Selected Topics in the Neuropathology of Epilepsy

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

24. Rasmussen's Syndrome

25. Rasmussen's Syndrome

26. 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 Normal Mesial Temporal Sclerosis

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

31. Hypothalamic Hamartoma

32. Hypothalamic Hamartoma

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

34. 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

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 plasma membrane P P GRB2 GEF Neurofibromin GAP ras-GTP ras-GDP Raf MEK 1/2 P MEK 1/2 P P Erk 1/2 Erk 1/2 P cytoplasm nucleus Ets Elk-1 c-fos c/n-myc stat 1/3 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. Pilocytic Astrocytoma: Immunohistochemistry GFAP MIB-1

41. Pilomyxoid Astrocytoma: Often no Telltale Radiographic Features

42. Pilomyxoid Astrocytoma

43. Pilomyxoid Astrocytoma

44. Pilomyxoid Astrocytoma

45. Pilomyxoid Astrocytoma Neurofilament Neurofilament for Axons MIB-1 GFAP

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. Pleomorphic Xanthroastrocytoma GFAP Immunohistochemistry

49. Gangliocytoma

50. Ganglioglioma