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Management of epilepsy in this millennium–recent perspectives in intrtactable seizures
1. MANAGEMENT OF EPILEPSY IN THIS MILLENNIUM –
RECENT PERSPECTIVES IN INTRTACTABLE SEIZURES
Prof. A.V. SRINIVASAN, MD, DM, Ph.D, F.A.A.N, F.I.A.N,
Emeritus Professor
The Tamilnadu
DR.M.G.R Medical University
CHENNAI-12- 03-10
2.
3. Epilepsy is A Fascinating Disorder
Affecting the the Three Functions of the
Brain
Cognition, Conation & Affect
Is Cure from this Disorder a mere
Stroke of Luck?
“My Opinions are founded on knowledge
but modified by experience”
4. Epilepsy – An Alarming issue
Epilepsy affects 50 million people the world
over
Prevalence rates of Epilepsy are 5-10 per
1000
Over 90 % of people with epilepsy in
developing countries are not on any
regular,even basic treatment. A significant
treatment gap.
If you think you can or you can’t You are always right
5. Living with epilepsy - 1992
15% no seizures, no
17% no seizures side effects
+ side effects 3% not taking AED
2% no answer
44% recurrent seizures 19% recurrent seizures,
+ side effects no side effects
n=760 The Roper Organization 1992
6. Living with epilepsy - 1996
Time since last seizure
2% no answer
29% <3 weeks
31% >2 years
10% 1-3 months
10% 1-2 years
18% 4-12 months
n=1023 Fisher et al, Epilepsy Res 2000
7. Classification of epilepsy
Localized Non-Localized
Idiopathic Symptomatic
(No known cause) (known or CNS disease)
Back pain – prize human beings pay for
their upright posture
Some people feel the rain; Others just get wet
8.
9. AN IDEAL ANTICONVULSANT DRUG
Prevent or inhibit excessive pathological
neuronal discharge
Without interfering with physiological
neuronal activity and
Without producing untoward effect
o Ideal compound not yet available
Many Ideas grow better when transplanted into another mind
than in the one where they sprang UP
O.W. Holmos
10. Spectrum of action
– Broad spectrum drugs
– Narrow spectrum drugs
– Intermediate spectrum drugs
“Character gets you out of bed
commitment moves you to action
faith, hope and Discipline follow through to completion”
11. When they tell you to grow up,
they mean stop growing - P. Diccaso
13. Pharmacokinetic properties of established AEDs
Carbama Phenyt Valpro Phenob Primi
zepine oin ate arbital done
Bioavailability +1 +2 +2 +2 +2
Parentral form -2 +2 +2 +2 0
Elimination of half life +1 +2 0 +2 -1
Linear kinetics +2 -2 +1 +2 +2
No auto induction -2 +2 +2 +2 +2
No interactions -1 -1 -1 -1 -1
A score of +2 is best and –2 is least desirable . A total “pharmacokinetic score” for each
drug should not be calculated from the table because different pharmacominetic
parameters may need to be weighted differently. The score +2 if it is suitable for
once daily dosing. +1 for twice daily dosing. 0 for 3 times daily dosing at times only,
and –1 for consistent 3 times daily dosing
14. Pharmacokinetic properties of newer AEDs
Felbam Gabape Lamot Oxcarba Tiaga Topir
ate ntin rigine zepine bine amate
Bioavailability +2 -1 +2 +2 +2 +2
Paenteral form -2 -2 -2 -2 -2 -2
Elimination half +1 -1 +1 +1 +1 -1
life
Linear kinetics +2 -1 +2 +2 +2 +2
No auto induction +2 +2 +2 +2 +2 +2
No interactions -2 +2 0 +1 0 0
A score of +2 is best and –2 is least desirable . A total “pharmacokinetic score” for each
drug should not be calculated from the table because different pharmacominetic
parameters may need to be weighted differently. The score +2 if it is suitable for
once daily dosing. +1 for twice daily dosing. 0 for 3 times daily dosing at times
only, and –1 for consistent 3 times daily dosing
15. Efficacy of antiepileptic drug for common seizure type
Drug Partial Tonic- Absence Myoclonic Atonic/
clonic tonic
Phenobarbital + + 0 ?+ ?
Phenytoin + + - - 0
Carbamazepine + + - - 0
Sodium valproate + + + + +
Ethosuximide 0 0 + 0 0
Benzodiazepines + + ? + +
Gabapentin + + - - 0
Lamotrigine + + + + +
Oxcarbazepine + + 0 0 0
The True Art of Memory is The Art of Attention
- S.Johnson
18. “Older” AEDs
Phenobarbital 1912
Dilantin (phenytoin) 1938
Mysoline (primidone) 1952
Zarontin (ethosuximide) 1960
Tegretol (carbamazepine) 1974
The True Art of Memory is The Art of Attention
- S.Johnson
19. Newer AEDS
Felbamate 1993
Gabapentin 1994
Lamotrigine 1995
Topiramate 1996
Tiagabine 1998
Levetiracetam 1999
Oxcarbazepine 2000
We learn by thinking and the quality
Zonisamide 2000 of the learning outcome is
determined by the quality of our
Pregabalin 2005 thoughts
R.B. Schmeck
20. Carbamazepine
First line drug for Side effects at just
partial seizures for above therapeutic range
years Not effective for some
Two long-acting seizure types
forms now avail Must start slowly due to
(2X/day) side effects
No IV form
Lots of interactions
In all of us, even in good men, there is a
wild - beast nature which peers out in sleep
21. Phenytoin
First line for Side effects at just above
partial seizures therapeutic range
for years Not effective for some
Once a day seizure types
IV form Side effects:
imbalance, sedation, cogni
tive, gum
problems, osteoporosis
felt promise to yourself
A true commitment is a heartMany interactionsfrom
which you will not back down
- D. Mcnally
22. Valproate
Works for all seizure Side effects, esp. weight
types gain & tremor
Around for decades Menstrual irregularities
Rare allergic reactions Not best for pregnancy
Helps prevent Significant drug
migraines interactions
New IV form
New long-acting form
“Character gets you out of bed commitment moves you to action
faith, hope and Discipline follow through to completion”
23. Barbiturates (primidone and
phenobarbital)
Effective
Sedation and
Once a day cognitive effects
(phenobarbital) Withdrawal
Cheap
IV form
(phenobarbital)
“By Nature All Men/ Women are alike but
by Education widely different”
- Chinese
24. Other old medications
Acetazolamide
Clonazepam & Lorazepam
Ethosuximide
Ketogenic diet
Acth/steroids
“Character gets you out of bed
commitment moves you to action
faith, hope and Discipline follow through to completion”
25. Limitations of older AEDS
Efficacy: Limited efficacy in complex
partial, absence , myoclonic and atypical
seizures.
Adverse Events: similar neurotoxicity
, idiosyncratic reactions
Teratogenicity
Pharmacokinetics: low aqueous
solubility, hepatic metabolism
Drug Interactions: enzyme induction –
CBZ, PHT, PB
26. Newer AEDs
Equally effective as older AEDs
Most better tolerated than older AEDs
Most have fewer interactions with other
medications than older AEDs
All expensive
Give us the GRACE to accept with serenity the things that cannot be
changed the COURAGE to change the things that should be changed and
the WISDOM to know the difference
27. Role of New epileptics
Different mechanism of action- treatment of
refractory seizures
Rational Polytherapy
Less adverse effects
Less Drug Interactions
A true commitment is a heart felt promise to yourself
from which you will not back down
- D. Mcnally
28. Rational Polytherapy
Combinations of different mechanism of
actions for synergy of antiepileptics
Avoid drug with similar effects
Neurology 1995: 45; S7-11
“ He who cannot forgive others destroys the bridge over
which he himself must pass” - Annoy
29. Choice of AED
Should be based on:
Spectrum of activity
Side-effect profile
Efficacy in other concomitant disease states
Memory, the daughter of attention ,
is the teeming mother of knowledge
- Martin Tupper
30. Newer antiepleptics
Unique features of newer antiepileptics
Gabapentin, Pregabilin and Levetiracetam: no hepatic
metabolism or protein binding
No important pharmacokinetic interactions with other
AEDs
Lamotrigine: associated with rash and must be titrated
slowly
Topiramate, Tiagabine, Zonisamide, Oxcarbazepine: must
titrate slowly to minimize cognitive side effects
Topiramate, Zonisamide:1-2% incidence of renal stones
Felbamate: aplastic anemia, hepatic failure, weight loss
It is the disease of not listening, the malady of not marking,
that I am troubled withal - Shakespeare
31. GABAPENTIN
Novel antiepileptic drug recognized as
GABA agonist
Recently, an inhibitory effect on the
receptor subunit of the calcium channel has
been shown and postulated to be
responsible for its antiepileptic effect
Treats ONLY partial seizures
May exacerbate absence seizures
Pak J Neurol Sci 2007; 2(4): 223-29
Success in life is a matter not so much of talent and opportunity
as of concentration and perseverance - C.W. Wendte
32. Gabapentin
ADVANTAGES
No interactions with other
drugs DISADVANTAGES
Extremely rare “allergic”
Three-times-a-day
reactions
dosing
Can be started quickly
Does not treat all
Well-tolerated
types of seizures
Treats
pain, anxiety, restless leg
syndrome
Generic availability
Liquid formulation Serious, sincere, systematic study
surely secures supreme success
33. LAMOTRIGINE
Well-established AED with proven efficacy
Also the most well –studied amongst the
newer drugs in both adults and children
Used in partial as well as generalized
seizures
Approved as monotherapy in partial
seizures
Effective in treating generalized epilepsy
syndrome
Pak J Neurol Sci 2007; 2(4): 223-29
34. Lamotrigine
ADVANTAGES DISADVANTAGES
– Minimal effect on other – Rash if started
medications quickly Must start
– Works for all types of slowly (~2 months
seizures to full dose)
– Very well tolerated
– Minimal sedation
– Probably safe in pregnancy
– Approved for >2 y.o.
– Monotherapy Mind is the great level of all things;
human thought is the process by
which human ends are ultimately
answered
- Daniel Webster
35. TOPIRAMATE
Broad spectrum AED with multiple mechanism of actions
MOA:
including inhibitory effects on sodium and calcium channels
as well as the kainate
subgroup of glutamate receptors. Additionally, it
potentiates effects on GABA receptors as well as on the
potassium channel.
Excellent efficacy in partial seizures in adults and children
Also effective in migraines
Pak J Neurol Sci 2007; 2(4): 223-29
Thinking is the hardest work there is, which is
probable reason why so few engage in it.
- Henry Ford
36. Topiramate
ADVANTAGES DISADVANTAGES
– Minimal interactions with – Cognitive side
other medications effects
– Probably works for all – 1-2% renal stones
seizure types – tingling/pins and
– Approved for >2 y.o needles
– Sprinkle form – Can decrease
efficacy of oral
– Approved for monotherapy contraceptives
– Weight loss
– Approved for migraine
prevention
Habit is either the best of servants or worst of masters
- Nathaniel Emmons
37. TIAGABINE
Selective GABA reuptake blocker
Adjunct in partial seizures
Multiple dosing
Pak J Neurol Sci 2007; 2(4): 223-29
Success is a prize to be won. Action is the road to it.
Chance is what may lurk in the shadows at the road side.
- O. Henry
38. Tiagabine
ADVANTAGES DISADVANTAGES
– Minimal effect on – Dose is dependent on
other medications concurrent AEDs
– Anxiety
– Occasionally makes
some seizure types
worse
People of mediocre ability often achieve success because they
don’t know enough to quit
- Bernard Baruch
39. LEVECTIRACETAM
Binds to synaptic vesicle protein SV2A
Effective adjunct in partial seizures
Lack of drug interaction can be used in
patients with complex multiple problems
Pak J Neurol Sci 2007; 2(4): 223-29
We possess by nature the factors out of which personality can be
made, and to organize them into effective personal life is every
man’s primary responsibility - Harry Emerson Fosdick
40. Levetiracetam
ADVANTAGES
DISADVANTAGES
No interactions
Behavioral/psych side
Minimal liver effects
metabolism
Twice per day
Works for most
seizure types
Can start quickly
Well tolerated
Liquid formulation
Opinion is ultimately determined by the feelings
and not by the intellect
41. OXCARBAMAZEPINE
Similar to CBZ
Adjunct and monotherapy in partial
seizures
Effective in patients who have failed
CBZ
Experience can be defined as
yesterday’s answer to today’s problems
42. Oxcarbazepine
As effective and better Not for all seizure
tolerated than CBZ types
Fewer interactions Low sodium, esp. if on
than CBZ diuretics also
Approved for children Lessens effectiveness
>4 of birth control pill
Approved for first-line
monotherapy
Three can be seen in the divisions of a human in mind, body and spirit
43. ZONISAMIDE
It has an inhibitory effect on both sodium
and calcium channels
Zonisamide is effective as adjunctive therapy in
patients
with partial epilepsy
Also used as a second or third line alternative in
refractory generalized epilepsy.
Presumed effects on dopaminergic pathways, there has
been some interest in treating Parkinson's disease with
zonisamide as well.
Discipline Weighs ounces Regret weighs Tons
44. Zonisamide
Used in Japan for many 1-2% kidney stones
years Occasional
Works for all seizure psychiatric or
types sedative side effects
Approved for children Sulfa drug
Once daily
Weight loss
Recent addition of 25
mg capsules
“Social Isolation is in itself a pathogenic
Factor for disease production”
45. Intranasal or Buccal Midazolam
Safe and effective (studies in UK, Israel): 5-
10 mg in adults
Easy to use
Less social stigma
Not approved in US for this usage
Not easy to obtain (controlled substance) in
a convenient form
Shorter acting than Diastat
“Knowledge can be communicated but not Wisdom”
- Hermann Hesse
46. New agents
Brivaracetam- structural analogue of levetiracetam
–more potent and efficacious in treatment of both
partial and generalized epilepsy
Lacosamide- Good efficacy in partial seizures.
Also useful neuropathic pain
Rufinamide- Efficacy seen in Lennox G Syndrome
patients but only modest effects see in partial
seizures
Retigabine – novel AED which activates a special
type of potassium
Through Action You Create your Own Education - D.B. ELLIS
47. Pregnancy in Women With Epilepsy
1.1 million women of childbearing age have epilepsy in the
USA
Issues with management of women:1
– Cosmetic consequences of some AEDs
– Catamenial epilepsy
– Effectiveness of hormonal contraceptives may be reduced by some
AEDs
– Pregnancy has a greater risk for complications
– Difficulties during labor and adverse outcomes are more likely
– The practitioner must choose a course that both prevents seizures
and minimizes fetal exposure to AEDs
With careful management the majority of women with
epilepsy will have a better than 90% chance of a normal
baby2
1. Yerby, 2000
2. Crawford, 1997
48. Drugs that decrease efficacy of
oral contraceptives
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Topiramate at higher doses
Oxcarbazepine
Whatever the Mind can conceive and Believe,
the mind can Achieve - Napoleon Hill
49. Weight Issues
Risk of weight gain “Risk” of weight loss
Valproate – Topiramate
Gabapentin – Zonisamide
Pregabalin – Felbamate
Weight Neutral
- Levetericetam
- Lamotigrine
Many Ideas grow better when transplanted into another mind than
in the one where they sprang UP
O.W. Holmos
50. Lifestyle changes to minimize seizures
Avoid sleep deprivation
Avoid alcohol
Treat fevers quickly
Occasional patients should avoid specific
factors such as strobe lights, etc
Pill boxes/reminders
“Men of Genius Admired:
Men of Wealth envied
Women of power feared
But only Women of character are trusted”
A- Friedman
51. Summary
Balance efficacy against side effects
Extended-release AEDs offer improved
tolerability, improved compliance and
improved seizure control
The benefits may be especially relevant in
special populations such as children and
women with epilepsy
Every discovery contains an irrational element or 4 creative
intuition
Khrl Popper
52. New AEDs: odds ratios for 50% responders
and withdrawal in randomised controlled trials
Drug 50% responders Withdrawals
Odds 95% CI Odds 95% CI
ratio ratio
GBP 2.3 1.5-3.4 1.4 0.7-2.5
LTG 2.3 1.5-3.7 1.2 0.8-1.8
OXC 3.4 2.3-4.8 2.3 1.9-2.8
TGB 3.0 2.0-4.6 1.8 1.2-2.7
TPM 4.1 2.9-5.8 2.6 1.6-4.0
VGB 3.7 2.4-5.5 2.6 1.3-5.3
ZSM 2.5 1.4-4.5 4.2 1.7-10.5
53. New vs Old AEDs as monotherapy
in previously untreated patients
New Old AEDs Efficacy Tolerability
AEDs (no. studies)
LTG CBZ (4) Similar LTG better
PHT (1)
VPA (1)
OXC PHT (2) Similar OXC better
CBZ (1) OXC better
VPA (1) Similar
VGB CBZ (4) Similar (2) VGB better
CBZ better (2)
54. Odds ratio – Meta analysis – New AEDs
Thought is the labour of the intellect
Reverie is its pleasure
55. Long-term use of
gabapentin, lamotrigine, and vigabatrin
Variable GBP LTG VGB
(n=361) (n=1050) (n=713)
Mean daily dose (mg) 1575 303 2444
Seizure free (%) 1 3 3
Reason for
withdrawal (%)
Lack of efficacy 42 25 36
Adverse event 10 13 12
Both 12 6 15
Standardised
mortality ratio 7.7 10.4 6.8
56. Economic aspects
of antiepileptic treatment
Cost of AEDs for 1 year of treatment in Italy
Drug Dose (mg/day) Cost (Euro)
PB 150 47
PRM 750 55
ESM 750 82
PHT 350 83
CBZ 1200 202
VPA 3000 472
VGB 3000 1420
GBP 1800 1705
LTG 400 1875
TPM 400 2716
FBM 3600 5987
57. Common long-term
AED side effects
energy level emotional and
school performance mental wellbeing
overall QoL coordination and balance
memory sex life
concentration job performance
thinking clearly
Fisher et al, Epilepsy Res 2000
Science is below the mind;
Spirituality is beyond the mind
58. Serious adverse effects of AEDs
Serious adverse effects of AEDs include
Dose-related
Chronic
Idiosyncratic
Teratogenic
Drug interaction disorders
Parent : Carbamazepine
Active metabolite : 10,11 carbamazepine epoxide
. Polymechanistic with metabolites with no antiepileptic activity but with
side effects
Parent : felbamate
Active metabolite : various
. Polymechanistic but metabolites with antiseizure activity
“ He who cannot forgive others destroys the bridge over which he himself must pass”
- Annoy
59. Summary
Seizure freedom in >50% of newly diagnosed
patients
Safe administration in all patients, especially
children and elderly
Birth defects in <3% of cases
Lower healthcare costs compared with cost of
treatment
Positive impact on QoL (if and when objective
measures are available)
When they tell you to grow up, they mean stop growing
60.
61. Combinations based on drug interactions
Least Useful Rationale
Carbamazepine with phenytoin Phenytoin induces carbamazepine
metabolism, leading to need for much
higher carbamazepine doses.
Phenobarbital with Phenobarbital is a powerful inducer of
carbamazepine
Phenytoin, valproate CYP 450 system
Valproate with phenobarbital Valproate decreases phenobarbital
metabolism
Valproate with phenytoin Both compete for protein binding
sites, reducing the value of total drug
level measurement
Discipline Weighs ounces Regret weighs Tons
62. Combinations based on drug interaction. contd
Least Useful Rationale
Felbamate with Many drug – drug interactions
phenytoin, carbamazepine and
valproate
Useful
Gabapentine with any drug No drug interaction
Valproate with lamotrigine Valproate inhibits metabolism of
Iamotrigine, reducing dose and
cost of treatment with
Iamotrigine
“Social Isolation is in itself a pathogenic
Factor for disease production”
63. Combination based on mechanism of action
Most Useful Rationale
Carbamazepine or phenytoin Widely different mechanisms of
with actions
gabapentine, tiagabine, topirama
te, felbamate
Least Useful
Carbamazepine and phenytoin Similar mechanisms of action
Tiagabine, gabapentine, and Similar mechanisms of action
vigabatrin
The art of medicine is caring for the heart of the patient
64. Combinations based on side effects
Possibly Useful Rationale
Valproate with felbamate or Felbamate and topiramate have been
topiramate associated with weight loss,
valproate with weight gain.
Least Useful
Carbamazepine and valproate Valproate and carbamazepine both
in women of child bearing may increase risk for spina bifida;
potential valproate inhibits metabolism of
10,11 carbamazepine epoxide,
which may be teratogenic
Give us the GRACE to accept with serenity the things that cannot be
changed the COURAGE to change the things that should be changed
and the WISDOM to know the difference
65. Medical outcome
The risk of recurrence after a first
unprovoked seizure
Remission from seizures
Relapse after drug withdrawal
Maintaining the right attitude is easier than
regaining the right mental attitude
66. Prognosis of a first unprovoked seizure
Overall risk of recurrence after 1 year varied between
16 & 36% among different studies
Risk is greatest in the first year of index seizures
Risk of another seizure following a second seizure is
79% (Camfield et al 1985)
Higher rate of recurrence in symptomatic than
idiopathic
10%, 24%, 29% at 1, 3, 5 years respectively in
idiopathic seizure
26%, 41%, 48% at 1, 3, 5 years respectively in
symptomatic seizure (Hauzer et al 1992)
NATURE, TIME AND PATIENCE
are the 3 great physicians
67. Prognosis of a first unprovoked seizure
Risk of recurrence is more if the index seizure is
1. Status epilepticus (Hauzer et al 1990)
2 Complex partial seizure (Camfield et al)
(CPS 78.9% Vs. GTCS 44%)
Risk of recurrence is more if there is previous history of febrile
seizures
Risk of recurrence is more if the EEG shows epileptiform
discharges
Normal EEG does not rule out seizure recurrence.
Recurrence risk is 12% after a first unprovoked seizure with a
normal EEG (Van Donselaar et al 1992)
Opinion is ultimately determined by the feelings
and not by the intellect
68. Remission of Epilepsy
Various studies show remission ranges of 50-70%,
depending upon 1 year - 5 year seizure-free intervals
The group for the study of prognosis of epilepsy in Japan
showed 3 year remission rate of 58.3% (1981)
Annegers et al used stringent criteria of 5 year seizure-free
interval – showed remission rate of 65% in 10 years and
76% in 20 years
With respect to specific seizure types, absence seizure,
GTCS, simple partial seizures, secondary GTCS and CPS,
all had remission rates of 68%, 69%, 50%, 60% and 61%
respectively
Truth comes out of error sooner than that of confusion
69. Remission of Epilepsy
Generalized idiopathic seizure is one of the
most important prognosticators of remission
Early age of seizure onset is a consistent
predictor of intractability (Berg et al – 1996)
Factors having no prognostic values in
remission include gender, race, family
history, time between diagnosis and initiation of
therapy
When they tell you to grow up,
they mean stop growing
P. Diccaso
70. Relapse after drug withdrawal
Overall relapse rate varies from 20 – 36.5%
(Emerson et al)
Children have lower relapse rates 12 – 36.3%
(Emerson et al)
50 – 80% relapses occur during medication
withdrawal
Mental retardation and abnormal neurological
examination are associated with poor outcome
Every discovery contains an irrational element or
4 creative intuition
- Karl Popper
71. Relapse after drug withdrawal
The quality standards of American Academy of Neurology
published their recommendation for discontinuing AEDs in
seizure-free patients
Their recommendations were based on a review of medical
literature from 1967 to 1996
The 9 factors related to the probability of successful
antiepileptic withdrawal are: sex, age of seizure
onset, seizure type, aetiology, neurological examination
and IQ, duration of seizure freedom on antiepileptic
drugs, treatment regimen, age at relapse and normalization
of the EEG
The secret of walking on water is
Knowing where the stones are
72. Relapse after drug withdrawal
Seizure-free for 2-5 years on AEDs
Single type of partial or generalized seizure
Normal neurological examination
Normal IQ
EEG normalizing with treatment
With all the above profiles, 69% chance in
children and 61% in adults, of a successful
withdrawal.
Thought is the labour of the intellect
Reverie is its pleasure
73. INTRACTABLE EPILEPSY
Definition
- one or more sz/mo over one y
- adequate trial: 2 first line AEDs and 1 or
more.
Burden of refractory epilepsy
.
- Physical injury.
- Psycho social costs.
- SUDEP
Take time to think; it is the source of power
Take time to read; it is the foundation of wisdom
Take time to work; it is the price of success
74. PRACTICE PEARLS IN NEUROLOGY–
RECENT PERSPECTIVES IN INTRTACTABLE SEIZURES
Prof. A.V. SRINIVASAN, MD, DM, Ph.D, DSc(Hon)
F.A.A.N, F.I.A.N,
Emeritus Professor
The Tamilnadu DR.M.G.R Medical University
CHENNAI- 21-1-11
76. Definitions
A seizure is the clinical manifestation of
excessive, synchronous, abnormal firing of
large populations of neurons
77. Intractable epilepsy
A persistent seizure activity that prevents
the individual from normal function or
development.
Characterized by two antiepileptic drug
(AED) failures, at least one seizure per
month for 18 months, and no seizure-free
periods longer than three months during that
time.
*no consensus
78. Epidemiology
Prevalence of epilepsy is 5 to 10 per 1000 in
the North American population
Second most common cause of mental health
disability
Approximately 20% of individuals with a
diagnosis of epilepsy have seizures that are
not adequately controlled by AEDs
79. Why do patients fail to respond?
Paroxysmal events that are not epileptic
Psychogenic seizures
Misdiagnosis of seizure type
Non-compliance with medication
Epileptic disorder with different
pathophysiologic mechanism than that
targeted by the AED
Unreliable reporting of seizures
80. When should we intervene
surgically?
Failed medical management with >2 AEDs
i.e. At least one seizure every 1-2 months
AND
Seizures are associated with any of:
- Impaired LOC
- Injury (e.g. from falls)
- Accompanied by stigmatizing behaviour (e.g.
disrobing, uttering obscenities)
- Accompanied by unpleasant or noxious auras (e.g.
vomiting, intense fear)
- Unpredictable occurrence
81. Factors to consider when making
the surgical decision
Patient’s social environment
Expectations
Level of function
Quality of life
Severity and frequency of seizures
Medical consequences of the epilepsy
83. Pathophysiology of epilepsy
Alteration in neuronal excitability by
changes in voltage-gated and transmitter-
gated ion channels
Focal reduction in inhibitory
neurotransmission
Alterations in gene expression
Changes in cellular plasticity of neurons
with age or in response to injury
Developmental alterations in cerebral cortex
84. Goal of resective epilepsy surgery
Complete resection of the epileptogenic zone
(the area of cortex that is required to
generate clinical seizures)
Its location and boundaries are defined by:
seizure semiology
electrophysiologic recordings
functional testing
neuroimaging techniques
85. Seizure Semiology
Clinical features of a seizure may suggest a
location for the symptomatogenic zone and
have lateralizing value
86. Seizure Semiology
Ictal speech Non-dominant temporal lobe
Dystonic limb posturing Contralateral to side of
temporal lobe seizure onset
Post-ictal nose wiping Ipsilateral to temporal lobe of
onset
Post-ictal dysnomia > 2 min Onset in the dominant
temporal lobe
Forceful head version Contralateral hemisphere
immediately prior to a
secondarily generalized tonic-
clonic seizure
nonforced head turning at ictal Ipsilateral hemisphere
onset without a tonic
component or hemifacial
clonic twitching
Asymmetric tonic limb The extended limb is usually
posturing, the "figure four contralateral to the hemisphere
sign," of onset
87. Seizure Semilogy
Localized contralateral clonic Broca’s area
activity and aphasia with
speech arrest
Assymetrical bilateral Supplementary motor area
proximal limb movement,
version of head, facial
grimacing with speech arrest
or vocalization, and preserved
consciousness
Olfactory, psychic, and Orbitofrontal and cingulate
emotional auras followed by seizures
complex automatisms
No warning, Bilateral tonic Prefrontal
clonic activity with version,
forced thinking, falls,
autonomic signs
88. Cortical zones
Symptomatogenic zone:
The area of cortex that, when activated by an epileptiform discharge, reproduces
the initial ictal symptoms. The zone is defined by careful analysis of the ictal
symptoms that can be done with a thorough seizure history and analysis of ictal
video recordings
Irritative zone:
The area of cortical tissue that generates interictal electrographic spikes
Seizure onset zone:
The area of cortex from which clinical seizures are generated. This may be larger or
smaller than the epileptogenic zone. When the epileptogenic zone is smaller than
the seizure onset zone, partial resection of the seizure onset zone may lead to
seizure freedom because the remaining seizure onset zone has been weakened
sufficiently, rendering it incapable of generating further seizures
Area of functional deficit:
Area of cortex that is functionally abnormal in the interictal period
89. EEG Recordings
Interictal and ictal Scalp EEG is used to localize
the seizure discharges. Detects radially oriented
electrical activity that is attenuated in strength and
spatially distorted by tissue between brain and
scalp
Limitation: capable of detecting a seizure
discharge only after it has extended considerably
and has activated a relatively large area of cortex
90. EEG Recordings
Patients with temporal lobe epilepsy (TLE)
have epileptiform activity consisting of
spikes and/or sharp waves that are usually
maximal at the anterior temporal (F7 and F8
electrodes) and the mid temporal regions
(T3 and T4 electrodes).
91. Indications for Invasive EEG monitoring
Bilaterally independent temporal lobe seizures
Extratemporal lobe-onset seizures with rapid
propagation to the medial temporal lobe
Temporal lobe seizures of localized onset, but with
normal MRI and FDG-PET findings
Discordant EEG localization and imaging findings
To distinguish neocortical from medial TLE
Lateralization of seizures to a particular lobe though
no abnormalities are seen on structural or functional
imaging
Epileptogenic zone located in or near eloquent
cortex
Intracranial electrode placement is associated with a 2-3% complication rate
92. Neuroimaging
The goal is to locate and define anatomic
epileptogenic lesions.
MRI: shown to have better chance of detecting
positive pathology than CT scan.
Limitation: cortical dysplasia may be subtle or not
visualized on MR imaging
FDG-PET: interictal cortical hypometabolism
correlates with the epileptogenic zone in temporal
and extratemporal epilepsy
94. FDG PET in a patient with mesial temporal epilepsy
showing hypometabolism in are aof left mesial temporal lobe
95. Neuroimaging
Ictal SPECT and functional MRI measure
local changes in cerebral blood flow (a
relative increase of ictal blood flow with
respect to the interictal state). This increase
of blood flow is a direct autoregulatory
response to the hyperactivity of neurons
during epileptogenic activation.
96. Functional Testing
Wada test is used mainly to lateralize
eloquent cortex with regard to language and
memory and is used only secondarily as a
supplementary method to determine the
localization of the epileptogenic zone
97. What is a Wada Test?
Injection of sodium amobarbital into one carotid artery to
temporarily inactivate the ipsilateral cerebral
hemisphere, allowing independent testing of memory and
language function of the contralateral hemisphere.
IAP is believed to anesthetize ipsilateral carotid artery
distribution, which includes the amygdala and the anterior
hippocampus.
Injection ipsilateral to the epileptogenic zone assesses the
functional adequacy of the contralateral hippocampus to sustain
memory
Contralateral hemiparesis and ipsilateral EEG slowing confirm
the adequacy of injection
99. Mesial Temporal Lobe Epilepsy
History of early insult in infancy or childhood
Hippocampal sclerosis and atrophy on MRI
Abnormal Creatine/NAA on MRS
Temporal hypometabolism on interictal PET
Characteristic pattern of hypoperfusion and
hyperperfusion on SPECT
Anteromedial epileptogenic zone on EEG
Memory deficits on Wada testing
Histology: loss of principal hippocampal
neurons, synaptic re-organization, sprouting of
mossy fibers, enhanced expression of glutamate
receptors
100. Figure 149-7 Diagram of a coronal slice through the medial temporal lobe. The hippocampus is composed of 2
<ss>U</ss>-shaped lamina of gray matter, the cornu ammonis (C) and dentate gyrus (D). Between them is the
white matter of the molecular layer (*). The hippocampus is bordered by the alveus (arrowheads), choroid fissure
(ChF), and temporal horn (TH) superiorly. The alveus converges medially to form the fimbria (F), which in turn is a
component of the fornix. The ambient cistern (AC) and brainstem (BS) are situated medially. Inferior to the
hippocampus is the parahippocampal white matter and gyrus (PHG). The temporal horn (TH) borders the
hippocampus on its lateral aspect. CS, collateral sulcus; FG, fusiform gyrus or lateral occipital-temporal gyrus;
ITG, inferior temporal gyrus. (From Bronen RA: Epilepsy: The role of MR imaging. AJR Am J Roentgenol 159:1165-
1174, 1992.)
101. Frontal Lobe Epilepsy
Second most common epilepsy syndrome
referred for surgery
Wide variety of seizure types depending on
origin and spread
Often prominent motor manifestations
Interictal EEG spikes in one or both frontal
lobes, temporal spikes may be seen
Neuroimaging is usually negative
102. Lesional partial epilepsy
30% of patients undergoing epilepsy
surgery have a structural lesion as
underlying pathology
e.g. Focal encephalomalacia, tumor, vascular
malformation, congenital developmental
anomaly
Anatomical location is primary determinant
of seizure presentation
103. Neocortical cryptogenic epilepsy
Clinical history and electrical data suggest
seizure of cortical origin but no structural
lesion is identified
Surgical treatment based on EEG delineation
of the epileptogenic zone.
104. Surgical Approaches for Epilepsy
Resective Surgery Temporal lobe resections (anteromedial
selective amygdalohippocampectomy);
Extratemporal resections; Lesional
resections; Anatomic or functional
hemispherectomy
Disconnection surgery Corpus callasotomy; Multiple subpial
transections; Keyhole hemispherotomies
Radiosurgery Mesial temporal lobe epilepsy;
hypothalamic hamartomas
Neuroaugmentative surgery Vagal nerve stimulators; Deep brain
stimulation
Diagnostic surgery Depth electrodes; subdural strip
electrodes; subdural grids
105. Summary of Surgical Procedures
for Epilepsy
Anteromedial temporal resection (AMTL): The superior temporal gyrus
is spared, and the middle and inferior temporal gyrus is resected 4-5 cm
from the tip of the nondominant side and 3-4 cm of the dominant side. The
amygdala is resected totally; the hippocampus and the parahippocampal
gyrus are resected to the level of the colliculus.
Standard en bloc anterior temporal lobectomy: This resection is similar
to the AMTL except that the superior temporal gyrus, 2 cm from the
temporal tip, also is resected.
Amygdalo-hippocampectomy: In this procedure, the
amygdala, hippocampus, and parahippocampal gyrus are resected, with
sparing of the lateral and basal temporal neocortex.
Lesionectomy: The lesion as delineated by MRI is resected, with a
margin. In some cases, electrocorticography may be recommended to
guide the margins of the resection.
106. Summary of Surgical Procedures
for Epilepsy
Tailored neocortical resection: This resection is based on imaging and EEG data and is
tailored on the basis of functional mapping data such that eloquent cortical regions are
spared. In some cases multiple subpial transections (MST) are recommended when the
epileptogenic zone involves eloquent cortex. With MST, the horizontal fibers that are
important for seizure propagation are interrupted at 5-mm intervals. The vertically
oriented fibers that are important for function remain intact.
Functional hemispherectomy: It consists of removal of sensorimotor cortex and the
temporal lobe. The frontal lobe and the parieto-occipital lobes are left intact but are
disconnected from cortical and subcortical structures.
Corpus callosotomy: The anterior two thirds of the corpus callosum is resected.
Sometimes, a complete callosotomy is performed; however, the risk of developing
disconnection syndrome is greater with this procedure. May be employed in the setting
of non-localized tonic, clonic, or atonic seizures that cause falls and injury.
Multilobar resection: This usually involves the frontoparietal, parieto-occipito-
temporal, or parieto-occipital lobes. The technique includes corticectomy (resection of
grey matter), lobe excision (resection of grey and white matter), lobe disconnection, or a
combination of these.
107. Is surgery for epilepsy effective?
At 1 year 58% of patients who underwent surgery were free of seizures impairing
awareness versus 8% of patients who received medical treatment. Patients
who underwent surgery also had significantly better HRQOL.
108. References
Engle J (2001) Intractable epilepsy: definition and neurobiology. Epilepsia
42(suppl 6):3
Wiebe S et al. (2001) A randomized controlled trial of surgery for temporal lobe
epilepsy. NEJM 345: 311-318.
Youman’s Neurological Surgery, 5th Edition
Zimmerman R and J Sirven (2003) An overview of surgery for chronic seizures.
Mayo Clin Proc. 78: 109-117
109. Factors that characterize refractory epilepsy
Intractable seizures
Excessive drug burden
Neurobiochemical plasticity changes
Cognitive deterioration
Psychosocial dysfunction
Dependent behavior
Restricted life style
Unsatisfactory quality of life
Increased mortality
Imagination is more Important than Knowledge
110. ADVERSE PROGNOSTIC FACTORS
Multiple seizure types.
High frequency of seizures.
Partial seizures.
Seizure onset in infancy.
Severe EEG abnormality.
Organic brain lesion.
Every thing should be made as simple as possible;
but not simpler
111. Interation of AE/Epilepsy:
Risk of aggravation
Carbamazepine: infantile spasms, epilepsies with
myoclonic (JME) or absence seizures.
EECSWS, Lennox-Gestaut syndrome.
Phenobarbital : infantile spasms, Dravet
syndrome.
Vigabatrin : epilepsy with myoclonus and
absences.
Lamotrigine : Dravet syndrome.
Benzodiazepines : Tonic spasms in LGS.
Tiagabine and Gabapentin : Absence and
myoclonus.
You are what you think and not what you think you are
112. INTENSIVE EEG MONITORING
Extracranial
Scalp electrodes,sphenoidal.
Semi invasive
Foramen ovale electrodes
Epidural pegs, pins,silver wires.
Invasive
Subdural strip, grid electrodes
Intracerebral electrodes.
“Healthy Mind and Healthy expression of Emotion
go hand in Hand”
113. NEURO IMAGING
CT Scan :
For gross structural lesions –
Cerebral tumours,Calcified lesions
MRI : Superior to CT- scan
Optimal MRI : High resolution
Special sequences
A great many people think they are thinking when they are merely re
arranging their prejudices
W. James
114. MR IMAGING
Hippocampal sclerosis
Developmental malformations
Disorders of neuronal migration
Cavernous haemangiomas
Dysembryoblastic neuro-epitheliomas
Indolent gliomas
Post-operative assesment
A open foe may prove a curse ; but a pretended friend is worse
115. SURGERY FOR EPILEPSY
Pre-surgical evaluation : Clincial
EEG, Video EEG, MR- imaging
SPECT, neuro-psychological evaluation,
WADA- test ( Occasional need for
intracranial electrodes, corticography,depth
recording, stimulation for localisation of
indispensable areas).
It is a great misfortune not to possess sufficient wit to speak well
nor sufficient judgment to keep silent
La Broyers character
116. RESULTS OF EPILEPSY SURGERY
SURGERY CURED IMPROVED
Temporal lobe 53 – 55 % 23 – 28 %
Extra temporal 43 % 27%
Hemispherectomy 63 % 25%
Corpus callosotomy 4–8% 80%
Truth comes out of error sooner than that of confusion
118. CONCLUSION
TEN STEP APPROACH FOR SUCCESSFUL DIAGNOSIS AND
MANAGEMENT OF EPILEPSY
1. Epilepsy is a disorder of the Brain and not of the Mind.
2. Epilepsy is broadly classified as Generalised or Partial.
3. This is a fascinating disorder affecting all the three
functions of the brain.(Cognition,Conation and affect).
Cognition- in simple definition means
perception plus thinking.
Conation – movement in general.
Affect- motor expression of an emotion.
We do not know one millionth of one percent
about anything – Thomas Edison
119. CONCLUSION
4. It represents four types of partial seizures coming from four lobes of
the brain.
I ) Frontal Lobe – supplementary motor area
i) Adversive seizures
ii) Epilepsia partialis continua (motor movement of the lip, thumb or toe).
II ) Parietal Lobe – Sensory seizure ( sudden benumbed feeling of the limb/ face.)
III ) Temporal Lobe – (Auditory, smell / aura , vertigo ) – clinically of three types
stare – automatisms- resolution.
Automatisms – resolution
Loss of consciousness with automatism
IV ) Occipital Lobe – visual aura seizures arising from all four lobes can result in secondary
generalization.
5. There are five types of generalized seizures – Tonic, clonic, Tonic clonic ,
Absence and Myoclonic .
The Truth is Fear & Immorality are two of the
greatest inhibitors of Performance to progress
120. CONCLUSION
6. Differential Diagnosis for epilepsy
i) Migraine. ii) Transient Ischemic Attacks (TIA).
iii ) Syncope. iv ) Narcolepsy.
v) Hypoglycemia ,Hyperglycemia. vi ) Psychogenic.
7. Seven investigations are mandatory : (rest are optional )
i ) Hemogram.
ii ) Blood sugar
iii ) Renal function tests ( Urea and Creatinine )
iv ) Liver functions (SGOT,SGPT, SERUM NH3 and GGT ).
v) EEG, (Telemetric recording ).
vi) CT / MRI ( If partial seizures are present ).
vii) Screening for malignancy. ( Epilepsy in elderly ). Optional ;
SPECT,PET,fMRI.
“The True Art of Memory is The Art of Attention” - S.Johnson
121. CONCLUSION
8. Treatment – Commonly effective in epilepsy
i) Commonly used : CPS Carbamazepine / Phenytion / Sodium Valproate.
ii) Latest drugs : TGL Topiramate – use it as add on or as monotherapy.
Gabapentin – primary drug in partial seizures
Lamotrigiine.
iii) Sparingly used : PV Old – Phenobarbitone New – Vigabatrine.
Thought is the labour of the intellect
Reverie is its pleasure
122. CONCLUSION
9. Etiology – Etiology of epilepsy in the finger tips.
T (thumb) – Trauma, Toxic,Tumour.
I (Index finger) – Infection ( bacterial / viral )
M ( Middle finger ) – Metabolic, endocrine
D (Diamond Ring finger ) – Degeneration, - Demyelination.
L ( Little finger ) - Little flow or absent flow of blood Vascular.
H ( Hand ) – Hereditary and Nutritional disorders.
Through Action You Create your Own Education - D.B. ELLIS
123. CONCLUSION
10. Epilepsy education
3 S – support group – tele film and video
self help group – information service
social skill – patient professional personal education
P – Patient – Physician give and talk.
D – Drugs do`s and don`ts
R – Role play
C – Compliance calendar .
Whatever the Mind can conceive and Believe, the mind can Achieve
Napoleon Hill
124. CONCLUSION
EXAMINE, EVALUATE ESTABLISH
PROVOCATIVE FACTORS.
IDIOPATHIC OR REMOTE SYMPTOMATIC-
LEGALLY (U.S.A)SINGLE SEIZURE-NO AED-NO
NEGLIGIENCE
EPILEPTIC SEIZURES ALWAYS TREAT
PROBABLITY ANALYIS OF RECURRENCES ARE
ACADEMIC
SURE CURE IF AED ARE TAKEN WITHOUT MISSING A
SINGLE DOSE
YET SUCCESS STORY IS VERY DISHEARTNING
We do not know one millionth of one percent
about anything – Thomas Edison
