suggestive for a predominant posterior hippocampal involvement in both verbal encoding and retrieval. [ABSTRACT FROM AUTHOR]

In patients with mesial temporal lobe epilepsy (MTLE) it remains an unresolved issue whether the interictal decrease in N-acetyl aspartate (NAA) detected by proton magnetic resonance spectroscopy (1H-MRS) reflects the epilepsy-associated loss of hippocampal pyramidal neurons or metabolic dysfunction. To address this problem, we applied high-resolution 1H-MRS at 14.1 Tesla to measure metabolite concentrations in ex vivo tissue slices from three hippocampal subfields (CA1, CA3, dentate gyrus) as well as from the parahippocampal region of 12 patients with MTLE. In contrast to four patients with lesion-caused MTLE, we found a large variance of NAA concentrations in the individual hippocampal regions of patients with Ammon's horn sclerosis (AHS). Specifically, in subfield CA3 of AHS patients despite of a moderate preservation of neuronal cell densities the concentration of NAA was significantly lowered, while the concentrations of lactate, glucose, and succinate were elevated. We suggest that these subfield-specific alterations of metabolite concentrations in AHS are very likely caused by impairment of mitochondrial function and not related to neuronal cell loss. A subfield-specific impairment of energy metabolism is the probable cause for lowered NAA concentrations in sclerotic hippocampi of MTLE patients. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of nonconvulsive status epilepticus (NCSE) is particularly challenging in elderly patients. Confusion, personality change, dysphasia, subtle motor activity and nystagmus may be the only presenting signs. Objective: To review current knowledge about NCSE with special focus on older people. Methods: Systematic review of the current literature via Medline search. Conclusion: Although prospective studies are still lacking, NCSE may be one of the most frequently missed diagnoses in patients presenting with altered mental status. Elderly patients are at particular risk of diagnostic errors because of the broad range of presentations of NCSE, significant comorbidities (especially cerebrovascular disease), limited awareness of this particular seizure emergency or difficulties with access to electroencephalography. Although diagnostic criteria and treatment remain controversial, the diagnosis of NCSE is important because it is potentially reversible. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To test whether increasing synchronization of neuronal activity might be causally related to seizure termination. Methods: Neuronal synchronization was assessed by the relative changes of the eigenvalue spectrum of the equal-time correlation matrix computed from a short window sliding along multi-channel EEGs, recorded with either intracranial or surface electrodes. Results: Synchronization dynamics of six status epilepticus EEG recordings from six patients were assessed. In all six recordings EEG synchronization fluctuated around relatively low levels during ongoing epileptiform activity. Synchronization only persistently increased before, or in one case, at the end of status epilepticus. Ongoing seizure activity stopped without pharmacological intervention in one patient. In four of the five other cases, the persistent increase of synchronization followed administration of anticonvulsant drugs. Conclusions: Our findings support the hypothesis that increasing synchronization of neuronal activity may be considered as an emergent self-regulatory mechanism for seizure termination. Significance: The traditional concept is challenged that increasing neuronal synchronization during epileptic seizures is always pathological and should be suppressed. On the contrary, our findings imply that therapeutic interventions to increase synchronization during seizures might be beneficial. [Copyright &y& Elsevier]

Abstract: Limbic encephalitis (LE) was described in the 1960s as a clinical–pathological syndrome in adults. Initially, the paraneoplastic form was the center of interest. An increasing number of diagnostically valuable autoantibodies in patients’ sera (and cerebrospinal fluid) have been identified. Lately, the impact of non-paraneoplastic LE cases has been acknowledged. In the serum of some of these patients, antibodies against voltage-dependent potassium channels (VGKC antibodies) have been detected. The characteristic MRI course of LE patients has recently been described in detail: hippocampal swelling and T2/FLAIR signal increase are early findings. After a few months, the swelling regresses, followed by hippocampal atrophy with continuous signal increase. A general consensus on formal diagnostic criteria for all LE subsyndromes has not yet been reached. This article proposes such diagnostic criteria and formulates suggestions for treatment. [Copyright &y& Elsevier]

Purpose: The optimal management of cerebral cavernous malformations (CCMs) with epileptic seizures is still a matter of debate. The aim of our study was to examine seizure outcome in the largest published series of surgically treated patients with epilepsy due to a supratentorial CCM, and to define predictors for good surgical outcome. Methods: We retrospectively studied 168 consecutive patients with a single supratentorial CCM and symptomatic epilepsy in a multicenter study. Pre- and postoperative clinical examinations, age at epilepsy onset, age at operation, type of symptoms due to the CCM (seizures, headache, hemorrhage, focal deficits), type and frequency of epileptic seizures, and the localization and size of the CCM were assessed. Seizure outcome was determined in the first, second, and third postoperative years. Results: The CCM was completely resected in all patients. More than two thirds of the patients were classified as seizure free in the first 3 postoperative years. Predictors for good seizure outcome were age older than 30 years at the time of surgery, mesiotemporal CCM localization, CCM size <1.5 cm, and the absence of secondarily generalized seizures. No mortality occurred in our series, but only mild postoperative neurologic deficits in 12 (7%) patients. Conclusions: Considering the natural history of CCMs, the favorable neurologic and seizure outcome, surgical resection of CCMs should be considered in all patients with supratentorial CCMs and concomitant epilepsy, irrespective of the presence or absence of predictors for a favorable seizure outcome. [ABSTRACT FROM AUTHOR]

Purpose: It is difficult to validly assess the long-term effect of epilepsy surgery. Here, this is attempted by comparing the outcome of surgically treated pharmacoresistant epilepsy patients to three different nonoperated comparison groups regarding seizure control, antiepilepsy drug (AED) usage, and health related quality of life (QOL). Methods: One hundred thirty-one operated patients (group 1, mean follow-up since presurgical assessment 6.9 years), 105 patients awaiting presurgical assessment (group 2, mean follow-up after assignment to waiting list 0.8 years), 99 patients considered to be presurgical candidates who chose to withdraw from waiting for presurgical assessment (group 3, mean follow-up after assignment to waiting list 5.5 years), and 49 patients who were not deemed to be eligible for surgery after comprehensive assessment (group 4, mean follow-up since presurgical assessment 6.5 years) were studied. The patients completed a questionnaire on seizures, AED usage, and QOL (ESI-55). Results: The surgical patients had a better outcome than all three comparison groups regarding seizure frequency, seizure freedom rate, and number of AEDs used. They scored higher than groups 2, 3, and 4 on 7/11, 6/11, and 3/11 ESI-55 domains, respectively. Conclusions: The superior long-term outcome of the operated patients was most marked if compared to the patients awaiting surgery. This is compatible with the assumption that patients present for presurgical candidacy selection and assessment at a “nadir” of their disease course. After several years, a regression to the mean occurs which reduces (but does not abolish) the differences between nonoperated and operated patients. [ABSTRACT FROM AUTHOR]

Purpose: Intellectual disabilities are often associated with bilateral or diffuse morphologic brain damage. The chances of becoming seizure free after focal surgery are therefore considered to be worse in patients with intellectual disabilities. The risk of postoperative cognitive deficits could increase because diffuse brain damage lowers the patient's ability to compensate for surgically induced deficits. Several studies in adult patients have indicated that IQ alone is not a good predictor of postoperative cognitive and seizure outcome. Our study evaluated this subject in children and adolescents. Methods: Pediatric patients with intellectual disabilities (IQ ≤ 70), subaverage intelligence (IQ between 71 and 85), or average-range intelligence (IQ > 85) were matched according to several clinical and etiologic criteria to determine the influence of IQ (N = 66). Results: No dependency of seizure outcome, postoperative cognitive development, and behavioral outcome on the IQ level was found. All groups slightly improved in attention while memory functions tended to decrease and executive functions were stable. School placement remained unchanged for the majority of patients. Between 67 and 78% were seizure free 1 year after surgery (Engel outcome class I). Conclusions: IQ alone is not a good predictor of postoperative outcome in pediatric patients with epilepsy. As with patients of average-range intelligence, the decision to operate on patients with a low level of intelligence should depend on the results of the presurgical diagnostics. If the results of the neuropsychological examination indicate diffuse functional impairment, this should not hinder further steps, if all other findings are consistent. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether seizure remission is a comprehensive marker of outcome in psychogenic nonepileptic seizures (PNESs). Methods: A postal questionnaire was returned by 147 patients with PNESs a mean of 4.2 years after diagnosis (mean age at follow-up, 38.1 years). The proportion of patients who were “unproductive” (receiving health-related state benefits) at follow-up was determined, with a comparison of markers of ongoing psychopathology (Global Severity Index, anxiety and depression scores of the Symptom Checklist 90, Somatization Index DSM of the SOMS-2) in three outcome groups: group 1, continuing seizures; group 2, seizures stopped but patients “unproductive;” and group 3, seizures stopped, patients “productive.” Results: Of the patients, 71.4% continued to have seizures, and 28.6% had achieved seizure remission; 60.0% of patients with continuing seizures and 42.7% of patients in remission were “unproductive” (difference, NS). Ongoing psychopathology was related to the factor “group membership” with higher values in groups 2 and 3 than in group 1 (GSI, p < 0.001; anxiety, p = 0.01; depression, p = 0.02; Somatization Index DSM, p < 0.001). Across all patients and in the subgroup with PNESs and additional epilepsy, differences were significant only between groups 2 and 3, not between groups 1 and 2. In patients with PNESs alone, differences were significant only between groups 1 and 2. Conclusions: Seizure remission is not a comprehensive measure of good medical or psychosocial outcome in PNESs. Nearly half the patients who become seizure free remain unproductive. Many of these patients continue to report symptoms of psychopathology. Seizure control should not be the only focus of treatment in clinical practice or outcome observation in research studies. [ABSTRACT FROM AUTHOR]

Purpose: The determination of language dominance as part of the presurgical workup of patients with pharmacoresistant epilepsies has experienced fundamental changes. With the introduction of noninvasive functional magnetic resonance imaging ( fMRI), the number of patients receiving intracarotid amobarbital procedures (IAPs) for assessment of language dominance has decreased considerably. However, recent studies show that because of methodologic limitations of fMRI, IAP remains an important tool for language lateralization. The current study examines whether unilateral instead of bilateral IAP is an adequate way to apply IAP with reduced invasiveness. Methods: We retrospectively examine the predictive value of unilateral IAP for the results of bilateral IAP based on a sample of 75 patients with various types of language dominance. Target parameters are the prediction of the language-dominant hemisphere and the identification of patients with atypical language dominance. For language assessment based on unilateral IAP, we introduce the measure hemispheric language capacity (HLC). Results: Unilateral IAP performed on the side of intended surgery quantifies language capacity contralateral to the intended surgery. It detects atypical (bilateral or right) language dominance in the majority of patients. Experience with a separate series of 107 patients requiring presurgical language lateralization shows that in >80%, bilateral IAPs are redundant. Conclusions: Unilateral IAP is principally sufficient for language lateralization in the presurgical evaluation of patients with pharmacoresistant epilepsies. Necessity of bilateral IAP is restricted to few indications (e.g., callosotomy). In times of noninvasive language lateralization, we propose unilateral IAP as the method of choice for the verification of doubtful (bilateral) fMRI activation patterns. [ABSTRACT FROM AUTHOR]

Purpose: After pilocarpine-induced epilepsy in rats, volumetric magnetic resonance imaging (MRI) reveals significant morphologic changes in functionally relevant structures of the brain. To relate structural changes to functional alteration, we studied the correlation of regional brain atrophy (e.g., of the hippocampus) with lesion-induced learning deficits in the Morris water maze. Methods: MRI experiments were performed on an MR scanner at 4.7 Tesla. For volumetric analysis, various cerebral structures were segmented in horizontal and coronal T2-weighted MR images. Before the MRI investigations, animals were trained for 10 days in a Morris water maze. Results: Volumetric MRI revealed a significant loss in hippocampal size in both the dorsal and ventral parts, correlated with an increase in ventricular size. Furthermore, significant losses were found in the relative size of thalamus, putamen, cortex, and the combined areas of perirhinal, entorhinal, and piriform cortices adjacent to the hippocampus. A significant correlation of learning performance in the Morris water maze with the relative hippocampal area and not with other areas tested was observed in pilocarpine-treated animals. Conclusions: The data provide a quantitative analysis of functionally relevant structural alterations in rats with chronic epilepsy. Water maze performance of pilocarpine-treated animals correlates with the degree of hippocampal but not with the degree of cortical damage, demonstrating the potential of this method for the investigation of cognitive impairments in relation to cerebral changes. In addition, the data point to an important role of even the residual hippocampus in memory formation. [ABSTRACT FROM AUTHOR]

Evidence for a response-control-related kind of declarative memory during deep propofol anesthesia has recently been reported. Connectivity within the mediotemporal lobe (MTL), and in particular rhinal-hippocampal synchronization within the gamma band, has been shown to be crucial for declarative memory formation. Thus, we analyzed EEG recordings obtained from the scalp, as well as directly from within the hippocampus and from the anterior parahippocampal gyrus, which is covered by rhinal cortex, in patients with unilateral temporal lobe epilepsy during propofol anesthesia, which preceded electrode explantation. For the gamma band a power decrease starting with induction of anesthesia was observed at scalp position Cz, but a power increase was detected at MTL locations. In contrast to prior results for sleep recordings, rhinal-hippocampal coherence did not decrease within the gamma band at deeper levels of anesthesia. These findings may represent an indirect electrophysiological correlate of partially intact declarative memory formation during deep propofol sedation. Furthermore, we investigated how well the plasma propofol level, as well as different stages of anesthesia including the burst suppression phase, could be monitored by different spectral as well as by nonlinear EEG measures. We observed that conventional spectral power measures, most prominently those recorded from mediotemporal locations, are most closely correlated with the plasma propofol level, whereas different stages of anesthesia can be distinguished best by nonconventional spectral as well as nonlinear measures. [ABSTRACT FROM AUTHOR]

Cognitive profiles in epilepsy are as heterogenous as the epileptic syndromes themselves; causes, topography of epileptogenic areas, pathogenetic mechanisms, and the diverse features characterising the clinical course all contribute to the effect on cognition. Chronic epilepsy generally impairs cognition, but it also induces processes of functional reorganisation and behavioural compensation. In most idiopathic epilepsies, cognition is only mildly deteriorated or even normal by clinical standards. Localisation-related cryptogenic and symptomatic epilepsy disorders are accompanied by focal deficits that mirror the specific functions of the respective areas. Poor cognitive outcome is generally associated with an early onset and a long duration of the disease and with poor seizure control. There is evidence that cognitive functions are already impaired at the onset of the disease, and that the maturation of cognitive functions in children is susceptible to the adverse influence of epilepsy. In adults, cognitive decline progresses very slowly over decades with an age regression similar to that of people without epilepsy. Successful epilepsy surgery can stop or partly reverse the unfavourable cognitive development, but left-temporal resections in particular have a high risk of additional postoperative verbal memory impairment. Cognitive recovery in the adult brain after successful surgery indicates functional compensation and, to some degree, functional reorganisation or a reactivation of functions previously suppressed by influence from distant but connected epileptogenic areas. [Copyright &y& Elsevier]

To explore the clinical significance of a history of recurrent psychogenic nonepileptic seizure status (PNES-status), this study describes the frequency of PNES-status in 85 consecutive PNES patients and examines whether there are relevant differences between patients with a history of recurrent PNES-status and other PNES-patients. PNES patients were also compared with 64 patients with epilepsy. Data were extracted from hospital records and a postal questionnaire (Dimensional Assessment of Personality Pathology-Basic Questionnaire; Screening for Somatoform Symptoms; Dissociative Experience Scale). Of the PNES-patients, 77.6% reported at least one seizure > 30 minutes (PNES-status), 27 % admission to intensive care with status. 38.8% reported recurrent hospital admissions with status (PNES-status group), the remaining patients served as PNES-controls. The only clinical difference between the two PNES groups was that status patients were younger than PNES-controls (mean age 20.3 vs. 30.3 years, p = 0.001). Our results suggest that PNES status is common and often unrecognised. There were no substantial psychometric differences between patients with recurrent PNES-status and other PNES patients although both PNES-groups had more abnormal somatisation, dissociation and personality scores than patients with epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug-resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival. Methods: Data were analyzed from 207 consecutive patients with intractable epilepsy (aged 2-54 years), who between 1988 and 1999 had ≥50% resection of supratentorial, neuroepithelial tumors. Extent of resection was assessed on postoperative magnetic resonance imaging (MRI); seizure outcome was classified according to Engel's outcome scale; and follow-up data were prospectively updated. Results: Median follow-up was eight years (range, 2-14 years). Histologic examination revealed 154 classic epilepsy-associated tumors (ganglioglioma, dysembryoplastic neuroep-ithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytomas) and 53 others (astrocytomas and oligoden-drogliomas). Four World Health Organization (WHO) grade III tumors were found (astrocytoma, n = 3; ganglioglioma, n = 1).After surgery, 82% of the patients were seizure free (class I). The following factors were associated with improved seizure outcome: Short duration of epilepsy before surgery, single EEG focus, absence of additional hippocampal sclerosis or cortical dysplasia, transsylvian approach, other than astrocytomas, and complete tumor resection. After 5 years, only nine (4%) patients had tumor recurrence, four (2%) with malignant transformation and death. None of the four patients with anaplastic tumors died. Even patients with astrocytomas of WHO grade II or III showed 10-year recurrence of only 25% and 10-year survival of 90%. Conclusions: Tumors associated with long-term epilepsy should be removed early for two different reasons: high rate of seizure freedom and rare but potential risk of malignant tumor progression. The unexpected long survival of these astro-cytomas should be investigated by using immunohistochemistry and molecular biology. [ABSTRACT FROM AUTHOR]

Abstract: Analysis of ictal semiology is essential to presurgical evaluation of patients with epilepsy. To assess the localizing value of behavioral arrest in temporal lobe epilepsy (TLE), we analyzed 107 video/EEG monitoring-documented seizures of 107 adult patients with TLE for a set of defined seizure phenomena with respect to frequency and sequence of occurrence in relation to epileptogenic (mesial vs extramesial, left vs right) origin. Behavioral arrest was observed more frequently in left-sided temporal seizures: 25.7% of left-sided mesial seizures and 25.0% of left-sided extramesial seizures exhibited behavioral arrest, whereas only 3.4% of right-sided mesial seizures and 10.5% of right-sided extramesial seizures were associated with behavioral arrest. In addition, occurence of behavioral arrest within the sequence of seizure phenomena was remarkably consistent, being observed mainly as the first apparent feature of seizure onset. Thus, behavioral arrest is a valuable early indicator of a left-sided temporal epileptogenic focus in adult patients with TLE. [Copyright &y& Elsevier]

Abstract: The medial temporal lobes (MTLs) are essential for both encoding and retrieval processes in declarative memory. In addition, they are a frequent seizure focus for medically refractory epilepsy. One of the major side effects of MTL resection is a decline in memory functions. Most functional imaging paradigms have been developed to find preoperative measures that, to obtain a prognosis of postoperative memory performance, employ explicit memory encoding strategies to elicit MTL activation, and require a great amount of cognitive effort. We applied three different implicit encoding tasks, which require less effort and time, to a group of healthy subjects. We found left-lateralized activation for verbal stimuli, bilateral activation for pictures, and right-lateralized activation for faces. The present study shows that even with an implicit memory-encoding paradigm, a lateralized activation of MTL structures can be achieved. This may lead to paradigms for routine clinical application that require less cognitive effort and time on the part of patients. [Copyright &y& Elsevier]

Abstract: The medial frontal cortex (MFC) has been implicated in the monitoring and selection of actions in the face of competing alternatives, but much remains unknown about its functional properties, including electrophysiological oscillations, during response conflict tasks. Here, we recorded intracranial EEG during a modified Flanker task from the MFC of two patients undergoing pre-surgical evaluation for the treatment of epilepsy. Performance on the task was associated with a suppression of beta (15–30 Hz) frequency oscillation power prior to and just following the response and an enhancement of theta (4–8 Hz) frequency power following the response. Beta (theta) power was anatomically distributed towards more dorsal/caudal (rostral/ventral) electrode sites along the cortex, suggesting an anatomical/functional specialization along the medial frontal wall for pre-response versus post-response action monitoring. Inter-site phase coherence analyses demonstrated that the ventral/rostral MFC theta oscillations were coupled with theta oscillations observed at scalp electrodes Fz and Cz. One patient was tested before and after having epileptogenic tissue in the MFC surgically removed; task performance increased from chance levels to near-perfect, and an ERP conflict effect was observed only following surgery. These findings provide novel evidence for the role of MFC oscillations and their relation to surface EEG-recorded potentials during action monitoring. [Copyright &y& Elsevier]

Summary: Rasmussen encephalitis (RE) is a rare form of severe unihemispheric epilepsy established to be an autoimmune disease. Here we demonstrate the presence of autoantibodies against Munc18-1 in 20% of patients collective with biopsy-proven RE. Intriguingly, brain biopsy specimens of these patients showed a striking perivascular accentuated infiltration of B-lymphocytes and plasma cells, suggesting a subgroup of RE patients harboring Munc18-1 antibodies and concomitant B- and plasma cell infiltration. [Copyright &y& Elsevier]

Summary: Purpose: Functional magnetic resonance imaging (fMRI) is being used increasingly for language dominance assessment in the presurgical work-up of patients with pharmacoresistant epilepsy. However, the interpretation of bilateral fMRI-activation patterns is difficult. Various studies propose fMRI-lateralization index (LI) thresholds between ±0.1 and ±0.5 for discrimination of atypical from typical dominant patients. This study examines if these thresholds allow identifying atypical dominant patients with sufficient safety for presurgical settings. Methods: 65 patients had a tight comparison, fully controlled semantic decision fMRI-task and a Wada-test for language lateralization. According to Wada-test, 22 were atypical language dominant. In the remaining, Wada-test results were compatible with unilateral left dominance. We determined fMRI-LI for two frontal and one temporo-parietal functionally defined, protocol-specific volume of interest (VOI), and for the least lateralized of these VOIs (“low-VOI”) in each patient. Results: We find large intra-individual LI differences between functionally defined VOIs irrespective of underlying type of language dominance (mean LI difference 0.33±0.35, range 0–1.6; 15% of patients have inter-VOI-LI differences >1.0). Across atypical dominant patients fMRI-LI in the Broca''s and temporo-parietal VOI range from −1 to +1, in the “remaining frontal” VOI from −0.93 to 1. The highest low-VOI-LI detected in atypical dominant patients is 0.84. Conclusions: Large intra-individual inter-VOI-LI differences and strongly lateralized fMRI-activation in patients with Wada-test proven atypical dominance question the value of the proposed fMRI-thresholds for presurgical language lateralization. Future studies have to develop strategies allowing the reliable identification of atypical dominance with fMRI. The low-VOI approach may be useful. [Copyright &y& Elsevier]

Abstract: Objective: The role of the hippocampus in sensory gating is unresolved as yet. The current study was conducted in order to examine the effects of hippocampal lesions on the function of auditory sensory gating. Methods: Epilepsy patients with unilateral and bilateral hippocampal sclerosis (HS) were investigated. Auditory-evoked potentials (AEPs) were recorded by multichannel scalp EEG in a double-click experiment. Gating was defined as the response decrease of the AEP components from 1st to 2nd click. Results: Diagnosis (left vs. right vs. bilateral HS) did not affect the amplitudes or gating of the P50, N100 or P200 components. However, diagnosis had an impact on the topography of the N100 component after its peak maximum: In right HS patients, the N100 was left-lateralized, while it was nearly symmetrically distributed in patients with left HS and right lateralized in patients with bilateral HS. Besides the N100, the topography of the P200 component was affected by diagnosis. Conclusions: Findings suggest that auditory activity, as reflected in the N100 and P200 components, is modulated by the hippocampus, but not sensory gating in its classical definition. Significance: Deficits in P50 gating in schizophrenia are unlikely to be explained by hippocampal deficits. [Copyright &y& Elsevier]

Summary: We recorded limbic event-related potentials (ERPs) with intrahippocampal depth electrodes in a more demanding verbal and an easier pictorial continuous recognition task in patients undergoing presurgical evaluations of their medical refractory mesial temporal lobe epilepsies (MTLE). In all cases depth electrodes were implanted because non-invasive studies could not demonstrate unilateral seizure-onset unequivocally. For the present study we only considered 24 patients who eventually were found to suffer from unilateral MTLE, in whom hippocampal sclerosis (HS) was confirmed histologically, and who were seizure-free post-operatively. We found that the rhinal anterior medial temporal lobe N400 (AMTL-N400) to first presentations of words but not to pictures was reduced in amplitude on the side of seizure origin. Our data suggest that limbic ERPs to words are more sensitive to the epileptogenic process than those to pictures. Thus, if limbic ERPs are recorded as part of invasive presurgical evaluations, verbal instead of pictorial recognition paradigms should be employed. [Copyright &y& Elsevier]

Abstract: The filtering of sensory information, also referred to as “sensory gating”, is impaired in various neuropsychiatric diseases. In the auditory domain, sensory gating is investigated mainly as a response decrease of the auditory evoked potential component P50 from one click to the second in a double-click paradigm. In order to relate deficient sensory gating to anatomy, it is essential to identify the cortical structures involved in the generation of P50. However, the exact cerebral topography of P50 gating remains largely unknown. In a group of 17 patients with drug-resistant focal epilepsy, P50 was recorded invasively via subdural electrodes, and the topography of functionally indispensable (“eloquent”) cortices was obtained by electrical stimulation mapping. These eloquent areas were involved in language, motor, and sensory functions. P50 could be identified in 13 patients in either temporal (n =8) or midfrontal sites (n =5). There were six occurrences (in five patients) of overlap of sites with maximal P50 responses and eloquent areas. Those were auditory (n =1), supplementary sensorimotor (n =3), primary motor (n =1), and supplementary negative motor (n =1). Results suggest that the early stage of sensory gating already involves a top–down modulation of sensory input by frontal areas. [Copyright &y& Elsevier]

Abstract: Up to 50 or 60% of patients with chronic epilepsy have various mood disorders including depression and anxiety. Whereas the relationship between epilepsy and depression has received much attention, less is known about anxiety disorders. It is now recognized that anxiety can have a profound influence on the quality of life of patients with epilepsy. The relationship between anxiety disorders and epilepsy is complex. It is necessary to distinguish between different manifestations of anxiety disorder: ictal, postictal, and interictal anxiety. Preexisting vulnerability factors, neurobiological factors, iatrogenic influences (antiepileptic drugs, epilepsy surgery), and psychosocial factors are all likely to play a role, but with considerable individual differences. Despite the high prevalence of anxiety disorders in patients with epilepsy, there are no systematic treatment studies or evidence-based guidelines for best treatment practice. Nevertheless, a practical approach based on the temporal relationship between anxiety and epileptic seizures allows clinicians to consider appropriate treatment strategies to reduce the psychiatric comorbidity in patients with epilepsy. [Copyright &y& Elsevier]

Abstract: Objective: An important issue in epileptology is the question whether information extracted from the EEG of epilepsy patients can be used for the prediction of seizures. Several studies have claimed evidence for the existence of a pre-seizure state that can be detected using different characterizing measures. In this paper, we evaluate the predictability of seizures by comparing the predictive performance of a variety of univariate and bivariate measures comprising both linear and non-linear approaches. Methods: We compared 30 measures in terms of their ability to distinguish between the interictal period and the pre-seizure period. After completely analyzing continuous inctracranial multi-channel recordings from five patients lasting over days, we used ROC curves to distinguish between the amplitude distributions of interictal and preictal time profiles calculated for the respective measures. We compared different evaluation schemes including channelwise and seizurewise analysis plus constant and adaptive reference levels. Particular emphasis was placed on statistical validity and significance. Results: Univariate measures showed statistically significant performance only in a channelwise, seizurewise analysis using an adaptive baseline. Preictal changes for these measures occurred 5–30min before seizures. Bivariate measures exhibited high performance values reaching statistical significance for a channelwise analysis using a constant baseline. Preictal changes were found at least 240min before seizures. Linear measures were found to perform similar or better than non-linear measures. Conclusions: Results provide statistically significant evidence for the existence of a preictal state. Based on our findings, the most promising approach for prospective seizure anticipation could be a combination of bivariate and univariate measures. Significance: Many measures reported capable of seizure prediction in earlier studies are found to be insignificant in performance, which underlines the need for statistical validation in this field. [Copyright &y& Elsevier]

Memory disorders and depressed mood are prominent psychological symptoms of temporal lobe epilepsies (TLEs). We examined the interaction of depressive mood and memory as a function of focus localization.One hundred fifty-two TLE patients with right mesial (n=37, RTLE-AHS), right lateral (n=31, RTLE-LAT), left mesial (n=42, LTLE-AHS), and left lateral (n=42, LTLE-LAT) lesions and epilepsies underwent comprehensive presurgical evaluation and neuropsychological assessment of mood and memory. Univariate and multivariate analyses of covariance (ANCOVAs) and partial correlation analyses were performed to reveal interactions of depression and memory as a function of focus localization.No differences between the study groups were revealed for depression, indicating a general risk of 30% for depressed mood (BDI>12) in patients with TLE. ANCOVAs revealed significant main effects of focus side (left: verbal learning deficits; right: figural learning deficits) and site (mesial at disadvantage) on learning and memory scores. Correlation analyses revealed interactions between memory and mood only in LTLE-LAT patients.Although the data provide evidence that side and site of the epileptogenic region differentially affect material specific memory performance, there was no evidence of a specific temporal target region for depressive mood. In the majority of the patients, depressed mood and memory impairment appeared as independent rather than as related symptoms of TLE. In LTLE-LAT, however, mood was significantly related to verbal and figural memory performance. Epilepsy-driven pathological left temporofrontal circuits are discussed as a prerequisite for the coupling of mood disorders and memory impairment in this specific patient subgroup which is also known from the psychiatric major depression syndrome. [Copyright &y& Elsevier]