Abstracts

Rationale: Focal cortical dysplasia (FCD) is a common cause of treatment-resistant epilepsy in children. Improved outcome is associated with complete resection of FCD in epileptogenic tissue. The mammalian target of rapamycin (mTOR) pathway appears to be up-regulated in FCD type IIb, hemimegalencephaly, and gangliogliomas. However, detailed investigations of mTOR in children with FCD are very limited. The aims of this study are: 1) to identify the pathological features of FCD in tissue resected during epilepsy surgery, and 2) to define clinical and pathological characteristics which predict improved surgical outcome. Methods: IRB approval was obtained. Inclusion criteria were: 1) age <21 y; 2) medically-refractory epilepsy determined by pediatric neurologists; 3) epilepsy surgery at CCHMC between Sep. 2007-Sep. 2011; 4) no known lesions (e.g. tumor, vascular malformation, hemimegalencephaly, or Rasmussen's encephalitis) other than cortical anomalies and mesial hippocampal sclerosis; and 5) at least one follow-up visit not <6 months postsurgery. Pathological evaluations included FCD classification (based on Palmini's criteria), H&E, mTOR, and Neu-N slides. Cortical gliosis, determined by glial fibrillary acidic protein (GFAP) stain, was reported as: superficial (sGFAP) (involving only subpial and first layer); diffuse mild (mGFAP) (sGFAP plus minimal involvement of other layers); or diffuse (dGFAP) involving all 6 layers. One high power field (hpf) at x40 with the highest number of mTOR positive neurons (mTOR_tot) was identified and counted. Logistic regression with backward elimination on seizure-free outcome, included GFAP group, cortical MRI abnormality, age at epilepsy onset, age at surgery, and mTOR_tot/hpf. Results: Fifty-one patients (median age at surgery 10.6, range 0.5-20.3y) met the inclusion criteria. Four, 13, 27 and 7 patients had FCD Ia, Ib, IIa, and IIb, respectively. Cortical gliosis was seen in all patients, including 13 sGFAP, 5 mGFAP and 33 dGFAP. The mTOR_tot ranged from 0-25/hpf, including 17 who had no mTOR positive neurons. Clinical, neurological, and neuroimaging characteristics were similar in FCD I (Ia+Ib) and FCD II (IIa+IIb) groups, but dGFAP and mTOR_tot were significantly increased in FCD II (P≤0.001). The univariate model with seizure free outcome vs. mTOR_tot was significant (Table). Logistic regression with backward elimination resulted in retaining two variables, mTOR_tot and age at surgery (Table). Because of improved goodness-of-fit, the final model included mTOR_tot and "mTOR_tot*age at surgery", but not the first-order term "age at surgery". Higher mTOR_tot improves the probability of a seizure-free outcome in younger patients (Figure). Conclusions: Younger patients with high mTOR_tot have increased probability of seizure-free surgical outcome than older individuals with low mTOR_tot. Quantitation of mTOR positive neurons in relation to age at surgery may predict seizure-free outcome for patients with FCD. Also activation of the mTOR pathway may be an important factor in epileptogenesis associated with FCD.