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

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 NormalMesial Temporal Sclerosis

Hypothalamic Hamartoma Gelastic seizures Precocious puberty Other endocrine abnormality (e.g., acromegaly)

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-GTP Raf MEK 1/2 P P Erk 1/2 P P Ets Elk-1 c-fos c/n-myc stat 1/3 cytoplasm nucleus 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

GFAPMIB-1 Pilocytic Astrocytoma: Immunohistochemistry

Pilomyxoid Astrocytoma: Often no Telltale Radiographic Features

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

GFAP Immunohistochemistry

Gangliocytoma

Ganglioglioma

Synaptophysin Immunohistochemistry

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

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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