1. Selected Topics in the Neuropathology of Epilepsy Ty Abel M.D., Ph.D October 9, 2013

2. 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

3. 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

4. Secondary Epilepsy Trauma Vascular malformations Cerebral malformations Rasmussen's Syndrome Mesial Temporal Sclerosis Neoplasms

5. 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

6. 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?

7. Vascular Malformations Cavernous Angioma Arterio-venous malformation Sturge-Weber Syndrome

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

9. Cavernous Angioma

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

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

12. 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.

13. Sturge-Weber Disease Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

14. Sturge-Weber syndrome Burger et al., Surgical Pathology of the Nervous System and its Coverings, 4th Ed, 2002

15. Cerebral Malformations Cortical Dysplasia Hemimegalencephaly

16. 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

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

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

19. 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

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

21. Hemimegalencephaly

22. 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

23. Rasmussen's Syndrome

27. 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

28. Chronic Temporal Lobe Epilepsy

29. Hippocampus NormalMesial Temporal Sclerosis

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

31. Hypothalamic Hamartoma

33. Neoplasms Pilocytic Astrocytoma Pleomorphic Xanthroastrocytoma (PXA) Ganglion Cell Tumors Dysembryoplastic Neuroepithelial Tumor

34. 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

35. 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

36. 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

37. Pilocytic Astrocytoma Intra-operative Smear Preparation

38. Pilocytic Astrocytoma: H&E

39. PA: Rosenthal fibers and EGBs

40. GFAPMIB-1 Pilocytic Astrocytoma: Immunohistochemistry

41. Pilomyxoid Astrocytoma: Often no Telltale Radiographic Features

42. Pilomyxoid Astrocytoma

45. Neurofilament for Axons GFAP Neurofilament MIB-1

46. 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.

47. Pleomorphic Xanthroastrocytoma

48. GFAP Immunohistochemistry

49. Gangliocytoma

50. Ganglioglioma

51. Synaptophysin Immunohistochemistry

52. Dysembryoplastic Neuroepithelial Tumor

54. Alcian Blue Stain H&E

55. Dysembryoplastic Neuroepithelial Tumor

56. 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

57. Neuro-imaging

58. Histopathology: H&E

61. NF MIB-1

62. Chromogranin MIB-1 GFAP

63. Diagnosis? Ganglioglioma, WHO Grade I

64. 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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