ISSN 0017-8748
doi: 10.1111/head.12202
Published by Wiley Periodicals, Inc.

Headache
© 2013 American Headache Society

Brief Communication
Catastrophic Reversible Cerebral Vasoconstriction Syndrome
Associated With Serotonin Syndrome
Seby John, MD; Megan Donnelly, DO; Ken Uchino, MD

Objectives.—To report fulminant cases of reversible cerebral vasoconstriction syndrome (RCVS) in the setting of serotonin syndrome.
Background.—RCVS is characterized by acute onset of severe headaches, with or without neurologic deficit, with evidence
of reversible cerebral vasoconstriction. It is often benign, and prognosis is generally considered favorable. In the largest
prospective study on RCVS, only 4% of patients were disabled from strokes and there were no fatalities.
Methods.—We report a case series.
Results.—We report 2 women with history of depression on selective serotonin re-uptake inhibitors who presented with
thunderclap headache and dizziness, respectively. Through the course of hospitalization, both patients developed rigidity,
diaphoresis, fever, tachycardia with labile blood pressures and clonus on examination. Since there was a recent addition/increase
in a known serotonergic agent, they met criteria for serotonin syndrome. Cerebrovascular imaging in both patients revealed
severe multi-focal vessel narrowing. The first patient developed large bi-hemispheric ischemic infarcts and increased intracranial pressure that was refractory to management, and she eventually expired. The second patient developed bilateral
parieto-occipital strokes and decerebrate posturing. Her course slowly stabilized, and she was eventually discharged with
residual left-sided hemiparesis. Repeat cerebrovascular imaging 1 month later showed normal vessels. In both patients,
intra-arterial nicardipine infusion improved angiographic appearance of stenoses, consistent with RCVS.
Conclusions.—Both cases satisfied the Sternbach criteria for serotonin syndrome. Fatality in case 1 prevents demonstration
of reversal of cerebral vasoconstriction, but improvement of arterial diameters with intra-arterial calcium channel blockers in
both cases suggests that both had RCVS. Serotonergic agents are known triggers of RCVS, but the concurrent presence of
serotonin syndrome likely precipitated the malignant course in our patients. Severe clinical and angiographic manifestations
should be considered as part of the spectrum of RCVS.
Key words: reversible cerebral vasoconstriction syndrome, serotonin syndrome, thunderclap headache, stroke
Abbreviations: CSF cerebrospinal fluid, CT computed tomographic, IA intra-arterial, INR international normalized ratio,
MRA magnetic resonance angiography, MRI magnetic resonance imaging, RCVS reversible cerebral vasoconstriction syndrome
(Headache 2013;••:••-••)

Reversible cerebral vasoconstriction syndrome
(RCVS) is characterized by acute onset of severe
headaches, with or without neurologic deficit, with
evidence of reversible cerebral vasoconstriction. The
course of RCVS is often benign, and prognosis is

From the Department of Neurology, Cleveland Clinic, Cleveland,
OH, USA (S. John and M. Donnelly); Cerebrovascular Center,
Cleveland Clinic, Cleveland, OH, USA (K. Uchino).
Address all correspondence to K. Uchino, Cerebrovascular
Center, Cleveland Clinic, 9500 Euclid Avenue/S80, Cleveland,
OH 44195, USA.

Conflict of Interest Statement: No conflict.
Accepted for publication July 8, 2013.

Grant Support/Funding: None.

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generally considered favorable. In the largest prospective study on RCVS patients, only 4% were disabled from strokes and there were no fatalities.1 We
report 2 patients who developed a fulminant course
of RCVS in the setting of serotonin syndrome.
Although serotonergic drugs are commonly implicated as putative agents for triggering RCVS,2 there
have been no reports of RCVS with concomitant
serotonin syndrome. We hypothesize that concurrent
presence of serotonin syndrome likely precipitated
the malignant course in our patients.

CASE 1
A 45-year-old female with depression on
escitalopram 10 mg daily presented to a local hospital
with thunderclap headache and confusion. Three
weeks prior, she had sustained accidental head
trauma, which was treated with hydrocodone. Past
medical history included migraine, and mechanical
aortic and mitral valve replacements secondary to
remote infectious endocarditis, for which she was
maintained on anticoagulation.
She was hospitalized and treated with intravenous dihydroergotamine and multiple doses of
hydromorphone. Her initial neurological examination was normal without focal neurological deficits.
International normalized ratio (INR) was >9 on
admission. Initial brain magnetic resonance imaging
(MRI) showed T2 hyperintensities in the cerebellum,
resembling posterior reversible encephalopathy syndrome, but did not demonstrate acute ischemia or
hemorrhage (Fig. 1A,B). Repeat MRI brain 2 days
after symptom onset showed focal T2 hyperintensity
in the bilateral parietal subarachnoid space consistent
with a bleed (Fig. 1C). Magnetic resonance venogram
was normal, and magnetic resonance angiography
(MRA) demonstrated narrowing in the proximal
anterior and middle cerebral arteries. The patient
was started on verapamil and corticosteroids for presumptive RCVS 2 days after onset of thunderclap
headache. During the hospital course, she also had
intermittent fevers, for which empiric meningitis coverage antibiotics were initiated. Cerebrospinal fluid
(CSF) was obtained and showed 1 red blood cell/μL,
1 white blood cell/μL, protein of 37 mg%, and negative cultures. Urine toxicology demonstrated pres-

ence of tetrahydrocannabinol. Antibiotics were
discontinued after CSF results were obtained. A
transthoracic echocardiogram was done, which
showed no evidence of valvular vegetation, thrombus,
or other source of cardiac embolism.
Fourteen days after symptom onset, she acutely
worsened with deteriorating mental status, fevers,
tachycardia, rigidity, and hyperreflexia. A repeat MRI
on that day showed patchy bilateral acute infarcts
predominantly in the parieto-occipital region
(Fig. 1D,E). She was intubated and transferred to our
institution 2 days later. Although we are not certain,
the escitalopram was presumably stopped after the
development of the above symptoms, and was off the
medication list when transferred to our institution.
Admission INR was 5. She was comatose on examination with decerebrate posturing but maintained
preserved brainstem reflexes. She was also extremely
rigid and had clonus, in addition to significant blood
pressure and heart rate lability. A computed tomographic (CT) head scan showed large bi-hemispheric
ischemic infarcts with mass effect and sulcal effacement. A cerebral angiogram on day 16 after symptom
onset showed severe segmental vessel narrowing in
all vascular distributions. Infusion of intra-arterial
(IA) nicardipine into the right and left internal
carotid artery and the right vertebral artery resulted
in moderate angiographic improvement. Aggressive
medical and surgical management of raised intracranial pressure was unsuccessful. Repeat MRI brain
revealed large bi-hemispheric infarcts, with significant
edema and midline shift (Fig. 1F). Worsening examination and imaging prompted family to withdraw
care, and the patient passed away few hours after
extubation.

CASE 2
A 57-year-old female with chronic opiate dependence on buprenorphine 8 mg t.i.d., and depression
on bupropion 200 mg b.i.d. and mirtazapine 15 mg
daily, with recent increase in citalopram dose (from
40 mg daily to 60 mg daily), presented to a local hospital with dizziness of 4 days duration. A day after
admission, she developed acute confusion, followed
by a seizure and unresponsiveness. On examination,
she was diaphoretic, febrile, tachycardic with mark-

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Fig 1.—Axial magnetic resonance imaging images of case 1. Diffusion weighted imaging (DWI) upon presentation demonstrated
absence of restricted diffusion (A). Fluid attenuated inversion recovery on admission (B) and 2 days after symptom onset (C)
showed hyperintensities in the cerebellum and then sulcal hyperintensities in addition, respectively. Repeat imaging 14 days after
symptom onset demonstrated acute infarcts on DWI (D) in the bilateral fronto-parietal lobes, and there was narrowing of the
bilateral middle and anterior cerebral arteries on intracranial magnetic resonance angiography (E). Large bi-hemispheric acute
infarcts seen on DWI, 19 days after symptoms onset (F).

edly labile blood pressures, rigidity, and hyperreflexia.
A CT head showed bilateral parieto-occipital hypodensities, and an MRI confirmed bilateral parietal
infarcts. She was intubated and transferred to our
hospital where initial exam was similar but also
revealed decerebrate posturing and clonus, although
she continued to remain awake and intermittently
follow commands. A CT head was repeated on day 8
after symptom onset, which showed new areas of
hypoattenuation in the posterior frontal lobes. A CT
angiogram demonstrated diffuse vessel narrowing. A
cerebral angiogram confirmed severe vessel narrowing worse in the posterior circulation. In the absence
of structural lesions, the decerebrate posturing was
hypothesized to be from brainstem hypoperfusion,
and IA nicardipine was administered into the right

and left internal carotid artery and the right vertebral
artery, which improved the narrowing slightly. The
antidepressants were stopped, and cyproheptadine
was started for presumed serotonin syndrome. She
was also started on verapamil. Twelve days after
symptom onset, due to a period of worsening decerebrate posturing, another cerebral angiogram was
performed and revealed improvement in narrowing
in all vascular territories. IA verapamil was injected
into the basilar artery, with marked improvement in
its caliber. Although her initial course was characterized by hemodynamic instability and worsening rigidity, she started to improve a day after the second
angiogram. At the time of discharge, she had residual
left-sided hemiparesis. An MRA repeated 26 days
after symptom onset was normal (Fig. 2). Three

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Fig 2.—Intracranial magnetic resonance angiography (MRA) images of case 2. MRA done 10 days after symptom onset (A)
showed diffuse distal vessel irregularity in the anterior cerebral and posterior cerebral arteries, and moderate degree of basilar
artery stenosis. MRA repeated 26 days after symptom onset (B) was normal.

months after hospital discharge, the patient did not
have any further episodes of thunderclap headache or
new neurological deficits, and the hemiparesis had
significantly improved.
An extensive evaluation for other causes of
ischemic stroke was unrevealing in both patients.
Serum did not reveal markers of systemic autoimmune disease, and CSF revealed was normal,
including nucleated cell count and protein (case 2
CSF: 29 red blood cells/μL, 1 white blood cell/μL,
protein of 22 mg%, normal immunoglobulin G synthesis, and negative cultures). A transthoracic and
transesophageal echocardiogram was done in case 2,
which did not show any evidence of valvular vegetations or thrombus.

DISCUSSION
We report 2 cases of RCVS with severe diffuse
vasospasm causing large ischemic strokes and death in
1, and severe functional ischemia in the other. Death in
case 1 prevents demonstration of reversal of cerebral
vasoconstriction, but improvement of arterial diameters with IA calcium channel blockers in both cases
suggests that both had RCVS.3 Tetrahydrocannabinol
is associated with and is a known precipitant of RCVS,
and could have precipitated the attack in case 1. Headache was conspicuously absent in case 2, and this is
exceptional in RCVS. Both cases satisfied the
Sternbach criteria of serotonin syndrome, which

require the recent addition of or increase in a known
serotonergic agent (escitalopram and dihydroergotamine in the first case, increased citalopram in the
second, with opiates contributing to both).The criteria
also require the absence of other possible etiologies
(infection, substance abuse, withdrawal, etc), plus no
recent addition or increase of a neuroleptic agent, and
at least 3 of the following symptoms: mental status
changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, or fever.4 Both cases also had
clonus, which is the cardinal feature for the diagnosis
of serotonin syndrome by the Hunter’s criteria.5
Posterior reversible encephalopathy syndrome
(PRES) is found in a significant proportion of
patients with RCVS,6-10 and patients with PRES also
demonstrate diffuse or focal vasculopathy and vessel
pruning in up to 87% of cases.11 Both conditions can
also have similar clinical presentations, including
acute onset headache, visual changes, and seizures. In
addition, both conditions can also have similar precipitating factors, like immunosuppressive and cytotoxic medications.12 As such, there is a significant
overlap between these syndromes, and they may
represent a continuum of the same disease with a
common pathophysiology. Impaired vascular autoregulation is hypothesized to cause PRES. Vascular
permeability contributes to vasogenic edema, and
progressive increase in vascular resistance causes

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vasoconstriction, which when severe produces irreversible ischemic infarction.11,12 Usually, ischemia is
contained within the area of vasogenic edema. In
case 1, patient had large bi-hemispheric infarcts
that clearly extended beyond the area of posterior
predominant vasogenic edema. In case 2, imaging
revealed cytotoxic edema from the acute ischemic
infarcts without any vasogenic edema. These factors
support the diagnosis of RCVS, with concurrent presence of PRES in case 1.
The long-term prognosis of RCVS is usually
benign and is generally considered favorable. Prognosis is dependent on the development of strokes, but
most patients recover gradually with minimal deficits.
In the 3 largest cohorts of RCVS patients, the combined fatality was less than 1%.8-10 However, the
course can be extremely variable, and some patients
can develop severe vasospasm with subsequent large
strokes and massive cerebral edema. Most fatal cases
of RCVS have been associated with post-partum
vasoconstriction.13-16 It is unclear why this is the case,
but there is female preponderance in RCVS, and both
of our cases are women.
Serotonergic agents, including selective serotonin
re-uptake inhibitors,2 serotonin and noradrenaline
re-uptake inhibitors,17 ergotamine derivatives,18
triptans,10,19 and 3,4-methylenedioxymethamphetamine (“ecstasy”),20 are commonly associated with
RCVS. It is unknown whether these drugs are present
coincidentally or causative, or whether they trigger
vasoconstriction in a susceptible individual.Serotonininduced vasoconstriction is mediated by its action on
the 5-HT1B and/or 5-HT2A receptors, which are
found on the smooth muscle cells in peripheral and
cerebral vessels.21 Upregulation of the 5-HT1B receptors in cerebral blood vessels has been show to occur
in subarachnoid hemorrhage22 and ischemia.23 As
such, the magnitude of the vascular response can vary
according to pathophysiological state.
Although a number of reports have described the
occurrence of RCVS with serotonergic agents, there
have been no reports of RCVS along with concomitant serotonin syndrome. The presence of the serotonin syndrome might have caused these patients to
take a malignant course. Continued inadvertent
administration of serotonergic agents in the presence

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of ischemia and subarachnoid hemorrhage could
have further worsened vasoconstriction and extended
the infarcts.
Severe clinical and angiographic manifestations
should be considered as part of the spectrum of
RCVS. Careful attention should be paid to patient
medication lists and recent drug exposures. We
hypothesize that excess serotonergic activity can
potentially cause severe vasospasm and precipitate a
fulminant course. Recognition of this syndrome and
the impact of serotonergic agents are important for
treating clinicians. The diagnosis of RCVS in the
acute setting is challenging, but this syndrome should
be considered especially with presentations of thunderclap headache. Recurrent thunderclap headache
after an initial negative evaluation with noncontrasted head CT and CSF should also raise the
suspicion for possible RCVS.

STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Seby John; Megan Donnelly; Ken Uchino
(b) Acquisition of Data
Seby John; Megan Donnelly; Ken Uchino
(c) Analysis and Interpretation of Data
Seby John; Megan Donnelly; Ken Uchino
Category 2
(a) Drafting the Manuscript
Seby John; Megan Donnelly; Ken Uchino
(b) Revising It for Intellectual Content
Seby John; Megan Donnelly; Ken Uchino
Category 3
(a) Final Approval of the Completed Manuscript
Seby John; Megan Donnelly; Ken Uchino

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