The document provides definitions of seizures and epilepsy. It then discusses epidemiology, noting incidence and prevalence statistics. Predictors of refractory epilepsy are listed, including early age of onset and structural brain abnormalities. Classification systems for intractable epilepsy are described. Common errors in diagnosis and treatment are reviewed. Mechanisms of drug resistance including multi-drug transporters and drug target alterations are summarized. A therapeutic strategy and treatment algorithm are outlined. Future challenges in management are mentioned.

1. ‫بسم ا‬
‫الرحمن الرحيم‬
‫قالوا سبحانك ل علم”‬
‫قالوا سبحانك ل علم”‬
‫لنا إل ما علمتنا‬
‫إنك أنت العليم‬
‫“ الحكيم‬
‫صدق ا العظيم‬
‫سورة البقرة ايه 23‬

2. By
Dr/ Ayman Al-malt
Assistant Lecturer Of Neurology
Faculty of medicine
.Tanta university
10/4/2013

3. Agenda

4. Definitions
� Seizure: the clinical manifestation of an
abnormal,
excessive
excitation
and
synchronization of a population of cortical
neurons.
� Epilepsy: recurrent seizures (two or more)
which are not provoked by systemic or acute
neurologic insults.

5. Epidemiology of Seizures and Epilepsy
� Seizures
• Incidence: 80/100,000 per year
• Cumulative lifetime incidence : 9% (1/3
febrile convulsions)
• � Epilepsy
• Incidence: 45/100,000 per year
• Prevalence: 0.5-1%
• Cumulative lifetime incidence: 3%

8. N.B
•At least one of the new AEDs must be used
before considering intractability.
•For the well known epileptic syndromes
with poor prognosis, intractability must be
considered earlier than 2 years.

9. Refractory Status Epilepticus
defined as:
seizures not responding to 1st line (benzodiazapines)
Or / and
2nd line ( phenytoin/ valproates/ phenobarbitone)
agents.
occurs in ~ 20% patients in status epilepticus.
mortality rate > 20%

10. How Serious Is The Problem?
-70% of epileptic pts. have a good prognosis.
-30-40 % may develop refractory epilepsy.
-70% pt retain their intractability versus remission.
-Refractory epileptic pts. are more prone to:
*Neurological and Psychosocial retardation.
*Risk of injury(seizure related).
*High mortality: 1.37 per 100 person-years.
Sudden unexplained death in epilepsy patients (SUDEP) is 40 times
more likely among patients who continue to have seizures than in

those who are seizure free.

11. 2- Predictors For Refractory
Epilepsy
1- Early age of onset.
2- Febrile and neonatal convulsions.
3- History Natal Disorders.
4- Mental subnormality.
5- Organic brain damage.
6- Seizure type, frequency, and number.
7- poor initial response to AED.

12. 8. Status epilepticus
9. Long duration of epilepsy on diagnosis.
10. Abnormal EEG, Abnormal CT.
11. Poor psychological andor socio-economic
background
12. Family history of epilepsy
13. genetic prediction (gene polymorphism )
14. localization of the epileptogenic zone

13. 3- Classification of Intractable
Epilepsy
*Medically intractable epilepsy:
.Pseudo intractable. 1
.True intractable. 2
:Medically and surgically intractable*
.Candidates unfit for surgery. 3
.Candidates with failed surgery. 4
(Aicardi, J.1988)

14. Intractable Epilepsy
Drug resistance may be present→
►
De novo
►
Develop later (MTS):
(Early age of onset, associated Glial proliferation,
dendritic sprouting , synaptic reorginization)
►
Wax-and-wane pattern

15. 4- Common Errors
In Diagnosis and Treatment of
Epilepsy (pseudo refractory)

17. Diagnostic errors
. Misdiagnosis of non-epileptic seizures.
. Misclassification of epileptic seizures.
. Unrecognized progressive brain disease.
.Failure to uncover precipitating factors.
Misdiagnosis is common; 26 percent of individuals
thought to have DRE were incorrectly diagnosed most
often as a result of incomplete historytaking and/or EEG misinterpretation

19. Treatment errors
. Improper choice of drug.
. Inadequate drug dose.
. Inappropriate combination of drugs.
. Drug interaction.

21. Epilepsy co-morbidities- 5
•
•
•
•
Psychosocial/psychiatric: anxiety,depression
Sleep disorders
Migraine
Cognitive Disorders
NB: Better management of epilepsy comorbidities and QOL improvement → better
seizure control and decrease drug resistance

22. Mechanisms (hypothesis) of- 6
drug resistance in epilepsy
• Two main hypothesis→
IMulti drug-efflux transporters
hypothesis.
II- Drug – target hypothesis.
(Wolfgang L, 2005)
→

23. (I)The multi-drug transporter hypothesis:
•
•
•
•
•
•
•
•
Transporters e.g. P-gp, MRP1,….
Interfere with pharmacological behavior of most drugs.
Mainly P-gp is involved in multi-drug resistance.
Expressed by tissues with excretory function & bloodbrain barrier,blood-testis barrier, placenta.
Over expressed in pts. with refractory epilepsy.
Is this over expression intrinsic or acquired or both ??
Most of the known AED are substrate for these
transporters.
Functional polymorphism of these transporters may
occur and play another role in pharmakoresistance.

24. :II) The Drug-target Hypothesis(
• Target brain molecules include→
► Voltage dependant-ion channels
► Neurotransmitter receptors
► Transporters or metabolic enzymes
involved in release, uptake & metabolism of
neurotransmitters.
• NB.
over
expression
of
multi-drug
transporters, AED-target alterations →
pharmacoresistance

25. Drug Target Alterations
• Decreased efficacy of drugs acting via Na
channels.
• Reduced or lost pharmacosensitivity of Na
channels.
• Down regulation of B1,B2 subunits of Na
channels.
• Decreased efficacy of drugs acting via GABA
mediated inhibition
• Change of GABA receptor subunits (alpha 1,
alpha and delta) expression.

26. 7- Therapeutic strategy for management
of intractable epilepsy
The following measures should be considered in
succession.
1.
Increase the dose of the 1st line antiepileptic drug has
been chosen for the patient, up to the maximum
clinically tolerated dose N.B* we have to treat the
patient not the serum level, On failure→
2.
Change for another drug of the first line drugs, and
also increase its dose gradually up to the maximum
tolerated dose, on failure →
3.
Permanent addition of a second drug, on failure →

27. 4.
At that point we have to do the following:
A. Re-evaluate the patient even with previous normal
investigations.
B. Look for hidden causes and precipitating factors.
C. Psychological assessment
support are needed more here.
and
psychosocial
D. Some questions should be asked now as:
- Can too much of one drug or too many drugs
may not only produce side effects, but also increase
seizures frequency?
- Can certain drug precipitate certain seizure

28. 5. Return to single drug therapy with the best clinically
tolerated of the previously used antiepileptic drugs
(avoid sedative and hypnotic drugs).
6. Addition of one of the new antiepileptic drugs can be
considered
now
as
add
monotherapy, on failure→
on
therapy
or
as

29. 7. We have to consider the following,
7.1-Alternative non antiepileptic drug therapy as add
on therapy under strict clinical selective criteria
such as:
a.Vagal nerve stimulation.
b.ketogenic diet.
c.Hormonal therapy.
d.Calcium antagonists.
e.Intravenous immunoglobulins.
7.2-Epileptic surgery.

30. Treatment Algorithm For Medical Management of Epilepsy
Months of
treatment
Patients with newly diagnosed, previously
untreated epilepsy
0
Monotherapy
(drug 1)
4
Success
Failure
Consider withdrawal after2- 5
years of complete seizure control
Alternative monotherapy
(drug 2)
Success
Failure
Consider withdrawal after 5 years
of complete seizure control
Polytherapy
(drug 1 and 2)
Success
Failure
Consider withdrawal after 5 years
(with patient considerations)
Substitution and transfer to
monotherapy with drug 3
Success
Failure
Consider withdrawal after 5 years
(with patient considerations)
Presurgical evaluation?
Diagnostic re-evaluation
8
12
16
(Gram L & Schmidit D. 2000)

43. Future challenges- 8
• To develop inhibitors for these transporters
e.g verapamil → inhibitor of P-gp.
• To design effective drugs that are not
substrates for these MDR protein.
• Development of new strategies to by-pass the
effect of these drug transporters.

46. Score for Assessment of Treatment Failure (D Schmidt,1986)
Index of intractability
Seizures persist despite treatment with
0
-A drug other than a 1st line drug regardless of daily
dose.
1
-1st line drug below the recommended daily dose.
2
-1st line drug within the recommended daily dose.
3
-1st line drug with therapeutic range of plasma
concentration.
4
-1st line drug with maximum tolerable dose.
5
-More than one 1st line drug with maximum tolerable
dose.
6
-More than one 1st line drug with maximum tolerable
dose and 2nd line drugs.