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Recent advances in treatment of epilepsy

Recent advances in treatment of epilepsy

DefinitionSeizure- The clinical manifestation of an abnormal, excessive, hypersynchronous discharge of a group of cortical neurons

Epilepsy- a disorder of the central nervous system characterized by recurrent seizures unprovoked by an acute systemic or neurologic insult

ILAE classification: The term partial seizures is no longer used.3

Pathophysiology of seizures

Neuronal hyperexcitability4

Seizure Sequence

Seizure Initiation

Paroxysmal Depolarizing Shift

Treatment strategies

Drugs acting on Na+ channel

Drugs enhancing GABAergic transmission

Drugs acting on Ca+2 channels

Classification of drugsOld reliables- classical drugsPhenobarbitonePrimidonePhenytoinValproic acidEthosuximide

OxcarbazepineFosphenytoinLamotrigineTopiramateGabapentinTiagabineVigabatrinLevetiracetamFelbamateEslicarbazepineRetigabineLacosamide Eslicarbazepine acetate Rufinamide Stiripentol

Newer Anti-epileptics

Newly Approved Drugs

Eslicarbazepine acetateProdrug of eslicarbazepineEslicarbazepine is the S-enantiomer of oxcarbazepineBlocks voltage-dependent sodium channelsHas minimal effect on CYP-450 enzymes & better tolerabilityApproved as adjunctive treatment for refractory focal seizuresDosage: 800-1200 mg/dayAEs: Dizziness, somnolence, headache, nausea

LacosamideA functionalized amino acidMechanism of action:Enhances slow inactivation of voltage-gated Na+ channelsAlso acts on CRMP-2 which is involved in neuronal differentiation and growth; however its role is unclearApproved as adjunctive treatment for treatment of refractory focal seizuresDose: 200-400 mg/day

RufinamideStructurally unrelated to other drugsEnhances slow inactivation of voltage-gated Na+ channels & limits repetitive firingApproved as an add-on drug for Lennox-Gastaut syndrome in children more than 4 yrs of age & in adultsDose: 10mg/kg/day upto a maximum of 45 mg/kg/dayAdverse effects: Dizziness, fatigue

StiripentolPositive modulator of GABAA receptorsActs on 3 subunitAlso decreases the metabolism of other anti-epileptic drugs by inhibition of CYP450 enzymesApproved as an add-on drug with valproate and topiramate in Rx of Dravets syndromeApproved only by EMA; FDA approval not yet granted

VigabatrinGABA transaminase inhibitor; potentiates GABA actionApproved as an adjunct for refractory complex partial seizuresAlso has orphan drug status for treatment of infantile spasmsAdverse effects- Behavioural changes, depression, psychosisCan also cause bilateral, permanent vision lossHence it is used when therapy with other drugs has failed

New Drug Targets

Kv7(KCNQ) channelKv7 channel has 5 subunits 7.1 to 7.5However , the Kv7 channel in CNS is composed of subunits Kv 7.2 and 7.3These 4 subunits form the M-channel and conduct potassium currents.

RetigabineMechanism of action:Acts on Kv7 channel to enhance M-type potassium currentGABAA agonistApproved as adjunctive treatment for treatment of focal seizuresAEs: Dizziness, somnolence, fatigueDose: 600-1200 mg/day

Synaptic Vesicle Protein 2A

SV2ALevetiracetamThe precise role of SV2A in neuronal excitability & epilepsy still remains to be elucidated

BrivaracetamAnalog of LevetiracetamMore potent than levetiracetam in animal modelsPhase 2: AE profile was similar to placeboCurrently undergoing Phase 3 trials

AMPA receptors

PerampanelAlthough NMDA receptors have been implicated in epilepsy, selective antagonists have failed in clinical trials.Hence, selective AMPA antagonists have been chosen and advanced to human testingPerampanel is currently in phase 3 testing

Role of neurosteroids in epilepsy

Neurosteroids, such as allpregnanolone, are synthesized within the brain Positive allostric modulators of GABAA and have anticonvulsant propertiesGanaxolone- synthetic analogPotentiates both phasic and tonic currents and thus prevents seizuresEvidence from animal models of kindling also shows that they may also possess anti-epileptogenic propertyCurrently in phase 2 trials

Somatostatinvia SRIF1 receptors in hipocampusReduce presynaptic release of glutamateSRIF1 agonist under development

Neuropeptide YNPY Y1 receptors present post-synaptically on glutamatergic neuronsIncrease excitability by reducing K+ currents NPY Y1 antagonists currently in preclinical development

Role of endogenous neuropeotides

Vagus Nerve Stimulation

Used in: Generalized Seizures & Lennox-Gastaut syndromePatients unfit for surgeryThose unable to tolerate anti-epileptic drugs

Disadvantages:ExpensiveDoes not provide complete seizure remission

Treatment guidelinesSeizure typeFirst line drugsSecond line drugsGTCCarbamazepineLamotrigineOxcarbazepineSodium valproateClobazamLevetiracetamTopiramate

AbsenceEthosuximideLamotrigineSodium valproateClobazamClonazepamLevetiracetamTopiramateZonisamideMyoclonicSodium valproateTopiramateClobazamClonazepamZonisamideLevetiracetam

Seizure typeFirst line drugsSecond line drugsTonic & Atonic typeSodium ValproateLamotrigineTopiramateRufinamideFocal seizures secondary generali-zationLamotrigineCarbamazepineSodium valproateGabapentinOxcarbazepineTopiramate

Epilepsy & PregnancyWomen should be counselled that - Seizure freedom for 9 months prior to conception is associated with high rate of remaining seizure-free during pregnancy - Epileptic women who smoke are at increased risk of preterm delivery

Folate supplementation: - 0.4 mg/day in pre-conception period & during pregnancyVitamin K supplementation: - No need for additional Vitamin K as neonates do receive routine supplementation at birthDrug therapy: - Prefer monotherapy: start with lowest dose - Avoid valproate (risk of teratogenicity) - TDM for Carbamazepine, phenytoin & Lamotrigine(as there is increased clearance of these drugs)

FDA WarningIn April 2009, FDA issued a warning regarding the risk of suicidal behaviour and ideation for antiepileptic drugsThis effect was consistent across all the studied drugs which had varying mechanisms of actionThus it was concluded that the risk applies to all anti-epileptic drugs used for any indication

ConclusionNewer & Better drugs available for seizure preventionHowever currently available drugs are only anti-seizure drugsThe ultimate goal is development of anti-epileptogenic drugsFuture research should be directed towards this cause



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