Newer antiepileptics and recent advance in management of epilepsy

1. Newer antiepileptics and recent
advance in management of epilepsy
Chairperson :Dr.Prakash Kori
Student :Dr. Vikram Rathod

2. CONTENTS
• The International League Against Epilepsy (ILAE)-
2017(DIFFERENCE BETWEEN OLD AND NEW)
• Approach To Seizure Disorders
• Mechanism Of Action Of Antiepileptics
• Salient Features Of Newer Antiepileptics
• Presurgical Evaluation
• Surgical Approach
• Other New Treatment Trials

3. • The International League Against Epilepsy
(ILAE) presents a revised operational
classification of seizure types
• 2017 Classification

4. Based on
• Previous classifications have been based on
anatomy, with temporal, frontal, parietal,
occipital seizures.
• Epilepsy to be a network disease and not only
a symptom of local brain abnormalities

5. • Seizure classification begins with the
determination of whether the initial
manifestations of the seizure are focal or
generalized.
• The onset may be missed or obscured, in
which case the seizure is of unknown onset.

6. Awareness
• Retained awareness means that the person is
aware of self and environment during the
seizure, even if immobile.
• Responsiveness does not equate to awareness

8. A focal aware seizure (with or
without any subsequent
classifiers) corresponds to prior
term
“Simple partial seizure.”
A focal impaired awareness
seizure (with or without any
subsequent classifiers) corresponds
to the prior term
“Complex partial seizure.”
Focal to bilateral tonic–clonic” is a
special seizure type, corresponding
to
“Partial onset with secondary
generalization
The term “Bilateral” is used for propagation patterns
“Generalized”-for seizures that engage bilateral networks from
onset

9. Discontinued terms Added terms
Simple/complex partial Aware/impaired awareness
Convulsion Hyperkinetic
Psychic
secondarily generalized seizure
Cognitive, Emotional, New focal
seizure types, Focal to bilateral tonic–
clonic seizure.
Cognitive- comprise phenomena such as deja vu, jamais vu, illusions, or
hallucinations
Emotional-Gelastic
New focal seizure types-epileptic spasms, myoclonic seizures.
Focal automatisms, autonomic, behavior arrest, emotional, and
hyperkinetic

10. Definations
Epileptic
Spasm
Sudden flexion, extension or mixed flexion-extension
of proximal and truncal muscles, lasting 1-2 seconds,
typically occurs in a series
Hypermotor Feature involves proximal limb or axial muscles,
producing irregular large amplitude ballistic
movements, such as pedaling, jumping, thrashing
and/or rocking movements.
Automatism Is a coordinated, repetitive motor activity usually
occurring when cognition is impaired and for which the
subject is usually amnesic afterward
Gelastic Bursts of laughter or giggling, usually without
appropriate affective tone
Autonomic Palpitations, nausea, chest pain, urge to urinate or
defecate, goosebumps, tachycardia.

11. ABSENCE - TYPICAL
Defination Typical absence seizure is a generalized
seizure with abrupt onset and offset of
altered awareness which can vary in
severity
At 3 hz Clonic movements of eyelids, head,
eyebrows, chin, perioral or other facial parts
may occur.
previously known
as
'petit mal' seizures
Individual absence seizure longer than 45
seconds or with a post-ictal phase consider
focal seizure

12. ABSENCE - ATYPICAL
1 An atypical absence seizure has less abrupt onset and offset
of loss of awareness than typical absence seizures
2 They are often associated with other features such as loss of
muscle tone of the head, trunk or limbs
3 Often occur in individuals with intellectual impairment
4 These seizures can be difficult to recognize in a patient with
ongoing slow (<2.5 Hz) generalized spike-and-wave on EEG,
careful correlation between EEG and clinical state is
recommended

13. ABSENCE MYOCLONIC
1 Rhythmic myoclonic jerks of the shoulders and
arms with tonic abduction that results in
progressive lifting of the arms during the seizure
2 The myoclonic jerks are typically bilateral but may
be unilateral or asymmetric
3 Seizures last 10-60 seconds and typically occur
daily
4 Level of awareness varies from complete loss of
awareness to retained awareness.

14. ABSENCE WITH EYELID MYOCLONIA
1 Absence seizures accompanied by brief,
repetitive, often rhythmic, fast (4-6 Hz)
myoclonic jerks of the eyelids with simultaneous
upward deviation of the eyeballs and extension
of the head.
2 Seizures are typically very brief (<6s in duration)
and multiple seizures occur on a daily basis
3 Awareness is retained most of the time.

15. • DIFFERENTIAL DIAGNOSIS OF SEIZURE

16. Features Seizure Syncope
Immediate
precipitating
Factors
Usually none Emotional stress,
Valsalva, orthostatic
hypotension, cardiac
etiologies
Premonitory
symptoms
None or aura (e.g.,
odd odor)
Tiredness, nausea,
diaphoresis,
tunneling of
vision
Posture at onset Variable Usually erect
Transition to
unconsciousness
Often immediate Gradual over seconds
Duration of
unconsciousness
Minutes Seconds

17. Facial appearance
during event
Cyanosis, frothing at
Mouth
Pallor
Disorientation and
sleepiness after event
Many minutes to
hours
<5 min
Duration of tonic or
clonic movements
30–60 s Never more than 15
Aching of muscles
after event
Often Sometimes
Biting of tongue Sometimes Rarely
Headache Sometimes Rarely

18. Psychogenic Nonepileptic Seizures
• Psychogenic nonepileptic seizures (PNES), also
called psychogenic nonepileptic events,
pseudoseizures, or pseudoepileptic seizures,
are the most common imitators of seizures
and epilepsy
• These are emotionally triggered attacks not
associated with any paroxysmal epileptic
activity in the brain

19. • Most are the result of somatoform disorder,
with a variety of reported traumatic
antecedents,
• particularly sexual or physical abuse in
women

20. EPILEPSY
• Epilepsy is a disease of the brain defined by any
of the following conditions:
At least two unprovoked seizures occurring more
than 24 hours apart
One unprovoked seizure and a probability of
further seizures similar to the general recurrence
risk (at least 60%) after two unprovoked seizures,
occurring over the next 10 years
Diagnosis of an epilepsy syndrome

22. “Older” Anti-Epileptic drugs
Phenobarbital 1912
Phenytoin 1938
Primidone 1952
Ethosuximide 1960
Carbamazepine 1974
Valproate 1978

23. Newer Antiepileptic drugs
• Since1990 ,15 new antiepileptics have been added
• 2nd generation
 Felbamate 1993
 Gabapentin 1993
 Lamotrigine 1994
 Topiramate 1996
 Tiagabine 1998
 Levetiracetam 1999
 Oxcarbazepine 2000
 Pregabalin 2005
 Vigabatrin
 Zonisamide

24. • 3rd generation-added in past 5 yrs
 Lacosamide
 Eslicarbazepine
 Ezogabine
 Rufinamide
 perampenal

25. Ideal property of antiepileptics
1 Broad spectrum activity against all seizure types
2 High Efficacy
3 Good tolerability
4 No risk of allergic or idiosyncratic reactions (including
teratogenicity)
5 Low interaction potential
6 Favorable pharmacokinetics ( linear kinetics, half life
compatible with once or twice daily dosage)

26. 7 No tolerance to antiepileptic effects
8 No withdrawal seizures
9 No need for intensive laboratory monitoring
10 Availability of convenient formulations (pediatric and
parenteral )

27. MECHANISM OF ACTION
• Block voltage-gated inward positive currents—
Na+ or Ca++
• Increase inhibitory neurotransmitter system—
GABA
• Decrease excitatory neurotransmitter
system—glutamate
• Increase outward positive current—K+
• Many AEDs pleiotropic—act via multiple
mechanisms

29. Na+ Channels as AED Targets
• 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

30. 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
AEDs That Act Primarily on Na+
Channels

32. Ca2+ Channels as Targets
• 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

34. Epilepsy—GABA
 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

35. AEDs That Act Primarily on GABA
• 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

36. Gabapentin
– May modulate amino acid transport into brain
– Interfere with GABA re-uptake
Tiagabine
– Interferes with GABA re-uptake
Vigabatrin
– elevates GABA levels by irreversibly inhibiting
its main catabolic enzyme, GABA-
transaminase
AEDs That Act Primarily on GABA

37. Epilepsy—Glutamate
 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

38. Glutamate Receptors as AED Targets
• NMDA receptor sites as targets
– Ketamine, phencyclidine, dizocilpine block channel
and have anticonvulsant properties but also
dissociative and/or hallucinogenic properties.
– Felbamate BLOCK NMDA .
• AMPA receptor sites as targets
– Topiramate antagonizes AMPA site

39. K+ channels
• 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

41. When to Initiate Antiepileptic Drug
Therapy
• Should be started in any patient with recurrent
seizures of unknown etiology or a known cause
that cannot be reversed.
• Patient with a single seizure ?
Seizure due to an identified lesion such as a
CNS tumor
Infection
Trauma
In which there is strong evidence that the lesion
is epileptogenic, should be treated.

42. Generally accepted risk factors
 An abnormal neurologic examination,
 Seizures presenting as status epilepticus,
 Postictal Todd’s paralysis,
A strong family history of seizures,
An abnormal EEG.

43. Rx and occupation
• Driver ,industrial worker,painter,swimmer
May prefer taking antiepileptic drugs rather
than risk a seizure recurrence .

44. APPROACH

45. When to Discontinue Therapy
The following patient profile yields the greatest
chance of remaining seizure free after drug
withdrawal:
(1)Complete medical control of seizures for 1–5
years
(2) Single seizure type, either focal or generalized;
(3) Normal neurologic examination,including
intelligence
(4) Normal EEG.

46. • The appropriate seizure free interval is
unknown and undoubtedly varies for different
forms of epilepsy.
• However, it seems reasonable to attempt
withdrawal of therapy after 2 years in a
patient who meets all of the above criteria

47. • Reduce the dose of the drug gradually over
2–3 months.
• Most recurrences occur in the first 3 months
after discontinuing therapy,
• Patients should be advised to avoid potentially
dangerous situations such as driving during
this period.

48. TREATMENT IN SPECIAL SITUATIONS
• Women with Epilepsy
 All Pts should be advised to plan their pregnancies.
 Pts in the reproductive age group should be started on
folic acid (5 mg/day) at the time of starting AED
 Seizures during labor should be terminated as soon as
possible using intravenous (IV) lorazepam (4 mg IV) or
diazepam (rule out CVT, Preeclampsia)
 There is no absolutely safe AED during pregnancy
 Lamotrigine is prefered drug

49. DRUG Advantages Disadvantages Selected important
adverse effects*
Carbamazepine Efficacious against focal
seizures, extensive
experience, mood
stabiliser, low cost
Enzyme inducer; can
aggravate absence and
myoclonic seizures
Hypersensitivity
reactions, cardiac
conduction
abnormalities,
hyponatraemia
Ethosuximide Efficacious against
absence seizures;
probably devoid of
enzyme-inducing
properties; low cost
Does not protect
against generalised
tonic–clonic
seizures, which can
coexist with absences
in some syndromes
Hypersensitivity
reactions,
gastrointestinal
side-effects
Gabapentin Virtually devoid of drug
interactions,
relatively well
tolerated, effective in
neuropathic pain
Relatively modest
efficacy, restricted to
focal
seizures; can
precipitate myoclonic
seizures
Weight gain

50. Drug Advantage Disadvantage Adverse effect
Lamotrigine Efficacious against focal
and most generalised
seizure types devoid of
enzyme inducing
properties, effective in
bipolar depression
Requires slow
titration; dosing
requirements
affected by
interactions with
valproate, enzyme
inducers, and
oestrogens; can
aggravate severe
myoclonic epilepsy
of infancy
Rash and other
hypersensitivity
reactions
Levetiracetam Efficacious against focal,
myoclonic, and
primarily generalised
tonic–clonic seizures;
virtually devoid of drug
interactions;
relatively well tolerated
Higher cost than
most other
antiepileptic drugs
Irritability, mood
changes
Irritability, mood
changes

51. Drug Advantage Disadvantage Adverse effect
Oxcarbazepine Similar to
carbamazepine in
efficacy profile,
with lower risk of
skin rashes and
lower
enzyme induction
potential
Reduces blood
levels of oral
contraceptives;
can aggravate
absence and
myoclonic
seizures
Rash and other
hypersensitivity
reactions;
hyponatraemia
more common
than with
carbamazepine
Topiramate Efficacious
against focal and
most
generalised
seizure types
effective
for migraine
prophylaxis
Slow titration Cognitive adverse
effects, weight
loss,
paraesthesias,
nephrolithiasis,
glaucoma

52. Drug Advantage Disadvantage Adverse effect
Vigabatrin Efficacious against
infantile spasms
Irreversible visual
field defects,
weight gain
Zonisamide Efficacious against
focal and, probably,
most generalised
seizure types
devoid of enzyme
inducing properties;
once-daily dosing
Limited experience
outside of Japan
and some
Pacific countries
Rash and other
hypersensitivity
reactions,
weight loss,
nephrolithiasis,
oligohydrosis

53. Antiepileptic drugs introduced in
after 2006
DRUG Approved indication Effective
maintenance daily
dose
Comment*
Eslicarbazepine Adjunctive therapy of
focal seizures
with or without
secondary
generalisation in adults
800–1200 mg once
daily
Lacosamide Adjunctive therapy of
focal seizures
with or without
secondary
generalisation in
patients aged
≥16 years
200–400 mg/day in
two divided daily
doses
Available as
parenteral
formulation

54. DRUG Approved
indication
Effective
maintenance daily
dose
Comment*
Retigabine
(also known as
ezogabine)
K channel opener
Adjunctive
therapy of drug-
resistant
focal seizures
with or without
secondary
generalisation in
patients aged ≥18
years, when other
appropriate drug
combinations
have proved
inadequate or
have not been
tolerated
600–1200
mg/day in three
divided daily
doses
Discoloration of
the ocular tissues
(including the
retina), skin, lips
and nails have
been reported at
high rates in long-
term studies; as a
result, retigabine
should be
regarded as a
drug of last
resort

55. DRUG Approved indication Comment*
Rufinamide Adjunctive therapy of seizures
associated with Lennox-Gastaut
syndrome in patients aged ≥4
years
Serum rufinamide
concentrations are
increased by valproic
acid

56. New drugs in pipeline
• Blockage of sodium channel
 Brivaracetam
 Carisbamate
• Inhibition of glutamate release
 NS 1209
 BGG 492
Drugs enhancing neronal inhibition
 Ganalaxone
 Stiripentol
 Valrocemide

57. The AEDs with FDA-approved
indications outside of epilepsy
1 Panic attacks Clonazepam
2 Trigeminal neuralgia Carbamazepine
3 Migraine prophylaxis, acute
treatment and maintenance for
mania/bipolar disorder
Valproate
4 Post herpetic neuralgia Gabapentin
5 Maintenance for bipolar
disorder
Lamotrigine
6 Migraine prophylaxis Topiramate
7 Diabetic peripheral neuropathy,
post herpetic neuralgia,
Pregabalin

59. PRESURGICAL EVALUATION
• Presurgical evaluation, the goal of which is to
localize the Epileptogenic Zone

60. DEFINATIONS
Epileptogenic zone defined as the zone whose resection is
necessary and sufficient to eliminate
seizures
Ictal onset zone (also
called seizure onset
zone or pacemaker
zone)
is the area of cortex that is generating
seizures
Irritative zone is the zone that generates interictal
epileptiform discharges
Ictal symptomatogenic
zone
is the region that produces the seizure
manifestations
Epileptogenic lesion is a structural brain abnormality that is
presumed to be the cause of the
epilepsy and is usually identified on MRI

61. Epileptogenic lesion
1 Intrinsically epileptogenic Cortical dysplasia and
hypothalamic
hamartoma
2 Seizures usually arise from
brain surrounding
Cavernous
malformations and
benign tumors
3 Accidental findings Arachnoid cysts and
venous malformations
not necessarily related
to the epilepsy

62. • To LOCALISE the lesion clues from
History
Investigation

63. Importance of HISTORY in localisation
1 Unilateral ictal clonic activity or ictal dystonia
suggests lateralization of the seizure to the
contralateral hemisphere
2 Early forced head version suggests lateralization
to the hemisphere contralateral to the direction
of the head version i.e. if the head turns to the
right, the seizure onset is in the left hemisphere.
3 Ictal speech lateralizes to the non-dominant
hemisphere
4 Ictal aphasia lateralizes to the dominant
hemisphere

64. 5 Postictal dysphasia lateralizes to the dominant
hemisphere.
6 Preserved awareness during ictal automatisms lateralizes to
the non-dominant hemisphere.
7 Post-ictal nose-wiping lateralizes to the hemisphere
ipsilateral to the hand used for nose-wiping.
8 Unilateral eye-blinking lateralizes to the hemisphere
ipsilateral to the eye-blinking.
9 Ictal vomiting lateralizes to the non-dominant hemisphere

65. OTHER INVESTIGATIONS
• EEG/video-EEG is a cornerstone of the
presurgical evaluation, contributing to the
localization .
• MRI-Images should ideally have a slice
thickness of at most 1.5 mm
• PET-uses positron emitting isotopes to image
metabolism(FDG), synthesis of
neurotransmitter(C-alfa methyl tryptophan),
receptor density(flumazenil)

66. • SPECT uses a gamma-emitting tracer to image
regional cerebral blood flow
• The main benefit of SPECT is ictal imaging.
When the ligand is injected intravenously (IV)
at the very onset of seizures, greater uptake is
noted in the ictal onset zone

67. • Magnetoencephalography
Just like EEG, MEG can track magnetic brain
activity in real time
It has an advantage over EEG in that magnetic
signals are not distorted by differences in
conductivity between the brain, skull, and
scalp

68. Surgical Approaches
• Either curative or palliative.
• The aim of curative surgery is to eliminate
seizures completely and potentially produce
permanent remission without the need for
AEDs.
• Palliative surgery is considered only if
“curative” surgery is not viable.

69. • Most common epilepsy localization is mesial
temporal, specifically amygdalohippocampal
• The most common surgical approach has been
a temporal lobectomy in which lateral
temporal cortex is resected first, followed by
resection of the amygdala and hippocampus.

70. OPERATIVE METHODS
Lesionectomy Is a suitable surgical approach when there is a
well-defined structural lesion such as benign
tumor or cavernous malformation
Nonlesional
neocortical
epilepsy
Usually requires a tailored resection after the
ictal onset zone and cortical functions have
been defined through different methods
Hemispherecto
my
Is the preferred surgical approach when the
epileptogenic zone is well lateralized but
widespread in one hemisphere
Eg:Rasmussen syndrome, Sturge-Weber
syndrome

71. Corpus callosotomy
(CC)
is a palliative surgical procedure
involving partial or complete
disconnection of the corpus callosum.
It thought to disrupt rapid bilateral
seizure spread responsible for sudden
loss of consciousness or loss of posture
without warning
Multiple subpial
transection
Involves disconnection of horizontal
intracortical fibers while preserving the
integrity of vertical connections. The
procedure is based on evidence that the
ictal discharge often spreads along
horizontal fibers

72. SUMMARY
In favour of surgery Against surgery
Seizure type Focal Generalised, mixed,
or uncertain
Cause Structural cause proven or highly suspected
Genetic (non-structural) or
metabolic cause
proven or suspected
Response to
antiepileptic
drugs
Persistence of seizures
on antiepileptic drug
therapy
Drug responsive
Location of the
epileptogenic
zone
Well localised; single;
or distant from
eloquent brain regions
Not localised; multiple; or within
or close to eloquent
brain regions

73. OTHER THERAPIES
ketogenic diet
1 Is a very low carbohydrate, high fat, and low to
adequate protein diet that includes some
restriction of total calories (≈75% of age
recommendations)
2 The ratio of fat to protein plus carbohydrate ranges
from 2 : 1 to 4 : 1.
3 The diet is typically initiated with a fasting
4 The onset of action is very fast, within 5 days
5 Improvement was unlikely if no benefit had been
seen by 2 months

74. Mechanism Is not well understood, Its benefit may
be related to acidosis, ketosis, calorie
restriction and decrease in blood
glucose, dehydration.
Adverse
effects
-Constipation and ,which can be
managed with stool softeners
-Acidosis may occur, mostly at
initiation, it can be managed with
hydration

75. Indications for the ketogenic diet
1 Refractory seizures, regardless of classification.
2 Individuals unable to tolerate AED therapy are particularly
good candidates for the diet.
3 Tuberous sclerosis
4 Rett syndrome
5 Dravet syndrome

76. Neurostimulation
• Neurostimulation was mainly developed as a
palliative treatment for patients with drug-
resistant epilepsy who are not candidates for
resective surgery
• Transcutaneous stimulation of the vagus and
trigeminal nerve.
• seizure reduction of 50% or more in more than a
half of treated patient

77. • Antioxidants and free-radical scavengers
Agents that are under investigation include lipoic
acid, adenosine, melatonin, edaravone, and
vitamins C and E
• Brain cooling
Possibly acts by reducing brain inflammation,
inhibiting neurotransmitter release, modifying
activation-inactivation kinetics in voltage-gated
ion channels, and slowing of catabolic processes

78. • Immunosuppressive treatments and agents
targeting brain (and peripheral) inflammation
Agents under investigation include
 Neuro-immunophilins,
 mTOR inhibitors (rapamycin or everolimus),
 Interleukin-1 receptor antagonists,
 Minocycline, corticosteroids

79. • Transplantation of cells
Neuronal precursor cells, embryonic stem
cells, induced pluripotent stem cells,
mesenchymal stem cells are under
investigation .

80. Thank you..