Recent advances in epilepsy

Recent advances in treatment of epilepsyDr Siddhartha DuttaMAMC, New Delhi

contentsIntroductionCurrent therapy and drug targetsNeed for newer moleculesNewer molecules on older targets Newer molecules on novel targetsNewer delivery systemsPregnancy and epilepsyNon pharmacological advancesSummary

Epilepsy is derived from Epilamvanein or EpilepsiaCharaka Samhita- ApasmaraOswei Temkin in 1780 B.C. in his Book THE FALLING SICKNESS

Hippocrates 400 BC: This is not a sacred disease rather disorder of brain Seizure: Paroxysmal event due to abnormal, excessive, hyper synchronous neuronal activity in the brain.

Epilepsy is derived from Epilamvanein or Epilepsia, which means to posses, to be seized, to be taken hold of, or to be attackedEpilepsy is derived from the Greek word Epilamvanein or Epilepsia, which means to be seized, to be taken hold of, or to be attackedCharaka Samhita- The Ayurvedic literature 400 BC: Describe epilepsy as Apasmara means loss of consciousness

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Worldwide about 50 million people have epilepsy80% of epilepsy cases worldwide are found in developing regions75-80 % of patients respond to standard therapy

Etiology

When to say?At least two unprovoked (or reflex) seizures occurring greater than 24 hours apart Probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.6

Classification of Seizures ILAE Classification I. Partial (Focal)seizures A. Simple partial seizures B. Complex Partial Seizures C. Partial Seizures evolving to secondary generalizationII. Generalized seizures A. Absence seizures i) Typical ii) Atypical B. Myoclonic seizuresC. Clonic seizuresD. Tonic seizuresE. Tonic-Clonic seizuresF. Atonic seizures

III. Unclassified epileptic seizures

Refractory partial epilepsyThe International League Against Epilepsy (ILAE) has proposed the followingdefinition of drug resistant epilepsy and suggests that this term be used instead of the term 'refractory epilepsy'.Drug resistant epilepsy occurs when a person has failed to become (and stay) seizure free with adequate trials of two seizure medications (called AEDs).These seizure medications must have been chosen appropriately for the persons seizure type, tolerated by the person, and tried alone or together with other seizure medications.

Partial seizuresSimple partial Focal with minimal spread of abnormal dischargeConsciousness is maintainedComplex partialLocal onset, then spreadsUsually starts with blank stare, followed by automatisms (random motor activity).Person appears unaware of surroundings. Partial seizures with secondary generalizationBegins focallyVaries in the duration and intensity of tonic and a clonic phasesLasts between 1-2minutes

Generalized seizures

Generalized tonicclonic (grand mal)Sudden cry, fall, rigidity, followed by muscle jerks, shallow breathing or temporarily suspended breathing, possible loss of bladder control (usually lasts a couple of minutes)

Absence (petit-mal) Blank stare (lasts few seconds)

AtonicSudden loss of postural tone (collapse and fall; 10 sec- 1 min)

Cellular Mechanisms of Seizure GenerationExcitation Ionic-inward Na+, Ca++ currents Neurotransmitter: glutamate, aspartateInhibition Ionic-inward Cl; outward K+ currents Neurotransmitter: GABA:

Therapeutic targets...

Lourence L.Brunton, Brause A .Chabner, Bjorn K,Knollmann, The pharmacological basis of therapeutics:12th edition, Section II. Neuropharmacology, Chapter 21. Pharmacotherapy of the Epilepsies

So, the therapeutic targets are, Inhibition of excitatory neurotransmission2. Enhancement of inhibitory transmission3 blockage of voltage gated ion channels

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Mechanism of action of current therapies

Modification of ion conductances (Na+, K+, Ca2+)

Increase inhibitory (GABA ergic) transmission.

Decrease excitatory (glutamatergic) activity.

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Targets of Anti Epileptics drug(AED)Blockade of voltage dependent sodium channels : CBZPHENYTOIN SODIUM VALPROATELACOSAMIDELAMOTRIGINEZONISAMIDERUFINAMIDETOPIRAMATE

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Drugs acting on Na+ channel

Drugs acting on sodium channel includemainly ..valproate, carbamazepine, phenytoin etc15

Targets Contd.Enhancement of inhibitory neurotransmitter GABA PHENOBARBITALBENZODIAZEPENESTIAGABINEVIGABATRINVALPROATEGABAPENTIN PREGABALIN

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Drugs enhancing GABAergic transmission

Drugs enhancing GABAnergic transmission include Vigabatrin, Tiagabine etc17

Targets contd..Reduction in the T type calcium currents :ETHOSUXIMIDESODIUM VALPROATE

Reduction in the N type calcium currents :GABAPENTINPREGABALINLAMOTRIGINE

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Drugs acting on Ca+2 channels

Drugs acting on calcium channel includemainly valproate and ethosuximide19

BLOCKADE OF AMPA OR NMDA RECEPTORSFELBAMATETOPIRAMATELAMOTRIGINEPHENOBARBITALVALPROATE

Synaptic vesicle protein 2A (SV2A) ligandlevetiracetam

Antiepileptic drugs

These first generation antiepileptic drugs evolved over a period of time had advantages like, efficacy was known Disadvantages of first generation AED:Cause hepatic enzyme induction (PB, PHT,CBZ, Primidone) or inhibition (VPA)Cause changes in hormones i.e sex steroids, Vit D (phenytoin, valproate)Produce interaction with commonly used medications (warfarin, oral contraceptives, chemotherapy agents)Category D (causes neural tube defects, cleft lip cleft palate)

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Efficacy Less expensiveEasily availableHepatic enzyme induction/ inhibitionDrug-drug interactionAlters hormonal & vitamin levels

Then came the second generation drugs like Carbamazepine and ValproateGabapentinLamotrigineTopiramateVigabatrin FosphenytoinTiagabineLevetiracetamOxcarbazepineZonisamide

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Joseph Sirven, Katherine Noe, Mathew Hoerth, Joseph Drazkowski. Antiepileptic Drugs 2012: Recent Advances and Trends. Mayo Clinic Proceedings Vol 87, Issue 9 (879889)

Since 1998, newer antiepileptics came like .. Gabapentin, Levetiracetam etc. I will very briefly tell you about the FDA approved indication of these agents, before going on to recent advances

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The dose, half-life, 'therapeutic range' and commonly observed adverse effects of the most widely used antiepileptic drugsDrugUsual adult dose mg/24 hrsAdverse effectsCarbamazepine800-1600drowsiness, blurred vision, diplopia, ataxia, blood dyscrasia, hyponatraemia, rash, Induction of liver enzymes CYP3A4Oxcarbazepine600-1200Less induction of enzymesPhenytoin300-400ataxia, dysarthria, gingival hypertrophy, hirsutism, osteomalacia, inhibition of ADH, rash, Induction of liver enzymes CYP3A4FosphenytoinSame dose in PEHypotension, arrythmia, cerebellar atrophy, ataxiaSodium valproate1000-3000GI upset, weight gain, hair loss, tremor, thrombocytopenia, liver failure, pancreatitisPhenobarbitone90-180sedation, depression, loss of concentration, mental dulling, hyperactivity, Induction of liver enzymes CYP2A,2B,2C, 3A, 6APrimidone750-1250sedation, dizziness, nausea, ataxia, depressionEthosuximide750-1500GI upset, mood changes, lethargy, hiccups, headache, fever, eosinophillia

THIRD GENERATIONDrugsMechanism of actionFDA approved indicationS/ELamotrigineInhibits voltage sensitive sodium channels Inhibits synaptic release of glutamateas adjunctive therapy of partial seizures in patients greater than or equal to 2 years of age and Primary GTC in patients 13 years of ageDizzinessHeadacheDiplopiaNauseaSomnolence

LevetiracetamBinds to synaptic vesicle protein SV2A and impedes nerve conduction Refractory Partial seizuresRefractory JMESomnolence.Dizziness.AstheniaGabapentinBinds to 2 subunit of voltage gated calcium channelsPartial seizure with or without secondary generalizationSomnolenceDizziness AtaxiaHeadache,Tremor

Tiagabine inhibits the GABA transporter GAT-1 and reuptake of GABAPartial seizures +/- secondary generalization (as add on therapyAsthenia, Dizziness, Nausea, Tremor, Depression

JME-Juvenile myoclonic epilepsy-28

THIRD GENERATIONDrugsDose FDA approved indicationS/ELamotrigine100-300 mg in divided doseAdjunctive therapy of partial seizures in patients greater than or equal to 2 years of age and Primary GTC in patients 13 years of ageDizzinessHeadacheDiplopiaNauseaSomnolence

Levetiracetam500-1500 mg B.D.Refractory Partial seizuresRefractory JMESomnolence.Dizziness.AstheniaGabapentin300-1800 mg/d divided dosePartial seizure with or without secondary generalizationSomnolenceDizziness AtaxiaHeadache,Tremor

Tiagabine 20-60 mg/day divided doses Partial seizures +/- secondary generalization (as add on therapyAsthenia, Dizziness, Nausea, Tremor, Depression

JME-Juvenile myoclonic epilepsy-29

DrugsMechanism of actionFDA approved indicationS/ELacosamideSodium channel modulationAdd-on for partial epilepsydizziness,ataxia, nausea vomiting,diplopiaRufinamide400-800 mg/day Sodium channel modulationLennox-Gastaut syndrome in children 4 years and older & adultsAtonic seizuresDiplopia,DizzinessFatigue,HeadacheSomnolence,NauseaVomiting, SJS

ZonisamideInhibition of sodium channels & T type of calcium channel currentsDecreases GABA uptake &increases glutamate uptakeFocal seizure DrowsinessCognitive impairmentAnorexiarenal stones, Nausea

Vigabatrin Irreversible inhibitor of GABA transaminaseInfantile spasmsAdjunctive for refractory partial epilepsysedation, drowsiness, aggression and rarely psychosis, weight gain

THIRD GENERATION

Sodium channel modulators Lacosamide, Rufinamide and Zonisamide are approved for partial seizures andVigabatrin for refractory partial epilepsy

LGS-Lennox-Gastaut syndrome occurs in children and is defined by the following triad: (1) multiple seizure types (usually including generalized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG showing slow ( 1400 mg/d 6% when < 1400 mg/d better avoided in first tm, if given then < 1000 mg/dPhenytoin 4.7% , monitoring requiredCarbamezepine (1-2%)Lamotrigine (2.3%)Phenobarbitone (1.62%) BZD- 1.2%Zonisamide (7.7%)poly & 2.7% monoLevetiracetam 2.7%Limited data on ethosuximide, topiramate, tiagabine and other AED

What should be done ?Preconceptual managementDiagnosisAttempt for monotherapyTaper dosages of AEDs to the lowest possible doseIn women who didnt had a seizure for 2-5 years, attempt complete withdrawal of AEDSupplement the diet withfolateat 4 mg/d

Pregnant womenEfficacy Teratogenecity Tolerability Monotherapy lowest efficacious doseNo need for routine monitoring of AED levels10 mg of vitamin K1 orally during the last month of gestation if they were on an enzyme-inducing AEDSupplement withfolateat 4 mg/d1 mg of vit K parenterally at delivery

Breastfeeding should be encouraged

Famous Persons with EpilepsyAristotleSocratesAlfred NobelNaepoleon BonaparteTony Greig

SUMMARYEpilepsy can be treated but complete cure ??Classical AED pros and consNeeds long term therapyNeed for new treatments with novel mechanisms of actionNon pharmacological therapy showing promiseSurgery has a role?

to serve as alternate or adjunct therapy for the treatment of drug-resistant or refractory epilepsy

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