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Abstract Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glial fibrillary acidic protein (GFAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

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

Abstract Objectives We compared the proteomic signatures of the hippocampal lesion induced in three different animal models of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS): the systemic pilocarpine model (PILO), the intracerebroventricular kainic acid model (KA), and the perforant pathway stimulation model (PPS). Methods We used shotgun proteomics to analyze the proteomes and find enriched biological pathways of the dorsal and ventral dentate gyrus (DG) isolated from the hippocampi of the three animal models. We also compared the proteomes obtained in the animal models to that from the DG of patients with pharmacoresistant MTLE+HS. Results We found that each animal model presents specific profiles of proteomic changes. The PILO model showed responses predominantly related to neuronal excitatory imbalance. The KA model revealed alterations mainly in synaptic activity. The PPS model displayed abnormalities in metabolism and oxidative stress. We also identified common biological pathways enriched in all three models, such as inflammation and immune response, which were also observed in tissue from patients. However, none of the models could recapitulate the profile of molecular changes observed in tissue from patients. Significance Our results indicate that each model has its own set of biological responses leading to epilepsy. Thus, it seems that only using a combination of the three models may one replicate more closely the mechanisms underlying MTLE+HS as seen in patients.

Traumatic atlanto-occipital dislocation (TAOD) are uncommon injuries associated with high immediate mortality rate and occurs more than twice in children than adults, due to biomechanical properties and immaturity of children's cervical spine. We report a pediatric patient with TAOD, who underwent occipitocervical stabilization and also developed a late hydrocephalus requiring a shunt procedure. A six-year-old boy was admitted to the emergency department after a car accident with refractory cervical pain. A cervical computed tomography (CT) scan showed an anterior C1–C2 level hematoma, and a dynamic CT scan demonstrated an increasing basion-dens interval on extension. Cervical magnetic resonance imaging (MRI) showed discontinuity of the tectorial membrane and diffused hyperintense signal on the left alar ligament. These findings were attributed to TAOD, and an occipitocervical fusion was performed. The pain and neurological status improved after surgery, but after 3 months he returned with persistent vomiting, headache, and a CT scan showing hydrocephalus. Then, a ventriculoperitoneal shunt was performed, improving the symptoms. One year after the injury, the patient remained asymptomatic, and a later radiography demonstrated satisfactory bone fusion. In conclusion, the decision-making process regarding treatment should consider several clinical and radiographic findings. Occipitocervical fusion is the treatment of choice, while hydrocephalus is not an unusual complication in children.

Apert syndrome is an uncommon autosomal dominant condition with a varied clinical spectrum which includes premature cranial and facial suture fusion and complex upper and lower limb syndactilies. In this manuscript, we share our posterior vault distraction osteogenesis (PVDO) experience regarding Apert syndrome patients so that a larger patient population may benefit. In addition, we aimed to determine an onset of elevated intracranial pressure in the long term follow up. A retrospective study was performed on consecutive patients with syndromic craniosynostosis who were diagnosed with Apert syndrome, underwent PVDO between 2012 and 2019, and received at least 2 years of follow-up care. Demographic data, diagnosis, surgery related data, and outcome data (perioperative and mid-term complications and need for additional surgery), were verified by means of medical records, clinical photographs, radiographic images, and interviews with all included patients and/or their parents. The present study included 14 patients who were diagnosed respectively with Apert syndrome (n = 14). The average posterior advancement distance achieved was 19.37 ± 3.0 mm. Two patients included in this study presented major complications, but neither experienced permanent sequelae or a lethal course. Two Apert patients presented cerebral spinal fluid (CSF) leakage (Clavien–Dindo type II). One patient presented a onset of elevated intracranial pressure at 4 years of follow up. PVDO is an effective procedure at alleviating intracranial pressure and present a low complication rate.

This is a surgical technique video of a right peri-insular hemispherotomy in a child with Rasmussen’s encephalitis. The patient is a 5-year-old boy with focal onset impaired awareness seizures started 6 months before surgery, developing different subtypes of focal seizures and evolving to drug-resistant epilepsy. In neurological examination, he already had a left-sided hemiparesis with pyramidal signs. Magnetic resonance imaging showed right-sided cortical atrophy and fronto-insular subcortical hyperintensity signal areas. The preoperative electroencephalogram revealed frequent right-sided central mid temporal spikes. The history and complementary exams raised a hypothesis of Rasmussen’s encephalitis, a rare neurological condition, characterized by unilateral chronic inflammation of the cerebral cortex, causing drug-resistant epilepsy, and evolving to progressive neurological decline1. The hemispherotomy is an effective procedure aimed to isolate the entire hemisphere functionally with minimal removal of brain tissue, and remains the only cure for seizures caused by Rasmussen’s encephalitis2,3. Long-term seizure freedom may be achieved in around 80% of patients and improves quality of life4. It’s already accepted that briefer duration of epilepsy preceding the surgery is associated to better adaptive functioning postoperatively due to the high neuroplasticity of young patients4. Three years after surgery, the patient remains seizure free, walking without help.

An 8-month-old boy was referred to our department with a protruding soft mass in the lumbosacral region since birth, with intact overlying skin. The patient had clubfoot, and congenital scoliosis. On neurological examination, he had preserved muscle strength, but evolved with distal weakness and increasing in the lumbar mass volume. MRI confirmed the diagnosis of terminal myelocystocele by the typical finding of a trumpet-like flaring meningocele. Terminal myelocystocele classically presents as a large lumbosacral mass with skin cover, containing fat, cerebrospinal fluid, and neural tissue1,2. The spinal cord herniates through the dysraphic spine and terminates at a neural placode, whereas the central canal opens into a CSF-filled, ependyma-lined cavity3. We present a 2D operative video comprising microsurgical repair of the defect, resection of the nonfunctional caudal cyst wall, reconstruction of the proximal neural placode, and duroplasty.

Hippocampal sclerosis (HS) is a common cause of pharmacoresistant focal epilepsy. Here, we (1) performed a histological approach to the anterior temporal pole of patients with HS to evaluate cortical and white matter (WM) cell populations, alteration of myelin integrity and markers of neuronal activity, and (2) correlated microscopic data with magnetic resonance imaging (MRI) findings. Our aim was to contribute with the understanding of neuroimaging and pathophysiological mechanisms of temporal lobe epilepsy (TLE) associated with HS. We examined MRIs and surgical specimens from the anterior temporal pole from TLE-HS patients (n = 9) and compared them with 10 autopsy controls. MRIs from healthy volunteers (n = 13) were used as neuroimaging controls. Histological techniques were performed to assess oligodendrocytes, heterotopic neurons, cellular proliferative index, and myeloarchitecture integrity of the WM, as well as markers of acute (c-fos) and chronic (ΔFosB) activities of neocortical neurons. Microscopic data were compared with neuroimaging findings, including T2-weighted/FLAIR MRI temporopolar blurring and values of fractional anisotropy (FA) from diffusion-weighed imaging (DWI). We found a significant increase in WM oligodendrocyte number, both in hematoxylin and eosin, and in Olig2-stained sections. The frequencies of oligodendrocytes in perivascular spaces and around heterotopic neurons were significantly higher in patients with TLE–HS compared with controls. The percentage of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase; a marker of myeloarchitecture integrity) immunopositive area in the WM was significantly higher in TLE-HS, as well as the numbers of c-fos- and ΔFosB-immunostained neocortical neurons. Additionally, we demonstrated a decrease in axonal bundle integrity on neuroimaging, with a significant reduction in the FA in the anterior temporal pole. No differences were detected between individuals with and without temporopolar blurring on visual MRI analysis, considering the number of oligodendroglial cells and percentage of WM CNPase-positive areas. Also, there was no relationship between T2 relaxometry and oligodendrocyte count. In conclusion, our histopathological data support the following: (1) the hypothesis that repetitive neocortical neuronal activity could induce changes in the WM cellular constitution and myelin remodeling in the anterior temporal pole from patients with TLE-HS, (2) that oligodendroglial hyperplasia is not related to temporal blurring or T2 signal intensity on MRI, and (3) that reduced FA is a marker of increase in Olig2-immunopositive cells in superficial temporopolar WM from patients with TLE-HS.