Precision Therapy for Epilepsy Related to Brain Malformations.

Malformations of cortical development (MCDs) represent a range of neurodevelopmental disorders that are collectively common causes of developmental delay and epilepsy, especially refractory childhood epilepsy. Initial treatment with antiseizure medications is empiric, and consideration of surgery is the standard of care for eligible patients with medically refractory epilepsy. In the past decade, advances in next generation sequencing technologies have accelerated progress in understanding the genetic etiologies of MCDs, and precision therapies for focal MCDs are emerging. Notably, mutations that lead to abnormal activation of the mammalian target of rapamycin (mTOR) pathway, which provides critical control of cell growth and proliferation, have emerged as a common cause of malformations. These include tuberous sclerosis complex (TSC), hemimegalencephaly (HME), and some types of focal cortical dysplasia (FCD). TSC currently represents the best example for the pathway from gene discovery to relatively safe and efficacious targeted therapy for epilepsy related to MCDs. Based on extensive pre-clinical and clinical data, the mTOR inhibitor everolimus is currently approved for the treatment of focal refractory seizures in patients with TSC. Although clinical studies are just emerging for FCD and HME, we believe the next decade will bring significant advancements in precision therapies for epilepsy related to these and other MCDs.

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

INTRODUCTION: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development. METHODS: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme. RESULTS: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses. CONCLUSION: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown.

Occult focal cortical dysplasia may predict poor outcome of surgery for drug-resistant mesial temporal lobe epilepsy.

PURPOSE: The results of surgery in patients with mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) are favorable, with a success rate over 70% following resection. An association of HS with focal cortical dysplasia (FCD) in the temporal lobe is one of the potential causes for poor surgical outcome in MTLE. We aimed to analyzed seizure outcome in a population of MTLE patients and recognize the role of occult FCD in achieving postoperative seizure control. METHODS: We retrospectively analyzed postoperative outcomes for 82 consecutive adult patients with the syndrome of MTLE due to HS, who had no concomitant lesions within temporal lobe in MRI and who underwent surgical treatment in the years 2005-2016, and correlated factors associated with seizure relapse. RESULTS: At the latest follow-up evaluation after surgery, 59 (72%) were free of disabling seizures (Engel Class I) and 48 (58,5%) had an Engel Class Ia. HS associated with FCD in neocortical structures were noted in 33 patients (40%). Analyzes have shown that dual pathology was the most significant negative predictive factor for Engel class I and Engel class Ia outcome. CONCLUSIONS: The incidence of dual pathology in patients with temporal lobe epilepsy seems to be underestimated. An incomplete epileptogenic zone resection of occult focal temporal dysplasia within temporal lobe is supposed to be the most important negative prognostic factor for seizure freedom after epilepsy surgery in MTLE-HS patients. The study indicates the need to improve diagnostics for other temporal lobe pathologies, despite the typical clinical and radiological picture of MTLE-HS.

Neuropathological spectrum of drug resistant epilepsy: 15-years-experience from a tertiary care centre.

Neuropathology of drug resistant epilepsy (DRE) has direct bearing on the clinical outcome. Classification of the most common pathologies, hippocampal sclerosis (HS) and focal cortical dysplasia (FCD) have undergone several revisions and studies on the surgical pathology of DRE employing the updated ILAE classification are scarce. Here, we report the neuropathological spectrum of 482 surgically treated cases of DRE from a single institute using the latest ILAE classifications along with clinicoradiologic correlation. Majority of the cases (324, 67.2%) had temporal lobe epilepsy (TLE), with 158 (32.8%) having extratemporal seizure focus. Among TLE, HS was most common (n = 208, 64.2%), followed by neoplasms (42, 13%), FCD (26, 8%) and dual pathology (23, 7%). Less frequent were vascular malformations (cavernoma-3, arteriovenous malformation-1), mild malformation of cortical development (mMCD, 3), gliotic lesions (5), cysticercosis (2), double pathology (2) and polymicrogyria (1). Among extratemporal epilepsies, FCD was most common (46, 29.1%), followed by neoplasms (29, 18.3%), gliotic lesions (27, 17.1%), Rasmussen encephalitis (18, 11.4%), hypothalamic hamartoma (12, 7.6%), malformations of cortical development (10, 6.3%) and vascular malformations (6, 3.8%). Less frequent were double pathology (2, cysticercosis + FCD type IIb, DNET + FCD type IIb), mMCD (2), cysticercosis (1) and dual pathology (1). No underlying pathology was detected in 12 cases (2.5%). Radiopathological concordance was noted in 83%. In 36 cases (7.5%), histopathology detected an unsuspected second pathology that included FCD type III (n = 16) dual pathology (n = 18) and double pathology (n = 2). Further, in four MRI negative cases, histopathology was required for a conclusive diagnosis.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Predicting mood decline following temporal lobe epilepsy surgery in adults.

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.

Incomplete hippocampal inversion and epilepsy: A systematic review and meta-analysis.

OBJECTIVE: Incomplete hippocampal inversion (IHI) is a relatively frequent radiological finding at visual inspection in both epilepsy and healthy controls, but its clinical significance is unclear. Here, we systematically retrieve and assess the association between epilepsy and IHI using a meta-analytic approach. Additionally, we estimate the prevalence of IHI in patients with malformation of cortical development (MCD). METHODS: We systematically searched two databases (Embase and PubMed) to identify potentially eligible studies from their inception to December 2019. For inclusion, studies were population-based, case-control, observational studies reporting on epilepsy and IHI. The risk of developing epilepsy in IHI (estimated with odds ratio [ORs]) and the frequency of IHI among patients with MCD are provided. RESULTS: We screened 3601 records and assessed eligibility of 2812 full-text articles. The final material included 13 studies involving 1630 subjects. Seven studies (1329 subjects: 952 epileptic and 377 nonepileptic) were included for the estimation of the risk of developing epilepsy in the presence of IHI. The estimated OR of active epilepsy in IHI was 1.699 (95% confidence interval = 0.880-3.281), with moderate heterogeneity across studies (I2  = 71%). Seven studies (591 patients) provided information about the frequency of IHI in MCD. Up to one third of patients with MCD (27.9%) presented coexistent IHI. SIGNIFICANCE: The present findings confirm that IHI is commonly observed in patients with MCD especially in periventricular nodular heterotopia or polymicrogyria. However, the estimated OR indicates overall weak increased odds of epilepsy in people with IHI, suggesting that the presence of isolated IHI cannot be considered a strong independent predictor for epilepsy development. Clear-cut neuroradiological criteria for IHI and advanced postprocessing analyses on structural magnetic resonance imaging scans are recommended to highlight differences between epileptogenic and nonepileptogenic IHI.

International consensus recommendations on the diagnostic work-up for malformations of cortical development.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.

Neurological outcomes of congenital Zika syndrome in toddlers and preschoolers: a case series.

BACKGROUND: Congenital Zika syndrome causes a spectrum of neurological symptoms with varying effects on function that require different therapeutic strategies. To date, this spectrum of effects and its clinical implications have not been completely described. We describe the neurological examination findings in toddlers and preschoolers, including predominant symptom complexes and comorbidities. METHODS: This study is a case-series neurological evaluation of 75 children with congenital Zika syndrome in Campina Grande, Brazil. The study is part of a cohort of children with congenital Zika syndrome that started in 2015 and is still ongoing. Children with Zika virus infection detected during pregnancy (mothers exhibited rash and were followed and diagnosed by fetal ultrasound abnormalities or RT-PCR) or through microcephaly screening after birth, using Intergrowth 21 guidelines, were selected by laboratory and radiological criteria. Children were examined during a 10-day period in September, 2018, and underwent neurological interview, examination, and assessment of functional outcomes and comorbidities. Children were divided in groups of predominant corticospinal or neuromuscular clinical signs and the associations between these groups and clinical comorbidities were assessed. FINDINGS: All of the children recruited to the study from Nov 29, 2015 to Nov 30, 2017 had imaging correlates of congenital Zika syndrome. Children were assigned to groups depending on the signs exhibited, either corticospinal or neuromuscular, with or without dyskinetic signs. 75 children completed the evaluation, 38 (51%) girls and 37 (49%) boys. Median age was 33 months (range 26-40 months; IQR 29-34). Microcephaly was present at birth in 56 (75%) children, and 19 (25%) children were born with normal head circumference, 15 of whom later developed microcephaly. Neurological examination grouped four children as having isolated dyskinetic signs, 48 children were assigned to the corticospinal group and 23 into the neuromuscular group. Dyskinetic findings were present in 30 (40%) children, either alone (four [5%]) or combined with corticospinal (19 [40%] of 48) or neuromuscular (seven [30%] of 23) findings. Comorbidities were highly prevalent, and the neuromuscular group had worse functional outcomes, evaluated by gross motor function (p=0·026), manual abilities (p=0·0013), and communication function (p<0·0005) classification scales, than the corticospinal group, whereas pneumonia (p<0·0005) and urinary tract infections (p<0·0005) were more frequent in the corticospinal group. Cortical hyperexcitability was supported by several clinical correlates, such as early onset epilepsy, persistence of primitive reflexes, and dystonia. INTERPRETATION: We describe distinct neurological profiles in the congenital Zika syndrome spectrum, with functional outcomes tending to correlate with these groups. The clinical division of children based on the disease signs proposed here is supported by the literature on central and peripheral nervous system pathology in congenital Zika syndrome. The high prevalence of dyskinetic symptoms merits special attention. FUNDING: Brazilian National Council for Scientific and Technological Development and by the Coordination for the Improvement of Higher Education Personnel.

Neuropsychological assessment and clinical evaluation in temporal lobe epilepsy with associated cortical dysplasia.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder, often associated to cognitive deficits. Focal cortical dysplasia (FCD), frequently associated to high risk of epilepsy, can lead to abnormalities in cognition. The aim of this study was to explore neuropsychological performance and to identify potential risk factors for cognitive impairment in TLE subjects with associated FCD. Our sample was composed by 46 TLE patients with FCD (37.76 ± 12.60 years; 29 females and 16 males) and 44 healthy controls (41.05 ± 9.74 years; 25 females and 19 males). All subjects performed a neuropsychological battery associated to a measurement of depression and anxiety. Results showed a poor performance of all domains of cognitive functioning and identified age of epilepsy onset as potential risk factor of cognitive impairment. These findings support the importance to focus on cognitive impairment in TLE patients with FCD to better clarify the impact of epilepsy features and FCD in therapeutic and everyday management.

Motor function in children with congenital Zika syndrome.

AIM: To evaluate gross motor function and associated factors in children with congenital Zika syndrome (CZS). METHOD: Fifty-nine children (30 males, 29 females) with CZS at a mean (SD) age of 14.7 (3.9), months (range 5-29mo) were evaluated using the Gross Motor Function Measure (GMFM) and classified according to the Gross Motor Function Classification System (GMFCS). Neurological damage was evaluated by neuroimaging. The mothers' sociodemographic characteristics and general data on the children were obtained from interviews with the mothers and from the children's medical records. Correlational and multiple regression analyses were performed to identify factors associated with these children's motor function. RESULTS: In 81% of the children, motor function impairment was severe, classified as GMFCS level V. The overall GMFM score ranged from 5 to 210 (median 18; interquartile range 11), with only four children receiving scores in the D and E dimensions. The factors found to affect motor function were the presence of severe malformations of cortical development and small head circumference at birth. INTERPRETATION: Although motor impairment may be mild in some children, it is generally severe. Severe malformations of cortical development and small head circumference at birth were factors associated with poorer motor function, reflecting the greater severity of brain damage. WHAT THIS PAPER ADDS: Motor impairment is severe in most children with congenital Zika syndrome (CZS). Motor skills are adequate or close to adequate for age in 7% of children with CZS. Severe malformations of cortical development are associated with poor motor control. Small head circumference at birth is also associated with poor motor control.

FUNCIÓN MOTORA EN NIÑOS CON SÍNDROME DE ZIKA CONGÉNITO: OBJETIVO: Evaluar la función motora gruesa y los factores asociados en niños con síndrome de Zika congénito (CZS). MÉTODO: Cincuenta y nueve niños (30 varones, 29 mujeres) con CZS a una edad media (DE) de 14,7 (3,9), meses (rango 5-29 meses) se evaluaron utilizando la Medida de la función motora gruesa (GMFM) y se clasificaron de acuerdo con el Sistema de Clasificación de la Función Motora Gruesa (GMFCS). El impacto estructural neurológico se evaluó mediante neuroimagen. Las características sociodemográficas de las madres y los datos generales de los niños se obtuvieron en entrevistas con las madres y de los registros médicos de los niños. Se realizaron análisis de regresión correlacional y múltiple para identificar los factores asociados con la función motora de estos niños. RESULTADOS: En el 81% de los niños, el deterioro de la función motora fue grave, clasificado como nivel V de GMFCS. El puntaje general de GMFM varió de 5 a 210 (mediana 18; rango intercuartil 11), y solo cuatro niños recibieron puntajes en las dimensiones D y E. Los factores que afectaron la función motora fueron la presencia de malformaciones graves del desarrollo cortical y la circunferencia de la cabeza (microcefalia) al nacer. INTERPRETACIÓN: Aunque el deterioro motor puede ser leve en algunos niños, generalmente el impacto de CZS es grave. Las malformaciones graves del desarrollo cortical y la microcefalia al nacer fueron factores asociados con una función motora más limitada, lo que refleja la mayor gravedad del daño cerebral.

FUNÇÃO MOTORA EM CRIANÇAS COM SÍNDROME CONGÊNITA DE ZIKA: OBJETIVO: Avaliar a função motora grossa e fatores associados em crianças com síndrome congênita de Zika (SCZ). MÉTODO: Cinquenta e nove crianas (30 do sexo masculino, 29 do sexo feminino) com SCZ com uma média (DP) de idade de 14,7 (3,9) meses (variação 5-29m) foram avaliadas usando a Medida da Função Motora Grossa (GMFM) e classificadas de acordo com o Sistema de Classificação da Função Motora Grossa (GMFCS). O dano neurológico foi avaliado por neuroimagem. As características sócio-demográficas da mãe e dados gerais sobre as crianças foram obtidos em entrevistas com as mães e a partir dos prontuários medicos. Análises de correlação e de regressão múltipla foram realizadas para identificar fatores associados com a função motora destas crianças. RESULTADOS: Em 81% das crianças, o comprometimento da função motora era severo, classificao como nível GMFCS V. O escore geral da GMFM various de 5 a 210 (mediana 18; intervalo interquartil 11), com apenas quatro crianças recebendo pontuações nas dimensões D e E. Os fatores que afetaram a função motora grossa foram a presença de malformações severas no desenvolvimento cortical, e o pequeno perímetro cefálico ao nascimento. INTERPRETAÇÃO: Embora a deficiência motora possa ser leve em algumas crianças, em geral ela é severa. Malformações severas no desenvolvimento cortical e o pequeno perímetro cefálico foram fatores associados com pior função motora, refletindo a maior severidade do dano cerebral.

Prevalence and clinical characteristics of malformations of cortical development and incomplete hippocampal inversion with medically intractable seizures in Chennai - A prospective study.

OBJECTIVE: To study the prevalence and clinical characteristics of malformation of cortical development (MCD) and incomplete hippocampal inversion (IHI) in adults with intractable seizures. MATERIALS AND METHODS: In this prospective study of 3220 epileptic patients in our epilepsy clinic between 2012 and 2014, 416 had intractable seizures. In all patients, a detailed clinical history, neurological examination, electroencephalography (EEG), computed tomography (CT) scan, magnetic resonance imaging (MRI) brain, and neuropsychological assessment was conducted to identify MCD and IHI. RESULTS: Out of 416 patients with intractable seizures, MCD and IHI were confirmed in 85 patients (48 males, 37 females). MCD was observed in 46 (11.05%) patients and IHI were observed in 39 (9.37%) patients. Chi square test revealed no signi cant difference between the MCD and IHI groups across the patients in different age groups, gender, type of seizure, duration and onset of seizure, seizure frequency, clustering, status epilepticus, EEG, febrile seizures, and family history. Statistically significant differences (P < 0.05) were observed between the MCD and IHI groups for change in seizure semiology and in intelligence quotient (IQ) and memory quotient (MQ) scores obtained using Wechsler's adult intelligence scale III and Wechsler's memory scale. The IHI group showed higher IQ and MQ scores when compared to the MCD group. Furthermore, IHI occurred along with MCD in 6.52% (N = 3) of the population. CONCLUSION: MCD and IHI patients are often associated with intractable complex partial seizures. Intractable epilepsy patients with normal intelligence and normal MRI should be investigated with hippocampal volumetric studies to identify the presence of IHI. Isolated IHI can be considered as a form of MCD because it mimics the clinical features of MCDs.

Can histologically normal epileptogenic zone share common electrophysiological phenotypes with focal cortical dysplasia? SEEG-based study in MRI-negative epileptic patients.

OBJECTIVE: We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome. METHODS: We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016. RESULTS: Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both "periodic" patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features. CONCLUSIONS: Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain. SIGNIFICANCE: Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.

Malformations of cortical development: New surgical advances.

Epilepsy related to malformations of cortical development is frequently drug resistant or requires heavy medication, therefore surgery is key in their management. The role of stereotactic surgery has recently changed the diagnosis and treatment of focal cortical dysplasias (FCD), hypothalamic hamartomas (HH) and periventricular nodular heterotopias (PNH). In HH, radiosurgery using Gammaknife® leads to 60 % of seizure control and is associated with excellent neuropsychological results without significant endocrine function impairment. The seizure control rate is even higher (more than 80 %) with monopolar multiple stereotactic thermocoagulations and Laser interstitial Thermal Therapy (LiTT). While the first technique is associated with a 2 % complications rate (but with excellent neuropsychological outcomes), the latest has up to 22 % side effects in some series. All three of these techniques have encouraging results, but controlled studies are still lacking to provide evidence-based new therapeutic algorithms. With regard to the PNH, surgical management has long been limited by the depth of the lesions and their close anatomical relations with the functional brain connectome. Stereotactic approaches required to perform a SEEG, to locate the part of the PNH responsible for the seizure onset, are later followed by a stereotactic lesioning procedure, therefore doubling the bleeding risk. That is why SEEG-guided radiofrequency-thermocoagulation (SEEG guided-RF-TC), which makes it possible to perform these two steps in a single procedure, was considered as a promising option. A recent meta-analysis confirmed this intuition and reported 38 % of seizure-free patients and 81 % of responders with only 0.3 % of complications, making this approach the first treatment line, followed by LiTT. Among the multiple advances in the FCD identification by non-invasive investigations, a new modality of per-operative diagnostic procedure, the three-dimensional electrocorticography may lead to simplify the preoperative investigation and enhance the accuracy of FCD delineation. Evidence is nevertheless still insufficient to validate this promising concept. Conventional surgical resection has also been concerned by significant conceptual advances during the past few years, in particular with the development of the hodotopic approach, initially in oncologic surgery. Associated with a better understanding of neuroplasticity in epilepsy and the setting up of functional mapping during SEEG or during awake surgery, the possibility of surgical resections grew up. A short-term perspective in this field, when surgical resection remains impossible, would be to target crucial nodes of the epileptic network, distinct from the core functional connectome.

Prevalence of neuropsychiatric symptoms associated with malformations of cortical development.

PURPOSE: Malformations of cortical development (MCD) are structural abnormality of the cortex or brain parenchyma with diverse clinical manifestations. Little is known about the association of psychiatric and behavioral problems in MCD. We aimed to determine prevalence and risk factors of neuropsychiatric symptoms in a cohort of adult patients with MCD. METHODS: We conducted a retrospective medical records review of 86 adult patients followed at the epilepsy clinic of the Montreal Neurological Hospital. Information on diagnosis of medical and psychiatric disorders, family history, intellectual disability, and psychiatric symptoms was obtained from their medical records. RESULTS: The cohort (n = 86) had a mean age of 39 ±â€¯14.07 (range: 18-74) years. The three most common MCD subtypes were focal cortical dysplasia (47.7%), periventricular nodular heterotopia (29.1%), and polymicrogyria (16.3%). Overall, prevalence of formally diagnosed psychiatric disorders and psychiatric symptoms were respectively 15.1% and 31.4%. The most frequently described symptoms were anxiety-related (59.3%), followed by irritability (40.7%) and agitation (37.0%). Patients with family psychiatric history (OR: 8.168, 95% CI: 1.44-46.48) and intellectual disability (OR: 5.824, 95% CI: 1.30-26.10) were significantly more likely to have psychiatric symptoms than those without. The prevalence of psychiatric symptoms did not defer between major groups of MCD. CONCLUSIONS: Neuropsychiatric symptoms are commonly associated with MCD, but psychiatric disorders may be underrecognized given that only half of the patients with psychiatric symptoms were referred for a specialized consultation. The presence of intellectual disability and family psychiatric history may help identify and predict risk of psychiatric manifestations in MCD.

Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia.

OBJECTIVE: The purpose of this study was to identify the risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia (FCD). METHODS: 77 patients with histopathologically confirmed FCD were studied. The statistical relationship between cognition levels and clinical factors at presurgical evaluation was analyzed. Cognitive function was evaluated by development quotient or intelligence quotient (DQ-IQ). RESULTS: Ages at seizure onset were younger than 15 years (mean ±â€¯SD; 5.0 ±â€¯4.2 years). Mean disease duration was 14.5 ±â€¯8.5 years. Mean age at pre-surgical DQ-IQ evaluation was 34.8 ±â€¯10.7 years. Mean DQ-IQ was 60.5 ±â€¯20.5, and 41 of 77 (53.2%) patients had mental retardation (DQ-IQ < 70). Younger seizure onset and seizure clustering were significantly associated with lower DQ-IQ (p < 0.001). A multiple regression study identified higher seizure frequency pattern, a history of epileptic spasm and status epilepticus as aggravating factors of DQ-IQ decline (R2 = 0.63, p < 0.001). On the other hand, the risk was decreased in patients with habitual focal aware seizure and transient seizure-free periods up to 6 months in the course of epilepsy. FCD location (FCD site, extent of radiological lesion and laterality) and histopathology of FCD did not affect DQ-IQ. CONCLUSIONS: Our study suggests that seizure characteristics including higher seizure frequency pattern, a history of epileptic spasm, status epilepticus, seizure clustering and early onset of seizure are risk factors of cognitive impairment in FCD patients.

Gray-matter-specific MR imaging improves the detection of epileptogenic zones in focal cortical dysplasia: A new sequence called fluid and white matter suppression (FLAWS).

Objectives: To evaluate the diagnostic value and characteristic features of FCD epileptogenic zones using a novel sequence called fluid and white matter suppression (FLAWS). Materials and methods: Thirty-nine patients with pathologically confirmed FCD and good surgery outcomes (class I or II, according to the Engel Epilepsy Surgery Outcome Scale) were retrospectively included in the study. All the patients underwent a preoperative whole-brain MRI examination that included conventional sequences (T2WI, T1WI, two-dimensional (2D) axial, coronal fluid-attenuated inversion recovery [FLAIR]) and FLAWS. An additional 3D-FLAIR MRI sequence was performed in 17 patients. To evaluate the sensitivity and specificity of FLAWS and investigate the cause of false-positives, 36 healthy volunteers were recruited as normal controls. Two radiologists evaluated all the image data. The detection rates of the FCD epileptogenic zone on different sequences were compared based on five criteria: abnormal cortical morphology (thickening, thinning, or abnormally deep sulcus); abnormal cortical signal intensity; blurred gray-white matter junction; abnormal signal intensity of the subcortical white matter, and the transmantle sign. The sensitivity and specificity of FLAWS for detecting the FCD lesions were calculated with the reviewers blinded to all the clinical information, i.e. to the patient identity and the location of the resected regions. To explore how many features were sufficient for the diagnosis of the epileptogenic zones, the frequency of each criterion in the resected regions and their combinations were assessed on FLAWS, according to the results of the assessment when the reviewers were aware of the location of the resected regions. Based on the findings of the 17 patients with an additional 3D-FLAIR scan when the reviewers were aware of the location of the resected regions, quantitative analysis of the regions of interest was used to compare the tissue contrast among 2D-axial FLAIR, 3D-FLAIR, and the FLAWS sequence. Visualization score analysis was used to evaluate the visualization of the five features on conventional, 3D-FLAIR, and FLAWS images. Finally, to explore the reason for false-positive results, a further evaluation of the whole brain FLAWS images was conducted for all the subjects. Results: The sensitivity and specificity for detecting the FCD lesions on the FLAWS sequence were 71.9% and 71.1%, respectively. When the reviewers were blinded to the location of the resected regions, the detection rate of the FLAWS sequence was significantly higher than that of the conventional sequences (P = 0.00). In the 17 patients who underwent an additional 3D FLAIR scan, no statistically significant difference was found between the FLAWS and the 3D-FLAIR (P = 0.25). All the patients had at least two imaging features, one of which was "the blurred junction of the gray-white matter." The transmantle sign, which is widely believed to be a specific feature of FCD type II, could also be observed in type I on the FLAWS sequence. The relative tissue contrast of FLAWS was higher than that of the 2D-FLAIR with respect to lesion/white matter (WM), deep gray matter (GM)/WM, and cortex/WM (P = 0.00 for all three measures) and higher than that of the 3D-FLAIR with respect to the lesion/WM (P = 0.01). The visualization score analysis showed that the visualization of FLAWS was more enhanced than that of the conventional and 3D-FLAIR images with respect to the blurred junction (P = 0.00 for both comparisons) and the abnormal signal intensity of the subcortical white matter (P = 0.01 for both comparisons). The thin-threadlike signal and individual FCD features outside the epileptogenic regions were considered the primary cause of the false-positive results of FLAWS. Conclusions: FLAWS can help in the detection of FCD epileptogenic zones. It is recommended that epileptogenic zone on FLAWS be diagnosed based on a combination of two features, one of which should be the "blurred junction of the gray-white matter" in types I and II. In type III, the combination of "the blurred junction of the gray-white matter" with "abnormal signal intensity of subcortical white matter" is recommended.

Effect of Temporal Neocortical Pathology on Seizure Freeness in Adult Patients with Temporal Lobe Epilepsy.

BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Focal cortical dysplasia is the most common dual pathology found in association with the hippocampal sclerosis. In this study, the effect of dual pathology on freedom from seizure was sought in patients with TLE. METHODS: This study performed a retrospective analysis of patients with TLE who underwent surgery between 2010 and 2017. Histopathologic analysis was performed on patients with and without dual pathology in the temporal neocortex. Seizure outcomes were compared. RESULTS: A total of 54 patients with TLE were included. The rate of overall favorable seizure outcome was found to be 96.3%. In 53.7%, dual pathology was present in the temporal cortices in addition to the hippocampal sclerosis. Patients without dual pathology showed significantly greater freedom from seizure (P = 0.02). CONCLUSIONS: Patients without dual pathology had a significantly higher seizure-free rate after anterior temporal resection than patients with dual pathology. Resection of the temporal cortex in addition to mesial temporal structures seems to be reasonable for better seizure outcome.

Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours.

PURPOSE: The age at epilepsy onset in patients with inborn or very early acquired brain lesions depends on the epileptogenic potential of the lesion and the patients' individual "susceptibility" to epileptic seizures. To gain insight into these determinants, we analysed the case history of patients with focal cortical dysplasias (FCDs) and neuroglial tumours. METHODS: In a systematic, retrospective analysis comprised of 233 patients who underwent surgery (116 with FCDs and 117 with neuroglial tumours), we evaluated the age at epilepsy onset according to histopathologic subgroups, lesion location and family history. RESULTS: Epilepsy onset was significantly earlier in patients with FCD than for those with neuroglial tumours (FCDs: 8.06 ±â€¯0.74 years, gangliogliomas: 15.86 ±â€¯1.24 years, dysembryoplastic neuroepithelial tumours (DNTs): 19.18 ±â€¯2.47 years; p < 0.00001). FCDs were most frequently located in the frontal, whereas neuroglial tumours most frequently in the temporal lobe. For FCD patients, the age at epilepsy onset was not dependent on lesion location, whereas DNTs in a temporal location were associated with a later epilepsy onset than gangliogliomas and extratemporal DNTs. A positive family history for epilepsy or epileptic seizures was found more frequently among patients with FCDs (FCDs: 20.4%, neuroglial tumours: 8.1%; p = 0.013). CONCLUSION: We postulate that the age difference at epilepsy onset between patients with FCDs and neuroglial tumours can be attributed - at least partially - to unidentified genetic factors underlying the epileptogenic potential of the brain tissue. Additionally, the large variance in the age at epilepsy onset is possibly also genetically determined.