Focal Type Research Articles

Differences in the incidence of obstetric complications depending on the extent and location of adenomyosis lesions

Objectives Although adenomyosis is reportedly associated with adverse pregnancy outcomes, clinical factors related to the high risk of obstetric complications are unclear. This study aimed to elucidate the characteristics of adenomyosis lesions associated with the increased incidence of obstetric complications based on imaging findings. Methods This was a retrospective, observational cohort study conducted in a tertiary perinatal care center. Eighty-eight singleton pregnant women with adenomyosis were included in the study. Based on magnetic resonance imaging or ultrasonography before and/or during pregnancy, patients were classified according to three types of image characteristics: the extent of adenomyosis lesion (focal type or diffuse type), location of the lesion (extrinsic type, intrinsic type, or indeterminate type), the positional relationship between the lesion and the placenta (placenta distant from adenomyosis or placenta over adenomyosis), and the incidence of obstetric complications were examined. Results Patients with diffuse type adenomyosis are significantly more likely to have spontaneous second-trimester miscarriage (diffuse type vs. focal type: 16.7 vs. 0%, p < .01), preterm premature rupture of membranes (19.4 vs. 1.9%, p < .01), and preeclampsia (25.0 vs. 7.7%, p = .02), as compared to those with focal type adenomyosis. In a comparison of the three location types, the incidence of placental malposition was higher in patients with the extrinsic type adenomyosis (extrinsic type vs. intrinsic type vs. indeterminate type: 20.0 vs. 6.7 vs. 2.3%, p = .03). Comparisons between the types of the placenta over or distant from adenomyosis lesion displayed no significant differences in the frequencies of obstetric complications. Conclusions We demonstrated that the frequency of obstetric complications related to adenomyosis varies depending on the extent and location of the lesion; patients with diffuse type adenomyosis have an increased risk of spontaneous second-trimester miscarriage, preterm premature rupture of membranes, and preeclampsia, while patients with extrinsic type adenomyosis have an increased risk of placental malposition. Imaging evaluation of adenomyosis prior to conception or early in pregnancy may be useful for the obstetrical risk assessment among patients with adenomyosis.

Cardiac troponin T, NT-proBNP and GDF-15 associate with future focal myocardial scar types, but not diffuse fibrosis assessed by cardiac magnetic resonance

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Akershus University Hospital Trust, Vestre Viken Hospital Trust, South-Eastern Norway Regional Health Authority, Roche Diagnostics provided reagents for hs-cTnT analyses Background In cardiovascular risk prediction, there is growing evidence that imaging and circulating cardiac biomarkers provide incremental prognostic value compared to single biomarkers or traditional risk factors. In patients with suspected or established cardiovascular disease (CVD), cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) associate with focal and diffuse fibrosis assessed by cardiac magnetic resonance (CMR) imaging. There is limited data on the associations between established and emerging circulating cardiac biomarkers with subsequent myocardial fibrosis in subjects without CVD recruited from the general population. Purpose Assess the associations between biomarkers of cardiac injury (cTnT), stress (NT-proBNP) and fibrosis and inflammation (growth differentiation factor-15, GDF-15), and subsequent focal and diffuse myocardial fibrosis assessed by CMR imaging. Methods We recruited 200 study participants born in 1950 from the general population. All participants were without known coronary artery disease or renal dysfunction. cTnT, NT-proBNP, and GDF-15 were measured in samples collected at baseline in 2012–2015, and CMR was performed 4–7 years later. Presence and type (ischemic/non-ischemic) of focal myocardial fibrosis were assessed by late gadolinium enhancement (LGE) imaging. Diffuse fibrosis was assessed by the extracellular volume (ECV) in the midventricular septum. Logistic regression analysis was used to examine relationships between log transformed concentrations of cardiac biomarkers and CMR parameters. Results The median age was 63.9 (63.4–64.5) and 52% were male (Table 1). cTnT was associated with presence of any LGE scar adjusted for common cardiovascular risk factors (OR 1.85, 95% CI 1.25–2.72), but this association was attenuated when left ventricular mass was added to the model (Table 2). NT-proBNP (OR 1.66, 95% CI 1.10–2.72) and GDF-15 (OR 4.45, 95% CI 1.29–15.27) were associated with presence of any LGE scar in the fully adjusted models (Table 2). cTnT (OR 1.90, 95% CI 1.06–3.39) and NT-proBNP (OR 2.72, 95% CI 1.29–5.76) were associated with ischemic scars. Only GDF-15 (OR 4.52, 95% CI 1.09–18.72) associated with non-ischemic scars in adjusted models. None of the biomarkers were significantly associated with ECV. Conclusion(s) In a general population cohort, biomarkers of myocardial injury and stress associate with ischemic type scars, but not diffuse fibrosis. GDF-15, an emerging circulating biomarker of fibrosis and inflammation, associates with non-ischemic type scars.

Factors Affecting Serum Vitamin D Level in Epilepsy

Objective: Our aim was evaluate the relationship between 25-Hydroxyvitamin D (25(OH)D) and old and new generation anti-seizure drugs (ASDs), seizure type and seizure frequency in epilepsy patients.&#x0D; Method: A total of 96 individuals aged 18 years and older with epilepsy were included in this study who were followed up in the SBU Adana City Training and Research Hospital Epilepsy outpatient clinic between January 1, 2020 and November 1, 2022 and met the inclusion criteria. Patients were grouped by age, gender, seizure type, frequency, and ASDs usage (according to their relationship with cytochrome P450 enzymes). Complete blood count, kidney functions, serum ASD levels and calcium, magnesium, phosphate and parathormone levels, season when 25(OH)D were measured, and sun exposure time was also obtained from patient file scans.&#x0D; Results: 55.2% of the patients were women and the mean age was 32.56±12.90 (Min:18 Max:71). 25(OH)D level was found to be deficient or insufficient in 95.8% of the patients. The 25(OH)D level was statistically significantly lower in patients with generalized and complex partial epilepsy who were exposed to the sun for less than one hour per week compared to the focal type and those exposed to the sun for more than one hour per week. p

COMPRESSION OF RENAL ARTERIES BY THE DIAPHRAGMATIC CRUS: PROPOSAL FOR A NEW CLASSIFICATION

Objective: Renal artery entrapment (RAE) is a rare cause of hypertension, and its management remains debated between surgical and endovascular approaches. The aim of this study was to propose an updated classification of RAEs. Design and method: This retrospective study included all patients referred to our center between 1995 and 2021 with a diagnosis of RAE confirmed by CT scan. The primary objective was to describe the type of renal artery (RA) compression (ostial or truncular location and focal or long extension). The association between the type of compression and age, side of compression and high origin of the RA was also evaluated. Results: Forty patients with 45 RAE were included. The compression was focal and ostial in 22 arteries (49%), long and truncular in 13 RA (29%) and focal and truncular in 10 RA (22%), of which 2 RA (4%) originated from the thoracic aorta with a transdiaphragmatic passage. From this distribution, an updated classification with 4 types of RAE was proposed including: type 1: ostial compression, type 2: long truncular compression, type 3: focal truncular entrapment and type 4: truncular entrapment with intrathoracic RA origin. There was no association between the type of RAE and the patient's age (p = 0.09) or the side of compression (p = 0.42). Type 2 and type 4 RAEs were associated with a higher origin of the compressed artery (p = 0.04). Conclusions: This study proposed an updated classification of RAE with four type of compressions. Knowledge of these conditions may be helpful for a future treatment algorithm.

Relationship between Full-Thickness Macular Hole Onset and Posterior Vitreous Detachment: A Temporal Onset Theory

PurposeTo evaluate the relationship between full-thickness macular hole (FTMH) onset and perifoveal posterior vitreous detachment using optical coherence tomography (OCT) data.DesignRetrospective study.ParticipantsA total of 742 patients with FTMH or impending macular hole (MH) in at least one eye, as determined by ophthalmoscopy and OCT.MethodsMHs were staged using OCT results. Patients with the posterior vitreous membrane clearly detected in the OCT images and vitreoretinal adhesion size ≤ 1500 μm—eyes with MH stages 1–3—were included in the study. The contralateral eyes were also included in the analyses if they showed the focal type of vitreomacular adhesion (VMA) (i.e., vitreoretinal adhesion ≤ 1500 μm). The distance between the posterior vitreous membrane and the surface of the retina was defined as the posterior vitreous separation height (PVSH). Using the OCT images, PVSHs of each eye in four directions (nasal, temporal, superior, and inferior) at 1 mm from the center of the MH or fovea were calculated.Main Outcome MeasuresThe main outcome measures were PVSHs according to the MH stage and VMA, the relationship of the foveal inner tear with PVSH, and the likelihood of a foveal inner tear based on the direction.ResultsThe PVSH trends in each of the four directions were as follows: VMA < MH stage 1 = MH stage 2 < MH stage 3. Initial MH stage 2 (onset of FTMH) was defined as the presence of a gap in only one of the four directions from the center of the MH. With increased PVSH, the likelihood of a gap increased (P = 0.002), and a temporal gap was more likely to occur than a nasal gap (P = 0.002).ConclusionsAt FTMH onset, a foveal inner tear likely appears on the temporal side or the side showing a high PVSH value.

Optimisation of Cycling Trends in Hamiltonian Systems of Economic Growth Models

The paper analyses dynamical growth models predicting the cyclic development of investigated economic factors. The provided research deals with an optimal control problem based on the economic growth model with the production function of Cobb–Douglas type. Following the Pontryagin maximum principle, we derived the Hamiltonian system and conducted its qualitative analysis, which reveals conditions for the cyclic behaviour of the optimal solutions around the isolate steady state. Numerical experiments visually illustrated the obtained results by demonstrating a phase portrait corresponding to a steady state of the focal type.

P319 MID VENTRICULAR TAKOTSUBO SYNDROME IN A PATIENT WITH COVID 19 PNEUMONIA: A CASE REPORT

Abstract Background Takotsubo Syndrome (TTS) is an acute and transient myocardial disfunction associated with chest pain, electrocardiographic changes and minimal myocardial enzymatic release mimicking acute myocardial infarction but without significant coronary artery disease. Physical or emotional stress play a central role in the pathogenesisof this cardiomyopathy. Several variants have been described including the classic type, reverse Takotsubo, midventricular type and focal type. Mid ventricular Takotsubo is characterized by circumferential mid–ventricular hypokinesia with hypercontractility of base and apex. This atypical variant is one of the most rare form that occurs in 15% of patients with Takotsubo syndrome. We report a Takotsubo case with mid–ventricular pattern in a postmenopausal woman with COVID–19 interstitial pneumonia. Clinical case A 56–year–old female patient was admitted to our intensive cardiac care unit for acute chest pain and dyspnea. In clinical history hypertension, dyslipidemia, anemia and schizophrenia were documented. COVID–19 molecular test was positive. CT scan showed multiple ground–glass opacities bilaterally. Hemodynamic parameters were normal but ECG showed ST–segment elevation and T waves inversion in the lateral precordial leads. Troponin–I was elevated and peaked at 1704 ng/mL. A transthoracic echocardiogram showed ballooning of the midventricular segments with hyperkinesis of the basal and apical segment. Coronary angiography showed normal coronaries. The patient was treated with beta–blockers and intravenous fluid infusion. After 10 days in hospital, echocardiography showed normalization of regional contractility and improvement of ejection fraction. The patient was discharged in good condition. Conclusions Recent studies have reported an increase in TTS incidence during the COVID–19 pandemic. SARS-CoV-2 infection induces physical and psychological stress in patients, which may lead to an increase in the risk of TTS development. The pathophysiology of COVID-19-induced TTS still remains unclear. The mortalityrate of TTS is higher (36.5%) in COVID–19 patients.

MTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy

The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The ‘mTORopathies’ comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.

Detection of brain somatic mutations in focal cortical dysplasia during epilepsy presurgical workup.

Brain-restricted somatic variants in genes of the mechanistic target of rapamycin signalling pathway cause focal epilepsies associated with focal cortical dysplasia type II. We hypothesized that somatic variants could be identified from trace tissue adherent to explanted stereoelectroencephalography electrodes used in the presurgical epilepsy workup to localize the epileptogenic zone. We investigated three paediatric patients with drug-resistant focal epilepsy subjected to neurosurgery. In the resected brain tissue, we identified low-level mosaic somatic mutations in AKT3 and DEPDC5 genes. We collected stereoelectroencephalography depth electrodes in the context of a second presurgical evaluation and identified 4/33 mutation-positive electrodes that were either located in the epileptogenic zone or at the border of the dysplasia. We provide the proof-of-concept that somatic mutations with low levels of mosaicism can be detected from individual stereoelectroencephalography electrodes and support a link between the mutation load and the epileptic activity. Our findings emphasize future opportunities for integrating genetic testing from stereoelectroencephalography electrodes into the presurgical evaluation of refractory epilepsy patients with focal cortical dysplasia type II to improve the patients' diagnostic journey and guide towards precision medicine.

A STUDY OF CLINICAL AND IMAGING FEATURES OF REFRACTORY EPILEPSY IN PATIENTS ATTENDING A TERTIARY CARE HOSPITAL

Background &amp; objectives Epilepsy is a chronic noncommunicable disease of the brain that affects people of all ages. It is estimated that 70% of people living with epilepsy could live seizure free if properly diagnosed and treated. The exact magnitude of medically intractable epilepsy in India is unknown. The factors that determine the outcome of epilepsy are age of onset and the type of seizure. The aim of our study was to identify the causes of refractory epilepsy To identify the clinical and imaging features i Objectives: n refractoriness. To determine the importance of early and proper evaluation of seizures in refractory epilepsy. It was an observational study Methods: in patients of refractory epilepsy. After taking informed consent, detailed history was taken and examination was done. 105 Patie Results: nts with refractory epilepsy were included in the study. Majority were between 21-30 years age group. 44% of the patients had the onset of seizures below 10 years. Focal seizure type (68 patients) was the most frequent type. Status epilepticus was found in 41.9% of the patients. Engel's seizure score showed the association of high seizure score with RE. The most common cause for refractoriness was found to be congenital anomalie Interpretation &amp; Conclusions: s in children and calcication in adults.

Use of sulthiame as add-on therapy in children with non-self-limited focal epilepsies of childhood

PurposeThis retrospective study aimed to evaluate the efficacy and tolerability of sulthiame (STM) as an add-on treatment in 49 patients with non-self-limited focal epilepsies of childhood (non-SeLFE) resistant to other antiseizure medications (ASM) and/or non-pharmacological treatment. MethodsPatients with non-SeLFE who had failed to respond to at least five previous ASM, alone or in combination, were included in the study. All patients underwent neurological examination, brain magnetic resonance imaging repeated prolonged electroencephalography (EEG) or video-EEG studies, and neurometabolic studies. School achievements and/or performance on neuropsychological tests were also assessed. Sulthiame was added in doses ranging from 10 to 40 mg/kg/day. Efficacy was measured by comparing seizure frequency before and after initiating STM therapy. ResultsTwenty-nine of 49 patients (59.1%) who received STM as add-on therapy had a greater than 50% decrease in seizures after a mean follow-up of 35 months. One patient (2%) became seizure-free. Fourteen patients (40%) had a 25–50% seizure reduction. The mean time of response was 5 months (range, 3.5 to 6 months). No differences were found either between patients with a response of more or less than 50% or between the response of the focal seizure types (motor or non-motor, with or without consciousness impairment). ConclusionIn our study, STM was found to be effective and well-tolerated in children and adolescents with non-SeLFE. In the patients who responded, improvement in the EEG was seen.

Distinct patterns of interictal intracranial EEG in focal cortical dysplasia type I and II

ObjectiveFocal cortical dysplasia (FCD) is the most common malformation causing refractory focal epilepsy. Surgical removal of the entire dysplastic cortex is crucial for achieving a seizure-free outcome. Precise presurgical distinctions between FCD types by neuroimaging are difficult, mainly in patients with normal magnetic resonance imaging findings. However, the FCD type is important for planning the extent of surgical approach and counselling. MethodsThis study included patients with focal drug-resistant epilepsy and definite histopathological FCD type I or II diagnoses who underwent intracranial electroencephalography (iEEG). We detected interictal epileptiform discharges (IEDs) and their recruitment into repetitive discharges (RDs) to compare electrophysiological patterns characterizing FCD types. ResultsPatients with FCD type II had a significantly higher IED rate (p < 0.005), a shorter inter-discharge interval within RD episodes (p < 0.003), sleep influence on decreased RD periodicity (p < 0.036), and longer RD episode duration (p < 0.003) than patients with type I. A Bayesian classifier stratified FCD types with 82% accuracy. ConclusionTemporal characteristics of IEDs and RDs reflect the histological findings of FCD subtypes and can differentiate FCD types I and II. SignificancePresurgical prediction of FCD type can help to plan a more tailored surgical approach in patients with normal magnetic resonance findings.

Diagnostic value of homogenous delayed enhancement in contrast-enhanced computed tomography images and endoscopic ultrasound-guided tissue acquisition for patients with focal autoimmune pancreatitis.

We aimed to investigate (1) promising clinical findings for the recognition of focal type autoimmune pancreatitis (FAIP) and (2) the impact of endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA) on the diagnosis of FAIP. Twenty-three patients with FAIP were involved in this study, and 44 patients with resected pancreatic ductal adenocarcinoma (PDAC) were included in the control group. (1) Multivariate analysis revealed that homogeneous delayed enhancement on contrast-enhanced computed tomography was a significant factor indicative of FAIP compared to PDAC (90% vs. 7%, p=0.015). (2) For 13 of 17 FAIP patients (76.5%) who underwent EUS-TA, EUS-TA aided the diagnostic confirmation of AIPs, and only one patient (5.9%) was found to have AIP after surgery. On the other hand, of the six patients who did not undergo EUS-TA, three (50.0%) underwent surgery for pancreatic lesions. Homogeneous delayed enhancement on contrast-enhanced computed tomography was the most useful clinical factor for discriminating FAIPs from PDACs. EUS-TA is mandatory for diagnostic confirmation of FAIP lesions and can contribute to a reduction in the rate of unnecessary surgery for patients with FAIP.

Abstract 3130: Extrachromosomal DNA in the cancerous transformation of Barrett’s esophagus

Abstract Oncogene amplification on extrachromosomal DNA (ecDNA) drives rapid tumor evolution, treatment resistance, and poor outcomes for patients. Computational tools can detect ecDNA in whole-genome sequencing (WGS) data from biopsies. However, the lack of longitudinal studies tracking patients from pre-cancer to cancer have made it difficult to determine how ecDNAs contribute to the malignant transformation. Two independent surveillance studies of Barrett’s esophagus (BE) patients enabled us to study this transition, as BE is the precursor lesion of esophageal adenocarcinoma (EAC). The studies included a longitudinal case-control study and an independent, cross-sectional surveillance cohort, both with histological correlatives, providing an unprecedented opportunity to study the role of ecDNA in the transition of BE to EAC. We analyzed WGS data from 206 patients in a cross-sectional surveillance cohort from Cambridge University UK, with biopsy-validated BE, including 42 patients who never developed high-grade dysplasia (HGD) or EAC during multi-year follow-ups, 25 patients with HGD, 51 patients with early-stage EAC, and 88 patients with late-stage EAC. ecDNA frequency increased between early-stage EAC (24%) and late-stage EAC (43%), suggesting continual ecDNA formation during cancer progression. We additionally analyzed WGS and histology data collected from multi-regional sampling of BE and EAC tissue at two time points from 80 BE patients in an observational case-control study at the Fred Hutchinson Cancer Center (FHCC), where 40 of the patients developed BE-associated EAC during the study and 40 did not. Among FHCC patients, 33% who developed EAC had at least one esophageal biopsy with ecDNA prior to, or at EAC diagnosis. In biopsies collected before cancer diagnosis, ecDNA presence in the biopsy was enriched among patients who later developed EAC compared to patients who did not. When linked to histology data, ecDNA-positive biopsies associated with worsened histological states before cancer diagnosis (p=0.015), and also at cancer diagnosis (p=0.037), with the pre-cancer timepoint being on average 2.1 years prior to cancer diagnosis. The ecDNAs had diverse collections of oncogenes and immunomodulatory genes, and showed higher copy number states than other focal amplification types. Furthermore, ecDNAs showed increasing copy number and structural complexity in more advanced disease stages highlighting their positive selection and ongoing structural evolution. In both FHCC and Cambridge cohorts, we found an association of TP53 loss with ecDNA formation demonstrating the role of prior genomic instability to form ecDNA. In total, our findings illustrate that oncogenic ecDNA can develop early in the malignant transformation, and that they are tied to worsening patient disease status. Citation Format: Jens Luebeck, Alvin W. Ng, Patricia C. Galipeau, Xiaohong Li, Annalise Katz-Summercorn, Hoon Kim, Sriganesh Jammula, Yudou He, Roel Verhaak, Carlo C. Maley, Ludmil B. Alexandrov, Rebecca C. Fitzgerald, Thomas G. Paulson, Howard Y. Chang, Sihan Wu, Vineet Bafna, Paul S. Mischel. Extrachromosomal DNA in the cancerous transformation of Barrett’s esophagus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3130.

Surgical Pathological Features of Epileptogenic Brain Lesions: Cortical Dysplasia and Tumors

Cortical dysplasia and tumors are representative brain lesions associated with intractable epilepsy. Focal cortical dysplasia type II is characterized by cortical cytoarchitectural abnormalities, dysmorphic neurons, and balloon cells, and is associated with somatic mutations of mTOR pathway molecules. Glioneuronal and neuronal tumors, including dysembryoplastic neuroepithelial tumor and ganglioglioma, are the major tumor types for the clinical phenotype. Recently, various subtypes and characterizing molecular profiles have been recognized.

Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: Insights into pathophysiology and tissue characterization.

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

An integrated genetic analysis of epileptogenic brain malformed lesions

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

Diffusion tensor imaging discriminates focal cortical dysplasia from normal brain parenchyma and differentiates between focal cortical dysplasia types

ObjectivesAlthough diffusion tensor imaging (DTI) may facilitate the identification of cytoarchitectural changes associated with focal cortical dysplasia (FCD), the predominant aetiology of paediatric structural epilepsy, its potential has thus far remained unexplored in this population. Here, we investigated whether DTI indices can differentiate FCD from contralateral brain parenchyma (CBP) and whether clinical features affect these indices.MethodsIn this single-centre, retrospective study, we considered children and adolescents with FCD-associated epilepsy who underwent brain magnetic resonance (MRI), including DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity, were calculated in both FCD and CBP. The DTI indices best discriminating between FCD and CBP were subsequently used to assess the link between DTI and selected clinical and lesion-related parameters.ResultsWe enrolled 32 patients (20 male; median age at MRI 4 years), including 15 with histologically confirmed FCD. FA values were lower (p = 0.03), whereas MD values were higher in FCD than in CBP (p = 0.04). The difference in FA values between FCD and CBP was more pronounced for a positive vs. negative history of status epilepticus (p = 0.004). Among histologically confirmed cases, the difference in FA values between FCD and CBP was more pronounced for type IIb versus type I FCD (p = 0.03).ConclusionsFA and MD discriminate between FCD and CBP, while FA differentiates between FCD types. Status epilepticus increases differences in FA, potentially reflecting changes induced in the brain. Our findings support the potential of DTI to serve as a non-invasive biomarker to characterise FCD in the paediatric population.

Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II.

Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low-level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. We included 2 independent cohorts consisting of 21 patients with mutation-negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra-low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p-S6) in frozen brain tissues using fluorescence-activated cell sorting (FACS). We then performed deep whole-genome sequencing (WGS; >90×) in p-S6+ cells in a cohort of 11 patients with mutation-negative. Then, we simplified the method to whole-genome amplification and target gene sequencing of p-S6+ cells in independent cohort of 10 patients with mutation-negative followed by low-read depth WGS (10×). We found that 28.6% (6 of 21) of mutation-negative FCDII carries ultra-low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p-S6+ cells (average VAF=5.84%) than in bulky brain tissues (average VAF=0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. Our method facilitates the detection of ultra-low level somatic mutations, in specifically p-S6+ cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082-1093.

Developing a deep learning model to predict epilepsy recurrence in patients with focal cortical dysplasia type III.

A sizable number of patients with focal cortical dysplasia (FCD) type III-related refractory epilepsy continue to experience seizures postsurgically. Deep learning models can automatically assess complex medical image characteristics and predict prognosis with higher efficiency. This study sought to determine whether T2-weighted fluid attenuated inversion recovery (T2W FLAIR) images could predict prognosis of FCD type III-related refractory epilepsy using a deep learning approach. Magnetic resonance imaging (MRI) images of 266 patients with FCD type III diagnosed between 2015 and 2019 were included in this retrospective analysis. A deep learning algorithm utilizing a convolutional neural network (CNN) was trained to classify T2W FLAIR images according to Engel's classification. The preprocessed original image and the region of interest (ROI) outlined by clinicians were input into our neural network separately and then together. Precision, sensitivity, specificity, receiver operating characteristic (ROC) curves, and areas under the ROC curves (AUCs) were computed as part of the statistical analyses of the network performance with varied inputs of the network model assessed. The overall performance met the following metrics when the original image only was input: AUC of 96.22%, sensitivity of 84.47%, and specificity of 97.21%. The metrics were as follows when the ROI only was input: area under the ROC curve of 94.76%, sensitivity of 84.92%, and specificity of 96.24%. For the combined inputs, the metrics were as follows: AUC of 97.17%, sensitivity of 90.86%, and specificity of 96.63%. Deep learning used with conventional MRI can effectively predict the recurrence conditions of epilepsy. Artificial intelligence may help the design of clinical management and enable more precise and individualized prediction for postsurgical prognosis of FCD type III-related refractory epilepsy.