• Clinical phenomenon rather than a single
• Seizure- A paroxysmal event due to abnormal,
excessive, hypersynchronous, rhythmic
discharges from an aggregate of central
nervous system (CNS) neurons.
3. • Epilepsy- Disorder characterized by recurrent
seizures (also known as “seizure disorder”) due to
chronic underlying process.
• Epilepsy syndrome- Disorders in which epilepsy is a
predominant feature and clinical and pathologic
characteristics are distinctive and suggest a specific
underlying etiology eg: Benign familial neonatal
• Status epilepticus- Continuous or repetitive,
discrete seizures with impaired consciousness in the
interictal period with duration of seizure activity 15 –
• The incidence of epilepsy is ~0.3–0.5% in different populations
throughout the world.
• The prevalence of epilepsy has been estimated as 5–10
persons per 1000.
• 5% of the population suffer a single seizure at some time.
• Chance of having a second seizure after an initial unprovoked
episode is 30%.
• 70% well controlled with drugs (prolonged remissions)
• 30% epilepsy at least partially resistant to drug treatments =
INTRACTABLE (PHARMACORESISTANT) EPILEPSY.
• Recurrence rate after the withdrawal of drugs is about 30%.
5. Seizure triggers
• Missed medication (#1 reason)
• Stress, anxiety
• Hormonal changes, Menses
• Lack of sleep, extreme fatigue
• Alcohol use
• Certain Medications-
• Fever in Some Children
6. Pathophysiology of seizures
• Due to shift in normal balance of excitement and inhibition in
• Central role for the excitatory neurotransmiter glutamate
(increased) and inhibitory gamma amino butyric acid (GABA)
• Excitability is affected by-
– Alteration in ion channel functioning
– Neurotransmitter level
– Receptor functioning(NMDA & non NMDA)
– Energy metabolism
7. Symptoms that may indicate
• Periods of blackout or confused memory
• Occasional “fainting spells”
• Episodes of blank staring
• Sudden falls for no apparent reason
• Episodes of blinking or chewing at inappropriate times
• A convulsion, with or without fever
• Clusters of swift jerking movements in babies
8. What if not treated
• Seizures can be potentially life threatening with:
– Brain failure
– Heart failure
– Lung failure
• Sudden Unexpected Death in Epilepsy (SUDEP)
• Even subtle seizures can cause small damage in brain
• Long Term problems:
– Fall in IQ
– Social problems
– Quality of life
• Clinical examination and history
• Routine investigation: Haematology, biochemistry, chest X-
ray, electroencephalogram (EEG).
• Neuroimaging :CT/MRI- in all persons aged 25 or more
presenting with first seizure
• Advanced investigations (in pts. with intractable focal epilepsy
where surgery is considered): Neuropsychology, Semiinvasive
or invasive EEG recordings, MR Spectroscopy, Positron
emission tomography (PET) and ictal Single photon emission
computed tomography (SPECT)
13. Basic rules for drug treatment:
• Started in pt with recurrent seizure( and cause is not reversed)
• Single seizure with epileptogenic lesion in the brain
• Drug treatment should be simple, preferably using one
anticonvulsant (monotherapy). “Start low, increase slow“.
• Add-on therapy is necessary in some patients (multiple drugs)
• Withdrawal of drugs-If pt is seizure-free for 2 years with
normal EEG and CNS examination.
• Dose is gradually reduced over 2-3 months
14. MECHANISM OF ACTION OF ANTI-
• Na channel inactivation- Inability of neurons to fire at high frequency eg:
phenytoin, carbamazepine, lamotrigine,felbamate, topiramate, valproic
• Ca+2 channel blockers- Ethosuximide,valproic acid,lamotrigine
• Enhanced GABAergic synaptic transmission – BZD, phenobarbital,
felbamate, topiramate, carbamazepine, Oxcarbazepine
• GABA uptake inhibitors/GABA transaminase inhibitors e.g. Tiagabine,
• Promotion of GABA release e.g. Gabapentin
• NMDA receptor antagonist- Felbamate
• AMPA/kianate receptor antagonist- Phenobarbital, topiramate,
• SV2A(synaptic vesicular protein) ligands- Levetiracetam
• Brain carbonic anhydrase inhibitors- acetazolamide, topiramate,
• Derivative of levetiracetam
• SV2A ligand-selectively bind to synaptic vesicles in
glutaminergic and GABAergic neurons, glutamate and
• Also inhibits voltage gated Na-channels.
• More potent and efficacious than levetiracetam
• Trial done in Partial onset seizures,uncontrolled with one or 2
AEDs(anti epileptic drugs)
• Dose 50 mg/day
• Rapidly and almost completely absorbed after oral administration.
• Elimination half life is 7 to 8 hours.
• Weakly bound to plasma protein (<20%)
• Metabolised by non-cytochrome P450 dependent hydrolysis and
• Excretion via renal route.
• No dose adjustment is needed when giving concomitantly with other AEDs.
• Do not change PK of OCPs when used together
• No effects on fertility, pregnancy or early embryonic development in
rat or rabbits in a dose upto 600mg and 120mg/kg respectively.
• Under phase III trial
• Derivative of felbamate
• New derivative of this compound, carisbamate, is designed to avoid toxic
• It is a novel neuromodulator.
• Mechanism of action still unknown
• Exhibits disease modifying effects as demonstrated by reduction in neuron
loss and prevention of recurrent seizures in a rodent model of status
• Dose- 300-1600mg/day.
• Completely absorbed after oral administration, not affected by food.
• Half life is 10.6 to 12.8 hours.
• Protein binding 44%.
• Extensively metabolised, metabolism pathways are O-glucuronidation and
hydrolysis followed by oxidation.
• 1.7% of the dose excreted unchanged in urine.
• Most common adverse events are dose dependent(>1000mg) and includes
somnolence , and
• safe in elderly patients.
• Under phase III trial
• Derivative of carbamazepine
• Does not undergo autoinduction.
• Inhibitor of voltage gated Na channels
• Fewer drug interactions
• Less tendency to raised blood cholesterol and lipids
• Dose- 800- 1200 mg/day
• Protein binding is 30%.
• Half life is 20 -24 hours and is consistent with first order kinetics.
• No relevant effect on the activity of the major cytochrome enzymes.
• Can lead to activation of UGT1A1-mediated glucuronidation of
• Primarily excreted renally.
• Most common adverse effects :
– Double vision
• Less neurotoxic than both carbamazepine and oxacarbazepine
in animals studies.
• No abnormal vital signs were seen in clinical laboratory tests.
• Affect a new target in the synapse,enhance the activity of KCNQ(kv7)
• Anticonvulsant activity in generalized seizures, partial seizures and
status epilepticus as adjunctive therapy.
• Also have neuroprotective effect.
• Dose- 200-400 mg t.i.d
• Oral bioavailability : 60%
• Half life : 6- 10 hours
• Protein binding <80%
• Metabolized via N-glucuronidation and N-acetylation/hydrolysis to
• Drug and metabolites are renally excreted.
28. Adverse effects-
• CNS effects
– Cognitive impairment
• Low potential of PK drug interactions with concomitant AEDs
• No Pk interaction with OCPs
• Phase III study is ongoing.
• Aromatic allylic alcohols.
• Broad spectrum antiseizure activity
• Cause enhancement of GABAergic neurotransmission by increasing
GABA release, inhibiting GABA reuptake and activation of GABAA
receptors in a barbiturate like manner.
• Approved in 2007 for dravet syndrome in europe
• Rapidly absorbed orally with a Cmax 1.5 hours after oral intake.
• 99% bound to plasma protein.
• Clearance increases with increasing dose as it has non-linear
• Potent inhibitor of CYP3A4, CYP1A2, CYP2C19 and thereby affects
numerous other drugs including other AEDs.
30. Adverse effect
• Most commonly reported adverse effect includes:
Loss of appetite,
Nause and abdominal pain.
• There is a tendency for liver hypertrophy on long term use,
possibly because of its intense drug metabolizing capacity.
• Approved in June 2011 as add-on therapy for the treatment of
partial epilepsy in adults.
• Reduction in seizure rate of 24% to 27%
• Dosage- 200mg to 400mg tds
• Approved in October 2012 as add-on therapy for the treatment of
partial epilepsy in patients 12 years old and older
• Reduction in seizure rate was 28.5%, 35.3%, and 35.0% for 4, 8, and
12 mg, respectively.
• MOA-Highly selective AMPA type glutamate receptor antagonist
• Rapid oral absorption
• Vd-77 L
• T1/2 ≈ 70 hr(once daily dosing strategy)
• Metabolize by CYP3A4
• Excreted 70% in feces in urine and 30%
• Analog of neurosteroid allopregnanolone(a metabolite of
• Significantly reduce seizure frequency in adults with POSs
• Positive allosteric modulator of GABA
• Useful for absence seizures, Infantile spasms and catamenial
• Dose- 1500 mg/day as adjunctive therapy
• Absorption is higher in fed state
• T1/2- 7-10 hr
• Plasma level rapidly decline due to metabolism and tissue
35. • No significant drug interactions
• CYP3A4 inhibitor(ketoconazole) blocks its metabolism.
• Safe and well tolerated in infants at dose up to 54 mg/kg
• Drug is under phase III trial
37. Drugs at early stage of
• 2 Deoxy-glucose-chemical analog of sugar but can not undergo
metabolism after being taken up into brain cells and finally
reduce the epileptogenesis.under phase II trial
• Huperazine A-in early phase II studies,derived from a club
moss,used in china to treat Alzheimers,fever,swelling,
• Galanin NAX 5055- Neuropeptide found in brain,its increased
activity is related with decreased brain activity
• MPP-021-congnitive enhancer
• NTP-2014-phase I trial,enhances inhibition in brain by a unique
mechanism that may not produce sedation
• ICA-105665-Highly selective Kv7 potassium channel opener
38. • Vigabatrin analog,CPP-115-increase levels of GABA without
loss of vision effects.
• P529,palomid-helpful to treat epilepsy in tuberous sclerosis(it
also has tumour decreasing property)
• Dynamin inhibitors- block dynamin and leads to excitation run
• YKP-3089-possible use are epilepsy,nerve pain,anxiety and
• There is a ray of hope for refractory patients with
epilepsy either as monotherapy or add on therapy
• Many of the drugs have advantage over older one of
having less toxicity and lesser drug interactions with
• Newer drugs are more safe with liver and renal
• More safer drugs are coming for children,elderly and
• Harrison’s practice 18th edition
• Goodman & Gilman’s 12th edition
• Seizures: Medical Causes and Management Carl J. Vaughan, MD, MRCPI and
Norman Delanty, MB, FRCPI
• Perampanel: newly approved,novel antiepileptic medication for partial-
onset seizures Expert Rev. Neurother. 13(2), 131–134 (2013)
• Basic Mechanisms Underlying Seizures and Epilepsy
• New developments in the treatment of partial-onset
epilepsy.Neuropsychiatric Disease and treatment 2012:8 455-64.
• Biolink.Dynamin inhibitors for epilepsy
• Progress report on new antiepileptic drugs: A summary of the Tenth
Eilat Conference (EILAT X). M. Bialer et al.2010.Elsevier
42. LACOSAMIDE (SPM927)
• Formerly known as harkoseride (ADD 2304037).
• Approved in June 2009 as add-on therapy for the treatment of partial
epilepsy in adults.
• Selectively enhances slow inactivation of voltage-gated Na channel
without affecting the fast inactivation current.
• 100mg twice daily- reduce the median seizure rate by 26%
• 200mg twice daily- reduced the median seizure rate by 39%.
• Synergistic anticonvulsant activity with the AEDs like topiramate,
gabapentin, lamotrigine, levetiracetam, and carbamazepine and less
profound with phenytoin and valproate.
• Rapidly and completely absorbed after oral administration.
• Negligible first pass effect.
• 95% of the oral dose was excreted in urine.
40% - in unchanged form
40% - converted to O-desmethyl
• Tmax reached 0.5-4 hours after oral dose.
• t1/2 -13 hours
• Plasma protein binding < 15%
diplopia and blurred vision
nausea and vomiting
• Triazol derivative
• Mechanisms of action are still under investigation.
• Invitro studies suggest- prolongation of inactivation state of voltage-
gated Na channels like many other AEDs.
• Oral bioavailability > 85%
• Low protein binding 34%
• Metabolized by enzymatic hydrolysis, independent of CYP
isoenzymes to an inactive metabolite.
• Primarily excreted by renal route.
• Half life : 6 – 10 hours
• It may increase the serum concentration of phenytoin , no interaction
with other AEDs.
45. • Dose - 45mg/kg/d in children (1600mg twice daily in adults) ,resulted
in a 32% reduction in median seizure rate.
• It was approved inapproved in November 2008 as add-on therapy for
the treatment of Lennox-Gastaut Syndrome in patients four years of
age and older
• Adverse effects-
– Vision blurred
– Balance difficulties.
46. Need for further advancement
• Treatment resistant seizures remain a problem for
1/3rd of patients despite advancement
• Still requirement to Improving lives of patients with
– Improved seizure control
– Improved side effect profiles
– Safer treatment
• Requires a robust pipeline of drugs and devices in
• Brivaracetam : Phase III
• Carisbamate : Phase III
• Eslicarbazepine acetate : Phase III
• Retigabine : Under review for FDA approval
• Perampanel : Phase III
• Ganaxolone : Phase III
• Clobazam : Approved
• Ezogabine : Approved in 2011
• Stiripentol : Approved in 2007
Notes de l'éditeur
Despite a half century of significant advances in epilepsy therapy and diagnosGcs, treatment-.‐resistant seizures remain a problem for 1/3rd of paGents
This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy. Epilepsy refers to a clinical phenomenon rather than a single disease entity,