Epileptic Encephalopathies:
Etiologies and Mechanisms
Kristen Park, MD
Assistant Professor of Pediatrics
and Neurology
UCHSC
Outline
• Overview
• Etiology and Mechanisms
Definition
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Age dependent syndrome
Unique types of frequent seizures
Abnormal interictal EEG
Heterogeneous causes
Pharmacoresistant
Frequently associated with developmental
impairment and/or regression
Epileptic Encephalopathies
• Otahara Syndrome (EIEE)
• Tonic seizures
0 – 3m • Burst suppression EEG
• West Syndrome
• Epileptic spasms
4m – 2y • Hypsarrhythmia
1 – 8y
• Lennox-Gastaut Syndrome
• Multiple seizure types – tonic, atonic, convulsions, atypical absence
• Slow spike and wave (2Hz)
• Doose syndrome (Myoclonic Astatic Epilepsy)
• Continuous spike and wave during sleep
• Spike wave index of >85% in slow wave sleep
2 –10y
• Variable clinical presentation
Etiology of Encephalopathy
• Epilepsy/epileptogenesis
• Interictal abnormalities
• Underlying pathophysiology
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
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
Epilepsy/Epileptogenesis
• Experimental evidence
– Mirror foci
– Kindling
– Animal models
– Cellular
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 earlylife seizure activity
From Rakhade and Jensen, 2009
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
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
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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
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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.
16, 13, 13,
, , , n 
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 -1 subunit expression is
increased
Excitatory Neurotransmission
• Extensive plasticity of excitatory neurotransmission occurs during
normal postnatal development
• This plasticity is activity-dependent and can be disrupted by earlylife 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-Pilocarpineinduced seizures and febrile seizures at P10
Interictal Abnormalities
Interictal Abnormalities
• Clinical evidence
– Resections of focal cortical abnormalities in
West syndrome can lead to resolution and
improved development
Interictal Abnormalities
• Functional data
– EEG-fMRI studies in West syndrome
– EEG in CSWS
– fMRI studies in CSWS
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
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
Tuberous Sclerosis Complex
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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 hyperactivation 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
Rett Syndrome
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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
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
From Garber, Science 2007
•An altered balance between
excitatory synapses (left) and
inhibitory (right) could affect learning
and social behavior as well as
contribute to epilepsy.
Interneuronopathies
• 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:
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ARX
NPN2
Lissencephaly (DCX)
SCN1A
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TSC1
Cortical dysplasia
PMG
CNTNAP2
Interneuronopathies
• SCN1A
– Selective knock-out in basal forebrain
– Disruption of learning and memory without
spontaneous seizures
– Dysregulation of hippocampal oscillations
– Spatial learning deficit
Genetic effects on Synaptic Plasticity
Seizure effects on Synaptic Plasticity
Conception
Birth
weeks
4
Neurulation
8
12
16
Neurogenesis
20
24
28
32
4
months 2
years
5
18
60+
Max. growth
Synaptogenesis
Competitive elimination
Migration from ventricular zone
Programmed cell death
Myelination
Dendritic and axonal arborization
Receptor and ion channel changes
Application
• Characterize
– Spectrum of clinical presentation
– Functional measurements
• EEG
• Neuropsychologic profile
• Correlate
– Genotype and functional expression
– Developmental and neuroanatomic factors
Conclusions