Selected Topics in the Neuropathology of Epilepsy

• Ty Abel M.D., Ph.D• October 9, 2013

Epilepsy

• "an episodic disorder of the nervous system arising from the excessively synchronous and sustained discharge of a group of nerve cells"

Hughlings Jackson, 1873

Epilepsy-Classification

• Primary: epilepsy that occurs in the absence of other syndromes or disorders. Presumed to have a genetic basis e.g., Benign Neonatal Familial Convulsions, Juvenile Myoclonic Epilepsy

• Secondary: a primary pathology exists independent from the epilepsy e.g., trauma, infection, neoplasm etc

Secondary Epilepsy

• Trauma• Vascular malformations• Cerebral malformations• Rasmussen's Syndrome• Mesial Temporal Sclerosis• Neoplasms

Epilepsy-General Concepts

• Cortical lesions (often temporal) more likely to produce seizures than deep-seated lesions

• If cause is neoplasm, most likely a well-differentiated one

• Radiographic features can aid in the differential diagnosis

• e.g., Focal vs Diffuse

Trauma

• Incidence of epilepsy > with penetrating injuries

• Incidence higher with injury to parietal, motor areas

• Disrupted function due to scar? Blood or blood products in neuropil?

Vascular Malformations

• Cavernous Angioma• Arterio-venous malformation• Sturge-Weber Syndrome

Cavernous Angioma

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Cavernous Angioma

Arteriovenous Malformation

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Arteriovenous Malformation

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Sturge-Weber Syndrome• Vascular malformations of the face, eye and brain• Proliferation of leptomeningeal vessels and

laminar cortical calcification• Associated with ipsilateral port-wine stain in

distribution of facial nerve, glaucoma, cerebral atrophy, mental retardation and seizures

• Considered a non-heriditary, developmental malformation cause by somatic mutation in the GNAQ gene.

Sturge-Weber Disease

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Sturge-Weber syndrome

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Cerebral Malformations

• Cortical Dysplasia• Hemimegalencephaly

Cortical Dysplasia

• Cause of chronic seizures in both children and adults

• Thickened cortex and blurred gray-white junction sometimes seen radiographically

• Microscopic: effacement of laminar cortical architecture with extremely large neurons, astrocytes and intermediate ballooned forms

Cortical Dysplasia

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Cortical Dysplasia

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Hemimegalencephaly

• Enlargement of one cerebral hemisphere associated with intractable seizures

• May lead to hemispherectomy• Pathologically, can be associated with diffuse

form of cortical dysplasia, gyral malformations and heterotopias

Hemimegalencephaly

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Hemimegalencephaly

Rasmussen's Syndrome

• Abrupt childhood onset of seizures with progressive unilateral neurological deficit

• Refractory to anticonvulsants• Etiology unknown-viral?, autoimmune?• Inflammatory process restricted to one hemisphere• Atrophy, leptomeningeal lymphocytes, perivascular

cuffing, microglial nodules, neuronophagia

Rasmussen's Syndrome

Rasmussen's Syndrome

Rasmussen's Syndrome

Rasmussen's Syndrome

Mesial Temporal Sclerosis

• Complex partial seizures• Cause or effect of seizures or both?• Association with prolonged initial seizure in

childhood or recurrent febrile convulsions• Loss of neurons in Ammon's horn, esp. CA1• Dentate granule cell dispersion• Chaslin's subpial gliosis

Chronic Temporal Lobe Epilepsy

Hippocampus

Normal Mesial Temporal Sclerosis

Hypothalamic Hamartoma

• Gelastic seizures• Precocious puberty• Other endocrine abnormality (e.g.,

acromegaly)

Hypothalamic Hamartoma

Hypothalamic Hamartoma

Neoplasms

• Pilocytic Astrocytoma• Pleomorphic Xanthroastrocytoma (PXA)• Ganglion Cell Tumors• Dysembryoplastic Neuroepithelial Tumor

Low-grade Neoplasms-Radiographic features

Ganglioglioma

Other features: superficial location, skull erosion and calcification

Pilocytic Astrocytoma

Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

Juvenile Pilocytic Astrocytoma• Most common childhood glioma• 10% of cerebral and 85% of cerebellar astrocytomas • Classic Radiologic Features• Classic Histology albeit diverse “looks”• Classic Association with NF1• New Association with alterations in BRAF

Peter Burger: Surgical Pathology of the Nervous System and its Coverings

EGF/PDGF

P P

GRB2 GEF

ras-GDP ras-GTPRaf

MEK 1/2

PP

Erk 1/2PP

EtsElk-1c-fosc/n-mycstat 1/3

cytoplasmnucleus

MEK 1/2

Erk 1/2

plasma membrane

GAP Neurofibromin

Pilocytic Astrocytoma and the Ras Pathway

RAF fusion protein results in constitutively active pathway in sporadic PA

Pilocytic Astrocytoma

Intra-operative Smear Preparation

Pilocytic Astrocytoma: H&E

PA: Rosenthal fibers and EGBs

GFAP MIB-1

Pilocytic Astrocytoma: Immunohistochemistry

Pilomyxoid Astrocytoma: Often no Telltale Radiographic Features

Pilomyxoid Astrocytoma

Pilomyxoid Astrocytoma

Pilomyxoid Astrocytoma

Pilomyxoid Astrocytoma

Neurofilament for Axons

GFAP

Neurofilament

MIB-1

Pilomyxoid: Summary

• No pathognomonic clinical or radiologic characteristics (age?)

• Perivascular tumor cells, myxoid change, cellular monomorphism

• Should be the predominant pattern• Propensity for recurrence, leptomeningeal

spread.

Pleomorphic Xanthroastrocytoma

Pleomorphic Xanthroastrocytoma

GFAP Immunohistochemistry

Gangliocytoma

Ganglioglioma

Ganglioglioma

Synaptophysin Immunohistochemistry

Dysembryoplastic Neuroepithelial Tumor

Dysembryoplastic Neuroepithelial Tumor

Dysembryoplastic Neuroepithelial Tumor

Alcian Blue Stain

H&E

Dysembryoplastic Neuroepithelial Tumor

Case study: 12-year-old female

• “Syncopal” episodes for last 9 months• Observed to have seizure in school• CT scan was obtained on the outside

– Outside CT shows heterogeneous, solid and cystic, left occipital lobe mass

• Patient underwent craniotomy on 11/15/2005

Neuro-imaging

Histopathology: H&E

Histopathology: H&E

Histopathology: H&E

NF

MIB-1

Chromogranin

MIB-1

GFAP

Diagnosis?

Ganglioglioma, WHO Grade I

Follow-up

• Resolution of seizures• Resolution of post-op surgical changes on

surveillance MRI• Last seen in clinic on 11/14/2012, without

deficits.

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