management of epilepsy in this millennium–recent perspectives in intrtactable seizures
TRANSCRIPT
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
Prof. A.V. SRINIVASAN, MD, DM, Ph.D, F.A.A.N, F.I.A.N,
Emeritus Professor
CHENNAI-12- 03-10CHENNAI-12- 03-10
The Tamilnadu
DR.M.G.R Medical University
Epilepsy is A Fascinating Disorder Epilepsy is A Fascinating Disorder Affecting the the Three Functions of Affecting the the Three Functions of
the Brain the Brain
Cognition, Conation & AffectCognition, Conation & Affect
Is Cure from this Disorder a mereStroke of Luck?
“My Opinions are founded on knowledge but modified by experience”
Epilepsy – An Alarming issue 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
Living with epilepsy - 1992 Living with epilepsy - 1992
The Roper Organization 1992
19% recurrent seizures, no side effects
44% recurrent seizures+ side effects
17% no seizures + side effects
2% no answer
3% not taking AED
15% no seizures, no side effects
n=760
29% <3 weeks
10% 1-2 years
31% >2 years
n=1023
18% 4-12 months
10% 1-3 months
Fisher et al, Epilepsy Res 2000
Time since last seizure
Living with epilepsy - 1996Living with epilepsy - 1996
2% no answer
Classification of epilepsyClassification 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
AN IDEAL ANTICONVULSANT DRUGAN IDEAL ANTICONVULSANT DRUG
Prevent or inhibit excessive pathological neuronal discharge
Without interfering with physiological neuronal activity and
Without producing untoward effecto 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
Spectrum of actionSpectrum 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”
When they tell you to grow up, they mean stop growing - P. Diccaso
PHARMACO KINETICSPHARMACO KINETICS
AbsorptionDistributionElimination
“By Nature All Men/ Women are alike butby Education widely different”
- Chinese
Pharmacokinetic properties of established AEDsPharmacokinetic properties of established AEDs
Carbamazepine
Phenytoin
Valproate
Phenobarbital
Primidone
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
Pharmacokinetic properties of newer AEDsPharmacokinetic properties of newer AEDs
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
Felbamate
Gabapentin
Lamotrigine
Oxcarbazepine
Tiagabine
Topiramate
Bioavailability +2 -1 +2 +2 +2 +2
Paenteral form -2 -2 -2 -2 -2 -2
Elimination half life
+1 -1 +1 +1 +1 -1
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
Efficacy of antiepileptic drug for common seizure typeEfficacy of antiepileptic drug for common seizure type
Drug Partial Tonic-clonic
Absence Myoclonic Atonic/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
Role of Newer Role of Newer Antiepileptic DrugsAntiepileptic Drugs
““Older” AEDsOlder” 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
Newer AEDSNewer AEDSFelbamate 1993
Gabapentin 1994
Lamotrigine 1995
Topiramate 1996
Tiagabine 1998
Levetiracetam 1999
Oxcarbazepine 2000
Zonisamide 2000
Pregabalin 2005
We learn by thinking and the quality of the learning outcome is
determined by the quality of our thoughts
R.B. Schmeck
Carbamazepine Carbamazepine
First line drug for partial seizures for years
Two long-acting forms now avail (2X/day)
Side effects at just above therapeutic range
Not effective for some seizure types
Must start slowly due to 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
Phenytoin Phenytoin
First line for partial seizures for years
Once a day IV form
Side effects at just above therapeutic range
Not effective for some seizure types
Side effects: imbalance, sedation, cognitive, gum problems, osteoporosis
Many interactions
A true commitment is a heart felt promise to yourself from which you will not back down
- D. Mcnally
Valproate Valproate
Works for all seizure types
Around for decades Rare allergic reactions Helps prevent migraines New IV form New long-acting form
Side effects, esp. weight gain & tremor
Menstrual irregularities Not best for pregnancy Significant drug
interactions
“Character gets you out of bed commitment moves you to action faith, hope and Discipline follow through to completion”
Barbiturates (primidone and Barbiturates (primidone and phenobarbital)phenobarbital)
Effective Once a day
(phenobarbital) Cheap IV form
(phenobarbital)
Sedation and cognitive effects
Withdrawal
“By Nature All Men/ Women are alike butby Education widely different”
- Chinese
Other old medicationsOther 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”
Limitations of older AEDSLimitations 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 Enzyme inhibition : Valproic acid
Newer AEDsNewer 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
Role of New epilepticsRole 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
Rational PolytherapyRational 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
Choice of AEDChoice 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
Newer antieplepticsNewer antiepleptics
Unique features of newer antiepileptics Gabapentin, Pregabilin and Levetiracetam: no hepatic
metabolism or protein bindingNo important pharmacokinetic interactions with other
AEDsLamotrigine: associated with rash and must be titrated
slowlyTopiramate, Tiagabine, Zonisamide, Oxcarbazepine: must
titrate slowly to minimize cognitive side effectsTopiramate, Zonisamide:1-2% incidence of renal stonesFelbamate: aplastic anemia, hepatic failure, weight loss
It is the disease of not listening, the malady of not marking, that I am troubled withal - Shakespeare
GABAPENTINGABAPENTIN
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
Gabapentin Gabapentin ADVANTAGES No interactions with other
drugs Extremely rare “allergic”
reactions Can be started quickly Well-tolerated Treats pain, anxiety,
restless leg syndrome Generic availability Liquid formulation
DISADVANTAGES Three-times-a-day
dosing Does not treat all
types of seizures
Serious, sincere, systematic study surely secures supreme success
LAMOTRIGINELAMOTRIGINE
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
Lamotrigine Lamotrigine
ADVANTAGES– Minimal effect on other
medications– Works for all types of
seizures– Very well tolerated– Minimal sedation– Probably safe in pregnancy– Approved for >2 y.o. – Monotherapy
DISADVANTAGES– Rash if started
quickly Must start slowly (~2 months to full dose)
Mind is the great level of all things; human thought is the process by which human ends are ultimately
answered- Daniel Webster
TOPIRAMATETOPIRAMATE 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
TopiramateTopiramate
ADVANTAGES– Minimal interactions with
other medications– Probably works for all
seizure types– Approved for >2 y.o – Sprinkle form– Approved for monotherapy– Weight loss– Approved for migraine
prevention
DISADVANTAGES– Cognitive side
effects– 1-2% renal stones– tingling/pins and
needles– Can decrease
efficacy of oral contraceptives
Habit is either the best of servants or worst of masters- Nathaniel Emmons
TIAGABINETIAGABINE
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
Tiagabine Tiagabine
ADVANTAGES– Minimal effect on
other medications
DISADVANTAGES– Dose is dependent on
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
LEVECTIRACETAMLEVECTIRACETAM
Binds to synaptic vesicle protein SV2A Effective adjunct in partial seizures Lack of drug interaction can be used in
patients with complex multiple problemsPak 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
Levetiracetam Levetiracetam
ADVANTAGES No interactions Minimal liver metabolism Works for most seizure
types Can start quickly Well tolerated Liquid formulation
DISADVANTAGES Behavioral/psych side
effects Twice per day
Opinion is ultimately determined by the feelings and not by the intellect
OXCARBAMAZEPINEOXCARBAMAZEPINE
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
Oxcarbazepine Oxcarbazepine
As effective and better tolerated than CBZ
Fewer interactions than CBZ
Approved for children > 4
Approved for first-line monotherapy
Not for all seizure types
Low sodium, esp. if on diuretics also
Lessens effectiveness of birth control pill
Three can be seen in the divisions of a human in mind, body and spirit
ZONISAMIDEZONISAMIDE
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
Zonisamide Zonisamide
Used in Japan for many years
Works for all seizure types
Approved for children Once daily Weight loss Recent addition of 25 mg
capsules
1-2% kidney stones Occasional
psychiatric or sedative side effects
Sulfa drug
“Social Isolation is in itself a pathogenicFactor for disease production”
Intranasal or Buccal MidazolamIntranasal 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
New agentsNew 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
Pregnancy in Women With EpilepsyPregnancy 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, 20002. Crawford, 1997
Drugs that decrease efficacy of Drugs that decrease efficacy of oral contraceptivesoral contraceptives
Phenytoin Carbamazepine Phenobarbital Primidone Topiramate at higher doses Oxcarbazepine
Whatever the Mind can conceive and Believe, the mind can Achieve - Napoleon Hill
Weight IssuesWeight Issues
Risk of weight gainValproate
Gabapentin
Pregabalin
“Risk” of weight loss– Topiramate– Zonisamide– 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
Lifestyle changes to minimize seizuresLifestyle 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
SummarySummary
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
New AEDs: odds ratios for 50% respondersNew AEDs: odds ratios for 50% respondersand withdrawal in randomised controlled trialsand withdrawal in randomised controlled trials
95% CI
1.5-3.4
1.5-3.7
2.3-4.8
2.0-4.6
2.9-5.8
2.4-5.5
1.4-4.5
Oddsratio
2.3
2.3
3.4
3.0
4.1
3.7
2.5
Drug
GBP
LTG
OXC
TGB
TPM
VGB
ZSM
1.4
1.2
2.3
1.8
2.6
2.6
4.2
95% CI
0.7-2.5
0.8-1.8
1.9-2.8
1.2-2.7
1.6-4.0
1.3-5.3
1.7-10.5
Oddsratio
50% responders Withdrawals
New vs Old AEDs as monotherapyNew vs Old AEDs as monotherapyin previously untreated patientsin previously untreated patients
Efficacy
Similar
Similar
Similar (2)CBZ better (2)
Old AEDs(no. studies)
CBZ (4)PHT (1)VPA (1)
PHT (2)CBZ (1)VPA (1)
CBZ (4)
NewAEDs
LTG
OXC
VGB
Tolerability
LTG better
OXC betterOXC better
Similar
VGB better
Odds ratio – Meta analysis – New AEDsOdds ratio – Meta analysis – New AEDs
Thought is the labour of the intellect
Reverie is its pleasure
Long-term use of gabapentin, Long-term use of gabapentin, lamotrigine, and vigabatrinlamotrigine, and vigabatrin
Variable
Mean daily dose (mg)
Seizure free (%)
Reason for withdrawal (%)
Lack of efficacy
Adverse event
Both
Standardisedmortality ratio
GBP(n=361)
1575
1
42
10
12
7.7
LTG(n=1050)
303
3
25
13
6
10.4
VGB(n=713)
2444
3
36
12
15
6.8
Economic aspectsEconomic aspectsof antiepileptic treatmentof antiepileptic treatment
Cost (Euro)
47
55
82
83
202
472
1420
1705
1875
2716
5987
Dose (mg/day)Drug
150
750
750
350
1200
3000
3000
1800
400
400
3600
PB
PRM
ESM
PHT
CBZ
VPA
VGB
GBP
LTG
TPM
FBM
Cost of AEDs for 1 year of treatment in Italy
Common long-termCommon long-termAED side effectsAED side effects
energy level
school performance
overall QoL
memory
concentration
thinking clearly
Fisher et al, Epilepsy Res 2000
emotional and mental wellbeing
coordination and balance
sex life
job performance
Science is below the mind; Spirituality is beyond the mind
Serious adverse effects of AEDsSerious 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 : felbamateActive metabolite : various
. Polymechanistic but metabolites with antiseizure activity
“ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy
SummarySummary 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
Combinations based on drug interactionsCombinations based on drug interactions
Least UsefulCarbamazepine with phenytoin
RationalePhenytoin induces carbamazepine metabolism, leading to need for much higher carbamazepine doses.
Phenobarbital with carbamazepine
Phenytoin, valproate
Valproate with phenobarbital
Valproate with phenytoin
Phenobarbital is a powerful inducer of
CYP 450 system
Valproate decreases phenobarbital metabolism
Both compete for protein binding sites, reducing the value of total drug level measurement
Discipline Weighs ounces Regret weighs Tons
Combinations based on drug interaction. Combinations based on drug interaction. contdcontd
Least UsefulFelbamate with phenytoin, carbamazepine and valproate
RationaleMany drug – drug interactions
UsefulGabapentine with any drug
Valproate with lamotrigine
No drug interaction
Valproate inhibits metabolism of Iamotrigine, reducing dose and cost of treatment with Iamotrigine
“Social Isolation is in itself a pathogenicFactor for disease production”
Combination based on mechanism of actionCombination based on mechanism of action
Most UsefulCarbamazepine or phenytoin with gabapentine, tiagabine, topiramate, felbamate
RationaleWidely different mechanisms of actions
Least UsefulCarbamazepine and phenytoin
Tiagabine, gabapentine, and vigabatrin
Similar mechanisms of action
Similar mechanisms of action
The art of medicine is caring for the heart of the patient
Combinations based on side effectsCombinations based on side effects
Possibly UsefulValproate with felbamate or topiramate
RationaleFelbamate and topiramate have been associated with weight loss, valproate with weight gain.
Least UsefulCarbamazepine and valproate in women of child bearing potential
Valproate and carbamazepine both may increase risk for spina bifida; 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
Medical outcomeMedical 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
Prognosis of a first unprovoked seizurePrognosis 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
Prognosis of a first unprovoked seizurePrognosis 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
Remission of EpilepsyRemission 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
Remission of EpilepsyRemission 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
Relapse after drug withdrawalRelapse 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
Relapse after drug withdrawalRelapse 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 isKnowing where the stones are
Relapse after drug withdrawalRelapse 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 intellectReverie is its pleasure
INTRACTABLE EPILEPSYINTRACTABLE 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 powerTake time to read; it is the foundation of wisdom
Take time to work; it is the price of success
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
Prof. A.V. SRINIVASAN, MD, DM, Ph.D, DSc(Hon)
F.A.A.N, F.I.A.N,
Emeritus Professor
CHENNAI- 21-1-11CHENNAI- 21-1-11
The Tamilnadu DR.M.G.R Medical University
OutlineOutline Definition Epidemiology Taxonomy Pathophysiology of intractable seizures Pre-operative diagnosis and work-up Management options
DefinitionsDefinitions
A seizure is the clinical manifestation of excessive, synchronous, abnormal firing of large populations of neurons
Intractable epilepsyIntractable 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
EpidemiologyEpidemiology
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
Why do patients fail to respond?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 Unknown factors
When should we intervene When should we intervene surgically?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
Factors to consider when making Factors to consider when making the surgical decisionthe surgical decision
Patient’s social environment Expectations Level of function Quality of life Severity and frequency of seizures Medical consequences of the epilepsy
Taxonomy of surgically remediable Taxonomy of surgically remediable epilepsy syndromesepilepsy syndromes
Pathophysiology of epilepsyPathophysiology 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
Goal of resective epilepsy surgeryGoal 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
Seizure SemiologySeizure Semiology
Clinical features of a seizure may suggest a location for the symptomatogenic zone and have lateralizing value
Seizure SemiologySeizure SemiologyIctal 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 immediately prior to a secondarily generalized tonic-clonic seizure
Contralateral hemisphere
nonforced head turning at ictal onset without a tonic component or hemifacial clonic twitching
Ipsilateral hemisphere
Asymmetric tonic limb posturing, the "figure four sign,"
The extended limb is usually contralateral to the hemisphere of onset
Seizure SemilogySeizure SemilogyLocalized contralateral clonic activity and aphasia with speech arrest
Broca’s area
Assymetrical bilateral proximal limb movement, version of head, facial grimacing with speech arrest or vocalization, and preserved consciousness
Supplementary motor area
Olfactory, psychic, and emotional auras followed by complex automatisms
Orbitofrontal and cingulate seizures
No warning, Bilateral tonic clonic activity with version, forced thinking, falls, autonomic signs
Prefrontal
Cortical zonesCortical 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
EEG RecordingsEEG 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
EEG RecordingsEEG 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).
Indications for Invasive EEG monitoringIndications 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
NeuroimagingNeuroimaging
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
Hippocampal SclerosisHippocampal Sclerosis
80-95% of patients with surgically proven hippocampal sclerosis have hippocampal atrophy and hyperintensity on T2-weighted MR
FDG PET in a patient with mesial temporal epilepsyshowing hypometabolism in are aof left mesial temporal lobe
NeuroimagingNeuroimaging
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.
Functional TestingFunctional 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
What is a Wada Test?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
Epilepsy syndromes Epilepsy syndromes amenable to surgeryamenable to surgery
Mesial Temporal Lobe EpilepsyMesial 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
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.)
Frontal Lobe EpilepsyFrontal 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
Lesional partial epilepsyLesional 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
Neocortical cryptogenic epilepsyNeocortical 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.
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
Surgical Approaches for Epilepsy
Summary of Surgical Procedures Summary of Surgical Procedures for Epilepsyfor 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.
Summary of Surgical Procedures Summary of Surgical Procedures for Epilepsyfor 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.
Is surgery for epilepsy effective?Is surgery for epilepsy effective?
At 1 year 58% of patients who underwent surgery were free of seizures impairingawareness versus 8% of patients who received medical treatment. Patientswho underwent surgery also had significantly better HRQOL.
ReferencesReferences
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
Factors that characterize refractory epilepsyFactors 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 mortalityImagination is more Important than Knowledge
ADVERSE PROGNOSTIC FACTORSADVERSE 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
Interation of AE/Epilepsy:Interation of AE/Epilepsy:Risk of aggravationRisk 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
INTENSIVE EEG MONITORINGINTENSIVE 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”
NEURO IMAGINGNEURO IMAGING
CT Scan :
For gross structural lesions –
Cerebral tumours,Calcified lesionsMRI : Superior to CT- scanOptimal MRI : High resolution
Special sequences
A great many people think they are thinking when they are merely re arranging their prejudices
W. James
MR IMAGINGMR 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
SURGERY FOR EPILEPSYSURGERY 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
RESULTS OF EPILEPSY SURGERYRESULTS 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
EFFICACY OF AEDSEFFICACY OF AEDS
Monotherapy
1st AED
Monotherapy
2nd AED
Monotherapy
3rd AED
Seizure free 47 %
Newly diagnosed epilepsy
N= 10
Seizure free
13 %
Uncontrolled
Seizure
53%
Seizure free
10 %
Seizure free
3%
Uncontrolled Sz
40%
Uncontrolled Sz
30 %
Uncontrolled Sz
36%Discipline Weighs ounces; Regret weighs Tons
CONCLUSIONCONCLUSION
We do not know one millionth of one percent about anything – Thomas Edison
TEN STEP APPROACH FOR SUCCESSFUL DIAGNOSIS AND MANAGEMENT OF EPILEPSY
Cognition- in simple definition means perception plus thinking.
Conation – movement in general. Affect- motor expression of an emotion.
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).
CONCLUSIONCONCLUSION
I ) Frontal Lobe – supplementary motor areai) Adversive seizuresii) 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 – resolutionLoss of consciousness with automatismIV ) Occipital Lobe – visual aura seizures arising from all four lobes can result in secondary generalization.
4. It represents four types of partial seizures coming from four lobes of the brain.
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
CONCLUSIONCONCLUSION6. 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
CONCLUSIONCONCLUSION
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 intellectReverie is its pleasure
CONCLUSIONCONCLUSION
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
CONCLUSIONCONCLUSION
10. Epilepsy education3 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
CONCLUSIONCONCLUSION
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
Dedicated to my family for Dedicated to my family for making everything worthwhilemaking everything worthwhile
THANK YOUTHANK YOU
READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
East west Pharma