By
Tamer Belal. MD (PhD)
Lecturer of Neurology
Mansoura University
Definitions
Simon Shorvon 2005 stated that “ epilepsy is regarded as
sufficently intractable to contemplate surgery if it has
been continuously active for 5 years (or less in severe
epilepsy) in spite of adequate trials of therapy with three
or more main-line antiepileptic drugs, and if seizures are
frequent (More than one per month) ”
Juan Carlos 2007 defined RE as the persistence of correctly
diagnosed unprovoked epileptic seizures that recur so
frequently that they interfere with patients’ daily lives and
cause personal dissatisfaction despite appropriate
antiepileptic drug treatment (Relevant to type of seizure or
epileptic syndrome ,maximum tolerated dose and good
compliance)
Definitions
Wolfgang Löscher 2009 define drug resistance as the
persistence of seizures despite treatment with a range of
AEDs used alone or in combination at maximum tolerated
doses
Definitions
 Failure of adequate trials of two tolerated, appropriately
chosen and used antiepileptic drug schedules (whether as
monotherapy or in combination) to achieve sustained seizure
freedom.
 With this definition, "drug resistant" replaces "intractable" or
"refractory.”
 Seizure free is either be
 Seizure free for at least 1 year OR
 3 times the longest preintervention inter-seizure interval (whichever is longer)
“Rule of 3"
ILAE Commission on Therapeutic Strategies Task Force (Kwan et al. 2010
• Earlier studies suggested that many patients respond to monotherapy but
fewer and fewer patients respond to combination therapy.
70%
controlled*
Monotherapy
30% controlled* on
2 drugs
30% poorly
managed
Combinations of two or
more drugs provide little
more benefit
* Controlled was defined as adequately managed but not
necessarily seizure-free
Mattson, 1992
• 525 untreated patients (470 drug-naïve)
60% controlled*
1st Monotherapy
2nd
1% controlled*
Monotherapy
3rd
40%
difficult to
control
Monotherapy
99% not
controlled
*Controlled was defined as seizure-free
• Only 3% were controlled with two AEDs, and none with three.
Brodie & Kwan, 2002
The costs of resistant epilepsy:
In the UK alone, where 80000 people have refractory epilepsy, the
cost of epilepsy overall is at least £2000 million/year
A US study in the early 1990s estimated that the annual cost of
refractory epilepsy in adults exceeds $11,745 per person
Costs were correlate with severity of illness and that patients who have
intractable seizures incur a cost eight times greater than in those whose
epilepsy is controlled
People with pharmacoresistant epilepsy are about two to 10 times more
likely to die compared with the general population and The risk is inversely
linked to seizure control.
Approximately 20-40% of patients with primary generalized epilepsy and
up to 60% of patients who have focal epilepsy develop drug resistance
during the course of their condition, which for many is lifelong
When seizures have failed to respond to two or three appropriate
antiepileptic drugs, the chance of significant benefit from other drugs is
10% or less.
Those who get no response or only a partial response to drugs continue
to have incapacitating seizures that lead to significant
Neuropsychiatric and social impairment,
Lower quality of life,
Greater morbidity, and
A higher risk of death.
Clinical predictors that have been associated with PRE
Early onset of seizures(before age of one year)
High seizure density (number of seizures per time) before treatment initiation
Having more than one type of seizure (Syndrome)
Long history of poor seizure control (failure of first drug)
Multiple seizures after treatment initiation
Family history of epilepsy
Remote symptomatic etiology (patients with a history of brain infection or head
trauma)
Certain structural abnormalities (cortical dysplasia, hippocampal sclerosis)
Certain EEG abnormalities, such as persistent focal slowing, or high frequency of
focal epileptiform abnormalities
Cognitive disability (Mental retardation)
History of status epilepticus.
Abnormal neurological examination
Psychiatric comorbidity
Causes of apparent or “false” pharmacoresistant epilepsy
Misdiagnosis of epilepsy
Example: patients with psychogenic non epileptic seizures
(misdiagnosed and inappropriately treated with multiple antiepileptic
drugs) and misdiagnosis of another condition (syncopal, cardiac,
neurological, metabolic )
Misdiagnosis of epilepsy type, leading to inappropriate drug
selection
Example: misdiagnosis of temporal lobe seizures for absence
seizures, or vice versa
Inappropriate assessment of response or lack of response
Examples: drug interactions leading to increased side effects and
decreased tolerability
Inappropriate patient behavior & Inadequate drug levels
Examples: poor compliance, detrimental lifestyle
Possible mechanisms of drug resistance
Disease-related mechanisms
Aetiology of disease (epilepsy syndromes)
Progression of disease
Structural brain alterations and/or network changes
 Alterations in drug target(s)
Alterations in drug uptake into the brain
Drug-related mechanisms
Ineffective mechanism of drug action
Low safety margin of AED precludes sufficiently high
brain levels
Loss of efficacy (tolerance) during chronic treatment
Pharmacogenetic mechanisms (patient characteristics)
Gene polymorphisms that affect pharmacokinetics or
pharmacodynamics of AEDs
Biologic basis of pharmacoresistant epilepsy
Biologic basis of pharmacoresistant epilepsy
Biologic basis of pharmacoresistant epilepsy
Biologic basis of pharmacoresistant epilepsy
Epileptic encephalopathies
Symptomatic partial epilepsies
Temporal lobe epilepsy
Biologic basis of pharmacoresistant epilepsy
Epilepsy may switch in a significant
proportion of patients in the course of
the disorder from being drug resistant
to becoming controlled and vice versa
Seizure clusters, defined as three or
more seizures per 24 h, occurring often
as many as 15 years after starting
treatment, increased the risk of
resistant epilepsy by 3 compared with
those without clusters
Biologic basis of pharmacoresistant epilepsy
The network hypothesis of drug
resistance after surgery is based on the
existence of nonresected limbic or
extralimbic seizure generators left
behind . ‘rewiring the brain’
Dentate gyrus functions as Gatekeeper
preventing the propagation of
synchronized activity from the entorhinal
cortex into the seizure-prone
hippocampus
Biologic basis of pharmacoresistant epilepsy
Acquired alterations to the structure
and/or functionality of target ion
channels and neurotransmitter receptors
Subunit composition of these channels
is altered, resulting in channels with
lower AED sensitivity
Receptor trafficking (internalisation)
Shift from adult inhibitory to neonatal
excitatory GABAA receptors
Biologic basis of pharmacoresistant epilepsy
Over expression of (multi)drug efflux
transporters in brain and other tissues.
Biologic basis of pharmacoresistant epilepsy
Pharmacokinetic
(metabolic)
 induction of AEDmetabolizing enzymes (firstgeneration AEDs)
Increasing the expression of
P-gp (newer AEDs)
Pharmacodynamic
(functional)
 adaptation’of AED targets
(loss of receptor sensitivity)
1
De novo drug
resistance
In some patients, resistance is present from the time of onset of the
very first seizure, before antiepileptic drug is even started.
Patients with newly diagnosed epilepsy for whom the first drug was
ineffective had only an 11% probability of future success, compared
with 41% to 55% in patients who had had to stop taking the drug
because of intolerable side effects or idiosyncratic reactions.
2
Progressive
drug
resistance
3
Waxing and
waning
resistance
In some patients, epilepsy is initially controlled but then gradually
becomes refractory. This pattern may be seen, in childhood epilepsies
or in patients with hippocampal sclerosis
In some patients, epilepsy has a waxing-and waning pattern: ie, it
alternates between a remitting (pharmacoresponsive) and relapsing
(pharmacoresistant) course.
Changes in drug bioavailability, local concentration of the drug in
the brain, receptor changes, the development of tolerance, and
interactions with new medications may be implicated, though the
exact mechanism is not understood
Pharmacokinetic or
“transporter”
hypothesis
Pharmacodynamic or
“target”
hypothesis
Increased action of membrane transporter proteins
involved in cellular defense that expel endogenous toxins
and xenobiotics (understood like biologic substances out
of its habitual place) to the outside of the cell, thus
preventing adequate concentrations of AEDs from being
reached in the brain despite adequate serum
concentrations, because these drugs do not penetrate the
blood-brain barrier well
Structural or functional modifications in different
“targets” where AEDs act, either ion channels,
neurotransmitter receptors or enzyme systems related to
the release, reuptake, and metabolism of
neurotransmitters
Alteration of the mechanisms of L-DOPA uptake in
basal ganglia
Alteration of the mechanisms regulating chloride and
potassium homeostasis
Specific alterations in certain genes involved in
susceptibility to seizures.
Antiepileptic Drugs
MRP
P-GP
Other
Blood-brain
Barrier
Blood
Endothelial cell
Brain
Concentration of AED in Tissue
Pharmacokinetic or transporter hypothesis of drug resistance. Increased expression of membrane
transporter proteins prevents adequate penetration of AEDs into the brain parenchyma
Pharmacokinetic or “transporter” hypothesis
 Membrane transporter proteins are involved in numerous vital
processes:
- Expulsion of toxic molecules
- The transport of nutrients
- The transport of peptides and hormones
- The transport of drugs
 These proteins are encoded by genes belonging to the ATP-binding
cassette (ABC) transporter superfamily, of which 7 subfamilies present in
humans are known
 Various genes belonging to the ABCB, ABCC, and ABCG subfamilies
are involved in MDR.
Pharmacokinetic or “transporter” hypothesis
1. P-glycoprotein (P-gp/MDR1)
2. The multidrug resistance associated proteins (MRP1, MRP2, and
probably MRP3, MRP4 and MRP5),
3. ABCG2 protein, an ABC half-transporter also called BCRP or Breast
Cancer Related Protein.
Oatp2
BRAIN
Oatp3
abluminal
Blood Brain Barrier
Brain Capillary Endothelium
ATP
ADP
ATP
ADP
ATP
ADP
Luminal
P-glycoprotein
Tight Junction
Tight Junction
abluminal
Luminal
BCRP
Mrp 1, 2, 4
Oatp2
BLOOD
The most important efflux transporters which so far identified at the blood–brain barrier belong to the class of ATPbindingcassette (ABC) transporters Oatp=Organic anion transporting polypeptide 3
Pharmacol Rev 60:196–209, 2008
P-glycoprotein may transport cytotoxic drugs directly from the cell membrane, before such drugs enter the cytoplasm (1),
or from the cytoplasm (2), limiting the concentration of such drugs at the target (DNA or tubulin). Highly lipophilic drugs
enter the cell by passive diffusion (3). Inhibitors of P-glycoprotein–mediated transport may be carried through the blood
supply (e.g., steroid hormones and agents that reverse the multidrug-resistance [MDR] phenotype) (4), or hypothetical
natural substrates may be produced in the cell (5).
Pharmacokinetic or “transporter” hypothesis
 The fact that some of these proteins are also found in glial cells and
neurons has led to the emergence of a new concept, that of the “second
barrier,” mediated by the protein transporters of the cellular components
of the brain parenchyma, which would act in concert with the blood-brain
barrier to restrict the access of certain drugs to the CNS
Overexpression of transporter proteins is regionally selective, affecting
the epileptogenic areas of the brain but not other unaffected areas
Pharmacokinetic or “transporter” hypothesis
A novel membrane transporter not belonging to the ABC transporter
family has recently been described, RLIP76 (RALBP1), which may have
a predominant role in resistance to AEDs.
It has been shown that it is expressed exclusively in brain endothelial
cells, and is especially prominent in epileptic tissue of patients operated
on for RE.
Pharmacokinetic or “transporter” hypothesis
Mechanisms of Overexpression of Membrane Transporter Proteins
It is still not known whether increased expression of these drug
transporters is acquired or constitutional.
The reason why seizures may cause this increase in transporter
proteins is also not known, but it could be explained by the “second
barrier” hypothesis, which would serve to protect the brain during
transient opening of the blood-brain barrier, which typically occurs in
response to prolonged seizure activity.
Pharmacokinetic or “transporter” hypothesis
 Modification of the functional consequence of membrane transporter
proteins that results in decreased distribution of AEDs in the brain is a
promising therapeutic strategy for the treatment of RE,
 Tariquidar (elacridar), a selective inhibitor of P-gp without antiepileptic
activity, in combination with phenytoin, almost completely controlled
seizures (although temporarily) in a rat model of temporal lobe epilepsy,
 Improvement in seizure control after the administration of verapamil (a
nonselective P-gp inhibitor),but, apart from their anecdotal character, it
should be kept in mind that verapamil also blocks calcium channels and
inhibits the metabolism of various AEDs, and so it cannot be assumed
that the improvement was due to the inhibitory effect on P-gp.
Pharmacokinetic or “transporter” hypothesis
P-Glycoprotein Activity is physiologically down regulated by:
• Nitric Oxide
• Endothelin 1
• VEGF
P-Glycoprotein Activity/Expression is Up regulated by:
• Dexamethasone
• Cyclooxygenase activity/Prostaglandin E2
• Pregnane X Receptor (Senses xenobiotic such as glucocorticoids,
anticancer drugs, or antiepileptic drugs)
• Glutamate/NMDA receptor signaling
• Wnt/β-catenin signaling
Pharmacology & Therapeutics 125 (2010) 118–127
Pharmacodynamic or “target” hypothesis
 The key element of this hypothesis is the existence of an intrinsic or
acquired structural or functional change in the molecular target of the
AED.
 The alteration in the target that interferes with the mechanism of action
of the AED and leads to RE may be
 Intrinsic genetically determined OR
 Acquired (develop over time as the consequence of
exogenous factors ).
 Broadly speaking, these therapeutic targets can be divided into 2 large
groups of molecules:
o Subunits of voltage-gated ion channels (Na, Ca, and K channels)
o Receptors of neurotransmitters related to neuronal excitation (GABA
and glutamic acid).
 Dopaminergic neurotransmission in the basal ganglia to RE and its
role as a modulator of cortical excitability, which may alter interindividual
response to AEDs
 Alterations in the mechanisms regulating chloride and potassium
levels in epileptogenic tissue may have a similar role.
 Genetic alterations (supported by some experimental studies).
A correlation has been established between a type of SNP in the IL-1 gene and
the development of hippocampal sclerosis, suggesting that it could be a
prototypical genetic mediator of intrinsic resistance to AEDs
 Gene encoding dopamine β-hydroxylase, suggested in initial studies
 SNPs in the cellular prion protein gene with the development of acquired
resistance to AEDs in temporal lobe epilepsy initially found a strong association
with particular type of polymorphism
Initiating event
e.g.,genetic malformations,head
trauma,febrile seizures,infections,
stroke, status epilepticus
Repair
(or control)
No consequence
Failure to Repair
Onset of epileptogenesis
e.g.,by “second hit”, polymorphism,
susceptibility genes, critical modulators,
comorbidities
Antiepileptogenic
/neuroprotective
Therapeutic
intervention
Anticonvulsant
Functional and structural alterations during epileptogensis
e.g.,hyperexcitability of neurons and/or neuronal circuits,
alterations in expression and function of receptors and ion channels(
in part recapitulating ontogenesis), neurnal loss, neurogenesis,
axonal and dendritic sprouting, gliosis, inflammation
Cognitive and behavioral
alteration
Spontaneous seizures
(clinical onset of epilepsy)
No Progression
Disease-modifying
Progression of epilepsy
Chronic epilepsy
often
pharmacoresistant
Steps in the development and progression of
temporal lobe epilepsy and possible therapeutic
interventions. The term epileptogenesis includes
processes that take place before the first
spontaneous seizure occurs to render the
epileptic brain susceptible to spontaneous
recurrent seizures and processes that intensify
seizures and make them more refractory to
therapy (progression). The concept illustrated in
the figure is based on both experimental and
clinical data.
Clinical approach to patients with pharmacoresistant epilepsy
OR
There has been relatively little improvement in AED efficacy since the
introduction of phenobarbital in 1912, so that still more than 30% of
epilepsy patients are resistant to AEDs with up to 90% with certain
types of focal epilepsies.
Failure of past drug developments is likely because of a neurocentric
approach neglecting the role of the blood–brain barrier, inflammation,
astrocytes, mitochondria and genetic disposition in the disease.
Future targeted therapies could be coupled to seizure-forecasting
systems to create “smart” implantable devices that predict, detect, and
preemptively treat the seizures in a “closed-loop” fashion
Targeted electrical stimulation
Direct stimulation targets presumed epileptogenic brain tissue such as
the neocortex or hippocampus
Indirect stimulation targets presumed seizure-gating networks such as
in the cerebellum and various deep brain nuclei in the basal ganglia or
thalamus (deep brain stimulation), which are believed to play a central
role in modulating the synchronization and propagation of seizure
activity.
Local drug delivery
Direct delivery of drugs into the epileptogenic brain tissue holds promise,
particularly for patients whose foci cannot be surgically removed.
Convection-enhanced delivery (CED) provides a wider, more homogenous
distribution than bolus deposition (focal injection) or other diffusion-based
delivery approaches.
CED infusions of non diffusible peptides that inhibit the release of
excitatory neurotransmitters, including ω-conotoxins and botulinum
neurotoxins, produce long-lasting (weeks to months) seizure protection in
the rat amygdala-kindling model
To date no clinical study has explored the utility of intraparenchymal or
intraventricular antiepileptic drug delivery in humans
Cell and gene therapies
In ex vivo gene therapy, bioengineered cells capable of delivering
anticonvulsant compounds might be transplanted into specific areas of
the brain.
In vivo gene therapy would involve delivering genes by viral
vectors to induce the localized production of antiepileptic
compounds in situ.
In epilepsy, particularly in TLE, cell transplantation could potentially be
of value in four different ways :
By repairing the damage in the hippocampus,
 By counteracting or modifying the development of epilepsy,
 By suppressing seizures in AED-resistant patients with
established epilepsy or
 By counteracting the progression of epilepsy.
Radiosurgery
Used in patients with focal epilepsy when the seizure focus is located
in eloquent or surgically challenging brain regions that are associated
with an unacceptably high incidence of complications after open
surgery
- lesional epilepsy associated with arteriovenous malformations,
cavernomas, and tumours
- Mesial temporal sclerosis and hypothalamic hamartomas
The antiseizure effect is commonly delayed and unpredictable late
complications
Results of transplantation of fetal neurons in rat models of
temporal lobe epilepsy
Potential candidates, and their known functions, associated
with pharmacogenetics of antiepileptic drugs
Enzymes involved in the metabolism of commonly
prescribed antiepileptic drugs
Genetic causes of refractory epilepsies
Genotype–phenotype correlations. DRPLA, dentate-rubro-pallido-Luysian atrophy; GEFSþ, epilepsy with febrile seizures plus; IGE, idiopathic generalized
epilepsy; LD, Lafora body disease; MAE, myoclonic astatic epilepsy; MERFF, yoclonic epilepsy with ragged red fibres; NCL, neuronal ceroid lipofuscinosis; TLE,
temporal lobe epilepsy; ULD, Unverricht–Lundborg disease.
A new AED is successful if it has at least one of the
following properties:
Greater efficacy than other drugs in the treatment of refractory
epilepsies
 The ability to prevent or delay the onset of epilepsy (epileptogenesis),
or at least modify its progression;
 Broad usefulness in non-epileptic CNS disorders
 Fewer adverse effects than available drugs
 Ease of use, such as rapid titration, linear pharmacokinetics, lack of
drug interactions, or a longer half-life that enables once or twice daily
doses or extended protection if a dose is missed.
A new AED is successful if it has at least one of the
following properties:
More than 20 compounds are at various stages of clinical development
These include
drugs with chemical structures that do not resemble existing
AEDs.
 derivatives of existing drugs that are developed as follow-up
compounds with potentially improved properties
Potential antiepileptic compounds in various stages of clinical
development
Principal mechanisms of action of the newer antiepileptic drugs include voltage-dependent ion channel blockade, enhancement of inhibitory
neurotransmission, and reduction of excitatory neurotransmission.
LaRoche, S. M. et al. JAMA 2004;291:605-614
Proposed mechanisms of action of currently available AEDs at excitatory and inhibitory synapses.
Anticonvulsant drugs together with the date their marketing
was approved in the US, UK and France
Drug
Brand
US
UK
acetazolamide
Diamox
27 July 1953
1988
carbamazepine
Tegretol
15 July 1974
1965
clobazam
Frisium
clonazepam
Klonopin/Rivotril
4 June 1975
diazepam
Valium
15 November 1963
divalproex sodium
Depakote
10 March 1983
ethosuximide
Zarontin
2 November 1960
ethotoin
Peganone
22 April 1957
felbamate
Felbatol
29 July 1993
fosphenytoin
Cerebyx
5 August 1996
gabapentin
Neurontin
lamotrigine
Lamictal
lacosamide
Vimpat
France
1963
1979
1974
1955
1962
30 December 1993
May 1993
October 1994
27 December 1994
October 1991
May 1995
Anticonvulsant drugs together with the date their marketing
was approved in the US, UK and France
Drug
Brand
US
UK
France
levetiracetam
Keppra
30 November
1999
29 September
2000
29 September
2000
mephenytoin
Mesantoin
23 October
1946
metharbital
Gemonil
1952
methsuximide
Celontin
8 February
1957
methazolamide
Neptazane
26 January
1959
oxcarbazepine
Trileptal
14 January
2000
phenobarbital
2000
1912
phenytoin
Dilantin/Epa
nutin
1938
phensuximide
Milontin
1953
1941
1920
Anticonvulsant drugs together with the date their marketing
was approved in the US, UK and France
Drug
Brand
US
UK
France
pregabalin
Lyrica
30 December
2004
6 July 2004
6 July 2004
primidone
Mysoline
8 March 1954 1952
sodium
valproate
Epilim
December
1977
June 1967
stiripentol
Diacomit
5 December
2001
5 December
2001
pregabalin
Lyrica
30 December
2004
6 July 2004
6 July 2004
primidone
Mysoline
8 March 1954 1952
1953
1953
Anticonvulsant drugs together with the date their marketing
was approved in the US, UK and France
Drug
Brand
US
UK
France
tiagabine
Gabitril
30 September
1998
1997
topiramate
Topamax
24 December
1996
trimethadione
Tridione
25 January
1946
valproic acid
Depakene/Co
nvulex
vigabatrin
Sabril
21 August
2009
1989
zonisamide
Zonegran
27 March
2000
10 March 2005 10 March 2005
November
1997
1995
28 February
1978
1993