Presented by : Mr. Eb

DEFINITION

Epilepsy is defined by the International League Against Epilepsy (ILAE) a “condition characterized by recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause.”

Seizures are the manifestation of abnormal hypersynchronous discharges of cortical neurons.

Epidemiology of Epilepsy

• Epilepsy is a chronic neurological disorder that affects people of all ages.

• There are over 50 million sufferers in the world today, 85% of whom live in developing countries;

• An estimated 2.4 million new cases occur each year globally;

• At least 50% of cases begin at childhood or adolescence;

• 70% to 80% of people with epilepsy could lead normal lives if properly treated;

• In developing countries, 60% to 90% of people with epilepsy receive no treatment due to inadequacies in health care resources and delivery, and due to social stigma.

Prevalence in Malaysia

• There is no previous community based prevalence study of epilepsy in Malaysia.

• The prevalence is assumed to be similar to Singapore, which shares many commonalities in history, ethnicity and culture, at about 5 per thousand populations.

Pathophysiology of EpilepsyPathophysiology of Epilepsy

In normal brain inhibitory circuits limits synchronous discharge. GABA is particularly play this role.When GABA receptors blocked Rhythmic and repetitive hypersynchronus discharge of neurons seizuresExcitatory NT Ach , Aspartate and Glutamate also involved to develop seizuresIntracellular recording shows burst of rapid action potential firing with reduction of transmembrane potential. inhibitory system + excitation genesis of seizuresAbnormalities in Ion Channel(Na+, K+, Ca-) may cause seizures.(Prolongation of depolarization state)

Pathophysiology of Epilepsy Pathophysiology of Epilepsy contdcontd

Repeated subthreshhold of a neuron generates an action potentials seizuresIt has been suggested that chronic epileptic discharges may lead to secondary epileptogenesis.Short, uncomplicated seizures cause no permanent/ progressive neorological dysfunctions in human brain

BUTuncontrolled generalized tonic-clonic seizures or status epilepticus is associated with high neurological morbidity and permanent brain damage ( due to hypo perfusion, hypoxia, acidosis and other metabolic disturbance).).

Etiology of Seizures and Epilepsy

Infancy and childhood– Prenatal or birth injury– Inborn error of metabolism– Congenital malformation

Childhood and adolescence– Idiopathic/genetic syndrome– CNS infection– Trauma

Etiology of Seizures and Epilepsy

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

• Seizure types are organised firstly according to whether the source of the seizure within the brain is localised (partial or focal onset seizures) or distributed (generalised seizures).

• Partial seizures are further divided on the extent to which consciousness is affected.

• If it is unaffected, then it is a simple partial seizure; otherwise it is a complex partial seizure.

Classification of Seizures

• A partial seizure may spread within the brain - a process known as secondary generalisation.

• Generalised seizures are divided according to the effect on the body but all involve loss of consciousness.

• These include absence (peitit mal), myoclonic, clonic, tonic, tonic-clonic (grand mal) and atonic seizures.

Classification of Seizures

ILAE Classification of Seizures

Seizures

Partial Generalized

Simple Partial

Complex Partial

Secondarily Generalized

Absence

Myoclonic

Atonic

Tonic

Tonic-Clonic

ILAE – International League Against Epilepsy 1981

SIMPLE PARTIAL SEIZURES

COMPLEX PARTIAL SEIZURES

TONIC-CLONIC SEIZURES

ABSENCE SEIZURES

ATONIC SEIZURE

MYCLONIC SEIZURES

Classification of the epilepsies and epileptic syndromes

Idiopathic / geneticepilepsies

• Localisation related:– Benign centrotemporal epilepsy– Benign occipital epilepsy– Autosom dominant nocturnal frontal

lobe epilepsy

• Idiopathic generalised epilepsy:

– Childhood and juvenile absence– Juvenile myoclonic epilepsy– Grand mal seizures on awakening

Symptomatic epilepsies

• Localisation related :– Temporal lobe

epilepsy– Frontal lobe epilepsies– Parietal, occipital lobe

epilepsies

• Symptomatic generalised epilepsies:

– West- syndrome– Lennox-Gastaut

syndrome Cryptogenic epilepsies

DIAGNOSIS

History (based on the history obtained from the patient and, most importantly, the observers).

Blood tests: CBC, electrolytes, glucose, calcium, magnesium, phosphate, hepatic and renal function

Lumbar puncture (only if meningitis or encephalitis suspected and potential for brain herniation is excluded)

Blood or urine screen for drugs Electroencephalogram (EEG) CT or MR brain scan

Differential DiagnosisDifferential Diagnosis

Condition mimicking Seizures:Condition mimicking Seizures:

• Syncope (eg, cardiac arrhythmia, vasovagal syncope, dysautonomia)

• Metabolic conditions (eg, hypoglycemia)• Migraine (eg, migrainous aura, migraine equivalent)• Vascular conditions (eg, transient ischemic attacks)• Sleep disorder (eg, cataplexy, narcolepsy, night terror)• Movement disorder (eg, paroxysmal dyskinesia)

Mechanism of action of AEDs

• Sodium Channel Blockers

• Carbamazepine • Phenytoin • Oxcarbazepine • Lamotrigine • Zonisamide

• GABA Receptor Agonists

• Clobazam • Clonazepam • Phenobarbital • Primidone

Mechanism of action of AEDs

GABA Reuptake Inhibitors

• Tiagabine

GABA Transaminase Inhibitor

• Vigabatrin

AEDs With a Potential GABA Mechanism of Action

• Gabapentin • Pregabalin• Valproate

Glutamate Blockers • Felbamate • Topiramate

AEDs With Other Mechanisms of Action

• Levetiracetam

Principals of pharmacological treatment• Use the right drug for the seizure type• Begin with low dose, review, increase gradually (6-8 weeks)• Use one drug and increase the dose until a therapeutic

effect is gained or toxicity appears (maximum tolerated dose)

• Monitor treatment including blood levels• If required add a second drug.

– If a response consider slowly removing the first drug

Principals of pharmacological treatment (cont.)• If monotherapy fails use two drugs

– Review and replace the combinations used

• Introduce alternative AED slowly if unable to control seizures, Withdraw first AED/ consider long-term 2 drug therapy

• Additional third AED, review diagnosis & compliance.• Evaluate for progressive structural lesions, especially

those with partial seizures.• May consider surgery

Choosing Antiepileptic Drugs

Broad-Spectrum Agents

ValproateFelbamateLamotrigineTopiramateZonisamideLevetiracetamRufinamide*Vigabatrin

Narrow-Spectrum Agents

Partial onset seizuresPhenytoinCarbamazepineOxcarbazepineGabapentinPregabalinTiagabineLacosamide*

AbsenceEthosuximide

* New AEDs (approved 2008) categorization may change* New AEDs (approved 2008) categorization may change

Antiepileptic Drug Monotherapy

Simplifies treatment

Reduces adverse effects

Conversion to monotherapy– Eliminate sedative drugs first– Withdraw antiepileptic drugs slowly over several months

Choosing Antiepileptic Drugs (cont.)

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

Azar NJ and BW Abou-Khalil. Seminars in Neurology. 2008; 28(3): 305-316.

[PubMed]

Choosing Antiepileptic Drugs (cont.)

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)

Choosing Antiepileptic Drugs (cont.)

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

Choosing Antiepileptic Drugs (cont.)

Myoclonic Seizures

Best evidence:Valproate Levetiracetam (FDA indication as adjunctive tx)Clonazepam (FDA indication)

Possibly effective:

Zonisamide, Topiramate

Choosing Antiepileptic Drugs (cont.)

Lennox-Gastaut Syndrome

Best evidence/FDA indication*:

Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide, Valproate

* FDA approval is for adjunctive treatment for all except clonazepam

Some evidence of efficacy:

Zonisamide, Levetiracetam

AED combinations

• Rules of AED combination:– Establish optimal dose of baseline AED– Avoid combining similar modes of action– Add drug with multiple mechanisms– Titrate new drug slowly– Be prepared to reduce dose of original drug– Replace either drug if response is poor

• Some effective combinations:– valproate-lamotrigine– valproate-carbamazepine/oxcarbazepine– valproate-topiramate– etc.

Dosage of commonly used AEDs

Dosage of commonly used AEDs

Dosage of commonly used AEDs

Pregnancy and Epilepsy 96% of pregnancies in mothers with epilepsy produce

normal children Spontaneous abortions and pre-term birth are more

common in women with epilepsy There is an increased rate of fetal malformations

associated with antiepileptic drug exposure Seizures during pregnancy may be harmful

Tonic-clonic seizures associated with intracranial hemorrhage, fetal bradycardia and lower IQ in children

Status associated with increased fetal and maternal mortality in some studies

Insufficient data on non-convulsive seizures

C-Slide 36

Harden CL et al. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]

Pregnancy and Epilepsy:Major Congenital Malformation (MCM) and AEDs

Most available data on risk of AEDs comes from pregnancy registries.

Main outcome variable of most registries are major congenital malformations (MCM)

MCM = malformation that affects physiologic function or requires surgery Neural tube defects Cardiac defects Genitourinary defects Oral clefts

MCMs are more common with AED exposure MCM risk in general population 1.6-2.1% MCM risk with AED monotherapy 4.5% (OR 2.6) MCM risk with Polytherapy 8.6% (OR 5.1)

Holmes et al. N Engl J Med. 2001;344:1132–1138. [PubMed]

Pregnancy and Epilepsy:Major Congenital Malformation and AEDs

Valproate consistently associated with poorer outcomes MCM rate with valproate monotherapy 6.2-13.2% across 5 registries Most studies show dose- related increase in risk with doses >

1000mg/day Polytherapy regimens including valproate also substantially increased

risk of MCM Valproate associated with lower IQs in exposed children

Phenobarbital probably also poses higher risk of MCM

compared with other monotherapy regimens.

C-Slide 38

Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]

Pregnancy and Epilepsy:Major Congenital Malformation and AEDs

MCM rate similar among other studied AEDs in monotherapy, but not enough data to show significant difference between them Levetiracetam

Early data promising (0% in monotherapy, 2.7% in polytx) Carbamazepine (2.2-3.9%)

Substantial data available, relatively good track record Lamotrigine (1.4-4.4%)

Increased risk (5.4%) with doses > 400/day Gabapentin (0-3.2%) Topiramate (0-4.8%) Phenytoin (3.2-6.7%) Zonisamide, Pregabalin

Limited monotherapy data

Meador KJ, Pennell PB, Harden CL, Gordon JC, Tomson T, Kaplan PW, Holmes GL, French JA, Hauser WA, Wells PG, Cramer JA., HOPE Work Group. Pregnancy registries in epilepsy: A consensus statement on health outcomes. Neurology. 2008;71:1109–1117. [PubMed]

Pregnancy and Epilepsy Guidelines for Management

All women of child-bearing potential should receive education and carefully considered management before and during pregnancy to optimize the chances of a good outcome for both mother and child.

Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.

Pregnancy and Epilepsy Guidelines for Management

Education

– Most women with epilepsy have normal children

– Risk of fetal malformations is increased with AED exposure

– AED teratogenicity is related to exposure in the first trimester of pregnancy

– Planning should begin well before pregnancy

– Seizures may be deleterious to the fetus

– Compliance with AED treatment is important

– Prenatal diagnosis of fetal malformations is possible

Pregnancy and Epilepsy Guidelines for Management

Before pregnancy

– Attempt AED monotherapy with lowest effective dose

– Consider switching AEDs prior to pregnancy, particularly if on valproate

– Establish baseline therapeutic levels

– Folate supplementation

• 0.4 – 5 mg/day

Pregnancy and Epilepsy Guidelines for Management

During pregnancy

– Monitor AED dose requirements to maximize seizure control

• Particularly with lamotrigine (levels fall > 50% and sz increase)

• Also increased clearance of levetiracetam, oxcarbazepine, phenobarbital and phenytoin

– Continue folate supplementation

– Consider Vit K (10 mg/day orally) starting at 36 weeks

Breast Feeding and Epilepsy

Breastfeeding should be encouraged unless clear risk posed

Probably safe:

– Carbamazepine

– Phenytoin

– Valproate

– Lamotrigine

“Use with caution” in lactating women:

– Primidone

– Phenobarbital

– Ethosuximide

Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref]

Status Epilepticus

• Definition:

A seizure or a series of seizures lasting more than 30 min, without recovery of full consciousness.

• Risk of mortality and morbidity rise with time.

Treatment of Status Epilepticus

Treatment of Status Epilepticus

Treatment of Status Epilepticus

Treatment of Status Epilepticus

Adverse Effects of AEDs: CommonTypically dose-related:

Dizziness , Fatigue , Ataxia, Diplopia all AEDs

Irritability levetiracetam

Word-finding difficulty topiramate

Weight loss/anorexia topiramate, zonisamide, felbamate

Weight gain valproate (also associated with polycystic ovarian syndrome ) carbamazepine, gabapentin, pregabalin

Adverse Effects of AEDs: Serious

Typically Idiosyncratic:

Renal stones topiramate, zonisamide

Anhydrosis, heat stroke topiramate

Acute closed-angle glaucoma topiramate

Hyponatremia carbamazepine, oxcarbazepine

Adverse Effects of AEDs: Serious

Typically Idiosyncratic:

Aplastic anemia felbamate, zonisamide, valproate, carbamazepine

Hepatic Failure valproate, felbamate, lamotrigine, phenobarbital

Peripheral vision loss vigabatrin

Rash phenytoin, lamotrigine, zonisamide, carbamazepine

AED-related rash in

adult patients with epilepsy

▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05)▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)

Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]

Return to index

Adverse Effects of AEDs: Rash

Drugs rarely associated with rash Valproate Gabapentin Pregabalin Levetiracetam Topiramate

AED-related rash in Asian patients

www.fda.gov

FDA alert 12/2007

Risk of “dangerous or even fatal skin reactions” such as Steven-Johnson Syndrome and Toxic epidermal necrolysis is incrased in patients with HLA-B*1502 allele Estimated absolute risk for those with the allele: 5%

This allele is almost exclusively found in Asians10-15% of population in China, Thailand, Malaysia, Indonesia, Phillipines and Taiwan

2-4% in India<1% in Japan and Korea

59/60 Asian patients w/ SJS/TEN had this allele vs 4% of CBZ tolerant patients

Asians “should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine”

These patients may also be at risk with other AEDs (phenytoin)

Drug interactions

Enzyme inductors

carbamazepine, phenytoinphenobarbital, primidon

Increase of metabolism / decrease of efficacy

valproate, lamotrigine, topiramate, carbamazepine

oral contraception

oral anticoagulation

Enzyme inhibitors

Valproate ,felbamate

Decrease of metabolism / increase in efficacy - toxicity

lamotrigine, carbamazepine, phenytoin

Does not cause interaction

lamotrigine, gabapentin, topiramate, vigabatrin, tiagabin

Compliance

• For a drug to be effective it has to be taken• Non compliance is an important issue in poor control• Patients must be fully involved in decisions• Patients views must be respected• Better knowledge and respect leads to better compliance

Why don’t patients comply?

• Poor communication• Poor memory• Poor understanding of instructions• Mis-information• Side effects• Poor dose regimes• Difficult to swallow/nasty taste medication

Good information makes medicines work

When should levels be monitored?

• Uncontrolled seizures• Recurrence of seizures• Side effects• Assessment of compliance• Confirmation of desired results• Assessment of therapy when seizures infrequent• Minor dose adjustments• Concurrent illness

But

• Blood concentrations are a guide only• Timing of sample important• Never look at the blood level in isolation• Always consider blood level with respect to:

– Side effects– Seizure frequency

When to stop treatment??

• > 60% of patients who remain seizure free, medication an be eventually withdrawn successfully.

• AEDs should be withdrawn slowly over 6 months to 1 year.

• Polytherapy, one drug at a time starting with the least useful drug.

• Discussion with patients, after 2 years of seizure free.

• Decision to stop must balance the risks of continuation with the implication of relapse.

Surgical treatment of Epilepsy

• 30% seizure continue despite appropriate drug therapy.• medically intractable seizures.• Patients whose seizures may be relatively well controlled

but have lesions that strongly suggest that surgical intervention might curative (eg low grade tumours, vascular malformations)

• Surgical types: anterior temporal lobectomy, lesionectomy, functional hemispherectomy, corpus callostomy.

• Outcomes: 40-80%, depending on the surgical procedures.• Complications: mortality risk < 1%, morbidity 2-5%.

Non-Drug Treatment/Lifestyle Modifications

Adequate sleep

Avoidance of alcohol, stimulants, etc.

Avoidance of known precipitants

Stress reduction

References• Consensus guideline on the management of epilepsy 2010• www.fda.gov• Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]

Harden CL et al. Practice parameter update: management issues for women with epilepsy. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]

Rowan AJ et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology. 2005 Jun 14;64(11):1868-73. [PubMed]

Azar NJ and BW Abou-Khalil. Considerations in the Choice of an Antiepileptic Drug in the Treatment of Epilepsy. Seminars in Neurology. 2008; 28(3): 305-316. [PubMed]

• Lanska MJ et al. Neurology. 1995 Apr;45(4):724–732. [PubMed]• Saliba RM et al. Am J Epidemiol. 1999;150:763–769. [PubMed]• Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] • Glauser T, Ben-Menachem, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of

antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47(7): 1094-1120. [PubMed]

• Harden CL et al. Neurology. 2009 Jul 14;73(2):133-41. [PubMed]• Holmes et al. N Engl J Med. 2001;344:1132–1138. [PubMed]• Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, andLiporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health, Menopause, and• Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref] Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9 [crossref]

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