FULL-LENGTH ORIGINAL RESEARCH

Epilepsy in children with tuberous sclerosis complex:

Chance of remission and response to antiepileptic drugs
*†Iris E. Overwater, †‡Karen Bindels-de Heus, *†Andr
e B. Rietman, †§Leontine W. ten Hoopen,
¶Yvonne Vergouwe, ‡Henriette A. Moll, and *†Marie-Claire Y. de Wit

Epilepsia, 56(8):1239–1245, 2015

doi: 10.1111/epi.13050

SUMMARY
Objective: To describe treatment and outcome of epilepsy in children with tuberous
sclerosis complex (TSC).
Methods: Seventy-one children with TSC and epilepsy treated at the ENCORE TSC
Expertise Center between 1988 and 2014 were included. Patient characteristics and
duration and effectiveness of antiepileptic treatments were extracted from our clinical
database. Correlations were made between recurrence of seizures after response to
treatment, and several patient characteristics.
Results: Median age at time of inclusion was 9.4 years (range 0.9–18.0). Seizure history
showed that 55 children (77%) of 71 became seizure-free for longer than 1 month, and
21 (30%) of 71 for longer than 24 months. Remission of seizures was associated with
higher IQ, and a trend was observed between seizure remission and age at onset of sei-
zures. A total of 19 antiepileptic drugs (AEDs) were used. Valproic acid, vigabatrin, lev-
etiracetam, and carbamazepine were used most frequently. Nonpharmacologic
therapies (ketogenic diet, epilepsy surgery, and vagus nerve stimulation) were used 13
times. Epilepsy surgery was most effective, with four of five children becoming seizure-
Iris E. Overwater is a free. AEDs prescribed as first and second treatment were most effective. Valproic acid
doctoral student in was prescribed most frequently as first and second treatment, followed by vigabatrin.
pediatric neurology at Thirty-one children had infantile spasms, preceded by focal seizures in 18 children
the ENCORE TSC (58%). Vigabatrin was used by 29 children (94%), and was first treatment in 15 (48%).
Expertise Center. Vigabatrin was more effective than other AEDs when prescribed as first treatment.
Significance: We showed that, although 77% of children with epilepsy due to TSC
reached seizure remission, usually after their first or second AED, this was sustained
for at least 24 months in only 38%. Almost half of those with 24 months of remission
later had relapse of seizures. Our results support vigabatrin as first choice drug, and
show the need for better treatment options for these children.
KEY WORDS: Anticonvulsants, Infantile spasms, Intellectual disability.

Tuberous sclerosis complex (TSC) is a genetic neurocog-

Accepted May 4, 2015; Early View publication June 4, 2015.
*Department of Neurology, Erasmus MC-Sophia Children’s Hospital,
nitive disorder, with an incidence of one in 6,000–10,000
Rotterdam, The Netherlands; †ENCORE TSC Expertise Center, Erasmus live births.1 Epilepsy is reported in up to 90% of TSC
MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; patients, and often starts in infancy.2 Seizure semiology var-
Departments of ‡Pediatrics and §Child and Adolescent Psychiatry/
Psychology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The
ies between patients and can change throughout a patient’s
Netherlands; and ¶Department of Public Health, Erasmus MC Rotterdam, lifetime. About 50% of children with epilepsy due to TSC
Rotterdam, The Netherlands present with infantile spasms, which are associated with a
Address correspondence to Marie-Claire Y. de Wit, Erasmus MC-
Sophia Children’s Hospital, Room Sk-1214, PO Box 2060, 3000 CB Rot-
worse cognitive outcome.3–5 Treatment of seizures due to
terdam, The Netherlands. E-mail: [email protected] TSC is notoriously difficult. Recently, a large study showed
Wiley Periodicals, Inc. that more than half of all studied patients have refractory
© 2015 International League Against Epilepsy epilepsy.6

1239
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I. E. Overwater et al.

Recently, mTOR protein inhibiting drugs have been U.S.

Food and Drug Administration (FDA)/European Medicines
Key Points Agency (EMA) approved as treatment for TSC-related sube-
pendymal giant cell astrocytomas (SEGAs) and renal angio-
• Seventy-seven percent of children in our population myolipomas (AMLs).21,22 These drugs are not yet registered
reached seizure remission of at least 1 month, which for the treatment of epilepsy in TSC, but animal studies and
was sustained for 24 months in only 38%. an open label study of 20 patients suggested a good antiepi-
• Almost half of the children with 24 months of remis- leptic effect (60% good response).23 In the light of this
sion had a later relapse of seizures. potential new treatment option, acquiring more insight into
• The first and second AEDs were most effective in the prognosis of seizure remission in TSC and into the bene-
achieving seizure remission. fit of conventional antiepileptic treatments in TSC would be
• Vigabatrin was confirmed as the most effective drug useful to help select patients that may benefit from new treat-
when prescribed as first treatment. ments. In this study we describe the use of antiepileptic treat-
• Remission of seizures was associated with higher IQ. ments in a large cohort of children with TSC and explore the
response to antiepileptic treatments and the chance of remis-
sion after the first and following AED regimens.
Clinical symptoms of patients with TSC are highly vari-
able. During brain development, neural cells can develop
aberrant morphology and migration, leading to typical fea-
Methods
tures of cortical tubers and radial migration lines. These Patients
pathologic changes in brain tissue have been implicated in All children (0–18 years) with a clinically definite diag-
causing epilepsy in patients with TSC.7 Possibly, mamma- nosis of TSC according to TSC diagnostic criteria24 who
lian target of rapamycin (mTOR) dysregulation in neurons were treated at the ENCORE TSC expertise center at the
can also independently contribute to epileptogenesis.8 Erasmus MC-Sophia Children’s Hospital between 1988 and
Developmental delay and autism spectrum disorders are 2014 were potentially eligible for inclusion (n = 106).
also frequent consequences of TSC, with 40% of patients Ninety-four children ever had epileptic seizures requiring
having intellectual disability (IQ < 70).9 treatment. Of those, 23 of 94 could not be included because
A large number of antiepileptic drugs (AEDs) are avail- of lack of data completeness on epileptic seizures and the
able for seizure treatment, as well as nonpharmacologic types of treatments that were used, despite our best efforts
approaches such as surgery and the ketogenic diet. Recent in obtaining all data, including interviewing the parents.
clinical recommendations made by the International TSC
Consensus Conference state that “anticonvulsant therapy Data collection
in TSC should generally follow that of other epilepsies,”10 All children treated at the TSC clinic are entered in a
and in 2012 the TSC expert panel specifically recom- clinical database at their first visit. From then on, all data
mended vigabatrin as first-line intervention for infants and are collected prospectively. Data on the clinical history
AEDs with c-aminobutyric acid (GABA)ergic mecha- before their first visit are obtained from hospitals and
nisms for older children.11 In general, first-line treatment other care providers the patient has visited. Of 71 chil-
for partial onset seizures in children is based on level C dren, all data were included until the end of follow-up in
evidence (clinical trials with <20 participants) and expert February 2014, or until they reached the age of 18 years.
experience.12 Data extracted from our clinical database were demo-
Etiology of epileptic seizures is known to be an important graphics, TSC diagnostic criteria, results of genetic test-
factor in the chance of intractability, and the International ing, seizure history of the child, and order of use, start
League Against Epilepsy (ILAE) recommends considering and stop date of all seizure treatments, including anti-
the underlying disease when choosing an AED. Vigabatrin epileptic drugs (AEDs), ketogenic diet, vagus nerve stim-
(VGB) is most effective in the treatment of infantile spasms ulation (VNS), and epilepsy surgery. If the exact start or
in TSC, and is the treatment of first choice.11,13,14 For other stop date of a treatment was unknown, the best estimate
seizure types, there is evidence for efficacy of lamotrigine was made as the middle date of the time period that was
(LTG),15 levetiracetam (LEV),16 and clobazam (CLB)17 certain. Such an estimate was made for 219 start and stop
from small patient studies. For other AEDs specific effec- dates (32%), and this period was longer than 30 days in
tiveness in TSC is unclear. Frequently used AEDs are valp- 66 instances (10%).
roic acid (VPA), LEV, topiramate (TPM), oxcarbazepine The response to treatment was classified into five catego-
(OXC), and carbamazepine (CBZ).18 Nonpharmacologic ries: seizure-free (defined as no seizures for at least
epilepsy treatments shown to be effective in patients with 1 month), temporarily seizure-free (defined as the need for
TSC are the ketogenic or low glycemic index diet and epi- a new treatment strategy after a seizure-free period of at
lepsy surgery.19,20 least 1 month), seizure reduction of >50%, no beneficial
Epilepsia, 56(8):1239–1245, 2015
doi: 10.1111/epi.13050
 1241
Epilepsy in TSC—Response to Treatment

effect, or increase of seizure frequency. Treatment success

Table 1. Patient characteristics (n = 71)
was defined as seizure freedom or >50% seizure frequency
reduction. Age in months at time of data collection, 114 (72–185)
The treatment response was extracted from reports of the median (25–75 percentile)
Gender male (%) 37 (52)
treating (pediatric) neurologist. The exact duration of Mutation TSC1/TSC2/NMI/not tested (%) 20/46/3/2 (28/65/4/3)
seizure freedom was not always clear from the patient Follow-up duration in months, 109 (68–177)
records and parents’ memory. Therefore, duration of seizure median (25–75 percentile)
freedom was defined as the interval between the start of the Age at first seizure in months, 7 (4–19)
AED causing seizure freedom, and the start of a subsequent median (25–75 percentile)
Infantile spasms (%) 31 (44)
treatment for seizure recurrence. Patients were considered Ever had status epilepticus (%) 21 (30)
to have sustained seizure freedom when they were seizure- Intellectual quotient (n = 58), median (range) 54.5 (5–97)
free for an interval of 24 months. Reasons for discontinuing
NMI, no mutation identified.
AEDs were recorded.
Results of intellectual development testing were available
for 57 children. Because of a broad range of developmental mutation were more likely to have had infantile spasms
and cognitive functioning, abilities were assessed using the (p = 0.027).
Wechsler intelligence scales (Wechsler Preschool and Pri-
mary Scale of Intelligence [WPPSI], Wechsler Intelligence Seizure freedom and relapse
Scale for Children [WISC], Wechsler Nonverbal Scale of Seizure freedom was reached in 55 (77%) of 71 patients
Ability [WNV]) (n = 32, 56%) and the Bayley Scales of for one or more periods of at least 1 month. Figure 1 shows
Infant Development (BSID) (n = 21, 37%). A minority of the recurrence of seizures after the first seizure-free period.
children were tested with the Snijders-Oomen Non-verbal Of these 55 children, 13 (24%) had a relapse of seizures
Intelligence Scale (SON-R) (n = 3, 5%) and the Vineland after 1–3 months. Thirty-two children (58%) had a recur-
Adaptive Behavior Scales (n = 1, 2%). rence of seizures during the first year after becoming
seizure-free. Sustained remission (24 months of seizure
Data analysis freedom) was reached in 21 children (38%), of whom 11
Continuous variables were not normally distributed. Chi- discontinued their AED treatment after a mean period of
square tests were used for categorical data regarding the 56 months (range 7–166). Nine of the 21 long-term seizure-
efficacy of the various order numbers of AEDs, and the free children (43%) had a recurrence after being seizure-free
analysis of genotype and epilepsy severity. Spearman’s Rho for more than 24 months. This recurrence occurred after a
was used for correlations of age at onset of epilepsy, infan- period of up to 14 years. Figure 1a shows seizure relapse
tile spasms, mutation type, and IQ with duration of seizure divided in age groups of seizure onset. Of the 21 children
freedom. Comparisons were considered statistically signifi- who reached sustained remission, almost half were older
cant if the two-sided alpha level was below 0.05. Survival than 12 months at onset of epileptic seizures. Six children
graphs were made by Kaplan-Meier analyses. Data were (28%) were aged 0–6 months when the first seizure was
analyzed by using IBM SPSS statistics 21. observed, five (24%) were aged between 7–12 months, and
10 children (48%) were aged 13 months or older. Children
with onset of epilepsy later in life seemed to have longer
Results periods of seizure freedom (ns). Figure 1b,c shows that
Patient characteristics there is no statistical difference in seizure relapse of children
Seventy-one children with TSC were included. Median with or without infantile spasms, and of children with a
age at end of follow-up was 9.4 years (range 0.9–18.0), TSC1 or TSC2 mutation. Intellectual development was
and the median follow-up duration was 109 months assessed in 49 patients with sustained seizure freedom. Fif-
(range 11–216). Genetic analysis showed a mutation of teen children (27%) had an IQ of 71 or higher, and 34 (62%)
the TSC1 gene in 20 (28%) of 71 patients, and a mutation had an IQ of 70 or lower (intellectual disability). Intellectu-
in TSC2 in 46 (65%) of 71. No mutation was identified in ally disabled children had a shorter duration of seizure free-
three patients, and two patients were not tested. Baseline dom (p = 0.006).
demographics and epilepsy characteristics are shown in
Table 1. Information about intellectual development was Various AEDs used
available for 57 children. Children with a mutation in the The patients in our cohort used a total of 19 different
TSC1 gene had a higher IQ, with a median of 65, com- AEDs. Table 2 shows the total number of AEDs and the
pared to children with a TSC2 mutation (median 47). number of treatments that were used simultaneously per
Children who had infantile spasms had lower cognitive child (polytherapy). The use of specific AEDs is presented
abilities (median IQ 43) than children who did not have in Figure 2. Most frequently used AEDs were VPA (85%),
infantile spasms (median IQ 60). Children with a TSC2 VGB (61%), LEV (46%), CBZ (41%), and CLB (41%).
Epilepsia, 56(8):1239–1245, 2015
doi: 10.1111/epi.13050
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I. E. Overwater et al.

A B

Figure 1.
Proportion of children with sustained
seizure remission (n = 55). (A)
Seizure recurrence shown by age of
onset of epilepsy; 0–6 months n = 25
(45%), 7–12 months n = 12 (22%),
13 months and older n = 18 (33%).
(B) Seizure recurrence shown by
history of infantile spasms; no history
of IS n = 27 (49%) and history of IS
C D n = 28 (51%). (C) Seizure recurrence
shown by mutation type; TSC1
n = 15 (27%) and TSC2 n = 36
(65%). (D) Seizure recurrence shown
by intellectual ability; IQ ≥ 71 n = 15
(27%) and IQ ≤ 70 n = 34 (62%)
(p = 0.006).
Epilepsia ILAE

Table 2. Seizure treatment characteristics

Total number of treatments used per childa, 4 (1–19)
median (range)
Maximum number of treatments used simultaneously, 2 (1–5)
median (range)
Patients who used ketogenic diet (%) 6 (8)
Patients who underwent epilepsy surgery (%) 6 (8)
Patients who used vagus nerve stimulator (%) 1 (1)
a
Subsequently and simultaneously, treatments include total number of
AEDs and all nonpharmacologic treatments.

Other treatments used in our study population were epilepsy

Figure 2.
surgery (8%), ketogenic diet (8%), and vagus nerve stimula-
Percentage of children who used a specific AED during follow-up.
tion (1%). The y-axis shows the percentage of the total study population.
Numbers in the graph depict number of children who used that
Response to AEDs per order number of treatment AED.
We examined the order in which AEDs were used for Epilepsia ILAE
which patients became seizure-free for the first time, and
the total number of times the order in which AEDs were AED. One child (1%) had his first seizure remission after
used caused seizure freedom, without taking the type of the fifth AED. No patient became seizure-free for the first
AED into account. Most children who became seizure-free time on an AED later than the fifth order number. Figure 3
experienced their first period of seizure freedom after the shows the order number of AEDs used during follow-up and
first or second AED. In total, 37 (52%) of 71 children their effectiveness in causing seizure reduction. The first
reached seizure freedom after the first AED, and an addi- and second prescribed AEDs were significantly more suc-
tional 11 (16%) had a decrease in seizure frequency of cessful in attaining both seizure freedom and treatment suc-
>50%. Fourteen children (20%) became seizure-free after cess than AEDs used as fourth or later treatment (first AED
the second AED, and four children (6%) after the third p < 0.001 and p = 0.002, second AED p = 0.002 and
Epilepsia, 56(8):1239–1245, 2015
doi: 10.1111/epi.13050
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Epilepsy in TSC—Response to Treatment

quently due to side effects (4% of total VGB use). A total of

seven different AEDs were reportedly associated with
increased seizure frequency, including OXC, VPA, and
CBZ.

Nonpharmacologic epilepsy therapies

Seizure freedom was achieved in four of the six children
who underwent epilepsy surgery. Two children remained
seizure-free, whereas the other two had a later recurrence of
seizures. The fifth child had a reduction of seizure fre-
Figure 3. quency of >50%. The ketogenic diet did not result in seizure
Response to AED use (n = 322, 16 missing due to unknown freedom in any of the six patients on the diet; however, in
response), according to their order number. Between parentheses two patients, seizure frequency was reduced by more than
are depicted the number of times an AED was used as that order 50%. A vagus nerve stimulator was used in one patient, but
number. Due to small numbers, AEDs 11–19 are summarized in did not cause seizure reduction.
one bar.
Epilepsia ILAE Treatment of infantile spasms
Thirty-one children in our cohort had infantile spasms. Of
p = 0.002). As is shown in Figure 3, seizure freedom did these, 29 children had a seizure onset before the age of
still occur with later treatment options, up to the tenth order 1 year. Focal seizures preceded infantile spasms in 10 chil-
number of AEDs. These are in children who already experi- dren (32%). Twenty-seven (87%) had at least one seizure-
enced a seizure-free period earlier during their treatment, free period. Eight children (26%) remained seizure-free for
which was followed by seizure relapse. Although treatment more than 24 months. The number of treatments used in the
benefit could still be achieved at a later order number of first 24 months of life ranged from 1 to 10 (median 3). VGB
AEDs, it decreased rapidly with subsequent AEDs. was used most often (94% of patients), and was used as the
first treatment in 15 children (48%), and second in 10 chil-
Sequence of AEDs during treatment dren (32%). The second most common treatment was VPA
Nine different drugs were prescribed as first treatment. (74% of children). All other treatments were used by five
VPA was prescribed most often (45%), followed by VGB children or less. In children receiving VPA as their first
(25%), phenobarbital (PB) (11%), CBZ (8%), and OXC treatment, VGB was prescribed second (7/9), or third (1/9).
(4%). LEV and phenytoin were both prescribed as first drug One child was seizure-free with VPA alone. Reasons for
to two children, and LTG and nitrazepam to one child. Sei- starting VPA before VGB included treatment in the time
zure freedom or treatment success was reached with VPA in period before the benefit of VGB was evident (4/9), focal
70% of children, with VGB in 78%, PB in 50%, CBZ in seizures at seizure onset (3/9), nontypical electroencepha-
67%, and with OXC in 67%. All first used drugs were used lography (EEG; 1/9) and other AED choice by a medical
as monotherapy. professional (1/9).
A second AED was used by 25 children (81%) and a third
Response to repeated use of the same AED by 17 children (55%). No significant differences were found
Fourteen children used 11 different AEDs on multiple when treatment success of all accounts of all different types
occasions, with a maximum of three times per child. If the of AEDs was analyzed (p = 0.160). However, when the first
first trial of a specific AED caused seizure freedom, in 60% AED was analyzed, VGB resulted in more seizure freedom
(6/10) the second trial also caused seizure freedom. If the and treatment success than other AEDs (p = 0.05 and
first trial did not result in seizure freedom, only 14% (2/13) p = 0.04, respectively).
of second trials did. If the first treatment resulted in a 50% Order number analysis showed that first, second, and
seizure reduction, in 11 (69%) of 16 the second time was third treatments were more effective in causing seizure free-
also successful. However, when the treatment did not cause dom when compared to effectiveness of later prescribed
50% seizure reduction the first time, none of the patients AEDs (p = 0.005, p = 0.02, and p = 0.04, respectively).
had a beneficial effect the second time (0/7). Steroids were used in five children, with one child receiving
two courses of steroids. The order number of steroids during
Side effects treatment ranged from 2 to 6, with a median of 3.5. Four of
In 38 (13%) accounts of use, discontinuation of AED these children had been treated with VGB before steroids.
treatment was reported to be caused by adverse effects. The On four accounts of steroid use the child became seizure-
mean percentage of discontinuation due to adverse effects free. One account of steroids caused >50% seizure fre-
per AED was 18% of all accounts, with a median of two quency reduction, and one child did not respond.
times per AED (range 1–8). VGB was stopped least fre-
Epilepsia, 56(8):1239–1245, 2015
doi: 10.1111/epi.13050
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I. E. Overwater et al.

data were checked with parents of the patients. Because

Discussion many children started their treatment many years ago, older
In this study, we confirm that epilepsy in TSC is difficult guidelines were followed, leading to use of AEDs that may
to treat and often relapses after a seizure-free period. In our be different from current practice. A strong point of our
cohort, only 21 (30%) of 71 patients attained a remission of study is the long follow-up of the children in our cohort,
longer than 24 months, with only 11 (15%) being able to spanning nearly their entire childhood. Our follow-up was
taper their AEDs. VGB was the most successful AED in done at a TSC clinic in a university hospital, which may
infantile spasms, but overall the first and second AED pre- have introduced a bias toward more severely affected
scribed were most effective, independent of which specific patients. However, we also had less severely affected chil-
AED was used. dren in our population, as eight children had only used one
AEDs used as a third or further option were still able to AED that caused them to be seizure-free for long periods.
cause seizure reduction; however, chances of remission New methods to improve the outcome of epilepsy in TSC
became small. Decreasing efficacy of AEDs used as later are needed. Recent insights suggest that close EEG monitor-
treatment options is also observed in the general epilepsy ing of children newly diagnosed with TSC can pick up epi-
population.25 Because effectiveness decreases rapidly after leptic discharges before the onset of clinical seizures.28
the first two or three failed AEDs, it might be advisable to Treatment of children with electrographic epilepsy with
start evaluating children for epilepsy surgery or other non- AEDs before the onset of clinical seizures may result in bet-
pharmacologic options early during treatment. Nondrug ter seizure control and better cognitive development.29
therapies used in our cohort were epilepsy surgery, ketogen- Another new promising treatment option is mTOR inhibi-
ic diet, and vagus nerve stimulation. Epilepsy surgery was tors. Case reports and an uncontrolled study suggested a
very effective in all five children, with seizure freedom good response in children with TSC and intractable epi-
achieved in four children. lepsy.23 The efficacy of mTOR inhibitors in TSC is cur-
In our population, a better intellectual development is rently under extensive investigation in two large clinical
related to a more successful treatment outcome and longer trials (www.trialregister.nl NTR3178, www.clinicaltrials.
periods of seizure remission. Children with a longer period gov NCT01713946). mTOR inhibitors may not only sup-
of seizure freedom had an onset of seizures at a later age and press seizures, but may also be able to reduce epileptogene-
had a higher IQ. In previous studies, the age of onset of epi- sis in TSC.
leptic seizures has been linked to the ability to reach seizure Our findings confirm previous research that epilepsy in
freedom.26,27 These studies showed that intractability is TSC is difficult to treat, and that better treatments are
associated with a higher rate of intellectual disability. It is needed. We show that a period of sustained seizure freedom
not certain whether this is cause or effect, or the result of a is achieved in 30% of children, but that almost half of them
common underlying brain pathology, but a good treatment relapse even after 2 years of remission. After failure of the
response may be taken as a positive marker for develop- first two AEDs, chances of success with subsequent AEDs
ment. are lower. Epilepsy surgery is a good option for those that
The patients in our cohort used several different AEDs, are eligible, and the adherence to new treatment guidelines
with VPA being the most frequently prescribed first treat- may improve outcome in future cohorts. For others, mTOR
ment. This was also the most frequent drug in infants pre- inhibitors may be a promising option.
senting with focal seizures, as was the practice at that time.
New recommendations (2012) advise the use of VGB in all Acknowledgments
seizure types in infants with TSC. We hope that this will
improve the outlook for newly presenting children. Because These investigations were supported by the Dutch Epilepsy Foundation.
randomized trials will not be feasible, comparing new
cohorts with old cohorts such as the one in this study will Disclosure of Conflicts of
give an idea of the additional benefit. In our cohort, VGB
was more effective than other AEDs when used as first treat-
Interest
ment for infantile spasms,13,14 but we could not show supe- The Erasmus MC has received honoraria from Novartis for lecturing by
riority of VGB for partial onset seizures or for infantile Marie-Claire Y. de Wit. The remaining authors have no conflict of interest
to disclose. We confirm that we have read the Journal’s position on issues
spasms when prescribed as a later treatment. involved in ethical publication and affirm that this report is consistent with
A limitation of our study is lack of data on the exact time those guidelines.
periods of different seizure types per patient, so these could
not be evaluated. Inherent to the retrospective nature of the References
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Epilepsia, 56(8):1239–1245, 2015

doi: 10.1111/epi.13050