Malformations of cortical development on fetal MRI

To investigate the role of fetal brain magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses with congenital cytomegalovirus (CMV) infection and normal neurosonography. This was a multicenter, retrospective cohort study of patients examined between 2012 and 2021 in 11 referral fetal medicine centers in Italy. Inclusion criteria were fetuses with congenital CMV infection diagnosed by polymerase chain reaction analysis of amniotic fluid, pregnancies that underwent detailed multiplanar ultrasound assessment of the fetal brain as recommended by the International Society of Ultrasound in Obstetrics and Gynecology, maternal age ≥ 18 years, normal fetal karyotype and MRI performed within 3 weeks after the last ultrasound examination. The primary outcome was the rate of central nervous system (CNS) anomalies detected exclusively on MRI and confirmed after birth or autopsy in fetuses with a prenatal diagnosis of congenital CMV infection and normal neurosonography at diagnosis. Additional CNS anomalies were classified into anomalies of the ventricular and the periventricular zone, intracranial calcifications in the basal ganglia or germinal matrix, destructive encephalopathy in the white matter, malformations of cortical development, midline anomalies, posterior fossa anomalies and complex brain anomalies. We evaluated the relationship between the incidence of structural CNS malformations diagnosed exclusively on fetal MRI and a number of maternal and gestational characteristics. Univariate and multivariate logistic regression analyses were used to identify and adjust for potential independent predictors of the MRI diagnosis of fetal anomalies. The analysis included 95 fetuses with a prenatal diagnosis of congenital CMV infection and normal neurosonography referred for prenatal MRI. The rate of structural anomalies detected exclusively at fetal MRI was 10.5% (10/95). When considering the type of anomaly, malformations of cortical development were detected on MRI in 40.0% (4/10) of fetuses, destructive encephalopathy in 20.0% (2/10), intracranial calcifications in the germinal matrix in 10.0% (1/10) and complex CNS anomalies in 30.0% (3/10). On multivariate logistic regression analysis, only CMV viral load in the amniotic fluid, expressed as a continuous variable (odds ratio (OR), 1.16 (95% CI, 1.02-1.21); P = 0.02) or categorical variable (> 100 000 copies/mL) (OR, 12.0 (95% CI, 1.2-124.7); P = 0.04), was independently associated with the likelihood of detecting fetal anomalies on MRI. Associated anomalies were detected exclusively at birth and missed by both prenatal neurosonography and fetal MRI in 3.8% (3/80) of fetuses with congenital CMV infection. Fetal brain MRI can detect additional anomalies in a significant proportion of fetuses with congenital CMV infection and negative neurosonography. Viral load in the amniotic fluid was an independent predictor of the risk of associated anomalies in these fetuses. The findings of this study support a longitudinal evaluation using fetal MRI in congenital CMV infection, even in cases with negative neurosonography at diagnosis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Malformations of cortical development (MCDs) comprise a variable spectrum of clinical, neuroradiologic, and histopathologic findings. MCDs are increasingly recognized as significant causes of epilepsy, developmental delays, and congenital neurologic deficits. The aim of this study was to determine the types, relative frequencies, and clinical and imaging features of MCDs. Data were collected in 2 hospitals and a medical imaging center during a 9-year period. Twenty-six patients (17 men and 9 women; age range, 5 mo to 29 y; mean age, 10.8 y) with an MCD were evaluated. The results of magnetic resonance imaging studies were retrospectively reviewed for type, extension, and classification of the malformations and for associated findings. Clinical findings were obtained by a review of the patients' medical records. Of the patients studied, epilepsy was present in 65%, mental and/or motor retardation was identified in 34.6%, and skin lesions were noted in 15%. The following types of MCD were identified: malformations of the heterotopic gray matter in 35% of the subjects, focal cortical dysplasia (23%), subependymal and cortical tubers (19%), pachygyria (15%), polymicrogyria (15%), schizencephaly (15%), and type 1 lissencephaly (8%). Approximately, 27% of the subjects had the following other types of cerebral malformation: callosal agenesis (8%), ventriculomegaly (8%), or agenesis of the septum pellucidum (4%). Our study indicated that the most common forms of MCD are heterotopia and focal cortical dysplasia. Patients with an MCD tended to have a higher prevalence of epilepsy, developmental delays, and neurologic deficits. Most patients with heterotopia had other malformations of cortical dysplasia. Some patients with an MCD also exhibited other malformations of the brain.

To determine the diagnostic accuracy of fetal magnetic resonance (MR) imaging for malformations of cortical development by using postnatal MR imaging as reference standard. Eighty-one patients who had undergone fetal and postnatal MR imaging of the brain were identified in this institutional review board-approved, HIPAA-compliant study. Images were retrospectively reviewed in consensus by two pediatric neuroradiologists who were blinded to clinical information. Sensitivity and specificity were calculated according to retrospective review of the images and clinical reports for fetal MR images. The Fisher exact test was used to compare results for fetuses imaged before and after 24 gestational weeks and for image review versus clinical reports for fetal MR images. Median gestational age at fetal MR imaging was 25.0 weeks (range, 19.71-38.14 weeks). Postnatal MR imaging depicted 13 cases of polymicrogyria, three cases of schizencephaly, and 15 cases of periventricular nodular heterotopia. Sensitivity and specificity of fetal MR imaging were 85% and 100%, respectively, for polymicrogyria; 100% each for schizencephaly; and 73% and 92%, respectively, for heterotopia. When heterotopia was seen in two planes, specificity was 100% and sensitivity was 67%. Sensitivity for heterotopia decreased to 44% for fetuses younger than 24 weeks. According to reports for fetal MR images, prospective sensitivity and specificity, respectively, were 85% and 99% for polymicrogyria, 100% and 99% for schizencephaly, and 40% and 91% for heterotopia. Fetal MR imaging had the highest sensitivity for polymicrogyria and schizencephaly. Specificity was 100% for all cortical malformations when the abnormality was seen in two planes. Sensitivity for heterotopia was lower for fetuses younger than 24 weeks. Knowledge of the gestational age is important, especially for counseling patients about heterotopia.

INTRODUCTION With the advent of minimally invasive surgical approaches for medically refractory epilepsy, we now have the ability to target specific epileptogenic foci with great precision. Previous studies have recognized the importance of complete resection of malformations of cortical development (MCD) in the success of epilepsy surgery. However, many of these lesions escape detection using standard epilepsy protocol MR imaging. This study seeks to evaluate the concurrence of radiographic and histopathologic findings of MCD in patients with refractory temporal lobe epilepsy (TLE) and describe the predictive value of interictal scalp EEG findings in the detection of MCD in an effort to inform surgical decision-making processes. METHODS We retrospectively identified 34 patients who underwent surgical resection for treatment of medically refractory TLE over a 10 yr period at Northwestern University. Preoperative MRI reports, VEEG reports, and postoperative surgical pathology reports were used to correlate radiographic findings of MCD with histopathologic findings of MCD and identify the predictive value of scalp video EEG (VEEG) abnormalities in the detection of MCD. RESULTS We found that 66.7% of focal cortical dysplasias (FCD) identified on pathology and all cases of histopathologically confirmed mild MCD were missed on preoperative MRI. The finding of a rhythmic or continuous interictal abnormality on preoperative VEEG corresponded to a sensitivity of 73.1% and a specificity of 62.5% in detecting either FCD or mild MCD. Of the patients who had a missed FCD on MRI, 80% had continuous or rhythmic interictal abnormalities on EEG. CONCLUSION MCDs are highly prevalent in medically refractory TLE and many of these MCDs are missed on preoperative MRI. The presence of a continuous and/or rhythmic interictal abnormality on scalp VEEG is suggestive of underlying MCD. The presence of one or both of these interictal findings may support the value of performing an intracranial EEG procedure prior to employing an ultraprecise minimally invasive surgical treatment option such as laser ablation.

Objective To approach the clinical pathological characteristics of epilepsy with malformations of cortical development(MCD).Method The clinical information and pathologic characteristic were studied retrospectively in 57 cases of epilepsy with MCD.Results Among the total operated epilepsy cases,the percentage of epilepsy with MCD was 43%(57/132).The ratio between man and woman was 3.8 to 1.0.The average age was 25.4 years old.The average history of epileptic attack was 10.4 years.Among the 57 cases of epilepsy with MCD,there were 8 cases in major disruption;8 cases in microdygenesis(MD);41 cases in focal cortical dysplasia(FCD).In FCD,there were 13 cases in FCD Ⅰ A;15 cases in FCD Ⅰ B;7 cases in FCDⅡA;6 cases in FCDⅡB.Further more,22 cases were accompanied with hippocampal sclerosis;1 case of FCDⅡB with dysembryoplastic neuroepithelial tumors(DNT);1 case of FCDⅡB with gangliogiiomas(GGs).Conclusions There is a close relationship between MCD and epilepsy:FCD Ⅰ type is the most common subtype of MCD;many cases have hippocampal sclerosis. Key words: Epilepsy; Focal cortical dysplasia; Pathology

Objective: To summarize the clinicopathological characteristics of "difficult to locate" intractable epilepsy patients, and investigate the causes of difficulty in their location. Method: Retrospective analysis was performed on the clinical data of 58 patients who underwent resection of the epileptogenic zones after intracranial electroencephalography (iEEG) detection at the Department of Neurosurgery of the First Affiliated Hospital of Fujian Medical University from January 2010 to December 2018. Clinicopathological characteristics and lesion lobes of "difficult to locate" intractable epilepsy were summarized. The prognosis of patients was assessed according to Engel grading.Univariate and multivariate logistic regression analysis were used to investigate the relevant factors affecting the prognosis of patients with "difficult to locate" intractable epilepsy related to malformation of cortical development(MCD). Results: Among the 58 patients, there were 47 cases of MCD (12 cases with mild malformation of cortical development (mMCD), 35 cases with focal cortical dysplasia (FCD)), and 11 cases of other types. Among the 47 MCD cases, univariate analysis showed that patients with preoperative magnetic resonance imaging(MRI) positive and completed resection of the epileptogenic zones had better prognosis (P<0.05). Multivariate analysis indicated that completed resection of epileptogenic zones was an independent factor affecting the postoperative efficacy of MCD (P=0.013,Wald χ(2)=6.149, 95%CI: 0.07-0.56). And among the 47 MCD cases, 18 cases were with mono-lobar lesions and 29 cases were with multi-lobar lesions, however, there was no significant difference of the efficacy between the two groups (P=0.511). Conclusions: MCD, especially FCD, is the main pathological types of patients with "difficult to locate" intractable epilepsy. Multi-lobar pathological changes, especially multi-lobar MCD, are the main reasons of being difficult to locate, however, accurate locating of epileptogenic zones and functional areas via effective use of iEEG can achieve satisfactory efficacy in these patients after resection of the epileptogenic zones.

Although the causes of some malformations of cortical development (MCD) have been established, others remain unclear. There are several lines of evidence supporting the theory of a complex mechanism that involves genetic and environmental factors. To investigate the interrelationship of genetics and prenatal injury in the genesis of MCD. A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of prenatal events. Whenever possible, magnetic resonance imaging was performed in other family members if MCD was suspected or in the presence of any neurological impairment. Patients were divided into 3 groups according to the type of MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria or schizencephaly. These findings were also compared with a disease-control group of 40 consecutive patients with epilepsy but without MCD. Neurology clinic of a university hospital. Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia, 19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria or schizencephaly. There were 39 men and 37 women, aged 2 to 52 years (mean age, 13 years). In group 2, 6 patients (32%) had a family history of MCD, mental retardation, or miscarriages, suggesting a genetic predisposition. In group 3, family history of MCD was present in 5 patients (14%). Prenatal events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria (P<.001). Conversely, epilepsy occurred in all patients in group 1, in 17 patients (89%) in group 2, and in 17 patients (47%) in group 3. In group 3, epilepsy was less frequent (P<.001) and also more easily controlled (P =.005) than in other forms of MCD. Our findings support the idea of a spectrum among the different types of MCD. Focal cortical dysplasia (group 1) is associated with more frequent and severe epilepsy and less important genetic and prenatal events, heterotopias and agyria-pachygyria (group 2) are frequently associated with genetic predisposition, and polymicrogyria and schizencephaly (group 3) are less frequently associated with epilepsy but have a stronger association with genetic and detectable prenatal events.

Background: Malformations of cortical development (MCD) comprise a vast and heterogeneous group of disrupted cerebral cortex formation. The MCD may be classified according to the predominant embryological stage compromised: a) abnormal proliferation or increased apoptosis of neurons or glial cells (microcephaly, hemimegalencephaly, focal cortical dysplasia - FCD); b) abnormal neuron migration (heterotopia, lissencephaly-pachygyria); c) abnormal cortical organization (polymicrogyria, schizencephaly). MCDs are the most common cause of refractory focal epilepsy in adults after hippocampal sclerosis and the most frequent in children. Objective: To evaluate seizure outcomes in patients with different types of epilepsy caused by MCD other than FCD. Methods: The clinical data of 36 patients with MCD (excluding FCD) and epilepsy from tertiary center outpatient clinics were obtained from medical records. Results: The mean follow-up was 19.5 years. Two patients had hemimegalencephaly, 14 heterotopia (2 double cortex and 12 nodular heterotopia), 8 polymicrogyria, 7 schizencephaly associated with polymicrogyria, and 5 had schizencephaly associated with polymicrogyria and heterotopia. One patient underwent callosotomy and 4 patients underwent resective surgery: 2 with associated FCD (1 with hemimegalencephaly and 1 with polymicrogyria), and 2 with associated hippocampal sclerosis (1 with nodular heterotopia and 1 with polymicrogyria, schizencephaly and heterotopia combined). Of these, one (25%) was seizure-free after the procedure, one (25%) was classified as Engel IB, one (25%) as class IIA, and one (25%) as class IVA. Only 2 patients were without antiseizure medication (one after surgery and one not operated). The remaining patients were taking 1 to 5 ASM (mean 2.6). Five of the 36 (14%) patients were seizure-free for at least one year: 3 with nodular heterotopia, 2 with polymicrogyria, and one with polymicrogyria, schizencephaly, and heterotopia combined. The mean seizure frequency was 23.5 per month in patients with nodular heterotopia, 15.5 per month in those with double cortex, 38.5 per month in those with polymicrogyria, 2 per month in those with polymicrogyria with schizencephaly, 14 per month in those with polymicrogyria, schizencephaly, and heterotopia combined. Family history of epilepsy was present in 10/36 (28%): 2 patients with nodular heterotopia, one with double cortex, one with polymicrogyria, 4 with polymicrogyria and schizencephaly, and one with polymicrogyria, schizencephaly, and heterotopia combined. Conclusion: This tertiary center cohort study characterizes the clinical data from patients with cortical malformation other than FCD. Interestingly, a few patients (14%) were under seizure control with the use of ASM. Among the four patients who underwent surgical treatment, excluding callosotomy, 3 (75%) had significant improvement (Engel IA-IIA).

To report on six patients with SCN1A mutations and malformations of cortical development (MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features. Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging (MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children. The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia (PNH) in two patients and focal cortical dysplasia (FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy (SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality. MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome.

Malformation of Cortical Development (MCD) corresponds to a broad spectrum of cerebral lesions resulting from cortical development abnormalities during embryogenesis. MCD are increasingly recognized as an important cause of epilepsy, especially refractory ones. Aims: Evaluation of pattern and clinical spectrum of MCD. Patients and methods: The data of children presented to the Pediatric Department, or Pediatric Neurology Clinic, Sohag University Hospital whom Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) brain showing MCD were collected retrospectively regarding their history, examinations, and developmental parameters, Electroencephalography (EEG), Intelligence Quotient (IQ). Results: during the study periods we reviewed the data of 50 Child with MCD, the mean age of the study group was 3.7 years with age range from 4 days to 15 years. The majority of the patients (50%) belonged to the age group 1-5 years old. Convulsions were the main complaint in the majority of children 21 (42%) out of 50 child, followed by global developmental delay in 20 out of 50 child. Seizures generally were present in (82%). Concerning type of seizures, multiple seizure types were found in 16 (39%) out of 41 child, partial seizures found in 13 (31.7%), generalized tonic in 6 (14.6%), infantile spasm in 4 (9.8%), and generalized tonic-clonic in 2 (4.8%). Types of malformation of cortical development in the studied children as defined by neuro-imaging, (42%) had lissencephaly, (16%) had bilateral Schizencephaly, (12%) had unilateral schizencephaly, (12%) had polymicrogyria, (10%) had focal cortical dysplasia, (6%) had periventricular heterotopia, and one child with subcortical laminar heterotopia. Conclusion: The common cortical malformations found in Sohag University Hospital were lissencephaly, bilateral Schizencephaly, unilateral schizencephaly. Also the most common clinical features of MCDs in our community are refractory seizures and/or global developmental delay, and the most valuable tool in diagnosis is brain MRI. Recommendations: Informing pediatricians to raise their clinical suspicion to MCDs in children presented by frequent, intractable, early onset, and partial or multiple types’ seizures and/or global developmental delay, and that MRI brain must be done then.

Genotypic and phenotypic analysis of epilepsy associated with NPRL2/NPRL3 genes.

Neuropsychological functioning in children and adolescents with pharmacoresistant epilepsy due to malformations of cortical development.

Malformations of cortical development (MCDs) are an important cause of pharmacoresistent epilepsy and are frequently diagnosed in surgical pathology. The lack of uniform tissue processing and standard histopathologic nomenclature to describe MCDs has resulted in diagnostic ambiguity. To describe the immunohistochemical findings of MCDs from a relatively large surgical epilepsy cohort and incorporate terminology that more adequately reflects the histopathologic findings into a contemporary classification of MCD. Utilizing the Mayo Clinic Rochester Surgical Pathology Database and patient records, 53 patients with previous intractable epilepsy and a known malformation of cortical development were identified. All of the cohort's paraffin embedded surgical specimens were resectioned and stained with hematoxylin-eosin, Luxol fast blue/cresyl violet, neurofilament protein, and glial fibrillary acidic protein. Each specimen was reviewed histologically and categorized according to a proposed focal MCD classification scheme that substitutes cytoarchitectural dysmorphism for cortical dysplasia and architectural disorganization for microdysgenesis. An MCD was recognized in 49 patients and grouped into 1 of the following 4 categories: (1) cytoarchitectural dysmorphism with balloon cells (n = 19), (2) cytoarchitectural dysmorphism without balloon cells (n = 12), (3) architectural disorganization (n = 8), or (4) polymicrogyria (n = 9). The histopathologic features of focal MCD in a large epilepsy surgical cohort by using practical immunohistochemistry and a contemporary MCD classification scheme are described. It is proposed that the term focal cortical dysplasia be renamed as focal malformations of cortical development.

Purpose:Malformation of cortical development(MCD) constitutes an important etiology of intractable epilepsy and is considered an indication for surgical treatments, though their efficacy is limited and variable depending on MCD's location or distribution. Ketogenic diets are widely known to be effective, but as little study has been made concerning their efficacy on epilepsy with MCD, we evaluated the efficacy of ketogenic diets on MCD patients compared with that of epileptic surgery, which is more invasive. Methods:We performed retrospective studies and analyse on 30 patients with MCD diagnosed by brain MRI and treated with ketogenic diets for intractable epilepsy since 1998, checking decreases in their seizure episodes after starting the diets. Results:Cortical dysplasia was observed in 24(80.0 percent) patients as the most common type of MCD. Also, MCD was observed in unilateral hemisphere most commonly, in 23(76.7 percent) patients; it was observed in both hemispheres in 7(23.3 percent) patients. Nine(30.0 percent) out of 30 patients became seizure-free after starting ketogenic diets, and 14(46.7 percent) patients experienced 50 percent seizure reductions as well. Age of starting the diet or the duration of epilepsy period before starting showed no statistical relationship with the efficacy of the diet. Though the younger the patient and the longer the treatment the more effective the diet seemed to be, there was no statistical correlation between them. The location of MCD showed no significance neither. Conclusion:Considering various limits and invasiveness of surgical treatment, a ketogenic diet could be a good tool in treating children with intractable epilepsy with MCD.

Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust