Epilepsy and Seizures

Epilepsy:Two or more unprovoked seizures that arise from abnormalelectrical discharges in the brain

Often Unknown Etiology:infections, tumors, trauma, toxins, metabolic disorders,cerebrovascular disorders, developmental abnormalities suchas cortical dysplasia, genetic disorders

Epileptogenesis - Factors leading to the development ofepilepsy (changes in gene expression/protein function, celldeath, abnormal synaptic circuitry)

a change in behavior caused by an abnormalsynchronous electrical discharge in the brain

Seizure:

Too muchexcitation or toolittle inhibition

Excessive, randomdischarge of a group ofneurons in the brain

Antiepileptic/anticonvulsant/antiseizure drugs

Carbamazepine (Tegretol)

Phenytoin (Dilantin) (1938)

Valproate (Depakote)

Phenobarbital (1912)

Primidone (Mysoline)

Ethosuximide (Zarontin)

Clonazepam (Klonopin)

‘First Generation’ (pre 1993)potassium bromide (1857-1930s)

Benzodiazepines, e.g.Clorazepate (Tranxene)

Clobazam (Frisium)

Antiepileptic/anticonvulsant/antiseizure drugs

Zonisamide (Zonegran)

Vigabatrin (Sabril)

‘Second Generation’ (since 1993)Felbamate (Felbatol)

Gabapentin (Neurontin)

Lamotrigine (Lamictal)

Topiramate (Topamax)

Tiagabine (Gabitril)

Oxcarbazepine (Trileptal)

Levetiracetam (Keppra)

Seizure classificationInternational Classification of Epileptic Seizures

I. Partial (focal, local) seizures

II. Generalized seizures

III. Unclassified seizures

seizure activity remains confined to local area

bilaterally symmetrical and without local onset

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)

I Partial seizures

B. Complex partial seizures (impaired consciousness)Also called temporal lobe epilepsy most often in thetemporal or frontal lobes

1 Beginning as simple partial seizures andprogressing to impairment of consciousness

2 Preceded by an aura3 Impaired memory of ictal (during seizure) phase

C. Partial seizures evolving into secondarily generalizedseizures1 Becomes tonic-clonic type2 Loss of consciousness3 Preceded by an aura

II. Generalized seizures

A. Absence seizures (petit mal seizures)sudden interruption of consciousness, blank stare no aura

B. Myoclonic seizures (random discharges in motor cortex)C. Tonic-clonic seizures (grand mal seizures)

abrupt onset usually no aurano symptoms of partial or complex seizuretonic - contractionclonic - shakingpostictal-flaccid and unconscious

Reading Perception of fear Alteredconsciousness

Righthemi-sphere

Lefthemi-sphere

EEG

Epileptic syndromes

Idiopathic epilepsies

Idiopathic epilepsies with partial seizurese.g. frontal lobe, temporal lobe

Idiopathic epilepsies with generalized seizuresmany childhood epilepsy syndromesneonatal convulsions, benign myoclonic seizures,absence seizures

Symptomatic epilepsies - e.g. trauma, tumor

Status Epilepticus

Seizures occurring acutely in greater intensity,number, or length than usual

A prolonged seizure that lasts longer than 10 minutes orrepeated seizures over the course of 30 minutes

Life threatening - emergency care should begin immediately

Treated with benzodiazepines: Diazepam or Lorazepam

Secondary generalized seizure

Primary generalized seizure

Seizurefocus

Seizurefocus

SeizureFocus

Thalamus

Partial seizure

Progression of a Partial Seizure:

1 Initiation - increased electrical activity in a single cell2 Synchronization of surrounding neurons3 Spread to adjacent areas (aura)4 Seizure begins when a group of neurons depolarize

suddenly

Paroxysmal depolarizing shiftLeads to abnormal succession of action

potentialsSurround inhibition normally should prevent

synchronization

Focal epileptiform activity (partial seizures)

EEG

Membrane potential

spike

Slow wave

Depolarizingshift (DS)

Post-DS hyperpolarization

Interictal discharge

Excitatory center Inhibitorysurround

Surround inhibition is critical for normalfunction of the CNS

Complex-partial / Temporal lobe epilepsy

• Usually caused by abnormal activity intemporal lobe/hippocampus + amygdala

• Classically preceded by aura• Altered consciousness• Impaired memory• Can be drug resistant/pharmacoresistant

Entorhinalcortex

Dentate gyrus

CA3

CA1subiculum

Perforant pathMossy fibers

Schaffercollaterals

cortex

Hippocampus circuitry

Normal activity

Entorhinalcortex

Dentate gyrus

CA3

CA1subiculum

Perforant pathMossy fibers

Schaffercollaterals

cortex

Hippocampus circuitry

interictal activity (abnormal )

Entorhinalcortex

Dentate gyrus

subiculum

Perforant pathMossy fibers

cortex

Hippocampus circuitry

ictal activity (seizure )

mesial temporal sclerosis due to excitotoxic cell death

Antiepileptic drugs

Three basic categories:1. Enhance Na+ channel-mediated inhibition2. Inhibit T-type calcium channels3. Enhance GABA-mediated inhibition

Basic mechanisms: antiepilepticdrugs (AED)

• Depends on type of epilepsy• Managed with drugs - may try to locate

focus of partial seizure (surgery?)• Manipulation of ion channels:

cellular level (Na+ channel inactivation)network level (GABA-mediated

inhibition)

Drug choice by seizure type Partial seizures

Carbamazepine (Tegretol)Phenytoin (Dilantin)Valproate (Depakote)

Drugs of choice:

Alternatives:

Zonisamide (Zonegran)

Gabapentin (Neurontin)Lamotrigine (Lamictal)

Topiramate (Topamax)Tiagabine (Gabitril)

Oxcarbazepine (Trileptal)Levetiracetam (Keppra)

PhenobarbitalPrimidone (Mysoline)

Vigabatrin (Sabril)Felbamate (Felbatol)

Drug choice by seizure type:Tonic-clonic (grand mal) seizures

Drugs of choice:Carbamazepine (Tegretol)Phenytoin (Dilantin)

Valproate (Depakote)

Alternatives:

Zonisamide (Zonegran)

Lamotrigine (Lamictal)Topiramate (Topamax)

Oxcarbazepine (Trileptal)Levetiracetam (Keppra)

PhenobarbitalPrimidone (Mysoline)

Felbamate (Felbatol)

Drugs that block voltage-dependent Na+ channelsInhibit high frequency repetitive firing

Carbamazepine (Tegretol)Phenytoin (Dilantin)Valproate (Depakote)

Zonisamide (Zonegran)

Felbamate (Felbatol)

Gabapentin (Neurontin)Lamotrigine (Lamictal)

Topiramate (Topamax)Oxcarbazepine (Trileptal) [active metabolite HCBZ]

Voltage/frequency/use-dependent block

Drug stabilizes inactivated state

open‘resting’ inactivated

open‘resting’ inactivatedblocked

voltage-gatedNa+ channels

depolarization

No drug drug

Lowfrequency

Highfrequency

Membranepotential

inactivation

time time

Drugs that increase GABA levels in brain

Valproate (Depakote)

Gabapentin (Neurontin)

Tiagabine (Gabitril)

Vigabatrin (Sabril)

glutamic acid

GABAaminotransferase

succinatesemialdehydedehydrogenase

GABA

GAT-1

GABA transporterGABA

glutamic aciddecarboxylase

valproate

+ valproate--

tiagabine

-- vigabatrin

gabapentin

decrease inefficacy.

increase inefficacy

inhibitory synapsesrepetitively activated

excitatory synapsesrepetitively activated

(might be desensitization of the GABAA receptor)

Interictal to Ictal transition

Inhibitory surround breaks down

GABAergicinterneuron

Glutamatergicpyramidalneuron

Cerebral cortex

Inhibitorysurround

Excitatory center

Pyramidalcell(glutamatergic)

Inhibitoryinterneuron(GABAergic)

- --- -

-- -

+

+ +

+

+

-

Excitatorysynapse

Inhibitorysynapse

Membrane potential

Inhibitory post-synaptic potential

Low interictal frequency High interictal frequency

No drug

(increasedGABAergic activity)

Drug

seizure

Excitatory center Inhibitorysurround

No seizure

Drugs that Increase activity of GABAA receptors

Barbiturates: Phenobarbital

Benzodiazepines Clonazepam (Klonopin)Clorazepate (Tranxene)

Clobazam (Frisium)

Topiramate (Topamax) - not fully understood

Levetiracetam (Keppra)- - not fully understood

GABABarbituratesIncrease

Efficacy ofGABA

Increaseduration

of opening

Benzodiazepenespotentiate GABAbinding enhance

the affinityIncrease

frequency ofchannel openingCl-

Treatment of status epilepticus is unique:

Diazepam (Diastat)

Lorazepam (Atavan)

Drug choice by seizure type:Absence (petit mal) seizures

Drugs of choice:

Alternatives:

Valproate (Depakote)

Ethosuximide (Zarontin)

Zonisamide (Zonegran)

Lamotrigine (Lamictal)Clonazepam (Klonopin)

Drug choice by seizure type

Drugs of choice:

Alternatives:

Atypical absence, myoclonic, atonic seizures

Valproate (Depakote)

Lamotrigine (Lamictal)

Clonazepam (Klonopin)

Zonisamide (Zonegran)Felbamate (Felbatol)

Topiramate (Topamax)

Drugs that block T-type Ca2+ channels

Valproate (Depakote)

Ethosuximide (Zarontin)

Zonisamide (Zonegran)

Clonazepam at reticular thalamicnucleus*may be a unique BDZ

EEGAbsence seizure

1 s50uV

‘Spike and wave’ activity in typical absence seizure

Slow wave sleep EEGAwake EEG

1 sec

cortex

nucleus reticularisthalami (NRT)

Thalamic relaynucleus

Ascending arousal systemand sensory afferents

+

+

GABAergicneurons

Thalamic neuronsAwakeRelay neurons “transmission mode” to cortex (single

spikes on EEG)Sleep“Burst mode” sensory information is not transmitted

to cortex (T-type calcium channel is active )Absence seizureInappropriate activation of T-type channel in an

awake state

Thalamic neuron has 2 firing modes

Oscillatory /burst mode

Tonic (single spike) /transmission / relay mode

Depolarization caused by ascendingarousal system and sensory afferents

2 sec-65 mV-58 mV

Absence seizure orslow-wave sleep

Awake

One burst

Thalamic neurons

T-type Ca2+ channels (IT)

Ih channels(hyperpolarization-activatedcation channels)

Voltage-dependent Na+ channelsVoltage-dependent K+ channels

Na+-dependent actionpotentials (spikes)

Pacemaker activity;enables oscillatorymode

Thalamic neuron – oscillatory mode

Ih opening

IT opening

Burst ofNa+-dependentaction potentials

Ih closingIT closing

Pacemakerpotential

IT recovering

Ca2+-dependentaction potential

-65 mV

0.5 sec

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)

?

+ -

K+ Ca2+GABA

GABAB

G-protein

Activation of GABAB receptors causes hyperpolarization

1 sec

Cortical neuron

Thalamic neuronNRTthalamus

cortex

+

++

+

-

---

Synchronized activity in Absence seizure

GABAAGABAB

GABAA

TiagabineVigabatrin

Barbiturates

Exacerbate absenceseizures(make them worse)

Valproate

Clonazepam

EthosuximideValproateZonisamide

Suppress absenceseizures

IncreaseGABA levels

ActivateGABAAreceptors

Block T-typeCa2+ channels

Drug effect

valvalval,gab,tia,vig

valIncreaseGABAlevels

bzd(clon),top

bzd(clon)barb,bzd,top,lev

barbActivateGABAA

val,zoneth,val,zonval,zonval,zonBlock T-type Ca2+

val,lam,top,zon,fel

val,lam,zoncar,pht,vallam,gab,topzon,oxc,fel

val,car,pht,lam,top,zon

oxc,fel

Block Na+

channels

Atypicalabsence,

myoclonic,atonic

Typicalabsence

PartialGeneralizedTonic-clonic

Drug treatment of seizuresModes of action

Block Na+ channels

Enhance GABAA receptor activityBlock T-type Ca2+ channels

Inhibit glutamate receptors?

Multiple actions, e.g. valproate

Increase GABA synthesisblock GABA degradationblock GABA reuptake

IncreaseGABAlevels

Block L-type Ca2+ channels?

Glutamate

Glutamate

Postsynapticneuron

Presynapticterminal

-

GAB?, FEL,LAM, HCBZ

TOP

-

Ca2+ channel(not T-type)

NMDAreceptor

AMPA/kainatereceptor

-FEL

Ca2+

Na+ channel

Na+, Ca2+

CAR,PHT,VALLAM,GAB,TOP,ZON,OXC,FEL

GABA

GABA-T

GABAGABA-T

GAD

Cl-

SSA

SSADH

GABAA receptorPostsynapticneuron

Presynapticterminal

Glial cell

VAL

-

-

-

VAL+

+

TIA

-

-

VIG

-

-

BZD, Barb,TOP, LEV

K+

GABAB

receptor

+

T-type Ca2+

channel

ETH, VAL,ZON

-GAT-1

Epileptogenesis

Changes in gene expression or protein function

NMDA receptorsAltered subunit expression in epileptic cortex

AMPA receptorsIncreased expression in epileptic cortex

GABAA receptorsDecreased expression in epileptic cortex

Genetics – nACh receptor

‘A-type’ K+ channelsLost in epileptic hippocampus

Loss of ‘A-type’ K+ channels

Axonal sprouting

SUMMARY

Epilepsy is characterized by recurrent seizures

Seizures are due to abnormal electrical activity in the brain

Epilepsy has many different causes

There are different types of seizure

Status epilepticus is life threatening

Main points (continued)

Voltage/frequency/use-dependent block of voltage-gatedNa+ channels suppresses high frequency firing in tonic-clonic and partial seizures.

We can make some rationalizations about relationshipsbetween mode of drug action and seizure type.

Main points (continued)

Interictal discharges are abnormal (may be containedin a focus no symptomatic pathology but seen on EEG)

An increase in interictal activity may lead to a seizureby breaking down the inhibitory surround.

Drugs that increase GABAergic transmission may suppresspartial seizures by enhancing the inhibitory surround.

Synchronized thalamocortical rhythms occur in slow-wavesleep and absence seizures.

Main points (continued)

T-type Ca2+ channels are required for the oscillatorymode of the thalamus.

Hyperpolarization of thalamic neurons allows theT-type Ca2+ channels to recover from inactivation.

Drugs that block T-type Ca2+ channels can suppressabsence seizures.

Drugs that increase GABA levels can exacerbateabsence seizures.

Main points (continued)

Epileptogenesis is a poorly understood process in which aninitial event leads to the development of epilepsy.

We don’t have any drugs that prevent epileptogenesis

Available antiepileptics only control seizures