Epileptic Seizure: Paroxysmal episode of neurological dysfunction caused by excessive electrical discharge of cortical neurons Variable clinical

presentation and depends on the location of the discharging neurons as well as routes of propagation

electroencephalographic recording correlate

Epilepsy: Recurrent unprovoked epileptic seizures 2 or more

Epilepsy is one of the most common disorders of the nervous system.

Epilepsy affects people of all ages, races, and ethnic backgrounds.

2.7 million individuals in the U.S. are living with epilepsy, 50 million worldwide.

10%of Americans will have a seizure in lifetime and 3% will have epilepsy by age 75

Cost is $15Billion per year direct/indirect cost

The condition can develop at any time of life, especially in early childhood and old age.

www.aesnet.org

Hauser In: Pedley and Engel 1998

Hauser In: Pedley and Engel 1998

Perinatal: metabolic

Child: Genetic Trauma

Teen/Young Adult Idiopathic Trauma, Drugs,

ETOH

Age 30-60 : Idiopathic Tumors Trauma

Age >60 : Vascular events Tumors Acute anoxic event

A. Which age groups below may be effected by

epilepsy. Select all that apply (Of those age groups selected, name the common causes in that age group)A. First 2 years of life (neonate/infant/toddler)B. ChildC. Young AdultD Middle Aged AdultE. Senior Citizen

B. Which 2 age groups have highest incidence of epilepsy?Pick 2 from above

Partial ( focal): Starts in part of brainSimple partial: No impairment of consciousnessComplex partial: Loss or alteration of

consciousness

Generalized: Entire brain involved at onsetLoss of Consciousness Convulsive or nonconvulsive

Partial with secondary generalization

No impairment of consciousness: Patient can describe the seizure.

Epileptic auras are usually simple partial

TypesMotor: Jacksonian march, focal motor status

epilepticus, epilipsia partialis continua (EPC)Sensory: taste, smell, auditory, visual,

vertiginousAutonomic: pupil, heat, cold, piloerection, Psychic: anger, fear, depression, elation

Loss or alteration of consciousnessMay begin with unresponsive stare or behavioral arrestThere may be unusual and repetitive behavior such as lip smacking or

hand movements (oral and manual automatisms)

Duration: Seconds to minutesBehavior may be complex but is not goal directedRarely violent, patient injury uncommon (except increase accidents)Postictal confusion may last for several minutes

May be preceded by a sensory or psychic aura (remember simple partial)

PathologyTemporal lobe >80%Frontal lobe 10-15%)

Generalized tonic clonic( grand mal)Tonic and then clonic phase

Each lasting 15-30 secondsEither may be omitted

Followed by postictal confusion/stuporOther types of Generalized Seizures

TonicClonicAtonicMyoclonicAbsenceInfantile spasm

Onset: childhood (1-10 years)10-30 seconds of detachment and LOCNo preceding auraNo post ictal confusion: Immediately go back

to what they were doing as if nothing has happened.

EEG shows 3/second spike and wave during or between seizures (ictal or interictal)

Identify the seizure type: Options : Simple partial, Complex Partial, Absence, GTC,

Combination 58 y/o man stares off into space an is unresponsive with oral

and manual automatisms. Afterwards the patient is tired for about 10 minutes

9 y/o boy stares into space with lip smacking for about 10 seconds while playing a video game. Immediately afterwards, he resumes playing video game as if nothing happened

4 y/o boy who wears helmet suddenly loses tone and drops to the floor. Identify seizure and state why wearing helmet.

67 y/o man has sudden onset of left face clonic jerks, which spreads to left arm, then left leg and then entire body starts having GTC. Identify seizure type(s) and state differential diagnosis

History: Recent/Remote trauma, drugs, alcohol, sleep deprivation Personal or Family history of similar events Other problems referable to the central nervous system

Physical and neurologic examination:CBC, electrolytes ( Na, K, Ca, Mg, glucose)Neuroimaging

CT with contrast may be sufficient These days MRIs quite common, especially if complex

partial to look for mesial temporal sclerosisElectroencephalogramLumbar puncture is usually not required

Strong familial history of epilepsyEEG showing clear epileptic abnormalitySeizure associated with neurologic deficitSeizure associated with MRI or CT

abnormalityIn adults, type of work, family and driving

status may influence physician’s decision Untreated, only half of young adults will

have a second seizure after their first convulsion

A 25 y/o man presented with a fever to 103 and had altered mental status followed by a GTC. Spinal tap is completed and consistent with bacterial meningitis. He got full course of antibiotics and is normal at the time of discharge. MRI and EEG completed one month later were normal.

A. Does this patient have epilepsy?B. How would you treat or counsel this patient?

Start treatment with one anti-epileptic drug (AED) known to be effective against that type of seizure

Determine blood level after an interval equal to 4-5 times of the drug’s half life.

If seizures continue despite reaching high serum levels (compare serum level to reference range for that AED) may add another AED

If seizures stop after the second AED, consider slowly withdraw the first AED to determine if the second AED is effective as monotherapy

Never stop anticonvulsant abruptly as that may provoke a seizure

Mechanisms of anticonvulsantsVoltage dependent Na channelsModulation of Ca channelsEnhancing GABA Block excitatory neurotransmitters

Phenobarbital 1912 Dilantin (phenytoin) 1938 Mysoline (primidone) 1954 Celontin (methsuximide) 1957 Zarontin (ethosuximide) 1960 Valium (diazepam) 1968 Tegretol (carbamazepine) 1974

Also Tegretol-XR and Carbatrol Klonopin (clonazepam) 1975 Depakote, Depakene (valproate) 1978

now IV form and Depakote-ER Tranxene (clorazepate) 1981

Side effects common to all: Skin Rash, diplopia, drowsiness, dizziness, ataxia

Pharmacology20 Hour half life, 90% protein boundExtended release form (phenytek)

Clinical considerationsPrimarily used for Partial Seizures But used for GTC in emergencies100 mg capsules, 300 mg/day dose,IV available15-20 µg blood levels

ProblemsAtaxia and nystagmusHirsutism, gingival hyperplasia, and rash

Pharmacology75% protein boundHalf life 9-17 hours; There are 2 extended release

formsCYP450 Inducer and metabolized by CYP450

Induces its own metabolismClinical considerations

Primarily used for partial seizures8-12 µg blood levelsOriginally approved for pain/Trigeminal Neuralgia

ProblemsDrowsiness on overdoseRash, diplopia, aplastic anemia, hepatic failure Blood counts (agranulocytosis) and LFT s ARE

recommended

Pharmacology90% Protein boundHalf life 6-16 hours, has ER formulation

Clinical ConsiderationsPartial and generalized epilepsyMigraine250 mg tabs, 2000 mg/day50-100 µg blood levels Oral, rectal, IV

ProblemsDrowsiness on overdoseWeight gain, hair loss, tremor, hepatic

failure Blood counts, coagulation studies, & LFT s

CYP450 Inducers: Phenytoin, Tegretol, PhenobarbitalMenomonic: PCP

CYP450 Inhibitor: Depakote Important to know because patient may already

be on agent metabolized by CYP450 so you should know how these agents will interact:Eg. If patient already on coumadin (warfarin)

which is metabolized by CYP450, what will starting dilantin (phenytoin) do to the patient’s INR?

Question: Your 38 y/o patient who you have been treating for epilepsy with carbamazepine just took a long flight from Australia and developed a pulmonary embolus. He was subsequently diagnosed with a hypercoagulable state and after being treated with IV heparin a decision was made to place him on warfarin. A. What issues must you consider when starting

warfarin in this patient?B. His seizures have always been fairly easily

controlled and there have been no other comborbidities including no psychiatric problems. What other seizure medication would you worry about interacting with warfarin: Pick all that apply.A. PhenytoinB. PhenobarbitalC. LevetiracetamD. GabapentinE. PregabalinF. Valproic Acid

Felbatol (felbamate) 1993 Neurontin (gabapentin) 1993 Lamictal (lamotrigine) 1994

Now Lamictal ER available (2009) Cerebyx (fosphenytoin) 1996 Topamax (topiramate) 1996 Gabatril (tiagabine) 1997 Keppra (levetiracetam) 1999

Now Keppra XR available (2009) Zonegran (zonisamide) 2000 Trileptal (oxcarbazepine) 2000 Lyrica (pregabalin) 2004 Lacosamide (Vimpat) 2009 Rufinamide (Banzel) 2009 Vigabatrin 2009 ?Coming Soon: Brivaracetam

Advantages

Effective as primary and/or secondary AED’s for

most forms of adult epilepsies

In general have low protein binding, less drug

interactions, and less serious side effects.

Disadvantages

Expensive

Long term complication are unknown

Pharmacology25 hours half life, XR form available55% Protein bound

IndicationsPartial and generalized epilepsyChildhood epilepsiesBipolar depressionMost neurologists/epileptologists (the ones I know)

prefer this agent in young womenDosage and management

Titration schedule depends on what other agents patient taking. Many pharmacies have starter kit with instructions

300-400 mg/day,

ProblemsInteractions

PTN and CBZ induce metabolismVPA slows metabolismDecreases OCP levels,

mechanism unknownComplications

Skin rash (not serious)SomnolenceAtaxiaEarly cases of Stevens Johnson

Pharmacology GABA analog No protein binding No enzyme induction Secreted by kidney Half life 7 hours (bid/tid) No blood studies required

Clinical Considerations Partial epilepsy Migraine Neuropathic pain Panic attacks 300mg tabs, Up to 1800mg a day

Side Effects Drowsiness, weight gain, careful dosing with renal

failure

PharmacologyHalf life of 7-8 hours, XR now availableAvailable in 500mg, 750mg, 1000mgLow protein binding (10%)Almost fully excreted by kidney

Clinical ConsiderationsPartial and Generalized epielpsyGood for myoclonusOral and IV formulations. Easy Conversion

Side Effects: Agitation, IrritableExacerbate psychiatric symptoms (eg. Psychosis)

PharmacologyHalf Life: 19-23 hours; PB=15%25 , 100, 200 mg tabs, 200-600 mg/dayStart with 25 mg bid and titrate

Clinical ConsiderationsBroad Spectrum: Partial and generalized epilepsyCauses weight Loss, will also treat migraine

ProblemsCarbonic anhydrase inhibitor so also functions as

diureticKidney stones and secondary angle closure glaucoma (Both uncommon). Encourage good hydration.

Somnolence, dizziness, word finding difficulty, behavior

DilantinTegretolvalproic acidZarontinGabapentinTopiramateTiagabineLevetiracetamZonisamideLamotrigine

HL:24h PB: 90%HL:12-17h PB:70%HL: 8-9h PB: 90%HL: 60hHL: 5-7h PB<3%HL:19-23h PB:15%HL: 7-9h PB: 97%HL: 7-8h PB:10%HL: 30h PB:40-60%HL: 25h PB: 55%

HL = Half Life PB = %Plasma Bound

Status EpilepticusSUDEP (Sudden Unexplained Death From

Epilepsy)DepressionDrivingPregnancyPharamcoresistant EpilepsyGeneric SubstitutionMilitary service: Will go into when we discuss

the case

Definition: recurrent seizures over a short time- patient does not regain consciousness between seizures

Can be convulsive or nonconvulsiveHow it happens: often no explanation

Physiologically: Failure of the brain’s inhibitor mechanisms to regain control

Associated with acute intra-cranial pathologyAfter hasty adjustment of medication in a

severely epileptic patient or non-adherence to med regimen

Associated with toxic or metabolic disorders

1st Monotherapy

(470)

2nd Monotherapy

(190)

3rd

Monotherapy or adjunctive therapy

(65)

4 drugs (25)

100

80

40

20

0

60

Kwan, Brodie. N Engl J Med 2000;342:314-319 Brodie, Kwan. Neurology 2002;58(suppl 5):S2-S8

Monotherapy: Primary agents60% complete control

Polypharmacy: New agents and how they are tested20 % complete control

Intractable: 20%

Pharmacoresistant=Failed 2 or more AEDs

Consider different types of surgery

Most common: Resection (Particularly temporal lobe)

If not candidate for resective surgery, consider for VNS

Additional options in special cases

Indication: patient with refractory epilepsy who is not a candidate for epilepsy surgery

A stimulating electrode is surgically attached to the left vagus nerve

The current travels through vagus nerve and synapses in Nucleus Tractus Solitarius, and then spreads to reticular formation, midbrain and limbic system

High frequency stimulation can decrease seizures 50-60%.

Stimulation of the Anterior Nucleus of the Thalamus (SANTE):

Responsive NeuroStimulator (RNS)Neuropace

Routine EEG typically a 30 to 45 minute “snapshot”—not enough to make clinical decisions in some patients. In such an instance LTM or longer EEG (hours)

Video recording time-locked with EEG so can characterize spells

Planning for Epilepsy surgery—localize epileptogenic zone

Common diagnoses from monitoring: Epilepsy, Nonepileptic seizures, Syncope, Cardiac arrythmias, parasomnias, Normal

23 y/o AD USA had a GTC in December 2008.Denies other medical problems and denies having had any

other spells.Normal neurological exam and normal intelligenceMRI of brain and multiple Routine EEGs were normal.On careful questioning,

Myoclonic jerks upon awakening since July 2006. Vision turns black and loses control for that 1 second and back to normal

Multiple falls. Worse if sleep deprived or after he has had ETOH night

before. He lives in barracks and says that he gets up earlier than

everyone else so that he can get the “shakes” out of his systemAdmitted to the medicine service for long term EEG

monitoring

These seizures are characterized by sudden, brief shocklike contractions that may be generalized or involve the face , trunk or one or more extremities.

Myoclonic jerks may be large enough to cause the individual to fall to the floor or drop things.

EEG Correlate of Generalized spike and wave discharges

Idiopathic generalized epilepsy syndromeMyoclonic jerks, GTC, Absence seizuresSpells typically occur first couple hours after awakeningFamily history

Precipitating factorsStress, sleep deprivation, non-adherence to med

regimen, alcohol, time of day, photic stimulation, Menses

ComplaintsMay report clumsiness: Myoclonic jerk while holding

objectEEG: generalized spike and wave/polyspike and wave

discharges

Probably autosomal dominant with incomplete penetranceGene mutations found to date: calcium channel,

GABA receptor subunit, Chloride channel Represent 5-10% of epilepsy cases in USTypically begins in adolescence (12-18y/o), but

age of onset varies from age 6 to 36 y/o.Prognosis: Good

Responds well to meds but require lifelong treatmentRisk of recurrence>80% if anticonvulsants

withdrawnRx: VPA, Keppra, Zonegran, Lamictal, Topamax

Started on KeppraNo Driving, particularly government vehicleNo handling firearmsNo swimming unattended/No bathsMed Board

Brodie MJ, Kwan P. Staged Approach to Epilepsy Management. Neurology. 2002 Apr 23;58(8 Suppl 5): S2-8

Browne TR, Holmes GL. Handbook of Epilepsy. 2nd ed. Philadelphia, PA:2000

Cossu M, et al. Epilepsy Surgery in Children: Results and Predictors of Outcome of Seizures. Epilepsia. 2007; Jul 21:1-8

Engel J, Pedley TA. Epilepsy: A Comprehensive Textbook. Philadelphia, PA:1998

Kwan P, Brodie MJ. Early Identification of Refractory Epilepsy. The New England Journal of Medicine. 2000 Feb 3;342(5):314-19

Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology. 1999 Nov 10;53(8):1731-5

Thiele, E. Assessing the Efficacy of Antiepileptic Treatments: The Ketogenic Diet. Epilepsia. 2003 44(Suppl. 7):26-29

Wiebe S, et al. A Randomized Controlled Trial of Surgery for Temporal-Lobe Epilepsy. The New England Journal of Medicine. 2001; Aug 345:311-318

Wyllie E. Treatment of Epilepsy Principles and Practice. 3rd ed. Philadelphia, PA: 2001

www.aesnet.org

Maintain vital signsProtect the patient from injuryDraw blood for CBC, electrolytes, glucose,

and blood gasesGive thiamine when plan to give glucose (esp

if alcoholic)Keep a large vein open

Lorazepam (2mg IV once). Followed by Fosphenytoin (15-20mg/kg)If ineffective within 15-20 minutes

More Lorazepam up to mg/Kg. Next Step is operator Dependent:Traditionally Phenobarbital 15-20mg/Kg slow

push – Recent data shows can use Levetiracetam

(Keppra) 2g IV pushMay need to place patient in pharmacologic

comaWatch for respiratory and circulatory failure

Pentobarbital: IV 5-6mg/kg followed by 1-2mg/h . Titrated according to the severity of seizures

Continuous EEG monitoringIf patient placed in pharmacologic coma,

optimal to have the EEG running continuously to follow therapeutic goals

Suppression burst pattern is desirable Versed and Propofol are also commonly used