Lesion volume and spike frequency on EEG impact perfusion values in focal cortical dysplasia: a pediatric arterial spin labeling study.

Arterial spin labelling (ASL), an MRI sequence non-invasively imaging brain perfusion, has yielded promising results in the presurgical workup of children with focal cortical dysplasia (FCD)-related epilepsy. However, the interpretation of ASL-derived perfusion patterns remains unclear. Hence, we compared ASL qualitative and quantitative findings to their clinical, EEG, and MRI counterparts. We included children with focal structural epilepsy related to an MRI-detectable FCD who underwent single delay pseudo-continuous ASL. ASL perfusion changes were assessed qualitatively by visual inspection and quantitatively by estimating the asymmetry index (AI). We considered 18 scans from 15 children. 16 of 18 (89%) scans showed FCD-related perfusion changes: 10 were hypoperfused, whereas six were hyperperfused. Nine scans had perfusion changes larger than and seven equal to the FCD extent on anatomical images. Hyperperfusion was associated with frequent interictal spikes on EEG (p = 0.047). Perfusion changes in ASL larger than the FCD corresponded to larger lesions (p = 0.017). Higher AI values were determined by frequent interictal spikes on EEG (p = 0.004). ASL showed FCD-related perfusion changes in most cases. Further, higher spike frequency on EEG may increase ASL changes in affected children. These observations may facilitate the interpretation of ASL findings, improving treatment management, counselling, and prognostication in children with FCD-related epilepsy.

Determinants of Functional Outcome after Pediatric Hemispherotomy.

OBJECTIVE: We aimed to evaluate determinants of functional outcome after pediatric hemispherotomy in a large and recent multicenter cohort. METHODS: We retrospectively investigated the functional outcomes of 455 children who underwent hemispherotomy at 5 epilepsy centers in 2000-2016. We identified determinants of unaided walking, voluntary grasping with the hemiplegic hand, and speaking through Bayesian multivariable regression modeling using missing data imputation. RESULTS: Seventy-five percent of children were seizure-free, and 44% stopped antiseizure medication at a 5.1-year mean follow-up (range = 1-17.1). Seventy-seven percent of children could walk unaided, 8% could grasp voluntarily, and 68% could speak at the last follow-up. Children were unlikely to walk when they had contralateral magnetic resonance imaging (MRI) abnormalities (40/73, p = 0.04), recurrent seizures following hemispherotomy (62/109, p = 0.04), and moderately (50/61, p = 0.03) or severely impaired (127/199, p = 0.001) postsurgical intellectual functioning, but were likely to walk when they were older at outcome determination (p = 0.01). Children were unlikely to grasp voluntarily with the hand contralateral to surgery when they had Rasmussen encephalitis (0/61, p = 0.001) or Sturge-Weber syndrome (0/32, p = 0.007). Children were unlikely to speak when they had contralateral MRI abnormalities (30/69, p = 0.002) and longer epilepsy duration (p = 0.01), but likely to speak when they had Sturge-Weber syndrome (29/35, p = 0.01), were older at surgery (p = 0.04), and were older at outcome determination (p < 0.001). INTERPRETATION: Etiology and bilaterality of structural brain abnormalities were key determinants of functional outcome after hemispherotomy. Longer epilepsy duration affected language outcomes. Not surprisingly, walking and talking ability increased with older age at outcome evaluation. ANN NEUROL 2024;95:377-387.

Scalp high-frequency oscillations differentiate neonates with seizures from healthy neonates.

OBJECTIVE: We aimed to investigate (1) whether an automated detector can capture scalp high-frequency oscillations (HFO) in neonates and (2) whether scalp HFO rates can differentiate neonates with seizures from healthy neonates. METHODS: We considered 20 neonates with EEG-confirmed seizures and four healthy neonates. We applied a previously validated automated HFO detector to determine scalp HFO rates in quiet sleep. RESULTS: Etiology in neonates with seizures included hypoxic-ischemic encephalopathy in 11 cases, structural vascular lesions in 6, and genetic causes in 3. The HFO rates were significantly higher in neonates with seizures (0.098 ± 0.091 HFO/min) than in healthy neonates (0.038 ± 0.025 HFO/min; P = 0.02) with a Hedge's g value of 0.68 indicating a medium effect size. The HFO rate of 0.1 HFO/min/ch yielded the highest Youden index in discriminating neonates with seizures from healthy neonates. In neonates with seizures, etiology, status epilepticus, EEG background activity, and seizure patterns did not significantly impact HFO rates. SIGNIFICANCE: Neonatal scalp HFO can be detected automatically and differentiate neonates with seizures from healthy neonates. Our observations have significant implications for neuromonitoring in neonates. This is the first step in establishing neonatal HFO as a biomarker for neonatal seizures.

Lesion Extent Negatively Impacts Intellectual Skills in Pediatric Focal Epilepsy.

BACKGROUND: Cognitive development in children and adolescents with focal lesional epilepsy is determined by the underlying epileptogenic lesion, in addition to epilepsy itself. However, the impact of lesion-related variables on intelligence quotient (IQ) and developmental quotient (DQ) remains largely unexplored. Here, we aimed to determine the effect of lesion-related predictors and their relation with epilepsy-related predictors of intellectual functioning. METHODS: We retrospectively analyzed data from children with focal lesional epilepsy who underwent standardized cognitive evaluation yielding IQ/DQ in our institution. RESULTS: We included 50 consecutive patients aged 0.5 to 17.5 years (mean, 9.3; S.D., 4.9) at cognitive assessment. Epilepsy duration was 0 to 15.5 years (mean, 3.8; S.D., 4.1). Of the total cohort, 30 (60%) patients had unilobar lesions, seven (14%) multilobar, 10 (20%) hemispheric, and three (6%) bilateral. Etiology was congenital in 32 (64%) cases, acquired in 14 (28%), and progressive in four (8%). For patients with unilobar lesions, the mean IQ/DQ was 97.1 ± 15.7, for multilobar 98.9 ± 20.2, for hemispheric 76.1 ± 20.5, and for bilateral 76.3 ± 4.5. Larger lesion extent, earlier epilepsy onset, and longer epilepsy duration correlated with lower IQ/DQ in the univariate analysis, whereas only lesion extent and epilepsy duration contributed significantly to the explanatory model in the multivariable analysis. CONCLUSIONS: The present study demonstrates that lesion extent and epilepsy duration are important risk factors for intellectual impairment in pediatric patients with focal lesional epilepsy. These findings are useful for family counseling and the early consideration of interventions that may limit the duration of epilepsy.

Not surgical technique, but etiology, contralateral MRI, prior surgery, and side of surgery determine seizure outcome after pediatric hemispherotomy.

OBJECTIVE: We aimed to assess determinants of seizure outcome following pediatric hemispherotomy in a contemporary cohort. METHODS: We retrospectively analyzed the seizure outcomes of 457 children who underwent hemispheric surgery in five European epilepsy centers between 2000 and 2016. We identified variables related to seizure outcome through multivariable regression modeling with missing data imputation and optimal group matching, and we further investigated the role of surgical technique by Bayes factor (BF) analysis. RESULTS: One hundred seventy seven children (39%) underwent vertical and 280 children (61%) underwent lateral hemispherotomy. Three hundred forty-four children (75%) achieved seizure freedom at a mean follow-up of 5.1 years (range 1 to 17.1). We identified acquired etiology other than stroke (odds ratio [OR] 4.4, 95% confidence interval (CI) 1.1-18.0), hemimegalencephaly (OR 2.8, 95% CI 1.1-7.3), contralateral magnetic resonance imaging (MRI) findings (OR 5.5, 95% CI 2.7-11.1), prior resective surgery (OR 5.0, 95% CI 1.8-14.0), and left hemispherotomy (OR 2.3, 95% CI 1.3-3.9) as significant determinants of seizure recurrence. We found no evidence of an impact of the hemispherotomy technique on seizure outcome (the BF for a model including the hemispherotomy technique over the null model was 1.1), with comparable overall major complication rates for different approaches. SIGNIFICANCE: Knowledge about the independent determinants of seizure outcome following pediatric hemispherotomy will improve the counseling of patients and families. In contrast to previous reports, we found no statistically relevant difference in seizure-freedom rates between the vertical and horizontal hemispherotomy techniques when accounting for different clinical features between groups.

Diffusion tensor imaging discriminates focal cortical dysplasia from normal brain parenchyma and differentiates between focal cortical dysplasia types.

OBJECTIVES: Although diffusion tensor imaging (DTI) may facilitate the identification of cytoarchitectural changes associated with focal cortical dysplasia (FCD), the predominant aetiology of paediatric structural epilepsy, its potential has thus far remained unexplored in this population. Here, we investigated whether DTI indices can differentiate FCD from contralateral brain parenchyma (CBP) and whether clinical features affect these indices. METHODS: In this single-centre, retrospective study, we considered children and adolescents with FCD-associated epilepsy who underwent brain magnetic resonance (MRI), including DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity, were calculated in both FCD and CBP. The DTI indices best discriminating between FCD and CBP were subsequently used to assess the link between DTI and selected clinical and lesion-related parameters. RESULTS: We enrolled 32 patients (20 male; median age at MRI 4 years), including 15 with histologically confirmed FCD. FA values were lower (p = 0.03), whereas MD values were higher in FCD than in CBP (p = 0.04). The difference in FA values between FCD and CBP was more pronounced for a positive vs. negative history of status epilepticus (p = 0.004). Among histologically confirmed cases, the difference in FA values between FCD and CBP was more pronounced for type IIb versus type I FCD (p = 0.03). CONCLUSIONS: FA and MD discriminate between FCD and CBP, while FA differentiates between FCD types. Status epilepticus increases differences in FA, potentially reflecting changes induced in the brain. Our findings support the potential of DTI to serve as a non-invasive biomarker to characterise FCD in the paediatric population.

Levetiracetam versus Phenobarbital for Neonatal Seizures: A Retrospective Cohort Study.

BACKGROUND: Although phenobarbital (PB) is commonly used as a first-line antiseizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol. METHODS: We conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020. RESULTS: First-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic) and neonatal epilepsy in 22% (5% structural due to brain malformation, 17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal-onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus versus rare seizures (P < 0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (P < 0.001). CONCLUSIONS: Our study suggests a potential noninferiority and a more acceptable safety profile for LEV, which may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses.

Seeing beyond the spikes: reconstructing the complete spatiotemporal membrane potential distribution from paired intra- and extracellular recordings.

Although electrophysiologists have been recording intracellular neural activity routinely ever since the ground-breaking work of Hodgkin and Huxley, and extracellular multichannel electrodes have also been used frequently and extensively, a practical experimental method to track changes in membrane potential along a complete single neuron is still lacking. Instead of obtaining multiple intracellular measurements on the same neuron, we propose an alternative method by combining single-channel somatic patch-clamp and multichannel extracellular potential recordings. In this work, we show that it is possible to reconstruct the complete spatiotemporal distribution of the membrane potential of a single neuron with the spatial resolution of an extracellular probe during action potential generation. Moreover, the reconstruction of the membrane potential allows us to distinguish between the two major but previously hidden components of the current source density (CSD) distribution: the resistive and the capacitive currents. This distinction provides a clue to the clear interpretation of the CSD analysis, because the resistive component corresponds to transmembrane ionic currents (all the synaptic, voltage-sensitive and passive currents), whereas capacitive currents are considered to be the main contributors of counter-currents. We validate our model-based reconstruction approach on simulations and demonstrate its application to experimental data obtained in vitro via paired extracellular and intracellular recordings from a single pyramidal cell of the rat hippocampus. In perspective, the estimation of the spatial distribution of resistive membrane currents makes it possible to distiguish between active and passive sinks and sources of the CSD map and the localization of the synaptic input currents, which make the neuron fire. KEY POINTS: A new computational method is introduced to calculate the unbiased current source density distribution on a single neuron with known morphology. The relationship between extracellular and intracellular electric potential is determined via mathematical formalism, and a new reconstruction method is applied to reveal the full spatiotemporal distribution of the membrane potential and the resistive and capacitive current components. The new reconstruction method was validated on simulations. Simultaneous and colocalized whole-cell patch-clamp and multichannel silicon probe recordings were performed from the same pyramidal neuron in the rat hippocampal CA1 region, in vitro. The method was applied in experimental measurements and returned precise and distinctive characteristics of various intracellular phenomena, such as action potential generation, signal back-propagation and the initial dendritic depolarization preceding the somatic action potential.

Scalp HFO rates are higher for larger lesions.

High-frequency oscillations (HFO) in scalp EEG are a new and promising noninvasive epilepsy biomarker, providing added prognostic value, particularly in pediatric lesional epilepsy. However, it is unclear if lesion characteristics, such as lesion volume, depth, type, and localization, impact scalp HFO rates. We analyzed scalp EEG from 13 children and adolescents with focal epilepsy associated with focal cortical dysplasia (FCD), low-grade tumors, or hippocampal sclerosis. We applied a validated automated detector to determine HFO rates in bipolar channels. We identified the lesion characteristics in MRI. Larger lesions defined by MRI volumetric analysis corresponded to higher cumulative scalp HFO rates (P = .01) that were detectable in a higher number of channels (P = .05). Both superficial and deep lesions generated HFO detectable in the scalp EEG. Lesion type (FCD vs tumor) and lobar localization (temporal vs extratemporal) did not affect scalp HFO rates in our study. Our observations support that all lesions may generate HFO detectable in scalp EEG, irrespective of their characteristics, whereas larger epileptogenic lesions generate higher scalp HFO rates over larger areas that are thus more accessible to detection. Our study provides crucial insight into scalp HFO detectability in pediatric lesional epilepsy, facilitating their implementation as an epilepsy biomarker in a clinical setting.

Variation of scalp EEG high frequency oscillation rate with sleep stage and time spent in sleep in patients with pediatric epilepsy.

OBJECTIVE: High frequency oscillations (HFO) in scalp EEG are a new and promising epilepsy biomarker. However, considerable fluctuations of HFO rates have been observed through sleep stages and cycles. Here, we aimed to identify the optimal timing within sleep and the minimal data length for sensitive and reproducible HFO detection. METHODS: We selected 16 whole-night scalp EEG recordings of paediatric patients with a focal structural epilepsy. We used an automated clinically validated HFO detector to determine HFO rates (80-250 Hz). We evaluated the reproducibility of HFO detection across intervals. RESULTS: HFO rates were higher in N3 than in N2 and REM (rapid eye movement) sleep and highest in the first sleep cycle, decreasing with time in sleep. In N3 sleep, the median reliability of HFO detection increased from 67% (interquartile range: iqr 57) to 78% (iqr 59) to 100% (iqr 70%) for 5-, 10-, and 15-min data intervals, improving significantly (p = 0.004, z = 2.9) from 5 to 10 min but not from 10 to 15 min. CONCLUSIONS: We identified the first N3 sleep stage as the most sensitive time window for HFO rate detection. At least 10 min N3 data intervals are required and sufficient for reliable measurements of HFO rates. SIGNIFICANCE: Our study provides a robust and reliable framework for scalp HFO detection that may facilitate their implementation as an EEG biomarker in paediatric epilepsy.

Scalp HFO rates decrease after successful epilepsy surgery and are not impacted by the skull defect resulting from craniotomy.

Epilepsy surgery can achieve seizure freedom in selected pediatric candidates, but reliable postsurgical predictors of seizure freedom are missing. High frequency oscillations (HFO) in scalp EEG are a new and promising biomarker of treatment response. However, it is unclear if the skull defect resulting from craniotomy interferes with HFO detection in postsurgical recordings. We considered 14 children with focal lesional epilepsy who underwent presurgical evaluation, epilepsy surgery, and postsurgical follow-up of ≥ 1 year. We identified the nearest EEG electrodes to the skull defect in the postsurgical MRI. We applied a previously validated automated HFO detector to determine HFO rates in presurgical and postsurgical EEG. Overall, HFO rates showed a positive correlation with seizure frequency (p < 0.001). HFO rates in channels over the HFO area decreased following successful epilepsy surgery, irrespective of their proximity to the skull defect (p = 0.005). HFO rates in channels outside the HFO area but near the skull defect showed no increase following surgery (p = 0.091) and did not differ from their contralateral channels (p = 0.726). Our observations show that the skull defect does not interfere with postsurgical HFO detection. This supports the notion that scalp HFO can predict postsurgical seizure freedom and thus guide therapy management in focal lesional epilepsy.

Scalp high-frequency oscillation rates are higher in younger children.

High-frequency oscillations in scalp EEG are promising non-invasive biomarkers of epileptogenicity. However, it is unclear how high-frequency oscillations are impacted by age in the paediatric population. We prospectively recorded whole-night scalp EEG in 30 children and adolescents with focal or generalized epilepsy. We used an automated and clinically validated high-frequency oscillation detector to determine ripple rates (80-250 Hz) in bipolar channels. Children < 7 years had higher high-frequency oscillation rates (P = 0.021) when compared with older children. The median test-retest reliability of high-frequency oscillation rates reached 100% (iqr 50) for a data interval duration of 10 min. Scalp high-frequency oscillation frequency decreased with age (r = -0.558, P = 0.002), whereas scalp high-frequency oscillation duration and amplitude were unaffected. The signal-to-noise ratio improved with age (r = 0.37, P = 0.048), and the background ripple band activity decreased with age (r = -0.463, P = 0.011). We characterize the relationship of scalp high-frequency oscillation features and age in paediatric patients. EEG intervals of ≥ 10 min duration are required for reliable measurements of high-frequency oscillation rates. This study is a further step towards establishing scalp high-frequency oscillations as a valid epileptogenicity biomarker in this vulnerable age group.

Revealing the distribution of transmembrane currents along the dendritic tree of a neuron from extracellular recordings.

Revealing the current source distribution along the neuronal membrane is a key step on the way to understanding neural computations; however, the experimental and theoretical tools to achieve sufficient spatiotemporal resolution for the estimation remain to be established. Here, we address this problem using extracellularly recorded potentials with arbitrarily distributed electrodes for a neuron of known morphology. We use simulations of models with varying complexity to validate the proposed method and to give recommendations for experimental applications. The method is applied to in vitro data from rat hippocampus.

The Retinal TNAP.

Accumulating evidence from recent literature underline the important roles of tissue non specific alkaline phosphatase (TNAP) in diverse functions as well as diseases of the nervous system. Exploration of TNAP in well characterized neural circuits such as the retina, might significantly advance our understanding regarding neural TNAP's roles. This chapter reviews the scarce literature as well as our findings on retinal TNAP. We found that retinal TNAP activity was preserved and followed diverse patterns throughout vertebrate evolution. We have consistently observed TNAP activity (1) in retinal vessels, (2) in photoreceptors and (3) in the majority of the studied species in the outer (OPL) and inner plexiform layers (IPL), where synaptic transmission occurs. Importantly, in some species the IPL exhibits several TNAP positive strata. These strata exactly corresponded those seen after quadruple immunohistochemistry with four canonical IPL markers (tyrosine hydroxylase, choline acetyltransferase, calretinin, protein kinase C α). Diabetes results in diminishing retinal TNAP activity before changes in canonical markers could be observed in a rat model. The presence of TNAP activity at critical sites of neurotransmission suggests its important and evolutionary conserved role in vision. In diabetes, the decreased TNAP activity indicates neurological alterations adding further evidence for the role of TNAP in brain diseases.

Localization of single-cell current sources based on extracellular potential patterns: the spike CSD method.

Traditional current source density (tCSD) calculation method calculates neural current source distribution of extracellular (EC) potential patterns, thus providing important neurophysiological information. While the tCSD method is based on physical principles, it adopts some assumptions, which can not hold for single-cell activity. Consequently, tCSD method gives false results for single-cell activity. A new, spike CSD (sCSD) method has been developed, specifically designed to reveal CSD distribution of single cells during action potential generation. This method is based on the inverse solution of the Poisson-equation. The efficiency of the method is tested and demonstrated with simulations, and showed, that the sCSD method reconstructed the original CSD more precisely than the tCSD. The sCSD method is applied to EC spatial potential patterns of spikes, measured in cat primary auditory cortex with a 16-channel chronically implanted linear probe in vivo. Using our method, the cell-electrode distances were estimated and the spatio-temporal CSD distributions were reconstructed. The results suggested, that the new method is potentially useful in determining fine details of the spatio-temporal dynamics of spikes.