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Pharmacoresistant epilepsy: Definition and explanation

Andreas V. Alexopoulos n

Staff Physician, Cleveland Clinic Epilepsy Center, Neurological Institute, 9500 Euclid Avenue, Desk S-51, Cleveland, OH 44195, USA

article info

Available online 23 April 2013

Keywords:

Drug resistance

Epilepsy drug therapy

Anticonvulsants

Epilepsy surgery

Treatment failure

abstract

Epilepsy is one of the commonest neurological disorders, estimated to affect more than 60 million

people worldwide. In the majority of these patients, seizures can be effectively suppressed with

antiepileptic drugs (AEDs). Still, a significant percentage of patients (estimated to exceed 40% in some

studies) exhibit pharmacoresistance during the course of their frequently lifelong condition.

We review our current understanding of some of the many missing pieces that constitute the puzzle

of pharmacoresistant epilepsy (PRE), which can be practically defined as failure to achieve seizure

freedom following adequate trials of two tolerated and appropriately chosen AEDs. The complexity of

PRE reflects the dynamic nature of the underlying disease biology and the multiplicity of mechanisms

of drug resistance.

We summarize some of the known clinical predictors, patterns and causes of treatment failure and

examine potential underlying pathophysiological mechanisms and implications for the development of

future therapies

& 2013 Published by Elsevier GmbH.

1. Introduction

Despite ongoing development of several new antiepileptic

drugs (AEDs) over the past two decades approximately 40% of

patients with epilepsy exhibit resistance to pharmacotherapy

(Kwan and Brodie, 2000; Sillanpaa et al., 1998). Pharmacoresis- tant epilepsy (PRE) exacts an enormous toll on patients and their

families, while the loss of employment potential and cost of

medical care has a substantial impact on society.

Individuals who fail to respond or respond only partially to

AEDs continue to experience incapacitating seizures that lead to

neuropsychological, psychiatric, and social impairments thereby

reducing quality of life and increasing morbidity and mortality.

PRE is usually a lifelong condition, which is strongly associated

with comorbid depression and/or anxiety, feelings of lack of

control and independence, and a host of AED-related adverse

effects (such as cognitive impairment, sexual dysfunction, weight

gain, etc.) (Alexopoulos et al., 2007).

Approximately 20–40% of patients with primary generalized

epilepsy (Faught, 2004), and up to 60% of patients with focal

epilepsies may manifest pharmacoresistance (Pati and

Alexopoulos, 2010). Managing these patients is challenging and

requires referral to specialized centers that utilize a structured

multidisciplinary approach (Fountain et al., 2011).

2. Risk of death

In any given interval of time individuals with PRE are about

2 to 10 times more likely to die compared with the general

population (Chapell et al., 2003). In fact ‘‘sudden unexpected

death in epilepsy’’ (SUDEP) is the leading cause of death in

patients with pharmacoresistant epilepsy (Tomson et al., 2008).

This condition excludes accidental deaths from trauma or drown- ing. Postmortem examination does not reveal a toxic or anatomic

cause of death, and the underlying mechanisms remain unknown.

Case-control studies have shown that the risk of SUDEP is closely

and inversely associated with seizure control (Langan et al.,

2005). Importantly, freedom from seizures, achieved after suc- cessful epilepsy surgery, has been shown to reduce the risk of

death from all causes (Sperling et al., 1999). Other causes of death

in patients with PRE may be directly related to seizures (acci- dental trauma, drowning, burns) and status epilepticus or to the

underlying condition causing the seizures. Lastly individuals with

PRE are at higher risk of suicide than the general population

(Lhatoo and Sander, 2005).

3. Economic considerations

Few investigators have examined the economic burden of

pharmacoresistant epilepsies. A US study conducted in the 1990s

concluded that the cost of PRE in adults (assuming a conservative

estimate of 29% of all adults with epilepsy) exceeded $3,905,183,463

(or $11,745/person) in a given year (Murray et al., 1996). In the UK

Contents lists available at SciVerse ScienceDirect

journal homepage: www.elsevier.com/locate/epilep

Epileptology

2212-8220/$ - see front matter & 2013 Published by Elsevier GmbH.

http://dx.doi.org/10.1016/j.epilep.2013.01.001

n Tel.: þ1 216 444 3629; fax: þ1 216 445 4378.

E-mail address: alexopa@ccf.org

Epileptology 1 (2013) 38–42

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Jacoby et al. found that the cost correlated with severity of illness

and that patients with intractable seizures incur a cost that is

8 times greater than those with controlled epilepsy (Jacoby et al.,

1998). A more recent single-center study from Germany concluded

that the total costs of PRE per patient were on average h

261074200 over a 3-month period (Hamer et al., 2006). Indirect

expenses (including lost productivity from unemployment, under- employment or lost work time and lost work of relatives and

friends, who care for the patient with PRE) accounted for up to

75% of total costs (Platt and Sperling, 2002). Cost driving factors

include higher seizure frequency, longer disease duration, seizure- related falls and accidents, and inappropriate behavior during or

after a seizure (Hamer et al., 2006).

4. Concept of pharmaco-resistance

Up to now there has been no uniformly accepted definition of

PRE. Notably, its contextual definition in published studies varies

according to the epilepsy syndrome and number and duration of

AEDs used (Semah, 2006).

A dedicated task force of the International League against

Epilepsy (ILAE) took a significant step forward by developing a

global consensus-definition of drug-resistant epilepsy (Kwan

et al., 2010). According to this proposal PRE may be defined as

failure of adequate drug trials of two tolerated and appropriately

chosen and used AED regimens (whether as monotherapy or in

combination) to achieve seizure freedom. The definition is con- sistent with the clinical observation that if seizure freedom is not

achieved with only two trials of appropriate AED regimens, the

likelihood of therapeutic success with subsequent regimens

declines sharply (Kwan et al., 2011). In fact, many clinicians

would argue against the trial of another AED following failure of

two rational AEDs in a patient, who is otherwise eligible for

resective epilepsy surgery that has a high rate of success (Pati and

Alexopoulos, 2010). Pragmatically, the number of AED trials

depends on the chances of perceived benefit from alternative

therapies such as epilepsy surgery [or in selected patients vagus

nerve stimulation (VNS), ketogenic diet and experimental medi- cation or device therapies], and the patient’s interest in available

and/or experimental procedures (Berg, 2004).

Taking into account the episodic and fluctuating nature of PRE

the task force defined the minimum interval of sustained seizure

freedom as either a period of at least 12 months, or as a period

that is at a minimum 3 times longer than the longest pre- intervention interseizure interval (determined based on the fre- quency of seizures occurring within the preceding 12 months)—

whichever of these two periods is longer (Kwan et al., 2010). The

task force emphasized that any definition should be considered as

work in progress, and therefore clinicians are encouraged to test,

apply and critically evaluate the proposed definition.

Identification of factors that contribute to therapeutic failure is

crucial for development of novel, targeted therapeutic approaches.

Moreover the definition of PRE will remain incomplete without better

understanding of its cellular and molecular mechanisms.

5. Predictors of pharmacoresistant epilepsy

One of the strongest predictors of future course is the history/

pattern of seizures over time. Variation over time may be attrib- uted, at least in part, to inherent maturational, maladaptive and/

or age-related changes and perhaps to secondary epileptogenesis.

Importantly the prognosis for the majority of patients with newly

diagnosed epilepsy, whether good or bad, becomes apparent

within a few years of starting treatment (Mohanraj and Brodie,

2006). Reliable, valid biomarkers of pharmacoresistance are

needed for early identification and monitoring of ‘‘high risk

patients’’. Such biological markers are not available at present

time. Clinical predictors that have been associated with PRE in

selected studies are presented in Table 1. Some of these associa- tions are incompletely understood and may be disputable given

inherent methodological differences and limitations of available

studies.

6. Ruling out other etiologies of apparent medication failure

Common causes of treatment failure, such as poor compliance,

diagnostic errors or inappropriate selection of first-line AEDs,

should be addressed early on. Erratic adherence to the prescribed

regimen is a very common cause of uncontrolled seizures. It is

critical therefore to inquire about reasons for noncompliance and

maintain good rapport with patients on chronic AED therapy.

Importantly, the presence of ‘‘false pharmacoresistance’’

(Table 2) may not be easily recognizable, and this possibility

needs to be investigated in any patient presenting with difficult- to-control seizures. In fact, up to 30% of patients referred with a

diagnosis of PRE may have been misdiagnosed, and many can be

helped by optimizing their treatment (Smith et al., 1999).

Patterns of drug-resistance adapted with permission from

(Pati and Alexopoulos, 2010):

Epidemiological studies have suggested three different

patterns of drug-resistance in epilepsy:

(1) De novo drug resistance: Some patients exhibit pharmacore- sistance from the time of onset of their very first seizure or at

least before initiating AED treatment. In one landmark study

patients with newly diagnosed epilepsy, for whom the first

Table 1

Clinical predictors that have been associated with PRE.

(1) High seizure density (number of seizures per time) before treatment initiation (Mohanraj and Brodie, 2006)

(2) Long history of poor seizure control (Kwan and Brodie, 2000)

(3) Early onset of seizures (Ko and Holmes, 1999)

(4) More than one seizure type (Steffenburg et al., 1998)

(5) Multiple seizures after treatment initiation (Sillanpaa, 1993)

(6) Remote symptomatic etiology (e.g., history of head trauma, infection, etc.) (Kwan and Brodie, 2000)

(7) Certain structural abnormalities (e.g., cortical dysplasia, hippocampal sclerosis etc.) (Semah et al., 1998)

(8) Certain EEG abnormalities, such as persistent focal slowing (Berg et al., 2001) or high frequency of focal epileptiform abnormalities (Ko and Holmes, 1999)

(9) Mental retardation (Callaghan et al., 2007)

(10) Psychiatric comorbidity (Hitiris et al., 2007)

(11) Abnormal neurological examination (Sillanpaa, 1993)

(12) History of status epilepticus (Callaghan et al., 2007)

A.V. Alexopoulos / Epileptology 1 (2013) 38–42 39

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drug was ineffective had only an 11% probability of future

success, compared with a success rate of 41–55% in patients,

who had to stop taking the drug because of intolerable side

effects or idiosyncratic reactions (Kwan and Brodie, 2000). In

daily clinical practice most patients for whom the first drug

fails will manifest resistance to most and often all AEDs

(Regesta and Tanganelli, 1999). These observations suggest that

seizures in many of the newly diagnosed patients are either easy

or difficult to control right from the start.

(2) Progressive drug resistance: In some patients seizures are

initially controlled, but then become refractory over time.

This pattern may be observed, for instance, in some childhood

epilepsies or patients with mesial temporal lobe epilepsies

(Berg et al., 2003, 2006).

(3) Waxing and waning resistance: In this case seizures follow a

waxing and waning pattern alternating between a remitting

(pharmacoresponsive) and relapsing (pharmacoresistant)

course. A small minority of patients, whose epilepsy behaves

in a pharmacoresistant manner, may become seizure-free

later on with additional AED trials, i.e. intractability is not

sustained. Although the exact mechanisms are poorly under- stood, issues related to compliance, interactions with

co-administered medications, changes in drug bioavailability

and tolerance to AEDs might also come into play (Loscher and ̈

Schmidt, 2006). A recently published prospective study of

individuals, who exhibited unequivocal evidence of pharma- coresistance at time of enrollment, suggested that up to 5% of

PRE patients could enter seizure remission every subsequent

Table 2

Causes of apparent or ‘‘false’’ PRE.

(1) Diagnostic errors

a. Patients with nonepileptic events (e.g., syncope or psychogenic nonepileptic events misdiagnosed and inappropriately treated with multiple AEDs)

b. Incorrect classification of epilepsy type, leading to inappropriate drug selection (e.g., misdiagnosis of a generalized for a focal epilepsy syndrome)

c. Failure to identify an underlying causative factor (e.g., metabolic or systemic illness)

(2) Treatment errors

a. Incorrect AED selection (e.g., wrong drug for epilepsy type or drug interactions leading to decreased efficacy)

b. Inappropriate assessment of response or lack of response (e.g., drug interactions leading to increased side effects and decreased tolerability)

c. Inappropriate dosage (e.g., injudicious reliance on ‘‘therapeutic serum range’’, blind dosage adjustments without clinical correlation, or both)

(3) Nonadherence to therapy

a. Poor compliance, detrimental lifestyle, alcohol misuse, etc

b. Inadequate patient education

c. Intolerable adverse effects

d. Prohibitive cost of medications

Table 3

Factors contributing to the biological basis of PRE with illustrative examples.

(A) Disease biology (independent of the host)

Etiology of seizures (e.g., progressive epilepsy syndromes such as Lennox-Gastaut syndrome, myoclonic encephalopathies, etc.)

Severity of the disease (e.g., frequent seizures early on trigger changes of cellular/molecular properties resulting in unstable network that can no longer harness

seizures); ‘‘intrinsic severity’’ hypothesis (Rogawski and Johnson, 2008)

Abnormal network plasticity and/or changes in the epileptogenic substrate/network (e.g., hippocampal sclerosis, cortical dysplasia) (Gorter and Potschka, 2012)

Seizure-induced synaptic reorganization: development of epileptic circuits within and between brain regions (e.g., mossy fiber sprouting in the hippocampus

leading to aberrant neuronal synchronization) (Beck and Yaari, 2012)

Ion channelopathies: mutation in sodium, calcium, potassium and ligand-gated channels

Reactive autoimmunity (e.g., anti-GAD antibodies, anti-GM1 antibodies, antibodies against GluR3 subunit of glutamate receptor in Rasmussen

encephalitis—cause and effect relationships not clearly established) (Kwan and Brodie, 2002)

Impaired antiepileptic drug penetration: over expression of P-glycoprotein and MRP in epileptogenic tissue (capillary endothelial cells, astrocytes of blood brain

barrier and neurons); ‘‘drug-transporter’’ hypothesis (Potschka, 2010)

Altered drug targets/receptors: loss of use-dependent voltage-gated sodium channels from dentate granule cells in carbamazepine-resistant patients; ‘‘drug

target’’ hypothesis (Marchi et al., 2004)

Disrupted integrity of blood-brain barrier; ‘‘blood-brain barrier’’ hypothesis (Marchi et al., 2012)

(B) Drug biology

Loss of anticonvulsant efficacy due to development of tolerance with chronic administration: pharmacokinetic ‘‘metabolic’’ tolerance due to induction of AED- metabolizing enzymes or other drug–drug interactions. Pharmacodynamic ‘‘functional’’ tolerance may be due to loss of receptor sensitivity (Loscher and ̈

Schmidt, 2006)

Restricted therapeutic/safety margin, which precludes sufficiently high brain penetration of the active drug (Loscher and Schmidt, 2009 ̈ )

Lack of antiepileptogenic ‘‘disease-modifying’’ properties, i.e. inability to halt or reverse the progression of the disease with available seizure-suppressing

medications (with the exception of few AEDs such as valproate, levetiracetam and others, where potential antiepileptogenic activity has been observed in

animal models; for instance kindling and kainate models of temporal lobe epilepsy. The clinical relevance of these findings remains unclear) (Dudek et al.,

2008; Loscher and Brandt, 2010 ̈ )

(C) Patient characteristics

Presence of absence of genes encoding drug transporters, of which AEDs are known substrates: e.g., genetic polymorphisms of the P-glycoprotein encoding

gene in patients with PRE (Remy and Beck, 2006)

Polymorphisms in genes encoding drug targets may result in altered pharmacodynamics of certain AEDs: e.g., altered neuronal sodium channels expressing a

mutant auxiliary b1-subunit encoded by the SCN1B gene (which is responsible for the monogenic epilepsy syndrome GEFSþ) exhibit reduced sensitivity to

phenytoin (Lucas et al., 2005)

Environmental influences (e.g., perinatal exposure to pathogens predisposing the immature brain to acquired malformations of cortical development) (Marı ́n- Padilla, 2000)

40 A.V. Alexopoulos / Epileptology 1 (2013) 38–42

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year. Importantly the majority of those will relapse after the

first year of remission, and therefore permanent seizure free- dom is unlikely (Callaghan et al., 2011).

7. Biological basis of pharmaco-resistant epilepsy

Pharmacoresistance is not unique to epilepsy: it is now recognized

in diverse brain disorders, including depression and schizophrenia

(Loscher and Potschka, 2005 ̈ ), and in other diseases affecting the

brain, such as human immunodeficiency virus infection and many

forms of malignant neoplasias (Siddiqui et al., 2003). Hence the

mechanisms of PRE are not necessarily the same as those underlying

the epileptogenic process per se (Granata et al., 2009). Multiple drug

resistance manifests with insensitivity to a broad spectrum of drugs

that presumably act on different receptors and by different mechan- isms. Conceptually, the variable response to AEDs can be attributed to

factors related to disease biology, patient characteristics, drug proper- ties and other unknown factors (Table 3). Of course, these factors are

not mutually exclusive and may be either constitutive or acquired

during the course of the disease (Pati and Alexopoulos, 2010).

8. Conclusions and outlook

The definition of pharmacoresistant epilepsy will remain

incomplete without better understanding of the underlying cel- lular and molecular mechanisms. From a practical standpoint,

patients who have not attained sustained seizure control after

two appropriate AED trials, are unlikely to experience extended

periods of remission and fulfill the diagnosis of PRE. These

patients should be identified and referred promptly for specialist

evaluation to confirm the diagnosis of epilepsy, optimize medical

management, and explore therapeutic alternatives, including

early surgical intervention.

The multi-faceted nature of PRE dictates a multidisciplinary

approach to future research and therapeutic interventions. Early

identification of patients at risk will require the development of

molecular, neuroimaging and/or electrophysiological biomarkers.

Our paucity of treatment options for a substantial number of

these patients underscores the need to develop novel pharmaco- logical approaches and non-pharmacological interventions such

as electrical stimulation, local drug delivery, cell transplantation,

and gene-based therapies. Future targeted therapies could be

coupled to seizure-forecasting systems to create ‘‘smart’’ implan- table devices that predict, detect, and preemptively treat seizures

in a ‘‘closed-loop’’ fashion. New experimental paradigms of PRE

and advances in pharmacogenomics will allow for individualized

therapies tailored not only to the pathophysiology of the disease,

but also the neurobiology of the host.

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