Treatment Strategies in Epilepsy: Sequential Monotherapy or Add-on Therapy

Bagian Ilmu Penyakit SarafRS Bayukarta

Karawang

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Marshall 2004

The UK National Institute of Clinical Excellence (NICE) has recommended that doctors in England and Wales should use the newer epilepsy drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin to treat epilepsy in adults who have not benefited from treatment with older drugs, such as carbamazepine or sodium valproate.

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Marshall 2004

NICE also recommends that patients should be treated with monotherapy wherever possible. If initial treatment is unsuccessful, monotherapy with an alternative drug should be tried. Combination therapy should only be an option when treatment with monotherapy has failed to prevent seizures. Lamotrigine, oxcarbazepine, and topiramate are licensed in the UK for use as monotherapy; all the drugs are licensed for use in combination therapy.

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Epilepsi (ILAE 1981)Bangkitan Parsial Bangkitan Umum T

IDAK

TERKLASIFIKASI

Bangkitan ParsialSederhana

Bangkitan ParsialKompleks

Bangkitan umum Sekunder (tonik, klonik,tonik-klonik)

(konvulsif & non-konvulsif)

Bangkitan mioklonik

Bangkitan lena (absence seizures)

Bangkitan klonik

Bangkitan tonik

Bangkitan atonik / astatik

Bangkitan tonik – klonik

Manifestasi motorikManifestasi sensorikManifestasi autonomikManifestasi psikik

Gambaran parsial sederhana diikuti serangan lena

Dg serangan lena pada awalnya

Etiologi Epilepsi

77%

5% 4% 4% 4%3%

2%1%

Primary - Idiopathic

Cerebrovascular

CNS Neoplasma

Congenital CNSMalformation

Trauma

CNS Infection

Other known

Birth asphyxia

Symptomatic or Cryptogenic (23%)

Primary – Idiopathic (77%)

Etiologi Epilepsi

10

20

30

40

50

60

Idiopathic

VascularTumor

TraumaTrauma lahirHerediter

Fre

ku

en

si re

lati

f

USIA

Perkiraan frekuensi macam-macam etiologi epilepsi berdasarkan usia

Algoritma Diagnosis EpilepsiSpells

Seizure Other

Non-epileptic Epileptic

Psychogenicpseudoseizures

Syncope with anoxic seizure

Recurent seizures Febrile seizure

Acute seizure (s)Single seizure(unprovoked)

Epilepsy Recurent febrileseizures

Seizure type(s) Etiology

Generalized,Partial, partial secondary generalization,Unclassified.

No syndromeSyndrome

Localization related Not localization related

Syncope, panic attack,migraine,TIA,movement disorder,Sleep disorder,etc

Metabolic, head trauma,stroke, drugs,

alcohol withdrawal,etc .

Seizure types,etiology,etc

All clinical and laboratory data, neuroimagingSeizure description and

EEG

TUJUAN PENGOBATAN PADA EPILEPSI Mengontrol gejala atau tanda (bangkitan) secara adekuat dengan

penggunaan obat yang minimal

PRINSIP PENGOBATAN1. Diberikan bila terdapat minimum 2 kali bangkitan dalam setahun2. Pengobatan mulai diberikan bila diagnosis telah ditegakkan dan

setelah penyandang dan atau keluarganya menerima penjelasan tujuan pengobatan dan kemungkinan efek samping

3. Pemilihan jenis obat sesuai dengan jenis bangkitan4. Seyogyanya pengobatan dengan monoterapi5. Pemberian obat dimulai dari dosis rendah dan dinaikkan bertahap

sampai dosis efektif tercapai6. Pada prinsipnya pengobatan dimulai dengan OAE lini pertama. Bila

diperlukan penggantian obat, obat pertama diturunkan bertahap dan obat kedua dinaikkan secara bertahap

7. Bila monoterapi gagal, dapat dipertimbangkan kombinasi OAE8. Bila memungkinkan dilakukan pemantauan kadar obat sesuai indikasi

Pedoman Tatalaksana Epilepsi, 2003

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AED Options for Specific Seizure Types

SEIZURE TYPE MONOTHERAPY ADJUNCTIVE 1st CHOICE 2nd CHOISE

Partial onset Carbamazepine Valproic acid GabapentinPhenytoin Phenobarbital LamotrigineOxcarbazepine Primidone Topiramate

TiagabineLevetiracetamZonisamideFelbamate

GeneralizedTonic-clonic Valproic acid Phenytoin Lamotrigine

Carbamazepine TopiramatePhenobarbital FelbamatePrimidone Zonisamide

Tonic, clonic, Valproic acid Phenobarbital Lamotrigineatonic Clonazepam Topiramate

FelbamateZonisamide

Absence Ethosuximide LamotrigineValproic acid Felbamate

AcetazolamideMyoclonic Valproic acid Phenobarbital Lamotrigine

Clonazepam TopiramateFelbamateZonisamide Blum, 2002

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DRUGS USED AS MONOTHERAPY

Partial and secondary generalized seizuresCarbamazepineSodium valproateOxcarbazepine Lamotrigine Levetiracetam Topiramate Phenytoin

Primary generalized seizures Sodium valproateLamotriginePhenytoinTopiramate Levetiracetam

Uncertain seizure typesSodium valproateLamotrigine

Faught, 2004

Newer drug proposedFewer long term side effectsRecommended with cautions

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AEDs should be offered after a first tonic-clonic seizure if :

The patient has had previous myoclonic, absence or partial seizures The EEG shows unequivocal epileptic discharges The patient has a congenital neurological deficit The patient considers the risk of recurrence unacceptable

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PHARMACOKINETICS OF COMMON AEDs

AED HALF-LIFE EFFECT UPON DOSING FREQUENCY (hours) HEPATIC ENZYMES (per day)

Phenytoin 7-42 Inducer 1-3Carbamazepine 12-17 Inducer 2-4Oxcarbazepine 9 Mild 2Phenobarbital 55-140 Inducer 1-3Valproic acid 6-16 Inhibitor 2-3Gabapentin 5-7 None 3Lamotrigine 25 Min Inducer 2-3Topiramate 18-30 Mild 2-3Levetiracetam 6-8 None 2

Adapted from Blum, 2002

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INITIATION SCHEDULE FOR COMMON AEDs

Phenytoin IV / oral load Carbamazepine Gradual initiation / 1-2 weeksOxcarbazepine Gradual initiation / 4-6 weeksValproic acid Immediate therapeutic doseGabapentin Immediate therapeutic doseLamotrigine Gradual initiation / 4-6 weeksTopiramate Gradual initiation / 4-6 weeksLevetiracetam Immediate therapeutic dose

Adapted from AAN, 2003

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SITE OF CLEARANCE FOR COMMON AEDs

Phenytoin > 90% hepaticCarbamazepine > 95% hepaticOxcarbazepine 45% renal; 45% hepaticValproic acid > 95% hepaticGabapentin 100%renalLamotrigine 85% hepaticTopiramate 30-50% hepatic; 50-70% renalLevetiracetam body water

Adapted from AAN, 2003

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SAFETY ISSUES ASSOCIATED WITH NEW ANDOLD AEDs

Phenytoin Aplastic anemia, hepatic failure, Steven-Johnson syndrome

Carbamazepine Aplastic anemia, hepatic failure, Steven-Johnson syndrome

Oxcarbazepine RashValproic acid Hepatic failure, pancreatitis, thrombocytopeniaGabapentin None knownLamotrigine Rash, Steven-Johnson syndrome, hypersensitivityTopiramate Renal calculi, hepatic failure, open-angle glaucoma,

hypohydrosisLevetiracetam None known

Adapted from AAN, 2003

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EFFECT OF NEWER AEDs ON OLDER AEDs

Adapted from AAN, 2003

Phenytoin Carbamazepine Valproic acid Phenobarbital

GabapentinTiagabineZonisamide none none none noneLevetiracetam

Lamotrigine none none ↓25% none

Topiramate may ↑ none none none

Oxcarbazepine may ↑ none slight ↑ none

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For most patients, antiepileptic monotherapy is both less likely to cause unwanted side effects and more likely to control seizure

Other advantages of monotherapy include lower costs, ease of compliance, and less chance for drug interactions.

Roughly 80% of patient with epilepsy are optimally treated with monotherapy

Use of the older generation of antiepileptic drugs is fraught with many pitfalls related to strong pharmacokinetic interactions, both among anticonvulsants and with other therapeutic classes

MONOTHERAPY vs POLYTHERAPY ???

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Partial Seizures First Choice: Carbamazepine

Not toleratedSodium valproateLamotriginePhenytoin

Continued seizure

If already taking: Add:Carbamazepine Sodium valproateSodium valproate LamotrigineLamotrigine Sodium valproatePhenytoin Sodium valproate

Controlled Improved but No improvement not controlled

Withdraw First drug Add one of

LamotrigineTopiramateGabapentinVigabatrin

Withdraw Second drug

SIGN 1999

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Primary GeneralizedSeizures

First Choice: Sodium valproate

Not toleratedEthosuximide / Lamotrigine(Absence)Lamotrigine / Clonazepam(Myoclonic/akinetic)Lamotrigine(Tonic clonic)

Continued seizure

If already taking: Add:Sodium valproate ABSENCE Ethosuximide / LamotrigineSodium valproate MYOCLONIC / AKINETIC Lamotrigine / ClonazepamSodium valproate TONIC-CLONIC Lamotrigine

If Sodium valproate not tolerated, and seizure control not achieved on second choice drug

Substitute: For:Lamotrigine / Clonazepam EthosuximideClonazepam LamotrigineLamotrigine Clonazepam

SIGN 1999

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Partial and secondary generalized seizures

First Line:CarbamazepineSodium valproateLamotrigineOxcarbazepine

Continued seizure

Withdraw First drug

Add one ofLevetiracetam/ Tiagabine/ LamotrigineTopiramate/ Gabapentin / VigabatrinOxcarbazepine

Withdraw Second drug

SIGN 2003

Controlled Improved but not

controlled

No improvement

Consider replace seconddrug or add third drug

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Marshall 2004

The majority of patients with newly-diagnosed epilepsy respond well to AEDs. Failure to do so may be due to:

An incorrect diagnosis of epilepsy An inappropriate choice of AED for the epilepsy syndrome Failure to take the prescribed AED An underlying cerebral neoplasm Covert drug or alcohol abuse

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ANTIEPILEPTIC DRUG BLOOD LEVELS

Routine monitoring of AED concentration is not indicated. Measurement can sometimes be useful in the following circumstances:

Adjustment of phenytoin doseAssessment of adherence and toxicity

Assay of lamotrigine, vigabatrine, gabapentin, topiramate, tiagabine, oxcarbazepine and levetiracetam concentrations should not be undertaken routinely

SIGN 2003

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DRUG-RESISTANT EPILEPSY

First Line AEDs

First Line AEDs

Improve seizure control but fails

to produce seizure freedom

at max dose

Failed

Failed

COMBINATION THERAPY

CONSIDER:• Patients seizure type (s)• Should be limited to two / at most three AEDs• Different mechanism of action• Side effect profile• Drug interaction

SIGN 2003

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ANTIEPILEPTIC DRUG WITHDRAWL

Prognostic index indicators can be used to give an estimate of the risks of seizure recurrence following AED withdrawal

The question of continued treatment or AED withdrawal should be discussed with people with epilepsy, who are at least two years seizure free, so that they can make an informed choice. Factors to be discussed should include driving, employment, fear and risks of further seizures and concerns about prolonged AED treatment.

The rate of withdrawal of AEDs should be slow, usually over few months, and longer with barbiturates and benzodiazepins.One drug should be withdrawn at a time

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Prognostic Index

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Prognostic Index

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Drug Failure

Generalizedseizure

Unclassifiable Partial seizures

TreatmentMonotherapyLamotrigineValproic acid

TreatmentChoicesTreat as generalizedinitially

TreatmentMonotherapyCarbamazepineLamotrigineValproate

Monotherapy Failure

Add-on:LevetiracetamTopiramate

Add-on:LevetiracetamGabapentinTopiramateTiagabine

Therapy Choices for People with Learning Disability

Trimble, 2003

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Treating patients with epilepsy need a therapuetic options. One of the most important consideration is drug selection, besides of type of epilepsy, age, gender, and special considerations like patient with learning disability. All of these must be placed in the context of treatment strategy.

When patients do not become seizure free on the first or second antiepileptic drug, there are several strategies for continued treatment. One very reasonable options is to convert the patient to another monotherapy. However, removing a drug may involve risk of worsening, and physicians and patiens opt to add a second drug. The concept of polytherapy was frowned upon in the past, but with the advent of new drugs with novel mechanism, and fewer drug interactions, “rational polytherapy” is becoming more appealing.

Clearly, this is where the newer drugs are at a substantial advantage as compared to older drugs. One of the new drugs is levetiracetam which has specific characteristics that make it an optimal choice for many patient populations.

SUMMARY

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