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