Epileptogenic modulation index and synchronization in hypsarrhythmia of West syndrome secondary to perinatal arterial ischemic stroke.

OBJECTIVE: Perinatal arterial ischemic stroke (PAIS) is associated with epileptic spasms of West syndrome (WS) and long term Focal epilepsy (FE). The mechanism of epileptogenic network generation causing hypsarrhythmia of WS is unknown. We hypothesized that Modulation index (MI) [strength of phase-amplitude coupling] and Synchronization likelihood (SL) [degree of connectivity] could interrogate the epileptogenic network in hypsarrhythmia of WS secondary to PAIS. METHODS: We analyzed interictal scalp electroencephalography (EEG) in 10 WS and 11 FE patients with unilateral PAIS. MI between gamma (30-70 Hz) and slow waves (3-4 Hz) was calculated to measure phase-amplitude coupling. SL between electrode pairs was analyzed in 9-frequency bands (5-delta, theta, alpha, beta, gamma) to examine inter- and intra-hemispheric connectivity. RESULTS: MI was higher in affected hemispheres in WS (p = 0.006); no differences observed in FE. Inter-hemispheric SL of 3-delta, theta, alpha, beta, gamma bands was significantly higher in WS (p < 0.001). In WS, modified Z-Score of intra-hemispheric SL values in 3-delta, theta, alpha, beta and gamma in the affected hemispheres were significantly higher than those in the unaffected hemispheres (p < 0.001) as well as 0.5-4 Hz (p = 0.004). CONCLUSIONS: The significantly higher modulation in affected hemisphere and stronger inter- and intra-hemispheric connectivity generate hypsarrhythmia of WS secondary to PAIS. SIGNIFICANCE: Epileptogenic cortical-subcortical transcallosal networks from affected hemisphere post-PAIS provokes infantile spasms.

Reliability and safety of Etomidate speech test in children with drug resistant focal epilepsy.

PURPOSE: To review our experience with the Etomidate speech test (EST) for lateralizing language in children undergoing epilepsy surgery evaluation METHODS: This retrospective study included children (<18 years) with drug refractory focal epilepsy undergoing EST for bilateral or poorly reliable language representation on functional MRI. Data for consecutive children who underwent EST between January 2013 to June 2017 were reviewed. RESULTS: Twenty-one children (mean age at EST, 13.1 ±â€¯4.4 years) were studied, with 19-right hemispheric and 20 left hemispheric injections. Six patients had neurological co-morbidities. Duration of ipsilateral EEG slowing was sufficient for speech testing in all children with a single bolus of Etomidate per carotid artery. Language was lateralized to one hemisphere in 17 (80.9%) and bilateral in two cases. EST was unsuccessful in two patients because of diffuse EEG slowing. Contralateral transient frontal EEG slowing was seen in 14 (73.7%) cases. EST was well tolerated in all the patients. CONCLUSIONS: The EST was found to be successful and safe in lateralizing language in most of our drug refractory pediatric epilepsy cohort.

Advanced dynamic statistical parametric mapping with MEG in localizing epileptogenicity of the bottom of sulcus dysplasia.

OBJECTIVE: To investigate whether advanced dynamic statistical parametric mapping (AdSPM) using magnetoencephalography (MEG) can better localize focal cortical dysplasia at bottom of sulcus (FCDB). METHODS: We analyzed 15 children with diagnosis of FCDB in surgical specimen and 3 T MRI by using MEG. Using AdSPM, we analyzed a ±50 ms epoch relative to each single moving dipole (SMD) and applied summation technique to estimate the source activity. The most active area in AdSPM was defined as the location of AdSPM spike source. We compared spatial congruence between MRI-visible FCDB and (1) dipole cluster in SMD method; and (2) AdSPM spike source. RESULTS: AdSPM localized FCDB in 12 (80%) of 15 children whereas dipole cluster localized six (40%). AdSPM spike source was concordant within seizure onset zone in nine (82%) of 11 children with intracranial video EEG. Eleven children with resective surgery achieved seizure freedom with follow-up period of 1.9 ±â€¯1.5 years. Ten (91%) of them had an AdSPM spike source in the resection area. CONCLUSION: AdSPM can noninvasively and neurophysiologically localize epileptogenic FCDB, whether it overlaps with the dipole cluster or not. SIGNIFICANCE: This is the first study to localize epileptogenic FCDB using MEG.

Utility of additional dedicated high-resolution 3T MRI in children with medically refractory focal epilepsy.

PURPOSE: In patients with medically refractory epilepsy and normal magnetic resonance imaging (MRI), high-resolution dedicated MRI may identify cryptic lesions. The aim of this study was to assess improvement in lesion detection and its impact on clinical management, using additional high-resolution dedicated 3T MRI in children with medically refractory epilepsy who had normal 3T epilepsy protocol MRI. MATERIALS AND METHODS: Children who had resective epilepsy surgery and suspected focal cortical dysplasia (FCD) or normal 3T epilepsy protocol MRI were included. Those with other diagnosis on MRI including tumor and hippocampal sclerosis were excluded. Patients who had normal MRI on 3T epilepsy protocol underwent dedicated high-resolution 3T MRI through the epileptogenic zone, guided by video EEG, Magnetoencephalography and FDG-PET data. RESULTS: 101 patients with at least 1 year follow-up were included. Twenty-nine of 44 (66%) patients who had normal epilepsy protocol MRI had a lesion identified on dedicated high-resolution MRI. The addition of dedicated high-resolution MRI to standard epilepsy protocol increased sensitivity from 53.1% (95%CI: 40%-66%) to 85.9% (95%CI: 75%-93%). Identified lesions were concordant to surgical resection in all patients and guided depth/strip electrode insertion in 20/25 (80%) patients who underwent staged resection. Dedicated MRI detected small deep seated lesions in 10/20 (50%), and guided depth electrodes placement, without which it would not be feasible, as the lobar location of epileptogenic zone from other non-invasive tests were not sufficiently precise. CONCLUSION: Patients with non-lesional epilepsy on standard epilepsy protocol MR may benefit from high-resolution dedicated MRI to aid identification of an underlying lesion, which could impact surgical management and improve seizure control.

Epilepsy: Transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.

The transition from a pediatric to adult health care system is challenging for many youths with epilepsy and their families. Recently, the Ministry of Health and Long-Term Care of the Province of Ontario, Canada, created a transition working group (TWG) to develop recommendations for the transition process for patients with epilepsy in the Province of Ontario. Herein we present an executive summary of this work. The TWG was composed of a multidisciplinary group of pediatric and adult epileptologists, psychiatrists, and family doctors from academia and from the community; neurologists from the community; nurses and social workers from pediatric and adult epilepsy programs; adolescent medicine physician specialists; a team of physicians, nurses, and social workers dedicated to patients with complex care needs; a lawyer; an occupational therapist; representatives from community epilepsy agencies; patients with epilepsy; parents of patients with epilepsy and severe intellectual disability; and project managers. Three main areas were addressed: (1) Diagnosis and Management of Seizures; 2) Mental Health and Psychosocial Needs; and 3) Financial, Community, and Legal Supports. Although there are no systematic studies on the outcomes of transition programs, the impressions of the TWG are as follows. Teenagers at risk of poor transition should be identified early. The care coordination between pediatric and adult neurologists and other specialists should begin before the actual transfer. The transition period is the ideal time to rethink the diagnosis and repeat diagnostic testing where indicated (particularly genetic testing, which now can uncover more etiologies than when patients were initially evaluated many years ago). Some screening tests should be repeated after the move to the adult system. The seven steps proposed herein may facilitate transition, thereby promoting uninterrupted and adequate care for youth with epilepsy leaving the pediatric system.

Utility of diffusion tensor imaging studies linked to neuronavigation and other modalities in repeat hemispherotomy for intractable epilepsy.

OBJECT Hemispherectomy for unilateral, medically refractory epilepsy is associated with excellent long-term seizure control. However, for patients with recurrent seizures following disconnection, workup and investigation can be challenging, and surgical options may be limited. Few studies have examined the role of repeat hemispherotomy in these patients. The authors hypothesized that residual fiber connections between the hemispheres could be the underlying cause of recurrent epilepsy in these patients. Diffusion tensor imaging (DTI) was used to test this hypothesis, and to target residual connections at reoperation using neuronavigation. METHODS The authors identified 8 patients with recurrent seizures following hemispherectomy who underwent surgery between 1995 and 2012. Prolonged video electroencephalography recordings documented persistent seizures arising from the affected hemisphere. In all patients, DTI demonstrated residual white matter association fibers connecting the hemispheres. A repeat craniotomy and neuronavigation-guided targeted disconnection of these residual fibers was performed. Engel class was used to determine outcome after surgery at a minimum of 2 years of follow-up. RESULTS Two patients underwent initial hemidecortication and 6 had periinsular hemispherotomy as their first procedures at a median age of 9.7 months. Initial pathologies included hemimegalencephaly (n = 4), multilobar cortical dysplasia (n = 3), and Rasmussen's encephalitis (n = 1). The mean duration of seizure freedom for the group after the initial procedure was 32.5 months (range 6-77 months). In all patients, DTI showed limited but definite residual connections between the 2 hemispheres, primarily across the rostrum/genu of the corpus callosum. The median age at reoperation was 6.8 years (range 1.3-14 years). The average time taken for reoperation was 3 hours (range 1.8-4.3 hours), with a mean blood loss of 150 ml (range 50-250 ml). One patient required a blood transfusion. Five patients are seizure free, and the remaining 3 patients are Engel Class II, with a minimum follow-up of 24 months for the group. CONCLUSIONS Repeat hemispherotomy is an option for consideration in patients with recurrent intractable epilepsy following failed surgery for catastrophic epilepsy. In conjunction with other modalities to establish seizure onset zones, advanced MRI and DTI sequences may be of value in identifying patients with residual connectivity between the affected and unaffected hemispheres. Targeted disconnection of these residual areas of connectivity using neuronavigation may result in improved seizure outcomes, with minimal and acceptable morbidity.

Changing global trends in seizure outcomes following resective surgery for tuberous sclerosis in children with medically intractable epilepsy.

Introduction. Tuberous sclerosis (TS) is the leading cause of genetic epilepsy worldwide. Here, we evaluate changes in seizure outcomes following resective epilepsy surgery in children with TS over time. Methods. A systematic review of the literature was performed to identify studies reporting seizure outcomes following resective epilepsy surgery in children with TS. Using an individual participant meta-analysis approach, seizure outcomes and associated covariates were combined. Multivariate logistic regression was used to determine significant associations between seizure outcomes and time of surgery. Results. Twenty studies from 1966 to present, yielding 186 participants, met the inclusion criteria for the study. On univariate analysis, there was a significant improvement in seizure outcomes in children who underwent resective epilepsy surgery within the last 15 years compared to older cohorts (chi-square 4.1; P = 0.043). On multivariate analysis, adjusting for length of followup, this trend was not significant (OR 0.52; 95% CI 0.23-1.17; P = 0.11). In the last 15 years, a greater proportion of younger children also underwent resective surgery compared to older cohorts (OR 0.93; 95% CI 0.89-0.97; P < 0.01). Conclusions. A trend towards improved seizure outcomes following resective surgery for TS was observed from 1966 to present on multivariate analysis.

Jeavons syndrome existing as occipital cortex initiating generalized epilepsy.

PURPOSE: Jeavons syndrome (JS) is one of the underreported epileptic syndromes characterized by eyelid myoclonia (EM), eye closure-induced seizures/electroencephalography (EEG) paroxysms, and photosensitivity. JS has been proposed as idiopathic generalized epilepsy (IGE) because of normal posterior dominant background activity and paroxysmal generalized ictal epileptiform discharges (EDs). However, we noticed subtle occipital EDs preceding EM and interictal posterior EDs using digital video-EEG. We studied clinical and EEG findings in JS to determine the specific occipital lobe relation to this "eye closure-induced" reflex IGE. METHODS: We identified 12 children who met the diagnostic criteria of JS from January 2004 to April 2009 at the Hospital for Sick Children, Toronto, Canada. All patients had EM captured by video-EEG. We reviewed and described ictal EEG patterns, interictal abnormalities, and demographics, clinical, and neuroimaging findings. KEY FINDINGS: All patients but one were female (92%). Age at seizure onset ranged from 1.5 to 9 years, with a mean age of 4.9 years. Six patients (50%) were previously diagnosed as having absence epilepsy and 10 patients were on antiepileptic medications. All 12 patients had normal posterior dominant alpha rhythm, reactive to eye opening and closure. Spiky posterior alpha activity was noted with sustained eye closure in six patients (50%). Interictally, there were generalized EDs found in 10 patients (83%); four of them also had focal interictal EDs over the posterior head region. Eleven patients (92%) had evidence of focal posterior ictal EDs. EM and/or paroxysmal EDs were induced by photic stimulation in 9 (75%) and hyperventilation in 7 (58%). SIGNIFICANCE: We observed two neurophysiologic findings in JS: (1) focal interictal EDs from posterior head region; and (2) predominant focal posterior ictal EDs preceding generalized EDs. Further clinical observations of seizures induced by eye closure, photic stimulation, and hyperventilation along with EEG paroxysms would raise the possibility of the occipital cortex initiating generalized epilepsy network involving the brainstem, and thalamocortical and transcortical pathways in JS.

Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men.

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS-742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS-742, form the framework for human trials.

Somatosensory-evoked fields on magnetoencephalography for epilepsy infants younger than 4 years with total intravenous anesthesia.

OBJECTIVE: Patients must remain immobile for magnetoencephalography (MEG) and MRI recordings to allow precise localization of brain function for pre-surgical functional mapping. In young children with epilepsy, this is accomplished with recordings during sleep or with anesthesia. This paper demonstrates that MEG can detect, characterize and localize somatosensory-evoked fields (SEF) in infants younger than 4 years of age with or without total intravenous anesthesia (TIVA). METHODS: We investigated the latency, amplitude, residual error (RE) and location of the N20m of the SEF in 26 infants (mean age=2.6 years). Seventeen patients underwent TIVA and 9 patients were tested while asleep, without TIVA. RESULTS: MEG detected 44 reliable SEFs (77%) in 52 median nerve stimulations. We found 27 reliable SEFs (79%) with TIVA and 13 reliable SEFs (72%) without TIVA. TIVA effects included longer latencies (p<0.001) and lower RE (p<0.05) compared to those without TIVA. Older patients and larger head circumferences also showed significantly shorter latencies (p<0.01). CONCLUSIONS: TIVA resulted in reliable SEFs with lower RE and longer latencies. SIGNIFICANCE: MEG can detect reliable SEFs in infants younger than 4 years old. When infants require TIVA for MEG and MRI acquisition, SEFs can still be reliably observed.

Spatiotemporal patterns of oscillatory brain activity during auditory word recognition in children: a synthetic aperture magnetometry study.

OBJECTIVE: We studied the task-induced spatiotemporal evolution and characteristics of cortical neural oscillations in children during an auditory word recognition task. METHODS: We presented abstract nouns binaurally and recorded the MEG response in eight healthy right-handed children (6-12 years). We calculated the event-related changes in cortical oscillations using a beamformer spatial filter analysis technique (SAM), then transformed each subject's statistical maps into standard space and used these to make group statistical inferences. RESULTS: Across subjects, the cortical response to words could be divided into at least two phases: an initial event-related synchronization in both the right temporal (100-300 ms, 15-25 Hz; 200-400 ms, 5-15 Hz) and left frontal regions (200-400 ms; 15-25 Hz); followed by a strong left-lateralized event-related desynchronization in the left temporal region (500-700 ms; 5-15 Hz). CONCLUSIONS: We found bilateral event-related synchronization followed by later left lateralized event-related desynchronization in language-related cortical areas. These data demonstrate the spatiotemporal time course of neural activation during an auditory word recognition task in a group of children. As well, this demonstrates the utility of SAM analyses to detect subtle sequential task-related neural activations.

Transgenic mice over-expressing GABA(B)R1a receptors acquire an atypical absence epilepsy-like phenotype.

In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABA(B)R1a receptor subtype in the etiology of atypical absence epilepsy.

Nonconvulsive seizures in the pediatric intensive care unit: etiology, EEG, and brain imaging findings.

PURPOSES: To determine the occurrence of nonconvulsive seizures (NCS) in the Pediatric Intensive Care Unit (PICU); to ascertain the relationship of NCS to past medical history, etiology, EEG, and brain imaging; and to determine the concordance between abnormal EEG findings and neuroimaging abnormalities. METHODS: A retrospective review was conducted of all pediatric patients who were admitted or transferred to the PICU from January 2000 to December 2003 with an unexplained decrease in level of consciousness, no overt clinical seizures, and EEG recordings performed within the 24 h of onset of an altered state of consciousness. RESULTS: Twenty-three of 141 patients who met criteria for inclusion in the study (16.3%) were found to have NCS. The male to female ratio was 1.9:1. The largest group of patients (43%) had no preexisting neurological condition prior to the onset of NCS. In the remainder, the etiology of NCS included: acute structural brain lesion (48%), acute nonstructural brain lesion (22%), epilepsy-related seizure (13%), and others (17%). Epileptic foci were lateralized to the right side in 39.2%, the left side in 30.4%, and were bilateral in 30.4%. Of 23 patients with NCS, 18 (78.3%) demonstrated abnormal neuroimaging. In 10 of 18 of these patients (55.6%), the findings on neuroimaging were concordant with the lateralization found on EEG (p < 0.05, Fisher's exact test). CONCLUSIONS: NCS are not uncommon in pediatric patients with an altered state of consciousness. Almost half of the patients were previously healthy especially if they were under 6 months of age. This report highlights the importance of clinical awareness of NCS in the PICU.

Focal cortical high-frequency oscillations trigger epileptic spasms: confirmation by digital video subdural EEG.

OBJECTIVE: To localize high-frequency oscillations (HFOs) on the cortex during epileptic spasms using video subdural EEG and Multiple Band Frequency Analysis (MBFA). METHODS: Using video subdural EEG sampled at 1 kHz, we studied a 14-year-old boy with asymmetric epileptic spasms of possible left frontal origin. We identified HFOs, then analyzed and localized their distributions by MBFA. We correlated HFO distribution to clinical spasm intensity. RESULTS: Ictal subdural EEG recorded HFOs at 60-150 Hz lasting 0.3-4 s. MBFA showed extensive but noncontiguous distribution of HFOs predominantly over the left frontal and temporal regions. HFOs began and became quasiperiodic before manifestation of clinical spasms. As clinical spasms intensified, HFOs persisted in regions where they initiated subclinically but were of higher frequency and greater power than HFOs in other regions. We performed cortical resections over the left frontal and temporal regions with predominant HFOs. Six months after surgery, the patient remained seizure free. CONCLUSIONS: HFOs were present over the ictal onset zone during epileptic spasms. Periodic spasms in this patient had the characteristics of partial seizures. SIGNIFICANCE: We show that HFOs occurred over the cerebral cortex during epileptic spasms, and we suggest that these focal cortical HFOs triggered the spasms.

Gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence.

gamma-Hydroxybutyric Acid (GHB) is thought to be a weak partial agonist at the gamma-aminobutyric acid(B) Receptor (GABA(B)R), but the precise relationship of the GHB receptor (GHBR) to the GABA(B)R remains unclear. In order to test the hypothesis that the GHBR is not identical to the GABA(B)R, we conducted two groups of experiments. First, GABA(B)R subtype 1 (R1) and/or subtype 2 (R2) were over expressed in HEK 293 cells and membrane binding studies on the transfected cells done using [(3)H]GHB and [(3)H] (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid ([(3)H]NCS-382). The latter is a specific antagonist at the GHB binding site. Second, [(3)H]GHB and [(3)H]NCS-382 autoradiographic binding studies were done on the brains of mice in which the gene for GABA(B)R1a was deleted. Such mice do not have a functioning GABA(B)R. There was no detectable specific [(3)H]GHB or [(3)H]NCS-382 binding in HEK 293 cells transfected with GABA(B)R1, R2, or R1/R2. Binding to [(3)H]CGP54626A, a high affinity GABA(B)R antagonist, was absent in GABA(B)R1a(-/-) mice. There was no difference in [(3)H]NCS-382 binding observed in the brains of GABA(B)R1a(-/-), GABA(B)R1a(+/-) or GABA(B)R1a(+/+) mice. Specific [(3)H]GHB binding was observed in the brain of GABA(B)R1a(-/-) mice but was significantly lower than in wild type mice. These data support the hypothesis that the GHB binding site is separate and distinct from the GABA(B)R.