Seizures & EpilepsySeizures & EpilepsySeizures & EpilepsySeizures & EpilepsyClinical Manifestations, Diagnosis, & TreatmentClinical Manifestations, Diagnosis, & Treatment

A. LeBron Paige, M.D.A. LeBron Paige, M.D.Assistant ProfessorAssistant Professor

Department of NeurologyDepartment of Neurology& Biomedical Engineering& Biomedical Engineering

A. LeBron Paige, M.D.A. LeBron Paige, M.D.Assistant ProfessorAssistant Professor

Department of NeurologyDepartment of Neurology& Biomedical Engineering& Biomedical Engineering

UAB Dental & Optometry Neurosciences – 1/22/2009

Epilepsy Clinical Epilepsy Clinical ManifestationsManifestations

SEIZURE VIDEOSSEIZURE VIDEOS#1 & #2#1 & #2

Primary GeneralizedPrimary Generalized

Secondary GeneralizedSecondary Generalized

What Is Epilepsy?What Is Epilepsy? EpilepsyEpilepsy is the Sx of chronic, unprovoked seizures is the Sx of chronic, unprovoked seizures

resulting from an underlying resulting from an underlying neurologicneurologic condition condition1,21,2

• SymptomaticSymptomatic – Likely due to a known lesion – Likely due to a known lesion• CryptogenicCryptogenic – Likely due to an unknown but suspected lesion. – Likely due to an unknown but suspected lesion.• IdiopathicIdiopathic – Unknown etiology, the genetic epilepsies. – Unknown etiology, the genetic epilepsies.

A A seizureseizure (Sz) is a sudden excessive synchronized (Sz) is a sudden excessive synchronized sequence of electrical discharge within the brain that sequence of electrical discharge within the brain that escapes normal inhibitory mechanisms.escapes normal inhibitory mechanisms.

Seizure symptoms may be positive or negative affecting Seizure symptoms may be positive or negative affecting motor, sensory, psychic, or autonomic systems.motor, sensory, psychic, or autonomic systems.

Prevalence:Prevalence: Chronic seizures affects over 2.5 million Chronic seizures affects over 2.5 million people in the United States (1-2%)people in the United States (1-2%)33

1Begley CE, et al. Epilepsia. 2000;41:342-351.2Kandel ER, et al. Principles of Neural Science. 4th ed. 1991:910-935.3Hauser AA, Hesdorffer D. Epilepsy: Frequency, Causes & Consequences. Epilepsy Foundation of America; 1990.

Incidence ofIncidence of Nonfebrile Convulsive Disorders Nonfebrile Convulsive Disorders

Hauser WA. Rochester, MN. 1935-1984.

300

250

200

150

100

50

00 20 40 60 80 100

AlcoholNeonatalOther provokedEpilepsySingle Total

Age

Inci

denc

e P

er 1

00,0

00 P

atie

nt Y

ears

Types of Seizures in EpilepsyTypes of Seizures in Epilepsy

I. I. Generalized seizuresGeneralized seizures

•Affects both hemispheresAffects both hemispheres

•More common in childrenMore common in children

•Lose awareness @ onsetLose awareness @ onset

•Sz subtypes Include:Sz subtypes Include: tonic-clonictonic-clonic seizures seizures absenceabsence seizures seizures myoclonicmyoclonic seizures seizures

Kandel ER, et al. Principles of Neural Science. 4th ed. 1991:910-935.Hauser AA, Hesdorffer D. Epilepsy: Frequency, Causes & Consequences. Epilepsy Foundation;

1990.

EEG of EEG of GeneralizedGeneralized Onset Seizure Onset Seizure

EKG

Types of Seizures in EpilepsyTypes of Seizures in Epilepsy

II. II. Partial SeizuresPartial Seizures•Affects limited area of the brainAffects limited area of the brain

•Most common Sz type (~60%) Most common Sz type (~60%)

•SimpleSimple PartialPartial-no cognitive effects-no cognitive effects

•Complex PartialComplex Partial-loss of awareness -loss of awareness

•Can spread, evolving into a Can spread, evolving into a secondary generalizedsecondary generalized seizure seizure

•Symptoms can affect any system:Symptoms can affect any system: MotorMotorSensorySensoryPsychicPsychicAutonomicAutonomic

Kandel ER, et al. Principles of Neural Science. 4th ed. 1991:910-935.Hauser AA, Hesdorffer D. Epilepsy: Frequency, Causes & Consequences. Epilepsy Foundation;

1990.

EEG of EEG of FocalFocal Onset Seizure Onset Seizure

SEIZURE VIDEOSSEIZURE VIDEOS#3, #4, #5#3, #4, #5

Simple Partial – MotorSimple Partial – Motor

Simple Partial – MixedSimple Partial – Mixed

Complex Partial – Right TLComplex Partial – Right TL

Localization Based on SemiologyLocalization Based on Semiology

FrontalFrontal – Motor, – Motor, bizarre, Often brief bizarre, Often brief and nocturnaland nocturnal

TemporalTemporal – Fear, – Fear, LOC, Amnesia, LOC, Amnesia, AutomatismsAutomatisms

ParietalParietal – Somato- – Somato-sensory, dizzinesssensory, dizziness

OccipitalOccipital – Visual, – Visual, often propagate with often propagate with false localizationfalse localization

SEIZURE VIDEOSSEIZURE VIDEOS#6, #7, #8#6, #7, #8

Complex Partial w/ 2Complex Partial w/ 2nd nd GenGen

Complex Partial – FrontalComplex Partial – Frontal

Complex Partial Frontal w/ 2Complex Partial Frontal w/ 2ndnd Gen Gen

Seizure ClassificationSeizure Classification

GeneralizedGeneralized• Generalized tonic-clonic (grand mal)Generalized tonic-clonic (grand mal)• Absence (petit mal)Absence (petit mal)• Others less common generalized Sz typesOthers less common generalized Sz types

(tonic, atonic, myoclonic, febrile)(tonic, atonic, myoclonic, febrile)

PartialPartial• Simple partialSimple partial• Complex partialComplex partial• Complex partial with 2nd generalizationComplex partial with 2nd generalization

Status Epilepticus (SE)Status Epilepticus (SE)

Most Sz are < 2-3 minutes in lengthMost Sz are < 2-3 minutes in length

DEFINITION: SE is defined as a seizure, or its DEFINITION: SE is defined as a seizure, or its effects, lasting >30min w/o full recoveryeffects, lasting >30min w/o full recovery

Sz > 5 min more likely to evolve into SESz > 5 min more likely to evolve into SE

Same SE types as seizure typesSame SE types as seizure types

Early and aggressive Rx saves livesEarly and aggressive Rx saves lives

Generalized Convulsive (GCSE) vs Non-Generalized Convulsive (GCSE) vs Non-convulsive (NCSE) convulsive (NCSE)

Lifestyle IssuesLifestyle Issues DrivingDriving

PregnancyPregnancy

EmploymentEmployment

Social StigmaSocial Stigma

Non-Epileptic SeizuresNon-Epileptic Seizures

Epilepsy DiagnosisEpilepsy Diagnosis

Etiologies of Transient EpisodesEtiologies of Transient Episodes SeizureSeizure Arrhythmia (Syncope)Arrhythmia (Syncope) TIA (Transient Ischemic Attack)TIA (Transient Ischemic Attack) HypoglycemiaHypoglycemia MigraineMigraine Psych: Non-epileptic Seizure (NES)Psych: Non-epileptic Seizure (NES) Movement disorderMovement disorder Sleep disorderSleep disorder

Initial Seizure WorkupInitial Seizure WorkupIN ED:IN ED:• History and physical, with good History and physical, with good

neurological examneurological exam• Electrolytes, glucose, CaElectrolytes, glucose, Ca2+2+, Mg, Mg2+2+, CBC, , CBC,

OO22 sat or arterial blood gas sat or arterial blood gas• Toxicology screenToxicology screen• NeuroimagingNeuroimaging

AS OUTPATIENT:AS OUTPATIENT:• EEGEEG• MRIMRI (CT in ER is (CT in ER is inadequateinadequate))

Seizure Risk FactorsSeizure Risk FactorsMay influenceMay influence AEDAED -- No AEDNo AED decision afterdecision after first Szfirst Sz

Seizure Risk FactorsSeizure Risk FactorsMay influenceMay influence AEDAED -- No AEDNo AED decision afterdecision after first Szfirst Sz

Gestational/Perinatal InjuryGestational/Perinatal Injury Developmental DelayDevelopmental Delay Febrile ConvulsionsFebrile Convulsions Family History of ConvulsionsFamily History of Convulsions Substance abuseSubstance abuse Head traumaHead trauma Meningitis, EncephalitisMeningitis, Encephalitis Focal Brain LesionsFocal Brain Lesions DementiaDementia

Video-EEG Epilepsy MonitoringVideo-EEG Epilepsy Monitoring

EPILEPSY ETIOLOGICAL EPILEPSY ETIOLOGICAL CLASSIFICATIONCLASSIFICATION

Symptomatic EpilepsySymptomatic Epilepsy• TumorTumor• Arterial-venous (AVM) MalformationArterial-venous (AVM) Malformation• Focal Cortical DisplasiaFocal Cortical Displasia• Mental Retardation – Cerebral PalsyMental Retardation – Cerebral Palsy

Cryptogenic EpilepsyCryptogenic Epilepsy

Idiopathic EpilepsyIdiopathic Epilepsy• GeneralizedGeneralized• Typically genetic basisTypically genetic basis

Epilepsy Epilepsy PharmacotherapyPharmacotherapy

Efficacy vs Side EffectsEfficacy vs Side Effects

Goals of Epilepsy TherapyGoals of Epilepsy Therapy

Long-term seizure controlLong-term seizure control Long-term quality-of-life benefitsLong-term quality-of-life benefits SafetySafety TolerabilityTolerability Assured complianceAssured compliance No interactions with other medicationsNo interactions with other medications

Brodie MJ, Kwan P. Neurology. 2002;58(suppl 5):S2-S8.

No Seizures No Side EffectsNo Seizures No Side Effects

best quality-of-lifebest quality-of-life

AED AED Introduction Introduction

HistoryHistory

20002000 ZonisamideZonisamide

20002000 OxcarbazepineOxcarbazepine

19781978 ValproateValproate

19931993 FelbamateFelbamate

19991999

19971997

19961996

19961996

19941994

19931993

19741974

19601960

19541954

19381938

19041904

INTRODUCEDINTRODUCED

LevetiracetamLevetiracetam

TiagabineTiagabine

TopiramateTopiramate

FosphenytoinFosphenytoin

LamotrigineLamotrigine

GabapentinGabapentin

CarbamazepineCarbamazepine

EthosuximideEthosuximide

PrimidonePrimidone

PhenytoinPhenytoin

PhenobarbitalPhenobarbital

ANTICONVULSANTANTICONVULSANT

Pregabalin (Lyrica)

September 2005

NEW Anticonvulsants

Lacosamide

Rufinamide

Carisbamate

Retigabine

Pharmacoresistant EpilepsyPharmacoresistant Epilepsy

13%

4%

36%

47%

Seizure-free with 1st drug

Seizure-free with 2nd drug

Seizure-free with 3rd ormultiple drugs

Pharmacoresistant epilepsy

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

Previously Untreated Epilepsy Patients (n=470)

Long-Term RecurrenceLong-Term Recurrenceby Seizure Typeby Seizure Type

Type of Epilepsy Sz Free

Symptomatic Generalized 27%

Idiopathic Generalized 82%

Symptomatic Partial 35%

Idiopathic Partial 45%

Hippocampal Sclerosis (HS) 11%

HS+ (dual pathology) 3%

Semah F, et al. Neurology. 1998; 51:1256-1262.

In patients > 16 yr. (mean age 33)2200 patients seen at Hôpital de la Salpêtrière, Paris, 1990-97

Medically Medically Refractory EpilepsyRefractory Epilepsy

Additional OptionsAdditional Options

13%

4%

36%

47%

Seizure-free with 1st drug

Seizure-free with 2nd drug

Seizure-free with 3rd ormultiple drugs

Pharmacoresistant epilepsy

Treatment Options for Medically Treatment Options for Medically Refractory EpilepsyRefractory Epilepsy

Resective SurgeryResective Surgery Investigational Drug TrialsInvestigational Drug Trials Vagus Nerve Stimulator (VNS)Vagus Nerve Stimulator (VNS) Intracranial StimulatorsIntracranial Stimulators Ketogenic DietKetogenic Diet Disconnection ProceduresDisconnection Procedures

Suspect Focal Seizures

VEEG 3T-MRI

Intracranial Monitoring

Resection

Implantable Stimulator

Psychiatric Evaluation

Medical Manageme

nt

Functional Studies

±WADA

Patient #1 Patient #1 Lesional Non-resectableLesional Non-resectable

Suspect Focal Seizures

VEEG 3T-MRI

Intracranial Monitoring

Resection

Implantable Stimulator

Psychiatric Evaluation

Medical Manageme

nt

Functional Studies

±WADA

Resection

How Effective is Surgery?How Effective is Surgery?

2003 study (Spencer S., Neurology)2003 study (Spencer S., Neurology)

• 355 patients followed for 1 year post-op (all 355 patients followed for 1 year post-op (all types)types)

• 75% with remission during the year75% with remission during the year

• 77% Mesial Temporal Sclerosis (MTS) 1 year 77% Mesial Temporal Sclerosis (MTS) 1 year remissionremission

• 56% Neocortical 1 year remission56% Neocortical 1 year remission

• 22% relapse in MTS group22% relapse in MTS group

• 4% neocortical relapse4% neocortical relapse

Patient #2 Patient #2 Non-esional ResectableNon-esional Resectable

Suspect Focal Seizures

VEEG 3T-MRI

Intracranial Monitoring

Resection

Implantable Stimulator

Psychiatric Evaluation

Medical Manageme

nt

Functional Studies

±WADA

Functional Studies

±WADA

EEG and Volume ConductionEEG and Volume Conduction

CORTEXCORTEX

WHITE MATTERWHITE MATTER

CSFCSF

SKULL (Inner Table)SKULL (Inner Table)

SKULL (Outer Table)SKULL (Outer Table)

SCALPSCALPPote

nti

al (V

olt

s)Pote

nti

al (V

olt

s)

Ictal-InterictalIctal-InterictalSPECTSPECT

www.mayo.edu/pediatrics-rst/ brain-epilepsy.html

Interictal PETInterictal PET

MagnetoencephalographyMagnetoencephalography

Suspect Focal Seizures

VEEG 3T-MRI

Intracranial Monitoring

Resection

Implantable Stimulator

Psychiatric Evaluation

Medical Manageme

nt

Functional Studies

±WADA

Intracranial Monitoring

Intracranial ElectrodesIntracranial Electrodes

Patient #2Patient #2

Non-lesional focus within Eloquent CortexNon-lesional focus within Eloquent Cortex

Intracranial EEG Showing Seizure Onset

Intracranial ElectrodesIntracranial Electrodes

Seizure Focus

MOTOR

SENSORY

LANGUAGECortical Mapping Results

Seizure Focus

MOTOR

SENSORY

LANGUAGECortical Mapping Results

Suspect Focal Seizures

VEEG 3T-MRI

Intracranial Monitoring

Resection

Implantable

Stimulator

Psychiatric Evaluation

Medical Manageme

nt

Functional Studies

+WADA

Vagal Nerve StimulatorVagal Nerve Stimulator

www.cyberonics.com

                                                                 

Vagus Nerve Vagus Nerve Projects to Key Brainstem RegionsProjects to Key Brainstem Regions

Henry TR. Neurology. 2002;59(suppl 4):S3-S14.

STN=spinal trigeminal nucleus; NTS=nucleus tractus solitarius; DMN=dorsal motor nucleus of the vagus; AP=area postrema; NA=nucleus ambiguus; CN-X=cranial nerve X; RF=reticular formation.

Bilateral projections on nucleus tractus solitarius (NTS)

Limbic structuresLimbic structures• AmygdalaAmygdala• InsulaInsula

Autonomic structuresAutonomic structures• Hypothalamus Hypothalamus • Periaqueductal grayPeriaqueductal gray

Reticular structuresReticular structures• ThalamusThalamus

Vagal Nerve Stimulator - Vagal Nerve Stimulator - ProgrammerProgrammer

Reactive NeurostimulatonReactive Neurostimulaton

RNS Theory of OperationRNS Theory of OperationSpontaneous epileptiform activity can be terminated acutely in Spontaneous epileptiform activity can be terminated acutely in

humans by applied cortical stimulationhumans by applied cortical stimulation..

Implementation of an External Responsive Neurostimulator System (eRNS) in Patients with Intractable Epilepsy Undergoing Intracranial Seizure Monitoring. Bergey GK, Britton JW, Cascino GD, et. al. Poster AES 2002

Fourier Transform of EEG

Stored EEG

STIM

Photo of RNS (with leads attached)Photo of RNS (with leads attached)

• Width = 41.5 mm

• Length = 60.0 mm

• Thickness = 7.0 mm

• Weight = 19.5g

6 cm

4 cm

Programmer

Dual 4-contact Leads

Reactive Neurostimulator (RNS)

NeuroPace DeviceNeuroPace Device

Skin

Skull

Depth Electrod

e

Strip Electrod

e

Patient #1 Patient #1 Lesional Non-resectableLesional Non-resectable

Open Loop Open Loop NeurostimulationNeurostimulation

ReactiveReactiveNeurostimulationNeurostimulation

Stimulation delivered continuously or on a

clock cycle

stim

stim

stim

stim

stim

stim

Examples: VNS and DBS Example: RNS

Stimulation in response to detected epileptiform activity

Seizure Detection

Stimulation

Seizure Aborted

Lesser, R. P. et al. Neurology 1999;53:2073

An example of the effect of a brief burst of pulse An example of the effect of a brief burst of pulse stimulation (BPS) on a run of afterdischargesstimulation (BPS) on a run of afterdischarges

Afterdischarge

Disruptive Burst of Pulses

Stimulation

Lesser, R. P. et al. Neurology 1999;53:2073

The cumulative proportions of afterdischarges (ADs) that persisted over time after brief burst of pulse stimulation (BPS) was applied and when no BPS was applied

Earlier Stimulation is BetterEarlier Stimulation is Better

Lifestyle IssuesLifestyle Issues DrivingDriving

PregnancyPregnancy

EmploymentEmployment

Social StigmaSocial Stigma

Non-Epileptic SeizuresNon-Epileptic Seizures