In the surgical management of epilepsy, the resection of cortex exhibiting interictal fast ripples (250-500Hz) on electrocorticography has been linked to postoperative seizure-freedom. Although fast ripples appear to accurately identify the epileptogenic zone-the minimum tissue that must be removed at surgery to achieve seizure-freedom-it has not been established that fast ripples are a superior biomarker in comparison with multimodal presurgical neuroimaging and other electrocorticography abnormalities. Hence, in the prediction of postoperative seizure-freedom, we compared the value of fast ripples with other intraoperative electocorticography abnormalities including focal slowing, paroxysmal fast activity, intermittent spike discharges, continuous epileptiform discharges, focal attenuation, and intraoperative seizures, as well as complete resection of the lesion defined by MRI and other neuroimaging. In a cohort of 60 children with lesional epilepsy and median postsurgical follow-up exceeding 4 years, who underwent resective epilepsy surgery with intraoperative electrocorticography, we evaluated the extent to which removal of each intraoperative electrocorticography abnormality impacts time to first postoperative seizure using the Kaplan-Meier method and Cox proportional hazards regression. Secondly, we contrasted the predictive value of resection of each competing electrocorticography abnormality using standard test metrics (sensitivity, specificity, positive predictive value, and negative predictive value). In contrast with all other intraoperative electrocorticography abnormalities, fast ripples demonstrated the most favorable combination of positive predictive value (100%) and negative predictive value (76%) in the prediction of postoperative seizures. Among all candidate electrocorticography features, time to first postoperative seizure was most strongly associated with incomplete resection of fast ripples (hazard ratio=19.8, p<0.001). In multivariate survival analyses, postoperative seizures were independently predicted by incomplete resection of cortex generating fast ripples (hazard ratio=25.4, 95%CI 6.71-96.0, p<0.001) and focal slowing (hazard ratio=5.79, 95%CI 1.76-19.0, p=0.004), even after adjustment for the impact of an otherwise complete resection. All children with incomplete resection of interictal FR-generating cortex exhibited postoperative seizures within six months. Notably, this cohort included many patients with large resections and thus limited opportunity to exhibit unresected fast ripples. Future study in a cohort with small resection volume, or a clinical trial in which resection margins are guided by fast ripple distribution, would likely yield a more precise estimate of the risk posed by unresected fast ripples. With a high detection rate during brief intraoperative electrocorticography and favorable positive and negative predictive value, interictal fast ripple characterization during surgery is a feasible and useful adjunct to standard methods for epilepsy surgery planning, and represents a valuable spatially-localizing biomarker of the epileptogenic zone, without the need for prolonged extraoperative electrocorticography.

High-frequency oscillations (HFOs), including ripples (Rs) and fast ripples (FRs), are promising biomarkers of epileptogenesis, but their clinical utility is limited by the lack of a standardized approach to identification. We set out to determine whether electroencephalographers experienced in HFO analysis can reliably identify and quantify interictal HFOs. Two blinded raters independently reviewed 10 intraoperative electrocorticography (ECoG) samples from epilepsy surgery cases, and 10 scalp EEG samples from epilepsy monitoring unit evaluations. HFOs were visually marked using bandpass filters (R, 80-250 Hz; FR, 250-500 Hz) with a sampling frequency of 2,000 Hz. There was agreement as to the presence or absence of epileptiform discharges (EDs), Rs, and FRs, in 17, 18, and 18 cases, respectively. Interrater reliability (IRR) was favorable with κ = 0.70, 0.80, and 0.80, respectively, and similar for ECoG and scalp electroencephalography (EEG). Furthermore, interclass correlation for rates of Rs (0.99, 95% confidence interval [CI] 0.96-0.99) and FRs (0.77, 95% CI 0.41-0.91) were superior in comparison to EDs (0.37, 95% CI -0.60 to 0.75). Our data suggest that HFO identification and quantification are reliable among experienced electroencephalographers. Our findings support the reliability of utilizing HFO data in both research and clinical arenas.

Tuberous sclerosis complex is an autosomal dominant genetic disorder that confers a high risk for neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability. Studies have demonstrated specific delays in visual reception skills that may predict the development of autism spectrum disorder and intellectual disability. Based on evidence for alterations in the retinogeniculate pathway in animal models of tuberous sclerosis complex, we asked whether children with tuberous sclerosis complex demonstrate alterations in early visual processing that may undermine the development of higher-level visual behaviors. Pattern-reversal visual evoked potentials were recorded in infants with tuberous sclerosis complex (n = 16) and typically developing infants (n = 18) at 12 months of age. Infants with tuberous sclerosis complex demonstrated remarkably intact visual evoked potentials even within the context of intellectual disability and epilepsy. Infants with tuberous sclerosis complex show intact visual cortical processing, suggesting that delays in visually mediated behaviors in tuberous sclerosis complex may not be rooted in early visual processing deficits.

Objective

Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena.

Methods

Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure.

Results

We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039).

Significance

We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Purpose

This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms.

Methods

Twenty-seven children with video electroencephalography (EEG)-confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered over 2 weeks and nonresponders were immediately transitioned to high dose (150 IU/m(2)/day) intramuscular adrenocorticotropic hormone (ACTH) for two additional weeks. Response was again determined by overnight video-EEG after ACTH therapy.

Key findings

Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone nonresponders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range [IQR] 4.8-25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response.

Significance

Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic syndrome that confers significantly increased risk for autism spectrum disorder (ASD), with 50-60% of infants with TSC meeting criteria for ASD by 3 years of age. In a previous study of the current longitudinal cohort, we found that infants with TSC who develop ASD (TSC/ASD) evidence decreased cognitive abilities that diverge from infants with TSC and no ASD (TSC/no ASD). We extended this work by asking whether TSC/ASD infants (n = 13) differed from TSC/no ASD infants (n = 10) and infants with low developmental risk and no ASD (LR; n = 21) in their social communication functioning during the first year of life. We measured early ASD symptoms with the Autism Observation Scale for Infants (AOSI) at 9 and 12 months of age. At both ages, infants in the TSC/ASD group had significantly higher AOSI total scores than infants in the TSC/no ASD and LR groups, which were not fully explained by differences in cognitive abilities. Several items on the AOSI at both ages were predictive of ASD outcome, particularly those representing core social communication deficits (e.g., social referencing). Our findings signal the need for further study of this population within the first year and provide strong justification for early identification and early intervention targeting social communication skills in infants with TSC. Autism Res 2017, 10: 1981-1990. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay summary

We examined early signs of autism spectrum disorder (ASD) in infants with tuberous sclerosis complex (TSC), approximately 50% of whom will meet criteria for ASD by age 3. Infants with TSC and ASD showed deficits in social communication behaviors by 9 months of age that were clearly distinguishable from behaviors in infants with TSC who do not develop ASD and low risk infants. Results support the importance of early ASD screening and intervention for infants with TSC.

Objective

To evaluate whether diffusion tensor imaging (DTI) can predict epileptogenic tubers by measuring apparent diffusion coefficient (ADC), fractional anisotropy, axial diffusivity, and radial diffusivity in both tubers and perituberal tissue in pediatric patients with tuberous sclerosis complex (TSC) undergoing epilepsy surgery.

Methods

We retrospectively selected 23 consecutive patients (aged 0.4-19.6 years, mean age of 5.2; 13 female, 10 male) who underwent presurgical DTI and subsequent surgical resection between 2004 and 2013 from the University of California-Los Angeles TSC Clinic. We evaluated presurgical examinations including video-EEG, brain MRI, (18)F-fluorodeoxyglucose-PET, magnetic source imaging, and intraoperative electrocorticography for determining epileptogenic tubers. A total of 545 tubers, 33 epileptogenic and 512 nonepileptogenic, were identified. Two observers generated the regions of interest (ROIs) of tubers (ROI(tuber)), the 4-mm-thick ring-shaped ROIs surrounding the tubers (ROI(perituber)), and the combined ROIs (ROI(tuber+perituber)) in consensus and calculated maximum, minimum, mean, and median values of each DTI measure in each ROI for all tubers.

Results

The Mann-Whitney U test demonstrated that the epileptogenic group showed higher maximum ADC and radial diffusivity values in all ROIs, and that maximum ADC in ROI(tuber+perituber) showed the strongest difference (p = 0.001). Receiver operating characteristic analysis demonstrated that maximum ADC measurements in ROI(tuber+perituber) (area under curve = 0.68 ± 0.05, p < 0.001) had 81% sensitivity and 44% specificity for correctly identifying epileptogenic tubers with a cutoff value of 1.32 μm(2)/ms.

Conclusions

DTI analysis of tubers and perituberal tissue may help to identify epileptogenic tubers in presurgical patients with TSC more easily and effectively than current invasive methods.

Objective

To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial.

Methods

We hypothesized that a seizure-free outcome could be expected in patients in whom the surgical planning included the majority of HFO-generating brain tissue while a poor seizure outcome could be expected in patients in whom only a few such areas were planned to be resected. Fifty-two patients were included from 3 tertiary epilepsy centers during a 1-year period. Ripples (80-250 Hz) and fast ripples (250-500 Hz) were automatically detected during slow-wave sleep with chronic intracranial EEG in 2 centers and acute intraoperative electrocorticography in 1 patient.

Results

There was a correlation between the removal of HFO-generating regions and seizure-free outcome at the group level for all patients. No correlation was found, however, for the center-specific analysis, and an individual prognostication of seizure outcome was true in only 36 patients (67%). Moreover, some patients became seizure-free without removal of the majority of HFO-generating tissue. The investigation of influencing factors, including comparisons of visual and automatic analysis, using a threshold analysis for areas with high HFO activity, and excluding contacts bordering the resection, did not result in improved prognostication.

Conclusions

On an individual patient level, a prediction of outcome was not possible in all patients. This may be due to the analysis techniques used. Alternatively, HFOs may be less specific for epileptic tissue than earlier studies have indicated.

Objective

To determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC.

Methods

Measures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests.

Results

Children with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC.

Conclusions

This study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.