Multilobar unilateral hypoplasia with emphasis on the posterior quadrant and severe epilepsy in children with FCD ILAE Type 1A

Abstract

Objective: Focal cortical dysplasia (FCD) Type 1 and its three subtypes have yet not been fully characterized at the clinical, anatomopathological, and molecular level (International League Against Epilepsy [ILAE] FCD classification from 2011). We aimed to describe the clinical phenotype of patients with histopathologically confirmed FCD1A obtained from a single epilepsy center between 2002 and 2016. Methods: Medical records were retrieved from the hospital's archive. Results from electroencephalography (EEG) video recordings, neuroimaging, and histopathology were reevaluated. Magnetic resonance imaging (MRI) post-processing was retrospectively performed in nine patients. DNA methylation studies were carried out from archival surgical brain tissue in 11 patients.Results: Nineteen children with a histopathological diagnosis of FCD1A were included. The average onset of epilepsy was 0.9 years (range 0.2-10 years). All children had severe cognitive impairment and one third had mild motor deficits, yet fine finger movements were preserved in all patients. All patients had daily seizures, being drug resistant from disease onset. Interictal electroencephalography revealed bilateral multi-regional epileptiform discharges. Interictal status epilepticus was observed in 8 and countless subclinical seizures in 11 patients.Regional continuous irregular slow waves were of higher lateralizing and localizing yield than spikes. Posterior background rhythms were normal in 16 of 19 children. Neuroimaging showed unilateral multilobar hypoplasia and increased T2-FLAIR signals of the white matter in 18 of 19 patients. All children underwent tailored multilobar resections, with seizure freedom achieved in 47% (Engel class I). There was no case with frontal involvement without involvement of the posterior quadrant by MRI and histopathology. DNA methylation profiling distinguished FCD1A samples from all other epilepsy specimens and controls.

The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission

“…Excellent seizure outcomes were associated with surgical resections involving FCDII 5 . But nonfavorable outcomes have been reported following resections of FCDI 41 with the outcomes of FCDIII depending mainly on the principal lesion associated with FCD 46 …”

“…Nine genes have been reported to cause canonical FCDII: AKT3, DEPDC5, MTOR, NPRL2, NPRL3, PIK3CA, RHEB, TSC1, and TSC2 . SLC35A2 should be included in the panel in order to differentiate MOGHE 13,17,61 from its most common differential diagnosis: FCDIa 41 . The diagnostic yield using such gene panel sequencing from routine FFPE or frozen tissue ranges from 32% when assessing various epilepsy‐related lesions 13,60 to 45% in patients selected for MOGHE, 19 and 63% in patients with hemimegalencephaly or FCDII 60 .…”

“…14 Methodological approaches aside, due consideration of clinically significant thresholds for methylation is warranted. 3.1.7 | Challenges identified in the first ILAE classification scheme Whereas FCDIa is hitherto confirmed in a series of 19 children with early seizure onset, subtle unilateral hemispheric hypoplasia, global developmental delay, and drug resistance from seizure onset, 41 a consistent clinico-pathological characterization of the patient cohort with FCDIb and FCDIc is still lacking and convincing examples are scarce in the current literature. [36][37][38][39] In addition, Figure 2C from the original ILAE publication in 2011 showed loss of layer 4 neurons in a young boy with focal epilepsy as an example of FCDIb with horizontal dyslamination 10 ; however, upon review, this should be classified as FCDIIId, since there is evidence that loss of layer 4 neurons results from early (perinatal) hypoxicischemic injury in the occipital lobe, predominantly in boys (Figure 1H).…”

“…[36][37][38][39] In addition, Figure 2C from the original ILAE publication in 2011 showed loss of layer 4 neurons in a young boy with focal epilepsy as an example of FCDIb with horizontal dyslamination 10 ; however, upon review, this should be classified as FCDIIId, since there is evidence that loss of layer 4 neurons results from early (perinatal) hypoxicischemic injury in the occipital lobe, predominantly in boys (Figure 1H). 76 This kind of confusion raises the issue of whether cortical architectural abnormalities other than the bona fide dyslamination of FCDIa in patients with diffuse unilateral lesions mentioned above 41 truly represents "dysplastic" abnormalities or simply variable architectural changes. Furthermore, histopathology of FCDIc was never described before the ILAE classification in 2011, and it quickly developed into a "wastebasket" of cases clinically suspected as FCD with no or very subtle MRI findings.…”

“…5 DNA methylation array analysis from routine FFPE tissue may increase the diagnostic yield in the near future. 41 Building on the most recent scientific advances, the TF proposes to include lesions compromising the white matter as new F I G U R E 3 Histopathological hallmarks of FCDIa. An 18-year-old female patient.…”