Consensus meeting report
A group of epilepsy specialist clinicians gathered to discuss the pharmacological management of focal epilepsy and the potential role of eslicarbazepine acetate (Zebinix). The meeting was organised and funded by Eisai and Bial.
The panel agreed that the focus would be the management of focal epilepsies, but that management of epileptic encephalopathies would be outside the scope of the discussions. Similarly, it was acknowledged that by its very nature epilepsy requires an individualised approach. So, while the aim of the meeting was to develop a consensus statement and propose a treatment algorithm best suited to the needs of various categories of patients with focal epilepsy, the heterogeneous nature of epilepsy, and therefore of its management, was fully acknowledged.
The group agreed to focus on newly diagnosed patients with focal epilepsy, and to broadly reflect current common specialist practice. Such practice does not necessarily mirror national guidelines, which were felt to be primarily intended as a broad framework to guide less specialist healthcare professionals. The aim would be to gain consensus on general guidance on the use of pharmacotherapy but at the same time to emphasise that this was not an exercise in dogma and that individual clinicians may well make different decisions based on the individual patients, their circumstances, priorities and needs. Indeed, NICE notes: ‘Treatment and care should take into account people’s needs and preferences. People with epilepsy should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals.’ NICE’s clinical guideline states: ‘The AED treatment strategy should be individualised according to the seizure type, epilepsy syndrome, co-medication and co-morbidity, the child, young person or adult’s lifestyle, and the preferences of the person and their family and/or carers as appropriate.’1
While the goal for newly diagnosed patients will usually be seizure freedom, in conversation with
patients it is clear that while seizure freedom remains the Holy Grail of epilepsy management, this is not the only measure of therapeutic success as reduced seizure severity and minimizing side effects are also important outcomes.
Patients are concerned about side effects.2,3 Sometimes, having trialled and failed several antiepileptic drugs (AEDs), avoidance of side effects is their major concern. Active attention to this aspect of treatment has been shown to improve quality of life.4 A recent study from Liverpool,5 presented at the Association of British Neurologists Annual Meeting, found that in return for a 100% improvement in treatment outcomes, the maximum acceptable risk was 30% for memory problems and 31-56% for depression. In other words, patients had a stronger preference to avoid risk, more than to improve seizure control.
When seizure freedom cannot be attained, changes in seizure type may bring more benefit than simple reduction of seizure frequency. A person who enjoys horse riding may be more concerned with retaining awareness during focal seizures than with seizure frequency as this aspect most influences the risk of falls leading to injury. By contrast, people whose livelihood depends on being able to drive will focus on seizure freedom as their main priority. Of course, neither changes in seizure type nor seizure freedom are the main outcome measures in most epilepsy drug trials. The reason why clinicians need access to the full range of licensed AEDs is to allow every patient an opportunity to receive individualised optimal treatment and to give treatment options in cases of drug-refractoriness when patients wish to continue trials of different medication. Cost is seen as the main barrier to prescribing newer and therefore more expensive drugs such as eslicarbazepine acetate, whose patent has not yet expired.
First-line and second-line monotherapy
There is a paucity of head-to-head trial evidence demonstrating significant efficacy differences between individual antiepileptic drugs and trial designs are flawed not least in their reliance on patient seizure diaries.6 Choice is influenced principally by comparative tolerability,7 largely as evidenced following complex statistical comparisons in the SANAD trials.8 A more recent study, SANAD 2,9 has yet to report results.
Other characteristics to be taken into account when choosing the first or second AED in monotherapy, are gender and child-bearing age, length of time needed for titration, available formulations and avoidance of drug-drug interactions, in particular in the elderly and in patients (of all ages) with complex medical or neuropsychiatric co-morbidities.
Carbamazepine has largely fallen out of favour among specialists because of its tolerability profile and multiple drug interactions,10 supported by the results of the SANAD study, and other small
Lamotrigine is a common first-choice option, particularly where rapid titration is not required, mainly due to evidence of good tolerability.12
Levetiracetam is a common first choice for patients with more frequent seizures who may require more rapid titration than is possible with lamotrigine. However, whilst effective,13 levetiracetam might not be suitable for patients with a history of serious mental health issues or at high risk of psychiatric disorders, including for example in the context of acute brain injury due to stroke, trauma or neurosurgery.14,15
Carbamazepine, oxcarbazepine, lacosamide or valproate are considered appropriate first choices for males and for females of non-childbearing potential at risk of developing treatment-emergent adverse mood disorders (see Figure 1). Predictors for these include personal psychiatric history, family psychiatric history and febrile convulsions.16
First add-on therapy
Generally, after two trials of monotherapy the most common next step would be adjunctive therapy with a second drug, unless there was a compelling reason to continue with monotherapy, for example in cases of potential pregnancy. The choice of drug to be used as a first add-on therapy widens considerably, reflecting the wide range of reasons for an additional drug being necessary. The further from first-line therapy a patient’s treatment travels the greater the influence exerted by specific individual characteristics, such as comorbidities and the other medications a patient may be taking.2 Key factors that might influence selection of an add-on drug in different clinical situations are shown in Table 1. In addition to those relevant for the choice of 1st and 2nd monotherapy (gender, formulation, and drug-drug interactions) key factors for the choice of 1st add-on therapy include:
• Mode of action
• Effects on weight, cognition, behaviour.
Clinicians, particularly in secondary and tertiary care, will be confronted with cases where there is little or no formal evidence to guide them. This reflects the fact that a significant proportion of patients are excluded from clinical trials, yet form the bulk of clinicians’ caseloads (see Tables 2, 3 and 4) including:17
• elderly patients
• patients with intellectual disabilities
• patients with comorbid psychiatric conditions such as depression.
Carbamazepine, eslicarbazepine acetate, lacosamide, oxcarbazepine, pregabalin, topiramate, valproate and zonisamide are the main drugs from which a choice would be made as 1st add-on therapy.
Second add-on therapy
Patients who reach the stage of the management process where further drugs are needed would be
considered treatment refractory. Clinical trial design has potentially failed to account for the inherent variability of epilepsy, particularly in those drug resistant cases.18 At this stage it is especially important to ensure that patients are realistically informed about the inherent variability of epilepsy, and not attributing chance fluctuations in seizure control or other symptoms to treatment. It would be beneficial to discuss and agree with the patient on the realistic outcomes, his/her priorities and expectations, how these outcomes are going to be measured (in terms of seizure frequency/severity and other effects), and the timeframe appropriate for that individual.
Although outside the scope of the meeting, clinicians also highlighted the importance at this stage of a review of syndromic diagnosis, including consideration of diagnoses that might influence treatment choice (eg stiripentol for Dravet syndrome, rufinamide for Lennox-Gastaut syndrome). Also, by this stage consideration should also be given to surgical options, and the possibility of pseudo-drug resistance due to poor adherence.
In addition to the drugs considered as 1st add-on therapy, at this stage, perampanel should be included in the group of drugs that would be offered as a second add-on therapy for patients with drug-resistant tonic clonic seizures, both in generalised and focal epilepsies, including nocturnal events.19,20 Other options at this stage are: brivaracetam, clobazam, clonazepam and phenytoin.
Quality of life
Quality of life is an important aspect of epilepsy care but it is difficult to measure, both from a
practical point of view and from a scientific perspective. Screening tools for quality of life and mood can be readily incorporated into routine practice and are also useful in combatting misattribution, for example where patients may report they felt better on a particular drug but their tracking tools actually tell a different story.21
Epilepsy clinics, however, are generally busy so that it can be a challenge for many to organise patient questionnaires or other instruments to measure quality of life. Quality of life is assessed
systematically often only in patients in epilepsy surgery programmes as a part neuropsychology assessment and postsurgery follow up. Available tools were developed primarily for use in these populations, and may not readily apply to other clinical practice. A number of centres have nonetheless managed to incorporate simple screening tools into routine practice, addressing risk, mood, adverse effects and quality of life, though all are dependent on user engagement with the process.2
To help improve and better inform choice of medication in epilepsy treatment in the future advisors would like to see improvements in the methods for measuring the efficacy of antiepileptic drugs. Monotherapy head-to-head studies in newly diagnosed patients would be desirable, and in this population seizure count, or more specifically seizure freedom, remains an appropriate outcome measure.
New trial designs would need to take account of the inherent variability of epilepsy. Incorporating longer periods of baseline and treatment monitoring than are currently the norm could help address that issue, and statistical tools which measure and adjust for variability in individuals have also been proposed.18 Long-term post randomised clinical trials observational studies (so called “real world data”) are a valuable source of information on how well the drug performs in clinical practice and may identify important side effects not sufficiently highlighted by RCTs, like depression and behavioural changes with levetiracetam.
For the individual patient in clinical practice based on current knowledge adding a new drug is in effect an “N of 1” trial, with the patient acting as their own control, so deserves similar attention to defining outcomes and timescales from the outset as in research trials. For example, a patient may be given, in double blind fashion, one active drug and then switched to a comparator some time later and some time after that switched back to the original drug, and so forth. In that way, by monitoring outcomes, it could be determined which drug might be most suitable for a particular patient, with data from multiple patients providing useful information about comparative efficacy and tolerability in general.
Newer techniques for measuring seizures, such as heart rate responsive vagal nerve stimulation or NeuroPace© Responsive Neurostimulation devices,31 may prove also beneficial for the assessment of new compounds. However, such technologies are still at an early stage of development in terms of seizure detection, and applicable to only a small minority of patients. Alternative non-invasive multimodal methods, such as those being explored with smart watches and other devices that can be worn on the body may prove more attractive, but again are in their infancy in terms of good reliability and reproducibility data, and mostly focus on tonic-clonic seizures only. There will, of course, be an element of bias in such methods in that it is likely that only those patients who can be expected to reliably use such equipment will be recruited into trials using them. However, if higher quality data can be collected than has been possible in the past, the number of subjects needed to produce clinically meaningful data may be fewer than with less reliable methods.
- National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management. Clinical guideline (CG137). London. NICE, 2012. (last accessed January 2018). www.nice.org.uk/guidance/cg137/chapter/Person-centred-care
- Mula M, Cock HR. More than seizures: improving the lives of people with refractory epilepsy. Eur J Neurol 2015;22(1):24-30.
- Gilliam FG, Fessler AJ, Baker G et al. Systematic screening allows reduction of adverse antiepileptic drug effect: a randomized trial. Neurology 2004;62(1):23-7.
- Taylor RS, Sander JW, Taylor RJ et al. Predictors of health-related quality of life and costs in adults with epilepsy: a systematic review. Epilepsia 2011;52(12):2168-80.
- Holmes E, Baker G, Jacoby A et al. 1151 Patients’ preferences for anti-epileptic drugs (aeds). Wednesday 3 May, Parallel Session 2: Clinical effectiveness. Association of British Neurologists (ABN) Annual Meeting 20172,3–5th May 2017 ACC, Liverpool. http://dx.doi.org/10.1136/jnnp-2017-ABN.10
- Shorvon S, Schmidt D. The right and the wrong with epilepsy and her science. Epilepsia Open 2016;1(3-4):76-85.
- Campos MS, Ayres LR, Morelo MR et al. Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. Pharmacotherapy 2016;36(12):1255-71.
- Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):1016-26.
- ISRCTN Registry. Trial comparing the effectiveness and cost effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of Standard And New Antiepileptic Drugs. www.isrctn.com/ISRCTN30294119 (last accessed January 2018).
- Novartis Pharmaceuticals UK Ltd. Summary of Product Characteristics. Tegretol Tablets 100mg, 200mg, 400mg. www.medicines.org.uk/emc/medicine/1328 (last accessed January 2018).
- Martin R, Meador K, Turrentine L et al. Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia 2001;42(6):764-71.
- Nevitt SJ, Tudur Smith C, Weston J et al. Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev 2016 Nov 14;11:CD001031.
- Pourzitaki C, Tsaousi G, Apostolidou E et al. Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta-analysis. Br J Clin Pharmacol 2016;82(1):315-25.
- UCB Pharma Limited. Summary of Product Characteristics. Keppra 250 mg film-coated tablets. www.medicines.org.uk/emc/product/2294 (last accessed January 2018).
- Verrotti A, Prezioso G, Di Sabatino F et al. The adverse event profile of levetiracetam: A meta-analysis on children and adults. Seizure 2015;31:49-55.
- Mula M, Trimble MR, Sander JW. Are psychiatric adverse events of antiepileptic drugs a unique entity? A study on topiramate and levetiracetam. Epilepsia 2007;48(12):2322-6.
- Steinhoff BJ, Staack AM, Hillenbrand BC. Randomized controlled antiepileptic drug trials miss almost all patients with ongoing seizures. Epilepsy Behav 2017;66:45-8.
- Goldenholz DM, Goldenholz SR, Moss R, et al. Does accounting for seizure frequency variability increase clinical trial power? Epilepsy Res 2017;137:145–51.
- French JA, Krauss GL, Wechsler RT et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial. Neurology 2015;85(11):950-7.
- Glauser T, Laurenza A, Yang H et al. Efficacy and tolerability of adjunct perampanel based on number of antiepileptic drugs at baseline and baseline predictors of efficacy: A phase III post-hoc analysis. Epilepsy Res 2016;119:34-40.
- Drinovac M, Wagner H, Agrawal N et al. Screening for depression in epilepsy: A model
of an enhanced screening tool. Epilepsy Behav 2015;44:67-72.
- BIAL – Portela & Cª, SA and Eisai Ltd. Summary of Product Characteristics. Zebinix 200mg and 800mg tablets. http://www.medicines.org.uk/emc/medicine/22376 (last accessed November 2017).
- Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics 2007;4:88-96.
- Nunes T, Rocha JF, Falcao A et al. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia 2013;54:108-16.
- Bonifacio MJ, Sheridan RD, Parada A et al. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia 2001;42:600-8.
- Gil-Nagel A, Elger C, Ben-Menachem E et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia 2013;54:98-107.
- Ben-Menachem E, Trinka E, Kowacs P et al. Efficacy of eslicarbazepine acetate versus controlled-release carbamazepine as monotherapy in patients with newly diagnosed partial-onset seizures. Poster presented at 68th AAN Annual Meeting, 15–21 April 2016, Vancouver, BC, Canada.
- Rogin J, Abou-Khalil B, Blum D et al. Eslicarbazepine acetate as adjunctive treatment for refractory partial-onset seizures: pooled analysis of safety data from three phase III controlled trials. Poster presented at 67th American Epilepsy Society Annual Meeting, Washington, DC, USA; 06–10 December 2013.
- Eisai Ltd. Summary of Product Characteristics. Zebinix 200mg and 800mg tablets. www.medicines.org.uk/emc/medicine/22376 (last accessed January 2018)
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- Bergey GK, Morrell MJ, Mizrahi EM et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology 2015;84(8):810-17.
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