The purpose of this study was to prospectively investigate the agreement between the epileptogenic zone(s) (EZ) localization by resting-state functional magnetic resonance imaging (rs-fMRI) and the seizure onset zone(s) (SOZ) identified by intracranial electroencephalogram (ic-EEG) using novel differentiating and ranking criteria of rs-fMRI abnormal independent components (ICs) in a large consecutive heterogeneous pediatric intractable epilepsy population without an a priori alternate modality informing EZ localization or prior declaration of total SOZ number. The EZ determination criteria were developed by using independent component analysis (ICA) on rs-fMRI in an initial cohort of 350 pediatric patients evaluated for epilepsy surgery over a 3-year period. Subsequently, these rs-fMRI EZ criteria were applied prospectively to an evaluation cohort of 40 patients who underwent ic-EEG for SOZ identification. Thirty-seven of these patients had surgical resection/disconnection of the area believed to be the primary source of seizures. One-year seizure frequency rate was collected postoperatively. Among the total 40 patients evaluated, agreement between rs-fMRI EZ and ic-EEG SOZ was 90% (36/40; 95% confidence interval [CI], 0.76–0.97). Of the 37 patients who had surgical destruction of the area believed to be the primary source of seizures, 27 (73%) rs-fMRI EZ could be classified as true positives, 7 (18%) false positives, and 2 (5%) false negatives. Sensitivity of rs-fMRI EZ was 93% (95% CI 78–98%) with a positive predictive value of 79% (95% CI, 63–89%). In those with cryptogenic localization-related epilepsy, agreement between rs-fMRI EZ and ic-EEG SOZ was 89% (8/9; 95% CI, 0.52–99), with no statistically significant difference between the agreement in the cryptogenic and symptomatic localization-related epilepsy subgroups. Two children with negative ic-EEG had removal of the rs-fMRI EZ and were seizure free 1 year postoperatively. Of the 33 patients where at least 1 rs-fMRI EZ agreed with the ic-EEG SOZ, 24% had at least 1 additional rs-fMRI EZ outside the resection area. Of these patients with un-resected rs-fMRI EZ, 75% continued to have seizures 1 year later. Conversely, among 75% of patients in whom rs-fMRI agreed with ic-EEG SOZ and had no anatomically separate rs-fMRI EZ, only 24% continued to have seizures 1 year later. This relationship between extraneous rs-fMRI EZ and seizure outcome was statistically significant (p = 0.01). rs-fMRI EZ surgical destruction showed significant association with postoperative seizure outcome. The pediatric population with intractable epilepsy studied prospectively provides evidence for use of resting-state ICA ranking criteria, to identify rs-fMRI EZ, as developed by the lead author (V.L.B.). This is a high yield test in this population, because no seizure nor particular interictal epilepiform activity needs to occur during the study. Thus, rs-fMRI EZ detected by this technique are potentially informative for epilepsy surgery evaluation and planning in this populatio...

Objective: Postoperative resting-state functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood. Methods: In a sample of children with intractable epilepsy who underwent prospective resting-state seizure onset zone (SOZ)-targeted epilepsy surgery, postoperative resting-state functional MRI (rs-fMRI) was performed 6 to 12 months later. Graded normalization of the postoperative resting-state SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics. Results: A total of 64 cases were evaluated. Network-targeted surgery, followed by postoperative rs-fMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rs-fMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rs-fMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rs-fMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity. Interpretation: Among seizure localization techniques in pediatric epilepsy, network-targeted surgery, followed by postoperative rs-fMRI normalization, has high correlation with seizure freedom. This study shows that rs-fMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rs-fMRI normalization is a biomarker for SOZ quiescence.

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OBJECTIVEThe authors’ goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning.METHODSFifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre– and post–rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar’s test.RESULTSResting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted.CONCLUSIONSThis study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

OBJECTIVEDetermining language laterality in patients with intractable epilepsy is important in operative planning. Wada testing is the gold standard, but it has a risk of stroke. Both Wada and task-based functional MRI (tb-fMRI) require patient cooperation. Recently, resting-state fMRI (rs-fMRI) has been explored for language lateralization. In the present study, the correlation between rs-fMRI and tb-fMRI in language lateralization is estimated in a pediatric population with intractable epilepsy.METHODSrs-fMRI and tb-fMRI language lateralization testing performed as part of epilepsy surgery evaluation was retrospectively reviewed.RESULTSTwenty-nine patients underwent rs-fMRI and tb-fMRI; a total of 38 rs-fMRI studies and 30 tb-fMRI studies were obtained. tb-fMRI suggested left dominance in 25 of 30 cases (83%), right in 3 (10%), and in 2 (7%) the studies were nondiagnostic. In rs-fMRI, 26 of 38 studies (68%) suggested left dominance, 3 (8%) right dominance, 6 (16%) bilateral, and 3 (8%) were nondiagnostic. When tb-fMRI lateralized to the left hemisphere (25 cases), rs-fMRI was lateralized to the left in 23 patients (92%) and it was bilateral/equal in 2 (8%). When tb-fMRI lateralized to the right (3 cases), rs-fMRI lateralized to the right in all cases (100%). The overall concordance rate was 0.93 (95% CI 0.76–0.99) when considering cases with tb-fMRI and rs-fMRI performed within 6 months of each other, and tb-fMRI results were not nondiagnostic.CONCLUSIONSrs-fMRI significantly correlated with tb-fMRI in lateralizing language and suggests the potential role for identifying hemispheric dominance via rs-fMRI. Further investigation and validation studies are warranted.

Background: An accurate and comprehensive test of integrated brain network function is needed for neonates during the acute brain injury period to inform on morbidity. In our first term neonatal acute brain injury (ABI) study we demonstrated resting state functional MRI (RS) acquired within 31 days of life, results in disrupted connectivity of the resting state fMRI networks, incrementally associated with consciousness, mortality, cognitive and motor development, and ongoing concern for seizures at 6 months post-gestation. In this retrospective cohort study, we evaluate extended 2-year outcomes in the same patients. Methods: Study subjects included the same 40 consecutive neonates from our prior study, with resting state functional MRI acquired within 31 days after suspected brain insult from March 2018 to July 2019. Acute-period exam and test results were assigned ordinal scores based on severity as documented by respective treating specialists. Analyses (Fisher exact, Wilcox Sum-Rank test ordinal/multinomial logistic regression) examined association of resting state networks with demographics, presentation, neurological exam, electroencephalogram, anatomical MRI, magnetic resonance spectroscopy, passive task functional MRI, and outcomes of inpatient and outpatient mortality, outpatient development measured by exam and the Pediatric Cerebral Performance Category Scale (PCPC), motor development and tone, and ongoing concern for seizure at up to 42 months of age. All statistical tests were 2-sided, with statistical significance and CI adjusted using a Bonferroni correction to account for multiple test comparisons for each network and other modality. Results: Subjects had a mean (standard deviation) gestational age of 37.8 (2.6) weeks, follow-up median age follow-up median age (interquartile range) 30.5 (23.6, 36.7) months, 68% were male, with a diagnosis of hypoxic ischemic encephalopathy (60%). Of the 40 patients, three died prior to discharge, and another four between 6-42 months, and 5 were lost to follow-up. Of the followed, findings at birth included mild distress (46%), moderately abnormal neurological exam (34%), and consciousness characterized as awake but irritable (37%). Significant associations after multiple testing corrections were detected for resting state networks: basal ganglia with PCPC (odds ratio [OR], 9.54; 99.4% confidence interval [CI], 1.89-48.1; P = 0.0003), inpatient mortality (OR, 57.5; 99% CI, 1.35->999; P = 0.006), outpatient mortality (OR, 65.7; 99% CI 1.47->999; P = 0.005), and motor tone/weakness (OR, 17.8; 99% CI, 2.2-143; P = 0.0004); language/frontoparietal network with developmental delay (OR, 3.64; 99% CI, 1.02-13.05; P = 0.009), PCPC (OR, 3.98; 99% CI, 1.09-14.45; P = 0.006), and outpatient mortality (OR, 9.2; 99% CI, 0.91-92.6; P = 0.01); default mode network with developmental delay (OR, 4.14; 99% CI, 1.19-14.43; P = 0.003); PCPC (OR, 4.1; 99% CI, 1.2-14.2; P = 0.004), inpatient mortality (OR, 20.41; 99% CI, 0.89-468; P = 0.01), and motor tone/weakness (OR, 3.35; 99% CI, 1.01-11.12; P = 0.009); and seizure onset zone with concern for seizures (OR, 4.02; 99% CI, 1.0-16.15; P = 0.01). Of the other acute phase tests, only anatomical MRI was showed association with and outcome, concern for seizure (OR, 2.40; 99% CI, 0.94-6.13; P = 0.01). Conclusions: This study provides level 3 evidence (OCEBM Levels of Evidence Working Group) demonstrating that in neonatal acute brain injury, the degree of abnormality of resting state networks is associated with mortality, ongoing concern for seizure and 2 year outcomes. These findings suggest RS is feasible and safe to implement in a busy tertiary neonatal ICU and the findings are of at least equivalent value to other standard of care diagnostics.

Background An accurate and comprehensive test of integrated brain network function is needed for neonates during the acute brain injury period to inform on morbidity. This retrospective cohort study aimed to assess whether integrated brain network function by resting state functional MRI, acquired during the acute period in neonates with brain injury, is associated with acute exam, neonatal mortality, and 5-month outcomes. Methods This study included 40 consecutive neonates with resting state functional MRI acquired 1-22 days after suspected brain insult from March 2018 to July 2019 at Phoenix Childrens Hospital. Acute period exam and test results were assigned ordinal scores based on severity as documented by respective treating specialists. Analyses (Fisher exact, Wilcoxon-rank sum test, ordinal/multinomial logistic regression) examined association of resting state networks with demographics, presentation, neurological exam, electroencephalogram, anatomical MRI, magnetic resonance spectroscopy, passive task functional MRI, and outcomes of discharge condition, outpatient development, motor tone, seizure, and mortality. Results Subjects had a mean (standard deviation) gestational age of 37.8 (2.6) weeks, a majority were male (63%), with diagnosis of hypoxic ischemic encephalopathy (68%). Other findings at birth included mild distress (48%), moderately abnormal neurological exam (33%), and consciousness characterized as awake but irritable (40%). Significant associations after multiple testing corrections were detected for resting state networks: basal ganglia with outpatient developmental delay (odds ratio [OR], 14.5; 99.4% confidence interval [CI], 2.00-105; P<.001) and motor tone/weakness (OR, 9.98; 99.4% CI, 1.72-57.9; P<.001); language/frontal-parietal network with discharge condition (OR, 5.13; 99.4% CI, 1.22-21.5; P=.002) and outpatient developmental delay (OR, 4.77; 99.4% CI, 1.21-18.7; P=.002); default mode network with discharge condition (OR, 3.72; 99.4% CI, 1.01-13.78; P=.006) and neurological exam (P=.002 (FE); OR, 11.8; 99.4% CI, 0.73-191; P=.01 (OLR)); seizure onset zone with motor tone/weakness (OR, 3.31; 99.4% CI, 1.08-10.1; P=.003). Resting state networks were not detected in only three neonates, who died prior to discharge. Conclusions This study provides level 3 evidence (OCEBM Levels of Evidence Working Group) that the degree of abnormality of resting state networks in neonatal acute brain injury is associated with acute exam and outcomes. Total lack of brain network detection was only found in patients who did not survive.