WSO December 2023 – Issue 3 - 1152

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International Journal of Stroke 18(10)
Table 1. Triggers and associated conditions.
Pregnancy
Headache disorder
Physiologic
Medications, drugs
and toxins
Early puerperium, late pregnancy, eclampsia, preeclampsia, delayed postpartum eclampsia
migraine, primary thunderclap headache, benign exertional headache, benign sexual headache, primary
cough headache
high altitude, winter climate, cold water exposure, typhoons, severe grief
Sympathomimetic: phenylpropanolamine, pseudoephedrine, phenylephrine, epinephrine, isometheptene,
midodrine, ergotamine tartrate, methylergonovine, lisuride, bromocriptine, methergine
Serotoninergic: selective serotonin-reuptake inhibitors (SSRIs), serotonin noradrenaline-reuptake
inhibitors (SNRIs), triptans
Immunossupressants/immunomodulators: tacrolimus (FK-506), cyclophosphamide, interferon, fingolimod,
etanercept, tocilizumab, etoricoxib, ustekinumab, adalidumab
Hormonal: oral-contraceptive pills, ovarian stimulation, levonorgestrel
Illicit drugs: cocaine, ecstasy, amphetamine derivatives, marijuana, lysergic acid diethylamide.
Other: indomethacin, hydroxycut, erythropoietin, intravenous immune globulin, nicotine patches, red
blood cell transfusions, Ma Huang (ephedra), khat leaves, atovaquone, isoflavones, licorice, caffeine
withdrawal, eucalyptus, ethylene oxide exposure, tetrodotoxin, oleoresin capsicum (pepper spray)
Procedures
Others
Post-carotid endarterectomy, carotid stenting, open neurosurgical procedures, tonsillectomy, neck
surgery, repetitive transcranial magnetic stimulation, dural puncture
Takotsubo cardiomyopathy, transient global amnesia, Covid-19 infection, Covid-19 vaccination, Leigh
Syndrome, hypercalcemia, porphyria, hemolytic uremic syndrome, thrombotic thrombocytopenic
purpura, elevated anti-phospholipid antibodies, thyrotoxicosis, pheochromocytoma, bronchial carcinoid
tumor, unruptured saccular cerebral aneurysm, head trauma, spinal subdural hematoma, cerebral venous
sinus thrombosis, carotid glomus tumor
subjected to brain biopsy and chronic immunosuppressive
treatment, as warranted for the management of PACNS. In
2007, we proposed " RCVS " as an umbrella term to bring
together the aforementioned entities.15 We emphasized its
usually benign outcome and outlined key features to enable
prompt recognition and differences from PACNS. There
was unity in diversity; individual entities could still have
some unique features.
Over the last 15 years, many groups have further characterized
RCVS and contributed to our understanding of
imaging abnormalities, triggers, and pathophysiology16-27
(see Table 1). Recognition has grown worldwide. The
International Headache Society has established diagnostic
criteria,28 the RCVS2 score has been shown to enable
prompt and accurate diagnosis,29,30 and an International
Classification of Diseases diagnostic code (ICD-10,
I67.841) has been assigned. Collectively these efforts have
further raised awareness and enabled national database
studies.31,32
Epidemiology
The estimated incidence is 3 per million adults,33 and 0.02
per 100,000 US inpatients.32 This is probably an under-estimate
due to relative lack of awareness and inadequate medical
coding. I have consistently encountered one new
inpatient every 3-4 weeks over the last two decades. RCVS
is probably the most common intracranial arteriopathy and
a frequent cause of stroke in young adults. It is reported
International Journal of Stroke, 18(10)
from virtually all continents, affecting individuals of
diverse racial and ethnic backgrounds. The female:male
ratio ranges from 2:1 to 10:1; the mean age range is 42-
51 years.16,17,21,31,32 There are increasing reports of RCVS in
children.34 Male RCVS is associated with younger age,
sexual activity, and more benign outcomes.22
Pathophysiology/related syndromes
There is limited understanding of the mechanism and interrelationship
of TCH and cerebral vasoconstriction. Table 1
shows the range of implicated conditions and triggers.
There may be substantial reporting bias; associated medications
have a well-established safety and efficacy profile,
and pharmaco-epidemiological studies are required to confirm
these observations.
While the conditions in Table 1 appear diverse, a common
thread appears to be increased serotonergic and sympathomimetic
activity. Between the two, serotonergic
mechanisms may be more important for several reasons.
First, RCVS patients have a high frequency of prior
migraine, depression, and anxiety,19,21 where serotonergic
mechanisms are implicated. Second, predominantly sympathomimetic
triggers (e.g. cocaine, amphetamines) are
less frequent than serotonergic triggers, and vasoconstriction
associated with cocaine usually affects the intracranial
carotid rather than the circle of Willis arteries and their
branches.9 Third, infusions of sympathomimetic agents
such as phenylephrine rarely precipitate RCVS. Fourth,
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