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(CEP)
[1–5] [PREPRINTER stage]
Brief Report
Diffuse cerebrovascular dilation: Case report of amezinium metilsulfate-induced reversible cerebral vasoconstriction syndrome
Cephalalgia 0(0) 1–5 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102415588326 cep.sagepub.com
Makoto Kobayashi Abstract Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries. Case description: A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months. Discussion: Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS. Keywords Amezinium metilsulfate, cerebrovascular dilation, magnetic resonance angiography, reversible cerebral vasoconstriction syndrome Date received: 25 January 2015; revised: 1 April 2015; accepted: 25 April 2015
Introduction
Case report
Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with thunderclap headache attacks (i.e. sudden-onset severe headaches reaching a pain zenith in less than a minute) over one to two weeks, frequently accompanied by moderate headaches between the attacks (1). Cerebral angiography often reveals no abnormality within one week after headache onset, followed by widespread segmental vasoconstriction (1–4). The vasoconstriction typically resolves in three months (5). Another important characteristic is that this syndrome is precipitated by various factors, including the postpartum state and vasoactive medications (e.g. illicit drugs, antidepressants, and sympathomimetics) (1–5). Here, we report a rare case of a patient with RCVS induced by amezinium metilsulfate (amezinium, an indirect sympathomimetic) in whom magnetic resonance angiography (MRA) revealed diffuse dilation of cerebral arteries before segmental vasoconstriction. In addition, MRAs were performed serially and mean sectional areas of cerebral arteries were measured for quantitative analysis.
A 34-year-old woman with no history of headache was prescribed amezinium 20 mg/day, difenidol hydrochloride 75 mg/day, and adenosine triphosphate disodium hydrate 0.3 g/day for hypotension and dizziness. Twelve days later, when she was cleaning house, a severe headache occurred suddenly, reaching a peak pain level in a few seconds. The headache was too excruciating for her to sit still but resolved after three hours, leaving her with a residual moderate headache. Although she stopped taking the prescribed medications, similar severe headaches recurred on days 2 and 5 after the headache onset. In addition, the moderate headache persisted all day. She was referred to our
Department of Neurology, Asahi General Hospital, Japan Corresponding author: Makoto Kobayashi, Department of Neurology, Asahi General Hospital, 1326 I, Asahi, Chiba 289-2511, Japan. Email: [email protected]
XML Template (2015) [22.5.2015–10:39am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150076/APPFile/SG-CEPJ150076.3d
(CEP)
[1–5] [PREPRINTER stage]
2 department; no neurological deficits were found. Nonenhanced brain computed tomography, routine blood tests, and vasculitis screening were normal. However, magnetic resonance imaging (MRI) performed on day 9 with a 3-Tesla Siemens Verio system revealed linear hyperintensities in a wide range of sulcal spaces, with a predominance in the temporo-occipital lobes on fluid-attenuated inversion recovery (FLAIR) images (Figure 1(a), left, arrows). Furthermore, MRA (three-dimensional time-of-flight MRA obtained from original images with the maximum intensity projection method) showed diffusely dilated anterior, middle, and posterior cerebral arteries (Figures 1(b), left and 2(a)) with vasoconstriction in the posterior cerebral arteries
Cephalalgia 0(0) (Figures 1(b), left and 2(a), arrowheads). Mild vasoconstriction was also observed in the second segment of the middle cerebral artery and basilar artery (Figure 1(b), left, arrowheads). The first segments of middle cerebral arteries (Figures 1(b), left and 2(a), arrows) were as thick as internal carotid arteries. The patient was tentatively diagnosed with RCVS; treatment with oral verapamil 120 mg/day was started on the same day. Lumbar puncture was not performed because the clinical manifestations and magnetic resonance findings suggested a low probability of other diseases. After treatment, the thunderclap headache did not recur, and the moderate headache disappeared on day 12. On day 15, follow-up MRA revealed widespread
Figure 1. Fluid-attenuated inversion recovery images ((a), axial view) and magnetic resonance angiography images ((b), frontal view) acquired on days 9 (left) and 15 (right) after symptom onset. (a) Linear hyperintensities (left, arrows) were prominent in the sulcal spaces of the temporo-occipital lobes on day 9. The linear lesions became unremarkable on day 15. (b) On day 9, the first segments of the middle cerebral arteries (left, arrows) were dilated and as thick as the precavernous portions of internal carotid arteries (left, asterisks), with vasoconstriction in the posterior cerebral arteries, the second segment of the middle cerebral artery, and the basilar artery (left, arrowheads). The vasoconstriction (right, arrowheads) became prominent, resulting in segmental vasodilation and vasoconstriction on day 15.
XML Template (2015) [22.5.2015–10:39am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150076/APPFile/SG-CEPJ150076.3d
(CEP)
[1–5] [PREPRINTER stage]
Kobayashi segmental vasodilation and vasoconstriction (Figures 1(b), right and 2(b), arrowheads), whereas the linear hyperintensities on FLAIR images disappeared (Figure 1(a), right). Repeated MRA indicated mild vasoconstriction on day 37 (Figure 2(c), arrowheads) and no abnormality on days 65 (Figure 2(d)) and 91, leading to a final diagnosis of RCVS (6). After we confirmed cerebrovascular normalization and stabilization on day 91, verapamil was tapered off without recurrence. We performed a quantitative analysis on the original MRA images (repetition time, 22 ms; echo time, 3.64 ms; flip angle, 20 degrees; image size, 384 384; thickness, 650 mm) using a DICOM viewer OsiriX 6.0. Vascular volumes were measured and vascular lengths were calculated by summing distances of the vascular central positions on two consecutive original images. Mean vascular sectional areas were calculated by
3 dividing the volumes with lengths. Mean sectional areas of the first segments of the middle cerebral arteries (M1; Figures 1(b), left and 2(a), arrows) and precavernous portions of the internal carotid arteries (pICA; Figure 1(b), left, asterisks) were measured serially (Table 1). On day 9 after symptom onset, the mean sectional areas of M1 (right, 10.1 mm2; left, 9.9 mm2) and pICA (right, 8.4 mm2; left, 11.2 mm2) were approximately the same size on average (M1, 10 mm2; pICA, 9.8 mm2). The M1 sectional areas became smaller on days 15 and 37, followed by mild rebound and stabilization on days 65 and 91 (right, 5.5 mm2; left, 6.0 mm2), whereas the pICA sectional areas did not change remarkably. Although three months may be insufficient for complete normalization of cerebral arteries (1–5), the M1 sectional areas on day 9 were obviously larger than those on day 91, and about the same size of the
Figure 2. Magnetic resonance angiographies (axial view) performed on days 9 (a), 15 (b), 37 (c), and 65 (d) after symptom onset. (a) On day 9, anterior, middle, and posterior cerebral arteries were diffusely dilated with vasoconstriction in the posterior cerebral arteries (arrowheads). The first segments of the middle cerebral arteries (arrows) were approximately the same size as internal carotid arteries. (b) The dilated cerebral arteries were constricted prominently (arrowheads) and partially changed to segmental vasodilation and vasoconstriction on day 15. (c) Mild vasoconstriction (arrowheads) remained on day 37. (d) Cerebral arteries were normalized on day 65.
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(CEP)
[1–5] [PREPRINTER stage]
4
Cephalalgia 0(0)
Table 1. Mean sectional areas of cerebral arteries. Sectional area (mm2)
MRA findings on MIP images
Right Left Interval from onset (day) M1 pICA M1 pICA M1
pICA
9 15
10.1 8.4 6.6 8.6
9.9 11.2 6.2 12
Normal Normal
37 65 91
4.6 8.2 5.6 7.6 5.5 7.6
5.4 12.1 6.0 12.2 6.0 12.4
Diffuse dilation Segmental dilation and constriction Mild constriction Normal Normal
Normal Normal Normal
M1: first segment of middle cerebral artery; MRA: magnetic resonance angiography; MIP: maximum intensity projection; pICA: precavernous portion of internal carotid artery.
pICA sectional areas, indicating that the M1 segments were dilated initially. The vasodilation disappeared on day 37 with residual mild vasoconstriction, corresponding to the smallest M1 sectional areas on the same day.
Discussion We have presented an adult female patient with RCVS induced by amezinium in whom MRA revealed diffuse cerebrovascular dilation before segmental vasoconstriction. Typically in patients with RCVS, MRA reveals no abnormality before vasoconstriction, although severe headaches are present (1–4). In the present case, MRA revealed diffuse vasodilation in the anterior, middle, and posterior cerebral arteries on day 9, followed by widespread segmental vasoconstriction on day 15. In addition, the linear FLAIR hyperintensities on day 9 probably suggested slow blood flow in small cerebral surface arteries or their leptomeningeal anastomotic collaterals in RCVS patients (1,7). The diffuse cerebrovascular dilation and FLAIR abnormalities were apparent simultaneously and possibly caused by a similar mechanism in RCVS. Although adenosine triphosphate, which was prescribed before headache onset, has a short-lived vasodilatory effect on cerebral arteries, the effect could not have lasted for nine days after discontinuation. In contrast to segmental arterial dilation on cerebral angiogram (1,2,4,5), the diffuse dilation
observed in this case has not been pointed out before, but may have pathophysiological implications. The diffuse vasodilation may be caused by vasoconstriction of small cerebral arteries. In RCVS, it has been proposed that the pathological process affects distal arteries initially, and subsequently progresses toward the branches of the circle of Willis (1,4). Therefore, in the initial stage of RCVS, small arteries that cannot be visualized on MRA images may be constricted selectively, leading to blocked blood flow and dilated arteries proximal to the constricted segments. The proximal artery dilation accompanied by blocked and slow blood flow in small arteries may correspond to the diffuse cerebrovascular dilation on MRA images and linear FLAIR hyperintensities. Amezinium probably induced RCVS in our case, although other drugs could not be neglected. The initial three drugs our patient took presumably have not been reported as etiologies of RCVS; however, amezinium was the most likely cause because of its sympathomimetic effect. Sympathomimetics such as phenylpropanolamine, pseudoephedrine, ephedrine, adrenaline, and noradrenaline are known to cause RCVS (1,8–10). Amezinium is an indirect sympathomimetic that inhibits monoamine oxidase and noradrenaline uptake with increased noradrenaline release at the terminals of peripheral sympathetic nerves, resulting in the enhanced effect of noradrenaline (11); therefore, it is logical to posit that amezinium can induce RCVS as well as noradrenaline. Although adenosine triphosphate, which also has a vasoactive effect, could trigger or cooperate together to trigger RCVS, we consider it probable that amezinium mainly induced RCVS in our case because of the above-mentioned sympathomimetic effect. In general, MRA is very sensitive to vascular narrowing and turbulent blood flow, thus the measured sectional areas may be different from actual ones; however, 3-Tesla MRA is employed as a useful and noninvasive method (12). Therefore, we consider the measured areas can at least be surrogate markers; the vasodilation is confirmatory. We described a patient with RCVS whose MRA revealed diffuse cerebrovascular dilation before typical vasoconstriction. The dilation may be associated with RCVS pathophysiology. Moreover, in clinical practice, physicians should bear in mind that amezinium can potentially induce RCVS.
Clinical implications . Early cerebral angiogram may reveal diffuse cerebrovascular dilation in patients with reversible cerebral vasoconstriction syndrome (RCVS). . Amezinium metilsulfate can potentially induce RCVS.
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(CEP)
[1–5] [PREPRINTER stage]
Kobayashi
5
Funding
6. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808. 7. Chen SP, Fuh JL, Lirng JF, et al. Hyperintense vessels on flair imaging in reversible cerebral vasoconstriction syndrome. Cephalalgia 2012; 32: 271–278. 8. Cantu C, Arauz A, Murillo-Bonilla LM, et al. Stroke associated with sympathomimetics contained in overthe-counter cough and cold drugs. Stroke 2003; 34: 1667–1672. 9. Mourand I, Ducrocq X, Lacour JC, et al. Acute reversible cerebral arteritis associated with parenteral ephedrine use. Cerebrovasc Dis 1999; 9: 355–357. 10. Palma JA, Fontes-Villalba A, Irimia P, et al. Reversible cerebral vasoconstriction syndrome induced by adrenaline. Cephalalgia 2012; 32: 500–504. 11. Traut M, Brode E and Hoffmann HD. Pharmacology of amezinium, a novel antihypotensive drug. IV. Biochemical investigations of the mechanism of action. Arzneimittelforschung 1981; 31: 1566–1574. 12. Schoonman GG, van der Grond J, Kortmann C, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 2008; 131: 2192–2200.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012; 11: 906–917. 2. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: Analysis of 139 cases. Arch Neurol 2011; 68: 1005–1012. 3. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010; 67: 648–656. 4. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007; 130: 3091–3101. 5. Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: Reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007; 146: 34–44.
(CEP)
[1–5] [PREPRINTER stage]
Brief Report
Diffuse cerebrovascular dilation: Case report of amezinium metilsulfate-induced reversible cerebral vasoconstriction syndrome
Cephalalgia 0(0) 1–5 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102415588326 cep.sagepub.com
Makoto Kobayashi Abstract Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries. Case description: A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months. Discussion: Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS. Keywords Amezinium metilsulfate, cerebrovascular dilation, magnetic resonance angiography, reversible cerebral vasoconstriction syndrome Date received: 25 January 2015; revised: 1 April 2015; accepted: 25 April 2015
Introduction
Case report
Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with thunderclap headache attacks (i.e. sudden-onset severe headaches reaching a pain zenith in less than a minute) over one to two weeks, frequently accompanied by moderate headaches between the attacks (1). Cerebral angiography often reveals no abnormality within one week after headache onset, followed by widespread segmental vasoconstriction (1–4). The vasoconstriction typically resolves in three months (5). Another important characteristic is that this syndrome is precipitated by various factors, including the postpartum state and vasoactive medications (e.g. illicit drugs, antidepressants, and sympathomimetics) (1–5). Here, we report a rare case of a patient with RCVS induced by amezinium metilsulfate (amezinium, an indirect sympathomimetic) in whom magnetic resonance angiography (MRA) revealed diffuse dilation of cerebral arteries before segmental vasoconstriction. In addition, MRAs were performed serially and mean sectional areas of cerebral arteries were measured for quantitative analysis.
A 34-year-old woman with no history of headache was prescribed amezinium 20 mg/day, difenidol hydrochloride 75 mg/day, and adenosine triphosphate disodium hydrate 0.3 g/day for hypotension and dizziness. Twelve days later, when she was cleaning house, a severe headache occurred suddenly, reaching a peak pain level in a few seconds. The headache was too excruciating for her to sit still but resolved after three hours, leaving her with a residual moderate headache. Although she stopped taking the prescribed medications, similar severe headaches recurred on days 2 and 5 after the headache onset. In addition, the moderate headache persisted all day. She was referred to our
Department of Neurology, Asahi General Hospital, Japan Corresponding author: Makoto Kobayashi, Department of Neurology, Asahi General Hospital, 1326 I, Asahi, Chiba 289-2511, Japan. Email: [email protected]
XML Template (2015) [22.5.2015–10:39am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150076/APPFile/SG-CEPJ150076.3d
(CEP)
[1–5] [PREPRINTER stage]
2 department; no neurological deficits were found. Nonenhanced brain computed tomography, routine blood tests, and vasculitis screening were normal. However, magnetic resonance imaging (MRI) performed on day 9 with a 3-Tesla Siemens Verio system revealed linear hyperintensities in a wide range of sulcal spaces, with a predominance in the temporo-occipital lobes on fluid-attenuated inversion recovery (FLAIR) images (Figure 1(a), left, arrows). Furthermore, MRA (three-dimensional time-of-flight MRA obtained from original images with the maximum intensity projection method) showed diffusely dilated anterior, middle, and posterior cerebral arteries (Figures 1(b), left and 2(a)) with vasoconstriction in the posterior cerebral arteries
Cephalalgia 0(0) (Figures 1(b), left and 2(a), arrowheads). Mild vasoconstriction was also observed in the second segment of the middle cerebral artery and basilar artery (Figure 1(b), left, arrowheads). The first segments of middle cerebral arteries (Figures 1(b), left and 2(a), arrows) were as thick as internal carotid arteries. The patient was tentatively diagnosed with RCVS; treatment with oral verapamil 120 mg/day was started on the same day. Lumbar puncture was not performed because the clinical manifestations and magnetic resonance findings suggested a low probability of other diseases. After treatment, the thunderclap headache did not recur, and the moderate headache disappeared on day 12. On day 15, follow-up MRA revealed widespread
Figure 1. Fluid-attenuated inversion recovery images ((a), axial view) and magnetic resonance angiography images ((b), frontal view) acquired on days 9 (left) and 15 (right) after symptom onset. (a) Linear hyperintensities (left, arrows) were prominent in the sulcal spaces of the temporo-occipital lobes on day 9. The linear lesions became unremarkable on day 15. (b) On day 9, the first segments of the middle cerebral arteries (left, arrows) were dilated and as thick as the precavernous portions of internal carotid arteries (left, asterisks), with vasoconstriction in the posterior cerebral arteries, the second segment of the middle cerebral artery, and the basilar artery (left, arrowheads). The vasoconstriction (right, arrowheads) became prominent, resulting in segmental vasodilation and vasoconstriction on day 15.
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(CEP)
[1–5] [PREPRINTER stage]
Kobayashi segmental vasodilation and vasoconstriction (Figures 1(b), right and 2(b), arrowheads), whereas the linear hyperintensities on FLAIR images disappeared (Figure 1(a), right). Repeated MRA indicated mild vasoconstriction on day 37 (Figure 2(c), arrowheads) and no abnormality on days 65 (Figure 2(d)) and 91, leading to a final diagnosis of RCVS (6). After we confirmed cerebrovascular normalization and stabilization on day 91, verapamil was tapered off without recurrence. We performed a quantitative analysis on the original MRA images (repetition time, 22 ms; echo time, 3.64 ms; flip angle, 20 degrees; image size, 384 384; thickness, 650 mm) using a DICOM viewer OsiriX 6.0. Vascular volumes were measured and vascular lengths were calculated by summing distances of the vascular central positions on two consecutive original images. Mean vascular sectional areas were calculated by
3 dividing the volumes with lengths. Mean sectional areas of the first segments of the middle cerebral arteries (M1; Figures 1(b), left and 2(a), arrows) and precavernous portions of the internal carotid arteries (pICA; Figure 1(b), left, asterisks) were measured serially (Table 1). On day 9 after symptom onset, the mean sectional areas of M1 (right, 10.1 mm2; left, 9.9 mm2) and pICA (right, 8.4 mm2; left, 11.2 mm2) were approximately the same size on average (M1, 10 mm2; pICA, 9.8 mm2). The M1 sectional areas became smaller on days 15 and 37, followed by mild rebound and stabilization on days 65 and 91 (right, 5.5 mm2; left, 6.0 mm2), whereas the pICA sectional areas did not change remarkably. Although three months may be insufficient for complete normalization of cerebral arteries (1–5), the M1 sectional areas on day 9 were obviously larger than those on day 91, and about the same size of the
Figure 2. Magnetic resonance angiographies (axial view) performed on days 9 (a), 15 (b), 37 (c), and 65 (d) after symptom onset. (a) On day 9, anterior, middle, and posterior cerebral arteries were diffusely dilated with vasoconstriction in the posterior cerebral arteries (arrowheads). The first segments of the middle cerebral arteries (arrows) were approximately the same size as internal carotid arteries. (b) The dilated cerebral arteries were constricted prominently (arrowheads) and partially changed to segmental vasodilation and vasoconstriction on day 15. (c) Mild vasoconstriction (arrowheads) remained on day 37. (d) Cerebral arteries were normalized on day 65.
XML Template (2015) [22.5.2015–10:39am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150076/APPFile/SG-CEPJ150076.3d
(CEP)
[1–5] [PREPRINTER stage]
4
Cephalalgia 0(0)
Table 1. Mean sectional areas of cerebral arteries. Sectional area (mm2)
MRA findings on MIP images
Right Left Interval from onset (day) M1 pICA M1 pICA M1
pICA
9 15
10.1 8.4 6.6 8.6
9.9 11.2 6.2 12
Normal Normal
37 65 91
4.6 8.2 5.6 7.6 5.5 7.6
5.4 12.1 6.0 12.2 6.0 12.4
Diffuse dilation Segmental dilation and constriction Mild constriction Normal Normal
Normal Normal Normal
M1: first segment of middle cerebral artery; MRA: magnetic resonance angiography; MIP: maximum intensity projection; pICA: precavernous portion of internal carotid artery.
pICA sectional areas, indicating that the M1 segments were dilated initially. The vasodilation disappeared on day 37 with residual mild vasoconstriction, corresponding to the smallest M1 sectional areas on the same day.
Discussion We have presented an adult female patient with RCVS induced by amezinium in whom MRA revealed diffuse cerebrovascular dilation before segmental vasoconstriction. Typically in patients with RCVS, MRA reveals no abnormality before vasoconstriction, although severe headaches are present (1–4). In the present case, MRA revealed diffuse vasodilation in the anterior, middle, and posterior cerebral arteries on day 9, followed by widespread segmental vasoconstriction on day 15. In addition, the linear FLAIR hyperintensities on day 9 probably suggested slow blood flow in small cerebral surface arteries or their leptomeningeal anastomotic collaterals in RCVS patients (1,7). The diffuse cerebrovascular dilation and FLAIR abnormalities were apparent simultaneously and possibly caused by a similar mechanism in RCVS. Although adenosine triphosphate, which was prescribed before headache onset, has a short-lived vasodilatory effect on cerebral arteries, the effect could not have lasted for nine days after discontinuation. In contrast to segmental arterial dilation on cerebral angiogram (1,2,4,5), the diffuse dilation
observed in this case has not been pointed out before, but may have pathophysiological implications. The diffuse vasodilation may be caused by vasoconstriction of small cerebral arteries. In RCVS, it has been proposed that the pathological process affects distal arteries initially, and subsequently progresses toward the branches of the circle of Willis (1,4). Therefore, in the initial stage of RCVS, small arteries that cannot be visualized on MRA images may be constricted selectively, leading to blocked blood flow and dilated arteries proximal to the constricted segments. The proximal artery dilation accompanied by blocked and slow blood flow in small arteries may correspond to the diffuse cerebrovascular dilation on MRA images and linear FLAIR hyperintensities. Amezinium probably induced RCVS in our case, although other drugs could not be neglected. The initial three drugs our patient took presumably have not been reported as etiologies of RCVS; however, amezinium was the most likely cause because of its sympathomimetic effect. Sympathomimetics such as phenylpropanolamine, pseudoephedrine, ephedrine, adrenaline, and noradrenaline are known to cause RCVS (1,8–10). Amezinium is an indirect sympathomimetic that inhibits monoamine oxidase and noradrenaline uptake with increased noradrenaline release at the terminals of peripheral sympathetic nerves, resulting in the enhanced effect of noradrenaline (11); therefore, it is logical to posit that amezinium can induce RCVS as well as noradrenaline. Although adenosine triphosphate, which also has a vasoactive effect, could trigger or cooperate together to trigger RCVS, we consider it probable that amezinium mainly induced RCVS in our case because of the above-mentioned sympathomimetic effect. In general, MRA is very sensitive to vascular narrowing and turbulent blood flow, thus the measured sectional areas may be different from actual ones; however, 3-Tesla MRA is employed as a useful and noninvasive method (12). Therefore, we consider the measured areas can at least be surrogate markers; the vasodilation is confirmatory. We described a patient with RCVS whose MRA revealed diffuse cerebrovascular dilation before typical vasoconstriction. The dilation may be associated with RCVS pathophysiology. Moreover, in clinical practice, physicians should bear in mind that amezinium can potentially induce RCVS.
Clinical implications . Early cerebral angiogram may reveal diffuse cerebrovascular dilation in patients with reversible cerebral vasoconstriction syndrome (RCVS). . Amezinium metilsulfate can potentially induce RCVS.
XML Template (2015) [22.5.2015–10:39am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150076/APPFile/SG-CEPJ150076.3d
(CEP)
[1–5] [PREPRINTER stage]
Kobayashi
5
Funding
6. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808. 7. Chen SP, Fuh JL, Lirng JF, et al. Hyperintense vessels on flair imaging in reversible cerebral vasoconstriction syndrome. Cephalalgia 2012; 32: 271–278. 8. Cantu C, Arauz A, Murillo-Bonilla LM, et al. Stroke associated with sympathomimetics contained in overthe-counter cough and cold drugs. Stroke 2003; 34: 1667–1672. 9. Mourand I, Ducrocq X, Lacour JC, et al. Acute reversible cerebral arteritis associated with parenteral ephedrine use. Cerebrovasc Dis 1999; 9: 355–357. 10. Palma JA, Fontes-Villalba A, Irimia P, et al. Reversible cerebral vasoconstriction syndrome induced by adrenaline. Cephalalgia 2012; 32: 500–504. 11. Traut M, Brode E and Hoffmann HD. Pharmacology of amezinium, a novel antihypotensive drug. IV. Biochemical investigations of the mechanism of action. Arzneimittelforschung 1981; 31: 1566–1574. 12. Schoonman GG, van der Grond J, Kortmann C, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 2008; 131: 2192–2200.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012; 11: 906–917. 2. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: Analysis of 139 cases. Arch Neurol 2011; 68: 1005–1012. 3. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010; 67: 648–656. 4. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007; 130: 3091–3101. 5. Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: Reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007; 146: 34–44.
