Download Epilepsy and Seizure Disorders

EPILEPSY AND SEIZURE
DISORDERS
PYSC 4080
By: Misha Nili
Contents
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Definitions
History
Seizure Stages
Classification
Mechanisms of Action
Neurotransmission
Genetics
Neuroanatomy
Neurodevelopment
Treatments
Cuttlefish
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https://www.youtube.com/watch?v=l1T4ZgkCuiM
Action Potentials & Epilepsy
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https://www.youtube.com/watch?v=MtJyHp_AZL8
Definitions
Seizure: A sudden episode of abnormal electrical
activity in the brain characterized by excessive
excitation and synchronization of neurons.
In other words...
Definitions
Epilepsy: A chronic neurological syndrome
characterized by at least two recurrent seizures that
occur without evident cause.
Important to note:
 Seizures that occur with apparent cause are not
labelled as epilepsy
 Seizures are the manifestations/symptoms of
epilepsy
Historical Overview
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Described in historical texts as a spiritual condition
In Babylonian texts – described as possession by
evil or angered spirits, treated with an exorcism
Greek mythology – the Sacred Disease
 Associated
with moon spirits
 Important figures like Hercules and Julius Caesar
described to be afflicted
Historical Overview
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Hippocrates first to associate it as a treatable
problem with the brain
Termed the word ‘grand mal’ or the Great Disease
Epidemiology
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Prevalence:
 Affects
0.6% of Canadians
 About 15,500 new cases every year
 1% of people worldwide =60 000 000!
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Age of onset:
 Often
occurs in childhood, but can develop at any point
in life
 30% of new cases begin in early childhood and
adolescence
 High prevalence in those aged 65+
Epidemiology –Age of Onset
Causes – A mystery to
neuropsychology!
Causes
Head trauma
 Brain malformations
 Lack of oxygen during birth
 Maternal drug use
 Brain tumors
 Congenital conditions (Down's syndrome, Autism spectrum)
 Genetic factors
 Drug use/substance abuse
 Kidney and liver defects
 Stroke
 Alzheimer's disease
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Stages of a seizure
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Typically, there are 3 stages:
 Preictal/prodromal
 Ictal
 postictal
Preictal/prodromal stage
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Auras
 Perceived
smells, sights, tastes
 Forced thinking
 Physical sensations – nausea, headaches, dizziness
 Unusual feelings
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Can happen minutes, hours, or even days before a
seizure
Can serve as warning sign
EEG readings show general decreased brain
activity
Ictal Stage
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The seizure itself – what others observe
Can be convulsive or non-convulsive
May include a temporary loss of consciousness
Post-ictal stage
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Body relaxes, after-effects
Loss of consciousness may persist
May also include:
 Numbness
 Headaches
 Fatigue
 Confusion
 Partial
paralysis
 Biting of the tongue
 Loss of bladder and bowel control
EEG
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Common way to study and diagnose epilepsy
Records electrical activity of cortical neurons by
measuring voltage fluctuations caused by ionic
currents
EEG – Non-epileptic patient
EEG – Patient undergoing a seizure
Classification by seizure type
Focal vs. Generalised – Stadium
Analogy
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Chattering
Chanting
Cheering
Sweeping Lady example
Clonic Seizures
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Repetitive and rhythmic jerking of muscle groups
No loss of consciousness
Can go straight back to activities after seizure
Classification by syndromes
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Classified based on common features, onset time, and
EEG findings
Less severe:
Benign rolandic epilepsy
 Childhood absence epilepsy
 Juvenile myoclonic epilepsy
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More severe, episodes may cause diffuse brain
dysfunction and are resistant to treatment:
Lennox-Gastaut syndrome
 West Syndrome
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Impact of Epilepsy
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Effects different for partial and generalised
seizures
Generalised – affect various functions
simultaneously
Partial seizures – vary with which part of the brain
the are initiated in
 Hippocampus
– memory
 Broca’s area, Wernicke’s area - language
 Outgoing
 Frontal
and incoming words
lobe – executive functions, planning
Mechanisms of Action
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Causes are more often unknown!
Something that triggers:
 Increased
capacity for excitation
 Decreased capacity for inhibition
Mechanisms of Action
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Initiation of a seizure:
 1)
high-frequency bursts of action potentials
 2) hypersynchronization of a neuronal population
At the single neuron level - Action
Potentials
Mechanisms of Action
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Bursts of action potentials become a paroxymal
depolarizing shift
 Has
a plateau-like depolarization
 Rapid repolarization, hyperpolarization follows
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Initiated by a Ca2+ depolarization, which leads to
the opening of Na+ channels
Hyperpolarization modulated by K+ channels and
Cl- influx (mediated by GABA)
Mechanisms of Action
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Kindling hypothesis of epileptogenesis
 “Seizures
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beget seizures”
Study with animal models – evoked repeated
seizures with low-intensity stimuli in the hippocampus
 Symptoms
intensified – freezing to convulsions
Mechanisms of Action
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Seizure propagates, recruits surrounding neurons via
local connections
Partial seizures spread into the other hemisphere via
the corpus callosum
Increase in extracellular K+ and accumulation of Ca2+ in
presynaptic terminals also causes recruitment of more
neurons
 Type, number and distribution of voltage- and ligand-gated
channels
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Channels determine the direction, degree, and rate of changes
that allow for the generation of APs
Mechanisms of Action
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Not understood how seizures end, typically under 2
minutes
Neurotransmission -Glutamate
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Major excitatory amino acid neurotransmitter
Receptors found on both principal and inhibitory
interneurons
 Ionotropic
 Metabotropic
Neurotransmission - Glutamate
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Ionotropic receptors
 Three
subtypes – AMPA, kainate, NMDA
 All allow for fast transmission by allowing ion influx
upon activation by glutamate
 Specifically
inflow of Na+, outflow of K+
 NMDA becomes permeable to Ca2+ during depolarization
Neurotransmission - Glutamate
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Interesting study involving rats:
 Agonists
 Induce
of ionotropic receptors
seizure activity
 Antagonists
 Suppresses
of ionotropic receptors
seizure activity
Neurotransmission - Glutamate
 Metabotropic
receptors
 Slow transmission - G-protein coupled
signalling pathways
Neurotransmission - GABA
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Major inhibitory neurotransmitter
Two receptor types:
 GABA
A
 Post-synaptic
 Permeable
to Cl- ions, which induces hyperpolarization, thus
inhibiting APs
 Study found that agonists, like barbiturates and
benzodiazepines, can suppress seizure activity
Neurotransmission - GABA
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Second receptor type:
 GABA
B
 Pre-synaptic,
therefore, modulate synaptic release
 Associated K+ channels
 K+ currents lead to hyperpolarization and the inhibition of
APs
 Agonists like baclofen suppress seizures
Factors Affect Excitability
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Biochemical modification
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Phosphorylation of glutamate receptors like NMDA may lead to
increased permeability to Ca2+, thus greater excitability
Modulating gene expression, as by RNA editing
 Change
the ion specificity of glutamate receptors
General Factors Affect Excitability
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Changes in circuitry
 Sprouting
of excitatory neurons
 Loss of inhibitory neurons
 Loss of excitatory neurons that “activate” inhibitory
neurons
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Shortening of axons leads to more effective
coupling of synaptic contacts
Changes in gap junction synaptic function
Genetics
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Mutations in expression of voltage-gated and ion
channels
Na+ channels:
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Cl- channels:
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SCN1A, SCN1B , SCN2A1
CLCN2A
GABA receptors:
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GABRG2 (GABA-receptor gamma-2 subunit)
GABRA1 (GABA-receptor alpha-1 subunit)
Genetics
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Twin studies
Study with 199 twins
Concordance rates were 4 times higher in MZ twins
than DZ twins
20% of affected twin pairs had an epileptic firstdegree relative
Concordance high for generalized epilepsies
compared to partial/focal epilepsies
Neuroanatomy-Hippocampus
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Focus of epileptic seizures
Hippocampal sclerosis – seen with temporal lobe
epilepsy
Not known whether epilepsy is caused by
hippocampal abnormalities or whether the
hippocampus is damaged by the effects of
repetitive seizures
Neuroanatomy-Hippocampus
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Why the hippocampus?
 Considered
one of the most excitable parts of the brain
 Limbic system
 One of the very few brain regions that is capable of
constant generation of new neurons
Neuroanatomy-Thalamus
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Childhood absence epilepsy
GABAergic neurons of the thalamic reticular nucleus
in the thalamocortical loop involved in producing
bilateral spike and wave discharge loop,
characteristic of this form of epilepsy
Neuroanatomy - Thalamus
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Increased activity of GABA A receptor – therefore
excessively pruned
 Decreased
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inhibition
Increased expression of Ca2+ channels in the
region
Neurodevelopment
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Defects in cell proliferation in the germinal zone
Impaired neuronal migration and differentiation can
lead to malformation of important cortical areas
 Some
conditions include focal cortical dysplasia,
lissencephaly, heterotopia, and polymicrogyria
Neurodevelopment
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Delayed or inadequate integration of inhibitory
neurons in neuronal circuits
GABAergic neurons do not migrate sufficiently to
cortical centres, leading to imbalance of
excitatory/inhibitory conditions
Defects in pruning and remodeling during early
critical periods can trigger hyperexcitability
Pilocarpine Model of Temporal Lobe
Epilepsy
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Pilocarpine – muscarinic agonist
Rats repeated injected with this
Represents human epileptic condition for complex
partial seizures
Induces 3 states:
 Acute
period that builds up to limbic status epilepticus
 Latent period – normalization of behaviour
 Chronic period with spontaneous recurrent seizures
Treatment - Surgical
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Temporal lobe resection or lesionectomy
 Remove
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seizure focus area
Multiple Subpial Transection
 Concerns
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only gray matter
Hemispherectomy
Corpus Callosotomy
Treatment - Medications
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Anti-epileptic and anti-convulsant drugs
Vary according to age and syndrome type
70% of patients are able to control seizures with
medications
Phenytoin, carbamazepine and valproate
Treatment - Neuropsychological
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Mind-over-body
Medical and surgical treatments can only treat
epilepsies with known causes
Treatment - Neuropsychological
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Aura treatments
 Certain
behaviours to offset aura
 Ex. olfactory auras and jasmine oil
 Eventually
 Ex.
could use imagination of smell to halt seizures!
Visualization of fishing
Treatment - Neuropsychological
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Biofeedback
 Countermeasures
treatment
 Fights the onset of seizures
 Ex. Relaxation of muscles and de-stressing exercises
 Ex. Heightening of arousal levels
Treatment - Neuropsychological
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EEG Biofeedback
 Seizures
must be evoked!
 “Feed back” EEG information in an easily
understandable form
 Ex.
musical tones, spaceship racing games for children
 Train
patients to recognize and control mind states
 Basically operant conditioning for the brain
 Rewarded
direction
for altering the brain states towards the desired
References
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Baars, B.J. and Nicole M. Gage. (2012). Fundamentals of cognitive neuroscience: A beginner's guide. Academic Press.
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Breitenfeld, T., Jurasic, M.J., Breitenfeld, D. (2014). Hippocrates: the forefather of neurology. Neurol Sci. 35:1349–1352
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Cavalheiro, E. A. (1995). The pilocarpine model of epilepsy. The Italian Journal of Neurological Sciences. 16(1): 33-37.
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Berkovic, S.F. Howell, R.A., Hay, D.A., Hopper J.L. (1998). Epilepsies in twins: genetics of the major epilepsy syndromes. Ann
Neurol. 43(2) 435-445.
Engel Jr, J. (2006). ILAE classification of epilepsy syndromes. Epilepsy research. 70: 5-10.
Gaitatzis, A., Carroll, K., Majeed A., Sander J.W. (2004). The epidemiology of the comorbidity of epilepsy in the general
population. Epilepsia. 45(12): 1613-1622.
Goldstein, L.H. (1997). Effectiveness of psychological interventions for people with poorly controlled epilepsy.J Neurol
Neurosurg Psychiatry. 63:137-142.
Johnston, D. and Brown, T. H. (1984), The synaptic nature of the paroxysmal depolarizing shift in hippocampal neurons. Ann
Neurol., 16: S65–S71.
Li, Y., Li, Q., Gong, H., Liang, P., Zhang P. (2014). Involvement of thalamus in initiation of epileptic seizures induced by
pilocarpine in mice. Neural Plasticity. 2014(1-15).

Meldrum, B.S. (1994). The role of glutamate in epilepsy and other CNS disorders. Neurology. 44(11 Suppl 8): S14-23.
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McNamara, J.O. (1986). Kindling model of epilepsy. Adv Neurol. 44:303-18.
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Slaght, S.J., Leresche N, Deniau J.M., Crunelli, V., Charpier, S. (2002). Activity of thalamic reticular neurons during spontaneous
genetically determined spike and wave discharges. J Neurosci. 22(6):2323–2334.
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Treiman, D.M. (2001). GABAergic mechanisms in epilepsy. Epilepsia. 3:8-12.
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Vezzani, A. (2009). Pilocarpine-induced seizures revisited: what does the model mimic? Epilepsy Curr. 9(5): 146–148.
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Zillmer, E., Spiers, M., Culbertson, W. (2007). Principles of neuropsychology. Nelson Education.