Intra‐Arterial Milrinone for Reversible Cerebral Vasoconstriction Syndrome

Article · January 2009with88 Reads
DOI: 10.1111/j.1526-4610.2008.01211.x · Source: PubMed
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.
1 Figures
the occurrence of seizures.This might result from instability
of cell membrane potential as a result of dysfunction of ion
channels.10 This explanation is especially relevant in cases of
FHM where mutations leading to specific ion channel dys-
function have been documented.1,2,3
The multimodality evaluation of our case demon-
strates that neuronal depression is a more plausible expla-
nation for the prolonged clinical course of FHM in our
patient.The cortical cytotoxic edema demonstrated on MRI
is explainable by the related channelopathy as found in
other cases.11
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6. Parsons AA, Strijbos PJLM. The neuronal versus vascular
hypothesis of migraine and cortical spreading depression.
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Martel A. Prolonged hemiplegic migraine associated with
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8. Chabriat H, Vahedi K,Clark CA, et al. Decreased hemis-
pheric water mobility in hemiplegic migraine related to
mutation of CACNA1A gene. Neurology. 2000;54:510-516.
9. Piccinelli P, Borgatti R, Nicoli F, et al. Relationship
between migraine and epilepsy in pediatric age. Headache.
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of familial hemiplegic migraine. Neuroradiology. 2003;
Intra-Arterial Milrinone for Reversible Cerebral
Vasoconstriction Syndrome
Manon Bouchard,MD;Steve Verreault,MD, FRCP(C);Jean-Luc Gariépy,MD, FRCP(C);
Nicolas Dupré,MD, MSc, FRCP(C)
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 deterio-
ration, she was treated with intra-arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained
neurological improvement.
Key words: headache,milrinone,reversible,vasoconstriction,vasospasm,thunderclap
From the Department of Neurological Sciences, CHA (Enfant-Jésus), Faculty of Medicine, Laval University, Quebec City, QC,
Address all correspondence to N. Dupré, Department of Neurological Sciences, CHA—Enfant-Jésus, 1401 18th Street, Quebec
City, QC, G1J 1Z4, Canada.
Accepted for publication April 24, 2008.
Conflict of Interest: None
142 January 2009
Abbreviations: CT computed tomography,IV intravenous,MRC Medical Research Council,MRI magnetic resonance
imaging,NIHSS National Institute of Health Stroke Score,RCVS reversible cerebral vasoconstriction syn-
drome,SAH subarachnoid hemorrhage,SSRI selective serotonin reuptake inhibitor
Reversible cerebral vasoconstriction syndrome
(RCVS) is characterized by multifocal and reversible
vasoconstriction of cerebral arteries and is generally asso-
ciated with recurrent, acute, and severe (thunderclap)
headaches, with or without focal neurological signs or
symptoms.1-4 Many different names are given to this syn-
drome 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 asso-
ciated, like pregnancy and puerperium, migraine, neuro-
surgical 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 treat-
ment. However, ischemic stroke or posterior reversible
leukoencephalopathy syndrome has been noted to compli-
cate RCVS in 14-83% of cases.6-8 Brain imaging is typi-
cally 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.8Calcium channel blockers some-
times associated with a short-time course of corticoster-
oids 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 main-
tained between 120 mm Hg and 140 mm Hg. While on
treatment, daily headaches worsened and were newly
accompanied by mental slowing, ataxia, and visual distur-
bances. 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 NationalInstitute of Health Stroke Score
(NIHSS) was calculated to be 5. At this moment, her blood
pressure was normal and there were no metabolic distur-
bances.A second cerebral angiography was done revealing
worsening of diffuse irregularities in all vascular territories
bilaterally (Fig. A,B).
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 mil-
rinone at a dose of 0.5 mg/kg/minute. We also maintained
generous hydration and iatrogenic hypertension with nore-
pinephrine 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
Within 48 hours, the patient’s strength in the left leg
was normal distally and only a minor weakness persisted
Headache 143
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 treat-
ment 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 neu-
rological 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 pseudoephe-
drine, 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 neu-
rological symptoms caused by RCVS.5,10-12 Because of
angiographic similarities and presumed vasospastic etiol-
ogy, we decided to treat our patient like SAH-induced
vasospasm. However, thepathophysiology of these 2 condi-
tions 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 papaver-
ine 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 cur-
rently being investigated. Recently, milrinone, a phosphodi-
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).
144 January 2009
esterase inhibitor, has been studied for SAH-induced
vasospasm either for intra-arterial use or for cisternal irri-
gation 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 sus-
tained 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
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 asso-
ciated with corticosteroids. If progression to focal neuro-
logical deficits occurs, intra-arterial milrinone followed
with IV perfusion should be considered as a therapeutic
1. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Nar-
rative review: Reversible vasoconstriction syndromes. Ann
Intern Med. 2007;146:34-44.
2. Singhal AB. Cerebral vasoconstriction syndromes. Top
Stroke Rehabil 2004;11:1-6.
3. Matharu MS, Schwedt TJ, Dodick DW. Thunderclap head-
ache:An approach to a neurologic emergency. Curr Neurol
Neurosci Rep. 2007;7:101-109.
4. Schwedt TJ, Matharu MS, Dodick DW. Thunderclap head-
ache. Lancet Neurol. 2006;5:621-631.
5. Sturm JW, Macdonell RAL. Recurrent thunderclap head-
ache associated with reversible intracerebral vasospasm
causing stroke. Cephalalgia. 2000;20:132-135.
6. Singhal AB, Topcuoglu MA, Caviness VS, Koroshetz WJ.
Call-Fleming syndrome versus isolated cerebral vasculitis:
MRI lesion patterns. Stroke. 2003;34:264.
7. Chen SP, Fuh JL, Lirng JF, Chang FC, Wang SJ. Recurrent
primary thunderclap headache and benign CNS angiopa-
thy. Neurology. 2006;67:2164-2169.
8. Singhal AB. Cerebral vasoconstriction without subarach-
noid hemorrhage: Associated conditions and clinical and
neuroimaging characteristics. Ann Neurol. 2002;S:59-
9. Roh JK, Park KS. Postpartum cerebral angiopathy with
intracerebral hemorrhage in a patient receiving lisuride.
Neurology. 1998;50:1152-1154.
10. Nowak DA, Rodiek SO, Henneken S, et al. Reversible seg-
mental cerebral vasoconstriction (Call-Fleming syn-
drome): Are calcium channel inhibitors a potential
treatment option? Cephalalgia. 2003;23:218-222.
11. Lu SR, Liao YC, Fuh JL, Lirng JF, Wang SJ. Nimodipine
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12. Dodick DW. Reversible segmental cerebral vasoconstric-
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nists. Cephalalgia. 2003;23:163-165.
13. Sayama CM, Liu JK, Couldwell WT. Update on endovas-
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mal subarachnoid hemorrhage. Neurosurg Focus.
14. Arakawa Y, Kikuta K, Hojo M, Goto Y, Ishii A, Yamagata
S. Milrinone for the treatment of cerebral vasospasm after
subarachnoid hemorrhage: Report of seven cases. Neuro-
surgery. 2001;48:723-728.
15. Arakawa Y, Kikuta K, Hojo M, et al. Milrinone reduces
cerebral vasospasm after subarachnoid hemorrhage of
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Headache 145
    • Direct intra-arterial administration of milrinone, nimodipine and prostacyclin, and balloon angioplasty, have been used with variable success (Song et al., 2004, Bouchard et al., 2009, Elstner et al., 2009, Grande et al., 2010 ). These interventions carry a high risk of reperfusion injury and should be reserved for patients exhibiting clear signs of clinical progression (Singhal et al., 2009 ).
    [Show abstract] [Hide abstract] ABSTRACT: Reversible cerebral vasoconstriction syndrome is characterized by severe headaches with or without focal neurologic deficits and/or seizures, and segmental constriction of cerebral arteries that resolves within 3 months. This increasingly recognized syndrome is supposedly due to a transient disturbance in the control of cerebral vascular tone with sympathetic overactivity. It can cause stroke in the young. It affects mainly middle-aged women. More than half the cases occur after exposure to vasoactive substances or during postpartum. The manifestations have a monophasic course, without new clinical symptom after 4 weeks, and range from pure cephalalgic forms with recurrent thunderclap headaches over 1-2 weeks to rare catastrophic forms with multiple hemorrhagic and ischemic strokes, brain edema and death. Diagnosis may be hampered by the dynamic nature of clinicoradiological features. Convexity subarachnoid hemorrhage or stroke may occur a few days after initial normal imaging, and cerebral vasoconstriction is maximal on angiography 2-3 weeks after clinical onset. Symptomatic treatment includes rest and removal of vasoactive substances. Nimodipine has been proposed to reduce thunderclap headaches within 48 hours, but has no proven effect on the hemorrhagic and ischemic complications.
    Full-text · Chapter · Dec 2014
    • It has been hypothesized that either the episodes of systemic hypertension lead to hyperperfusion, or cerebral vasoconstriction and therefore hypoperfusion result in vasogenic edema observed in PRES [52]. Mainstay of treatment remains calcium-channel blockers including intravenous nimodipine [49@BULLET@BULLET] , intravenous prosta- cyclin [53] and intra-arterial delivery of milrinone [54], nimodipine [55], verapamil [56] that have been reported to be beneficial. Occurrence of headaches is a well-known manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is a result of mutation of the NOTCH3 gene.
    [Show abstract] [Hide abstract] ABSTRACT: Cranial or cervical vascular disease is commonly associated with headaches. The descriptions may range from a thunderclap onset of a subarachnoid hemorrhage to a phenotype similar to tension type headache. Occasionally, this may be the sole manifestation of a potentially serious underlying disorder like vasculitis. A high index of clinical suspicion is necessary to diagnose the disorder. Prompt recognition and treatment is usually needed for many conditions to avoid permanent sequelae that result in disability. Treatments for many conditions remain challenging and are frequently controversial due to paucity of well controlled studies. This is a review of the recent advances that have been made in the diagnosis or management of these secondary headaches.
    Article · May 2013
    • In severe cases, intra-arterial therapy may be considered. The use of intra-arterial nimodipine, papaverine or the phosphodiesterase inhibitore milrinone has been reported with googd results, although experience is limited to case reports[150][151][152]. Despite the considerable number of studies, a convincing breakthrough has not been achieved.
    [Show abstract] [Hide abstract] ABSTRACT: In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vaso-spasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.
    Full-text · Article · Jan 2013
    • Intra-arterial (IA) vasodilators injected during DSA with and without angioplasty are also used. These include IA milrinone [30], IA verapamil [32], and IA nimodipine as both a therapeutic and diagnostic agent [33], with the evidence, again, limited to case reports. IA verapamil has been shown to improve radiological vasospasm [34, 35], but whether this translates to improved clinical outcomes remains to be proven.
    [Show abstract] [Hide abstract] ABSTRACT: Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized and important cause of acute headache. The majority of these patients develop potentially serious neurological complications. Rigorous investigation is required to exclude other significant differential diagnoses. Differentiating RCVS from subarachnoid haemorrhage (SAH) and primary angiitis of the central nervous system (PACNS) may be difficult but has important therapeutic implications. This paper describes what is currently known about the epidemiology, pathophysiology, clinical, and diagnostic features of the syndrome, an approach to investigation, a summary of treatments, and what is known of prognosis.
    Full-text · Article · Jul 2012
    • The variability in reported treatment success may result from small sample sizes and/or variable definitions of treatment success, which have included cessation of headaches, resolution of vasospasm, or lack of further neurological symptoms and/or stroke. In refractory cases, intra-arterial nimodipine, papaverine or milrinone have been used with good results reported, although experience is limited to case reports [12,26]. Other treatment modalities have been reported less often.
    [Show abstract] [Hide abstract] ABSTRACT: Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular disorder associated with multifocal arterial constriction and dilation. RCVS is associated with nonaneurysmal subarachnoid hemorrhage, pregnancy and exposure to certain drugs. The primary clinical manifestation is recurrent sudden-onset and severe (‘thunderclap’) headaches over 1–3 weeks, often accompanied by nausea, vomiting, photophobia, confusion and blurred vision. The primary diagnostic dilemma is distinguishing RCVS from primary CNS arteritis. Diagnosis requires demonstration of the characteristic ‘string of beads’ on cerebral angiography with resolution within 1–3 months, although many patients will initially have normal vascular imaging. Many treatments have been reported to ameliorate the headaches of RCVS, but it is unclear whether they prevent hemorrhagic or ischemic complications.
    Full-text · Article · Oct 2010
    • In patients with refractory vasoconstrictions, intra-arterial therapy might be considered. Calcium channel blockers such as nimodipine [Elstner et al. 2009; Klein et al. 2009] or the phosphodiesterase inhibitor milrinone [Bouchard et al. 2009] have been employed in some cases and led to satisfactory outcomes. However, more studies are required.
    [Show abstract] [Hide abstract] ABSTRACT: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches and reversible cerebral vasoconstrictions. RCVS is more common than previously thought and should be differentiated from aneurismal subarachnoid hemorrhage. RCVS can be spontaneous or evoked by pregnancy or exposure to vasoactive substances. Patients tend to be middle-aged women but pediatric patients have been seen. Up to 80% of sufferers have identifiable triggers. Thunderclap headaches tend to recur daily and last for a period of around 2 weeks, while the vasoconstrictions may last for months. About one-third of patients have blood pressure surges accompanying headache attacks. The potential complications of RCVS include posterior reversible encephalopathy syndrome, ischemic strokes over watershed zones, cortical subarachnoid hemorrhage and intracerebral hemorrhage. Magnetic resonance images including angiography and venography and lumbar punctures are the studies of choice, whereas catheter angiography should not be implemented routinely. Patients with a mean flow velocity of the middle cerebral artery greater than 120 cm/s shown by transcranial color-coded sonography have a greater risk of ischemic complications than those without. The pathophysiology of RCVS remains unknown; sympathetic hyperactivity may play a role. Open-label trials showed calcium channel blockers, such as nimodipine may be an effective treatment in prevention of thunderclap headache attacks. In severe cases, intra-arterial therapy may be considered. Most patients with RCVS recover without sequelae; however, relapse has been reported in a small proportion of patients.
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