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Objective: Subclinical seizures (SCS) are often captured during intracranial EEG monitoring of pediatric patients with refractory focal epilepsy. However, their clinical significance remains uncertain. We aimed to characterize features associated with SCS and whether their presence impacts epilepsy outcomes post-surgically., Methods: A single center retrospective chart review of patients with refractory focal epilepsy who underwent intracranial EEG monitoring at Boston Children's Hospital between 2004 and 2014 was conducted. Patient and seizure characteristics as well as post-operative outcome data were collected., Results: Of the 104 patients included in the study, SCS were recorded in 66 (63%). Fifty-eight had electroclinical seizures (ECS) and SCS (ECS + SCS), and eight patients only had SCS. There were no significant patient characteristics associated with the presence of SCS. One hundred one of the 104 patients (97%) underwent surgical resection after the intracranial EEG monitoring, 53 of which had Engel 1 outcomes (52%). Incomplete resection (OR 0.15, 95% confidence interval (CI) [0.06, 0.40], p < 0.001) or presence of temporal plus epilepsy (OR 0.23, 95% CI [0.06, 0.80], p = 0.04) was associated with poor Engel outcomes (Engel 2-4). Presence of SCS was not associated with epilepsy surgical outcomes (p = 0.99)., Significance: Nearly 2/3 of patients in our study had SCS captured on intracranial EEG monitoring, and arose in overlapping regions with the ictal onset zone of ECS. Completeness of resection remains the most important predictor of seizure outcome, regardless of the presence of SCS. In the absence of ECS during intracranial EEG monitoring, SCS onset zones may provide useful localization information to guide surgical resection plans. This is the largest cohort reported in the literature describing characteristics associated with the presence of SCS and the impact of SCS on pediatric epilepsy surgery outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Infantile spasms (IS) are the most frequent epilepsy syndrome in children with Down syndrome (DS). In DS, cellular (synaptic/dendritic changes) and molecular mechanisms are believed to contribute to epileptogenesis, rather than gross structural anomalies. Neuroimaging is a standard part of the evaluation of newly diagnosed infantile epilepsy including IS and, in this age group, often requires sedation. It is unclear if neuroimaging provides additional clinically useful etiologic information in IS associated with DS., Methods: We conducted a retrospective chart review and detailed neuroimaging review in 36 patients (24 males) with IS and DS, cared for at Boston Children's Hospital., Results: Incidental imaging abnormalities were common (42%), but potentially relevant etiologic abnormalities were rare (16%). Structural congenital or acquired abnormalities were associated with ongoing antiepileptic drug (AED) use (p = 0.02), as well as refractory epilepsy (p = 0.04). However, neuroimaging did not alter the treatment plan for any of these patients., Conclusions: Clinicians must carefully weigh the benefits and risks of neuroimaging in infants with DS and IS, as neuroimaging did not lead to any changes in clinical management in our patients but may offer information regarding prognosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Presurgical evaluation with antiseizure medication tapering in patients with refractory epilepsy places them at risk for seizure clustering or prolonged seizures. We looked at the occurrence of seizure clustering (3 or more seizures within 24h) and prolonged seizures and the factors that influence seizure clustering and affect length of stay (LOS) in pediatric patients during presurgical monitoring., Methods: We retrospectively reviewed the medical records of all consecutive admissions to the epilepsy monitoring unit (EMU) and included patients undergoing noninvasive presurgical evaluation. Data were extracted regarding demographics, seizure history, details of the EMU admission including occurrence of seizure clusters, prolonged seizures, status epilepticus, treatment, and LOS., Results: Sixty-nine patients met our inclusion criteria. Seizure clustering during monitoring was observed in 33 patients (48%). Prolonged seizures lasting >5min was observed in 14 (20%) patients including 2 with status epilepticus (3%). Seizure clusters necessitated rescue treatment in around 30%. History of seizure clustering at home was the only factor associated with the occurrence of seizure clustering during the EMU stay (p<0.0001). The LOS did not differ significantly between patients who had seizure clustering during monitoring versus those who did not (p=0.369)., Conclusions: Seizure clustering was common in children undergoing presurgical monitoring and seen especially in those with a history of seizure clustering at home. Occurrence of seizure clustering did not prolong the LOS but necessitated the use of rescue medications in about a third of the patients with seizure clusters due to multiple seizures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

While brain tumors are a frequent cause of seizures, they rarely cause epileptic spasms (ES). The objective of this study was to investigate features of tumor-associated ES. We conducted a retrospective review of patients with ES and a brain tumor. Demographics; pathologic, radiologic, and EEG data; treatment response; and long-term outcome were collected. Twenty four patients were identified; 11 met inclusion criteria. Epileptic spasm (ES) onset occurred prior to tumor diagnosis in seven patients (63%), and after tumor resection in 4 patients (36%). Spasms and ictal EEG often had focal features (45%). Gross total tumor resection resulted in ES freedom in 3/7 patients. There was poor response to first-line therapy (ACTH/vigabatrin; 1/5 with ES freedom). Low grade tumors predominated (8/11) with dual pathology (associated cortical malformation) in 2 patients. All tumors involved cortex; half involved subcortical regions and/or brainstem. Ten patients developed other seizure types; eight experienced refractory epilepsy, and nine had a Modified Rankin Scale of >3. In summary, EEG in tumor-associated ES often has focal features of either the semiology or EEG. Complete tumor resection yielded ES freedom in only a subset of patients. Most patients developed refractory epilepsy and adverse developmental outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30min), intermediate (4-6h) and long-term (24h) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The induction, formation and maintenance of memory represent dynamic processes modulated by multiple factors including the circadian clock and sleep. Chronic sleep restriction has become common in modern society due to occupational and social demands. Given the impact of cognitive impairments associated with sleep deprivation, there is a vital need for a simple animal model in which to study the interactions between chronic sleep deprivation and memory. We used the marine mollusk Aplysia californica, with its simple nervous system, nocturnal sleep pattern and well-characterized learning paradigms, to assess the effects of two chronic sleep restriction paradigms on short-term (STM) and long-term (LTM) associative memory. The effects of sleep deprivation on memory were evaluated using the operant learning paradigm, learning that food is inedible, in which the animal associates a specific netted seaweed with failed swallowing attempts. We found that two nights of 6h sleep deprivation occurring during the first or last half of the night inhibited both STM and LTM. Moreover, the impairment in STM persisted for more than 24h. A milder, prolonged sleep deprivation paradigm consisting of 3 consecutive nights of 4h sleep deprivation also blocked STM, but had no effect on LTM. These experiments highlight differences in the sensitivity of STM and LTM to chronic sleep deprivation. Moreover, these results establish Aplysia as a valid model for studying the interactions between chronic sleep deprivation and associative memory paving the way for future studies delineating the mechanisms through which sleep restriction affects memory formation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: It is estimated that nearly 80% of the 50 million people affected with epilepsy globally live in regions where specialist care and diagnostic tests are scarce and care is often delivered through a primary health provider with limited training. To improve diagnostic accuracy of the history and physical examination, we developed and piloted a questionnaire to discriminate between focal versus generalized epilepsy, with the future goal to guide medication choices., Methods: Through literature review and retrospective chart review of 75 children with epilepsy at Boston Children's Hospital, a 15-item questionnaire was developed. Simple motor seizures were excluded for the purposes of this questionnaire. The questionnaire was then translated in local dialects and prospectively validated at Muhimbili National Hospital in Dar Es Salaam, Tanzania, and University Teaching Hospital in Lusaka, Zambia. Children 6months-18years of age with suspected or active epilepsy were identified, and a nonphysician administered the questionnaire to the patient's caregiver. Next, each patient was evaluated by a pediatric neurologist blinded to the questionnaire results, and together with locally obtained but remotely interpreted EEG, an electroclinical diagnosis was made. The questionnaire data were compared with this clinical gold standard., Results: A total of 59 children participated: 28 from Tanzania and 31 from Zambia. Sixteen patients were excluded: 5 were excluded because of incomplete data, and 11 did not meet criteria for epilepsy based on initial screening questions. Of the remaining 43 patients, 28 had focal or multifocal epilepsy (65%), and 15 (35%) had generalized epilepsy. The questionnaire had a sensitivity of 78% and positive predictive value of 81.5%. Data were analyzed using a Rasch model, testing the questionnaire's internal consistency, reliability, and its discriminative validity in classifying focal versus generalized epilepsy against an electroclinical diagnosis. The mean epilepsy score for focal epilepsy was 0.084 logits compared with -1.147 logits for generalized epilepsy, demonstrating a large effect size [F (1, 41)=13.490, p<0.001]., Conclusions: Our questionnaire provides a straightforward method to improve diagnostic accuracy, and could assist in bridging the diagnostic gap in pediatric epilepsy in resource-limited settings. This tool was specifically designed to be easily implemented by any healthcare provider. This pilot study prompts broader prospective validation in additional settings for further refinement, and for performance assessment of impact on provider's practice, ability to guide medication choices, and ultimately improve treatment outcomes in resource-limited regions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The risk of developing epilepsy following febrile seizures (FS) varies between 2% and 10%, with complex febrile seizures (CFS) having a higher risk. We examined the utility of detected epileptiform abnormalities on the initial EEG following a first CFS in predicting subsequent epilepsy., Methods: This was a retrospective study of consecutive patients (ages 6-60 months) who were neurologically healthy or mildly delayed, seen in the ED following a first CFS and had both an EEG and minimum of 2-year follow-up. Data regarding clinical characteristics, EEG report, development of subsequent epilepsy, and type of epilepsy were collected. Established clinical predictors for subsequent epilepsy in children with FS and EEG status were evaluated for potential correlation with the development of subsequent epilepsy. Sensitivity, specificity, and positive and negative predictive values of an abnormal EEG (epileptiform EEG) were calculated., Results: A group of 154 children met our inclusion criteria. Overall, 20 (13%) children developed epilepsy. The prevalence of epilepsy was 13% (CI 8.3-19.6%). Epileptiform abnormalities were noted in 21 patients (13.6%), EEG slowing in 23 patients (14.9%), and focal asymmetry in six (3.8%). Epileptiform EEGs were noted in 20% (4/20) of patients with epilepsy and 13% (17/134) of patients without epilepsy (p=0.48). At an estimated risk of subsequent epilepsy of 10% (from population-based studies of children with FS), we determined that the PPV of an epileptiform EEG for subsequent epilepsy was 15%. None of the clinical variables (presence of more than 1 complex feature, family history of epilepsy, or status epilepticus) predicted epilepsy., Conclusions: An epileptiform EEG was not a sensitive measure and had a poor positive predictive value for the development of epilepsy among neurologically healthy or mildly delayed children with a first complex febrile seizure. The practice of obtaining routine EEG for predicting epilepsy after the first CFS needs clarification by well-defined prospective studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) has been applied with variable success to terminate the seizures of epilepsia partialis continua. The rationale for using this technique to suppress ongoing seizures is the capacity of rTMS to interrupt ongoing neuronal activity, and to produce a lasting decrease in cortical excitability with low-frequency (1 Hz) stimulation. We report a case of epilepsia partialis continua in a child with Rasmussen's encephalitis, in whom seizures were transiently suppressed by 1-Hz rTMS delivered in nine daily 30-minute sessions. In this case, total ictal time was significantly reduced during stimulation, but the daily baseline seizure rate remained unchanged. Notably, the detection and quantification of this short-lived improvement were enabled by recording EEG continuously during the rTMS session. Thus, we present this case to illustrate a potential utility of combined continuous EEG recording and rTMS in seizure treatment.