Bioenergetics in Human Epilepsy: Relevance for Etiology, Mechanisms, and Management

Frank Gilliam, MD, MPH Professor of Neurology University of Kentucky

Disclosure

• None

Path to Bioenergetics in Epilepsy

• Genomics of Human Epilepsy Surgery Tissue • Preliminary Findings in Cortical Dysplasias • Intracellular Bioenergitics and Hyerexcitability • Search for Pharmacological Treatment • Possible Role for Metformin

1997: 3750 Subjects 3000 Controls

Nucleic Acids Research 43: 893-899, 2015

Nucleic Acids Research 43: 893-899, 2015

PSU Epilepsy Surgery Tissue Bank

T1

FLAIR

FDG-PET

Interictal EEG

Ictal EEG

Epilepsia 53: 1481–1488, 2012

PLoS 2007

“Finally, two genes are unique to HHV-6 … U83 encodes a chemokine with chemotactic activity for monocytic cells, and is expressed in two forms. The spliced variant is expressed as an early protein, before DNA replication, and the full length protein is expressed only after DNA replication (Dewin et al., 2006).”

Journal of Neuroimmunology 224, 22–27, 2010

Epilepsia, 51:2478–2483, 2010

Focal Cortical Dysplasia with Migrational Abnormality

Dysmorphic neurons Neurofilament immunohistochemistry highlighting disorganization

• HPV 16 E6 robustly expressed in 50 epilepsy brains with balloon cells.

• Not expressed in 20 normal control samples

Ann Neurol. 72:881-92, 2012.

22

Gilliam F. Epilepsy Curr. 14:259-60, 2014

ANN NEUROL 2015;78:375–386

2015 Apr;21(4):395-400

Tuberous Sclerosis Complex

Cruratolo et al 2002

371:733-43, 2014

RO RPC LPC

LMC

LH RH

ANN NEUROL 2015;78:375–386

2015 Apr;21(4):395-400

Mammalian target of rapamycin (mTOR) pathways in neurological diseases

Wong, M. Biomed. J. 36:40-50, 2013

Posterior Band Heterotopia/ Double Cortex Syndrome (PAFAH1B1)

Neuropace RNS Effect after Optimal Programming: Double Cortex Syndrome

Typical Electrographic seizure now: No clinical effect

Typical initial seizure prior to RNS optimization: Staring and decrease responsiveness

Seizure Onset in Right Mesial Temporal Region