Epilepsy and Seizures

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Epilepsy and Seizures
objectives
1. Know the definition of epilepsy
2. Know the definition of seizure
3. Know the different seizure types
4. Know the meaning of status epilepticus
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Epilepsy and Seizures
objectives
5. Know the relationships between interictal and
ictal activity
6. Know the mechanisms of thalamocortical rhythms
and absence seizures
7. Know the principle modes of action and
specific uses of anti-seizure drugs
8. Know the possible mechanisms of epileptogenesis
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Antiepileptic/anticonvulsant/antiseizure drugs
First Generation (pre 1993)
potassium bromide (1857-1930s)
Phenobarbital (1912)
Phenytoin (Dilantin) (1938)
Primidone (Mysoline)
Carbamazepine (Tegretol)
Clorazepate (Tranxene)
Clonazepam (Klonopin)
Benzodiazepines, e.g.
Clobazam (Frisium)
Ethosuximide (Zarontin)
Valproate (Depakote)
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Antiepileptic/anticonvulsant/antiseizure drugs
Second Generation (since 1993)
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Tiagabine (Gabitril)
Oxcarbazepine (Trileptal)
Zonisamide (Zonegran)
Vigabatrin (Sabril)
Levetiracetam (Keppra)
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Antiepileptic/anticonvulsant/antiseizure drugs
Used for treatment of status epilepticus
Diazepam (Diastat)
Lorazepam (Atavan)
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Epilepsy and Seizures
Epilepsy Two or more unprovoked seizures that
arise from abnormal electrical discharges in the
brain
Etiology
infections, tumors, trauma, toxins, metabolic
disorders, cerebrovascular disorders,
developmental abnormalities such as cortical
dysplasia, genetic disorders
Cause often unknown
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Seizure
a change in behavior caused by an abnormal
electrical discharge in the brain
Too much excitation or too little inhibition
Excessive, random discharge of a group of neurons
in the brain
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Drug choice by seizure type
Tonic-clonic (grand mal) seizures
Drugs of choice
Valproate (Depakote)
Carbamazepine (Tegretol)
Phenytoin (Dilantin)
Alternatives
Lamotrigine (Lamictal)
Topiramate (Topamax)
Zonisamide (Zonegran)
Oxcarbazepine (Trileptal)
Levetiracetam (Keppra)
Primidone (Mysoline)
Phenobarbital
Felbamate (Felbatol)
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Drug choice by seizure type
Partial seizures
Carbamazepine (Tegretol)
Drugs of choice
Phenytoin (Dilantin)
Valproate (Depakote)
Alternatives
Lamotrigine (Lamictal)
Gabapentin (Neurontin)
Topiramate (Topamax)
Tiagabine (Gabitril)
Zonisamide (Zonegran)
Oxcarbazepine (Trileptal)
Levetiracetam (Keppra)
Primidone (Mysoline)
Felbamate (Felbatol)
Phenobarbital
Vigabatrin (Sabril)
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Drug choice by seizure type
Absence (petit mal) seizures
Drugs of choice
Ethosuximide (Zarontin)
Valproate (Depakote)
Alternatives
Lamotrigine (Lamictal)
Clonazepam (Klonopin)
Zonisamide (Zonegran)
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Drug choice by seizure type
Atypical absence, myoclonic, atonic seizures
Drugs of choice
Valproate (Depakote)
Lamotrigine (Lamictal)
Alternatives
Clonazepam (Klonopin)
Topiramate (Topamax)
Zonisamide (Zonegran)
Felbamate (Felbatol)
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Seizure classification
International Classification of Epileptic
Seizures
I. Partial (focal, local) seizures
seizure activity remains confined to local area
II. Generalized seizures
bilaterally symmetrical and without local onset
III. Unclassified seizures
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International Classification of Epileptic
Seizures
I. Partial seizures
A. Simple partial seizures (consciousness not
impaired) 1. with motor symptoms (changes in
movement) 2. with somatosensory or special
sensory symptoms (e.g. tingling, flashing
lights) 3. with autonomic symptoms (e.g. heart
rate) 4. with psychic symptoms (alteration of
consciousness, e.g. hallucinations)
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International Classification of Epileptic
Seizures
I. Partial seizures

• B. Complex partial seizures (impairment of
  consciousness)
• (Psychomotor or temporal lobe seizures)
• most often in the temporal or frontal lobes
• beginning as simple partial seizures and
  progressing to impairment of consciousness
• 2. with impairment of consciousness at onset
• type 1 or type 2
• a) With no other features
• b) With features as in I.A.1-4
• c) With automatisms (aberrations of behavior,
  automatic movements)

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International Classification of Epileptic
Seizures
I. Partial seizures
C. Partial seizures evolving into secondarily
generalized seizures
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International Classification of Epileptic
Seizures
II. Generalized seizures
A. Absence seizures (petit mal seizures) 1.
typical 2. atypical B. Myoclonic seizures
(random discharges in motor cortex) C. Clonic
seizures (grand mal seizures) D. Tonic seizures
(grand mal seizures) E. Tonic-clonic seizures
(grand mal seizures) F. Atonic seizures (drop
attack/akinetic fall)
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Altered consciousness
reading
Perception of fear
Left hemi-sphere
Right hemi-sphere
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Epileptic syndromes
Idiopathic epilepsies (genetic)
Idiopathic epilepsies with partial seizures e.g.
frontal lobe, temporal lobe
Idiopathic epilepsies with generalized
seizures many childhood epilepsy syndromes
neonatal convulsions, benign myoclonic
seizures, absence seizures
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Epileptic syndromes
Symptomatic epilepsies
Symptomatic epilepsies with partial seizures
trauma, tumors or local vascular abnormality
Rasmussens syndrome
Symptomatic epilepsies with generalized seizures
usually indicative of a severe underlying
neurological disorder
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Epileptic syndromes
Epilepsies that are difficult to categorize
Wests Syndrome
Lennox-Gastaut Syndrome
Acquired epileptic aphasia (Landau-Kleffner
syndrome)
Epilepsy with continuous spike-wave during slow
wave sleep
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Status Epilepticus
Seizures occurring acutely in greater intensity,
number, or length than usual
A prolonged seizure that lasts longer than 10
minutes or repeated seizures over the course of
30 minutes
Life threatening - emergency care should begin
immediately
Treated with benzodiazepines Diazepam or
Lorazepam
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Drug categories by mechanism
Block voltage-dependent Na channels
Inhibit high frequency repetitive firing
Carbamazepine (Tegretol)
Phenytoin (Dilantin)
Valproate (Depakote)
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Oxcarbazepine (Trileptal) active metabolite HCBZ
Zonisamide (Zonegran)
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Drug categories by mechanism
Block T-type Ca2 channels
Ethosuximide (Zarontin)
Valproate (Depakote)
Zonisamide (Zonegran)
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Drug categories by mechanism
Increase activity of GABAA receptors
Barbiturates Phenobarbital
Clorazepate (Tranxene)
Clonazepam (Klonopin)
Benzodiazepines
Clobazam (Frisium)
Topiramate (Topamax)
Levetiracetam (Keppra) opposes action of
negative GABAA modulators
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Drug categories by mechanism
Increase GABA levels in brain
Valproate (Depakote)
Gabapentin (Neurontin)
Tiagabine (Gabitril)
Vigabatrin (Sabril)
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Voltage/frequency/use-dependent block
open
resting
inactivated
voltage-gated Na channels
depolarization
open
resting
inactivated
blocked
Drug stabilizes inactivated state
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No drug
drug
Membrane potential
Low frequency
inactivation
High frequency
time
time
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glutamic acid
succinate semialdehyde dehydrogenase
-
valproate
glutamic acid decarboxylase

valproate
-
GABA aminotransferase
-
GABA
-
vigabatrin
tiagabine
GAT-1
GABA
GABA uptake carrier
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Seizure mechanisms
Focal epileptiform activity (partial seizures)
Interictal discharge
spike
EEG
Slow wave
Depolarizing shift (DS)
Membrane potential
Post-DS hyperpolarization
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Cerebral cortex
GABAergic interneuron
Glutamatergic pyramidal neuron
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Pyramidal cell (glutamatergic)
Inhibitory surround
Excitatory center
Inhibitory interneuron (GABAergic)

Excitatory synapse
-
Membrane potential
Inhibitory synapse
Inhibitory post-synaptic potential
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Seizure mechanisms
Initiation and spread of partial seizures
seizures can develop
directly from interictal discharges (interictal
to ictal transition)
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interictal to ictal transition
decrease in efficacy.
inhibitory synapses repetitively activated
(might be desensitization of the GABAA receptor)
increase in efficacy
excitatory synapses repetitively activated
Inhibitory surround breaks down
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Low interictal frequency
High interictal frequency
seizure
No drug
Inhibitory surround
Excitatory center
Drug
No seizure
(increased GABAergic activity)
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Seizure mechanisms
Initiation and spread of partial seizures
seizures can develop
after cessation of interictal discharges
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Temporal lobe epilepsy
mesial temporal sclerosis selective loss of
neurons in hippocampus, including CA1 and CA3
Loss of interictal activity in hippocampal
circuit may predispose to ictal (seizure) activity
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Hippocampus circuitry
Dentate gyrus
Mossy fibers
Perforant path
CA3
Entorhinal cortex
Schaffer collaterals
subiculum
CA1
cortex
Normal activity
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Hippocampus circuitry
Dentate gyrus
Mossy fibers
Perforant path
CA3
Entorhinal cortex
Schaffer collaterals
subiculum
CA1
cortex
interictal activity (abnormal )
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Hippocampus circuitry
Dentate gyrus
Mossy fibers
Perforant path
Entorhinal cortex
mesial temporal sclerosis
subiculum
cortex
ictal activity (seizure )
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Seizure mechanisms
Initiation and spread of partial seizures
seizures can develop
directly from interictal discharges (interictal
to ictal transition)
or
after cessation of interictal discharges
or
independent of interictal discharges
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Seizure mechanisms
Absence seizures
Spike and wave activity in typical absence
seizure
50 uV
1 s
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Slow wave sleep EEG
Awake EEG
1 sec
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cortex
Thalamic relay nucleus
nucleus reticularis thalami (NRT)

GABAergic neurons

Ascending arousal system and sensory afferents
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Thalamic neuron 2 firing modes
Absence seizure or slow-wave sleep
Awake
One burst
Oscillatory / burst mode
Tonic (single spike) / transmission / relay mode
-58 mV
-65 mV
2 sec
Depolarization caused by ascending arousal system
and sensory afferents
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Thalamic neurons
Voltage-dependent Na channels
Na-dependent action potentials (spikes)
Voltage-dependent K channels
T-type Ca2 channels (IT)
Pacemaker activity enables oscillatory mode
Ih channels (hyperpolarization-activated cation
channels)
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Thalamic neuron oscillatory mode
Burst of Na-dependent action potentials
Ca2-dependent action potential
Ih deactivation
IT activation
-65 mV
IT inactivation
Ih activation
Pacemaker potential
IT de-inactivation/recovery
0.5 sec
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Thalamic neurons
At awake resting potential T-type Ca2
channels inactivated
Hyperpolarization by NRT neurons (GABAA and GABAB
receptors)
T-type channels recover (de-inactivate)
Oscillatory mode
(slow-wave sleep or absence seizure)
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Synchronized activity in Absence seizure
cortex
Cortical neuron

1 sec


-
-
GABAA GABAB
-
GABAA
-
thalamus

NRT
Thalamic neuron
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Activation of GABAB receptors causes
hyperpolarization
Ca2
K
GABA
GABAB
-

G-protein
?
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cortex
Thalamic relay nucleus
nucleus reticularis thalami (NRT)

GABAergic neurons
barbiturates

benzodiazepines
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Drug treatment of seizures
Modes of action
Block Na channels
Block T-type Ca2 channels
Enhance GABAA receptor activity
Increase GABA synthesis
Increase GABA levels
block GABA degradation
block GABA reuptake
Inhibit glutamate receptors?
Block L-type Ca2 channels?
Multiple actions, e.g. valproate
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Epileptogenesis
Factors leading to the development of epilepsy
Changes in gene expression or protein function
Selective cell death
Abnormal synaptic connections
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Epileptogenesis
Changes in gene expression or protein function
NMDA receptors
Altered subunit expression in epileptic cortex
AMPA receptors
Increased expression in epileptic cortex
GABAA receptors
Decreased expression in epileptic cortex
A-type K channels
Lost in epileptic hippocampus
Genetics nACh receptor
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Loss of A-type K channels
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Epileptogenesis
Selective cell death
Mesial temporal sclerosis some cell types die
excitotoxicity
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Epileptogenesis
Abnormal synaptic connections
genetics
Axonal sprouting
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Axonal sprouting
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Here are the main points again
Epilepsy is characterized by recurrent seizures
Epilepsy has many different causes
Seizures are due to abnormal electrical activity
in the brain
There are different types of seizure
Status epilepticus is very serious
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Main points (continued)
We can make some rationalizations about
relationships between mode of drug action and
seizure type.
Voltage/frequency/use-dependent block of
voltage-gated Na channels suppresses high
frequency firing in tonic-clonic and partial
seizures.
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Main points (continued)
Interictal discharges are abnormal
An increase in interictal activity may lead to a
seizure by breaking down the inhibitory surround.
Drugs that increase GABAergic transmission may
suppress partial seizures by enhancing the
inhibitory surround.
A decrease in interictal activity may lead to a
seizure
(example of hippocampus)
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Main points (continued)
Synchronized thalamocortical rhythms occur in
slow-wave sleep and absence seizures.
Hyperpolarization of thalamic neurons allows the
T-type Ca2 channels to recover from inactivation.
T-type Ca2 channels are required for the
oscillatory mode of the thalamus.
Drugs that block T-type Ca2 channels can
suppress absence seizures.
Drugs that increase GABA levels can exacerbate
absence seizures.
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Main points (continued)
Epileptogenesis is a poorly understood process in
which an initial event leads to the development
of epilepsy.
We dont have any drugs that prevent
epileptogenesis
Available antiepileptics only control seizures