Atrial septal defect closure and de novo migraine: Exclusive ticlopidine efficacy

Abstract

Background:

De novo onset or aggravation of migraine has been observed after atrial septal defect closure (ASDC), whereas antiplatelet drugs, such as clopidogrel, used to prevent post-ASDC thromboembolic events, have been associated with migraine amelioration.

Case:

We report the case of a woman who, after ASDC, experienced de novo severe migraine with aura. Whereas use of acetylsalicylic acid or clopidogrel had no effect, ticlopidine use was associated with migraine amelioration. Migraine relapsed after two ticlopidine dechallenges, and disappeared after drug rechallenges.

Conclusion:

A ticlopidine trial could be proposed to patients with migraine which occurs or worsens immediately after ASDC and does not improve with clopidogrel.

Introduction

Percutaneous closure of atrial septal defects (ASD) is a procedure used to correct, by percutaneous catheterization and positioning of a septal occluder, the left-to-right atrial connection due to a septum defect. Although these findings have not always been confirmed (1), a number of reports have described the de novo onset, or higher frequency and/or intensity, of migraine attacks after percutaneous closure of ASD (2–7). Clopidogrel, the most commonly recommended treatment to prevent thromboembolic events after ASD closure, has been associated with amelioration of migraine attacks which occur for the first time or worsen after ASD closure (3,5,6). Moreover, a clinical trial is currently being performed to assess the efficacy of clopidogrel in preventing migraine appearing after ASD percutaneous closure (8). There is only one report indicating that ticlopidine, another antiplatelet medicine used to prevent thromboembolic events, is associated with migraine amelioration (4).

The present case report provides Class IV evidence (9) that the use of ticlopidine, but not acetylsalicylic acid (ASA) or clopidogrel, was associated with marked reduction in de novo migraine attacks occurring after ostium secundum percutaneous closure with an Amplatzer device.

Patient and methods

A 34-year-old woman was found to have an ostium secundum ASD when she was 23 years old. The ASD was documented by two-dimensional transthoracic echocardiography performed for an episode of thoracic pain occurring after a surgical dental procedure. Transthoracic electrocardiography (EKG) showed no pathological alteration, but the diagnosis was confirmed by transoesophageal EKG. Five years later (in 2004, when the patient was 28 years old) closure of the ASD was successfully performed with an Amplatzer septal occluder positioned using a percutaneous right femoral venous approach. Intervention was followed by an uneventful clinical course. Before the closure, the patient underwent a brain CT scan with no evidence of pathological signs. Double antiplatelet treatment with ASA 100 mg and clopidogrel 75 mg was started immediately after the operation.

On day 3 after the surgical procedure, the patient experienced visual disturbances with scotoma and flickering lights lasting 30 minutes, preceding bilateral pulsating severe headache with more intense right-side pain. The pain was localized to the temporal and occipital regions, was accompanied by photophobia and phonophobia, and lasted more than 4 hours. After recovery from the headache, the patient did not report any neurological signs or symptoms. The patient did not have any personal or family history of headache. After this first attack, the patient had similar episodes that occurred up to two times each day for the first week, and a minimum of five attacks per month until November 2009. In particular, the patient reported that she did not experience any headache-free period lasting longer than 5–6 days. Visual disturbances were preceded by asthenia, and in one episode the patient experienced transient dysarthria before the onset of the headache.

The consultant cardiologist considered it appropriate to continue double antiplatelet treatment for a period longer than usually recommended. However, in November 2009 the patient, according to Italian National Health System drug prescription rules, was advised to discontinue ASA and clopidogrel, and start ticlopidine 250 mg twice daily. After the initiation of ticlopidine, the episode of either visual disturbances or headache expected to occur within the successive 5–6 days, and those thereafter, did not occur. While on ticlopidine, the patient did not experience any further asthenia episodes. Hypermenorrhea occurred 30 days after the initiation of ticlopidine, and for this reason the daily dosage was halved, but the beneficial effect on the headache attacks and associated symptoms remained unchanged.

In August 2010, ticlopidine treatment was suspended for a dental surgery procedure. On day 5 after ticlopidine withdrawal, the patient again experienced visual disturbances and headache, with symptoms and frequency identical to those reported before ticlopidine initiation. In September 2010 the patient had a cerebral MRI, showing two minimal areas of hyperintensity in the periventricular white matter, defined as non-specific in nature. In November 2010 the patient re-started ticlopidine treatment and, again, the attack expected to occur within the successive 5–6 days, and those thereafter, did not occur. In December 2010 the patient was referred to our Headache Centre, at the Careggi University Hospital in Florence. A diagnosis of migraine with aura, code 1.2.1 according to International Headache Society diagnostic criteria (10) was posed and continuation of ticlopidine was recommended. However, in January 2011, ticlopidine was stopped for a dental extraction, and 5 days after drug discontinuation migraine and aura re-appeared. Ten days after drug withdrawal, and the day after dental extraction, the patient re-started ticlopidine, and for the third time the attack expected to occur within the successive 5–6 days, and those thereafter, did not occur.

One possible explanation for the selective response to ticlopidine could be that clopidogrel failure occurred as a result of genetically determined, altered pharmacokinetics. This could be because of reduced absorption and/or accelerated metabolism of the drug, resulting in a lower and therefore ineffective plasma drug concentration. To investigate this hypothesis, in April 2011 we performed a pharmacogenetic analysis of genes involved in clopidogrel adsorption (C3435T ABCB1 - rs1045642) and metabolism (CYP2C19*2 - rs4244285, CYP2C19*3 - rs4986893, CYP2C19*4 - rs28399504, CYP2C19*5 - rs56337013, CYP2C19*17 - rs12248560). Our analysis, performed by TaqMan validated single nucleotide polymorphism (SNP) assays with the 7900HT sequence detection system (Applied Biosystems), showed a heterozygosis solely for ABCB1.

Discussion

The present case has some clinical characteristics in common with previously reported cases (2,3) which have been considered risk factors for the development of headache after ASD closure, including age, type of ASD and use of the Amplatzer device. The time lag between ASD closure and headache onset is similar to that reported previously (2,3). However, the present case shows some peculiar pharmaco-clinical features, never described before.

Migraine with visual aura in our patient was exquisitely sensitive to ticlopidine treatment. The patient experienced one positive challenge, two positive dechallenges and two positive rechallenges. Although effects in the functioning of platelets or serotonin have been proposed (6), the mechanism of thienopyridines as preventive drugs for migraine after ASD closure is not known. Progressive spontaneous amelioration of migraine attacks after ASD closure has been reported (7). This does not seem to have happened in our case, because migraine attacks recurred on ticlopidine discontinuation over a period of 5 years, and abruptly disappeared 5 days after both the first and second ticlopidine rechallenges. Furthermore, whereas a Japanese patient who responded to ticlopidine had no recurrence of migraine after stopping a 2-month treatment (4), our patient relapsed with attacks of migraine with aura shortly after each ticlopidine treatment discontinuation.

A unique feature of the present case is that our patient was challenged with three different antiplatelet agents (ASA, clopidogrel and ticlopidine), and selectively responded only to ticlopidine. When treated for 5 years with ASA in combination with clopidogrel, the patient did not refer any pain relief. For ASA, this may be due to the difference between the analgesic and antiplatelet doses (325 mg and 100 mg, respectively). In the case of clopidogrel pharmacogenetic analysis, the only variation found in our patient was the heterozygosis for C3435T ABCB1 - rs1045642. However, no conclusive evidence exists on the relationship between ABCB1 mutations and variability in the absorption of clopidogrel (11). Thus, pharmacogenetic results do not offer a conclusive explanation for the selective response to ticlopidine. For ethical reasons, we did not perform a pharmacokinetic study by rechallenging the patient with clopidogrel to measure drug plasma concentration. Nevertheless, temporal association, multiple positive challenges and dechallenges, absence of alternative reasons for clinical evolution and a prior similar report (4), suggest that the favourable course of migraine was caused by ticlopidine treatment. Our observation cannot be used to establish a strong recommendation. However, because of the lack of a general consensus on how to treat patients developing migraine after ASD closure, if not contraindicated, a ticlopidine trial could be performed, especially in patients who, like the present one, do not show any benefit from clopidogrel, which represents the antiplatelet drug normally prescribed immediately after ASD closure.