Published Ahead of Print on March 4, 2016 as 10.1212/WNL.
0000000000002545
VIEWS & REVIEWS
Simona Lattanzi, MD
Claudia Cagnetti, MD
Nicoletta Foschi, MD
Leandro Provinciali, MD
Mauro Silvestrini, MD
Correspondence to
Dr. Lattanzi:
alfierelattanzisimona@gmail.com
Supplemental data
at Neurology.org
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Brivaracetam add-on for refractory focal
epilepsy
A systematic review and meta-analysis
ABSTRACT
Objective: To evaluate the efficacy and safety of the new antiepileptic drug brivaracetam (BRV) as
add-on treatment for drug-resistant partial epilepsy using meta-analytical techniques.
Methods: Randomized, placebo-controlled, single- or double-blind, add-on trials of BRV in adult
patients with drug-resistant partial epilepsy were identified through a systematic literature
search. The following outcomes were assessed: 50% or greater reduction in seizure frequency,
seizure freedom, incidence of treatment-emergent adverse events (TEAEs), and treatment with-
drawal. Risk ratio (RR) with 95% confidence interval was estimated for each outcome.
Results: Six trials were included involving 2,399 participants according to the intent-to-treat,
1,715 for BRV, and 684 for placebo groups, respectively. The pooled RRs for the 50% respond-
ers and seizure freedom were 1.79 (1.51–2.12) and 4.74 (2.00–11.25), respectively. The sub-
analysis by levetiracetam (LEV) status did not show a statistically significant difference in the
50% responder rate when comparing BRV with placebo in patients with concomitant assumption
of LEV. The TEAEs significantly associated with BRV were irritability (2.99 [1.28–6.97]), fatigue
(2.19 [1.44–3.33]), somnolence (1.97 [1.45–2.68]), and dizziness (1.66 [1.19–2.31]). The over-
all RRs for treatment withdrawal due to TEAEs or any reason were 1.58 (1.04–2.40) and 1.27
(0.93–1.73), respectively.
Conclusions: In adults with drug-refractory focal epilepsy, add-on BRV was effective to reduce
seizure frequency and fairly well-tolerated. Further studies are needed to draw definitive conclu-
sions about its efficacy in non-LEV-naive participants and evaluate its long-term safety profile.
Neurology® 2016;86:1–9
GLOSSARY
AED 5 antiepileptic drug; BRV 5 brivaracetam; CI 5 confidence interval; ITT 5 intent-to-treat; LEV 5 levetiracetam; RR 5
risk ratio; SV2A 5 synaptic vesicle protein 2A; TEAE 5 treatment-emergent adverse event.
Epilepsy is one of the most common disabling neurologic disorders, affecting about 65 million
people worldwide.1,2 Although a long-term remission is gained in the majority of individuals, up
to 30% of patients will not respond adequately and continue to have seizures despite treat-
ment.3,4 As such, there remains the need to explore new antiepileptic drugs (AEDs) with
improved efficacy and better tolerability profile.
Brivaracetam (BRV) (UCB Pharma, Brussels, Belgium) is a rationally developed third-
generation AED characterized by high-affinity binding to synaptic vesicle protein 2A (SV2A)
and chemical structure similar to levetiracetam (LEV).5–8
The aim of our study was to evaluate the efficacy and safety of BRV as add-on treatment in
refractory partial epilepsy.
METHODS Search strategy. The study was performed according to the recommendations of the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses statement.9 We systematically searched (May week 1, 2015; update October week 4, 2015)
PubMed, the Cochrane Central Register of Controlled Trials, and the US NIH Clinical Trials Registry (http://www.clinicaltrials.gov)
(search strategies are outlined in appendix e-1 on the Neurology® Web site at Neurology.org). There were no date limitations or
language restrictions. The manufacturer of BRV was contacted for information about any unpublished or ongoing studies. The
reference lists of retrieved studies were reviewed to search for additional reports of relevant trials. The protocol was not registered
previously.
From the Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
© 2016 American Academy of Neurology 1
 Eligibility criteria. Studies were selected when they met the fol-
lowing entry criteria: randomized, double- or single-blind,
placebo-controlled, parallel-group or crossover, add-on studies
with active and control groups receiving oral BRV and matched
placebo, respectively, in addition to conventional AED
treatment, minimum treatment period of 7 weeks. Participants
had to meet the following criteria: any sex, any ethnicity, adult
age (.16 years), drug-resistant focal epilepsy (simple partial,
complex partial, secondary generalized tonic-clonic seizures).
Seizures were considered drug-resistant if uncontrolled by one
or more concomitant AEDs at optimal stable dosage.
Outcome measures. The efficacy outcomes were the propor-
tion of participants with 50% or greater reduction in seizure fre-
quency in the treatment period in comparison to the
prerandomization baseline and the proportion of participants
with complete seizure freedom over the entire treatment period.
The safety and tolerability outcomes were the proportion of pa-
tients who experienced any treatment-emergent adverse events
(TEAEs) and the following ones, chosen since considered by
the review authors as common and important AED-related side
effects: headache, dizziness, somnolence, fatigue, nausea,
nasopharyngitis, irritability, insomnia, depression, and anxiety.
We also assessed the proportion of patients who withdrew from
treatment for TEAEs and for any reason. The effects on
laboratory tests, ECG, vital signs, and physical and neurologic
examinations were narratively reviewed.
Study selection, data extraction, and assessment of the
risk of bias. Two review authors (S.L. and C.C.) independently
assessed trials for inclusion and extracted the information from
included trials. Any disagreements were resolved by discussion
with a third review author (N.F.). Trial authors were contacted
for any information missing from the published article that was
deemed relevant. The risk of bias of the identified studies was as-
sessed in accordance with the recommendations of the Cochrane
Collaboration.
Statistical analysis. Heterogeneity among the trials was assessed
by the x2 test and the I2 statistics for heterogeneity.10,11 Provided
no significant heterogeneity was present (p . 0.05), results were
synthesized using a fixed effect model. If the probability value was
#0.05, the heterogeneity was interpreted according to the I 2
statistic.12 Heterogeneity will determine the choice of a fixed or
random effects model (for I2 ,40% or $40%, respectively).
Mantel-Haenszel risk ratios (RRs) with 95% confidence
intervals (CIs) were used as measures of the associations
between treatment and outcomes. The intent-to-treat (ITT)
population data were used for the analysis. We planned to
perform subgroup analysis by BRV daily dose (5, 20, 50, 100,
150, and 200 mg) and LEV status (never, prior, or concomitant
LEV use).
RESULTS Results of the search. A total of 126 records
were identified by a database and trial registers search; a
total of 6 studies13–18 were included in the review, all of
which were included in the meta-analyses (figure 1).
Characteristics and risk of bias of included studies. All
included studies were randomized, double-blind,
placebo-controlled, multicenter, parallel-group trials.
The studies included 2,399 participants according to
the ITT, 1,715 for BRV and 684 for placebo
groups, respectively. Details of the studies and
2 Neurology 86 April 5, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
participants are given in table 1 and table e-1,
respectively. All trials used adequate methods of
sequence generation and allocation concealment. We
rated all included trials as low risk of selective reporting
bias since there was no suspicion of selective outcome
reporting. The funnel plots did not suggest evidence of
publication bias (appendix e-2). All trials were
sponsored by the BRV manufacturer.
Fifty percent or greater reduction in seizure frequency.
A x2 test for heterogeneity indicated no significant
statistical heterogeneity between trials (x2 5 2.43,
df 5 5, p 5 0.787) and a fixed-effects model was
used. The overall RR (95% CI) for 50% responders
across the trials was 1.79 (1.51–2.12). The estimated
RRs for each dose compared to placebo are shown in
figure 2. The data of the flexible-dose trial17 were only
included in the overall analysis regardless of the
dosage.
According to the analysis by LEV status, the
greater numerical effect was observed for BRV com-
pared with placebo among patients who were LEV-
naive at study entry: the estimated overall RR across
the trial was 1.91 (1.52–2.41). The RRs for each dose
are presented in figure 3. At the dosage of 50 mg/day,
45% of the LEV-naive patients responded to BRV
and 19% to placebo, implying a 25% real response
rate not attributable to placebo. The number of par-
ticipants needed to treat for an additional beneficial
effect to get a responder with a 50% or greater reduc-
tion in seizure frequency during treatment on BRV at
this dose in LEV-naive patients was 4 (95% CI 3–9).
The overall RR (95% CI) for 50% responders across
the trials was 1.66 (1.21–2.47) and 0.88 (0.46–1.68)
in participants with previous and concomitant
assumption of LEV, respectively; the RRs for the dif-
ferent doses are given in table e-2. In the study by Van
Paesschen et al.,14 data on seizure reduction according
to LEV status referred to the maintenance period
compared to baseline.
Seizure freedom. A x2 test for heterogeneity indicated
no significant statistical heterogeneity between trials
(x2 5 0.17, df 5 5, p 5 0.999) and a fixed-effects
model was used. The overall RR (95% CI) was 4.74
(2.00–11.25). The estimated RRs for each dose
compared to placebo are shown in figure 4. The
data of the flexible-dose trial17 were only included
in the overall analysis regardless of the dosage. We
could not perform the prespecified subanalysis as the
included trials did not report data about seizure
freedom outcome according to LEV status.
TEAEs. A x2 test for heterogeneity suggests no signif-
icant statistical heterogeneity for the development of
TEAEs (x2 5 3.51, df 5 4, p 5 0.476). In the study
by Klein et al.,18 the safety population data were used.

Figure 1 Flow diagram of study selection process
The overall RR (95% CI) to develop at least one TEAE
during treatment was 1.08 (1.00–1.16) according to a
fixed-effects model. The RRs for the selected TEAEs are
reported in table 2. The corresponding incidence rates
among the BRV-treated participants were as follows:
headache 10.4%, dizziness 9.6%, somnolence 12.4%,
fatigue 7.7%, nasopharyngitis 4.2%, nausea 4.9%,
irritability 2.8%, insomnia 2.5%, depression 1.9%,
and anxiety 2.0%. The TEAEs significantly associated
with BRV in the overall analysis were dizziness,
somnolence, fatigue, and irritability. The analysis per
daily dose is reported in table e-3. There were no
clinically meaningful changes from baseline in blood
chemistry, urinalysis parameters, vital signs, ECG
measurements, and physical and neurologic
examinations. In one trial,15 increased body weight
was reported by 7 BRV-treated (2.3%; four 20 mg/
day, two 50 mg/day, one 100 mg/day) and no
placebo-treated participants; decreased body weight
was reported by 4 patients of the BRV group (1.3%;
two 20 mg/day, one 50 mg/day, one 100 mg/day) and
1 control patient (1.0%). Four deaths occurred during
2 studies.16,18 One patient (BRV at 20 mg/day) died of
cardiorespiratory arrest following a seizure on the first
day of the 1-week downtitration; the second patient
was randomized to receive BRV 50 mg/day but had
permanently discontinued the study drug 2 weeks prior
to death due to subarachnoid hemorrhage.16 Two
patients receiving BRV at 200 mg daily dose died,
one of sudden unexplained death in epilepsy and one
of unknown cause; neither of the deaths was related to
BRV treatment according to the investigators.18
Treatment withdrawal. A x2 test for heterogeneity sug-
gests no significant statistical heterogeneity for treat-
ment withdrawal due to any cause (x2 5 7.28, df 5
5, p 5 0.200) or TEAEs (x2 5 3.09, df 5 5, p 5
0.686). A fixed-effects model was adopted. In the
study by Klein et al.,18 the safety population data
were used. The overall RRs (95% CI) for
withdrawal for any reason and TEAEs were 1.27
(0.93–1.73) and 1.58 (1.04–2.40), respectively.
The analysis per daily dose is given in table e-4.
DISCUSSION Brivaracetam was demonstrated to be
more effective than placebo in reducing the frequency
of seizures by 50% or greater when added to conven-
tionally AEDs at dosages from 20 to 200 mg/day in
participants with refractory partial epilepsy. Further-
more, although there were insufficient available data
to undertake a dose response regression analyses,
the results suggested a dose-dependent effect
saturated when the dosage reached the 50 mg daily,

Table 1 Characteristics of included studies

Reference study Study design Treatment arms

French et al., 2010 (study Phase IIb, double-blind RCT, 4-week prospective baseline, 7-week Placebo, BRV: 5,
N01193)13 treatment period 20, 50 mg BID

Van Paesschen et al., 2013 Phase IIb, double-blind RCT, 4-week prospective baseline, 10-week Placebo, BRV: 50,
(study N01114)14 treatment period (3-week uptitration plus 7-week maintenance) 150 mg BID

Ryvlin et al., 2014 (study Phase III, double-blind RCT, 8-week prospective baseline, 12-week Placebo, BRV: 20,
N01252) 15 treatment period 50, 100 mg BID

Biton et al., 2014 (study Phase III, double-blind RCT, 8-week prospective baseline, 12-week Placebo, BRV: 5,
N01253)16 treatment period 20, 50 mg BID

Kwan et al., 2014 (study Phase III, double-blind RCT, 4-week prospective baseline, 16-week Placebo, BRV:
N01254)17 treatment period (8-week dose-finding plus 8-week stable dose 20–150 mg BID
maintenance)

Klein et al., 2015 (study Phase III, double-blind RCT, 8-week prospective baseline, 12-week Placebo, BRV: 100,
N01358)18 treatment period 200 mg BID

Abbreviations: BRV 5 brivaracetam; RCT 5 randomized controlled trial.

Neurology 86 April 5, 2016 3

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 2 Efficacy of add-on brivaracetam vs placebo

CI 5 confidence interval; M-H 5 Mantel-Haenszel.

without additional benefit with higher doses. The the daily dosage of 50 mg, 45% of the treated
subanalysis by LEV status showed how the efficacy patients were expected to be 50% responder in
of BRV was greater in the LEV-naive patients; at comparison to the 19% in the placebo group, with

4 Neurology 86 April 5, 2016

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 3 Efficacy of add-on brivaracetam vs placebo in levetiracetam-naive patients

CI 5 confidence interval; M-H 5 Mantel-Haenszel.

a risk ratio of response near 2.5-fold greater in favor of observed among patients who had previously received
BRV and a number needed to treat for an additional LEV. One post hoc analysis suggested that the
beneficial outcome of 4. Lower treatment effects were efficacy of BRV could be greater in patients who

Neurology 86 April 5, 2016 5

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 4 Seizure freedom for add-on brivaracetam vs placebo

CI 5 confidence interval; M-H 5 Mantel-Haenszel.

previously tried and discontinued LEV due to participants included in the subanalysis. This issue
intolerability and adverse effects than to poor will need to be kept in mind when adding BRV to
seizure control,18 but definitive conclusions could a preexisting drug regimen and would need to be
not be drawn due to the small number of explored robustly. Further investigations are

6 Neurology 86 April 5, 2016

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 200 mg daily, and an acceptable tolerability typical of
Table 2 Side effects for add-on brivaracetam vs placebo
other AEDs with a low incidence and mostly mild to
No. of participants Risk ratio (M-H, moderate severity of the emerging TEAEs. With
Side effect (BRV/placebo) fixed, 95% CI) p Value
respect to the investigated adverse events, fatigue,
Headache 1,717/686 0.89 (0.70–1.14) 0.344 somnolence, and dizziness were significantly more
Dizziness 1,717/686 1.66 (1.12–2.31) a
0.003a likely to occur, in absence of a clear dose-response
Somnolence 1,717/686 1.97 (1.45–2.68)a ,0.001a relationship, in the BRV-treated group compared to
Fatigue 1,717/686 2.19 (1.44–3.33) a
,0.001a
placebo; they all represent very common side effects
and substantially overlap the safety profile of the
Nasopharyngitis 1,060/371 1.26 (0.69–2.31) 0.448
majority of the AEDs.19
Nausea 1,060/371 0.82 (0.51–1.32) 0.404
Psychiatric disorders are common in patients
a
Irritability 1,563/632 2.99 (1.28–6.97) 0.011a with epilepsy and have a multifactorial etiology:
Insomnia 1,265/532 1.44 (0.69–2.99) 0.325 the seizures themselves, the underlying epileptic dis-
Depression 1,160/480 2.01 (0.70–5.82) 0.196 order, and the antiepileptic pharmacotherapy are
Anxiety 801/359 1.83 (0.62–5.44) 0.276
variably involved and, directly or indirectly, related
to both biological and psychosocial factors as the
Abbreviations: BRV 5 brivaracetam; CI 5 confidence interval; M-H 5 Mantel-Haenszel.
a
individual susceptibility and the psychiatric history
Significant.
or condition.20 The knowledge of the potential pos-
itive or negative psychotropic drug effects repre-
warranted to better evaluate the relationships between sents, therefore, a relevant issue in the choice of
treatment efficacy and AED history and explore the the optimal individual treatment; in this respect,
underlying causes. At the same time, it is noteworthy the psychiatric adverse events most commonly re-
that BRV was not demonstrated to be effective in ported with the AEDs are represented by behavioral
reducing seizure frequency by 50% or more when problems followed by affective and psychotic
added to patients who were simultaneously taking disorders.21,22
LEV, a drug that shares many similarities with BRV The most frequent reported adverse effects per-
in chemical structure and pharamcodynamic activity taining to changes in behavior were irritability,
of binding to SV2A. This evidence strongly suggests insomnia, depression, and anxiety, which were re-
that concomitant drug mechanisms of action may ported by from near 2% to almost 3% of the BRV-
reduce efficacy of BRV and influence the clinical treated participants. Other psychiatric effects re-
response. ported to a lesser extent included aggression, agita-
Freedom from seizures represents one of the main tion, and memory impairment. Although a
targets of AED treatment and BRV was demonstrated statistically significant difference between BRV and
to achieve this outcome from the dosage of 50 mg. control groups emerged only in the incidence of irri-
The greatest effect was reached with the 100 mg daily tability, it is noteworthy that psychiatric disorders
dose, at which the drug is estimated to be 7 times have been reported as the most common type of
more effective in stopping seizures than placebo. This TEAEs leading to premature discontinuation in 2
result represents a meaningful goal taking into of the larger trials,15,16 and this needs to be explored.
account that all participants recruited in the add-on The highlighted profile is closely reminiscent of that
clinical trials were characterized by difficult-to-treat of LEV and may be related to the drug action on the
epilepsy and occurrence of partial-onset seizures SV2A and the consequent effects on cortical func-
despite the antiepileptic polytherapy. Although tions and alertness.23 Although a post hoc analysis
BRV was clearly demonstrated to improve seizure suggested a lower incidence of nonpsychotic behav-
freedom when compared with placebo, the unavail- ioral adverse effects in BRV than LEV-treated partic-
ability of evidence by LEV status did not allow us ipants despite the higher affinity binding of the
to draw definitive conclusions. It is plausible that in former to the receptors,24 to date no head-to-head
LEV-naive participants, BRV may achieve seizure studies have been performed at confirmation and
freedom to even a greater extent than estimated by the findings should be interpreted cautiously since
the unstratified analysis, but it may present a lower the original studies did not contemplate sensible
treatment effect or fail to reach statistical significance and specific tools for mood measures in their
in the cohorts of non-LEV-naive patients. methods.
Across phase II and phase III trials in patients with In the last 2 decades, many second- and third-
drug-resistant partial-onset seizures, adjunctive BRV generation AEDs have been licensed for the treatment
demonstrated a favorable safety profile, as shown by of intractable partial epilepsy. The newer drugs have
the treatment withdrawal rates due to any reason sim- been demonstrated to be more effective with respect
ilar to placebo across all BRV doses ranging from 5 to to seizure control and associated with a higher

Neurology 86 April 5, 2016 7

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 incidence of overall adverse effects and withdrawal
rates than placebo.25–37 There is little evidence, how-
ever, of how these AEDs should be trialed when
monotherapy fails, and in which order they should
be prescribed as an adjunct, since no direct head-to-
head trials are available. Although the results of this
meta-analysis of randomized controlled clinical trials
clearly indicated that BRV is effective to reduce the
frequency of refractory partial-onset seizures and rea-
sonably tolerated as adjunctive treatment, it cannot
compare BRV to other AEDs, and the application
field in the management of adult refractory epilepsy
remains to be clearly established for BRV, as well as
for many other newer AEDs.
Our systematic review and meta-analysis provides
the best currently available evidence for the efficacy
and safety of add-on BRV in refractory partial-onset
seizures and updated the previous attempts.38–40
Owing to the inclusion of a greater number of ran-
domized controlled trials, the statistical analysis we
performed pooled a larger population and allowed
us to better estimate the real effect size of the drug,
evaluate its efficacy and safety when administered at
the daily dose of 200 mg, and more comprehensively
characterize its spectrum of adverse effects. Further-
more, we performed targeted subgroups analysis ac-
cording to the patients’ LEV status—namely prior,
concomitant, or never LEV use—which could have
great clinical relevance and meaningful practical
implications.
Different limits of this review should be taken into
account. First, few trials were included and all were
funded by pharmaceutical companies. Evidence for
the 150 and 200 mg doses derived from only one trial
for each dosage and should be interpreted with cau-
tion. Although in exploratory studies BRV has been
demonstrated to have a broad spectrum of activity
and to be efficacious towards generalized seizures,41
this review focused on the use of BRV in drug-
resistant focal epilepsy and the results cannot be
extrapolated to generalized epilepsy. Furthermore,
despite the need for long-term therapy of the partic-
ipants with epilepsy, the treatment period of the trials
included in this review ranged only from 7 to 12
weeks; in this respect, 5 open-label long-term
follow-up studies in adult patients are ongoing to
date. Likewise, this meta-analysis cannot provide
information about the efficacy and tolerability of
BRV as monotherapy or in comparison with other
AEDs, the safety of BRV during pregnancy and lac-
tation, the occurrence of rare but serious adverse
events that may be seen with AEDs such as
Stevens-Johnson syndrome or aplastic anemia, or
phenomena such as habituation and tolerance, as well
as the quality of life or the health economic outcomes.
Further investigations including longer term studies,
8 Neurology 86 April 5, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
head-to-head trials, and pharmaco-epidemiologic sur-
veys will be needed to address all these issues.
Brivaracetam was demonstrated to be effective and
to have a favorable safety and tolerability profile as add-
on treatment in adults with drug-refractory focal epi-
lepsy. In participants who were not under concomitant
treatment with LEV or had not previously used it, the
estimated risk ratios favored BRV most strongly at the
dose of 50 mg/day to reduce the seizure frequency by
50% or greater. Further studies are needed to draw
definitive conclusions about BRV when used at higher
doses, to explore the mechanisms underlying the differ-
ent efficacy profile in non-LEV-naive participants, and
to evaluate long-term efficacy and safety.
AUTHOR CONTRIBUTIONS
Simona Lattanzi: drafting/revising the manuscript, study concept or
design, analysis or interpretation of data, accepts responsibility for conduct
of research and final approval, statistical analysis. Claudia Cagnetti: drafting/
revising the manuscript, accepts responsibility for conduct of research and
final approval, acquisition of data. Nicoletta Foschi: drafting/revising the
manuscript, accepts responsibility for conduct of research and final
approval, acquisition of data. Leandro Provinciali: drafting/revising the
manuscript, accepts responsibility for conduct of research and final
approval. Mauro Silvestrini: drafting/revising the manuscript, study concept
or design, analysis or interpretation of data, accepts responsibility for con-
duct of research and final approval, study supervision.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received July 25, 2015. Accepted in final form December 23, 2015.
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Neurology 86 April 5, 2016 9
 Brivaracetam add-on for refractory focal epilepsy: A systematic review and
meta-analysis
Simona Lattanzi, Claudia Cagnetti, Nicoletta Foschi, et al.
Neurology published online March 4, 2016
DOI 10.1212/WNL.0000000000002545

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