Intra-Arterial Milrinone for Reversible Cerebral Vasoconstriction Syndrome


  • Manon Bouchard MD,

    1. From the Department of Neurological Sciences, CHA (Enfant-Jésus), Faculty of Medicine, Laval University, Quebec City, QC, Canada.
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  • Steve Verreault MD, FRCP(C),

    1. From the Department of Neurological Sciences, CHA (Enfant-Jésus), Faculty of Medicine, Laval University, Quebec City, QC, Canada.
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  • Jean-Luc Gariépy MD, FRCP(C),

    1. From the Department of Neurological Sciences, CHA (Enfant-Jésus), Faculty of Medicine, Laval University, Quebec City, QC, Canada.
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  • Nicolas Dupré MD, MSc, FRCP(C)

    1. From the Department of Neurological Sciences, CHA (Enfant-Jésus), Faculty of Medicine, Laval University, Quebec City, QC, Canada.
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  • Conflict of Interest: None

N. Dupré, Department of Neurological Sciences, CHA—Enfant-Jésus, 1401 18th Street, Quebec City, QC, G1J 1Z4, Canada.


Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with recurrent thunderclap headaches and is characterized by multifocal and reversible vasoconstriction of cerebral arteries that can sometimes evolve to severe cerebral ischemia and stroke. We describe the case of a patient who presented with a clinically typical RCVS and developed focal neurological symptoms and signs despite oral treatment with calcium channel blockers. Within hours of neurological deterioration, she was treated with intra-arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained neurological improvement.


computed tomography




Medical Research Council


magnetic resonance imaging


National Institute of Health Stroke Score


reversible cerebral vasoconstriction syndrome


subarachnoid hemorrhage


selective serotonin reuptake inhibitor


Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by multifocal and reversible vasoconstriction of cerebral arteries and is generally associated with recurrent, acute, and severe (thunderclap) headaches, with or without focal neurological signs or symptoms.1-4 Many different names are given to this syndrome in the literature, often according to the clinical context: postpartum angiopathy, migrainous vasospasm, benign angiopathy of the central nervous system, Call-Fleming syndrome.1-4 The pathophysiology of this disorder is not well understood but many conditions can be associated, like pregnancy and puerperium, migraine, neurosurgical procedures, trauma or exposure to certain drugs (pseudoephedrine, selective serotonin reuptake inhibitors [SSRI], triptans, ergot derivatives, cocaine, amphetamines, etc).1-5 The course is usually benign, even without treatment. However, ischemic stroke or posterior reversible leukoencephalopathy syndrome has been noted to complicate RCVS in 14-83% of cases.6-8 Brain imaging is typically normal, although some cases have presented intraparenchymal or subarachnoid hemorrhages (SAH) attributed to reperfusion.1,9 In one study, 16% of patients with RCVS had intracranial bleeds, commonly in cortical border zone regions.8 Calcium channel blockers sometimes associated with a short-time course of corticosteroids are a largely used therapeutic strategy.1-3 There is no standard treatment for the management of a patient with acute focal neurological deficits associated with RVCS. Particularly, the use of milrinone has never been described in the literature as a treatment option.


A 57-year-old migrainous woman presented to us after a 4-day history of daily, unusual, short-lasting (30-75 minutes) thunderclap headaches different from her migraines. She had used zolmitriptan without success and was also taking pseudoephedrine for a recent cold and an SSRI for a mood disorder. Neurological examination was normal on admission. Computed tomography (CT) of her brain showed small bilateral SAH at the high convexity. Cerebrospinal fluid analysis was normal and cerebral magnetic resonance imaging (MRI) confirmed CT findings without giving any more information. Standard cerebral angiography did not reveal any aneurysm but showed multiple arterial narrowings of medium and small caliber arteries. A diagnosis of RCVS was made and the patient was started on verapamil sustained release (SR) 80 mg daily with a rapid upward titration to 360 mg daily over 4 days. Despite a high dosage of calcium channel blockers, systolic blood pressure did not drop and was always maintained between 120 mm Hg and 140 mm Hg. While on treatment, daily headaches worsened and were newly accompanied by mental slowing, ataxia, and visual disturbances. The patient was neurologically normal between headaches. Prednisone 60 mg daily was added on the fourth day of treatment.

In spite of medical treatment, she acutely developed after 5 days of treatment a severe paresis of her left leg (1/5 according to the Medical Research Council [MRC] scale) and persistent visual disturbances with mental status changes. The National Institute of Health Stroke Score (NIHSS) was calculated to be 5. At this moment, her blood pressure was normal and there were no metabolic disturbances. A second cerebral angiography was done revealing worsening of diffuse irregularities in all vascular territories bilaterally (Fig. A,B).

Figure Figure.—.

Standard cerebral angiography showing narrowing of distal right carotid artery (A) and basilar artery (B). Notice also diffuse irregularities of small cerebral arteries (A, B). Eight weeks later, there is complete reversibility of all previously observed narrowings (C, D).

Based on our experience in the treatment of SAH-induced vasospasm, we infused 10 mg of milrinone (25% dilution in normal saline) in her right carotid artery over 30 minutes. Less than 5 minutes after intra-arterial injection, the paresis had improved greatly and the narrowings were less severe at contrast injection. After the procedure, the patient was left on an intravenous (IV) perfusion of milrinone at a dose of 0.5 µg/kg/minute. We also maintained generous hydration and iatrogenic hypertension with norepinephrine bitartrate titrated for systolic blood pressure between 160 mm Hg and 180 mm Hg. These measures were maintained for 6 hours and were then weaned slowly over 13 hours. Nimodipine 60 mg every 4 hours was introduced during milrinone downward titration and prednisone was discontinued.

Within 48 hours, the patient's strength in the left leg was normal distally and only a minor weakness persisted proximally (4+/5 MRC scale), with an improved NIHSS of only 1. Visual disturbances also resolved within a few days and no more headaches were reported. A cerebral MRI with diffusion-weighted images obtained 7 days after treatment showed recent ischemic lesions in both occipital lobes, left frontal cortex and right frontal subcortical white matter. Prior to discharge, nimodipine was replaced by verapamil SR 360 mg daily. A control cerebral angiogram done 8 weeks later confirmed complete reversibility of all observed arterial narrowings (Fig. C,D). At follow-up visit 3 months later, the patient reported no headache recurrence, no neurological symptom and was left only with mild spasticity in her left leg on examination.


Our patient had many predisposing factors for RCVS, notably a migrainous past and recent use of pseudoephedrine, triptan, and an SSRI. The diagnosis was suspected on the initial cerebral angiogram and could be confirmed later when reversibility was proven. Despite medical treatment with verapamil and corticosteroids, she progressed over 10 days to develop severe neurological deficits. There is very scarce literature concerning the management of acute neurological symptoms caused by RCVS.5,10-12 Because of angiographic similarities and presumed vasospastic etiology, we decided to treat our patient like SAH-induced vasospasm. However, the pathophysiology of these 2 conditions may be different. Indeed, it is not known for sure if the narrowings observed in RCVS correspond to vasospasm and what causes it.

When vasospasm occurs following SAH, the most studied endovascular therapies are intra-arterial papaverine and balloon angioplasty.13 In our patient, we could not proceed to balloon angioplasty because vasoconstriction was diffuse and involved mostly small cerebral arteries. Although papaverine was traditionally the agent of choice in this setting, many other pharmacological agents are currently being investigated. Recently, milrinone, a phosphodiesterase inhibitor, has been studied for SAH-induced vasospasm either for intra-arterial use or for cisternal irrigation with promising results.14,15 Although milrinone also has a short duration of action, one of the advantages over papaverine is the possibility to give a prolonged IV infusion following intra-arterial use, presumably offering a more sustained effect. In our center, we have been using it for this indication in a number of patients. Following the intra-arterial procedure, we induced hypertension, hemodilution, and hypervolemia and we introduced nimodipine, all of which are recommended medical treatment for post-SAH vasospasm.13


Although generally benign, RCVS is a potentially severe condition that neurologists must recognize. The treatment of non-complicated cases can be limited to observation or calcium channel blockers use, maybe associated with corticosteroids. If progression to focal neurological deficits occurs, intra-arterial milrinone followed with IV perfusion should be considered as a therapeutic avenue.