Marvin A. Rossi

Where Have All the Temporal Lobe Epilepsy Surgeries Gone

Commentary Mesial temporal lobe epilepsy (mTLE) is the most prevalent form of focal-onset epilepsy. Although poorly understood, a majority of patients diagnosed with mTLE are expected to develop hippocampal sclerosis (HS) as evidenced by either mesial temporal atrophy and or signal change on MRI T2/FLAIR sequences (1). In addition, subgroups of mTLE patients will develop hippocampal changes not evident by visual inspection on standard high-resolution MRI studies (2). It is expected that a majority of patients with mTLE-HS will develop pharmacological resistance. In HS patients, data show that anterior temporal lobectomies (ATL) that include the anteromesial portion of the hippocampal formation provide a much greater likelihood of seizure freedom than does medical therapy (3). As a result, mTLE with HS is recognized as the most common indication for resective surgery for the treatment of pharmacoresistant epilepsy. Surgical evaluations for ATL have increased since the 1990s worldwide; however, ATL corrected for population growth have remained relatively stable (4). Furthermore, some studies even suggest that patients with early-onset mTLE-HS are decreasing. On the surface, such findings contradict the utility of developing sophisticated diagnostic methods and improved surgical techniques, producing successful longterm outcomes for pharmacoresistant mTLE . Helmstaedter et al. presented a retrospective multicenter study that reviewed the development of temporal lobe surgery over a 20-year period (1988–2008) at three major epilepsy centers in Germany. This period marked the beginning of modern ATL in Germany since the end of World War II. The authors discovered that despite stable numbers of patients with mTLE-HS over time—and contrary to the trends in other identified pathology groups—age and duration of epilepsy in mTLE-HS increased over time. They concluded that these data supported the notion of a decreasing incidence of mTLE-HS. The authors discussed possible explanations for this trend including 1) disease-modifying factors that have changed the incidence of classical TLE-HS, 2) relatively recent developments in antiepileptic drug (AED) treatment, and 3) the economic incentives for treatment options other than surgery. Inherent Temporal Lobe Surgery in Germany from 1988 to 2008: Diverse Trends in Etiological Subgroups.

SCN1A and Febrile Seizures in Mesial Temporal Epilepsy: An Early Signal to Guide Prognosis and Treatment?

Commentary Although uncommon, the progression of febrile seizures (FS) early in life to mesial temporal lobe epilepsy with MTS is well-described; however, underlying mechanisms and predictors are poorly understood. Proposed mechanisms include prolonged FS at an early age damaging the hippocampus, initial hippocampal injury perior prenatally, or a hippocampal formation genetically predisposed to MTS triggered or activated by remote FS. This latter proposed mechanism is associated with the largest number of epilepsies demonstrating a history of FS and an association with variants within the alpha 1 subunit of voltage dependent sodium channels (SCN1A) (8). The SCN1A-related epilepsies compose a continuum of disorders with incomplete penetrance and variable expressivity. The febrile-associated epilepsies range from self-limited simple FS and generalized epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI). SCN1A phenotypes also include myoclonic-astatic epilepsy, or Doose syndrome, LennoxGastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures (7). The overall prevalence of SCN1A-related epilepsies is not known. MTS is a relatively uncommon finding in these epilepsies (1,6). In fact, Dravet syndrome is not associated with hippocampal sclerosis (7). SCN1A-associated epilepsies can be inherited in an autosomal dominant manner, or as a de novo mutation. SCN1A is part of a cluster of sodium channel genes encoded on chromoEpilepsy, Hippocampal Sclerosis and Febrile Seizures Linked by Common Genetic Variation Around SCN1A.

Regaining white matter integrity and neurocognitive development in rolandic epilepsy after the storm.

Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencephalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner’s scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left preand postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy 412 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy 412 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings.

Improving Patient-Centered Care Coordination for Children With Epilepsy: Version 2.0 Upgrade Required

10. Buettgens M, Kenney GM, Recht H, Lynch V. Eligibility for assistance and projected changes in coverage under the ACA: Variation across states. City, State: Robert Wood Johnson Foundation Urban Institute, October 2013. http://www.urban.org. Accessed Feb 22, 2014.

Localizing the Ictal Onset: Visualizing the Epileptogenic Target

Commentary Localizing epileptogenic sources in medically refractory focal-onset epilepsy is entering a new generation. A growing number of innovative diagnostic technologies and techniques used in combination for identifying epileptogenic foci are at various stages of deployment across well-established epilepsy centers. A multimodal non-invasive diagnostic armamentarium has evolved since the 1990s to facilitate visualizing the ictalonset zone (1–3). Interictal electrical source imaging (ESI) using high-density scalp electrodes is a computationally intensive method that solves the inverse problem. That is, ESI estimates probable solutions for localizing focal interictal epileptiform activity within the cortical irritative zone. The most probable inverse solutions, represented as so-called equivalent dipoles, are generated by patches of synchronous epileptogenic neurons oriented perpendicular to the scalp. The neuronal generators of these dipoles arise from the six-layered neocortical ribbon, or the deep three-layered allocortical hippocampal formation. In comparison, ESI is less sensitive to epileptogenic neuronal populations tangentially oriented to the scalp. Such tangential dipoles, also known as horizontal equivalent dipoles, however, can be detected to some extent with this technique. Computationally intensive algorithms can superimpose these interictal equivalent dipoles on high-resolution MRI datasets to estimate the location and orientation of the classically termed “irritative zones.” As a result, ESI can find probable solutions for cortical interictal epileptiform sources that generate often-complex scalp surface voltage topography. A prerequisite for solving such inverse problems for interictal activity requires high-density EEG scalp electrode arrays (64– 256 contacts) (4). Such electrode densities are well beyond the standard-density 10/20 electrode sets (21–27 scalp contacts) typically used in the epilepsy monitoring unit (EMU). Arguably, however, a threshold exists above which more scalp electrodes do not contribute to a greater confidence or improved resolution of determining localization of the irritative zone. Nemtsas et al. aim to demonstrate that, although more challenging than capturing interictal epileptiform waveforms, high-density ictal ESI in an EMU setting can provide robust complementary information for identifying the ictal-onset zone. Although it is well known that the irritative zone and ictal-onset zone can overlap (5), the authors suggest that high-density ictal ESI is more relevant than relying on interictal ESI alone. Increasing the number of scalp electrodes improves the resolution of source estimation. However, maintaining high-density scalp electrode arrays is challenging in an EMU from both a technical and a patient comfort standpoint. Therefore, the yield of capturing ictal events with high-density scalp electrode nets can be low. Conversely, solving the so-called forward problem can be potentially improved by optimizing the head model used in Source Localization of Ictal Epileptic Activity Based on High-Density Scalp EEG Data.

Epileptic Activity and Cognitive Impairment: Hijacking Plasticity During Sleep

Commentary Electrical status epilepticus during sleep (ESES) of childhood, and density of interictal activity in both children and adults impact sleep homeostasis (1). Boly et al. hypothesized that the frequency and extent of epileptic activity can disrupt sleep homeostasis, and, in turn, potentially contribute to cognitive impairment in adults with focal-onset epilepsy. The authors capitalized on a neurophysiological measure known as slow wave activity (SWA) power, a scalp EEG-derived delta power range of 1 to 4 Hz (2). SWA power dramatically decreases through a night of sleep, and therefore is thought to be a sensitive indicator of sleep need, and its underlying homeostatically regulated recovery process (3). Because sleep, especially slow wave sleep, is in a quantitative and predictive relationship with prior wakefulness, sleep disruption is associated with a proportional increase in delta range power, and a decrease with adequate to excessive sleep (2). A decrease in sleep SWA power during nonrapid eye movement (NREM) sleep is associated with promoting learning and memory consolidation (3). Enhanced synaptic strength is also associated with slow waves on EEG of larger amplitudes and steeper slopes, an example of synaptic potentiation (4, 5). In humans and animals, both global and regional sleep SWA power have been shown to increase after learning new tasks (6, 7). Boly et al. proposed that epileptic activity in adults can negatively impact sleep SWA power, and the negative slope of sleep slow waves, and correlate with cognitive impairment. Neurophysiologically, the authors investigated the potential influence of both nocturnal interictal spikes and seizures on the homeostatic alterations of NREM sleep EEG markers of SWA. The patient group in the study displayed overall shorter sleep time and sleep efficiency compared with controls. In addition, at the group level, the frequency of interictal spikes during epochs of NREM sleep was negatively correlated with the overnight decrease in negative slow wave slope. The authors demonstrated a correlation of these sleep EEG biomarkers with neuropsychological outcomes of global (full-scale) intelligence quotient and visual learning measures using the Wechsler Adult Intelligence Scale and Brief Visuospatial Memory Test-Revised, respectively. The cohort in the study included adults with either temporal or extratemporal focal-onset epilepsies. The pathophysiological underpinnings of sleep-associated thalamocortical networks, and their interplay with the ictal onset region, were inherent in the paper’s discussion of the EEG biomarkers. The authors approached network connectivity from an electrophysiological perspective using high-density scalp EEG. That is, they facilitated visualizaAltered Sleep Homeostasis Correlates With Cognitive Impairment in Patients With Focal Epilepsy.

The Malrotated Hippocampal Formation: How Often Must We Judge Function by Shape?

Commentary Attempting to visualize normal hippocampal development to better understand function dates back to the early 20th century when the Golgi staining technique was pioneered by Cajal, and later his protégé Lorente de Nó. Tsai and coauthors explored the relationship of incomplete infolding or malrotation of the mesial temporal structures in adult patients with MRI-negative temporal lobe epilepsy compared with healthy control volunteers. The patient cohort included both intractable and medication-responsive temporal lobe epilepsy. The goal of this work was to understand whether such incomplete mesial temporal infolding increased the likelihood of an epileptogenic hippocampal network, or simply identified a normal developmental variant of the hippocampal formation. Such an objective is crucial for surgical decision making, particularly when considering MRI-negative intractable temporal lobe epilepsy. The anatomy of the so-called malrotated human hippocampal formation resembles that of early fetal development seen at 14 to 20 weeks gestation. Hippocampal inversion may not be complete until up to 25 weeks gestation (1). In normal hippocampal development, the hippocampal formation inverts within the medial temporal lobe. That is, the disproportionately slower maturation of this region (also known as the allocortex), compared with that of the neocortex, results in medial displacement and internal inversion of the hippocampal formation into the medial temporal horn. Such a finding is seen on MRI as incomplete rotation of the hippocampus (2). The malrotated hippocampal formation predominantly has been reported in the literature as normal in size and signal intensity on MRI. However, such a hippocampus is characterized as atypically rounded in appearance with verticalization of the dominant inferior temporal sulcus. This deep verticalized sulcus, as seen on MRI, demonstrates significant individual variation. For example, the expected location of the collateral sulcus may be displaced by the typically more lateral occipitotemporal sulcus. The corpus callosum and the temporal lobe itself have been reported to appear normal in size, although the temporal horn may be enlarged. Therefore, hippocampal malrotation technically extends beyond the medial hippocampal structures. Published reports attempting to relate such malrotation with ipsilateral intractable temporal lobe epilepsy have explored the possibility that such neuroanatomy is not only abnormal but predisposes to hippocampal epileptogenesis Hippocampal Malrotation Is an Anatomic Variant and Has No Clinical Significance in MRI-Negative Temporal Lobe Epilepsy.

Planning Resective Surgery Using Structural Connectivity Modeling: The Next-Generation Presurgical Evaluation

Commentary It is well-demonstrated that resective epilepsy surgery for pharmacoresistant mesial temporal lobe epilepsy (mTLE) is superior over medical therapies (1, 2). The term “pharmacoresistant” is defined here as persistent disabling seizures despite at least two appropriate antiepileptic drug trials at maximally tolerated dosages. Decades of peer-reviewed literature validate the probability of favorable postresective seizure outcomes surpassing the efficacy of medical management strategies for pharmacoresistant localizable mTLE. However, long-term postresective outcome data for both lesional and nonlesional TLE reveal that between 30 and 55 percent of patients inevitably experience a recurrence of unprovoked disabling seizures (3). Epilepsy specialists strive to integrate and interpret the many factors for predicting the probability of prolonged seizure freedom following resective epilepsy surgery. However, a large proportion of patients do not fall into straightforward categories regarding postresective outcomes. One proposed strategy is to implement organized scales (or nomograms) where a set of validated classic outcome measures can be used to predict with individual specificity, favorable seizure control prior to resection (4–6). The study by Hutchings et al. deviates from the strategy of targeting sublobar regions for TLE resective surgery by modeling axonally connected networks consisting of “critical nodes” responsible for sustaining the unstable epileptogenic network. This computationally intensive algorithm was developed for simulating resection of these critical nodes in a structural connectivity model of a pharmacoresistant epileptogenic brain network. In effect, the term “focal-onset” becomes a misnomer when such a structural “connectome-based” network strategy is used. Patient-specific diffusion tensor imaging (DTI) was used to derive the epileptogenic networks from baseline brain DTI datasets of 22 patients and 39 controls. The algorithm modeled success rates for patients with left TLE epilepsy comparable to the extensive published postresective outcome literature. The model was reported as potentially capable of providing useful patient-specific recommendations for TLE resective surgery. DTI was used to visualize the extent of a white matterconnected epileptogenic circuit with individual specificity. DTI has a long history of detecting seizure-related changes in white matter-associated water diffusion. An evolution of water diffusion-related DTI abnormalities have been wellestablished to occur both long-term as seen interictally, and subacutely during complex partial status epilepticus. Diffusion Predicting Surgery Targets in Temporal Lobe Epilepsy through Structural Connectome Based Simulations.

Postresective Outcome Nomograms: A Patient-Specific Prediction Tool for the Clinic?

OBJECTIVE: We aim to develop a new scale that predicts seizure outcomes after resective epilepsy surgery. METHODS: We retrospectively reviewed patients who underwent surgery for medically refractory epilepsy at our center between 1999 and 2012. Four predictive outcome indicators were selected: preoperative seizure frequency, history of generalized tonic–clonic seizures, brain magnetic resonance imaging (MRI), and epilepsy duration. A score of 0 or 1 was given if the indicator was associated with poor or good outcome, respectively. A seizure freedom score (SFS) was calculated by adding these four categories (total score ranged from 0 to 4). A modified SFS (m-SFS) was then calculated with two additional outcome indicators: invasive electroencephalography (EEG) evaluation (IEI) (performed or not performed) and lobe of resection (temporal vs. extratemporal), for a score ranging from 0 to 6. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom in the overall group. Statistical significance was tested using the log-rank test and comparison of 95% confidence intervals (CIs). RESULTS: The study population included 466 patients with 244 (52%) male. Seizure freedom rates were directly correlated with the SFS score: at 10 years, 36.9% of patients with SFS of 0 were seizure-free, as opposed to 45% for SFS = 1, 60% for SFS = 2, 72% for SFS 3 or above (p = 0.002). When calculated including the IEI and the localization, the score’s performance improved: 24% of patients with a m-SFS of 0 were seizure-free at 10 years, as opposed to 38–59% for m-SFS = 1–3, and 75–79% for m-SFS of 4–6 (p < 0.001). SIGNIFICANCE: An easily measurable seizure freedom score could be a reliable tool to synthesize multiple seizure outcome predictors into a single simple score to predict postoperative seizure freedom. This tool will help with patient and family counseling and estimation of surgical candidacy at both early (SFS) and advanced (m-SFS) stages of a surgical evaluation.

Focal Cortical Dysplasia-Associated Tumors: Resecting Beyond the Lesion

Commentary Low-grade supratentorial tumors constitute 10 to 40% of the pathological diagnoses in patients following resective surgery for refractory focal-onset epilepsy (1, 2). The most common tumor subtypes in this group include inherently indolent and intrinsically epileptogenic gangliogliomas (GG) (3) and dysembryoplastic neuroepithelial tumors (DNT). Temporal lobe tumors in this group exhibit certain distinct features. About 90% of such tumors were found within or adjacent to the gray–white junction or hippocampal formation with frequent involvement of associated mesial temporal structures (4, 5). Several studies have identified young age, male predominance, long history of refractory epilepsy, healthy neurological examination, an indolent biological nature with long-term survival, and favorable surgical outcome as common characteristics in this group (6, 4, 5). Supratentorial GG and DNT tumors demonstrate a strong association with focal cortical dysplasias (FCD). It is notable that FCD are a common cause of intractable epilepsy in both children and adults. It is well-known that FCD are associated with epileptogenic brain tissue, although surgical resection achieves seizure control to a variable extent (7, 8). The optimal surgical strategy for these patients continues to be debated. Some centers typically recommend, when possible, isolated tumor resection while others include resection of surrounding epileptogenic structures guided by electrocorticography (ECoG). Such ECoG studies have challenged the idea that epilepsy in a subgroup of FCD is associated with a solitary epileptogenic lesion. That is, epileptogenic areas remote from the primary dysplastic lesion are often associated with less favorable clinical outcomes. All forms of FCD lead to disorganization of the normal structure of the cerebral cortex. Characteristic findings include often subtle aberrant radial or tangential lamination of the neocortex (FCD Type I) and/or cytological abnormalities (FCD Type II). FCD in combination with GG and DNT tumors appear to occur isolated in temporal and/or extratemporal regions. In particular, FCD Type I is associated with subtle neuroimaging, histopathology, and less favorable post resective seizure outcomes. The indolent progression and associated epileptogenicity of glioneural tumors have raised the hypothesis of a developmental rather than neoplastic origin of these lesions (9). A recent International League Against Epilepsy (ILAE) task force has re-evaluated available data and proposed a neuropathological classification system of FCD (10). The major modification to the previous classification includes the introEpilepsy Surgery of Focal Cortical Dysplasia–Associated Tumors