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Cortical dysplasia: A histopathologic study of 52 cases of partial lobectomy in patients with epilepsy
Cortical Dysplasia: A Histopathologic Study of 52 Cases of Partial Lobectomy in Patients With Epilepsy RICHARD A. PRAYSON, MD AND MELINDA L. ESTES, MD In utero migrational abnormalities account for most cases of cortical dysplasia. The histopathologic appearance of cortical dysplasia is often varied, making recognition and classification difficult. We studied 52 patients with cortical dysplasia w h o underwent partial lobectomy for medically intractable seizures in order to devise a simple histopathologic classification schema. The incidence of observed dysplasia in lobectomy specimens over an ll-year period (n = 360) was 14%. Patients ranged in age from 3 months to 47 years at the time of surgery (mean, 19 years; 29 male and 23 female patients). T h e temporal lobe was involved in 34 patients, frontal lobe in 18, parietal lobe in four, and occipital lobe in three. In three patients multiple lobes showed dysplasia. Dysplasia was right-sided in 29 patients and left-sided in 23 patients. Dysplasia was focal in 23 patients, multifocal in four patients, and diffuse in 25 patients. Three main histologic patterns of cortical dysplasia were observed: (1) a cortical
laminar architectural disorganization a n d / o r malalignment of neurons (26 patients), (2) clusters of atypical n e u r o n s and glia within the cortex (28 patients), and (3) a hypercellular molecular layer with increased numbers of n e u r o n s and glia (31 patients). In 23 patients more than one pattern o f dysplasia was identified. Coexistent tumors were present in 13 patients, including ganglioglioma (eight patients), dysembryoplastic neuroepithelial tumor (three patients), and lowgrade astrocytoma (two patients). Tuberous sclerosis was present in four patients. We conclude that most types of cortical dysplasia can be divided into three main histologic patterns, facilitating the recognition of dysplasia. In addition to the known association with tuberous sclerosis, tumors may coexist with cortical dysplasia. HUM PATHOL 26:493--500. Copyright © 1995 by W.B. Sannders Company Key words: cortical dysplasia, neuron migration abnormalities, microdysgenesis, partial lobectomy, tuberous sclerosis.
T h e t e r m cortical dysplasia (neuronal migration abnormalities, microdysgenesis) has b e e n used in the literature to refer to a wide range of lesions. I n c l u d e d a m o n g these abnormalities are aberrations of gyration and sulcation (agyria, pachygyria, polymicrogyria), cerebral heterotopias (laminar and nodular), nodular cortical dysplasia, m e n i n g e a l and l e p t o m e n i n g e a l heterotopias, persistence of subpial granular cells, persistence of the horizontal cells of Cajal in the molecular layer, c o l u m n a r a r r a n g e m e n t s of nerve cells in the cortex, archicortical laminar architecture, n e u r o n a l heterotopias, focal dysplasia, dentate dispersion or duplication, indistinct b o u n d a r y between cortical layers o n e and two (caused by increased molecular layer cellularity), various white matter abnormalities, a diffusely thickened cortex, and phacomatoses-associated dysplasia (yon Recklinghausen's disease or neurofibromatosis type I and tuberous sclerosis).1-22 It is well known that cortical dysplasia is associated with the d e v e l o p m e n t o f epilepsy. I'2'11'17A°'23-26Recent work has suggested that patients with medically intractable epilepsy and cortical dysplasia may derive some benefit f r o m surgical excision of the lesion. 2732 As a result of the increase in the n u m b e r of partial lobectomy p r o c e d u r e s being perf o r m e d for medically intractable epilepsy, this specimen is m o r e likely to be e n c o u n t e r e d in the context of the surgical pathology desk.
Because of the wide variation and complexity of r e p o r t e d cortical dysplasia lesions and the frequent misuse of the term in reference to noncortical lesions, recognition of cortical dysplasia may be difficult. Therefore, we studied a series of 52 patients who u n d e r w e n t partial lobectomy in o r d e r to examine the histopathologic features of these specimens to devise an overall systematic a p p r o a c h for dealing with partial lobectomy specimens in epilepsy patients. In particular the study presented an opportunity to specifically examine cortical dysplasia in the context of epilepsy in an a t t e m p t to devise a practical pathological a p p r o a c h to aid in its recognition.
From the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH. Accepted for publication August 23, 1994. Presented in part at the United States and Canadian Academy of Pathology, International Academy of Pathology 82nd Annual Meeting, Chicago, Illinois, March 1993. Address correspondence and reprint requests to Richard A. Prayson, MD, Department of Anatomic Pathology (L25), The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5138. Copyright © 1995 by W.B. Saunders Company 0046-8177/95/2605-000655.00/0
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MATERIALS AND METHODS The surgical pathology files at The Cleveland Clinic Foundation were searched by computer between January 1980 and August 1992 for cases in which a partial lobectomy was performed for intractable epilepsy. All available slides from each case in which a diagnosis of cortical dysplasia was made were reviewed. Cortical dysplasia was defined as a malformative disorganization of the cytoarchitecture of the cortex relative to neurons. Cases in which the primary abnormalities related exclusively to the leptomeninges and white matter alone were specifically excluded from this study. Of 360 partial lobectomy specimens, cortical dysplasia was identified in 52 cases (14%). In all cases the surgery was performed at The Cleveland Clinic Foundation. In t7 cases all tissue submitted for pathological evaluation was examined histologically. In 29 patients at least haft of the submitted tissue was examined microscopically and in six patients less than half of the tissue submitted was evaluated. The number of slides examined in each case ranged from two to 48 (mean, 16 slides). Microscopic slides were prepared from formalin-fixed, paraffin-embedded tissue. Sections were cut 4 #m thick and stained with hematoxylin-eosin. Pathology reports, operative notes, and clinical records were reviewed in each case for information
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regarding patient age and sex, lesion location (including lobe and laterality), age at the time of seizure onset, duration of seizures before surgery, surgical procedure, and occurrence of seizures postoperatively during follow-up. Histologically cortical dysplasia was classified into three main pattern groups: (1) a disruption of the normal laminar architecture of the cortex caused by malposition/malalignment of cortical neurons, (2) a discrete cluster of atypical neuronal cells and glial cells located within the cortex, and (3) a hypercellular molecular layer characterized by the presence of an increased number of molecular layer neurons. Cortical dysplasia was further characterized as focal, multifocal, or diffuse in distribution. Focal cortical dysplasia was defined as the presence of a dysplasia pattern in a single microscopic section. Multifocal cortical dysplasia was characterized by multiple foci of a dysplasia pattern involving more than one microscopic section from a noncontiguous location or in multiple noncontiguous areas of the same microscopic slide. Diffuse cortical dysplasia was defined as the presence of a dysplasia pattern on two or more contiguous areas on consecutive microscopic sections. Gross architectural abnormalities, if present, were noted. Fragmentation of the surgical specimen frequently made evaluation of gross abnormalities difficult. The presence of coexistent tumors, heterotopic neurons within the white matter, meningeal fibrosis and/or inflammation, subpial gliosis, and iatrogenic related lesions (contusions, infarctions) was tabulated.
RESULTS Clinical Findings
A total of 52 cases, including 29 male and 23 female patients, fulfilled o u r definition of cortical dysplasia and were included for study. At the time of surgery patients ranged in age f r o m 3 m o n t h s to 47 years (mean, 19 years). All patients presented with seizures, most with medically intractable c o m p l e x partial seizures. Seizure duration before surgery r a n g e d f r o m 1 to 390 m o n t h s (mean, 139 months). Patient age at the time of initial seizure presentation r a n g e d f r o m birth to 33 years (mean, 7.3 years). Four patients had b e e n diagnosed clinically with tuberous sclerosis a n d one patient h a d von Recklinghausen's disease with a previous history of multiple m e n i n g i o m a resections. Partial lobectomies were p e r f o r m e d in all cases. In 49 patients a single lobe was partially excised. In two patients a portion of all four lobes on one side was removed; in o n e patient a portion of the left frontal and t e m p o r a l lobes was excised. Lesions involved the t e m p o r a l lobe in 34 patients, frontal lobe in 18 patients, parietal lobe in four patients, a n d occipital lobe in three patients. T h e excised lobe (s) were located on the right side in 29 patients and on the left side in 23 patients. N o n e of the patients received postoperative radiation therapy or chemotherapy. O f the 46 patients for w h o m follow-up was available, 24 (52%) have h a d no postoperative seizure r e c u r r e n c e at the time of the most recent follow-up, ranging f r o m 2 to 64 m o n t h s (mean, 18 months). Postoperative seizure r e c u r r e n c e occurred in 22 patients (48%) f r o m within 1 day of surgery to 61 m o n t h s postoperatively (mean, 13 months). T h r e e patients were lost to follow-up because they reside in ano t h e r country. T h r e e cases are recent or current cases.
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FIGURE 1, The pial surface (top) and underlying molecular layer (cortical layer one). The molecular layer appears slightly hypercellular because of ~ncreased numbers of neurons (arrows) and glial cells. (Hematoxylin-eosin, original magnification x500.)
P a t h o l o g y o f C o r t i c a l Dysplasia
Recognizable abnormalities of gyration or sulcation were n o t e d in nine patients, including h e m i m e g a encephaly in three patients, polymicrogyria in four patients, and focal gyral fusion in eight patients. All patients with polymicrogyria had histologic evidence of gyral fusion. T h e distribution of cortical dysplasia was characterized histopathologically as focal in 23 patients (44%), multifocal in five patients (10%), and diffuse in 24 patients (46%). In all cases at least o n e of three major histologic patterns of dysplasia was observed. T h e most c o m m o n l y observed pattern of cortical dysplasia (31 patients, 59%) was related to abnormalities of the molecular layer. In all of these cases there was an increase in the cellularity of the molecular layer due, in part, to an increase in the n u m b e r of molecular layer neurons (Fig 1). Frequently increased n u m b e r s of glial cells were observed within the molecular layer as well. Rarely the increased cellularity of the molecular layer m a d e distinction between cortical layers one and two difficult. T h e next most frequently observed pattern of dysplasia was the cluster form, seen in 28 patients (54%). In these cases atypical neuronal, glial, and occasional microglial cells were haphazardly a r r a n g e d in a discrete cluster located within the cortex (Fig 2). Clusters were observed at all levels of the cortex, including, in rare instances, the molecular layer. Most frequently, however, clusters were situated in cortical layers three, four, and five. Cytologically atypical n e u r o n a l elements were sometimes observed within the dysplastic foci. Atypia observed included irregular nuclear and cytoplasmic contours, an a b n o r m a l nuclear chromatin pattern, multinucleolation, and an a b n o r m a l distribution of Nissl substance within the cytoplasm. Frequently areas adjacent to the n e u r o n a l clusters contained few neurons or were totally devoid of neurons. W h e t h e r this p h e n o m e n o n is part of the dysplastic process or related to hypoxia or ischemia c a n n o t be d e t e r m i n e d with cer-
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FIGURE 2. A focus of cortical dysplasia involving cortical layer five. The cortical dysplasia consists of a disorganized and hypercellular aggregate of both neuronal and glial ceils. A number of the neurons have processes that are arranged parallel to rather than perpendicular to the surface (more superficial cortex is oriented toward the top of the field), (Hematoxylineosin, original magnification ×250.)
one patient. T h e tumor was located on the right side in eight patients and on the left side in five patients. The tumors included eight gangliogliomas, three dysembryoplastic neuroepithelial tumors, and two lowgrade astrocytomas. Gangliogliomas were characterized by atypical arrangements of large pleomorphic neuronal cells with vesicular nuclei and p r o m i n e n t nucleoli. Binucleate neuronal cells were present in all cases. The backg r o u n d glioma histologically resembled a low grade astrocytoma in all cases. Necrosis and mitoses were not identified in any of the tumors. The dysembryoplastic neuroepithelial tumors all had a multinodular appearance and were located primarily in white matter. The p r o m i n e n t cellular c o m p o n e n t was the oligodendrocyte. Interspersed among the oligodendrocytes were smaller numbers of neurons and astrocytes. No significant cytological atypia was observed in any of the tumor's cellular components. The arcuate vascular pattern seen in oligodendrogliomas, hemorrhage, necrosis, calcification, and mitoses was not identified. The low grade astrocytoma was characterized by a pro-
tainty. In 26 patients (50%) cortical dysplasia consisted of a disorganization of the normal cortical laminar architecture (other than the aforementioned discrete clusters). This pattern of dysplasia was characterized by disruptions in the lamination of the cortex, a malposition of cortical neurons with large pyramidal neurons prominently located in cortical layers two and four, disruption in the normal cellularity of a particular cortical layer (generally caused by neuronal loss), or a malalignm e n t of cortical neurons involving loss of the normal perpendicular orientation of neurons relative to the surface (Figs 3 and 4). Occasionally, atypical neuronal cells and glial cells were observed to participate in this dysplastic process. In 29 patients (56%) only one pattern of dysplasia was found. Two dysplasia patterns were observed in 13 patients (25%) and all three patterns were identified in 10 patients (19%). Laminar architectural abnormalities were observed in all three patients with hemimegaencephaly, in three of four patients with polymicrogyria, and in six patients with gyral fusion. T h e cluster form of dysplasia was seen in two patients with hemimegaencephaly, one patient with polymicrogyria, and four patients with gyral fusion. An abnormal molecular layer was observed in all three hemimegaencephalic patients, in two patients with polymicrogyria, and in four patients with gyral fusion. Tumors and Cortical Dysplasia
Thirteen tumors were coexistent with, yet separate from, the cortical dysplasia in the partial lobectomy specimens (previously reported). 33 Patients ranged in age from 4 to 29 years (mean, 16 years). Seizure duration ranged from 1 m o n t h to 21 years before surgery (mean duration, 72 months). The tumor and cortical dysplasia were located in the temporal lobe in 10 patients, parietal lobe in two patients, and frontal lobe in 495
FIGURE 3. An area of disrupted cortical architecture, Cortical layers are indicated to the right of the figure. The molecular layer appears slightly hypercellular with an increased number of neurons. There is a focal loss of neurons involving cortical layer two and superficial cortical layer three (arrow). (Hematoxylin-eosin, original magnification ×75.)
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FIGURE 4. Marked architectural disorganization constituting cortical dysplasia. Cortical layers are indicated to the right of the picture. There is a hypercellular, haphazard arrangement of both neuronal and glial elements primarily involving cortical layer three (arrow). (Hematoxylin-eosin, original magnification ×75.)
liferation o f unevenly distributed atypical astrocytes with mild nuclear pleomorphism and nuclear hyperchromasia. Mitoses, necrosis, and vascular or endothelial proliferation were not present in both cases. No particular pattern or distribution of dysplasia appeared to be associated with t u m o r type. Dysplasia was focal in seven cases, diffuse in five cases, and multifocal in one case. A disrupted/disorganized laminar architecture was observed in seven of the 13 patients with tumors. The cluster pattern of dysplasia was seen in six patients, and in three cases the dysplasia consisted of an abnormal molecular layer.
flammation of the meninges in 38 patients (73%). Cortical contusions were observed in six cases (12%) and microscopic loci of recent infarction in three patients (6%). In four patients (8%) small subacute infarctions, most likely corresponding to depth electrode placement, were observed. Mesial temporal sclerosis (Ammon's horn sclerosis), characterized by a dense gliosis with loss of pyramidal neurons in the hippocampus, was observed in one of 11 patients (9%) in whom the hippocampus was seen on histologic examination of the excised mesial structures. A focal necrotizing vasculifts of the meninges was observed in one patient. In two patients in whom coexistent tumors were not seen, dystrophic calcification was present. In two patients loci of white matter were observed within the cortex. Meningioangiomatosis, characterized by a thickened meninges and proliferation of vessels primarily in the cortex surrounded by cuffs of meningothelial cells, was observed in one patient in the absence of von Recklinghausen's disease. In all four patients who had tuberous sclerosis, large astrocytic and neuronal cells with abundant eosinophilic cytoplasm, vesicular nuclei, and p r o m i n e n t nucleoli were observed in both gray and white matter (Figs 5 and 6). Occasional binucleate and rarely multinucleated forms of these large cells were present in each case. These large cells were not confined exclusively to patients with tuberous sclerosis; they were observed focally or diffusely in both gray and white matter in 10 other patients with cortical dysplasia. Prominent subpial gliosis was observed in all tuberous sclerosis patients and in two patients sheaf-like gliosis was seen in the superficial cortical layers.
DISCUSSION Recognition of cortical dysplasia may be difficult because of the wide spectrum of reported pathological manifestations of the entity. In addition, there appears
O t h e r P a t h o l o g i c a l Findings
Heterotopic neurons situated in the white matter, separate from the interface of cortical layer six and superficial white matter, were observed in all 52 patients (100%). O t h e r c o m m o n histopathologic findings included focal subpial gliosis (Chaslin's gliosis) of the molecular layer in 50 patients (96%), focal meningeal fibrosis in 46 patients (88%), and focal chronic in-
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FIGURE 5. White maffer in a patient with tuberous sclerosis. Several large atypical cells containing abundant eosinophilic cytoplasm are present. A rare multinucleated cell is present. (Hematoxylin-eosin, original magnification x500.)
CORTICAL DYSPLASIA (Prayson & Estes)
FIGURE 6. Molecular layer (cortical layer one) and pial surface (top) in the same patient as in Fig 5. Similar large atypical cells with abundant eosinophilic cytoplasm are seen within the molecular layer (arrows). (Hematoxylin-eosin, original magnification >(500.)
to be some confusion regarding what should be included u n d e r the designation of cortical dysplasia. Lesions like neuronal heterotopia, m e n i n g e a l / l e p t o m e n ingeal heterotopia, dentate dispersion or duplication, and heterotopia within the white matter are probably best not considered cortical dysplasia in that the abnormalities are situated primarily outside the cortex. However, these lesions may be etiologically related, as suggested by s o m e 2'11'17'18 who designate most of them u n d e r the term "microdysgenesis." The major purpose of this study was to attempt, by examining a large number of lobectomy specimens from epilepsy patients, to distill the myriad of reported cortical dysplasia lesions into generally recognizable patterns, thereby facilitating the recognition of dysplasia. Most types of cortical dysplasia are caused by abnormalities of neuronal migration, occurring before the twenty-fourth week of gestation. 26'34-37Neuroblastic cells migrate, starting the sixth week of gestation, from the germinal matrix region along radial glial fibers to the neocortex where they occupy specific positions in terms of laminar architecture and orientation relative to the pial surface. Earlier migrating cells take up positions in the d e e p e r cortex, as opposed to the later migrating cells that assume positions in the more superficial cortex. The exact cause underlying the migration abnormalities seen in cortical dysplasias is poorly understood and may include (1) an intrinsic abnormality of the migrating cells a n d / o r the environment in which they migrate, (2) an imbalance in factors that induce or suppress migration, or (3) an assault (radiation, toxic, fever, ischemia) to the nervous system during the p e r i o d o f d e v e l o p m e n t b e f o r e or d u r i n g migration. 1°'38-42 In patients with phacomatoses and in rare cases of apparently inherited dysplasias, additional genetic factors may play a role. O t h e r possible pathogenetic factors in the development of cortical dysplasia may include abnormal postdevelopment neuronal differentiation/proliferation or an aberrant response to an outside factor, such as radiation. 43-44The end result 497
of most forms of dysplasia is a disruption in axodendritic connections and synaptogenesis. This likely represents the main mechanism underlying the seizure activity that occurs in some patients with dysplasia. However, not all patients with dysplasia have seizures; Kaufman and Galaburda 45 found loci they called "microdysgenesis" or dysplasia in 26% of " n o r m a l " brains in neurologically normal subjects. It would appear that other factors, such as location and distribution of the dysplasia, may also play a role in determining which patients experience seizures. Because cortical dysplasia is associated with the development of epilepsy, recognition of dysplasia is important. By examining 52 cases of dysplasia it is apparent that there are three major histologic patterns of dysplasia. The most commonly observed pattern in our series was that of a hypercellular molecular layer caused by increased numbers of neuronal and glial cells. Although probably not directly related to neuronal migration, glial cells were frequently observed to participate in the dysplastic process. Normal molecular layer contains few, if any, neurons. An increased n u m b e r of neurons suggests an abnormality of migration occurring in the later stages of development during which time neuroblastic cells are migrating into the more superficial layers of cortex. ~7 This pattern of dysplasia would correspond to previous reports of persistence of the horizontal cells of Cajal, 1° persistence of the subpial granular cell layer, 4 and an increase of partially dystopic neurons in the stratum moleculare or part of microdysgenesis as described by Meencke and Janz. 17'1s The second most commonly observed pattern of dysplasia involved the formation of discrete clusters of atypical neurons and glia within the cortex. Clusters were more frequently, although not exclusively, observed in the middle and d e e p e r cortical layers, suggesting that most result from early rather than later migration abnormalities. Occasional cytologic atypia was observed in the neuronal c o m p o n e n t of dysplasia. Again, glial cells and occasional microglial cells also were observed to participate in the dysplastic process. This pattern of dysplasia corresponds to previously reported nodular cortical dysplasia, 3 some cases of focal dysplasia as described by Taylor et al, 22 dysplasia observed in patients with yon Recklinghausen's disease, 2° and neuronal clustering as described by Hardiman et al.u The least commonly observed pattern of dysplasia involved laminar architectural distortion of the cortex or malposition of neuronal elements within the cortex. This pattern of dysplasia corresponds to previously described agyria and pachygyria, 7'~°'1s laminar heterotoP ias, 1° P olymicrogyr]a,6'1°c- olumnar arrangements of nerve cells, 5'17 archicortical laminar structure, 1° and some of the focal dysplasia of Taylor et al. 22 In addition, the dysplasia typically observed as a forme fruste of tuberous sclerosis would also best correspond to this pattern. In 23 patients (44%) more than one pattern of dysplasia was observed. All three patterns coexisted in 10 patients (19%). The coexistence of multiple forms
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of dysplasia affecting both superficial and d e e p cortical layers may be indicative o f multiple insults occurring at different times during development, an ongoing insult over a period o f time, or an intrinsic abnormality of the migrating cells or their environment. T h e r e appears to be no correlation between the observed dysplasia pattern and seizure recurrence postoperatively. Postoperative seizure recurrence probably m o r e closely correlates with completeness of excision and the extent of the dysplasia rather than the specific type of dysplasia. 32 Because a significant n u m b e r of dysplasias are not grossly a p p a r e n t lesions and some are not discernible using magnetic resonance i m a g i n g , the completeness of the resection of potentially seizure-causative dysplasia may be difficult to assess. Recognition of dysplasia as a possible causative lesion of epilepsy is of primary importance. 25'26'36'41 Subtyping dysplasia is still of arguable clinical significance at this time, except in rare inherited forms 10 a n d in the phacomatoses-related dysplasias. Distinction between the cluster pattern of dysplasia and focal laminar architectural disruption is somewhat d e p e n d e n t on how extensively the specimen is sampled. Likewise, the distribution of dysplasia is particularly dep e n d e n t on specimen sampling. Because all of the tissue submitted at the time of surgery was e x a m i n e d microscopically in 17 cases, the actual incidence of certain patterns of dysplasia as well as assessments of distribution is likely to be underestimated. For a m o r e accurate incidence of dysplasia to be attained, all tissue submitted would n e e d to be e x a m i n e d histologically. Because this was n o t the case in this series, the 14% observed incidence of cortical dysplasia most likely represents an underestimate of the true incidence of dysplasia. In addition, we did not routinely use ancillary immunohistochemical or special staining techniques, such as serial Bodian stains, looking for m o r e subtle abnormalities of n e u r o n a l processes or their orientation. In certain instances, use of additional stains may be helpful in elucidating an abnormality or in characterizing the cell types participating in the dysplastic process. An association between t u m o r and cortical dysplasia is not well d o c u m e n t e d in the literature. T h e coexistence of these two lesions occurred in 4% of the total partial lobectomy population studied. T h e lack of literature regarding the coexistence of t u m o r and dysplasia may either be due to the rarity of such an event or, m o r e likely, to a lack of diagnosis of the dysplasia in the face of a diagnosed neoplasia. T h e incidence of tumors in the cortical dysplasia population (25%) reflects, in part, a bias of o u r institution in terms of the type of patient selected for surgery and the referral nature of our epilepsy practice. These biases also may partially account for the a p p a r e n t temporal lobe predilection of dysplasia and coexistant dysplasia/neoplasia. T h e most c o m m o n t u m o r f o u n d associated with dysplasia was ganglioglioma (eight of 13 cases). T h e relatively benign clinical course of most gangliogliomas and dysembryoplastic neuroepithelial tumors as well as their coexistence or admixture with cortical dysplasia suggests a possible h a m a r t o m a t o u s or dysplastic nature to a subset of these t u m o r s . 46-49 O n superficial examination
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there is no a p p a r e n t relation between astrocytoma and cortical dysplasia. T h e two cases r e p o r t e d here may represent a pure coincidence. O n the other hand, glial elements are frequently observed to participate in the dysplastic process. It is possible that neoplasia could arise f r o m glial cells in a focus of dysplasia. H e t e r o t o p i c n e u r o n s situated in the white matter were observed in all cases. Neurons located within the white matter are a c o m m o n finding when examining lobectomy specimens in patients with a history of epilepsy. Normal white matter contains few, if any, neurons. T h e presence of n e u r o n a l elements in white matter may be indicative of a migration abnormality. Therefore, it is not surprising to see such a high incidence of n e u r o n a l heterotopia a c c o m p a n y i n g cortical dysplasia. However, an increase in the n u m b e r of white matter n e u r o n s also has b e e n r e p o r t e d to occur in the setting of posttraumatic epilepsy, raising the question of whether or not they represent an effect of seizures. 16 Likewise, some of the atypical glial cells that frequently a c c o m p a n y cortical dysplasia and n e u r o n a l heterotopia may be an effect of the seizures rather than exclusively a part of the malformative process. 2 T h e functional Significance of white matter n e u r o n a l heterotopias is uncertain, Similar to cortical dysplasia, the presence of white matter h a m a r t o m a s within the cortex is likely related to developmental abnormalities of cellular migration. Mesial t e m p o r a l sclerosis is a n o t h e r r e p o r t e d finding in lobectomy specimens f r o m patients with chronic seizures. 2'5°-51 Because of the nature of surgical resection, most h i p p o c a m p a l sections are fragmented, resulting in an underestimate of the incidence of mesial temporal sclerosis in this series. T h e exact nature o f mesial t e m p o r a l sclerosis is still controversial; however, it does not a p p e a r to represent a migrational disorder. In cases where there is dual pathology (ie, a primary h i p p o c a m p u s lesion, such as mesial temporal sclerosis, and an e x t r a h i p p o c a m p a l lesion in the temporal lobe), the question arises regarding where the seizure focus lies and w h e t h e r the t u m o r or dysplasia may somehow be responsible for the loss of n e u r o n s seen in mesial temporal sclerosis. O t h e r c o m m o n l y observed lesions included subpial gliosis and meningeal fibrosis. Iatrogenic changes related to invasive seizure m o n i t o r i n g p r o c e d u r e s due to electrode plates or d e p t h electrode needles included meningeal fibrosis, chronic meningeal inflammation, small infarcts, and cortical contusions. Meningioangiomatosis is most likely a malformative h a m a r t o m a t o u s lesion involving meningothelial and glial cells, respectively. Meningioangiomatosis has b e e n described outside the setting of von Recklinghausen's disease as a cause for seizures. 91'5254 To o u r knowledge coexisting cortical dysplasia a n d meningioangiomatosis outside of von Recklinghausen's disease has not b e e n described previously. T h e association of cortical dysplasia with the phacomatoses is well known and suggests a genetic compon e n t to at least some cases of dysplasia. In the case of tuberous sclerosis the presence of enlarged and cytolog-
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ically atypical neuronal and astrocytic cells in the cortex and white matter is considered a forme fruste of the disease. 21 Nevertheless, similar cells were observed, generally in fewer numbers, outside the setting of tuberous sclerosis and thus are not diagnostic of tuberous sclerosis. Dysplasia and h a m a r t o m a have been described in the setting of yon Recklinghausen's disease. Most frequently they involve a cluster of atypical and disorganized glial cells; however, neuronal cells can be occasionally seen, as was the case with our patient. 2°'21 Continued careful histopathologic examination of tissues submitted from these patients and correlation of such findings with clinical symptomatology, imaging studies, and electroencephalogram studies are important. With time certain patterns of dysplasia may be able to be predicted based on a thorough presurgical evaluation of the patient. Likewise, correlation of surgical strategies with patterns and the extent of dysplasia and follow-up will be important in optimizing treatment in those padents requiring surgical intervention.
REFERENCES 1. Anderman F, Olivier A, Melanson D: Epilepsy due to focal cortical dysplasia with macrogyria and the forme fruste of tuberous sclerosis: A study of 15 patients, in Wolf P, Dan M, Janz D, et al (eds): Advances in Epileptology. New York, NY, Raven, 1987, pp 35-38 2. Armstrong DD: The neuropathology of temporal lobe epilepsy. J Neuropathol Exp Neurol 52:433-443, 1993 3. Brun A: Marginal glioneural heterotopias of the central nervous system. Acta Pathol Microbiol Stand 65:221-233, 1965 4. Brun A, Borjeson M, Forssman H: An inherited syndrome with mental deficiency and endocrine disorder. A patho-anatomical study. J Ment Defic Res 18:317-325, 1974 5. Caviness VS, Jr, Evrard P, Lyon G: Radial neuronal assemblies, ectopia and necrosis of developing cortex: A case analysis. Acta Neuropathol (Berl) 41:67-72, 1978 6. Crome L: Microgyria. J Pathol Bacteriol 64:479-495, 1952 7. Crome L: Pachygyria. J Pathol Bacteriol 71:335-352, 1956 8. Dekaban A: Large defects in cerebral hemispheres associated with cortical dysgenesis. J Neuropathol Exp Neurol 24:512-530, 1965 9. Dvorak K, Feit J: Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats. Contribution to problems of morphological development and developmental period of cerebral mierogyria. Histological and autoradiographic study. Acta Neuropathol (Berl) 38:203-212, 1977 10. Friede RL: Dysplasias of the cortex, in Developmental Neuropathology. Berlin, Germany, Springer-Verlag, 1989, pp 330-346 11. Hardiman O, Burke T, Phillips J, et al: Microdysgenesis in resected temporal neocortex: Incidence and clinical significance in focal epilepsy. Neurol 38:1041-1047, 1988 12. Hoffman SF, Rorke LB: On finding striated muscle in the brain. J Neurol Neurosurg Psychiatry 34:761-764, 1971 13. Jellinger K, Rett A: Agyria-Pachygyria (lissencephaly syndrome). Neuropadiatrie 7:66-91, 1976 14. Marchal G, Andermann F, Tampieri D, et al: Generalized cortical dysplasia manifested by diffusely thick cerebral cortex. Arch Neurol 46:430-434, 1989 15. Mathieson G: Pathology of temporal lobe foci. Adv Neurol 11:163-185, 1975 16. Meencke HJ: The density of dystrophic neurons in the white matter of the gyrus frontalis inferior in epilepsies. J Neurol 230:171181, 1983 17. Meencke HJ, Janz D: Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 25:8-21, 1984 18. Meencke HJ, Janz D: The significance of microdysgenesia in primary generalized epilepsy: An answer to the considerations of Lyon and Gastaut. Epilepsia 26:368-371, 1985
19. Meldrum BS, Bruton CF: Epilepsy, in AdamsJH, Duchen LW (eds) : Greenfield's Neuropathology. New York, NY, Oxford University Press, 1992, pp 1246-1283 20. Rubinstein LJ: Tumors of the Central Nervous System. Armed Forces Institute of Pathology, Washington, DC, 1970, pp 300309 21. Russell DS, Rubinstein LJ: Dysgenetic syndromes (phacomatoses) associated with tumours and hamartomas of the nervous system, in, Pathology of Tnmours of the Nervous System. Baltimore, MD, Williams and Wilkins, 1989, pp 766-808 22. Taylor DC, Falconer MA, Bruton CJ, et al: Focal dysplasia of the cerebral cortex in epilepsy.J Neurol Neurosurg Psychiatry 34:369387, 1971 23. Barth PG: Disorders of cerebral migration. Can J Neurol Sci 14:1-16, 1987 24. LiebJP, EngelJ, Brown WJ, et al: Neuropathological findings following temporal lobectomy related to surface and deep EEG patterns. Epilepsia 22:539-549, 1981 25. Mathieson G: Pathology, in Laidlow J, Richens A, Oxley J (eds) : Textbook of Epilepsy. New York, NY, Churchhill Livingstone, 1988, pp 183-202 26. Palmini A, Andermann F, Olivier A, et al: Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann Neurol 30:741-749, 1991 27. Cascino GD, Boon P, Fish D: Surgically remediable lesional syndromes, in Engel J, Jr (ed): Surgical Treatment of the Epilepsies. New York, NY, Raven, 1993, pp 77-86 28. EngelJ,Jr, Van Ness PC, Rassmussen TB, et al: Outcome with respect to epileptic seizures, in EngelJ,Jr (ed): Surgical Treatment of Epilepsies. New York, NY, Raven, 1993, pp 609-621 29. Fried I, Cascino G: Lesional surgery, in Engel J, Jr (ed): Surgical Treatment of the Epilepsies. New York, NY, Raven, 1993, pp 501-509 30. Kim HI, Olivier A, Jones-Gotman M, et al: Corticoamygdalectomy in memory-impaired patients. Neurosurg 1992; 58:162-167 31. Levesque MF, Nakasato N, Vinters HV, Babb TL. Surgical treatment of limbic epilepsy associated with extrahippocampal lesions: The problem of dual pathology. J Neurosurgery 75:364-370, 1991 32. Palmini A, Andermann F, Olivier A, et al: Focal neuronal migration disorders and intractable partial epilepsy: Results of surgical treatment. Ann Neurol 30:750-757, 1991 33. Prayson RA, Estes ML, Morris HH: The coexistence of neoplasia and cortical dysplasia in patients presenting with seizures. Epilepsia 34:609-615, 1993 34. HanawayJ, Lee SI, Netsky MG: Pachygyria: Relation of findings to modern embryologic concepts. Neurology 18:791-799, 1968 35. Pinto-Lord ML, Evrard P, Caviness VS: Obstructed neuronal migration along radial glial fibers in the neocortex of the reeler mouse: A Golgi-EM analysis. Dev Brain Res 4:379-393, 1982 36. Rakic P: Defects of neuronal migration and the pathogenesis of cortical malformations. Prog Brain Res 72:15-37, 1988 37. Sarnat HS: Disturbances of late neuronal migration in the perinatal period. Am J Dis Child 141:969-980, 1987 38. Choi BH, Lapham LW, Amin-Zaki L, et al: Abnormal neuronal migration, deranged cerebral cortical organization, and diffuse white matter astrocytosis of human fetal brain: A major effect of methylmercury poisoning in utero.J Neuropathol Exp Neuro137:719733, 1978 39. Ferrer I, Xumetra A, Santamaria J: Cerebral malformation induced by prenatal X-irradiation: An autoradiographic and Golgi study. J Anat 138:81-93, 1984 40. Pleet H, Graham JM, Jr, Smith DW: Central nervous system and facial defects associated with maternal hyperthermia at four to 14 weeks' gestation. Pediatrics 67:785-789, 1981 41. Riggs HE, McGrath ~ , Sehwarz HP: Malformation of the adult brain (albino rat) resulting from prenatal irradiation. J Neuropathol Exp Neurol 15:432-447, 1956 42. Roper SN, Houser CR: Experimentally induced heterotopias contain GAD-immunoreactive neurons. Epilepsia 33(suppl):75, 1992 43. Caccamo D, Herman MM, Ulrich H, et al: Focal neuronal gigantism and cerebral cortical thickening after therapeutic irradiation of the central nervous system. Arch Pathol Lab Med 113:880885, 1989
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44. Lampert PW, Davis RL: Delayed effects of radiation on the human central nervous system: "Early" and "late" reactions. Neurology 14:912-917, 1964 45. Kaufman WE, Galaburda AM: Cerebrocortical microdysgenesis in neurologically normal subjects: A histopathologic study. Neurology 39:238-244, 1989 46. CavanaghJB: On certain small tumours encountered in the temporal lobe. Brain 81:389-405, 1958 47. Daumas-Duport C, Scheithauer BW, Chodkiewicz J-P, et ah Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Report of thirtynine cases. Neurosurgery 23:545-556, 1988 48. Prayson RA, Estes ML: Dysembryoplastic neuroepithelial tumor. A m J Clin Pathol 97:398-401, 1992 49. Hirose T, Scheithauer BW, Lopes MBS, et al: Dysembroplastic neuroepithelial tumor (DNT): An immunohistochemical and ultrastructural study. J Neuropathol Exp Neurol 53:184-195, 1994
50. Fried J, Kim JH, Spencer DD: Hippocampal pathology in patients with intractable seizures and temporal lobe masses.J Neurosurg 76:735-740, 1992 51. Margerison JH, Corsellis JAN: Epilepsy and the temporal lobe: A clinical, electroencephalographic and neuropathologic study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 89:499-530, 1966 52. HalperJ, Scheithauer BW, Okasaki H, et al: Meningioangiomatosis: A report of six cases with special reference to the occurrence of neurofibrillary tangles. J Neuropathol Exp Neurol 45:426446, 1986 53. Kunishio K, Yamamoto Y, Sunami N, et al: Histopathologic investigation of a case of meningioangiomatosis not associated with von Recklinghausen's disease. Surg Neurol 27:575-579, 1987 54. Sakaki S, Nakagawa K, Nakamura K, et al: Meningioangiomatosis not associated with yon Recklinghausen's disease. Neurosurgery 20:79%801, 1987
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laminar architectural disorganization a n d / o r malalignment of neurons (26 patients), (2) clusters of atypical n e u r o n s and glia within the cortex (28 patients), and (3) a hypercellular molecular layer with increased numbers of n e u r o n s and glia (31 patients). In 23 patients more than one pattern o f dysplasia was identified. Coexistent tumors were present in 13 patients, including ganglioglioma (eight patients), dysembryoplastic neuroepithelial tumor (three patients), and lowgrade astrocytoma (two patients). Tuberous sclerosis was present in four patients. We conclude that most types of cortical dysplasia can be divided into three main histologic patterns, facilitating the recognition of dysplasia. In addition to the known association with tuberous sclerosis, tumors may coexist with cortical dysplasia. HUM PATHOL 26:493--500. Copyright © 1995 by W.B. Sannders Company Key words: cortical dysplasia, neuron migration abnormalities, microdysgenesis, partial lobectomy, tuberous sclerosis.
T h e t e r m cortical dysplasia (neuronal migration abnormalities, microdysgenesis) has b e e n used in the literature to refer to a wide range of lesions. I n c l u d e d a m o n g these abnormalities are aberrations of gyration and sulcation (agyria, pachygyria, polymicrogyria), cerebral heterotopias (laminar and nodular), nodular cortical dysplasia, m e n i n g e a l and l e p t o m e n i n g e a l heterotopias, persistence of subpial granular cells, persistence of the horizontal cells of Cajal in the molecular layer, c o l u m n a r a r r a n g e m e n t s of nerve cells in the cortex, archicortical laminar architecture, n e u r o n a l heterotopias, focal dysplasia, dentate dispersion or duplication, indistinct b o u n d a r y between cortical layers o n e and two (caused by increased molecular layer cellularity), various white matter abnormalities, a diffusely thickened cortex, and phacomatoses-associated dysplasia (yon Recklinghausen's disease or neurofibromatosis type I and tuberous sclerosis).1-22 It is well known that cortical dysplasia is associated with the d e v e l o p m e n t o f epilepsy. I'2'11'17A°'23-26Recent work has suggested that patients with medically intractable epilepsy and cortical dysplasia may derive some benefit f r o m surgical excision of the lesion. 2732 As a result of the increase in the n u m b e r of partial lobectomy p r o c e d u r e s being perf o r m e d for medically intractable epilepsy, this specimen is m o r e likely to be e n c o u n t e r e d in the context of the surgical pathology desk.
Because of the wide variation and complexity of r e p o r t e d cortical dysplasia lesions and the frequent misuse of the term in reference to noncortical lesions, recognition of cortical dysplasia may be difficult. Therefore, we studied a series of 52 patients who u n d e r w e n t partial lobectomy in o r d e r to examine the histopathologic features of these specimens to devise an overall systematic a p p r o a c h for dealing with partial lobectomy specimens in epilepsy patients. In particular the study presented an opportunity to specifically examine cortical dysplasia in the context of epilepsy in an a t t e m p t to devise a practical pathological a p p r o a c h to aid in its recognition.
From the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH. Accepted for publication August 23, 1994. Presented in part at the United States and Canadian Academy of Pathology, International Academy of Pathology 82nd Annual Meeting, Chicago, Illinois, March 1993. Address correspondence and reprint requests to Richard A. Prayson, MD, Department of Anatomic Pathology (L25), The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5138. Copyright © 1995 by W.B. Saunders Company 0046-8177/95/2605-000655.00/0
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MATERIALS AND METHODS The surgical pathology files at The Cleveland Clinic Foundation were searched by computer between January 1980 and August 1992 for cases in which a partial lobectomy was performed for intractable epilepsy. All available slides from each case in which a diagnosis of cortical dysplasia was made were reviewed. Cortical dysplasia was defined as a malformative disorganization of the cytoarchitecture of the cortex relative to neurons. Cases in which the primary abnormalities related exclusively to the leptomeninges and white matter alone were specifically excluded from this study. Of 360 partial lobectomy specimens, cortical dysplasia was identified in 52 cases (14%). In all cases the surgery was performed at The Cleveland Clinic Foundation. In t7 cases all tissue submitted for pathological evaluation was examined histologically. In 29 patients at least haft of the submitted tissue was examined microscopically and in six patients less than half of the tissue submitted was evaluated. The number of slides examined in each case ranged from two to 48 (mean, 16 slides). Microscopic slides were prepared from formalin-fixed, paraffin-embedded tissue. Sections were cut 4 #m thick and stained with hematoxylin-eosin. Pathology reports, operative notes, and clinical records were reviewed in each case for information
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regarding patient age and sex, lesion location (including lobe and laterality), age at the time of seizure onset, duration of seizures before surgery, surgical procedure, and occurrence of seizures postoperatively during follow-up. Histologically cortical dysplasia was classified into three main pattern groups: (1) a disruption of the normal laminar architecture of the cortex caused by malposition/malalignment of cortical neurons, (2) a discrete cluster of atypical neuronal cells and glial cells located within the cortex, and (3) a hypercellular molecular layer characterized by the presence of an increased number of molecular layer neurons. Cortical dysplasia was further characterized as focal, multifocal, or diffuse in distribution. Focal cortical dysplasia was defined as the presence of a dysplasia pattern in a single microscopic section. Multifocal cortical dysplasia was characterized by multiple foci of a dysplasia pattern involving more than one microscopic section from a noncontiguous location or in multiple noncontiguous areas of the same microscopic slide. Diffuse cortical dysplasia was defined as the presence of a dysplasia pattern on two or more contiguous areas on consecutive microscopic sections. Gross architectural abnormalities, if present, were noted. Fragmentation of the surgical specimen frequently made evaluation of gross abnormalities difficult. The presence of coexistent tumors, heterotopic neurons within the white matter, meningeal fibrosis and/or inflammation, subpial gliosis, and iatrogenic related lesions (contusions, infarctions) was tabulated.
RESULTS Clinical Findings
A total of 52 cases, including 29 male and 23 female patients, fulfilled o u r definition of cortical dysplasia and were included for study. At the time of surgery patients ranged in age f r o m 3 m o n t h s to 47 years (mean, 19 years). All patients presented with seizures, most with medically intractable c o m p l e x partial seizures. Seizure duration before surgery r a n g e d f r o m 1 to 390 m o n t h s (mean, 139 months). Patient age at the time of initial seizure presentation r a n g e d f r o m birth to 33 years (mean, 7.3 years). Four patients had b e e n diagnosed clinically with tuberous sclerosis a n d one patient h a d von Recklinghausen's disease with a previous history of multiple m e n i n g i o m a resections. Partial lobectomies were p e r f o r m e d in all cases. In 49 patients a single lobe was partially excised. In two patients a portion of all four lobes on one side was removed; in o n e patient a portion of the left frontal and t e m p o r a l lobes was excised. Lesions involved the t e m p o r a l lobe in 34 patients, frontal lobe in 18 patients, parietal lobe in four patients, a n d occipital lobe in three patients. T h e excised lobe (s) were located on the right side in 29 patients and on the left side in 23 patients. N o n e of the patients received postoperative radiation therapy or chemotherapy. O f the 46 patients for w h o m follow-up was available, 24 (52%) have h a d no postoperative seizure r e c u r r e n c e at the time of the most recent follow-up, ranging f r o m 2 to 64 m o n t h s (mean, 18 months). Postoperative seizure r e c u r r e n c e occurred in 22 patients (48%) f r o m within 1 day of surgery to 61 m o n t h s postoperatively (mean, 13 months). T h r e e patients were lost to follow-up because they reside in ano t h e r country. T h r e e cases are recent or current cases.
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FIGURE 1, The pial surface (top) and underlying molecular layer (cortical layer one). The molecular layer appears slightly hypercellular because of ~ncreased numbers of neurons (arrows) and glial cells. (Hematoxylin-eosin, original magnification x500.)
P a t h o l o g y o f C o r t i c a l Dysplasia
Recognizable abnormalities of gyration or sulcation were n o t e d in nine patients, including h e m i m e g a encephaly in three patients, polymicrogyria in four patients, and focal gyral fusion in eight patients. All patients with polymicrogyria had histologic evidence of gyral fusion. T h e distribution of cortical dysplasia was characterized histopathologically as focal in 23 patients (44%), multifocal in five patients (10%), and diffuse in 24 patients (46%). In all cases at least o n e of three major histologic patterns of dysplasia was observed. T h e most c o m m o n l y observed pattern of cortical dysplasia (31 patients, 59%) was related to abnormalities of the molecular layer. In all of these cases there was an increase in the cellularity of the molecular layer due, in part, to an increase in the n u m b e r of molecular layer neurons (Fig 1). Frequently increased n u m b e r s of glial cells were observed within the molecular layer as well. Rarely the increased cellularity of the molecular layer m a d e distinction between cortical layers one and two difficult. T h e next most frequently observed pattern of dysplasia was the cluster form, seen in 28 patients (54%). In these cases atypical neuronal, glial, and occasional microglial cells were haphazardly a r r a n g e d in a discrete cluster located within the cortex (Fig 2). Clusters were observed at all levels of the cortex, including, in rare instances, the molecular layer. Most frequently, however, clusters were situated in cortical layers three, four, and five. Cytologically atypical n e u r o n a l elements were sometimes observed within the dysplastic foci. Atypia observed included irregular nuclear and cytoplasmic contours, an a b n o r m a l nuclear chromatin pattern, multinucleolation, and an a b n o r m a l distribution of Nissl substance within the cytoplasm. Frequently areas adjacent to the n e u r o n a l clusters contained few neurons or were totally devoid of neurons. W h e t h e r this p h e n o m e n o n is part of the dysplastic process or related to hypoxia or ischemia c a n n o t be d e t e r m i n e d with cer-
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FIGURE 2. A focus of cortical dysplasia involving cortical layer five. The cortical dysplasia consists of a disorganized and hypercellular aggregate of both neuronal and glial ceils. A number of the neurons have processes that are arranged parallel to rather than perpendicular to the surface (more superficial cortex is oriented toward the top of the field), (Hematoxylineosin, original magnification ×250.)
one patient. T h e tumor was located on the right side in eight patients and on the left side in five patients. The tumors included eight gangliogliomas, three dysembryoplastic neuroepithelial tumors, and two lowgrade astrocytomas. Gangliogliomas were characterized by atypical arrangements of large pleomorphic neuronal cells with vesicular nuclei and p r o m i n e n t nucleoli. Binucleate neuronal cells were present in all cases. The backg r o u n d glioma histologically resembled a low grade astrocytoma in all cases. Necrosis and mitoses were not identified in any of the tumors. The dysembryoplastic neuroepithelial tumors all had a multinodular appearance and were located primarily in white matter. The p r o m i n e n t cellular c o m p o n e n t was the oligodendrocyte. Interspersed among the oligodendrocytes were smaller numbers of neurons and astrocytes. No significant cytological atypia was observed in any of the tumor's cellular components. The arcuate vascular pattern seen in oligodendrogliomas, hemorrhage, necrosis, calcification, and mitoses was not identified. The low grade astrocytoma was characterized by a pro-
tainty. In 26 patients (50%) cortical dysplasia consisted of a disorganization of the normal cortical laminar architecture (other than the aforementioned discrete clusters). This pattern of dysplasia was characterized by disruptions in the lamination of the cortex, a malposition of cortical neurons with large pyramidal neurons prominently located in cortical layers two and four, disruption in the normal cellularity of a particular cortical layer (generally caused by neuronal loss), or a malalignm e n t of cortical neurons involving loss of the normal perpendicular orientation of neurons relative to the surface (Figs 3 and 4). Occasionally, atypical neuronal cells and glial cells were observed to participate in this dysplastic process. In 29 patients (56%) only one pattern of dysplasia was found. Two dysplasia patterns were observed in 13 patients (25%) and all three patterns were identified in 10 patients (19%). Laminar architectural abnormalities were observed in all three patients with hemimegaencephaly, in three of four patients with polymicrogyria, and in six patients with gyral fusion. T h e cluster form of dysplasia was seen in two patients with hemimegaencephaly, one patient with polymicrogyria, and four patients with gyral fusion. An abnormal molecular layer was observed in all three hemimegaencephalic patients, in two patients with polymicrogyria, and in four patients with gyral fusion. Tumors and Cortical Dysplasia
Thirteen tumors were coexistent with, yet separate from, the cortical dysplasia in the partial lobectomy specimens (previously reported). 33 Patients ranged in age from 4 to 29 years (mean, 16 years). Seizure duration ranged from 1 m o n t h to 21 years before surgery (mean duration, 72 months). The tumor and cortical dysplasia were located in the temporal lobe in 10 patients, parietal lobe in two patients, and frontal lobe in 495
FIGURE 3. An area of disrupted cortical architecture, Cortical layers are indicated to the right of the figure. The molecular layer appears slightly hypercellular with an increased number of neurons. There is a focal loss of neurons involving cortical layer two and superficial cortical layer three (arrow). (Hematoxylin-eosin, original magnification ×75.)
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FIGURE 4. Marked architectural disorganization constituting cortical dysplasia. Cortical layers are indicated to the right of the picture. There is a hypercellular, haphazard arrangement of both neuronal and glial elements primarily involving cortical layer three (arrow). (Hematoxylin-eosin, original magnification ×75.)
liferation o f unevenly distributed atypical astrocytes with mild nuclear pleomorphism and nuclear hyperchromasia. Mitoses, necrosis, and vascular or endothelial proliferation were not present in both cases. No particular pattern or distribution of dysplasia appeared to be associated with t u m o r type. Dysplasia was focal in seven cases, diffuse in five cases, and multifocal in one case. A disrupted/disorganized laminar architecture was observed in seven of the 13 patients with tumors. The cluster pattern of dysplasia was seen in six patients, and in three cases the dysplasia consisted of an abnormal molecular layer.
flammation of the meninges in 38 patients (73%). Cortical contusions were observed in six cases (12%) and microscopic loci of recent infarction in three patients (6%). In four patients (8%) small subacute infarctions, most likely corresponding to depth electrode placement, were observed. Mesial temporal sclerosis (Ammon's horn sclerosis), characterized by a dense gliosis with loss of pyramidal neurons in the hippocampus, was observed in one of 11 patients (9%) in whom the hippocampus was seen on histologic examination of the excised mesial structures. A focal necrotizing vasculifts of the meninges was observed in one patient. In two patients in whom coexistent tumors were not seen, dystrophic calcification was present. In two patients loci of white matter were observed within the cortex. Meningioangiomatosis, characterized by a thickened meninges and proliferation of vessels primarily in the cortex surrounded by cuffs of meningothelial cells, was observed in one patient in the absence of von Recklinghausen's disease. In all four patients who had tuberous sclerosis, large astrocytic and neuronal cells with abundant eosinophilic cytoplasm, vesicular nuclei, and p r o m i n e n t nucleoli were observed in both gray and white matter (Figs 5 and 6). Occasional binucleate and rarely multinucleated forms of these large cells were present in each case. These large cells were not confined exclusively to patients with tuberous sclerosis; they were observed focally or diffusely in both gray and white matter in 10 other patients with cortical dysplasia. Prominent subpial gliosis was observed in all tuberous sclerosis patients and in two patients sheaf-like gliosis was seen in the superficial cortical layers.
DISCUSSION Recognition of cortical dysplasia may be difficult because of the wide spectrum of reported pathological manifestations of the entity. In addition, there appears
O t h e r P a t h o l o g i c a l Findings
Heterotopic neurons situated in the white matter, separate from the interface of cortical layer six and superficial white matter, were observed in all 52 patients (100%). O t h e r c o m m o n histopathologic findings included focal subpial gliosis (Chaslin's gliosis) of the molecular layer in 50 patients (96%), focal meningeal fibrosis in 46 patients (88%), and focal chronic in-
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FIGURE 5. White maffer in a patient with tuberous sclerosis. Several large atypical cells containing abundant eosinophilic cytoplasm are present. A rare multinucleated cell is present. (Hematoxylin-eosin, original magnification x500.)
CORTICAL DYSPLASIA (Prayson & Estes)
FIGURE 6. Molecular layer (cortical layer one) and pial surface (top) in the same patient as in Fig 5. Similar large atypical cells with abundant eosinophilic cytoplasm are seen within the molecular layer (arrows). (Hematoxylin-eosin, original magnification >(500.)
to be some confusion regarding what should be included u n d e r the designation of cortical dysplasia. Lesions like neuronal heterotopia, m e n i n g e a l / l e p t o m e n ingeal heterotopia, dentate dispersion or duplication, and heterotopia within the white matter are probably best not considered cortical dysplasia in that the abnormalities are situated primarily outside the cortex. However, these lesions may be etiologically related, as suggested by s o m e 2'11'17'18 who designate most of them u n d e r the term "microdysgenesis." The major purpose of this study was to attempt, by examining a large number of lobectomy specimens from epilepsy patients, to distill the myriad of reported cortical dysplasia lesions into generally recognizable patterns, thereby facilitating the recognition of dysplasia. Most types of cortical dysplasia are caused by abnormalities of neuronal migration, occurring before the twenty-fourth week of gestation. 26'34-37Neuroblastic cells migrate, starting the sixth week of gestation, from the germinal matrix region along radial glial fibers to the neocortex where they occupy specific positions in terms of laminar architecture and orientation relative to the pial surface. Earlier migrating cells take up positions in the d e e p e r cortex, as opposed to the later migrating cells that assume positions in the more superficial cortex. The exact cause underlying the migration abnormalities seen in cortical dysplasias is poorly understood and may include (1) an intrinsic abnormality of the migrating cells a n d / o r the environment in which they migrate, (2) an imbalance in factors that induce or suppress migration, or (3) an assault (radiation, toxic, fever, ischemia) to the nervous system during the p e r i o d o f d e v e l o p m e n t b e f o r e or d u r i n g migration. 1°'38-42 In patients with phacomatoses and in rare cases of apparently inherited dysplasias, additional genetic factors may play a role. O t h e r possible pathogenetic factors in the development of cortical dysplasia may include abnormal postdevelopment neuronal differentiation/proliferation or an aberrant response to an outside factor, such as radiation. 43-44The end result 497
of most forms of dysplasia is a disruption in axodendritic connections and synaptogenesis. This likely represents the main mechanism underlying the seizure activity that occurs in some patients with dysplasia. However, not all patients with dysplasia have seizures; Kaufman and Galaburda 45 found loci they called "microdysgenesis" or dysplasia in 26% of " n o r m a l " brains in neurologically normal subjects. It would appear that other factors, such as location and distribution of the dysplasia, may also play a role in determining which patients experience seizures. Because cortical dysplasia is associated with the development of epilepsy, recognition of dysplasia is important. By examining 52 cases of dysplasia it is apparent that there are three major histologic patterns of dysplasia. The most commonly observed pattern in our series was that of a hypercellular molecular layer caused by increased numbers of neuronal and glial cells. Although probably not directly related to neuronal migration, glial cells were frequently observed to participate in the dysplastic process. Normal molecular layer contains few, if any, neurons. An increased n u m b e r of neurons suggests an abnormality of migration occurring in the later stages of development during which time neuroblastic cells are migrating into the more superficial layers of cortex. ~7 This pattern of dysplasia would correspond to previous reports of persistence of the horizontal cells of Cajal, 1° persistence of the subpial granular cell layer, 4 and an increase of partially dystopic neurons in the stratum moleculare or part of microdysgenesis as described by Meencke and Janz. 17'1s The second most commonly observed pattern of dysplasia involved the formation of discrete clusters of atypical neurons and glia within the cortex. Clusters were more frequently, although not exclusively, observed in the middle and d e e p e r cortical layers, suggesting that most result from early rather than later migration abnormalities. Occasional cytologic atypia was observed in the neuronal c o m p o n e n t of dysplasia. Again, glial cells and occasional microglial cells also were observed to participate in the dysplastic process. This pattern of dysplasia corresponds to previously reported nodular cortical dysplasia, 3 some cases of focal dysplasia as described by Taylor et al, 22 dysplasia observed in patients with yon Recklinghausen's disease, 2° and neuronal clustering as described by Hardiman et al.u The least commonly observed pattern of dysplasia involved laminar architectural distortion of the cortex or malposition of neuronal elements within the cortex. This pattern of dysplasia corresponds to previously described agyria and pachygyria, 7'~°'1s laminar heterotoP ias, 1° P olymicrogyr]a,6'1°c- olumnar arrangements of nerve cells, 5'17 archicortical laminar structure, 1° and some of the focal dysplasia of Taylor et al. 22 In addition, the dysplasia typically observed as a forme fruste of tuberous sclerosis would also best correspond to this pattern. In 23 patients (44%) more than one pattern of dysplasia was observed. All three patterns coexisted in 10 patients (19%). The coexistence of multiple forms
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of dysplasia affecting both superficial and d e e p cortical layers may be indicative o f multiple insults occurring at different times during development, an ongoing insult over a period o f time, or an intrinsic abnormality of the migrating cells or their environment. T h e r e appears to be no correlation between the observed dysplasia pattern and seizure recurrence postoperatively. Postoperative seizure recurrence probably m o r e closely correlates with completeness of excision and the extent of the dysplasia rather than the specific type of dysplasia. 32 Because a significant n u m b e r of dysplasias are not grossly a p p a r e n t lesions and some are not discernible using magnetic resonance i m a g i n g , the completeness of the resection of potentially seizure-causative dysplasia may be difficult to assess. Recognition of dysplasia as a possible causative lesion of epilepsy is of primary importance. 25'26'36'41 Subtyping dysplasia is still of arguable clinical significance at this time, except in rare inherited forms 10 a n d in the phacomatoses-related dysplasias. Distinction between the cluster pattern of dysplasia and focal laminar architectural disruption is somewhat d e p e n d e n t on how extensively the specimen is sampled. Likewise, the distribution of dysplasia is particularly dep e n d e n t on specimen sampling. Because all of the tissue submitted at the time of surgery was e x a m i n e d microscopically in 17 cases, the actual incidence of certain patterns of dysplasia as well as assessments of distribution is likely to be underestimated. For a m o r e accurate incidence of dysplasia to be attained, all tissue submitted would n e e d to be e x a m i n e d histologically. Because this was n o t the case in this series, the 14% observed incidence of cortical dysplasia most likely represents an underestimate of the true incidence of dysplasia. In addition, we did not routinely use ancillary immunohistochemical or special staining techniques, such as serial Bodian stains, looking for m o r e subtle abnormalities of n e u r o n a l processes or their orientation. In certain instances, use of additional stains may be helpful in elucidating an abnormality or in characterizing the cell types participating in the dysplastic process. An association between t u m o r and cortical dysplasia is not well d o c u m e n t e d in the literature. T h e coexistence of these two lesions occurred in 4% of the total partial lobectomy population studied. T h e lack of literature regarding the coexistence of t u m o r and dysplasia may either be due to the rarity of such an event or, m o r e likely, to a lack of diagnosis of the dysplasia in the face of a diagnosed neoplasia. T h e incidence of tumors in the cortical dysplasia population (25%) reflects, in part, a bias of o u r institution in terms of the type of patient selected for surgery and the referral nature of our epilepsy practice. These biases also may partially account for the a p p a r e n t temporal lobe predilection of dysplasia and coexistant dysplasia/neoplasia. T h e most c o m m o n t u m o r f o u n d associated with dysplasia was ganglioglioma (eight of 13 cases). T h e relatively benign clinical course of most gangliogliomas and dysembryoplastic neuroepithelial tumors as well as their coexistence or admixture with cortical dysplasia suggests a possible h a m a r t o m a t o u s or dysplastic nature to a subset of these t u m o r s . 46-49 O n superficial examination
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there is no a p p a r e n t relation between astrocytoma and cortical dysplasia. T h e two cases r e p o r t e d here may represent a pure coincidence. O n the other hand, glial elements are frequently observed to participate in the dysplastic process. It is possible that neoplasia could arise f r o m glial cells in a focus of dysplasia. H e t e r o t o p i c n e u r o n s situated in the white matter were observed in all cases. Neurons located within the white matter are a c o m m o n finding when examining lobectomy specimens in patients with a history of epilepsy. Normal white matter contains few, if any, neurons. T h e presence of n e u r o n a l elements in white matter may be indicative of a migration abnormality. Therefore, it is not surprising to see such a high incidence of n e u r o n a l heterotopia a c c o m p a n y i n g cortical dysplasia. However, an increase in the n u m b e r of white matter n e u r o n s also has b e e n r e p o r t e d to occur in the setting of posttraumatic epilepsy, raising the question of whether or not they represent an effect of seizures. 16 Likewise, some of the atypical glial cells that frequently a c c o m p a n y cortical dysplasia and n e u r o n a l heterotopia may be an effect of the seizures rather than exclusively a part of the malformative process. 2 T h e functional Significance of white matter n e u r o n a l heterotopias is uncertain, Similar to cortical dysplasia, the presence of white matter h a m a r t o m a s within the cortex is likely related to developmental abnormalities of cellular migration. Mesial t e m p o r a l sclerosis is a n o t h e r r e p o r t e d finding in lobectomy specimens f r o m patients with chronic seizures. 2'5°-51 Because of the nature of surgical resection, most h i p p o c a m p a l sections are fragmented, resulting in an underestimate of the incidence of mesial temporal sclerosis in this series. T h e exact nature o f mesial t e m p o r a l sclerosis is still controversial; however, it does not a p p e a r to represent a migrational disorder. In cases where there is dual pathology (ie, a primary h i p p o c a m p u s lesion, such as mesial temporal sclerosis, and an e x t r a h i p p o c a m p a l lesion in the temporal lobe), the question arises regarding where the seizure focus lies and w h e t h e r the t u m o r or dysplasia may somehow be responsible for the loss of n e u r o n s seen in mesial temporal sclerosis. O t h e r c o m m o n l y observed lesions included subpial gliosis and meningeal fibrosis. Iatrogenic changes related to invasive seizure m o n i t o r i n g p r o c e d u r e s due to electrode plates or d e p t h electrode needles included meningeal fibrosis, chronic meningeal inflammation, small infarcts, and cortical contusions. Meningioangiomatosis is most likely a malformative h a m a r t o m a t o u s lesion involving meningothelial and glial cells, respectively. Meningioangiomatosis has b e e n described outside the setting of von Recklinghausen's disease as a cause for seizures. 91'5254 To o u r knowledge coexisting cortical dysplasia a n d meningioangiomatosis outside of von Recklinghausen's disease has not b e e n described previously. T h e association of cortical dysplasia with the phacomatoses is well known and suggests a genetic compon e n t to at least some cases of dysplasia. In the case of tuberous sclerosis the presence of enlarged and cytolog-
CORTICAL DYSPLASIA (Prayson & Estes)
ically atypical neuronal and astrocytic cells in the cortex and white matter is considered a forme fruste of the disease. 21 Nevertheless, similar cells were observed, generally in fewer numbers, outside the setting of tuberous sclerosis and thus are not diagnostic of tuberous sclerosis. Dysplasia and h a m a r t o m a have been described in the setting of yon Recklinghausen's disease. Most frequently they involve a cluster of atypical and disorganized glial cells; however, neuronal cells can be occasionally seen, as was the case with our patient. 2°'21 Continued careful histopathologic examination of tissues submitted from these patients and correlation of such findings with clinical symptomatology, imaging studies, and electroencephalogram studies are important. With time certain patterns of dysplasia may be able to be predicted based on a thorough presurgical evaluation of the patient. Likewise, correlation of surgical strategies with patterns and the extent of dysplasia and follow-up will be important in optimizing treatment in those padents requiring surgical intervention.
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44. Lampert PW, Davis RL: Delayed effects of radiation on the human central nervous system: "Early" and "late" reactions. Neurology 14:912-917, 1964 45. Kaufman WE, Galaburda AM: Cerebrocortical microdysgenesis in neurologically normal subjects: A histopathologic study. Neurology 39:238-244, 1989 46. CavanaghJB: On certain small tumours encountered in the temporal lobe. Brain 81:389-405, 1958 47. Daumas-Duport C, Scheithauer BW, Chodkiewicz J-P, et ah Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Report of thirtynine cases. Neurosurgery 23:545-556, 1988 48. Prayson RA, Estes ML: Dysembryoplastic neuroepithelial tumor. A m J Clin Pathol 97:398-401, 1992 49. Hirose T, Scheithauer BW, Lopes MBS, et al: Dysembroplastic neuroepithelial tumor (DNT): An immunohistochemical and ultrastructural study. J Neuropathol Exp Neurol 53:184-195, 1994
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