|
|
INVITED REVIEW |
|
|
|
| Year : 2008 | Volume
: 3
| Issue : 1 | Page : 55-64 |
| |
Surgical pathology of pediatric epilepsy
Vani Santosh, TC Yasha
Department of Neuropathology, NIMHANS, Bangalore, India
Correspondence Address:
Vani Santosh
Department of Neuropathology, NIMHANS, Bangalore
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1817-1745.40591
 Abstract | | |
The underlying pathological substrates of localization-related epilepsy are varied. In children, the foremost among these are the malformative disorders of cortical development of which focal cortical dysplasia (FCD) is the most prominent. Other conditions include tuberous sclerosis, Sturge-Weber syndrome, vascular malformations, ischemic lesions and epilepsy-associated tumors. As in adults, medial temporal sclerosis is also a common histopathological finding. Resective surgery for extratemporal lesions is now the treatment of choice as more accurate identification of lesion with modern imaging and electrophysiological techniques is possible and a good surgical outcome is seen in most cases. This review describes the common causal histopathological substrates of epilepsy in children.
Keywords: Dysembryoplastic neuroepithelial tumor, focal cortical dysplasia, ganglioglioma, hemimegalencephaly, medial temporal sclerosis, pediatric epilepsy
How to cite this article:
Santosh V, Yasha T C. Surgical pathology of pediatric epilepsy. J Pediatr Neurosci 2008;3:55-64 |
| Introduction | |  |
The temporal lobe is the most common site for a seizure focus resulting in complex partial seizures, the characteristic seizure-type in temporal lobe epilepsy (TLE). In approximately one-third to one-half of patients with TLE and in many others with focal epilepsy originating outside the temporal lobe, the seizures are refractory to pharmacotherapy. [1],[2] Surgery has become the established mode of therapy in patients with intractable focal epilepsy. [3],[4],[5] More recently, increasing numbers of pediatric patients with intractable epilepsy are being referred to epilepsy surgery centers with the aim of seizure control, reduction in morbidity and improvement in the quality of life. This can be attributed to better recovery of function after surgery in children as the immature brain is more plastic. [4],[6],[7],[8] In most series, the outcome of surgery has been good [6],[9] with a significant reduction in the seizure frequency. On the other hand, the outcome in patients with an extratemporal seizure focus after resection has been worse than in those with a temporal focus. This is probably due to the more diffuse nature of such lesions. [7],[10],[11],[12],[13] Furthermore, in view of the relatively smaller numbers of cases of extratemporal lobe resection compared with temporal lobe resections seen in most epilepsy centers, series examining the histopathologic features of epileptogenic lesions in the extratemporal regions have been much smaller than those that describe temporal lesions. [6],[8],[14]
The nature of surgically resected specimens received in the laboratory often varies depending on the location of the lesional tissue and the surgical approach. The histopathological examination depends greatly on the structural integrity of the specimen, which in turn depends on the surgical technique. The majority of surgical procedures are performed for the treatment of TLE. The resection in this case includes portions of the anterior temporal cortex, hippocampal formation and corpus amydaloideum and when present, a seizure focus elsewhere in the temporal lobe. [3],[4] These should be submitted to the laboratory as separate, labeled tissue fragments or en bloc . In patients with Rassmusen's encephalitis or other unilateral hemispheric pathology, extensive specimens from functional hemispherectomies are received. While evaluating surgically resected specimens in chronic seizure disorders, the neuropathologist should consider the following points: 1. Composition of the specimen, i.e ., the size of the specimen and its anatomical parts such as neocortex, subcortical white matter, hippocampal formation, corpus amydaloideum etc. 2. The presence or absence of focal lesions such as tumors and hamartias and 3. The presence or absence of Ammon's horn sclerosis. [15],[16],[17] In this way, histopathological evaluation can provide prognostically relevant information and help in guiding further therapy.
This review briefly outlines some of the more common lesions underlying localization-specific epilepsy, namely cortical malformations, medial temporal sclerosis (MTS), vascular malformations, ischemic lesions and epilepsy-associated tumors.
| Malformations of Cortical Development | | |
Cortical dyslamination was first reported by Alzheimer and subsequently, developmental disorders affecting neuronal proliferation, migration as well as cortical lamination and differentiation, together termed as malformation of cortical development (MCD) have been recognized as important causes of epilepsy, though seizures may not be the major presenting symptom in some. Various classification schemes have attempted to link the pathology of MCD with the timing of the neonatal insult, severity of clinical features, imaging and surgical outcome. [18],[19],[20]
A short review of normal development is necessary for an understanding of the pathogenesis of MCD. Briefly, the three-layered cortex at six weeks of gestation comprises the periventricular (PZ), intermediate (IZ) and marginal zones (MZ). At seven weeks, the first wave of neuroblasts migrate from the PZ through the IZ and form the preplate (PP) beneath the MZ. The PP is later split by the succeeding waves of migrating neuroblasts, which ultimately form the cortical plate (CP), into the subplate (SP) and an outer layer. Most of the cells of the SP undergo apotosis in the normal course of development. Subsequently, the CP forms the six-layered cortex in an 'inside-out' pattern, wherein the early migrating cells form the deepest layers. The migration is guided by the cell processes of the radial glia that extend from the ventricular zone to the glia limitans. Neuronal migration disorders of varying severity result from disruption of this pattern. Additionally, the cue for final cell differentiation, whether neuronal or glial, appears to be coded at the time of cell proliferation in the PZ considerably before migration. Therefore, in lesions which contain cells with aberrant differentiation, the timing of injury is likely to be during early development. [21]
MCD resulting from migration disorders leads to architectural abnormalities with laminar or columnar disorganization of cells while cytological abnormalities result in dysmorphic, enlarged cells. Some of the underlying causative factors of MCD include genetic disorders such as lissencephaly (LIS), subcortical band heterotopia (SBH) and tuberous sclerosis (TS) which are single gene disorders while the pathogenesis of others such as focal cortical dysplasia (FCD), hemimegalencephaly (HME) and polymicrogyria (PMG) are largely unknown. [22] Other causative factors include prenatal infections and ischemia. FCD is the most common malformative substrate for medically intractable epilepsy particularly in the pediatric group.
| Focal Cortical Dysplasia | | |
Definition: The impetus for the study of FCD was initiated by Taylor's report in 1971, [23] which attributed focal clusters of large ballooned cells in the cortex to be the pathological substrate in 8/10 cases of localization-related epilepsy. Attempting to bring clarity to the confusing and overlapping terminologies used subsequently, a panel of experts suggested that the term 'focal cortical dysplasia (FCD)' be restricted only to those cases of MCD where the pathology is restricted entirely or largely to the cortex. [18] Palmini et al . [18] and Tassi et al . [19] have provided the currently most followed classifications which have brought some uniformity in clinicopathological correlation between various studies. The following cell types are seen in FCD, based on which FCD is classified as Types I and II [18] [Figure - 1].
Giant neurons [Figure - 1]A: Resemble normal neurons except for size and have a large, centrally placed nucleus with nucleolus; no cytoskeletal abnormalities are present.
Immature neurons [Figure - 1]B: Medium-sized, round to oval, homogenous cells with clear cytoplasm; round vesicular nucleus without prominent nucleolus.
Dysmorphic neurons [Figure - 1]C: Neurons with cytoskeletal abnormalities, malalignment and irregular dendritic processes. They appear dark and irregular and are not ischemic neurons. The cytoskeletal pathology is reflected as phosphorylated neurofilament [Figure - 2]E or ubiquitin accumulation in the cell soma and can be seen by immunohistochemistry. These cells are also highlighted by silver stains [Figure - 2]D.
Balloon cells [Figure - 1]D: These are large cells with abundant, glassy, eosinophilic cytoplasm and peripherally placed nuclei, with or without prominent nucleoli. They do not have cytoskeletal abnormalities and immunohistochemically show aberrant, overlapping phenotype-largely astrocytic with positivity for glial fibrillary acidic protein (GFAP) and often with markers of neuronal phenotype in the same cells.
The presence of dysmorphic and balloon cells have correlated with MRI abnormalities and a more severe clinical phenotype.
FCD I is defined as an anomaly of architecture-either laminar or columnar and without the presence of either dysmorphic or balloon cells.
FCD 1A: Architectural abnormality only (dyslamination). This may include mild MCD in which occasional ectopic or heterotopic neurons can be present.
FCD IB: Architectural abnormality with either giant neurons or immature neurons but without dysmorphic neuron s.
FCD II also called Taylor type of FCD is characterized by the presence of dysmorphic neurons,
FCD IIA: Presence of dysmorphic neurons
FCD IIB: Presence of dysmorphic neurons and balloon cells
FCD I lesions are more often seen in the temporal lobe in association with MTS whereas FCD II commonly involves extratemporal areas. The role of FCD I lesions in epileptogenesis is debatable as they are often seen in control, nonepileptic brains also. In Tassi's scheme, [19] FCD is classified as architectural, cytoarchitectural and Taylor type (with balloon cells) which roughly correspond to mild MCD/FCD IA, FCD IB/FCDIIA and FCD IIB respectively. A more recent exhaustive classification incorporates the known developmental steps, pathology, genetic alterations and when necessary, the neuroimaging features. [20] Another recent report highlights the presence of micro columns of cortical neurons in layer III in pediatric patients with intractable seizures. [24]
Imaging
MRI scans typically show focal thickening of the cortical ribbon, blurring of gray and white matter distinction and subcortical hyperintense T2 signals. [25] These correspond largely with FCD type II [25] lesions while FCD I is often undetectable. FCD II commonly affects extratemporal areas and can be lobar or multilobar. All histologically proven FCDs have at least two of the above radiological features and 78% have all three irrespective of lesion size. [26] Newer developments with postimaging processing with voxel-based 3D MRI analysis have greatly improved the detection of FCD. [27] Delayed myelination in children less than one year of age may mask the gray-white distinction and hence, it is advisable to repeat a scan after one year of age to detect FCD. Other techniques include MRS and diffusion tensor imaging (DTI). Functional/metabolic techniques like positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional MRI (fMRI) can enhance the sensitivity. [28] In histologically proven FCD, the sensitivity of MRI in detecting the lesions in children ranged from 63 to 98%. [29]
Prevalence of FCD
With high resolution MRI, FCD was seen in 24% patients with localization-related, refractory epilepsy. [30] In epilepsy surgical material, the incidence of FCD varies from 12-40% [31] to nearly 80% in children younger than three years of age. [32] Both imaging and pathological estimation of prevalence are not likely to truly reflect the actual prevalence of FCD in epilepsy as there is a patient selection bias of those undergoing surgery; patients partially responsive to medication, those not suitable for surgery and those with normal MRI being excluded from a more detailed work-up.
Surgical outcome
Increasingly, excision of the epileptogenic focus has given gratifying results in medically refractory epilepsy. Resective surgery for FCD in recent years has resulted in long-term complete seizure control in 50-72% of patients. An additional 4-20% experience significant reduction in seizure frequency. [19],[33],[34],[35] Complete removal of the lesion is the most important factor affecting the outcome, the identification of which is aided by high-resolution MRI, video-telemetry and electroencephalography (EEG) including introperative monitoring with electrocorticography and cortical motor stimulation. Lesions that involve the temporal and frontal lobes have a better surgical outcome compared with those outside these areas. A poorer outcome is seen with extensive lesions or multilobar involvement. [34],[35]
Correlation of the histological type of FCD with the outcome has shown a trend that patients with FCD I do better than those with FCD II while FCD IIA patients fare worse than FCD IIB patients. [36] In contrast, occasional series report better seizure control in FCD II [19] or no distinction between the groups. [33]
Pathogenesis
The basis of epileptogenesis in FCD is attributed to increased hyperexcitability combined with a decreased inhibitory action on the dysplastic neurons, which permits an abnormal and synchronized electrical stimulation causing sustained depolarization. Hyperexcitability is possibly due to the action of alpha-glutamic acid on a subset of excitatory N-methyl-D-aspartic acid (NMDA) receptors (NR2 A/B), which are upregulated in the dysplasic cells of FCD. Furthermore, these cells have markedly reduced types 1 and 3 Glu-R receptors which mediate gamma aminobutyric acid (GABA) function, the chief inhibitory neurotransmitter. Also, GABA-producing inhibitory interneurons identified by parvalbumin and calbindin positivity, are reduced in the dysplastic cortex and foci. [18],[35],[37]
Molecular Neuropathology
The histopathological features of FCD, especially FCD IIB, are very similar to the cortical tubers of tuberous sclerosis (TS) which often shows mutations of TSC1 (hamartin) or TSC2 (Tuberin) genes although patients of FCD lack cutaneous markers. Gangliogliomas (GG) also show morphological similarities to tubers. Recent studies [38] to analyze the potential pathogenetic role of TSC1/TSC2 in FCD and GG have shown that a) two-thirds of FCD IIB cases have sequence alterations (polymorphisms) in one TSC1 gene region and LOH (loss of heterozygosity) in the other TSC1 gene region. b) Similarly GGs showed several sequence alterations in the TSC2 gene, which was restricted to the glial component. c) FCD I and white matter neuronal heterotopia revealed abundant polymorphisms in TSC1. d) FCD IIA showed allelic variants only of the TSC2 gene and not of TSC1. This data favors the concept that TSC genes play a certain role in FCD and GG and that different pathogenetic events occur in FCD IIA and FCD IIB. Clinical observations support this idea as FCD IIB patients have a better surgical outcome as compared to FCD IIA patients. [38]
| Tuberous Sclerosis Complex (TSC) | | |
Although rare, TSC is one of the more common autosomal dominant phakomatoses with variable penetrance and multisystem involvement. Hamartomas and benign neoplasms that may be present are renal angiomyolipoma, pulmonary hamartoma, cardiac rhabdomyoma, skin (adenoma sebaceum, ash leaf, shagreen patches) and central nervous system (CNS) (cortical tubers, subcortical and periventricular heterotopia and subependymal giant cell astrocytoma) lesions. TSC is familial in one third and sporadic in two thirds of all cases indicating the high prevalence of spontaneous mutations. [39] Seizures occur in 78-90% of patients with onset in the first decade; the epileptogenic focus is the nonneoplastic cortical tuber. Cortical tubers are firm nodules that appear as rounded or flattened protrusions on the surface and are composed of aggregates of large, ballooned and bizarre cells widening and distorting the cortex and extending into the white matter.
Many cells show concurrent neuronal and glial differentiation and appear as 'ganglioid astrocytes' with abundant glassy eosinophilic cytoplasm with prominent nucleoli. Immunomarkers too show indeterminate features with inconsistent and overlapping profiles in several cells. The tubers may be associated with calcification.
Mutations in TSC1 (chromosome 16p13) and TSC2 (chromosome 16p13.3) encoding the tumor suppressor genes 'hamartin' and 'tuberin' respectively are mutated in almost all familial TSC accounting for 50% each. [40] Recent reports suggest that TSC2 tuberin gene mutations are more common both in familial and sporadic cases. [41] TSC1 mutations are associated with milder phenotypes and may escape detection.
Good seizure control has been noted in about 75% in TSC by resective surgery with best results when clinical, MRI and EEG data are concordant and a single primary epileptogenic focus can be identified. [42] Although all tubers are potentially epileptogenic, the responsible tuber is often the largest, well-defined and calcified. [43]
This sporadic syndrome is a neurocutaneous phakomatosis characterized by vascular dysplasia leading to leptomeningeal angiomatosis, nevus flammeus (port-wine stain) over the trigeminal distribution of the face and ocular angioma. Clinically, 75% of patients present with seizures, often intractable when onset is in the first year of life [44] and may be accompanied by hemiparesis. Tortuous blood vessels with capillary and venous angiomatosis are seen in the meninges, usually unilateral on the same side of the facial nevus commonly in the occipital or temporal lobes. Underlying ischemia is the causative factor for seizures. Dense calcification in the superficial layers of the cortex and vessel walls in the opposing surfaces of the sulci give rise to 'railroad' pattern seen on imaging. Chronic lesions lead to hemiatrophy. Polymicrogyria and heterotopia may occasionally be present. [21] Patients with extensive SWS are candidates for surgery (hemispherectomy and focal resections) [7] and the outcome is generally good in more than 80% of the cases. [45]
Surgical expertise is crucial as the hemodynamic effects of the vascular pathology may compromise the contralateral hemisphere and increase operative risks. [7]
| Hemimegalencephaly | | |
[Figure - 2]
HME is a severe form of MCD with unilateral enlargement of the cerebral hemisphere [Figure - 2]A which may additionally involve the brainstem, cerebellum, cranium and rarely hemihypertrophy of the limbs as well. [44] Intractable seizures and mental retardation are prominent. HME may be an isolated malformation (47%) or part of a syndrome (53%) which may not be immediately evident. [46] The associated neurocutaneous syndromes are neurofibromatosis, epidermal nevus syndrome, Ito's hypomelanosis and Klippel-Trenonay-Weber syndrome. [47] The brain shows few broad gyri with shallow sulci (pachygyria), a markedly thickened cortex without distinct gray white distinction featuring totally distorted laminar architecture [Figure - 2]B interspersed with glioneuronal nodules extending into the white matter and deep nuclear masses. Several balloon cells of glial origin, large dysmorphic neurons with cytoskeletal pathology [Figure - 2]C, D and E and a columnar orientation of cells are present. [44],[48] Some of the cells express both glial (GFAP) and neuronal (neurofilament, synaptophysin) markers indicating aberrant maturation. [49] The pathogenesis of HME is unknown. Neuronal cell densities and numbers determined by NeuN (Neuronal Nuclei) staining are increased in FCD and HME in the molecular and superficial layers of the gray matter as compared to controls despite normal total volume MRI suggesting increased neurogenesis in the later stages of cortical formation and decreased apoptosis. [50] Seizures are possibly caused by abnormal interactions of the immature and mature neurons forming anomalous circuits. [50]
Hemispherectomy is indicated for HME and selected cases of SWS, Rasmussen's encephalitis and multilobar cortical dysplasia. The outcome depends on the underlying pathology; overall good seizure control is achieved in 60-94%. [45] HME fared poorer (67-88%) than Rasmussen's and other congenital lesions(89-100%). [51],[52]
Other MCDs
Bihemispheric MCDs are not amenable for resective surgery. Corpus callosotomy is performed in selected instances with good results in the reduction of drop attacks. [53] Examples of bihemispheric MCDs encompass Lissencephaly (smooth brain) types I and II, Subcortical band heterotopia, Polymicrogyria (small excessively folded and fused gyri), Schizencephaly (full thickness defect in the cerebral hemisphere) and Periventricular nodular heterotopia.
| Temporal Lobe Epilepsy and Medial Temporal Sclerosis | | |
In children, TLE contributes 30% of intractable epilepsy requiring surgery although it forms only 1.8% of all epilepsy. [54] MTS/Ammon's horn sclerosis (AHS) is an important major pathological substrate of TLE characterized by selective neuronal loss in CA1 (Sommer sector) [Figure - 3], CA4 (endfolium)and CA3 regions of the hippocampus of which CA1 is the most vulnerable. The debate continues on whether AHS is the cause or effect of seizure disorders. About 50% [55] of patients have documented early insults, 34-70% of which are complex febrile seizures. Following a latent period of several years during which several structural and molecular reorganization are assumed to occur, there is an onset of spontaneous seizure activity from the hippocampus resulting in excitotoxicity-associated cell damage and loss. Dentate granule cell abnormalities are closely linked to and are an important component of AHS-cell loss, bilamination [Figure - 3]B and dispersion being the most common and seen in 50% of patients. The reelin signaling pathway plays a key role in the laminar organization of neocortex and hippocampus. Produced by the Cajal-Retzius cells at these sites, its decreased expression correlates with the extent of migration defects in the dentate gyrus. [56],[57],[58]
In adults, MTS is the most common histopathological substrate of TLE. In children, low grade neoplasms and cortical dysplasia are more frequent than MTS. [59],[60] Resected material for intractable TLE in children showed tumors including GG, astrocytoma, dysembryoplastic neuroepithelial tumor (DNT) and meningioangiomatosis in 32%, MTS in 30% and developmental abnormalities such as FCD and TS in 20% of the patients. [61] Less common substrates are porencephalic cyst, neurocysticercosis [62] and in a small proportion, no pathology is found. Surgery for temporal lobe epilepsy in children less than five years of age featured FCD most often (40%) followed by DNT, GG and malignant tumors and MTS was present in 20% always as dual pathology. [63]
The term 'dual pathology' is applied classically to the occurrence of extrahippocampal lesions and MTS, the most common of which is cortical dysplasia (CD). Patients with MTS and extrahippocampal CD have an earlier onset of epilepsy and a longer duration of seizures. [29] A milder form of CD, namely FCD I with mild cortical dyslamination with a few displaced neurons, is seen more frequently in the temporal lobe in association with MTS and does not have a worse outcome. [29],[64] Similarly, presence of heterotopic neurons in the white matter is often noted and only a high density of > ten per high power field is believed to be significant. [65] The role of mild MCD and FCD I in pathogenesis of the TLE is debatable as it has been found in nonepileptic controls as well, although in lesser numbers and is not likely to be epileptogenic. 'Dual pathology' has also been used for the presence of FCD with other lesions particularly when found in the tissue adjacent to low-grade glioneuronal tumors. [66]
Surgical outcome is excellent (85-90%) for temporal lobectomy in children, comparable with results in adults [61] while in extratemporal locations, it is lower at about 60%. [67]
| Vascular Malformations | | |
Cavernous angiomas present in the pediatric age group in 25% of cases, often with an acute onset of neurological features. Majority (80%) are sporadic and the rest familial with autosomal dominant inheritance. [68] Seizures at onset occur in 45.4% in the pediatric age group [69] and are localized more commmonly in the temporal and frontal lobes. [68] These angiographically silent lesions [70] are composed of thin-walled, vascular channels of varying sizes ranging from medium to large ectatic vessels to small vascular spaces, clustered together with no intervening brain parenchyma [Figure - 4]A and B. There is reactive gliosis with a few infiltrating strands of glial tissue at the periphery. Fresh hemorrhage, hemosiderin-containing macrophages and vascular calcification may be present. Lesionectomy is associated with a good outcome.
Arterivenous malformations are uncommon causes of epilepsy in children and seizures was the presenting feature in five in a series of 54 patients. [71] When visible grossly they are pyramid-shaped with the apex towards the center of the brain. They form a mass of irregularly thickened, fibrotic veins and an occasional artery with intervening brain parenchyma. [72]
| Rasmussen's Encephalitis | | |
Rasmussen's encephalitis (RE) is a rare, acquired chronic, inflammatory disorder of unknown etiology characterized by unilateral seizures progressing to secondary generalization. This is followed by gradual loss of unilateral function and hemiparesis with atrophy of the affected hemisphere and intractable seizures. Hemispherectomy and lobar specimens show cortical atrophy, hydrocephalus and small cortical scars. Histology reveals multifocal perivascular inflammation and neuronophagia in the acute stages and reactive astrocytosis and striking subpial gliosis in more chronic lesions. Entire cortical thickness, white matter and the basal ganglia may be variably affected. [73] Cellular T cell and CD 68 positive macrophage rich infiltrates are seen. [74] Similarities to tick-borne and viral encephalitides led to an extensive search for an infective etiological agent which has so far been unsuccessful. An autoimmune mechanism is postulated as rabbits used for raising antibody to Glutamate receptor type 3 (Glu R3) developed seizures and showed histological features of encephalitis. Few patients also had anti-GluR-3 IgG antibodies in the serum, laying the basis for plasmapheresis and intravenous immunoglobulin therapies in RE, which has given encouraging results. [75] It has also been postulated that the occasional CD that accompanies RE may cause seizures leading to an altered blood brain barrier, which then permits a viral or autoimmune disorder to develop. Hemispherectomy or partial resections in intractable cases have given good seizure control. [76]
Neuroinfections like neurocysticercosis (NCC) in endemic areas [77] and sparganosis [78] continue to be important infective causes of seizures.
| Hypoxic-ischemic Injury | | |
Hypoxic encephalopathy in preterm infants causes seizure disorders due to selective neuronal injury or a more widespread tissue necrosis. Infarction with resultant cavitation that is more common in the middle cerebral artery territory results in a porencephalic cyst. [44]
| Tumors | | |
Wolf and Wiestler have reviewed the histopathologic findings in 279 consecutive surgical specimens of patients with chronic pharmacoresistant epileptic disorders. [79] Neoplastic lesions constituted 31.2% cases. Majority were of low histopathological grade (WHO grade I /II). The most common tumors were ganglioglioma (GG), pilocytic astrocytoma (PA), oligodendroglioma, fibrillary astrocytoma and dysembryoplastic neuroepithelial (DNT) tumors. In another series reported by Kim et al ., [80] the most common tumors were DNT (39.2%), GG (21.8%) and oligodendroglioma (20.1%). A retrospective analysis of neoplastic lesions surgically resected for intractable epilepsy over a seven year period at the NIMHANS, Bangalore, showed GG and pilocytic astrocytoma to be the most common among the 24 neoplastic lesions encountered.
Ganglioglioma
Although GG account for approximately 0.4% of all intracranial neoplasms, [81] they have been found to be the most common neoplasm in patients with chronic seizure disorders. [79],[82],[83],[84] Some series report their incidence in 15-25% of patients undergoing surgery for refractory epilepsy. [79],[86] These are circumscribed, slowly growing, benign, well-differentiated neuroepithelial tumors composed of mature neoplastic ganglion cells often with dysplastic features in combination with neoplastic glial cells [Figure - 4]D. Immunohistochemical expression of synaptophysin, neuron-specific enolase, neurofilament protein and glial fibrillary acidic protein (GFAP) have been valuable adjuncts to aid histopathological diagnosis whenever the biopsied sample is small or fragmented. [79] Tumors in the medial temporal region are amenable for complete excision and are associated with good prognosis. [87]
Dysembryoplastic neuroepithelial tumor (DNT)
This is an unusual glioneuronal neoplasm occurring in children and young adults characterized by an intracortical location in the temporal cortex and resulting in pharmacoresistant, complex, partial seizures. [87] The histological hallmark of DNT is the 'specific glioneuronal element' composed of columns oriented perpendicularly to the cortical surface. These are composed of bundles of axons lined by small 'oligodendroglia-like' cells. Between these columns, there are normal or dystrophic neurons that seem to float in a pale eosinophilic matrix [87],[88] [Figure - 4]C. Few GFAP-positive astrocytes are embedded in these columns. Associated cortical dysplasia is seen in several cases. In the series by Wolf and Weistler, there were six cases of DNT seen mainly in pediatric patients. [79] As this tumor occurs exclusively in patients with long-standing seizures, the pathologist who examines surgical specimens from such cases should be aware of the complex histological features of this tumor. [89],[90],[91] Long-term clinical follow-up demonstrates no evidence of recurrence even in patients with partial surgical removal. [88],[91],[92] It is hypothesized that DNTs arise from malformative foci including cortical dysplasia and ectopic neurons in the region of the temporal cortex. [88],[91],[92] An admixture of glial and neuronal elements is seen both in DNTs and GGs and is also a prominent feature of glioneuronal hamartias. This raises the question as to whether the two tumors actually arise from preexisting glioneuronal hamartias. In fact, in small fragmented surgical samples, it may be difficult to differentiate GG from a glioneuronal hamartia.
Pilocytic astrocytoma
Among astrocytomas, low-grade tumors, particularly pilocytic astrocytoma (WHO grade I) and pleomorphic xanthoastrocytoma (WHO grade II), are often associated with seizure disorders in children. [79],[86] Pilocytic astrocytomas in the temporal lobe comprise about 19.5% of tumors which result in chronic pharmacoresistant epilepsy disorders. Histologically, the tumors in the temporal lobe are similar to those occurring in typical locations such as cerebellum and optochiasmatic or hypothalamic regions. [79]
Pleomorphic xanthoastrocytoma (PXA)
This is a circumscribed variant of astrocytoma with a favourable prognosis typically occurring in young adults and children, in superficial cerebral hemispheres, in close association with leptomeninges, often as a cystic neoplasm with a mural nodule. Most patients have long-standing seizures given its superficial location. The tumor is composed of closely packed, highly pleomorphic giant and lipidized cells. A dense pericellular reticulin network and lymphocytic infiltrates are typical microscopic features. Necrosis and mitosis are usually absent. The behavior of PXA is generally that of an indolent tumor. [93]
Among other glial tumors, low-grade oligodendrogliomas (grade II) are known to cause long-standing seizures and in one series on pediatric epilepsy, they comprised nearly 27% of cases. [80] It is important to note that in most series, the tumors associated with pharmacoresistant seizures are benign in nature and there have been no (or) exceptional malignant gliomas. [79] Some studies however, report a higher incidence of malignant gliomas to be associated with epilepsy. [82],[94] It is possible that these studies included patients with seizures of shorter duration, thus resulting in the higher incidence of malignant gliomas.
Meningioangiomatosis
This is a plaque-like lesion composed of meningothelial and fibroblast-like cells in the subarachnoid space centered around blood vessels and extending into the superficial gray matter along the penetrating vessels. When associated with seizures, the lesion is often single, sporadic and seen in children and young adults. [95] It may also be seen as part of Neurofibromatosis type 2, often being asymptomatic, multifocal and not associated with seizures except for a rare case report. [96] Gross total resection is the treatment of choice in symptomatic cases. [97]
This review highlights the microstructural basis of medically intractable epilepsy in children and the increasing role of resection in providing excellent to good outcomes in neoplastic and nonneoplastic lesions. Accurate presurgical identification of the epileptogenic focus is critical to the outcome, which is possible with the advanced imaging modalities and electrophysiological techniques currently available that increasingly recognize even subtle abnormalities of cortical development.
| Acknowledgments | | |
We thank Drs. Aparna Govindan and Shrijeet Chakraborti for the assistance in manuscript preparation and Mr. Manjunath K. for help in preparing the montages.
| References | | |
| 1. | Dasheiff RM. Epilepsy surgery: Is it an effective treatment? Ann Neurol 1989;25:506-10.  [PUBMED] |
| 2. | Sutula T. Experimental models of temporal lobe epilepsy: New insights from the study of kindling and synaptic reorganization. Epilepsia 1990;31:S45-54. |
| 3. | Engel J Jr, Ojemann GA. The next step. In : Engel J Jr, editor. Surgical treatment of the epilepsies. 2 nd ed. Raven Press: New York; 1993. p. 319-29. |
| 4. | Engel J Jr. Surgery for seizures. N Engl J Med 1996;334:647-52. [PUBMED] [FULLTEXT] |
| 5. | Estes M, Morris HH 3 rd , Ludres H, Dudley AJ Jr, Lesser RP. Surgery for intractable epilepsy: Clinicopathological correlates in 60 cases. Clev Clin J Med 1988;55:441-7. |
| 6. | Frater JL, Prayson RA, Morris HH 3 rd , Bingaman WE. Surgical pathologic findings of extratemporal-based intractable epilepsy: A study of 133 consecutive resections. Arch Pathol Lab Med 2000;124:545-9. |
| 7. | Cross JH, Jackson GD, Neville BG, Connelly A, Kirkham FJ, Boyd SG, et al . Early detection of abnormalities in partial epilepsy using magnetic resonance. Arch Dis Child 1994;69:104-9. |
| 8. | Centeno RS, Yacubian EM, Sakamoto AC, Ferraz AF, Junior HC, Cavalheiro S. Pre-surgical evaluation and surgical treatment in children with extratemporal epilepsy. Childs Nerv Syst 2006;22:945-59. [PUBMED] [FULLTEXT] |
| 9. | Khajavi K, Comair YG, Wyllie E, Palmer J, Morris HH, Hann JF. Surgical management of pediatric tumor-associated epilepsy. Child Neurol 1999;14:15-25. |
| 10. | Silander HC, Blom S, Malmgren K, Rosen I, Uvebrant P. Surgical treatment of epilepsy: A retrospective Swedish multicenter study. Acta Neurol Scand 1997;95:321-30. |
| 11. | Fish DR, Smith SJ, Quesney LF, Andermann F, Rasmussen T. Surgical treatment of children with medically intractable epilepsy: Results and highlights of 40 years' experience. Epilepsia 1993;34:244-7. [PUBMED] |
| 12. | Holmes MD, Dodrill CB, Ojemann LM, Ojemann GA. Five-year outcome after epilepsy surgery in nonmonitored and monitored surgical candidates. Epilepsia 1996;37:748-52. |
| 13. | MacKenzie RA, Matheson JM, Smith JS, Dwyer M. Surgery for refractory epilepsy. Med J Aust 1990;153:69-72. [PUBMED] |
| 14. | 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. |
| 15. | Davidson S, Falconer MA. Outcome of surgery in 40 children with temporal lobe epilepsy. Lancet 1975;1:1260-3. [PUBMED] |
| 16. | Duncan JS, Sagar HJ. Seizure characteristics, pathology and outcome after temporal lobectomy. Neurology 1988;37:405-9. |
| 17. | Bruten CJ. The neuropathology of temporal lobe: Epilepsy. Oxford University Press: Oxford; 1988. |
| 18. | 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. [PUBMED] [FULLTEXT] |
| 19. | Tassi L, Colombo N, Garbelli R, Francione S, Lo Russo G, Mai R, et al . Focal cortical dysplasia: Neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002;125:1719-32. [PUBMED] [FULLTEXT] |
| 20. | Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005;27:65:1873-87. |
| 21. | Harding BN, Copp AJ. Malformations. In : Graham DI, Lantos PL editors. Greenfield's Neuropathology. 7 th ed. Arnold: London; 2002. p. 357-483. |
| 22. | Kuzniecky RI. Malformations of cortical development and epilepsy, part 1: Diagnosis and classification scheme. Rev Neurol Dis 2006;3:151-62. [PUBMED] [FULLTEXT] |
| 23. | Taylor DC, Falconer MA, Bruton CJ, Corsellis JA. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369-87. [PUBMED] [FULLTEXT] |
| 24. | Hildebrandt M, Pieper T, Winkler P, Kolodziejczyk D, Holthausen H, Blümcke I. Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies. Acta Neuropathol 2005;110:1-11. |
| 25. | Colombo N, Tassi L, Galli C, Citterio A, Lo Russo G, Scialfa G, et al . Focal cortical dysplasias: MR imaging, histopathologic and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol 2003;24:724-33. [PUBMED] [FULLTEXT] |
| 26. | Colliot O, Antel SB, Naessens VB, Bernasconi N, Bernasconi A. In vivo profiling of focal cortical dysplasia on high-resolution MRI with computational models. Epilepsia 2006;47:134-42. [PUBMED] [FULLTEXT] |
| 27. | Huppertz HJ, Grimm C, Fauser S, Kassubek J, Mader I, Hochmuth A, et al . Enhanced visualization of blurred gray-white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 2005;67:35-50. [PUBMED] [FULLTEXT] |
| 28. | Ruggieri PM, Najm I, Bronen R, Campos M, Cendes F, Duncan JS, et al . Neuroimaging of the cortical dysplasias. Neurology 2004;62:S27-9. [PUBMED] [FULLTEXT] |
| 29. | Bast T, Ramantani G, Seitz A, Rating D. Focal cortical dysplasia: Prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 2006;113:72-81. [PUBMED] [FULLTEXT] |
| 30. | Chan S, Chin SS, Nordli DR, Goodman RR, DeLaPaz RL, Pedley TA. Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the non-balloon cell subtype. Ann Neurol 1998;44:749-57. [PUBMED] |
| 31. | Rickert CH. Cortical dysplasia: Neuropathological aspects. Childs Nerv Syst 2006;22:821-6. [PUBMED] [FULLTEXT] |
| 32. | Cepeda C, Andrι VM, Levine MS, Salamon N, Miyata H, Vinters HV, et al . Epileptogenesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis. Epilepsy Behav 2006;9:219-35. |
| 33. | Kloss S, Pieper T, Pannek H, Holthausen H, Tuxhorn I. Epilepsy surgery in children with focal cortical dysplasia (FCD): Results of long-term seizure outcome. Neuropediatrics 2002;33:21-6. [PUBMED] [FULLTEXT] |
| 34. | Kral T, Clusmann H, Blümcke I, Fimmers R, Ostertun B, Kurthen M, er al. Outcome of epilepsy surgery in focal cortical dysplasia. J Neurol Neurosurg Psychiatry 2003;74:183-8. |
| 35. | Wang VY, Chang EF, Barbaro NM. Focal cortical dysplasia: A review of pathological features, genetics and surgical outcome. Neurosurg Focus 2006;20:E7. |
| 36. | Fauser S, Schulze-Bonhage A, Honegger J, Carmona H, Huppertz HJ, Pantazis G, et al . Focal cortical dysplasias: Surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 2004;127:2406-18. [PUBMED] [FULLTEXT] |
| 37. | Najm I, Ying Z, Babb T, Crino PB, Macdonald R, Mathern GW, Spreafico R. Mechanisms of epileptogenicity in cortical dysplasias. Neurology 2004;62:S9-13. [PUBMED] [FULLTEXT] |
| 38. | Becker AJ, Blümcke I, Urbach H, Hans V, Majores M. Molecular neuropathology of epilepsy-associated glioneuronal malformations. J Neuropathol Exp Neurol 2006;65:99-108. |
| 39. | Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al . Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64-80. [PUBMED] [FULLTEXT] |
| 40. | van Bakel I, Sepp T, Ward S, Yates JR, Green AJ. Mutations in the TSC2 gene: Analysis of the complete coding sequence using the protein truncation test (PTT). Hum Mol Genet 1997;6:1409-14. [PUBMED] [FULLTEXT] |
| 41. | Langkau N, Martin N, Brandt R, Zügge K, Quast S, Wiegele G, et al . TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios. Eur J Pediatr 2002;161:393-402. |
| 42. | Jansen FE, van Huffelen AC, Algra A, van Nieuwenhuizen O. Epilepsy surgery in tuberous sclerosis: A systematic review. Epilepsia 2007;48:1477-84. [PUBMED] [FULLTEXT] |
| 43. | Koh S, Jayakar P, Dunoyer C, Whiting SE, Resnick TJ, Alvarez LA, et al . Epilepsy surgery in children with tuberous sclerosis complex: Presurgical evaluation and outcome. Epilepsia 2000;41:1206-13. [PUBMED] |
| 44. | Armstrong DD, Mizrahi EM. Pathology of epilepsy in childhood. In : Scaravilli F, editor. Neuropathology of epilepsy. World Scientific: London; 1998. p. 169-338. |
| 45. | Ellenbogen RG, Cline MJ. Hemispherectomy: Historical perspective and current surgical overview. In : Miller JW, Silbergeld DL, editors. Epilepsy surgery: Principles and controversies. Taylor and Francis Group: New York; 2006. p. 563-76. |
| 46. | Tinkle BT, Schorry EK, Franz DN, Crone KR, Saal HM. Epidemiology of hemimegalencephaly: A case series and review.Am J Med Genet A 2005;139:204-11. [PUBMED] [FULLTEXT] |
| 47. | Di Rocco C, Battaglia D, Pietrini D, Piastra M, Massimi L. Hemimegalencephaly:clinical implications and surgical treatment. Childs Nerv Syst 2006;22:852-66. [PUBMED] [FULLTEXT] |
| 48. | Yasha TC, Santosh V, Das S, Shankar SK. Hemimegalencephaly--morphological and immunocytochemical study. Clin Neuropathol 1997;16:17-22. [PUBMED] |
| 49. | Pal L, Shankar SK, Santosh V, Yasha TC. Glioneuronal migration and development disorders: Histological and immunohistochemical study with a comment on evolution. Neurol India 2002;50:444-51. |
| 50. | Mathern GW, Andres M, Salamon N, Chandra PS, Andre VM, Cepeda C, et al . A hypothesis regarding the pathogenesis and epileptogenesis of pediatric cortical dysplasia and hemimegalencephaly based on MRI cerebral volumes and NeuN cortical cell densities. Epilepsia 2007;48:74-8. |
| 51. | Vining EP, Freeman JM, Pillas DJ, Uematsu S, Carson BS, Brandt J, et al . Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996. Pediatrics 1997;100:163-71. |
| 52. | Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha-Khadem F, et al . Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003;126:556-66. [PUBMED] [FULLTEXT] |
| 53. | Kawai K, Shimizu H, Yagishita A, Maehara T, Tamagawa K. Clinical outcomes after corpus callosotomy in patients with bihemispheric malformations of cortical development. J Neurosurg 2004;101:7-15. [PUBMED] |
| 54. | Sales LV, Velasco TR, Funayama S, Ribeiro LT, Andrade-Valenηa LP, Neder L, et al . Relative frequency, clinical, neuroimaging and postsurgical features of pediatric temporal lobe epilepsy. Braz J Med Biol Res 2006;39:1365-72. |
| 55. | Blümcke I, Thom M, Wiestler OD. Ammon's horn sclerosis: A maldevelopmental disorder associated with temporal lobe epilepsy. Brain Pathol 2002;12:199-211. |
| 56. | Heinrich C, Nitta N, Flubacher A, Müller M, Fahrner A, Kirsch M, et al . Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 2006 26;26:4701-13. |
| 57. | Haas CA, Dudeck O, Kirsch M, Huszka C, Kann G, Pollak S, et al . Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neurosci 2002;22:5797-802. [PUBMED] [FULLTEXT] |
| 58. | Gong C, Wang TW, Huang HS, Parent JM. Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci 2007;27:1803-11. [PUBMED] [FULLTEXT] |
| 59. | Sinclair DB, Aronyk K, Snyder T, McKean J, Wheatley M, Bhargava R, et al . Pediatric temporal lobectomy for epilepsy. Pediatr Neurosurg 2003;38:195-205. [PUBMED] [FULLTEXT] |
| 60. | Porter BE, Judkins AR, Clancy RR, Duhaime A, Dlugos DJ, Golden JA. Dysplasia: A common finding in intractable pediatric temporal lobe epilepsy. Neurology 2003;61:365-8. [PUBMED] [FULLTEXT] |
| 61. | Sinclair DB, Wheatley M, Aronyk K, Hao C, Snyder T, Colmers W, et al . Pathology and neuroimaging in pediatric temporal lobectomy for intractable epilepsy. Pediatr Neurosurg 2001;35:239-46. [PUBMED] [FULLTEXT] |
| 62. | Singla M, Singh P, Kaushal S, Bansal R, Singh G. Hippocampal sclerosis in association with neurocysticercosis. Epileptic Disord 2007;9:292-9. [PUBMED] [FULLTEXT] |
| 63. | Maton B, Jayakar P, Resnick T, Morrison G, Ragheb J, Duchowny M. Surgery for medically intractable temporal lobe epilepsy during early life. Epilepsia 2008;49:80-7. [PUBMED] [FULLTEXT] |
| 64. | Mohamed A, Wyllie E, Ruggieri P, Kotagal P, Babb T, Hilbig A, et al . Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology 2001;56:1643-9. [PUBMED] [FULLTEXT] |
| 65. | Kasper BS, Stefan H, Buchfelder M, Paulus W. Temporal lobe microdysgenesis in epilepsy versus control brains. J Neuropathol Exp Neurol 1999;58:22-8. [PUBMED] |
| 66. | Thom M. Dysplasia associated with mesial temporal sclerosis is a common finding related to epileprogenesis. In : Miller JW, Silbergeld DL, editors. Epilepsy surgery: Principles and controversies. Taylor and Francis Group: New York; 2006. p. 105-12. |
| 67. | Kan P, Van Orman C, Kestle JR. Outcomes after surgery for focal epilepsy in children. Childs Nerv Syst 2007 Dec 6;[Epub ahead of print]. |
| 68. | Brunon J, Nuti C. Natural history of cavernomas of the central nervous system. Neurochirurgie 2007;53:122-30. [PUBMED] [FULLTEXT] |
| 69. | Fortuna A, Ferrante L, Mastronardi L, Acqui M, d'Addetta R. Cerebral cavernous angioma in children. Childs Nerv Syst 1989;5:201-7. [PUBMED] |
| 70. | Mottolese C, Hermier M, Stan H, Jouvet A, Saint-Pierre G, Froment JC, et al . Central nervous system cavernomas in the pediatric age group. Neurosurg Rev 2001;24:55-71. [PUBMED] [FULLTEXT] |
| 71. | Hladky JP, Lejeune JP, Blond S, Pruvo JP, Dhellemmes P. Cerebral arteriovenous malformations in children: Report on 62 cases. Childs Nerv Syst 1994;10:328-33. [PUBMED] |
| 72. | Venkat Challa. Vascular malformations and angiomas. In : Kalimo H, editor. Pathology and genetics. Cerebrovascular diseases. ISN Neuropath Press: Basel; 2005. p. 119-24. |
| 73. | Honavar M, Meldrum BS. Epilepsy. In : Graham DI, Lantos PL editors. Greenfield's Neuropathology. 7 th ed. Arnold: London; 2002. p. 899-941. |
| 74. | Deb P, Sharma MC, Gaikwad S, Tripathi M, Chandra PS, Jain S, et al . Neuropathological spectrum of Rasmussen encephalitis. Neurol India 2005;53:156-60. |
| 75. | Gibbs JW 3 rd , McNamara JO. Immunotherapy for Rasmussen's Encephalitis. In : Miller JW, Silbergeld DL, editors. Epilepsy surgery: Principles and controversies. Taylor and Francis Group: New York; 2006. p. 161-5. |
| 76. | Freeman JM. What are the roles of medical and surgical Management in Rasmussen's Encephalitis. In : Miller JW, Silbergeld DL, editors. Epilepsy surgery: Principles and controversies. Taylor and Francis Group: New York; 2006. p. 157-60. |
| 77. | Rajshekhar V, Chacko G, Haran RP, Chandy MJ, Chandi SM. Clinicoradiological and pathological correlations in patients with solitary cysticercus granuloma and epilepsy: Focus on presence of the parasite and oedema formation. J Neurol Neurosurg Psychiatry 1995;59:284-6. [PUBMED] [FULLTEXT] |
| 78. | Sundaram C, Prasad VS, Reddy JJ. Cerebral sparganosis. J Assoc Physicians India 2003;51:1107-9. [PUBMED] |
| 79. | Wolf HK, Weistler OD. Surgical pathology of chronic epileptic seizure disorders. Brain Pathol 1993;3;371-80. |
| 80. | Kim SK, Wang KC, Hwang YS, Kim KJ, Cho BK. Intractable epilepsy associated with brain tumors in children: Surgical modality and outcome. Childs Nerv Syst 2001 17;445-52. |
| 81. | Luyken C, Blumcke I, Fimmers R, Urbach H, Weistler OD, Lynch J, et al . Supratentorial gangliogliomas: Histopathologic grading and tumor recurrence in 184 patients with a median follow up of 8 years. Cancer 2004;101:146-55. |
| 82. | Plate KH, Weiser HG, Yasargil MG, Weistler OD. Neuropathological findings in 224 patients with temporal lobe epilepsy. Acta Neuopathologica 1993;86:433-8. |
| 83. | Vinters HV, Armstrong DL, Babb TL, Daumas-Duport C, Robitaile Y. The neuropathology of human symptomatic epilepsy. In : Engel J Jr, editor. Surgical treatment of epilepsies.Raven Press: New York; 1993. p. 593-608. |
| 84. | Wolf HK, Campos MG, Zentner J, Hufnagel A, Schramm J, Elger CE, et al . Surgical pathology of temporal lobe epilepsy: Experience with 216 cases. J Neuropathol Exp Neurol 1993;52:499-506. [PUBMED] |
| 85. | Radhakrishnan A, Abraham M, Radhakrishnan VV, Sarma SP, Radhakrishnan K. Medically refractory epilepsy associated with temporal lobe ganglioglioma: Characteristics and postoperative outcome. Clin Neurol Neurosurg 2006;108:648-54. [PUBMED] [FULLTEXT] |
| 86. | Wolf HK, Muller MB, Spanle M, Zentner J, Schramm J, Weistler OD. Ganglioglioma: A detailed histopathological and immunohistochemical analysis of 61 cases. Acta Neuropathologica 1994;88:166-73. |
| 87. | Becker AJ, Weistler OD, Figarella-Branger D, Blumke I. Ganglioglioma and gangliocytoma. In : Louis DN, Ohgaki H, Wiestler OD, Cavanee WK, editors. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon; 2007. p. 103-5. |
| 88. | Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws ER Jr, Vedrenne C. Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures: Report of thirty nine cases. Neurosurgery 1988;23:545-56. [PUBMED] |
| 89. | Honaver M, Ansari S, Janota I, Polkey CE. Dysembryoplastic neuroepithelial tumor. Neuropathol Appl Neurobiol 1991;17:242-43. |
| 90. | Koeller KK, Dillon WP. Dysembryoplastic neuroepithelial tumors: MR appearance. AJNR 1992;13:1319-25. [PUBMED] |
| 91. | Daumas-Duport C. Dysembryoplastic Neuroepithelial tumors. Brain Pathol 1993;3:283-95. [PUBMED] |
| 92. | Daumas-Duport C. Patterns of tumor growth and problems associated with histological typing of low-grade gliomas. In : Apuzzo LJ, editor. Benign cerebral gliomas. AANS: Park Ridge; 1995. p. 125-47. |
| 93. | Giannini C, Scheithauer BW, Burger PC, Brat DJ, Wollan PC, Lach B, et al . Pleomorphic xanthoastrocytoma: What do we really know about it? Cancer 1999;85:2033-45. [PUBMED] [FULLTEXT] |
| 94. | Rich KM, Goldring S, Gado M. Computed tomography in chronic seizure disorder caused by glioma. Arch Neurol 1985;42:26-7. [PUBMED] |
| 95. | Stemmer-Rachamimov AO, Wiestler OD, Louis DN. Neurofibromatosis type 2. In : Louis DN, Ohgaki H, Wiestler OD, Cavanee WK, editors. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon; 2007. |
| 96. | Omeis I, Hillard VH, Braun A, Benzil DL, Murali R, Harter DH. Meningioangiomatosis associated with neurofibromatosis: Report of 2 cases in a single family and review of the literature. Surg Neurol 2006;65:595-603. [PUBMED] [FULLTEXT] |
| 97. | Jallo GI, Kothbauer K, Mehta V, Abbott R, Epstein F. Meningioangiomatosis without neurofibromatosis: A clinical analysis. J Neurosurg 2005;103:319-24. [PUBMED] |
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
|
