The curse of in silico transformation from Palmini's into the ILAE classification system of focal cortical dysplasia: A critical comment


To the Editors:

In their article, Fauser et al. (2013) could detect neither clinical nor outcome differences when comparing patients with temporal lobe epilepsy (TLE) with patients with focal cortical dysplasia alone (FCD International League Against Epilepsy [ILAE] type I) or when associated with hippocampal sclerosis (HS; FCD ILAE type IIIa). One hundred patients with TLE and “histopathology” diagnosis of “focal cortical dysplasia” were retrieved from their hospital files. Histopathology diagnosis of FCD was classified originally according to Palmini et al. (2004) and transformed into the 2011 ILAE system (Blumcke et al., 2011). As an example, Palmini's FCD type 1a (20 cases) and type 1b (61 cases) were reclassified in silico and sine microscopium as ILAE type I (n = 31, with no imaging and/or histopathology evidence for HS), or ILAE type IIIa (n = 50, with imaging and/or histopathology evidence for HS). Only histories of febrile seizures were significantly more common in patients with ILAE FCD type IIIa compared to the cohort presenting with isolated ILAE FCD type I. Other clinical features did not allow any distinction between both FCD subtypes. Postsurgical seizure control was also not different between FCD ILAE type I versus type IIIa. Kaplan-Meier curves demonstrated >60% seizure control at 1-year follow-up and <50% long-term seizure freedom for both entities. In addition, they included a series of patients with FCD type II in their analysis. Microscopic parameters were identical between Palmini and ILAE classification systems for this diagnostic entity, and can be safely transformed. However, their analysis failed to statistically show significant long-term outcome differences compared to FCD types I and IIIa. These findings are interesting and partially also contradict previous results (Tassi et al., 2012), which urgently require more studies assessing the clinicopathologic relationship and predictive value of specific disease entities. However, such studies need also careful consideration of methodologic limitations to allow unambiguous interpretation of results. With this commentary, we would like to discuss the methodologic limitation of Fauser's study in transforming histopathologic disease classification systems from one into another without careful microscopical reevaluation (i.e., in silico or sine microscopium). Although this approach may be used already in some other epilepsy centers, it is not appropriate for research purposes. It is our expectation that future work and study design will benefit from the discussion stimulated by this commentary.

Palmini's classification system has been widely accepted in the international epileptology community. It was revisited by an ILAE Task Force in 2011, for the reason that some histopathology definitions of FCD subtypes were not proven reliable. As a prominent example, in an agreement study among nine North American neuropathologists, least agreement was achieved when judging Palmini FCD type Ib, reflecting the challenge to properly distinguish this subtype from normal cortical tissue (Chamberlain et al., 2009). It was the consensus of the ILAE Task Force to propose a classification system relying on careful histopathologic evaluation, giving at hand a microscopic description of histology features to better distinguish FCD subtypes. The ILAE classification system has been validated by a panel of 30 international neuropathologists with different access levels to epilepsy surgery material and achieved good interobserver and intraobserver agreement in the evaluation of the new FCD classification (Coras et al., 2012).

In Fauser's work, the majority of patients with TLE presented with Palmini type Ib, which were subsumed as ILAE type I when imaging (or histopathology) excluded the presence of hippocampal sclerosis. No further subclassification into FCD ILAE type Ia, Ib, or Ic was made, thus there was a failure to specify patterns of aberrant radial architecture (FCD type Ia), tangential architecture (FCD type Ib), or a combination of both histopathology patterns (FCD type Ic). Indeed, the ILAE classification requires such specific histopathologic criteria for the diagnosis of FCD subtypes, and this should be always accomplished for research purposes to allow reliable comparison of data from different epilepsy centers by using the same terminology and thereby most probably describing similar patient series (Blumcke & Spreafico, 2011). Instead, Palmini's FCD type has a vague definition as “architectural abnormality with giant or immature, but not dysmorphic neurons.” Such abnormalities can be also seen in other pathologic conditions and not always associated with FCD or any other epileptogenic brain lesion.

FCD associated with other principal brain lesions, that is, hippocampal sclerosis (FCD ILAE type IIIa), is specifically defined by the ILAE classification system and should refer to an architectural abnormality of supragranular layers 2 and 3, previously described as temporal lobe sclerosis in 10% of TLE patients with HS (Thom et al., 2009). Thom et al. also raised the discussion about this peculiar neuronal cell loss patterns representing an associated degenerative rather than independent dysplastic nature. This controversy remains to be clarified, as Tassi et al. (2010) did not observe any clinically significant differences when comparing TLE-HS patients with FCD or without FCD.

In conclusion, faint cellular abnormalities such as hypertrophic neurons in the cortical ribbon should be weighed with great caution and not regarded as unique or unmistaken criteria for FCD type I or III. Proper evaluation requires microscopic review of surgical specimens when used for scientific analysis of FCD or TLE patient cohorts. In silico transformation of Palmini's FCD subtypes into the ILAE classification scheme is not justified, with the exception of FCD type IIa or IIb, as the ILAE classification defines and requires more refined histopathologic criteria. Therefore, Fauser's data probably tells us that a patient series with humble histopathologic emphasis and expertise will not be helpful to better characterize the broad clinicopathologic spectrum of FCD.


The authors have no conflict of interest to declare. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.