Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. Dysmorphic neurons are the major histopathological feature of type II FCD, but their role in seizure genesis in FCD is unclear. Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients. Quantitative analyses revealed distinct morphological and electrophysiological characteristics of the upper layer dysmorphic neurons in type II FCD, including an enlarged soma, aberrant dendritic arbors, increased current injection for rheobase action potential firing, and reduced action potential firing frequency. Intriguingly, the upper layer dysmorphic neurons received decreased glutamatergic and increased GABAergic synaptic inputs that were coupled with upregulation of the Na⁺-K⁺-Cl^- cotransporter. In addition, we found a depolarizing shift of the GABA reversal potential in the CamKII-cre::PTEN^flox/flox mouse model of drug-resistant epilepsy, suggesting that enhanced GABAergic inputs might depolarize dysmorphic neurons. Thus, imbalance of synaptic excitation and inhibition of dysmorphic neurons may contribute to seizure genesis in type II FCD.
Animals ; Drug Resistant Epilepsy/surgery* ; Epilepsy/pathology* ; Malformations of Cortical Development/pathology* ; Malformations of Cortical Development, Group I ; Mice ; Neurons/pathology* ; Seizures/pathology*

Objective: To investigate clinicopathological features of multinodular and vacuolar neurodegenerative tumor (MVNT) of the cerebrum, and to investigate its immunophenotype, molecular characteristics and prognosis. Methods: Four cases were collected at the General Hospital of Southern Theater Command, Guangzhou, China and one case was collected at the First People's Hospital of Huizhou, China from 2013 to 2021. Clinical, histological, immunohistochemical and molecular characteristics of these five cases were analyzed. Follow-up was carried out to evaluate their prognoses. Results: There were four females and one male, with an average age of 42 years (range, 17 to 51 years). Four patients presented with seizures, while one presented with discomfort on the head. Pre-operative imaging demonstrated non-enhancing, T2-hyperintense multinodular lesions in the deep cortex and superficial white matter of the frontal (n=1) or temporal lobes (n=4). Microscopically, the tumor cells were mostly arranged in discrete and coalescent nodules primarily within the deep cortical ribbon and superficial subcortical white matter. The tumors were composed of large cells with ganglionic morphology, vesicular nuclei, prominent nucleoli and amphophilic or lightly basophilic cytoplasm. They exhibited varying degrees of matrix vacuolization. Vacuolated tumor cells did not show overt cellular atypia or any mitotic activities. Immunohistochemically, tumor cells exhibited widespread nuclear staining for the HuC/HuD neuronal antigens, SOX10 and Olig2. Expression of other neuronal markers, including synaptophysin, neurofilament and MAP2, was patchy to absent. The tumor cells were negative for NeuN, GFAP, p53, H3K27M, IDH1 R132H, ATRX, BRG1, INI1 and BRAF V600E. No aberrant molecular changes were identified in case 3 and case 5 using next-generation sequencing (including 131 genes related to diagnosis and prognosis of central nervous system tumors). All patients underwent complete or substantial tumor excision without adjuvant chemoradiotherapy. Post-operative follow-up information over intervals of 6 months to 8 years was available for five patients. All patients were free of recurrence. Conclusions: MVNT is an indolent tumor, mostly affecting adults, which supports classifying MVNT as WHO grade 1. There is no tumor recurrence even in the patients treated with subtotal surgical excision. MVNTs may be considered for observation or non-surgical treatments if they are asymptomatic.
Adult ; Female ; Humans ; Male ; Brain Neoplasms/pathology* ; Cerebrum/pathology* ; Neurons/metabolism* ; Seizures ; Temporal Lobe/pathology* ; Biomarkers, Tumor/metabolism*

The prevalence of human taeniasis has decreased in Korea. The stool egg positive proportion decreased from 1.9% in 1971 to 0% in 2004 in nationwide surveys. The neurocysticercosis (NCC) is also presumed to decrease. However, detailed information regarding the recent status of NCC in Korea is lacking. We retrospectively reviewed NCC cases from 1990 to 2016 at Asan Medical Center, a 2700-bed tertiary referral hospital in Korea. We identified patients based on clinical symptoms, brain imaging, pathology and serological assay. The cases were classified as parenchymal, extraparenchymal, and mixed NCC. Eighty-one patients were included in the analysis. The mean age was 54.5 years, and 79.0% were male. The number of NCC cases was highest from 1995 to 1999, and continuously decreased thereafter. Forty (49.4%) patients had parenchymal NCC, while 25 (30.9%) patients had extraparenchymal NCC, and 16 (19.8%) patients had mixed NCC. The seizure and headache were most common symptom of parenchymal NCC and extraparenchymal NCC respectively. Hydrocephalus was more common in extraparenchymal NCC, and patients with extraparenchymal NCC were more likely to require a ventriculoperitoneal shunt. Cases of NCC are decreasing accordingly with human taeniasis and lesion location was the most important determinant of clinical presentation and outcome of NCC in Korea.
Chungcheongnam-do ; Headache ; Humans ; Hydrocephalus ; Korea ; Male ; Neurocysticercosis ; Neuroimaging ; Ovum ; Pathology ; Prevalence ; Retrospective Studies ; Seizures ; Taenia solium ; Taeniasis ; Tertiary Care Centers ; Ventriculoperitoneal Shunt

Micturition is a complex process involving the bladder, spinal cord, and the brain. Highly sophisticated central neural program controls bladder function by utilizing multiple brain regions, including pons and suprapontine structures. Periaqueductal grey, insula, anterior cingulate cortex, and medial prefrontal cortex are components of suprapontine micturition centers. Under pathologic conditions such as epilepsy, urinary dysfunction is a frequent symptom and it seems to be associated with increased suprapontine cortical activity. Interestingly, micturition can also trigger seizures known as reflex epilepsy. During voiding behavior, frontotemporal cortical activation has been reported and it may induce reflex seizures. As current researches are only limited to present clinical cases, more rigorous investigations are needed to elucidate biological mechanisms of micturition to advance our knowledge on the process of micturition in physiology and pathology.
Brain ; Epilepsy* ; Epilepsy, Reflex ; Gyrus Cinguli ; Pathology ; Physiology ; Pons ; Prefrontal Cortex ; Reflex ; Seizures ; Spinal Cord ; Urinary Bladder ; Urination*

Venipuncture is a routine and relatively safe and painless medical procedure, necessary for accurate diagnosis and treatment. However, given that pain related to medical procedures may have adverse effects for children, could venipuncture cause deaths in infants and children? We analyzed our cases of unexpected death after venipuncture and conducted a literature review on them. A vasovagal response to noxious stimuli may explain such a sudden death immediately after venipuncture, commonly presented as needle phobia, breath-holding spell, and reflex anoxic seizure in the literature, despite the fact that the current medical evidence is not enough to prove their casual relationship. In addition, pain prevention and management during medical procedure is incorporated in clinical guidelines for pediatric patients, because painful medical procedures negatively affect child development. Thus, prevention and management of pain related to medical procedure may be helpful to avoid an adverse vasovagal response to noxious stimuli from occurring.
Autopsy ; Child ; Child Development ; Death, Sudden ; Diagnosis ; Forensic Pathology ; Humans ; Infant ; Infant Death ; Needles ; Phlebotomy ; Phobic Disorders ; Reflex ; Seizures

Patients afflicted with low-grade glioma frequently suffer from seizures. The mechanisms for seizure initiation in these patients remain poorly understood. Tumor location is correlated with seizure initiation. However, these correlative studies rely on dichotomized data analysis which is based on arbitrary lobe assignments. As a result, the lesion-symptom correlation may be incorrectly interpreted. Categorizing patients according to tumor involvement in a single brain lobe might cause the neglect of important information, such as lesion location and lesion volume. Tumors that invaded more than one brain lobe may could be counted repeatedly. The anatomic correlation of the tumor-induced seizures is therefore difficult to be identified. Investigations based on voxel-wise quantitative lesion analysis could avoid the above statistical bias. According to the voxel-wise analysis, the increased seizure risks were identified for patients with low-grade gliomas that involved the left premotor area.
Brain ; pathology ; Brain Neoplasms ; complications ; pathology ; Glioma ; complications ; pathology ; Humans ; Seizures ; etiology

Temporal lobe epilepsy (TLE) is a common and severe neurological disorder which is often intractable. It can not only damage the normal structure and function of hippocampus, but also affect the neurogenesis in dentate gyrus (DG). It is well documented from researches on the animal models of TLE that after a latent period of several days, prolonged seizure activity leads to a dramatic increase in mitotic activity in the hippocampal DG. However, cell proliferation returns to baseline levels within 3-4 weeks after status epilepticus (SE). Meanwhile, there are two major abnormalities of DG neurogenesis, including the formation of hilar basal dendrites and the ectopic migration of newborn granule cells into the polymorphic cell layer, which may affect epileptogenesis and seizure onset. However, the specific contribution of these abnormalities to seizures is still unknown. In other words, whether they are anti-epileptic or pro-epileptic is still under heated discussion. This article systematically reviews current knowledge on neurogenesis and epilepsy based on the results of studies in recent years and discusses the possible roles of neurogenesis in epileptogenesis and pathologic mechanisms, so as to provide information for the potential application of neurogenesis as a new clinical therapeutic target for temporal lobe epilepsy.
Animals ; Brain ; Cell Movement ; physiology ; Cell Proliferation ; physiology ; Dendrites ; pathology ; Dentate Gyrus ; growth & development ; pathology ; Epilepsy, Temporal Lobe ; etiology ; pathology ; physiopathology ; Hippocampus ; growth & development ; pathology ; Humans ; Mitosis ; physiology ; Neurogenesis ; physiology ; Neurons ; pathology ; Seizures ; etiology ; physiopathology ; Status Epilepticus ; physiopathology

Here we present an autopsy case of chronic traumatic encephalopathy (CTE) in a 36-year-old man. He had a history of febrile seizures at the age of four and was severely demented at age 10 when he was admitted to a mental hospital. He had suffered repetitive self-harm, such as frequent banging of the head on the wall in his hospital record, but he had no clear history between the ages of four and ten. Autopsy revealed global cerebral atrophy, including the basal ganglia, thalamus, hippocampus, amygdala, mammilary bodies and lateral geniculate bodies. This case showed typical pathological features of CTE. Phosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs) and neuropil threads (NT) we are widely distributed in the brain, especially in the depth of the cerebral sulci. NFT and NT were also found in the basal ganglia, thalamus, amygdala and brainstem. Scanty β-amyloid deposits were found in the motor and sensory cortices, but α-synuclein was completely negative in the brain. This example showed that CTE can occur in young ages and that even children can experience CTE dementia.
Adult ; Amygdala ; Atrophy ; Autopsy* ; Basal Ganglia ; Brain ; Brain Injuries ; Brain Injury, Chronic* ; Brain Stem ; Child* ; Dementia ; Geniculate Bodies ; Head ; Hippocampus ; Hospital Records ; Hospitals, Psychiatric ; Humans ; Neurofibrillary Tangles ; Neuropil Threads ; Pathology ; Seizures, Febrile ; Thalamus

Analgesics, Opioid ; adverse effects ; Female ; Humans ; Lung Neoplasms ; pathology ; Meperidine ; adverse effects ; Middle Aged ; Seizures ; chemically induced ; Tomography, X-Ray Computed