Characteristics and predictive biomarkers of drug resistant epilepsy

Objective: A task force of the International League Against Epilepsy (ILAE) proposed that drug-resistant be defined as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure drugs (whether as monotherapy or in combination) to achieve seizure freedom. They also recommended replacing the term intractable with drug-resistant epilepsy (DRE). Several prognosticators seem relevant to predict medically intractable epilepsy. A biomarker is defined as an objectively measured characteristic of a normal or pathological biological process.Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmaco vigilance in epilepsy Methods:MEDLINE and PUBMED were searched for valid studies(from Jan2010-SEP2018) reporting on predictive biomarkers of drug resistant epilepsy. Valid articles, full-text was obtained and their quality was assessed, using the QUIPS checklist. Results:Multivariate analysis indicated four factors with independent predictive value for development of intractable epilepsy:frequency of seizure,polymorphism of seizure, polytherapy, and epileptiform EEG abnormalities. Younger age at seizure onset, symptomatic etiology, high initial seizure frequency, medical history,epileptic EEG abnormalities,and failure of previous antiepileptic-drugs (AEDs) were documented as independent prognostic factors of intractability in at least 2 of the 11 studies; none of these factors was reported in all 11 studies. In such settings, having the clinically meaningful diagnostic and prognostic criteria for early recognition of patients with increased risk of development of drug resistant epilepsy would facilitate timely implementation of non-medicamentous interventions. Currently the epilepsy field suffers from a lack of biomarkers to reliably identify at or near diagnosis patients who will develop drug-resistant epilepsy.Biomarkers have been defined as cellular, biochemical or molecular alterations that are measurable in biological media such as human tissues, cells, or fluids. In the case of epilepsy,the spectrum of biomarkers ranges from brain imaging and electrophysiologic markers through to molecular and cellular markers in peripheral fluids and tissues.Recent experimental studies reveal that neurologic inflammation can both precipitate seizures and sustain seizure activity. Furthermore, peripheral inflammation can influence epileptic discharges through alterations in ion and glutamate homeostasis.Consequently, biologic markers of inflammation represent a potential means to identify patients in whom aberrant inflammation plays a key role in epileptogenesis and/or maintenance of the epileptic state. Furthermore, immunomodulatory drugs, including steroids and intravenous immunoglobulins, have proven successful strategies in some children with epileptic encephalopathies that are otherwise intractable to conventional antiepileptic drugs (AEDs).This suggests that inflammation may be involved not only in the generation of seizures but also in the development of the drug-resistant phenotype.Surprisingly, even children with focal seizures not traditionally believed to be inflammatory in nature, responded to steroids.Experiments done in parallel with animal models suggested that the target of steroids appeared to be the blood–brain barrier. Targeting inflammation may represent a novel therapeutic strategy for the treatment of epilepsy, and circulating biomarkers able to demonstrate target engagement and treatment response are of high value in drug discovery.Individuals with focal drug-resistant epilepsy have been shown to exhibit a pro-inflammatory disequilibrium in the interleukin-1β/interleukin-1 receptor antagonist (IL-1β/IL-1Ra) ratio.6 IL-1β is a mediator of brain inflammation and is counteracted by its cognate anti-inflammatory receptor antagonist (IL-1Ra). In rodents, pharmacologic blockade of IL-1β biosynthesis significantly reduces seizures by targeting specifically the IL-1 converting enzyme responsible for production of the bioactive form.7 This pro-inflammatory cytokine profile in peripheral blood consisting of elevated IL-6 with low IL-1β)/IL-1Ra ratio, may indicate patients in whom persistent, unresolved inflammation leads to neuromodulation associated with alterations in neuronal excitability (reviewed in Ref 8). These findings are further supported by subsequent human epilepsy studies examining pro-inflammatory cytokines in peripheral blood.9,10 In addition, higher serum and CSF levels of IL-1β have been associated with an increased risk of developing epilepsy following moderate-to-severe brain injury.11 Furthermore, those with the C to T genotype rs1143634 displayed significantly lower serum IL-1β levels with higher IL-1β CSF/serum ratios, and this affected both seizure frequency and the probability of developing epilepsy. Conclusion: Prognostic value of genetic, neurobiological and immunological factors yet unclear. Knowledge of early prediction prognostic factors, in an early therapeutic stage of epilepsy, herald intractability could facilitate patient management.Beyond misconceptions about surgical risks and poor communication between epileptologists and community physicians, the lack of clear criteria for early identification of potential drug resistant cases among primary or secondary health care practitioners is problematic.In the case of epilepsy, the spectrum of biomarkers ranges from brain imaging and electrophysiologic markers through to molecular and cellular markers in peripheral fluids and tissues.Recent experimental studies reveal that neurologic inflammation can both precipitate seizures and sustain seizure activity.