This document discusses refractory epilepsy, including definitions, epidemiology, mechanisms, diagnosis, and treatment approaches. It defines refractory epilepsy as the absence of response to two anti-epileptic drugs at reasonable doses, with a minimum seizure frequency of one per month. It estimates that 20% of people with epilepsy have refractory seizures, totaling around 1 million people in India. Causes of refractory epilepsy include drug transporter issues, target resistance, and intrinsic disease severity. Surgical treatment and alternative therapies like the ketogenic diet, vagus nerve stimulation, polymers, and electrical brain stimulation are reviewed as potential treatment options.

1. DR.SRIRAMA.ANJANEYULU
MD;DM
NEUROLOGIST
GUNTUR

2. Terminology
 “Treatment nonresponder”
 “Refractory”
 “Intractable”
 “Drug resistant”

3. CONSEQUENCES OF RE
 Bodily injuries - hospitalization.
 Shortened life spans-risk of sudden unexpected death.
 Significant neuropsychological, psychiatric, and social
impairments.
 Limited employment, reduce marriage rates, and
decrease quality of life.

4. PROGNOSTIC GROUPS IN EPILEPSY
 (1) Spontaneous remission (20–30%) - benign epilepsy
with centrotemporal spikes or childhood absences.
 (2) Remission on AEDs (20–30%) - most focal epilepsy
and myoclonic juvenile epilepsy syndromes;.
 (3) Persistent seizures under AEDs (30–40%) .

5. DEFINITION
 (1) Absence of response to 2 AEDs tolerated at
reasonable doses.
 (2) Minimum frequency of seizures (e.g. 1 seizure per
month) to be considered refractory or the duration of
minimum remission (e.g. 6– 12 months) to be qualified
as non refractory.
 (3) Duration of 1 year to 1 decade of non controlled
epilepsy.

6. EPIDEMIOLOGY
 (i) No unifying definition of RE.
 (ii) Same pt might be refractory at one time, but treatment
responsive at another.
 (iii) Response to medication is assessed without a
pretreatment baseline, as most pts are treated rapidly after
diagnosis.
It is unclear whether or not so-called refractory pts have
had a substantial response to treatment.
 (iv) There is evidence from trials that pts defined as
refractory will respond readily, although not completely to
therapy.

7. EPI…………
 Epilepsy - prevalence ~ 5/1000
 Incidence ~ 50/100,000/year.
 Assuming that 20% of patients with active epilepsy
would be resistant to AED treatment
 One bn population of India,
 There would be about one mn people with medically
refractory epilepsy.

11. PREDICTING REFRACTORINESS
 Type of syndrome.
 Etiology.
 13% of all patients with IGE , and no case with
idiopathic partial epilepsy, were refractory.
 78% of patients with symptomatic generalized
epilepsy and 49% of patients with symptomatic partial
epilepsy were not in remission.

12.  Younger age.
 High sz frequency.
 Presentation with SE.
 Abnormal NE.
 Mixed seizure types with dev.delay.
 Multiple sz types prior to treatment and after
treatment.
 Quantity of interictal spikes.

13.  Human factors-
 Wrong drug,
 Dose,
 Frequency,
 Compliance.
 Environmental –trauma ,drug exposure.
 Genetic -

14. Mechanisms of Refractoriness
 Drug transporter hypothesis
 Target hypothesis
 Intrinsic disease severity

15. REFRACTRORINESS
 Drug fails to reach the neuronal target
(pharmacokinetic hypothesis).
 Drug fails to act at the neuronal target
(pharmacodynamic hypothesis).
 Seizure phenotype and history of seizures determine
the “level of refractoriness” (the inherent disease
severity hypothesis).

17.  Pathobiosis- process whereby malfunctioning cells are
allowed to survive in an otherwise hostile
environment; this phenomenon would in turn
promote survival of defective glia.

20. Diagnosis of Refractory Epilepsy
Exclude false refractoriness related to -
 Nonepileptic seizures. (20%)
 Inadequate AEDs.
 Noncompliance .
 Seizure-precipitating factors.

21. Confirm refractoriness
 Inadequate control of seizures despite at least 2
potentially effective AEDs (mono- or polytherapy)
taken in tolerable doses.
 Occurrence of an average of one sz per month for 18
months or more.
 Not more than 3 month sz free hiatus during this
period of 18 months.

22. AED FOR RE
FIRST LINE DRUGS
 Partial epilepsies-CBZ
 Generalized epilepsies-VPA
ADD ON DRUGS
 Partial-PHB,CLB;/LEV,TPM
 Generalized-ZNS,LEV,LTG
 VPA+TPM=hyper ammonaemia
 LEV+ZNS=SZ++++.

27. Approaches to the
treatment of refractory epilepsy
 Continue on present course and accept a 5%per year
remission rate.
 Try to develop a blockbuster magic bullet that cures
everyone.
 Attempt to target drug therapy for each individual
patient.

28. EPILEPTIC SURGERY

32. Types of surgical procedures for medically refractory
epilepsy

33. Ideal candidates for anterior temporal lobectomy with
amygdalohippocamectomy

34. Classification of postoperative seizure outcome (modified
Engel classification)

35. Predictors of seizure outcome following epilepsy surgery

36.  KD-chronic ketosis,GABA synthesis
increase,hyperpolarize neurons and glia.
 VNS

37. Treatments under Investigation
 Polymers
 Electrical brain stimulation
 Prediction of seizures

38. POLYMERS
 Polymers containing AEDs - 2- to 3-mm microspheres ,
placed near the epileptogenic zone.
 (1) new AEDs could be used which do not cross the BBB or
show systemic toxicity.
 (2) useful when the epileptogenic zone is near eloquent
cortex.
 (3) prevent noncompliance .
 Implanting wafers impregnated with chemotherapeutic
agents into the resection cavity results in prolongation of
survival without an increased incidence of adverse events .
 Studies in animals have been promising as the application
of polymers containing phenytoin to the epileptogenic
zone in mice has reduced epileptogenic indexes .

39. ELECTRICAL STIMULATION
 Still not accepted as a routine treatment for epilepsy-
no consensus regarding the better region to stimulate
and in what type of seizure it is most effective.
 The epileptogenic zone and the centromedian or
anterior nuclei of the thalamus seem to be the most
effective targets for electrical stimulation .
 The efficacy similar to vagal nerve stimulation which
has a lower risk and less comorbidity .

40. FUTURE…..
 Seizure detector coupled with a trigger AED infusion
pump has been developed with success in the mouse .
 Research has also been done in predicting seizures .
 Device may predict seizures and automatically
administer AEDs to prevent them from occurring.

41. Thank you