Epilepsy Research 123 (2016) 68–74

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Epilepsy Research

journa l homepage: www.elsevier.com/locate/epilepsyres

Clobazam and use in epilepsy: Results from a UK

database incident user cohort study

a,∗ b c d d

Martin J. Brodie , Steve Chung , Alan Wade , Céline Quelen , Alice Guiraud-Diawara ,

e d f f

Clément Franc¸ ois , Patrice Verpillat , Vivienne Shen , Jouko Isojarvi

a

Epilepsy Unit West Glasgow, ACH-Yorkhill, Glasgow G3 8SJ, Scotland, UK

b

Neuroscience Institute, Banner University Medical Center, 1111 McDowell Road, Phoenix, AZ, USA

c

Patients Direct, 3 Todd Campus, Glasgow G20 OXA, Scotland, UK

d

Health Economics and Epidemiology and Global Analytics, SAS, Quai du Président Roosevelt 37-45, 92445 Issy-les-Moulineaux, France

e

Health Economics and Outcomes Research, Lundbeck LLC, 4 Parkway North Suite 200, Deerfield, IL 60015, USA

f

Medical Affairs, Lundbeck LLC, 4 Parkway North Suite 200, Deerfield, IL 60015, USA

a

r t a b

i c l e i n f o s t r a c t

Article history: Objective: To compare patient characteristics and treatment patterns among clobazam (CLB) and clon-

Received 17 July 2015

azepam (CZP)-treated patients with epilepsy in a longitudinal primary care database.

Received in revised form 14 March 2016

Methods: In this pharmacoepidemiological study, real-life usage data from the Clinical Practice Research

Accepted 8 April 2016

Database (CPRD) were evaluated. The CPRD collects data from approximately 690 primary care practices

Available online 11 April 2016

throughout the UK. Data included were from patients with ≥1 incident CLB or CZP prescription from 1995

to 2011 and were present in the database for ≥182 days prior to the index date (date patient was first

Keywords:

prescribed CLB or CZP within the study period).

Cohort studies

Results: Of 21,099 patients who met inclusion criteria, 18.4% were receiving CLB and 81.6% were receiving

All epilepsy/seizures

CZP. More patients used CLB for epilepsy than CZP (76.1% vs 8.7%). CLB-treated adults (≤18 years) were

Antiepileptic drugs

≤

Outcome research younger than those treated with CZP (41.0 vs 48.2 years; p < 0.001), while CLB-treated children ( 18

Clobazam years) were older than those treated with CZP (8.8 vs 7.3 years, p < 0.001). The median CLB dosage did

Clonazepam not change from baseline to last follow-up, while median CZP dosage increased 25% in adults and 50% in

children. Median treatment duration, as well as retention rate up to 10 years, was similar between CLB

and CZP in each age group.

Conclusions: Among adult and pediatric patients in the UK, CLB is more often prescribed for epilepsy than

CZP. The median CLB dosage used by both adults and children remained stable over the 16-year study

period, while the median CZP dosage increased in both adults and children.

© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Benzodiazepines (BZDs) have been used to treat a variety

of disorders, including , depression, insomnia,

withdrawal, and seizures. While BZDs are the most commonly

prescribed class of psychotropic medications (Olfson et al., 2015),

Abbreviations: AED, antiepileptic drug; BNF, British National Formulary; BZD, select few are used to treat epilepsy: and for

; CLB, clobazam; CZP, clonazepam; CPRD, Clinical Practice Research

seizure emergencies; for refractory

Database; ISAC, Independent Scientific Advisory Committee; LGS, Lennox–Gastaut

and seizure emergencies; for myoclonic seizures, infan-

syndrome; MHRA, Medicines and Healthcare Products Regulatory Agency; NDD,

numeric daily dosage; NICE, National Institute for Health and Care Excellence. tile spasms and other childhood seizures; , clonazepam

∗

Corresponding author at: Medicine and Clinical Pharmacology, Epilepsy Unit and clobazam for long-term epilepsy management (Riss et al., 2008;

West Glasgow, ACH-Yorkhill Glasgow G3 8SJ, Scotland UK. Schatzberg and Nemeroff, 2009). Though BZDs are the drugs of first

E-mail addresses: [email protected] (M.J. Brodie),

choice for seizure emergencies (De Waele et al., 2013), their use as

[email protected] (S. Chung), [email protected] (A. Wade),

maintenance treatments declined over recent decades due to con-

[email protected] (C. Quelen), [email protected] (A. Guiraud-Diawara),

cerns regarding potential for abuse, tolerance, excessive sedation

[email protected] (C. Franc¸ ois), [email protected] (P. Verpillat),

[email protected] (V. Shen), [email protected] (J. Isojarvi).

http://dx.doi.org/10.1016/j.eplepsyres.2016.04.003

0920-1211/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/).

M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74 69

and cognitive decline with chronic use (Olfson et al., 2015; Paterniti Characteristics of patients with epilepsy at follow-up included

et al., 2002; Sankar et al., 2014; Stewart, 2005). The availability of time of follow-up, treatment duration, and drug dosage. Drug

several new antiepileptic drugs (AEDs) for maintenance therapy dosage was not directly available in the database and was therefore

also reduced BZD use for epilepsy. computed at the last prescription date using the following formula:

®

The BZDs clobazam (CLB; Onfi , Deerfield, IL, US) and clon- dosage = substance strength × numeric daily dosage (NDD), where

®

azepam (CZP; Klonopin , San Francisco, CA, US) have been used NDD corresponds to number of pills/tablets/milliliters per day. No

worldwide since the 1970s. CZP is approved in the EU for all forms imputation was performed when NDD was 0 or missing.

of epilepsy and for panic attacks in adults, and in the US for panic The evaluation of the development of dependence was a

disorder and as mono- or adjunct therapy in a broad range of seizure secondary objective of the study. Drug dependency cases were

disorders, including Lennox–Gastaut syndrome (LGS). CLB has been identified by the presence of one record with a drug dependence

successfully used for many years in the EU as both an AED and diagnosis (Read code: E24*—Drug dependence, Eu19211—[X]

an , but was approved only recently in the US (October Drug addiction NOS) or a drug dependence detoxification (Read

2011) for the adjunctive treatment of seizures associated with LGS code: 8BA9*—Detoxification dependence drug) during follow-up.

in patients ≥2 years (Ng et al., 2011). Patients with a history of drug dependency before treatment initi-

As use of CLB in the EU has been well established, data from ation were not included in this analysis.

the UK-based Clinical Practice Research Datalink were evaluated to

compare real-world use of CLB versus CZP for epilepsy.

2.4. Statistical analysis

2. Methods Statistical comparisons between CLB- and CZP-treated groups

were performed using the student t test for continuous variables

2

2.1. Data source and either the X or Fisher exact tests for categorical variables. For

treatment duration and analysis of drug dependence, curves were

The Clinical Practice Research Datalink (CPRD), which fur- drawn using the Kaplan-Meier method and statistical comparisons

thers the research developments of the General Practice Research were performed using the log-rank test. For the analysis of drug

Database (GPRD) (Lawson et al., 1998), comprises more than 62 dependence, the incidence rate per person year was also calculated:

million patient-years of data collected from approximately 10

million patients throughout the United Kingdom (UK). It is the

Incidence rate / person-year =

largest computerized database of anonymous, longitudinal, pri-

mary care clinical records. CPRD data, which are currently being

Number of patients with drug dependency

collected from 690 primary care practices, are directly generated by

Total time of exposure to treatment for all patients (years)

computer from general practitioner (GP) practices equipped with

specialized software. Data from the CPRD have been extensively

used in over 890 clinical reviews and papers, including numer-

2.5. Standard protocol approvals, registrations, and patient

ous pharmacoepidemiological studies. The principal information

consents

available for analysis includes patient demographics, prescriptions

of medicine, clinical diagnoses, hospital or specialist referrals, and

All research undertaken using data obtained from CPRD is

laboratory test results (Garcia Rodriguez and Perez Gutthann, 1998;

approved by, as appropriate, an ethics committee, a scientific com-

Wood and Martinez, 2004).

mittee, and the National Information Governance Board Ethics and

Confidentiality Committee. Protocol 13 043R entitled “Treatment

2.2. Study design and inclusion criteria

Patterns in Patients With Epilepsy in Primary Care in the UK” was

approved April 3, 2013 by the Independent Scientific Advisory Com-

In this historical, longitudinal, incident-user (Johnson et al.,

mittee (ISAC) for Medicines and Healthcare Products Regulatory

2012) cohort study, patient data were obtained from the externally

Agency (MHRA) Database Research for CPRD.

validated CPRD database (Jick et al., 1991; Jick et al., 2003). Epilepsy

patients who had at least one incident prescription of CLB or CZP

3. Results

within the study period (1995–2011) were included in the analysis

(Fig. 1). To ensure patients had not been previously prescribed CLB

3.1. CPRD patient population

or CZP, patient data must have been present in the database for at

least 182 days prior to the index date and without any prescription

Of 21,099 patients who met inclusion criteria, 3882 (18.4%)

for CLB or CZP. The index date is defined as the date of first CLB or

received CLB and 17,217 (81.6%) received CZP (Fig. 1). Overall, CLB

CZP prescription within the study period.

was more widely used for the treatment of epilepsy than CZP as

76.1% of patients received CLB for epilepsy, while only 8.7% of

2.3. Patient characteristics and treatment patterns evaluated

patients received CZP for epilepsy (Fig. 1).

The primary objectives were to evaluate demographic charac-

teristics and treatment patterns between patients prescribed CLB 3.2. Adult patients with epilepsy

and those prescribed CZP. Demographics and baseline characteris-

tics for patients with epilepsy included age, sex, drug dosage, and 3.2.1. Baseline characteristics

concomitant AED use. Patients with an epilepsy diagnosis at the In the CPRD database, 2312 adults (≥18 years) with epilepsy

index date were those who had at least one record with an epilepsy had received CLB and 1268 had received CZP (Table 1). A greater

diagnosis any time prior to the index date or within 90 days follow- percentage of adults with epilepsy were women, but the female-

ing the index date. Primary AEDs of interest were selected according to-male patient ratio was the same in either treatment group.

to the National Institute for Health and Care Excellence (NICE) clin- On average, CLB-treated adults were younger than those treated

ical guidelines regarding the management of epilepsy and grouped with CZP (41.0 vs 48.2 years, respectively; p < 0.0001). The median

according to the British National Formulary (BNF) classification sys- (range) CLB dose was 10.0 mg (5.0–60.0); the median (range) CZP

tem. dose was 0.8 mg (3.0–8.0).

70 M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74

a b

Fig. 1. Study flow.

A significantly greater percentage of CLB-treated adults were with CZP (8.8 vs 7.3 years, p < 0.001). The median (range) CLB dose

receiving concomitant AEDs than those treated with CZP (93% CLB was 20.0 mg (5.0–60.0); the median (range) CZP dose was 1.0 mg

vs 79% CZP; p < 0.0001). Significantly fewer CLB-treated adults used (0.3–7.5).

concomitant BZDs (eg, diazepam) than those receiving CZP (9% CLB A comparable number of CLB- and CZP-treated children were

vs 12% CZP; p = 0.002). The most commonly used concomitant AEDs receiving concomitant AEDs (92% CLB vs 89% CZP; p = 0.18),

≥

( 15%) among both treatment groups were (30%), including BZDs (9% vs 10%; p = 0.73). The most commonly used con-

sodium (29%), (28%) and (20%). comitant AEDs (≥15%) in either pediatric treatment group were

sodium valproate (40%), lamotrigine (30%), carbamazepine (20%)

and (16%).

3.2.2. Follow-up characteristics

The average time of follow up for both CLB- and CZP-treated

patients was similar and greater than 5 years (5.5 years CLB vs 5.2 3.3.2. Follow-up characteristics

years CZP; Table 2). The median CLB dosage did not change from Children treated with CLB had a shorter follow-up period than

baseline to last follow-up, while median CZP dosage increased 25% those treated with CZP (5.5 vs 6.3 years; p = 0.027). The median CLB

(Tables 1 and 2). The median duration of treatment was similar dosage did not increase from baseline to last follow up, while the

between CLB and CZP (28.3 months CLB vs 27.5 months CZP; Fig. 2). median CZP dosage increased 50% (Tables 1 and 2). The median

Retention rates up to 10 years were similar between CLB- and CZP- treatment duration was similar between groups (34.6 months CLB

treated patients. vs 31.2 months CZP; Fig. 3). Retention rates up to 10 years were

similar between treatment groups.

3.3. Children with epilepsy

3.4. Dependence analysis for patients with epilepsy: all ages

3.3.1. Baseline characteristics

In the CPRD database, 574 pediatric patients (<18 years) with A total of 26 CLB- and CZP-treated patients (13 in each treatment

epilepsy had received CLB and 171 had received CZP (Table 1). A group: 0.5% CLB, 0.9% CZP) had a confirmed drug dependency diag-

greater percentage of children with epilepsy were males, but the nosis, indicating a 1.6 and 3.3 incidence rate (per 1000 person-year)

ratio of male-to-female patients was the same in either treatment in the respective treatment groups. Overall, at least 11 patients

group. CLB-treated pediatric patients were older than those treated were identified as having benzodiazepine dependence, though the

M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74 71

Table 1

Demographics and baseline characteristics of patients with epilepsy receiving CLB or CZP.

Pediatric patients (<18 years) Adult patients (≥18 years)

a a

Clobazam (n = 574) Clonazepam (n = 171) p-value Clobazam (n = 2312) Clonazepam (n = 1268) p-value

Sex Male 311 (54%) 92 (54%) 0.93 1035 (45%) 567 (45%) 0.98

Female 263 (46%) 79 (46%) 1277 (55%) 701 (55%)

Age (years) Mean ± SD 8.8 ± 5.0 7.3 ± 5.4 <0.001 41.0 ± 14.9 48.2 ± 18.6 <0.001

Age groups (years) 0–5 144 (25%) 72 (42%) <0.001 NA NA

6–12 261 (45%) 57 (33%) NA NA

13–17 169 (29%) 42 (25%) NA NA

18–64 NA NA 2134 (92%) 996 (79%) < 0.001

65 and older NA NA 178 (8%) 272 (21%)

± ± ± ± ±

Dose (mg) Mean SD 18.4 11.9 1.7 1.6 NA 14.9 7.0 1.0 1.0 NA

Median 20.0 1.0 10.0 0.8

[Range] [5.0–60.0] [0.3–7.5] [5.0–60.0] [0.3–8.0]

Missing 320 (56%) 75 (44%) 1083 (47%) 445 (35%)

Any AEDs 529 (92%) 152 (89%) 0.18 2144 (93%) 1000 (79%) < 0.001

Number of AEDs 0 45 (8%) 19 (11%) 0.44 168 (7%) 268 (21%) <

1 312 (54%) 91 (53%) 1080 (47%) 567 (45%) 0.001

2 185 (32%) 49 (29%) 808 (35%) 349 (28%)

≥3 and more 32 (6%) 12 (7%) 256 (11%) 84 (7%)

Co-prescription AEDs

Barbiturates (eg, ) 11 (2%) 8 (5%) 0.05 68 (3%) 50 (4%) 0.11

Hydantoins (eg, , ) 23 (4%) 7 (4%) 0.96 299 (13%) 181 (14%) 0.26

Succinimides (eg, ) 20 (3%) 4 (2%) 0.46 9 (0%) 3 (0%) 0.56

Benzodiazepines (eg, CLB, CZP, diazepam) 52 (9%) 17 (10%) 0.73 206 (9%) 154 (12%) 0.002

Carboxamides (eg, 131 (23%) 30 (18%) 0.14 818 (35%) 313 (25%) < 0.001

carbamazepine, ,

)

Fatty acid derivatives (eg, 229 (40%) 92 (54%) 0.001 694 (30%) 391 (31%) 0.61

valproate, )

Others AEDs 314 (55%) 70 (41%) 0.002 1408 (61%) 441 (35%) < 0.001

CLB, clobazam; CZP, clonazepam; SD, standard deviation; NA, not applicable.

a 2

Student t-test for continuous variables and ␹ or Fisher’s exact tests for categorical variables.

Table 2

Follow-up characteristics of patients with epilepsy receiving CLB or CZP.

Pediatric patients (<18 years) Adult patients (≥18 years)

a a

Clobazam (n = 574) Clonazepam (n = 171) p-value Clobazam (n = 2312) Clonazepam (n = 1268) p-value

±

Time of follow up, years (mean ± SD) 5.5 3.8 6.3 ± 4.4 0.027 5.5 ± 3.9 5.2 ± 4.1 0.0023

Treatment duration, months (mean ± SD) 35.4 ± 40.6 36.8 ± 46.6 0.70 34.7 ± 42.8 32.4 ± 42.8 0.12

Median dosage at last prescription, mg/day [range] 20.0 [5.0–60.0] 1.5 [0.5–8.0] NA 10.0 [5.0–60.0] 1.0 [0.3–8.0] NA

CLB, clobazam; CZP, clonazepam; SD, standard deviation; NA, not applicable. a

Student t-test.

particular type of BZD was not specified in the database. The likeli- (≥18 years) and pediatric patients (<18 years). Overall, CLB was

hood of patients remaining free of drug dependency over a 5-year more widely used for the treatment of epilepsy than CZP (76.1%

treatment period was 99.4% among CLB-treated patients and 98.5% vs 8.7%, respectively). These results mirror the trend observed in a

among CZP-treated patients (Fig. 4). The incidence rate per 1000 previously conducted primary care cohort study that evaluated AED

Patient Year Exposure was 1.55 among CLB-treated patients and utilization in the UK from 1993 to 2008 (Nicholas et al., 2012). In

3.29 among CZP-treated patients. that study, CLB use exceeded CZP use by the end of the study period

(CLB: 2.2% person-years in 1993–3.3% in 2008; CZP: 2.6% person-

years in 1993–2.9% in 2008), though both drugs were among the

4. Discussion

less frequently prescribed AEDs overall (Nicholas et al., 2012).

Because of its unique 1,5 chemical structure, receptor binding

In addition to the treatment of anxiety and other disorders,

properties, and clinical effects, CLB may offer an improved safety

both CLB and CZP have long been used in Europe for the treatment

profile over the 1,4-BZDs, as well as sustained efficacy that may

of epilepsy, primarily idiopathic generalized and partial epilepsy.

not be evident with other BZDs used to treat epilepsy (Riss et al.,

While concerns over safety with both acute treatment (eg, sedation,

2008; Wheless and Phelps, 2013). CLB is highly selective for the

psychomotor and cognitive impairment) and chronic use (toler-

subunit of the GABAA receptor that is associated with antiepileptic

ance, withdrawal syndrome) (Lader, 2008; Paterniti et al., 2002)

activity (␣2) with less affinity toward the subunit that is known

should be considered when making treatment decisions, the ben-

to contribute to sedation (␣1), while CZP is nonselective for either

efits of BZDs for epilepsy appear to outweigh the risks for many

subunit (Jensen et al., 2014). Furthermore, though the exact manner

patients, including children (Conry et al., 2014; Mehndiratta et al.,

in which tolerance can occur with particular BZDs remains to be

2003; Montenegro et al., 2001; Silva et al., 2006).

determined, the differential expression of GABAA receptor subunits

In the longitudinal cohort study of data from the UK-based CPRD

in the brain and the variable affinities of BZDs for those subunits

presented here, patient characteristics and treatment patterns for

CLB and CZP use from 1995 to 2011 were evaluated in both adult

72 M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74

a Number of patients still on follow-up and for whom no events have occurred

Fig. 2. Median duration of treatment in adult patients with epilepsy.

a Number of patients still on follow-up and for whom no events have occurred

Fig. 3. Median duration of treatment in pediatric patients with epilepsy.

have been implicated in the mechanisms underlying tolerance with patients that was not apparent in CLB-treated patients in this study.

BZDs (Sankar, 2012; Vinkers and Olivier, 2012; Vinkers et al., 2012). From baseline to the follow-up period, the median CLB dosage did

Differences in the mechanism of action between CLB and CZP not increase for either patient population, while the median CZP

could explain the median dosage increase observed in CZP-treated dosage increased 25% in adults and 50% in children. As the initial

M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74 73

Fig. 4. Kaplan-Meier Analysis of Time to Drug Dependency.

dosages of CLB and CZP appeared to be equivalent (10–15 mg/day 5. Future directions

CLB:1 mg/day CZP) (Sankar et al., 2014), these results suggest that

there was a therapeutic need to increase the CZP dose over time, Further analysis of the CPRD database supplemented with data

possibly due to loss of efficacy, and perhaps indicating the devel- from a managed care database could include comparisons of AED

opment of tolerance to CZP that was not observed with long-term effectiveness through an evaluation of surrogates for effectiveness,

CLB use. Indeed, a loss of efficacy in approximately 30% of CZP- such as rates of hospitalizations, in-patient and out-patient office

treated patients within 3 months of use has been suggested (Bacia visits, as well as changes in AED prescriptions (dosage changes,

et al., 1980; Pinder et al., 1976), yet CLB use over a period of 3 years newly added medications).

has resulted in sustained improvements in drop- and total seizures

in patients with LGS (Conry et al., 2014). Similarly, although the

analysis of dependence using dependence diagnosis is likely to

lack sensitivity, the higher incidence of dependence diagnosis for 6. Conclusions

CZP versus CLB further supports a possible difference in tolerance

profile between the drugs. A difference in tolerance between CLB In the UK, stable doses of CLB have been used for

and CZP treatment can have important clinical implications: CZP years—primarily for the treatment of epilepsy in both adult and

may be more appropriate for shorter-term use for non–epilepsy- pediatric patients—while CZP use in epilepsy is limited. An increase

related disorders, while clobazam may be considered an effective, in the median dose of CZP used was evident in the 16-year study

long-term therapy for various forms of epilepsy. period, but no such dose increase was observed in patients treated

Overall, CLB-treated adults in this study were receiving more with CLB. The results from this study suggest that UK physicians

concomitant AEDs than CZP-treated adults, an observation that prefer CLB over CZP for the treatment of epilepsy.

may be attributed to the fact that CLB is primarily used as an adjunc-

tive epilepsy therapy in the UK. A less likely explanation is that such

differences in AED usage might indicate greater disease severity

Author contributions

among those in the CLB group or possibly reflect variable use of

these two BZDs for different types of epilepsy; such conclusions

M.J. Brodie: conceptualization of the study, data interpretation,

cannot be made without additional patient information and analy-

and revising the manuscript for intellectual content.

ses. Though the CPRD database is broadly representative of the UK

S. Chung: conceptualization of the study, data interpretation,

population, there are some inherent limitations of this database

and revising the manuscript for intellectual content.

including the possibility of missing data (which may be due to the

A.G. Wade: conceptualization of the study, data interpretation,

inability to capture prescriptions from neurologists), a lack of con-

and revising the manuscript for intellectual content.

sideration for confounding effects, and the inability to identify the

C. Quelen: design and conceptualization of the study, data anal-

type of epilepsy for which patients are receiving either CLB or CZP.

ysis and interpretation, and revising the manuscript for intellectual

The median treatment duration was similar between CLB- and

content.

CZP-treated groups in both adult and pediatric populations, but

A. Guiraud-Diawara: design and conceptualization of the study,

the follow-up period was slightly shorter for CLB-treated children

data interpretation, and revising the manuscript for intellectual

compared to their CZP-treated counterparts (5.5 vs 6.3 years). The

content.

reason for the slight variation in length of follow-up among the

C. Franc¸ ois: conceptualization of the study, data interpretation,

CLB- and CZP-treated pediatric population is unclear, as is the cause

and revising the manuscript for intellectual content.

for the opposing pattern of CLB vs CZP use by age: adult patients

P. Verpillat: conceptualization of the study, data interpretation,

treated with CLB for epilepsy were younger than those treated with

and revising the manuscript for intellectual content.

CZP, while CLB-treated children were older than their CZP-treated

V. Shen: design and conceptualization of the study, data inter-

counterparts. These results may simply reflect variability in patient

pretation, and revising the manuscript for intellectual content.

care among the physicians in the UK who issue the majority of long-

J. Isojarvi: conceptualization of the study, data interpretation,

term prescriptions and manage the continuity of AED treatments.

and revising the manuscript for intellectual content.

74 M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74

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