This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 7-month-old boy presented with a history of seizure. The day of presentation the infant’s mother reported an episode of shaking and stiffness for 40 seconds, followed by another similar episode 20 minutes later. There was no concurrent fever or other sign of illness. He subsequently began to seize with left upward gaze and generalized stiffening. Lorazepam was administered after transport to the hospital, and seizure activity eventually resolved. CT of the head was negative. Electroencephalogram (EEG) demonstrated slowing and attenuation in the right frontal and temporal lobes as well as bursts of arrhythmic bifrontal delta slowing. MRI revealed a mildly-expansile, nonenhancing, T2-hyperintense lesion centered in the left parahippocampal gyrus. A subcortical cystic component was noted in the inferior uncus, abutting or communicating with the temporal horn of the lateral ventricle. MR spectroscopy was performed and showed a profile considered suggestive of low-grade glioma. He underwent mesial left temporal lobe resection.
Brain, left temporal lobe
Whole Slide Image
The whole slide image provided is an H&E-stained slide of the cortex from the temporal lobe resection.
What is the best diagnosis?
Focal cortical dysplasia, ILAE type IIa
Focal cortical dysplasia, ILAE type IIb
Focal cortical dysplasia, ILAE type III
Ganglioglioma, WHO grade I
Normal cortex with reactive changes
Which of the following features distinguishes focal cortical dysplasia type IIa from type IIb?
Absence of balloon (giant) cells
Absence of dysmorphic neurons
Clinical history of focal epilepsy
Presence of concomitant hippocampal sclerosis
The microscopic appearance of focal cortical dysplasia type IIb can be similar or identical to which of the following syndrome-associated lesions?
Cortical tuber (tuberous sclerosis)
Dysplastic gangliocytoma (Cowden disease)
Hemangioblastoma (von Hippel-Lindau disease)
Optic pathway glioma (neurofibromatosis type 1)
Pleomorphic xanthoastrocytoma (mismatch repair syndrome)
Discussion and Diagnosis
The final diagnosis in this case was focal cortical dysplasia, a malformation of cortical development that, in this case, involved the temporal lobe. Patients with seizures and focal MRI findings often raise a differential diagnosis including low-grade gliomas and cortical dysplasias. The low-grade gliomas commonly cited in this scenario are dysembryoplastic neuroepithelial tumor (DNT), ganglioglioma, and diffuse astrocytoma or oligodendroglioma. MRI characteristics for this differential diagnosis may include increased T2/FLAIR signal of the involved parenchyma as well as mild volumetric expansion. The white matter may show T2 signal hyperintensity in the adjacent area. There is generally no enhancement after contrast administration.
The extensive gliosis and tissue shrinkage in this case may have created the cystic component which initially raised suspicion for a neoplasm being the favored diagnosis. Tumors with intracortical extension and slow growth rate can present with seizures and be difficult to clinically distinguish from dysplasia. Marked cortical expansion or intralesional calcifications are more suggestive of a neoplastic process. In this case, the mimicry of a neoplasm was supported by misleading MR spectroscopy results. The correct diagnosis was established after histopathologic review revealed extensive cortical dyslamination (Image B), neuronal dysmorphism (Image C and Image D), and no evidence of a neoplastic cell population. After surgical resection, the patient experienced no seizures in two years of available follow-up. His EEG findings postoperatively were normal.
Focal cortical dysplasia (FCD) is a presumed developmental malformation of the cortical plate resulting in focally abnormal cytoarchitecture. The resulting lesion is often associated with partial epilepsy which is, in many cases, not controllable with medication. FCD includes a spectrum of histologic findings, most recently classified into three tiers by the International League Against Epilepsy (ILAE). FCD type I shows abnormal radial and/or tangential lamination, FCD type II has cytologic abnormalities of the neurons (“dysmorphic neurons”), and FCD type III occurs in association with an adjacent distinct lesion (eg, hippocampal sclerosis, vascular malformation, or tumor). The type II category is further divided into types IIa and IIb. FCD type IIa lesions are characterized by disrupted lamination accompanied by dysmorphic neurons, as was seen in this case. FCD type IIb has both of these features and an additional population of “balloon cells,” enlarged cells with abundant glassy cytoplasm and vesicular nuclei, often found in clusters.
Dysmorphic neurons are often enlarged (up to twice normal soma size) and accumulate neurofilament proteins within their cell bodies. IHC stains for neurofilament proteins, NeuN, or microtubule-associated protein 2 (MAP2), as shown in the case above, should highlight the abnormal shape, size, and orientation of dysmorphic neurons. These neurons often display aberrant polarity and tortuous thick dendrites (Image D) and may be seen trailing through the underlying white matter. Identification of dysmorphic neurons and their underlying disrupted lamination can be enhanced by IHC stains such as MAP2 (compare Image D to Image E which shows a fragment of normal cortex). FCD type IIb may be accompanied by dysmyelination which is well demonstrated by Luxol fast blue staining and can often be detected by MRI. The microscopic appearance of FCD type IIb overlaps with that of the cortical tuber characteristic of tuberous sclerosis. A patient newly presenting with FCD type IIb who is found to have subependymal nodules or additional cortical lesions on MRI should prompt clinical consideration of tuberous sclerosis.
Reactive changes in epileptic cortex may include astrogliosis, particularly of the subpial region, and mild inflammation. The placement of grids or strips of electrodes for seizure characterization via intracranial EEG prior to epilepsy surgery may also create iatrogenic lesions. These include meningeal or parenchymal inflammation as well as acute/subacute infarcts marked by aggregates of macrophages. The neuropathologist should be aware of any history of invasive monitoring to avoid mistaking these lesions as evidence of vascular or inflammatory disease. After surgery, many FCD patients experience freedom from seizures, and recent evidence suggests they may show improvements in cognitive function as well.
Take Home Points
- FCD shares some imaging characteristics with low-grade glioma including focal T2/FLAIR signal abnormalities and mild volumetric expansion.
- FCD is a cause of focal epilepsy and has been categorized by the ILAE into three main types (I, II, and III).
- FCD type IIa is characterized by dysmorphic neurons and cortical dyslamination.
- FCD type IIb is characterized by dysmorphic neurons, cortical dyslamination, and balloon cells.
- The microscopic appearance of cortical tubers in the setting of tuberous sclerosis overlaps with that of FCD type IIb, and clinical correlation is critical.
- 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;52:158-74.
- Blümcke I, Spreafico R, Haaker G, et al. Histopathological findings in brain tissue obtained from epilepsy surgery. N Engl J Med. 2017;377:1648-56.
- Fong JS, Alexopoulos AV, Bingaman WE, Gonzalez-Martinez J, Prayson RA. Pathologic findings associated with invasive EEG monitoring for medically intractable epilepsy. Am J Clin Pathol. 2012;138(4):506-10.
- Veersema TJ, van Schooneveld MMJ, Ferrier CH, et al. Cognitive functioning after epilepsy surgery in children with mild malformation of cortical development and focal cortical dysplasia. Epilepsy Behav. 2019;94:209-15.
- What is the best diagnosis?
- A. Focal cortical dysplasia, ILAE type IIa
- B. Focal cortical dysplasia, ILAE type IIb
- C. Focal cortical dysplasia, ILAE type III
- D. Ganglioglioma, WHO grade I
- E. Normal cortex with reactive changes
- Which of the following features distinguishes focal cortical dysplasia type IIa from type IIb?
- A. Absence of balloon (giant) cells
- B. Absence of dysmorphic neurons
- C. Clinical history of focal epilepsy
- D. Multifocality
- E. Presence of concomitant hippocampal sclerosis
- The microscopic appearance of focal cortical dysplasia type IIb can be similar or identical to which of the following syndrome-associated lesions?
- A. Cortical tuber (tuberous sclerosis)
- B. Dysplastic gangliocytoma (Cowden disease)
- C. Hemangioblastoma (von Hippel-Lindau disease)
- D. Optic pathway glioma (neurofibromatosis type 1)
- E. Pleomorphic xanthoastrocytoma (mismatch repair syndrome)