The document discusses factors to consider in the differential diagnosis of epilepsy, including syncope attacks, cardiac arrhythmias, migraine, hypoglycemia, narcolepsy, panic attacks, and pseudoseizures. It provides guidelines for routine investigations such as bloodwork, imaging, and EEG. It also lists advanced investigations that may be used when epilepsy is intractable, including neuropsychological evaluations and specialized EEG and imaging tests. Common and newer antiepileptic drugs are also discussed, along with their mechanisms of action and metabolic pathways.

1. Dr Anoop.K.R
Asst professor,Dept of general medicine
MMCH

2. The following should be considered in the diff. dg. of epilepsy:
 Syncope attacks (when pt. is standing; results from global reduction
of cerebral blood flow; prodromal pallor, nausea, sweating; jerks!)
 Cardiac arrythmias (e.g. Adams-Stokes attacks). Prolonged arrest of
cardiac rate will progressively lead to loss of consciousness – jerks!
 Migraine (the slow evolution of focal hemisensory or hemimotor
symptomas in complicated migraine contrasts with more rapid
“spread“ of such manifestation in SPS. Basilar migraine may lead to
loss of consciousness!
 Hypoglycemia – seizures or intermittent behavioral disturbances may
occur.
 Narcolepsy – inappropriate sudden sleep episodes
 Panic attacks
 PSEUDOSEIZURES – psychosomatic and personality disorders

3.  The concern of the clinician is that epilepsy may be symptomatic
of a treatable cerebral lesion.
 Routine investigation: Haematology, biochemistry (electrolytes,
urea and calcium), chest X-ray, electroencephalogram (EEG).
Neuroimaging (CT/MRI) should be performed in all persons aged
25 or more presenting with first seizure and in those pts. with
focal epilepsy irrespective of age.
 Specialised neurophysiological investigations: Sleep deprived
EEG, video-EEG monitoring.
 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)

4.  The majority of pts respond to drug therapy
(anticonvulsants). In intractable cases surgery may be
necessary. The treatment target is seizure-freedom and
improvement in quality of life!
 The commonest drugs used in clinical practice are:
Carbamazepine, Sodium valproate, Lamotrigine (first line drugs)
Levetiracetam, Topiramate, Pregabaline (second line drugs)
Zonisamide, Eslicarbazepine, Retigabine (new AEDs)
 Basic rules for drug treatment: Drug treatment should
be simple, preferably using one anticonvulsant
(monotherapy). “Start low, increase slow“.
Add-on therapy is necessary in some patients…

5.  Increase inhibitory neurotransmitter system—
GABA
 Decrease excitatory neurotransmitter system—
glutamate
 Block voltage-gated inward positive currents—
Na+ or Ca++
 Increase outward positive current—K+
 Many AEDs pleiotropic—act via multiple
mechanisms
dr shabeel

9.  The brain’s major excitatory neurotransmitter
 Two groups of glutamate receptors
 Ionotropic—fast synaptic transmission
 NMDA, AMPA, kainate
 Gated Ca++
and Gated Na+ channels
 Metabotropic—slow synaptic transmission
 Quisqualate
 Regulation of second messengers (cAMP and
Inositol)
 Modulation of synaptic activity
 Modulation of glutamate receptors
 Glycine, polyamine sites, Zinc, redox site
dr shabeel

10.  NMDA receptor sites as targets
 Ketamine, phencyclidine, dizocilpine block channel
and have anticonvulsant properties but also
dissociative and/or hallucinogenic properties; open
channel blockers.
 Felbamate antagonizes strychnine-insensitive glycine
site on NMDA complex
 AMPA receptor sites as targets
 Topiramate antagonizes AMPA site
dr shabeel

11.  Major inhibitory neurotransmitter in
the CNS
 Two types of receptors
 GABAA—post-synaptic, specific
recognition sites, linked to CI-
channel
 GABAB—presynaptic autoreceptors,
mediated by K+
currents
dr shabeel

12.  Benzodiazepines (diazapam, clonazapam)
 Increase frequency of GABA-mediated chloride
channel openings
 Barbiturates (phenobarbital, primidone)
 Prolong GABA-mediated chloride channel
openings
 Some blockade of voltage-dependent sodium
channels
dr shabeel

13. Gabapentin
 May modulate amino acid transport into brain
 May interfere with GABA re-uptake
Tiagabine
 Interferes with GABA re-uptake
Vigabatrin (not currently available in US)
 elevates GABA levels by irreversibly inhibiting
its main catabolic enzyme, GABA-transaminase
dr shabeel

14.  Neurons fire at high frequencies during
seizures
 Action potential generation is dependent on
Na+ channels
 Use-dependent or time-dependent Na+
channel blockers reduce high frequency firing
without affecting physiological firing
dr shabeel

15. Phenytoin, Carbamazepine
 Block voltage-dependent sodium channels at high firing
frequencies—use dependent
Oxcarbazepine
 Blocks voltage-dependent sodium channels at high firing
frequencies
 Also effects K+ channels
Zonisamide
 Blocks voltage-dependent sodium channels and T-type
calcium channels
dr shabeel

16.  Absence seizures are caused by oscillations
between thalamus and cortex that are
generated in thalamus by T-type (transient) Ca2+
currents
 Ethosuximide is a specific blocker of T-type
currents and is highly effective in treating
absence seizures
dr shabeel

17.  K+ channels have important inhibitory control
over neuronal firing in CNS—repolarize
membrane to end action potentials
 K+ channel agonists would decrease
hyperexcitability in brain
 So far, the only AED with known actions on K+
channels is valproate
 Retiagabine is a novel AED in clinical trials that
acts on a specific type of voltage-dependent K+
channel
dr shabeel

18. Felbamate
 Blocks voltage-dependent sodium channels at high firing
frequencies
 May modulate NMDA receptor via strychnine-insensitive
glycine receptor
Lamotrigine
 Blocks voltage-dependent sodium channels at high firing
frequencies
 May interfere with pathologic glutamate release
 Inhibit Ca++ channels?
dr shabeel

19. Topiramate
 Blocks voltage-dependent sodium channels at high firing
frequencies
 Increases frequency at which GABA opens Cl- channels
(different site than benzodiazepines)
 Antagonizes glutamate action at AMPA/kainate receptor
subtype?
Valproate
 May enhance GABA transmission in specific circuits
 Blocks voltage-dependent sodium channels
 May also augment K+ channels
 T-type Ca2+ currents?
dr shabeel

20.  The enzymes most involved with drug
metabolism
 Enzymes have broad substrate specificity,
and individual drugs may be substrates for
several enzymes
 The principle enzymes involved with AED
metabolism include CYP2C9, CYP2C19,
CYP3A
dr shabeel

21.  Inducers: Increase clearance and decrease
steady-state concentrations of other drugs
 Inhibitors: Decrease clearance and increase
steady-state concentrations of other drugs
dr shabeel

22. Inducers Inhibitors
phenobarbital valproate
primidone topiramate (CYP2C19)
phenytoin oxcarbazepine (CYP2C19)
carbamazepine felbamate (CYP2C19)
dr shabeel

23.  The enzymes most involved with drug metabolism
 Nomenclature based upon homology of amino acid
sequences
 Enzymes have broad substrate specificity, and
individual drugs may be substrates for several
enzymes
 The principle enzymes involved with AED metabolism
include CYP2C9, CYP2C19, CYP3A4

24. Inducers Inhibitors
phenobarbital erythromycin
primidone nifedipine/verapamil
phenytoin trimethoprim/sulfa
carbamazepine propoxyphene
tobacco/cigarettes cimetidine
valproate

25. C a t e g o r y C Y P 3 A 4 C Y P 2 C 9 C Y P 2 C 1 9 U G T
In h ib it o r Erythromycin
Clarithromycin
Diltiazem
Fluconazole
Itraconazole
Ketoconazole
Cimetidine
propoxyphene
Grapefruit
juice
VPA
Fluconazole
metronidazole
Sertraline
Paroxetine
Trimethoprim/
sulfa
Ticlopidine
Felbamate
OXC/MHD
Omeprazole
VPA
In d u c e r CBZ
PHT
PB
felbamate
Rifampin
TPM
OXC/MHD
CBZ
PHT
PB
Rifampin
CBZ
PHT
PB
rifampin
CBZ
PHT
PB
OXC/MHD
LTG (?)

26.  Phenytoin CYP2C9 CYP2C19
− Inhibitors: valproate, ticlopidine,
fluoxetine, topiramate, fluconazole
 Carbamazepine CYP3A4 CYP2C8
CYP1A2
− Inhibitors: ketoconazole, fluconazole,
erythromycin, diltiazem
 Lamotrigine UGT 1A4
− Inhibitor: valproate

27.  Valproate
− UDP glucuronosyltransferase (UGT)
⇑ plasma concentrations of Lamotrigine, Lorazepam
− CYP2C19
⇑ plasma concentrations of Phenytoin, Phenobarbital
 Topiramate & Oxcarbazepine
− CYP2C19
⇑ plasma concentrations of Phenytoin
 Felbamate
− CYP2C19
⇑ plasma concentrations of Phenytoin, Phenobarbital

28.  Although many AEDs can cause pharmacokinetic
interactions, several newer agents appear to be less
problematic.
 AEDs that do not appear to be either inducers or
inhibitors of the CYP system include:
Gabapentin
Lamotrigine
Tiagabine
Levetiracetam
Zonisamide
dr shabeel

29.  First line drug for partial seizures
 Inhibits Na+ channels—use dependent
 Prodrug fosphenytoin for IM or IV administration.
Highly bound to plasma proteins.
 Half-life: 22-36 hours
 Adverse effects: CNS sedation (drowsiness, ataxia,
confusion, insomnia, nystagmus, etc.), gum
hyperplasia, hirsutism
 Interactions: carbamazapine, phenobarbital will
decrease plasma levels; alcohol, diazapam,
methylphenidate will increase. Valproate can displace
from plasma proteins. Stimulates cytochrome P-450, so
can increase metabolism of some drugs.
dr shabeel

30.  First line drug for partial seizures
 Inhibits Na+ channels—use dependent
 Half-life: 6-12 hours
 Adverse effects: CNS sedation. Agranulocytosis and
aplastic anemia in elderly patients, rare but very serious
adverse. A mild, transient leukopenia (decrease in white
cell count) occurs in about 10% of patients, but usually
disappears in first 4 months of treatment. Can
exacerbate some generalized seizures.
 Drug interactions: Stimulates the metabolism of other
drugs by inducing microsomal enzymes, stimulates its
own metabolism. This may require an increase in dose
of this and other drugs patient is taking.
dr shabeel

31.  Partial seizures, effective in neonates
 Second-line drug in adults due to more severe CNS
sedation
 Allosteric modulator of GABAA receptor (increase open
time)
 Absorption: rapid
 Half-life: 53-118 hours (long)
 Adverse effects: CNS sedation but may produce excitement
in some patients. Skin rashes if allergic. Tolerance and
physical dependence possible.
 Interactions: severe CNS depression when combined with
alcohol or benzodiazapines. Stimulates cytochrome P-450
dr shabeel

32.  Partial seizures
 Mechanims—see phenobarbital
 Absorption: Individual variability in rates. Not highly
bound to plasma proteins.
 Metabolism: Converted to phenobarbital and
phenylethyl malonamide, 40% excreted unchanged.
 Half-life: variable, 5-15 hours. PB ~100, PEMA 16 hours
 Adverse effects: CNS sedative
 Drug interactions: enhances CNS depressants, drug
metabolism, phenytoin increases conversion to PB
dr shabeel

33.  Status epilepticus (IV)
 Allosteric modulator of GABAA receptors—increases
frequency
 Absorption: Rapid onset. Diazapam—rectal
formulation for treatment of SE
 Half-life: 20-40 hours (long)
 Adverse effects: CNS sedative, tolerance, dependence.
Paradoxical hyperexcitability in children
 Drug interactions: can enhance the action of other CNS
depressants
dr shabeel

34.  Partial seizures, first-line drug for generalized seizures.
 Enhances GABA transmission, blocks Na+ channels, activates
K+ channels
 Absorption: 90% bound to plasma proteins
 Half-life: 6-16 hours
 Adverse effects: CNS depressant (esp. w/ phenobarbital),
anorexia, nausea, vomiting, hair loss, weight gain, elevation of
liver enzymes. Hepatoxicity is rare but severe, greatest risk <2
YO. May cause birth defects.
 Drug interactions: May potentiate CNS depressants, displaces
phenytoin from plasma proteins, inhibits metabolism of
phenobarbital, phenytoin, carbamazepine (P450 inhibitor).
dr shabeel

35.  Absence seizures
 Blocks T-type Ca++ currents in thalamus
 Half-life: long—40 hours
 Adverse effects: gastric distress—pain, nausea,
vomiting. Less CNS effects that other AEDs,
transient fatigue, dizziness, headache
 Drug interactions: administration with
valproate results in inhibition of its metabolism
dr shabeel

36. dr shabeel

37. Newer Antiepileptic drugs
Drugs Mechanism of
action
FDA approved indication
Lamotrigine Inhibits voltage
sensitive sodium
channels
Inhibits synaptic
release of
glutamate
as adjunctive therapy of partial
seizures in patients greater than or
equal to 2
years of age and Primary GTC in
patients ≥ 13 years of age
Levetiracetam Binds to synaptic
vesicle protein
SV2A and
impedes nerve
conduction
Refractory Partial seizures
Refractory JME
Gabapentin Binds to α2δ
subunit of
voltage gated
calcium channels
Partial seizure with or without
secondary generalization

38. Drugs Mechanism of action FDA approved indication
Lacosamide Sodium channel
modulation
Add-on for partial epilepsy
Rufinamide Sodium channel
modulation
Lennox-Gastaut syndrome in
children 4 years and older and
adults
Atonic seizures
Zonisamide Inhibition of sodium
channels & T type of
calcium channel
currents
Decreases GABA
uptake & increases
glutamate uptake
Focal seizure
Vigabatrin Irreversible inhibitor
of GABA
transaminase
Infantile spasms
As an adjunctive for refractory
partial epilepsy
Newer Antiepileptic drugs

39.  Approved for add-on therapy, monotherapy in
partial seizures that are refractory to other AEDs
 Activity-dependent blockade of Na+ channels, may
also augment K+ channels
 Half-life: 1-2 hours, but converted to 10-
hydroxycarbazepine 8-12 hours
 Adverse effects: similar to carbamazepine (CNS
sedative) but may be less toxic.
 Drug interactions: less induction of liver enzymes,
but can stimulate CYP3A and inhibit CYP2C19
dr shabeel

40.  Add-on therapy for partial seizures, evidence that it is
also effective as monotherapy in newly diagnosed
epilepsies (partial)
 May interfere with GABA uptake
 Absorption: Non-linear. Saturable (amino acid
transport system), no protein binding.
 Metabolism: none, eliminated by renal excretion
 Half-life: 5-9 hours, administered 2-3 times daily
 Adverse effects: less CNS sedative effects than classic
AEDs
 Drug interactions: none known
dr shabeel

41.  Add-on therapy, monotherapy for refractory partial
seizures. Also effective in Lennox Gastaut Syndrome
and newly diagnosed epilepsy. Effective against
generalized seizures.
 Use-dependent inhibition of Na+ channels, glutamate
release, may inhibit Ca++ channels
 Half-life—24 hours
 Adverse effects: less CNS sedative effects than classic
AEDs, dermatitis potentially life-threatening in 1-2% of
pediatric patients.
 Drug interactions: levels increased by valproate,
decreased by carbamazepine, PB, phenytoin
dr shabeel

42.  Third-line drug for refractory partial seizures
 Frequency-dependent inhibition of Na+
channels, modulation of NMDA receptor
 Adverse effects: aplastic anemia and severe
hepatitis restricts its use (black box)
 Drug interactions: increases plasma phenytoin
and valproate, decreases carbamazapine.
Stimulates CYP3A and inhibits CYP2C19
dr shabeel

43.  Add-on therapy for partial seizures
 Binds to synaptic vesicle protein SV2A, may
regulate neurotransmitter release
 Half-life: 6-8 hours (short)
 Adverse effects: CNS depresssion
 Drug interactions: minimal
dr shabeel

44.  Add-on therapy for partial seizures
 Interferes with GABA reuptake
 Half-life: 5-8 hours (short)
 Adverse effects: CNS sedative
 Drug interactions: minimal
dr shabeel

45.  Add-on therapy for partial and generalized
seizures
 Blocks Na+ channels and T-type Ca++
channels
 Half-life: 1-3 days (long)
 Adverse effects: CNS sedative
 Drug interactions: minimal
dr shabeel

46.  Add-on for refractory partial or generalized seizures.
Effective as monotherapy for partial or generalized
seizures, Lennox-Gastaut syndrome.
 Use-dependent blockade of Na+ channels, increases
frequency of GABAA channel openings, may interfere
with glutamate binding to AMPA/KA receptor
 Half-life: 20-30 hours (long)
 Adverse effects: CNS sedative
 Drug interactions: Stimulates CYP3A and inhibits
CYP2C19, can lessen effectiveness of birth control pills
dr shabeel

47.  Add-on therapy for partial seizures, monotherapy for
infantile spasms. (Not available in US).
 Blocks GABA metabolism through actions on GABA-
transaminase
 Half-life: 6-8 hours, but pharmacodynamic activity is
prolonged and not well-coordinated with plasma half-
life.
 Adverse effects: CNS sedative, ophthalmologic
abnormalities
 Drug interactions: minimal
dr shabeel

48.  First consideration is efficacy in stopping
seizures
 Because many AEDs have overlapping,
pleiotropic actions, the most appropriate
drug can often be chosen to reduce side
effects. Newer drugs tend to have less CNS
depressant effects.
 Potential of long-term side effects,
pharmokinetics, and cost are other
considerations
dr shabeel

49. Current treatment
Seizure type First line treatment Second line treatment
Partial seizures Carbamazepine
Lamotrigine
Oxcarbazepine
Levetiracetam
Topiramate
Valproate
Clobazam
Zonisamide
Generalized seizures
Tonic-clonic Sodium Valproate
Carbamazepine
Lamotrigine
Clobazam
Absence Ethosuximide
Sodium valproate
Clobazepam
Lamotrigine
Atypical absence Clobazepam
Clobazam
Lamotrigine
Carbamazepine
Myoclonic Sodium valproate
Clonazepam
Levitiracetam
Topiramate

50.  With secondary generalization
 First-line drugs are carbamazepine and phenytoin
(equally effective)
 Valproate, phenobarbital, and primidone are also
usually effective
 Without generalization
 Phenytoin and carbamazepine may be slightly more
effective
 Phenytoin and carbamazepine can be used
together (but both are enzyme inducers)
dr shabeel

51.  Adjunctive (add-on) therapy where
monotherapy does not completely stop
seizures—newer drugs felbamate, gabapentin,
lamotrigine, levetiracetam, oxcarbazepine,
tiagabine, topiramate, and zonisamide
 Lamotrigine, oxcarbazepine, felbamate
approved for monotherapy where phenytoin
and carbamazepine have failed.
 Topirimate can effective against refractory
partial seizures.
dr shabeel

52.  Tonic-clonic, myoclonic, and absence seizures
—first line drug is usually valproate
 Phenytoin and carbamazepine are effective on
tonic-clonic seizures but not other types of
generalized seizures
 Valproate and ethoxysuximide are equally
effective in children with absence seizures, but
only valproate protects against the tonic-clonic
seizures that sometimes develop. Rare risk of
hepatoxicity with valproate—should not be
used in children under 2.
dr shabeel

53.  Clonazepam, phenobarbital, or primidone can
be useful against generalized seizures, but may
have greater sedative effects than other AEDs
 Tolerance develops to clonazepam, so that it
may lose its effectiveness after ~6 months
 Carbamazepine may exacerbate absence and
myoclonic, underscoring the importance of
appropriate seizure classification
 Lamotrigine, topiramate, and zonisamide are
effective against tonic-clonic, absence, and tonic
seizures
dr shabeel

54.  A condition when consciousness does not return
between seizures for more than 30 min. This state
may be life-threatening with the development of
pyrexia, deepening coma and circullatory collapse.
Death occurs in 5-10%.
 Status epilepticus may occur with frontal lobe
lesions (incl. strokes), following head injury, on
reducing drug therapy, with alcohol withdrawal,
drug intoxication, metabolic disturbances or
pregnancy.
 Treatment: AEDs intravenously ASAP, event.
general anesthesia with propofol or thipentone
should be commenced immediately.

55.  Treatment
 Diazepam, lorazapam IV (fast, short acting)
 Followed by phenytoin, fosphenytoin, or
phenobarbital (longer acting) when control is
established
dr shabeel

56. No evidence that any new AED was superior in efficacy to old
AEDs
Eg. CBZ and VPA in efficacy in well-controlled trials of recent-
onset epilepsy.
Although seizure control may have improved in rare epilepsies
(Vigabatrin for West-Syndrome , Felbamate for LGS), but , seizure
control has not improved dramatically in the last 30 years for
common seizures (focal, myoclonic and absence)
Further, one in three patients has drug resistant seizures.

57. Recent advances…
FDA approved
drugs
New
applications of
existing drugs
New
formulations
in pipeline
Drugs in
pipeline

58. Clobazam
• Acts by potentiation of GABAnergic transmission via binding to
GABA-A receptor
 A benzodiazepine with low tendency to produce sedation
 Lower incidence of loss of therapeutic effect over time,
rendering it appropriate for long term management
• Oct 2011: FDA approved for Clobazam as adjunctive
treatment for seizures associated with Lennox-Gestaut
syndrome in adults and children 2 years of age and older in a
dose of 5-40 mg/day.
Effectiveness was established in two multi-centre controlled
studies.
• Most common adverse effects: sedation, lethargy and fatigue
In Dec 2013, FDA issued warning against serious skin reactions
that can result in permanent harm and death and
approved label changes
Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of Clobazam in Lennox-Gastaut syndrome.
Neurology. 2011 Oct 11;77(15):1473-81

59. Ezogabine
• First neuronal potassium channel opener developed for the
treatment of epilepsy
 Acts by enhancement of potassium currents mediated by
KCNQ ion channels, thereby reducing hyper excitability
 Also potentiates GABA-A receptors via activation of beta 1 &
beta 2 subtype of GABA receptor
 Also, weakly blocks sodium and calcium channels
Nov 2011: FDA approved Ezogabine as an adjunctive treatment in
refractory partial-onset seizures based on RESTORE I & II trials
Owen RT Ezogabine: a novel antiepileptic as adjunctive therapy for partial onset seizures. Drugs Today 2010 Nov;46(11):815-22

60. Ezogabine (Retigabine)
• Absorption is unaffected by food with an absolute
bioavailability of 50–60%
• Peak plasma concentration within 1.5 h and half life is 8 – 11
hours
• Not metabolized by the cytochrome P450 system, so minimal
drug interactions seen, as below,
 Phenytoin & Carbamazepine decrease Ezogabine
concentration
 Ezogabine inhibits renal clearance of digoxin
 Alcohol can increase serum Ezogabine concentrations
Serious adverse effects include urinary retention,
neuropsychiatric symptoms and QT-interval lengthening that
need careful monitoring
French J A et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology.2011 May 3; 76(18): 1555-63

61. Oxcarbazepine ER
• Acts by blockade of voltage sensitive sodium channels
Less potent enzyme inducer than carbamazepine
• Oct 2012: FDA approved a once-daily extended-release
formulation as an adjunctive therapy for partial seizures in
adults and in children > 6 years
• Dose: 1200 – 2400 OD on empty stomach
• PROSPER study, a multicentre, randomized, double-blind trial
in 366 patients with refractory partial epilepsy showed efficacy
• Most common adverse effects include headache, dizziness and
diplopia
Rare and Serious adverse effects are hyponatremia and suicidal
ideation
French JA, Baroldi P, Brittain ST, Johnson JK; PROSPER Investigators Study Group. Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™)
as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial. Acta Neurol Scand. 2014 Mar;129(3):143-53

62. Eslicarbazepine
• Third generation AED
• S-licarbazepine: effective component of carbamazepine
with,
 fewer cognitive and psychiatric adverse effects
 crosses BBB more effectively
 lacks a toxic epoxide
 minimal interaction with the cytochrome P450 liver
enzymes
 Elger et al. showed less incidence of hyponatremia
compared to oxcarbazepine
Elinor Ben-Menachem. Eslicarbazepine Acetate: A Well-Kept Secret? Epilepsy Curr. Jan 2010; 10(1): 7–8

63. • Acts by blockade of fast acting voltage gated sodium
channels
• Nov 2013: US FDA approved as an adjunctive
treatment for partial onset seizures
• Based on 3 randomized, double blind, multi-centre
trials in 1049 patients with partial onset seizures
• Dose: 400-1200 mg/day ; once daily dosing
• Most adverse effects include headache, nausea, ataxia,
tremors
Eslicarbazepine
Gil-Nagel A, Elger C, Ben-Menachem E, Halász P, Lopes-Lima J, Gabbai AA, Nunes T, Falcão A, Almeida L, da-Silva PS. Efficacy and safety of
eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies.
Epilepsia. 2013 Jan;54(1):98-107

64. Parampanel
• First-in-class drug, a highly selective, non competitive AMPA
type glutamate receptor antagonist
• Nov 2012: FDA approved for treatment of refractory partial-
onset seizures in patients 12 years and older,
based on 3 clinical trials in 1037 adults and adolescents
which showed reduced seizure frequency
Dose: 4 – 12 mg OD
• Boxed warning about the risk for serious neuropsychiatric
events
• Common adverse effects include dizziness, fatigue,
irritability, anxiety, aggression, etc
Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, Squillacote D, Yang H, Zhu J, Laurenza A. Efficacy and safety of adjunctive
perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia. 2013 Aug;54(8):1481-9

65. Topiramate –extended release
 Blockage of voltage-dependent sodium channels
 Augmentation of the activity of the neurotransmitter GABA
 Antagonism of the AMPA/ kainate subtype of the glutamate
receptor
• March 2014: US FDA approved
 As monotherapy for focal seizure and primary GTC in
patients > 10 years and,
 As an adjunctive therapy in patients > 2 years for focal
seizures, primary GTC and seizures associated with
Lennox-Gestaut syndrome.

66.  Withdrawal should be carried out only if pt is
satisfied that a further attack would not ruin
employment etc. (e.g. driving licence). It should be
performed very carefully and slowly! 20% of pts will
suffer a further sz within 2 yrs.
 The risk of teratogenicity is well known (~5%),
especially with valproates, but withdrawing drug
therapy in pregnancy is more risky than continuation.
Epileptic females must be aware of this problem and
thorough family planning should be recommended.
Over 90% of pregnant women with epilepsy will
deliver a normal child.

67.  A proportion of the pts with intractable epilepsy will
benefit from surgery.
 Epilepsy surgery procedures: Curative (removal of
epileptic focus) and palliative (seizure-related risk
decrease and improvement of the QOL)
 Curative (resective) procedures: Anteromesial
temporal resection, selective
amygdalohippocampectomy, extensive lesionectomy,
cortical resection, hemispherectomy.
 Palliative procedures: Corpus callosotomy and Vagal
nerve stimulation (VNS).

68. THANK YOU