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‫بسم ا‬
‫الرحمن الرحيم‬
‫قالوا سبحانك ل علم”‬

‫قالوا سبحانك ل علم”‬
‫لنا إل ما علمتنا‬
‫إنك أنت العليم‬
‫“ الحكيم‬
‫صدق ا...
By
Dr/ Ayman Al-malt
Assistant Lecturer Of Neurology
Faculty of medicine
.Tanta university

10/4/2013
Agenda
Definitions
� Seizure: the clinical manifestation of an
abnormal,
excessive
excitation
and
synchronization of a population...
Epidemiology of Seizures and Epilepsy
� Seizures
• Incidence: 80/100,000 per year
• Cumulative lifetime incidence : 9% (1/...
N.B
•At least one of the new AEDs must be used
before considering intractability.
•For the well known epileptic syndromes
...
Refractory Status Epilepticus
defined as:
seizures not responding to 1st line (benzodiazapines)
Or / and
2nd line ( phenyt...
How Serious Is The Problem?
-70% of epileptic pts. have a good prognosis.
-30-40 % may develop refractory epilepsy.
-70% p...
2- Predictors For Refractory
Epilepsy
1- Early age of onset.
2- Febrile and neonatal convulsions.
3- History Natal Disorde...
8. Status epilepticus
9. Long duration of epilepsy on diagnosis.
10. Abnormal EEG, Abnormal CT.
11. Poor psychological and...
3- Classification of Intractable
Epilepsy
*Medically intractable epilepsy:
.Pseudo intractable. 1
.True intractable. 2
:Me...
Intractable Epilepsy
Drug resistance may be present→
►
De novo
►
Develop later (MTS):
(Early age of onset, associated Glia...
4- Common Errors
In Diagnosis and Treatment of
Epilepsy (pseudo refractory)
Diagnostic errors
. Misdiagnosis of non-epileptic seizures.
. Misclassification of epileptic seizures.
. Unrecognized prog...
Treatment errors
. Improper choice of drug.
. Inadequate drug dose.
. Inappropriate combination of drugs.
. Drug interacti...
Epilepsy co-morbidities- 5
•
•
•
•

Psychosocial/psychiatric: anxiety,depression
Sleep disorders
Migraine
Cognitive Disord...
Mechanisms (hypothesis) of- 6
drug resistance in epilepsy
• Two main hypothesis→
IMulti drug-efflux transporters
hypothesi...
(I)The multi-drug transporter hypothesis:
•
•
•
•
•
•
•
•

Transporters e.g. P-gp, MRP1,….
Interfere with pharmacological ...
:II) The Drug-target Hypothesis(
• Target brain molecules include→
► Voltage dependant-ion channels
► Neurotransmitter rec...
Drug Target Alterations
• Decreased efficacy of drugs acting via Na
channels.
• Reduced or lost pharmacosensitivity of Na
...
7- Therapeutic strategy for management
of intractable epilepsy
 The following measures should be considered in
succession....
4.

At that point we have to do the following:
A. Re-evaluate the patient even with previous normal
investigations.
B. Loo...
5. Return to single drug therapy with the best clinically
tolerated of the previously used antiepileptic drugs
(avoid seda...
7. We have to consider the following,
7.1-Alternative non antiepileptic drug therapy as add
on therapy under strict clinic...
Treatment Algorithm For Medical Management of Epilepsy
Months of
treatment

Patients with newly diagnosed, previously
untr...
Future challenges- 8
• To develop inhibitors for these transporters
e.g verapamil → inhibitor of P-gp.
• To design effecti...
Score for Assessment of Treatment Failure (D Schmidt,1986)
Index of intractability

Seizures persist despite treatment wit...
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Ref.epilepsy final
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  • Sudep 24 t gp
    40 seizure free
    epilepsy 2-3 t gp
    Burns fracture head injury
  • Transcript of "Ref.epilepsy final"

    1. 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. 2. By Dr/ Ayman Al-malt Assistant Lecturer Of Neurology Faculty of medicine .Tanta university 10/4/2013
    3. 3. Agenda
    4. 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. 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%
    6. 6. 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.
    7. 7. 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%
    8. 8. 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.
    9. 9. 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.
    10. 10. 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
    11. 11. 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)
    12. 12. 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
    13. 13. 4- Common Errors In Diagnosis and Treatment of Epilepsy (pseudo refractory)
    14. 14. 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
    15. 15. Treatment errors . Improper choice of drug. . Inadequate drug dose. . Inappropriate combination of drugs. . Drug interaction.
    16. 16. 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
    17. 17. Mechanisms (hypothesis) of- 6 drug resistance in epilepsy • Two main hypothesis→ IMulti drug-efflux transporters hypothesis. II- Drug – target hypothesis. (Wolfgang L, 2005) →
    18. 18. (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.
    19. 19. :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
    20. 20. 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.
    21. 21. 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 →
    22. 22. 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
    23. 23. 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
    24. 24. 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.
    25. 25. 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)
    26. 26. 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.
    27. 27. 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.
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