Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.

Clinical recommendations for conducting pediatric functional language and memory mapping during the phase I epilepsy presurgical workup.

Objective: Pediatric epilepsy surgery effectively controls seizures but may risk cognitive, language, or memory decline. Historically, the intra-carotid anesthetic procedure (IAP or Wada Test) was pivotal for language and memory function. However, advancements in noninvasive mapping, notably functional magnetic resonance imaging (fMRI), have transformed clinical practice, reducing IAP's role in presurgical evaluations. Method: We conducted a critical narrative review on mapping technologies, including factors to consider for discordance. Results: Neuropsychological findings suggest that if pre-surgery function remains intact and the surgery targets the eloquent cortex, there is a high chance for decline. Memory and language decline are particularly pronounced post-left anterior temporal lobe resection (ATL), making presurgical cognitive assessment crucial for predicting postoperative outcomes. However, the risk of functional decline is not always clear - particularly with higher rates of atypical organization in pediatric epilepsy patients and discordant findings from cognitive mapping. We found little research to date on the use of IAP and other newer technologies for lateralization/localization in pediatric epilepsy. Based on this review, we introduce an IAP decision tree to systematically navigate discordance in IAP decisions for epilepsy presurgical workup. Conclusions: Future research should be aimed at pediatric populations to improve the precision of functional mapping, determine which methods predict post-surgical deficits and then create evidence-based practice guidelines to standardize mapping procedures. Explicit directives are needed for resolving conflicts between developing mapping procedures and established clinical measures. The proposed decision tree is the first step to standardize when to consider IAP or invasive mapping, in coordination with the multidisciplinary epilepsy surgical team.

Shortened Motor Evoked Potential Latency in the Epileptic Hemisphere of Children With Focal Epilepsy.

PURPOSE: Motor evoked potential (MEP) amplitude and latency are acquired routinely during neuronavigated transcranial magnetic stimulation, a method of functional mapping of the motor cortex before epilepsy surgery. Although MEP amplitude is routinely used to generate a motor map, MEP latency in patients with focal epilepsy has not been studied systematically. Given that epilepsy may alter myelination, we tested whether intrinsic hand muscle MEPs obtained from the hemisphere containing a seizure focus differ in latency from MEPs collected from the opposite hemisphere. METHODS: Latencies of abductor pollicis brevis MEPs were obtained during routine motor mapping by neuronavigated transcranial magnetic stimulation in children with intractable, unihemispheric focal epilepsy. The primary motor cortex was stimulated bilaterally in all cases. Only data from patients without a lesion involving the corticospinal tract were included. We tested whether abductor pollicis brevis MEP latency varied as a function of seizure focus lateralization. RESULTS: In the 17 patients who met the inclusion criteria, the mean latency of MEPs with amplitudes in the top and bottom quartiles was shorter in the epileptic hemisphere. Interhemispheric latency difference was greater in patients with lesional epilepsy than in those with nonlesional epilepsy (0.7 ± 0.4 vs. 0.1 ± 0.6 milliseconds, P = 0.02). CONCLUSIONS: Motor evoked potential latency was shortened in the epileptic hemisphere of children with focal epilepsy.

Influence of extent and age at corpus callosotomy on seizure outcomes. A single center experience.

Corpus callosotomy (CC) is a palliative treatment for drop seizures in patients with drug-resistant nonlocalizable epilepsy. We compared drop seizure outcomes between patients undergoing anterior CC versus complete CC and examined factors impacting outcomes for drop seizures including age at CC and duration of epilepsy. A retrospective review of patients who underwent CC between 2003 and 2022 with a minimum of 6 months postsurgical follow-up was included. Outcome measure for drop seizures included seizure reduction ≥50% from baseline as well as elimination of drop seizures. Thirty-eight patients were included. Overall, ≥50% reduction in drop seizures occurred in nearly 70% (23 out of 33) patients with complete elimination in 58% (19 out of 33). Compared with anterior CC (n = 13), patients undergoing complete CC (n = 25) had increased likelihood of ≥50% reduction (p = 0.006) or elimination (p = 0.024) of drop seizures. Regression analysis showed that complete CC was the primary predictor for improved drop seizure outcomes (elimination, p = 0.014 or ≥50% reduction, p = 0.006), while age at CC and duration of epilepsy did not impact the outcomes. Compared to anterior CC, complete CC was significantly more likely to lead to improvement/freedom from drop seizures. Age at CC or duration of epilepsy did not influence drop seizure outcomes.

Focal drug-resistant temporal lobe epilepsy associated with an ipsilateral anterior choroidal artery aneurysm: illustrative case.

BACKGROUND: The occurrence of both an intracranial aneurysm and epilepsy, especially drug-resistant epilepsy (DRE), is rare. Although the overall incidence of aneurysms associated with DRE is unclear, it is thought to be particularly infrequent in the pediatric population. Surgical ligation of the offending aneurysm has been reported in conjunction with resolving seizure activity, although few cases have cited a combined approach of aneurysm ligation and resection of an epileptogenic focus. OBSERVATIONS: We present the case of a 14-year-old female patient with drug-resistant temporal lobe epilepsy and an ipsilateral supraclinoid internal carotid artery aneurysm. Seizure semiology, electroencephalography monitoring, and magnetic resonance imaging all indicated a left temporal epileptogenic focus, in addition to an incidental aneurysm. The authors recommended a combined surgery involving resection of the temporal lesion and surgical clip ligation of the aneurysm. Near-total resection and successful ligation were achieved, and the patient has remained seizure free since surgery at 1 year postoperatively. LESSONS: In patients with focal DRE and an adjacent intracranial aneurysm, a combined surgical approach involving both resection and surgical ligation can be used. Several surgical timing and neuroanesthetic considerations should be made to ensure the overall safety and efficacy of this procedure.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

AIM: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. METHOD: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. RESULTS: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 µM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. INTERPRETATION: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.

The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

OBJECTIVE: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. METHODS: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements. RESULTS: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 µmol·L-1 (p = .002), GHB < 143.6 µmol·L-1 (p = .004), and GBA < .075 µmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008). SIGNIFICANCE: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Stereoelectroencephalography followed by combined electrode removal and MRI-guided laser interstitial thermal therapy or open resection: a single-center series in pediatric patients with medically refractory epilepsy.

OBJECTIVE: Stereoelectroencephalography (SEEG) and MRI-guided laser interstitial thermal therapy (MRgLITT) have emerged as safe, effective, and less invasive alternatives to subdural grid placement and open resection, respectively, for the localization and treatment of medically refractory epilepsy (MRE) in children. Reported pediatric experience combining these complementary techniques is limited, with traditional workflows separating electrode removal and ablation/resection. The authors describe the largest reported series of pediatric epilepsy patients who underwent MRgLITT following SEEG contrasted with a cohort that underwent craniotomy following SEEG, combining ablation/resection with electrode explantation as standard practice. METHODS: The medical records of all patients with MRE who had undergone SEEG followed by MRgLITT or open resection/disconnection at Boston Children's Hospital between November 2015 and December 2020 were retrospectively reviewed. Primary outcome variables included surgical complication rates, length of hospital stay following treatment, and Engel classification at the last follow-up. RESULTS: Of 74 SEEG patients, 27 (median age 12.1 years, 63% female) underwent MRgLITT and 47 (median age 12.1 years, 49% female) underwent craniotomy. Seventy patients (95%) underwent SEEG followed by combined electrode removal and treatment. Eight MRgLITT cases (30%) and no open cases targeted the insula (p < 0.001). Complication rates did not differ, although trends toward more subdural/epidural hematomas, infarcts, and permanent unanticipated neurological deficits were evident following craniotomy, whereas a trend toward more temporary unanticipated neurological deficits was seen following MRgLITT. The median duration of hospitalization after treatment was 3 and 5 days for MRgLITT and open cases, respectively (p = 0.078). Seizure outcomes were similar between the cohorts, with 74% of MRgLITT and craniotomy patients attaining Engel class I or II outcomes (p = 0.386) at the last follow-up (median 1.1 and 1.9 years, respectively). CONCLUSIONS: MRgLITT and open resection following SEEG can both effectively treat MRE in pediatric patients and generally can be performed in a two-surgery workflow during a single hospitalization. In appropriately selected patients, MRgLITT tended to be associated with shorter hospitalizations and fewer complications following treatment and may be best suited for focal deep-seated targets associated with relatively challenging open surgical approaches.

Interictal Connectivity Revealed by Granger Analysis of Stereoelectroencephalography: Association With Ictal Onset Zone, Resection, and Outcome.

BACKGROUND: Stereoelectroencephalography (sEEG) facilitates electrical sampling and evaluation of complex deep-seated, dispersed, and multifocal locations. Granger causality (GC), previously used to study seizure networks using interictal data from subdural grids, may help identify the seizure-onset zone from interictal sEEG recordings. OBJECTIVE: To examine whether statistical analysis of interictal sEEG helps identify surgical target sites and whether surgical resection of highly ranked nodes correspond to favorable outcomes. METHODS: Ten minutes of extraoperative recordings from sequential patients who underwent sEEG evaluation were analyzed (n = 20). GC maps were compared with clinically defined surgical targets using rank order statistics. Outcomes of patients with focal resection/ablation with median follow-up of 3.6 years were classified as favorable (Engel 1, 2) or poor (Engel 3, 4) to assess their relationship with the removal of highly ranked nodes using the Wilcoxon rank-sum test. RESULTS: In 12 of 20 cases, the rankings of contacts (based on the sum of outward connection weights) mapped to the seizure-onset zone showed higher causal node connectivity than predicted by chance ( P ≤ .02). A very low aggregate probability ( P < 10 -18 , n = 20) suggests that causal node connectivity predicts seizure networks. In 8 of 16 with outcome data, causal connectivity in the resection was significantly greater than in the remaining contacts ( P ≤ .05). We found a significant association between favorable outcome and the presence of highly ranked nodes in the resection ( P < .05). CONCLUSION: Granger analysis can identify seizure foci from interictal sEEG and correlates highly ranked nodes with favorable outcome, potentially informing surgical decision-making without reliance on ictal recordings.

Discrepant expressive language lateralization in children and adolescents with epilepsy.

Neuronavigated transcranial magnetic stimulation (nTMS) has emerged as a presurgical language mapping tool distinct from the widely used functional magnetic resonance imaging (fMRI). We report fMRI and nTMS language-mapping results in 19 pediatric-epilepsy patients and compare those to definitive testing by electrical cortical stimulation, Wada test, and/or neuropsychological testing. Most discordant results occurred when fMRI found right-hemispheric language. In those cases, when nTMS showed left-hemispheric or bilateral language representation, left-hemispheric language was confirmed by definitive testing. Therefore, we propose nTMS should be considered for pediatric presurgical language-mapping when fMRI shows right-hemispheric language, with nTMS results superseding fMRI results in those scenarios.

Clinical characteristics and outcomes after new-onset seizure among Zambian children with HIV during the antiretroviral therapy era.

OBJECTIVE: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported. METHODS: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed. RESULTS: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure. SIGNIFICANCE: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV.

Biomarkers Obtained by Transcranial Magnetic Stimulation in Neurodevelopmental Disorders.

SUMMARY: Transcranial magnetic stimulation (TMS) is a method for focal brain stimulation that is based on the principle of electromagnetic induction where small intracranial electric currents are generated by a powerful fluctuating magnetic field. Over the past three decades, TMS has shown promise in the diagnosis, monitoring, and treatment of neurological and psychiatric disorders in adults. However, the use of TMS in children has been more limited. We provide a brief introduction to the TMS technique; common TMS protocols including single-pulse TMS, paired-pulse TMS, paired associative stimulation, and repetitive TMS; and relevant TMS-derived neurophysiological measurements including resting and active motor threshold, cortical silent period, paired-pulse TMS measures of intracortical inhibition and facilitation, and plasticity metrics after repetitive TMS. We then discuss the biomarker applications of TMS in a few representative neurodevelopmental disorders including autism spectrum disorder, fragile X syndrome, attention-deficit hyperactivity disorder, Tourette syndrome, and developmental stuttering.

Transcranial Magnetic Stimulation in Succinic Semialdehyde Dehydrogenase Deficiency: A Measure of Maturational Trajectory of Cortical Excitability.

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a disorder of GABA degradation with use-dependent downregulation of postsynaptic GABAA/B receptors. We aim to measure the resulting cortical excitation: inhibition ratio using transcranial magnetic stimulation. METHODS: In this single-center observational study, 18 subjects with SSADHD and 8 healthy controls underwent transcranial magnetic stimulation. Resting motor threshold, cortical silent period, and long-interval intracortical inhibition were measured in both groups. Resting motor threshold in focal epilepsy patients from an institutional transcranial magnetic stimulation database were also included. RESULTS: SSADHD subjects had higher resting motor threshold than healthy controls but lower relative to focal epilepsy patients. Resting motor threshold decreased with age in all groups. Cortical silent period was longer in SSADHD subjects than in healthy controls. No difference was detected in long-interval intracortical inhibition between the 2 groups. CONCLUSION: Findings suggest abnormal corticospinal tract physiology in SSADHD, but with preserved developmental trajectory for corticospinal tract maturation. Defining features of these transcranial magnetic stimulation metrics in SSADHD will be better elucidated through this ongoing longitudinal study.

CHL1 deletion is associated with cognitive and language disabilities - Case report and review of literature.

BACKGROUND: There is a small, but growing number of reports of pediatric patients with terminal deletions at 3p26.3 involving only the cell adhesion molecule L1-like (CHL1) gene that has been found to have language delays and intellectual disability. Here we report a one month of age patient who developed seizures and tone abnormalities, with persistent and prominent gross and fine motor delays. The patient has microcephaly and deficits in language and cognitive delays, similar to what has been seen in previous case reports. METHODS: Chromosome and microarray comparative genomic hybridization (aCGH) analysis was performed to identify clinically significant copy number variants (CNVs). In addition, Fluorescent in-situ hybridization (FISH) was performed to confirm the aCGH findings. RESULTS: Chromosome analysis revealed an apparently normal (46,XX) female karyotype. Microarray CGH analysis revealed a 639 kb loss at 3p26.3 from 62199 to 701052 base pairs encompassing the whole CHL1 gene that was confirmed by FISH. Parental follow-up revealed the deletion as maternal in origin. CONCLUSION: This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays. Further studies are needed to understand the degree of phenotypic heterogeneity associated with CHL1 gene deletion and whether the size of the deletion or presence of additional copy number variants (CNVs) which were seen in other case reports help predict the expected phenotype for a patient.

Subclinical seizures detected on intracranial EEG: Patient characteristics and impact on surgical outcome in a single pediatric epilepsy surgery center.

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.

Review of Transcranial Magnetic Stimulation in Epilepsy.

PURPOSE: Despite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures. METHODS: A focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures. FINDINGS: Studies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results. IMPLICATIONS: TMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug-device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics.

Photoplethysmography: A measure for the function of the autonomic nervous system in focal impaired awareness seizures.

OBJECTIVES: Photoplethysmography (PPG) reflects variations of blood perfusion in tissues, which may signify seizure-related autonomic changes. The aim of this study is to assess the variability of PPG signals and their value in detecting peri-ictal changes in patients with focal impaired awareness seizures (FIASs). METHODS: PPG data were recorded using a wearable sensor placed on the wrist or ankle of children with epilepsy admitted for long-term video-electroencephalographic monitoring. We analyzed PPG data in four different periods: seizure-free, preictal, ictal, and postictal. Multiple features were automatically extracted from the PPG signal-frequency, duration, amplitude, increasing and decreasing slopes, smoothness, and area under the curve (AUC)-and were used to identify preictal, ictal, or postictal changes by comparing them with seizure-free periods and with each other using a linear mixed-effects model. RESULTS: We studied PPG in 11 patients (18 FIASs), including seizure-free, preictal, and postictal periods, and a subset of eight patients (12 FIASs) including the ictal period. Compared to the seizure-free period, we found significant changes in PPG (1) during the ictal period across all features; (2) during the preictal period in amplitude, duration, increasing slope, and AUC; and (3) during the postictal period in decreasing slope. SIGNIFICANCE: Specific PPG changes can be seen before, during, and after FIASs. The peri-ictal changes in the PPG features of patients with FIASs suggest potential applications of PPG monitoring for seizure detection.

Biomarkers Obtained by Transcranial Magnetic Stimulation of the Motor Cortex in Epilepsy.

Epilepsy is associated with numerous neurodevelopmental disorders. Transcranial magnetic stimulation (TMS) of the motor cortex coupled with electromyography (EMG) enables biomarkers that provide measures of cortical excitation and inhibition that are particularly relevant to epilepsy and related disorders. The motor threshold (MT), cortical silent period (CSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) are among TMS-derived metrics that are modulated by antiepileptic drugs. TMS may have a practical role in optimization of antiepileptic medication regimens, as studies demonstrate dose-dependent relationships between TMS metrics and acute medication administration. A close association between seizure freedom and normalization of cortical excitability with long-term antiepileptic drug use highlights a plausible utility of TMS in measures of anti-epileptic drug efficacy. Finally, TMS-derived biomarkers distinguish patients with various epilepsies from healthy controls and thus may enable development of disorder-specific biomarkers and therapies both within and outside of the epilepsy realm.

Assessing the localization accuracy and clinical utility of electric and magnetic source imaging in children with epilepsy.

OBJECTIVE: To evaluate the accuracy and clinical utility of conventional 21-channel EEG (conv-EEG), 72-channel high-density EEG (HD-EEG) and 306-channel MEG in localizing interictal epileptiform discharges (IEDs). METHODS: Twenty-four children who underwent epilepsy surgery were studied. IEDs on conv-EEG, HD-EEG, MEG and intracranial EEG (iEEG) were localized using equivalent current dipoles and dynamical statistical parametric mapping (dSPM). We compared the localization error (ELoc) with respect to the ground-truth Irritative Zone (IZ), defined by iEEG sources, between non-invasive modalities and the distance from resection (Dres) between good- (Engel 1) and poor-outcomes. For each patient, we estimated the resection percentage of IED sources and tested whether it predicted outcome. RESULTS: MEG presented lower ELoc than HD-EEG and conv-EEG. For all modalities, Dres was shorter in good-outcome than poor-outcome patients, but only the resection percentage of the ground-truth IZ and MEG-IZ predicted surgical outcome. CONCLUSIONS: MEG localizes the IZ more accurately than conv-EEG and HD-EEG. MSI may help the presurgical evaluation in terms of patient's outcome prediction. The promising clinical value of ESI for both conv-EEG and HD-EEG prompts the use of higher-density EEG-systems to possibly achieve MEG performance. SIGNIFICANCE: Localizing the IZ non-invasively with MSI/ESI facilitates presurgical evaluation and surgical prognosis assessment.