Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

Blümcke, Ingmar; Spreafico, Roberto; Haaker, Gerrit; Coras, Roland; Kobow, Katja; Bien, Christian G.; Pfäfflin, Margarete; Elger, Christian E.; Widman, Guido; Schramm, Johannes; Becker, Albert; Kp, Braun; Leijten, Frans S.S.; Jc, Baayen; Aronica, Eleonora; Chassoux, Francine; Hamer, Hajo M.; Stefan, Hermann; Rössler, Karl; Thom, Maria; Walker, Matthew C.; Sisodiya, S; Duncan, John S.; McEvoy, A; Pieper, Tom; Holthausen, Hans; Kudernatsch, Manfred; Hj, Meencke; Kahane, Philippe; Schulze‐Bonhage, Andreas; Zentner, Josef; Dh, Heiland; Urbach, Horst; Bj, Steinhoff; Bast, Thomas; Tassi, Laura; Russo, Giorgio Lo; Özkara, Çiğdem; B, Öz; Kršek, Pavel; Vogelgesang, Silke; Runge, Uwe; Lerche, Holger; Weber, Yvonne G.; Honavar, Mrinalini; Pimentel, José; Arzimanoglou, Alexis; Ulate‐Campos, Adriana; Noachtar, Soheyl; Härtl, Elisabeth; Schijns, Olaf; Guerrini, Renzo; Barba, Carmen; Jacques, TS; Cross, J. Helen; Feucht, Martha; Mühlebner, Angelika; Grünwald, Thomas; Trinka, Eugen; Winkler, PA; Gil‐Nagel, Antonio; R, Toledano Delgado; Mayer, Thomas; Lutz, M.; Zountsas, Basilios; Garganis, Kyriakos; Rosenow, Felix; Hermsen, A.; Oertzen, Tim J. von; Tl, Diepgen; Avanzini, G.

doi:10.1056/nejmoa1703784

Cited by 629 publications

(635 citation statements)

References 23 publications

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“…1 reported as "FCD not otherwise specified." FCD II was found in more than half of the patients (FCD type IIb 33%, type IIA 23%).…”

Section: Discussionmentioning

confidence: 99%

“…1 The 2011 International League Against Epilepsy (ILAE) classification system differentiates FCD type I and II as lesions that are isolated from type III, which is associated with other adjacent pathology. 1 The 2011 International League Against Epilepsy (ILAE) classification system differentiates FCD type I and II as lesions that are isolated from type III, which is associated with other adjacent pathology.…”

Section: Introductionmentioning

confidence: 99%

“…1 We aimed to elucidate differences in clinical characteristics and seizure outcomes between mMCD and FCD subtypes, and to identify determinants of postoperative seizure freedom. 1 We aimed to elucidate differences in clinical characteristics and seizure outcomes between mMCD and FCD subtypes, and to identify determinants of postoperative seizure freedom.…”

Section: Introductionmentioning

confidence: 99%

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Long‐term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia

et al. 2018

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Summary Focal cortical dysplasia (FCD) and mild malformation of cortical development (mMCD) are frequent histopathologic diagnoses in patients who undergo surgery for refractory epilepsy. Literature concerning surgical outcome in patients with mMCD, as well as its contrast with FCD, has been scarce. We studied 88 patients with a histopathologic diagnosis of isolated FCD (n = 57) or mMCD (n = 31), revised according to the latest International League Against Epilepsy (ILAE) guidelines, who underwent resective or disconnective surgery. Our findings suggest differences between mMCD and FCD in clinical presentation and surgical outcome after surgery. Patients with mMCD developed seizures later in life, and their lesions had a predilection for location in the temporal lobe and remained undetected by magnetic resonance imaging (MRI) more frequently. A diagnosis of mMCD has a less favorable surgical outcome. Still, 32% of these patients reached continuous seizure freedom (Engel class 1A) at a latest median follow‐up duration of 8 years, compared to 59% in FCD. A histopathologic diagnosis of mMCD, extratemporal surgery, and indication of an incomplete resection each were independent predictors of poor outcome.

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“…1 reported as "FCD not otherwise specified." FCD II was found in more than half of the patients (FCD type IIb 33%, type IIA 23%).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long‐term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia

et al. 2018

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“…Focal malformations of cortical development (MCDs), including FCD and HME, are caused by somatic activation of the mTOR pathway and represent the most important causes of surgically treated intractable childhood epilepsy (Blumcke et al, 2017; Harvey et al, 2008). FCDs, classified into several subtypes by the International League Against Epilepsy (Blumcke et al, 2011), involve small regions of radiographically and histopathologically abnormal cortex, whereas HME shows abnormal enlargement of much or all of a cerebral hemisphere (Blumcke et al, 2011; Poduri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

et al. 2017

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Summary Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27/66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA, and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional PIK3CA activation in mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

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“…Hippocampal sclerosis (HS) is the most common pathology in adult epilepsy surgery series,1 and accounts for 15% of all resections in children. On histopathology, HS is characterized by segmental neuronal loss and gliosis within the hippocampal formation,2, 3 yet postmortem studies indicate neuronal loss and gliosis is also present in a proportion of patients in the amygdala,4 entorhinal cortex,5 temporal neocortex6 and extra‐temporal neocortex 2, 7…”

Section: Introductionmentioning

confidence: 99%

Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis

Adler

Blackwood

Northam

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIn contrast to adult cohorts, neocortical changes in epileptic children with hippocampal damage are not well characterized. Here, we mapped multimodal neocortical markers of epilepsy‐related structural compromise in a pediatric cohort of temporal lobe epilepsy and explored how they relate to clinical factors.MethodsWe measured cortical thickness, gray–white matter intensity contrast and intracortical FLAIR intensity in 22 patients with hippocampal sclerosis (HS) and 30 controls. Surface‐based linear models assessed between‐group differences in morphological and MR signal intensity markers. Structural integrity of the hippocampus was measured by quantifying atrophy and FLAIR patterns. Linear models were used to evaluate the relationships between hippocampal and neocortical MRI markers and clinical factors.ResultsIn the hippocampus, patients demonstrated ipsilateral atrophy and bilateral FLAIR hyperintensity. In the neocortex, patients showed FLAIR signal hyperintensities and gray–white matter boundary blurring in the ipsilesional mesial and lateral temporal neocortex. In contrast, cortical thinning was minimal and restricted to a small area of the ipsilesional temporal pole. Furthermore, patients with a history of febrile convulsions demonstrated more pronounced FLAIR hyperintensity in the ipsilesional temporal neocortex.InterpretationPediatric HS patients do not yet demonstrate the widespread cortical thinning present in adult cohorts, which may reflect consequences of a protracted disease process. However, pronounced temporal neocortical FLAIR hyperintensity and blurring of the gray–white matter boundary are already detectable, suggesting that alterations in MR signal intensities may reflect a different underlying pathophysiology that is detectable earlier in the disease and more pervasive in patients with a history of febrile convulsions.

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Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

Cited by 629 publications

References 23 publications

Long‐term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia

Long‐term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis

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