Georges A. Ghacibeh, MD, MS

Hackensack University Medical CenterHackensack University Medical Center

Comprehensive Epilepsy CenterComprehensive Epilepsy Center

A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain

Incidence: approximately 80/100,000 per year

Lifetime prevalence: 9% (1/3 benign febrile convulsions)

A disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition

Incidence: approximately

45/100,000 per year

Point prevalence: 0.5-1% (2.5 million) Cumulative risk of epilepsy: 1.3% - 3.1%

Seizures Epilepsy

Sz Sz

Epilepsy

Treatment

Diagnosis

Seizure-free

Stop Treatment

No Sz

No Epilepsy

Classification of Seizures

Focal - Focal - OnsetOnset

Simple partialComplex

partialSecondarily

generalized

Generalized - Generalized - OnsetOnset

AbsenceMyoclonicGeneralized tonic-clonicTonicClonicAtonic

GeneralizedGeneralized FocalFocal

FocusFocus

Classification of Epilepsy

Juvenile Myoclonic Childhood Absence Primary GTC

Lennox-Gastaut Other developmental disorders

Benign Rolandic Benigh Occipital

Focal-Onset Epilepsy

EtiologyEtiology

Sei

zure

On

set

Sei

zure

On

set Primary Secondary

Focal

Generalized

010

2030

4050

6070

8090

0 10 20 30 40 50 60 70 80

Age

Inci

den

ce p

er 1

00,0

00

Partial

Generalized tonic-clonic

Primary Generalized

Epilepsy: Incidence Rates by Seizure Type*Epilepsy: Incidence Rates by Seizure Type*

*Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF.

In: The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:165-172.

Seizure Risk FactorPrenatal and Birth InjuryFebrile ConvulsionsDevelopmental DelayHead TraumaCNS InfectionsBrain TumorsBrain SurgeryFamily History

Evaluation and DiagnosisHistory from patient and family

EEG: standard 20-30 minutes

EEG Monitoring:Ambulatory EEGVideo EEG

Neuroimaging

The Tracing

Video-EEG MonitoringContinuous synchronized EEG and Video

recording

Monitors patient’s behavior and EEG

Scalp: Electrodes Similar to EEG

Invasive: Electrodes within or on the surface of the brain.

Paroxysmal EventsEpileptic

Focal (Partial) onsetGeneralized onset

Non-Epileptic: PsychogenicCardiacVasovagalSleep disorderMigraine…

Partial (focal) SeizuresSimple Partial Seizure

no loss of awareness

Complex Partial Seizure Impaired consciousness w w/o aura Clinical manifestations vary with origin & degree of

spread

Clinical Manifestations: Automatisms (manual, oral) Bicycling and fencing posture (frontal)

Duration (typically 30 seconds to 3 minutes)

Amnesia for event

Partial Seizure with Secondary Generalization

Primarily Generalized SeizuresAbsence: Brief staring (<30sec )

Myoclonic: Brief, shock-like muscle contractions

Atonic: Loss of muscle tone

Tonic: Sustained muscle contraction

Tonic-Clonic

Psychogenic

Cardiovascular

Syncope

Metabolic (glucose, Na, Ca, Mg)

Sleep disorders (parasomnias, cataplexy)

New Onset SeizureAfter the first seizure, no clear indication for

treatment

Routine EEG is usually of low yield

Long term EEG monitoring is sometimes indicated to determine need for long term treatment with AEDs.

What Type of Seizure was it?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.

Discontinue AEDsPatients who are seizure-free for over 2 years

wanting to come-off AEDs

Monitoring for 48 – 72 hourse OFF anti-epileptic drugs

Seizure activity (spikes) on EEG indicate high risk of seizure recurrence.

Treatment of EpilepsyMedicationsDiet TherapyHormonal TherapySurgical:

Resective Multiple Subpial Transaction Vagus Nerve Stimulator

Experimental: Deep Brain Stimulation Radiosurgery Cortical Stimulation

Anti-Epileptic Drugs (AED)A drug that decreases the frequency and/or

severity of seizures in patients with epilepsy

Treats the symptom of seizures, not the underlying epileptic condition

Goal—maximize quality of life by minimizing seizures and adverse drug effects

Available AEDs Phenobarbital Mysoline Primidone Dilantin phenytoin Tegretol carbamazepine Depakote valproic acid Zorantin ethosuxamide Felbatol felbamate Neurontin gabapentin Lamictal lamotrigine Topamax topiramate Gabitril tiagabine Trileptal oxcarbazepine Zonegran zonisamide Keppra levetiracetam Lyrica pregabaline Frisium clobazam Klonopin clonazepam Tranxene chlorazepate Banzel rufinamide Vimpat lacosamide

Rational Use of AEDs Indication / Guidelines by FDA, AES, AANSeizure type/ Epilepsy syndromeAdverse effects (acute; chronic)Comorbid conditionsCostAgeGenderConcomitant medicationsSocial factorsPharmacokinetic profile

Side Effects Co-morbid Conditions

Drug Interactions

Age / Sex

SleepinessCognitiveBehavioralMetabolic : Liver Electrolytes Hyperthermia Weight gain OstioporosisBone Marrow

Co-TRTCo-TRT AvoidAvoid

MigrainePainMood

Kidney StonesPsychiatricLiver DiseaseBone Marrow

Cytochrome P-450:SteroidsChemotherapyCoumadinMany others…Young Women

Elderly

DilantinPhenobarbitalMysolineTegretolDepakoteZorantinFelbatolNeurontinLamictalTopamaxGabitrilTrileptalZonegranKeppraLyrica FrisiumKlonopinTranxeneBanzelVimpat

FDA: Use of AEDsMonotherapy

Carbamazepine

Valproate

Ethosuximide

Oxcarbazepine

Phenobarbital

Phenytoin

Primidone

Felbamate

Lamotrigine

Topiramate

Adjunct Therapy

Carbamazepine Lacosimide

Levetiracetam Rufinamide

Gabapentin Zonisamide

Ethosuximide Phenobarbital

Oxcarbazepine Phenytoin

Tiagabine Primidone

Topiramate Valproate

Pregabaline Lacosamide

AED Treatment Options

Tonic-Clonic

Atonic MyoclonicInfantileSpasms

AbsenceTonic

GeneralizedPartialSimple

Complex

SecondaryGeneralized

ACTHTPMTGBVGB

ESXPHT, CBZ, GBP, OXC, TGB, LCS

PGB

VPA, LTG, TPM, ZNS, LVT, FBM

Rufinamide

AED TherapyEpilepsy

First AEDIncrease Dosage

Switch AED

Combine AEDs

Polytherapy

Trial and Error MethodTrial and Error Method

Time

TRIALTRIAL ERRORERROR

Adjust Dosage

Change AED

Combine AEDs

Recurrent Seizures

Side Effects

Rational Use of AEDs

PharMetrics. April 2002 to June 2003IMS NPA, Dec 2003.Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

Success With Antiepileptic Drugs

Kwan P, Brodie MJ. N Engl J Med. 2000;342(5):314-319

Previously Untreated Epilepsy Patients (N=470)

Common Side Effects

DizzinessSleepinessDrowsinessAtaxiaBlurred vision

Diet Therapy

Diet Treatment For Epilepsy

Ketogenic Diet Modified AtkinsLow Glycemic Index Treatment

Carbohydrates

Fat

Glucose

Brain Body

Fatty Acids

Carbohydrates

Fat

KetoneKetoness

Brain Body

Fatty Acids

Ketogenic DietVery High Fat, Low Carbohydate And

Protein DietFat Used As Alternative Energy SourceGoal = Ketosis

Why? Elevated Ketones Correlate With Optimal Seizure

Control

Fluid And Calorie RestrictedBased On Ratio – 3:1 or 4:1Food Must Be Weighed

Ketogenic DietAdmission to the hospital 3-5 daysPrecise amounts of carbohydrates, proteins

and fatAll food needs to be weighed

Strict monitoring of urine ketones and blood work

All medications, including over-the-counter medications, such as Motrin and Tylenol have to be keto-friendly

Modified Atkins DietEasier than the ketogenic dietMany advantages over ketogenic diet:

No admission to the hospital Only carbohydrates are measured and

restricted Start at 10 gm per day, then increase to 15-20 gm

per day No Protein Restriction No Fluid Restriction No Weighing Food

www.atkinsforseizures.com

Compare And Contrast Carbohydrate Fat Protein

Ketogenic 2% 90% 8%

Modified Atkins

6% 64% 30%

Average American

~50-55% ~25-30% ~10-15%

Low Glycemic Index DietNo Hospital Admission RequiredAllowance: 40 – 60 grams CHO/dayOnly Foods With Low Glycemic Index are

allowedFoods quantities are not weighed but are

based on portion sizeMore Flexible Lifestyle

Hormone TherapiesSome women experience increase in seizure

frequency around their menstrual periodCatamenial seizures

This is believed to be due to sudden changes in levels of hormones

There are three types of catamenial seizures

E2 = estradiol; P = progesterone.

Estradiol g/mLProgesterone ng/mL

0

5

10

15

50

20100

30150

E2 P

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Day of the Cycle

Ser

um

Ho

rmo

ne

Lev

els

25

C1 = catamenial 1 (seizure pattern); C2 = catamenial 2; E2 = estradiol; P = progesterone.

Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

Estradiol g/mLProgesterone ng/mL

0

5

10

15

50

20100

30150

E2 P

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Day of the Cycle

C1

Ser

um

Ho

rmo

ne

Lev

els

25

C2

C3 = catamenial 3.

Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

1

0

520

1040

1560

2080

25100

E2 P

3 5 7 9 11 13 15 17 19 21 23 25 27

Day of the Cycle

C3Estradiol g/mLProgesterone ng/mL

Ser

um

Ho

rmo

ne

Lev

els

Catamenial EpilepsyKatamenios = “monthly”The tendency for increased seizures

related to the menstrual cycleAffects 30%-40% of women with epilepsy

Note: Catamenial seizure patterns will be apparent only during ovulatory cycles, and 30% of cycles in women with epilepsy are anovulatory

Herzog AG, et al. Epilepsia. 1997;38:1082-1088.

Hormone TherapySupplementation of Progesterone during the

period of increased seizures is effective in reducing seizures

Oral natural progesterone is the most effective Give for 7 days starting on day 23 of the cycle

Treatment with intramuscular progesterone is sometimes effective (Depo-Provera)

Some seizure medications shorten the half-life of Depo-Provera and more frequent injections are necessary (every 10 or 8 weeks instead of every 12 weeks)

Herbal MedicinesNo proven benefits in epilepsySome herbal medicines may increase the risk of

seizuresSome herbal medicines may interact with

seizure medicationsIf you plan on trying an herbal medicine, first

research it thoroughly and consult with your doctor

NEVER substitute an herbal medicine for your regular seizure medications

http://www.mskcc.org/mskcc/html/11570.cfm

Herbal MedicinesSome Herbal Substances

Used In Borage Caffeine Chamomile Ephedra Evening Primrose Ginkgo Ginseng Herbal Essential Oils Kava Passionflower St. John's Wort Valerian

Some may cause seizures Some may have bad

interactions with seizure medications or other medications

Caution

Anxiety Depression Low Energy Arthritis Memory difficulties

SupplementsVitaminsVitamins: A - E

MineralsMinerals: Magnesium, Selenium, Zinc…

OtherOther: CoQ10, Carnitine, anti-oxidants, …

Supplements: The RuleMost supplements are probablyprobably safe if taken

at the recommended doseNo proven efficacy in treating seizuresBUTBUT: Some supplements are recommended

in certain metabolic disorders affecting the function of the mitochondria

Mitochondria are small organelles inside the cells, including the brain cells. Their function is to generate energy for the cell

Mitochondria and SeizuresCertain mitochondrial diseases can cause

seizuresIt is possible that some patients with

epilepsy might have an un-diagnosed mitochondrial disease as a cause of their seizures

It is not know if repeated seizures exhaust the energy source of the brain and lead to mitochondrial dysfunction

SupplementsIn some cases, a combination of

supplements and vitamins that support the energy production in the brain might be helpful

These are not recommended in everybody, but are safe

Some supplements include: Co-Q10, Carnitine, Vitamin B1, B5, B6, C, and E, Lipoic Acid

Folic acid is recommended in all women of child-bearing age

Vitamin D and Calcium are recommended for all patients taking seizure medications

Sleep Seizures

Cognition

Behavior

Seizures in sleep disordersIn patient with epilepsy

Evaluation for a sleep disorder should be done if the patient has the right symptoms

Treatment of the sleep disorder often leads to marked improvement in seizure control

In children, sleep disorder sometimes manifest as behavioral and learning problems. Treatment can improve both.

Sleep in patients with epilepsyMany patients with epilepsy have disrupted

sleepThis is usually caused by:

Nighttime seizuresNighttime seizure activitySide effects of seizure medicationsDepression and anxiety

Sleep in patients with epilepsyThe most common sleep symptoms in

patients with epilepsy are:

Insomnia: Trouble falling asleep Frequent night time arousals

Excessive sleepiness: Frequently due to side effects of medications Sometimes due to sleep disruption form nighttime

seizures and seizure activity

AttentionThe relationship between sleep and seizures is

very complex

Memory, attention difficulties and sleepiness can be due either to:

Seizure medicationsLack of proper sleep

Nighttime seizures and seizure activity Specific sleep disorder

The correct diagnosis is essential!

Nighttime seizure activityIn some patients, the EEG reveals very

frequent spikes (seizure activity) during sleep, with minimal seizure activity while awake

NOTENOTE: Routine 20 minute EEG usually do not reveal this activity

Overnight EEG is necessary to capture and quantify this activity

SignificanceRecent evidence suggests that patients,

especially children, with frequent nighttime spikes may develop:

Cognitive problemsLearning difficultiesBehavioral problems

Autism and SeizuresAbout 30% of patients with autism

experience seizures

About 60% of patients with autism have seizure activity on the EEG

The relationship between Autism and Seizures is complex

Seizures, EEG and AutismSeizures in Autistic patients should be

treated like any other seizures

Some patients with Autism who have frequent spikes (seizure activity) during sleepIt is believed that seizure activity can interfere

with learning ability, sleep and behaviorIn some cases, treating the seizure activity can

help improve learning ability and behaviorTreatment options include medications and diet

ConclusionEpilepsy is a very complex medical conditionMany effective treatment options are availableMost patients with epilepsy achieve seizure

freedom and can live a normal and productive lifeSeizure medications are the main treatment

modalityDiet therapy should be considered in some casesPatients who don’t respond well to medications,

may consider epilepsy surgery