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Epilepsy

Dr.Yotin Chinvarun M.D., Ph.D.

Comprehensive Epilepsy and Sleep disorder Program

PMK hospital

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Definitions

•! Seizure: the clinical manifestation of an abnormal

and excessive excitation of a population of cortical

neurons

•! Epilepsy: a tendency toward recurrent seizures

unprovoked by systemic or neurologic insults

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Epidemiology of Seizures and Epilepsy

•! Seizures

–!Incidence: approximately 80/100,000 per year

–!Lifetime prevalence: 9%

(1/3 benign febrile convulsions)

•! Epilepsy

–!Incidence: approximately 45/100,000 per year

–!Point prevalence: 0.5-1%

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Classification of epilepsy

•! Seizure classification is important, guiding the

investigation, therapy, and prognosis of seizure

types. The major subdivisions are

•! Primarily generalised seizures

•! Partial seizures

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International classification of epilepsies

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International classification of epilepsies

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International classification of epilepsies

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Seizures

Partial Generalized

Simple Partial

Complex Partial

Secondarily

Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

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Partial Seizures

•! Simple

•! Complex

•! Secondary generalized

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Seizures

Partial Generalized

Simple Partial

Complex Partial

Secondarily Generalized

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Simple Partial Seizure Subclassification

•! With motor signs

•! With somatosensory or special sensory symptoms

•! With autonomic symptoms or signs

•! With psychic symptoms (disturbance of higher cerebral function)

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EEG: Simple Partial Seizure

•! Left parietal-

posterior

temporal

seizure

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Seizures

Partial Generalized

Simple Partial

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! Impaired

consciousness

! Clinical manifestations vary

with site of origin and

degree of spread

•! Presence and nature

of aura

•! Automatisms

•! Other motor activity

! Duration typically < 2

minutes

Seizures

Partial Generalized

Complex Partial

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Complex Partial Seizures

•! Impaired consciousness

•! Clinical manifestations vary with site of origin and degree of

spread

–! Presence and nature of aura

–! Automatisms

–! Other motor activity

•! Duration (15 sec.—3 min.)

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! Begins focally, with or without focal neurological symptoms

! Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases

! Typical duration 1-3 minutes

! Postictal confusion, somnolence, with or without transient focal deficit

Seizures

Partial Generalized

Secondarily

Generalized

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Secondarily Generalized Seizures

•! Assumed or observed to begin as simple and/or complex partial

seizures

•! Variable symmetry, intensity, and duration of tonic (stiffening)

and clonic (jerking) phases

•! Usual duration 30-120 sec.

•! Postictal confusion, somnolence, with or without transient focal

deficit

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Right temporal

seizure with

maximal phase

reversal in the

right sphenoidal

electrode

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Continuation of same

seizure

Right temporal

seizure with maximal

phase reversal in the

right sphenoidal

electrode

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Seizures

Partial Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

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! Brief staring spells (“petit mal”) with impairment of awareness

!! 3-20 seconds

!! Sudden onset and sudden resolution

!! Often provoked by hyperventilation

!! Onset typically between 4 and 14 years of age

!! Often resolve by 18 years of age

! Normal development and intelligence

! EEG: Generalized 3 Hz spike-wave discharges

Seizures

Partial Generalized

Absence

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Seizures

Partial Generalized

Simple Partial

Complex Partial

Secondarily

Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

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Primary generalized seizures

•! Have a bilateral symmetrical onset.

•! The clinical manifestations are diverse, and include:-

•! Tonic,

•! clonic, or

•! tonic-clonic(‘grand mal’)

•! Absence

•! Myoclonus

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EEG: Absence Seizure

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! Brief staring spells with variably reduced responsiveness

!! 5-30 seconds

!! Gradual (seconds) onset and resolution

!! Generally not provoked by hyperventilation

!! Onset typically after 6 years of age

! Often in children with global cognitive impairment

! EEG: Generalized slow spike-wave complexes (<2.5 Hz)

! Patients often also have Atonic and Tonic seizures

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

! Epileptic myoclonus

!! Typically bilaterally synchronous

!! Impairment of consciousness difficult to assess (seizures <1 second)

!! Clonic seizure – repeated myoclonic seizures (may have impaired awareness)

! Differentiate from benign, nonepileptic myoclonus (e.g., while falling asleep)

! EEG: Generalized 4-6 Hz polyspike-wave discharges

Seizures

Partial Generalized

Myoclonic

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Tonic seizures

!! Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck

!! Duration - 2-20 seconds.

!! EEG – Sudden attenuation with generalized, low-voltage fast activity (most common) or generalized polyspike-wave.

Atonic seizures

!! Sudden loss of postural tone

!! When severe often results in falls

!! When milder produces head nods or jaw drops.

!! Consciousness usually impaired

!! Duration - usually seconds, rarely more than 1 minute

!! EEG – sudden diffuse attenuation or generalized polyspike-wave

Seizures

Partial Generalized

Tonic

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!! Associated with loss of consciousness and post-ictal confusion/lethargy

!! Duration 30-120 seconds

!! Tonic phase

!! Stiffening and fall

!! Often associated with ictal cry

!! Clonic Phase

!! Rhythmic extremity jerking

!! EEG – generalized polyspikes

Seizures

Partial Generalized

Tonic-

Clonic

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Epilepsy Syndrome

Grouping of patients that share similar:

•! Seizure type(s)

•! Age of onset

•! Natural history/Prognosis

•! EEG patterns

•! Genetics

•! Response to treatment

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Epilepsy Syndromes

•! Partial epilepsies

–! Idiopathic (genetic related)

–!Symptomatic (lesion)

–!Cryptogenic (unknown cause)

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Epilepsy Syndromes (cont.)

•! Generalized epilepsies

–! Idiopathic

–! Symptomatic

–! Cryptogenic

•! Undetermined epilepsies

•! Special syndromes

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Etiology of Seizures

and Epilepsy

•! Infancy and childhood

–! Birth injury

–! Inborn error of metabolism

–! Congenital malformation

•! Childhood and adolescence

–! Idiopathic/genetic syndrome

–! CNS infection

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Etiology of Seizures

and Epilepsy (cont.)

•! Adolescence and young adult

–! Head trauma

–! Drug intoxication and withdrawal*

•! Older adult

–! Stroke

–! Brain tumor

–! Acute metabolic disturbances*

–! Neurodegenerative

*causes of acute symptomatic seizures, not epilepsy

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Questions Raised by a

First Seizure

•! Seizure or not?

•! Focal onset?

•! Evidence of CNS dysfunction?

•! Metabolic precipitant?

•! Seizure type? Syndrome type?

•! Studies?

•! Start AED?

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Seizure Precipitants

•! Low (less often, high) blood glucose

•! Low sodium

•! Low calcium

•! Low magnesium

•! Stimulant/other proconvulsant intoxication

•! Sedative or AEDs withdrawal

•! Severe sleep deprivation

•! Stress

•! Infection, fever

•! Concussion, closed head trauma

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Evaluation of a First Seizure

•! History, physical

•! Blood tests: CBC, electrolytes, glucose, Ca, Mg,

hepatic and renal function

•! Lumbar puncture only if meningitis or encephalitis

suspected and potential for brain herniation is ruled out

•! Blood or urine screen for drugs

•! Electroencephalogram

•! CT or MR brain scan

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EEG Abnormalities

•! Background abnormalities: significant asymmetries and/or

degree of slowing inappropriate for clinical state

•! Transient abnormalities associated with seizures and epilepsy

–! Spikes

–! Sharp waves

–! Spike-wave complexes

•! May be focal, lateralized, generalized

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Medical Treatment of

First Seizure

Whether to treat first seizure is

controversial

•! 16-62% will recur within 5 years

•! Relapse rate is reduced by antiepileptic drug treatment

•! Abnormal imaging, abnormal EEG or family history

increase relapse risk

•! Quality of life issues are important

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Choosing Antiepileptic Drugs

•! Seizure type

•! Epilepsy syndrome

•! Pharmacokinetic profile

•! Interactions/other medical conditions

•! Efficacy

•! Expected adverse effects

•! Cost

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!! Limited placebo-controlled trials available, particularly of newer AEDs

!! In practice, several drugs are commonly used for indications other than those for which they are officially approved/recommended

!! Choice of AED for partial epilepsy depends largely on drug side-effect profile and patient’s preference/concerns

!! Choice of AED for primary generalized epilepsy depends on predominant seizure type(s) as well as drug side-effect profile and patient’s preference/concerns

!! ILAE and AAN recommendations indications listed in the appendix

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Broad-Spectrum Agents

Valproate

Felbamate

Lamotrigine

Topiramate

Zonisamide

Levetiracetam

Rufinamide*

Narrow-Spectrum Agents

Partial onset seizures

Phenytoin

Carbamazepine

Oxcarbazepine

Gabapentin

Pregabalin

Tiagabine

Lacosamide*

Absence

Ethosuximide

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Choosing Antiepileptic Drugs (cont.)

•! Partial onset seizures

phenytoin* gabapentin

carbamazepine* phenobarbital

valproate primidone

lamotrigine felbamate**

topiramate

Tiagabine

Lacosamide

* considered by many as drugs of choice

**associated with aplastic anemia and hepatic failure

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Monotherapy for Partial Seizures

Best evidence and FDA indication:

Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate

Similar efficacy, likely better tolerated:

Lamotrigine, Gabapentin, Levetiracetam

Also shown to be effective:

Valproate, Phenobarbital, Felbamate, Lacosamide

Limited data but commonly used:

Zonisamide, Pregabalin

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Choosing Antiepileptic Drugs (cont.)

•! Generalized onset seizures

Absence: valproate* = ethosuximide

Myoclonic: valproate, clonazepam

Tonic-clonic: valproate = phenytoin

Seizures in Lennox-Gastaut Syndrome:

valproate, lamotrigine, felbamate**

* the risk of valproate-induced hepatic failure must be carefully

weighed in young children

** associated with aplastic anemia and hepatic failure

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Monotherapy for Generalized-Onset Tonic-Clonic Seizures

Best evidence and FDA Indication:

Valproate, Topiramate

Also shown to be effective:

Zonisamide, Levetiracetam

Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )

Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies

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Absence seizures

Best evidence:

Ethosuximide (limited spectrum, absence only)

Valproate

Also shown to be effective:

Lamotrigine

May be considered as second-line:

Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam

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Myoclonic Seizures

Best evidence: Valproate

Levetiracetam (FDA indication as adjunctive tx)

Clonazepam (FDA indication)

Possibly effective:

Zonisamide, Topiramate

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Lennox-Gastaut Syndrome

Best evidence/FDA indication*:

Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide

* FDA approval is for adjunctive treatment for all except clonazepam

Also effective:

Valproate

Some evidence of efficacy:

Zonisamide, Levetiracetam

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Antiepileptic Drug Monotherapy

•! Simplifies treatment, reduces adverse effects

•! Conversion to monotherapy from polytherapy

–! Eliminate sedative drugs first

–! Withdraw antiepileptic drugs slowly over

several months

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!! Drugs that may induce metabolism of other drugs:

!! carbamazepine, phenytoin, phenobarbital, primidone

!! Drugs that inhibit metabolism of other drugs:

!! valproate, felbamate

!! Drugs that are highly protein bound:

!! valproate, phenytoin, tiagabine

!! carbamazepine, oxcarbazepine

!! topiramate is moderately protein bound

!! Other drugs may alter metabolism or protein binding of antiepileptic drugs (especially antibiotics, chemotherapeutic agents and antidepressants)

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Drugs that may decrease the efficacy of hormonal contraception

–! Phenytoin

–! Carbamazepine

–! Phenobarbital

–! Topiramate*

–! Oxcarbazepine*

–! Felbamate*

*at high doses

“High-dose” birth control pills are recommended for patients taking

these medications.

Lamotrigine levels decreased by hormonal contraception

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“Therapeutic Range” of AED Serum

Concentrations

A guide not a goal

•! Limited data

•! Broad generalizations

•! Individual differences

•! Useful in:

–! Providing initial target in patients with infrequent

seizures

–! Understanding unexpected seizures or side effects,

especially with polypharmacy

–! Verifying compliance

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Often dose-related:

Dizziness

Fatigue

Ataxia

Diplopia

Irritability

!! levetiracetam

Word-finding difficulty

!! topiramate

Weight loss/anorexia

!! topiramate, zonisamide, felbamate

Weight gain

!! valproate (also associated with polycystic ovarian syndrome in young women)

!! carbamazepine, gabapentin, pregabalin

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Typically idiosyncratic:

Renal stones

!! topiramate, zonisamide

Hyponatremia

!! carbamazepine, oxcarbazepine

Aplastic anemia

!! felbamate, zonisamide, valproate, carbamazepine

Agranulocytosis

!! carabamazepine

Hepatic Failure

!! valproate, felbamate, lamotrigine, phenobarbital

Anhydrosis, heat stroke

!! topiramate

Acute closed-angle glaucoma

!! topiramate

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!! 15.9% patients ever experienced a rash attributed to an AED

!! Average rate of AED-related rash for a given AED 2.8%, 2.1% causing AED discontinuation.

!! Predictors significant in multivariate analysis: !! occurrence of another AED-rash

Arif H et al. Neurology 2007!59 60

Stevens-Johnson Syndrome (SJS) and

Toxic Epidermal Necrolysis (TENS)

!! severe life threatening allergic reaction

!! blisters and erosions of the skin, particularly palms/soles and

mucous membranes

!! fever and malaise

!! rare: severe risk roughly 1-10/10,000 for many AEDs

!! rapid titration of lamotrigine especially in combination with

valproate increases risk

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