Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches,
with or without other acute neurological symptoms, and diffuse segmental constriction
of cerebral arteries that resolves spontaneously within 3 months.[1] It can occur spontaneously, especially in middle-aged women[1]; at least half the cases occur after exposure to vasoactive drugs or post-partum.
This syndrome is often associated with a favorable outcome in 95% of cases.[1] However, the prognosis of RCVS is especially determined by stroke occurrence. Its
management is inspired by what is applied in aneurysmal subarachnoid hemorrhage (aSAH),
whose main complication is vasospasm and delayed cerebral ischemia (DCI). Although
the physiopathology of RCVS is unclear, it appears to be distinct from aSAH. Indeed,
the vasoconstriction in RCVS may be dependent on the activity and sensitivity of vascular
receptors, which can lead to a more systemic effect on all brain vessels, as opposed
to being dependent on the vasospasm induced by local clot lysis, as has been suggested
in aSAH.[2] As cerebral arteries are densely innervated, the release of norepinephrine or neuropeptide
Y from the sympathetic nerve endings may cause vasoconstrictions.[3] Angiographically, SAH-induced vasospasm is more commonly long-segmental and mainly
around the bleeding focus, compared with the multiple, short-segmental, and diffuse
changes seen in RCVS.[4] However, by analogy, RCVS is treated by nimodipine, and in some rare cases, the
use of milrinone might be considered.[3]
Milrinone is a phosphodiesterase III inhibitor leading to smooth muscle relaxation
in both arterial and venous vasculatures. Intra-arterial and intravenous administration
of milrinone has been evaluated for the treatment of DCI and appears safe and associated
with improved clinical outcomes.[5] The role of intravenous milrinone in reversing arterial vasospasm refractory to
oral nimodipine is highlighted in the literature.[6] However, whatever its route, mode, and duration of administration, milrinone has
been insufficiently assessed. Therefore, no specific recommendation exists.
A 54-year-old woman with no past medical history except for smoking and cannabis use
began suffering from sustained and unusual headaches. They lasted about 20 minutes
and recured twice daily. At first examination, the patient had no focal neurological
deficit with a Glasgow coma score (GCS) of 15. A computed tomography angiography was
performed and demonstrated a reduction in the caliber of both middle cerebral arteries
and both posterior cerebral arteries without repercussion on the parenchyma. The patient
was admitted to the neurology department for suspicion of either vasculitis or reversible
vasoconstriction syndrome. Vessel wall-magnetic resonance imaging (MRI) after gadolinium
injection demonstrates absent arterial enhancement ([Fig. 1E]) ruling out the differential diagnosis of vasculitis. Antiplatelet therapy (75 mg
of aspirin-based drug Kardegic) was initiated.
Fig. 1 (A) Cerebral digital subtraction angiography: diffuse, multifocal, segmental narrowing
of large/medium-sized arteries with dilated segments that appear like string of beads
or sausage strings (arrows). (B) Time of flight (TOF) magnetic resonance (MR) angiography: Initial TOF shows multiple
narrowing (arrows) of both middle cerebral arteries and posterior cerebral arteries.
(C) Resolution of abnormalities at 3 months. (D) Computed tomography perfusion: Axial CBF (cerebral blood flow), CBV (cerebral blood
volume), MTT (mean transit time), and TTD (time to drain) parametric maps show MTT
and TTD prolongation with CBF decrease and normal CBV in the parieto-occipital lobe.
(E) Coronal three-dimensional vessel wall-MRI after contrast injection: no vessel wall
enhancement.
A digital subtraction angiography (DSA) performed 4 days from the beginning of the
symptoms demonstrated diffuse irregularity with multifocal narrowings throughout the
cerebral vasculature with a beaded appearance, most pronounced in bilateral distal
middle cerebral arteries, bilateral proximal posterior cerebral arteries, right proximal
superior cerebellar artery, and right proximal posterior inferior cerebellar artery
([Fig. 1A]). RCVS was diagnosed as DSA is the gold standard. The patient received nimodipine,
60mg orally every 4 hours.
At 10 days from the onset of symptoms, the patient was still experiencing repeated
headaches two to three times a day for approximately 20 minutes. Despite treatment,
she experienced for the first-time weakness of the right lower limb, bilateral apraxia,
ataxia and central right facial paralysis. Time-of-flight MR angiography showed multiple
narrowing of both middle cerebral arteries and both posterior cerebral arteries ([Fig. 1B]). As such, the patient was transferred to intensive care unit (ICU) to receive a
continuous intravenous infusion of milrinone (1µg/kg/min) with no bolus via central
access with continuous monitoring of blood pressure. A mean arterial pressure of 90 mm
Hg was targeted via dose adjustments of noradrenaline. The clinical response was immediate.
A weaning attempt was undertaken at day 2 with a decrease to 0.75µg/kg/min but with
immediate reappearance of headache. Computed tomography perfusion, which was performed
on day 15 of the beginning of symptoms (day 5 of milrinone administration), showed
delayed cerebral perfusion in the left parieto-occipital territories. ([Fig. 1D]). Milrinone was progressively weaned with success from day 5 within 30 hours. At
ICU discharge (day 7), the GCS score was still 15 with no residual deficit and without
headache.
Through this case, we wish to point out the utility of milrinone in severe RCVS complicated
by DCI. The use of this treatment in ICU is based on experience gained in the management
of DCI following aSAH. This report is among the few on nonobstetric patients where
milrinone could help treat severe RCVS and potentially prevent the occurrence of DCI.
Continuous administration of milrinone seems to be safe. The main adverse effects
(hypotension, rhythm disorders, hyponatremia) have not been observed despite a relatively
high dose from 0.5 to 2µg/kg/min.[5] An intra-arterial injection during DSA could help differentiate RCVS from vasculitis
and thus allow the choice of appropriate etiological treatment.[7]
To avoid drawing definitive conclusions about this case, we remind that RCVS resolves
itself spontaneously within 12 weeks with substantial or complete normalization of
arteries ([Fig. 1C]). Therefore, it is possible that the clinical improvement is not totally due to
the use of milrinone.
In summary, RCVS, in most cases, is benign. By analogy to the treatment of the vasospasm
due to aSAH, milrinone, by its inodilatory properties, seems to be an attractive therapeutic
option to consider in a severe form of RCVS.
