Epileptic Encephalopathy: NDC Executive Summary

1. Epileptic Encephalopathy: NDC Executive Summary Brandy Fureman, PhD NINDS/NIH October 7, 2015

2. Disclosures • Federal Government Employee: • I have no financial relationships relevant to this presentation • Typo in program: I’m not an MD!

3. Priorities in pediatric epilepsy research: Improving children’s futures today What’s wrong with my child? What’s happening in her brain? What’s the best treatment option? What can we hope for? From: Berg et al., Neurology. 2013 Sep 24;81(13):1166-75

4. Clinical AspectsWhat’s wrong? • Infantile Spasms: • Clusters of jerks over 10-20 min, most are mixed, may be subtle • Hypsarhythmia is characteristic* and may evolve; vEEG can be helpful to determine timelock to spasm • Etiology: Broad, cause may be symptomatic or unknown but most common are HIE and genetic (new genes identified). Etiology influences prognosis. • Frequent misdiagnosis; poor outcome related to delay in diagnosis • Prognosis: mortality 12%, spontaneous remission 30%, other seizure types 50-70% • 20-50% patients transition to LGS, intellectual disability in ~70-90% • Faster effective treatment = better prognosis? • Infantile Spasms Prospective Database enrolling patients across PERC consortium – beginning to develop data on outcomes*

5. Clinical AspectsWhat’s wrong? • Lennox-Gastaut Syndrome: • Diagnosis triad: multiple seizure types, cognitive impairment, abnormal EEG (not all display triad at same time point) • Typically diagnosed between 2-8 years (peak 3-5yo) • Elevated risk of mortality, SUDEP • The path to LGS – multiple etiologies, often begins with IS, clinical presentation can vary by etiology • Genetics – many genes, but 3 of every 4 involved in synaptic regulation • Evaluation-clinical assessments + investigation AND chromosome microarray*, NGS for EE gene panels, WES (enroll in Epilepsy Genetics Initiative*) • Research directions: Common neuronal network: significant brainstem and thalamus activation (DBS?) and pons involved in tonic seizures; secondary network disorder resulting from breakdown of normal network behavior • LGS Foundation supports families, education and research – look into enrolling into the Rare Epilepsy Network*

6. Clinical AspectsWhat’s wrong? • Electrographic Status Epilepticus during Sleep/Landau Kleffner Syndrome • EEG pattern, not a syndrome itself: are we treating epilepsy or seizures? • Continuum between BECTS, aBECTSand ESES/LKS • Presentation: Psychotic phase, with evolution of seizure types, sleep consolidation problems, network dysfunction and cognitive dysfunction • Treatment: Benzos, steriods, immunoglobulins, other • Multiple etiologies • Some question about immune-mediated etiology* – needs more research • Genetics: GRIN2A may be associated with epilepsy with language difficulties* – part of explanation is genetic, involving NMDA receptor • Emerging relationship between EEG activity, blood flow and sleep – glymphatic system to drive metabolic clearance, which may be disrupted in ESES/LKS • International study needed on ESES/LKS pathophysiology, therapy, etiology*

7. Clinical AspectsWhat’s wrong? • Autoimmune Encephalopathies: • Antibody mediated diseases –usually cause LOF and/or damage to cell, patients can improve with immunotherapies or plasma exchange • “grey matter” Ab diseases in children: seizures, cognitive dysfunction, new onset psychological problems • Anti-VGKCs: incidence in children not clear but Ab may be 2ndary biomarker of neuroinflammatory disease? • Anti-NMDA-R encephalitis: prodrome of fever + headache leading up to psychiatric features and seizures, movement disorders, autonomic dysfunction • GlyR Abs– rigidity, spasms, sweating, autonomic – some found in children, treatment responsive • GABAAR Abs – not often found routinely but have occurred • Quick and effective treatment is critical • How often are Ab found in typical epilepsy? 10% of pediatric patients with new onset seizures of unknown cause may benefit from Ab screening (cautious recommendation)

8. Neurobiology and Pathogenesis: What’s happening? • Vulnerability in the developing brain: EEs are more than seizures – comorbidities are equally difficult • Cognition and EE – Which is most important for encephalopathy, the etiology or the seizures? • In normal neonatal rats, 7-10 sz per day causes cognitive problems (but no cell loss), deficit in ability of place cells to fire in phase procession relationship to theta rhythm, and coherence between hipp and PFC. Find that some animals with early seizures fail to learn spatial task, while some do learn with additional training - due to adaptive strategies? • IIS – memory retrieval interrupted by IIS in hipp, and IIS in PFC may lead to inattention. Transitory cognitive impairment in TLE associated with spiking during acquisition task. These are single spikes – what happens in ESES??? • Dravet syndrome: can separate out seizures and cognitive dysfunction in a rat with local KO of NaV1.1 – alters theta in hippocampus – these rats don’t have seizures, but they have deficits in theta and don’t respond to novel object as normal. • Cause of EE may be a major determinant of cognitive outcome

9. Neurobiology and Pathogenesis: What’s happening? • Neuroinflammation • Microglia – the resident antigen presenting cells in the CNS, rapidly activated after injury, involved in synapse elimination • Postnatal development of microglia in hipp: peak of proliferation then decline and plateau (sensitive period?) • Priming effect of ELS: increase susceptibility to seizure-induced brain damage in adulthood (2-hit hypoth), which can be prevented by dexameth or minocycline post-treatment. • Enriched environment is anti-inflammatory: Environmental enrichment can normalize lowered seizure threshold after ELS, and also attenuates microglial activation after second hit. • Sz cause microglial activation and monocyte infiltration into brain – progressive cell death = progressive cognitive impairment? • Antigen presenting cells (not microglia) correlate with szfreq • LGS (with highest seizure counts) have infiltrating APCs at levels comparable to Rasmussen’s encephalitis. • Hypothesis: do drug-resistant epilepsies evolve into immune-mediated disease?*

10. Neurobiology and Pathogenesis: What’s happening? • Can neurobiology inform therapy? • Genetic, epigenetic, neuronal and non-neuronal mechanisms in EEs • Mechanistic clusters might enable precision medicine • How does a mutation in a single gene cause EE? • Neuronal dysfunction (large scale gene changes) • Genome and epigenome (environment/experience) influence phenome • eg insult creates metabolic imbalance, activates epigenomic processes which alters gene expression persistently • Dysfunction which leads to neuronal death • Circuit re-organization/dysfunction • Non-neuronal effects (inflammation, deficits in synaptic regulation and metabolic homeostasis) • Nodes for intervention: epigenetics, metabolism, inflammation – need to understand the relative contribution of each to the phenome to tailor therapy for individual patients.

11. Therapeutic Targets and Translational Opportunities: What’s the best treatment option? • Current: medically refractory, conventional AED therapy not helpful, goals to control seizures AND prevent loss of function • Infantile Spasms: hdACTH effective (low BBB penetration). Oral corticosteroids likely effective. Vigabatrin effective esp for TSC*. Dietary Tx not first-line. Surgery can lead to seizure freedom in appropriate cases. New ILAE recommendations for infantile seizures. Future research needed for optimal treatment of IS and long-term cognitive outcomes, need new animal models, new agents. • LGS: Drugs approved don’t achieve seizure freedom and don’t prevent long-term cognitive decline, don’t have comparative trial data. Little data on hormonal or immune therapies. Ketogenic diet has most success in LSG (~10% Sz free rate). Surgery can be effective, but no consensus on approach.* • ESES: Non-randomized series: Surgery, then steroids, then benzos, with classic AEDs were least effective for EEG and cognition. (European trial RESCUE ESES currently recruiting) • Autoimmune encephalopathies: no consensus guidelines, Sz treated with AEDs, immunotherapies most effective. Need RCTs to determine optimal therapy. Early effective treatment = better outcome – need RCTs and new agents

12. Therapeutic Targets and Translational Opportunities: What can we hope for? • Targeting mTORpathways • TSC is a model “mTOR-opathy” (genetic and acquired)– hyperactivation of mTOR pathway, but role in epileptogenesis is not clear. • IS occurs in 1/3 TSC patients, epilepsy in ~90%. Some patients diagnosed in utero/early infancy prior to seizures (prevention???) • Convergence: mTOR inhibitors (rapamycin, everolimus), animal models of TSC, read-outs of mTOR activity, targets for intervention (GluT expression) RCT recruiting now for drug resistant epilepsy patients. Future directions include prevention studies.

13. Therapeutic Targets and Translational Opportunities: What can we hope for? • Cannabinoids • Endocannabinoids are rapid regulators of neuronal activity via retrograde signaling to CB1 GPRC to influence subsequent neurotransmitter release from presynaptic cell (circuit level effects?*) • Preclinical support for CBD effects on seizures • Clinical evidence: “no reliable conclusions can be drawn at present” • Open label trial completed (51% had >50% reduction, 9% seizure free (better for Dravet), AEs included somnolence, diarrhea, fatigue, SAE included SE, potential interaction with Clobazam • RCT ongoing for Dravet syndrome and LGS* • CNS Toxicities: structural & functional changes in brain, frontal connectivity, smaller brain volumes in early users, learning and memory deficits in animal models and MS patients, possible sleep and psychiatric issues • Regulatory issues: CBD is Schedule I • State policies: not uniform, but 18 states specifically permit with additional state laws pending. • Federal policy: Aug 2013 memo from Dep Attorney General of DOJ • Legislative activity for rescheduling and improved access to artisanal products • Colorado experience: parental report of 33% of patients with >50% sz reduction; a predictor was move to Colorado from out-of-state • Future directions: Children’s Colorado Protocol* and RCTs

14. Therapeutic Targets and Translational Opportunities: What can we hope for? • Engineering stem cells • Neural (and glial) differentiation of human PSCs • Gene editing approaches allow isogenic controls and virtual patient lines • Multiple iPSC models of epilepsies exist (eg, SCN8A and PCDH19) to study EE and SUDEP • Therapeutics: drug screening for precision therapy, cerebral organoids, transplantation of stem cells for therapy on the horizon.

15. Thank you! • NDC PI & Course Directors • Bernard Maria, MD • Tallie Baram, MD, PhD • Shlomo Shinnar, MD • Speakers • Susan Koh, MD • James Wheless, MD • Edouard Hirsch, MD • Angela Vincent, PhD • Greg Holmes, MD • SookyongKoh, MD, PhD • Mike Wong, MD, PhD • Amy Brooks-Kayal, MD • Jack Parent, MD • NDC Coordinator • RashidaAlston

16. NINDS/AES Benchmarks for Epilepsy Research http://www.ninds.nih.gov/research/epilepsyweb/2014Bechmarks-Final-PDF.pdf • I. Understand the causes of the epilepsies and epilepsy-related conditions • II. Prevent epilepsy and its progression. • III. Improve treatment options for controlling seizures and epilepsy-related conditions without side effects. • IV. Limit or prevent adverse consequences of seizures and their treatment across the lifespan.