Pharmacoresistance – Epidemiology, mechanisms, and impact on epilepsy treatment

doi:10.1016/j.neuropharm.2019.107790

Neuropharmacology

Volume 168, 15 May 2020, 107790

https://doi.org/10.1016/j.neuropharm.2019.107790 Get rights and content

Highlights

•
Drug resistant epilepsy remains prevalent.
•
The ILAE consensus definition provides an operational benchmark for identifying patients with drug-resistant epilepsy.
•
No hypothesis in isolation adequately explains pharmacoresistance.
•
Advances in precision medicine, disease-modification and therapeutic modalities are expected to improve outcomes.

Abstract

Understanding the natural history of and factors associated with pharmacoresistant epilepsy provides the foundation for formulating mechanistic hypotheses that can be evaluated to drive the development of novel treatments. This article reviews the modern definition of drug-resistant epilepsy, its prevalence and incidence, risk factors, hypothesized mechanisms, and the implication of recognizing pharmacoresistance in therapeutic strategies.

This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.

Section snippets

Definition

Epidemiological studies on drug-resistant epilepsy have until recently been limited by lack of a standardized definition. In 2010, a taskforce appointed by the International League Against Epilepsy (ILAE) proposed an operational definition for drug resistant epilepsy as “the failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan et al., 2010a). There is

Epidemiology

Determining with certainty the worldwide prevalence of epilepsy has been challenging due to variation in case ascertainment methodologies, lack of door-door studies and disparities in definitions of active epilepsy (Bell et al., 2014). Much of the same challenges would apply to epidemiological studies of pharmacoresistant epilepsy with the added level of complexity of ascertaining and identifying drug-resistant patients. Door-to-door studies have estimated the prevalence of active epilepsy to

Predictors of drug resistant epilepsy

Predictors of pharmacoresistance have been studied in several outcome studies. A review provided pooled odd ratios (ORs) from epidemiological studies assessing risk factors of drug resistance (Kalilani et al., 2018). Age at onset of epilepsy (<1 year vs. ≥ 1 year) showed a pooled OR of 5.49. Idiopathic epilepsy has more favorable outcomes compared to other types of epilepsies (pooled OR 0.33), while symptomatic epilepsy had a pooled OR of 3.42 (increased risk). Abnormal EEG (OR 2.08), status

Prevailing theories

The mechanisms of drug resistance to this date remain hypothetical but various models have been advanced (Tang et al., 2017a). These include the hypothesis that relates to membrane efflux transporters playing a fundamental role in resistance pathogenesis by reducing the concentrations of antiseizure drugs at the intended targets. This drug transporter hypothesis was initially proposed by Tishler and co-workers (Tishler et al., 1995) after finding evidence of increased P-glycoprotein (P-gp) in

Impact on treatment

At the suspicion of encountering pharmacoresistance, a reassessment of epilepsy diagnosis and exclusion of psychogenic non-epileptic seizures is essential since 20–40% of patients admitted to video-EEG monitoring units have non-epileptic seizures (Asadi-Pooya and Sperling, 2015). An aetiological or syndromic diagnosis should be made and suitability of previously used drug trials should be scrutinized for appropriateness and efficacy.

Various approaches are considered once a patient is confirmed

Epilepsy surgery

Ideally referral to specialised epilepsy centres should be made if seizures are not controlled after 12 months of treatment (Labiner et al., 2010). Epilepsy surgery remains highly underutilized due to misperceptions by both patients and treating physicians (Dewar and Pieters, 2015). Two randomized controlled studies have shown clear superiority of seizure outcomes in both early drug resistant and long standing epilepsy for temporal lobe resections. The first trial showed seizure freedom rates

Current and future directions

Several drugs are currently in clinical trials whose mode of action is either historical, novel or adapted from previous AEDs. Everolimus, a compound which had been in use primarily for other clinical indications (renal cancer, organ transplant immunosuppression, metastatic neuroendocrine tumors) was approved in 2018 and has shown promise as an antiepileptogenic agent in patients with tuberous sclerosis. It works as an inhibitor of an overactive and dysregulated mTOR pathway. EXIST-3 trial (

Fundings and disclosures

Mubeen Janmohamed receives support through an “Australian Government Research Training Program (RTP) Scholarship” for PhD at Monash University, Central Clinical School, Melbourne Australia. Patrick Kwan is supported by the Medical Research Future Fund Practitioner Fellowship (MRF1136427).

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Drug-resistant epilepsy in adults: outcome trajectories after failure of two medications

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Invited reviewPharmacoresistance – Epidemiology, mechanisms, and impact on epilepsy treatment

Highlights

Abstract

Section snippets

Definition

Epidemiology

Predictors of drug resistant epilepsy

Prevailing theories

Impact on treatment

Epilepsy surgery

Current and future directions

Fundings and disclosures

Epilepsy Behav.

Neuroimage

Epilepsy Behav.

Epilepsy Behav.

Epilepsy Res.

Neurobiol. Dis.

Epilepsy Res.

Neurobiol. Dis.

Seizure

Epilepsy Behav.

Seizure

Neuromodulation Technol. Neural Interface

The Lancet

Epilepsy Behav.

Epilepsy Res.

Neurobiol. Dis.

Epilepsy Res.

Brain Res. Rev.

Epilepsy Res.

Epilepsy Res.

Epilepsy Behav.

Epilepsy Res.

Epilepsy Res.

Seizure

An unknown quantity-The worldwide prevalence of epilepsy

Epilepsia

Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures

Epilepsia

Clinical and Advanced Techniques for Optimizing MRI in Refractory Focal Epilepsy. MRI-Negat. Epilepsy Eval. Surg. Manag.

Patterns of treatment response in newly diagnosed epilepsy

Neurology

Effect of dosage failed of first antiepileptic drug on subsequent outcome

Epilepsia

Selective changes in single cell GABA A receptor subunit expression and function in temporal lobe epilepsy

Nat. Med.

Likelihood of seizure remission in an adult population with refractory epilepsy

Ann. Neurol.

FDG-PET improves surgical outcome in negative MRI Taylor-type focal cortical dysplasias

Neurology

Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study

JAMA Neurol

Cannabidiol: a new hope for patients with Dravet or lennox-gastaut syndromes

Ann. Pharmacother.

Drug-resistant epilepsy in adults: outcome trajectories after failure of two medications

Epilepsia

Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis

BMC Neurol.

Quantitative in vivo microdialysis study on the influence of multidrug transporters on the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoamines as pharmacodynamic markers for the anticonvulsant activity

J. Pharmacol. Exp. Ther.

Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial

J. Am. Med. Assoc.

Rates and predictors of long-term seizure freedom after frontal lobe epilepsy surgery: a systematic review and meta-analysis

J. Neurosurg.

Rates and predictors of seizure freedom with vagus nerve stimulation for intractable epilepsy

Neurosurgery

Prevalence, classification, and severity of epilepsy and epileptic syndromes in children

Epilepsia

P‐glycoprotein imaging in temporal lobe epilepsy: in vivo PET experiments with the Pgp substrate [11C]‐verapamil

Epilepsia

Prevalence and incidence of epilepsy

Neurology

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

Epilepsia

Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of “new” antiepileptic drugs: Parmacoresistance in Focal Epilepsies

Epilepsia

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial

Neurology

Impact of drug manipulation on seizure freedom in adults with uncontrolled epilepsy: a prospective controlled study in rural China

Invited review
Pharmacoresistance – Epidemiology, mechanisms, and impact on epilepsy treatment