Epileptic Encephalopathies: Etiologies and Mechanisms

1. Epileptic Encephalopathies: Etiologies and Mechanisms Kristen Park, MD Assistant Professor of Pediatrics and Neurology UCHSC

2. Outline • Overview • Etiology and Mechanisms

3. Definition • Age dependent syndrome • Unique types of frequent seizures • Abnormal interictal EEG • Heterogeneous causes • Pharmacoresistant • Frequently associated with developmental impairment and/or regression

4. Epileptic Encephalopathies

5. Etiology of Encephalopathy • Epilepsy/epileptogenesis • Interictal abnormalities • Underlying pathophysiology

6. Epilepsy/Epileptogenesis • Clinical evidence • Longitudinal study of Dravet patients did not correlate intellectual profile with seizure control • Early appearance of absence seizures associated with worst developmental outcome • 2 patients with truncation mutations followed and demonstrated progressive cognitive decline • Variable timing between onset of encephalopathy and seizures in different syndromes • Dravet, Doose vs Rett

7. Epilepsy/Epileptogenesis • Functional data • MRS in patients with cortical malformations showed abnormal NAA in the epileptogenic zone • Normal levels when seizures controlled • In patients with ongoing seizures, anatomically abnormal regions that were not epileptogenic showed normal NAA • Decrements shown in contralateral hippocampus and thalamus • Reversible after successful temporal lobectomy

8. Epilepsy/Epileptogenesis • Experimental evidence • Mirror foci • Kindling • Animal models • Cellular

9. Maturation of Excitatory and Inhibitory Neurotransmission • Extensive plasticity of neurotransmitter systems occurs during early postnatal development • This plasticity is activity-dependent and critically important for normal “critical periods” for learning that may be disrupted by early-life seizure activity From Rakhade and Jensen, 2009

10. Epileptogenesis: Synaptic Plasticity • Molecular • Increased Inhibitory Neurotransmission • Accelerated changes in chloride gradient • Increased postsynaptic GABAA receptor expression • Altered Excitatory Neurotransmission • Post-translational changes in GluR1 and GluR2 • Decreased dendritic spine density • Reduced AMPA and NMDA receptor expression

11. 1–6, 1–3, 1–3,, , , and  Inhibitory Neurotransmission • GABA is the main inhibitory transmitter in mature neurons • GABAA receptors mediate most fast-synaptic inhibition • Different subtypes confer distinct receptor function and pharmacology • Undergoes developmental changes including alteration of GABA reversal potential (EGABA) and changes in subunit expression • Enhancement of GABAA receptor function with benzodiazepines disrupts LTP and memory formation and diminishes anxiety and learned fear responses • GABAA receptor 1 subunit is a key regulator of “critical periods” for cortical plasticity 1. Del Cerro et al., 1992; Sarter et al., 1995; Seabrook et al., 1997. 2. Vicini and Ortinski, 2004; Corcoran et al., 2005. 3. Rudolph and Mohler, 2004. 4. Fagiolini et al., 2004. 5. Hsu et al., 2003.

12. Inhibitory Neurotransmission • Depolarizing GABA currents are critical for Ca++ dependent developmental processes including neuronal proliferation, migration, targeting & synaptogenesis • Early-life seizures accelerate the switch of EGABA from depolarizing to hyperpolarizing in hippocampal CA1 neurons and are associated with spatial learning deficits • GABAA receptor changes after prolonged early-life seizures • Total GABAA receptor and a-1 subunit expression is increased

13. Excitatory Neurotransmission • Extensive plasticity of excitatory neurotransmission occurs during normal postnatal development • This plasticity is activity-dependent and can be disrupted by early-life seizure activity • Excitatory signaling through both the AMPA and NMDA receptors are critical for different types of LTP and hippocampal learning • Mutant mice lacking subtypes of AMPA receptors (GluR1 or GluR2 subunits) or NMDA receptors have impaired learning and behavioral abnormalities. • Decreased AMPA Receptor GluR2 subunit expression has been shown after hypoxia-induced seizures, Lithium-Pilocarpine-induced seizures and febrile seizures at P10

14. Interictal Abnormalities

15. Interictal Abnormalities • Clinical evidence • Resections of focal cortical abnormalities in West syndrome can lead to resolution and improved development

16. Interictal Abnormalities • Functional data • EEG-fMRI studies in West syndrome • EEG in CSWS • fMRI studies in CSWS

17. Underlying Pathophysiology • Clinical evidence • Dravet • Milder phenotypes associated with missense mutations • More severe phenotype associated with pore mutations • KCNQ2E – pore domain vs BFNC scattered • Cognitive impairments often related to age at onset with infantile being more severe

18. Fragile X Syndrome • Caused by an expanded triplet repeat in the FMR1 gene that codes for the fragile X mental retardation protein (FMRP), an mRNA-binding protein that binds to and regulates 4% of brain mRNA, including many RNAs important for synaptic plasticity • FMRP regulates mRNA transport in dendrites and regulates local protein synthesis important for dendritic spine development, synaptic formation and plasticity. • In the absence of FMRP, excess and dysregulated mRNA translation leads to altered synaptic function and loss of protein synthesis-dependent plasticity • The hallmark of FXS pathology is the hyperabundance of dendritic spines with a long, thin, and otherwise immature morphology Comery et al., 1997; Penagarikano et al., 2007; Basel and Warren, 2008; Antar et al., 2004; Feng et al., 1997b; Laggerbauer et al., 2001; Li et al., 2001, Lu et al.,2004; Muddashetty et al., 2007; Zalfa et al., 2003; Gibson et al., 2008

19. Tuberous Sclerosis Complex • Results from mutations of Hamartin (TSC1) or Tuberin (TSC2), which inhibit the the mammalian target of rapamycin (mTOR) pathway and a cascade of other downstream kinases and translational factors that stimulate protein translation, cell growth and proliferation. • TSC mutations lead to hyper-activation of these signaling pathways resulting in increased cell growth, proliferation and abnormal gene expression. • Exact mechanisms of epilepsy and ASD in TSC not known, but alterations in trafficking of AMPARs, and in expression of glutamate and GABA-A receptors and decreases in the glutamate transporter GLT-1 may contribute White et al., 2001; Wong et al., 2003

20. Rett Syndrome • Caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene, a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing. • In resting neurons, MeCP2 regulates gene expression by binding to methylated CpG dinucleotides and recruiting HDAC complexes and chromatin remodeling proteins. This leads to chromatin compaction, making the promoter inaccessible to the transcriptional machinery. • Neuronal activity induces MeCP2 phosphorylation and leads to its release from the promoter region, dissociation of the corepressor complex, and transcription of target genes. • In Rett, the absence of MeCP2 causes a loss of activity dependent changes in gene expression that may disrupt synaptic plasticity From Charhour and Zoghbi, Neuron, 2007

21. Neuroligin/Neurexin Mutations • Neuroligins and neurexins are proteins crucial for aligning and activating both excitatory and inhibitory synapses during development. • Mutations in a number of these genes, and the associated Shank3 scaffolding protein, have been implicated in autism. • NRXN1 deletions have been identified in a family presenting with severe early onset epilepsy & profound developmental delay • An altered balance between excitatory synapses (left) and inhibitory (right) could affect learning and social behavior as well as contribute to epilepsy. From Garber, Science 2007

22. Interneuronopathies • TSC1 • Cortical dysplasia • PMG • CNTNAP2 • Experimental evidence • Critical role of interneurons • Complex networks coordinate higher functions; excitatory and inhibitory, variable firing patterns • Developmental abnormalities resulting in reduced numbers of cortical and hippocampal interneuron subtypes have been reported to cause severe early life epilepsies, ID and autism: • ARX • NPN2 • Lissencephaly (DCX) • SCN1A

23. Interneuronopathies • SCN1A • Selective knock-out in basal forebrain • Disruption of learning and memory without spontaneous seizures • Dysregulation of hippocampal oscillations • Spatial learning deficit

24. Conception Birth weeks 4 months years 4 8 12 16 20 24 28 32 2 5 18 60+ Neurulation Neurogenesis Max. growth Synaptogenesis Competitive elimination Migration from ventricular zone Programmed cell death Myelination Receptor and ion channel changes Dendritic and axonal arborization Genetic effects on Synaptic Plasticity Seizure effects on Synaptic Plasticity

25. Application • Characterize • Spectrum of clinical presentation • Functional measurements • EEG • Neuropsychologic profile • Correlate • Genotype and functional expression • Developmental and neuroanatomic factors

26. Conclusions