A 34-year-old right-handed woman with a history of intractable epilepsy underwent a right frontal craniotomy for resection of a brain lesion.
She experienced her first seizure episode at age 23. Her seizures consisted of a fidgeting movement, speech interruption and feeling of anxiety, as well as occasional left head turn, or pacing in circles while she is standing. Interictal EEG displayed potential epileptogenic activity in the bifrontal regions (R>L), as well as infrequent right temporal activity. A brain MRI, as shown below, revealed a mildly abnormal contour in the anterior paramedian right frontal gyrus, with underlying T2 hyperintensity in the subcortical white matter, with no apparent mass effect.
The correct answer is ...
This lesion is caused by alterations of TSC1/TSC2 genes.
The correct diagnosis is focal cortical dysplasia, ILAE type IIb. H&E on representative sections shows portions of cerebral cortex and subcortical white matter with multifocal collections of balloon cells, which are alpha-beta crystallin immunoreactive. NeuN demonstrates focal disorganization of the laminar neuronal architecture of the background cerebral cortex, with a focal collection of dysmorphic neurons. GFAP highlights subpial and subcortical reactive gliosis. No evidence of an atypical infiltrating glial cell population is identified; IDH1 R132H immunohistochemistry is negative in tissue. These findings support the diagnosis.
Focal cortical dysplasia (FCD) is a malformation of cortical development, which can lead to interactable focal epilepsy.2 Characterized by specific cytological and architectural abnormalities, it usually involves a small portion of one gyrus (that may be enlarged).4 Histologically, cortical lamination and organization is disrupted (choice A). In the most recent classification by the International League Against Epilepsy (ILAE) there are three main types each with several subtypes introduced with revisions to the criteria.5
FCD types I and III are characterized by dyslamination and disrupted organization of tissue architecture, but with morphologically normal neurons and glial cells.5 FCD II is distinguished from FCD I and III by dysplastic, megalocytic neurons admixed with normal neurons. Subtype IIb is further characterized by the presence of balloon cells, which express both neuronal and glial protein transcription products; hence, are considered to be from a mixed lineage.2
Balloon cells can also be present in hemimegalencephaly (HME) (choice D) and tuberous sclerosis. In fact, microscopically, FCD II and HME are identical, with both showing similar dyslaminated cortex, abnormal glial cells, dysplastic neurons, and balloon cells mixed with normal glia and neurons.5 The main difference between FCD IIb and HME is the extent of the lesion. Being derived from an earlier developmental stage, HME tends to involve much larger areas up to a lobe or even entire hemisphere.6 Similar histopathological findings can be seen in the cortical tubers of tuberous sclerosis, however, it is distinguished from FCD and HME with dystrophic calcifications, and absence of the characteristic alterations of TSC1 (tuberin) and TSC2 (hamartin) (choice B).1 However, the pathogenesis of these three disorders similarly involves the activation of mammalian target of rapamycin (mTOR) signalling pathway3 and phosphorylation of tau; hence known collectively as infantile tauopathies (choice C).8
Amir Nazem, M.D., Ph.D.
Jorge Lopez-Trejo, M.D.
Senior Associate Consultant, Anatomic Pathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science