Focal cortical dysplasia (FCD) and long-term epilepsy-associated tumors (LEATs) — including dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma, pleomorphic xanthoastrocytoma (PXA), and others — together account for a substantial proportion of refractory focal epilepsy cases. They are often surgically curable. The foundational ILAE FCD classification was published in 2011, with a substantive 2022 ILAE update proposing a multilayered integration of histopathology, imaging, and genetics and adding new categories. Many LEATs share BRAF V600E mutations and respond to BRAF/MEK inhibitors, opening targeted therapy options. This page covers FCD and LEATs in detail.

Focal Cortical Dysplasia (FCD)

ILAE Classification (2011, updated 2022)

The 2011 ILAE classification (Blümcke et al., Epilepsia 2011) established the three-tiered FCD framework (Types I, II, III). The 2022 ILAE update (Najm et al., Epilepsia 2022) preserved this framework but added categories and emphasized multilayered integration:

  • Mild Malformation of Cortical Development (mMCD): subtle cortical disorganization not meeting full FCD criteria.
  • MOGHE (mild MCD with oligodendroglial hyperplasia in epilepsy): increased subcortical oligodendroglial cell density with heterotopic neurons; associated with frontal lobe epilepsy and often somatic SLC35A2 mutations.
  • “No definite FCD on histopathology”: a new category for surgical specimens where clinical and imaging features support FCD but histopathology is non-diagnostic — emphasizing that integrated diagnosis can outweigh isolated histology.
  • Multilayered framework: histopathology + MRI/imaging + genetics together generate the final classification, mirroring the WHO CNS5 integrated-diagnosis approach for tumors.

FCD Type I — Abnormal Cortical Lamination

  • Abnormal cortical architecture without dysmorphic neurons or balloon cells.
  • Type Ia: abnormal radial cortical lamination.
  • Type Ib: abnormal tangential cortical lamination.
  • Type Ic: abnormal radial AND tangential lamination.
  • Often subtle on imaging; may be missed.
  • Frequently in temporal lobe.

FCD Type II — Dysmorphic Neurons

  • Type IIa: dysmorphic neurons + abnormal lamination; NO balloon cells.
  • Type IIb: dysmorphic neurons + abnormal lamination + balloon cells.
  • Dysmorphic neurons: enlarged, abnormally oriented, with accumulated neurofilaments.
  • Balloon cells: large cells with eosinophilic cytoplasm, eccentric nuclei; similar to those in TSC tubers.
  • Frontal lobe and other extratemporal locations common.
  • Often refractory epilepsy.
  • Resection often curative.

FCD Type III — Associated with Other Pathology

  • Type IIIa: with hippocampal sclerosis.
  • Type IIIb: with epilepsy-associated tumor (LEAT).
  • Type IIIc: with vascular malformation.
  • Type IIId: with other lesion (acquired during early life — TBI, stroke, infection).

Molecular Genetics of FCD

  • FCD type II: somatic mosaic mutations in mTOR pathway genes — MTOR, AKT3, PIK3CA, TSC1, TSC2, DEPDC5.
  • Mutations occur in a subset of cells during cortical development.
  • Often not detectable in blood; require analysis of resected tissue.
  • Same pathway as TSC; explains histologic overlap with TSC tubers.
  • FCD type I genetics less well-defined.

Imaging

  • FCD IIb (most distinctive):
    • Cortical thickening.
    • T2/FLAIR hyperintensity.
    • Transmantle sign: T2/FLAIR hyperintense band from cortex to ventricle.
    • Blurring of gray-white junction.
  • FCD I and IIa: often subtle.
  • Multiplanar reconstruction and 7T MRI improve detection.
  • FDG-PET may show hypometabolism in lesion (despite being epileptogenic).

Treatment

  • Anti-epileptic drugs; often refractory.
  • Epilepsy surgery: resection of dysplastic cortex.
  • Outcomes depend on complete resection and FCD subtype (better for IIb than I or IIa).
  • mTOR inhibitors emerging as adjunctive therapy.
  • Laser interstitial thermal therapy (LITT) for selected lesions.

Long-Term Epilepsy-Associated Tumors (LEATs)

Dysembryoplastic Neuroepithelial Tumor (DNET)

  • Children, young adults.
  • Cortically based, temporal lobe predilection.
  • “Specific glioneuronal element”: multinodular pattern with bundles of axons traversing mucinous matrix, with floating neurons (mature neurons in mucinous pools).
  • Oligodendrocyte-like cells.
  • BRAF V600E mutations: common.
  • FGFR1 mutations: common.
  • Bubbly appearance on MRI.
  • CNS WHO grade 1.
  • Surgical resection often curative for epilepsy.

Ganglioglioma

  • Children, young adults.
  • Temporal lobe common.
  • Mixed neuronal + glial elements.
  • Dysplastic ganglion cells + astrocytic component.
  • EGBs (eosinophilic granular bodies) common.
  • BRAF V600E mutations: ~50%.
  • CNS WHO grade 1.
  • Surgical resection often curative.

Pleomorphic Xanthoastrocytoma (PXA)

Covered in circumscribed gliomas page. BRAF V600E in ~70%. Often presents with seizures.

Pilocytic Astrocytoma

Covered in circumscribed gliomas page. Can be epileptogenic if cortical.

Angiocentric Glioma

  • Children, young adults.
  • Cortical lesions.
  • MYB-QKI fusion.
  • Angiocentric growth around vessels.
  • CNS WHO grade 1.
  • Often presents with epilepsy; surgery curative.

PLNTY (Polymorphous Low-Grade Neuroepithelial Tumor of the Young)

  • Recently recognized entity.
  • Young patients; cortical location.
  • BRAF V600E or FGFR fusions.
  • Calcifications common.
  • Drug-resistant epilepsy.
  • Indolent; surgical resection curative.

Epilepsy Surgery for FCD and LEATs

Preoperative Evaluation

  • Detailed clinical history including semiology.
  • Video-EEG monitoring.
  • MRI (often dedicated epilepsy protocol).
  • FDG-PET; sometimes SPECT.
  • Magnetoencephalography (MEG) in select cases.
  • Functional MRI for eloquent cortex mapping.
  • Wada test for language lateralization (largely replaced by fMRI).
  • Intracranial electrodes if lesion-EEG mismatch.

Surgical Approaches

  • Lesionectomy with margin.
  • Lobectomy.
  • Multiple subpial transections for eloquent cortex involvement.
  • Hemispherectomy for catastrophic hemispheric epilepsies (e.g., Rasmussen).
  • Laser interstitial thermal therapy (LITT).

Outcomes

  • LEATs: 70-80% seizure-free with complete resection.
  • FCD IIb: 60-70% seizure-free.
  • FCD I: less favorable, often subtle and incompletely resected.

Targeted Therapies in Development

  • mTOR inhibitors for FCD II (somatic mTOR pathway mutations) and TSC tubers.
  • BRAF V600E inhibitors (dabrafenib + trametinib) for BRAF-mutant LEATs (PXA, ganglioglioma, etc.).
  • FGFR inhibitors for FGFR-mutant tumors.
  • Personalized epilepsy therapy based on tumor / dysplasia genetics emerging.

🔍 Did You Know?

The convergence of focal cortical dysplasia type II and tuberous sclerosis complex at the molecular level is one of the most elegant connections in neuropathology. Both conditions share the same histologic features: dysmorphic neurons, balloon cells, and disorganized cortical architecture. Both share the same underlying molecular mechanism: hyperactive mTOR signaling. The difference is that TSC has germline mutations in TSC1 or TSC2 (causing constitutive mTOR hyperactivity), while FCD type II has somatic mosaic mutations in MTOR, AKT3, PIK3CA, or other mTOR pathway genes (causing localized mTOR hyperactivity in a subset of cells during cortical development). Essentially, FCD IIb is “somatic mosaic TSC of one cortical region.” The clinical implication is direct: mTOR inhibitors (everolimus, sirolimus) — already used for TSC SEGAs and angiomyolipomas — are being investigated for FCD-related refractory epilepsy. Early trials suggest reduction in seizures. The recognition has also unified our understanding of related cortical malformations (hemimegalencephaly, dysembryoplastic neuroepithelial tumor) as part of an “mTORopathy” spectrum. The lesson generalizes: molecular pathology often reveals that apparently distinct conditions share underlying pathways, and recognition of shared pathways enables shared therapeutic strategies. The “mTOR” or “mTORopathy” spectrum exemplifies this beautifully — and the targeted therapies that have transformed TSC are likely to transform other mTOR-driven cortical disorders in the coming decade.

Pitfalls and Pearls

  • FCD type I: abnormal lamination; often subtle.
  • FCD type II: dysmorphic neurons + balloon cells (IIb); mTOR pathway somatic mosaic mutations.
  • FCD type III: with HS, LEAT, vascular malformation, or other.
  • Transmantle sign: cortex-to-ventricle T2/FLAIR hyperintensity; FCD IIb.
  • Balloon cells: FCD IIb (also in TSC tubers).
  • DNET: specific glioneuronal element + floating neurons; BRAF V600E common; CNS WHO grade 1.
  • Ganglioglioma: dysplastic ganglion cells + glial; BRAF V600E ~50%.
  • PXA: pleomorphic + xanthomatous; BRAF V600E ~70%; reticulin-rich.
  • Angiocentric glioma: MYB-QKI fusion; angiocentric pattern.
  • PLNTY: calcifications + BRAF or FGFR; refractory epilepsy.
  • BRAF V600E + MEK inhibitor combination: targeted therapy for BRAF V600E LEATs.
  • mTOR inhibitors: emerging for mTOR-pathway FCD and TSC.
  • Epilepsy surgery for LEATs and FCD: often curative.
  • LITT: less invasive option for selected lesions.
  • Complete resection: most important predictor of seizure freedom.

References

  1. Blümcke I, Thom M, Aronica E, 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. 2011;52(1):158-174.
  2. Najm IM, Coras R, Kobow K, et al. Reappraisal of the ILAE classification of focal cortical dysplasias by integration of histology, imaging, and genetics: ILAE 2022 update. Epilepsia. 2022;63(8):1899-1919.
  3. Lim JS, Kim WI, Kang HC, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015;21(4):395-400.
  4. Slegers RJ, Blumcke I. Low-grade developmental and epilepsy associated brain tumors. Acta Neuropathol Commun. 2020;8(1):27.
  5. Thom M, Blümcke I, Aronica E. Long-term epilepsy-associated tumors. Brain Pathol. 2012;22(3):350-379.
  6. Engel J Jr. Surgical treatment for epilepsy: too little, too late? JAMA. 2008;300(21):2548-2550.
  7. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7):733-745.