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Long-term control of epileptic drop attacks with the combination of valproate, lamotrigine, and a benzodiazepine: A ‘proof of concept,’ open label study
2011; Wiley; Volume: 52; Issue: 7 Linguagem: Inglês
10.1111/j.1528-1167.2011.03075.x
ISSN1528-1167
AutoresVitor Hugo Vaz Machado, André Palmini, Fernanda Almeida Bastos, Rosana Rotert,
Tópico(s)Bipolar Disorder and Treatment
ResumoEpilepsiaVolume 52, Issue 7 p. 1303-1310 FULL-LENGTH ORIGINAL RESEARCHFree Access Long-term control of epileptic drop attacks with the combination of valproate, lamotrigine, and a benzodiazepine: A 'proof of concept,' open label study Vitor Hugo Machado, Vitor Hugo Machado Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this authorAndre Palmini, Andre Palmini Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, Brazil Porto Alegre Epilepsy Surgery Program, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil Department of Internal Medicine, Faculty of Medicine, PUCRS, Porto Alegre, Brazil The Brain Institute (InsCer), PUCRS, Porto Alegre, BrazilSearch for more papers by this authorFernanda Almeida Bastos, Fernanda Almeida Bastos Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this authorRosana Rotert, Rosana Rotert Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this author Vitor Hugo Machado, Vitor Hugo Machado Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this authorAndre Palmini, Andre Palmini Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, Brazil Porto Alegre Epilepsy Surgery Program, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil Department of Internal Medicine, Faculty of Medicine, PUCRS, Porto Alegre, Brazil The Brain Institute (InsCer), PUCRS, Porto Alegre, BrazilSearch for more papers by this authorFernanda Almeida Bastos, Fernanda Almeida Bastos Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this authorRosana Rotert, Rosana Rotert Severe Epilepsies Outpatient Clinic, Neurology Service, Porto Alegre, BrazilSearch for more papers by this author First published: 19 April 2011 https://doi.org/10.1111/j.1528-1167.2011.03075.xCitations: 15 Address correspondence to Andre Palmini, MD, PhD, Serviço de Neurologia, Hospital São Lucas da PUCRS, Avenida Ipiranga 6690, 90610-000, Porto Alegre, RS, Brazil. E-mail: apalmini@uol.com.br Prof. Dr. Mario Wagner, a consultant in epidemiology and biostatistics, performed the statistical analyses. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary Purpose: Long-term medical management of epileptic drop attacks is usually unsatisfactory and more effective antiepileptic drug (AED) regimens are needed. The present study aimed at providing proof of concept that previously refractory epileptic drop attacks could be significantly and safely controlled by the specific combination of valproate, lamotrigine, and a benzodiazepine. Methods: An open label trial providing class IV evidence of efficacy, including 32 patients with cryptogenic/symptomatic, generalized or multifocal epilepsies, and refractory drop attacks. Following baseline, the combination under study was introduced and patients followed for 12 months. Frequency of drop attacks was compared at 3-month intervals with that during baseline and correlated with clinical, electroencephalography (EEG), and imaging variables. A list of putative side effects was read to patients and caregivers at each visit. Key Findings: Four patients were excluded, one due to a Stevens-Johnson syndrome (SJS). Median number of drop attacks decreased 96% between baseline and the fourth trimester of the study (from 50 to 2; p < 0,001). Intention-to-treat (ITT) analysis showed that 15 patients (47%) had complete control, 7 (21%) had a 75% and 5 (15%) had a 50–74% reduction in the frequency of falls in the fourth trimester. Twenty-two patients (68%) had side effects, but except for the three excluded because of early rash, caregivers did not consider discontinuation. Mean final dose of valproate was 35.9 mg/kg/day and that of lamotrigine 4.9 mg/kg/day. Twenty patients used clobazam, eight nitrazepam, and the other four clonazepam as the elected benzodiazepine. Outcome did not correlate with clinical, EEG, and imaging variables. Significance: This open label study suggests that the combination of valproate, lamotrigine, and a benzodiazepine can markedly reduce the frequency of epileptic drop attacks in patients with generalized or multifocal epilepsies. Careful clinical monitoring for early signs of SJS is needed. The efficacy of antiepileptic drugs (AEDs) to control epileptic drop attacks is limited. Several AED regimens have been tested (Schuele & Lüders, 2008; Vining, 2009) but alleviation is only partial for the majority of patients. Furthermore, most clinical trials provide only short-term efficacy data (Ritter et al., 1993; Motte et al., 1997; Sachdeo et al., 1999; Glauser et al., 2008; Conry et al., 2009), and studies testing specific AED regimens for longer periods are needed. Because valproate, lamotrigine, and benzodiazepines are used for treatment of generalized seizures (Sherard et al., 1980; Brodie, 1996; Donaldson et al., 1997; French et al., 2004), and accepting that the mechanisms of epileptic drop attacks involve generalized interference with motor systems (Tassinari & Ambrosetto, 1988), we hypothesized that the combination of these three AEDs could be useful to control these falls. There are no monotherapy studies with these medications for treatment of drop attacks in severe epilepsies, and the few studies in which combinations of two of these AEDs were tested have yielded unsatisfactory results (Thomé-Souza et al., 2003; Arzimanoglou et al., 2009). Therefore, we decided to evaluate the effectiveness of the combination of these three drugs for patients with generalized or multifocal epilepsies seriously disabled by drop attacks, in an open trial, "proof of concept" design. Patients and Methods From January 2007 to January 2009, we followed a consecutive series of 32 patients with cryptogenic/symptomatic generalized or multifocal epilepsies and refractory drop attacks attending the Epilepsy Outpatient Clinic of the Neurology Service, Hospital São Lucas da PUCRS, in Porto Alegre. All underwent laboratory, epileptologic, electroencephalographic, and neuroimaging evaluation. Caregivers were instructed to fill a seizure diary registering drop attacks, considered as episodes of sudden fall, either to the ground or to a chair, sofa, or bed. Patients had to have at least three drop attacks per month during the 2 months of baseline. Seven patients had Lennox-Gastaut syndrome (LGS), in that they also had tonic seizures during slow sleep with bursts of bilateral trains of fast spikes (10 Hz or more), generalized spike-slow wave complexes at 1.5–2.5 Hz, and cognitive disability (Arzimanoglou et al., 2009). No patient was using or had previously received the specific combination of valproate, lamotrigine, and a benzodiazepine (Table 1). Following baseline, patients were progressively switched to the regimen proposed by the study with adjustments as needed. The target dosage of valproate was 30–80 mg/kg/day for children and a maximum of 3,000 mg/day for adults. Starting doses were 5–10 mg/kg/day for children up to age 16 years and 250 mg for adults, with increases every 3 days. The target doses of lamotrigine were 4–12 mg/kg/day. Lamotrigine was introduced at a dose of 12.5 mg/day (0.17–0.6 mg/kg/day), with similar increments every second week. When patients were already using lamotrigine, dosages were also increased at 12.5 mg and adjusted according to efficacy. Clobazam, clonazepam, and nitrazepam were started at the following respective daily doses: 2.5, 0.5, and 2.5 mg for children, and 10, 1.0, and 5 mg for adults. When side effects ensued, doses were transiently reduced. All adjustments were clinically based and we did not use data on serum levels. Blood chemistry and hematologic tests were performed during baseline and again between 6 and 9 months into the study. Table 1. Clinical data on 32 patients with epileptic drop attacks previously refractory to AED Patient Age Sex Duration of epilepsy (years) Abnormalities neurological exam IQ Mean frequency of DA at baseline Medication at baseline EEG Presumed etiology MRI 1 16 M 13 N/A 81 30 CBZ, TPM GPSW CCT L post atrophy 2 24 M 17 N/A 82 300 VPA, PHT, CZP GSSW Midline Cyst Midline cyst 3 18 M 18 Dev dysphasia 52 195 CBZ, VPA, LTG MED, FPS Hypoxia Normal 4 7 M 6,5 N/A 68 20 CBZ, VPA, CLB Normal Cryptogenic Normal 5 23 F 17 Dev dysphasia 54 300 CBZ, PB, VPA GPSW Hypoxia Normal 6 8 M 4, 5 Dev dysphasia N/A 60 VPA, LTG, PB GPSW Radiotherapy Diff ctx atrophy 7 10 M 7 Dev dysphasia 69 120 OXC, CLB GSSW, FPS Cryptogenic Normal 8 48 M 46 Normal N/A 76 CBZ, VPZ, FNT, CLB MED Meningitides Normal 9 1 1 M 10 Dev dysphasia N/A 4 PB, VPA, LTG GPSW Cryptogenic Normal 10 10 M 9, 5 N/A 65 150 VPA, PB, CLB GSSW, FPS MCD Multiple tuberous 1 1 18 F 15, 5 N/A 55 20 CBZ, VPA, PB, LTG GSSW MCD Bilat double cortex 12 12 M 9 N/A 43 150 CBZ, PHT, AZM GSSW Cryptogenic Normal 13 20 F 17 N/A 73 5 CBZ, PRM, VPA, CLB GPSW Hypoxia Normal 14 14 M 11 N/A 62 40 CBZ, VGB, CLB MED Cryptogenic Normal 15 29 M 22 Dysphasia N/A 12 CBZ, TPM GS Cryptogenic Normal 16 12 M 3 R hemiparesis 71 350 PB, VPA, CBZ GSSW Meningitides L encephalomalacia 17 9 M 7 Dev dysphasia, ataxia 59 150 VPA, LTG GPSW, FPS Hypoxia Hippocampal atrophy 18 20 M 12 R hemiparesis 81 20 CBZ, PHT, PB, VPA Normal MCD Perisylvian PMG 19 18 F 16 Dysphasia N/A 20 VPA, PB Normal Cryptogenic Normal 20 10 F 10 N/A 65 30 PB, VPA, CBZ, CLB GSSW MCD Cortical dysplasia 21 26 M 26 N/A 72 3 CBZ, NZP GSSW Hypoxia Normal 22 34 F 29, 5 L hemiparesis 80 30 CBZ, VPA, CZP MED MCD R polymicrogyria 23 44 M 30 N/A 69 12 OXC, VPA Bifrontal Spikes Cryptogenic Cerebellar atrophy 24 15 M 15 Dev dysphasia 47 150 PB, VPA, CZP MED, FPS Hypoxia Normal 25 32 M 31, 5 Dev dysphasia 80 3 CBZ, VPA MED Hypoxia Normal 26 5 M 3 Dev dysphasia, ataxia N/A 120 CBZ, VPA, CLB GPSW, FPS Hypoxia Normal 27 15 M 11 Ataxia N/A 90 CBZ, PB, VPA GPSW, FPS Cryptogenic Cerebellar atrophy 28 9 M 8, 5 Dev dysphasia 32 60 VGB, NTZ GSSW MCD Multiple tuberous 29 17 F 7 N/A 77 20 VPA, OXC Normal MCD Bilat double cortex 30 6 M 3 Dev dysphasia, ataxia N/A 900 TPM, PB GSSW Hypoxia Diff ctx atrophy 31 9 F 13 Normal N/A 25 CBZ, VPA, TPM, NZP GSSW Cryptogenic Normal 32 18 M 13 N/A 34 150 CBZ, VPA, ACTZ GPSW Cryptogenic Normal MCD, malformation of cortical development; CCT, craniocerebral trauma; GE, generalized slowing; GPSW, generalized polyspike slow waves; GSSW, generalized spike slow waves; MED, multifocal epileptiform discharges; FPS, fast polyspikes; Dev, development; R, right; L, left; Diff ctx, diffuse cortical; PMG, polymicrogyria; AZM, acetazolamide; CBZ, carbamazepine; CZP, clonazepam; CLB, clobazam; ETX, ethosuximide; LTG, lamotrigine; NZP, nitrazepam; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; TPM, topiramate; VPA, valproate; VGB, vigabatrin. Parents were informed about the objectives and risks of the study, particularly of severe rash and other immunologic reactions, and patients were included only after their formal agreement and written consent, according to the rules of resolution 196/96 of the National Health Council of the Ministry of Health of Brazil. The study was also approved by the Ethics Committee of our Institution. Follow-up visits were at 3-month intervals, when the frequency of epileptic drop attacks from the previous 3 months was entered into a database and a list of potential AED side effects was read to patients and caregivers. We emphasized the presence of rash, gastric intolerance, somnolence, dizziness, ataxia, tremor, alopecia, and weight gain. Tonic–clonic, generalized tonic and absences, and typical and atypical were the most frequent other seizure types in this sample. We did not ask caregivers to keep record of the frequency of these other seizure types. However, at each visit, we did ask whether it was noticeable that any of these had worsened in comparison with the previous 3-month interval. At least two outpatient 30-min EEG recordings were performed, one at enrollment and the other 6–9 months later. Discharges were classified as generalized or multifocal and their frequency noted before and after institution of the three-drug regimen. This was an outpatient study and patients did not undergo long-term video-EEG. Magnetic resonance imaging (MRI) was performed in all with a 1.5-T Siemens Magneton (Siemens, Erlangen, Germany). Presence and severity of mental retardation were evaluated with a battery of neuropsychological tests (Wechsler, 2005). The diagnosis of the epilepsy syndrome and presumed etiology was based on clinical evaluation, EEG, and MRI. A hypoxic–ischemic etiology was considered when parents reported perinatal cyanosis, need for oxygen immediately after delivery, and Apgar score ≤7. Eleven patients (34%) had cryptogenic and the others had variable etiologies of symptomatic generalized or multifocal epilepsies (Table 1). Mean IQ of the 23 patients tested was 63.9 [standard deviation (SD): 14.5; range 32–82; Table 1]. The median frequency of epileptic drop attacks at baseline was the comparator to establish the efficacy of the new AED regimen. With the exception of four patients who discontinued the combination early, the other 28 received the study medication for 12 months. The adjustment of AED dosages was dynamic, dictated by titration schedule, efficacy, and tolerability. Therefore, the final, stabilized doses of the three AEDs were reached at month 3 in 4 patients, between months 3 and 6 in 6 patients, and between 6 and 12 months in the other 18 patients. The efficacy of the treatment was assessed as percent reduction of the frequency of epileptic drop attacks in each 3-month period compared to baseline: 100% (free of drop attacks), 75–99%, 50–74%, 25–49%, and <25% reduction. Finally, clinical, cognitive, etiological, demographic, and EEG data were correlated with degree of control of drop attacks. The primary efficacy end point was percent reduction in the median number of epileptic drop attacks in the fourth trimester after institution of the study medication regimen in comparison with the median number of drop attacks in the 2 months of baseline. One secondary outcome was the percentage reduction in the median number of drop attacks at each 3-month interval compared with the median number of drop attacks at baseline. This secondary outcome established the timing of improvement and the stability of the results over time. Another secondary outcome was the correlation between epileptologic and imaging variables with response to treatment. All outcome analyses included the 32 patients originally enrolled in an intention-to-treat design. To describe the occurrence of drop attacks we used median, minimum, and maximum values. To evaluate the statistical significance of reductions in the frequency of drop attacks during the period of observation, we used a nonparametric analysis of variance (ANOVA) for repeated measures (Friedman's test). The percent reduction of drop attacks between visits was obtained according to a simple formula: First, we subtracted the median frequency of drop attacks at each visit (representing the previous 3-month interval) from the median frequency of drop attacks at baseline. The result was then divided by the median frequency of drop attacks at baseline and multiplied by 100. Therefore, the larger the median reduction of drop attacks at each visit compared to baseline, the larger the numerator of the final equation and, therefore, the larger the percent reduction of drop attacks. Data were analyzed using SPSS version 17.0 (IBM Corporation, Somers, NY, U.S.A.). Results Demographic and clinical data are summarized in Table 1. Twenty-eight patients (22 male) aged 5–44 years (mean 16.5) were followed for 12 months. Four were excluded: three had rash at the first 3 months of treatment—one of whom progressed to Stevens-Johnson syndrome (SJS), which resolved with treatment discontinuation—and a fourth was lost to follow-up after the first visit. Twenty-two of the 32 patients (68%) originally included, and 18 of the 28 who completed the study, had side effects that caregivers considered relevant to report, most commonly gastric intolerance, tremor, sedation, and hair loss. Table 2 details the side effects and provides the dosage of each medication associated with each side effect. Mean final dosage of valproate was 35.9 mg/kg/day (range 10.4–76.9, SD: 14.48) and that of lamotrigine was 4.9 mg/kg/day (range 0.8–11.5, SD: 2.5). Twenty patients used clobazam, eight nitrazepam, and the other four clonazepam as the benzodiazepine of the regimen under study. Clobazam, clonazepam, and nitrazepam were used at the following respective mean doses: 0.45 mg/kg/day (range 0.12–0.9, SD: 0.22), 0.05 mg/kg/day (range 0.03–0.09, SD: 0.03), and 0.25 mg/kg/day (range 0.06–0.5, SD: 0.14). Table 2. Side effects during treatment with the AED combination under study Patient Side effects Drugs (mg/kg/day) VPA LTG BZD 1 Tremors 38.8 3.5 0.35 CLB 2 Weight gain 32.3 6.6 0.06 NZP 3 Gastric intolerance, sedation, hair loss 24.0 4.8 0.14 CLB 4 NR 56.2 9.4 0.31 CLB 5 NR 58.8 4.9 0.2 NZP 6 Gastric intolerance, sedation 10.4 8.3 0.4 NZP 7 Gastric intolerance, sedation, hair loss, ataxia 22.2 5.8 0.8 CLB 8 Rash 37.4 2.3 0.15 CLB 9 Gastric intolerance 36.0 7.5 0.6 CLB 10 Gastric intolerance, sedation 68.2 6.8 0.5 NZP 1 1 Tremors, weight gain 40.0 3.0 0.4 CLB 12 NR 16.9 4.2 0.16 CLB 13 NR 27.1 6.5 0.6 CLB 14 NR 26.8 2.7 0.5 CLB 15 Rash 42.3 3.1 0.4 CLB 16 Gastric intolerance, hair loss 40.5 0.8 0.5 CLB 17 Gastric intolerance, ataxia 20.2 7.4 0.3 NZP 18 Sedation 28.1 3.8 0.09 CZP 19 SJS 31.5 1.4 0.13 NZP 20 NR 33.3 2.9 0.3 CLB 21 Gastric intolerance 40.0 4.0 0.03 CZP 22 Tremors, hair loss 28.8 2.9 0.6 CLB 23 Tremors 23.4 3.9 0.5 CLB 24 NR 33.3 2.5 0.25 NZP 25 Hair loss, weight gain 28.6 1.8 0.4 CLB 26 NR 54.5 9.1 0.9 CLB 27 Weight gain, sedation 33.3 3.3 0.06 CZP 28 Gastric intolerance 27.5 5.6 0.75 CLB 29 Hair loss, weight gain 26.6 2.7 0.03 CZP 30 NR 76.9 1 1.5 0.12 CLB 31 NR 45.0 5.0 0.4 CLB 32 NR 41.0 6.7 0.22 NZP AED, antiepileptic drugs; NR, none relevant; CLB, clobazam; CZP, clonazepam; NZP, nitrazepam; SJS, Steven-Johnson syndrome. Seven patients had electrical decrement, following irregular spike and wave complexes and bursts of fast activities, as seen in LGS. These abnormalities were significantly reduced on the follow-up EEG, after institution of the study AED regimen. Twenty patients had predominantly generalized and six multifocal EEG discharges. One other had bifrontal spikes and one other generalized slowing. For four patients, the first EEG was completely normal. The two EEG studies performed in three patients did not show epileptic discharges, despite unequivocal diagnosis of epilepsy and previously epileptogenic EEG recording. One had "double cortex," another bilateral perisylvian polymicrogyria, and the third had a normal MRI. In five patients, the second EEG recording 6 months into the study showed disappearance of the epileptic discharges. Figure 1 displays the evolution of the median frequency of drop attacks at 3-month intervals in the group of patients. It shows that the most impressive improvement occurred during the first 3 months after the institution of the treatment with valproate, lamotrigine, and a benzodiazepine, with posterior stabilization. Baseline median frequency of drop attacks in the seven patients with LGS was 120 (range, 3–900), whereas it was 30 (range, 4–195) in the other 25 patients (p = 0.19). The median number of drop attacks in the fourth trimester of the study in patients with LGS was reduced to 3 (0–51), and in the 21 non-LGS patients continuing in the study it was 0 (0–90). The magnitude of the reduction was not related to the presence of an LGS (p = 0.79) (Fig. 2). Figure 1Open in figure viewerPowerPoint Median frequency of drop attacks during the 12 months of treatment in the 28 patients who completed at least 1 year into the study. Figure 2Open in figure viewerPowerPoint Median frequency of drop attacks during treatment in patients with and without Lennox-Gastaut syndrome. For the whole group, the median number of drop attacks during the 2 months of baseline was 50 (3–900). In the fourth trimester with the AED regimen under study, the median number of epileptic falls was two, representing a reduction of (96%) (p < 0.001). More specifically, 15 patients (47%) were free of drop attacks, 7 (21%) had 75%, and 5 others had a 50–74% reduction in the frequency of falls in the fourth trimester (percent data relate to the original sample of 32 patients in the ITT design). Only one of the 28 patients completing the study had a reduction of 75% reduction, and 28% of the patients had a 50–75% improvement in falls. Nevertheless, because dose regimens were predetermined and fixed in the studies with felbamate and topiramate, in contrast to the real-life adjustments "as needed" used in the
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