Functional MRI study of the brain with malformations of cortical development

The most common subtypes of malformations of cortical development (MCDs) are gray matter heterotopia (GMH), focal cortical dysplasia (FCD), and polymicrogyria (PMG). This study aimed to characterize the possible neurometabolic abnormalities and heterogeneity in different MCDs subtypes using proton magnetic resonance spectroscopy (1H-MRS). In this prospective cross-sectional study, we recruited 29 patients with MCDs and epilepsy, including ten with GMH, ten with FCD, and nine with PMG, as well as 25 age- and sex-matched healthy controls (HC) from the Epilepsy Center of West China Hospital of Sichuan University between August 2018 and November 2021. Inclusion criteria for the patients were based upon typical magnetic resonance imaging (MRI) findings of MCDs and full clinical assessment for epilepsy. Single-voxel point-resolved spectroscopy was used to acquire data from both the lesion and the normal-appearing contralateral side (NACS) in patients and from the frontal lobe in HC. Metabolite measures, including N-acetyl aspartate (NAA), myoinositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glx) concentrations, were quantitatively estimated with linear combination model (LCModel) software and corrected for the partial volume effect of cerebrospinal fluid (CSF). The NAA concentration was lower and the Ins concentration was higher in the MCDs lesions than in the NACS and in HC (P=0.002-0.007), and the Cho and Cr concentrations were higher in MCDs lesions than in HC (P=0.001-0.016). Moreover, the Cho concentration was higher in NACS than in HC (P=0.015). In the GMH lesions, the only metabolic alteration was an NAA reduction (GMH_lesion vs. HC: P=0.001). In the FCD lesions, there were more metabolite abnormalities than in the other two subtypes, particularly a lower NAA and a higher Ins than in HC and NACS (P=0.012-0.042). In the PMG lesions, Cr (lesion vs. HC or NACS: P=0.017-0.021) and Glx (lesion vs. NACS: P=0.043) were increased, while NAA was normal. Correlation analysis revealed that the Cr concentration in MCDs lesions was positively correlated with seizure frequency (r=0.411; P=0.027). Based upon 1H-MRS, our study demonstrated that different MCDs subtypes exhibited variable metabolic features, which may be associated with distinct functional and cytoarchitectural properties.

Objective To evaluate the value of magnetic source imaging(MSI) in localizing the epileptic foci of patients with histologically proved grey matter heterotopia(GMH) and seizure. Methods MSI examinations were performed on 8 patients with GMH and seizure. The location of the epileptic foci defined by MSI was compared with the results of the ECoG. After imaging examinations, all patients received operation with 13-48 months follow up to observe the effectiveness of the operation. Results Among the 8 patients, 1 had hippocampal sclerosis,2 had focal cortical dysplasiaof type Ⅰ B and 1 had focal cortical dysplasia of type Ⅱ B. MRI showed normal findings in 2 cases, subcortical heterotopia in 4 cases, and nodulor heterotopia in 2 cases with one having schizencephaly. The epileptic foci defined by MSI were at right temporal lobe in 2 cases, left frontal lobe in 2 cases, biparietal lobe in1 case, left parietal lobe in 1 case, left temporal lobe in 1 case, and left frontal-parietal lobe in 1 case. The epileptic foci defined by MSI were completely overlaid with area of GMH in 4 cases, closely behind the area of GMH in case, and partly overlaid with area of GMH in 1 cases with size larger than that of the latter. One patient showed two epileptic foci with one located within the area of GMH and the other one 2 centimeters anterior to the area of GMH.One case's epileptic focus located 2 centimeters posteolateral to the area of GMH . The locations of the epileptic foci defined by MSI showed no difference with those defined by ECoG in all patients. According to Engel classification of treatment effect of epilepsy, 6 patients achieved Engle class Ⅰ ( seizure free after operation ), and 2 patients Engel class Ⅳ ( no changes in the frequcenty of occurrence of seizures before and after operation ). Conclusion MSI can noninvasively and precisely localize the epileptic foci before operation in patients with GMH and seizure. Key words: Epilepsy; Magnetoencephalography; Magnetic resonance imging

Malformations du développement cortical : quelles stratégies ?

Malformations of cortical development (MCDs) are a frequent cause of drug-resistant epilepsy and a common indication for resective epilepsy surgery. As magnetic resonance imaging (MRI) lacks sensitivity for subtle MCDs, supplemental diagnostic tools are needed. This study aimed to characterize scalp electroencephalographic (EEG) patterns in MCDs and investigate their association with surgical outcomes. This was a retrospective case-control study including patients who underwent inpatient video-EEG monitoring at two Australian hospitals. Cases were individuals with MCDs confirmed on MRI or histopathology; controls included patients with other focal epilepsies. Two epileptologists independently reviewed interictal and seizure-onset EEG patterns using a standardized classification framework. Patterns were compared between cases and controls and assessed with respect to postoperative seizure outcomes, adjusting for antiseizure medication reduction. We included 38 cases with MCDs (52.6% females, median age = 34 years) and 114 controls (45.6% females, median age = 41 years). Among interictal patterns, repetitive epileptiform discharges type 1 and type 2 were more prevalent in patients with MCDs than controls (p = .002 and .005, respectively). Focal fast epileptiform discharges were also more frequent in MCD patients, after excluding nonlesional focal epilepsy controls (p = .038). Among seizure-onset patterns, paroxysmal fast activity was more prevalent in MCDs (p < .001). Among 38 patients who underwent surgery, 70.0% of MCDs and 75.0% of controls had favorable outcomes. No EEG pattern predicted postoperative seizure outcomes. Distinct scalp EEG patterns may support differentiation of MCDs from other focal epilepsies. Larger prospective studies are needed to clarify their role in detecting MRI-negative MCD or guiding targeted imaging.

Differential electrographic seizure patterns in malformations of cortical development, early life brain injury, and later life brain injury

The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non-lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

Objective:Periventricular nodular heterotopia (PVNH) is a malformation of cortical development (MCD) characterized by aggregates of gray matter adjacent to the lateral ventricular walls. Clinical presentation is heterogeneous with higher rates of seizures and reading impairments typically in the setting of average IQ (Felker et al. 2011). The majority of neuropsychological inquiry has focused on reading fluency, though a single case study showed a neurocognitive profile consistent with nonverbal learning deficits in a 7-year old boy with suspected autosomal dominant bilateral heterotopia (McCann et al., 2008). Given the periventricular focus and potential for unilateral presentations, non-linguistic neurocognitive sequelae may be expected in cases affecting the non-dominant hemisphere, yet this remains largely unexplored. Surgical ablation by laser interstitial thermal therapy (LITT) is increasingly used for epilepsy management in PVNH (Thompson et al., 2016, Whiting et al. 2020). However, there are no reported studies exploring cognitive outcomes following LITT of focal PVNH.Participants and Methods:A 46-year-old, right handed, Black female with 16 years of education presented for management of medically refractory epilepsy. Epilepsy monitoring captured intermittent slow waves in the right temporal lobe, interictal polyspikes in the right temporal lobe, and three epileptic events all emanating from the right temporal lobe. MRI showed extensive migrational anomalies involving the right hemisphere posteriorly consistent with PVNH with no associated mesial temporal sclerosis. Pre-surgical neuropsychological evaluation showed a significant split in IQ, with verbal IQ = 99 and performance IQ = 76. Testing indicated circumscribed deficits in visuoperceptual judgement, visuoconstruction, visuospatial reasoning, non-verbal recall, and several executive weaknesses in the context of otherwise average neurocognitive functioning. Fine motor speed was impaired bilaterally. Her profile was suggestive of non-dominant fronto-parieto-temporal dysfunction, concordant with the remainder of her work-up. By history she reported longstanding academic weaknesses in math and organization with strong verbal and reading abilities.Results:The patient underwent partial LITT of right PVNH sparing areas involved in visual function. At 6-month follow-up she was seizure free (Engel outcome 1A). Post-surgical neuropsychological evaluation showed reliable improvements in perceptual reasoning, aspects of learning/memory, and verbal naming. Visuoconstruction remained impaired but qualitatively improved. She also reported subjective experience of improved mental clarity and was applying for jobs after regaining driving privileges.Conclusions:This case demonstrates symptoms and history concerning for a nonverbal learning disorder in an adult woman with epilepsy secondary to right hemisphere PVNH and underscores the importance of exploring the range of neurocognitive profiles in MCD. Her notable neurocognitive and functional improvements following surgical ablation and seizure freedom suggest a possible release of function in the absence of inhibitory neurophysiological influences. This raises interesting questions about the endurance of her developmental profile. This case report contributes to our understanding of neuroanatomical correlates of neurocognitive and neurodevelopmental presentations. Future investigations should explore neuropsychological changes following LITT for PVNH.

Epilepsy surgery in children and adolescents with malformations of cortical development—Outcome and impact of the new ILAE classification on focal cortical dysplasia

To elucidate the biological significance of dysplastic cells in malformations of cortical development, an immunohistochemical study was performed to investigate fibroblast growth factor-2 (FGF-2) expression in corticectomy specimens from epilepsy patients, including focal cortical dysplasia (FCD) with balloon cells (BCs) (n=4; age/sex=2M, 14F, 24M, 45M), tubers of tuberous sclerosis complex (TSC-tubers) (n=2; 1F, 3F), FCD without BCs (n=3; 23F, 23M, 25M), and gliotic lesions (n=3; 12M, 25M, 29M). The nucleus and/or cytoplasm of astrocytes in all cases examined were positive for FGF-2; however, FGF-2 immunoreactivity was not detected in oligodendroglial cells. In all dysplastic lesions, FGF-2 was detected in the astrocytic nuclei, and cytoplasm and/or nuclei of BCs. Dysplastic neurons (DNs) in FCD with BCs and TSC-tubers were variably positive for FGF-2 in the cytoplasm, but FGF-2 was not detected in the neurons of FCD without BCs. The number of FGF-2 immunoreactive cells (FGF-2-IR%) in FCD with BCs (46.0+/-4.1%) was higher than that in FCD without BCs (19.8+/-3.1%) and gliotic lesions (19.5+/-3.3%) with statistical significance (P<0.001). These results, together with previous reports showing FGF-2 expression in neuroblasts and glioblasts in human fetal brain, and mainly in astrocytes in adult brain, suggest that FGF-2 expression in MCDs reflects incomplete differentiation and maturation of dysplastic cells, and that FGF-2-IR% is associated with histological subtypes of MCD, reflecting the timing of insults underlying the pathogenesis of each disorder.

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). 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. 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. 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.

We examined the localization of cerebral functions in 28 patients with focal epilepsy and malformations of cortical development (MCDs). Polymicrogyria occurred in nine, hemimegalencephaly in four, heterotopia in eight, and focal cortical dysplasia (FCD) in nine cases. We used simple (sensomotor, visual) or complex (language, memory) functional magnetic resonance imaging (fMRI) paradigms. Two thirds of MCDs were activated by simple fMRI paradigms, whereas they less frequently showed activity during complex cognitive fMRI paradigms. During simple paradigms, all disturbances of cortical organization (polymicrogyria, schizencephaly, and mild-type FCD) showed activity, whereas other MCDs (disturbances of earlier steps of cortical development: hemimegalencephaly, Taylor-type FCD, and heterotopia) showed activity in only 44% (p < 0.01). The association between the pathophysiology and morphology of MCDs confirms the recently proposed classification system. Both focal neurological signs (p < 0.05) and focal electroencephalogram slowing (p < 0.05) independently correlated with MCD inactivity, confirming that fMRI showed neuronal functions of MCDs. Conclusively, fMRI visualizes the MCD functions and their relationship to the eloquent cortex, providing useful information before epilepsy surgery. Surgery of cortical organization disturbances should be cautiously performed because these malformations may participate to some degree in brain functions.

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.

Objective To explore the clinicopathologic features, diagnosis and differential diagnosis methods of focal cortical dysplasia (FCD)Ⅱb. Methods The clinical and pathologic findings of 8 FCDⅡb patients were examined by the gross, microscopic and immunohistochemical methods. Results All the cases were drug-resistant epilepsy patients with the onset in childhood. Most of the patients with epilepsy semiology were the complex partial seizure. Histology features included cortical disorganization, dyslamination, blurred grey and white matter boundary, mouse anti-nonphosphorylated neuronfilament H positive dysmorphic neurons and balloon cells. The balloon cells were enlarged cells with opalescent glassy eosinophilic cytoplasm and with mostly immunohistochemical staining as vimentin, nestin (+ ) and neun, glial fibrillary acidic protein (-). Conclusion Comprehensive analyses of clinical, radiological, microscopic and immunohistochemical findings were important to the accurate diagnosis of FCDⅡb and the critical preoperative localization was crucial for the better prognosis. Key words: Epilepsy; Malformation of cortical development; Biopsy; Balloon cells

Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Precision Therapy for Epilepsy Related to Brain Malformations.