Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Impact of development and recent-onset epilepsy on language dominance.

OBJECTIVE: Reorganization of the language network from typically left-lateralized frontotemporal regions to bilaterally distributed or right-lateralized networks occurs in anywhere from 25%-30% of patients with focal epilepsy. In patients who have been recently diagnosed with epilepsy, an important question remains as to whether it is the presence of seizures or the underlying epilepsy etiology that leads to atypical language representations. This question becomes even more interesting in pediatric samples, where the typical developmental processes of the language network may confer more variability and plasticity in the language network. We assessed a carefully selected cohort of children with recent-onset epilepsy to examine whether it is the effects of seizures or their underlying cause that leads to atypical language lateralization. METHODS: We used functional magnetic resonance imaging (fMRI) to compare language laterality in children with recently diagnosed focal unaware epilepsy and age-matched controls. Age at epilepsy onset (age 4 to 6 years vs age 7 to 12 years) was also examined to determine if age at onset influenced laterality. RESULTS: The majority of recent-onset patients and controls exhibited left-lateralized language. There was a significant interaction such that the relationship between epilepsy duration and laterality differed by age at onset. In children with onset after age 6, a longer duration of epilepsy was associated with less left-lateralized language dominance. In contrast, in children with onset between 4 and 6 years of age, a longer duration of epilepsy was not associated with less left language dominance. SIGNIFICANCE: Our results demonstrate that although language remained largely left-lateralized in children recently diagnosed with epilepsy, the impact of seizure duration depended on age at onset, indicating that the timing of developmental and disease factors are important in determining language dominance.

Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study.

OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

Highlights From AES2020, a Virtual American Epilepsy Society Experience.

Due to COVID-19 a live, in-person meeting was not possible for the American Epilepsy Society in 2020. An alternative, virtual event, the AES2020, was held instead. AES2020 was a great success with 4679 attendees from 70 countries. The educational content was outstanding and spanned the causes, treatments, and outcomes from epileptic encephalopathy to the iatrogenicity of epilepsy interventions to neurocognitive disabilities to the approach to neocortical epilepsies. New gene therapy approaches such as antisense oligonucleotide treatment for Dravet syndrome were introduced and neuromodulation devices were discussed. There were many other topics discussed in special interest groups and investigators' workshops. A highlight was having a Nobel prize winner speak about memory processing. Human intracranial electrophysiology contributes insights into memory processing and complements animal work. In a special COVID symposium, the impact of COVID on patients with epilepsy was reviewed. Telehealth has been expanded rapidly and may be well suited for some parts of epilepsy care. In summary, the epilepsy community was alive and engaged despite being limited to a virtual platform.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

OBJECTIVE: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Differential antiseizure medication sensitivity of the Affective Reactivity Index: A randomized controlled trial in new-onset pediatric focal epilepsy.

BACKGROUND: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). METHOD: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. RESULTS: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. CONCLUSION: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

Imaging episodic memory during development and childhood epilepsy.

Epilepsy affects 2.2 million adults in the USA, with 1 in 26 people developing epilepsy at some point in their lives. Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy as medial structures, and the hippocampus in particular, are prone to generating seizures. Selective anterior temporal resection (which removes the hippocampus) is the most effective intractable TLE treatment, but given the critical role of the mesial temporal lobe in memory functioning, resection can have negative effects on this crucial cognitive skill. To minimize the adverse impact of temporal lobe surgery on memory functioning, reliable pre-surgical guides are needed. Clinical functional magnetic resonance imaging (fMRI) provides reliable, noninvasive guidance of language functioning and plays a growing role in the pre-surgical evaluation for epilepsy patients; however, localization of memory function in children with epilepsy using fMRI has not been established. Aside from the lack of neuroimaging memory studies in children with TLE, studies of typical development are limited. This review will focus on the functional anatomy of memory systems throughout development, with a focus on TLE. TLE provides the ideal model from which to understand memory function and the limits of plasticity and compensation/reorganization throughout development.

Weaker semantic language lateralization associated with better semantic language performance in healthy right-handed children.

INTRODUCTION: The relationship between language abilities and language lateralization in the developing brain is important for our understanding of the neural architecture of language development. METHODS: We investigated 35 right-handed children and adolescents aged 7-16 years with a functional magnetic resonance imaging language paradigm and a comprehensive language and verbal memory examination. RESULTS: We found that less lateralized language was significantly correlated with better language performance across areas of the brain and across different language tasks. Less lateralized language in the overall brain was associated with better in-scanner task accuracy on a semantic language decision task and out-of-scanner vocabulary and verbal fluency. Specifically, less lateralized frontal lobe language dominance was associated with better in-scanner task accuracy and out-of-scanner verbal fluency. Furthermore, less lateralized parietal language was associated with better out-of-scanner verbal memory across learning, short- and long-delay trials. In contrast, we did not find any relationship between temporal lobe language laterality and verbal performance. CONCLUSIONS: This study suggests that semantic language performance is better with some involvement of the nondominant hemisphere.

The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism.

BACKGROUND: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions. OBJECTIVE: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism. METHODS: We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up. RESULTS: Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 µmol/L (median); range 823-1647 µmol/L (normal value <50 µmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI. CONCLUSIONS: Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma.

Sudden Death in Epilepsy: Knowledge among Pediatric Providers.

A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP.

Cortical cartography reveals political and physical maps.

Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised.

Regional differences in the developmental trajectory of lateralization of the language network.

The timing and developmental factors underlying the establishment of language dominance are poorly understood. We investigated the degree of lateralization of traditional frontotemporal and modulatory prefrontal-cerebellar regions of the distributed language network in children (n = 57) ages 4 to 12--a critical period for language consolidation. We examined the relationship between the strength of language lateralization and neuropsychological measures and task performance. The fundamental language network is established by four with ongoing maturation of language functions as evidenced by strengthening of lateralization in the traditional frontotemporal language regions; temporal regions were strongly and consistently lateralized by age seven, while frontal regions had greater variability and were less strongly lateralized through age 10. In contrast, the modulatory prefrontal-cerebellar regions were the least strongly lateralized and degree of lateralization was not associated with age. Stronger core language skills were significantly correlated with greater right lateralization in the cerebellum.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Center for Neuroscience and Behavioral Medicine: an innovative administrative structure and possible paradigm for the future.

Child neurology has evolved from a primarily diagnostic to a therapeutic subspecialty. Despite well-documented manpower shortages, child neurology programs at major children's hospitals have expanded, and the optimal administrative structure for child neurology programs has not been clearly defined. The Division of Child Neurology at Children's National Medical Center in Washington, DC, is a part of the Center for Neuroscience and Behavioral Medicine. This center includes multiple medical, behavioral health, and surgical subspecialties, and fosters the development of child neurology. During the 10 years of its existence, the number of board-certified or eligible child neurologists within the center has tripled to over 30. Because of its success, the Division of Child Neurology was split into three free-standing divisions and two institutes. This unique structure has fostered the development of numerous multidisciplinary programs, and is fiscally sustainable. The strengths, limitations, and challenges of this structure in terms of child neurology are reviewed. This administrative structure has been successful and may act as a model for other programs.

Functional anatomy of listening and reading comprehension during development.

Listening and reading comprehension of paragraph-length material are considered higher-order language skills fundamental to social and academic functioning. Using ecologically relevant language stimuli that were matched for difficulty according to developmental level, we analyze the effects of task, age, neuropsychological skills, and post-task performance on fMRI activation and hemispheric laterality. Areas of supramodal language processing are identified, with the most robust region being left-lateralized activation along the superior temporal sulcus. Functionally, this conjunction has a role in semantic and syntactic processing, leading us to refer to this conjunction as "comprehension cortex." Different from adults, supramodal areas for children include less extensive inferior frontal gyrus but more extensive right cerebellum and right temporal pole. Broader neuroanatomical pathways are recruited for reading, reflecting the more active processing and larger set of cognitive demands needed for reading compared to listening to stories. ROI analyses reveal that reading is a less lateralized language task than listening in inferior frontal and superior temporal areas, which likely reflects the difficulty of the task as children in this study are still developing their reading skills. For listening to stories, temporal activation is stable by age four with no correlations with age, neuropsychological skills or post-task performance. In contrast, frontal activation during listening to stories occurs more often in older children, and frontal activation is positively correlated with better performance on comprehension questions, suggesting that the activation of frontal networks may reflect greater integration and depth of story processing.

Functional imaging of developmental and adaptive changes in neurocognition.

Characterization of brain-behavior relationships through functional magnetic imaging (fMRI) within typically or atypically developing populations poses methodological and interpretational challenges. We consider theoretical, methodological, and artifactual factors that influence characterization of developmental and adaptive changes in childhood. Findings from anatomical and physiological brain development studies are highlighted as they may influence functional imaging results. Then, we consider several patterns of functional activation within the context of developmental processes as well as neurologic disease. Hypotheses regarding the development of cognitive networks are proposed to account for the individual differences seen in normal and atypical development. We also identify potential sources of unwanted variability related to experimental design and task performance and suggest possible solutions to help minimize these effects. Lastly, a challenge for current studies is a lack of group and individual analysis methods that can be reliably applied to capture and quantify factors that contribute to variability introduced by developmental and disease processes. We review current methods and propose potential solutions.

Functional MR imaging of language, memory, and sensorimotor cortex.

fMR imaging is a versatile technology that allows for the noninvasive identification of sensory, motor,and cognitive functions that may be impaired by surgical resection. fMR imaging provides the capacity to probe several brain functions, and when results are uncertain, to repeat or modify them. There are some limitations, MR contraindications to scanning, motion, and cooperation among them. Yet for most patients fMR imaging provides a reliable way to lateralize language dominance and to guide localization of language functions. Memory paradigms lag behind language in practical application, but the impediments to its utility will likely be resolved in the near future.

Neuroimaging reveals automatic speech coding during perception of written word meaning.

The extent to which visual word perception engages speech codes (i.e., phonological recoding) remains a crucial question in understanding mechanisms of reading. In this study, we used functional magnetic resonance imaging techniques combined with behavioral response measures to examine neural responses to focused versus incidental phonological and semantic processing of written words. Three groups of subjects made simple button-pressing responses in either phonologically (rhyming-judgment) or semantically (category-judgment) focused tasks or both tasks with identical sets of visual stimuli. In the phonological tasks, subjects were given both words and pseudowords separated in different scan runs. The baseline task required feature search of scrambled letter strings created from the stimuli for the experimental conditions. The results showed that cortical regions associated with both semantic and phonological processes were strongly activated when the task required active processing of word meaning. However, when subjects were actively processing the speech sounds of the same set of written words, brain areas typically engaged in semantic processing became silent. In addition, subjects who performed both the rhyming and the semantic tasks showed diverse and significant bilateral activation in the prefrontal, temporal, and other brain regions. Taken together, the pattern of brain activity provides evidence of a neural basis supporting the theory that in normal word reading, phonological recoding is automatic and facilitates semantic processing of written words, while rapid comprehension of word meaning requires devoted attention. These results also raise questions about including multiple cognitive tasks in the same neuroimaging sessions.