1. Dr Parag Moon
Senior Resident
Dept of Neurology
GMC Kota

2. Definition
In investigational studies, criteria of refractoriness
include:
(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 nonrefractory,
(3) duration of 1 year to 1 decade of noncontrolled
epilepsy

3. Flexible scale of refractoriness
potential (no seizure freedom with AEDs taken less
than 1 year and predictive factors for refractoriness)
probable (no seizure freedom more than 1 year with at
least 2 AEDs)
definitely refractory(catastrophic epilepsy or no
freedom of seizure for more than 1 year after 5 years of
treatment with at least 3 AEDs)

4. Predictive Factors of Refractoriness
1. Epileptic syndrome
Only 13% with idiopathic generalized epilepsy, and no
case with idiopathic partial epilepsy, were refractory.
Typical refractory generalized epilepsy of pediatric
ages are the Ohtahara syndrome, early myoclonic
encephalopathy (neonatal period), West syndrome,
Dravet syndrome (infancy) and Lennox-Gastaut
syndrome (early childhood) .
In focal epilepsy, hippocampal sclerosis, cortical
dysplasia and hemorrhage are associated with
refractoriness .

5. 2. Localization of the epileptogenic zone
The temporal lobe ,striate cortex, namely the fourth
layer .
3.Response to AEDs-Absence of seizure freedom when
2 past AEDs proved inefficient
4.Younger Age of onset
5.Seizure frequency at epilepsy onset

6. 6. Electroencephalography -Quantity of interictal
spikes is predictive of severity in temporal lobe
epilepsy
Oligospikers-less than 1 spike per hour less severe
epilepsy
Association between multifocal spikes and
intractability

7. Frequency of refractory epilepsy varies from 10 to
37.5%

8. Diagnosis of Refractory Epilepsy
Exclude false refractoriness related to nonepileptic
seizures, inadequate AEDs, noncompliance and
seizure-precipitating factors
Defined as inadequate control of seizures despite at
least 2 potentially effective AEDs (mono- or
polytherapy) taken in tolerable doses

9. Treatment of Refractory Epilepsy
Non pharmacologic
Classic ketogenic diet -high fat content and low
carbohydrate Content
The medium chain triglyceride (MCT) diet
Modified Atkins diet (MAD)
Low glycemic index treatment (LGIT).

10. Classic ketogenic diet is a high fat and low
carbohydrate diet that uses long chain fatty acids
(LCFAs) as its main source of fat.
Patient must consume 3–4 grams of fat for every 1 gram
of carbohydrate plus protein
In MCT more carbohydrates and proteins can be
consumed for every gram of fat and is more ketogenic
No limit on the amount of protein consumed or the
total number of calories per day in MAD

11. Typical MAD uses a ratio of 1 gram of fat for every
gram of carbohydrate plus protein, is less restrictive
than the other two high fat diets.
LGIT restricts carbohydrate intake to food items with a
glycemic index of less than 50 at 40–60 grams per day,
in order to prevent large fluctuations in blood glucose
concentrations, which are thought to exacerbate
seizures.

12. 15.6%–15.8% of patients on the diet can achieve seizure
freedom whilst 33.0%–55.8% of the patients can have a
>50% reduction in number of seizures
West syndrome (infantile spasms)-ketogenic diet is
used as a first line agent.
Also recommended for patients suffering from glucose
transporter defects and pyruvate dehydrogenase
deficiency,

13. Effects of a ketogenic diet can be seen within a few
days and is cost effective
Side effects of dietary treatments are constipation,
acidosis, temporary hypercholesterolemia, kidney
stones and hunger, Growth restriction
Contraindicated in pyruvate decarboxylase
deficiency, primary carnitine deficiency, fatty acid
oxidation abnormalities, the porphyrias and some
mitochondrial disorders

14. Herbal medicine
Cannabinoids have the largest body of evidence
supporting their use as anticonvulsant.
Approved in canada and licensed in 14 states of
America
Other -kava (Piper methysticum) and mistletoe
(Viscum sp)

15. Surgical management
Candidates for Epilepsy Surgery
Ideally have a single epileptogenic focus in a non-eloquent
cortical region
Intractable epilepsy
Present for a substantial duration (usually years)
Refractory to medical therapy
Substantially impairing quality of life
Benefit of surgery should outweigh the risks

16. Evaluation of Candidates for
Epilepsy Surgery
Localization of seizures by interictal EEG
Localization by brain imaging-MRI; PET scanning
Localization by video-EEG monitoring of seizures (
may combine with ictal SPECT)
Localization by neuropsychological testing
Other methods-Depth electrodes,Cortical grids or
strips,Nuclear magnetic resonance
scans,Magnetoencephalography

17. Types of Resective Epilepsy Surgery
Temporal lobectomy
Extratemporal resections (lobar: frontal, occipital)
Corpus Callosotomy
Hemispherectomy
Multiple subpial transections

18. 68% of the patient who received temporal lobectomies
experienced seizure remission for 2 years.
Side effects – period of disability, infection, transient
endocrine abnormalities, transient dysphoria,
depression,occasionally mania
Permanent neurological and neuropsychological
complications
Possibility to create new lesions which may become
epileptogenic

19. Vagus Nerve Stimulation (VNS)
Approved by FDA in July 1997
Patients with intractable epilepsy ≥ 12 yo
• Intermittent electrical stimulation is
delivered to the left vagus nerve, which
has ascending fibers with widespread
connections to the limbic, autonomic
and reticular brain regions

20. Proposed Mechanisms of Action
for VNS
Desynchronization of EEG
Suppression of spikes
Block ictal rhythmic build-up in a seizure
Release of GABA and Glycine
Effects on limbic and brainstem systems
Increased thalamic blood flow

21. Benefits of Vagus Nerve
Stimulation
Median seizure reduction of 24.5%–28.0% in the group
receiving high level VNS compared to just 6.1%–15.0%
in patients receiving low level VNS
Effect increases over time
Seizure severity decreased
Improved level of alertness (medication may be
decreased)
Few adverse effects-Hoarseness, sleep
apnoea,infection (rare)
Batteries require replacement every ~ 10 yrs

22. Deep brain stimulation
DBS involves electrical stimulation of specific
subcortical nuclei, which have widespread neural
connections.
Anterior nucleus of the thalamus is often the target of
DBS.
Centromedian nucleus is also a potential location for
DBS

23. Complications -Infection, hemorrhage and
stimulation-induced seizures
Impaired memory and higher levels of depression

24. Responsive neurostimulation (RNS)
Does not deliver electrical stimulation throughout the
day.
RNS device is composed of a combined recorder and
stimulator device
Detects clinically relevant epileptiform discharges and
delivers an appropriate electrical stimuli in response
Reduction in seizure frequency of 37.9% in the
treatment arm compared to 17.3% in the control group

25. Other modalities available-repetitive transcranial
magnetic stimulation (rTMS).
Based on principles of electromagnetic induction,
where small intracranial electric currents are
generated by a strong fluctuating extracranial
magnetic field.
Risk of precipitating seizures

26. Thanks

27. References
Pharmacotherapeutic and Non-Pharmacological Options
for Refractory and Difficult-to-Treat Seizures ;James W.
Mitchell et al ; Journal of Central Nervous System Disease
2012:4 ;105–115
Refractory Epilepsy: A Clinically Oriented Review;Pedro
Beleza; Eur Neurol 2009;62:65–71
Schuele SU, Luders HO: Intractable epilepsy: management
and therapeutic alternatives. Lancet Neurol 2008; 7: 514–
524
Treatment of refractory epilepsy: Barbara Oslon: Adv Stud
Med 2005:5:470-473