Recent advances in treatment of epilepsy

Definition

• Seizure- 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

Hyper-excitable

state

Decreased inhibitory

input- GABA

Increased excitatory

input- Glutamate

Voltage-gated ion channels in favour of excitation

Pathophysiology of seizures

Seizure Sequence

Burst of action potentials

Hypersynchronization

Seizure Propagation

Seizure Initiation

Paroxysmal Depolarizing Shift

Inhibition of excitatory neurotransmission

• Glutamate antagonists

Enhancement of inhibitory neurotransmission

• GABA agonists

Reduce inward positive current• Drugs acting on Na+ & Ca++ channels

Treatment strategies

Drugs acting on Na+ channel

Drugs enhancing GABAergic transmission

Drugs acting on Ca+2 channels

Classification of drugs

• ‘Old reliables’- classical drugs

Phenobarbitone

Primidone

Phenytoin

Valproic acid

Ethosuximide

• Oxcarbazepine

• Fosphenytoin

• Lamotrigine

• Topiramate

• Gabapentin

• Tiagabine

• Vigabatrin

• Levetiracetam

• Felbamate

• Eslicarbazepine

• Retigabine

• Lacosamide

• Eslicarbazepine acetate

• Rufinamide

• Stiripentol

Newer Anti-epileptics

Newly Approved Drugs

Eslicarbazepine acetate• Prodrug of eslicarbazepine• Eslicarbazepine is the S-enantiomer of oxcarbazepine• Blocks voltage-dependent sodium channels• Has minimal effect on CYP-450 enzymes & better

tolerability• Approved as adjunctive treatment for refractory focal

seizures• Dosage: 800-1200 mg/day• AEs: Dizziness, somnolence, headache, nausea

Lacosamide• A functionalized amino acid

• Mechanism of action:

1. Enhances slow inactivation of voltage-gated Na+ channels

2. Also acts on CRMP-2 which is involved in neuronal differentiation and growth; however its role is unclear

• Approved as adjunctive treatment for treatment of refractory focal seizures

• Dose: 200-400 mg/day

Rufinamide

• Structurally unrelated to other drugs• Enhances slow inactivation of voltage-gated Na+

channels & limits repetitive firing• Approved as an add-on drug for Lennox-Gastaut

syndrome in children more than 4 yrs of age & in adults

• Dose: 10mg/kg/day upto a maximum of 45 mg/kg/day

• Adverse effects: Dizziness, fatigue

Stiripentol

• Positive modulator of GABAA receptors

• Acts on α3 subunit

• Also decreases the metabolism of other anti-epileptic drugs by inhibition of CYP450 enzymes

• Approved as an add-on drug with valproate and topiramate in Rx of Dravet’s syndrome

• Approved only by EMA; FDA approval not yet granted

Vigabatrin• GABA transaminase inhibitor; potentiates GABA action• Approved as an adjunct for refractory complex partial

seizures• Also has orphan drug status for treatment of infantile

spasms• Adverse effects- Behavioural changes, depression,

psychosis• Can also cause bilateral, permanent vision loss• Hence it is used when therapy with other drugs has failed

New Drug Targets

Kv7(KCNQ) channel

• Kv7 channel has 5 subunits 7.1 to 7.5

• However , the Kv7 channel in CNS is composed of subunits Kv 7.2 and 7.3

• These 4 subunits form the M-channel and conduct potassium currents.

Retigabine• Mechanism of action:

1. Acts on Kv7 channel to enhance M-type potassium current

2. GABAA agonist

• Approved as adjunctive treatment for treatment of focal seizures

• AEs: Dizziness, somnolence, fatigue

• Dose: 600-1200 mg/day

Synaptic Vesicle Protein 2A

SV2A Levetiracetam

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

Brivaracetam

• Analog of Levetiracetam

• More potent than levetiracetam in animal models

• Phase 2: AE profile was similar to placebo

• Currently undergoing Phase 3 trials

AMPA receptors

Perampanel

• Although 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 testing

• Perampanel 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 properties

• Ganaxolone- synthetic analog• Potentiates both phasic and tonic currents and thus

prevents seizures• Evidence from animal models of kindling also shows

that they may also possess anti-epileptogenic property

• Currently in phase 2 trials

Somatostatin• via SRIF1 receptors in hipocampus• Reduce presynaptic release of glutamate• SRIF1 agonist under development

Neuropeptide Y• NPY Y1 receptors present post-synaptically on glutamatergic

neurons• Increase 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 syndrome

Patients unfit for surgery

Those unable to tolerate anti-epileptic drugs

Disadvantages:

Expensive

Does not provide complete seizure remission

Treatment guidelinesSeizure type First line drugs Second line drugs

GTCCarbamazepineLamotrigineOxcarbazepineSodium valproate

ClobazamLevetiracetamTopiramate

AbsenceEthosuximideLamotrigineSodium valproate

ClobazamClonazepamLevetiracetamTopiramateZonisamide

MyoclonicSodium valproateTopiramate

ClobazamClonazepamZonisamideLevetiracetam

Seizure type First line drugs Second line drugs

Tonic & Atonic type Sodium Valproate

LamotrigineTopiramateRufinamide

Focal seizures ± secondary

generali-zation

LamotrigineCarbamazepineSodium valproate

GabapentinOxcarbazepineTopiramate

Epilepsy & Pregnancy Women 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

pregnancy Vitamin K supplementation: - No need for additional Vitamin K as neonates do

receive routine supplementation at birth Drug 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 Warning

• In April 2009, FDA issued a warning regarding the risk of suicidal behaviour and ideation for antiepileptic drugs

• This effect was consistent across all the studied drugs which had varying mechanisms of action

• Thus it was concluded that the risk applies to all anti-epileptic drugs used for any indication

Conclusion

• Newer & Better drugs available for seizure prevention

• However currently available drugs are only anti-seizure drugs

• The ultimate goal is development of ‘anti-epileptogenic’ drugs

• Future research should be directed towards this cause

THANK YOU