MANAGEMENT OF EPILEPSYDr. Theresia ChristinDepartment of NeurologyUniversity of Sriwijaya

is a disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures, with more than 24 hours interval and is unprovoked (unknown cause)

Epilepsy

SeizuresSeizures are sudden, transitory, and uncontrolled episodes of brain dysfunction, resulting from abnormal electrical discharge in cerebral neuronal cells, associated with prolonged depolarisation of cerebral neurons result in motor, sensory or behavioral changes.

ILAE Classification

Hauser WA. Epilepsia. 1992;33(suppl 4):S10.Complex Partial (36%)Unclassified (3%)Myoclonic (3%)Absence (6%)Partial Unknown (7%)Other Generalized (8%)Simple Partial (14%)Generalized TC (23%)Epidemiology by Seizure Types

First aid for Seizures

First aid for Seizures

First aid for Seizures

The goal of the therapy is to improve the patients quality of life through:maximize the seizure control minimize drug side effects

Drug choice is based on:Classification of seizures. Patients age & health stateData on efficacy, tolerability, safety and pharmacokinetics

Management of Epilepsy

Classification of AnticonvulsantsClassicalPhenytoinPhenobarbitalPrimidoneCarbamazepineEthosuximideValproic AcidbenzodiazepinesNewerFelbatol (felbamate) 1993Neurontin (gabapentin) 1994Lamictal (lamotrigine) 1995Topamax (topiramate) 1996Gabitril (tiagabine) 1998Keppra (levetiracetam) 1999Trileptal (oxcarbazepine) 2000Zonegran (zonisamide) 2000Lyrica (pregabalin) 2005EzogabineRufinamide, Lacosamide, other

When to Start?As soon as diagnosis is confirmedTriggers for seizures can be avoided (alcohol consumption, sleep deprivation, stress, etc)Minimum of 2 attacks in a yearThe patient and their family has been informed of the therapeutic goal and side effects

How to Start?Therapy should start as monotherapy accordingly to seizure types and syndromesCareful titration is a must- START LOW, GO SLOW2nd AED is added if 1st AED is already titrated to max dose and fail to control seizure3rd AED is added if 1st and 2nd AED are already titrated to max dose and fail

Anti-Epileptic Drugs (AEDs)AEDs act to:- Block the initiation of the electrical discharge from the focal area- Prevent the spread of abnormal electrical discharge to adjacent brain areaAEDs prevent depolarisation of neurones by:- Modification of ion conductance (direct membrane stabilisation) - Inhibition of excitatory (glutamergic) activity- Stimulation of inhibitory (GABAergic) transmission.

They do their actions by- axonal conduction by preventing Na+ influx through fast Na+ channels

Example: Carbamazepine, Oxcarbazepine, Phenytoin, Barbiturates, Valproic Acids. Lamotrigine, Felbamate, and Topiramate

- presynaptic Ca+2 influx through type T channels in thalamic neurons

Example: Ethosuximide, Valproic Acids and Lamotrigine

They do their actions by:- inhibitory tone through Facilitation of GABA-mediated hyperpolarization : Barbiturates and Benzodiazepines. Inhibiting GABA metabolism : Valproic Acid and Vigabatrin or action on the reuptake of GABA : Tiagabine- excitatory effects of glutamic acidBlockage of AMPA receptors : Lamotigrine and Topiramate Blockage of NMDA receptors : Felbamate and Phenobarbital

Mechanism of action of AEDs

Ion Channels#Na+: Phenytoin, Carbamazepine, LamotrigineTopiramateValproic acid# For general tonic-clonic and partial seizuresCa++ #: EthosuximideValproic acidZonisamide# For Absence seizuresEnhance Inhibitory aa #Benzodiazepines(diazepam, clonazepam) Barbiturates (phenobarbital)Valproic acid GabapentinVigabatrinTopiramateFelbamate# Most effective in myoclonic but also in tonic-clonic and partialClonazepam: for AbsenceInhibit Excitatory aaFelbamateTopiramateClassification of Anticonvulsants

ILAE GUIDELINES

Based on the best evidence available, what is the optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy?

Partial Seizures: AdultsAvailable EvidenceA total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizuresLevel A: CBZ, PHTLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGBLevel D: CZP, PRMLevel E: OthersLevel F: None

Partial Seizures: ChildrenAvailable EvidenceA total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT,TPM, VPALevel D: LTG,VGBLevel E: OthersLevel F: None

Partial Seizures: ElderlyAvailable EvidenceA total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizuresLevel A: GBP, LTGLevel B: NoneLevel C: CBZLevel D: TPM, VPALevel E: OthersLevel F: None

Generalized Tonic Clonic Seizures: Adults Available EvidenceA total of 23 RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures Level A: NoneLevel B: NoneLevel C: CBZ,LTG,OXC, PB, PHT,TPM,VPALevel D: GBP,VGBLevel E: OthersLevel F: None

Generalized Tonic Clonic Seizures: Children Available EvidenceA total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures Level A: NoneLevel B: NoneLevel C: CBZ,PB, PHT,TPM,VPALevel D: OXCLevel E: OthersLevel F: None

Other Types of Seizures and DOC

AED Dosages

AEDINITIAL (mg/day)MAINTAIN (mg/day)DIVIDED DOSETITRATIONCBZ400-600400-16002-3x 200-300 mg/day per 1-4 weeksPHT200-300200-4001-2x 100mg/day per 3-7 days.VPA500-1000500-25002-3x 500mg/day per 7 days. PB 50-10050-2001x 30-50mg/day per 10-15 days.OXC600-900600-30002-3x 300mg/day per 1-3 weeks LVT1000-20001000-30002x 500-1000mg/day per 2 weeks

AED Dosages

AEDINITIAL (mg/day)MAINTAIN (mg/day)DIVIDED DOSETITRATIONTPM100100-4002x 25-50mg/day per 2 weeksGBP900-1800900-36002-3x 300-900mg/day per 5-10 daysLTG50-10050-2001-2x 25mg for first 2 weeks. 50mg for next 2 weeks. ZOS100-200100-4001-2x to target in 1-2 weeksPGB50-7550-6002-3x 50-100 per 2 weeks

PHENYTOINAdverse Effects: Ataxia and nystagmus.Cognitive impairment.HirsutismGingival hyperplasia, Coarsening of facial features.folate dependent megaloblastic anaemia,Osteomalacia, Inhibition of ADH,inhibition of insulin secretionhyperglycemia and glycosuriaHypoprothrominemiacoagulopathyExacerbates absence seizures.

Fetal hydantoin syndrome include:cleft lip, cleft palate congenital heart diseaseslowed growth mental deficiency

PHENYTOIN

CARBAMAZEPINEAdverse Effects :Stupor, coma, respiratory depression, drowsiness, dizziness, vertigo, ataxia, blurred vision, diplopia, bradycardia, skin rashes, GI upsets. Hyponatremia in elderly

SODIUM VALPROATE

Adverse Effects :Elevated liver enzymesTremor, hair loss, changes in hair growthIncreased appetite weight gain.Coagulopathy (inhibition of platelet aggregation), Hepatotoxicity.Negative interactions with other antiepileptics.Teratogen: spina bifida

FELBAMATEEffective against partial seizures but has severe side effects.Thus, used only for refractory cases.One of the metabolites; ,-unsaturated aldehyde, 2-phenylpropenal is chemically reactive, like acrolein covalently linking proteins as well as DNA, it can cause liver and bone marrow toxicity

GABAPENTINAdverse Effects :Ataxia DizzinessSomnolenceHeadache Tremor

VIGABATRINAdverse Effects :DepressionPsychosisVisual disturbances

LAMOTRIGINEAdverse effects:DizzinessHeadacheDiplopiaNauseaSomnolenceRash

Presently use as add-on therapy with valproic acid.Almost completely absorbedT1/2 = 24 hrsLow plasma protein binding Blocks sodium channels, & high voltage Ca+2 channelthus its effective in partial, generalized, myoclonic, absence seizures & Lennox-Gastaut syndrome (LGS).Approved for use in bipolar disorder

LEVETIRACETAMAdjunct Rx of refractory Partial SeizureUnknown mechanism of action but binds to presynaptic vesicle proteinADVERSE EFFECTDizziness, sleep disturbances, headache, and asthenia (LACK OF ENERGY)

TIAGABINEAdverse effects:DizzinessNervousnessTremorDifficulty concentratingDepressionAstheniaEmotionalPsychosisSkin rash

100% bioavailable,highly protein bound.T1/2 = 5 -8 hrsEffective against partial and generalized tonic-clonic seizures.GABA uptake inhibitor GAT-1.

TOPIRAMATE Adverse effects:SomnolenceFatigueDizzinessCognitive slowingParesthesiasNervousnessConfusionUrolithiasisWeight lossBroad spectrum antiseizure activity, also used in migraineRapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrsblocking of voltage-dependent sodium channelsAdditionally the frequency of Cl- channel opening by binding to GABA receptor.High-voltage calcium currents (L-type) are reduced Depresses excitatory action of kainate on AMPA receptors.Carbonic anhydrase inhibiter effectTeratogenic in animal models.

ZONISAMIDESulfonamide derivativeOrally active half-life 50-60 hrsBoth focal and generalizedMechanism of action Blocks voltage-gated Na+ channels and T-type Ca+2 current, enhancement of GABA-receptor function Adverse effects: somnolence, Ataxia, hyperthermia (children)Kidney stone

Seizure is very harmful for pregnant women.Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects)Significant risk of neural tube defects, folic acid is recommended to be given for every pregnant women with epilepsyPhenytoin, sodium valproate are absolutely contraindicated and oxcarbamazepine is better than carbamazepine.

Special Cases: Pregnancy

Monotherapy usually better than drugs combination.Experience with new anticonvulsants still not reliableNewborns of mothers receiving phenobarbitone, or phenytoin may develop hypoprothrominemia, heamorrhage prevented by Vit. KDrugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly)

Special Cases: Pregnancy

AED DRUG INTERACTIONSWith other drugs:antibiotics phenytoin, phenobarb, carb.anticoagulantsphenytoin and phenobarb metabolism.cimetidinedisplaces pheny, v.a. and BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylatesdisplaces phenytoin and v.a. theophylinecarb and phenytoin may effect.

VAGAL NERVE STIMULATION (VNS)VNS requires surgical implant of a small pulse generator with a battery and a lead wire for stimulus. The device is implanted and its lead wires wrapped around the patients vagal nerve. This treatment was approved in 1997. The device is also approved for treatment of depression. The mechanism of action is unknown. VNS has been effective in treatment of partial onset seizures and has enabled reduction of drug therapy in some cases. It is an alternative for patients whose conditions have been refractory to multiple drugs and in those who are sensitive to the many adverse effects of antiseizure drugs and those who have difficulty adhering to medication schedules. However, VNS is a costly and invasive procedure.

DEEP BRAIN STIMULATION (DBS) DBS therapy uses a pacemaker-like device to deliver targeted electrical stimulation to the anterior nucleus of the thalamus.The therapy is FDA approved with conditions for adjunctive treatment for partial-onset seizures in adults with medically refractory epilepsy. DBS is also FDA approved for treatment of advanced Parkinson disease and essential tremor.

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