Reversible cerebral vasoconstriction syndrome

Abstract

Reversible cerebral vasoconstriction syndrome is characterised by severe headaches with or without seizures and focal neurological deficits, and constriction of cerebral arteries which resolves spontaneously in 1-3 months. It affects females slightly more than males, and mean age of onset is around 45 years. Approximately 60% of cases are secondary, mainly postpartum and after exposure to vasoactive substances. The major complications are localised cortical subarachnoid haemorrhage (22%) and parenchymal ischaemic or haemorrhagic strokes (7%) which may leave permanent sequelae. Diagnosis requires the demonstration of the "string of beads" appearance of cerebral arteries on angiography, with complete or almost complete resolution on repeat angiography 12 weeks after onset. Nimodipine seems to reduce thunderclap headaches within 48 h but has no definite effect on the haemorrhagic and ischaemic complications.

Full text

REVIEW Pract Neurol 2009; 9: 256–267
Reversible cerebral
vasoconstriction syndrome
Anne Ducros,
1
Marie-Germaine Bousser
2
1
Consultant Neurologist,
Emergency Headache Centre,
Assistance Publique des Hoˆpitaux
de Paris, Lariboisie`re Hospital, Head
and Neck Centre, Paris, France
2
Professor of Neurology, Neurology
Department, Assistance Publique
des Hoˆpitaux de Paris, Lariboisie`re
Hospital, Head and Neck Centre,
Paris, France
Correspondence to:
Dr Anne Ducros
Consultant Neurologist, Urgences
Ce´phale´es, Hoˆpital Lariboisie`re,
2 rue Ambroise Pare´,
75475 Paris Cedex 10, France;
anne.ducros@lrb.aphp.fr
Reversible cerebral vasoconstriction syndrome is characterised by severe
headaches with or without seizures and focal neurological deficits, and
constriction of cerebral arteries which resolves spontaneously in 1–3 months.
It affects females slightly more than males, and mean age of onset is around
45 years. Approximately 60% of cases are secondary, mainly postpartum and
after exposure to vasoactive substances. The major complications are localised
cortical subarachnoid haemorrhage (22%) and parenchymal ischaemic or
haemorrhagic strokes (7%) which may leave permanent sequelae. Diagnosis
requires the demonstration of the ‘‘string of beads’’ appearance of cerebral
arteries on angiography, with complete or almost complete resolution on
repeat angiography 12 weeks after onset. Nimodipine seems to reduce
thunderclap headaches within 48 h but has no definite effect on the
haemorrhagic and ischaemic complications.
Reversible cerebral vasoconstriction
syndrome is characterised by the
association of severe headaches with
or without additional neurological
symptoms, and constriction of cerebral arteries
which resolves spontaneously in 1–3
months.
1, 2
The most common clinical feature
is a severe acute headache, often thunderclap
in nature—a sudden excruciating headache that
peaks in less than 1 min, like a ‘‘clap of
thunder’’—mimicking that of a ruptured aneur-
ysm. The major complications are localised
cortical subarachnoid haemorrhages (20–25%)
and ischaemic or haemorrhagic strokes
(5–10%).
3–6
In contrast with the arterial
abnormalities that are reversible within a few
weeks, these strokes may leave permanent
sequelae and can even be fatal.
2, 7–9
Reversible cerebral vasoconstriction syn-
drome was the name proposed in 2007 by
Calabrese et al to group all the rather similar
cases reported over the years under many
different appellations (table 1).
2, 3, 10, 11
These
illustrate the fact that the diagnosis may be
challenging. On the one hand, severe forms
have been considered to be mild forms of
cerebral angiitis because of the similar angio-
graphic features,
12, 13
while on the other hand,
purely cephalalgic forms have been considered
as varieties of primary headache syndromes (ie,
headaches spontaneously produced by the
activation of cerebral/cranial pain circuits
without an underlying lesion
10, 14
).
However, during the past 5–10 years, it has
been increasingly recognised as a distinct
syndrome due to a transient and reversible
disturbance of arterial tone regulation, with-
out inflammation of the arteries, mainly
characterised by severe headaches, which
are secondary and symptomatic of the
underlying vascular abnormality.
AN UNDERDIAGNOSED
CONDITION
Reversible cerebral vasoconstriction syn-
drome has been reported in patients aged
256 Practical Neurology
10.1136/jnnp.2009.187856

13–70 years.
3, 15
Mean age of onset is around
45 years with a female to male preponder-
ance from between about 2 and 10:1.
3, 13, 14
The exact incidence is unknown. This syn-
drome, although rare, is probably still under-
diagnosed, particularly the pure cephalalgic
form. Only three series including more than
10 patients have been published.
NA retrospective American series of 16
patients hospitalised for suspected CNS
angiitis, of whom 10 had repeat angio-
graphy to assess reversibility of vasocon-
striction.
13
NA prospective Taiwanese series of 56
patients with recurrent thunderclap
headaches of whom 22 had proven initial
vasoconstriction, then a series of 32
patients (including 12 from the first
series) with the proven syndrome.
6, 14
NOur prospective French series of 67 cases,
seen in a single institution between 2004
and 2007, who all had vasoconstriction
and repeat angiography showing its
resolution.
3
MECHANISMS AND CAUSES
Although the pathophysiology remains
unknown, the prevailing hypothesis is of a
transient disturbance in the control of
cerebral vascular tone leading to segmental
and multifocal arterial constriction and
dilatation.
2
This disturbance may be spontan-
eous (so-called idiopathic reversible cerebral
vasoconstriction syndrome), while 25–60% of
cases are secondary, mostly to exposure to
vasoactive sympathomimetic or serotoniner-
gic substances, and/or to the postpartum
state (table 2).
2, 3, 9, 13, 16
Vasoactive substances
The incriminated substances include various
medications such as selective serotonin
reuptake inhibitors and all a-sympathomim-
etics, often used as over the counter nasal
decongestants, some diet pills and herbal
medications, and most illicit drugs, including
cannabis (which is the most frequent cause in
France).
2, 3, 7, 8, 16, 17
In some patients, the
syndrome occurs after just a few days of
exposure while in others it occurs after
several months of either regular or irregular
exposure to one or several of these sub-
stances, at normal or excessive doses. Acute
alcoholic intoxication may be an additional
precipitating factor but has only been
incriminated in association with exposure to
other drugs, such as cannabis and/or ecstasy/
and or cocaine.
3
Postpartum
Postpartum reversible cerebral vasoconstric-
tion syndrome starts in two-thirds of cases
TABLE 1 Various appellations of the reversible cerebral vasoconstriction
syndrome
lIsolated benign cerebral vasculitis or angiopathy
lCall–Fleming syndrome
lCNS pseudovasculitis
lBenign angiopathy of the central nervous system
lPostpartum angiopathy
lMigrainous vasospasm
lMigraine angiitis
lIdiopathic thunderclap headache with reversible vasospam
lDrug induced cerebral vasculopathy
lFatal vasospasm in migrainous infarction
TABLE 2 Causes of reversible cerebral vasoconstriction syndrome and
associated conditions
Postpartum
lWith or without exposure to vasoactive substances, eclampsia/pre-
eclampsia
Exposure to vasoactive substances
lCannabis, cocaine, ecstasy, amphetamines, LSD, binge drinking
lSelective serotonin reuptake inhibitors
lNasal decongestants—phenylpropanolamine, pseudoephedrine, ephedrine
lErgotamine tartrate
lMethergine
lBromocriptine, lisuride
lTriptans
lIsometheptine
lNicotine patches
lGinseng
Catecholamine secreting tumours
lPhaeochromocytoma, bronchial carcinoid tumour, glomus tumours
Exposure to immunosuppressants or blood products
lTacrolimus (FK-506), cyclophosphamide, erythropoietin, intravenous
immunoglobulin, red blood cell transfusion, interferon a
Miscellaneous
lHypercalcaemia, porphyria, head trauma, subdural spinal haematoma,
carotid endarterectomy, neurosurgical procedures, CSF hypotension
Extra or intracranial large artery disorders
lCervical dissection, unruptured intracranial aneurysm, dysplasia
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www.practical-neurology.com

during the first week after delivery, usually
after a normal pregnancy.
8, 9, 16
In 50–70% of
cases, it is associated with the intake of
vasoconstrictors, mostly ergots used to treat
postpartum haemorrhage or to inhibit lacta-
tion (eg bromocriptine, methergine).
9
Other causes
Many other causes have been reported, such
as catecholamine secreting tumours, head
trauma, neurosurgical procedures, carotid
endarterectomy and intracranial hypoten-
sion.
2, 8, 16, 18
The syndrome may also be
associated with other extra or intracranial
arterial lesions such as cervical artery dissec-
tion, especially postpartum, unruptured intra-
cranial aneurysm, and arterial dysplasia.
3, 16, 19
The mechanism of the link between these
arterial abnormalities and the vasospastic
process is unknown.
It is important to emphasise that the
headaches are secondary headaches, sympto-
matic of the vascular disorder; they have
nothing to do with migraine which is a
primary headache without any underlying
causal lesion.
1
A history of migraine is found
in only 16–20% of reversible cerebral vaso-
constriction syndrome cases, no different
from the prevalence of migraine in the
general population.
3, 14
Overlap with the posterior
reversible encephalopathy
syndrome
The reversible cerebral vasoconstriction syn-
drome may complicate severe conditions such
as intravenous immunoglobulin therapy in
Guillain–Barre´ syndrome, immunosuppression
for transplantation or septic shock. In these
complex cases it is almost always associated
with a neurotoxic state called the ‘‘posterior
reversible encephalopathy syndrome’’ or
PRES. This clinicoradiological syndrome has
similar clinical features to severe reversible
cerebral vasoconstriction syndrome (acute
headache, confusion, seizures, cortical blind-
ness) but a characteristic MR imaging pattern,
better visualised on FLAIR than on T2
sequences.
20
There is bilateral symmetrical
hemispheric junctional/boundary zone high
signal affecting the cortex, and subcortical
and deep white matter to varying degrees.
Lesions affect mainly parietal/occipital
regions (98%) but also the superior frontal
sulcus, temporal–occipital junction and may
also be seen in the cerebellum, basal ganglia,
brainstem and deep white matter.
21, 22
This
vasogenic oedema is usually totally reversible
in a few days. However, infarction or tissue
injury with cytotoxic oedema (leading to focal
areas of restricted MR diffusion) may occur
in areas of severe hypoperfusion.
21, 23
Haemorrhage (focal haematoma or subarach-
noid blood) is seen in about 15% of cases.
21
The posterior reversible encephalopathy
syndrome was initially described in associa-
tion with eclampsia or during ciclosporin
treatment after transplantation, always in the
setting of severe hypertension. But it is now
recognised as a complication of many other
conditions, including pre-eclampsia/eclamp-
sia, immunosuppression after allogenic bone
marrow or organ transplantation, autoim-
mune disease, high dose chemotherapy and
septic shock.
21, 24
Like the reversible cerebral vasoconstriction
syndrome, the exact pathophysiology of the
posterior reversible encephalopathy syndrome
is unknown, and two hypotheses are debated.
25
The most popular is that severe arterial
hypertension leads to a failure of cerebral
autoregulation with subsequent hyperperfu-
sion and vasogenic oedema. In the emerging
second hypothesis, T cell and/or endothelial cell
activation may trigger cerebral vasoconstriction
leading to hypoperfusion with subsequent
brain ischaemia and vasogenic oedema.
Whatever the pathophysiology, numerous
recent studies have shown that:
Nreversible cerebral vasoconstriction is a
frequent if not a constant feature of the
posterior reversible encephalopathy syn-
drome
N20–30% of cases are normotensive
Nnormotensive cases have vasogenic
oedema that is more extensive than
hypertensive cases which suggests that
hypertension may sometimes be a reac-
tion to the increase in cerebral blood flow
in some cases.
21, 23–26
Besides the association of reversible cere-
bral vasoconstriction syndrome and the
posterior reversible encephalopathy syndrome
in the setting of severe conditions, it is
important to appreciate that about 10% of
the former cases are associated with the
The headaches are
secondary
headaches,
symptomatic of the
vascular disorder;
they have nothing
to do with migraine
258 Practical Neurology
10.1136/jnnp.2009.187856

posterior reversible encephalopathy syn-
drome, regardless of the cause: idiopathic,
secondary to a vasoactive substance or to the
postpartum state, or associated with arterial
dissection.
3, 16
SYMPTOMS AND SIGNS
Headache
Headache is often the only symptom, as in
75% of our French series.
3
It is severe in most
patients and is often of the thunderclap
type—very sudden, peaking in less than 1 min
and very intense.
3, 6, 13, 14
Multiple thunderclap
headaches recurring every day or so over 1–
4 weeks are almost pathognomonic.
2, 3, 6, 14
The headache is typically bilateral, with a
posterior onset rather than diffuse, of severe
to very severe intensity, sometimes excruciat-
ing, with agitation, shouting and yelling,
often associated with nausea, vomiting,
photophobia and phonophobia. Migraineurs
clearly identify the thunderclap headaches as
different from their usual headaches. Severe
pain usually lasts 1–3 h (but ranges from a
few minutes to several days) and 50–75% of
patients describe a permanent mild back-
ground headache between thunderclap
attacks. About 80% of patients report at
least one trigger factor: sexual activity,
straining, emotion, physical effort, coughing,
sneezing, urinating without effort, bathing or
showering and sudden head move-
ment.
2, 3, 6, 14
In some patients, all their
thunderclap headaches are triggered by one
or several of these factors while in others
some thunderclap headaches occur at rest,
and some after a trigger. In our experience
in an emergency headache centre, patients
presenting with recurrent sexual thunderclap
headaches over a few days almost always
have reversible cerebral vasoconstriction
syndrome.
Some patients have a single thunderclap
headache. Some patients describe acute
headache attacks awaking them from
sleep, a situation that does not allow
them to be sure of the thunderclap onset.
Rarely, the headache is more progressive
and moderate. In the presence of lateral or
posterior neck pain, it is important to
carefully look for carotid or vertebral
artery dissection.
3, 19
Focal deficits and seizures
The frequency of other neurological signs and
symptoms depends on how the patients are
recruited into the studies and varies from 9%
to 63%, and for seizures from 0% to
21%.
3, 6, 13, 14
Indeed, it is the presence of
such features that usually leads to extensive
investigations which, by contrast, are fre-
quently not performed when the patient has
isolated headaches (even though for a
thunderclap headache a normal CT scan
should be followed by a lumbar puncture to
look for blood in the CSF followed often by
imaging of the cervical and cerebral arteries
and the intracranial veins).
Deficits and seizures are of many types.
Some transient focal deficits have a sudden
onset like transient ischaemic attacks, while
others begin progressively and successively
over a few minutes, with positive visual and/
or sensory symptoms mimicking migrainous
auras. Persistent focal deficits are usually due
to a haematoma or infarction. Impairment of
consciousness is infrequent and usually mild,
but coma may occur in rare severe cases with
multiple strokes.
General examination
The general physical examination is usually
normal, except in complex conditions asso-
ciated with the syndrome and the posterior
reversible encephalopathy syndrome in the
setting of eclampsia, septic shock, immuno-
suppression, etc. About 25–30% of patients
have blood pressure surges during the
thunderclap headaches and some patients
also have a facial flush.
INVESTIGATIONS
Brain CT and MRI
Non-contrast CT brain scan is usually normal
while the more sensitive MRI was abnormal in
about one-third of patients in the prospective
series.
2, 3, 14
In our patients with purely the
cephalalgic reversible cerebral vasoconstric-
tion syndrome, MRI showed a cortical sub-
arachnoid haemorrhage (SAH) in 20% and the
appearance of posterior reversible encephalo-
pathy in 10%; and in patients that presented
with a persistent focal deficit, MRI showed an
infarct or haematoma in 100%. In our 67
patients, the most frequent abnormality was
a small localised cortical SAH (22%), unilateral
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or bilateral, visible as high signal on FLAIR
in some sulci near the convexity
(fig 1).
3, 4, 13, 16, 27–29
Focal intracerebral hae-
morrhage occurred in 6% of our 67 cases.
3
This may be single or multiple, cortical or deep
and of variable volume (fig 2).
3, 5, 30
Subdural
haemorrhage has also been reported.
30
There
may be more than one type of haemorrhage
in any one patient. Infarction is rare; 4% in
our series.
3
The infarcts may be single or
multiple and often have a boundary zone
distribution (fig 3).
2
In 10% of patients,
symmetrical high signal on FLAIR is consistent
with the posterior reversible encephalopathy
syndrome (fig 4).
3
Finally, cervical FAT/SAT
sequences are very useful to search for any
associated cervical artery dissection.
Cerebral angiography
Angiography shows segmental narrowing and
dilatation (string of beads) of one or more
cerebral arteries (fig 5).
2, 31
Non-invasive angio-
graphy (MRA or CTA) was only 80% sensitive in
our series compared with the gold standard of
catheter angiography which is by definition
100% sensitive (because it defines the syn-
drome), although nowadays rarely necessary
(fig 6).
3
If another condition or another lesion is
very unlikely, and if the initial MRA/CTA is
definitely normal, and if there is no cortical SAH
and no stroke on MRI, we do not perform a
catheter angiogram. But depending on the
clinical state of the patient, we may repeat
transcranial Doppler ultrasound (see below)
with or without repeat MRA/CTA, or we simply
follow-up. Of course, in these patients,
no definite diagnosis is possible. The first
angiogram, whatever its type, may be normal
if performed very early, within 4–5 days of
onset of symptoms; therefore, if the first MRA
or CTA is normal, a second angiogram a few
days later may be diagnostic.
3
Calibre irregularities may affect the anterior
as well as the posterior cerebral circulation,
and are mostly bilateral and diffuse; large
arteries such as the basilar or the carotid
siphon may also be involved.
10
The narrowings
are not fixed, and a repeat angiogram after a
few days may show the resolution of some
with new zones of constriction often involving
more proximal vessels.
The syndrome may be associated with single
or multiple unruptured cerebral aneurysms
(6% in our French series which is not that
much more frequent than in the general
middle aged population, but these patients
had no red blood cells in the CSF and no
extravasation of contrast on catheter angio-
graphy), arterial dysplasia, and vertebral or
carotid dissection.
3, 16
The association with
dissection seems more frequent in females,
particularly postpartum.
3, 19
Ultrasound
Cervical ultrasound examination is usually
normal except in cases associated with
arterial dissection. Transcranial Doppler on
the other hand is very useful for monitoring
the temporal evolution of cerebral vasocon-
striction. In the prospective Taiwanese study
of 32 patients, the maximal mean flow
velocity in the middle cerebral artery exceeded
80 cm/s in 81% of patients and 120 cm/s in
47%, but never exceeded 200 cm/s.
6
Sequential studies are more sensitive than a
single investigation because velocities may be
normal during the first few days, then begin
to increase and reach a peak at the end of the
third week after headache onset.
3, 6
Transcranial Doppler is also useful to monitor
the vasospam but may not be sufficient to
reliably assess reversibility which still requires
a repeat angiogram. Moreover, some patients
still have raised velocities at the end of the
third month, even when their MRA has
returned to normal.
6
Cerebrospinal fluid
There are mild abnormalities in more than
half of the patients with an excess of white
Figure 1
Cortical subarachnoid haemorrhage in
reversible cerebral vasoconstriction
syndrome. (A) CT brain scan showing a
small right frontal haemorrhage. (B) In
another patient with a normal CT scan,
MRI (FLAIR) shows bilateral cortical
subarachnoid haemorrhage with high
signal in several sulci.
260 Practical Neurology
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blood cells (5–35/mm
3
) and red blood cells
(with or without visible subarachnoid blood
on MRI) and increased protein levels up to
1 g/l.
2, 3
If the lymphocytic reaction exceeds
10 cells/mm
3
, it is better to repeat the lumbar
puncture after a few weeks to make sure it is
normal and exclude chronic meningitis.
Other investigations
Blood tests are usually normal but may show
a moderate and transient inflammatory
response, notably in patients with orophar-
yngeal infections who took nasal deconge-
stants. Urine toxicology can be useful
(cannabis, cocaine, amphetamines, ecstasy).
If there are blood pressure surges during the
headache phase, urinary amines have to be
tested for pheochromocytoma.
TEMPORAL
CLINICORADIOLOGICAL COURSE
One of the main characteristics of reversible
cerebral vasoconstriction syndrome is the
temporal pattern of the clinical features and
the associated arterial abnormalities (table 3).
3
The first symptom is usually a thunderclap
headache that recurs during the first week,
with the last attack at a mean of 7–8 days
after onset. Mild background headache may
then persist in about 75% of patients, and
finally all significant headaches have gone by
about 3 weeks.
3, 6
Any intracranial haemor-
rhage and posterior reversible encephal-
opathy are early complications during the
first week while ischaemic complications
(transient ischaemic attacks and infarction)
occur later, at the end of the second week,
sometimes when the headaches have
improved or even resolved.
3, 6, 14
Moreover, as already stressed, vasocon-
striction may not be disclosed by early
angiography but found only later on repeat
investigation. Maximal intracranial flow velo-
cities are reached at a mean of 22 days after
onset; these velocities are thus maximal when
the headache has disappeared.
6
The temporal
course of the clinical and radiological features
suggests a dynamic process starting in distal
arteries not visualised on angiography, which
progresses towards moderate to large calibre
arteries.
DIAGNOSIS
The diagnosis should be suspected in all
patients with thunderclap headache, with or
without other neurological symptoms, after
the exclusion of all other causes (table 4).
1, 32
With the current diagnostic criteria, it is
impossible to make the diagnosis in the
Figure 2
CT showing intracerebral haemorrhage
in the reversible cerebral
vasoconstriction syndrome which may
be single (A, C, D) or multiple (B), lobar
(A, B, D) or deep (C), isolated or
associated with cortical subarachnoid
haemorrhage (B, right frontal cortical
subarachnoid haemorrhage, arrows) or
with an acute subdural haemorrhage
(D, occipital subdural blood, arrow).
Figure 3
Infarction in reversible cerebral
vasoconstriction syndrome: MRI (FLAIR)
3 months after the acute phase
showing the sequelae of bilateral
occipital and left temporoparietal
infarcts.
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www.practical-neurology.com

absence of headache. However, reversible
cerebral vasoconstriction syndrome without
headache or with very minimal headache
does probably exist. We had a young women
with multiple infarcts and minimal headache,
smoking cannabis, with a characteristic MRA
and transcranial Doppler which were both
normal again at 2 months, and no other
cause to better explain her illness.
As already stressed, recurrent thunderclap
headaches over a few days immediately
suggests the syndrome as does non-aneur-
ysmal subarachnoid haemorrhage and/or
cryptogenic stroke, notably when the patient
has severe headache as well.
3, 28
Appropriate
investigations, including transcranial Doppler,
CTA, MRA or eventually catheter angiography
should be performed to demonstrate the typical
angiographic pattern. The definitive diagnosis
can however only be confirmed when the
reversibility of the arterial abnormalities is
assessed at 12 weeks from onset although
complete resolution may be slower in some
patients.
2
Indeed, in the Taiwanese series of 32
patients, although two-thirds had complete
normalisation of their vessels on MRA at
3 months, only marked improvement was
noted in the rest.
6
DIFFERENTIAL DIAGNOSIS
Thunderclap headache revealing
subarachnoid haemorrhage
Every thunderclap headache must be con-
sidered symptomatic and requires immediate
investigation which will reveal an underlying
cause in half of the patients, mainly a
vascular disorder (table 4).
32, 33
The most
important cause is SAH. Therefore, a non-
contrast CT scan, followed by CSF analysis for
blood products if the scan is normal, is
mandatory in all patients. Aneurysmal rupture
is the most frequent cause of SAH (85%)
while other less frequent causes include
reversible cerebral vasoconstriction syndrome
itself which of course can be confusing.
3, 28
Figure 4
Posterior reversible encephalopathy
syndrome during reversible cerebral
vasoconstriction syndrome: MR FLAIR
high signal is mainly symmetrical and
may be confluent, predominating in the
occipital region (A, a postpartum case)
or patchy and moderate (C, an
idiopathic case) with resolution in both
patients on MRI at 1 month (B, D).
Diagnostic criteria for reversible cerebral vasoconstriction syndrome
(adapted from the International Headache Society diagnostic criteria
for ‘‘acute reversible cerebral angiopathy’’ and the criteria proposed
in 2007 by Calabrese
et al
1, 2
)
lAcute and severe headache (often thunderclap headache) with or without focal
neurological deficits or seizures
lMonophasic course without new symptoms more than 1 month after clinical onset
lSegmental vasoconstriction of cerebral arteries demonstrated by angiography (MRA, CTA
or catheter)
lExclusion of subarachnoid haemorrhage due to a ruptured aneurysm
lNormal or near normal CSF (protein ,1 g/l, white cells ,15/mm
3
, normal glucose)
lComplete or marked normalisation of arteries demonstrated by a repeat angiogram (MRA,
CTA or catheter) after 12 weeks, although they may be normal earlier
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However, several features help to distinguish
one from the other.
2–4, 29
The crucial point is
that cortical SAH due to reversible cerebral
vasoconstriction syndromes does not corre-
late with the site and severity of vasospasm in
contrast with aneurysmal SAH which does
correlate with the site and severity of
vasospasm. Indeed, SAH due to reversible
cerebral vasoconstriction syndrome is typi-
cally localised, overlying the lateral or super-
ior cortical surface, with only a minimal or
moderate amount of blood, while the vaso-
constriction is widespread and multifocal,
affecting medium and large arteries remote
from the site of bleeding. Moreover, the
typical angiographic pattern of reversible
cerebral vasoconstriction syndrome includes,
in addition to the multifocal vasoconstriction,
multifocal segmental dilatations that are
easily seen and sometimes large, producing
the characteristic ‘‘string of beads’’ or
‘‘sausage-string’’ appearance. By contrast,
aneurysmal haemorrhage tends to be more
obvious near the ruptured aneurysm where it
directly triggers the vasospasm, which is thus
not multifocal but affects only one or two
medium sized arteries close to the site of
bleeding.
Other causes of thunderclap
headache
Besides SAH, thunderclap headache may be
the presenting symptom of several other
vascular and non-vascular disorders.
32, 33
NOther intracranial haemorrhages, notably
cerebellar or intraventricular, are respon-
sible for 5–10% of thunderclap head-
aches, and the diagnosis is easily made by
CT scan.
NRarely infarcts, notably cerebellar infarcts,
may present with an isolated thunderclap
headache with a normal CT scan within
the first few hours, MRI (diffusion
sequences) being much more sensitive.
Some cerebellar infarcts present with
‘‘pseudo SAH’’ without even vertigo, and
it may be difficult to examine patients for
gait ataxia who are vomiting and have a
very severe headache.
NSeveral other vascular disorders may
present with isolated thunderclap head-
ache: cervical and intracranial arterial
dissection, intracranial venous thrombo-
sis, giant cell arteritis, pituitary apoplexy
and some symptomatic but as yet
unruptured aneurysms (although bleed-
ing may be visible within the wall on
MRI). A number of these causes have a
normal CT brain scan and CSF, making it
mandatory to perform brain MRI with
cervical and cerebral angiography and
venography (table 4).
Figure 5
Catheter angiography in the reversible
cerebral vasoconstriction syndrome:
multiple segmental narrowings and
dilatations affecting medium sized
arteries (A, B) and/or large sized arteries
(B, C), from the anterior (A, C) or
vertebrobasilar circulation (B).
Figure 6
MR angiography in the reversible
cerebral vasoconstriction syndrome
performed 8 days after headache onset:
multiple narrowings (arrows) of the
right middle cerebral artery and both
posterior cerebral arteries, with
segmental dilatation of the left middle
cerebral artery (large arrow) (A).
Resolution of abnormalities at
3 months (B).
263Ducros, Bousser
www.practical-neurology.com

NFinally, an isolated thunderclap headache
may be the presentation of several non-
vascular disorders including acute sinu-
sitis, meningitis or meningoencephalitis,
acute tumoral or non-tumoral intracra-
nial hypertension, and CSF hypoten-
sion.
32, 33
The problem of primary cerebral
angiitis
The rare severe forms of reversible cerebral
vasoconstriction syndrome raise the possibi-
lity of cerebral angiitis, notably primary
angiitis of the CNS,
2, 12, 13, 34, 35
when it is
crucial to start steroids and immunosuppres-
sants as early as possible. On the other hand,
in reversible cerebral vasoconstriction syn-
drome it is important not to expose the
patient to the risks of a brain biopsy and
prolonged immunosuppression. Of course, in
the acute phase it may be impossible to
distinguish the two conditions on the basis of
angiography (see below) but there are some
distinguishing features:
NClinically, reversible cerebral vasocon-
striction syndrome has an acute onset
followed by a monophasic course usually
without any new complications after
4 weeks
3
; this can only be a retrospective
criterion.
NOnset in the postpartum phase or after
exposure to vasoactive substances is very
suggestive of reversible cerebral vasocon-
striction syndrome.
NIn primary angiitis of the CNS, the onset
is more insidious, and the headache is not
of the thunderclap type, but rather
subacute and progressive, then accom-
panied by transient deficits, and even-
tually multiple infarcts.
NMRI is often normal in reversible cerebral
vasoconstriction syndrome (70%) but is
abnormal in most cases of primary
angiitis of the CNS (90%) showing small,
multiple, deep or superficial infarcts of
different ages, with or without associated
white matter abnormalities.
NThe CSF is markedly abnormal in most
cases of primary angiitis of the CNS
(.95%) showing an inflammatory reac-
tion, while it is normal (40–80%) or
shows only mild abnormalities in rever-
sible cerebral vasoconstriction syndrome.
NCatheter angiography is frequently nor-
mal in primary angiitis of the CNS while it
is by definition always abnormal in
reversible cerebral vasoconstriction syn-
drome. Some aspects are suggestive of
angiitis and are not observed in reversible
cerebral vasoconstriction syndromes: irre-
gular and asymmetrical arterial stenoses
or multiple occlusions.
2, 34
If there is persistent uncertainty it may be
best to wait a few days; reversible cerebral
vasoconstriction syndrome should stabilise
and improve quickly with regression of the
vasoconstriction while any arterial irregula-
rities in primary angiitis of the CNS do not
improve so fast. Treatment with immunosup-
pressants should be reserved for patients with
biopsy proven vasculitis (a few patients with
reversible cerebral vasoconstriction syndrome
and persisting diagnostic uncertainty have
had to have a brain biopsy but this did not
show vasculitis).
5, 13, 36, 37
PROGNOSIS
The eventual prognosis is determined by any
stroke which occurred in 6–9% of cases in the
prospective series.
3, 6, 14
Higher percentages
have been reported in retrospective series and
literature reviews
2, 9, 13
but are probably an
overestimate because of publication bias,
recruitment of severe cases in stroke units,
and because cases with headache only might
have been overlooked. However, a few fatal
cases have been published, notably postpar-
tum.
9
During the months following the acute
phase, one-third of the patients report
TABLE 3 Mean delay from headache onset to the other features of
reversible cerebral vasoconstriction syndrome (adapted from Ducros
et
al
3
)
Delay from headache onset to
No of days
(mean (SD) [range])
Diagnosis of cerebral haematoma 1.7 (2) [0–4]
Diagnosis of subarachnoid haemorrhage 5 (5) [0–20]
First seizure 3 (1.4) [2–4]
Posterior reversible encephalopathy syndrome 4 (1.9) [1–6]
Last recurrent thunderclap headache 7.4 (5.6) [0–28]
Transient neurological deficit 11.6 (4.9) [0–23]
Symptoms of cerebral infarction 13.5 (2.1) [12–15]
Diagnosis of cerebral infarction* 12 (3) [9–15]
*Diagnosis of infarction may precede symptoms of infarction because an
asymptomatic infarct was found in one patient who had a repeat MRI at day 9.
264 Practical Neurology
10.1136/jnnp.2009.187856

persistent mild headaches often with fatigue.
Some patients develop depression. Relapses
do occur but without long term follow-up
studies the rate is unknown.
27
In our series of 67 patients followed for a
mean of 3.2 years (range 26–62 months), we
have so far not observed any angiographically
proven recurrence. However, 3 years after a
severe attack complicated by an occipital
haemorrhage, one patient had a recurrence of
multiple thunderclap headaches over 1 week,
after smoking cannabis. He did not seek
medical advice and it was thus impossible to
make a firm diagnosis. In another patient not
included in our first case series, who had a
proven syndrome, multiple sexual thunderclap
headaches recurred 6 months later, 2 days
after starting a selective serotonin reuptake
inhibitor. He did not seek medical attention
but remembered our recommendation,
stopped the antidepressant and had no more
thunderclap headaches.
TREATMENT
Symptomatic treatment includes analgesics
(sometimes even morphine), antiepileptic
drugs for any seizures, monitoring blood
pressure, hospitalisation in an intensive care
unit in severe cases, and rest for all other
patients for a few days to a few weeks
according to the severity of their headaches.
Patients having triggered thunderclap head-
aches should be advised to avoid the trigger,
such as sexual activity and any other physical
TABLE 4 Investigation of a thunderclap headache
Investigation Indications
Causes that may be detected by this
investigation
Non-contrast CT brain scan
(with visualisation of sinuses
if symptoms suggest acute
sinusitis)
All thunderclap headaches as first
investigation
Subarachnoid haemorrhage (90% within the
first 24 h), intracerebral haematoma,
intraventricular haemorrhage, subdural
haematoma (rare cause of thunderclap
headache), some infarcts particularly in the
cerebellum, hydrocephalus, tumours, acute
sinusitis
CSF All CT normal thunderclap headaches Subarachnoid haemorrhage, meningitis
ESR and C reactive protein Age .60 years Giant cell arteritis (very rare cause of
thunderclap headache)
MRI (diffusion, FLAIR,
gradient-echo, sagittal T1, T1
with gadolinium, cervical
FAT/SAT), MRA and MRV
All thunderclap headaches after
normal CT and normal or near normal
CSF.
Intracranial venous thrombosis, dissection of
cervical arteries (extra or intracranial, carotid or
vertebral), pituitary apoplexy, reversible cerebral
vasoconstriction syndrome, unruptured but
symptomatic aneurysm (eg, third cranial nerve
palsy).
Fewer sequences if cervical and
transcranial Doppler shows abnormalities
suggesting dissection or an increase in
intracranial flow velocities suggesting
reversible cerebral vasoconstriction
syndrome
Acute infarct less than 3 h not visualised on CT
scan, CSF hypotension, and better visualisation
of all abnormalities previously seen on CT.
Catheter angiography Gold standard for subarachnoid
haemorrhage. Particularly if increasing
headaches, and occurrence/increase of
focal deficits, unexplained after
CT scan, CSF analysis and complete
MRI/MRA/MRV
Ruptured aneurysm in 85% of patients with
subarachnoid haemorrhage, intracranial venous
thrombosis, dissection (cervical, intracranial),
reversible cerebral vasoconstriction syndrome,
differential diagnosis of cerebral arteritis,
unruptured but symptomatic aneurysm (third
nerve palsy)
ESR, erythrocyte sedimentation rate; MRA, MR angiography; MRV, MR venography.
265Ducros, Bousser
www.practical-neurology.com

effort for 1 or 2 weeks. Finally, it is important
to search for all possible vasoactive sub-
stances (repeated questioning is sometimes
necessary), stop them and firmly suggest to
the patient that he or she avoid these kinds of
drugs and medications in the future.
In the absence of any randomised trial,
empirical treatment is based on nimodipine,
started when the typical angiographic pattern
is demonstrated.
2, 14, 38, 39
This may be given
intravenously for a few days, in the same
doses as for aneurysmal SAH (1–2 mg/kg/h
with monitoring of blood pressure). More
often, nimodipine is given orally, the dose
varying from 60 mg every 4–8 h, for 4–
12 weeks. The effect this has on the various
symptoms and complications is unclear.
Thunderclap headaches seem to stop within
48–72 h but transient ischaemic attacks or
even infarction have been reported in patients
treated for several days.
3, 38
Moreover, in our
experience, some patients have an increase in
their background headaches on nimodipine,
and rarely a thunderclap headache triggered
by a nimodipine tablet. Finally, nimodipine
should be avoided in patients with low blood
pressure and in patients with an associated
dissection with haemodynamic compromise.
Steroids are not recommended. In a severe
case without improvement on nimodipine,
Canadian authors have tried intra-arterial
milrinone with a good outcome.
40
ACKNOWLEDGEMENTS
This article was reviewed by Keith Muir,
Glasgow, UK.
Competing interests: None.
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