the occurrence of seizures.This might result from instability
of cell membrane potential as a result of dysfunction of ion
channels.10This 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
1. Joutel A, Ducros A,Vahedi K, et al. Genetic heterogeneity
of familial hemiplegic migraine. Am J Hum Genet. 1994;
2. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial
hemiplegic migraine and episodic ataxia type 2 are caused
by mutations in the CA2+ channel gene CACNL1A4.Cell.
3. Dichgans M, Freilinger T, Eckstein G. Mutation in the
neuronal voltage-gated sodium channel SCN1A in familial
hemiplegic migraine. Lancet. 2005;366:371-377.
4. Leão AAP. Spreading depression of activity in the cerebral
cortex. J Neurophysiol. 1944;7:359-390.
5. Tepper SJ,Rapoport A,Sheftell F. The pathophysiology of
migraine. Neurology. 2001;7:279-286.
6. Parsons AA, Strijbos PJLM. The neuronal versus vascular
hypothesis of migraine and cortical spreading depression.
Curr Opin Pharmacol. 2003;3:73-77.
7. Lindhal AJ, Allder S, Jefferson D, Allder S, Moody A,
Martel A. Prolonged hemiplegic migraine associated with
unilateral hyperperfusion on perfusion weighted magnetic
resonance imaging. J Neurol Neurosurg Psychiatry. 2002;
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.
10. Agostoni E, Aliprandi A. The complications of migraine
with aura. Neurol Sci. 2006;27:S91-S95.
11. Butteriss DJA,Ramesh V,Birchall D. Serial MRI in a case
of familial hemiplegic migraine. Neuroradiology. 2003;
Intra-Arterial Milrinone for Reversible Cerebral
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
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
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
(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.1-4Many 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.1-4The 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).1-5The 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.6-8Brain imaging is typi-
cally normal, althoughsome
intraparenchymal or subarachnoid hemorrhages (SAH)
attributed to reperfusion.1,9In 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.1-3There 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
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
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.5,10-12Because 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.13In 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).
esterase inhibitor, has been studied for SAH-induced
vasospasm either for intra-arterial use or for cisternal irri-
gation with promising results.14,15Although 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
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