The Frequency of Focal Cortical Dysplasia-Like Histologic Features Near Adult-Type Diffuse Gliomas.

While the coexistence of focal cortical dysplasia (FCD) and grade 1 noninfiltrative gliomas has been described, to date, only rare case reports have described FCD adjacent to infiltrating gliomas. We therefore sought to determine how often FCD-like findings occur near adult-type diffuse gliomas. This was a retrospective survey of 186 consecutive, newly diagnosed, en bloc glioma resections. Fifty-nine (31.7%) had sufficient adjacent cortex to evaluate for FCD-like features. Among IDH mutant ("IDHmut") gliomas, 40/77 (52%) had adjacent evaluable cortex, whereas only 19/109 (17%) of IDH wild-type ("IDHwt") gliomas did (p < 0.0001). Among cases with evaluable cortex, 15 (25.4%) contained features suggestive of FCD, including radial/tangential dyslamination and/or maloriented neurons. In a multivariable analysis, increasing glioma grade (OR = 4.0, 95% CI = 1.2-13.5, p = 0.027) and IDHmut (OR = 6.5, 95% CI = 1.3-32.2, p = 0.022) emerged as independently positive correlates with the appearance of FCD-like findings. However, FCD-like features were also found in 13/32 (40.6%) cortical samples from adult brains without any neoplastic disease or seizure histories (p = 0.16). Together, these data suggest that, while FCD-like histologic features can be incidentally found in at least a subset of diffusely infiltrative gliomas, the frequencies are not significantly different from that seen in otherwise non-neoplastic brains, and are therefore most likely nonpathologic.

Circulating MicroRNAs from Serum Exosomes May Serve as a Putative Biomarker in the Diagnosis and Treatment of Patients with Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a congenital malformation of cortical development where the cortical neurons located in the brain area fail to migrate in the proper formation. Epilepsy, particularly medically refractory epilepsy, is the most common clinical presentation for all types of FCD. This study aimed to explore the expression change of circulating miRNAs in patients with FCD from serum exosomes. A total of nine patients with FCD and four healthy volunteers were enrolled in this study. The serum exosomes were isolated from the peripheral blood of the subjects. Transmission electron microscopy (TEM) was used to identify the exosomes. Both exosomal markers and neuronal markers were detected by Western blotting analysis to prove that we could obtain central nervous system-derived exosomes from the circulation. The expression profiles of circulating exosomal miRNAs were assessed using next-generation sequencing analysis (NGS). We obtained a total of 107 miRNAs with dominant fold change (>2-fold) from both the annotated 5p-arm and 3p-arm of 2780 mature miRNAs. Based on the integrated platform of HMDD v3.2, miRway DB and DIANA-miRPath v3.0 online tools, and confirmed by MiRBase analysis, four potentially predicted miRNAs from serum exosomes in patients with FCD were identified, including miR194-2-5p, miR15a-5p, miR-132-3p, and miR-145-5p. All four miRNAs presented upregulated expression in patients with FCD compared with controls. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and pathway category of four target miRNAs, we found eight possible signaling pathways that may be related to FCD. Among them, we suggest that the mTOR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, and cell cycle regulation and TGF-beta signaling pathway are high-risk pathways that play a crucial role in the pathogenesis of FCD and refractory epilepsy. Our results suggest that the circulating miRNAs from exosomes may provide a potential biomarker for diagnostic, prognostic, and therapeutic adjuncts in patients with FCD and refractory epilepsy.

Single stage epilepsy surgery in children and adolescents with focal cortical dysplasia type II - Prognostic value of the intraoperative electrocorticogram.

OBJECTIVE: To evaluate prospectively the informative/prognostic value of epileptic discharges in the post-resection ECoGs of children with drug-resistant epilepsies and Focal Cortical Dysplasia type II (FCD-II). METHODS: Included were consecutive patients with focal epilepsies and suspected FCD-II who were planned for single-stage epilepsy surgery based on non-invasive presurgical evaluation results. Intraoperative ECoGs were recorded using a 32-channel system with strip- and/or grid-electrodes. Spikes were defined as transients with a mainly negative component and duration of 20-70 ms. Fast activity was defined as rhythmic bursts of polyspikes >13 Hz. All ECoGs were analysed visually. The significance of both spikes and fast activity in the post-resection ECoG for seizure outcomes 24 months after surgery was evaluated. RESULTS: Data from 18 patients (five girls) were analysed. 10/18 patients (55.6%) showed spikes in their post-resection ECoGs, five of them showed additional fast activity. 24 months after surgery, 12/18 patients (66.7%) were seizure-free. There was a significant correlation between unfavorable seizure outcomes and fast activity in the post-resection ECoGs (p = 0.009), whereas spikes alone were not predictive (p = 0.502). CONCLUSION: Even when recorded with non-sophisticated techniques, presence of fast activity in post-resection ECoGs might be a valid negative outcome-predictor after surgery in paediatric patients with FCD-II associated drug-resistant epilepsies. SIGNIFICANCE: Fast activity recorded with a relatively simple ECoG equipment seems also to have prognostic significance and by this might be an alternative to HFOs recorded with highly sophisticated and expensive technologies.

Surgical outcomes in two different age groups with Focal Cortical Dysplasia type II: Any real difference?

OBJECTIVE: Focal Cortical Dysplasias (FCDs) represent a common architectural cortical disorder underlying drug-resistant focal epilepsy. So far, studies aimed at evaluating whether age at surgery is a factor influencing surgical outcome are lacking, so that data on the comparison between patients harboring Type II FCD operated at younger age and those operated at adult age are still scarce. We compared presurgical clinical features and surgical outcomes of patients with histopathologically diagnosed Type II FCD undergoing surgery at an earlier age with those operated after 20 years of age. METHODS: We retrospectively analyzed 1660 consecutive patients operated at the "Claudio Munari" Epilepsy Surgery Centre. There were 289 patients (17.4%) with a neuropathological diagnosis of Type II FCD. We included two different groups of patients, the first one including patients operated on at less than 6years, the second sharing the same seizure onset age but with delayed surgery, carried out after the age of 20. Seizure characteristics and, neuropsychological and postoperative seizure outcomes were evaluated by study group. RESULTS: Forty patients underwent surgery before the age of 6 and 66 patients after the age of 20. Surgical outcome was favorable in the whole population (72.6% were classified in Engel's Class Ia+Ic), independently from age at surgery. In the children group, 32 patients were classified in Class I, including 30 (75%) children in classes Ia and Ic. In the adult group, 53 belonged to Class I of whom 47 (71%) were in classes Ia and Ic. The percentage of permanent complications, the surgical outcomes, and AED withdrawal did not significantly differ by study group. CONCLUSION: Our results indicate that there is no difference between the groups, suggesting that outcome depends mainly on the histological findings and not on timing of surgery.

Trends in epilepsy surgery: stable surgical numbers despite increasing presurgical volumes.

INTRODUCTION: Despite the success of epilepsy surgery, recent reports suggest a decline in surgical numbers. We tested these trends in our cohort to elucidate potential reasons. PATIENTS AND METHODS: Presurgical, surgical and postsurgical data of all patients undergoing presurgical evaluation in between 1990 and 2013 were retrospectively analysed. Patients were grouped according to the underlying pathology. RESULTS: A total of 3060 patients were presurgically studied, and resective surgery was performed in 66.8% (n=2044) of them: medial temporal sclerosis (MTS): n=675, 33.0%; benign tumour (BT): n=408, 20.0%; and focal cortical dysplasia (FCD): n=284, 13.9%. Of these, 1929 patients (94.4%) had a follow-up of 2 years, and 50.8% were completely seizure free (Engel IA). Seizure freedom rate slightly improved over time. Presurgical evaluations continuously increased, whereas surgical interventions did not. Numbers for MTS, BT and temporal lobe resections decreased since 2009. The number of non-lesional patients and the need for intracranial recordings increased. More evaluated patients did not undergo surgery (more than 50% in 2010-2013) because patients were not suitable (mainly due to missing hypothesis: 4.5% in 1990-1993 up to 21.1% in 2010-2013, total 13.4%) or declined from surgery (maximum 21.0% in 2010-2013, total 10.9%). One potential reason may be that increasingly detailed information on chances and risks were given over time. CONCLUSIONS: The increasing volume of the presurgical programme largely compensates for decreasing numbers of surgically remediable syndromes and a growing rate of informed choice against epilepsy surgery. Although comprehensive diagnostic evaluation is offered to a larger group of epilepsy patients, surgical numbers remain stable.

Cytochrome c oxidase deficit is associated with the seizure onset zone in young patients with focal cortical dysplasia Type II.

It has been postulated that mitochondrial dysfunction may be an important factor in epileptogenesis of intractable epilepsy. The current study tests the hypothesis that mitochondrial Complex IV (CIV) or cytochrome c oxidase dysfunction is associated with the seizure onset zone (SOZ) in patients with focal cortical dysplasia (FCD). Subjects were selected based on: age <19y; epilepsy surgery between May, 2010 and October, 2011; pathological diagnosis of isolated focal cortical dysplasia Type I (FCDI) or Type II (FCDII); and sufficient residual cortical tissue to conduct analysis of electron transport chain complex (ETC) activity in SOZ and adjacent cortical regions. In this retrospective study, patients were identified who had sufficient unfixed, frozen brain tissue for biochemical analysis in tissue homogenates. Specimens were subtyped using ILAE classification for FCD, and excluded if diagnosed with FCD Type III or dual pathology. Analysis of ETC activity in resected tissues was conducted independently and without knowledge of the identity, diagnosis, or clinical status of individual subjects. Seventeen patients met the inclusion criteria, including 6 FCDI and 11 FCDII. Comparison of adjacent cortical resections showed decreased CIV activity in the SOZ of the FCDII group (P = 0.003), but no significant CIV difference in adjacent tissues of the FCDI group. Because of the importance of CIV as the terminal and rate-limiting complex in the mitochondrial electron transport chain, these authors conclude that 1) a deficit of CIV is associated with the SOZ of patients with FCDII; 2) CIV deficiency may contribute to the spectrum of FCD neuropathology; and 3) further investigation of CIV in FCD may lead to the discovery of new targets for neuroprotective therapies for patients with intractable epilepsy.

Failure to detect human papillomavirus in focal cortical dysplasia type IIb.

OBJECTIVE: Recent studies have reported evidence of human papillomavirus 16 (HPV-16) in a very high proportion of pathological specimens of focal cortical dysplasia type IIb, but not in control specimens, motivating the proposal that viral infection during fetal development may play a causal role in the pathogenesis of focal cortical dysplasias. However, the significance of the association between HPV infection and focal cortical dysplasia type IIb, and its reproducibility across surgical centers, remain unclear. Here we sought evidence for HPV-16 in an independent cohort of surgical specimens. METHODS: We identified 14 specimens of focal cortical dysplasia type IIb from a single surgical center between 1995 and 2013. Multiple methods were used to establish presence or absence of HPV, including DNA polymerase chain reaction, conventional in situ hybridization, chromogenic in situ hybridization, and immunohistochemistry for p16. RESULTS: We found no conclusive evidence of HPV in any of the specimens. All but 1 of the cases were negative by >1 method. INTERPRETATION: These results raise questions about the prevalence of HPV infection in focal cortical dysplasias and about its potential importance as a causative agent.