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Efficacy of a third or later antiepileptic drug regimen according to epilepsy syndrome among adult patients
Accepted Manuscript Title: Efficacy of a Third or Later Antiepileptic Drug Regimen According to Epilepsy Syndrome among Adult Patients Authors: Go Ito, Akihisa Okumura, Kousuke Kanemoto PII: DOI: Reference:
S0920-1211(17)30125-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2017.07.018 EPIRES 5781
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
7-3-2017 25-6-2017 27-7-2017
Please cite this article as: Ito, Go, Okumura, Akihisa, Kanemoto, Kousuke, Efficacy of a Third or Later Antiepileptic Drug Regimen According to Epilepsy Syndrome among Adult Patients.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2017.07.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Ito et al. 1 Efficacy of a Third or Later Antiepileptic Drug Regimen According to Epilepsy Syndrome among Adult Patients Running title: A third or later AED regimen
Go Ito 1, 2, Akihisa Okumura 2, 3, Kousuke Kanemoto 1, 2
1
Department of Psychiatry, Aichi Medical University
2
Epilepsy Center, Aichi Medical University Hospital
3
Department of Pediatrics, Aichi Medical University
Corresponding author: Go Ito Department of Psychiatry, Aichi Medical University 1-1 Yazako Karimata, Nagakute, Aichi, 480-1195 Japan TEL +81-561-62-3311 FAX +81-561-63-8270 Email [email protected]
Number of text pages; 12 Number of words; 2996 Number of references; 26 Number of figures; 0 Number of tables; 6
Highlights
Patients with TLE became seizure-free with the third AED regimen or later more frequently than did those with JME or extratemporal FE in real world scenarios.
The number of the AED regimens preceding seizure freedom can be affected by the AED that was first administered to the patient.
Ito et al. 2
Appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant.
Abstract Objective: To evaluate the efficacy of third or later antiepileptic drug (AED) regimens in adult patients with epilepsy according to epilepsy syndrome. Methods: The time courses of AEDs and their efficacy were evaluated in 449 adults with temporal lobe epilepsy (TLE, n = 153), juvenile myoclonic epilepsy (JME, n = 33), or extratemporal focal epilepsy (FE, n = 263) based mainly on clinical symptoms and EEG findings. Any change in AEDs after their initiation demarcated the end of one regimen, whereas changes in dose did not. Patients were judged to be seizure-free when they had no seizures for at least 1 year with no changes in AED regimen. Results: Only 55 of 153 patients in the TLE group were free of seizures at the last visit, and the rate was significantly lower in the TLE group than the extratemporal FE group. The rate of seizure freedom with the first regimen was lower in TLE group than in the other groups, whereas the rate at the third regimen or later was significantly higher in the TLE group than the JME group. In the TLE group, a greater proportion of patients who became seizure-free with the first regimen were first treated with carbamazepine (CBZ), whereas a greater proportion of patients who became seizure-free with the fourth regimen were first treated with valproate (VPA). Significance: Our study represented real world scenarios of AED treatment according to epilepsy syndrome. Our study indicated that appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant.
Ito et al. 3
Introduction The outcome of epilepsy is dependent on the epileptic syndrome involved. The outcome is invariably poor in epileptic encephalopathies, such as infantile spasms and Lennox-Gastaut syndrome. In contrast, the outcome is mostly favorable in self-limited age-dependent epileptic syndromes, such as childhood epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, and childhood absence epilepsy 1). Temporal lobe epilepsy (TLE) is considered to be refractory to antiepileptic drug (AED) treatment 2), whereas surgical treatment has been established as effective for TLE, especially in cases with mesial temporal sclerosis 3). The opportunities for surgical treatment in extratemporal focal epilepsy (FE) are increasing with advances in the optimal use or postprocessing of neuroimaging data 4-7). It is becoming increasingly important to evaluate the efficacy of AED treatment because early referral to specialized epilepsy surgery centers has been emphasized in patients with epilepsy refractory to such treatment. Previous studies have indicated that the first and second AEDs can achieve freedom from seizures in two-thirds of appropriately selected adult patients with drug-naïve epilepsy 8, 9). These studies also emphasized that the seizure-free ratio in patients receiving a third-line AED was markedly lower and that the prospects of successful fourth-line AED treatment are not promising. Therefore, drug resistance in patients with epilepsy is now defined as a failure of adequate trials of two AED regimens 10). However, this is not always true in real world clinical settings. In Japan, the number of specialists with sufficient experience in treatment of adult patients with epilepsy is far from satisfactory. Most
Ito et al. 4 adult patient with epilepsy visit general physicians who do not always have detailed knowledge regarding epilepsy, and access to specialized adult epileptologists is not always readily available. Therefore, some patients with drug-resistant epilepsy may receive inadequate and insufficient AED treatment for a long time. The diagnosis of such patients and the selection of AEDs may sometimes be inappropriate. Therefore, it is often difficult to determine drug resistance based only on the number of AED regimens applied to a patient, and drug resistance should be judged on an individual basis. We consider the possibility that third or later AED regimens can be effective in some portion of adult patients with epilepsy. This study was performed to evaluate the efficacy of third or later AED regimens in adult epilepsy patients. We hypothesized that the efficacy of the third or later AED regimen would differ according to type of epilepsy. We compared the efficacy of third or later AED regimens among TLE, juvenile myoclonic epilepsy (JME), and extratemporal FE. We also considered the possibility that the selection of the first AED would affect the efficacy of each AED regimen. Therefore, we compared the efficacy of two AED regimens, each of which used one of the two most commonly prescribed AEDs as the first-line treatment: carbamazepine (CBZ) or valproate (VPA).
Methods We retrospectively analyzed the medical records of patients aged > 12 years who had been referred to the outpatient unit of Aichi Medical University Hospital for
Ito et al. 5 epilepsy between 2001 and 2013 and were followed up for at least 1 year. Among 1396 patients seen during the study period, 947 were excluded from the study because of at least one of the following: insufficient follow-up period; a single unprovoked seizure; poor adherence to treatment; seizures secondary to drug or alcohol abuse; presence of psychogenic non-epileptic seizures; self-limited epilepsy syndromes, such as childhood epilepsy with centrotemporal spikes; refractory epileptic encephalopathies, such as Lennox-Gastaut syndrome; or incomplete clinical information, especially with regard to pharmacotherapy prior to referral. Consequently, the records of 468 patients were included in this study. Whereas 104 patients were newly diagnosed at our institution, the other 364 had been diagnosed at other hospitals prior to referral. The main sources of information were interviews with the patient and family members, past medical records, and telephone discussions with previous physicians. We reviewed patient background, medical history, current and previous AEDs, achievement of seizure-free status, and EEG and neuroimaging findings. Epileptic syndromes were defined according to the criteria of the 2010 International League Against Epilepsy (ILAE) 11) except for types of focal epilepsy. In this study, a diagnosis of juvenile myoclonic epilepsy (JME) was made in patients with both generalized tonic-clonic seizures and myoclonic seizures associated with generalized polyspike waves on EEG and the first seizure ≥ 10 years of age. TLE was diagnosed with reference to the 1989 classification12) based on the presence of at least two of the following 13): focal features with impaired awareness 14); auras presumed to be mesial temporal in origin, such as déjà vu, ictal fear, and epigastric aura; and
Ito et al. 6 temporal spikes on EEG. Extratemporal FE was defined as FE diagnosed mainly based on seizure semiology and EEG and neuroimaging findings without features consistent with TLE. Finally, 153 patients were classified into the TLE group, 33 into the JME group, and 263 into the extratemporal FE group. Nineteen patients were not classified into any of these three groups. The regimen order was defined as follows: any change in AED after initiation of pharmacotherapy (i.e., substitutions or additions) was used to define the end of one regimen, whereas changes in the dose of a single drug were not considered reflective of changes in regimen. Examples of scenarios are listed in Table 1. Patients were judged to be seizure-free when they had no seizures for at least 1 year with no changes in AED regimen. Statistical analysis was performed using EZR ver. 1.33 (available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) 15). The Kruskal– Wallis test was used for the comparison of numerical variables among the three groups. When the Kruskal–Wallis test showed a significant difference, the Steel–Dwass post hoc test was used. The Mann–Whitney U test was used to compare numerical variables between two groups. The chi-square test was applied for comparison of categorical variables. Comparison of categorical variables among the three groups was performed as follows. First, the chi-square test was conducted to identify significant differences among the three groups. If the initial chi-square test revealed a significant difference (P < 0.05), additional chi-square tests were performed to identify significant differences in each pair of groups. To allow for multiple comparisons, Bonferroni’s correction was
Ito et al. 7 applied, and significance levels of 0.05 and 0.01 corresponded to P-values of 0.0166 and 0.0033, respectively.
Results 1) Patient backgrounds (Table 2) The proportion of male patients was higher in the extratemporal FE group than in the TLE group. The age at the start of the AED regimen was older in the TLE group, although the age at onset of epilepsy did not differ among groups. The age at the last visit was significantly older in the TLE group than in the JME and extratemporal FE groups. There were no significant differences in the duration of AED treatment prior to referral to our hospital or in the follow-up period among the groups.
2) AED regimen and outcome (Tables 3 and 4) Longitudinal changes in AED regimen and outcomes are shown on Table 3, and the outcomes of patients according to AED regimen are summarized in Table 4. The median number of AED regimens at the last visit was four in the TLE group, which was significantly larger than those in the JME (P < 0.001) and extratemporal FE (P < 0.001) groups. Only 55 (36%) of 153 patients with TLE had achieved seizure freedom at the last visit. The rate of seizure freedom at the last visit in the TLE group was significantly lower than that in the extratemporal FE group (P < 0.01), and it was lower than that in the JME group, although this difference was not statistically significant. The rate of seizure freedom with the first regimen was 6.5% in the TLE group, which was lower
Ito et al. 8 than those in the other groups (P < 0.001 vs. both the JME group and the extratemporal FE group). On the other hand, the rates of patients that became newly seizure-free at the second, third, or fourth regimen did not significantly differ across groups. Among patients who were seizure-free at the last visit, the median number of AEDs at the point of achieving seizure freedom was significantly higher in the TLE group than in the JME (P < 0.01) and extratemporal FE (P < 0.01) groups. Twenty-six (47%) of 55 patients with TLE achieved seizure freedom at the third regimen or later. The interval between the start of AED and seizure freedom did not significantly differ across groups.
3) Comparison according to first AED (Table 5) The proportion of patients who became seizure-free with each regimen was compared within each group according to the first AED: VPA or CBZ (Table 5). In the TLE group, 7 of 76 patients first treated with CBZ achieved seizure freedom, whereas no patients first treated with VPA became seizure-free. Statistical analysis reflected a marginal result (P = 0.061). In contrast, the proportion of patients who became newly seizure-free with the fourth regimen was higher in those who first received VPA than in those who first received CBZ. Among patients with TLE that achieved seizure freedom at latest the fourth regimen, the rate of becoming seizure-free at the third regimen or later was significantly higher in patients first treated with VPA than in those first treated with CBZ. In the JME group, the seizure-free ratios with each regimen did not differ according to the first AED. In the extratemporal FE group, the rate of patients who
Ito et al. 9 became seizure-free at the fourth regimen was higher in those who first received VPA than in those who first received CBZ.
4) Comparison between TLE patients who became seizure-free with the second regimen and those who became seizure-free with the third or later regimen (Table 6) Among 55 patients with TLE who were seizure-free at the last visit, 29 became seizure-free with the second regimen, and 26 did so with the third regimen or later. In patients who became seizure-free with the third regimen or later, VPA as the first AED was more frequent and the duration of treatment prior to referral was longer than in those who achieved seizure freedom with the second regimen (P < 0.01 and P < 0.001, respectively). There were no significant differences in age at onset of epilepsy, age at the start of AEDs, age at the last visit, or follow-up period between the two groups.
Discussion The present study represented real world scenarios where patients have been treated with AEDs according to the type of epilepsy. This study found that about half of the patients with TLE who became seizure-free within the study period did so with the third AED regimen or later. In the TLE group, the seizure-free proportions were 6.5% with the first regimen, 13.8% with the second regimen, 11.4% with the third regimen, and 6.5% with the fourth regimen. A favorable outcome with the third regimen or later was more evident in patients with TLE who were treated with VPA as the first AED. In the present study, the number of patients with TLE who became seizure-free
Ito et al. 10 with the second regimen was similar to the number who became seizure-free with the third or later regimen. This result is similar to those of previous studies. Del Felice et al. compared patients with newly diagnosed epilepsy with regard to whether they showed early or late remission and reported that focal seizures and number of seizures prior to treatment were independent predictors of late remission 16). Choi et al. investigated the outcome trajectories after failure of two medication regimens and showed that patients with TLE were more likely to have poorer outcome than those with FE of the occipital lobe, generalized genetic epilepsy, unclear epilepsy type, and both focal and generalized epilepsy 17). These results suggest that the third or fourth AED regimen may be useful in some patients with TLE, although the proportion of patients who would become seizure-free may not be high. It is clear that a large percentage of patients with TLE require surgical treatment and benefit from surgery. However, it is also certain that there are patients with mild phenotypes of TLE who achieve freedom from seizures with appropriate AEDs 3, 18, 19). Trials of a third or fourth AED regimen may be an option in patients with TLE after careful evaluation of appropriateness and completeness of previous therapy and consideration regarding their actual situation, including the severity of seizures, disturbance in activities of daily living, availability of surgical treatment, and intention to undergo surgery. It is interesting that some patients with extratemporal FE also achieved seizure freedom with the third regimen or later, although the percentage was not high. In the extratemporal FE group, the seizure-free proportion was 23.2% with the first regimen, 17.4% with the second regimen, 14.8% with the third regimen, and 10.6% with the
Ito et al. 11 fourth regimen. The post-surgery outcome of patients with extratemporal FE was poorer than that of patients with TLE 4-6). The identification of seizure onset zone is essential but challenging in patients with MRI-negative intractable FE 20, 21). Surgical treatment will be available less frequently in patients with extratemporal FE. Thus, trials of the third or fourth AED regimen will often be unavoidable in some patients with extratemporal FE. The results of the present study will support physicians who seek effective third or later AED regimens as they also consider surgical treatment. CBZ and VPA were the most commonly used AEDs in all groups in the present study. We believe that CBZ will be more effective for FE, including TLE, than VPA, and that VPA will be more suitable for generalized epilepsy, including JME, than CBZ. Therefore, we compared the efficacy of each regimen according to the first AED. The fourth AED regimen was more effective in patients first treated with VPA than in those first treated with CBA in the TLE and extratemporal FE groups. Additionally, the proportion of patients with TLE who achieved freedom from seizures with the third regimen or later was higher in patients first treated with VPA than in those first treated with CBA. These observations indicated that the appropriateness of the AED selected will affect the number of AED regimens until seizure freedom. In our patients, the choice of AED was presumed to be based on an insufficient differential diagnosis of seizure types, because most AEDs were started by primary care physicians who do not specialize in epilepsy. This explains why the rates at which CBZ and of VPA were used as the first AED did not markedly differ in the TLE group and why the first AED regimen was less effective than the second and third regimens in the TLE group.
Ito et al. 12 Our study indicated that appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant. Drug-resistant epilepsy is currently defined as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules to achieve sustained seizure freedom 10). Prompt referral to specialist centers for evaluation is recommended based on this generally accepted definition. The problem remains how to define the appropriateness of AED treatment. There are several guidelines regarding epilepsy and its treatment. However, the descriptions may not be the same in all of these guidelines. VPA is offered as an option of first-line treatment to children, young people and adults with newly diagnosed focal seizures when CBZ and lamotrigine are unsuitable or not tolerated in the National Institute for Health and Care Excellence (NICE) guidelines 22). VPA is also offered as an option of adjunctive treatment to children, young people and adults with focal seizures in the NICE guidelines 22). According to the ILAE review of evidence for AED efficacy and effectiveness as an initial monotherapy for epileptic seizures and syndromes 23), CBZ is listed in the adequate AEDs for adults with partial onset seizures and VPA is listed in the probably effective AEDs for the same category. The inconsistency among guidelines represents the difficulty of judging the adequacy of AED regimens. VPA will not be the most suitable AED for the patients with TLE as shown in our study, whereas it is difficult to judge VPA as totally inappropriate. Before judging drug resistance, one should evaluate the adequacy of AED regimens carefully rather than apply the proposed definition automatically. There were several limitations to our study. Due to the retrospective design of this
Ito et al. 13 study, the majority of patients had been treated for several years by non-specialists before referral to our hospital. It is possible that the AED regimens applied before referral were inappropriate for a considerable portion of patients. A large majority of eligible patients were excluded from our study for several reasons including insufficient follow-up period and/or clinical data. This could have biased the results of our study. Prospective studies are necessary in order to evaluate the efficacy of AED regimens more accurately. The low efficacy of the first AED regimen in the TLE group may have been related to this issue. The results related to tendency toward late remission in the TLE group may have differed if the subjects in the study were limited to patients at our hospital with newly diagnosed epilepsy. The reasons for changes in AED regimen were not investigated in this study. Bonnett et al. studied treatment outcome after the failure of the first AED and showed that treatment failure because of inadequate seizure control was associated with the highest risk of a second treatment failure 24). The efficacy of later regimens may differ according to the reason for change in AED regimen. Adherence to treatment was not assessed in our study. Therefore, treatment failure due to insufficient adherence could not be excluded and may have affected the results of this study. In our study, the differentiation between TLE and extratemporal FE was made mainly based on seizure semiology, and EEG and neuroimaging findings. More sophisticated evaluation such as ictal VTR-EEG will be necessary in order to differentiate TLE from extratemporal FE more correctly. Information concerning neuropsychological findings, or the presence or absence of structural abnormalities was not investigated in this study. The efficacy of AED can be different according to these
Ito et al. 14 factors. Because of retrospective review of the data, efficacy of new AEDs such as levetiracetam, lacosamide, and perampanel was not assessed in our study. In conclusion, our study suggested that a third or later AED regimen may be worth trying in patients with TLE. Patients with mesial temporal sclerosis or a well-circumscribed tumor will be preferentially referred to a surgical center following failure of the second regimen 25, 26). In contrast, it may be permissible to attempt a third or later AED regimen in patients with MRI-negative TLE 4) before referring them to a surgical center, especially when the adequacy of prior AED regimens is uncertain. It is important to cautiously consider both risks and benefits before giving up pharmacotherapy, because late remission by AEDs may as beneficial for patients as successful surgical therapy. Further studies must be performed to understand the role of AED treatment in uncontrolled epilepsy. Disclosure of Conflicts of Interest None of the authors has any conflict of interest to disclose.
Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (26293252 and 26461551), and a grant from the Ministry of
Ito et al. 15 Health, Labour and Welfare (H29-Nanji-Ippan-010). References 1) Fernando-Dongas MC, Radtke RA, et al. Characteristics of valproic acid resistant juvenile myoclonic epilepsy. Seizure 2000; 9: 385-388. 2) Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998; 51: 1256-1262. 3) Kurita T, Sakurai K, Takeda Y, et al. Very long-term outcome of non-surgically treated patients with temporal lobe epilepsy with hippocampal sclerosis: A retrospective study. PLoS One 2016; 11: e0159464. 4) Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol 2014; 13: 1114-1126. 5) Simasathien T, Vadera S, Najm I, et al. Improved outcomes with earlier surgery for intractable frontal lobe epilepsy. Ann Neurol 2013; 73: 646-654. 6) Noe K, Sulc V, Wong-Kisiel L, et al. Long-term outcomes after nonlesional extratemporal lobe epilepsy surgery. JAMA Neurol 2013; 70: 1003-1008. 7) Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005; 128: 1188-1898. 8) Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008; 70: 54-65 9) Gelisse P, Genton P, Thomas P. Clinical factors of drug resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 2001; 70: 240-243.
Ito et al. 16 10) Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51: 1069-1077. 11) Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51: 676-685 12) Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30: 389-399. 13) Guerrini R. Epilepsy in children. Lancet 2006; 367: 499-524. 14) Fisher RS, Cross JH, French JA, et al. Operational Classification of Seizure Types by the International League Against Epilepsy. http://www.ilae.org/Visitors/Centre/documents/ClassificationSeizureILAE-2016.pdf accessed on Jan. 29, 2017. 15). Kanda R. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013; 48: 452-458. 16) Del Felice A, Beghi E, Boero G, et al. Early versus late remission in a cohort of patients with newly diagnosed epilepsy. Epilepsia 2010; 51: 37-42 17) Choi H, Hayat MJ, Zhang R, et al. Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications. Epilepsia 2016; 57: 1152-1160.
Ito et al. 17 18) Hernández-Ronquillo L, Buckley S, et al. How many adults with temporal epilepsy have a mild course and do not require epilepsy surgery? Epileptic Disord 2016; 18: 137-147. 19) AlQassmi A, Burneo JG, McLachlan RS, et al. Benign mesial temporal lobe epilepsy: A clinical cohort and literature review. Epilepsy Behav 2016; 65: 60-64. 20) So EL, Lee RW. Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol 2014; 27: 206-212. 21) Wang ZI, Alexopoulos AV, Jones SE, et al. Linking MRI postprocessing with magnetic source imaging in MRI-negative epilepsy. Ann Neurol 2014; 75: 759-770. 22) Epilepsies: diagnosis and management. https://www.nice.org.uk/guidance/cg137 accessed on Jan. 29, 2017. 23) Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54: 551-563. 24) Bonnett LJ, Tudur Smith C, Donegan S, et al. Treatment outcome after failure of a first antiepileptic drug. Neurology 2014; 83: 552-560. 25) Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA 2015; 31: 285-293. 26) Jayalakshmi S, Vooturi S, Vadapalli R, et al. Outcome of surgery for temporal lobe epilepsy in adults - A cohort study. Int J Surg 2016; 36: 443-447.
Ito et al. 18 Table 1. Examples of the number of regimen according to the scenarios
Scenario 1 The patient with JME was first treated with CBZ. Seizures of this patient persisted and VPA was added 3 months later. Thereafter, no seizures were observed. CBZ was discontinued 2 years later. 1st regimen: CBZ, 2nd regimen: CBA+VPA, 3rd and 4th regimen: not assessed
Scenario 2 The patient with TLE was first treated with VPA. PHT was added 5 months later. Seizures of this patient persisted and CLB was added 3 months later. CBZ was switched from VPA. Thereafter, no seizures were observed. 1st regimen: VPA, 2nd regimen: VPA+PHT, 3rd regimen: VPA+PHT+CLB, 4th regimen: CBZ+PHT+CLB
Scenario 3 The patient with extratemporal FE was first treated with PHT. ZNS was added 5 months later. Seizures of this patient persisted and CBZ was switched from ZNS due to psychiatric side effect. Thereafter, no seizures were observed. 1st regimen: PHT, 2nd regimen: PHT+ZNS, 3rd regimen: PHT+CBZ, 4th regimen: not assessed
JME: juvenile myoclonic epilepsy, CBZ: carbamazepine, VPA: valproate, TLE: temporal lobe epilepsy, PHT: phenytoin, CLB: clobazam, FE: focal epilepsy, ZNS: zonisamide
Ito et al. 19 Table 2. Background of the patients TLE
JME
Extratemporal FE
Number of patients
153
33
263
Sex (M:F)
75:78
14:19
167:96
P = 0.003 *2
Age at the onset of epilepsy
16 (0-84)
14 (10-25)
16 (0-77)
P = 0.33
Age at the start of AED (yrs)*1
20 (0-84)
15 (10-31)
17.5 (0-78)
P = 0.044 *3
Age at the last visit (yrs)*1
39 (14-86)
26 (12-48)
36 (14-86)
P < 0.001 *4
Duration of AED treatment
10 (0-66)
4 (0-33)
7 (0-56)
P = 0.19
Follow-up in our hospital (yrs)
4.9
4.4
5.1 (1.0-29.9)
P = 0.54
*1
(1.0-39.7)
(1.1-24.3)
CBZ
76
6
75
Not tested
VPA
52
23
121
PHT
7
3
35
PB
6
0
14
ZNS
2
1
8
TPM
2
0
4
LTG
4
0
1
Others
3
0
5
(yrs)*1
prior to our hospital (yrs)*1
The first AED
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, AED: anti-epileptic drug, CBZ: carbamazepine, VPA: valproate, PHT: phenytoin, PB: phenobarbital, ZNS: zonisamide, TPM: topiramate, LTG: lamotrigine *1: Data are shown as median (range) *2: Significance level < 0.05 between TLE and extratemporal FE *3: The Steel-Dwass test did not show significant differences among the three groups. *4: P < 0.01 between TLE and JME, P < 0.05 between TLE and extratemporal FE, P < 0.01 between JME and extratemporal FE
Ito et al. 20
Ito et al. 21 Table 3. Longitudinal change in AED regimen and outcome First regimen
Second regimen
Third
Fourth regimen
regimen TLE group Sz free
10
Sz persist
143
Sz free
19
Not tried
5
Sz persist
119
Sz free
12
Not tried
14
Sz persist
93
Sz free
5
Not tried
16
Sz persist
72
Sz free
1
Not tried
5
Sz persist
4
Sz free
9
Not tried
30
Sz persist
76
JME group Sz free
13
Sz persist
20
Sz free
4
Not tried
5
Sz persist
11
Sz free
0
Not tried
1
Sz persist
10
Extratemporal FE group Sz free
61
Sz persist
202
Sz free
32
Not tried
18
Sz persist
152
Sz free
20
Not tried
17
Sz persist
115
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure
Ito et al. 22
Ito et al. 23 Table 4. AED regimen and outcome Extratemporal TLE
JME
FE
Number of patients
153
33
263
Regimen numbers at the last visit
4 (1-13)
2 (1-8)
3 (1-16)
All patients
*1
P < 0.001 *2
Sz free at last visit Sz free at the first regimen Sz free at the second regimen
55/153
19/33
P = 0.004
(35.9%)
(57.6%)
135/263 (51.3%) *3
10/153
13/33
61/263 (23.2%)
(6.5%)
(39.4%)
19/138
4/15 (26.7%)
32/184 (17.4%)
P = 0.37
0/10 (0%)
20/135 (14.8%)
P = 0.34
1/5 (20%)
9/85 (10.6%)
P = 0.45
19
135
P < 0.001 *4
(13.8%) Sz free at the third regimen
12/105 (11.4%)
Sz free at the fourth regimen
5/77 (6.5%)
Patients who were Sz free at the last visit Number of patients
55
Regimen numbers at the Sz 1
freedom *
P < 0.001 2 (1-10)
Sz free at the third regimen or later 26 (47.3%)
1 (1-5)
2 (1-9)
*5
2 (10.5%)
42 (31.1%)
P = 0.009 *6
Interval between start of AED and Sz freedom (yrs) *
4 (0-34)
2 (0-33)
6 (0-53)
1
AED: antiepileptic drug, TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure *1: Data are shown as median (range) *2: P < 0.001 between TLE and JME, P < 0.001 between TLE and extratemporal FE, P < 0.05 between JME and extratemporal FE *3: Significance level < 0.01 between TLE and extratemporal FE *4: Significance level < 0.001 between TLE and JME, significance level < 0.001 between TLE and extratemporal FE
P = 0.24
Ito et al. 24 *5: P < 0.01 between TLE and JME, P < 0.01 between TLE and extratemporal FE *6: Significance level < 0.05 between TLE and JME
Ito et al. 25 Table 5. Seizure free ratio according to the first antiepileptic drugs TLE VPA
CBZ
0/53 (0%)
7/76 (9.2%)
P = 0.061
The second regimen
7/51 (13.7%)
7/66 (10.6%)
P = 0.82
The third regimen
7/40 (17.5%)
3/52 (5.8%)
P = 0.15
The fourth regimen
4/27 (14.8%)
0/42 (0%)
P = 0.041
The first regimen
Sz free at the third regimen or later / All Sz free
P = 0.023 11/18 (61.1%)
3/17 (17.6%)
JME VPA
CBZ
10/23 (43.5%)
2/6 (33.3%)
P > 0.99
The second regimen
2/8 (25%)
1/4 (25%)
P > 0.99
The third regimen
0/4 (0%)
0/3 (0%)
NA
The fourth regimen
0/2 (0%)
0/1 (0%)
NA
The first regimen
Sz free at the third regimen or later / All Sz free
NA 0/12 (0%)
0/3 (0%)
Extratemporal FE VPA The first regimen
CBZ
29/133
P = 0.23
(21.8%)
23/76 (30.3%)
The second regimen
21/96 (21.9%)
5/46 (10.9%)
P = 0.18
The third regimen
14/65 (21.5%)
3/37 (8.1%)
P = 0.14
The fourth regimen
7/39 (17.9%)
0/28 (0%)
P = 0.049
Sz free at the third regimen or later / All Sz free
P = 0.054 21/71 (29.6%)
3/31 (9.7%)
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure, VPA: valproate, CBZ: carbamazepine
Ito et al. 26 Table 6. The comparison of patients with TLE between those who became seizure free by the second regimen and those who became seizure free at the third or later regimen. Sz free by the second
Sz free at the third
regimen
regimen or later
Number of patients
29
26
Sex (M:F)
14:15
13:13
P > 0.99
Age at the onset of epilepsy
21 (5-67)
15 (3-69)
P = 0.69
16 (5-69)
P = 0.17
(yrs) *1 Age at the start of AED (yrs) 22.5 (5-67) *1 First AED VPA
6 (21%)
15 (58%)
P < 0.01
CBZ
15 (52%)
7 (27%)
P = 0.059
Age at the last visit (yrs) *1
36 (17-71)
41.5 (18-71)
P = 0.63
Duration of treatment prior
0 (0-27)
10.5 (0-31)
P < 0.001
5.5 (1.2-17.4)
4.3 (1.1-28.0)
P = 0.17
to our hospital (yrs) *1 Follow-up period (yrs) *1
TLE: temporal lobe epilepsy, AED antiepileptic drug, Sz: seizure *1: Data are shown as median (range)
S0920-1211(17)30125-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2017.07.018 EPIRES 5781
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
7-3-2017 25-6-2017 27-7-2017
Please cite this article as: Ito, Go, Okumura, Akihisa, Kanemoto, Kousuke, Efficacy of a Third or Later Antiepileptic Drug Regimen According to Epilepsy Syndrome among Adult Patients.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2017.07.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Ito et al. 1 Efficacy of a Third or Later Antiepileptic Drug Regimen According to Epilepsy Syndrome among Adult Patients Running title: A third or later AED regimen
Go Ito 1, 2, Akihisa Okumura 2, 3, Kousuke Kanemoto 1, 2
1
Department of Psychiatry, Aichi Medical University
2
Epilepsy Center, Aichi Medical University Hospital
3
Department of Pediatrics, Aichi Medical University
Corresponding author: Go Ito Department of Psychiatry, Aichi Medical University 1-1 Yazako Karimata, Nagakute, Aichi, 480-1195 Japan TEL +81-561-62-3311 FAX +81-561-63-8270 Email [email protected]
Number of text pages; 12 Number of words; 2996 Number of references; 26 Number of figures; 0 Number of tables; 6
Highlights
Patients with TLE became seizure-free with the third AED regimen or later more frequently than did those with JME or extratemporal FE in real world scenarios.
The number of the AED regimens preceding seizure freedom can be affected by the AED that was first administered to the patient.
Ito et al. 2
Appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant.
Abstract Objective: To evaluate the efficacy of third or later antiepileptic drug (AED) regimens in adult patients with epilepsy according to epilepsy syndrome. Methods: The time courses of AEDs and their efficacy were evaluated in 449 adults with temporal lobe epilepsy (TLE, n = 153), juvenile myoclonic epilepsy (JME, n = 33), or extratemporal focal epilepsy (FE, n = 263) based mainly on clinical symptoms and EEG findings. Any change in AEDs after their initiation demarcated the end of one regimen, whereas changes in dose did not. Patients were judged to be seizure-free when they had no seizures for at least 1 year with no changes in AED regimen. Results: Only 55 of 153 patients in the TLE group were free of seizures at the last visit, and the rate was significantly lower in the TLE group than the extratemporal FE group. The rate of seizure freedom with the first regimen was lower in TLE group than in the other groups, whereas the rate at the third regimen or later was significantly higher in the TLE group than the JME group. In the TLE group, a greater proportion of patients who became seizure-free with the first regimen were first treated with carbamazepine (CBZ), whereas a greater proportion of patients who became seizure-free with the fourth regimen were first treated with valproate (VPA). Significance: Our study represented real world scenarios of AED treatment according to epilepsy syndrome. Our study indicated that appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant.
Ito et al. 3
Introduction The outcome of epilepsy is dependent on the epileptic syndrome involved. The outcome is invariably poor in epileptic encephalopathies, such as infantile spasms and Lennox-Gastaut syndrome. In contrast, the outcome is mostly favorable in self-limited age-dependent epileptic syndromes, such as childhood epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, and childhood absence epilepsy 1). Temporal lobe epilepsy (TLE) is considered to be refractory to antiepileptic drug (AED) treatment 2), whereas surgical treatment has been established as effective for TLE, especially in cases with mesial temporal sclerosis 3). The opportunities for surgical treatment in extratemporal focal epilepsy (FE) are increasing with advances in the optimal use or postprocessing of neuroimaging data 4-7). It is becoming increasingly important to evaluate the efficacy of AED treatment because early referral to specialized epilepsy surgery centers has been emphasized in patients with epilepsy refractory to such treatment. Previous studies have indicated that the first and second AEDs can achieve freedom from seizures in two-thirds of appropriately selected adult patients with drug-naïve epilepsy 8, 9). These studies also emphasized that the seizure-free ratio in patients receiving a third-line AED was markedly lower and that the prospects of successful fourth-line AED treatment are not promising. Therefore, drug resistance in patients with epilepsy is now defined as a failure of adequate trials of two AED regimens 10). However, this is not always true in real world clinical settings. In Japan, the number of specialists with sufficient experience in treatment of adult patients with epilepsy is far from satisfactory. Most
Ito et al. 4 adult patient with epilepsy visit general physicians who do not always have detailed knowledge regarding epilepsy, and access to specialized adult epileptologists is not always readily available. Therefore, some patients with drug-resistant epilepsy may receive inadequate and insufficient AED treatment for a long time. The diagnosis of such patients and the selection of AEDs may sometimes be inappropriate. Therefore, it is often difficult to determine drug resistance based only on the number of AED regimens applied to a patient, and drug resistance should be judged on an individual basis. We consider the possibility that third or later AED regimens can be effective in some portion of adult patients with epilepsy. This study was performed to evaluate the efficacy of third or later AED regimens in adult epilepsy patients. We hypothesized that the efficacy of the third or later AED regimen would differ according to type of epilepsy. We compared the efficacy of third or later AED regimens among TLE, juvenile myoclonic epilepsy (JME), and extratemporal FE. We also considered the possibility that the selection of the first AED would affect the efficacy of each AED regimen. Therefore, we compared the efficacy of two AED regimens, each of which used one of the two most commonly prescribed AEDs as the first-line treatment: carbamazepine (CBZ) or valproate (VPA).
Methods We retrospectively analyzed the medical records of patients aged > 12 years who had been referred to the outpatient unit of Aichi Medical University Hospital for
Ito et al. 5 epilepsy between 2001 and 2013 and were followed up for at least 1 year. Among 1396 patients seen during the study period, 947 were excluded from the study because of at least one of the following: insufficient follow-up period; a single unprovoked seizure; poor adherence to treatment; seizures secondary to drug or alcohol abuse; presence of psychogenic non-epileptic seizures; self-limited epilepsy syndromes, such as childhood epilepsy with centrotemporal spikes; refractory epileptic encephalopathies, such as Lennox-Gastaut syndrome; or incomplete clinical information, especially with regard to pharmacotherapy prior to referral. Consequently, the records of 468 patients were included in this study. Whereas 104 patients were newly diagnosed at our institution, the other 364 had been diagnosed at other hospitals prior to referral. The main sources of information were interviews with the patient and family members, past medical records, and telephone discussions with previous physicians. We reviewed patient background, medical history, current and previous AEDs, achievement of seizure-free status, and EEG and neuroimaging findings. Epileptic syndromes were defined according to the criteria of the 2010 International League Against Epilepsy (ILAE) 11) except for types of focal epilepsy. In this study, a diagnosis of juvenile myoclonic epilepsy (JME) was made in patients with both generalized tonic-clonic seizures and myoclonic seizures associated with generalized polyspike waves on EEG and the first seizure ≥ 10 years of age. TLE was diagnosed with reference to the 1989 classification12) based on the presence of at least two of the following 13): focal features with impaired awareness 14); auras presumed to be mesial temporal in origin, such as déjà vu, ictal fear, and epigastric aura; and
Ito et al. 6 temporal spikes on EEG. Extratemporal FE was defined as FE diagnosed mainly based on seizure semiology and EEG and neuroimaging findings without features consistent with TLE. Finally, 153 patients were classified into the TLE group, 33 into the JME group, and 263 into the extratemporal FE group. Nineteen patients were not classified into any of these three groups. The regimen order was defined as follows: any change in AED after initiation of pharmacotherapy (i.e., substitutions or additions) was used to define the end of one regimen, whereas changes in the dose of a single drug were not considered reflective of changes in regimen. Examples of scenarios are listed in Table 1. Patients were judged to be seizure-free when they had no seizures for at least 1 year with no changes in AED regimen. Statistical analysis was performed using EZR ver. 1.33 (available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) 15). The Kruskal– Wallis test was used for the comparison of numerical variables among the three groups. When the Kruskal–Wallis test showed a significant difference, the Steel–Dwass post hoc test was used. The Mann–Whitney U test was used to compare numerical variables between two groups. The chi-square test was applied for comparison of categorical variables. Comparison of categorical variables among the three groups was performed as follows. First, the chi-square test was conducted to identify significant differences among the three groups. If the initial chi-square test revealed a significant difference (P < 0.05), additional chi-square tests were performed to identify significant differences in each pair of groups. To allow for multiple comparisons, Bonferroni’s correction was
Ito et al. 7 applied, and significance levels of 0.05 and 0.01 corresponded to P-values of 0.0166 and 0.0033, respectively.
Results 1) Patient backgrounds (Table 2) The proportion of male patients was higher in the extratemporal FE group than in the TLE group. The age at the start of the AED regimen was older in the TLE group, although the age at onset of epilepsy did not differ among groups. The age at the last visit was significantly older in the TLE group than in the JME and extratemporal FE groups. There were no significant differences in the duration of AED treatment prior to referral to our hospital or in the follow-up period among the groups.
2) AED regimen and outcome (Tables 3 and 4) Longitudinal changes in AED regimen and outcomes are shown on Table 3, and the outcomes of patients according to AED regimen are summarized in Table 4. The median number of AED regimens at the last visit was four in the TLE group, which was significantly larger than those in the JME (P < 0.001) and extratemporal FE (P < 0.001) groups. Only 55 (36%) of 153 patients with TLE had achieved seizure freedom at the last visit. The rate of seizure freedom at the last visit in the TLE group was significantly lower than that in the extratemporal FE group (P < 0.01), and it was lower than that in the JME group, although this difference was not statistically significant. The rate of seizure freedom with the first regimen was 6.5% in the TLE group, which was lower
Ito et al. 8 than those in the other groups (P < 0.001 vs. both the JME group and the extratemporal FE group). On the other hand, the rates of patients that became newly seizure-free at the second, third, or fourth regimen did not significantly differ across groups. Among patients who were seizure-free at the last visit, the median number of AEDs at the point of achieving seizure freedom was significantly higher in the TLE group than in the JME (P < 0.01) and extratemporal FE (P < 0.01) groups. Twenty-six (47%) of 55 patients with TLE achieved seizure freedom at the third regimen or later. The interval between the start of AED and seizure freedom did not significantly differ across groups.
3) Comparison according to first AED (Table 5) The proportion of patients who became seizure-free with each regimen was compared within each group according to the first AED: VPA or CBZ (Table 5). In the TLE group, 7 of 76 patients first treated with CBZ achieved seizure freedom, whereas no patients first treated with VPA became seizure-free. Statistical analysis reflected a marginal result (P = 0.061). In contrast, the proportion of patients who became newly seizure-free with the fourth regimen was higher in those who first received VPA than in those who first received CBZ. Among patients with TLE that achieved seizure freedom at latest the fourth regimen, the rate of becoming seizure-free at the third regimen or later was significantly higher in patients first treated with VPA than in those first treated with CBZ. In the JME group, the seizure-free ratios with each regimen did not differ according to the first AED. In the extratemporal FE group, the rate of patients who
Ito et al. 9 became seizure-free at the fourth regimen was higher in those who first received VPA than in those who first received CBZ.
4) Comparison between TLE patients who became seizure-free with the second regimen and those who became seizure-free with the third or later regimen (Table 6) Among 55 patients with TLE who were seizure-free at the last visit, 29 became seizure-free with the second regimen, and 26 did so with the third regimen or later. In patients who became seizure-free with the third regimen or later, VPA as the first AED was more frequent and the duration of treatment prior to referral was longer than in those who achieved seizure freedom with the second regimen (P < 0.01 and P < 0.001, respectively). There were no significant differences in age at onset of epilepsy, age at the start of AEDs, age at the last visit, or follow-up period between the two groups.
Discussion The present study represented real world scenarios where patients have been treated with AEDs according to the type of epilepsy. This study found that about half of the patients with TLE who became seizure-free within the study period did so with the third AED regimen or later. In the TLE group, the seizure-free proportions were 6.5% with the first regimen, 13.8% with the second regimen, 11.4% with the third regimen, and 6.5% with the fourth regimen. A favorable outcome with the third regimen or later was more evident in patients with TLE who were treated with VPA as the first AED. In the present study, the number of patients with TLE who became seizure-free
Ito et al. 10 with the second regimen was similar to the number who became seizure-free with the third or later regimen. This result is similar to those of previous studies. Del Felice et al. compared patients with newly diagnosed epilepsy with regard to whether they showed early or late remission and reported that focal seizures and number of seizures prior to treatment were independent predictors of late remission 16). Choi et al. investigated the outcome trajectories after failure of two medication regimens and showed that patients with TLE were more likely to have poorer outcome than those with FE of the occipital lobe, generalized genetic epilepsy, unclear epilepsy type, and both focal and generalized epilepsy 17). These results suggest that the third or fourth AED regimen may be useful in some patients with TLE, although the proportion of patients who would become seizure-free may not be high. It is clear that a large percentage of patients with TLE require surgical treatment and benefit from surgery. However, it is also certain that there are patients with mild phenotypes of TLE who achieve freedom from seizures with appropriate AEDs 3, 18, 19). Trials of a third or fourth AED regimen may be an option in patients with TLE after careful evaluation of appropriateness and completeness of previous therapy and consideration regarding their actual situation, including the severity of seizures, disturbance in activities of daily living, availability of surgical treatment, and intention to undergo surgery. It is interesting that some patients with extratemporal FE also achieved seizure freedom with the third regimen or later, although the percentage was not high. In the extratemporal FE group, the seizure-free proportion was 23.2% with the first regimen, 17.4% with the second regimen, 14.8% with the third regimen, and 10.6% with the
Ito et al. 11 fourth regimen. The post-surgery outcome of patients with extratemporal FE was poorer than that of patients with TLE 4-6). The identification of seizure onset zone is essential but challenging in patients with MRI-negative intractable FE 20, 21). Surgical treatment will be available less frequently in patients with extratemporal FE. Thus, trials of the third or fourth AED regimen will often be unavoidable in some patients with extratemporal FE. The results of the present study will support physicians who seek effective third or later AED regimens as they also consider surgical treatment. CBZ and VPA were the most commonly used AEDs in all groups in the present study. We believe that CBZ will be more effective for FE, including TLE, than VPA, and that VPA will be more suitable for generalized epilepsy, including JME, than CBZ. Therefore, we compared the efficacy of each regimen according to the first AED. The fourth AED regimen was more effective in patients first treated with VPA than in those first treated with CBA in the TLE and extratemporal FE groups. Additionally, the proportion of patients with TLE who achieved freedom from seizures with the third regimen or later was higher in patients first treated with VPA than in those first treated with CBA. These observations indicated that the appropriateness of the AED selected will affect the number of AED regimens until seizure freedom. In our patients, the choice of AED was presumed to be based on an insufficient differential diagnosis of seizure types, because most AEDs were started by primary care physicians who do not specialize in epilepsy. This explains why the rates at which CBZ and of VPA were used as the first AED did not markedly differ in the TLE group and why the first AED regimen was less effective than the second and third regimens in the TLE group.
Ito et al. 12 Our study indicated that appropriateness and completeness of therapy should be evaluated before considering epilepsy as truly drug resistant. Drug-resistant epilepsy is currently defined as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules to achieve sustained seizure freedom 10). Prompt referral to specialist centers for evaluation is recommended based on this generally accepted definition. The problem remains how to define the appropriateness of AED treatment. There are several guidelines regarding epilepsy and its treatment. However, the descriptions may not be the same in all of these guidelines. VPA is offered as an option of first-line treatment to children, young people and adults with newly diagnosed focal seizures when CBZ and lamotrigine are unsuitable or not tolerated in the National Institute for Health and Care Excellence (NICE) guidelines 22). VPA is also offered as an option of adjunctive treatment to children, young people and adults with focal seizures in the NICE guidelines 22). According to the ILAE review of evidence for AED efficacy and effectiveness as an initial monotherapy for epileptic seizures and syndromes 23), CBZ is listed in the adequate AEDs for adults with partial onset seizures and VPA is listed in the probably effective AEDs for the same category. The inconsistency among guidelines represents the difficulty of judging the adequacy of AED regimens. VPA will not be the most suitable AED for the patients with TLE as shown in our study, whereas it is difficult to judge VPA as totally inappropriate. Before judging drug resistance, one should evaluate the adequacy of AED regimens carefully rather than apply the proposed definition automatically. There were several limitations to our study. Due to the retrospective design of this
Ito et al. 13 study, the majority of patients had been treated for several years by non-specialists before referral to our hospital. It is possible that the AED regimens applied before referral were inappropriate for a considerable portion of patients. A large majority of eligible patients were excluded from our study for several reasons including insufficient follow-up period and/or clinical data. This could have biased the results of our study. Prospective studies are necessary in order to evaluate the efficacy of AED regimens more accurately. The low efficacy of the first AED regimen in the TLE group may have been related to this issue. The results related to tendency toward late remission in the TLE group may have differed if the subjects in the study were limited to patients at our hospital with newly diagnosed epilepsy. The reasons for changes in AED regimen were not investigated in this study. Bonnett et al. studied treatment outcome after the failure of the first AED and showed that treatment failure because of inadequate seizure control was associated with the highest risk of a second treatment failure 24). The efficacy of later regimens may differ according to the reason for change in AED regimen. Adherence to treatment was not assessed in our study. Therefore, treatment failure due to insufficient adherence could not be excluded and may have affected the results of this study. In our study, the differentiation between TLE and extratemporal FE was made mainly based on seizure semiology, and EEG and neuroimaging findings. More sophisticated evaluation such as ictal VTR-EEG will be necessary in order to differentiate TLE from extratemporal FE more correctly. Information concerning neuropsychological findings, or the presence or absence of structural abnormalities was not investigated in this study. The efficacy of AED can be different according to these
Ito et al. 14 factors. Because of retrospective review of the data, efficacy of new AEDs such as levetiracetam, lacosamide, and perampanel was not assessed in our study. In conclusion, our study suggested that a third or later AED regimen may be worth trying in patients with TLE. Patients with mesial temporal sclerosis or a well-circumscribed tumor will be preferentially referred to a surgical center following failure of the second regimen 25, 26). In contrast, it may be permissible to attempt a third or later AED regimen in patients with MRI-negative TLE 4) before referring them to a surgical center, especially when the adequacy of prior AED regimens is uncertain. It is important to cautiously consider both risks and benefits before giving up pharmacotherapy, because late remission by AEDs may as beneficial for patients as successful surgical therapy. Further studies must be performed to understand the role of AED treatment in uncontrolled epilepsy. Disclosure of Conflicts of Interest None of the authors has any conflict of interest to disclose.
Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (26293252 and 26461551), and a grant from the Ministry of
Ito et al. 15 Health, Labour and Welfare (H29-Nanji-Ippan-010). References 1) Fernando-Dongas MC, Radtke RA, et al. Characteristics of valproic acid resistant juvenile myoclonic epilepsy. Seizure 2000; 9: 385-388. 2) Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998; 51: 1256-1262. 3) Kurita T, Sakurai K, Takeda Y, et al. Very long-term outcome of non-surgically treated patients with temporal lobe epilepsy with hippocampal sclerosis: A retrospective study. PLoS One 2016; 11: e0159464. 4) Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol 2014; 13: 1114-1126. 5) Simasathien T, Vadera S, Najm I, et al. Improved outcomes with earlier surgery for intractable frontal lobe epilepsy. Ann Neurol 2013; 73: 646-654. 6) Noe K, Sulc V, Wong-Kisiel L, et al. Long-term outcomes after nonlesional extratemporal lobe epilepsy surgery. JAMA Neurol 2013; 70: 1003-1008. 7) Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005; 128: 1188-1898. 8) Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008; 70: 54-65 9) Gelisse P, Genton P, Thomas P. Clinical factors of drug resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 2001; 70: 240-243.
Ito et al. 16 10) Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51: 1069-1077. 11) Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51: 676-685 12) Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30: 389-399. 13) Guerrini R. Epilepsy in children. Lancet 2006; 367: 499-524. 14) Fisher RS, Cross JH, French JA, et al. Operational Classification of Seizure Types by the International League Against Epilepsy. http://www.ilae.org/Visitors/Centre/documents/ClassificationSeizureILAE-2016.pdf accessed on Jan. 29, 2017. 15). Kanda R. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013; 48: 452-458. 16) Del Felice A, Beghi E, Boero G, et al. Early versus late remission in a cohort of patients with newly diagnosed epilepsy. Epilepsia 2010; 51: 37-42 17) Choi H, Hayat MJ, Zhang R, et al. Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications. Epilepsia 2016; 57: 1152-1160.
Ito et al. 17 18) Hernández-Ronquillo L, Buckley S, et al. How many adults with temporal epilepsy have a mild course and do not require epilepsy surgery? Epileptic Disord 2016; 18: 137-147. 19) AlQassmi A, Burneo JG, McLachlan RS, et al. Benign mesial temporal lobe epilepsy: A clinical cohort and literature review. Epilepsy Behav 2016; 65: 60-64. 20) So EL, Lee RW. Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol 2014; 27: 206-212. 21) Wang ZI, Alexopoulos AV, Jones SE, et al. Linking MRI postprocessing with magnetic source imaging in MRI-negative epilepsy. Ann Neurol 2014; 75: 759-770. 22) Epilepsies: diagnosis and management. https://www.nice.org.uk/guidance/cg137 accessed on Jan. 29, 2017. 23) Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54: 551-563. 24) Bonnett LJ, Tudur Smith C, Donegan S, et al. Treatment outcome after failure of a first antiepileptic drug. Neurology 2014; 83: 552-560. 25) Jobst BC, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA 2015; 31: 285-293. 26) Jayalakshmi S, Vooturi S, Vadapalli R, et al. Outcome of surgery for temporal lobe epilepsy in adults - A cohort study. Int J Surg 2016; 36: 443-447.
Ito et al. 18 Table 1. Examples of the number of regimen according to the scenarios
Scenario 1 The patient with JME was first treated with CBZ. Seizures of this patient persisted and VPA was added 3 months later. Thereafter, no seizures were observed. CBZ was discontinued 2 years later. 1st regimen: CBZ, 2nd regimen: CBA+VPA, 3rd and 4th regimen: not assessed
Scenario 2 The patient with TLE was first treated with VPA. PHT was added 5 months later. Seizures of this patient persisted and CLB was added 3 months later. CBZ was switched from VPA. Thereafter, no seizures were observed. 1st regimen: VPA, 2nd regimen: VPA+PHT, 3rd regimen: VPA+PHT+CLB, 4th regimen: CBZ+PHT+CLB
Scenario 3 The patient with extratemporal FE was first treated with PHT. ZNS was added 5 months later. Seizures of this patient persisted and CBZ was switched from ZNS due to psychiatric side effect. Thereafter, no seizures were observed. 1st regimen: PHT, 2nd regimen: PHT+ZNS, 3rd regimen: PHT+CBZ, 4th regimen: not assessed
JME: juvenile myoclonic epilepsy, CBZ: carbamazepine, VPA: valproate, TLE: temporal lobe epilepsy, PHT: phenytoin, CLB: clobazam, FE: focal epilepsy, ZNS: zonisamide
Ito et al. 19 Table 2. Background of the patients TLE
JME
Extratemporal FE
Number of patients
153
33
263
Sex (M:F)
75:78
14:19
167:96
P = 0.003 *2
Age at the onset of epilepsy
16 (0-84)
14 (10-25)
16 (0-77)
P = 0.33
Age at the start of AED (yrs)*1
20 (0-84)
15 (10-31)
17.5 (0-78)
P = 0.044 *3
Age at the last visit (yrs)*1
39 (14-86)
26 (12-48)
36 (14-86)
P < 0.001 *4
Duration of AED treatment
10 (0-66)
4 (0-33)
7 (0-56)
P = 0.19
Follow-up in our hospital (yrs)
4.9
4.4
5.1 (1.0-29.9)
P = 0.54
*1
(1.0-39.7)
(1.1-24.3)
CBZ
76
6
75
Not tested
VPA
52
23
121
PHT
7
3
35
PB
6
0
14
ZNS
2
1
8
TPM
2
0
4
LTG
4
0
1
Others
3
0
5
(yrs)*1
prior to our hospital (yrs)*1
The first AED
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, AED: anti-epileptic drug, CBZ: carbamazepine, VPA: valproate, PHT: phenytoin, PB: phenobarbital, ZNS: zonisamide, TPM: topiramate, LTG: lamotrigine *1: Data are shown as median (range) *2: Significance level < 0.05 between TLE and extratemporal FE *3: The Steel-Dwass test did not show significant differences among the three groups. *4: P < 0.01 between TLE and JME, P < 0.05 between TLE and extratemporal FE, P < 0.01 between JME and extratemporal FE
Ito et al. 20
Ito et al. 21 Table 3. Longitudinal change in AED regimen and outcome First regimen
Second regimen
Third
Fourth regimen
regimen TLE group Sz free
10
Sz persist
143
Sz free
19
Not tried
5
Sz persist
119
Sz free
12
Not tried
14
Sz persist
93
Sz free
5
Not tried
16
Sz persist
72
Sz free
1
Not tried
5
Sz persist
4
Sz free
9
Not tried
30
Sz persist
76
JME group Sz free
13
Sz persist
20
Sz free
4
Not tried
5
Sz persist
11
Sz free
0
Not tried
1
Sz persist
10
Extratemporal FE group Sz free
61
Sz persist
202
Sz free
32
Not tried
18
Sz persist
152
Sz free
20
Not tried
17
Sz persist
115
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure
Ito et al. 22
Ito et al. 23 Table 4. AED regimen and outcome Extratemporal TLE
JME
FE
Number of patients
153
33
263
Regimen numbers at the last visit
4 (1-13)
2 (1-8)
3 (1-16)
All patients
*1
P < 0.001 *2
Sz free at last visit Sz free at the first regimen Sz free at the second regimen
55/153
19/33
P = 0.004
(35.9%)
(57.6%)
135/263 (51.3%) *3
10/153
13/33
61/263 (23.2%)
(6.5%)
(39.4%)
19/138
4/15 (26.7%)
32/184 (17.4%)
P = 0.37
0/10 (0%)
20/135 (14.8%)
P = 0.34
1/5 (20%)
9/85 (10.6%)
P = 0.45
19
135
P < 0.001 *4
(13.8%) Sz free at the third regimen
12/105 (11.4%)
Sz free at the fourth regimen
5/77 (6.5%)
Patients who were Sz free at the last visit Number of patients
55
Regimen numbers at the Sz 1
freedom *
P < 0.001 2 (1-10)
Sz free at the third regimen or later 26 (47.3%)
1 (1-5)
2 (1-9)
*5
2 (10.5%)
42 (31.1%)
P = 0.009 *6
Interval between start of AED and Sz freedom (yrs) *
4 (0-34)
2 (0-33)
6 (0-53)
1
AED: antiepileptic drug, TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure *1: Data are shown as median (range) *2: P < 0.001 between TLE and JME, P < 0.001 between TLE and extratemporal FE, P < 0.05 between JME and extratemporal FE *3: Significance level < 0.01 between TLE and extratemporal FE *4: Significance level < 0.001 between TLE and JME, significance level < 0.001 between TLE and extratemporal FE
P = 0.24
Ito et al. 24 *5: P < 0.01 between TLE and JME, P < 0.01 between TLE and extratemporal FE *6: Significance level < 0.05 between TLE and JME
Ito et al. 25 Table 5. Seizure free ratio according to the first antiepileptic drugs TLE VPA
CBZ
0/53 (0%)
7/76 (9.2%)
P = 0.061
The second regimen
7/51 (13.7%)
7/66 (10.6%)
P = 0.82
The third regimen
7/40 (17.5%)
3/52 (5.8%)
P = 0.15
The fourth regimen
4/27 (14.8%)
0/42 (0%)
P = 0.041
The first regimen
Sz free at the third regimen or later / All Sz free
P = 0.023 11/18 (61.1%)
3/17 (17.6%)
JME VPA
CBZ
10/23 (43.5%)
2/6 (33.3%)
P > 0.99
The second regimen
2/8 (25%)
1/4 (25%)
P > 0.99
The third regimen
0/4 (0%)
0/3 (0%)
NA
The fourth regimen
0/2 (0%)
0/1 (0%)
NA
The first regimen
Sz free at the third regimen or later / All Sz free
NA 0/12 (0%)
0/3 (0%)
Extratemporal FE VPA The first regimen
CBZ
29/133
P = 0.23
(21.8%)
23/76 (30.3%)
The second regimen
21/96 (21.9%)
5/46 (10.9%)
P = 0.18
The third regimen
14/65 (21.5%)
3/37 (8.1%)
P = 0.14
The fourth regimen
7/39 (17.9%)
0/28 (0%)
P = 0.049
Sz free at the third regimen or later / All Sz free
P = 0.054 21/71 (29.6%)
3/31 (9.7%)
TLE: temporal lobe epilepsy, JME: juvenile myoclonic epilepsy, FE: focal epilepsy, Sz: seizure, VPA: valproate, CBZ: carbamazepine
Ito et al. 26 Table 6. The comparison of patients with TLE between those who became seizure free by the second regimen and those who became seizure free at the third or later regimen. Sz free by the second
Sz free at the third
regimen
regimen or later
Number of patients
29
26
Sex (M:F)
14:15
13:13
P > 0.99
Age at the onset of epilepsy
21 (5-67)
15 (3-69)
P = 0.69
16 (5-69)
P = 0.17
(yrs) *1 Age at the start of AED (yrs) 22.5 (5-67) *1 First AED VPA
6 (21%)
15 (58%)
P < 0.01
CBZ
15 (52%)
7 (27%)
P = 0.059
Age at the last visit (yrs) *1
36 (17-71)
41.5 (18-71)
P = 0.63
Duration of treatment prior
0 (0-27)
10.5 (0-31)
P < 0.001
5.5 (1.2-17.4)
4.3 (1.1-28.0)
P = 0.17
to our hospital (yrs) *1 Follow-up period (yrs) *1
TLE: temporal lobe epilepsy, AED antiepileptic drug, Sz: seizure *1: Data are shown as median (range)