Original Article

Efficacy of Lacosamide as AdjunctiveTherapy in Children WithRefractory Epilepsy

William R. Yorns Jr, DO1, Divya S. Khurana, MD1,Karen S. Carvalho, MD1, H. Huntley Hardison, MD1,Agustı́n Legido, MD1, and Ignacio Valencia, MD1

AbstractLacosamide is a US Food and Drug Administration (FDA)–approved antiepileptic drug for patients 17 years or older with partialepilepsy. There are sparse data on children. The objective of our study was to evaluate its efficacy/safety in children withrefractory epilepsy. Forty children (mean age 14.3 years) were treated with lacosamide at our institution (adjunctive therapy in 36,monotherapy in 4). Fifteen patients had symptomatic focal epilepsy, 2 had cryptogenic focal epilepsy, 20 had symptomaticgeneralized epilepsy, and 3 had cryptogenic generalized epilepsy. Two had juvenile myoclonic epilepsy and 5 had Lennox-Gastautsyndrome. Forty-two percent had at least >50% reduction in seizure frequency, and 6 became seizure free. Average dose was 7mg/kg/d and average follow-up was 9.2 months. Responders had a 76.5% mean decrease in seizures. Fifteen children experiencedan adverse reaction and 7 discontinued lacosamide (4: Ineffective, I: insurance denial, 1: tremor, 1: behavior). Lacosamide is effec-tive and well-tolerated in children with refractory epilepsy.

Keywordslacosamide, epilepsy, antiepileptic

Received June 18, 2012. Received revised August 27, 2012. Accepted for publication August 27, 2012.

Lacosamide is a novel antiepileptic drug approved as

adjunctive treatment of refractory partial-onset epilepsy in

patients 17 years of age or older.1 Lacosamide is a functionalized

amino acid compound that, in adults, has 100% oral absorption

with linear pharmacokinetics, low protein binding (<19%), peak

blood concentration in 1 to 2 hours with a 13-hour half-life, renal

clearance, limited hepatic metabolism, and no known significant

drug interactions.2 Considering the encouraging pharmacoki-

netics, lacosamide should be a favorable option for treatment

in children as well.

Lacosamide selectively enhances the slow inactivation of

voltage-gated sodium channels.3 Sodium channels are responsi-

ble for the generation and propagation of nerve action potentials

and control of overall neuronal excitability. Lacosamide action

on the slow inactivation of the voltage-gated sodium channel

is a new area of attack on an ion channel that has long been the

target of many of the older antiepileptic drugs. It is well known

that some seizure phenotypes have specific neuronal membrane

or ion channel defects that can predispose to excessive cortical

excitability.4 This will undoubtedly lead to many targeted

treatment approaches to these channelopathies. It is not yet well

delineated whether antiepileptic drugs with actions on distinct

ion channels have better response rates when treating epilepsies

associated with channelopathies. On the other hand, it has been

previously shown that some medications that act on sodium

channels, such as lamotrigine and carbamazepine, can worsen

seizures associated with Dravet syndrome, a defect of the

SCN1A channel.5,6

Initial studies also found that lacosamide modulates collapsin

response mediator protein-2 (CRMP-2), a phosphoprotein

involved in axonal outgrowth and neuronal differentiation.7 It

is unclear whether this interaction has an impact on epileptogen-

esis, as unregulated or disorganized neuronal connections are

hypothesized to be involved in seizure propagation. This interac-

tion with collapsin response mediator protein-2 also causes con-

cern about potential adverse effects on the developing brain.

This mechanism of action warrants further investigation, as most

1 Section of Neurology, Department of Pediatrics, St. Christopher’s Hospital

for Children, Drexel University College of Medicine, Philadelphia, PA, USA

Corresponding Author:

Ignacio Valencia, MD, St Christopher’s Hospital for Children, Section of

Neurology, 3601 A Street, Philadelphia, PA 19134.

Email: Ignacio.Valencia@drexelmed.edu

Journal of Child Neurology2014, Vol 29(1) 23-27ª The Author(s) 2012Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0883073812462887jcn.sagepub.com

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recent evidence suggests that lacosamide does not actually bind

to this protein.8

Despite treatment with many of the classic and new antiepilep-

tic drugs, more than 30% of patients with epilepsy become

refractory to current treatments.9 Surgical intervention, vagal

nerve stimulation, and the ketogenic diet can also fail in these

patients. New pharmaceutical approaches for the treatment of

seizures are important for these individuals who have failed other

therapies.

Clinical studies have shown that lacosamide has a good

response rate in adults with a favorable side-effect profile.10,11

There is a sparse amount of data that exists on the efficacy of

lacosamide in the pediatric population. The present single-

center retrospective study reviews the efficacy and tolerability

of lacosamide as adjunctive treatment or monotherapy in

children with epilepsy.

Methods

This study was approved by the Institutional Review Board of St.

Christopher’s Hospital for Children, Drexel University College of

Medicine. We retrospectively reviewed the records of children and

adolescents with epilepsy treated with lacosamide as adjunctive treat-

ment and as monotherapy at our institution between 2009 and 2011.

Patients younger than 21 years of age with refractory epilepsy (gener-

alized or focal) at the time of the initiation of treatment with lacosa-

mide were included in the study. The daily dose of lacosamide was

the optimal dose determined individually for each patient as required

to improve efficacy and/or reduce adverse effects. The following data

were collected: gender, age, developmental/cognitive level, seizure

type and etiology, age at seizure onset and at initiation of lacosamide

treatment, number of antiepileptic drugs used, lacosamide dose and

dosing schedule, previous use of vagal nerve stimulator or ketogenic

diet, follow-up duration, treatment response, and adverse events.

The response to treatment was quantified using data on seizure

frequency before and while on lacosamide treatment. It was based

on caregiver reports during follow-up visits and classified as seizure

free, >75% reduction, >50% reduction, and ineffective (all <50%responders). Children and adolescents with more than 50% reduction

in seizure frequency were considered responders. Adverse events were

also collected based on caregiver reports at each follow-up visit.

Categorical data were expressed as percentages and quantitative data

as mean, standard deviation (SD), and range. Categorical variables were

compared between groups with chi-square test and quantitative

variables with student’s t test. Statistical significance was set at

P <.05. All statistical analyses were performed with the SPSS statistical

software package (SPSS for Windows, v.19, SPSS, Inc., Chicago, IL).

Results

We identified 40 children with refractory epilepsy treated with

lacosamide (Table 1). There were 55% boys and 45% girls with

a mean age of 12.3 years (SD 4.8; range 1.4-20.8 years) at the

initiation of treatment. The mean age of onset of seizures was

4.1 years (SD 4.6; range birth to 15.4 years). The average

follow-up was 9.2 months (SD 4.7; range 1.7-28.3 months)

after starting treatment with lacosamide.

There was a positive family history of seizures in 27.5% of

patients. Nineteen children (47.5%) had tried treatment with

vagal nerve stimulator and 9 (22.5%) were previously treated

with ketogenic diet. Seizure types are shown in Table 1. Most

patients (70%) experienced multiple seizure types.

A total of 17 patients (42.5%) had at least a >50% decrease

in the frequency of seizures with a mean decrease in seizure

frequency of 76.5% (Figure 1). Six of these patients (15%)

were seizure free at the latest follow-up. Patients who had

generalized epilepsy had a similar reduction in seizure

Table 1. Patient Demographics and Epilepsy Characteristics (n¼ 40).

Demographic characteristic

Age (y, mean [SD]) 13.1 (4.9)Gender (n [%])Male 22 (55.0)Age at onset of seizures (y, mean [SD]) 4.0 (4.6)Age at onset of lacosamide effects (y, mean [SD]) 12.3 (4.7)Developmental delay (n [%]) 35 (87.5)Epilepsy characteristics (n [%])

Symptomatic focal 15 (37.5)Cryptogenic focal 2 (5)Symptomatic generalized 20 (50)Cryptogenic generalized 3 (7.5)

Epilepsy syndromes (n [%])Juvenile myoclonic epilepsy 2 (5)Lennox-Gastaut syndrome 5 (12.5)

Seizure types (n [%])Generalized tonic clonic 36 (88)Atonic 12 (30)Tonic 11 (27.5)Myoclonic 10 (25)Simple partial 6 (15)Complex partial 30 (75)Absence 15 (37.5)Multiple types 28 (70)

Number of previously used AEDs (mean [SD]) 6.2 (3.0)Number of concurrent AEDs (mean [SD]) 1.9 (1.0)Starting dose (mg/kg/d, mean [SD]) 2.0 (0.7)Maintenance dose (mg/kg/d, mean [SD]) 7.0 (4.2)

Abbreviation: AED, antiepileptic drug.

Figure 1. Seizure frequency reduction.

24 Journal of Child Neurology 29(1)

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frequency as compared to patients with partial-onset epilepsy

(w2 ¼ 2.796, df ¼ 5, P ¼ .731). The average lacosamide

starting dose was 2.03 mg/kg (SD 0.73) and maintenance

dosing at follow-up was 7.04 mg/kg (SD 4.23). All patients

in the study had their medicine dosed twice a day. Seizure

response was not significantly determined by average dosing,

although we did find a tendency toward an inverse relationship

between average maintenance dosing and seizure frequency

reduction. Patients who were nonresponders on lacosamide

averaged 7.5 mg/kg/d while patients who were seizure free

averaged 5.4 mg/kg/d. Those patients who responded the

poorest to lacosamide were more likely to have tried at least

6 or more antiepileptic drugs in the past (w2 ¼ 4.269, df ¼ 1,

P ¼ .039) compared to patients who had tried fewer than 6

medications prior to lacosamide. Linear regression analysis

was conducted between each antiepileptic drug combined with

lacosamide and there was no statistically significant reduction

in seizure frequency with any particular combination.

Side effects of lacosamide were seen in 15 patients (37.5%)

and included lethargy in 4 (10%), worsening behavior in 4

(10%), weight loss in 2 (5%), dizziness in 2 (5%), mild memory

impairment in 1 (2.5%), depression in 1 (2.5%), and tremor in 1

(2.5%). Seven patients (17.5%) discontinued lacosamide

during the study, 4 for lack of efficacy (10%), 1 for head tremor

(2.5%), and 1 for worsening behavior (2.5%), and 1 for lack of

insurance approval (2.5%). Of the 3 patients who had worsen-

ing seizures, one had an increase in seizure frequency of 20%,

and the other 2 had reported longer seizures than usual with

preserved frequency. Patients who experienced side effects

were taking maintenance lacosamide at an average dose of

8.07 mg/kg/d, whereas those who did not have any received

an average dose of 5.5 mg/kg/d.

Lacosamide was used as monotherapy in 4 patients (10%),

but was never used as first-line treatment. They had an average

age of seizure onset of 9.6 years and started lacosamide at an

average age of 11.1 years. Two of them had cryptogenic

generalized epilepsy, 1 had symptomatic generalized epilepsy,

and 1 cryptogenic partial-onset epilepsy. The average number

of antiepileptic drugs tried prior to lacosamide was 3.8, and the

average dosing in these children was 6.34 mg/kg/d. Three

became seizure free on lacosamide and one had 80% of seizure

reduction, which was a significantly better response than our

adjunctive therapy cohort (w2 ¼ 15.962, df ¼ 5, P ¼ .007).

Mild memory impairment was reported as a side effect in one

of these patients, but it did not lead to discontinuing the

treatment.

Discussion

Three randomized, multicenter, placebo-controlled studies

were completed to test the efficacy of lacosamide in adults with

refractory partial-onset epilepsy.10,11,12 Simoens et al13

published the accumulated data from these studies and their

economic impact. The median percentage reduction in seizure

frequency from baseline was 18.4% for placebo, 33.3% for

lacosamide 200 mg/d (P < .01), 36.8% for lacosamide 400

mg/d (P < .001) and 9.4% for lacosamide 600 mg/d. The per-

centage of patients with a seizure frequency reduction of

�50% was 22.6% for placebo, 34.1% with lacosamide 200

mg/d (P < .05), 39.7% with lacosamide 400 mg/d (P < .001),

and 39.6% with lacosamide 600 mg/d. One study showed that

30% to 50% of adults had up to a 96% decrease in frequency of

partial seizures with secondary generalization.10

The experience with the use of oral lacosamide in children

has been limited, so far, to 4 recent retrospective studies, total-

ing 67 patients (Table 2).14-17 In our study, the response rate of

>50% seizure reduction was slightly higher, 42% versus a mean

of 37% of the 4 pediatric studies14-17 and 39% from the best

results of adult studies. The percentage of patients experiencing

side effects (37.5%) was similar to the other pediatric studies

except Heyman et al,16 who reported a 59% rate of side effects.

Our 17.5% lacosamide discontinuation rate was lower than the

mean of 36% from the other pediatric studies.14-17

The FDA indication for the use of lacosamide is for adjunc-

tive therapy for partial epilepsy only. There have been previous

data showing seizure frequency reduction following lacosa-

mide administration in some rat models of generalized seizure

disorders.18 Rastogi and Ng17 used lacosamide in 8 patients

with generalized epilepsy, and Heyman et al16 used lacosamide

in 5 patients with focal and generalized seizures, 2 of them with

Lennox Gastaut syndrome. We have successfully used

lacosamide on 23 patients with symptomatic or cryptogenic

generalized epilepsy. In our study, 42.5% of children with

partial-onset epilepsy had an improvement with lacosamide

compared with 57.5% of children with generalized epilepsy,

although this difference did not reach statistical significance.

Table 2. Summary of Studies Assessing the Effects of Lacosamide on Epilepsy in Children.

Author Seizure type (n)Number of

subjectsSubject age(y, range)

Maintenance dosing(mg/kg/d)

>50%response

rateSeizure

freedom (n)

Guilhoto et al15 Focal (16) 16 14.9 (8-21) 4.7 37.5% 18.8% (3)Heyman et al16 Focal (12), combined (5) 17 8 (1.5-16) 12.4 35% 11.8% (2)a

Gavatha et al14 Focal (18) 18 10.6 (3-18) 6.3 36% 11.1% (2)Rastogi and Ng17 Focal (8), generalized (8) 16 8.6 (1-16) 9.4 50% 18.8% (3)a

Yorns et al22 Focal (14), combined (7),generalized (19)

40 12.3 (1.4-20.8) 7.0 42% 15% (6)

aData are for >90% seizure reduction.

Yorns Jr et al 25

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One of our patients with refractory juvenile myoclonic epilepsy

averaging several generalized tonic-clonic seizures per day has

not had a single seizure for over a year after the introduction of

lacosamide. This is the largest group of pediatric patients with

refractory generalized epilepsy in the literature, showing that

lacosamide can also be effective in this type of epilepsy.

Heyman et al,16 as indicated above, reported the use of

lacosamide monotherapy in 4 children, with a 25% response

rate. We also successfully used lacosamide as monotherapy in

4 children, but with a 100% response rate, 3 patients becoming

seizure free and 1 achieving 80% decrease in seizure frequency.

We found that there was no significant association between

dosing and seizure reduction. Patients who were started on

lacosamide generally responded soon after treatment initiation

and they did not necessarily improve after upward titration. The

nonresponders in our study averaged a higher daily dose than

the patients achieving seizure freedom.

Those patients who had tried more than 6 antiepileptic drugs

in the past were less likely to respond to lacosamide. This find-

ing is consistent with prior studies showing that there is an

increased chance of developing resistance with each successive

attempted antiepileptic drug.19

Adverse events in other studies have been reported to be

dose dependent and included a variety of symptoms previously

described in the summary of the pediatric studies.14-17 Side

effects tended to happen early in our cohort of patients, which

may have limited the upward titration of lacosamide in order to

treat the seizures. Side effects are hypothesized to occur more

frequently when lacosamide is used in conjunction with other

antiepileptic drugs that act on the sodium channel (ie, carbama-

zepine, oxcarbazepine, lamotrigine, phenytoin, and topira-

mate). Our data show that there was no significant

association between side effects and the use of a specific con-

comitant antiepileptic drug with lacosamide. Gavatha et al14

also found a lack of association between lacosamide side

effects and other antiepileptic drugs acting on the sodium

channels.

It was the goal of this study to review the medical records of

our pediatric epilepsy patients and summarize the effectiveness

and tolerability of lacosamide in a pediatric population. Our data

are consistent with the currently available adult and pediatric

studies and provides the largest collection of patients on the use

of lacosamide in children. We conclude that lacosamide is effec-

tive as adjunctive therapy in children with refractory epilepsy,

both partial and generalized, and is well tolerated. The overall

efficacy in patients with severe refractory epilepsy and the good

response in patients with monotherapy suggest that lacosamide

may be more effective as a first choice for antiepileptic treatment

than other antiepileptic drugs, and theoretically could have the

potential of reducing the risk of progressing to refractory

epilepsy.9 Its availability as an intravenous formulation makes

it also a good choice to treat status epilepticus, particularly

refractory status, both in adults and children.20,21 There is a need

for studies with larger populations of pediatric patients to better

define the role of lacosamide in the therapeutic armamentarium

of pediatric epilepsy.

Acknowledgments

These data were presented at the Annual American Academy of

Neurology meeting on April 14, 2011, in Honolulu, Hawaii.

Author Contributions

WRY drafted the original manuscript and performed the data

collection and analysis. AL and IV contributed to the statistical

analysis, writing, and revision of the final manuscript. DK, KC, and

HH contributed to the drafting and editing of the manuscript and

provided clinical information.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship,

and/or publication of this article.

Ethical Approval

This study was approved by the Institutional Review Board of

St. Christopher’s Hospital for Children, Drexel University College

of Medicine.

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