Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Grief-­induced reversible cerebral vasoconstriction
syndrome (RCVS)
Pooja Rao,1 Michael Francis McCullough,2 Jessica Stevens,3 Matthew A Edwardson4
1

Neurology, Georgetown
University Hospital, Washington,
DC, USA
2
Radiology, MedStar
Georgetown University Hospital,
Washington, DC, USA
3
Neurology, MedStar
Washington Hospital Center,
Washington, DC, USA
4
Neurology, Georgetown
University Medical Center,
Washington, DC, USA
Correspondence to
Dr Pooja Rao;
​poojamohanrao@​gmail.​com
Accepted 20 December 2019

SUMMARY
Stress is under-­recognised as a potential causative
factor for reversible cerebral vasoconstriction syndrome
(RCVS). Here we present a case of RCVS occurring
during a time of extreme emotional duress. A 46-­year-­old
female patient with medical history of bipolar disorder
developed a severe headache during her father’s funeral.
The following day she was discovered to have bilateral
hemiparesis, aphasia, encephalopathy and was brought
emergently to the hospital. Neuroimaging revealed a
33 mL left fronto-­parietal haematoma with subarachnoid
blood near the vertex bilaterally. She underwent
craniotomy, haematoma evacuation and external
ventricular drain placement. The patient received two
cerebral angiograms, the first showing multifocal cerebral
vasoconstriction and the second showing resolution of
these changes. She improved significantly over the course
of her 3-­week hospitalisation and eventually made a
full recovery, including the ability to speak fluently in
six languages with no significant deficits other than
hypersomnia; she now requires 10 hours of sleep each
night as compared with 7 hours prior to her brain injury.

Background

© BMJ Publishing Group
Limited 2020. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Rao P,
McCullough MF, Stevens J,
et al. BMJ Case Rep
2020;13:e232204.
doi:10.1136/bcr-2019232204

Reversible cerebral vasoconstriction syndrome
(RCVS) is a group of conditions that are caused
by reversible multifocal narrowing of the cerebral
arteries with clinical manifestations that can include
headache, stroke and seizure.
The pathophysiology of RCVS remains unclear.
Female predominance may suggest hormonal influences, particularly given the increased risk during
pregnancy and the postpartum period.1 Increased
sympathomimetic activity triggered by sexual
activity, ingestion of sympathomimetic drugs and
the increased incidence of RCVS in patients with
a prior history of serotonergic antidepressant use
could alternatively suggest biochemical triggers.2 3
Identification of aetiologies that could potentially
lead to RCVS, such as severe emotional stress, may
help to further our understanding of the pathophysiology of this disease.

Case presentation

A 46-­year-­old female patient with medical history
of bipolar disorder presented to an outside hospital
after she was found in an obtunded state by her
family on the morning of presentation.
Per family, the patient developed a sudden severe
headache during her father’s funeral. She was given
ibuprofen, which initially helped with her headache.

She described this as the worst headache of her life.
Her son later gave her 1–2 tablets of naproxen
which did not seem to help. She then vomited and
subsequently went to bed. She had no prior history
of headaches or migraines.
One day later, the patient woke up and was able
to walk a few steps, but became obtunded and unresponsive shortly thereafter. Emergency medical
services (EMS) were called, and she was transferred
to an outside hospital. On arrival, the patient’s vital
signs were blood pressure (BP): 103/84, heart rate
(HR): 66 and temperature: 36.4. She was intubated
for airway protection given her decreased level of
consciousness.
Head CT revealed a left basal ganglia/fronto-­
parietal haematoma measuring 33 mL in volume
with mild subarachnoid haemorrhage near the
vertex (figure 1). She was transferred to MedStar
Georgetown University Hospital for neurosurgical evaluation. A CT angiogram of the head and
neck performed on arrival showed no vascular
abnormalities. The patient underwent emergent
craniotomy, haematoma evacuation and external
ventricular drain placement after transfer from the
outside hospital. There was no history of hypertension (HTN), bleeding disorders, tobacco use or
substance abuse. The patient’s only home medication was lithium, and she had been on a stable dose
for several years. Family history was significant for
father with Lewy body dementia.

Investigations

Cerebrospinal fluid (CSF) analysis (post craniotomy) revealed white blood cell (WBC) count :
406, red blood cell (RBC) count: 71 000, glucose:
81, protein: 223. The analysis was repeated 2 days
later and revealed the following: WBC count: 14,
RBC count: 2000, glucose: 84, protein: 56. Infectious workup, including CSF bacterial culture and
herpes simplex virus (HSV) PCR were negative.
A urine drug screen and initial lab results were
all within normal limits. Rheumatological labs
including antineutrophil cytoplasmic antibody
(ANCA), proteinase 3 (PR3) antibody, myeloperoxidase (MPO) antibody, antinuclear antibody (ANA),
erythrocyte sedimentation rate (ESR), C reactive
protein (CRP), rheumatoid factor and double-­
stranded DNA were negative with the exception of
CRP, which was elevated at 137.
MRI brain did not reveal an underlying infarct or
mass; magnetic resonance venogram (MRV) of the
brain showed no venous sinus thrombosis. A transthoracic echocardiogram was within normal limits.

Rao P, et al. BMJ Case Rep 2020;13:e232204. doi:10.1136/bcr-2019-232204

1

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Case report

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

The patient underwent two catheter-­
based cerebral angiograms, the first (figure 2, section A-­C) on hospital day 2 revealed
mild to moderate diffuse vascular irregularity with multiple
areas of alternating dilatation and vasoconstriction, most prominent within the posterior circulation, especially the left superior
cerebellar artery. Within the anterior circulation, these changes
were most prominent in the pericallosal arteries. There was no
associated intracranial atherosclerosis. A subsequent cerebral
angiogram on day 16 (figure 2) showed complete resolution of
the previously noted alternating dilation and vasoconstriction
changes.

Differential diagnosis

Common causes of intraparenchymal haemorrhage (IPH)
include HTN, trauma, cerebral amyloid angiopathy (CAA) and
ruptured arteriovenous malformation (AVM). We felt hypertensive IPH was unlikely, as her systolic blood pressures were
routinely in the range 110–140 with a peak of 158 during her
entire hospital course and she did not have a known history

Treatment

She underwent emergent craniotomy with clot evacuation
followed by close monitoring in the neurological intensive care
unit. She was started on oral nimodipine 60 mg every 6 hours
once RCVS was suspected on angiography, which was discontinued at the time of discharge.

Outcome and follow-up

Figure 2 Catheter-­based digital subtraction angiography of the
brain on hospital day 2 (A–C) and day 16 (D–F). Panels (A) and (D)
show reversal of segmental narrowing in the left superior cerebellar
artery. Panels (B) and (E) show reversal of segmental narrowing in
the pericallosal arteries. Panels (C) and (F) show an absent right A1
segment of the anterior cerebral artery (ACA) due to vasospasm that
later reversed to show normal filling of the ACA. Areas of reversible
vasoconstriction are marked by red arrows.
2

The patient’s mental status improved significantly over time.
Post extubation she was intermittently confused about where
she was and had a moderate expressive aphasia. Her inpatient
hospitalisation lasted 20 days and her subsequent stay in an
inpatient rehabilitation facility lasted around 2 weeks. Of note,
the patient's job required her to speak at least two different
languages—English and Chinese. In addition, the patient, prior
to her brain injury, spoke six languages. Around 1 week into her
hospital course she was able to speak three languages and by the
time she saw speech therapy as an outpatient after discharge from
inpatient rehabilitation, and at her initial follow-­up, she was able
Rao P, et al. BMJ Case Rep 2020;13:e232204. doi:10.1136/bcr-2019-232204

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Figure 1 Non-­contrast head CT on hospital admission. Thirty-­three
mL left basal ganglia fronto-­parietal intraparenchymal haemorrhage
with intraventricular extension (A). Subarachnoid haemorrhage near the
vertex on the left (B) and the right (C) marked by red arrows.

of hypertension. She reported no history of trauma and there
was no evidence of a scalp contusion. She was too young for
CAA and the MRI showed no evidence of old microbleeds on
susceptibility-­weighted imaging. Neither of her catheter-­based
cerebral angiograms suggested an underlying AVM.
Rarer causes of IPH include cerebral sinus venous thrombosis
(SVT), septic embolism leading to haemorrhage from a ruptured
mycotic aneurysm, central nervous system infection such as
herpes simplex encephalitis, central nervous system (CNS)
vasculitis and RCVS. SVT was effectively ruled out by a normal
MRV of the brain. We felt septic embolism was unlikely given her
normal transthoracic echocardiogram, negative blood cultures
and no fevers except for a 12 hour period during her hospital
course. Despite the initial CSF pleocytosis, CNS infection was
unlikely given a lack of clinical signs of infection, relatively
benign CSF profile 2 days later and negative CSF HSV PCR and
bacterial cultures. While CNS vasculitis can demonstrate similar
areas of cerebral constriction with post stenotic dilatation on
cerebral angiogram we felt this was unlikely because: (1) she
had no prior history of stroke or signs of cognitive dysfunction, (2) her headache was sudden in onset which is twice as
common in RCVS as opposed to the more insidious subacute
headaches described with CNS vasculitis, (3) her second CSF
profile showed no evidence of elevated protein or lymphocytic
pleocytosis, (4) her rheumatological workup was mostly negative
except for an elevated CRP and (5) her monophasic course of
illness which improved with supportive treatment.4 5
Our patient met criteria for RCVS according to the recently
developed RCVS2 score as well as the third edition of the International Classification of Headache Disorders (ICHD-3). The
RCVS2 score was developed to accurately distinguish RCVS
from non-­
RCVS arteriopathy including CNS vasculitis.6 Our
patient’s RCVS2 score was 7—a score >5 suggests 90% sensitivity and 99% specificity for RCVS. Our patient also met all
of the ICHD-3 criteria for acute headache attributed to RCVS7
including: (1) headache with focal deficits has led to angiography with ‘string of beads’ appearance and diagnosis of RCVS
and (2) new thunderclap headache triggered by sexual activity,
exertion, valsalva manoeuvres, emotion, bathing and/or showering with no new significant headache after >1 month. In addition to meeting the RCVS2 and ICHD-3 criteria, our patient had
non-­aneurysmal subarachnoid haemorrhage at the convexities,
which is seen in around one-­third of RCVS cases.8

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Discussion

RCVS is known to affect younger individuals with a female
predominance as in the case of our patient. RCVS has a mean
incidence around age 42 years, however cases have been
described from age 4 months to age 65 years.9 The most common
presentation is multiple recurrent thunderclap headaches over a
period of 1 week. The major complication is subsequent cerebral
infarction/haemorrhages resulting in permanent residual neurological deficits.2 RCVS is characterised by prolonged segmental
vasoconstriction of anterior and posterior circulation cerebral
arteries seen on non-­invasive or invasive angiography. RCVS
demonstrates a bilateral multiple ‘string of beads’ appearance of
the cerebral arteries caused by segmental vasoconstrictions and
post-­stenotic dilatations. RCVS is sometimes missed on non-­
invasive neuroimaging with computed tomography angiogram
(CTA)/magnetic resonance angiogram (MRA) and may only be
seen using invasive, catheter-­based angiography, as in our case.9
Vasoconstriction can be symptomatic or persist after resolution
of symptoms. The vasospasm reversibility must be demonstrated
by an angiographic control within 12 weeks after presentation.2
Reversible cerebral oedema may also be seen in a minority of
RCVS patients.
RCVS may occur in pregnancy, post partum, after exposure to
drugs with serotonergic and sympathomimetic actions, trauma,
HTN, migraine, hypercalcaemia, porphyria or other related
conditions. There are no clinical or preclinical studies that
clearly delineate the pathophysiology of RCVS, but increased
sympathetic drive has consistently been described as a possible
inciting factor. Circulating catecholamines are elevated in conditions like pheochromocytoma or after ingestion of sympathomimetic drugs and have resulted in secondary RCVS.10 In addition,
there are multiple reports suggesting that consumption of diet
pills and energy drinks containing sympathomimetic compounds
have triggered RCVS. The possible inciting ingredients in these
reports include green tea, L-­carnitine, conjugated linoleic acid,
the weight-­
loss supplement Hydroxycut, Chinese medicine
containing ephedra and ‘energy drink’ containing numerous
sympathomimetic herbal compounds.8 11–13
Stress could conceivably trigger RCVS through activation
of sympathetic pathways and catecholamine surge. Physiological situations, including emotional stress, recent surgery,
sexual intercourse, bathing, high altitude and others, have been
reported as potential triggers of RCVS.3 One study showed the
presence of cerebral vasospasm in patients with post-­traumatic
stress disorder.14 Two prior case reports specifically describe
grief as the probable inciting factor. Fisher detailed a case of
RCVS triggered when the patient’s favourite horses were taken
to the glue factory.15 Ducros and Wolff later described a case in
which the thunderclap headache started when a woman placed
flowers on her husband’s grave during his funeral.3 Given our
case and these prior examples, it is conceivable that grief is a
stress-­related trigger leading to catecholamine surge. Grief may
be an under-­recognised trigger for RCVS.
Serotonergic pathways have also been implicated as a possible
trigger for RCVS. For example, a study by Noskin et al discovered a possible relationship between starting an Selective
Serotonin Reuptake Inhibitor (SSRI) and the development of
Rao P, et al. BMJ Case Rep 2020;13:e232204. doi:10.1136/bcr-2019-232204

Patient’s perspective
I have no recollection of being a patient in the neurology/
neurosurgery ICU for around 20 days.
I only remember waking up in the rehabilitation hospital,
having been told by my mother that I had a neurosurgery due to
massive bleeding in my brain because of a condition called RCVS.
My last memory is of speaking about my father at our shiva
service (the prayer service for the dead) during the evening of
January 11, 2016; I don’t remember but I was told by my mother
that I went upstairs to my bedroom, where I must have lost my
consciousness that evening. The next morning, I was transported
to a hospital and then to another hospital for the emergency
neurosurgery on 12 January 2016.
I do remember that the date of my father’s funeral service,
10 January 2016, was one of the most emotionally painful days
of my life. I also remember exactly when I got my thunderclap
headache, which was about half an hour before the funeral
service for my father started. It was the most painful, throbbing
headache I have ever experienced; I am amazed that I was able
to speak at my Dad’s funeral service and recite a poem on him,
and that I was able to lead his burial that afternoon—even with
the most painful headache ever. How lucky am I that today I
can do everything I could do then, with the exception that I now
sleep 10 hours daily!
I feel a depth of gratitude to my amazing neurosurgeon, who
saved my life, along with all doctors, nurses, and other hospital
personnel, who took care of me in the ICU that I have been able
to make a full recovery.
I was glad to be a neurology/neurosurgery Grand Rounds
patient at the 30 March 2017 Grand Rounds presentation.
Having this article published also will hopefully help others
dealing with RCVS. Having my life saved has inspired me to want
to help others. There are really no words to describe the extent of
my gratitude for surviving such a dangerous life-­death situation.

Learning points
►► Reversible cerebral vasoconstriction syndrome (RCVS) is a

group of conditions characterised by reversible constriction of
cerebral arteries.
►► Most patients present with a thunderclap headache.
►► Approximately one-­third of patients develop ischaemic
or haemorrhagic strokes or reversible brain oedema on
neuroimaging.
►► Emotional stress and grief, based on our case could be a
potential trigger for RCVS.
RCVS.16 Of note, there are no documented cases of lithium use
and the development of RCVS, which was the only medication
our patient was taking.
RCVS is typically managed by supportive care. Our patient was
managed surgically with haematoma evacuation/external ventricular drain (EVD) placement and medically with nimodipine. Data
from two case series suggested that nimodipine does not affect
the time course of cerebral vasoconstriction but it may relieve
the number and intensity of headaches.17 18 However, a study by
Ducros et al revealed that nimodipine may not be very effective
as more than 30% of patients had headache recurrences.9
In our case of RCVS, grief was the suspected trigger and likely
cause of the condition. Hence to the best of our knowledge, this
3

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to speak four languages without any deficits. One year after her
brain injury, the patient was able to speak all six languages. The
only change has been that she now requires 10 hours of sleep at
night. She is currently back at work and able to perform all of
her prior job duties.

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

Twitter Pooja Rao @poojara52867811
Contributors PR: she was involved in planning the write up and additional data
acquisition. She was also the point of contact for the patient in obtaining follow-­up
information and consent. MFM: he helped acquire accurate images of the patients
angiogram and CT head during hospitalisation. JS: she was involved in editing the
article and providing data in the discussion section with important feedback which
was helpful. MAE: he was involved in the conception and design of the case report.
He made sure all the data were presented in a succinct and precise manner.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work
is properly cited and the use is non-­commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/4​ .​0/.

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4

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is one of only a few case reports of grief-­induced RCVS. Prompt
evaluation and early recognition of this condition can help in
the management of RCVS patients. Awareness that grief could
be an inciting factor may help increase early detection of future
RCVS cases.