Modeling epileptic spasms during infancy: Are we heading for the treatment yet?
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ABSTRACT:
SUBMITTER: Velisek L
PROVIDER: S-EPMC7299814 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveAmong standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one-half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017.MethodsWe conducted a retrospective nationwide study in Japan on the long-term seizure outcome of ES. Long-term seizure outcome was evaluated by seizure-free rate, seizure-free period, and Kaplan-Meier curve. Seizure-free was defined as seizure control for longer than 2 months.ResultsFrom the medical history of 501 patients, 325 patients had generalized ES only (GES group) at the start of the first treatment, 125 patients had generalized ES after focal seizure onset (FS-GES group), seven patients had focal ES after focal seizure onset (FS-FES group), and 24 patients had generalized ES combined with focal seizures after focal seizure onset (FS-GES + FS group). Seizure-free period of ES (generalized ES and focal ES) [mean (95% confidence interval)] was 2.7 (0.0-5.4) months in GES group, 1.1 (0.1-2.2) months in FS-GES group, 1.0 (0.2-1.9) months in FS-GES + FS group, and 0.1 (-0.2-0.5) months in FS-FES group. Seizure-free rate, seizure-free period, and Kaplan-Meier curve of generalized ES were almost the same in GES group and FS-GES group, with characteristics of superior response to ACTH. Mean seizure-free period of generalized ES combined with focal seizures was significantly shorter in FS-GES + FS group than in GES group. Mean seizure-free period of focal ES in FS-FES group was extremely short with exceedingly early relapse.SignificancePharmacoresistance was different in generalized ES, focal ES, and generalized ES combined with focal seizures. ES with focal features or with focal seizures may have focal lesions, thus consider surgical options earlier in the course.
| S-EPMC8886099 | biostudies-literature
Project description:ObjectiveWe reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms.MethodsData were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded.ResultsMean age at surgery was 5.1 (range 0.2-19) years, with mean postsurgical follow-up of 45.3 (6-120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2-8), which decreased to 1.2 (0-4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome. Thirty-seven (79%) of 47 patients with lesional MRI had class-I outcome, whereas 9 (50%) of 18 with normal MRI had class I outcome. Positron emission tomography (PET) scan was abnormal in almost all patients [61 (97%) of 63 with lateralizing/localizing findings in 56 (92%) of 61 patients, thus helping in surgical decision making and guiding subdural grid placements, particularly in patients with nonlesional MRI. Fifteen patients had postoperative complications, mostly minor.SignificanceCurative epilepsy surgery in ES patients, with or without history of infantile spasms, is best accomplished at an early age and in those patients with lesional abnormalities on MRI with electroencephalography (EEG) concordance. Good outcomes can be achieved even when there is no MRI lesion but positive PET localization.
| S-EPMC4679547 | biostudies-literature
Project description:ObjectiveTo determine the structural networks that constrain propagation of ictal oscillations during epileptic spasm events, and compare the observed propagation patterns across patients with successful or unsuccessful surgical outcomes.MethodsSubdural electrode recordings of 18 young patients (age 1-11 years) were analyzed during epileptic spasm events to determine ictal networks and quantify the amplitude and onset time of ictal oscillations across the cortical surface. Corresponding structural networks were generated with diffusion magnetic resonance imaging (MRI) tractography by seeding the cortical region associated with the earliest average oscillation onset time, and white matter pathways connecting active electrode regions within the ictal network were isolated. Properties of this structural network were used to predict oscillation onset times and amplitudes, and this relationship was compared across patients who did and did not achieve seizure freedom following resective surgery.ResultsOnset propagation patterns were relatively consistent across each patient's spasm events. An electrode's average ictal oscillation onset latency was most significantly associated with the length of direct corticocortical tracts connecting to the area with the earliest average oscillation onset (p < .001, model R2 = .54). Moreover, patients demonstrating a faster propagation of ictal oscillation signals within the corticocortical network were more likely to have seizure recurrence following resective surgery (p = .039). In addition, ictal oscillation amplitude was associated with connecting tractography length and weighted fractional anisotropy (FA) measures along these pathways (p = .002/.030, model R2 = .31/.25). Characteristics of analogous corticothalamic pathways did not show significant associations with ictal oscillation onset latency or amplitude.SignificanceSpatiotemporal propagation patterns of high-frequency activity in epileptic spasms align with length and FA measures from onset-originating corticocortical pathways. Considering the data in this individualized framework may help inform surgical decision-making and expectations of surgical outcomes.
| S-EPMC9283246 | biostudies-literature
Project description:To assess factors associated with favorable seizure outcome after surgery for symptomatic epileptic spasms and improve knowledge on pathophysiology of this seizure type.Inclusion criteria were: (1) age between 6 months and 15 years at surgery; (2) active epileptic spasms; (3) follow-up after surgery >1 year.We retrospectively studied 80 children (aged 1.3 ± 2 years at seizure onset; 5.8 ± 4 years at surgery, 11.7 ± 5.7 years at last follow up). Magnetic resonance imaging (MRI) revealed structural abnormalities in 77/80 patients (96.3%; unilateral in 69: 89.6%). We performed invasive recordings in 24 patients (30%). In 21 patients in whom MRI or histopathology detected a lesion, electrodes exploring it constantly captured initial ictal activity at spasm onset. Fifty-eight patients (72.5%) underwent unilobar and 22 (27.5%) multilobar or hemispheric procedures. At last follow-up, 49 patients (61.3%) were in Engel class I. Multivariate logistic models showed completeness of resection of the seizure onset zone (OR = 0.016, 95%CI: 0.002, 0.122) and of the MRI visible lesion (OR = 0.179, 95% CI: 0.032, 0.999) to be significantly associated with Engel class IA outcome. Unfavorable outcome was associated with an older age at surgery, when it reflected a longer duration of epilepsy (OR = 1.383, 95% CI: 0.994,1.926).Data emerging from invasive recordings and the good seizure outcome following removal of discrete epileptogenic lesions support a focal cortical origin of spasms. In patients with discrete epileptogenic lesions, the pragmatic approach to surgery should follow the same principles applied to focal epilepsy favoring, whenever possible, unilobar, one-stage resections.
| S-EPMC5221449 | biostudies-other
Project description:ObjectiveTo assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms.MethodsWe performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants.ResultsWe identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable.ConclusionsWhile recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.
| S-EPMC4807908 | biostudies-literature
Project description:Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K+/Cl- co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-Daspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed betamethasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.
| S-EPMC6751866 | biostudies-literature
Project description:ObjectiveEpileptic spasms (ES) are associated with pathological neuronal networks, which may underlie characteristic EEG patterns such as hypsarrhythmia. Here we evaluate EEG functional connectivity as a quantitative marker of treatment response, in comparison to classic visual EEG features.MethodsWe retrospectively identified 21 ES patients and 21 healthy controls. EEG data recorded before treatment and after ≥10 days of treatment underwent blinded visual assessment, and functional connectivity was measured using cross-correlation techniques. Short-term treatment response and long-term outcome data were collected.ResultsSubjects with ES had stronger, more stable functional networks than controls. After treatment initiation, all responders (defined by cessation of spasms) exhibited decreases in functional connectivity strength, while an increase in connectivity strength occurred only in non-responders. There were six subjects with unusually strong pre-treatment functional connectivity, and all were responders. Visually assessed EEG features were not predictive of treatment response.ConclusionsChanges in network connectivity and stability correlate to treatment response for ES, and high pre-treatment connectivity may predict favorable short-term treatment response. Quantitative measures outperform visual analysis of the EEG.SignificanceFunctional networks may have value as objective markers of treatment response in ES, with potential to facilitate rapid identification of personalized, effective treatments.
| S-EPMC6193760 | biostudies-literature
Project description:Ictal electrographic changes were analyzed on intracranial electrocorticography (ECoG) in children with medically refractory epileptic spasms to assess the dynamic changes of ictal discharges associated with spasms and their relation to interictal epileptiform activity and neuroimaging findings.We studied a consecutive series of 15 children (age 0.4 to 13 years; nine girls) with clusters of epileptic spasms recorded on prolonged intracranial subdural ECoG recordings, which were being performed for subsequent cortical resection, and in total, 62 spasms were analyzed by using quantitative methods.Spasms were associated with either a "leading" spike followed by fast-wave bursts (type I: 42 events analyzed quantitatively) or fast-wave bursts without a "leading" spike (type II: 20 events analyzed quantitatively). Twenty-three of the 42 type I spasms but none of the 20 type II spasms were preceded by a focal seizure. A "leading" spike had a focal origin in all 42 type I spasms and involved the pre- or postcentral gyrus within 0.1 s in 37 of these spasms. A leading spike was associated with interictal spike activity >1/min in 40 of 42 type I spasms and originated within 2 cm from a positron emission tomography glucose hypometabolic region in all but two type I spasms. Failure to resect the cortex showing a leading spike was associated with poor surgical outcome (p = 0.01; Fisher's exact probability test). Fast-wave bursts associated with spasms involved neocortical regions extensively at least in two lobes within 1.28 s in all 62 spasms and involved the pre- or postcentral gyrus in 53 of 62 spasms.Epileptic spasms may be triggered by a focal neocortical impulse in a subset of patients, and a leading spike, if present, might be used as a marker of the trigger zone for epileptic spasms. Rapidly emerging widespread fast-wave bursts might explain the clinical semiology of epileptic spasms.
| S-EPMC1360692 | biostudies-literature
Project description:CDKL5 deficiency disorder (CDD) is a devastating neurodevelopmental disorder characterized by early-onset epilepsy, severe intellectual disability, cortical visual impairment and motor disabilities. Epilepsy is a central feature of CDD, with most patients having intractable seizures, but seizure frequency and severity can vary. Clinical reports demonstrate a diversity in seizure semiology and electrographic features, with no pattern diagnostic of CDD. Although animal models of CDD have shown evidence of hyperexcitability, spontaneous seizures have not been previously reported. Here, we present the first systematic study of spontaneous seizures in mouse models of CDD. Epileptic spasms, the most frequent and persistent seizure type in CDD patients, were recapitulated in two mouse models of CDD carrying heterozygous mutations, Cdkl5R59X and Cdkl5KO. Spasm-like events were present in a significant proportion of aged heterozygous female mice carrying either of the two Cdkl5 mutations with significant variability in seizure burden. Electrographically, spasms were most frequently associated with generalized slow-wave activity and tended to occur in clusters during sleep. CDD mice also showed interictal and background abnormalities, characterized by high-amplitude spiking and altered power in multiple frequency bands. These data demonstrate that aged female heterozygous Cdkl5 mice recapitulate multiple features of epilepsy in CDD and can serve to complement existing models of epileptic spasms in future mechanistic and translational studies.
| S-EPMC8855336 | biostudies-literature
Project description:We assessed 636 epileptic spasms seen in 11 children (median 44 spasms per child) and determined the spatial and temporal characteristics of ictal high-frequency oscillations (HFOs) in relation to the onset of spasms.Electrocorticography (ECoG) signals were sampled from 104-148 cortical sites per child, and the dynamic changes of ictal HFOs were animated on each individual's three-dimensional (3D) magnetic resonance (MR) image surface.Visual assessment of ictal ECoG recordings revealed that each spasm event was characterized by augmentation of HFOs. Time-frequency analysis demonstrated that ictal augmentation of HFOs at 80-200 Hz was most prominent and generally preceded those at 210-300 Hz and at 70 Hz and slower. Recruitment of HFOs in the rolandic cortex preceded the clinical onset objectively visualized as electromyographic deflection. The presence or absence of ictal motor symptoms was related more to the amplitude of HFOs in the Rolandic cortex than in the seizure-onset zone. In a substantial proportion of epileptic spasms, seizure termination began at the seizure-onset zone and propagated to the surrounding areas; we referred to this observation as the "ictal doughnut phenomenon." Univariate analysis suggested that complete resection of the sites showing the earliest augmentation of ictal HFOs was associated with a good surgical outcome.Recruitment of HFOs at 80-200 Hz in the rolandic area may play a role in determining seizure semiology in epileptic spasms. Our study using macroelectrodes demonstrated that ictal HFOs at 80-200 Hz preceded those at 210-300 Hz.
| S-EPMC3051422 | biostudies-literature