4. Introduction
o The term seizure refers to a transient alteration of behavior due to the
disordered, synchronous, and rhythmic firing of populations of brain
neurons.
o The term epilepsy refers to a disorder of brain function characterized by the
periodic and unpredictable occurrence of seizures.
o Seizures arise from cortical, thalamocortical, limbic, or even brainstem
circuits.
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6. Classification of seizures (ILAE)
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GeneralizedFocal Unknown
Unknown type includes:
Tonic-clonic, atonic and
epileptic spasms
7. Types of Focal Seizures
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Type Feature Conventional Drugs
Focal Aware
Manifestation depends on the area
affected
Awarness preserved
Carbamazepine,
phenytoin, valproate
Focal (Impaired awareness)
Purposeless movements
Lasting 30 sec to 2 min
Carbamazepine,
phenytoin, valproate
Focal to Bilateral
Tonic Clonic
Focal aware or impaired awareness
converts into tonic clonic affecting both
lobes
Awareness is impaired
Carbamazepine,
phenobarbital,
phenytoin, primidone,
valproate
8. Types of Generalized Seizures
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Type Feature Conventional Drugs Newer drugs
Generalized Absence
Impaired consiousness.
Random starring and cessation of
ongoing activites
Lasting less than 30 sec
Ethosuximide,
valproate,
Clonazepam
Lamotrigine
Generalized
Myoclonic
Shock-like contraction of muscle.
Restricted to one extremity or maybe
generalized
Valproate,
clonazepam
Levetiracetam
Generalized
Tonic-Clonic
Tonic clonic affecting both lobes
Awareness is impaired
Not preceded by focal seizure
Carbamazepine,
phenobarbital,
phenytoin,
primidone,
valproate
Lamotrigine
Levetiracetam
Topiramate
9. Animal Models to Induce Epilepsy
o Kindling, periodic administration of brief, low-intensity electrical stimulation of
the amygdala (limbic structure). Result in progressive tonic-clonic seizures that,
once established, persist for the life of the animal.
o Chemo-convulsant, such as kainic acid or pilocarpine, or sustained electrical
stimulation (for status epilepticus).
o After status epilepticus spontaneous seizures are seen parallel to complicated
febrile seizures
o The maximal electroshock seizure test is extremely valuable because drugs that
are effective against the tonic hind limb extension induced by corneal
electroshock generally have proven to be effective against focal and generalized
tonic-clonic.
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10. o Seizures induced by the chemo convulsant pentylenetetrazol are most
useful in the identification of ASDs that are effective against myoclonic
seizures in humans
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12. Focal Seizures
o Focal seizures contributes to about 60%
o Focal with impaired awareness generally arises in temporal lobe.
o The etiology of focal seizures commonly consists of a cortical lesion, such as a tumor,
developmental malformation, or damage due to trauma or stroke.
o Antagonists of the GABA-A receptor or agonists of different glutamate-receptor subtypes
(NMDA, AMPA, or kainic acid) trigger seizures in experimental animals in vivo.
o Subtle reductions (20%) of inhibitory synaptic function could lead to epileptiform activity
and that activation of excitatory synapses could be pivotal in seizure initiation
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13. Focal Seizures
o Electrophysiological analyses of individual neurons during a focal seizure
demonstrate that the neurons undergo depolarization and fire action potentials
at high frequencies.
o Inhibition of the high-frequency firing is thought to be mediated by reducing
the ability of Na+ channels to recover from inactivation
o Activation of the GABA-A receptor inhibits the postsynaptic cell by increasing
the inflow of Clā ions into the cell.
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16. Generalized Seizures
o Generalized-onset seizures arise from the reciprocal firing of the thalamus and
cerebral cortex
o The EEG hallmark of an absence seizure is generalized spike-and-wave
discharges at a frequency of 3 Hz (3/s). It is due to T- type calcium channel
current.
o T-type Ca2+ channels are activated at a much more negative membrane
potential ( ālow thresholdā) than most other voltage-gated Ca2+ channels
expressed in the brain.
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17. Genetic Point of view
o Mutations in more than 70 genes are known to contribute to epilepsy.
o Genes that encode voltage- or ligand-gated ion channels, signaling pathways,
transporters, and even synaptic vesicle proteins are susceptible.
o Generalized epilepsy with febrile seizures is caused, in some cases, by a point mutation
in the Ī² subunit of a voltage-gated Na+ channel (SCN1B)
o Spontaneous mutations in SCN1A (encoding the Ī± subunit of the major voltage-gated
Na+ channel in neurons) results in presumed loss of Na+ channel function have been
identified in some infants of Dravet syndrome (Myoclonic).
o Patients with these mutations are generally found to be refractory to ASDs that block
Na+ channels.
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19. Phenytoin
o Slows the rate of recovery of voltage-activated Na+ channels from inactivation.
o 90% bound to protein. Valproate competes for protein-binding sites and inhibits
phenytoin metabolism.
o Metabolized by CYP2C9
o Induces CYP2C9 and CYP3A4 (oral contraception diminishes)
o Low water solubility of phenytoin hindered its IV use and led to production of
Fosphenytoin, a water-soluble prodrug.
o Converted into phenytoin by phosphatases in liver and RBC
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20. Phenytoin
o Cardiac arrhythmias (when infused at a greater speed in Status Epilepticus).
o Gingival hyperplasia occurs in about 20% of all patients during chronic administration
Drug-induced systemic lupus erythematosus; potentially fatal hepatic necrosis
o Osteomalacia (altered metabolism, hindered absorption), increases the metabolism of
vitamin K (explaining why Vit-D supplements donāt ameliorate Osteomalacia)
o Hyperglycaemia and glycosuria (insulin secretion inhibited)
o In Toxic doses, it may produce excitatory signs and at lethal levels a type of decerebrate
rigidity and Nystagmus.
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21. Phenytoin
o Effective against focal and generalized tonic-clonic, focal-to-bilateral tonic-
clonic, tonic-clonic of unknown onset (tonic-clonic), but not generalized
absence seizures.
o Trigeminal and related neuralgias occasionally respond to phenytoin, but
carbamazepine may be preferable
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23. benzodiazipines
o Clonazepam is unusually potent in antagonizing the effects of
pentylenetetrazol, but it is almost without action on seizures induced by
maximal electroshock.
o Suppress the spread of kindled seizures and generalized seizures produced
by stimulation of the amygdala.
o Benzodiazepines act at subsets of GABAA receptors and increase the
frequency, but not duration, of openings at GABA-activated.
o t 1/2 of diazepam in plasma is ~43 h and that of N-desmethyl-diazepam is
about 60 h.
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24. benzodiazipines
o Used in absence seizures and myoclonic seizures but tolerance develops
after 1-6 months.
o Clonazepam intranasal spray is designated as an orphan drug for recurrent
acute repetitive seizures.
o Diazepam is not useful as an oral agent for the treatment of seizure
disorders
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25. Phenobarbital
o Phenobarbital increases the GABAA receptorāmediated current by increasing
the duration of bursts of GABAA receptorāmediated currents without
changing the frequency of bursts.
o Phenobarbital is an effective agent for generalized tonic-clonic, focal-to-
bilateral tonic-clonic, tonic-clonic of unknown onset (generalized tonic-clonic),
and focal seizures.
o t1/2 of phenobarbital varies widely, 50ā140 h in adults and 40ā70 h in
children younger than 5 years of age, often longer in neonates.
o Phenobarbital induces UGT enzymes as well as the CYP2C and CYP3A
subfamilies.
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26. Primidone
o Metabolized to two active metabolites: phenobarbital and
phenylethylmalonamide (PEMA). Primidone and its two metabolites each have
antiseizure effects on focal and generalized tonic-clonic seizures
o Primidone is still considered to be a first-line therapy for essential tremor with
the Ī² blocker propranolol but in epilepsy has now largely been replaced earlier
used for focal or generalized seizures.
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27. Carbamazepine
o Slows the rate of recovery of Na+ channels from inactivation.
o The carbamazepine metabolite 10,11-epoxycarbamazepine limits sustained
repetitive firing at therapeutically relevant concentrations.
o Carbamazepine induces CYP2C, CYP3A, and UGT, thus enhancing the
metabolism of drugs degraded by these enzymes.
o Carbamazepine is useful in patients with generalized tonic-clonic and both focal
aware and focal with impaired awareness seizures
o Also used in bipolar disorder. Carbamazepine is the primary agent for treatment
of trigeminal and glossopharyngeal neuralgias.
o Aplastic anaemia is concerning side effect.
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28. oxcarbazepine
o Oxcarbazepine (10,11-dihydro-10-oxocarbamazepine) is a keto analogue of
carbamazepine and is a prodrug that is rapidly converted to its metabolite,
eslicarbazepine.
o Eslicarbazepine is then extensively converted to its S(+) enantiomer, the active
metabolite S-licarbazepine.
o Oxcarbazepine has a mechanism of action similar to that of carbamazepine but
is a less-potent enzyme inducer than carbamazepine
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29. Ethosuximide
o Ethosuximide reduces low threshold T-type Ca2+ currents in thalamic
neurons.
o The plasma t1/2 of ethosuximide averages between 40 and 50 h in adults and
about 30 h in children.
o Ethosuximide is effective against absence seizures, but not tonic-clonic seizure
o Parkinson-like symptoms and photophobia have been reported
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30. Ezogabine
o Ezogabine enhances transmembrane K+ currents mediated by the KCNQ family
of ion channels (Kv7.2āKv7.5).
o In vitro studies suggested that ezogabine may also enhance GABA-mediated
currents.
o Increase in ezogabine dosage should be considered when adding phenytoin or
carbamazepine.
o Treatment of focal-onset seizures in patients aged 18 years and older with
inadequate response to alternative ASD.
o Serious side effects include skin discoloration, QT prolongation, and
neuropsychiatric symptoms, including suicidal thoughts and behavior,
psychosis, and hallucinations.
o Retinal abnormalities
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31. Felbamate
o Felbamate inhibit NMDA-evoked responses and potentiate GABA-evoked
responses in whole-cell. Yet its anti seizure mech remains unknown.
o Drug-induced aplastic anemia or liver failure is known
o Lennox-Gastaut syndrome, and focal and generalized seizures which are poorly
controlled
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32. Gabapentin - pregabalin
o Gabapentin inhibits tonic hind limb extension in the electroshock seizure model.
o Also inhibits clonic seizures induced by pentylenetetrazol.
o They do not mimics GABA when iontophoretically applied to neurons in primary
culture.
o These compounds bind with high affinity to a protein in cortical membranes with
an amino acid sequence identical to that of the Ca2+ channel subunit Ī±2Ī“-1.
o This interaction with the Ī±2Ī“-1 protein may mediate the anticonvulsant effects
of gabapentin, but true mech remains unclear.
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33. Gabapentin - pregabalin
o Used focal onset seizures, with and without progression to bilateral tonic-clonic
seizures
o Management of fibromyalgia and the neuropathic pain associated diabetic
peripheral neuropathy, postherpetic neuralgia, or spinal cord injury.
o Gabapentin and pregabalin are both listed in pregnancy category C.
o No interaction with any other ASD
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34. Lacosamide
o Stereoselective enantiomer of the amino acid, L-serine.
o Enhance (prolong) the slow inactivation of voltage-gated Na+ channels
o Also binds collapsin response mediator protein-2 (CRMP-2), a phosphoprotein
involved in neuronal differentiation and axon outgrowth, but the contribution of
CRMP-2 to lacosamideās antiseizure efficacy remains unclear.
o Highly effective in numerous preclinical animal models of seizures and epilepsy,
including maximal electroshock, hippocampal kindling, Frings and 6-Hz models,
giving lacosamide a unique preclinical profile compared to other Na+ channel
blockers.
o Approved as adjunctive therapy for focal-onset seizures in patients older than 17
year.
o Lacosamide may contribute to suicidal ideations and suicide
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35. Lamotrigine
o Suppresses tonic hind limb extension in the maximal electroshock model and
focal and secondarily generalized seizures in the kindling model, but does not
inhibit clonic motor seizures induced by pentylenetetrazol.
o Delays the recovery from inactivation of recombinant Na+ channels, mechanisms
similar to those of phenytoin and carbamazepine.
o It may inhibits synaptic release of glutamate by acting at Na+ channels
themselves.
o Focal and secondarily generalized tonic-clonic seizures in adults and Lennox-
Gastaut syndrome in both children and adults.
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36. Levetiracetam
o Inhibits focal and secondarily generalized tonic-clonic seizures in the kindling
model.
o Synaptic vesicle protein SV2A mediates the anticonvulsant effects of
levetiracetam. SV2A can function as a galactose transporter.
o Inhibits N-type Ca2+ channels and Ca2+ release from intracellular stores.
o Adjunctive treatment of focal seizures in adults and children, for primary onset
tonic-clonic seizures, and for myoclonic seizures of JME.
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37. perampanel
o Perampanel is a first-in class selective, noncompetitive antagonist of the AMPA-
type ionotropic glutamate receptor.
o NMDA antagonists, which shorten the duration of repetitive discharges, AMPA
receptor antagonists prevent repetitive neuronal firing.
o t1/2 of about 105 h.
o Adverse behavioral reactions, including hostility, aggression, and suicidal
thoughts and behaviors,
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38. rufinamide
o Rufinamide prolongs slow inactivation of voltage-gated Na+ channels and limits
sustained repetitive firing.
o Shown to be effective against all seizure phenotypes in Lennox-Gastaut syndrome
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39. stiripentol
o Inhibition of synaptosomal uptake of GABA or by inhibition of GABA
transaminase.
o Stiripentolās elimination kinetics are nonlinear, with a t1/2 ranging from 4 to 13h
o It is a potent inhibitor of CYPs 3A4, 1A2, and 2C19.
o Adjunctive therapy for refractory generalized tonic-clonic seizures in patients with
severe myoclonic epilepsy in infancy (Dravet syndrome).
o Stiripentol in children with Dravet syndrome who fail to respond to valproate and
clobazam have a 71% response rate.
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40. tiagabine
o Tiagabine inhibits the GABA transporter GAT-1 and thereby reduces GABA
uptake into neurons and glia and prolongs the dwell time of GABA.
o Tiagabine inhibits maximum electroshock seizures and both limbic and
secondarily generalized tonic clonic seizures in the kindling model.
o Add-on therapy for refractory focal seizures with or without secondary
generalization.
o Tiagabine may be contraindicated in patients with generalized absence epilepsy.
Paradoxically, tiagabine has been associated with the occurrence of seizures in
patients without epilepsy.
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41. topiramate
o Topiramate reduces voltage-gated Na+ currents in cerebellar granule cells and
may act on the inactivated state of the channel similarly to phenytoin.
o Hyperpolarizing K+ current, enhances postsynaptic GABAA receptor currents,
and limits
o activation of the AMPA-kainate subtype.
o Drug is a weak inhibitor of carbonic anhydrase.
o Inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as
focal and secondarily generalized tonic-clonic seizures in the kindling model.
o The agent is effective as monotherapy for refractory focal epilepsy. Refractory
generalized tonic-clonic seizures.
o It may precipitate renal calculi (kidney stones), probably due to inhibition of
carbonic anhydrase
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42. valproate
o Inhibits tonic hind limb extension in maximal electroshock seizures and kindled
seizures.
o Like ethosuximide, valproate at subtoxic doses inhibits clonic motor seizures
induced by pentylenetetrazol
o Prolongs recovery of voltage-activated Na+ channels from inactivation. reduces T-
type currents.
o Valproate is a broad-spectrum ASD effective in the treatment of absence,
myoclonic, focal, and tonic-clonic seizures.
o Elevation of hepatic transaminases in plasma is observed in up to 40% of
patients
o This agent can also produce teratogenic effects, such as neural tube defects.
o Inhibits the metabolism of drugs that are substrates for CYP2C9
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43. vigabatrin
o Structural analogue of GABA, irreversibly inhibits the major degradative enzyme
for GABA, GABA transaminase
o Used in Infantile spasms in children
o Progressive and permanent bilateral vision loss. Therefore only advisable to
patients that are refractory to all treatments
o Pregnancy category C. Vigabatrin is excreted in the milk of nursing mothers.
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44. Zonisamide
o Prolongs the inactivated state of voltage-gated Na+ channels in a manner similar
to actions of phenytoin.
o Inhibits T-type Ca2+ currents and reduces the influx of calcium. Zonisamide can
also inhibit carbonic anhydrase and scavenge free radicals.
o Causes renal caliculi and metabolic acidosis.
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45. Clinical approach
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Focal, Focal to bilateral tonic clonic
Carbamazepine and phenytoin
preferred
Valproate also used
Gabapentin,
lamotrigine, and topiramate.
For newly diagnosed focal or mixed
seizure
disorders
Generalized absence seizures
Valproate
First choice
Lamotrigine.
For newly diagnosed absence
seizures
Myoclonic seizures
Valproate, also in JME (myoclonic
seizures often coexist with tonic-
clonic and
absence seizures)
Levetiracetam adjuvant for
refractory cases
46. Clinical Approach
o Between 2% and 4% of children experience a convulsion associated with a
febrile illness; 25%ā33% of these children will have another febrile convulsion.
Only 2%ā3% become epileptic in later years.
o For children at high risk of developing recurrent febrile seizures and epilepsy,
rectally administered diazepam at the time of fever may prevent recurrent
seizures
o Infantile spasms with hypsarrhythmia (abnormal interictal high-amplitude slow
waves and multifocal asynchronous spikes on EEG) are refractory to the usual
ASD.
o Corticotropin or glucocorticoids are commonly used.
o Ganaxolone orphan drug for infantile spasms.
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47. Clinical Approach
o RAMPART trial indicated that midazolam (intramuscular) is as effective as
intravenous lorazepam and was not associated with respiratory distress or
seizure recurrence. (For status epilepticus)
o Failure of contraceptives is possible, due to this 2 fold increase in teratogenic
potential
o Teratogenic ā malformations include congenital heart defects, neural tube
defects, cleft lip, cleft palate.
o Phenytoin, carbamazepine, valproate, lamotrigine, and phenobarbital all have
been associated with teratogenic effects.
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48. Current researches
o Cooling, or focal hypothermia has shown some promise
(https://doi.org/10.1016/j.seizure.2020.09.018)
o Long half life ASD are better than short half llife ASD
(https://doi.org/10.1016/j.yebeh.2019.106634)
o Extracts of osmium sanctum (Tulsi) had adjuvant effects in neuroprotection of
seizures with CBZ and Phenytoin (https://doi.org/10.1016/j.jsps.2020.09.010)
o LFES shows AS effects maybe by GABA-B fraction.
(https://doi.org/10.1016/j.brs.2020.07.013)
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