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Authors and Disclosures

Sanjay Sisodiya

Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology,Queen Square, London WC1N 3BG, UK. s.sisodiya@ion.ucl.ac.uk

From Nature Reviews Neurology

The New Order—Classifying Focal Cortical Dysplasias

Sanjay Sisodiya

Posted: 03/28/2011; Nat Rev Neurol. 2011;7(3):129-130. © 2011 Nature Publishing Group

Abstract and IntroductionAbstract

Focal cortical dysplasia (FCD) is a commonly encountered neuropathology in drug-resistant focalepilepsy; the bizarre pathological appearance of FCD reflects molecular disorder bridgingneurodevelopment and neurodegeneration. A new classification stands to resolve discrepancies inFCD categorization and accelerate advances in fundamental understanding and clinical managementof drug-resistant epilepsy.

Introduction

Drug resistance in epilepsy is a major clinical problem, affecting ≈30% of people with epilepsy. One ofthe more common structural changes in the brain associated with such epilepsy is focal corticaldysplasia (FCD), an intriguing neuropathology of unknown cause that was first described by Taylorand colleagues in 1971.[1] FCD is a common pathology observed in surgical resection specimens frompatients with drug-resistant epilepsy. A somewhat broader range of conditions has become looselyand variably subsumed within the term FCD, leading to some confusion and lack of comparabilitybetween reports. In an important and thoughtful effort, an ad hoc task force—under the auspices ofthe International League Against Epilepsy (ILAE)—has generated a comprehensive classification ofFCD subtypes to improve FCD characterization and provide a consensus framework for clinical useand further research.[2]

Why is this new consensus FCD classification important, and have the ILAE task force succeeded?Surgical resection of an epileptogenic lesion is a potentially curative treatment for drug-resistantepilepsy. Evaluations for surgery constitute a well-honed multidisciplinary process, and should alwaysinclude a preoperative MRI brain scan. One factor that generally supports surgical treatment, beingassociated with a high likelihood of successful surgical control of seizures, is the presence of a

resectable focal lesion (such as hippocampal sclerosis, vascular malformation, low-grade glioneuronaltumor or FCD) on MRI. Nevertheless, seizure outcomes reported after resective surgery often varyconsiderably between centers and publications. Moreover, the reported underlying causes of epilepsy(identified via histological examination of the resected material) sometimes differ markedly betweencenters operating on comparable patients, without obvious explanations as to why. Patterns ofreporting may be inconsistent for several reasons,[3] not limited to pathology reporting itself.[4] All thisvaried information renders informed, evidence-based decision-making a complex prospect forphysicians and patients. For FCD, these problems are aggravated by a lack of understanding of theunderlying disease processes and are compounded by systematic differences between centers in thenomenclature and definitions of such lesions. Clinicians cannot learn from the collective experience ofFCD treatment until disease nomenclature and definitions are clear.

Previous consensus statements or agreed systems of reporting have addressed some of the issues

with FCD definitions. For example, a reasonably straightforward 2001 outcome scale has gainedwidespread acceptance as a measure of seizure outcome after surgery,[5] facilitating cross-centercomparisons. Furthermore, the 2004 Palmini FCD classification system[6] has already proved useful.[7]

The new classification is an advance on these systems in several important ways. The ILAEclassification[2] retains previous categories of FCD (subtypes Ia, Ib, IIa and IIb), which aredistinguished by their cortical laminar structure, cytoarchitectural disruption and cell composition, and

Focal cortical dysplasia (FCD)10 Ocak 2012 Salı

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also introduces, but does not illustrate, a new disease subcategory (FCD type Ic). Additionally, thesystem takes the essential step of collating and molding robust definitions of FCD histopathologicalcharacteristics, which can be applied readily in clinical practice, and outlines standards for tissuepreparation to permit practical application of the definitions. Most of the existing subtypes arehandsomely illustrated. Blümcke et al .[2] rightly consider the clinical feasibility and utility of theseestablished FCD categories, noting that currently only clinical data can validate these classifications.With well-developed technology to host large image datasets online now available, the ILAE taskforce might consider whether more detailed, comprehensive, interactively searchable andanonymized neuropathological images could be made freely available for centers that lack expertisein epilepsy neuropathology. This development would broaden the appeal of the new classification. Inaddition, were the small expert cadre of epilepsy neuropathologists able to remotely review data fromcenters without specialist provision, a truly impressive global service would be achieved with potentialbenefits to all concerned and to the classification itself.

The major advance of the 2011 reclassification[2] relates to pathological findings, which werepreviously difficult to categorize. The reclassification includes subtle pathological changes found inassociation with other epileptogenic lesions, which are now grouped into FCD type III, with furthersubclassification depending on the association observed. For example, FCD type IIIa (Figure 1) isspecified as a broad range of cortical or subcortical abnormalities occurring with hippocampalsclerosis, while the less homogeneous category of type IIId is defined as altered cortical architectureor cytoarchitecture found adjacent to other lesions acquired during early life, such as lesions resultingfrom traumatic brain injury, perinatal ischemia or Rasmussen encephalitis.

Figure 1. Histopathological findings of FCD type IIIa. A temporal lobectomy specimen immunolabeledfor the neuronal antigen NeuN (neuronal nuclei) showing malorientated neurons (brown staining) inlayer II of the temporal neocortex. The specimen also shows hippocampal sclerosis. Scale bar 100

μm. Abbreviation: FCD, focal cortical dysplasia. Courtesy of M. Thom, University College LondonInstitute of Neurology, UK.

FCD classification, especially type III, is based on morphological criteria. For FCD types I and II,basing classification on histological criteria seems reasonable, as improved homogeneity seems to beemerging in postoperative outcomes grouped by pathology.[7,8] Fundamental research into patterns ofmolecular disruption, especially in FCD type II, is nurturing a coherent theory of what goes awry inthese lesions,[9] leading to important insights into development and degeneration in the humanbrain.[10] Less progress has been made in understanding FCD type I and much work remains toimprove understanding of FCD type III. Many of the defining characteristics of type III are shared withtype I, although this observation does not signify shared causation or biology. Indeed, the ILAE taskforce considers that some type III FCDs may be 'acquired' or secondary in some way to the 'principallesion', such as hippocampal sclerosis. By contrast, most researchers consider FCD type II to be

developmental in origin. Whether separation of type I and type III FCD leads to improvedunderstanding and management of FCD remains to be determined. The consensus reclassification is,however, an important step towards this goal. With further clinicopathological correlative studiesbased on this new classification, we may conclude that FCD type III is not independentlyepileptogenic, but merely a reactive change or an epiphenomenon. Such testing of the classification isvital; otherwise, FCD type III may simply be accepted as an established entity without adequate justification.

The 2011 consensus classification on FCD[2] does succeed in separating disease entities that hadbeen prone to variable and confusing reporting, and provides an important new framework. Thechallenge ahead is for all centers capable of testing the framework to do so in a coordinated way.Increased collaboration within the scientific community augurs well for the success of suchendeavors. Whether FCD type III is pathological and epileptogenic needs to be confirmed. Additionalchallenges exist, chief among which is improvement of preoperative identification and delineation of

all types of FCD by neuroimaging. Several hypotheses have been postulated for the low probability ofa favorable outcome in epilepsy surgery in the absence of a preoperatively identified lesion on MRI,including the presence of a nonstructural or multifocal cause, the lesion being not amenable tosurgical resection, and the occurrence of an extensive region capable of causing seizures that has notbeen, or cannot be, fully resected. Substantial advances are necessary from other disciplines to

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address these key problems, and this consensus statement will provide the neuropathological 'goldstandard' against which other measures can be judged, especially for MRI. Blümcke and colleagues [2]

are to be congratulated on their efforts. We should now look forward, in due course, to their own re-evaluation of the new classification, which will be tested through the imaging, surgery andpathological study of drug-resistant epilepsy.

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1. Taylor, D. C., Falconer, M. A., Bruton, C. J. & Corsellis, J. A. Focal dysplasia of the cerebral

cortex in epilepsy. J. Neurol. Neurosurg. Psychiatry 34, 369 –387 (1971).2. Blümcke, I. et al . The clinicopathologic spectrum of focal cortical dysplasias: a consensus

classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission.Epilepsia 52, 158 –174 (2011).

3. Sisodiya, S. M., Fauser, S., Cross, J. H. & Thom, M. Focal cortical dysplasia type II: biologicalfeatures and clinical perspectives. Lancet Neurol. 8, 830 –843 (2009).

4. Chamberlain, W. A. et al . Interobserver and intraobserver reproducibility in focal corticaldysplasia (malformations of cortical development). Epilepsia 50, 2593 –2598 (2009).

5. Wieser, H. G. et al . ILAE Commission Report. Proposal for a new classification of outcome withrespect to epileptic seizures following epilepsy surgery. Epilepsia 42, 282 –286 (2001).

6. Palmini, A. et al . Terminology and classification of the cortical dysplasias. Neurology 62, S2 –S8(2004).

7. Lerner, J. T. et al . Assessment and surgical outcomes for mild type I and severe type II cortical

dysplasia: a critical review and the UCLA experience. Epilepsia 50, 1310 –1335 (2009).8. Tassi, L. et al . Type I focal cortical dysplasia: surgical outcome is related to histopathology.Epileptic Disord. 12, 181 –191 (2010).

9. Crino, P. B. Focal brain malformations: seizures, signaling, sequencing. Epilepsia 50 (Suppl. 9),3 –8 (2009).Sen, A., Thom, M., Nikolić, M. & Sisodiya, S. M. The potential role of cyclin-dependent kinase 5in focal cortical dysplasia. Dev. Neurosci. 30, 96 –104 (2008).

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References

Competing interestsThe author declares no competing interests.Nat Rev Neurol. 2011;7(3):129-130. © 2011 Nature Publishing Group

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