Theta-phase locking of single neurons during human spatial memory.

The precise timing of single-neuron activity in relation to local field potentials may support various cognitive functions. Extensive research in rodents, along with some evidence in humans, suggests that single-neuron activity at specific phases of theta oscillations plays a crucial role in memory processes. Our fundamental understanding of such theta-phase locking in humans and its dependency on basic electrophysiological properties of the local field potential is still limited, however. Here, using single-neuron recordings in epilepsy patients performing a spatial memory task, we thus aimed at improving our understanding of factors modulating theta-phase locking in the human brain. Combining a generalized-phase approach for frequency-adaptive theta-phase estimation with time-resolved spectral parameterization, our results show that theta-phase locking is a strong and prevalent phenomenon across human medial temporal lobe regions, both during spatial memory encoding and retrieval. Neuronal theta-phase locking increased during periods of elevated theta power, when clear theta oscillations were present, and when aperiodic activity exhibited steeper slopes. Theta-phase locking was similarly strong during successful and unsuccessful memory, and most neurons activated at similar theta phases between encoding and retrieval. Some neurons changed their preferred theta phases between encoding and retrieval, in line with the idea that different memory processes are separated within the theta cycle. Together, these results help disentangle how different properties of local field potentials and memory states influence theta-phase locking of human single neurons. This contributes to a better understanding of how interactions between single neurons and local field potentials may support human spatial memory.

Ripple-locked coactivity of stimulus-specific neurons and human associative memory.

Associative memory enables the encoding and retrieval of relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves temporally correlated spiking of medial temporal lobe (MTL) neurons that exhibit stimulus-specific tuning. Using single-neuron recordings from patients with epilepsy performing an associative object-location memory task, we identified the object-specific and place-specific neurons that represented the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object-specific and place-specific neurons activated together during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients' associative learning progressed. Between encoding and retrieval, the ripple-locked timing of coactivity shifted, suggesting flexibility in the interaction between MTL neurons and hippocampal ripples according to behavioral demands. Our results are consistent with a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.

Cyclical underreporting of seizures in patient-based seizure documentation.

OBJECTIVE: Circadian and multidien cycles of seizure occurrence are increasingly discussed as to their biological underpinnings and in the context of seizure forecasting. This study analyzes if patient reported seizures provide valid data on such cyclical occurrence. METHODS: We retrospectively studied if circadian cycles derived from patient-based reporting reflect the objective seizure documentation in 2003 patients undergoing in-patient video-EEG monitoring. RESULTS: Only 24.1% of more than 29000 seizures documented were accompanied by patient notifications. There was cyclical underreporting of seizures with a maximum during nighttime, leading to significant deviations in the circadian distribution of seizures. Significant cyclical deviations were found for focal epilepsies originating from both, frontal and temporal lobes, and for different seizure types (in particular, focal unaware and focal to bilateral tonic-clonic seizures). INTERPRETATION: Patient seizure diaries may reflect a cyclical reporting bias rather than the true circadian seizure distributions. Cyclical underreporting of seizures derived from patient-based reports alone may lead to suboptimal treatment schemes, to an underestimation of seizure-associated risks, and may pose problems for valid seizure forecasting. This finding strongly supports the use of objective measures to monitor cyclical distributions of seizures and for studies and treatment decisions based thereon.

Trends in referral patterns to presurgical evaluation at a European reference center.

PURPOSE: To determine if growing evidence for epilepsy surgery as an early treatment option is reflected in the decrease of latencies between epilepsy onset and referral for presurgical evaluation METHODS: Retrospective analysis of latencies in 1646 patients (children and adults) from the time of epilepsy diagnosis to first presurgical workup in the period from 1999 to 2019 based on electronic patient charts at a tertiary epilepsy center. Time spans 1999-2009 and 2010-2019, prior to and following the ILAE definition of pharmacoresistance, and the role of etiological factors were assessed. RESULTS: Over the whole period, the mean latency between diagnosis and a presurgical workup was 15.3 y. There was a significant reduction in the latencies between the periods 1999-2009 (16.9 y) and 2010-2019 (13.4 y), (p < 0.0001). In a linear regression analysis, the latency decreased by 2.6 months/year from 17.4 in 1999 to 13.1 y in 2019 (p < 0.001). Subgroup analyses showed significant decreases in latency to presurgical evaluation in patients with hippocampal sclerosis from 24.4 to 19.5 y, in malformations of cortical development from 16.4 to 13.2 y, and in nonlesional patients from 18.1 to 12.8 y, in contrast to patients with MR evidence for brain tumors with similar latencies across time (10.5 vs. 9.5 y, n.s.). CONCLUSION: The reduction of the time span to a first presurgical evaluation was highly significant over time, yet moderate in its degree. Overall, the aim of early diagnostic evaluation for epilepsy surgery options after established pharmacoresistance was only achieved for a minority of patients.

A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.

Differentiation of subclinical and clinical electrographic events in long-term electroencephalographic recordings.

OBJECTIVE: With the advent of ultra-long-term recordings for monitoring of epilepsies, the interpretation of results of isolated electroencephalographic (EEG) recordings covering only selected brain regions attracts considerable interest. In this context, the question arises of whether detected ictal EEG patterns correspond to clinically manifest seizures or rather to purely electrographic events, that is, subclinical events. METHODS: EEG patterns from 268 clinical seizures and 252 subclinical electrographic events from 50 patients undergoing video-EEG monitoring were analyzed. Features extracted included predominant frequency band, duration, association with rhythmic muscle artifacts, spatial extent, and propagation patterns. Classification using logistic regression was performed based on data from the whole dataset of 10-20 system EEG recordings and from a subset of two temporal electrode contacts. RESULTS: Correct separation of clinically manifest and purely electrographic events based on 10-20 system EEG recordings was possible in up to 83.8% of events, depending on the combination of features included. Correct classification based on two-channel recordings was only slightly inferior, achieving 78.6% accuracy; 74.4% and 74.8%, respectively, of events could be correctly classified when using duration alone with either electrode set, although classification accuracies were lower for some subgroups of seizures, particularly focal aware seizures and epileptic arousals. SIGNIFICANCE: A correct classification of subclinical versus clinical EEG events was possible in 74%-83% of events based on full EEG recordings, and in 74%-78% when considering only a subset of two electrodes, matching the channel number available from new implantable diagnostic devices. This is a promising outcome, suggesting that ultra-long-term low-channel EEG recordings may provide sufficient information for objective seizure diaries. Intraindividual optimization using high numbers of ictal events may further improve separation, provided that supervised learning with external validation is feasible.

Diagnostic yield and limitations of in-hospital documentation in patients with epilepsy.

OBJECTIVE: To determine the diagnostic yield of in-hospital video-electroencephalography (EEG) monitoring to document seizures in patients with epilepsy. METHODS: Retrospective analysis of electronic seizure documentation at the University Hospital Freiburg (UKF) and at King's College London (KCL). Statistical assessment of the role of the duration of monitoring, and subanalyses on presurgical patient groups and patients undergoing reduction of antiseizure medication. RESULTS: Of more than 4800 patients with epilepsy undergoing in-hospital recordings at the two institutions since 2005, seizures with documented for 43% (KCL) and 73% (UKF).. Duration of monitoring was highly significantly associated with seizure recordings (p < .0001), and presurgical patients as well as patients with drug reduction had a significantly higher diagnostic yield (p < .0001). Recordings with a duration of >5 days lead to additional new seizure documentation in only less than 10% of patients. SIGNIFICANCE: There is a need for the development of new ambulatory monitoring strategies to document seizures for diagnostic and monitoring purposes for a relevant subgroup of patients with epilepsy in whom in-hospital monitoring fails to document seizures.

Ictal semiology of epileptic seizures with insulo-opercular genesis.

OBJECTIVE: Epileptic seizures with insular genesis are often difficult to distinguish from those originating in the temporal lobe due to their complex and variable semiology. Here, we analyzed differentiating characteristics in the clinical spectrum of insulo-opercular seizures. METHODS: Ictal semiology in patients with a diagnosis of insulo-opercular epilepsy (IOE) based on imaging of epileptogenic lesions or electrophysiological evidence of an insulo-opercular seizure origin was retrospectively analyzed and compared to age-matched controls with mesial temporal lobe epilepsy (MTE). RESULTS: Forty-six IOE and 46 matched MTE patients were included. The most prominent ictal features in IOE were focal motor phenomena in 80.4% of these patients. Somatosensory sensations, version, tonic and clonic features, when present, were more frequent contralateral to the SOZ in MTE patients, while they occurred about equally often ipsilateral and contralateral to the SOZ in IOE patients. Ipsilateral manual automatisms were significantly more frequent in MTE patients than in IOE (p = 0.010). Multivariate analysis correctly identified IOE in 78.3% and MTE in 84.8% using five semiologic features (Chi-square = 53.79 with 5 degrees of freedom, p < 0.0001). A subanalysis comparing patients with purely insular lesions with MTE patients using only the earliest ictal signs showed that somatosensory sensations are significantly more frequent in insular epilepsy (p = 0.010), while automatisms were significantly more frequent in MTE patients (p = 0.06). SIGNIFICANCE: Our study represents the first in-depth analysis of ictal semiology in IOE compared to MTE. Use of these differentiating characteristics can serve for a correct syndrome classification and to steer appropriate diagnostic and local therapeutic procedures.

Interictal spikes with and without high-frequency oscillation have different single-neuron correlates.

Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these 'HFO-IEDs' at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from 'non-HFO-IEDs'. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit's firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit's firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.

A neural code for egocentric spatial maps in the human medial temporal lobe.

Spatial navigation and memory rely on neural systems that encode places, distances, and directions in relation to the external world or relative to the navigating organism. Place, grid, and head-direction cells form key units of world-referenced, allocentric cognitive maps, but the neural basis of self-centered, egocentric representations remains poorly understood. Here, we used human single-neuron recordings during virtual spatial navigation tasks to identify neurons providing a neural code for egocentric spatial maps in the human brain. Consistent with previous observations in rodents, these neurons represented egocentric bearings toward reference points positioned throughout the environment. Egocentric bearing cells were abundant in the parahippocampal cortex and supported vectorial representations of egocentric space by also encoding distances toward reference points. Beyond navigation, the observed neurons showed activity increases during spatial and episodic memory recall, suggesting that egocentric bearing cells are not only relevant for navigation but also play a role in human memory.

Intracranial correlates of small sharp spikes.

OBJECTIVE: To identify cortical correlates of scalp small sharp spikes (SSS) using simultaneous scalp and intracranial EEG recordings. METHODS: Patients were retrospectively evaluated based on a database of intracranial long-term recordings at the Epilepsy Center Freiburg. Inclusion criteria were: simultaneous recordings with intracranial and scalp EEGs and the presence of at least five unequivocal SSS in the scalp EEG. Intracranial recordings were analyzed regarding the co-occurring intracranial potentials during scalp SSS. RESULTS: 33 patients, aged 9-60y, 17 females, fulfilled the above-mentioned criteria. Almost all patients had intracranial SSS correlates in the form of spike/polyspike-waves in the temporal lobe, predominantly in the hippocampus (24/28), less frequently involving the amygdala (5/29), temporal basal (3/18), lateral neocortical (4/32), entorhinal cortices (1/12), and the parietal lobe (2/13). Amplitudes of intrahippocampal spikes or polyspikes co-occurring with SSS were significantly higher than intracranial discharges without scalp correlates. In 45% of patients, intracranial spikes accompanying SSS were located within the seizure onset zone (SOZ). CONCLUSIONS: Our results strongly support an epileptic origin of SSS and provide evidence about their heterogenous generators. SIGNIFICANCE: This study suggests that SSS cannot with certainty be classified as "benign" but rather considered as one of the EEG manifestations of focal epilepsy.

Epilepsy surgery: Late seizure recurrence after initial complete seizure freedom.

OBJECTIVE: This study was undertaken to improve understanding of late relapse following epilepsy surgery in pharmacoresistant epilepsy. METHODS: Retrospective comparison was made of 99 of 1278 patients undergoing surgery during 1999-2015 with seizure relapses after at least 2 years of complete seizure freedom with matched controls experiencing continued long-term seizure freedom. Univariate and multivariate analyses were performed. RESULTS: With a mean follow-up of 9.7 years, mean time to seizure relapse was 56.6 months. In multivariate analysis, incomplete resection based on magnetic resonance imaging (MRI), bilateral lesions on preoperative MRI, and epilepsy onset in the first year of life carried a significantly higher risk of late relapse. In patients with late relapse, additional functional imaging with positron emission tomography had been performed significantly more often. Although the differences were not significant in multivariate analysis, doses of antiepileptic drugs were higher in the relapse group preoperatively and in the first 24 months and complete withdrawal was more frequent in the control group (68% vs. 51%). Regarding seizure frequency, most patients had mild seizure relapse (single relapse seizure or <1/month). SIGNIFICANCE: In our predominantly lesional cohort, complete resection of the MRI lesion is the most important factor to maintain long-term seizure freedom. Two patterns of recurrence were identified: (1) incomplete resected lesions with seizure generation in proximity to the initial resection and (2) epileptogenic networks not detected preoperatively or evolving in the postoperative interval and manifesting with new clinical and diagnostic features.

Effects of Spatial Memory Processing on Hippocampal Ripples.

Human High-Frequency-Oscillations (HFO) in the ripple band are oscillatory brain activity in the frequency range between 80 and 250 Hz. HFOs may comprise different subgroups that either play a role in physiologic or pathologic brain functions. An exact differentiation between physiologic and pathologic HFOs would help elucidate their relevance for cognitive and epileptogenic brain mechanisms, but the criteria for differentiating between physiologic and pathologic HFOs remain controversial. In particular, the separation of pathologic HFOs from physiologic HFOs could improve the identification of epileptogenic brain regions during the pre-surgical evaluation of epilepsy patients. In this study, we performed intracranial electroencephalography recordings from the hippocampus of epilepsy patients before, during, and after the patients completed a spatial navigation task. We isolated hippocampal ripples from the recordings and categorized the ripples into the putative pathologic group iesRipples, when they coincided with interictal spikes, and the putative physiologic group isolRipples, when they did not coincide with interictal spikes. We found that the occurrence of isolRipples significantly decreased during the task as compared to periods before and after the task. The rate of iesRipples was not modulated by the task. In patients who completed the spatial navigation task on two consecutive days, we furthermore examined the occurrence of ripples in the intervening night. We found that the rate of ripples that coincided with sleep spindles and were therefore putatively physiologic correlated with the performance improvement on the spatial navigation task, whereas the rate of all ripples did not show this relationship. Together, our results suggest that the differentiation of HFOs into putative physiologic and pathologic subgroups may help identify their role for spatial memory and memory consolidation processes. Conversely, excluding putative physiologic HFOs from putative pathologic HFOs may improve the HFO-based identification of epileptogenic brain regions in future studies.

Mossy fiber sprouting into the hippocampal region CA2 in patients with temporal lobe epilepsy.

Hippocampal sclerosis (HS) in Temporal Lobe Epilepsy (TLE) shows neuronal death in cornu ammonis (CA)1, CA3, and CA4. It is known that granule cells and CA2 neurons survive and their axons, the mossy fibers (MF), lose their target cells in CA3 and CA4 and sprout to the granule cell layer and molecular layer. We examined in TLE patients and in a mouse epilepsy model, whether MF sprouting is directed to the dentate gyrus or extends to distant CA regions and whether sprouting is associated with death of target neurons in CA3 and CA4. In 319 TLE patients, HS was evaluated by Wyler grade and International League against Epilepsy (ILAE) types using immunohistochemistry against neuronal nuclei (NeuN). Synaptoporin was used to colocalize MF. In addition, transgenic Thy1-eGFP mice were intrahippocampally injected with kainate and sprouting of eGFP-positive MFs was analyzed together with immunocytochemistry for regulator of G-protein signaling 14 (RGS14). In human HS Wyler III and IV as well as in ILAE 1, 2, and 3 specimens, we found synaptoporin-positive axon terminals in CA2 and even in CA1, associated with the extent of granule cell dispersion. Sprouting was seen in cases with cell death of target neurons in CA3 and CA4 (classical severe HS ILAE type 1) but also without this cell death (atypical HS ILAE type 2). Similarly, in epileptic mice eGFP-positive MFs sprouted to CA2 and beyond. The presence of MF terminals in the CA2 pyramidal cell layer and in CA1 was also correlated with the extent of granule cell dispersion. The similarity of our findings in human specimens and in the mouse model highlights the importance and opens up new chances of using translational approaches to determine mechanisms underlying TLE.

Multilobar Epilepsy Surgery in Childhood and Adolescence: Predictors of Long-Term Seizure Freedom.

BACKGROUND: Although multilobar resections correspond to one-fifth of pediatric epilepsy surgery, there are little data on long-term seizure control. OBJECTIVE: To investigate the long-term seizure outcomes of children and adolescents undergoing multilobar epilepsy surgery and identify their predictors. METHODS: In this retrospective study, we considered 69 consecutive patients that underwent multilobar epilepsy surgery at the age of 10.0 ± 5.0 yr (mean ± SD). The magnetic resonance imaging revealed a lesion in all but 2 cases. Resections were temporo-parieto(-occipital) in 30%, temporo-occipital in 41%, parieto-occipital in 16%, and fronto-(temporo)-parietal in 13% cases. Etiologies were determined as focal cortical dysplasia in 67%, perinatal or postnatal ischemic lesions in 23%, and benign tumors in 10% of cases. RESULTS: At last follow-up of median 9 yr (range 2.8-14.8), 48% patients were seizure free; 33% were off antiepileptic drugs. 10% of patients, all with dysplastic etiology, required reoperations: 4 of 7 achieved seizure freedom. Seizure recurrence occurred mostly (80%) within the first 6 mo. Among presurgical variables, only an epileptogenic zone far from eloquent cortex independently correlated with significantly higher rates of seizure arrest in multivariate analysis. Among postsurgical variables, the absence of residual lesion and of acute postsurgical seizures was independently associated with significantly higher rates of seizure freedom. CONCLUSION: Our study demonstrates that multilobar epilepsy surgery is effective regarding long-term seizure freedom and antiepileptic drug withdrawal in selected pediatric candidates. Epileptogenic zones-and lesions-localized distant from eloquent cortex and, thus, fully resectable predispose for seizure control. Acute postsurgical seizures are critical markers of seizure recurrence that should lead to prompt reevaluation.

Reactivated Spatial Context Guides Episodic Recall.

The medial temporal lobe (MTL) is known as the locus of spatial coding and episodic memory, but the interaction between these cognitive domains as well as the extent to which they rely on common neurophysiological mechanisms is poorly understood. Here, we use intracranial electroencephalography and a hybrid spatial-episodic memory task (29 subjects, 15 female) to determine how spatial information is dynamically reactivated in subregions of the human MTL and how this reactivation guides recall of episodic information. Our results implicate theta oscillations across the MTL as a common neurophysiological substrate for spatial coding in navigation and episodic recall. We further show that our index of retrieved spatial context is high in the hippocampus (HC) in an early time window preceding recall. Closer to recall, it decreases in the HC and increases in the parahippocampal gyrus. Finally, we demonstrate that hippocampal theta phase modulates parahippocampal gamma amplitude during retrieval of spatial context, suggesting a role for cross-frequency coupling in coding and transmitting retrieved spatial information.SIGNIFICANCE STATEMENT By recording from the human medial temporal lobe (MTL) while subjects recall items experienced in a virtual environment, we establish a direct relation between the strength of theta activity during memory search and the extent to which memories are organized by their spatial locations. We thereby pinpoint a role for theta oscillations in accessing the "cognitive map" during episodic retrieval and further highlight the dynamic interplay of hippocampus and extrahippocampal MTL in representing retrieved spatial context. Our results provide an important step toward a unified theory of MTL function encompassing its role in spatial navigation and episodic memory.

Hippocampal theta phases organize the reactivation of large-scale electrophysiological representations during goal-directed navigation.

Humans are adept in simultaneously following multiple goals, but the neural mechanisms for maintaining specific goals and distinguishing them from other goals are incompletely understood. For short time scales, working memory studies suggest that multiple mental contents are maintained by theta-coupled reactivation, but evidence for similar mechanisms during complex behaviors such as goal-directed navigation is scarce. We examined intracranial electroencephalography recordings of epilepsy patients performing an object-location memory task in a virtual environment. We report that large-scale electrophysiological representations of objects that cue for specific goal locations are dynamically reactivated during goal-directed navigation. Reactivation of different cue representations occurred at stimulus-specific hippocampal theta phases. Locking to more distinct theta phases predicted better memory performance, identifying hippocampal theta phase coding as a mechanism for separating competing goals. Our findings suggest shared neural mechanisms between working memory and goal-directed navigation and provide new insights into the functions of the hippocampal theta rhythm.

Epilepsy Surgery in the First 3 Years of Life: Predictors of Seizure Freedom and Cognitive Development.

BACKGROUND: Although the majority of children undergoing epilepsy surgery are younger than 3 yr at epilepsy manifestation, only few actually receive surgical treatment in early childhood. Past studies have, however, suggested that earlier intervention may correlate with superior developmental outcomes. OBJECTIVE: To identify predictors for long-term seizure freedom and cognitive development following epilepsy surgery in the first 3 yr of life and determine the appropriate timing for surgical treatment in this age group. METHODS: We retrospectively analyzed the data of 48 consecutive children aged 1.1 ± 0.7 yr at surgery. RESULTS: Final surgeries comprised 52% hemispherotomies, 13% multilobar, and 35% intralobar resections. Etiology included cortical malformations in 71%, peri- or postnatal ischemic lesions in 13%, and benign tumor or tuberous sclerosis in 8% each. At last follow-up (median 4.3, range 1-14.3 yr), 60% of children remained seizure-free: 38% had discontinued antiepileptic drugs. Intralobar lesionectomy resulted more often in seizure control than multilobar or hemispheric surgery. Postsurgical seizure freedom was determined by the completeness of resection. Early postsurgical seizures were key markers of seizure recurrence. Presurgical adaptive and cognitive developmental status was impaired in 89% children. Longer epilepsy duration and larger lesion extent were detrimental to presurgical development, which, in turn, determined the postsurgical developmental outcome. CONCLUSION: Our study demonstrates that epilepsy surgery in very young children is safe as well as efficient regarding long-term seizure freedom and antiepileptic drug cessation in selected candidates. Longer epilepsy duration is the only modifiable predictor of impaired adaptive and cognitive development, thus supporting early surgical intervention.

Multilobar Resections for 3T MRI-Negative Epilepsy: Worth the Trouble?

OBJECTIVE: Multilobar resection in magnetic resonance imaging (MRI)-negative drug-resistant epilepsy warrants attention because they account for up to one third of MRI-negative epilepsy surgery. Despite their high prevalence, data are sparse, and the risk/benefit ratio continues to be debated. The present study investigated the postoperative seizure outcomes in this especially challenging subgroup. METHODS: We retrospectively analyzed the data of 4 consecutive patients with 3T MRI-negative findings and drug-resistant focal epilepsy who had undergone multilobar epilepsy surgery at our institution. RESULTS: The mean age at first surgery was 28.5 years (range, 14-48); 1 patient required 2 consecutive reoperations. The final resection was in the frontotemporal and temporo-parieto-occipital regions in 2 patients each. Histopathological examination revealed mild malformations of cortical development in 2 patients and focal cortical dysplasia type Ia and type IIa in 1 patient each. At the last follow-up examination (median, 3.3 years; range, 1-11), 2 patients were completely seizure free (Engel class Ia), 1 patient had experienced some disabling seizures after surgery but had been free of disabling seizures for 2 years at the last follow-up examination (Engel class Ic), and 1 patient had experienced worthwhile improvement (Engel class IIb) and had been seizure free for 1 year at the last follow-up examination. No surgical complications developed. CONCLUSIONS: Our results have demonstrated that multilobar epilepsy surgery is effective for lasting seizure control for selected 3T MRI-negative candidates, leading to favorable outcomes for all 4 of our patients. Comprehensive multimodal preoperative evaluation is a prerequisite for postoperative success. Reevaluation should be considered for patients with seizure recurrence, because reoperation could be especially beneficial for selected patients who have not responded to an initially limited resection.

Long-term seizure outcome in pediatric patients with focal cortical dysplasia undergoing tailored and standard surgical resections.

PURPOSE: Focal cortical dysplasia (FCD) is the major cause of focal intractable epilepsy in childhood. Here we analyze the factors influencing the success of surgical treatment in a large cohort of children with histologically ascertained FCD. METHOD: A retrospective study of the effects of FCD type, surgical intervention, and age at surgery in a pediatric cohort. RESULTS: A total of 113 patients (71 male; mean age at surgery 10.3 years; range 0-18) were analyzed; 45 had undergone lesionectomy, 42 lobectomy, 18 multi-lobectomy, and eight hemispherotomy. Complete seizure control (Engel Ia) was achieved in 56% after two years, 52% at five years, and 50% at last follow-up (18-204 months). Resections were more extensive in younger patients (40% of the surgeries affecting more than one lobe in patients aged nine years or younger vs. 22% in patients older than nine years). While resections were more limited in older children, their long-term outcome tended to be superior (42% seizure freedom in patients aged nine years or younger vs. 56% in patients older than nine years). The outcome in FCD I was not significantly inferior to that in FCD II. CONCLUSIONS: Our data confirm the long-term efficacy of surgery in children with FCD and epilepsy. An earlier age at surgery within this cohort did not predict a better long-term outcome, but it involved less-tailored surgical approaches. The data suggest that in patients with an unclear extent of the dysplastic area, later resections may offer advantages in terms of the precision of surgical-resection planning.