- Email: [email protected]
Tolerability of lacosamide or zonisamide in elderly patients with seizures
Seizure 49 (2017) 1–4
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Tolerability of lacosamide or zonisamide in elderly patients with seizures Rani A. Sarkis* , Johny Nicolas, Jong Woo Lee Department of Neurology, Edward B. Bromfield Epilepsy Center, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 November 2016 Received in revised form 9 March 2017 Accepted 5 April 2017 Available online xxx
Purpose: The prevalence of seizures in the elderly will increase as populations age. Data is currently limited regarding treatment and especially tolerability of newer antiseizure medications (ASMs). In the current study we aimed to investigate the tolerability of lacosamide (LCS) and zonisamide (ZNS). Method: We performed a retrospective chart review of patients with seizures older than 60 treated with LCS or ZNS in the outpatient setting. We examined seizure variables, medical comorbidities, and concomitant medications. Primary outcomes were the retention rates at last follow up, and the discontinuation rate due to side effects. Results: Seventy-one (71) LCS and 39 ZNS patients were identified. Average age at LCS initiation was 71.0 7.0 years and 49% were medically refractory. Average duration of follow up was 23.1 21.2 months. At last follow up, the retention rate was 60% and seizure freedom rate 52%. Of the 19 discontinuations due to side effects, 7 (37%) were due to dizziness/gait instability. No predictors of discontinuation were identified. Average age at ZNS initiation was 69.7 6.9 years and 51% were medically refractory. Average duration of follow up was 46.3 38.3 months. At last follow up, the retention rate was 64% and seizure freedom rate was 67%. Of the 12 discontinuations due to side effects, 4 (33%) were due to cognitive or behavioral side effects. Predictors of discontinuation included a lower starting dose. Conclusions: Lacosamide and zonisamide are viable options for the treatment of epilepsy in the elderly and have similar retention rates. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is most prevalent in elderly patients especially after the age of 60 reaching a prevalence rate of approximately 1.5% by age 75 [1,2]. As the world's population is aging and the number of people living after the age of 60 is increasing, so will the prevalence of epilepsy. Although it is generally easier to control seizures in this age group, the age-related physiological changes can alter the pharmacokinetic and pharmacodynamic properties of anti-seizure medications (ASMs) making them less tolerable [3]. Unfortunately, the amount of information available in the literature on the tolerability of certain medications in the elderly is still limited because of the scarcity of randomized clinical trials and open label studies involving this age group [4]. In addition, due to the concerns for drug-drug interactions and long term effects of enzyme induction, first generation medications are preferably avoided highlighting the importance of identifying the tolerability of the newer medications [5].
* Corresponding author. E-mail address: [email protected] (R.A. Sarkis).
Zonisamide and lacosamide are two commonly used second and third generations ASMs predominantly used in the treatment of epilepsy, with limited information about their tolerability profile in the elderly. Zonisamide, a benzisoxazole derivative, has a special chemical structure that allows it to act through various complementary mechanisms: blockage of voltage-gated sodium channels, inhibition of T-type Ca2+ channels, increased g-aminobutyric acid release and inhibition of glutamate release [6,7]. Lacosamide, a functionalized amino acid, selectively enhances the slow inactivation of voltage-gated sodium channels [8]. The aim of the current study is to investigate the retention rates and tolerability of these two medications in a population of elderly patients with seizures. 2. Methods A retrospective chart review of epilepsy patients aged 60 years and older treated with lacosamide or zonisamide in the outpatient setting at Brigham and Women's Hospital (tertiary referral center) and South Shore Hospital (secondary referral center) was performed using the Research Patient Data Registry query tool
http://dx.doi.org/10.1016/j.seizure.2017.04.010 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
2
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
[9] with zonisamide and lacosamide as search terms and an age cut-off of 60. These two medications were selected given the paucity of data available about their tolerability in the elderly, their common use, and the fact they are predominantly used for epilepsy and have been available for >5 years. Only patients treated for seizures and followed up at least once after medication initiation were included. Inpatient initiation of lacosamide was excluded due to concerns about the effect of IV loading doses and concomitant acute neurologic illnesses. Data extraction included seizure variables (etiology, epilepsy duration, seizure frequency, seizure semiology), concomitant medications, BMI, presence or absence of renal insufficiency (estimated GFR < 60 ml/min/1.73 m2) or liver failure (elevated liver function tests), and medical comorbidities. The Charlson medical comorbidities score [10] was also calculated for each individual patient. The drug load at which the medication was initiated and at last follow up was calculated as prescribed daily dose/defined daily dose of the World Health organization (300 mg for lacosamide and 200 mg for zonisamide) [11]. The concomitant use of other ASMs where the major mechanism of action was sodium channel blocking was also noted: carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and eslicarbazepine acetate. The primary outcomes were the retention rates at last follow up, and the discontinuation rate due to side effects. Each cohort was analyzed separately. The goal was not to perform a head to
head comparison given that some patients were on both medications and that the underlying etiology and types of epilepsy were different. The study was an investigator initiated unfunded study with no pharmaceutical company involvement. 3. Statistics Descriptive statistics were first obtained with means, and standard deviations for continuous variables and frequencies for categorical variables. A Kaplan–Meier survival method was used to determine the retention rates at 6 months, 1 year, and last follow up for each medication. A univariate Cox proportional hazards regression model was used to determine whether age, BMI the Charlson comorbidity index, initial drug load, number of ASMs, and concomitant sodium channel blockers were predictors of discontinuation. All statistical analyses were performed using the JMP (SAS) 11.0 software. 4. Results A total of 71 patients in the lacosamide group and 39 patients in the zonisamide group were analyzed. The clinical characteristics of the cohort are summarized in Table 1. Eleven patients were exposed to both medications during the follow up period.
Table 1 Clinical characteristics of the cohorts. Lacosamide (n = 71)
Zonisamide (n = 39)
Gender: female (%) Age at initiation of medication (years SD)
63% 71.0 7.0
67% 69.7 6.9
Race Caucasian (%) Non-Caucasian (%) Epilepsy duration years (SD) Focal epilepsy (%) Number of failed AEDs (SD) Medically refractory
90% 10% 14.6 19.5 94% 1.7 1.5 49%
80% 20% 24.0 21.4 85% 2.0 2.0 46%
Seizure types Seizures with no LOC (%) Dyscognitive seizures (%) Generalized tonic clonic seizures (%)
46.5% 39.4% 43.4%
33.3% 57.6% 43.6%
Seizure frequency Daily (%) Weekly (%) Monthly (%) Yearly/rare (%)
8% 29% 37% 38%
10% 18% 33% 38%
Etiology Cerebrovascular (%) Neoplastic (%) Idiopathic (%) Post-traumatic (%) Inflammatory/infectious (%) Neurodegenerative (%) Others (%) BMI (SD) Chronic renal insufficiency (%) Charlson Comorbidity Score (SD) Number of concomitant AEDs (SD) Monotherapy (%) Use of concomitant sodium channel blocker (%) Follow up period (months SD) Median initial dose (mg) Median final dose (mg) Initial drug load (SD) Last drug load (SD) Seizure free at last follow up (%)
20% 24% 32% 20% 1% 1% 1% 26.7 4.6 11% 2.9 2.6 1.5 0.9 8% 34% 23.1 21.2 100 200 0.46 ( 0.22) 0.68 ( 0.3) 52%
30% 10% 36% 10% 8% 3% 2% 27.8 4.7 13% 2.3 2.0 1.0 0.9 31% 38% 46.3 38.3 100 200 0.63 ( 0.33) 1.19 (0.77) 67%
LOC: loss of consciousness.
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
3
The discontinuation rate was 22/71 for lacosamide with 19 patients discontinuing the medication due to side effects. The discontinuation rate for zonisamide was 12/39 with 11 patients discontinuing due to side effects. The most common side effects are listed in Table 2. Retention rates are shown in Fig. 1. The 6 months, 1 year and last follow up retention rates were the following for lacosamide: 86%, 75%, and 60% and for zonisamide: 82%, 82%, 64% respectively. The only predictor of discontinuation was the initial drug load of zonisamide (risk ratio 0.29, 95% CI: 0.05–0.95, p = 0.038). 5. Discussion In a retrospective analysis of elderly patients with seizures in a real world setting, we found good retention rates of 60% and 64% for lacosamide and zonisamide respectively at last follow up. Dizziness and gait instability were the most frequent side effects with lacosamide while cognitive and behavioral complains were the most common with zonisamide. We chose to focus on these two medications given the limited data available in the elderly and since they are predominantly used for epilepsy. The treatment of elderly patients with seizures requires special considerations given a number of physiological changes including changes in gastric acidity, liver metabolism, renal excretion, and volume of distribution [3,12]. Receptor hypersensitivity has also been noted [3]. Randomized clinical trials to guide treatment have been few; in a trial of gabapentin, lamotrigine, and carbamazepine in new onset geriatric epilepsy, early termination was highest for carbamazepine at 64% and lowest for lamotrigine at 44% with a seizure free rate of 63.4% at 1 year [13]. A comparison of lamotrigine vs. extended release carbamazepine, also in new onset geriatric epilepsy, yielded a better retention rate for lamotrigine at 10 months, 73% vs. 67% [14]. More recent trials looking at levetericaetam vs. lamotrigine vs. carbamazepine in the same population noted higher retention rates at 1 year for levetiraetam 61.5% vs. 51.6% for lamotrigine and 45.8% for carbamazepine while the seizure freedom rates were similar at 33.3–42.6% [15]. In an open label study of levetiracetam add-on therapy in geriatric epilepsy, only 10.8% of patients experienced an adverse event and the seizure free rate at 1 year was 58% [16]. Although the current findings are roughly similar to the retention rates quoted in the literature, a direct comparison to other studies cannot be made given the very heterogeneous nature of our cohorts with different epilepsy types (focal vs. generalized), different etiologies (cerebrovascular vs. neoplastic), higher rates of prior ASM exposure (as opposed to monotherapy trials), and different titration schedules. Lacosamide is a third generation ASM currently approved as an add-on or monotherapy agent in the treatment of epilepsy. A pooled analysis of the initial phase II and III trials highlighted dizziness and nystagmus as common treatment related side effects [17], similar dizziness rates were also noted in a large multicenter open label trial [18]. The neurotoxic side effects are especially
Table 2 Side effects leading to discontinuation. Lacosamide (n = 19) Zonisamide (n = 11) Dizziness/gait instability Fatigue Cognitive or behavioral difficultiesa Othersa
7 4 6 2
(37%) (21%) (32%) (11%)
0 2 (18%) 4 (36%) 5 (45%)
a Other side effects included. Lacosamide: memory loss/cognitive slowing 3, depression/irritability 2, anxiety 1, paresthesias 1, diplopia 1. Zonisamide: memory loss/cognitive slowing 2, depression/irritability 2, rash 2, nephrolithiasis 1, increased bruising 1, palpitations 1.
Fig. 1. Longitudinal retention rates of lacosamide and zonisamide.
problematic when it is added to other sodium channel blockers [19]. In our analysis we found dizziness again to be a major complaint in our cohort, as well as gait instability. This is especially important in this patient population due to the risk of falls; the concomitant use of a sodium channel blocker was not a predictor of discontinuation. Retention rates overall were similar to other age groups. In a longitudinal follow up of 403 patients in the UK, the retention rate as an add-on agent was 68% at one year [20]. In an observational study of a cohort of patients treated in Germany with lacosamide added to one antiseizure medication with flexible dosing, a subgroup analysis of elderly patients showed higher rates of seizure freedom (56% at 6 months) and similar rates of treatment emergent adverse events compared to younger patients. Interestingly the maintenance dose was also similar to younger patients with an average of 260 mg per day [21]. Zonisamide is a second generation ASM currently approved as adjunctive treatment for focal epilepsy. It is considered a broad spectrum agent with a convenient once a day dosing given its long half life [22]. Specific concerns related to this medication and especially in elderly patients include the risk of nephrolithiasis and weight loss [12]. In a large open label study, the 1 year retention rate was 62%, 46% at 2 years, with cognitive and behavioral side effects being the most common reason for discontinuation [23]. Predictors of discontinuation included the patient being on more than three ASMs and starting the titration at a lower dose, 25 vs. 50 mg. We found that lower initial drug load was also a predictor of discontinuation in our study. We hypothesize that the treating physician was concerned about side effects given the patient's history and favored a slower titration schedule. Metabolism of
4
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
acetylcholine, serotonin, and dopamine is slightly affected by zonisamide, which could explain some of the side cognitive and behavioral effects of the drug [22,24]. In a pooled analysis of clinical trials of zonisamide as monotherapy or adjunctive therapy a subgroup analysis of elderly patients revealed a treatment emergent adverse event rate of 18%, and a lower rate of severe adverse events as compared to the younger cohort. Fatigue and dizziness were to most common side effects in this cohort while weight loss was not a significant side effects [25]. Similarly, we found a low rate of weight loss leading to discontinuation in our cohort, and only one patient developed nephrolithiasis. 6. Limitations The study has several limitations including its retrospective observational nature, the overall small sample size especially for zonisamide preventing a more detailed analysis of co-morbidities, and the non-uniform medication titration based on physician preference. The cohorts were also predominantly Caucasian limiting generalizability to other races. Side effects were also retrieved from the chart rather than reported systematically by the patient. Furthermore, a number of patients on lacosamide were excluded as they received their first dose as an inpatient. 7. Conclusion Lacosamide and zonisamide are viable options for the treatment of seizures in the elderly, with gait instability and dizziness being the most prominent side effect for lacosamide and cognitive and behavioral side effects being most prominent for zonisamide. References [1] Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993;34:453–68. [2] Forsgren L, Beghi E, Oun A, Sillanpaa M. The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol 2005;12:245–53. [3] Stefan H. Epilepsy in the elderly: facts and challenges. Acta Neurol Scand 2011;124:223–37. [4] Roberson ED, Hope OA, Martin RC, Schmidt D. Geriatric epilepsy: research and clinical directions for the future. Epilepsy Behav: E&B 2011;22:103–11. [5] Arain AM, Abou-Khalil BW. Management of new-onset epilepsy in the elderly. Nat Rev Neurol 2009;5:363–71. [6] Brodie MJ, Ben-Menachem E, Chouette I, Giorgi L. Zonisamide: its pharmacology, efficacy and safety in clinical trials. Acta Neurol Scand Suppl 2012; (194):19–28.
[7] Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 2007;30:230–40. [8] Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci 2014;1329:18–32. [9] Nalichowski R, Keogh D, Chueh HC, Murphy SN. Calculating the benefits of a research patient data repository. AMIA. Annu Symp Proc/AMIA Symp 20061044:. [10] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [11] World Health Organization. WHO Collaborating Centre for Drug Statistics Methodology. 2015;2016. [12] Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci 2010;1184:208–24. [13] Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868–73. [14] LAM 40089 Study Group. Saetre E, Perucca E, Isojarvi J, Gjerstad L. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48:1292–302. [15] Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56:450–9. [16] Werhahn KJ, Klimpe S, Balkaya S, Trinka E, Kramer G. The safety and efficacy of add-on levetiracetam in elderly patients with focal epilepsy: a one-year observational study. Seizure 2011;20:305–11. [17] Chung S, Ben-Menachem E, Sperling MR, Rosenfeld W, Fountain NB, Benbadis S, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010;24:1041–54. [18] Zadeh WW, Escartin A, Byrnes W, Tennigkeit F, Borghs S, Li T, et al. Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: a multicentre open-label trial. Seizure 2015;31:72–9. [19] Novy J, Patsalos PN, Sander JW, Sisodiya SM. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction? Epilepsy Behav: E&B 2011;20:20–3. [20] Flores L, Kemp S, Colbeck K, Moran N, Quirk J, Ramkolea P, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy: a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure 2012;21:512–7. [21] Runge U, Arnold S, Brandt C, Reinhardt F, Kuhn F, Isensee K, et al. A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: the VITOBA study. Epilepsia 2015;56:1921–30. [22] Hoy SM. Zonisamide: a review of its use in the management of adults with partial seizures. Drugs 2013;73:1321–38. [23] Catarino CB, Bartolini E, Bell GS, Yuen AW, Duncan JS, Sander JW. The longterm retention of zonisamide in a large cohort of people with epilepsy at a tertiary referral centre. Epilepsy Res 2011;96:39–44. [24] Kothare SV, Kaleyias J. Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol 2008;4:493–506. [25] Trinka E, Giorgi L, Patten A, Segieth J. Safety and tolerability of zonisamide in elderly patients with epilepsy. Acta Neurol Scand 2013;128:422–8.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Tolerability of lacosamide or zonisamide in elderly patients with seizures Rani A. Sarkis* , Johny Nicolas, Jong Woo Lee Department of Neurology, Edward B. Bromfield Epilepsy Center, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 November 2016 Received in revised form 9 March 2017 Accepted 5 April 2017 Available online xxx
Purpose: The prevalence of seizures in the elderly will increase as populations age. Data is currently limited regarding treatment and especially tolerability of newer antiseizure medications (ASMs). In the current study we aimed to investigate the tolerability of lacosamide (LCS) and zonisamide (ZNS). Method: We performed a retrospective chart review of patients with seizures older than 60 treated with LCS or ZNS in the outpatient setting. We examined seizure variables, medical comorbidities, and concomitant medications. Primary outcomes were the retention rates at last follow up, and the discontinuation rate due to side effects. Results: Seventy-one (71) LCS and 39 ZNS patients were identified. Average age at LCS initiation was 71.0 7.0 years and 49% were medically refractory. Average duration of follow up was 23.1 21.2 months. At last follow up, the retention rate was 60% and seizure freedom rate 52%. Of the 19 discontinuations due to side effects, 7 (37%) were due to dizziness/gait instability. No predictors of discontinuation were identified. Average age at ZNS initiation was 69.7 6.9 years and 51% were medically refractory. Average duration of follow up was 46.3 38.3 months. At last follow up, the retention rate was 64% and seizure freedom rate was 67%. Of the 12 discontinuations due to side effects, 4 (33%) were due to cognitive or behavioral side effects. Predictors of discontinuation included a lower starting dose. Conclusions: Lacosamide and zonisamide are viable options for the treatment of epilepsy in the elderly and have similar retention rates. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is most prevalent in elderly patients especially after the age of 60 reaching a prevalence rate of approximately 1.5% by age 75 [1,2]. As the world's population is aging and the number of people living after the age of 60 is increasing, so will the prevalence of epilepsy. Although it is generally easier to control seizures in this age group, the age-related physiological changes can alter the pharmacokinetic and pharmacodynamic properties of anti-seizure medications (ASMs) making them less tolerable [3]. Unfortunately, the amount of information available in the literature on the tolerability of certain medications in the elderly is still limited because of the scarcity of randomized clinical trials and open label studies involving this age group [4]. In addition, due to the concerns for drug-drug interactions and long term effects of enzyme induction, first generation medications are preferably avoided highlighting the importance of identifying the tolerability of the newer medications [5].
* Corresponding author. E-mail address: [email protected] (R.A. Sarkis).
Zonisamide and lacosamide are two commonly used second and third generations ASMs predominantly used in the treatment of epilepsy, with limited information about their tolerability profile in the elderly. Zonisamide, a benzisoxazole derivative, has a special chemical structure that allows it to act through various complementary mechanisms: blockage of voltage-gated sodium channels, inhibition of T-type Ca2+ channels, increased g-aminobutyric acid release and inhibition of glutamate release [6,7]. Lacosamide, a functionalized amino acid, selectively enhances the slow inactivation of voltage-gated sodium channels [8]. The aim of the current study is to investigate the retention rates and tolerability of these two medications in a population of elderly patients with seizures. 2. Methods A retrospective chart review of epilepsy patients aged 60 years and older treated with lacosamide or zonisamide in the outpatient setting at Brigham and Women's Hospital (tertiary referral center) and South Shore Hospital (secondary referral center) was performed using the Research Patient Data Registry query tool
http://dx.doi.org/10.1016/j.seizure.2017.04.010 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
2
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
[9] with zonisamide and lacosamide as search terms and an age cut-off of 60. These two medications were selected given the paucity of data available about their tolerability in the elderly, their common use, and the fact they are predominantly used for epilepsy and have been available for >5 years. Only patients treated for seizures and followed up at least once after medication initiation were included. Inpatient initiation of lacosamide was excluded due to concerns about the effect of IV loading doses and concomitant acute neurologic illnesses. Data extraction included seizure variables (etiology, epilepsy duration, seizure frequency, seizure semiology), concomitant medications, BMI, presence or absence of renal insufficiency (estimated GFR < 60 ml/min/1.73 m2) or liver failure (elevated liver function tests), and medical comorbidities. The Charlson medical comorbidities score [10] was also calculated for each individual patient. The drug load at which the medication was initiated and at last follow up was calculated as prescribed daily dose/defined daily dose of the World Health organization (300 mg for lacosamide and 200 mg for zonisamide) [11]. The concomitant use of other ASMs where the major mechanism of action was sodium channel blocking was also noted: carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and eslicarbazepine acetate. The primary outcomes were the retention rates at last follow up, and the discontinuation rate due to side effects. Each cohort was analyzed separately. The goal was not to perform a head to
head comparison given that some patients were on both medications and that the underlying etiology and types of epilepsy were different. The study was an investigator initiated unfunded study with no pharmaceutical company involvement. 3. Statistics Descriptive statistics were first obtained with means, and standard deviations for continuous variables and frequencies for categorical variables. A Kaplan–Meier survival method was used to determine the retention rates at 6 months, 1 year, and last follow up for each medication. A univariate Cox proportional hazards regression model was used to determine whether age, BMI the Charlson comorbidity index, initial drug load, number of ASMs, and concomitant sodium channel blockers were predictors of discontinuation. All statistical analyses were performed using the JMP (SAS) 11.0 software. 4. Results A total of 71 patients in the lacosamide group and 39 patients in the zonisamide group were analyzed. The clinical characteristics of the cohort are summarized in Table 1. Eleven patients were exposed to both medications during the follow up period.
Table 1 Clinical characteristics of the cohorts. Lacosamide (n = 71)
Zonisamide (n = 39)
Gender: female (%) Age at initiation of medication (years SD)
63% 71.0 7.0
67% 69.7 6.9
Race Caucasian (%) Non-Caucasian (%) Epilepsy duration years (SD) Focal epilepsy (%) Number of failed AEDs (SD) Medically refractory
90% 10% 14.6 19.5 94% 1.7 1.5 49%
80% 20% 24.0 21.4 85% 2.0 2.0 46%
Seizure types Seizures with no LOC (%) Dyscognitive seizures (%) Generalized tonic clonic seizures (%)
46.5% 39.4% 43.4%
33.3% 57.6% 43.6%
Seizure frequency Daily (%) Weekly (%) Monthly (%) Yearly/rare (%)
8% 29% 37% 38%
10% 18% 33% 38%
Etiology Cerebrovascular (%) Neoplastic (%) Idiopathic (%) Post-traumatic (%) Inflammatory/infectious (%) Neurodegenerative (%) Others (%) BMI (SD) Chronic renal insufficiency (%) Charlson Comorbidity Score (SD) Number of concomitant AEDs (SD) Monotherapy (%) Use of concomitant sodium channel blocker (%) Follow up period (months SD) Median initial dose (mg) Median final dose (mg) Initial drug load (SD) Last drug load (SD) Seizure free at last follow up (%)
20% 24% 32% 20% 1% 1% 1% 26.7 4.6 11% 2.9 2.6 1.5 0.9 8% 34% 23.1 21.2 100 200 0.46 ( 0.22) 0.68 ( 0.3) 52%
30% 10% 36% 10% 8% 3% 2% 27.8 4.7 13% 2.3 2.0 1.0 0.9 31% 38% 46.3 38.3 100 200 0.63 ( 0.33) 1.19 (0.77) 67%
LOC: loss of consciousness.
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
3
The discontinuation rate was 22/71 for lacosamide with 19 patients discontinuing the medication due to side effects. The discontinuation rate for zonisamide was 12/39 with 11 patients discontinuing due to side effects. The most common side effects are listed in Table 2. Retention rates are shown in Fig. 1. The 6 months, 1 year and last follow up retention rates were the following for lacosamide: 86%, 75%, and 60% and for zonisamide: 82%, 82%, 64% respectively. The only predictor of discontinuation was the initial drug load of zonisamide (risk ratio 0.29, 95% CI: 0.05–0.95, p = 0.038). 5. Discussion In a retrospective analysis of elderly patients with seizures in a real world setting, we found good retention rates of 60% and 64% for lacosamide and zonisamide respectively at last follow up. Dizziness and gait instability were the most frequent side effects with lacosamide while cognitive and behavioral complains were the most common with zonisamide. We chose to focus on these two medications given the limited data available in the elderly and since they are predominantly used for epilepsy. The treatment of elderly patients with seizures requires special considerations given a number of physiological changes including changes in gastric acidity, liver metabolism, renal excretion, and volume of distribution [3,12]. Receptor hypersensitivity has also been noted [3]. Randomized clinical trials to guide treatment have been few; in a trial of gabapentin, lamotrigine, and carbamazepine in new onset geriatric epilepsy, early termination was highest for carbamazepine at 64% and lowest for lamotrigine at 44% with a seizure free rate of 63.4% at 1 year [13]. A comparison of lamotrigine vs. extended release carbamazepine, also in new onset geriatric epilepsy, yielded a better retention rate for lamotrigine at 10 months, 73% vs. 67% [14]. More recent trials looking at levetericaetam vs. lamotrigine vs. carbamazepine in the same population noted higher retention rates at 1 year for levetiraetam 61.5% vs. 51.6% for lamotrigine and 45.8% for carbamazepine while the seizure freedom rates were similar at 33.3–42.6% [15]. In an open label study of levetiracetam add-on therapy in geriatric epilepsy, only 10.8% of patients experienced an adverse event and the seizure free rate at 1 year was 58% [16]. Although the current findings are roughly similar to the retention rates quoted in the literature, a direct comparison to other studies cannot be made given the very heterogeneous nature of our cohorts with different epilepsy types (focal vs. generalized), different etiologies (cerebrovascular vs. neoplastic), higher rates of prior ASM exposure (as opposed to monotherapy trials), and different titration schedules. Lacosamide is a third generation ASM currently approved as an add-on or monotherapy agent in the treatment of epilepsy. A pooled analysis of the initial phase II and III trials highlighted dizziness and nystagmus as common treatment related side effects [17], similar dizziness rates were also noted in a large multicenter open label trial [18]. The neurotoxic side effects are especially
Table 2 Side effects leading to discontinuation. Lacosamide (n = 19) Zonisamide (n = 11) Dizziness/gait instability Fatigue Cognitive or behavioral difficultiesa Othersa
7 4 6 2
(37%) (21%) (32%) (11%)
0 2 (18%) 4 (36%) 5 (45%)
a Other side effects included. Lacosamide: memory loss/cognitive slowing 3, depression/irritability 2, anxiety 1, paresthesias 1, diplopia 1. Zonisamide: memory loss/cognitive slowing 2, depression/irritability 2, rash 2, nephrolithiasis 1, increased bruising 1, palpitations 1.
Fig. 1. Longitudinal retention rates of lacosamide and zonisamide.
problematic when it is added to other sodium channel blockers [19]. In our analysis we found dizziness again to be a major complaint in our cohort, as well as gait instability. This is especially important in this patient population due to the risk of falls; the concomitant use of a sodium channel blocker was not a predictor of discontinuation. Retention rates overall were similar to other age groups. In a longitudinal follow up of 403 patients in the UK, the retention rate as an add-on agent was 68% at one year [20]. In an observational study of a cohort of patients treated in Germany with lacosamide added to one antiseizure medication with flexible dosing, a subgroup analysis of elderly patients showed higher rates of seizure freedom (56% at 6 months) and similar rates of treatment emergent adverse events compared to younger patients. Interestingly the maintenance dose was also similar to younger patients with an average of 260 mg per day [21]. Zonisamide is a second generation ASM currently approved as adjunctive treatment for focal epilepsy. It is considered a broad spectrum agent with a convenient once a day dosing given its long half life [22]. Specific concerns related to this medication and especially in elderly patients include the risk of nephrolithiasis and weight loss [12]. In a large open label study, the 1 year retention rate was 62%, 46% at 2 years, with cognitive and behavioral side effects being the most common reason for discontinuation [23]. Predictors of discontinuation included the patient being on more than three ASMs and starting the titration at a lower dose, 25 vs. 50 mg. We found that lower initial drug load was also a predictor of discontinuation in our study. We hypothesize that the treating physician was concerned about side effects given the patient's history and favored a slower titration schedule. Metabolism of
4
R.A. Sarkis et al. / Seizure 49 (2017) 1–4
acetylcholine, serotonin, and dopamine is slightly affected by zonisamide, which could explain some of the side cognitive and behavioral effects of the drug [22,24]. In a pooled analysis of clinical trials of zonisamide as monotherapy or adjunctive therapy a subgroup analysis of elderly patients revealed a treatment emergent adverse event rate of 18%, and a lower rate of severe adverse events as compared to the younger cohort. Fatigue and dizziness were to most common side effects in this cohort while weight loss was not a significant side effects [25]. Similarly, we found a low rate of weight loss leading to discontinuation in our cohort, and only one patient developed nephrolithiasis. 6. Limitations The study has several limitations including its retrospective observational nature, the overall small sample size especially for zonisamide preventing a more detailed analysis of co-morbidities, and the non-uniform medication titration based on physician preference. The cohorts were also predominantly Caucasian limiting generalizability to other races. Side effects were also retrieved from the chart rather than reported systematically by the patient. Furthermore, a number of patients on lacosamide were excluded as they received their first dose as an inpatient. 7. Conclusion Lacosamide and zonisamide are viable options for the treatment of seizures in the elderly, with gait instability and dizziness being the most prominent side effect for lacosamide and cognitive and behavioral side effects being most prominent for zonisamide. References [1] Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993;34:453–68. [2] Forsgren L, Beghi E, Oun A, Sillanpaa M. The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol 2005;12:245–53. [3] Stefan H. Epilepsy in the elderly: facts and challenges. Acta Neurol Scand 2011;124:223–37. [4] Roberson ED, Hope OA, Martin RC, Schmidt D. Geriatric epilepsy: research and clinical directions for the future. Epilepsy Behav: E&B 2011;22:103–11. [5] Arain AM, Abou-Khalil BW. Management of new-onset epilepsy in the elderly. Nat Rev Neurol 2009;5:363–71. [6] Brodie MJ, Ben-Menachem E, Chouette I, Giorgi L. Zonisamide: its pharmacology, efficacy and safety in clinical trials. Acta Neurol Scand Suppl 2012; (194):19–28.
[7] Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 2007;30:230–40. [8] Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci 2014;1329:18–32. [9] Nalichowski R, Keogh D, Chueh HC, Murphy SN. Calculating the benefits of a research patient data repository. AMIA. Annu Symp Proc/AMIA Symp 20061044:. [10] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [11] World Health Organization. WHO Collaborating Centre for Drug Statistics Methodology. 2015;2016. [12] Leppik IE, Birnbaum AK. Epilepsy in the elderly. Ann N Y Acad Sci 2010;1184:208–24. [13] Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868–73. [14] LAM 40089 Study Group. Saetre E, Perucca E, Isojarvi J, Gjerstad L. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48:1292–302. [15] Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56:450–9. [16] Werhahn KJ, Klimpe S, Balkaya S, Trinka E, Kramer G. The safety and efficacy of add-on levetiracetam in elderly patients with focal epilepsy: a one-year observational study. Seizure 2011;20:305–11. [17] Chung S, Ben-Menachem E, Sperling MR, Rosenfeld W, Fountain NB, Benbadis S, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010;24:1041–54. [18] Zadeh WW, Escartin A, Byrnes W, Tennigkeit F, Borghs S, Li T, et al. Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: a multicentre open-label trial. Seizure 2015;31:72–9. [19] Novy J, Patsalos PN, Sander JW, Sisodiya SM. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction? Epilepsy Behav: E&B 2011;20:20–3. [20] Flores L, Kemp S, Colbeck K, Moran N, Quirk J, Ramkolea P, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy: a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure 2012;21:512–7. [21] Runge U, Arnold S, Brandt C, Reinhardt F, Kuhn F, Isensee K, et al. A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: the VITOBA study. Epilepsia 2015;56:1921–30. [22] Hoy SM. Zonisamide: a review of its use in the management of adults with partial seizures. Drugs 2013;73:1321–38. [23] Catarino CB, Bartolini E, Bell GS, Yuen AW, Duncan JS, Sander JW. The longterm retention of zonisamide in a large cohort of people with epilepsy at a tertiary referral centre. Epilepsy Res 2011;96:39–44. [24] Kothare SV, Kaleyias J. Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol 2008;4:493–506. [25] Trinka E, Giorgi L, Patten A, Segieth J. Safety and tolerability of zonisamide in elderly patients with epilepsy. Acta Neurol Scand 2013;128:422–8.