338 CLINICAL Original Article

NEUROPHARMACOLOGY
Volume 29, Number 6
November - December 2006

Levetiracetam in the Prophylaxis of

Migraine With Aura: A 6-Month
Open-label Study
Filippo Brighina, MD,* Antonio Palermo, MD,* Antonina Aloisio, MD,†
Margherita Francolini, MD,* Giuseppe Giglia, MD,*
and Brigida Fierro, MD*

(Clin Neuropharmacol 2006;29:338Y342)

*Neurophysiology Unit,
Department of Neurology,
University of Palermo, Palermo
Italy; and †Neurophysiopathology
Unit, Civic Hospital, Palermo, Italy.
Address corespondence and
reprint requests to Brigida Fierro,
MD, Neurophysiology Unit,
Department of Neurology,
University of Palermo, Via G. La
Loggia 1, 90129, Palermo, Italy;
E-mail: fierro@unipa.it
Copyright Ó 2006 by Lippincott
Williams & Wilkins
Abstract
Objective:
To evaluate the efficacy of levetiracetam as pro-
phylactic treatment for migraine with aura with
high frequency of attacks.
Background:
Migraine with aura with high frequency of attacks
could represent a very demanding therapeutic
problem. Efficacy of the antiepileptic drug, lamo-
trigine, has been reported in this form of migraine.
Levetiracetam is a new antiepileptic drug with an
excellent tolerability profile. Mechanisms of action
of this drug remain largely unknown, but recently,
it has been shown to exert inhibitory effects on
neuronal-type calcium channels.
Methods:
We performed a small open-label trial treating 16
patients affected by migraine with aura with high
frequency of attacks. After a 1-month run-in
period, patients were treated with levetiracetam
at a dosage of 1000 mg/d for 6 months.
Results:
The number of attacks per month was signifi-
cantly reduced during the first month (compared
with run-in; P G 0.001), and it was reduced further
during the second (second month vs first month;
P G 0.001) and the third months (third month vs
second month; P G 0.001) of the treatment. This
improvement persisted unchanged for the remain-
ing 3 months of treatment. In 7 (44%) of the 16
patients, the attacks were completely abolished
after 3 months of treatment. Severity of headache
and duration of headache and aura were also
significantly reduced at the third and sixth
months of treatment (P G 0.001). Levetiracetam
was well tolerated (6 patients complained of slight
dizziness, nervousness, and somnolence).
Conclusions:
Levetiracetam seems to be a safe and effective
treatment for migraine with aura. Controlled trials
are needed to confirm the observed results.
Key Words: levetiracetam, prophylaxis, migraine,
aura
I t has recently been suggested that calcium
channel dysfunction, as reported in familial
hemiplegic migraine,1 could play a pathoge-
netic role in migraine.2 This alteration would
indeed predispose to cortical spreading
depression (CSD), a phenomenon thought
to represent the pathophysiological basis of
migraine aura. Moreover, as shown by Bolay
et al,3 CSD is able to induce the activation of
the trigeminovascular system, giving rise to
migraine headaches.
In agreement with the calcium channel
hypothesis, it has been shown that patients
affected by migraine with aura present subtle
cerebellar or neuromuscular dysfunctionsV
both compatible with systemic calcium chan-
nel disease.4,5
Migraine with aura with high fre-
quency of attacks could represent a demand-
ing therapeutic problem. Attacks with aura
recur many times in a month, and patients
often undergo many prophylactic treatments
with no or only moderate benefit.
D’Andrea et al6 showed that the anti-
epileptic drug, lamotrigine, is effective in
this form of migraine, drastically reducing
attack frequency and duration of the aura.
Levetiracetam (LEV) is a new antiepi-
leptic drug with an excellent tolerability
profile. The mechanisms of action of this
drug remain still largely unknown, although
some evidence has recently been reported
that LEV is able to induce inhibitory effects

DOI: 10.1097/01.WNF.0000236766.08409.03

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 Levetiracetam in the Prophylaxis of Migraine With Aura
on neuronal (N)-type high-voltage calcium
channels.7Y9
Moreover, recent evidence from studies
in experimental animals shows that blockade
of the N-type calcium channel is able to
inhibit repetitive CSD and reduce firing of
trigeminal neurons that is either spontaneous
or evoked by dural stimulation.10,11
On these grounds, we tested the effi-
cacy of LEV in treating patients affected by
migraine with aura with high frequency of
attacks.
SUBJECTS AND METHODS
We carried out a prospective open-
label trial. Patients participating in the study
were consecutively recruited from the Head-
ache Outpatient department of the Neu-
rology department of the University of
Palermo.
Inclusion criteria are the following:
1. diagnosis of migraine with aura meeting
the new classification criteria of the
International Headache Society (IHS;
Headache Classification Subcommittee of
the IHS),12
2. attack frequency of 4 or more attacks per
month for at least 3 months,
3. a history of at least 2 years of migraine
with aura.
Patients were excluded for the follow-
ing reasons:
1. affected by headaches other than
migraine,
2. affected by systemic or organic disease,
3. they had used prophylactic medication
for the last 2 months,
4. pregnant or at risk of pregnancy
According to these criteria, we en-
rolled 16 patients, 11 female subjects and 5
male subjects aged 16 to 59 years (Table 1).
No one had a history of mood disorders or
epilepsy. Electroencephalogram examination
performed on all patients did not show any
paroxysmal activity. Patients gave their
informed consent, and the study was con-
ducted according to the Helsinki Declara-
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CLINICAL
NEUROPHARMACOLOGY
339
Volume 29, Number 6
November - December 2006
tion. Ten patients were drug-naive, whereas
6 patients had previously responded inade-
quately to other preventive medication.
Patient 4 (Table 1) had been treated with
flunarizine (10 mg/d for 2 months) which
had not been effective and then with val-
proate (1000 mg/d for 6 months) which
reduced attack frequency by approximately
50% but caused intense day-time sleepi-
ness. Patient 11 had been given valproate
(1000 mg/d for 3 months) which only had
a slight effect on headache duration, leav-
ing attack frequency quite unaffected.
Patients 2 and 8 had received propanolol
for 3 months (the first at 80 mg/d and the
other at 120 mg/d), with nonsignificant
reduction of attack frequency and duration.
Pizotifen (1.5 mg/d for 3 months) had
been prescribed in patients 10 and 12,
with no benefit.
The study began with a 1-month run-in
period, the inclusion criteria being re-
examined at the end of this period. Subse-
quently, all the patients were given 1000 mg
of LEV (500 mg BID) for 6 months. The drug
was titrated, starting with a dosage of 250
mg/d and was increased by 250 mg/wk until
the final dosage of 1000 mg/d was reached.
The patients were free to take symptomatic
medication, if needed; 11 patients used
rescue analgesics, and 5 patients used trip-
tans. Other regular medications were
allowed unless known to affect the course
of migraine.
Attack frequency and severity (rated as
the following: 1, mild; 2, moderate; and 3,
severe) and aura and headache duration
were recorded daily by the patients by
means of specific headache diaries through-
out the entire study period (run-in and
treatment phases).
Headache frequency per month was
the main outcome measure, and it was
assessed by the number of migraine pe-
riods. A migraine period was defined as
any occurrence of migraine headache that
started or recurred within 24 hours. Pain
persisting for more than 24 hours after its
initial onset was considered to be a new,
 CLINICAL Brighina et al
340 NEUROPHARMACOLOGY
Volume 29, Number 6
November - December 2006

TABLE 1. Details of Patients Enrolled in the Study

Attack Frequency by Month
Disease Duration, Third Sixth
Patient Sex Age, yr Diagnosis yr Run-in Month Month

1 F 23 1.2.1, 1.1 5 4 0 0
2 F 57 1.2.1 20 8 2 1
3 M 32 1.2.1 10 6 0 0
4 F 16 1.2.2 3 8 3 2
5 F 34 1.2.1 12 4 0 0
6 F 24 1.2.1 8 9 1 1
7 F 31 1.2.2 8 6 0 0
8 F 30 1.2.1, 1.1 7 4 0 0
9 F 59 1.2.1, 1.1 20 6 1 1
10 M 41 1.2.1 18 7 2 1
11 F 43 1.2.2 20 8 2 2
12 F 48 1.2.2 23 6 1 2
13 M 24 1.2.2 8 8 2 2
14 M 25 1.2.1 9 5 0 0
15 M 35 1.2.1 11 5 0 1
16 F 26 1.2.1 6 5 1 0
*Diagnostic code according to the new IHS Classification: 1.1, migraine without aura; 1.2.1, typical aura with
migraine headache; 1.2.2, typical aura with nonmigraine headache.
F indicates female; M, male.

distinct migraine period. Secondary efficacy Repeated-measures analysis of variance

measures included severity and duration of
the headache and the aura phases. Statisti-
cal analysis to assess the efficacy of the
treatment was performed by means of
analysis of variance for repeated measures,
comparing the monthly frequency of at-
tacks during the treatment period. The
paired t test was used to compare the mean
severity of attacks and the mean duration of
headache and aura in the run-in period with
those measured during the third and the sixth
month of treatment.
RESULTS
Levetiracetam was generally well toler-
ated, and no serious adverse effects or
dropping out were recorded. The following
adverse events were reported, only during
the titration phase: somnolence (2 patients),
dizziness (1 patient), and nervousness (3
patients).
showed a significant reduction in migraine
attacks during the treatment (F6,90 = 178, 81;
P = 0.0001). Tukey Honestly Significant
Differences post hoc analysis revealed that
the number of attacks was significantly
reduced during the first month of the treat-
ment (first month vs run-in; P G 0.001) and it
further lowered along the second (second
month vs first month; P G 0.001) and the
third months (third month vs second month;
P G 0.001) of the treatment. This improve-
ment persisted unchanged for the remaining
3 months of treatment.
Attack frequency per month decreased
from 6.20 T 1.6 in the run-in period to 0.81 T
0.8 in the sixth month of treatment (Fig. 1).
Seven (44%) of the 16 patients were com-
pletely headache-free by the third month of
treatment.
All the remaining 9 patients expe-
rienced a reduction in monthly migraine
frequency.

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 Levetiracetam in the Prophylaxis of Migraine With Aura
FIGURE 1. Mean (TSD) attack frequency per
month during run-in and the whole treatment
period.
In the patients with residual attacks,
the mean severity of headache was signifi-
cantly decreased from 2.56 T 0.44 during
run-in to 1.48 T 0.45 at the third month (P G
0.0001) and to 1.32 T 0.46 at the sixth
month of the treatment (P G 0.0001).
Duration of the headache phase, as com-
pared with run-in (10.9 T 4.4 hours), showed
a significant decrease (P G 0.001) at the third
(4.4 T 2.1 hours) and the sixth months (3.5 T
2.1 hours) of treatment.
By the third month of treatment, the
aura had completely disappeared in 7
patients; in the remaining patients, its mean
duration was significantly decreased (P G
0.001) in the third (11.4 T 6.2 minutes) and
the last months (16 T 8.6 minutes) of the
treatment, as compared with run-in (41.3 T
14.4 minutes).
Three patients also presented migraine
attacks without aura, the frequency of which
was not significantly reduced at the end of
the treatment.
DISCUSSION
In this study, LEV therapy was well
tolerated, and only mild and transitory
adverse events were reported by our patients.
Our findings show that this drug is
effective in preventing migraine with aura
attacks; the major outcome measure (ie,
attack frequency per month) significantly
decreased in the first month of treatment as
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CLINICAL
NEUROPHARMACOLOGY
341
Volume 29, Number 6
November - December 2006
compared with the run-in period. This effect
became more evident in the third month of
the treatment and remained constant until
the end the treatment. The improvement
was particularly evident in 7 patients who
were completely attack-free since the third
month of therapy.
Levetiracetam was also able to affect
the other efficacy measures, significantly
reducing the intensity and duration of the
residual attacks of headache at the third and
sixth months of treatment with respect to
run-in. Moreover, during the treatment, we
observed in our patients a significant reduc-
tion in the mean duration of the aura, as
previously reported by D’Andrea et al6 in
patients treated by lamotrigine.
To our knowledge, this is the first
prospective study of LEV as preventive treat-
ment for migraine with aura.
Recently, 2 retrospective studies have
been published, exploring the efficacy of
LEV in the prophylaxis of migraine in
adults13 and children.14 Other preliminary
data coming from studies of migraine
patients treated with LEV have also been
published as abstracts.15Y18
All these studies report the efficacy of
LEV in preventing migraine attacks; how-
ever, none of these specifically investigated
patients affected by migraine with aura,
neither were the effects on the duration
and frequency of the aura attacks specified.
Our results suggest a possible role of
LEV on the physiopathogenetic mechanisms
of migraine aura.
Although the action of LEV still remains
to be elucidated, the ability of the drug to re-
duce the N-type activity of high-voltageYgated
calcium channels9 could at least in part
explain its efficacy in preventing aura attacks.
Indeed, inhibition of the N-type calcium
channels, as shown in experimental animals,
is able to control the initiation and propagation
of CSD, the mechanism suggested to be at the
basis of the aura phenomena.10 In our cases,
attacks of migraine without aura, present in a
very few number of patients (3 of 16), were
not responsive to LEV treatment. This result,
 CLINICAL Brighina et al
342 NEUROPHARMACOLOGY
Volume 29, Number 6
November - December 2006
if confirmed in further studies on larger
series, could add arguments to the hypothesis
of a peculiar pathogenetic mechanism for the
initiation of migraine aura. On the other
hand, a specific efficacy on migraine with
aura was also reported by using another
antiepileptic drug, lamotrigine, to prevent
migraine attacks.6
In the present study, we did not
consider symptomatic medications (triptans,
and rescue analgesics) as a secondary out-
come measure. Moreover, considering the
small number of patients using triptans (5 of
16), we did not explore the difference in the
use or effect of symptomatic drugs between
patients who responded to LEV and those
who did not or between patients with
attacks of migraine with aura only and those
with attacks both with and without aura.
This interesting issue is worth to be
addressed in further studies of LEV in more
patients with headache.
Taking into account the open design of
the study, the present results should be
interpreted with caution, considering the
variability of the disease course and the high
placebo effects observed in trials of preven-
tive medications in migraine.
In our study, however, the persistence
of therapeutic effects for the full treatment
period, with 44% of patients being attack-
free since the third month, can hardly be
attributed to a purely placebo effect.
Moreover, we selected only patients
with a quite stable history (disease duration
of at least 2 years with a frequency of 4 or more
attacks per month for the last 3 months);
therefore, nonspecific changes because of
disease variability seem to be unlikely.
On this basis, further investigations
with placebo-controlled trials seem worth-
while to assess the real efficacy of LEV as a
new therapeutic option for preventing
migraine with aura attacks.
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