Pediatric Triptan-induced Reversible Cerebral Vasoconstriction Syndrome with Both Hemorrhagic and Ischemic Stroke: Case Report and Literature Review

Abstract

Reversible cerebral vasoconstriction syndrome is characterized by severe headaches and diffuse, segmental constriction of cerebral arteries. We report a rare pediatric case of triptan-induced reversible cerebral vasoconstriction syndrome, complicated by both subarachnoid hemorrhage and cerebral infarction. A 10-year-old boy presented with persistent severe headaches initially suspected to be migraines, for which he was prescribed rizatriptan. Five days after starting rizatriptan, he developed impaired consciousness (Japan Coma Scale 10) and partial right-sided hemiparesis, prompting emergency hospitalization. A head computed tomography scan revealed subarachnoid hemorrhage in the left frontal cortical region. Cerebral angiography showed stenotic changes in the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. Suspecting triptan-induced reversible cerebral vasoconstriction syndrome, rizatriptan was discontinued, and verapamil treatment was initiated. Subsequent magnetic resonance imaging and magnetic resonance angiography revealed cerebral infarction in the right cerebellum, left middle cerebral artery territory, and right occipital lobe, with persistent stenotic changes from earlier findings. Edaravone was added to the treatment regimen. The patient's condition gradually improved, and follow-up magnetic resonance angiography showed almost complete resolution of the prior stenotic changes. His partial right-sided hemiparesis nearly resolved, and he was discharged home. Triptans should be used with caution, as they may precipitate reversible cerebral vasoconstriction syndrome or exacerbate cerebral vasoconstriction. Careful monitoring and vascular imaging are essential for patients presenting with symptoms following triptan administration.

Introduction

Reversible cerebral vasoconstriction syndrome (RCVS) is marked by severe headaches, often accompanied by other acute neurological symptoms, as well as diffuse, segmental constriction of cerebral arteries that typically resolves spontaneously within three months. This condition can be associated with three types of stroke: cortical subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral infarction (CI). While it may occur spontaneously, particularly in middle-aged women, with pediatric cases being exceptionally rare, at least half of the cases are triggered by exposure to vasoactive drugs or arise in the postpartum period.¹⁾ Triptans are among the drugs known to induce this syndrome, although triptan-related instances remain relatively rare.²⁾

Herein, we report a pediatric case of RCVS induced by rizatriptan, complicated by both SAH and CI, and provide a review of triptan-induced RCVS. This study was approved by the Institutional Review Board of our institute (IRB 2024-048).

Case Report

The patient is a 10-year-old boy with no notable abnormalities in growth or development, except for a single episode of severe headache and vomiting at the age of 8. He presented with severe, bilateral, pulsatile headaches accompanied by nausea or vomiting, with each episode lasting between 6 and 12 hrs. During these episodes, he was unable to attend school, remained confined to bed, and refrained from engaging in activities of daily living.

He visited a nearby clinic 5 days after the onset, where he was prescribed non-steroidal anti-inflammatory drugs. However, his headaches continued to fluctuate in severity, prompting a visit to a general hospital on day 9. A head computed tomography (CT) scan was performed, showing no abnormalities, so he was advised to undergo follow-up observation. On day 11, he returned to the clinic, where head magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) were conducted; these showed no clear abnormalities, and the intracranial major arteries were well-visualized (Fig. 1A-C). Up to this point, he had experienced five such headache episodes, based on which a diagnosis of migraine was made,³⁾ and he was prescribed rizatriptan. On day 16 (five days after beginning rizatriptan), he developed impaired consciousness (Japan Coma Scale 10) and right-sided partial hemiparesis, leading to emergency transport to the general hospital. A head CT scan revealed SAH in the left frontal cortical area (Fig. 2A), and he was subsequently transferred to our hospital.

Fig. 1

On day 11, a head magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) showed no clear abnormalities (A), and the intracranial major arteries were well-visualized (B, C).

Fig. 2

On day 16, a head computed tomography (CT) scan revealed subarachnoid hemorrhage (SAH) in the left frontal cortical area (A). Bilateral common carotid angiography revealed stenotic changes in the terminal segments of both internal carotid arteries, as well as in the proximal segments of the middle cerebral artery (MCA) and anterior cerebral artery (ACA) on both sides (B, C; white arrow). Left common carotid angiography demonstrated diffuse stenotic changes in the distal segment of the ACA (D; white circle). Vertebral angiography displayed stenotic alterations in the left posterior cerebral artery (PCA) (E; white arrow).

At our hospital, cerebral angiography was performed, revealing no apparent source of hemorrhage, such as cerebral aneurysms or arteriovenous malformations. However, stenotic changes were noted in the terminal segments of both internal carotid arteries (ICAs), the proximal middle cerebral artery (MCA) and anterior cerebral artery (ACA) segments on both sides, the distal segment of the left ACA, and the left posterior cerebral artery (PCA) (Fig. 2B-E). Suspecting rizatriptan-induced RCVS, rizatriptan was discontinued, and verapamil was initiated as a treatment. During treatment, systolic blood pressure was generally maintained within the range of 110 to 130 mmHg. No significant hypotension associated with the use of verapamil was observed. The headache gradually subsided, and there was no further deterioration in consciousness or neurological symptoms. However, on day 19, a follow-up MRI/MRA revealed CI in right cerebellum, the left MCA region, and the right occipital lobe, along with stenosis in the terminal portions of both ICAs, the proximal segments of the left MCA and ACA, the distal ACA, and both PCAs (Fig. 3A-E). Treatment with edaravone was added. The patient's condition gradually improved: his headache completely resolved, his consciousness became clear, and his right-sided partial hemiparesis showed improvement. On day 26, MRA imaging showed almost complete resolution of the previous stenotic findings (Fig. 3F and G). Although he had residual mild right hemiparesis, he was independent in activities of daily living and was assessed as modified Rankin Scale (mRS) 2 at discharge home.

Fig. 3

On day 19, diffusion weighted image (DWI) demonstrated cerebral infarction (CI) in right cerebellum (A), the left middle cerebral artery (MCA) region (B, C), and right occipital lobe (C) along with stenosis in the terminal portions of both internal carotid arteries, proximal segments of the left MCA and anterior cerebral artery (ACA) (D; white arrow), the distal ACA (E; white circle), and both posterior cerebral arteries (PCAs) on MRA (D; white arrow head). On day 26, MRA showed almost complete resolution of the previous stenotic findings (F, G).

Discussion

Triptans are used to treat migraines and can occasionally induce cerebral vasoconstriction. A review of past literature reveals 10 reported cases of triptan-induced RCVS. Of these, 4 were male and 6 females, with a mean age of 35.8 ± 14.2 years; only one pediatric case (under 15 years) was reported. Among the triptan formulations identified as triggers, sumatriptan was the most common, accounting for 7 cases, followed by one case each involving eletriptan, naratriptan, and rizatriptan. Symptoms typically appeared within a few days to 10 days after triptan administration. Presentations included SAH in 3 cases, ICH in 1 case, and CI in 4 cases. Treatment involved calcium channel blockers in 3 cases, while the remaining cases were managed with observation alone. Among these, 8 cases, including those treated with calcium channel blockers, achieved mRS 0-1; however, one case resulted in mRS 4, and another resulted in death (mRS 6)^2,4-11) (Table 1).

Table 1

Case Reports of Triptan-Induced RCVS

Case, year	Age/sex	Trigger drug	Number of triptan use	Postpartum period	SAH	Stroke
Meschia et al., 1998	43/M	Sumatriptan	23 tab	-	-	Ischemia
Granier et al., 1999	20/F	Sumatriptan	1 s.c	+	-	Ischemia
Nighoghossian et al., 1998	37/M	Sumatriptan	2 s.c	-	-	Hemorrhage
Singhal et al., 2002	34/M	Sumatriptan	2 s.c	-	-	Ischemia
Yoshioka et al., 2012	12/M	Eletriptan	More than once	-	+	-
Ba et al., 2012	39/F	Naratriptan	6 tab	-	+	-
Robert et al., 2013	68/F	Sumatriptan	Daily use	-	-	Ischemia
Kato et al., 2016	43/F	Sumatriptan	1 tab	-	+	-
Kato et al., 2016	30/F	Sumatriptan	1 nasal drop	+	-	-
Ramineni et al., 2018	32/F	Rizatriptan	More than 10 tabs	-	-	-
Present case	10/M	Rizatriptan	1 tab	-	+	Ischemia

Onset after triptan use	Headache characteristics	Location of vasoconstriction	Treatment	Outcome (mRS)
ACA; anterior cerebral artery; ICA; internal carotid artery; F: female; M: male; MCA; middle cerebral artery; mRS: modified Rankin Scale; PCA; posterior cerebral artery; RCVS: reversible cerebral vasoconstriction syndrome; SAH: subarachnoid hemorrhage; s.c.: subcutaneous; tab: tablet
Day 3	Bioccipital, Throbbing	Bilateral ACA and MCA	Nicardipine	1
Day 2	Frontal and occipitonuchal, Severe	Left ICA, Right MCA and ACA	None	0
Day 1	Bifrontal, Throbbing	Bilateral ACA	None	4
Day 1	Explosive	Bilateral ACA, MCA, and PCA	None	0
Day 5	Acute, Severe	Bilateral ACA, MCA, and PCA	None	0
Day 6	Bifrontal, Severe, Throbbing	Bilateral ACA and MCA	Nimodipine	0
Unknown	Thundercap	Left ICA and ACA	None	6
One hour	Thundercap	Bilateral MCA and PCA	None	0
Day 9	Bifrontal, Throbbing	Bilateral ACA, MCA, and PCA	None	0
Day 10	Thundercap	Bilateral ACA	Nimodipine	0
Day 5	Bifrontal, severe	Bilateral ICA, ACA, MCA, and PCA	Verapamil	2

The American Headache Society, in association with the American Academy of Neurology, published the most recent practice guidelines in 2019 for the acute treatment of migraine in pediatrics.¹²⁾ The guideline recommends acetaminophen, ibuprofen, and naproxen as first-line treatments for pediatric migraine, and also supports the efficacy of triptan agents. Rizatriptan is Food and Drug Admininstration-approved for use in children aged 6 years and older, while almotriptan, sumatriptan/naproxen, and zolmitriptan nasal spray are approved for those aged 12 years and above. Importantly, the lack of efficacy or the occurrence of adverse effects with one triptan does not imply that other triptans will produce similar outcomes. Moreover, as a single patient may experience different types of migraine attacks, the use of multiple triptan agents tailored to specific attack profiles may be necessary.

Based on these previous reports, our case represents an extremely rare pediatric instance of RCVS induced by rizatriptan. The largest review of pediatric RCVS cases included only 26 patients, with most available pediatric cases consisting of individual case reports or small series.¹³⁾ The majority of patients were male, and the incidences of infarcts and hemorrhages were similar. Another significant finding was that most pediatric patients developed secondary RCVS. One-third of the pediatric patients in this review had hematologic or rheumatologic disorders, and treatments such as blood transfusions or immunosuppressants in these conditions are thought to potentially induce the characteristic vasoconstriction seen in RCVS. Therefore, such patients are likely at increased risk of developing RCVS. In our case, however, there was no history of hematologic or rheumatologic disorders, making it highly likely that the onset of RCVS was triggered by the triptan.

Moreover, it is the first reported case of triptan-induced RCVS presenting with both SAH and CI. Although the exact pathophysiology of RCVS remains unclear, dysregulation of cerebral vascular tone and disruption of the blood-brain barrier might play key roles in its development. The breakdown of the blood-brain barrier and excessive central pulsatile flow may result in convexity SAH or ICH. In contrast, vasoconstriction of major arteries may lead to ischemic complications, which could subsequently exacerbate the SAH or ICH.¹⁴⁾ In our case, both these mechanisms are thought to be involved, leading to the development of both hemorrhage and infarction. Furthermore, in the present case, cerebral vasoconstriction occurred in the PCA, accompanied by cerebellar infarction. While RCVS most commonly involves arteries within the circle of Willis, particularly the MCA, it has also been reported to affect arteries in the posterior circulation.^2,7,8,15-17) Although rare, clinicians should remain aware of the possibility that RCVS can involve arteries in the posterior circulation.

Treatment of RCVS is generally supportive, with a broad consensus on discontinuing the causative vasoactive drugs. No randomized controlled trials have been conducted on RCVS treatment, so it remains unclear whether certain therapies are more effective. Calcium channel blockers are often administered, though their efficacy is uncertain. In our case, they were used and resulted in a favorable outcome. There have been reports of cases similar to ours that achieved favorable outcomes with conservative treatment, suggesting that the use of calcium channel blockers could be worth considering for triptan-induced RCVS.

On the other hand, it is possible that vasoconstrictive changes in the distal branches of the PCA were already present on the initial MRA, prior to the administration of the triptan. If this were the case, the possibility cannot be excluded that the triptan exacerbated pre-existing RCVS. However, in this case, RCVS was observed in both the anterior and posterior circulations. Given that RCVS most frequently affects arteries in the anterior circulation, particularly the MCA, it would be more likely to observe vasoconstriction in the MCA if RCVS had already been present at the time of the initial MRA. Although vasoconstriction of distal PCA branches was suspected on the initial MRA, it cannot be ruled out that the findings were influenced by image quality or resolution. Demonstrating clear evidence of triptan-induced RCVS remains challenging. However, in addition to the above reasons, considering the onset following rizatriptan administration, the timing of symptom development, and the absence of other medications that could have triggered RCVS, it seems reasonable to conclude that this was a case of triptan-induced RCVS, consistent with previous reports.

Conclusions

We report a rare case of pediatric triptan-induced RCVS presenting with both SAH and CI. Triptans should be administered with caution, as they may precipitate RCVS or exacerbate cerebral vasoconstriction. Careful monitoring and vascular imaging are essential for patients presenting with symptoms following triptan administration.

Ethics Approval and Consent to Participate

The patient and her family gave their informed consent prior to inclusion in the study. This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Conflicts of Interest Disclosure

All authors have no conflict of interest.

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