Received: 21 February 2021 | Revised: 14 April 2021 | Accepted: 2 May 2021

DOI: 10.1111/ane.13469

ORIGINAL ARTICLE

Efficacy of lacosamide and phenytoin in status epilepticus:

A systematic review

Prateek Kumar Panda1 | Pragnya Panda2 | Lesa Dawman3 | Indar Kumar Sharawat1

1
Pediatric Neurology Division,
Department of Pediatrics, All India
Institute of Medical Sciences, Rishikesh,
India
2
Department of Pediatrics, Post Graduate
Institute of Medical Education and
Research, Chandigarh, India
3
Department of Neurology, King George
Medical University, Lucknow, India
Correspondence
Indar Kumar Sharawat, Associate
Professor and Chief, Pediatric Neurology
Division, Department of Pediatrics,
All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India-­249203.
Email: sherawatdrindar@gmail.com
Funding information
This research did not receive any specific
grant from funding agencies in the public,
commercial, or not-­for-­profit sectors.
Abstract
Objectives: To compare the evidence on efficacy, safety, tolerability, and impact on
short term/long functional outcome of lacosamide (LCM) and phenytoin (PHT) in pa-
tients with status epilepticus.
Materials & Methods: We conducted a systematic literature search of relevant elec-
tronic databases using a suitable search strategy to identify studies directly compar-
ing PHT and LCM, irrespective of dose and duration in patients with convulsive and/
or nonconvulsive status epilepticus (SE). We used a standardized assessment form
to extract information on the study design, data sources, methodologic framework,
efficacy, and adverse events attributed to PHT and LCM from included studies and
compared the efficacy and safety outcomes, using a fixed/random effect model.
Results: Five studies were found to be eligible for inclusion out of 192 search items,
enrolling a total of 115 and 166 participants (predominantly with SE) in LCM and PHT
arm, respectively. Baseline characteristics were comparable between both arms. The
proportion with seizure control was comparable between both arms (57.3% in LCM
vs. 45.7% in PHT arm, p = 0.28) and even in the subgroup analysis separately for con-
vulsive and non-­convulsive SE. Proportion with treatment-­emergent adverse events
(TEAE) were comparable in both (17.6% vs. 12.2%, p = 0.20), but serious adverse
events (SAE) were higher in PHT arm (5.1% vs. 0.8%, p = 0.049). The proportion with
all-­cause mortality and survival with moderate-­severe disability were comparable be-
tween both arms (p = 0.23 and 0.37, respectively).
Conclusion: LCM has comparable efficacy with fewer SAEs as compared to PHT for
achieving seizure control in patients with SE.

KEYWORDS
antiepileptic drugs, antiseizure medications, electroencephalogram, epilepsy, focal seizures,
status epilepticus

1 | I NTRO D U C TI O N control.1,2 However, in the last two decades, other medications

like levetiracetam, lacosamide, topiramate, and lamotrigine have
Historically, phenytoin (PHT), valproate, and carbamazepine are become increasingly popular, as the older ASMs are known to
considered first-­line anti-­s eizure medications (ASMs) for epilepsy have more frequent and more severe treatment-­e mergent adverse
patients on an outpatient basis or even in cases for acute seizure effects(TEAEs). Moreover, the new generation ASMs had been

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Acta Neurol Scand. 2021;00:1–9.  wileyonlinelibrary.com/journal/ane | 1

2 |
shown to have similar efficacy in some recent studies, thereby
2,3
making the clinicians choose them more frequently. Lacosamide
(LCM) enhances the slow inactivation of voltage-­g ated sodium
channels unlike phenytoin, without affecting their fast inactiva-
tion.4 This inactivation helps in ending the action potential by pre-
venting the channel from opening. Initially, it was used as add-­on
5
therapy for refractory focal seizures. However, over the years it
is especially useful in cases with status epilepticus (SE) and even
in patients with generalized seizures. In 2017, it was approved
by FDA for children with focal seizures as young as four years
and in November 2020 in adults with primary generalized tonic-­
clonic seizures, both as monotherapy and adjunctive therapy. 6
Many placebo-­controlled trials have shown its efficacy in various
types of epilepsy. On the other hand, the efficacy of phenytoin
has been undisputed in focal seizures and status epilepticus over
many decades, although adverse effects (AEs) occur in a consider-
able proportion of cases.7,8 Some studies have directly compared
the efficacy of these two medications in patients with convulsive
or non-­convulsive SE. However, no systematic review and meta-­
analysis have not been performed yet to collate the results of all
these studies.
2 | M E TH O D S
2.1 | Search methods
The systematic review was performed to compare the evidence on
efficacy, safety, tolerability, and impact on short-­term/long-­term
functional outcome of LCM and PHT in patients with status epilep-
ticus from the currently available literature. The primary research
question was whether there is any significant difference between
the efficacy of PHT and LCM in controlling seizure/achieving seizure
cessation in patients with SE irrespective of age and etiology of epi-
lepsy. As such, the primary objective of this review was to compare
the pooled estimate for the efficacy of PHT and LCM in patients
with SE, in terms of achieving seizure freedom. Secondary objec-
tives were to compare the efficacy of PHT and LCM in obtaining
seizure freedom in cases with convulsive SE and non-­convulsive SE,
change in electroencephalogram (EEG) parameters, the proportion
of the patients requiring addition of another ASM to achieve sei-
zure control, proportion of each ASM recipients with any TEAEs/
serious adverse events (SAEs), nature and frequency of these TEAEs
and SAEs, short-­term and long-­term functional outcome, in terms of
the number of deaths, patients surviving with severe disability with
PHT and LCM. The predominant adverse effects, the review concen-
trated on were hypotension, arrhythmias, bradycardia, respiratory
depression, dizziness, ataxia, diplopia, and nausea/vomiting.
While performing the meta-­analysis and systematic review, and
reporting its results, the PRISMA and the MOOSE guidelines/rec-
ommendations were adhered with. The review has been applied for
registration to the International prospective register of systematic
PANDA et al.
reviews (PROSPERO). The study was approved by an ethics commit-
tee and/or follows the tenants of the Declaration of Helsinki.
Before commencing the review process, a predefined search
strategy was developed. Two authors (PKP and IKS) independently
performed a systematic literature search (on 15th January 2021)
for all articles published till 14th January 2021 on the following
databases: “MEDLINE/PUBMED, Cochrane Central Register of
Controlled Trials (CENTRAL), EMBASE, Ovid, Web of Science and
Google Scholar”. We used the following keywords/MESH terms
while searching: “Phenytoin”, “lacosamide”, “seizure”, “convulsion”,
“status epilepticus”, and “non-­convulsive status epilepticus”. After
initial scrutiny, as described below, relevant search items were se-
lected and the references of these search items and pertinent re-
view articles were screened to identify additional studies. We also
attempted to identify additional ongoing or upcoming trials with
recently published results by searching the Internet for the recent
conference proceedings and ongoing trial registers (clinicaltrials.gov)
with preliminary published results.
2.2 | Eligibility of studies
We only included those studies with both prospective/retrospective
study designs, but at least two comparison arms: patients receiving
LCM and patients receiving PHT. The studies with/without randomi-
zation and with/without allocation concealment were included. The
studies which compared the efficacy in terms of proportion with
seizure freedom or any other parameters and/or short-­term/long-­
term functional outcome of both these ASMs were included. The
studies were included in the review irrespective of the fact whether
it enrolled patients with both clinically and/or electrographically
confirmed seizures, irrespective of etiology of seizures in patients,
irrespective of the dosage regimen, irrespective of the sequence of
ASM followed for administering these two ASMs. The studies com-
paring the efficacy of phenytoin/fosphenytoin and lacosamide for
indication of convulsive and/or non-­convulsive SE directly were only
included and for other indications like prophylactic ASM/chronic
epilepsy were excluded (as fosphenytoin is considered the prodrug
of phenytoin). The studies comparing these two ASMs for any other
indication with seizures like structural epilepsy, focal epilepsy, gen-
eralized epilepsy, or traumatic head injury in any age group of pa-
tients were excluded from the review.
The studies with a sample size <10 in either LEV or PHB arm
were excluded. The studies describing patients receiving only one
of the two above-­mentioned ASMs without comparator arm/com-
parator arm with other ASM were also excluded. Case series and
case reports were also excluded from the final inclusion in the re-
view process.
The studies with incomplete details of parameters determined
for requiring primary outcomes were also excluded. The review
excluded those studies which tried both these ASMs in the same
patient without a crossover design, thus making it difficult to
PANDA et al.
individually separate the efficacy of each ASM. Duplicate entries
and publications enrolling repeated populations were excluded.
2.3 | Study selection, data extraction, and
assessment of the risk of bias
The full-­text review was performed by two independent review-
ers for all the selected search items, included after initial scrutiny
of title, study design, and abstract. After applying the above-­
mentioned inclusion and exclusion criteria, a final set of studies
were selected to be included in the quantitative review/meta-­
analysis, based on the consensus opinion of both reviewers. In
case any dispute occurred between both reviewers, the opinion
of a third reviewer was taken to resolve the dispute. The included
studies subsequently underwent assessment of the methodologi-
cal quality, using validated quality assessment tools. The relevant
data which were extracted after full-­text review from the included
articles were the following clinical and outcome variables: study
design, study period, sample population, number of patients in-
cluded, demographic and clinical profile, epilepsy characteristics,
ASMs already administered, neuroimaging, and EEG findings,
baseline seizure burden, dose and dosing schedule of PHT and
LCM, the proportion with seizure freedom, proportion requir-
ing the addition of another ASM, TEAEs and SAEs, mortality and
short/long-­term functional outcomes.
A standardized predetermined form was used for the uniform
and systematical extraction of data and subsequently, that data
was digitally transferred to a Microsoft Excel spreadsheet. Any
discrepancies regarding inclusion in the review were resolved by
mutual discussion. The extracted data was again subjected to a
quality check by another independent investigator to ensure the
accuracy and completeness of extracted data. All possible efforts
were made to avoid duplication of data. The final analysis included
only those cases, which were not previously included as part of
another series.
The quality check of observational studies was performed
with the help of the Newcastle Ottawa scale. The studies were
classified as good, fair, and poor quality.9 The risk of bias was
determined by using either the Cochrane Collaboration's tool
for assessing the risk of bias in RCTs or the Risk Of Bias In Non-­
randomized Studies-­of Interventions (ROBINS-­I) tool.10 Initially,
two investigators independently determined these parameters for
each included study, and subsequently, if any disagreement oc-
curred between them then it was settled by taking the opinion of
a third investigator.
2.4 | Outcome measures
The primary efficacy outcome was the difference in seizure ces-
sation rate between PHT and LCM recipients. The secondary
| 3
outcomes were the difference in short-­term and long-­term func-
tional outcomes between recipients of these two ASMs.
The safety and tolerability outcomes were the difference in the
proportion of patients experiencing any of the TEAEs/SAEs, the pro-
portion of patients who developed each of the adverse effects, the
proportion of neonates with SAEs (serious adverse events), mortal-
ity specifically related to each of the ASMs.
2.5 | Data synthesis and statistical analysis
Qualitative variables were presented with appropriate pro-
portions/ratios, while quantitative variables were presented
with mean/standard deviation or median/ interquartile range.
Whenever it seemed feasible, the pooled estimate of included var-
iables in the review was determined along with upper and lower
95% confidence intervals. Comparisons of the pooled estimate
of these parameters, including a meta-­analysis of data regarding
various parameters, were performed using Revman 5.4 software
and SPSS statistical software package. Higgins and Thompson's I2
method and Cochran's Q statistics with the chi-­s quare test were
utilized to assess heterogeneity in studies. The presence of pub-
lication bias was assessed by Egger's test. We utilized a random
effect model when I2 was more than 50% and a fixed-­effect model
for the rest of the parameters.
3 | R E S U LT S
3.1 | Results of the search
After the initial targeted search, a total of 198 search items were
retrieved. Out of these, 83 were found to be duplicates and hence
excluded from subsequent scrutiny. Initial evaluation for eligibility
was limited to the remaining 115 articles. Among these, 86 articles
were found to be irrelevant based on either the title, type of article,
or abstract and hence removed accordingly (Figure 1). Subsequently,
a full-­text review was performed for 29 articles, and finally, five arti-
cles satisfied all the inclusion criteria for our review.11–­15
Out of these one was RCT and four were retrospective studies
with two or more comparator arms. The RCT was a non-­inferiority,
prospective, multicenter, randomized treatment trial.
3.2 | Characteristics and risk of bias of
included studies
The RCT was of good quality, with a low risk of selection, per-
formance, reporting, and attrition bias. Out of the four retro-
spective studies, three were of good quality and one was of fair
quality. The risk of bias in all these studies was moderate according
to the ROBINS-­I tool. None of the studies were of poor quality. No
4 |
F I G U R E 1 Flow diagram of the study selection process
significant publication bias was observed. The summary of the re-
sults of these studies has been described in Table 1.
3.3 | Efficacy of phenytoin and lacosamide
In the included 5 studies, a total of 115 and 166 cases receiving LCM
and PHT were enrolled, respectively. The baseline demographic,
clinical and epilepsy characteristics including seizure burden, previ-
ous ASMs tried were comparable in both arms (Table 2). While one
study enrolled only cases with NCSE, two studies enrolled cases
with convulsive status epilepticus and two enrolled cases with both
convulsive and non-­convulsive SE.
The seizure control parameters used in most studies were com-
plete seizure cessation with/without rebolus of the same drug for a
variable duration (at least up to 24 h). While numerically the seizure
cessation rate with LCM was higher (57.3%, 95% CI−47.6%–­66.5%)
than with phenytoin (45.7%, 95% CI−38.3%–­53.2%), the differ-
ence was not statistically significant (p = .28). The odds ratio for
seizure cessation with PHT as compared to LCM was 0.75 (95%
CI−0.44–­1.27) (Figure 2). The median dose used was 20 mg/kg of
PHT or PHT equivalent and 400 mg LCM administered IV over 30
minutes and dose for rebolus was 5 mg/kg of PHT or PHT equivalent
PANDA et al.
and 200 mg LCM, followed by maintenance dose at 12 hourly in-
tervals. The proportion of patients requiring rebolus dose was also
not statistically different between these two ASMs (36.2% in PHT
arm vs. 45.7% in LCM arm, p = .29). Crossover was possible only in
one study, in which the efficacy with crossover was also similar with
both ASMs (27% in LCM arm vs. 42.9% in PHT arm, p = .18), as well
as the requirement of rebolus of the second ASM (30% in PHT arm
vs. 26.7% in PHT arm, p = .56). The percentage reduction in absolute
seizure burden was also comparable between both arm, although
only a few studies mentioned information about this variable (79%
in PHT arm vs 94% in LCM arm, p = .13).
3.4 | Adverse effects and functional outcome
The proportion of patients with at least one TEAE was higher with PHT,
but the difference did not reach the point of statistical significance
(17.6% vs. 12.2%, p = .20, OR−1.59, 95% CI−0.79–­3.20). However, the
proportion with SAE was significantly higher with PHT (5.1% vs. 0.8%,
p = .049) (Figure 3). Cardiac arrhythmias, bradycardia, hypotension,
respiratory failure, cerebellar ataxia, nystagmus were seen in more
patients with PHT, although the difference was not statistically sig-
nificant for individual adverse effects. Other adverse effects like drug

TA B L E 1 A summary of the results of the included studies
Author, year, country
Schaidle et al, 2019, USA
Redecker et al, 2015,
Germany
Orlandi et al, 2020, Italy
Kellinghaus et al, 2014,
Germany
Husain et al, 2018, USA
The TRENdS (Treatment
of Recurrent
Electrographic Non-­
convulsive Seizures)
study)
Abbreviations: ECG, Electrocardiogram, fPHT, Fosphenytoin, ICU, Intensive care unit, LCM, Lacosamide, LFT, Liver function tests, NCSE, Non-­convulsive status epilepticus, PHT, Phenytoin; SBP: Systolic
blood pressure.
Type of study Sample population and study methodology
Retrospective study Neurosurgical ICU patients ≥18 years of age, 52
PHT, and 18 LCM arm, excluding pregnant
women and those having status epilepticus,
already on levetiracetam. The primary
endpoint was treatment failure requiring the
third medication.
Retrospective study 68 ± 17 years, 12 with PHT, 6 with LCM,
status epileptics after administration of
benzodiazepine
Retrospective study 14–­98 years-­old cases with status epilepticus, 55
in phenytoin arm vs 40 in lacosamide arm,
Retrospective study LCM was used as third drug in 21 patients
(median bolus 400 mg) and PHT in 15 patients
(median bolus 1500 mg)
Non-­inferiority, Seventy-­four subjects were enrolled (37 LCM,
prospective, 37 fPHT) with NCSE The mean age was
multicenter, 63.6 years; 38 were women. IV LCM 400 mg
randomized vs fPHT 20 mg phenytoin equivalent/kg was
treatment trial used
Efficacy outcome
25% vs 22.2% success in PHT and LCM arm
16.7% vs 50% success in PHT and LCM
arm, medication was administered
after a median of 8 and 14.5 minutes,
respectively, median first dosage and
total dosage was 504 mg, 1006 mg vs
125 mg and 367 mg of PHT and LCM,
respectively
71% vs 77% success rate in phenytoin and
lacosamide arm, mortality, the proportion
with return to baseline and mRS >3 at
30 days were comparable in both arms
Pretreatment was similar regarding
substance groups (benzodiazepine as
first-­line, levetiracetam as second-­line
drug) and bolus doses. Status epilepticus
was terminated in six patients (40%) of
the PHT group and in seven patients
(33%) of the LCM group.
Electrographic seizures were controlled at
24 hours in 19 of 30 (63.3%) subjects in
the LCM arm and 16 of 32 (50%) subjects
in the fPHT arm. LCM was non-­inferior
to fPHT (p = .02), with a risk ratio of 1.27
(90% CI = 0.88–­1.83).
PANDA et al.
Adverse effects
Decrease in SBP in PHT and LCM arm was
20.9 and 9.8 mm Hg (p = .01), other
adverse effects, changes in ECG, heart
rate, LFT were comparable between
both arms
Cerebellar Ataxia−1, thrombocytopenia−1,
skin rash−2, arrhythmias−1, diplopia−1,
mental confusion−1 in PHT arm and
cerebellar ataxia, diplopia, skin rash in 1
patient each in LEV arm
Four patients (27%) of the PHT group and
no patient of the LCM group suffered
from a relevant, treatment-­related side
effect during the administration of the
third drug.
Treatment emergent adverse events
(TEAEs) were similar in both arms,
occurring in 9 of 35 (25.7%) LCM and 9
of 37 (24.3%) fPHT subjects (p = 1.0).
|
5
6 | PANDA et al.

TA B L E 2 Comparison of baseline
Patients receiving Patients receiving p-­
characteristics of participants in
Variable lacosamide (n = 115) phenytoin (n = 166) value
lacosamide and phenytoin arm
Age (years)(mean, SD) 55.3 ± 13.2 56.1 ± 14.8 .41
Male 54% 53% .93
Female 46% 47%
Previous history of epilepsy 31% 29% .87
Previous history of status 5% 6% .91
epilepticus
Number of medications already 1.7 ± 0.6 1.3 ± 0.4 .11
tried before administering
PHT or LCM (mean, SD)
Focal onset seizures 71% 65% .33
Generalized onset seizures 24% 31%
Unknown onset seizures 5% 4%
Structural abnormality in 47% 45% .88
neuroimaging
NCSE 22% 18% .59

F I G U R E 2 Meta-­analysis forest plot showing the comparison of the pooled estimate for the efficacy of phenytoin and lacosamide in
terms of the proportion of the patients who achieved seizure control

F I G U R E 3 Meta-­analysis forest plot showing the comparison of the pooled estimate for the proportion of patients receiving phenytoin
and lacosamide having any adverse effect

fever, rash, diplopia, and hallucination were reported rarely with one
or both the medications. No mortality occurred in both the arms di-
rectly caused by any of the ASMs, but all-­cause mortality during hos-
pitalization was comparable in both arms, although numerically higher
with PHT (4% vs. 7%, with LCM and PHT, p = .23). While dividing into
convulsive and non-­convulsive status epilepticus, the proportion with
TEAE, SAE, and all-­cause mortality all remained higher with the PHT
arm but did not reach the point of statistical significance in subgroup
analysis. The proportion with the return to baseline and proportion
with moderate-­severe disability (mRS >3 at 30 days) were comparable
in both arms (p = .43, .37, respectively), although only a few studies
mentioned these variables.
PANDA et al.
4 | DISCUSSION
The current review compared the efficacy and safety of two sodium
channel blocking anti-­seizure medications, phenytoin and lacosa-
mide in achieving control in patients with status epilepticus. Both
the drugs were found to have comparable efficacy, while phenytoin
was found to have more frequent serious adverse effects. The indi-
cations for which the medications were used, sample population, and
dose of the medications varied to some extent across the studies.
However, given the availability of only a few studies directly compar-
ing the two medications, we thought collating the study results for
studies including both convulsive and non-­convulsive status epilep-
ticus. We excluded studies comparing lacosamide for acute sympto-
matic seizure prevention in cases with traumatic head injury cases
to include a homogeneous sample only and to provide a meaning-
ful pooled estimate. There was only minimal heterogeneity in study
results suggesting all performed studies found more or less similar
results and future studies are less likely to change the evidence gen-
erated in our review, unless and until RCTs with large sample sizes
are performed. Thus, it can be safely said that in status epilepticus
lacosamide can be used in place of phenytoin with comparable ef-
ficacy and better tolerability. But this finding can be generalized to
other chronic epilepsy conditions only after future studies explor-
ing the efficacy of these two ASMs for these indications. Not many
studies have been done comparing these two medications head-­
to-­head for various other indications. Like levetiracetam, the ready
availability of intravenous preparation of this medication makes it
a suitable ASM choice in acute emergencies like status epilepticus.
Moreover, the intravenous preparation of LCM can be changed to
oral route without dose adjustment and rapid up-­titration without
any untoward effects is possible with lacosamide.6,8,11
Strzelczyk et al16 performed a systematic review in 2016 about
the efficacy of LCM in various SE and they found that LCM was ef-
ficacious in 57% of 522 SE episodes. Our review also showed similar
results. While the efficacy was better for focal convulsive SE (92%),
for generalized convulsive SE (61%), and NCSE (57%), it was compa-
rable but inferior to focal convulsive SE. Predominant side effects
were also similar to our review results, including dizziness, abnormal
vision, ataxia, and diplopia. This systematic review although did not
compare with any other ASM, but they concluded that lacosamide
has excellent safety records. Unlike phenytoin, it does not have sig-
nificant drug-­drug interaction and it does not have much impact on
CYP3A4 in the liver. In refractory epilepsy, where polytherapy is
usually practiced, this interaction between ASMs becomes an im-
portant factor in modifying serum ASM levels.5
17
Liu et al in another meta-­analysis that included four RCTs with
1199 adult patients and concluded that adjunctive lacosamide treat-
ment results in a 50% higher responder rate and seizure freedom
rate, as compared to placebo, but with more TEAEs like nausea,
18
vomiting, increased dizziness, diplopia, and SAEs. Yasiry et al in
another meta-­analysis in 2013 compared 5 ASMs including LCM
and PHT in benzodiazepine (BZD) resistant convulsive status epilep-
ticus and found that valproate, levetiracetam, and phenobarbitone
| 7
were equally effective, whereas the efficacy of PHT was found to
be lower and there were insufficient data regarding the efficacy of
LCM at that time.
Predominantly our review compares the efficacy of these two
ASMs in cases with SE. Comparing the efficacy of LCM with that
of other first-­line ASMs for SE like valproate and levetiracetam was
out of the scope of our review, but such reviews in the future are
needed. A network meta-­analysis in this regard would have been an
ideal option to provide a comprehensive overview of the efficacy
of various medications for SE. Most of the systematic reviews per-
formed in cases with SE till now mainly focused on conventional
ASMs like phenytoin, levetiracetam, and valproic acid. One study in-
cluded in the review by Redecker et al13 compared these four ASMs
and did not find any significant difference in their efficacy.
In one study, authors suggested that LCM has low protein bind-
ing, less drug interaction, highly suitable for neurocritical care pa-
tients, and even a better choice than levetiracetam, as patients often
required high doses (3 to 4 grams per day) to achieve therapeutic
concentrations.8 At this dose, it is likely to cause somnolence and
behavioral abnormalities. However, the opinion of these authors
needs to be substantiated by direct comparison studies. While in our
review phenytoin was found to have a higher incidence of cardio-
vascular and other adverse effects, most adverse effects with LCM
were mild and rarely required discontinuation of the drug.6,8,11,19
None of the studies in review specifically studied pharmacokinetic
and pharmacodynamics properties of LCM in critically ill patients.
But studies in other epilepsy patients and healthy adults suggest a
safe profile, unlike phenytoin which follows zero-­order kinetics at
higher concentrations. 20
The initial bolus or “loading” dose of phenytoin (15–­20 mg/kg) is
well established, whereas, the optimal bolus and maintenance dose
of LCM in neurocritical patients is less clear. But we know the ther-
apeutic range of LCM in epilepsy patients and in SE cases in adults
a bolus of 400 mg followed by even a rebolus of 200 mg has been
safely used, based on the dose range from non-­critically ill patients
with epilepsy. This rebolus dose is used when a breakthrough seizure
occurs or when seizures remain refractory after the initial loading
dose.11 Whether a higher dose of an initial bolus of LCM will be more
effective without any adverse effects, remains to be answered in
future studies.
In the uncontrolled studies exploring the efficacy of LCM in
status epilepticus, the success rate and bolus dose were similar.
In the study by Santamarina et al, 21 the median loading dose was
400 mg (range:100–­600 mg). The weight-­adjusted dose was 5 mg/
kg (range−3–­6 mg/kg). The response rate was 63.3% among 165 pa-
tients, and 55.1% responded within the first 12 hours. On the other
hand, in the small prospective observational study by Legros et al, 22
an initial dose of 400 mg of intravenous LCM was associated with
a higher chance of early termination of refractory status epilepti-
cus and with a trend toward a higher response rate. Ramsay et al23
in 2015 found that a weight-­based loading dose of 10–­12 mg/kg of
LCM at an infusion rate of 0.4 mg/kg/min was safe and produced
levels of 15 μg/ml and higher. Chimakurthy et al24 found that larger
8 |
doses of >8 mg/kg of intravenous LCM can be safely administered
in ICU patients to produce effective plasma levels of 15–­20 μg/ml
with a relatively constant volume of distribution. Perrenoud et al25
in 2017 documented in a retrospective study a somewhat different
finding like high intravenous loading dose of LCM >9 mg/kg was as-
sociated with serum levels within the reference interval, but there
was no correlation with the clinical response.
While the pooled estimate of serious adverse effects showed
more prevalence with PHT and the nature of adverse effects also
being more severe with PHT, the overall results in the review, how-
ever, suggested a comparable rate of TEAEs and SAEs with both
these ASMs. Even the adverse events of special interest in neurocrit-
ical care patients such as hypotension, bradycardia, cardiac arrhyth-
mia, respiratory failure, and multiple organ dysfunction were similar
in both arms. While these studies with similar rates of adverse ef-
fects were prospective studies or RCTs, the studies in review which
showed fewer AE with LCM were retrospective and open-­label stud-
ies. This discrepancy might be because in retrospective studies some
adverse effects were missed and secondly, in critically ill patients
with SE, with multiple ASMs, interventions, and co-­
morbidities,
often it is difficult to assess the presence of subjective adverse ef-
fects like altered mental status and to objectively pinpoint adverse
effects like hypotension to one particular ASM.
Our review has several limitations. Apart from one RCT, all in-
cluded studies were of retrospective study design, which is often
subjected to documentation error, selection bias, and other biases,
especially regarding adverse effects. One retrospective study did
not mention anything about adverse effects. Few of the retrospec-
tive studies were of small sample size. The time point and the se-
quence after which LCM was administered during convulsive and
non-­convulsive SE were also different across the included studies.
In some studies, it was administered as the second drug, while in
others it was administered as the third drug. None of the studies
mentioned much information about the impact of these two ASMs
on short-­term and long-­term functional outcomes, although previ-
ous clinical studies have shown that LCM does not have much im-
pact on the long-­term functional outcome of epilepsy patients. No
pediatric studies could be found, which could be because FDA ap-
proved the medication for 4 y and older in 2017. Therapeutic drug
level monitoring was not performed in most of the included studies
and the dose of LCM also slightly varied across the studies. Despite
these limitations, this is the first systematic review till date which
has directly compared the efficacy and safety of two sodium channel
blocking ASMs. This review will help clinicians in designing future
RCTs with relevant outcomes and in their decision-­making while
managing cases with status epilepticus.
5 | CO N C LU S I O N
LCM has comparable efficacy with fewer serious adverse effects
as compared to PHT for achieving seizure control in patients with
SE. More RCTs are needed between these two ASMs for status
PANDA et al.
epilepticus and various other clinical indications like chronic epilepsy
to generate more robust evidence.
D EC L A R AT I O N S
Not applicable.
AC K N OW L E D G M E N T S
None.
C O N FL I C T S O F I N T E R E S T
None.
DATA AVA I L A B I L I T Y S TAT E M E N T
NA
ORCID
Prateek Kumar Panda https://orcid.org/0000-0001-7831-9271
Indar Kumar Sharawat https://orcid.org/0000-0002-7003-7218
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How to cite this article: Panda PK, Panda P, Dawman L,
Sharawat IK. Efficacy of lacosamide and phenytoin in status
epilepticus: A systematic review. Acta Neurol Scand.
2021;00:1–9. https://doi.org/10.1111/ane.13469