Hajime Miyata

Leptomeningeal angiomatosis (LMA) in Sturge–Weber syndrome (SWS) typically presents with cortical calcifications on computed tomography (CT) scans and is often accompanied by enlarged, low‐signal deep medullary veins seen on susceptibility‐weighted magnetic resonance imaging (MRI) that lack flow‐void signs on T2‐weighted MRI. However, subcortical calcifications on CT and concurrent developmental venous anomaly (DVA), visible as deep medullary veins with prominent flow‐void signs on T2‐weighted MRI, are uncommon. We describe atypical clinicopathological features in a surgical case of a 6‐year‐old female patient with SWS, who had early‐onset intractable epilepsy due to LMA, complicated by subcortical calcifications and DVA on neuroimaging. Presurgical MRI revealed a hypoplastic left frontal lobe covered with an LMA, and a DVA extending from the ipsilateral frontal periventricular white matter to the deep middle cerebral vein. She underwent resection of the left central and prefrontal regions and remained seizure‐free postoperatively. Histopathology confirmed the presence of an LMA, dilated veins in the subcortical white matter, focal microscopic polymicrogyria, and cortical pseudolaminar sclerosis consistent with focal cortical dysplasia type IIIc. Four atypical findings were observed: (1) absent or minimal cortical calcifications; (2) clearly defined areas of fibrillary gliosis bordered by a linear band of prominent calcifications, encasing non‐dilated veins in the subcortical white matter; (3) a localized cortical venous malformation; and (4) subarachnoid arterial abnormalities, including fibromuscular intimal thickening, internal elastic lamina degeneration, irregular medial thickness, and segmental medial losses replaced by dense calcifications. These findings, considered in the context of the intrinsic cerebral venous system, suggest that the non‐dilated white matter veins encased by calcified gliosis represent superficial medullary veins, while the dilated veins correspond with deep medullary veins draining into the DVA. The latter possibly serve as collateral venous drainage pathways, compensating for abnormal cortical and subarachnoid venous development. The observed arterial abnormalities likely reflect secondary regressive changes.

BACKGROUND: A mild malformation of cortical development (MCD) with oligodendroglial hyperplasia and epilepsy (MOGHE) is characterized by increased Olig2-positive atypical cells in the white matter and is associated with drug-resistant intractable epilepsy, typically the frontal and temporal lobes. MOGHE is a newly classified subtype of focal cortical dysplasia associated with epilepsy, according to the latest International League Against Epilepsy guidelines. There have been no reports of MOGHE without epilepsy and associated with extensive lesions. OBSERVATIONS: A 31-year-old man was incidentally diagnosed with an extensive right cerebral hemispheric lesion on MRI. Pathological examination of the biopsy sample showed no evidence of an invasive tumor but revealed an increase in Olig2-positive cells, consistent with MOGHE. Sanger sequencing showed no IDH1/2 , histone H3 TERT promoter, or SLC35A2 mutations. Electroencephalography showed no evidence of epilepsy. LESSONS: This case suggests the existence of a condition with similar histological findings to MOGHE but without epilepsy. The authors propose naming this condition “mild malformation of cortical development with oligodendroglial hyperplasia and no epilepsy.” https://thejns.org/doi/10.3171/CASE24827

A light microscopy-based histopathology diagnosis of human brain specimens obtained from epilepsy surgery remains the gold standard to confirm the underlying cause of a patient’s focal epilepsy and further inform postsurgical patient management. The differential diagnosis of neocortical specimens in the realm of epilepsy surgery remains, however, challenging. Herein, we developed an open access, deep learning-based classifier to histopathologically assess whole slide microscopy images (WSI) and to automatically recognize various subtypes of Focal Cortical Dysplasia (FCD), according to the ILAE consensus classification update of 2022. We trained a convolutional neuronal network (CNN) with fully digitalized WSI of hematoxylin–eosin stainings obtained from 125 patients covering the spectrum of mild malformation of cortical development (mMCD), mMCD with oligodendroglial hyperplasia in epilepsy (MOGHE), FCD ILAE Type 1a, 2a and 2b using 414 formalin-fixed and paraffin-embedded archival tissue blocks. An additional series of 198 postmortem tissue blocks from 59 patients without neurological disorders served as control to train the CNN for homotypic frontal, temporal and occipital areas and heterotypic Brodmann areas 4 and 17, entorhinal cortex and dentate gyrus. Special stains and immunohistochemical reactions were used to comprehensively annotate the region of interest. We then programmed a novel tile extraction pipeline and graphical dashboard to visualize all areas on the WSI recognized by the CNN. Our deep learning-based classifier is able to compute 1000 × 1000 µm large tiles and recognizes 25 anatomical regions and FCD categories with an accuracy of 98.8% (F1 score = 0.82). Microscopic review of regions predicted by the network confirmed these results. This deep learning-based classifier will be made available as online web application to support the differential histopathology diagnosis in neocortical human brain specimens obtained from epilepsy surgery. It will also serve as blueprint to build a digital histopathology slide suite addressing all major brain diseases encountered in patients with surgically amenable focal epilepsy.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine‐adenine‐guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34‐year‐old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair‐dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action‐related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26‐year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine‐immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine‐positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico‐pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular‐genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro‐clinical‐imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico‐pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and “no definite FCD on histopathology” as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi‐layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

The definite diagnosis of central nervous system vasculitis requires pathological verification by biopsy or surgical resection of the lesion, which may not always be feasible. A 74-year-old woman with a history of allergic rhinitis, but not asthma, presented with slowly progressive left hemiparesis. Magnetic resonance imaging of the head revealed a heterogeneously enhancing mass involving the right internal capsule and corona radiata. Histological examination of the resected specimen revealed eosinophil-rich non-granulomatous small vessel vasculitis with no neutrophil infiltration or foci of microbial infection. Epstein-Barr virus in situ hybridization was negative, and polymerase chain reaction tests for both T-cell receptor gamma and immunoglobulin heavy-chain variable region genes did not show rearrangements, excluding the possibility of lymphoma and lymphoproliferative disorders. Blood hypereosinophilia and elevated erythrocyte sedimentation rate were observed; however, anti-neutrophil cytoplasmic antibodies were not detected. A biopsy of the erythema in the hips and thighs revealed perivasculitis with eosinophilic infiltration within the dermis. Chest computed tomography revealed multiple small nodules in the lungs. Her symptoms, aside from hemiparesis, disappeared after corticosteroid administration. The clinicopathological features were similar to eosinophilic granulomatosis with polyangiitis but did not meet its current classification criteria and definition. This patient is the first reported case of idiopathic eosinophilic vasculitis or idiopathic hypereosinophilic syndrome-associated vasculitis affecting the small vessels in the brain. Further clinicopathological studies enrolling similar cases are necessary to establish the disease concept and unravel the underlying pathogenesis.

Focal cortical dysplasia type IIIc (FCD‐IIIc) is histopathologically defined by the International League Against Epilepsy's classification scheme as abnormal cortical organization adjacent to epilepsy‐associated vascular malformations (VM). However, the incidence of FCD‐IIIc, its pathogenesis, or association with the epileptogenic condition remains to be clarified. We reviewed a retrospective series of surgical brain specimens from 14 epilepsy patients with leptomeningeal angiomatosis of Sturge‐Weber syndrome (LMA‐SWS; n = 6), cerebral cavernous malformations (CCM; n = 7), and an arteriovenous malformation (AVM; n = 1) to assess the histopathological spectrum of FCD‐IIIc patterns in VM. FCD‐IIIc was observed in all cases of LMA‐SWS and was designated as cortical pseudolaminar sclerosis (CPLS). CPLS showed a common pattern of horizontally organized layer abnormalities, including neuronal cell loss and astrogliosis, either manifesting predominantly in cortical layer (L) 3 extending variably to deeper areas with or without further extension to L2 and/or L4. Another pattern was more localized, targeting mainly L4 with extension to L3 and/or L5. Abnormal cortical layering characterized by a fusion of L2 and L3 or L4–L6 was also noted in two LMA‐SWS cases and the AVM case. No horizontal or vertical lamination abnormalities were observed in the specimens adjacent to the CCM, despite the presence of vascular congestion and dilated parenchymal veins in all VM. These findings suggest that FCD‐IIIc depends on the type of the VM and developmental timing. We further conclude that FCD‐IIIc represents a secondary lesion acquired during pre‐ and/or perinatal development rather than following a pathomechanism independent of LMA‐SWS. Further studies will be necessary to address the selective vulnerability of the developing cerebral neocortex in LMA‐SWS, including genetic, encephaloclastic, hemodynamic, or metabolic events.

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult‐to‐treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.Methods: Four web‐based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD‐relevant genes in paired brain and blood samples from the same 22 epilepsy patients.Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype–phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype–phenotype diagnosis in the near future.

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six‐month‐old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure‐free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34‐positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon‐like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule‐like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.

End folium sclerosis or hippocampal sclerosis (HS) type 3 is often associated with another coexisting epileptogenic lesion (dual pathology); however, the pathogenesis of HS type 3 remains elusive. A 46‐year‐old man presented with medically intractable focal aware seizures and focal impaired awareness seizures (FIAS) with occasional focal to bilateral tonic–clonic seizures (FBTCS) two years after surgical treatment with extensive cranial reconstruction for a brain abscess in the right temporal lobe associated with intracranial extension of ipsilateral cholesteatoma. Head magnetic resonance imaging (MRI) at age 49 revealed atrophy of the right cerebral hemisphere including the hippocampus and amygdala. The patient's first epilepsy surgery was a lateral temporal lobectomy, in which the mesial temporal structures were preserved because no epileptiform discharge was detected on the intraoperative electrocorticogram. However, FIAS with FBTCS started 15 months after the operation. The second surgery, amygdalohippocampectomy, at age 52, resulted in the patient being seizure‐free again for one year before seizures of the right lateral temporal origin recurred. He underwent a third surgery, resection of the Heschl's and supramarginal gyri, at age 53, but he continued to have drug‐resistant epilepsy over two years after that. Histopathological examination revealed dual pathology consisting of glial scar in the lateral temporal lobe and ipsilateral HS type 3 with an unusually severe lesion in the subiculum. No significant inflammatory change was observed. The clinicopathological features in the present case indicate that HS developed secondarily in the context of neocortical epilepsy due to glial scar, suggesting a role of repetitive abnormal electrical input from neocortical epileptogenic lesions into the hippocampus finally via the perforant pathway in the pathogenesis of HS type 3. Severe hippocampal atrophy on preoperative MRI together with its silent electrocorticogram recording at initial epilepsy surgery may represent clinically pre‐epileptogenic HS in a seizure‐free “silent or latent period” before completion of hippocampal epileptogenesis to the extent that clinical epileptic seizures occur.