Drug Resistant Epilepsy

1. Drug Resistant Epilepsy:
Pathophysiology, Clinical overview
and Management

2. INTRODUCTION
• Majority of patients with epilepsy - 70% to
80% - well controlled on AEDs
• Breakthrough seizures despite treatment with
two or more AEDs - drug-resistant
epilepsy(DRE)
• Approximately 30% - DRE

3. • Epilepsy surgery should be considered
• Number of epilepsy surgery procedures
performed per year in the US - around 1500
• Underutilized therapy in DRE
• AAN - CPS who have failed appropriate trials
of first-line antiepileptic drugs - considered for
referral to an epilepsy surgical center

4. • Chances of seizure freedom - significantly
higher compared with further medication
trials
• Other therapeutic options - diet and electrical
stimulation
• Do not achieve the same percentage of
seizure-free results

5. Need for epilepsy surgery
• Considerable impairments in daily activities, education,
employment, and social interaction due to continuing
seizures and medication adverse effects
• Higher risk of developing various psychological
problems, such as depression, anxiety and psychosis
• Additional morbidity and mortality of the continued
seizures - accidental injury, cognitive decline and
sudden unexpected death in epilepsy (SUDEP)
• Rates for employment, marriage and fertility are
considerably lower

6. ILAE Proposal

7. DEFINITION OF
DRUG-RESISTANT EPILEPSY
• ILAE, 2010 – global consensus definition
• Failure of adequate trials of two tolerated,
appropriately chosen and appropriately used
anticonvulsant drug schedules (whether as
monotherapies or in combination) to achieve
sustained seizure freedom

8. Points
To Be Emphasized
• Medication should be appropriately selected
for the individual’s seizure or epilepsy type
• Adequate dose should be used for a
significant length of time prior to
discontinuing the medication trial
• AED therapy should be well tolerated and free
from disabling side effects

9. Sustained Seizure Freedom
•seizure freedom
•minimum of twelve months or
•for a period three times the previous longest
seizure-free period,
•whichever is longer
•greater emphasis on seizure freedom
•only meaningful outcome which can lead to
sustained improvement in the quality of life

10. PATHOPHYSIOLOGY

11. Mechanisms Of Drug Resistance
• not completely understood
• likely to be variable and multifactorial
• Three major categories
• Disease-related mechanisms
• Drug-related mechanisms
• Pharmacogenetic mechanisms

13. DISEASE-RELATED MECHANISMS

14. Epilepsy syndrome associated with
drug resistance
• Underlying epilepsy syndrome - significant
predictor for drug resistance
• Epileptic encephalopathies - very likely to
have drug-resistant epilepsy
• Symptomatic partial epilepsies - more likely to
be drug resistant than those with
idiopathic/cryptogenic partial and unclassified
epilepsies

15. Severity and progression of epilepsy
• Intrinsic severity hypothesis
• Increased disease severity leads to drug
intractability
• Epilepsy severity exists on a continuum
• More severe epilepsies - more difficult to treat
• Pharmacoresistance - an inherent property of
the epilepsy related to disease severity

16. • Seizure frequency - marker of severity
• High seizure frequency before onset of AED
therapy - single most important factor
associated with a low chance of long-term
remission of seizures on treatment

17. • Disease-related mechanisms of drug
resistance can change in the course of the
epilepsy
• Epilepsy can switch from being drug resistant
to becoming controlled and vice versa

18. Structural brain alterations and/or
network changes
• Network hypothesis
• Resective surgery - standard care for DRE
• Structural brain alterations and/or network
changes lead to drug resistance
• Following temporal lobe surgery
• 50–66% - seizure free with continued medical
treatment
• 20–25% - seizure-free without AEDs

19. • Hippocampal sclerosis - common finding in
pharmacoresistant TLE
• May have a causal role in the mechanisms
underlying AED resistance

20. How can hippocampal sclerosis
contribute to drug resistance?
• Dentate gyrus - normally functions as a high-
resistance gate or filter
• Prevents the propagation of synchronized activity
from the entorhinal cortex into the seizure-prone
hippocampus
• TLE - filter or ‘gatekeeper’ attribute of the dentate
gyrus is compromised

21. DRUG-RELATED MECHANISMS

22. Hypothesized Biologic Mechanisms of
Drug Resistance in Epilepsy
• 1 - Overexpression of efflux transporters in
capillary endothelial cells that constitute the
blood–brain barrier
• 2 - Altered expression/function of neuronal
voltage-gated ion channels that are known
targets of antiepileptic drugs
• 3 - Mechanisms not targeted by current AED -
autoantibodies to neurotransmitter receptors

23. Kwan P et al. N Engl J Med 2011;365:919-926

24. Failure of Drugs to Reach Their Targets
• “transporter hypothesis”
• Overexpression of multidrug efflux transporters
at the epileptic focus - ATP-binding cassette
(ABC) transmembrane proteins
• Extrude substrates from the cell against the
concentration gradient
• Reducing the cerebral accumulation of substrate
drugs
• P-glycoprotein - Most extensively studied

25. • Surgically resected brain specimens from
patients with DRE- upregulation of P-
glycoprotein and other efflux transporters
• Whether human P-glycoprotein transports
antiepileptic drugs to a significant extent
remains controversial
• Compelling evidence regarding the clinical
relevance of the transporter hypothesis
remains lacking

26. Alteration of Drug Targets
• “target hypothesis”
• Alteration in the cellular targets of AEDs
• Leads to a reduction in their sensitivity to
treatment
• Studies - blockade of the fast sodium current in
dentate granule cells by carbamazepine was lost
in hippocampi resected from patients with
carbamazepine-resistant temporal-lobe epilepsy
• Polymorphisms of the SCN2A gene - found to be
associated with resistance to AEDs

27. • Altered expression of subtypes of the GABAa
receptor – drug resistant TLE
• Main weakness of the target hypothesis -
presumption of a working knowledge of the
• Mechanisms of action of antiepileptic drugs are
incompletely understood
• Cannot account for the observation that patients
often have epilepsy that is resistant to multiple
drugs with different modes of action

28. Drugs Missing the Real Targets
• Current antiepileptic drugs are intended only
to prevent seizures
• May not be targeting the appropriate
pathogenic processes
• Autoantibodies to ion channels involved in
neuronal excitation and inhibition - voltage-
gated potassium and calcium channels and
NMDA and GABAB receptors

29. • Other proposed cellular mechanisms of
seizures and epileptogenesis
• Mitochondrial oxidative stress and
dysfunction
• electrical coupling through gap junctions in
neurons or even glial cells

30. Development of tolerance
• Tolerance to AEDs - an adaptive response of
the body to prolonged exposure to the drug
• Tolerance develops to some drug effects
much more rapidly than to others
• Extent of tolerance depends on the drug and
individual genetic factors
• Leads to loss of efficacy of AEDs

31. • Two major types of tolerance
• Pharmacokinetic (metabolic) tolerance - due
to induction of AED metabolizing enzymes
• Shown for most first generation AED
• Easy to overcome by increasing dosage

32. • Pharmacodynamic (functional) tolerance
• brought about by ‘adaptation’ of AED targets
(e.g. by loss of receptor sensitivity)
• Leads to complete loss of AED activity and cross-
tolerance to other AEDs
• There is convincing experimental evidence that
almost all first, second and third generation AEDs
lose their antiepileptic activity during prolonged
treatment although to a different extent

33. PHARMACOGENETIC MECHANISMS

34. Pharmacogenetic mechanisms
• Drug treatment of epilepsy is characterized by
unpredictability of efficacy, adverse drug
reactions and optimal doses in individual
patients,
• Could be a consequence of genetic variation
• Genetic variation - integral role in variability of
both AED pharmacokinetics and
pharmacodynamics

35. • SNPs - most frequent form of sequence
variations in the human genome
• Drug targets and drug transporters can be
affected
• AED targets - genetic variation in SCN1A
• Polymorphisms in various candidate drug
transporter gene - variation in the MDR1
(ABCB1) gene which encodes P-gp

36. Proof-of-concept of drug resistance
hypotheses
• Sisodiya
• Proposed that at least four criteria must be satisfied
for a proposed drug-resistance mechanism of epilepsy
to be accepted
• Mechanism must:
• be detectable in epileptogenic brain tissue
• have appropriate functionality
• be active in drug resistance (and not be an
epiphenomenon)
• drug resistance should be affected when the
mechanism is overcome

37. • The only hypothesis with clinical proof-of-
concept - network hypothesis
• Resection of the epileptogenic focus reverses
AED resistance in at least 60% of surgical
patients

39. Ruling out Pseudoresistance
• Pseudoresistance - seizures persist because
the underlying disorder has not been
adequately or appropriately treated
• Must be ruled out or corrected before drug
treatment can be considered to have failed
• May arise in a number of situations

40. Some Reasons for Pseudoresistance to Antiepileptic Drug Therapy.
Kwan P et al. N Engl J Med 2011;365:919-926

41. Wrong Diagnosis
• Misdiagnosis of epilepsy is probably the most
common
• 20% to 25% - do not have epilepsy
• Majority have psychogenic nonepileptic seizures
• Conditions that frequently mimic epileptic
seizures - vasovagal syncope, cardiac
arrhythmias, metabolic disturbances, and other
neurologic disorders with episodic manifestations
- TIA and migraine

42. Wrong Drug
• Inadequate understanding of the
pharmacologic properties of AEDs
• Phenytoin, carbamazepine, gabapentin,
oxcarbazepine, vigabatrin, tiagabine, and
pregabalin can worsen absence epilepsy and
myoclonic seizures
• Lamotrigine can also exacerbate some
myoclonic epilepsy syndromes

43. Wrong Dose
• AEDs may fail to control seizures satisfactorily
if not prescribed at the optimal dosage
• may result from an injudicious reliance on
monitoring of serum drug concentrations

44. Lifestyle Issues
• Insufficient adherence to the therapeutic
regimen
• Abuse of alcohol and recreational drugs
• Sleep deprivation and stress are also common
seizure precipitating factors

45. RESECTIVE EPILEPSY SURGERY
• Gold standard therapeutic option
• DRE that has been determined to be of focal
origin

46. Surgically remediable epilepsy
syndromes

47. Patients who require functional imaging/mapping and/
or invasive studies
Temporal lobe epilepsy with
•Discordant electroclinical data
•Bilateral mesial temporal sclerosis
•Normal MRI
Extratemporal circumscribed epileptogenic
lesions close to eloquent area
Malformations of cortical development
Dual pathologies

48. Selection of ideal candidates for
epilepsy surgery
• Main objective of the presurgical evaluation –
• to identify an abnormal area of cortex from
which the seizures originate
• to determine whether it can be removed without
producing any significant functional impairment
• Goal of epilepsy surgery –
• to remove the minimal amount of tissue required
to make the patient seizure-free, and no more

49. Prerequisites and contraindications for
epilepsy surgery

51. Epileptogenic Zone
• Area necessary and sufficient for initiating
seizures - the removal or disconnection of
which is necessary for abolition of seizures
• Final success of epilepsy surgery depends
upon the accurate delineation and complete
removal of the “epileptogenic zone”
• Difficult to accurately define the epileptogenic
zone preoperatively

52. • Can be approximated by identifying other important
zones
• Symptomatogenic zone - cortical areas responsible for
ictal symptoms
• Ictal onset zone - cortical area from where seizures
originate
• Irritative zone - cortical areas generating interictal
spikes
• Lesional zone - area showing lesion on MRI
• Functional deficit/hypofunctional zone - areas of brain
showing interictal dysfunction

53. • These zones and dysfunctions can be identified
using different modalities
• Clinical history - symptomatogenic and
hypofunctional zones
• Neuropsychological testing - hypofunctional zone
• Interictal EEG - irritative zone
• Seizure phenomenology, ictal EEG, ictal SPECT -
ictal onset zone
• Structural MRI - lesional zone
• Interictal PET - hypofunctional zone

54. • further supplemented by identifying the
important functional areas
• functional MRI
• cortical stimulation and mapping (functional
deficit zone)
• Wada testing

55. • All the different modalities provide different
information
• Information provided by none of the
modalities is absolute
• Chances of surgical success increase with
increasing concordance between different
modalities

56. PRESURGICAL EVALUATION

57. Comprehensive epilepsy care facility
• Presurgical evaluation involves multiple
diagnostic modalities
• Requires a multidisciplinary approach
• Main challenge - address the medical and
psychosocial issues together

58. • It is often necessary to consult psychologists,
psychiatrists, occupational therapists and
social workers during the process of the
presurgical evaluation
• These, along with the neurologists,
neurosurgeons, radiologists, trained EEG
technologists and epilepsy nurses, constitute
an organized team of the comprehensive
epilepsy care program

59. Presurgical evaluation strategy
• Extent of presurgical evaluation required in an
individual case - varies according to the degree of
complexity involved
• MTLE and confirmed unilateral mesial temporal
sclerosis on MRI - only requires VEEG monitoring
to verify the ictal onset zone and to rule out non-
epileptic seizures
• Extratemporal seizures and normal MRI - require
all available investigations, including invasive
monitoring

60. The primary components of the presurgical
evaluation
•Detailed clinical history and physical
examination
•Video-EEG monitoring
•Advanced neuroimaging
•Neuropsychological testing
•Assessment of psychosocial functioning

61. • Second stage
• Functional studies - SPECT and PET
• Other modalities
• Magnetic source imaging (MSI)
• EEG-functional MRI (EEG-fMRI)
• Electrical source imaging (ESI)
• Intracranial monitoring - reserved as a last
stage

62. • Other important part of the presurgical
evaluation
• Predict and minimize the postoperative
functional deficits
• Wada test and fMRI - language and memory
functions
• DTI
• Cortical stimulation and mapping during
intracranial monitoring

64. Clinical evaluation
• Obtain reliable information about seizure
semiology
• Ascertain adequacy of AED therapy and
impact of seizures on the quality of life
• Detailed inquiry regarding the presence of
various risk factors for epilepsy - perinatal
injury, febrile seizures, meningoencephalitis
and head trauma

65. Long-term video-EEG monitoring
• Provides information about seizure semiology,
interictal abnormalities, and ictal rhythms
• Differentiates between seizures and non-
epileptic events
• Classify seizures
• Localize the ictal onset zone
• Focal IEDs, ictal patterns - provides useful
information on localizing the ictal onset zone

66. • Gradual reduction of AEDs is required during long
term VEEG monitoring for the induction of
seizures
• Number of seizures required for the selection of
patients for surgery varies between studies and
among the centres
• Unilateral MTLE - recording one or two habitual
seizures is sufficient
• Bitemporal epileptogenicity - at least five seizures
of unitemporal origin are necessary to be fairly
certain that a patient has unifocal seizure origin

67. MRI
• Complete removal of the MRI-detected
structural lesion is the most important factor
determining seizure freedom following
surgery
• MRI - most important tool in the presurgical
evaluation
• Common lesions in patients with refractory
epilepsy - mesial temporal sclerosis, focal
cortical dysplasias, and benign neoplasms

68. • 20-30% of patients with classic temporal lobe
epilepsy do not have any MRI-defined
abnormality
• Advances structural imaging - allow the
detection of subtle abnormalities
• Various methods - hippocampal volumetry, T2
relaxometry, magnetic resonance
spectroscopy, and peri-ictal diffusion-
weighted MRI

69. • Newly developed MRI techniques and
postprocessing methods –
• phased array surface coil, higher MRI fields
(3T), double inversion recovery, magnetization
transfer imaging
• identify focal lesions in patients with normal
conventional MRI

70. • DTI and tractography
• help in minimizing the postoperative deficits
following epilepsy surgery by delineating the
white matter tracts in the vicinity of the lesion
• Tractography of the Meyer’s loop
• used to reduce the risk of superior quadrantic
visual field deficit
• frequent complication of anterior temporal
lobectomy

71. Neuropsychological evaluation
• Best single means of quantifying the cognitive
abilities and psychosocial status
• valuable information regarding the
lateralization and localization of the seizure
focus
• helps in counselling patients about potential
risk of postoperative memory impairment
• essential part of to detect and treat the
associated depression, anxiety and psychosis

72. SPECT & FDGPET
• provide localizing information for patients
when baseline non-invasive investigations are
either non-localizing or discordant
• help in guiding invasive monitoring in patients
with normal MRI or with multifocal or diffuse
MRI abnormalities

73. Ictal SPECT
• Shows focal hyperperfusion at the seizure focus
• Can provide the localizing value in 70-90% of
temporal lobe seizures and 60% of extratemporal
epilepsies
• Advances in the post-acquisition processing of
the SPECT images - enhanced its value
• Subtraction ictal SPECT co-registered to MRI
(SISCOM)
• Statistical parametric mapping (SPM)

75. FDG-PET
• Assesses aspects of interictal brain dysfunction distinct
from those assessed by IEDs
• Useful in MRI-negative patients
• Hypometabolism predominating in the epileptogenic
lobe
• Lateralizing information in about 60-90% of temporal
lobe epilepsies
• Less sensitive in extratemporal epilepsies
• Can provide useful localizing information to guide
intracranial monitoring in patients with normal MRI

76. • PET study combined with other non-invasive
investigations can obviate the need for
invasive monitoring
• MRI-negative neocortical epilepsies - FDG-PET
coregistered on MRI helps to detect occult
focal cortical dysplasia
• reducing the proportion of patients needing
intracranial EEG investigation

77. fMRI
• two important uses in the management of
epilepsy
• to identify eloquent areas in relation to an
epileptic lesion being considered for resection
• to detect fMRI activity in relation to interictal
epileptic spikes on EEG
• may be helpful in the localization of seizure focus
• Spike-related blood oxygen level dependent
(BOLD) activation can be used for source
localization by simultaneous continuous fMRI
with scalp EEG recording (EEG-fMRI)

78. • Functional MRI for language, motor and
sensory tasks have been well standardized
and are routinely used to minimize the deficits
while planning resection near these eloquent
• Recently, memory fMRI has been shown to
predict postoperative memory outcome in
patients undergoing temporal resections

79. Wada test
• gold standard for determining the hemispheric
dominance for language functions
• role in predicting memory outcome following
temporal lobectomy is being increasingly
questioned
• many centres have abandoned its use as a
routine test before temporal lobectomy
• Non-invasive evaluation with fMRI, PET and MEG
may largely obviate the need for the Wada test in
the future

80. Magnetic source imaging
• Magnetic source imaging (MSI) -
Magnetoencephalography (MEG) combined with
source modelling and co-registered to MRI
• can provide the source localization of the interictal
spikes
• indications are more or less the same as those of
SPECT and PET
• helps in the localization of stimulus-induced normal
neuronal function
• used for mapping the location of somatosensory,
motor, language and other cognitive functions while
planning surgical resection

81. Electrical source imaging
• source modelling technique which utilizes
realistic head models and inverse source
estimation methods to detect the source of
EEG spikes
• Can improve the spatial resolution of EEG
signals and can provide better source
localization than the EEG
• Overall, ESI is an additional emerging toll in
the presurgical evaluation

82. Intracranial monitoring
• indicated when the results of non-invasive
methods are conflicting or noncontributory
• suspected MTLE - broadly indicated in four
scenarios in patients with:
• – normal MRI
• – bilateral mesial temporal sclerosis on MRI
• – dual pathology
• – electroclinical discordance where either of the
investigations is equivocal or contradictory

83. • extratemporal epilepsy - indications
• - define the epileptogenic zone in patients
with indistinct or very large lesions
• - suspected epileptogenic zone is located in or
near eloquent cortex
• - extensive extraoperative cortical stimulation
studies are required to confirm its relationship
with eloquent cortex

87. Surgical Options
• Various epilepsy surgical options are available
• most common form of resective surgery in
epilepsy
• anterior temporal lobe resection
• superior to medical therapy - Class I evidence
• Lesionectomy - efficacious in cases of
cavernous angioma or glioneural tumors -
Class II evidence

88. • Corpus callosotomy
• children or patients with significant cognitive
impairment
• Class III evidence
• Multiple subpial transections
• resection of the epileptic focus is not possible
because of its proximity to eloquent cortex -
Class IV evidence

89. • Hemispherectomy and functional
hemispherectomy
• pathology affecting an entire hemisphere,
usually in the setting of preexisting neurologic
impairments such as hemiplegia, visual field
defects, or language impairments
• entire hemisphere is removed or functionally
disconnected
• Class IV evidence

90. Outcome
Engel Epilepsy Surgery Outcome Scale
Basic Outcome Scale
•Class I: Free of disabling seizures
•Class II: Rare disabling seizures ("almost
seizure-free")
•Class III: Worthwhile improvement
•Class IV: No worthwhile improvement

92. ELECTRICAL STIMULATION
THERAPY FOR EPILEPSY
• Two modalities have obtained US Food and
Drug Administration (FDA) approval
• vagus nerve stimulation - possible alternative
for patients over the age of 12 years with
medically intractable epilepsy when epilepsy
surgery is not an option
• Patients with generalized epilepsy,
posttraumatic epilepsy, and tuberous sclerosis
may benefit

93. • responsive neurostimulation - patients 18
years and older with medically refractory
partial epilepsy who have no more than two
epileptic foci

94. KETOGENIC DIET
• The classic ketogenic diet - high-fat, low-
carbohydrate diet that induces urinary ketosis
and mimics starvation while preserving
necessary calorie intake
• Modified Atkins diet and low-glycemic-index
diet – also prescribed in the treatment of
epilepsy

95. REFERENCES
• Kwan P, Schachter SC, Brodie MJ. Drug-resistant
epilepsy. N Engl J Med. 2011 Sep 8;365(10):919-26.
• Nair DR. Management of Drug-Resistant Epilepsy.
Continuum (Minneap Minn). 2016Feb;22(1
Epilepsy):157-72
• Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in
children and adults. Lancet Neurol. 2014
Nov;13(11):1114-26
• Rathore C, Radhakrishnan K. Concept of epilepsy
surgery and presurgical evaluation. Epileptic Disord.
2015 Mar;17(1):19-31