The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented?

Despite the many therapeutic options for epilepsy available today


Background
Epilepsy is a multidimensional disorder characterized by distinctive seizure types, each of which affects individuals differently.It is one of the most common neurological conditions, affecting approximately 50-70 million people worldwide, with 4-10 people in every 1,000 of the general population having active epilepsy or seizures requiring treatment [1,2].To date, medical treatments focus on preventing or suppressing the generation and propagation of seizures and modulating seizure severity [3][4][5].Hence, we have antiseizure medication (ASM), rather than true disease-modifying anti-epilepsy therapies.There are examples of therapies that do modify the disease trajectory, such as the prompt treatment of infantile spams with adrenocorticotropic hormone and vigabatrin and the modulation of metabolically determined epilepsies.For the majority of adults, however, there is no agent with the poten-tial to modify the biology of epilepsy [3][4][5], and seizures may return when the medication is stopped.
Pharmacological treatments comprise over 30 different drugs featuring diverse modes of action (MoA), pharmacokinetics (PK), and pharmacodynamics (PD), allowing multiple options for polytherapy and dose adjustments to personalise treatment and balance outcomes in terms of seizure control, adverse effects (AEs) and potential treatment of comorbidities [6][7][8].There is clearly no one-size-fits-all strategy for the epilepsies, and no single pharmacological treatment has come close to absolute seizure freedom at a population level [3][4][5].Although a large portion of people with epilepsy (PWE) treated with ASMs succeed in reaching a 5-year seizure-free period, approximately 30-40% of PWE manifest drug-resistant epilepsy (DRE) [4,6,8].Among patients diagnosed with DRE, only one-fifth of patients undergoing further trials of ASMs will achieve seizure freedom [9][10][11].
The overall management of epilepsy, however, remains complex; seizures represent only one of many issues typically affecting PWE [12][13][14][15][16]. Typically, particularly early in their epilepsy journey, seizure freedom will be the absolute focus.Epilepsy is a network disorder, and this may be one of the associated comorbidities [17,18]; epilepsy is often associated with psychiatric and cognitive impairment [13][14][15][16].Cardiovascular and endocrine-metabolic comorbidities are also more common among PWE compared with the general population [2,19].It can be challenging to dissect which comorbidities are associated with the aetiology of epilepsy, which are associated with the treatment of epilepsy, and which are associated with social deprivation.Importantly, epilepsy entails a three-fold higher risk of premature mortality and a 24-fold higher risk of sudden unexpected death in epilepsy (SUDEP) compared with the general population (with 1.2 cases of SUDEP per 1,000 adults with epilepsy) [20][21][22].
From a quality-of-life (QoL) perspective, epilepsy can significantly interfere with an individual's daily functioning and social interaction, in many cases triggering anxiety or exacerbating underlying depressive symptoms [20,[23][24][25][26]. Health-related quality of life (HR-QoL) is an under-researched area of patient need.This is no better reflected than in priority-setting partnerships in which clinicians and patients produce a unanimous top 10 of unanswered research priorities [27][28].
In the last decade, an increasing number of studies have highlighted the impaired QoL in PWE beyond seizure occurrence and have described the burden of the disease in terms of years lived with disability [29].We explore the factors impairing patients' QoL and what can be done to reduce this impact.Given the breadth of the epilepsy spectrum, the review focuses specifically on the setting of seizure-persistence/uncontrolled seizures and DRE in adults.

Methods for literature review
The review was designed after an expert meeting and supported by a thorough literature search (PubMed) based on the term's epilepsy, DRE, refractory epilepsy, quality of life and burden of disease in epilepsy, and epilepsy treatments.Publications chosen for the review included narrative reviews, systematic reviews, metaanalyses, original research, or economic healthcare evaluations (in English or Italian), reflecting the most recent evidence available within the last decade.

Drug-resistance in focal onset epilepsy
DRE is currently defined as the failure of adequate trials of two tolerated, appropriately chosen, and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [30].Although it is difficult to predict, it can be suspected after the failure of 1 or 2 ASMs, typically within 6-12 months into the patient's epilepsy journey [5,10,12,14,20,30].So-called 'pseudo resistance' is a common clinical problem.This occurs when factors that provoke seizures (such as stress and insomnia) are not fully recognised and remedied, or when incomplete adherence is not addressed [31].Misclassification of epilepsy (focal vs. generalised) can also lead to the appearance of DRE [32].

Determinants of uncontrolled seizures and drug resistance
DRE is more frequently associated with psychiatric and neurological comorbidities [5,12,20].The relationship is thought to be bidirectional.People with depression have a poorer response to ASMs, and depression [33] may precede the first seizure.These associations are unexplained but may involve shared pathogenic mechanisms that include endocrine disorders, neuroinflammatory processes, disturbances of neurotransmitters, and mechanisms triggered by stress [13][14][15][16]20].Psychiatric comorbidities and epilepsy are independent covariates.Focal epilepsy is more likely to be drug-resistant than idiopathic generalised epilepsy, particularly in structural epilepsies such as cortical dysplasia, mesial temporal sclerosis, or tuberous sclerosis [12].
People with DRE are more likely to have features that predict structural epilepsy (such as intellectual disability, abnormal neurological examination, and electroencephalography results), as well as neuropsychiatric disorders (e.g., depression, anxiety, bipolar disorder, suicidal thoughts, drug dependency, and sleep disorders), febrile seizures, and status epilepticus [5,13,34].They also seem to be of younger age at the onset of seizures and have a higher burden of physical disease (e.g., headache, neuropathy, muscularskeletal disorders, and traumatic brain injury).Taken together, the presence of these characteristics may aid in the early diagnosis of drug-resistant forms and suggest how a patient might respond to future treatments [34].

Burden on health-related quality of life
From a patient perspective, epilepsy causes considerable social and psychological burden across all age groups.PWE bear a constant sense of fear and anxiety and perceive their lives as marked by social sacrifices [3,35,36].This perception concerns both daily activities (such as leaving one's home or one's ability to focus on studying) as well as long-term goals and achievements (educational goals, obtaining a driving licence, pursuing a relationship, or employment opportunities).Other health-related aspects involve dealing with perceived social stigma, medication dependence, or emotional disorders and depression [35,37].Family represents a safe shelter from stigma or injury and is often the main source of social interaction [35,38].
Among the medical factors affecting QoL, seizure frequency is critical, as well as drug side effects and depression [24,35,39].If PWE are able to promptly achieve seizure control, they can restore their QoL back to baseline [39].Yet, when control is achieved after many years of persistent seizures and DRE, the return to normalcy may be hindered by a paradoxical effect in which patients are unable to adjust to a seizure-free routine and may even manifest symptoms of depression [38,39].

Current scores for assessing quality of life in epilepsy
A number of studies have explored the QoL in epilepsy and attempted to quantify the multidimensional factors that exert worse impact.HR-QoL in epilepsy can be estimated with several scales.The Quality of Life in Epilepsy Inventory (QOLIE-31/P) [40] measures seizure worry, overall QoL, emotional well-being, energy fatigue, cognitive functioning (including memory) medication effects, social functioning, and an overall score.For each domain, it also explores how much distress a person feels about problems and worries related to epilepsy.The EuroQoL 5-Dimensions Scale, 3 Levels (EQ-5D-3L) [41], which is an adaptation of the more general EQ-5D, measures five dimensions as follows: mobility, selfcare, usual activities, pain or discomfort, and anxiety or depression.Other scales used in the epilepsy setting include the Hospital Anxiety and Depression Scale (HADS) [42] and the more recently developed Quality of Life in Newly Diagnosed Epilepsy Instrument-Six Dimensions (NEWQOL-6D) [43].Recently, a new epilepsy-specific QoL measurement has been proposed for adults with DRE without comorbid cognitive or developmental disability, called the ''Quality of Life Core Outcome Set", which assesses seizure burden, seizure unpredictability, seizure types or manifestations, cognition, mental health, medication side effects, driving privileges, and family impact [44].

Evidence from the literature on health-related burden and QoL in PWE
An online epilepsy community platform was used to explore factors impacting HR-QoL in PWE [23].It collected data on sociodemographic and disease characteristics, treatments, symptoms, side effects perceived as medication-related, seizure occurrence, and standardized questionnaires (namely, QOLIE-31/P, EQ-5D-3L, and HADS).Recent occurrences of seizures and moderate or severe depression (by both the QOLIE-31/P and EQ-5D-3L) were highly predictive of poor HR-QoL.Other factors included are as follows: problems concentrating, depression, memory problems, treatment side effects, occurrence of tonic-clonic seizures, epilepsy duration one year (as measured by QOLIE-31/P), pain, depression, and comorbidities (as measured by the EQ-5D-3L9).Patients on newer ASMs were less likely to report poor HR-QoL (QOLIE-31/P) [23].
A study of adults with long-term DRE (mean age 41.7 years, mean disease duration was 18 years) reported that PWE had almost double the rates of unemployment or economic inactivity (despite having post-secondary education) and higher rates of being single, compared with the general population [22].Nearly half reported additional medical or psychiatric conditions, more than half reported current anxiety, and a quarter reported current depression symptoms at the borderline or case level, with twothirds reporting perceived stigma.Specifically, lower QOLIE-31/P scores were associated (from greatest to lowest magnitude) with depression, low self-mastery, anxiety, feelings of stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency [24].
The EPISODE study [37] investigated the burden of illness in a population with severe medically refractory epilepsy with two or more seizures a week over a three-year period by means of both generic and epilepsy-specific measures of HR-QoL.Comorbidities were common; sixty percent of participants had at least one comorbidity among cognitive impairment, developmental, learning, or behavioural disorder, or motor impairment.QUALIE-31/P scores were lowest in the social function, seizure worry, and cognition domains.Across all domains, the lowest impact was observed on emotional well-being and medication effects.The distress score, which reflects the weight of the degree of concern felt by the individual about each domain, revealed that participants were most distressed by cognitive decline and seizure worry.Comparatively, medication effects and emotional well-being were felt to be the least burdensome to participants.
In a more recent real-life observational study of patients with refractory epilepsy, the patient's perceived QoL was estimated with self-administered scales of anxiety disorders (GAD-7), the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), the Epworth Sleepiness Scale (ESS), and QOLIE-31/P [45].Sleep disturbance produced a worse QoL (especially related to energy, mood, and overall QoL), and women had lower QUALIE-31/P scores.Seizure frequency was significantly associated only with the QOLIE-31-P mood score.Depression was linked to focal epilepsy in general, whereas anxiety was more common in temporal lobe epilepsy.Additional risk factors contributing to the neurobehavioral phenotypes of epilepsy have been postulated, namely, social factors (support, neighbourhood), psychological factors (personal adversities), resilience (or lack of), medical risk, brain structure, and genetic risk [46].
Finally, a few studies have also investigated QoL in terms of relationships with family members, mostly partners or spouses [31,47,48].A supportive family helped PWE adjust to the illness [43].The patient's quality of life is significantly influenced by family support and the subjective QoL of the family members, perceived social support within the family (highest significance), emotional well-being, and lack of concern about the seizures, along with age, gender, and full employment [47].On the other hand, the QoL of the relatives was positively influenced by perceived social support within the family and network size [47].

Targeted strategies for improving QoL in DRE
The heterogeneity of the tools used to measure QoL, the inherent limitations of this method, and the differences in the patient population make true generalisations challenging.However, it is clear there is the need for a broader approach to the management of DRE, aiming at (i) alleviating the disease burden in the short term and (ii) at preventing years of unnecessary deterioration of quality of life in the long term.

Balancing benefit over impact on DRE: The choice of pharmacological treatments
The primary goal for most people is seizure freedom with minimal side effects [3].After ensuring a prompt and correct diagnosis and investing in patient education, the mainstay of current treatment is rational polytherapy [3,4,7], which entails combining ASMs with different MoAs.The choice of the adjunctive ASM is commonly driven by its added effects on reducing seizure severity and frequency, its effects on the molecule's PK and PD, the patient's age, reproductive plans, side effects, and, in some healthcare settings, access to medication and costs [3,7].Preference may also be driven by additional benefits provided by some molecules, such as alleviating symptoms of comorbidities like migraine [49], stabilising mood [50], improving quality of sleep [51], or being associated to weight loss [52].Or by being less likely to affect cognition and behaviour, which may be a decision-maker for treating a specific patient population (individuals with either cognitive impairment, disability, psychological conditions, or older age) [6,7,[53][54][55].
The last 10 years have seen the launch of several thirdgeneration ASMs: brivaracetam, cenobamate eslicarbazepine acetate, lacosamide, and perampanel.Meta-analysis network reviews have begun to identify some efficacious combinations, such as valproate + lamotrigine, and lacosamide + levetiracetam [12].The lack of recent head-to-head comparisons do not allow any conclusions on more recent drugs available.As for concomitant ASMs, cenobamate has reported the best efficacy, whereas brivaracetam and lacosamide have reported the best tolerance [56,57].

Drug-drug interactions
Misprescribing medication, not by poor choice of agent but by injudicious dosing, can lead to poor treatment outcomes.The PK and PD properties of the molecule represent a key aspect of efficacy, tolerance, and adherence to treatment [9,58].Drug-drug interactions (DDIs) between the primary and add-on drugs may affect the new drug's efficacy or enhance adverse events caused by the primary drug that might have been kept at subclinical levels or tolerated up to that moment.Titration is a decisive moment that can decide the success or failure of the new drug.The motto ''start low and go slow" is imperative for succeeding in combining ASMs with different mechanisms of action as well as interactions.
The titration strategy needs to be driven by the circumstances in which the add-on intervention is made, considering the order and magnitude in which drugs are added to or removed from a patient's regimen.Importantly, it needs to be planned in consideration of the molecule's PK, PD, and inducing or inhibiting properties [58].PK interactions (mostly changes in drug metabolism but also absorption, distribution, and elimination) likely involve changes in blood concentrations of the drugs administered or their metabolites and occur early in titration -even at lower doses of concomitant ASMs.Conversely, PD interactions (synergism or antagonism at target site) may not be associated to immediate changes in blood concentrations and are observed at the target site of the drug (i.e., the brain or peripheral organs), manifesting later in the titration schedule and/or at the final doses of the ASM [58,59].Based on the PK and PD of the drug being titrated, the prescriber should adjust the primary ASM (rather than the add-on), taking a proactive approach in reducing at an early phase in titration those drugs with known PK or PD interactions with the new add-on ASM that could enhance AEs [59].DDIs between add-on drugs may also increase or decrease the plasma concentration of the primary drugs, leading to changes in efficacy or patient exposure [59].
Accordingly, the choice of an add-on ASM, its proper introduction within an ongoing therapy, and the titration process have a pivotal influence on QoL.Conversely, many cases of epilepsy labelled as drug-resistant may actually be cases of poor response due to inadequate treatment choice or dosing regimen or poor patient compliance.
Further considerations in the choice of ASM mentioned above are those with additional advantages or those having the least side effects and impairment on domains or issues most relevant to patients (such as impact on cognitive function in relation to work performance, influence on behaviour, fertility and birth control, and others).Such factors need to be considered in order to individualise therapies for each patient.The earlier the appropriate adjunctive treatment is introduced in the treatment strategy, the sooner the patient will be able to restore a better QoL.
Table 1 provides a summary of characteristics and main DDIs of newer ASMs approved as add-on drugs for DRE since 2009 (brivaracetam, cenobamate, eslicarbazepine acetate, lacosamide, and perampanel).

Add-on treatments approved for DRE since 2009
Brivaracetam (BRV): Brivaracetam is structurally related to levetiracetam and features similar MoA, binding to SV2A but with approximately 20-fold higher affinity and greater selectivity, as well as higher brain permeability.Its half-life is approximately 7 to 8 hours.It is renally excreted after extensive metabolism, primarily by hydrolysis and, to a lesser extent, hydroxylation, mainly via CYP2C19.
BRV may be preferred over levetiracetam in virtue of its fewer and lesser behavioural side effects vs. levetiracetam, making it well tolerated [7], but it has a greater number of DDIs, and there is a paucity of safety data for use in pregnancy.
Cenobamate (CNB): CNB is currently approved by the EMA as an adjunctive treatment, and by the FDA as monotherapy.It is an alkyl-carbamate with two mechanisms of action: blocking the sodium channel, preferentially attenuating the persistent sodium current, and enhancing GABA activity through positive allosteric modulation of the GABA A receptor [60][61][62].It is extensively metabolised by glucuronidation and oxidation.Its half-life is 50 to 60 hours, justifying once-daily dosing.It has several important interactions with its concentration reduced by enzyme inducers.It is an inhibitor of CYP2C19, which reduces the clearance of phenytoin and phenobarbital, as well as the active metabolite of clobazam.However, it induces CYP3A4, which may result in effects such as reduction in efficacy of oral contraceptives and does reduce the concentration of lamotrigine [43].In general, it has shown a significant reduction in seizure frequency [60][61][62][63][64], with a greater number of patients attaining 50% reduction in seizure frequency than similar third-generation drugs.This may make it cost-effective for health care systems [65].There are a number of adverse effects, most of which are typical of sodium channel drugs and may lead to drug discontinuation [57].The large number of DDIs may be partially the cause of these early emergent side effects, as they can increase serum levels of concomitantly taken ASMs.These DDIs, however, do not seem to affect CNB's efficacy [58,59].
Eslicarbazepine actete (ESL): ESL is approved in Europe as an add-on, and as monotherapy in the United States and United Kingdom.It acts by blocking sodium channels and stabilising the inactive state of the voltage-gated sodium channel (VGSC) [7].ESL inhibits sodium currents in a voltage-dependent way by an interaction predominantly with the inactivated state of the VGSC, thus selectively reducing the activity of rapidly firing (epileptic) neurons.ESL reduces VGSC availability through enhancement of slow inactivation [66].Unlike oxcarbazepine, ESL is metabolised into inactive compounds, but more than 50% is excreted in the urine as unchanged eslicarbazepine.It is possible to swap to ESL immediately overnight from carbamazepine or oxcarbazepine [67].The half-life of ESL is 13 to 20 hours in plasma and 20 to 24 hours in cerebrospinal fluid (CSF) (hence once-daily dosing) and is not followed by a CSF spike, as with oxcarbazepine [7].Eslicarbazepine is a weak inducer of CYP3A4, potentially decreasing plasma con- Abbreviations: AEs: adverse events, AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DDI: drug-drug interaction; DRESS: drug reaction with eosinophilia and systemic symptoms; GABA: c-aminobutyric acid; hrs: hours; MoA: mechanism of action; SCB: sodium channel blocker.
Note: The magnitude and clinical relevance of the interactions will vary on a patient-basis (dose, serum concentrations, clinical status, genetic profile) [64].centrations of estrogen and other molecules metabolised by this enzyme, and a weak inhibitor of CYP2C19, potentially increasing the plasma concentration of phenytoin and other drugs metabolized by this enzyme [7].Lacosamide (LCM): Lacosamide is approved as adjunctive therapy for focal seizures (and monotherapy by the FDA).Lacosamide blocks sodium channels, enhancing slow inactivation, unlike most classic sodium channel blockers, which enhance fast sodium channel inactivation [7].Lacosamide has also been used acutely to terminate status epilepticus [68].Lacosamide may produce a dosedependent prolongation in the PR interval, which could be clinically significant in patients with known cardiac conduction problems or if it is combined with other drugs that have a similar effect.Its concomitant use with another sodium channel blocker doubles the occurrence of dizziness, whereas its efficacy and tolerability may be enhanced when used with non-SCBs [7,54].From a practical perspective, compared with other ASMs for focal onset seizures [69]; it may also be used in pediatric age and is available in parenteral formulation [7].
Perampanel (PER): Perampanel (also approved as monotherapy in the US) is a selective, noncompetitive AMPA glutamate receptor antagonist.It is extensively metabolised in the liver.With regards to rational polytherapy, PER benefits, as no other ASM works primarily on AMPA receptors.It has a long half-life of about 105 hours.From a practical perspective, its long half-life may be an advantage, with two studies reporting its use to be associated with a reduction in health care resource utilisation, including hospitalisations and outpatient visits [70].However, at a dose of 12 mg (not 8 mg), PER accelerates the metabolism of levonorgestrel, a progesterone component of the oral contraceptive pill [7].Moreover, aggression and hostility may occur, with an estimated incidence of about 20% at a dose of 12 mg/d.Behavioural changes were more common in patients with intellectual disability [7].

Non-pharmacological interventions
In addition to the many pharmacological treatments available, there are also non-pharmacological treatments which include epilepsy surgery, neurostimulation and the ketogenic diet as alternative or complementary therapies with variable effectiveness to reduce or eliminate seizures.

Neuromodulation
The use of neuromodulation (modulation of electrical activity in pathological neural circuitry) in epilepsy distinguishes five different techniques depending on the various stages: vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), transcranial stimulation, including transcranial magnetic stimulation (TMS), and transcranial electrical stimulation.Neuromodulation was found to be effective, especially for patients who are drug-resistant and not suitable for surgery, and safe as compared with medical treatment alone [71,72].The efficacy is mild to moderate, reducing seizure frequency and epileptiform discharges but seldom leads to seizure-freedom.VNS provides benefits as it is unlikely to be teratogenic and does not contribute to neurotoxic side effects such as ataxia and sedation.Recently, the long-term outcomes of a prospective trial of brain RNS reported an improving seizure frequency reduction from 58% to 75% over 9 years of follow-up, and a subset of patients achieved at least 6 months or 1 year of seizure freedom (28.1% and 18.4%, respectively) [9,[71][72][73].Encouraging results are observed for VNS and DBS [72].

Surgery
Surgical resection can be transformative for properly selected patients, especially in the cases of mesio-temporal lobe epilepsy or lesional focal epilepsy.Seizure freedom rates vary, and predication models focus on group-level rather than individualised predictions of seizure freedom.[31,74,75].Success is generally higher for identifiable temporal lobe lesions [76,77].Many patients achieve considerable reductions in seizure frequency, whereas some achieve seizure freedom in a delayed manner.Some patients might undergo seizure recurrence in the long-term [73], though late recurrence tends to follow a milder course than early recurrence, and patients are often subsequently able to newly achieve remission with medical management [73].
Today, direct referral to surgery is rare, as not all patients with refractory epilepsy fit the criteria for surgery [78].It requires extensive screening and involves high healthcare costs (return of investment after three years) [73].Accordingly, it would be worth attempting a further pharmacological option in patients being considered for surgery because the efficacy of the newer ASMs might yield satisfactory results for the patient in terms of seizure control and QoL.

Cognitive rehabilitation
This is the main path towards the patient's wellbeing, but it is not commonly available.A recent work highlighted the steps to cover with the patient starting from learning about epilepsy [78].This can help the patient unearth personal characteristics of their epilepsy and help the patient to accept what cannot be changed, or develop a strategy to overcome issues that can be dealt with.
Social interaction and competence should be included more frequently in the management strategy [79].Chiang et al. have identified a Core Outcome Set in QoL for adults with DRE (without comorbid cognitive or developmental disability), which includes three main factors related to seizures (burden, unpredictability, and types or manifestations), cognition, mental health, medication side effects, driving privileges, family impact, concerns about the future, sleep, and overall QOL [80].

Ketogenic diet
For people who have DRE or who are unsuitable for surgical intervention, ketogenic diets (KDs) represent a valid option.Characterised by high fat and low carbohydrate intake, in rare cases, such as in the GLUT1 deficiency syndrome, KD can improve both seizures and cognitive function [12].Although there is some evidence suggesting that KDs could demonstrate effectiveness in children with DRE, the evidence for the use of KDs in adults remains uncertain as studies are few and sample sizes are small [80,82].Of these, only one study has assessed the impact on KD on QoL [80,82].This study, which investigated, among others, cognitive or behavioural functioning, suggested that the KD group was more active, more productive, and less anxious [82].

Referral to specialists
In many countries, PWE are referred to a neurologist only for an initial diagnosis and are then followed by their general practitioner (GP) for long-term monitoring.Depending on the health-care setting, referral to epileptologists or specialised epilepsy centres is rare, and mostly limited to cases of drug resistance or complex comorbidities [72,73].This management, which does not take advantage of competencies, indirectly affects the patient's QoL and prevents the patient's access to the most effective strategies.Nonetheless it is reasonable to identify different roles and tasks among the clinicians within the patient's journey of care.Proper referral is fundamental and optimises the information collected and processed by each healthcare professional at each level of assistance (primary vs. secondary and tertiary).Certainly, GPs have a privileged role in the long-term relationship with the patient that can support the patient in initial screening, diagnosis, and patient compliance to ASM therapy.Yet, they do not always have the resources to manage complex cases that require specialist care.

Next steps
There is an urgent unmet clinical need for novel pharmacological and non-pharmacological methods for controlling seizures; this in turn needs major research investment.However, we are not fully utilising all of our current knowledge about epilepsy and service level investment to ensure parity of access to specialist opinion-both within and between countries-which would make a significant impact on the QoL of all PWE [83].There are also critical research gaps that prevent the enthusiastic uptake of new treatments, such as knowledge of the safety of these drugs in pregnancy.
Interventions, though, must rely on recent and accurate data in order to understand the magnitude of interventions and the options available in the short and long term.To date, the epidemiological data on the prevalence and incidence of epilepsy reported in the literature are quite heterogeneous and do not provide distinction between patients based on different aetiologies, on their frequency of seizures, or between controlled vs. refractory, adults vs. adolescents, those with focal epilepsy vs. developmental disorders, and vs. special syndromes.Moreover, the data seem to be an underestimation of true figures, with many forms (such as developmental disorders) that are not accounted for.
Despite drug resistance being broadly documented, it is presented inconsistently under different terms, such as uncontrolled seizures, persistent seizures, and refractory epilepsy [28], making it complicated to use the information for planning healthcare interventions.All such terms broadly refer to a clinical picture or treatment gap whereby the patient continues to experience seizures despite receiving pharmacological or non-pharmacological interventions.DRE, though, as pointed out by some authors, is based on the single variable of treatment failure in attaining seizure freedom alone, whereas it does not contemplate the type of seizures, the seizure frequency, side effects, nor the other epilepsyrelated complications that are relevant in describing the impact on QoL [5,9].Hence, the first step would be to gather updated figures for DRE and QoL in consideration of recent definitions, epilepsy classification, and, not least, the newer drugs available.
Further steps forward would certainly be envisioning a holistic approach to patient management within a structured multidisciplinary network (Fig. 1) [24] and the early identification of patients who need a more in-depth assessment, starting from the evidence available so far on the determinants of DRE.
In order to implement effective patient pathways of care, there is the need for a bottom-up approach by first raising awareness among general practitioners who are in the best position to screen the patient population.Ongoing education on epilepsy could help GPs gain insight on aspects beyond seizures, such as clinical burden of epilepsy and on DDIs, and on when to refer their patients to a specialist.Alongside training for GPs, updated education for neurologists would improve the stratification of different types of epilepsy and their prognosis, treatments by specific epilepsy type, and managing polytherapy rationally as updated evidence becomes available.Lastly, epilepsy specialists retain a position of influence for initiating new ASMs and managing potential challenges of titration in polytherapy.
In reference to new ASMs, there is the need for real-world clinical trials to determine their efficacy when introduced in the early stages of epilepsy therapy, firstly in patients who have features of DRE and secondly in newly diagnosed patients, to avoid unnecessary mental distress, and reduce morbidity and premature disease-related mortality [13].Moreover, given the availability of more effective ASMs, there is the need for a new measurement paradigm shifting from seizure reduction to seizure freedom.Despite As these steps fall into place, the need for joint efforts on the side of social inclusion will be imperative.We need to expand existing efforts to help patients with epilepsy continue working in their intended or trained occupations or to enable them to work in other occupational environments compatible with epilepsy through targeted counselling and retraining programmes, as suggested elsewhere [84].

Conclusions
Patients with DRE perceive a considerable burden of disease, which goes beyond the direct effects of seizure frequency and type.Their quality of life is impaired by the interference of medical and psychological comorbidities in their daily activities and anxiety in engaging in social interactions.Neurologists can work with the patient towards a better QoL by acting on several fronts: addressing side-effects and what the patient is willing to tolerate in favour of seizure reduction, taking advantage of the added benefits of newer ASMs, promptly referring patients with complex management to specialised centres as needed, or to less-known interventions such as cognitive rehabilitation.If we are serious about minimising the QoL burden that accompanies DRE, we should be ambitious about reducing seizure frequency, whilst screening for and adequately treating remediable comorbidities such as psychiatric disorders and obesity.

Ethics statements
This manuscript was prepared according to the International Society for Medical Publication Professionals' ''Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.All named authors meet the International Committee of Medical Journal Editors criteria for authorship.All authors reviewed and approved the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy of integrity of any part of the work are appropriately investigated and resolved.

Disclosures
The expert meeting was funded by Angelini Pharma S. p.a.

Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EBM has received consulting fees/and or honoraria from UCB, Angelini, GW Pharma.BS has received speaker honoraria or consultancy fees from Angelini Pharma, Desitin, Eisai, Precisis, Sanofi, and UCB-Pharma.RK has received speaker fee/honoraria from Angelini Pharma, Eisai, Finnish IBE chapter, Omamedical, GW Pharmaceuticals, Marinus, Orion, Sandoz, Takeda, UCB Pharma; consulting fees from Orion; grants from Angelini Pharma.She covers the role of Neurocenter Finland, EAN Epilepsy Scientific Panel management Group, EpiCARE ERN executive group.PK has served as a consultant, advisory board member or speaker for Abbott, Angelini, Aquestive, Arvelle Therapeutics, Aucta Pharmaceuticals, Dr. Reddy's, Eisai, Neurelis, Neurona, Paladin, SK Life Science, Sunovion, UCB Pharma, UNEEG, UniQure, is a member of the Medical Advisory Board of Stratus and of the Scientific Advisory Board of OB Pharma, is the CEO of PrevEp, Inc, and has received research support from CURE/Department of Defense and from the NIH/SBIR.TR has received unrestricted grants from Angelini and UNEEG, consulting fees from Angelini, Bial, Biocodex, Eisai, Jazz/GW Pharma, Neuraxpharm, Sanofi, Takeda, UCB Pharma, Zogenix, payment and honoraria from Angelini, Bial, Eisai, Jazz/GW Pharma, UCB Pharma, UNEEG, Zogenix.

Fig. 1 .
Fig. 1.Strategies for improving quality of life in DRE.