•Surgery is a promising therapeutic option in drug refractory epilepsy in older age.•Longer duration of epilepsy before surgery did not correlate with poorer outcome.•Patients of older age may be at ...greater risk for postoperative memory disturbances.•The risk for postoperative hygroma was higher in the older patient group.•In older patients, invasive EEG monitoring was as effective as in younger patients.
The incidence of epilepsy in older adults is growing, as does the incidence of comorbidities. Therefore, when it comes to epilepsy surgery in medically intractable epilepsy, age is often seen as a limiting factor. To investigate the outcome after epilepsy surgery in a population of older adults, we compared the benefit for patients aged 50–59 years with those aged 60 years and older in respect of efficacy and safety.
Patients aged ≥50 years with medically intractable epilepsy who underwent epilepsy surgery from 1990 to 2013 were selected from the database of a German epilepsy center. All of them received a standardised and detailed presurgical diagnostic evaluation. Follow-up included at least four scheduled visits with EEG, MRI and neuropsychological testing. Outcome was assessed using the Engel outcome scale.
79 patients aged between 50 and 67 years were followed-up for a median of 4.7 years (2–16 years). 68% of patients were free of disabling seizures (Engel class I, ≥60 years: 75%) and 58% were seizure-free (Engel class IA, ≥60 years: 70%). 90% of our patients suffered from temporal lobe epilepsy (TLE), 9% from frontal lobe epilepsy (FLE) and one occipital lobe epilepsy (OLE). After surgery, 9% discontinued or tapered their medication. Permanent surgical complications occurred in 10% of cases and transient neurological deficits were seen in 11%. Older patients had a higher risk for postoperative hygroma (≥60 years 15%; <60 years 8%) and were more prone to postoperative memory deficits (≥60 years 45%), especially after resection of the dominant temporal lobe. Verbal and figural memory testing did not differ significantly between the groups.
The results support the view that in selected older patients, epilepsy surgery shows equal or even higher success rates as compared to younger patients. However, patients of older age may be at greater risk for postoperative hygroma and memory deficits, especially after dominant temporal lobe resections.
Gangliogliomas represent the most frequent tumor entity in young patients suffering from chronic focal epilepsies. In a series of 326 gangliogliomas collected from the University of Bonn Epilepsy ...Surgery Program and other departments of neuropathology in Germany, Austria, and Switzerland, epidemiological findings and histopathological hallmarks of gangliogliomas are systematically reviewed. The majority of these tumors occur within the temporal lobe and reveal a biphasic histological architecture characterized by a combination of dysplastic neurons and neoplastic glial cell elements. However, gangliogliomas exhibit a considerable variability in their histopathological appearance. Immunohistochemical studies are an important tool to discriminate these neoplasms from other tumor entities. Almost 80% of gangliogliomas reveal immunoreactivity for CD34, a stem cell epitope not expressed in normal brain. Immunohistochemical reactions for MAP2 or NeuN can be employed to characterize the dysplastic nature of neurons in those areas difficult to discriminate from pre-existing brain parenchyma. Less than 50% of the cases display binucleated neurons. With the frequent finding of “satellite” tumor clusters in adjacent brain regions, gangliogliomas are microscopically less circumscribed than previously assumed. The distinction from diffusely infiltrating gliomas is of considerable importance since tumor recurrence or malignant progression are rare events in gangliogliomas. Only little is known about the molecular pathogenesis of these glioneuronal tumors. Our findings support a dysontogenic origin from a glioneuronal precursor lesion with neoplastic, clonal proliferation of the glial cell population. Candidate genes appear to associate with neurodevelopmental signaling cascades rather than cell cycle control or DNA repair mechanisms. The reelin signaling and tuberin/insulin growth receptor pathways have recently been implicated in ganglioglioma development. Powerful new molecular genetic and biological tools can now be employed to unravel the pathogenesis of these intriguing lesions.
Rasmussen encephalitis is a devastating neurological disorder characterised by seizures, brain inflammation, and progressive hemispheric atrophy. The objective of the current study was to ...systematically characterise patterns of structural lesions in children with Rasmussen encephalitis, referred for modified anatomical hemispherectomy at the Tsinghua University Epilepsy Center in Beijing. Seven consecutive patients were investigated with a mean age at operation of 4.5 years, who suffered from medically intractable seizures for a mean of 1.6 years. Foci of abnormally increased T2 signal intensity were observed in all patients. With the exception of one child, all patients presented with progressive unilateral cerebral atrophy. FDG-PET imaging revealed extensive regions of hypometabolism within the affected cerebral hemisphere in 3 of 4 patients. Diagnosis of Rasmussen encephalitis was confirmed histologically, demonstrating CD68 positive microglial nodules, as well as CD3 and CD8 positive T lymphocytes invading the cerebral parenchyma. An intriguing observation was the heterogenous distribution of patterns of lesions throughout the affected hemisphere, suggesting multifocal manifestation and distinct sequences of disease progression, from discrete foci of inflammatory infiltrates (stage 1) to extensive cortical destruction (stage 4). Atypical hippocampal sclerosis (HS), with neuronal cell loss affecting most prominently the CA4 region (HS type 3 or end folium sclerosis), was evident in 5 of 7 cases. Four hippocampi also showed chronic inflammation. In addition, we observed associated focal cortical dysplasia (FCD; ILAE type IIId) in 4 of 7 children, supporting the concept of acquired and postmigratory FCD pathomechanisms. Postsurgical seizure freedom was achieved in all children with a mean follow-up period of 2.7 years and continuous antiepileptic medication.
Summary
Surgery for seizures arising from the rolandic area can be performed effectively, and accurate mapping of eloquent regions may improve seizure and functional outcome. Noninvasive cortical ...mapping is, however, hardly feasible in young children. We studied two children with epileptogenic focal cortical dysplasia (FCD) type IIb in the rolandic area, in whom preoperative passive task functional MRI (fMRI) during sedation helped planning a tailored surgical approach. In one patient the dysplastic cortex was functionally activated. After complete lesionectomy both children exhibited motor impairment that readily improved. Repeat fMRI, performed after complete (Patient 1) or partial (Patient 2) recovery, demonstrated relocation of motor‐related activations posterior to the area of resection. fMRI during sedation can be used to demonstrate postsurgical functional reorganization of the motor cortex in young children. There is interindividual variability in functional activation of FCD type IIb.
Surgical treatment of unilateral mesial temporal lobe epilepsy (mTLE) particularly bears the risk of episodic memory decline. The present study investigates the role of the ipsilateral hippocampal ...integrity for postoperative change in material-specific memory performance. In 104 patients who had undergone epilepsy surgery for unilateral mTLE, we analyzed pre- to postoperative changes of verbal and figural memory as a function of segmental neuronal cell densities of the resected hippocampus (cornu ammonis, CA1–4; internal and external limb of the dentate gyrus, DG). Results were controlled for side of surgery and hemispheric dominance. Surgery caused significant memory decline, especially with regard to verbal memory after left temporal resections. Seizure freedom (65 % Engel Ia) did not affect memory outcome. Higher neuronal cell densities of the resected left hippocampus were associated with greater declines in verbal memory parameters (
r
= −0.27 to
r
= −0.39,
p
< 0.05), especially when excluding patients with atypical hemispheric dominance (
r
= −0.34 to
r
= −0.60,
p
< 0.05; significant correlations across all hippocampal subfields). There were no systematic correlations between neuronal cell densities of the resected right hippocampus and memory changes. The results emphasize the role of the structural and functional integrity of the hippocampus within the left dominant hemisphere for the degree of verbal memory decline after temporal lobe surgery. Presurgical verbal memory performance may be taken as a marker of ipsilateral left hippocampal integrity and may contribute to individual risk–benefit evaluations before epilepsy surgery. Finally, more precise neuropsychological markers of right hippocampal integrity are needed.
Background: Processing whole-slide images (WSI) to train neural networks can be intricate and labor intensive. We developed an open-source library dealing with recurrent tasks in the processing of ...WSI and helping with the training and evaluation of neuronal networks for classification tasks. Methods: Two histopathology use-cases were selected and only hematoxylin and eosin (H&E) stained slides were used. The first use case was a two-class classification problem. We trained a convolutional neuronal network (CNN) to distinguish between dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma (GG), two neuropathological low-grade epilepsy-associated tumor entities. Within the second use case, we included four clinicopathological disease conditions in a multilabel approach. Here we trained a CNN to predict the hormone expression profile of pituitary adenomas. In the same approach, we also predicted clinically silent corticotroph adenoma. Results: Our DNET-GG classifier achieved an AUC of 1.00 for the ROC curve. For the second use case, the best performing CNN achieved an area under the curve (AUC) of 0.97 for the receiver operating characteristic (ROC) for corticotroph adenoma, 0.86 for silent corticotroph adenoma, and 0.98 for gonadotroph adenoma. All scores were calculated with the help of our library on predictions on a case basis. Conclusions: Our comprehensive and fastai-compatible library is helpful to standardize the workflow and minimize the burden of training a CNN. Indeed, our trained CNNs extracted neuropathologically relevant information from the WSI. This approach will supplement the clinicopathological diagnosis of brain tumors, which is currently based on cost-intensive microscopic examination and variable panels of immunohistochemical stainings.
Summary
The properties and structure of tissue can be visualized without labeling or preparation by multiphoton microscopy combining coherent anti‐Stokes Raman scattering (CARS), addressing lipid ...content, second harmonic generation (SHG) showing collagen, and two‐photon excited fluorescence (TPEF) of endogenous fluorophores. We compared samples of sclerotic and nonsclerotic human hippocampus to detect pathologic changes in the brain of patients with pharmacoresistant temporomesial epilepsy (n = 15). Multiphoton microscopy of cryosections and bulk tissue revealed hippocampal layering and micromorphologic details in accordance with reference histology: CARS displayed white and gray matter layering and allowed the assessment of axonal myelin. SHG visualized blood vessels based on adventitial collagen. In addition, corpora amylacea (CoA) were found to be SHG‐active. Pyramidal cell bodies were characterized by intense cytoplasmic endogenous TPEF. Furthermore, diffuse TPEF around blood vessels was observed that co‐localized with positive albumin immunohistochemistry and might indicate degeneration‐associated vascular leakage. We present a label‐free and fast optical approach that analyzes pathologic aspects of HS. Hippocampal layering, loss of pyramidal cells, and presence of CoA indicative of sclerosis are visualized. Label‐free multiphoton microscopy has the potential to extend the histopathologic armamentarium for ex vivo assessment of changes of the hippocampal formation on fresh tissue and prospectively in vivo.
Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein ...defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.
Abstract Correct positioning and differentiation of neurons during brain development is a key precondition for proper function. Focal cortical dysplasias (FCDs) are increasingly recognized as causes ...of therapy refractory epilepsies. Neuropathological analyses of respective surgical specimens from neurosurgery for seizure control often reveal aberrant cortical architecture and/or aberrantly shaped neurons in FCDs. However, the molecular pathogenesis particularly of FCDs with aberrant lamination (so-called FCD type I) is largely unresolved. Lipoproteins and particularly low-density lipoprotein receptor-related protein 12 (LRP12) are involved in brain development. Here, we have examined a potential role of LRP12 in the pathogenesis of FCDs. In vitro knockdown of LRP12 in primary neurons results in impaired neuronal arborization. In vivo ablation of LRP12 by intraventricularly in utero electroporated shRNAs elicits cortical maldevelopment, i.e. aberrant lamination by malpositioning of upper cortical layer neurons. Subsequent epilepsy phenotyping revealed pentylenetetrazol (PTZ)-induced seizures to be aggravated in cortical LRP12-silenced mice. Our data demonstrates IUE mediated cortical gene silencing as an excellent approach to study the role of distinct molecules for epilepsy associated focal brain lesions and suggests LRP12 and lipoprotein homeostasis as potential molecular target structures for the emergence of epilepsy-associated FCDs.
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