Abstract
Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant ...focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.
López-Rivera et al. discover differences in genetic architecture across major epileptic brain lesion types. They describe novel somatic chromosomal alterations, identify novel genes and genotype–phenotype associations, and provide support for the role of genetics in the histopathological diagnosis of epileptic lesions.
This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist ...clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline.
A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making.
Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval CI ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%-12% (CI ± 10%-19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines.
In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability.
Highlights • A complete removal of type I ripples was associated with seizure freedom in neocortical epilepsy. • Fast ripples help localize the epileptogenic zone despite being less frequently ...detected. • EEG characteristics associated with ripples help classify ripples with different epileptogenicity.
Abstract
BACKGROUND:
Despite the use of invasive subdural recording, failure to localize or resect the epileptogenic zone (EZ) occurs. Potential causes for this include EZ originating outside of the ...subdural grid coverage area, involvement of eloquent cortex, or complications requiring removal of electrodes without seizure localization. No study has examined the safety and efficacy of stereoelectroencephalography (SEEG) after subdural grid placement.
OBJECTIVE:
To determine the efficacy of SEEG in patients who have previously undergone subdural grid placement.
METHODS:
A prospective analysis was performed on 14 patients who had subdural grid evaluation and underwent subsequent SEEG monitoring. The follow-up period after the SEEG-guided resections ranged from 11 months to 34 months with an average follow-up of 20.1 months. Magnetic resonance imaging findings, EZ localization, outcomes, type of surgery, and perioperative complications were evaluated.
RESULTS:
Ten patients (71%) underwent a resection after SEEG reimplantation. Of the 4 patients (29%) not undergoing resection, 2 had seizures arising from eloquent cortex, 1 had bitemporal epilepsy, and 1 had a previous temporal lobectomy contralateral to the EZ. An estimate of the EZ was achieved in all patients based on interictal and ictal recordings. In patients undergoing resection, 60% were seizure-free at 11 months. Perioperative complications were minimal and included 1 abscess, which required burr-hole drainage and antibiotics.
CONCLUSION:
SEEG is a safe and effective method after subdural grid placement is inconclusive, providing an additional opportunity for seizure freedom in this highly challenging group of patients.
We aim to provide detailed imaging-electroclinicopathologic characterization of the black line sign, a novel MRI marker for focal cortical dysplasia (FCD) IIB.
7T T2*-weighted gradient-echo ...(T2*w-GRE) images were retrospectively reviewed in a consecutive cohort of patients with medically intractable epilepsy with pathology-proven FCD II, for the occurrence of the black line sign. We examined the overlap between the black line region and the seizure-onset zone (SOZ) defined by intracranial EEG (ICEEG) and additionally assessed whether complete inclusion of the black line region in the surgical resection was associated with postoperative seizure freedom. The histopathologic specimen was aligned with the MRI to investigate the pathologic underpinning of the black line sign. Region-of-interest-based quantitative MRI (qMRI) analysis on the 7T T1 map was performed in the black line region, entire lesional gray matter (GM), and contralateral/ipsilateral normal gray and white matter (WM).
We included 20 patients with FCD II (14 IIB and 6 IIA). The black line sign was identified in 12/14 (85.7%) of FCD IIB and 0/6 of FCD IIA on 7T T2*w-GRE. The black line region was highly concordant with the ICEEG-defined SOZ (5/7 complete and 2/7 partial overlap). Seizure freedom was seen in 8/8 patients whose black line region was completely included in the surgical resection; in the 2 patients whose resection did not completely include the black line region, both had recurring seizures. Inclusion of the black line region in the surgical resection was significantly associated with seizure freedom (
= 0.02). QMRI analyses showed that the T1 mean value of the black line region was significantly different from the WM (
< 0.001), but similar to the GM. Well-matched histopathologic slices in one case revealed accumulated dysmorphic neurons and balloon cells in the black line region.
The black line sign may serve as a noninvasive marker for FCD IIB. Both MRI-pathology and qMRI analyses suggest that the black line region was an abnormal GM component within the FCD. Being highly concordant with ICEEG-defined SOZ and significantly associated with seizure freedom when included in resection, the black line sign may contribute to the planning of ICEEG/surgery of patients with medically intractable epilepsy with FCD IIB.
This study provides Class II evidence that in individuals with intractable focal epilepsy undergoing resection who have a 7T MRI with adequate image quality, the presence of the black line sign may suggest FCD IIB, be concordant with SOZ from ICEEG, and be associated with more seizure freedom if fully included in resection.
Objective
To develop a model to predict the probability of mood decline in adults following temporal lobe resection for the treatment of pharmacoresistant epilepsy.
Methods
Variable selection was ...performed on 492 patients from the Cleveland Clinic using best subsets regression. After completing variable selection, a subset of variables was requested from four epilepsy surgery centers across North America (n = 100). All data were combined to develop a final model to predict postoperative mood decline (N = 592). Internal validation with bootstrap resampling was performed. A clinically significant increase in depressive symptoms was defined as a 15% increase in Beck Depression Inventory–Second Edition score and a postoperative raw score > 11.
Results
Fourteen percent of patients in the Cleveland Clinic cohort and 22% of patients in the external cohort experienced clinically significant increases in depressive symptoms following surgery. The final prediction model included six predictor variables: psychiatric history, resection side, relationship status, verbal fluency score, age at preoperative testing, and presence/absence of malformation of cortical development on magnetic resonance imaging. The model had an optimism‐adjusted c‐statistic of .70 and good calibration, with slight probability overestimation in higher risk patients.
Significance
Clinicians can utilize our nomogram via a paper tool or online calculator to estimate the risk of postoperative mood decline for individual patients prior to temporal lobe epilepsy surgery.
Objective
Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, ...particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory.
Methods
Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease‐related variables. Total RNA‐Seq and small RNA‐Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed.
Results
We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain‐related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA‐Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA‐predicted DET targets impact brain‐related pathways and biological processes also pertinent to memory and cognition.
Significance
TLE‐associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE.
Purpose: It is generally accepted that blood–brain barrier (BBB) failure occurs as a result of CNS diseases, including epilepsy. However, evidences also suggest that BBB failure may be an etiological ...factor contributing to the development of seizures.
Methods: We monitored the onset of seizures in patients undergoing osmotic disruption of BBB (BBBD) followed by intraarterial chemotherapy (IAC) to treat primary brain lymphomas. Procedures were performed under barbiturate anesthesia. The effect of osmotic BBBD was also evaluated in naive pigs.
Results: Focal motor seizures occurred immediately after BBBD in 25% of procedures and originated contralateral to the hemisphere of BBBD. No seizures were observed when BBB was not breached and only IAC was administered. The only predictors of seizures were positive indices of BBBD, namely elevation of serum S100β levels and computed tomography (CT) scans. In a porcine model of BBBD, identical procedures generated an identical result, and sudden behavioral and electrographic (EEG) seizures correlated with successful BBB disruption. The contribution of tumor or chemotherapy to acute seizures was therefore excluded.
Conclusion: This is the first study to correlate extent of acute BBB openings and development of seizures in humans and in a large animal model of BBB opening. Acute vascular failure is sufficient to cause seizures in the absence of CNS pathologies or chemotherapy.
Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are ...often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.
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