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
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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 welldifferentiated 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
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Pilocytic Astrocytoma
Pleomorphic Xanthroastrocytoma (PXA)
Ganglion Cell Tumors
Dysembryoplastic Neuroepithelial Tumor
Low-grade Neoplasms-Radiographic features
Ganglioglioma
Pilocytic Astrocytoma
Other features: superficial location, skull erosion and calcification
Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002
Juvenile Pilocytic Astrocytoma
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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
Pilocytic Astrocytoma and the Ras Pathway
EGF/PDGF
plasma membrane
P
P
GRB2 GEF
GAP
Neurofibromin
ras-GDP ras-GTP
Raf
MEK 1/2
P
P
MEK 1/2
Erk 1/2
Ets
Elk-1
c-fos
c/n-myc
stat 1/3
RAF fusion
protein results in
constitutively
active pathway
in sporadic PA
Erk 1/2
cytoplasm
nucleus
Pilocytic Astrocytoma
Intra-operative Smear Preparation
Pilocytic
Astrocytoma: H&E
PA: Rosenthal fibers
and EGBs
Pilocytic Astrocytoma:
Immunohistochemistry
GFAP
MIB-1
Pilomyxoid Astrocytoma: Often no Telltale
Radiographic Features
Pilomyxoid Astrocytoma
Pilomyxoid
Astrocytoma
Pilomyxoid Astrocytoma
Pilomyxoid Astrocytoma
Neurofilament
Neurofilament for Axons
MIB-1
GFAP
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
H&E
Alcian Blue Stain
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
GFAP
MIB-1
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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