J Cardiol 2007 Jun; 49（6）: 357 – 360

Efficacy of Ticlopidine for Preventing Migraine After Transcatheter
Closure of Atrial Septal Defect WithAmplatzer Septal Occluder : A Case
ReportHideshiTOMITA, MD, FJCC

Kinya

HATAKEYAMA, MD

WataruSODA, MD

Toshiki

KOBAYASHI, MD＊Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────Transcatheter closure of an atrial septal defect using the Amplatzer septal occluder is a current treatment
option in Japan, but is occasionally associated with transient exacerbation or new onset migraine.
Clopidogrel is effective in such a situation, but the efficacy of ticlopidine, an analog of clopidogrel, onmigraine remains unclear. A 15-year-old girl presented with typical migraine attacks with aura 11 days
after transcatheter closure of an atrial septal defect with an Amplatzer septal occluder. All examinations
excluded thromboembolic origin of the migrain. Her symptoms disappeared completely after medication
with ticlopidine.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Jun; 49（6）: 357−360

Key Words■ Congenital heart disease■ Drug therapy（ticlopidine）■ Heart catheterization（Amplatzer septal occluder）■ Complications（migraine）

INTRODUCTION
Transcatheter closure of an atrial septal defect（ASD）using the Amplatzer septal occluder is acurrent treatment option in Japan. Right-to-leftshunts associated with ASD or persistent foramen
ovale have been suggested as a mechanism of
migraine with aura, but paradoxically, transient
exacerbation or new onset migraine has occasionally been reported following transcatheter closure of
an ASD or persistent foramen ovale.1−4）Clopidogrel is effective in such a situation,3,4）but the efficacy of ticlopidine, an analog of clopidogrel, onmigraine with aura remains unknown.
We treated a 15-year-old girl with typicalmigraine with aura 11 days after transcatheter closure of an ASD with the Amplatzer septal occluder,and her symptoms completely disappeared after
medication with ticlopidine.
CASE REPORT
A 15-year-old girl had been found on healthscreening when 4 months old to have a systolicmurmur at the upper left sternal border. The diagnosis was ASD but closure was deferred until
approval of the Amplatzer septal occluder in Japan.
She remained asymptomatic during follow-up atour hospital. Two-dimensional transthoracic
echocardiography documented the presence of anostium secundum ASD complicated by significant──────────────────────────────────────────────
北海道立小児総合保健センター 循環器科 : 〒 047−0261 北海道小樽市銭函 1 丁目 10−1 ; ＊埼玉医科大学 小児心臓科，埼玉Department of Cardiology, Hokkaido Children s Hospital and Medical Center, Hokkaido ; ＊ Department of Pediatric Cardiology,Saitama Medical School Hospital, Saitama
Address for correspondence: TOMITA H, MD, FJCC, Department of Cardiology, Hokkaido Children s Hospital and Medical Center,Zenibako 1−10−1, Otaru, Hokkaido 047−0261 ; E-mail : tomitah@sapmed.ac.jp
Manuscript received February 16, 2007 ; revised March 9, 2007 ; accepted March 19, 2007357

358ATomita, Hatakeyama, Soda et alBCDFig. 1 Computed tomography scans（A−D）at the onset of migraine
There were no abnormal findings.

volume overload of the right heart. Cardiac
catheterization revealed a Qp/Qs ratio of 2.8 : 1with normal pulmonary artery pressure, and transesophageal echocardiography confirmed a defect of18 mm with adequate margins. Consequently, wereferred her to Saitama Medical University for transcatheter closure of the ASD with the Amplatzer
septal occluder. As the balloon occlusion diameterwas 21.4 mm, a 22 mm device was implanted successfully, with immediate complete closure of thedefect. Detailed procedures to implant the device
have been extensively described in previous
reports.5,6）Aspirin（200 mg/day）was administeredfrom 2 days before the procedure and thereafter,
and intravenous heparin was given during thecatheterization to keep the activated clotting time
longer than 200 sec. The clinical course after theprocedure was uneventful and she returned home
after 2 days.
Eleven days after ASD closure, the patient presented with photophobia, flickering lights, and scotoma followed by severe pulsating headache
accompanied by nausea and vomiting. The symptoms lasted several hours and occurred at least oncea day ; there was no previous history of similar
symptoms. After recovery from the headache, she
had no neurological signs or symptoms. Computed
tomography of the brain showed no abnormalities（Fig. 1）, and transthoracic echocardiography confirmed the device to be perfectly positioned in theatrial septum, with no evidence of a shunt or thrombus on the device or anywhere else in her heart（Fig. 2）. A consultant neurologist diagnosed theepisodes as migraine with aura that met the diagnostic criteria of the International Headache

Fig. 2 Echocardiogram at the onset of migraine
The device（arrows）was perfectly positioned in the atrial septum with no evidence of thrombus.

Society.7）
In Japan, clopidogrel is only approved for theprevention of recurrent cerebrovascular ischemic
events, excluding thromboembolic episodes of cardiac origin. Therefore, we added 200 mg/day of
ticlopidine to the aspirin medication therapy.
Informed consent for prescription of ticlopidine andnecessity of blood examination at least once in 2weeks during medication was obtained from thepatient and her parents. Since ticlopidine administration was started, migraine with aura, previously adaily event, has resolved completely. Ticlopidine
administration was decreased to 100 mg/day after 1
month without migraine, and was stopped 2 months
after the onset of migraine. There has been norecurrence of migraine, and she had no clinical sign
J Cardiol 2007 Jun; 49（6）: 357 – 360

Migraine Following Amplatzer Septal Occluder

or abnormality of laboratory data which suggested
side effects of ticlopidine.
DISCUSSION
Transient exacerbation of existing migraine or
new onset migraine have been reported in 10−40%
of patients following transcatheter closure of ASD
or persistent foramen ovale.2−4）The presence of
microemboli on the left side surface of the device
or the liberation of vasoactive substances, such as
serotonin, from platelets is regarded as the pathological mechanism of such migraine.1,2,4）Standard
medications for migraine, for example, amytriptyline, or anticoagulation with heparin or warfarin arereported to be effective for this type of migraine.1,2）
In addition, there are a few reports on the efficacy
of antiplatelet medication with clopidogrel in addition to the standard regimen of aspirin,3,4）whichfurther suggests that platelet activation may be
involved in migraine etiology under some circumstances.
Clopidogrel and ticlopidine are thienopyridine
derivatives which inhibit platelet aggregation
through antagonism of the adenosine diphosphate
receptor, P2Y12.8−10）Ticlopidine effectively pre要359

vents cardiovascular events in cerebrovascular, cardiovascular, and peripheral vascular disease, but
has been replaced by clopidogrel in North America
and Europe because of its significant and sometimes fatal adverse reactions, specifically neutropenia and bone marrow suppression. 8,9）In Japan
clopidogrel is only approved for prevention ofrecurrent cerebrovascular ischemic events.
In our patient, ticlopidine prevented recurrenceof migraine with aura as did clopidogrel in previous
reports.3,4）This is not surprising as there are several
reports on the similar efficacy of ticlopidine andclopidogrel in preventing cardiovascular
events. 8−10） Further randomized studies on theefficacy of thienopyridine derivatives in the prevention of migraine developing after transcatheter closure of ASD are necessary. Once its efficacy is confirmed, official approval of migraine as an indication for clopidogrel will prevent serious adverse
actions from ticlopidine.
Acknowledgements
We thank Dr. Peter M. Olley, Professor Emeritus ofPediatrics, University of Alberta, and Dr. Setsuko Olley for language consultation.

約Amplatzer Septal Occluder 留置後の片頭痛にチクロピジンが有効であった
心房中隔欠損の 1 例
富 田英

畠山欣也

早 田航

小林俊樹

我が国でも Amplatzer septal occluder による心房中隔欠損の経カテーテル的閉鎖術が行われるようになったが，術後に一過性の片頭痛増悪や新たな発症が報告されている．この片頭痛にクロピドグレルが有効との報告があるが，チクロピジンの有効性に関する報告はみられない．Amplatzer septaloccluder による心房中隔欠損閉鎖術の 11 日後に片頭痛を発症した 15 歳の女児を経験した．血栓，塞栓症の所見はなく，この片頭痛にはチクロピジンが著功した．

J Cardiol 2007 Jun; 49（6）: 357−360

References
1）Rodes-Cabau J, Molina C, Serrano-Munuera C, CasaldaligaJ, Alvarez-Sabin J, Evangelista A, Soler-Soler J : Migrainewith aura related to the percutaneous closure of an atrial
septal defect. Catheter Cardiovasc Interv 2003 ; 60 : 540−5422）Yew G, Wilson NJ : Transcatheter atrial septal defect closure with the Amplatzer septal occluder : Five-year followup. Catheter Cardiovasc Interv 2005 ; 64 : 193−196

J Cardiol 2007 Jun; 49（6）: 357 – 3603）Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL :Clopidogrel reduces migraine with aura after transcatheter
closure of persistent foramen ovale and atrial septal defects.
Heart 2005 ; 91 : 1173−11754）Sharifi M, Dehghani M, Mehdipour M, Al-Bustami O,Emrani F, Burks J : Intense migraines secondary to percutaneous closure of atrial septal defects. J Interven Cardiol
2005 ; 18 : 181−1835）Masura J, Gavora P, Formanek A, Hijazi ZM :Transcatheter closure of secundum atrial septal defect using

360

Tomita, Hatakeyama, Soda et al

the new self-centering amplatzer septal occluder : Initialhuman experience. Cathet Cardiovasc Diagn 1997 ; 42 :388−3936）Du ZD, Hijazi ZM, Klienman CS, Silverman NH, Larntz
K ; Amplatzer Investigators : Comparison between transcatheter and surgical closure of secundum atrial septal
defect in children and adults : Results of a multicenter nonrandomized trial. J Am Coll Cardiol 2002 : 39 : 1836−18447）Headache Classification Subcommittee of the International
Headache Society : The International Classification ofHeadache Disorders : 2nd edition. Cephalalgia 2004 ; 24（Suppl 1）: 9−1608）Quinn MJ, Fitzgerald DJ : Ticlopidine and clopidogrel.
Circulation 1999 ; 100 : 1667−16729）Kam PC, Nethery CM : The thienopyridine derivatives（platelet adenosine diphosphate receptor antagonists）,
pharmacology and clinical developments. Anaethesia
2003 ; 58 : 28−3510）Savi P, Herbert JM : Clopidogrel and ticlopidine : P2Y12
adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005 ;31 : 174−183

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