EPILEPSY AND FIRST SEIZUREEVALUATION AND TREATMENT

MATTHEW M EVANS, DOPROVIDENCE BRAIN AND SPINE INSTITUTE

Define Epilepsy

Review seizure types (classification)

Evaluation and diagnosis of epilepsy

Evaluation of first seizure

Treatment

OBJECTIVES

SEIZURE vs EPILEPSYSEIZURE

physical symptom caused by excessive excitation and synchronization of a population of neurons

EPILEPSYrecurrent seizures (two or more*) which

are not provoked*new definition of epilepsy can be made after one

unprovoked seizure

http://imgkid.com/neuron

“The Sacred Disease"

Attack by demons

Visions “sent by the Gods”.

EPILEPSY

http://www.soborna.org/duxp/en/083.html

Luke 9:42

- Hippocrates400 BC

“epilepsy is no more sacred or divine than any other disease, it has a natural cause”

“epilepsy would be considered divine only until it was understood”

http://classics.mit.edu/Hippocrates/sacred.htmlhttp://classics.mit.edu/Hippocrates/sacred.html

EPILEPSY

Seizures8-10% of people may have a seizure in their lifetime (1/3 are febrile convulsions)

Epilepsy 1% of the population, 3.4 million in the US150,000 new cases diagnosed in US each year4th most common neurological disorder

England, MJ ,Liverman, CT et al 2012. Epilepsy across the spectrum.

HOW COMMON ARE

Seizures

HOW COMMON ARE SEIZURES?

Hauser WA, et al. Neurology, 1990.

Epilepsia, 2014; 55 (4): 475Epilepsia, 2014; 55 (4): 475-Epilepsia, 2014; 55 (4): 475-482

WHAT IS EPILEPSY?

Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34:453

AGE OF ONSET

Nature Reviews Neurology 10, 283Nature Reviews Neurology 10, 283–Nature Reviews Neurology 10, 283–292 (2014)

ETIOLOGY

NewbornsBrain malformationsHypoxiaIntracranial hemorrhage

Infants and ChildrenFeverInfection

WHAT CAUSES EPILEPSY?

Adolescence and young adultTraumatic brain injuryInfection30% of autistic patientsGenetic factors

Older adultStrokeBrain tumorAlzheimer’s and other dementias

Adolescence and young adultWHAT CAUSES EPILEPSY?

TYPES OF SEIZURES

ILAE – International League Against Epilepsy

TYPES OF SEIZURESSeizures

Focal Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

Aura

Motor

Autonomic

Dyscognitive

SecondaryGeneralized

FOCAL SEIZURES

ILAE – International League Against Epilepsy

FOCAL SEIZURES

Aura

Motor

Autonomic

Dyscognitive

Secondary Generalized

Sensory, Psychic, Abdominal, Visual, Taste, Smell

simple movements or more complex

heart rate, goose bumps

Focal Seizures

Aware Loss of awareness

Seizures

Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

SeizuresSeizures

GENERALIZED SEIZURESGENERALIZED SEIZURES

ILAE – International League Against Epilepsy

Epilepsy Volume 58, Issue 4 April 2017 Pages 522–530

SEIZURE TYPES

MayoClin Proc, June1996,

Vol 7

FOCAL SEIZURES

http://classes.midlandstech.edu/

Symptoms depend on the region of the brain that is activated

(aka Simple Partial Seizures)Aura

SensoryMotorPsychicAutonmic

Typically last < 2 minutes

FOCAL ONSET

(aka Simple Partial Seizures)

FOCAL ONSETAWARE

(aka Complex Partial Seizures)Focal seizure with impaired consciousness

loss of awarenessconfusion

Typically last < 2 minutes

FOCAL ONSETFOCAL ONSETIMPAIRED AWARENESS

(aka secondary generalized)Focal seizure spreads to both sides of the brain.May appear like a generalized seizure if subtle focal seizure signs are not apparentFollowed by confusion, fatigue, and sometimes with temporary paralysisTypically last 1-3 minutes

FOCAL TO BILATERAL TONICFOCAL TO BILATERAL TONIC-FOCAL TO BILATERAL TONICCLONIC

Right Frontal seizure

FOCAL SEIZURE

Continuation of the same seizure with change in amplitude and frequency

FOCAL SEIZURE

Continuation of the same seizure with spread to the other hemisphere

FOCAL SEIZURE

Loss of consciousness and post-ictal confusion/lethargyLasting1-2 minutes Tonic phase

Stiffening and fallOften make a crying sound

Clonic PhaseRhythmic arm/leg jerking

GENERALIZED TONICGENERALIZED TONIC-

Loss of consciousness and post-ictal confusion/lethargy

GENERALIZED TONICCLONIC

ABSENCE SEIZURES

Brief staring spells (“petit mal”)3-20 seconds Triggered by hyperventilationOnset 4 and 14 years of ageOften resolve by 18 years of age

Normal development and intelligence

Brief, shock-like jerk of a muscle or group of muscles

Lasting< 1 second

May cluster

MYOCLONIC SEIZURE

Tonic seizurestonic contraction of muscles

Atonic seizures Sudden loss of muscle toneFalls, head nods or jaw drops. Consciousness usually impairedDuration - usually seconds, rarely more than 1 minute

TONIC AND ATONIC TONIC AND ATONIC SEIZURE

EVALUATIONEVALUATION OF SEIZURE

HISTORY

Neurologic Exam

Brain imaging: CT or MRI

Electroencephalogram (EEG)

Blood tests (including drug screen)

Lumbar puncture (if meningitis is suspect)

Seizure or not?Provoked or UnprovokedSeizure type? (focal vs. generalized)What tests should be ordered?Start treatment?Which drug?What about driving?

EVALUATION OF SEIZURE

Syncope Cardiac (arrhythmia)Non-Cardiac (hypotension)

TIA/Stroke Metabolic (hypoglycemia, hyponatremia)MigraineSleep Disorders (Narcolepsy)Movement Disorders (Paroxysmal Dyskinesia)

WAS IT A SEIZUREWAS IT A SEIZURE?

Psychogenic Non-Epileptic Spells (PNES)

Malingering

Panic Attacks

Intermittent Explosive Disorder

Breath-holding Spells

*Misdiagnosis is usually worse than delayed diagnosis*

Pohlmann-Eden B, et al. BMJ, 2006

WAS IT A SEIZUREWAS IT A SEIZURE?

FIRST SEIZURE

25-30% of first seizures are “provoked”“first” was really the “first”?

Type Recurrence Risk (2 years)

Provoked, no brain injury 3%

Provoked, brain injury 10%

Single, Unprovoked 42%

Recurrent, Unprovoked 70-80%

Pohlmann-Eden, BMJ, 2006.

Neurology 2015;84:1705–1713

RISK OF EPILEPSY

Hauser et al. Risk of recurrent seizures after two unprovoked seizures. NEJM 1998;338:429.

• After 2 unprovoked seizures, risk of 3rd by 5 yrs: 73%

(59-87%, 95% CI

SEIZURE EVALUATION

Assess structureMRI brain

Assess functionEEG

Medication indicated?

NEUROIMAGING

MRI brain

(3T Epilepsy Protocol)

TESTING

researchgate.net

TESTING

King MA, et al. Lancet, 1998.

EEG within 24hrs has up to 51% yield

Sleep deprived EEG up to 34% yield

TREATMENT

FACTORS:Provoked vs. Unprovoked seizureSingle seizure vs. Recurrent seizuresTesting results (CT/MRI, EEG)Type: Focal (partial) vs. Generalized epilepsy

TREATMENT

Maximize Quality of Life

The Treatment has be right for the seizure typeFocal vs Generalized

The Treatment has to be right for the individualComorbid medical conditions, gender

Ultimate goal is no seizures, no side effects

TREATMENT

Anticonvulsant medication

Diets: ketogenic, MAD, LGIT

Devices: VNS, RNS

Surgery: resection, transection, laser ablation, Surgery: resection, transection, laser ablation, radiosurgerySurgery: resection, transection, laser ablation,

AEDs in US• 1857 1857 -- bromides (Br)•

1857 1912 1857 1912 1912 -

bromides (Br)bromides (Br)bromides (Br)-- phenobarbital (PB)

•1912 1937 1912 1937 1937 -

phenobarbital (PB)phenobarbital (PB)phenobarbital (PB)-- phenytoin (PHT)

•1937 1944 1937 1944 1944 -

phenytoin (PHT)phenytoin (PHT)phenytoin (PHT)-- trimethodione (TMD)

•1944 1954 1944 1954 1954 -

trimethodione (TMD)trimethodione (TMD)trimethodione (TMD)-- primidone (PMD)

•1954 1960 1954 1960 1960 -

primidone (PMD)primidone (PMD)primidone (PMD)-- ethosuximide (ESM)

• 1974 1974 -- carbamazepine (CBZ)•

1974 1975 1974 1975 1975 -

carbamazepine (CBZ)carbamazepine (CBZ)carbamazepine (CBZ)-- clonazepam (CZP)

•1975 1978 1975 1978 1978 -

clonazepam (CZP)clonazepam (CZP)clonazepam (CZP)-- valproate (VPA)

• 1993 1993 -- felbamate (FBM)•

1993 1993 1993 1993 1993 -

felbamate (FBM)felbamate (FBM)felbamate (FBM)-- gabapentin (GBP)

•1993 1995 1993 1995 1995 -

gabapentin (GBP) gabapentin (GBP) gabapentin (GBP) -- lamotrigine (LTG)

•1995 1997 1995 1995 1997 1997 1997 -

lamotrigine (LTG)lamotrigine (LTG)lamotrigine (LTG)lamotrigine (LTG)--- topiramate (TPM)

•1997 1997 1997 1997 1997 -

topiramate (TPM)topiramate (TPM)topiramate (TPM)-- tiagabine (TGB)

•1997 1999 1997 1999 1999 -

tiagabine (TGB)tiagabine (TGB)tiagabine (TGB)-- levetiracetam (LEV)

• 2000 2000 -- oxcarbazepine (OXC)•

2000 2000 2000 2000 2000 -

oxcarbazepine (OXC)oxcarbazepine (OXC)oxcarbazepine (OXC)-- zonisamide (ZNS)

•2000 2005 2000 2005 2005 -

zonisamide (ZNS) zonisamide (ZNS) zonisamide (ZNS) -- pregabalin (PGB)

•2005 2008 2005 2008 2008 -

pregabalin (PGB)pregabalin (PGB)-- rufinamide (RUF)

•2008 2009 2008 2009 2009 -

rufinamide (RUF)rufinamide (RUF)rufinamide (RUF)-- Vigabatrin (VGB)

•2009 2009 2009 2009 2009 -

Vigabatrin (VGB)Vigabatrin (VGB)Vigabatrin (VGB)-- lacosamide(LCM)

• 2010 2010 -- ezogabine (EZB) •

2010 2014 2010 2014 2014 -

ezogabine (EZB) ezogabine (EZB) ezogabine (EZB) -- clobazam (CLB)

•2014 2014 2014 2014 2014 -

clobazam (CLB)clobazam (CLB)clobazam (CLB)-- eslicarbazepine (ESL)

•2014 2014 2014 2014 2014 -

eslicarbazepine (ESL) eslicarbazepine (ESL) eslicarbazepine (ESL) -- perampanel (PER)

• 2017 2017 -- brivaracetam (BRV)

AED’s target Mechanism of Action PlayersNa channel blockersCa channel blockers

GABA enhancersAgonistsReuptake inhTransaminase inh

Glutamate blockersCarbonic anhydrase inhHormonesUnknown

Inactivate Na chInhibit TInhibit TInhibit T-Inhibit TInhibit T-type Ca chInhibit LInhibit LInhibit LInhibit L-Inhibit LInhibit LInhibit L-type Ca chGABAGABAGABA-GABAGABA-A receptor: ↑ Clhyperpolarizing cell

Antagonize GLU receptCause intracellular KGABAGABAGABA-GABAGABA-A receptor: ↑ Cl

SV2a receptor

CBZ, PHT ,FosPHT, OXC, LTG, CBZ, PHT ,FosPHT, OXC, LTG, ZSM

ESM, GBP, PGB

BZDs, Barbituates, Primidone

TiagbineVigabatrinFlebamate, TopiramateTPM, ZSM, AZMProgesterone, Allopregnanolone ValproateLevetiracetam

ketamine perampanel

brivaracetam

Excitatory Synapse

Nature Reviews Drug Discovery Nature Reviews Drug Discovery 99, 68, 68-, 68-82 (January 2010)

Inhibitory Synapse

Nature Reviews Drug Discovery Nature Reviews Drug Discovery 99, 68, 68-, 68-82 (January 2010)

● First Generation○ Phenytoin (Dilantin)○ Carbamazepine (Tegretol)○ Phenobarbital/Mysoline

● Second Generation○ Levetiracetam (Keppra)○ Topiramate (Topamax)○ Lamotrigine (Lamictal)○ Lacosamide (Vimpat)

● First Generation○ Valproate (Depakote)○ Zarontin (Ethosuximide)

● Second Generation○ Lamotrigine (Lamictal)○ Topiramate (Topamax)○ Zonisamide (Zonegran)○ Rufinamide (Banzel)

Focal Seizures Generalized Seizures

Overview of Medical Therapy(Partial List)

PROS

Known EfficacyFamiliarity/ExperienceCostCoverage

CONS

Side effectsHepatic inducersDrug-Drug interactionsHormonal changesTeratogenicity

1st Generation AEDs

Broad spectrum anticonvulsants

(If you don’t know if it’s partial or generalized)

LevetiracetamLamotrigineTopiramateZonisamideValproate

Overview of Medical Therapy(Partial List)

HELP

Referral for Neurology Consult

1st Seizure Clinic Study

Is this Epilepsy?

3 CASES

48 M: first time convulsion

32 F: uncontrolled convulsions x 2 years

20 F: New onset convulsion

48 M

First time convulsionHistory: no medical issuesNeuro exam: subtle left arm weaknessBlood work: normalCT: right frontal tumorEEG: right frontal slowing

DIAGNOSIS: provoked seizure, not necessarily epilepsy

TREATMENT: tumor removal, +/- AED (most would start Tx)

Neuro exam: subtle left arm weakness

http://learningneuroradiology

32 F

Uncontrolled convulsions x 2 yearsHistory: migraine and “spells”, tried 8 different AED’s

Neuro exam: normal

Blood work: normal

MRI: normal

Labs: normal

Video-EEG: “seizures” of body thrusting and flailing arms

DIAGNOSIS: PNES (psychogenic non-epileptic spells)

TREATMENT: psychological evaluation

Uncontrolled convulsions x 2 yearsHistory: migraine and “spells”, tried 8 different AED’s

EEG: “seizures” of body thrusting and flailing

Andrea del Sarto 1508.

20 FNew onset convulsion

History: febrile seizures as infantNeuro exam: normalBlood work: normalMRI: left mesial temporal sclerosisEEG: left temporal epileptiform activity

DIAGNOSIS: left temporal lobe epilepsyTREATMENT: anticonvulsants(if refractory refer for epilepsy surgery)

http://teddybrain.wordpress.com/

Define Epilepsy

Review seizure types (classification)

Evaluation and diagnosis of epilepsy

Evaluation of first seizure

Treatment

SUMMARY