When to start, which drugs and when to stop

When to start, which drugs and when to stop Dr. Suthida Yenjun, MD. PMK Epilepsy Annual Meeting 2016 The main factors to consider in making the decision The risk for recurrent seizures, which varies based on clinical factors The approximate benefit that can be expected from immediate drug therapy on the risk of recurrent seizure The main factors to consider in making the decision The side effect profiles of various drug options, which vary based on individual patient comorbidities and age Patient values and preferences, particularly with regard to the social consequences of a recurrent seizure (eg, implications for driving or employment) The risk of seizure recurrence following a first unprovoked seizure: a quantitative review Systematic review of 13 observational studies assessing outcome following a first unprovoked seizure Overall seizure recurrence risk : 46%, the 2- year recurrence risk : 42% Neurology1991;41:965-972 Independent risk factors Partial onset seizures Abnormal EEG Neurological abnormality : learning difficulty, neurological signs Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2005 1847 patients with single seizures and early epilepsy Compare policies of immediate vs deferred treatment and to assess the effects of these policies on short-term recurrence and longterm outcomes Neurology1991;41:965-972 Lancet 2005;365:2007-2013 1

Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2005 Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2006 Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1-2 years To assess the role of patient characteristics and treatment in the prediction of seizure recurrence At 5-years follow-up, 76% of immediate treatment group and 77% of deferred treatment group were seizure free between 3 and 5 years after randomisation, and did not differ with respect to quality of life outcomes or serious complications. A prognostic model was developed based on individual patient data from MESS to enable identification of patients at low, medium, or high risk of seizure recurrence Lancet 2005;365:2007-2013 Lancet Neurol 2006;5:317-322 Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2006 Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2006 Lancet Neurol 2006;5:317-322. Lancet Neurol 2006;5:317-322. Multicentre Study of Early Epilepsy and Single Seizures(MESS) 2006 The model shows that there is little benefit to immediate treatment in patients at low risk of seizure recurrence, but potentially worthwhile benefits are seen in those at medium and high risk An evidence-based guideline of the American Academy of Neurology and the American Epilepsy Society on the management of an unprovoked first seizure in adults 2015 an individualized approach that weighs the risk of seizure recurrence against the adverse effects of AEDs considers educated patient preferences Lancet Neurol 2006;5:317-322 Neurology 2015;84:1705 2

AAN and AES guideline 2015 AAN and AES guideline 2015 Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first two years (21 to 45 percent). Clinical variables associated with an increased risk may include a prior brain insult, an EEG with epileptiform abnormalities, a significant brain imaging abnormality, and a nocturnal seizure. Immediate AED therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first two years but may not improve quality of life. Over a longer term (>3 years), immediate AED treatment is unlikely to improve prognosis as measured by sustained seizures remission. Patients should be advised that the risk of AED adverse events may range from 7 to 31 percent and that these adverse events are likely predominantly mild and reversible. Desirable pharmacokinetic properties of an AED High oral bioavailability Low plasma protein binding Ready penetration across the BBB Long T1/2 Significant renal elimination Desirable pharmacokinetic properties of an AED Elimination by routes not involving oxidation or conjugation Linear kinetics No active metabolites Low vulnerability to drug interactions Low propensity to cause drug interactions Antiepileptic drugs Carbamazepine, sodium valproate, lamotrigine, and oxcarbazepine : first-line treatments for partial and secondary generalized seizures (evidence level A) Mechanisms of action of antiepileptic drugs. Clinically approved antiepileptic drugs such as perampanel display a spectrum of mechanisms of action, with effects on both inhibitory (left-hand side) and excitatory (right-hand side) nerve terminals. Reprinted with permission from Macmillan Publishers Ltd, Bialer M, White HS. Nat Rev Drug Discov. 2010;9:68 82.9 Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium- and chloride-depended GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Therapeutics and Clinical Risk Management. 2013:9 285 293. Sodium valproate and lamotrigine: first-line treatments for primary generalized seizures (and for any doubt about the seizure types and/or syndrome classification ( evidence level A) 3

Antiepileptic drugs Monotherapy is preferable to reduce poor compliance, drug interactions, teratogenicty, long-term side effects and costs If one first-line drug fails at the maximum tolerated dose, another first-line drug should be substituted Antiepileptic drugs Combination therapy : treatment with two first line AEDs has failed or when the first welltolerated drug substantially improves seizure control but fails to produce seizure-freedom at maximal dosage The choice of drugs in combination should be matched to the patient s seizure type(s) and should be limited to two or at most three AEDs ILAE report on monotherapy 2013 ILAE report on monotherapy 2013 BMJ 2014;348:g254 4

What is the length of the seizurefree period required to start drug withdrawal? Cochrane Database Syst Rev 2015 Feb 11;2:CD001902. The review of trials found that there is evidence to support waiting at least two years or more seizure free before discontinuing AEDs in children, especially if they had partial seizures or abnormal EEG. There is not enough evidence to show the best time to withdraw antiepileptic drugs in adults with epilepsy who are free of seizures. There is not enough evidence that demonstrates the optimal time to remove antiepileptic drugs in people (children or adults) with generalised seizures (if the electrical discharges affect the whole brain, causing global symptoms). 5

Should we consider withholding treatment in patients with an abnormal EEG at time of discontinuation? A total of 37 studies (mostly done in children) examined the role of EEG as a predictor of seizure recurrence An abnormal EEG at the time of treatment discontinuation predicted a higher risk of relapse in 21studies. The results were confirmed by multivariate analysis in six studies In a meta-analysis of 25 published studies, Berg and Shinnar(1994) found that patients with abnormal EEG carry a 1.45 higher risk of relapse and EEG epileptiform abnormalities were found frequently associated with a higher risk of relapse in a systematic review of published reports (Specchio & Beghi, 2004) A patient with abnormal EEG (with or without epileptiform activity) at the time of treatment discontinuation should be informed of an increased risk of relapse but should not be encouraged to withhold treatment if abnormal EEG is the only negative prognostic predictor. The decision to stop treatment should be considered in the light of social and personal complications of a seizure relapse [Strength of recommendation: B] Should we consider withholding treatment in patients with a documented etiology of epilepsy (including mental retardation and perinatal insults)? In a prospective study in 216 children, remote symptomatic etiology (with global developmental delay/mental retardation, motor deficit and abnormal neuroimaging) was an independent predictor of relapse(ramos-lizana et al., 2010) In a randomized trial of early versus delayed discontinuation of treatment in 161seizure-free children, cryptogenic and remote symptomatic etiology carried a twofold risk of relapse (Peters et al., 1998) Mental retardation was assessed in 15 studies and resulted in a significantly higher risk of relapse in 10(multivariate analysis, 3) A patient with a documented seizure etiology of his/her seizures should be informed of an increased risk of relapse, but should not be encouraged to withhold treatment if this is the only negative prognostic predictor A patient with an abnormal EEG pattern and a documented etiology of his/her seizures should be advised not to dis-continue the antiepileptic treatment [Strength of recommendation: B] 6

Should we consider withholding treatment in patients with partial seizures? The prognostic role of seizure type was investigated in38 studies (children 21; adults 10; mixed 7). Partial seizures carried a higher risk of recurrence in 14studies (confirmed by multivariate analysis in 7) In the randomized trial by Peters et al. (1998),partial epilepsy was the most important predictor of relapse Generalized tonic clonic seizures with or without myoclonic or absence seizures predicted an increased risk of relapse in a cohort of 59 children and adolescents with idiopathic generalized epilepsy (Pavlovic et al., 2011) The presence of partial seizures should not be considered per se a reason for withholding treatment in a patient who is seizure free and does not have other relevant predictors of relapse (abnormal EEG and documented etiology) Should age at onset be a factor influencing the decision to stop or withhold treatment? Seizure type should be assessed along with other variables when the decision to stop treatment must betaken [Strength of recommendation: B] Age at onset of seizures was assessed in 41 studies and found to affect the risk of relapse in 18. However, only in 6 studies were the results confirmed by multivariate analysis Age at onset older than 12 years was an independent predictor of seizure relapse in a cohort of 264 seizurefree children (Shinnar et al., 1994) The systematic review by Berg and Shinnar (1994) found adolescent-onset epilepsy to carry a higher risk of relapse (relative risk 1.79) compared to childhood-onset epilepsy; the corresponding value for adult-onset epilepsy was 1.34 Age at onset of seizures should be considered along with other factors when deciding to stop or withhold treatment Older age at onset of seizures should not affect the decision to stop treatment if other negative prognostic predictors are not present [Strength of recommendation: B] 7

Should we exclude treatment withdrawal in patients with some epilepsy syndromes? Epilepsy type was investigated in 23 studies (two thirds of them in children) and found to be associated with seizure outcome in 12 (multivariate analysis, 2) Specific epilepsy syndromes like juvenile myoclonic epilepsy (associated with an increased risk of relapse) and benign epilepsy with centrotemporal spikes (associated with a reduced risk of relapse) were significant outcome predictors in the study of Shinnar et al. (1994) A population-based study investigating long-term prognosis of epilepsy syndromes in 148 patients with childhood-onset epilepsy 5-year terminal remission in 59% of patients with symptomatic partial epilepsies and in 13% of patients with symptomatic/cryptogenic generalized epilepsies (Sillanpaa & Schmidt,2006) Epilepsy syndrome should be always included in the decision process at the time of treatment discontinuation. A case should be made to stop treatment in benign epilepsy with centrotemporal spikes and in most idiopathic generalized epilepsies In contrast, withholding treatment even in seizurefree patients might be an option for cryptogenic or symptomatic generalized epilepsies, juvenile myoclonic epilepsy, and symptomatic partial epilepsies Is a patient taking two or more drugs at higher risk of relapse compared to a patient on monotherapy? the patient should be informed of the possibility that on occasion seizures might not occur and treatment stop should not be denied if required [Strength of recommendation: B] 8

Twenty-three studies investigated the number of drugstaken at time of withdrawal. In 8 studies, taking two or more drugs carried a higher risk of relapse than taking monotherapy (multivariate analysis, 2) A study involving 266 children discontinuing treatment after wo or more years of seizure freedom the total number of antiepileptic drugs taken was the only risk factor for seizure recurrence (Vurucu et al.,2010) The patient should be warned that taking two or more drugs at the time of treatment discontinuation may be associated with an increased risk of relapse However, dis-continuation of AEDs might be considered, in particular when no other concurrent negative prognostic factors occurs [Strength of recommendation: C] How long should we monitor patients after treatment discontinuation? The studies investigating the risk of seizure recurrence after drug discontinuation had follow-up periods ranging from few months to >20 years The relapse rates were highest in the first 6 months after completion of treatment stop and decreased thereafter In the meta-analysis by Berg and Shinnar (1994), the cumulative probability of relapse at 1 year after initiating AED withdrawal was 25% and at 2 years was 29% [Level of evidence: 2] A patient discontinuing treatment for seizure freedom should be followed for no fewer than 2 years [Strength of recommendation: B] 9