Association of Early MRI Characteristics With Subsequent Epilepsy and Neurodevelopmental Outcomes in Children With Tuberous Sclerosis Complex.

BACKGROUND AND OBJECTIVES: Multiple factors have been found to contribute to the high risk of epilepsy in infants with tuberous sclerosis complex (TSC), including evolution of EEG abnormalities, TSC gene variant, and MRI characteristics. The aim of this prospective multicenter study was to identify early MRI biomarkers of epilepsy in infants with TSC aged <6 months and before seizure onset, and associate these MRI biomarkers with neurodevelopmental outcomes at 2 years of age. The study was part of the EPISTOP project. METHODS: We evaluated brain MRIs performed in infants younger than 6 months with TSC. We used harmonized MRI protocols across centers and children were monitored closely with neuropsychological evaluation and serial video EEG. MRI characteristics, defined as tubers, radial migration lines, white matter abnormalities, cysts, calcifications, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA), were visually evaluated and lesions were detected semiautomatically. Lesion to brain volume ratios were calculated and associated with epilepsy and neurodevelopmental outcomes at 2 years. RESULTS: Lesions were assessed on MRIs from 77 infants with TSC; 62 MRIs were sufficient for volume analysis. The presence of tubers and higher tuber-brain ratios were associated with the development of clinical seizures, independently of TSC gene variation and preventive treatment. Furthermore, higher tuber-brain ratios were associated with lower cognitive and motor development quotients at 2 years, independently of TSC gene variation and presence of epilepsy. DISCUSSION: In infants with TSC, there is a significant association between characteristic TSC lesions detected on early brain MRI and development of clinical seizures, as well as neurodevelopmental outcomes in the first 2 years of life. According to our results, early brain MRI findings may guide clinical care for young children with TSC. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in infants with TSC, there is a significant association between characteristic TSC lesions on early brain MRI and the development of clinical seizures and neurodevelopmental outcomes in the first 2 years of life.

May intraoperative detection of stereotactically inserted intracerebral electrodes increase precision of resective epilepsy surgery?

OBJECT: Epilepsy surgery is an effective treatment for selected patients with focal intractable epilepsy. Complete removal of the epileptogenic zone significantly increases the chances for postoperative seizure-freedom. In complex surgical candidates, delineation of the epileptogenic zone requires a long-term invasive video/EEG from intracranial electrodes. It is especially challenging to achieve a complete resection in deep brain structures such as opercular-insular cortex. We report a novel approach utilizing intraoperative visual detection of stereotactically implanted depth electrodes to inform and guide the extent of surgical resection. METHODS: We retrospectively reviewed data of pediatric patients operated in Motol Epilepsy Center between October 2010 and June 2020 who underwent resections guided by intraoperative visual detection of depth electrodes following SEEG. The outcome in terms of seizure- and AED-freedom was assessed individually in each patient. RESULTS: Nineteen patients (age at surgery 2.9-18.6 years, median 13 years) were included in the study. The epileptogenic zone involved opercular-insular cortex in eighteen patients. The intraoperative detection of the electrodes was successful in seventeen patients and the surgery was regarded complete in sixteen. Thirteen patients were seizure-free at final follow-up including six drug-free cases. The successful intraoperative detection of the electrodes was associated with favorable outcome in terms of achieving complete resection and seizure-freedom in most cases. On the contrary, the patients in whom the procedure failed had poor postsurgical outcome. CONCLUSION: The reported technique helps to achieve the complete resection in challenging patients with the epileptogenic zone in deep brain structures.

The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) present with drug-resistant epilepsy in about 60% of cases, and evaluation for epilepsy surgery may be warranted. Correct delineation of the epileptogenic zone (EZ) among multiple dysplastic lesions on MRI represents a challenging step in pre-surgical evaluation. METHODS: Two experienced neuroradiologists evaluated pre- and post-surgical MRIs of 28 epilepsy surgery patients with TSC, assessing characteristics of tubers, cysts, calcifications, and focal cortical dysplasia (FCD)-resembling lesions. Utilizing multiple metrics, we compared MRI features of the EZ-defined as the resected area in TSC patients who achieved seizure-freedom 2 years after epilepsy surgery-with features of other brain areas. Using combinatorial analysis, we identified combinations of dysplastic features that are most frequently observed in the epileptogenic zone in TSC patients. RESULTS: All TSC-associated dysplastic features were more frequently observed in the EZ than in other brain areas (increased cortical thickness, gray-white matter blurring, transmantle sign, calcifications, and tubers; Kendal's tau 0.35, 0.25, 0.27, 0.26, and 0.23, respectively; P value <.001 in all). No single feature could reliably and independently indicate the EZ in all patients. Conversely, the EZ was indicated by the presence of the combination of three of the following features: tubers, transmantle sign, increased cortical thickness, calcifications, and the largest FCD-affected area. Out of these, the largest FCD-affected area emerged as the most reliable indicator of the EZ, combined either with calcifications or tubers. SIGNIFICANCE: The epileptogenic zone in TSC patients harbors multiple dysplastic features, consistent with focal cortical dysplasia. A specific combination of these features can indicate the EZ and aid in pre-surgical MRI evaluation in epilepsy surgery candidates with TSC.

Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes.

OBJECTIVE: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). METHODS: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy - Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). RESULTS: Eighty-three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value <.001). SIGNIFICANCE: Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.

Fetal Brain Magnetic Resonance Imaging Findings Predict Neurodevelopment in Children with Tuberous Sclerosis Complex.

OBJECTIVE: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling. STUDY DESIGN: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores. RESULTS: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics. CONCLUSIONS: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC.

GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?

BACKGROUND: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. METHODS: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. RESULTS: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. CONCLUSION: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial.

OBJECTIVE: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants. METHODS: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure. RESULTS: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted. INTERPRETATION: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial (recorded at a median gestational age 42 4/7 weeks) was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients (Bayley Scales of Infant and Toddler Development III) at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1, p-value = 0.027) and more specifically a dysmature EEG background (OR = 4.6, p-value = 0.017) was associated with a higher probability of ASD traits at the age of 24 months. This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment (adjusted OR = 4.2, p-value = 0.029). A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.

The clinical utility of intraoperative electrocorticography in pediatric epilepsy surgical strategy and planning.

OBJECTIVE: In this study, the authors aimed to determine 1) whether the use of intraoperative electrocorticography (ECoG) affects outcomes and complication rates of children undergoing resective epilepsy surgery; 2) which patient- and epilepsy-related variables might influence ECoG-based surgical strategy; and 3) what the predictors of epilepsy surgery outcomes are. METHODS: Over a period of 12 years, data were collected on pediatric patients who underwent tailored brain resections in the Motol Epilepsy Center. In patients in whom an abnormal ECoG pattern (e.g., spiking, suppression burst, or recruiting rhythm) was not observed beyond presurgically planned resection margins, the authors did not modify the surgical plan (group A). In those with significant abnormal ECoG findings beyond resection margins, the authors either did (group B) or did not (group C) modify the surgical plan, depending on the proximity of the eloquent cortex or potential extent of resection. Using Fisher's exact test and the chi-square test, the 3 groups were compared in relation to epilepsy surgery outcomes and complication rate. Next, multivariate models were constructed to identify variables associated with each of the groups and with epilepsy surgery outcomes. RESULTS: Patients in group C achieved significantly lower rates of seizure freedom compared to groups A (OR 30.3, p < 0.001) and B (OR 35.2, p < 0.001); groups A and B did not significantly differ (p = 0.78). Patients in whom the surgical plan was modified suffered from more frequent complications (B vs A+C, OR 3.8, p = 0.01), but these were mostly minor (duration < 3 months; B vs A+C, p = 0.008). In all cases, tissue samples from extended resections were positive for the presence of the original pathology. Patients with intended modification of the surgical plan (groups B+C) suffered more often from daily seizures, had a higher age at first seizure, had intellectual disability, and were regarded as MR-negative (p < 0.001). Unfavorable surgical outcome (Engel class II-IV) was associated with focal cortical dysplasia, incomplete resection based on MRI and/or ECoG findings, negative MRI finding, and inability to modify the surgical plan when indicated. CONCLUSIONS: Intraoperative ECoG serves as a reliable tool to guide resection and may inform the prognosis for seizure freedom in pediatric patients undergoing epilepsy surgery. ECoG-based modification of the surgical plan is associated with a higher rate of minor complications. Children in whom ECoG-based modification of the surgical plan is indicated but not feasible achieve significantly worse surgical outcomes.

Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration.

BACKGROUND: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. MATERIAL AND METHODS: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. RESULTS: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. CONCLUSION: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.

PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

A novel effective paradigm of intraoperative electrical stimulation mapping in children.

OBJECTIVE: Resective epilepsy surgery is an established treatment method for children with focal intractable epilepsy, but the use of this method introduces the risk of postsurgical motor deficits. Electrical stimulation mapping (ESM), used to define motor areas and pathways, frequently fails in children. The authors developed and tested a novel ESM protocol in children of all age categories. METHODS: The ESM protocol utilizes high-frequency electric cortical stimulation combined with continuous intraoperative motor-evoked potential (MEP) monitoring. The relationships between stimulation current intensity and selected presurgical and surgery-associated variables were analyzed in 66 children (aged 7 months to 18 years) undergoing 70 resective epilepsy surgeries in proximity to the motor cortex or corticospinal tracts. RESULTS: ESM elicited MEP responses in all children. Stimulation current intensity was associated with patient age at surgery and date of surgery (F value = 6.81, p < 0.001). Increase in stimulation current intensity predicted postsurgical motor deficits (F value = 44.5, p < 0.001) without effects on patient postsurgical seizure freedom (p > 0.05). CONCLUSIONS: The proposed ESM paradigm developed in our center represents a reliable method for preventing and predicting postsurgical motor deficits in all age groups of children. This novel ESM protocol may increase the safety and possibly also the completeness of epilepsy surgery. It could be adopted in pediatric epilepsy surgery centers.

Cognitive performance in distinct groups of children undergoing epilepsy surgery-a single-centre experience.

BACKGROUND: We aimed first to describe trends in cognitive performance over time in a large patient cohort (n = 203) from a single tertiary centre for paediatric epilepsy surgery over the period of 16 years divided in two (developing-pre-2011 vs. established-post-2011). Secondly, we tried to identify subgroups of epilepsy surgery candidates with distinctive epilepsy-related characteristics that associate with their pre- and post-surgical cognitive performance. Thirdly, we analysed variables affecting pre-surgical and post-surgical IQ/DQ and their change (post- vs. pre-surgical). METHODS: We analysed IQ/DQ data obtained using standardized neuropsychological tests before epilepsy surgery and one year post-surgically, along with details of patient's epilepsy, epilepsy surgery and outcomes in terms of freedom from seizures. Using regression analysis, we described the trend in post-operative IQ/DQ. Cognitive outcomes and the associated epilepsy- and epilepsy surgery-related variables were compared between periods before and after 2011. Using multivariate analysis we analysed the effect of individual variables on pre- and post-operative IQ/DQ and its change. RESULTS: Epilepsy surgery tends to improve post-surgical IQ/DQ, most significantly in patients with lower pre-surgical IQ/DQ, and post-surgical IQ/DQ strongly correlates with pre-surgical IQ/DQ (Rho = 0.888, p < 0.001). We found no significant difference in pre-, post-surgical IQ/DQ and IQ/DQ change between the periods of pre-2011 and post-2011 (p = 0.7, p = 0.469, p = 0.796, respectively). Patients with temporal or extratemporal epilepsy differed in their pre-surgical IQ/DQ (p = 0.001) and in IQ/DQ change (p = 0.002) from those with hemispheric epilepsy, with no significant difference in post-surgical IQ/DQ (p = 0.888). Groups of patients with different underlying histopathology showed significantly different pre- and post-surgical IQ/DQ (p < 0.001 and p < 0.001 respectively) but not IQ/DQ change (p = 0.345).Variables associated with severe epilepsy showed effect on cognitive performance in multivariate model. DISCUSSION: Post-surgical IQ/DQ strongly correlates with pre-surgical IQ/DQ and greatest IQ/DQ gain occurs in patients with lower pre-surgical IQ/DQ scores. Cognitive performance was not affected by changes in paediatric epilepsy surgery practice. Pre- and post-operative cognitive performances, as well as patients' potential for cognitive recovery, are highly dependent on the underlying aetiology and epileptic syndrome.

Generalized quasiperiodic epileptiform activity in sleep is associated with cognitive impairment in children with drug-resistant focal lesional epilepsy.

OBJECTIVE: To evaluate the impact of generalized quasiperiodic epileptiform discharges ("hurdles") observed in non-rapid eye movement (NREM) sleep on cognitive function in children with intractable focal epilepsy. "Hurdles" pattern does not meet the criteria of the electrical status epilepticus in slow-wave sleep (ESES). METHODS: In a retrospective analysis, 24 patients with "hurdles" and their 24 peers matched for demographic and epilepsy-related variables were compared in terms of neuropsychological domains and electroencephalography (EEG)-derived quantifiers. Both "hurdles" and controls were children between 2 and 19 years of age who had intractable focal epilepsy evaluated as candidates of resective epilepsy surgery. RESULTS: Full-scale intelligence quotient/developmental quotient (FSIQ/DQ) (P = .002) and visuoconstructional skills (P = .004) were significantly lower in children with "hurdles" compared to controls. Patients with "hurdles" presented with higher interictal spike indexes in sleep (P < .001, median difference -0.9, 95% confidence interval [CI] -1.4, -0.6) and wakefulness (P < .001, median difference -0.3, 95% CI -0.5, -1). Relative time of sleep spindles in NREM sleep was significantly reduced (P < .001, median difference 0.1, 95% CI 0.0, 0.1) in the "hurdles" group. The time proportion of sleep spindles represented a significant positive (P = .008) and spike index of generalized spikes in sleep a significant negative explanatory variable (P = .004) of FSIQ/DQ scores. The proportion of seizure-free patients 2 years after epilepsy surgery did not differ significantly between the two groups (P = .19). SIGNIFICANCE: Although the "hurdles" pattern does not fulfill the criteria of ESES, it is associated with a pronounced cognitive dysfunction. Disturbed sleep structure marked by reduced sleep spindles and generalized spiking in sleep is associated with worse cognitive performance. Despite having a generalized nature, we did not find a lower probability of postsurgical seizure freedom in patients with "hurdles" pattern.

Early Clinical Predictors of Autism Spectrum Disorder in Infants with Tuberous Sclerosis Complex: Results from the EPISTOP Study.

Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6-24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development-BSID, and Autism Diagnostic Observation Schedule-ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy-Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6-12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies.

Brain volumetric correlates of dysarthria in multiple sclerosis.

Although dysarthria is a common pattern in multiple sclerosis (MS), the contribution of specific brain areas to key factors of dysarthria remains unknown. Speech data were acquired from 123 MS patients with Expanded Disability Status Scale (EDSS) ranging from 1 to 6.5 and 60 matched healthy controls. Results of computerized acoustic analyses of subtests on spastic and ataxic aspects of dysarthria were correlated with MRI-based brain volume measurements. Slow articulation rate during reading was associated with bilateral white and grey matter loss whereas reduced maximum speed during oral diadochokinesis was related to greater cerebellar involvement. Articulation rate showed similar correlation to whole brain atrophy (r = 0.46, p < 0.001) as the standard clinical scales such as EDSS (r = -0.45, p < 0.001). Our results support the critical role of the pyramidal tract and cerebellum in the modification of motor speech timing in MS.

Evolution of pediatric epilepsy surgery program over 2000-2017: Improvement of care?

PURPOSE: We assessed trends in spectrum of candidates, diagnostic algorithm, therapeutic approach and outcome of a pediatric epilepsy surgery program between 2000 and 2017. METHODS: All pediatric patients who underwent curative epilepsy surgery in Motol Epilepsy Center during selected period (n = 233) were included in the study and divided into two groups according to time of the surgery (developing program 2000-2010: n = 86, established program 2011-2017: n = 147). Differences in presurgical, surgical and outcome variables between the groups were statistically analyzed. RESULTS: A total of 264 resections or hemispheric disconnections were performed (including 31 reoperations). In the later epoch median age of candidates decreased. Median duration of disease shortened in patients with temporal lobe epilepsy. Number of patients with non-localizing MRI findings (subtle or multiple lesions) rose, as well as those with epileptogenic zone adjacent to eloquent cortex. There was a trend towards one-step procedures guided by multimodal neuroimaging and intraoperative electrophysiology; long-term invasive EEG was performed in fewer patients. Subdural electrodes for long-term invasive monitoring were almost completely replaced by stereo-EEG. The number of focal resections and hemispherotomies rose over time. Surgeries were more often regarded complete. Histopathological findings of resected tissue documented developing spectrum of candidates. 82.0% of all children were seizure-free two years after surgery; major complications occurred in 4.6% procedures; both groups did not significantly differ in these parameters. CONCLUSION: In the established pediatric epilepsy surgery program, our patients underwent epilepsy surgery at younger age and suffered from more complex structural pathology. Outcomes and including complication rate remained stable.

Correction to: The landscape of epilepsy-related GATOR1 variants.

The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.

The landscape of epilepsy-related GATOR1 variants.

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Correction: The landscape of epilepsy-related GATOR1 variants.

The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.