Terminology and classification of the cortical dysplasias

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

A. Palmini, MD PhD, I. Najm, MD, G. Avanzini, MD, T. Babb, PhD, R. Guerrini, MD, N. Foldvary-Schaefer, DO, G. Jackson, MD, H. O. Lders, MD PhD, R. Prayson, MD PhD, R. Spreafico, MD PhD and H. V. Vinters, MD + Author Affiliations

12. From the Pontificia Universidade Catlica do Rio Grande do Sul (PUCRS) (Dr. Palmini), Porto Alegre, Brazil; The Cleveland Clinic Foundation (Drs. Najm, Foldvary-Schaefer, Lders, and Prayson), Cleveland, OH; Istituto Nazionale Neurologico C. Besta (Drs. Avanzini and Spreafico), Milan, Italy; Wayne State University (Dr. Babb), Detroit, MI; Istituto de Neuropsichiatria Infantile (R. Guerrini), University of Pisa, Italy; Austin Hospital (Dr. Jackson), Melbourne, Australia; and University of California Los Angeles Medical Center (Dr. Vinters), Los Angeles, CA. 13. Address correspondence and reprint requests to Andr Palmini, Servio de Neurologia, Hospital So Lucas da PUCRS, Avenida Ipiranga 6690, Porto Alegre, RS, Brazil, CEP 90610-000; e-mail: apalmini@uol.com.br Next Section
Abstract

Background: There have been difficulties in achieving a uniform terminology in the literature regarding issues of classification with respect to focal cortical dysplasias (FCDs) associated with epilepsy. Objectives: To review and refine the current terminology and classification issues of potential clinical relevance to epileptologists, neuroradiologists, and neuropathologists dealing with FCD. Methods: A panel discussion of epileptologists, neuropathologists, and neuroradiologists with special expertise in FCD was held. Results: The panel proposed 1) a specific terminology for the different types of abnormal cells encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the different histopathologic abnormalities usually subsumed under the term microdysgenesis, and suggested that this terminology be abandoned; and 3) a more detailed yet straightforward classification of the various histopathologic features that usually are included under the heterogeneous term of focal cortical dysplasia.

Conclusion: The panel hopes that these proposals will stimulate the debate toward more specific clinical, imaging, histopathologic, and prognostic correlations in patients with FCD associated with epilepsy.
Malformations caused by abnormalities of cortical development (MCD),1 also known as disorders of cortical development,2 cortical dysplasias,35 cortical dysgenesis,6,7 or neuronal migration disorders (NMDs),8,9 have been recognized increasingly in patients with drug-resistant epilepsy. Advances in basic and clinical neurosciences have opened exciting avenues for research on the mechanisms of epileptogenicity and cerebral dysfunction in patients with MCD. The advent of various MRI techniques has facilitated the in vivo identification of a large group of cortical malformations in patients with epilepsy.5,1012 There has been progress in the understanding of various pathogenetic mechanisms,1318 engineering and testing of various animal models of MCD;1921 description of direct clinical-electrographic correlations,2225 and the delineation of surgical strategies2629 for management of the various types of MCD associated with epilepsy. Despite these advances, it has become obvious that there was a lack of uniform, well-defined clinically sound histopathologic nomenclature for and classification of these disorders. Such classification may allow for further progress in understanding these entities through improved communication at the clinical/electrographic, histopathologic, and basic scientific levels of research. Previous studies indicated that the pathogenesis of the various histopathologic patterns is multifactorial: genetic mutations,13,14,30,31 in utero injuries at different stages of brain development,6,3235 and even perinatal or postnatal insults may contribute to their etiology.36,37 The type, timing, and severity of environmental insults or the nature of genetic mutation and the impact of an abnormal gene product at different stages of brain development will likely influence the expression of the histopathologic and anatomic types of MCD. Previous attempts to classifying MCDs provided either simplistic or complex classification schemes that addressed specific aspects of these disorders.5,26,38 Thus far, the most comprehensive classification is that proposed by Barkovich et al.,1 who have included embryologic, histopathologic, imaging, and genetic aspects within their scheme. The major merit of this classification is its organization of the various types of MCD within an embryologic-pathophysiologic framework, recognizing that MCD could be caused by abnormalities during specific stages of cortical development (neuroglial proliferation and differentiation, neuronal migration, and postmigratory cortical organization). This classification1 did not emphasize a key issue in current epileptology, the existence of focal cortical dysplasias (FCDs), which are localized malformations increasingly associated with refractory seizures and currently operated on at most epilepsy centers.3942 A good clinical correlation to the different aspects of the histopathologic findings within FCDs has not been described. Thus, we suggest that it may be time for a reappraisal of nomenclature and classification issues in patients with MCD, particularly for those harboring FCD and other subtle microscopic abnormalities, usually encompassed under the term microdysgenesis. This panel of epileptologists working in the area of epilepsy surgery, neuropathologists, neuroradiologists, and basic scientists attempted to organize a scheme that could be of practical and broad application. We hope that the use of the proposed classification scheme in everyday practice and for research purposes will refine and validate its usefulness. Our proposal is divided into three parts: 1) definition of terminology for the histopathologic description of FCDs; 2) description of selected aspects of FCDs; and 3) a classification proper, in which different histopathologic subtypes are described and correlated with their current status of identification by MRI, as well as with some clinical features and prognostic aspects. Previous SectionNext Section
Definition of terms: toward a uniform nomenclature.

The first issue debated was the preferred denomination for this entire group of entities. There are developmental factors that may be independent of the mechanism of injury (genetic, intrauterine, or even perinatal) and that substantially affect cortical mantle formation.36,37 Because one or more of the mechanisms important in corticogenesis can be affected and because even the malpositioning of nodular or laminar aggregates of neuroblasts and glial cells in heterotopic positions actually represent interferences with cortical formation (these cells were destined originally for the cerebral cortex), the panel agreed with the denomination malformations due to abnormal cortical development. Accordingly, the panel suggested that the denomination cortical dysplasias should be applied only to the subtype of MCD in which the developmental abnormality is strictly or mostly intracortical. Thus, FCD would be a good term within this framework only. Additional subdivision of FCD based on histologic/cellular characteristics will be presented. Likewise, the term neuronal migration disorder, historically applied to all forms of MCD in the early 1990s,8,9 would suggest that all MCDs were caused by predominant interferences with migratory mechanisms affecting cortical neuronal precursors. It is clear that other pathogenetic mechanisms apply as well; therefore, NMDs are more correctly considered a subtype of MCD. Moreover, MCD would be descriptive of the microdysgeneses that were proposed originally by Meencke et al.43 to describe minimal, subtle abnormalities of intracortical architecture in patients with generalized epilepsies undergoing autopsy studies. Furthermore, the panel thought that the following terms should be either more clearly defined or replaced. Previous SectionNext Section
Microdysgenesis.

This term has been the focus of significant confusion since it was proposed originally.43 Some authors have used the term to describe subtle derangements of focal cortical architecture such as 1) cortical laminar disorganization; 2) single (or small aggregates of) heterotopic white matter neurons and neurons in the molecular layer; 3) persistent subpial granular layer; and 4) marginal glioneuronal heterotopia.41 In contrast, others have used the term microdysgenesis to describe any type of MRI-negative MCD.44 Because many instances of MRI-negative MCDs can be associated with severe histopathologic abnormalities, including dysplastic neurons and balloon cells, there is a clear histologic lack of congruence between the two uses of the term microdysgenesis.22,26,4547 The panel recommended that the use of the term microdysgenesis should be abandoned. Because most of the mild abnormalities reviewed by Mischel et al.41 involve cortical layer I, a proposal was made to subdivide the mildest forms of MCD into those characterized by ectopically placed neurons in or adjacent to layer I, and those in which abnormalities are outside layer I (see below). Previous SectionNext Section
Cellular abnormalities. Dysmorphic neurons.

Dosyalanmam Notlar Sayfa 1

Dysmorphic neurons.

These are misshapen cells with abnormal orientation, size, cytoskeletal structure, and atypical dendritic processes. Nissl substance can be seen in clumps, and the cells are rich in cytoplasmic neurofilaments (SMI 31; figure 1).48,49

View larger version: In this window In a new window Figure 1. Cresylecht violet staining shows the dysmorphic neurons. Note the high Nissl stain density and the various directions of the neurons; scale bar, 50 m.
Balloon cells.

These are abnormal cellular elements with a thin membrane; pale, glassy, and eosinophilic cytoplasm; and eccentric nucleus (or nuclei, because some are multinucleated). Balloon cells usually are of increased size compared with gemistocytic astrocytes. Previous immunocytochemical studies have shown that these cells have neuronal or glial characteristics.49,50 Most balloon cells are vimentin positive, but others are glial (e.g., glial fibrillary acidic protein) or neuron-specific enolase/MAP/NeuN-immunoreactive (Najm et al., personal communication).49 These data suggest some degree of heterogeneity among the cells with partial commitment toward glial or neuronal differentiation (figure 2).

View larger version: In this window In a new window Figure 2. H-E staining shows a large balloon cell in the subcortical white matter. Note the large opalescent cytoplasm and the eccentric nucleus; scale bar, 100 m.
Giant neurons.

These are neurons of increased size (compared with layer V pyramidal neurons) with central nuclei. However, they preserve a pyramidal morphology (i.e., are not dysmorphic) and do not overexpress cytoplasmic neurofilaments (figure 3).

View larger version: In this window In a new window

Figure 3. H-E staining shows a giant neuron with central nucleus. Note the presence of smaller dysmorphic neurons; scale bar, 100 m.
Immature neurons.

These are round (or oval) cells, all homogeneous, with a large (immature) nucleus and a thin rim of cytoplasm. They are not dysmorphic or giant but sometimes are seen in association with giant or dysmorphic neurons. They are occasionally the most common cell types in macroscopically visible heterotopic nodules.7,49 Previous SectionNext Section
(Microscopic) neuronal heterotopias.

These microscopic abnormalities are mainly caused by architectural disorganization. They are clusters of misplaced neurons. Conversely, the macroscopic heterotopia (periventricular, subcortical nodular, and band heterotopia) are grossly apparent well-defined abnormalities of neuroblast migration (see below). Previous SectionNext Section
Histopathology of FCDs.

As discussed previously, there are several cellular elements, which may occur in variable combinations, leading to specific histopathologic features in cortical dysplastic lesions. There is increasing information on correlations between the histopathologic and electroclinical and MRI abnormalities of FCD.2,46,5155 Thus, the panel decided to re-evaluate the several histopathologic scenarios that have been subsumed under the general term focal cortical dysplasias, with a view to a more clinically meaningful classification. Over the years, there has been some degree of heterogeneity in the clinical, surgical, and histopathologic literature, and terms like focal cortical dysplasia, mild cortical dysplasia, Taylor-type focal cortical dysplasia, balloon cell dysplasia, nonballoon cell dysplasia, and microdysgenesis all have been applied to describe architectural and cellular abnormalities of the cortical mantle.5,16,44,46,48,55,56 For example, some authors use the descriptor Taylor-type FCD only when balloon cells are present,16,57 whereas others, including Taylor et al.3 in their original report, include some patients whose lesions had dysmorphic neurons but lacked balloon cells. Although the panel accepted that a definitive understanding of the relevance of each cell type or architectural abnormality among the various possible combinations relies on further developments on the mechanisms of corticogenesis and their relation to clinical and imaging findings, a tentative practical approach was attempted. As a first step, it was consensually accepted that one or more of the following might be present in these lesions: dyslamination and other mild abnormalities (architectural abnormalities), immature neurons, giant neurons, dysmorphic neurons, and balloon cells. The most frequent histopathologic pictures combining these elements then were agreed on and considered to be the following.
Isolated architectural abnormalities (dyslamina-tion).

These are intracortical lesions that are characterized by dyslamination and columnar disorganization. These lesions represent the mildest end of the histopathologic spectrum of FCD and may most closely approximate the original description of microdysgenesis. In the medial temporal lobe, particularly in the hippocampus, abnormalities of the infolding of the dentate gyrus and focal dyslamination may occur.58
Architectural abnormalities associated with giant neurons.

Dosyalanmam Notlar Sayfa 2

Architectural abnormalities associated with giant neurons.

In these lesions, the defining abnormality is the presence of giant neurons. These lesions do not contain dysmorphic or balloon cells. Whether the presence of these cells has any clinical meaning and thus differentiates the lesions from those harboring only dyslamination is unclear.
Architectural abnormalities associated with dysmorphic neurons.

Irrespective of the occasional co-occurrence of giant or immature neurons, the hallmark of these lesions is the presence of clearly dysmorphic neurons as defined previously.48,49 Accumulation of neurofilaments within neuronal cytoplasm of these cells leads to distorted morphology of the perikarya, proximal axons, and dendrites. It is theoretically conceivable that these reflect more severe abnormalities from a histopathologic standpoint.41 In the original publication of Taylor et al.,3 4 of 10 patients had this histopathologic picture.
Architectural abnormalities associated with dysmorphic neurons and balloon cells.

These lesions are characterized mainly by the presence of balloon cells that are intermixed typically with dysmorphic neurons in patients with severe architectural disorganization. Six of the 10 original patients reported by Taylor et al.3 had a similar histopathologic pattern. These lesions are considered to represent the most severe end of the spectrum of histopathologic abnormalities of FCD.41 There is preliminary evidence that the presence of dysmorphic neurons, with or without balloon cells, is associated with higher degrees of epileptogenicity.2 Moreover, recent studies suggest that the main histopathologic subtypes that show MRI abnormalities are those that contain dysmorphic neurons with or without balloon cells.4,46,47,54 These results suggest the separation of the histologic subtypes as delineated will allow much better electroclinical, imaging, and histopathologic correlations. Previous SectionNext Section
A classification scheme: imaging, histopathology, and potential clinical relevance.

Considering the definition of terms and the re-evaluation of the histopathologic scenarios mentioned here, the following classification is proposed.
Mild MCD

Type I: with ectopically placed neurons in or adjacent to layer I

Type II: with microscopic neuronal heterotopia outside layer I

Structural imaging: both types probably are not detectable by current MRI techniques Histopathology: as described previously
Potential clinical relevance.

It has been shown that these mild MCDs may be related to epilepsy and other behavioral and cognitive abnormalities.44,5961 Because diagnosis usually is retrospective, clear clinical and epileptic profiles of patients with these mild malformations are not available. Thus, there is some debate on the role of these mild changes in the causation of epilepsy in general but especially when the histologic abnormalities are found in mesial temporal structures, leading to microscopic heterotopia in the dentate or parahippocampal gyri.60,61 Likewise, the association of mesial limbic malformations with schizophrenia and autism has attracted the attention of nonepileptologists to the putative clinical consequences of mild MCD.6264

FCDs
Type I: no dysmorphic neurons or balloon cells Type IA: isolated architectural abnormalities (dyslamination, accompanied or not by other abnormalities of mild MCD) Type IB: architectural abnormalities, plus giant or immature, but not dysmorphic neurons Structural imaging: it is unclear at the time of this report whether type I FCD as defined here can be identified in vivo by current MRI techniques. Should a common nomenclature be used by various centers, it is likely that imaging-histopathologic correlations soon will clarify this issue. Histopathology: as described previously (figure 4)

View larger version: In this window In a new window Figure 4. Cresylecht violet staining of sections representing normal neocortex and type I, type IIA, and type IIB malformations of cortical development; scale bar, 100 m.
Potential clinical relevance.

It is likely that some of these patients will have epilepsy, whereas others will not; those without epilepsy may be either asymptomatic or instead seek treatment for learning disorders or other types of cognitive impairment. There are no specific data delineating a clinical or neurophysiologic profile of patients with epilepsy and type IA/B FCDs. Because hitherto most of these mild abnormalities defy in vivo imaging recognition, the only available evidence is from patients undergoing epilepsy surgery in whom such mild abnormalities were the only histopathologic finding.5,55 This suggests that at least some patients with type IA/B FCD can have medically refractory epilepsy. However, whether this is a common occurrence or represents only the most severe end of a spectrum is unclear. Interestingly, surgical patients in whom these mild MCDs were found retrospectively tend to have much better results compared with the surgical results obtained from patients with other types of FCDs. Type II: Taylor-type FCD (dysmorphic neurons without or with balloon cells) Type IIA: architectural abnormalities with dys morphic neurons but without balloon cells Type IIB: architectural abnormalities with dys morphic neurons and balloon cells

Structural imaging: these are the focal lesions most commonly identified on MRI. However, one should be aware that several different imaging possibilities might be observed in patients with Taylor-type FCD. MRI can be either normal,45,47 despite the use of high-resolution techniques, or may demonstrate one or more of the following characteristics: 1) focal areas of increased cortical thickness;46,47 2) blurring of the cortex (gray)/white matter junction;51,54 3) increased signal on T2-weighted, proton density, or fluid-attenuated inversion recovery sequences (more likely to occur in balloon cell-containing lesions);51,54 and 4) extension of cortical tissue with increased signal from the surface to the ventricle (transmantle dysplasia).6567
Histopathology: as detailed previously
Potential clinical relevance.

Type IIA/B FCDs are characterized by truly abnormal, grossly dysmorphic cellular elements, which are accompanied by unquestionable abnormalities in inhibitory and excitatory neurotransmission. Data collected through immunocytochemical studies support an increase in excitatory amino acid neurotransmission and an overall decrease in intralesional and perilesional inhibition.16,48,49 The net result is a high degree of intrinsic epileptogenicity, which has been demonstrated by experimental and clinical studies.22,23,26,42,68,69 Most patients diagnosed by imaging studies (see above) as having lesions identified as type IIA/B FCD have medically intractable partial epilepsy, with frequently disabling motor and secondary generalized seizures. Many patients have a history of status epilepticus, including epilepsia partialis continua, and scalp EEG and acute electrocorticography often show continuous spiking or other highly epileptogenic patterns, attesting to some type of re-entrant excitatory circuitry unopposed by faulty inhibition.26,52,55 These patients often are correctly diagnosed before surgery, but surgical results still are

Dosyalanmam Notlar Sayfa 3

patterns, attesting to some type of re-entrant excitatory circuitry unopposed by faulty inhibition.26,52,55 These patients often are correctly diagnosed before surgery, but surgical results still are not fully satisfactory in many of them. Issues related to a preferential localization around the perirolandic cortex and to a microscopic extension of abnormal tissue beyond the MRI lesional margins often are mentioned to explain unsatisfactory results.
Dysplastic tumors.

There are at least two types of tumor that may represent a more extreme end of the histopathologic spectrum of FCDs. Dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas may be associated with surrounding cortical regions displaying abnormal cytoarchitecture (dyslamination) and large, at times dysmorphic, neurons and glial cells.70,71 Subcortical heterotopic neurons also can be seen.40,72
Structural imaging and histopathology.

Both lesions usually are restricted to the cortex and may present a combination of cystic and calcified areas. Perhaps the most striking imaging aspect is that the MRI signal often is irregular and poorly delineated, attesting to the presence of different histopathologic elements and the association of perilesional dysplastic and immediately subcortical heterotopic cells. There is no perilesional edema or mass effect.40,72
Clinical relevance.

DNETs and gangliogliomas are (with rare exception) benign lesions from an oncologic point of view. However, they often are associated with medically refractory partial seizures, which usually manifest clinically before 20 years of age. Patients with DNETs and epilepsy may be cured with surgery, providing complete resection is feasible. Remaining tumoral or dysplastic tissue may be associated with persistent seizures, despite major lesion resection.40,72 Previous SectionNext Section
Challenges for the future.

This report represents an attempt toward a simple yet practical classification for FCDs that may be beneficial for cliniciansand researchers who are interested in the management of FCDs and an understanding of mechanisms by which they cause epilepsy. Some imaging and histopathologic correlations were suggested, but there has been no attempt to include an embryologic perspective in the classification. It is likely that advances in the molecular neurobiology of these disorders will significantly change our views in terms of pathogenesis. To further understand these disorders and to validate the usefulness of this proposed classification, there is need for the following: 1) clinical-electrical-pathologic correlations in patients with epilepsy who are undergoing electrocorticographic and depth electrode recording evaluations;73 2) imaging-pathologic-functional correlations based on careful studies of surgically resected cortical samples; and 3) cellularmolecular studies of the mechanisms of epileptogenicity through direct correlation with electrocorticographic data obtained through invasive recordings.18
Note added in proof.

Recent utilization of this classification framework has generated initial data suggesting that the different types of FCD indeed tend to be associated with some specific anatomical, clinical, electrographic, and imaging characteristics.74,75 Thus, Type I focal cortical dysplastic lesions have been shown to be most often localized to the temporal lobes, to lack highly specific electrographic patterns, and to present on MRI as hypoplasia of the temporal pole and/or increased signal in the white matter core, with poorly defined limits. On the other hand, Type II (Taylor type) FCD has been increasingly shown to represent an extratemporal entity, with lesions localized to one of four major anatomical subcompartments: frontal lobe only, fronto-central, perirolandic, or in the posterior quadrant. In addition, it has been confirmed that these lesions are frequently associated with ictal-like patterns or direct cortical recordings.22,76,77 Finally, a recent report advances one step further, suggesting that the subdivisions of Type II FCD may be differently related to ictal generation and preservation of function.78 In patients with peri-rolandic FCD, those portions of the lesions classified as Type IIA were shown to harbor the ictal onset zone and to retain motor function, in contrast to those portions of the lesions containing balloon cells (Type IIB), which were functionally silent and not associated with seizure onset. If confirmed, these findings may have a significant impact in surgical planning, and will emphasize even more the need for in vivo MRI identification of subtypes of FCD. Previous SectionNext Section
Acknowledgments

I.N. was supported by grants K08-NS02046 and R21-NS42354 from the NIH. Previous Section 14.
References

Barkovich A, Kuzniecky R, Dobyns W, Jackson G, Becker L, Evrard P. A classification scheme for malformations of cortical development. Neuropediatrics. 1996;27: 5963. Medline 15. Palmini A. Disorders of cortical development. Curr Opin Neurol. 2000;13: 183192. CrossRefMedline

16. Taylor DFM, Bruton C, Corsellis J. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry. 1971;34: 369387. Abstract/FREE Full Text
17. Adamsbaum CRO, Cohen PA, Delalande O, Fohlen M, Kalifa G. Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol. 1998;28: 583590. CrossRefMedline 18. Kuzniecky R, Garcia J, Faught E, Morawetz R. Cortical dysplasia in temporal lobe epilepsy: magnetic resonance imaging correlations. Ann Neurol. 1991;29: 293298. CrossRefMedline

19. Roper S. In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review. Epilepsy Res. 1998;32: 6374. CrossRefMedline
20. Van BP, David P, Gillain C, et al. Perisylvian dysgenesis. Clinical, EEG, MRI and glucose metabolism features in 10 patients. Brain. 1998;121: 22292238. Abstract/FREE Full Text 21. Palmini A, Andermann F, de Grissac H, et al. Stages and patterns of centrifugal arrest of diffuse neuronal migration disorders. Dev Med Child Neurol. 1993;35: 331339. Medline 22. Simone I, Federico F, Tortorella C, et al. Metabolic changes in neuronal migration disorders: evaluation by combined MRI and proton MR spectroscopy. Epilepsia. 1999;40: 872879. CrossRefMedline 23. Palmini A, Andermann F, Aicardi J, et al. Diffuse cortical dysplasia, or the double cortex syndrome: the clinical and epileptic spectrum in 10 patients. Neurology. 1991;41: 16561662.

Dosyalanmam Notlar Sayfa 4

1991;41: 16561662. Abstract/FREE Full Text 24. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol. 1991;30: 750757. CrossRefMedline 25. Barkovich A, Chuang S, Norman D. MR of neuronal migration anomalies. AJR Am J Roentgenol. 1988;150: 179187. Abstract/FREE Full Text

26. Gleeson J, Minnerath S, Fox J, et al. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol. 1999;45: 146153. CrossRefMedline
27. Fox J, Lamperti E, Eksioglu Y, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998;21: 13151325. CrossRefMedline 28. Yamanouchi H, Jay V, Otsubo H, Kaga M, Becker L, Takashima S. Early forms of microtubule-associated protein are strongly expressed in cortical dysplasia. Acta Neuropathol (Berl). 1998;95: 466470. CrossRefMedline 29. Ferrer I, Pineda M, Tallda M, et al. Abnormal local circuit neurons in epilepsia partialis continua associated with focal cortical dysplasia. Acta Neuropathol. 1992;83: 647652. CrossRefMedline

30. Ying Z, Babb T, Comair Y, Bingaman W, Bushey M, Touhalisky K. Induced expression of NMDAR2 proteins and differential expression of NMDAR1 splice variants in dysplastic neurons of human epileptic neocortex. J Neuropathol Exp Neurol. 1998;57: 4762. Medline
31. Najm I, Ying Z, Babb T, et al. NMDA receptor 2A/B subtype differential expression in human cortical dysplasia: correlation with in situ epileptogenicity. Epilepsia. 2000;41: 971976. CrossRefMedline 32. Chevassus-Au-Louis N, Congar P, Represa A, Ben-Ari Y, Gaiarsa J. Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. Proc Natl Acad Sci USA. 1998;95: 1026310268. Abstract/FREE Full Text 33. Holmes G, Sarkisian M, Ben-Ari Y, Liu Z, Chevassus-Au-Louis N. Consequences of cortical dysplasia during development in rats. Epilepsia. 1999;40: 537544. Medline 34. Chevassus-au-Louis N, Baraban S, Gaiarsa J, Ben-Ari Y. Cortical malformations and epilepsy: new insights from animal models. Epilepsia. 1999;40: 811821. CrossRefMedline 35. Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol. 1995;37: 476487. CrossRefMedline 36. Gambardella A, Palmini A, Andermann F, et al. Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol. 1996;98: 243249. CrossRefMedline 37. Dubeau F, Palmini A, Fish D, et al. The significance of electrocorticographic findings in focal cortical dysplasia: a review of their clinical, electrophysiological and neurochemical characteristics. Electroencephalogr Clin Neurophysiol Suppl. 1998;48: 7796. Medline 38. Guerrini R, Dravet C, Raybaud C, et al. Epilepsy and focal gyral anomalies detected by MRI: electroclinico-morphological correlations and follow up. Dev Med Child Neurol. 1992;34: 706718. Medline 39. Palmini A, Gambardella A, Andermann F, et al. Operative strategies for patients with cortical dysplastic lesions and intractable epilepsy. Epilepsia. 1994;35: S57 S71. 40. Palmini A, Andermann F, Olivier A, et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol. 1991;30: 741749. CrossRefMedline 41. Hirabayashi S, Binnie C, Janota I, Polkey C. Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings. J Neurol Neurosurg Psychiatry. 1993;56: 765770. Abstract/FREE Full Text

42. Najm I, Bingaman W, Luders H. The use of subdural grids in the management of focal malformations due to abnormal cortical development. Neurosurg Clin N Am. 2002;13: 8792. Medline
Dosyalanmam Notlar Sayfa 5

Medline 43. Granata T, Farina L, Faiella A, et al. Familial schizencephaly associated with EMX2 mutation. Neurology. 1997;48: 14031406. Abstract/FREE Full Text

44. Kato M, Kimura T, Lin C, et al. A novel mutation of the doublecortin gene in Japanese patients with X-linked lissencephaly and subcortical band heterotopia. Hum Genet. 1999;104: 341344. CrossRefMedline
45. Roper S, Gilmore R, Houser C. Experimentally induced disorders of neuronal migration produce an increased propensity for electrographic seizures in rats. Epilepsy Res. 1995;21: 205219. CrossRefMedline 46. Roper S, King M, Abraham L, Boillot M. Disinhibited in vitro neocortical slices containing experimentally induced cortical dysplasia demonstrate hyperexcitability. Epilepsy Res. 1997;26: 443449. CrossRefMedline 47. Kondo S, Najm I, Kunieda T, Perryman S, Yacubova K, Luders H. Electroencephalographic characterization of an adult rat model of radiation-induced cortical dysplasia. Epilepsia. 2001;42: 12211227. CrossRefMedline

48. Palmini A, Andermann E, Andermann F. Prenatal events and genetic factors in epileptic patients with neuronal migration disorders. Epilepsia. 1994;35: 965973. CrossRefMedline
49. Lombroso C. Can early postnatal closed head injury induce cortical dysplasia? Epilepsia. 2000;41: 245253. CrossRefMedline 50. Sarnat H. Disturbances of late neuronal migrations in the perinatal period. Am J Dis Child. 1987;141: 969980. Abstract/FREE Full Text 51. Palmini A, Andermann F, Olivier A, et al. Neuronal migration disorders: a contribution of modern neuroimaging to the etiologic diagnosis of epilepsy. Can J Neurol Sci. 1991;18: 580587. Medline 52. Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol. 1995;37: 476487.

53. Raymond A, Fish D, Sisodiya S, Alsanjari N, Stevens J, Shorvon S. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain. 1995;118: 629660. Abstract/FREE Full Text 54. Mischel P, Nguyen L, Vinters H. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol. 1995;54: 137153. Medline
55. Morioka T, Nishio S, Ishibashi H, et al. Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography. Epilepsy Res. 1999;33: 177187. CrossRefMedline 56. Meencke H, Janz D. The significance of microdysgenesia in primary generalized epilepsy: an answer to the considerations of Lyon and Gastaut. Epilepsia. 1985;26: 368371. Medline 57. Keene D, Jimenez C, Ventureyra E. Cortical microdysplasia and surgical outcome in refractory epilepsy of childhood. Pediatr Neurosurg. 1998;29: 6972. CrossRefMedline 58. Desbiens R, Berkovic S, Dubeau F, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia. Arch Neurol. 1993;50: 695700. Abstract/FREE Full Text 59. Chan S, Chin S, Nordli D, Goodman R, DeLaPaz R, Pedley T. Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the nonballoon cell subtype. Ann Neurol. 1998;44: 749757. CrossRefMedline 60. Bastos A, Comeau R, Andermann F, et al. Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three-dimensional magnetic resonance imaging. Ann Neurol. 1999;46: 8894. CrossRefMedline 61. Spreafico R, Battaglia G, Arcelli P, et al. Cortical dysplasia: an immunocytochemical study of three patients. Neurology. 1998;50: 2736. Abstract/FREE Full Text 62. Spreafico R, Pasquier B, Minotti L, et al. Immunocytochemical investigation on dysplastic human tissue from epileptic patients. Epilepsy Res. 1998;32: 3448. CrossRefMedline

Dosyalanmam Notlar Sayfa 6

CrossRefMedline 63. Barbosa-Coutinho L, Hilbig A, Calcagnotto M, et al. Neuropathology of hard to control epilepsy. Study of 300 consecutive cases [Portuguese]. Arq Neuropsiquiatr. 1999;57: 40514. Medline 64. Bronen R, Vives K, Kim J, Fulbright R, Spencer S, Spencer D. Focal cortical dysplasia of Taylor, balloon cell subtype: MR differentiation from low-grade tumors. AJNR Am J Neuroradiol. 1997;18: 11411151. Abstract

65. Palmini A, da Costa J, Calcagnotto M, Pagliolo-Neto E, Paglioli E, Coutinho L. Patients with specific histopathological types of cortical dysplasia have specific degrees of severity of the epileptic condition. Epilepsia. 1997;38: 5.
66. Guerrini R, Genton P, Bureau M, et al. Multilobar polymicrogyria, intractable drop attack seizures, and sleep-related electrical status epilepticus. Neurology. 1998;51: 504512. Abstract/FREE Full Text 67. Lee B, Schmidt R, Hatfield G, Bourgeois B, Park T. MRI of focal cortical dysplasia. Neuroradiology. 1998;40: 675683. CrossRefMedline 68. Rosenow F, Lders H, Dinner D, et al. Histopathological correlates of epileptogenicity as expressed by electrocorticographic spiking and seizure frequency. Epilepsia. 1998;39: 850856. CrossRefMedline 69. Palmini A, Andermann F, Olivier A, et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol. 1991;30: 741749. 70. Garbelli R, Munari C, De Biasi S, et al. Taylors cortical dysplasia: a confocal and ultrastructural immunohistochemical study. Brain Pathol. 1999;9: 445461. Medline 71. Lehericy S, Dormont D, Semah F. Developmental abnormalities of the medial temporal lobe in patients with temporal lobe epilepsy. AJNR Am J Neuroradiol. 1995;16: 617626. Abstract 72. Raymond G, Bauman M, Kemper T. Hippocampus in autism: a Golgi analysis. Acta Neuropathol (Berl). 1996;91: 117119. Medline

73. Akil M, Lewis D. Cytoarchitecture of the entorhinal cortex in schizophrenia. Am J Psychiatry. 1997;154: 10101012. Medline
74. Galaburda A, Sherman G, Rosen G, Aboitiz F, Geschwind N. Developmental dyslexia: four consecutive patients with cortical anomalies. Ann Neurol. 1985;18: 222233. CrossRefMedline 75. Akbarian S, Bunney W, Potkin S, et al. Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry. 1993;50: 169177. Abstract/FREE Full Text 76. Bunney B, Potkin S, Bunney W. New morphological and neuropathological findings in schizophrenia: a neurodevelopmental perspective. Clin Neurosci. 1995;3: 8188. Medline 77. Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol. 1997;7: 269278. CrossRefMedline 78. Barkovich A, Kuzniecky R, Bollen A, Grant P. Focal transmantle dysplasia: a specific malformation of cortical development. Neurology. 1997;49: 11481152. Abstract/FREE Full Text

79. Barkovich A, Kuzniecky R, Bollen A, Grant P. Focal transmantle dysplasia: a specific malformation of cortical development. Neurology. 1997;49: 11481152.
80. Bronen R, Spencer D, Fulbright R. Cerebrospinal fluid cleft with cortical dimple: MR imaging marker for focal cortical dysgenesis. Radiology. 2000;214: 657663. Abstract/FREE Full Text 81. Dubeau F, Palmini A, Fish D, et al. The significance of electrocorticographic findings in focal cortical dysplasia: a review of their clinical, electrophysiological and neurochemical characteristics. Electroencephalogr Clin Neurophysiol Suppl. 1998;48: 7796. 82. Avoli M, Bernasconi A, Mattia D, Olivier A, Hwa G. Epileptiform discharges in the human dysplastic neocortex: in vitro physiology and pharmacology. Ann Neurol. 1999;46: 816826. CrossRefMedline 83. Wolf HK, Mller MB, Spanle M, et al. Ganglioglioma: a detailed histopathological and immunocytochemical analysis of 61 cases. Acta Neuropathol. 1994;88: 166173. Medline

Dosyalanmam Notlar Sayfa 7

Medline 84. Prayson RA, Khajavi K, Comair YG. Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors. J Neuropathol Exp Neurol. 1995;54: 513520. Medline 85. Daumas-Duport CSB, Scheithauer BW, Chodkiewicz JP, et al. Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery. 1988;23: 545556. Medline

86. Munari C, Francione S, Kahane P, et al. Usefulness of stereo EEG investigations in partial epilepsy associated with cortical dysplastic lesions and gray matter heterotopia. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin B, Pfanner P, eds. Dysplasias of Cerebral Cortex and Epilepsy. Philadelphia: LippincottRaven, 1995:383394.
87. Tassi L, Colombo N, Garbelli R, et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain. 2002;125: 17191732. Abstract/FREE Full Text 88. Colombo N, Tassi L, Galli C, et al. Focal cortical dysplasias: MR imaging, histopathologic, and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol. 2003;24: 724733. Abstract/FREE Full Text

89. Chassoux F, Devaux B, Landr E, et al. Stereoelectroencephalography in focal cortical dysplasia: a 3D approach to delineating the dysplastic cortex. Brain Dev. 2000;123: 17331755.
90. Ferrier CH, Alarcon G, Engelsman J, et al. Relevance of residual histologic and electrocorticographic abnormalities for surgical outcome in frontal lobe epilepsy. Epilepsia. 2001;42: 363371. CrossRefMedline 91. Boonyapisit K, Najm I, Klem G, et al. Epileptogenicity of focal malformations due to abnormal cortical development: direct electrocorticographic-histopathologic correlations. Epilepsia. 2003;44: 6976. Medline
Articles citing this article

Morphometric MRI analysis improves detection of focal cortical dysplasia type II Brain October 1, 2011 134:2844-2854 Abstract Full Text Full Text (PDF) Brain Tumors in Adults With Medically Intractable Epilepsy Am J Clin Pathol October 1, 2011 136:557-563 Abstract Full Text Full Text (PDF) Altered Firing Rates and Patterns in Interneurons in Experimental Cortical Dysplasia Cereb Cortex July 1, 2011 21:1645-1658 Abstract Full Text Full Text (PDF) Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development Brain April 1, 2011 134:1015-1032 Abstract Full Text Full Text (PDF) Combined 7-T MRI and histopathologic study of normal and dysplastic samples from patients with TLE Neurology March 29, 2011 76:1177-1185 Abstract Full Text Full Text (PDF) Expression of connexin 43 in the human epileptic and drug-resistant cerebral cortex Neurology March 8, 2011 76:895-902 Abstract Full Text Full Text (PDF) Multimodality imaging in the surgical treatment of children with nonlesional epilepsy Neurology January 4, 2011 76:41-48 Abstract Full Text Full Text (PDF) FDG-PET improves surgical outcome in negative MRI Taylor-type focal cortical dysplasias Neurology December 14, 2010 75:2168-2175 Abstract Full Text Full Text (PDF) Characteristics and Surgical Outcomes of Patients With Refractory Magnetic Resonance Imaging-Negative Epilepsies Arch Neurol December 1, 2009 66:1491-1499 Abstract Full Text Full Text (PDF) [18F] Fluorodeoxyglucose-Positron-Emission Tomography and MR Imaging Coregistration for Presurgical Evaluation of Medically Refractory Epilepsy Am. J. Neuroradiol. November 1, 2009 30:1811-1816 Abstract Full Text Full Text (PDF) Balance of Inhibitory and Excitatory Synaptic Activity Is Altered in Fast-Spiking Interneurons in Experimental Cortical Dysplasia J. Neurophysiol. October 1, 2009 102:2514-2525 Abstract Full Text Full Text (PDF) Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABAA receptors microtransplanted to Xenopus oocytes Proc. Natl. Acad. Sci. USA September 15, 2009 106:15927-15931 Abstract Full Text Full Text (PDF) Selective changes in GABAA receptor subtypes in white matter neurons of patients with focal epilepsy Brain September 1, 2009 132:2449-2463 Abstract

Dosyalanmam Notlar Sayfa 8

Abstract Full Text Full Text (PDF) Multi-focal occurrence of cortical dysplasia in epilepsy patients Brain August 1, 2009 132:2079-2090 Abstract Full Text Full Text (PDF) Clinical prediction of postoperative seizure control: structural, functional findings and disease histories J. Neurol. Neurosurg. Psychiatry February 1, 2009 80:196-200 Abstract Full Text Full Text (PDF) Small focal cortical dysplasia lesions are located at the bottom of a deep sulcus Brain December 1, 2008 131:3246-3255 Abstract Full Text Full Text (PDF) Neuroimaging in Pediatric Epilepsy: A Multimodality Approach1 RadioGraphics July 1, 2008 28:1079-1095 Abstract Full Text Full Text (PDF) GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations Physiol. Rev. October 1, 2007 87:1215-1284 Abstract Full Text Full Text (PDF) Developmental lineage of cell types in cortical dysplasia with balloon cells Brain September 1, 2007 130:2267-2276 Abstract Full Text Full Text (PDF) Contralateral hemimicrencephaly and clinical-pathological correlations in children with hemimegalencephaly Brain February 1, 2006 129:352-365 Abstract Full Text Full Text (PDF) Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia J. Neurosci. October 19, 2005 25:9649-9657 Abstract Full Text Full Text (PDF) Quantitative post-mortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss Brain June 1, 2005 128:1344-1357 Abstract Full Text Full Text (PDF) Adult-onset epilepsy in focal cortical dysplasia of Taylor type Neurology May 24, 2005 64:1771-1774 Abstract Full Text Full Text (PDF) Mild forms of focal cortical dysplasia: how certain are we? Brain March 1, 2005 128:E22 Full Text Full Text (PDF)
Yaptrma kayna <http://www.neurology.org/content/62/6_suppl_3/S2.full>

Dosyalanmam Notlar Sayfa 9