management of epilepsy in this millennium–recent perspectives in intrtactable seizures

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


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


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).


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


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


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


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


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

management of epilepsy in this millennium–recent perspectives in intrtactable seizures

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