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  Table of Contents    
REVIEW ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 176-188
Pathology of surgically remediable epilepsy: How to evaluate


Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum, Kerala, India

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Date of Submission20-Oct-2021
Date of Decision10-Dec-2021
Date of Acceptance11-Dec-2021
Date of Web Publication11-May-2022
 

   Abstract 


Epilepsy surgery is a well-established treatment modality in selected cases of medically refractory epilepsy. Advances in neuroimaging technology has greatly facilitated detection of lesions that are surgically amenable. Hippocampal sclerosis is the most common pathology encountered among specimens from epilepsy-related surgeries. Other common pathologies are malformations of cortical development including focal cortical dysplasia, neoplasms, vascular malformations, inflammatory conditions including Rasmussen encephalitis and glial scars. Proper handling of surgical specimens is necessary for microscopic evaluation. Accurate interpretation and classification of lesions will help define clinically relevant etiologies. In this review, neuropathological aspects of the common etiologies underlying drug-resistant epilepsies are discussed.

Keywords: Drug-resistant, epilepsy, neuropathology, specimen, surgery

How to cite this article:
Poyuran R. Pathology of surgically remediable epilepsy: How to evaluate. Indian J Pathol Microbiol 2022;65, Suppl S1:176-88

How to cite this URL:
Poyuran R. Pathology of surgically remediable epilepsy: How to evaluate. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:176-88. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/176/345028





   Introduction Top


Epilepsy is a common neurological disorder in which patients have recurrent unprovoked focal or generalized seizures. The first line of management is pharmacotherapy with antiseizure drugs. However, about one-third of patients develop drug resistance and nearly half of them will require surgical management.[1],[2] The aim of epilepsy surgery is to resect or disconnect an epileptogenic lesion or focus, without inducing new neurological deficit, in order to attain long-term seizure control.[3] The decision of surgery is made after multidisciplinary evaluation comprising of clinical, electrophysiological, neuroimaging, and neuropsychological assessment.[4],[5] Resective surgeries are offered in cases with radiological evidence of structural abnormalities/lesions and include lesionectomy, extended lesionectomy, hippocampectomy, cortisectomy, lobectomy, or quadrantectomy. When the underlying cause for epilepsy is not amenable to resection, disconnections such as corpus callosotomy, hemispherotomy, etc., are performed in which the epileptogenic focus is disconnected from the rest of the parenchyma and is aimed at reducing the frequency and severity of epilepsy.[4] In the latter surgical modalities, only limited tissue may be submitted for histopathological examination which may not be from the epileptic focus or lesion. The first epilepsy surgery in India was performed on August 25, 1952 at Christian Medical College, Vellore[1] and an estimated 7143 epilepsy surgeries had been performed in India until July 2016.[6]

Common etiologies identified in surgically amenable cases of epilepsy are hippocampal sclerosis (HS), malformations of cortical development including focal cortical dysplasia (FCD), neoplasms, vascular malformations, inflammatory conditions including Rasmussen encephalitis and glial scars resulting from hypoxic ischemic brain injuries or other ischaemic insults.

Temporal vs extratemporal causes of epilepsy: Based on the site of epileptogenesis, cases can be clinically classified as temporal lobe and extratemporal epilepsies, the former being more common in surgical series. HS is the most common cause of temporal lobe epilepsy followed by neoplasm, FCD, dual pathology, and cysticercal cyst. Among extratemporal epilepsies, FCDs are the most common etiology identified followed by neoplasms, gliotic lesions, malformations of cortical development, and encephalitis.[7–12]

This review is intended to provide an overview of the neuropathological features of these lesions with a brief discussion on handling of relevant surgical specimens.


   Specimen: Gross examination and technical aspects Top


Common specimens in epilepsy-related surgeries include lesionectomies, cortical resections/lobectomies and hippocampectomies which may be intact or fragmented. Histopathological evaluation is best performed on intact specimens, especially for non-neoplastic epilepsy pathologies. As a general rule, specimens are sectioned serially at 5 mm interval, preferably in coronal plane and grossly evaluated for the presence of any lesion or abnormality. [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d Special care should be taken in cases of hippocampectomy specimens, where hippocampus is always sectioned in coronal plane and slices from midbody and tail are best suited for assessing hippocampal pathology. For lobectomy/cortisectomy specimens, cuts should run perpendicular to the cortical surface and include all the gyri in each slice. After sectioning, look for presence of any lesion, gyral atrophy, increased cortical thickness, or blurring of the gray-white junction. Slices from both abnormal and normal-appearing areas should be processed for microscopic examination. If fresh samples are received, some of the slices can be frozen and stored at -80°C for future research after ensuring that sufficient and representative tissue is submitted for diagnostic histopathological examination.[13],[14]
Figure 1: Grossing of specimens. En-bloc hippocampectomy specimen (a) containing the head (anterior) and body is serially sectioned coronally as indicated by the dashed lines. The corresponding slices are displayed in (b) and slices from the midbody level (*) are best suited for assessing hippocampal pathology. Intact cortisectomy specimen (c) is serially sectioned perpendicular to the cortical surface as indicated by the dashed lines. The corresponding slices (d) here show preserved gray-white distinction. Histopathological evaluation: Schematic (e) representing sequential histopathological assessment of samples for the diagnoses of major pathological entities encountered in surgically amenable cases of epilepsy. (FCD: focal cortical dysplasia, HS: hippocampal sclerosis, TLS: temporal lobe sclerosis)

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For microscopic evaluation, 4 μm sections are cut. Routine hematoxylin and eosin (H&E) and histochemical stains such as Luxol fast blue (LFB) and Cresyl violet are an integral part of microscopic evaluation. In addition, application of a set of antibodies is recommended and essential for evaluating and accurate subtyping of lesions associated with epilepsy,[13] which are listed in [Table 1]. Use of NeuN, neurofilament, and GFAP antibodies on all samples is advised. Inclusion of synaptophysin is not only useful in the evaluation of neoplasms, but also in FCDs where it provides additional information on the subcortical synaptic plexi.[15],[16] For neoplasms, additional immunohistochemical markers should be performed as per the WHO classification of the CNS tumors. [Figure 1]e summarizes the histopathological assessment and diagnoses of the major pathological entities encountered in surgical samples of drug-resistant epilepsy.
Table 1: Recommended set of antibodies used in the evaluation of epilepsy pathologies

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   Neuropathological Substrates of Epilepsy in Surgical Specimens Top


Hippocampal sclerosis (HS)

HS accounts for about 20–40% of epilepsy cases undergoing surgery.[7],[8],[9],[10],[11] It is associated with the clinical syndrome of mesial temporal lobe epilepsy. Mesial temporal sclerosis and Ammon's horn sclerosis are terms used interchangeably with HS; however, for histopathological examination, HS is preferred.[17] HS is histopathologically characterized by segmental pyramidal neuronal loss and astrogliosis in Ammon's horn sectors. This is detected as hippocampal volume loss and T2 hyperintensity on MRI and as atrophic and firm hippocampus on gross examination. Diagnosis of HS is based on the assessment of neuronal loss in the Ammon's horn, and the term “sclerosis” in HS in fact refers to the neuronal loss rather than the associated gliosis. Segmental pattern of neuronal loss was first described in 1880 by Sommer.[18] Various schemes have been used to subtype HS since then, with the latest being the International League against Epilepsy (ILAE) 2013 classification system which is based on semiquantitative assessment of hippocampal subfield neuronal loss.[19] This system classifies HS into three types microscopically. [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f In HS type 1, there is severe neuronal loss and gliosis in CA1 and CA4 sectors of Ammon's horn with variable degree of loss in CA3 and CA2 sectors. HS type 2 is characterized by severe loss of neurons in CA1 sector, while other sectors show near normal to mild neuronal loss. HS type 3 shows severe neuronal loss in CA4 and was previously termed end folium sclerosis. HS type 1 is the most common subtype accounting for about 60–85% of all HS cases and is also called “classic” HS. HS type 2 and type 3 are considered “atypical” forms and constitute only about 5–14% and 1–8%, respectively.[11],[20],[21] Cases with varying degree of gliosis and lacking significant neuronal loss in Ammon's horn are classified as “No HS/gliosis only,” which is noted in about 20% of cases of temporal lobe epilepsies.[20] Accurate classification of HS is possible on intact hippocampal specimens. Cases of mesial temporal lobe epilepsy with fragmented specimen precluding assessment of all the Ammon's horn sectors and showing significant neuronal loss in CA1 or CA4 are classified as “probable HS.”
Figure 2: Types of hippocampal sclerosis (HS) as per the ILAE 2013 classification. HS type 1 (a, b) with severe neuronal loss (a) and gliosis (b) involving CA1 and CA4 sectors. HS type 2 (c, d) with severe neuronal loss (c) and gliosis (d) in CA1 sector. Gliosis is also seen in CA4 sector in this case. HS type 3 (e, f) with severe neuronal loss (e) and gliosis (f) involving CA4 sector. Normal hippocampus (g) for comparison. Dentate gyrus pathology in HS includes severe depletion (h), dispersion (i) and duplication (j) of granule neurons. In some cases of HS, few neurofilament-positive neurons can also be noted, especially in CA4 sector (k). (CA1–CA4: sectors of Ammon's horn, DG: Dentate gyrus, ml: molecular layer, NF-P: phosphorylated neurofilament) [a-k: immunoperoxidase, magnification = scale bar (a-g: 2 mm; h-j: 100 μm; k: 50 μm)]

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Although this classification is based on the assessment of Ammon's horn, dentate gyrus pathology is also frequent in HS and includes granule cell dispersion, severe depletion/loss, or a combination of both [Figure 2]h, [Figure 2]i, [Figure 2]j. Normally, dentate gyrus is composed of compact layers of granule neurons. In dispersion, the neurons are more loosely arranged resulting in heterotopic neurons in molecular layer and even duplication of the gyrus. Although there is no definite criteria, thickness more than 10 cell layers or 120 μm is considered as dispersion.[17],[22],[23] The presence of granule cell dispersion should be assessed only in areas without curvature in dentate gyrus. Granule cell dispersion is evident in about 40–60% of HS.[23],[24]

In addition, mesial temporal structures can also exhibit pathological changes in cases of temporal lobe epilepsy. Neuronal loss and gliosis have been documented in amygdala especially involving the lateral nucleus.[25],[26] Similarly, entorhinal cortex also shows varying degree of neuronal loss and gliosis, particularly involving layer 3.[27],[28] Temporal neocortex can show subcortical white matter gliosis, atrophy, subpial gliosis, and increased corpora amylacea. Increased corpora amylacea can also be noted in hippocampal specimens and is related to the duration of epilepsy.[12],[29]

Malformations of cortical development (MCD)

Malformations of cerebral cortical development are a group of developmental disorders that are common causes of developmental delay and epilepsy. Based upon the stage of brain development at which the developmental process is disturbed, MCDs are categorized into: malformations of cell proliferation, malformations of neuronal migration, and malformations of postmigrational cortical organization and connectivity. With the ever-expanding spectrum of genetic and molecular alterations in MCDs, the latest classification proposed by Barkovich also incorporates these information.[30] FCD are the most frequent MCDs among surgical specimens.

Focal cortical dysplasia (FCD)

FCDs are localized malformations of cerebral cortex constituting about 10–15%[7–11] to as high as 50% of cases[31] in large surgical series. As a group, they are more common in extratemporal location as compared to temporal (22–29% vs 8–12%).[8],[11] The term FCD was coined by David Taylor and colleagues in 1971 who described its quintessential features.[32] Following this, many classification systems were developed, of which the most widely recognized was the one proposed by Andre Palmini in 2004.[33] However, with this system, interobserver concordance among neuropathologists for FCD subtyping was found to be only moderate.[34] To improve interobserver concordance and to identify clinically distinct entities, an ILAE task force in 2011 proposed a three-tiered classification system which is presently being followed worldwide.[35] This classification system broadly classifies FCD into isolated FCDs (FCD types I and II) and those associated with other principal lesions (FCD types IIIa–IIId). Classification of FCD is based on two features: (a) cortical laminar architecture and (b) cytological abnormalities. Intact and properly oriented specimens are essential for accurate typing. In instances where only fragmented specimens are submitted for histopathological evaluation, identification and subtyping of FCDs will be difficult (except perhaps for FCD type II) and only descriptive diagnosis can be offered.

Orderly arrangement of pyramidal neurons in normal neocortex results in six cortical layers (hexalaminar architecture) [Figure 3]a. FCD type I is defined by an altered cortical architecture or dyslamination. FCD type Ia is characterised by “radial dyslamination” identified by the presence of neuronal microcolumns [Figure 3]b. Microcolumns are vertical arrangement of more than eight small diameter neurons, most pronounced in cortical layer 3. FCD type Ia with neuronal microcolumns resembles fetal cortex in the first half of gestation and is thought to occur due to maturation arrest during development. Synaptophysin in FCD type Ia demonstrates radial or vertical arrangement of synaptic layers alternating with neuronal microcolumns. This pattern is abnormal and not observed during normal development.[16],[36] FCD type Ib is characterized by “tangential dyslamination,” evident as either loss of architecture of the entire cortex without any recognizable layering or absence or severe depletion of neurons in a specific cortical layer, commonly involving layer 2 or layer 4 [Figure 3]c. FCD type Ic has a combination of both type Ia and type Ib. Recent analysis of FCDs' type Ib and type Ic have raised questions on them being true cortical malformations.[36],[37] Neuronal loss restricted to the specific cortical layer resembling FCD type Ib has been noted in association with acquired pathologies such as hypoxic-ischemic injuries[38] and hence probably are not “developmental” in nature. FCD type Ib might be reclassified as FCD type IIId (see below) in the next classification system for FCD.[36],[37]
Figure 3: Types of focal cortical dysplasia (FCD) as per the ILAE 2011 classification. Normal neocortical architecture with six layers (a) for comparison. FCD type Ia: radial dyslamination with presence of neuronal microcolumns (b). FCD type Ib: tangential dyslamination with loss of neurons in layer 2 (c). FCD type IIb: Specimen (d) showing blurring of gray-white junction in one gyrus (*, compare with adjacent gyri), which is also clearly evident on sections stained with Luxol fast blue (* in e). There is generalized cortical dyslamination (f) with the presence of dysmorphic neurons (g) and balloon cells (j). Dysmorphic neurons stain strongly with neurofilament protein – both phosphorylated (h) and nonphosphorylated (i) isoforms. Balloon cells are GFAP (k) and vimentin (l) positive. FCD type IIa will show similar features except for the absence of balloon cells. Variants of FCD type IIIa: HS with temporal lobe sclerosis (m, n) and HS with small lentiform heterotopia (arrows in o, p) in the subcortical white matter. (LFB: Luxol fast blue, NF-P: phosphorylated neurofilament, NF-nP: nonphosphorylated neurofilament) [g, j: hematoxylin and eosin; a–c, f, h, i, k, l–p: immunoperoxidase, Magnification = scale bar (a, b: 200 μm; c: 2 mm; f: 500 μm; g–l: 20 μm; m, n: 500 μm; o, p: 200 μm)]

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Note:

  1. Architectural assessment should be performed on NeuN-stained sections and in areas where the sections are perpendicular to cortical surface avoiding zones with gyral bends.
  2. Dyslamination patterns diagnostic of FCD type I described above apply to neocortex. The criteria should be applied with caution on samples from temporal pole and non-six-layered periallocortical and proisocortical areas such as insular cortex, subiculum, parahippocampal gyrus, and cingulate gyrus.[14]
  3. Sections from occipital lobe, especially around calcarine sulcus, often show some degree of microcolumnar arrangement of neurons. Only an excess than normal and prominent microcolumns should be labelled as FCD type Ia.
  4. During evaluation of neuronal loss in specific layers or geographic regions, one should remember that the absence of NeuN staining may be due to loss of NeuN immunoreactivity or expression rather than neuronal loss, which can result due to crush artefact or haemorrhage. Also, rough handling of tissues during surgery or injury related to surface or depth electrode may result in geographic area of neuronal loss and needs careful interpretation and exclusion of such artefacts.[36]


FCD type II is characterized by cortical dyslamination and specific cytologic abnormalities. Dyslamination in type II is a generalized architectural disarray involving all the cortical layers [Figure 3]f. The characteristic features are the cellular changes which in FCD type IIa are in the form of dysmorphic neurons and in FCD type IIb as dysmorphic neurons and balloon cells [Figure 3]g, [Figure 3]h, [Figure 3]i, [Figure 3]j, [Figure 3]k, [Figure 3]l. Dysmorphic neurons generally maintain the pyramidal morphology but are considerably larger with abnormal peripherally distributed Nissl substance and maloriented dentritic processes. They are positive for neurofilament proteins, both phosphorylated and nonphosphorylated isoforms. Balloon cells are large rounded cells with abundant glassy eosinophilic cytoplasm (lacking Nissl substance), vesicular nuclei, and prominent nucleoli. Bi or multinucleate forms can be encountered. They are positive for vimentin and nestin and variably for GFAP and neurofilament proteins. The coexpression of both GFAP and neurofilament in balloon cells suggests that they have a mixed glial and neuronal lineage. A proportion of these cells may also express CD34 on the cell surface. Dysmorphic neurons and balloon cells can be present in any of the cortical layers and can also extend into the subcortical white matter. FCD type II, especially type IIb, is associated with myelin loss in the underlying white matter which can be recognized on gross examination as poor gray-white differentiation [Figure 3]d and [Figure 3]e and on MRI as increased cortical thickness on T1-weighted images, white matter hyperintensities on T2-weighted and FLAIR images. The typical radiological description of “transmantle sign” is generally associated with FCD type IIb.

FCD type III refers to cortical dyslamination (similar to FCD type I) occurring adjacent to a principal lesion, usually adjacent to or affecting the same cortical area/lobe. There are four subtypes: cortical dyslamination associated with HS is type IIIa, with neoplasms is type IIIb, with vascular malformations (cavernous haemangiomas, arteriovenous malformations, leptomeningeal vascular malformations, telangiectasias, or meningioangiomatosis) is type IIIc, and with any other principal lesion (glial scar, lesions associated with prenatal or perinatal ischemic injury or bleeding, inflammatory, or infectious diseases) is type IIId. At present, FCD type IIId is a “wastebasket” category used for any lesions that are not IIIa, IIIb, or IIIc. It is being proposed to restrict the use of IIId to ischemic lesions occurring during development including cases with laminar loss of neurons resembling FCD type Ib. A new subtype of IIIe may be applied to lesions other than IIIa to IIId such as inflammatory or traumatic lesions.[36]

Note:

  1. In addition to the temporal cortical dyslamination associated with HS, the following are also recognized as FCD type IIIa variants: (a) HS with temporal lobe sclerosis: severe neuronal loss in layers 2 and 3 with laminar gliosis resulting in an abnormal band of small and clustered small-sized neurons in the outer part of layer 2 [Figure 3]m, [Figure 3]n. (b) HS with small ''lentiform'' heterotopia in subcortical white matter: small oblong or oval neuronal clusters in the subcortical white matter running parallel to the gray-white junction. They are better visualized by synaptophysin [Figure 3]o and [Figure 3]p and MAP2.
  2. For the diagnosis of FCD type IIIb, dyslamination should be observed in cortex devoid of tumor infiltration. Immunohistochemistry for CD34 and Ki67 can aid in identifying the cortical areas with tumor infiltration.


In FCDs type I and type II, cortical border towards white matter is less defined as compared to normal. This is due to increase in number of neurons in the U-fiber layer (white matter immediately beneath the cortex), which are best demonstrated by NeuN and MAP2. Synaptophysin will highlight the increase in synaptic plexi around these U-fiber neurons, which are seen as punctate synapses around neuronal soma and their axonal projections into the overlying cortex. These axonal projections are postulated to contribute to epileptogenecity by establishing excitatory circuitry and epileptic networks in the cortex.[15]

FCD type II (type IIb much more than IIa) are the most frequent among FCDs and are easily recognisable microscopically. However, diagnosing FCD type I and type III, which is dependent on identification of architectural alterations, is challenging. Depending on how strictly the criteria for dyslamination are applied, their proportion can vary widely between different studies.[7–11] FCD type II is known to have genetic alterations involving the mTOR pathway or DEPDC5 gene, similar to hemimegalencephaly and tuberous sclerosis. Recent data shows that FCD type I are genetically distinct and have been noted to have alteration in SLC35A2 gene.[36],[39],[40]

Other malformations of cortical development

Common malformations that can be encountered in surgical specimens are hemimegalencephaly, polymicrogyria, cortical tuber, nodular or band heterotopia, and hypothalmic hamartoma.[7],[9],[11],[31] Their diagnosis is largely aided by neuroimaging and genetic work-up. Microscopic features of cortical tubers and hemimegalencephaly are similar to that of FCD type IIb and differentiating them just based on histopathology is not possible. Polymicrogyria is characterized grossly by numerous small gyri producing an irregular cortical surface with lumpy appearance. Its involvement can vary from a single gyrus to an entire hemisphere to bilateral.[41] Etiopathogenically, it is heterogeneous and can represent a primary genetic malformation or result due to destructive insults to the developing cortex and can also be associated with other lesions. Microscopically, the cortical ribbon is thin, excessively folded with the fusion of the molecular layer of the adjacent gyri and festooning of the cortical surface. The fusion of the molecular layer results in the entrapment of blood vessels and leptomeningeal collagen within the cortex. Two cortical architectural patterns are described: the most common being an unlayered pattern with a neuronal layer lacking any laminar organization and the overlying molecular layer of adjacent gyri showing fusion. Less commonly, a four-layered architecture is noted composed of molecular layer followed by two neuronal layers separated by a cell-sparse zone. At times, the cortex may exhibit normal lamination but with reduced number of neurons in all layers.[42] The type of cortical architecture does not have any clinical implication. Leptomeninges have been consistently noted to be thickened and adherent over the affected gyri with the pial surface showing discontinuity and thickening.[43],[44] Pial membrane discontinuity and the resultant fusion of molecular layers establish synaptic continuity and circuit for the excitatory network between the two fused gyri and may facilitate epileptogenesis and propogation.[45] This synaptic continuity between the fused gyri can be demonstrated by synaptophysin immunohistochemistry.[46] Heterotopias are defined by the presence of apparently normal neurons in abnormal locations. They result from the failure of clusters of neurons to migrate away from the embryonic ventricular zone to the developing cortex. Nodular heterotopias are heterotopic nodules of gray matter in subependymal/periventricular, subcortical, or leptomeningeal location. Periventricular nodular heterotopias are the most frequent, found along the walls of lateral ventricles and typically protrude into the lumen. They may also be associated with FCD type I in overlying cortex[47] or with polymicrogyria.[48],[49] Subcortical laminar heterotopia show sheets of gray matter between the cortical mantle and the ventricles.

Hypothalamic hamartomas are congenital, nonprogressive, tumor-like masses that arise from the ventral hypothalamus and tuber cinereum. Majority of the patients become symptomatic during early childhood with gelastic (laughing) seizures and some may develop precocious puberty.[11],[50],[51] Microscopically, they are composed of admixture of neurons and glial cells dispersed in neuropil (synaptophysin positive) and often arranged as nodules. The neurons are usually small to medium sized and highlighted by NeuN. Myelinated axons (LFB stain or phosphorylated neurofilament IHC) and large neurons are rare within the lesion, which help differentiate the hamartoma from normal hypothalamus [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d, [Figure 4]e, [Figure 4]f.[11],[50]
Figure 4: Hypothalamaic hamartoma (a–f): composed of small to medium sized neurons dispersed in neuropil (a). NeuN highlights the neurons with evident nodular architecture (b). The stroma is synaptophysin rich (c). Interspersed small glial cells are highlighted by OLIG2 (d) and GFAP (e). The adjacent normal hypothalamus (* in f) shows preserved phosphorylated neurofilament (NF-P)-positive axonal bundles, which is depleted in the lesion (f). [a: hematoxylin and eosin; b–f: immunoperoxidase, magnification = scale bar (a: 20 μm; b, d, e: 50 μm; c, f: 200 μm)]. Gliotic lesions (g–l): Resection specimen (g) showing multiple mushroom-shaped atrophic gyri (ulegyria) indicated by arrow. Microscopic examination of another case (h, i) showing multifocal gliosis (h) involving the cortex and white matter with loss of cortical architecture and residual neuronal nodules (i). A case of multicystic encephalomalacia (j) showing multiple cystic spaces with intervening gliotic parenchyma involving the white matter and cortex. A case of porencephalic cyst (k, l) with a thin cyst wall and severely atrophic cortical ribbon (*) overlying it. [j, k: hematoxylin and eosin; h, i, l: immunoperoxidase, magnification = scale bar (h-l: 200 μm)]. Rasmussen encephalitis (m–t): Cortical atrophy and gliosis (m) with microglial proliferation (n, o) and a T-cell predominant reactive lymphocytic infiltration (p). Microglial nodule (q), neuronophagia (r), astrogliosis (s), and cortical neuronal loss (t). [m, q, r: hematoxylin and eosin; n–p, s, t: immunoperoxidase, magnification = scale bar (q, r: 20 μm; n–p, s: 50 μm; m: 100 μm; t: 200 μm)]

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Mild malformations of cortical development (mMCD) are mild abnormalities characterized by excess heterotopic neurons in layer 1 of cortex (mMCD type I) or in deep white matter (mMCD type II). These terms should be used only in the absence of any other specific lesion. Their significance is not known and they are probably nonspecific findings.[35] Recently, a new type of mMCD referred to as mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) has been described, which is characterized microscopically by increased white matter oligodendroglial cell density, hypomyelination, and heterotopic neurons.[52]

Neoplasms

Though any neoplasm with cortical involvement can result in seizure, those that are commonly associated with drug-resistant epilepsy are discussed here which have also been called long-term or low-grade epilepsy-associated tumors (LEAT). They constitute about 15–30% of surgical samples.[7],[8],[9],[10],[11],[31] Their diagnosis is as per the WHO classification of CNS tumors and the immunohistochemical workup should be tailored accordingly. In the setting of epilepsy surgery, glioneuronal tumors are by far the most common neoplasms encountered, of which a large majority is constituted by ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET).[7],[8],[9],[10],[11],[31],[53] Other less common neoplasms include pleomorphic xanthoastrocytoma, pilocytic astrocytoma, angiocentric glioma, papillary glioneuronal tumor, diffuse gliomas, very rarely meningioangiomatosis, meningioma, etc. Recent advances in molecular profiling have identified novel tumors such as multinodular and vacuolating neuronal tumors (MVNT) and polymorphous low-grade neuroepithelial tumors of the young (PLNTY) as substrates for epilepsy.

Gangliogliomas [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d have glial and neuronal components and can exhibit marked heterogeneity in morphology. The glial component frequently exhibits astrocytic morphology, and the characteristic neuronal cells are ganglion cells. CD34 positivity is noted in about 70–80% of cases with characteristic positivity of cell membrane and ramified cellular processes.[54],[55],[56] CD34 is also helpful in highlighting satellite cortical nodules that would go unnoticed on H and E stain.[57] [Figure 5]e and [Figure 5]f. Gangliogliomas harbor BRAF gene alterations including BRAF V600E point mutation in 40–50% and KIAA1549-BRAF fusion in 10–15%.[58],[59],[60]
Figure 5: Glioneuronal neoplasms. Ganglioglioma (a–d) with glial (b) and neuronal (c) components and the characteristic CD34 staining pattern (d). CD34 helps identify satellite tumor nodules in the cortex (e). Such cortical areas will show dyslamination (f), but this should not be diagnosed as FCD type IIIb. Dysembryoplastic neuroepithelial tumor (i–l) with the specific glioneuronal elements with small round OLIG2-positive oligodendrocyte-like cells (j) arranged along phosphorylated neurofilament (NF-P)-positive axonal columns (k). NeuN (l) highlights the floating neurons. Some glioneuronal tumors may have an ill-defined morphology (g) with loosely dispersed small round to oval cells and CD34 positivity aids in their identification (h). [a, g, i: hematoxylin and eosin; b–f, h, j–l: immunoperoxidase, magnification = scale bar (a–d, g, i: 20 μm; h: 50 μm; e, f: 200 μm; j–l: 100 μm)]

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DNETs [Figure 5]i, [Figure 5]j, [Figure 5]k, [Figure 5]l have multinodular growth pattern with specific glioneuronal element. Glioneuronal element is characterized by phosphorylated neurofilament-positive axonal columns along which OLIG2-positive and GFAP-negative small oligodendrocyte-like cells are arranged. Between the axonal columns, mature appearing pyramidal neurons called “floating neurons” are seen in a myxoid matrix, which are NeuN positive. CD34 positivity has been described in 17–25% of simple DNETs,[54],[55],[61] while in complex and so-called diffuse DNET, it is noted in about 55–80% of cases.[61] Common genetic alterations involve FGFR1 gene with internal tandem duplication and point mutations in 20–30% each and fusion with TACC1 in 10–15%. BRAF V600E mutation is detected only in 5–10% of cases.[58],[59],[60],[62]

Although gangliogliomas and DNETs are classically described as well-defined neoplasms, they do show involvement of adjoining parenchyma as satellite nodules or as diffuse cell-sparse infiltration. Also, some “glioneuronal” neoplasms have a very diffuse growth pattern with presence of mild to moderately cellular parenchyma, containing small round to oval cells without forming proper mass and exhibiting focal to extensive CD34 positivity [Figure 5]g and [Figure 5]h. Some authors have called them “glioneuronal tumor-not otherwise specified”, and molecular analysis on such tumors has shown BRAF and FGFR1 gene alterations.[62] Furthermore, with the increasing use of molecular diagnostics, some of these ill-defined neoplasms might turn out to be one of the newly described epilepsy associated neoplasms; further studies are needed to resolve their true nature.

Angiocentric glioma microscopically consists of monomorphic, bipolar spindled cells with a characteristic angiocentric arrangement around parenchymal blood vessels. Some cases can also exhibit solid growth pattern with compact fascicles and nodules of spindle cells. The cells are GFAP-positive and exhibit dotlike positivity with EMA. Recurrent molecular alteration involving MYB gene is documented in angiocentric glioma, predominantly as MYB-QKI fusion.[59],[63] MVNT is microscopically identified by a distinctive nodular pattern and stromal vacuolation. The cells are neuronal, exhibit intracellular vacuolation, and are synaptophysin and OLIG2 positive. There is no evidence of mutation in BRAF, FGFR1, or MYB gene. Recently, MAP2K1 Q56P mutation and single-nucleotide polymorphisms have been identified in DEPDC5, SMO, and TP53 genes.[64],[65] PLNTY microscopically has a diffuse growth pattern composed of round cells with oligodendrocytic morphology and minimal pleomorphism. Occasional cases may have astrocytic morphology. Calcification is a common finding and the tumor lacks Rosenthal fibers, eosinophilic granular bodies, myxoid microcysts, dysmorphic neurons, or ganglion cells. The cells are strongly GFAP positive and show widespread CD34 expression. Molecular profiling revealed BRAF V600E mutation and gene fusions involving FGFR2 and FGFR3.[66]

Gliotic lesions

Gliotic lesions as a cause of drug resistant epilepsy constitute about 5–23% of surgically treated cases.[7],[9],[11],[31] Gliosis can result due to traumatic and nontraumatic injuries to the brain. The nontraumatic destructive insult/injury to the developing brain is most commonly due to a vascular event. The resultant morphological phenotype depends on the type and time of insult and includes porencephaly, multicystic encephalomalacia, ulegyria, hemiatrophy, leukomalacia, etc [Figure 4]g, [Figure 4]h, [Figure 4]i, [Figure 4]j, [Figure 4]k, [Figure 4]l. These lesions are heterogeneous and show varying degree of glial scarring involving white matter or cortex or both. Cortical atrophy can be unifocal or multifocal and the affected gyri are narrow and gliotic with neuronal loss and varying degree of white matter atrophy, gliosis, and cystic change. If the gliosis affects the sulci predominantly, leaving the crests of gyri intact, it results in mushroom-shaped gyral appearance called ulegyria. Porencephaly is a smooth-walled defect in cerebral hemisphere extending from the surface to varying depths in the parenchyma, and in severe cases, the cystic defect can communicate with the ventricle. The surrounding cortex shows abnormal gyral pattern and neuronal architecture. Porencephaly results due to ischemic events at the end of the second or the beginning of the third trimester of pregnancy. Occlusion of large artery, typically middle cerebral artery, results in a cavity with smooth walls, precise limits, and little or no perilesional gliosis. In contrast, multicystic encephalomalacia results from insults occurring later during development (end of pregnancy, during delivery, or first few days of life). There is occlusion of multiple cerebral arterioles and capillary beds resulting in multiple infarcts of varying sizes, subsequently leading to formation of multiple cysts with ill-defined limits and severe gliosis in white matter and deep cortical layers giving a sponge-like appearance.[67],[68]

Other lesions

Vascular malformations constitute about 2–6% of cases in surgical series of drug-resistant epilepsy, of which cerebral cavernous malformation/cavernous haemangioma is the most common followed by arteriovenous malformation. Cavernous hemangioma is composed of tightly packed dilated vascular channels without intervening brain parenchyma. Thrombosis, calcification, and hemosiden-laden foamy macrophages are commonly encountered. Arteriovenous malformation shows a nidus of large caliber muscular blood vessels of venous and arterial types with irregular wall thickening. Intervening parenchyma is evident in between the blood vessels. The adjacent or the entrapped parenchyma shows varying degrees of gliosis and hemosiderin deposition, which have been implicated in epilepstogensis.

Rasmussen encephalitis is a syndrome of unknown etiology typically presenting in childhood with medically refractive epilepsy with polymorphic seizures, frequent occurrence of epilepsia partialis continua, progressive cerebral hemiatrophy, and neurological deficits such as hemiparesis.[69] It is a T-cell-mediated disorder and histopathologically characterized by perivascular and interstitial lymphocytic infiltration, microglial proliferation with formation of microglial nodules, neuronophagia, and associated varying degrees of gliosis and atrophy of the cerebral parenchyma. These features resemble a viral encephalitis. The lymphocytes are T-cell predominant and constituted largely by CD8-positive T cells.[70],[71] CD20 for B-cells can be performed simultaneously to determine the ratio between T and B cells and ascertaining the predominance of the former. CD68 and HLA-DR immunohistochemistry aids assessment of the microglial response [Figure 4]m, [Figure 4]n, [Figure 4]o, [Figure 4]p, [Figure 4]q, [Figure 4]r, [Figure 4]s, [Figure 4]t. Robitaille in 1991 described four stages of pathological changes in the tissue with the early stages dominated by active inflammation and less gliosis and the late stages with prominent gliosis and atrophy.[72] Stage 1 or the early stage shows mild focal inflammation, gliosis and neuronal loss in the cortex. Stage 2 or intermediate stage has panlaminar cortical inflammation, gliosis, and moderate to severe gliosis. Stages 3 and 4 have severe panlaminar gliosis, atrophy, severe neuronal loss, and cavitatory changes with variable microglial response and minimal (stage 3) to very rare (stage 4) lymphocytic infiltration. These pathological changes are multifocal with skip areas in between, and within a single case, there is heterogeneity in the stage of inflammation and cortical damage.[70]

Neurocysticercosis is an important cause of seizure in endemic regions. Seizure is the most common manifestation of neurocysticercosis detected in 80% of cases and show excellent seizure control with medical management. Among surgical samples from epilepsy, it constitutes about 1–2% of all cases.[8],[11],[31] There is a strong association between cysticercosis and HS (dual pathology) or rarely it can be associated with adjacent cortical dyslamination (FCD type IIId) or FCD type IIb (double pathology).[11],[73],[74]

In about 2–15% of cases, there may not be any evidence of any specific lesion even after thorough microscopic examination.[7],[8],[9],[11],[31]


   Terminology used for multiple lesions Top


Double pathology: it refers to two independent lesions affecting one or multiple lobes, but not including HS,[35] e.g., co-occurrence of vascular malformations or neoplasms with FCD type IIa or type IIb.

Dual pathology: it refers to cases of HS with a second principal lesion, which may be located within or outside the ipsilateral temporal lobe,[35] e.g., occurrence of HS with neoplasms, vascular malformations, FCD type IIa, or type IIb. Association of HS with architectural abnormalities (that resembles FCD type I) in ipsilateral temporal lobe is classified as FCD type IIIa and not dual pathology.


   Relevance of Histopathological Examination and Future Direction Top


  1. Histopathological examination can help identify an additional pathology which might not have been picked up on neuroimaging and helps detect lesions such as FCD types III, dual pathology, and double pathology.
  2. Postsurgical outcome may be influenced by the type of underlying pathology. The best postoperative seizure control is noted with LEATs, vascular malformations, and HS, while FCD type I, mMCD, MCD, and gliosis have poor outcome.[75]
  3. Following standardized and uniform criteria for histopathological diagnosis facilitates comparison among different studies and provides better clinicopathological correlation.
  4. Further studies are required for clinical and genetic characterization of rare lesions such as FCD types Ib, Ic, and III.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Santhosh NS, Sinha S, Satishchandra P. Epilepsy: Indian perspective. Ann Indian Acad Neurol 2014;17:S3-11.  Back to cited text no. 1
    
2.
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314-9.  Back to cited text no. 2
    
3.
McKhann GM, Bourgeois BF, Goodman RR. Epilepsy surgery: Indications, approaches, and results. Semin Neurol 2002;22:269-78.  Back to cited text no. 3
    
4.
Rao MB, Arivazhagan A, Sinha S, Bharath RD, Mahadevan A, Bhat M, et al. Surgery for drug-resistant focal epilepsy. Ann Indian Acad Neurol 2014;17:S124-31.  Back to cited text no. 4
    
5.
Rathore C, Radhakrishnan K. Concept of epilepsy surgery and presurgical evaluation. Epileptic Disord 2015;17:19-31.  Back to cited text no. 5
    
6.
Rathore C, Radhakrishnan K. Epidemiology of epilepsy surgery in India. Neurol India 2017;65:S52-9.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Pasquier B, Péoc'H M, Fabre-Bocquentin B, Bensaadi L, Pasquier D, Hoffmann D, et al. Surgical pathology of drug-resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections. Epileptic Disord 2002;4:99–119.  Back to cited text no. 7
    
8.
Sarkar C, Sharma MC, Deb P, Singh VP, Chandra PS, Gupta A, et al. Neuropathological spectrum of lesions associated with intractable epilepsies: A 10-year experience with a series of 153 resections. Neurol India 2006;54:144-50. discussion 150-151.  Back to cited text no. 8
    
9.
Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med 2017;377:1648-56.  Back to cited text no. 9
    
10.
Blümcke I. Neuropathology of focal epilepsies: A critical review. Epilepsy Behav 2009;15:34-9.  Back to cited text no. 10
    
11.
Poyuran R, Mahadevan A, Mhatre R, Arimappamagan A, Sinha S, Bharath RD, et al. Neuropathological spectrum of drug resistant epilepsy: 15-years-experience from a tertiary care centre. J Clin Neurosci 2021;91:226-36.  Back to cited text no. 11
    
12.
Radhakrishnan VV, Rao MB, Radhakrishnan K, Thomas SV, Nayak DS, Santoshkumar B, et al. Pathology of temporal lobe epilepsy: An analysis of 100 consecutive surgical specimens from patients with medically refractory epilepsy. Neurol India 1999;47:196-201.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Blümcke I, Aronica E, Miyata H, Sarnat HB, Thom M, Roessler K, et al. International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: A consensus Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 2016;57:348-58.  Back to cited text no. 13
    
14.
Blümcke I, Mühlebner A. Neuropathological work-up of focal cortical dysplasias using the new ILAE consensus classification system-Practical guideline article invited by the Euro-CNS Research Committee. Clin Neuropathol 2011;30:164-77.  Back to cited text no. 14
    
15.
Sarnat HB, Hader W, Flores-Sarnat L, Bello-Espinosa L. Synaptic plexi of U-fibre layer beneath focal cortical dysplasias: Role in epileptic networks. Clin Neuropathol 2018;37:262-76.  Back to cited text no. 15
    
16.
Sarnat HB, Flores-Sarnat L. Radial microcolumnar cortical architecture: Maturational arrest or cortical dysplasia? Pediatr Neurol 2013;48:259-70.  Back to cited text no. 16
    
17.
Thom M. Review: Hippocampal sclerosis in epilepsy: A neuropathology review. Neuropathol Appl Neurobiol 2014;40:520-43.  Back to cited text no. 17
    
18.
Sommer W. Erkrankung des Ammonshorns als aetiologisches moment der epilepsie. Arch Psychiatr Nervenkr 1880;10:631-75.  Back to cited text no. 18
    
19.
Blümcke I, Thom M, Aronica E, Armstrong DD, Bartolomei F, Bernasconi A, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE commission on diagnostic methods. Epilepsia 2013;54:1315-29.  Back to cited text no. 19
    
20.
Blümcke I, Pauli E, Clusmann H, Schramm J, Becker A, Elger C, et al. A new clinico-pathological classification system for mesial temporal sclerosis. Acta Neuropathol 2007;113:235-44.  Back to cited text no. 20
    
21.
Thom M, Liagkouras I, Elliot KJ, Martinian L, Harkness W, McEvoy A, et al. Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome. Epilepsia 2010;51:1801-8.  Back to cited text no. 21
    
22.
Lurton D, El Bahh B, Sundstrom L, Rougier A. Granule cell dispersion is correlated with early epileptic events in human temporal lobe epilepsy. J Neurol Sci 1998;154:133-6.  Back to cited text no. 22
    
23.
Wieser H-G, ILAE Commission on Neurosurgery of Epilepsy. ILAE commission report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695-714.  Back to cited text no. 23
    
24.
Blümcke I, Kistner I, Clusmann H, Schramm J, Becker AJ, Elger CE, et al. Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta Neuropathol 2009;117:535-44.  Back to cited text no. 24
    
25.
Wolf HK, Aliashkevich AF, Blümcke I, Wiestler OD, Zentner J. Neuronal loss and gliosis of the amygdaloid nucleus in temporal lobe epilepsy. A quantitative analysis of 70 surgical specimens. Acta Neuropathol 1997;93:606-10.  Back to cited text no. 25
    
26.
Yilmazer-Hanke DM, Wolf HK, Schramm J, Elger CE, Wiestler OD, Blümcke I. Subregional pathology of the amygdala complex and entorhinal region in surgical specimens from patients with pharmacoresistant temporal lobe epilepsy. J Neuropathol Exp Neurol 2000;59:907-20.  Back to cited text no. 26
    
27.
Du F, Whetsell WO, Abou-Khalil B, Blumenkopf B, Lothman EW, Schwarcz R. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res 1993;16:223-33.  Back to cited text no. 27
    
28.
Dawodu S, Thom M. Quantitative neuropathology of the entorhinal cortex region in patients with hippocampal sclerosis and temporal lobe epilepsy. Epilepsia 2005;46:23-30.  Back to cited text no. 28
    
29.
Radhakrishnan A, Radhakrishnan K, Radhakrishnan VV, Mary PR, Kesavadas C, Alexander A, et al. Corpora amylacea in mesial temporal lobe epilepsy: Clinico-pathological correlations. Epilepsy Res 2007;74:81-90.  Back to cited text no. 29
    
30.
Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: Update 2012. Brain 2012;135:1348-69.  Back to cited text no. 30
    
31.
Piao Y-S, Lu D-H, Chen L, Liu J, Wang W, Liu L, et al. Neuropathological findings in intractable epilepsy: 435 Chinese cases. Brain Pathol 2010;20:902-8.  Back to cited text no. 31
    
32.
Taylor DC, Falconer MA, Bruton CJ, Corsellis JA. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369-87.  Back to cited text no. 32
    
33.
Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, Foldvary-Schaefer N, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2-8.  Back to cited text no. 33
    
34.
Chamberlain WA, Cohen ML, Gyure KA, Kleinschmidt-DeMasters BK, Perry A, Powell SZ, et al. Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 2009;50:2593-8.  Back to cited text no. 34
    
35.
Blümcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, et al. The clinico-pathological spectrum of Focal Cortical Dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE diagnostic methods commission. Epilepsia 2011;52:158-74.  Back to cited text no. 35
    
36.
Najm IM, Sarnat HB, Blümcke I. Review: The international consensus classification of focal cortical dysplasia – A critical update 2018. Neuropathol Appl Neurobiol 2018;44:18-31.  Back to cited text no. 36
    
37.
Coras R, Holthausen H, Sarnat HB. Focal cortical dysplasia type 1. Brain Pathol 2021;31:e12964.  Back to cited text no. 37
    
38.
Wang D-D, Piao Y-S, Blumcke I, Coras R, Zhou W-J, Gui Q-P, et al. A distinct clinicopathological variant of focal cortical dysplasia IIId characterized by loss of layer 4 in the occipital lobe in 12 children with remote hypoxic-ischemic injury. Epilepsia 2017;58:1697-705.  Back to cited text no. 38
    
39.
Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S, Bulteau C, et al. Dissecting the genetic basis of focal cortical dysplasia: A large cohort study. Acta Neuropathol 2019;138:885-900.  Back to cited text no. 39
    
40.
Kobow K, Ziemann M, Kaipananickal H, Khurana I, Mühlebner A, Feucht M, et al. Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia. Epilepsia 2019;60:1091-103.  Back to cited text no. 40
    
41.
Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res 2006;173:322-33.  Back to cited text no. 41
    
42.
Judkins AR, Martinez D, Ferreira P, Dobyns WB, Golden JA. Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal cortical laminar organization. J Neuropathol Exp Neurol 2011;70:438-43.  Back to cited text no. 42
    
43.
Jansen AC, Robitaille Y, Honavar M, Mullatti N, Leventer RJ, Andermann E, et al. The histopathology of polymicrogyria: A series of 71 brain autopsy studies. Dev Med Child Neurol 2016;58:39-48.  Back to cited text no. 43
    
44.
Squier W, Jansen A. Polymicrogyria: Pathology, fetal origins and mechanisms. Acta Neuropathologica Communications 2014;2:80.  Back to cited text no. 44
    
45.
Diamandis P, Chitayat D, Toi A, Blaser S, Shannon P. The pathology of incipient polymicrogyria. Brain Dev 2017;39:23-39.  Back to cited text no. 45
    
46.
Sarnat HB, Flores-Sarnat L. Excitatory/inhibitory synaptic ratios in polymicrogyria and down syndrome help explain epileptogenesis in malformations. Pediatr Neurol 2021;116:41-54.  Back to cited text no. 46
    
47.
Meroni A, Galli C, Bramerio M, Tassi L, Colombo N, Cossu M, et al. Nodular heterotopia: A neuropathological study of 24 patients undergoing surgery for drug-resistant epilepsy. Epilepsia 2009;50:116-24.  Back to cited text no. 47
    
48.
Wieck G, Leventer RJ, Squier WM, Jansen A, Andermann E, Dubeau F, et al. Periventricular nodular heterotopia with overlying polymicrogyria. Brain 2005;128:2811-21.  Back to cited text no. 48
    
49.
Mandelstam SA, Leventer RJ, Sandow A, McGillivray G, van Kogelenberg M, Guerrini R, et al. Bilateral posterior periventricular nodular heterotopia: A recognizable cortical malformation with a spectrum of associated brain abnormalities. AJNR Am J Neuroradiol 2013;34:432-8.  Back to cited text no. 49
    
50.
Coons SW, Rekate HL, Prenger EC, Wang N, Drees C, Ng Y, et al. The histopathology of hypothalamic hamartomas: Study of 57 cases. J Neuropathol Exp Neurol 2007;66:131-41.  Back to cited text no. 50
    
51.
Téllez-Zenteno JF, Serrano-Almeida C, Moien-Afshari F. Gelastic seizures associated with hypothalamic hamartomas. An update in the clinical presentation, diagnosis and treatment. Neuropsychiatr Dis Treat 2008;4:1021-31.  Back to cited text no. 51
    
52.
Schurr J, Coras R, Rössler K, Pieper T, Kudernatsch M, Holthausen H, et al. Mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy: A new clinico-pathological entity. Brain Pathol 2017;27:26-35.  Back to cited text no. 52
    
53.
Radhakrishnan A, Abraham M, Vilanilam G, Menon R, Menon D, Kumar H, et al. Surgery for “Long-term epilepsy associated tumors (LEATs)”: Seizure outcome and its predictors. Clin Neurol Neurosurg 2016;141:98-105.  Back to cited text no. 53
    
54.
Blümcke I, Giencke K, Wardelmann E, Beyenburg S, Kral T, Sarioglu N, et al. The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies. Acta Neuropathol 1999;97:481-90.  Back to cited text no. 54
    
55.
Chappé C, Padovani L, Scavarda D, Forest F, Nanni-Metellus I, Loundou A, et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF (V600E) mutation and expression. Brain Pathol 2013;23:574-83.  Back to cited text no. 55
    
56.
Deb P, Sharma MC, Tripathi M, Sarat Chandra P, Gupta A, Sarkar C. Expression of CD34 as a novel marker for glioneuronal lesions associated with chronic intractable epilepsy. Neuropathol Appl Neurobiol 2006;32:461-8.  Back to cited text no. 56
    
57.
Blümcke I, Wiestler OD. Gangliogliomas: An intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol 2002;61:575-84.  Back to cited text no. 57
    
58.
Stone TJ, Rowell R, Jayasekera BAP, Cunningham MO, Jacques TS. Review: Molecular characteristics of long-term epilepsy-associated tumours (LEATs) and mechanisms for tumour-related epilepsy (TRE). Neuropathol Appl Neurobiol 2018;44:56-69.  Back to cited text no. 58
    
59.
Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 2016;131:833-45.  Back to cited text no. 59
    
60.
Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun 2020;8:30.  Back to cited text no. 60
    
61.
Thom M, Toma A, An S, Martinian L, Hadjivassiliou G, Ratilal B, et al. One hundred and one dysembryoplastic neuroepithelial tumors: An adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol 2011;70:859-78.  Back to cited text no. 61
    
62.
Stone TJ, Keeley A, Virasami A, Harkness W, Tisdall M, Izquierdo Delgado E, et al. Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathol 2018;135:115-29.  Back to cited text no. 62
    
63.
Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R, et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 2016;48:273-82.  Back to cited text no. 63
    
64.
Huse JT, Edgar M, Halliday J, Mikolaenko I, Lavi E, Rosenblum MK. Multinodular and vacuolating neuronal tumors of the cerebrum: 10 cases of a distinctive seizure-associated lesion. Brain Pathol 2013;23:515-24.  Back to cited text no. 64
    
65.
Thom M, Liu J, Bongaarts A, Reinten RJ, Paradiso B, Jäger HR, et al. Multinodular and vacuolating neuronal tumors in epilepsy: Dysplasia or neoplasia? Brain Pathol 2018;28:155-71.  Back to cited text no. 65
    
66.
Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): An epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 2017;133:417-29.  Back to cited text no. 66
    
67.
Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol 2000;5:3-16.  Back to cited text no. 67
    
68.
Low C, Garzon E, Carrete H, Vilanova LC, Yacubian EM, Sakamoto AC. Early destructive lesions in the developing brain: Clinical and electrographic correlates. Arq Neuropsiquiatr 2007;65:416-22.  Back to cited text no. 68
    
69.
Bien CG, Granata T, Antozzi C, Cross JH, Dulac O, Kurthen M, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: A European consensus statement. Brain 2005;128:454-71.  Back to cited text no. 69
    
70.
Pardo CA, Vining EPG, Guo L, Skolasky RL, Carson BS, Freeman JM. The pathology of Rasmussen syndrome: Stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 2004;45:516-26.  Back to cited text no. 70
    
71.
Prayson RA, Frater JL. Rasmussen encephalitis: A clinicopathologic and immunohistochemical study of seven patients. Am J Clin Pathol 2002;117:776-82.  Back to cited text no. 71
    
72.
Robitaille Y. Neuropathologic aspects of chronic encephalitis. In: Andermann F, editor. Chronic Encephalitis and Epilepsy. Rasmussen's Syndrome. Boston: Butterworth-Heinemann; 1991. p. 79–110.  Back to cited text no. 72
    
73.
Mhatre R, Poyuran R, Arimappamagan A, Sinha S, Kulanthaivelu K, Kenchaiah R, et al. Dual/double pathology in neurocysticercosis causing drug resistant epilepsy-Chance association or causal? Epilepsy Res 2020;168:106472. doi: 10.1016/j.eplepsyres. 2020.106472.  Back to cited text no. 73
    
74.
Rathore C, Thomas B, Kesavadas C, Radhakrishnan K. Calcified neurocysticercosis lesions and hippocampal sclerosis: Potential dual pathology? Epilepsia 2012;53:e60-2.  Back to cited text no. 74
    
75.
Lamberink HJ, Otte WM, Blümcke I, Braun KPJ. European Epilepsy Brain Bank writing group; study group; European Reference Network EpiCARE. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: A retrospective multicentre cohort study. Lancet Neurol 2020;19:748-57.  Back to cited text no. 75
    

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Correspondence Address:
Rajalakshmi Poyuran
Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum – 695 011, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_1026_21

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