Reversible Cerebral Vasoconstriction Syn

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REVIEWPract Neurol 2009; 9: 256267

Reversible cerebralvasoconstriction syndromeAnne Ducros,1 Marie-Germaine Bousser2

1Consultant Neurologist,

Emergency Headache Centre,

Assistance Publique des Hopitaux

de Paris, Lariboisiere Hospital, Head

and Neck Centre, Paris, France

2Professor of Neurology, Neurology

Department, Assistance Publique

des Hopitaux de Paris, Lariboisiere

Hospital, Head and Neck Centre,

Paris, France

Correspondence to:

Dr Anne Ducros

Consultant Neurologist, Urgences

Cephalees, Hopital Lariboisiere,

2 rue Ambroise Pare,

75475 Paris Cedex 10, France;[email protected]

Reversible cerebral vasoconstriction syndrome is characterised by severeheadaches with or without seizures and focal neurological deficits, and

constriction of cerebral arteries which resolves spontaneously in 13 months.It affects females slightly more than males, and mean age of onset is around45 years. Approximately 60% of cases are secondary, mainly postpartum andafter exposure to vasoactive substances. The major complications are localisedcortical subarachnoid haemorrhage (22%) and parenchymal ischaemic orhaemorrhagic strokes (7%) which may leave permanent sequelae. Diagnosisrequires the demonstration of the string of beads appearance of cerebralarteries on angiography, with complete or almost complete resolution onrepeat angiography 12 weeks after onset. Nimodipine seems to reducethunderclap headaches within 48 h but has no definite effect on thehaemorrhagic 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 13

months.1, 2 The most common clinical feature

is a severe acute headache, often thunderclap

in naturea sudden excruciating headache that

peaks in less than 1 min, like a clap of

thundermimicking that of a ruptured aneur-

ysm. The major complications are localised

cortical subarachnoid haemorrhages (2025%)

and ischaemic or haemorrhagic strokes

(510%).36 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, 79

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 manydifferent 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 lesion10, 14).

However, during the past 510 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 UNDERDIAGNOSEDCONDITION

Reversible cerebral vasoconstriction syn-drome has been reported in patients aged

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1370 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 than10 patients have been published.

N A retrospective American series of 16patients hospitalised for suspected CNSangiitis, of whom 10 had repeat angio-graphy to assess reversibility of vasocon-striction.13

N A prospective Taiwanese series of 56patients with recurrent thunderclapheadaches of whom 22 had proven initialvasoconstriction, then a series of 32patients (including 12 from the first

series) with the proven syndrome.6, 14

N Our prospective French series of 67 cases,seen in a single institution between 2004and 2007, who all had vasoconstrictionand repeat angiography showing itsresolution.3

MECHANISMS AND CAUSESAlthough 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 2560% 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 , 1 3, 1 6

Vasoactive substancesThe 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 , 1 6, 1 7 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 toother drugs, such as cannabis and/or ecstasy/

and or cocaine.3

PostpartumPostpartum reversible cerebral vasoconstric-

tion syndrome starts in two-thirds of cases

TABLE 1 Various appellations of the reversible cerebral vasoconstrictionsyndrome

l Isolated benign cerebral vasculitis or angiopathyl CallFleming syndromel CNS pseudovasculitisl Benign angiopathy of the central nervous systeml Postpartum angiopathyl Migrainous vasospasml Migraine angiitisl Idiopathic thunderclap headache with reversible vasospaml Drug induced cerebral vasculopathyl Fatal vasospasm in migrainous infarction

TABLE 2 Causes of reversible cerebral vasoconstriction syndrome andassociated conditions

Postpartuml With or without exposure to vasoactive substances, eclampsia/pre-

eclampsiaExposure to vasoactive substancesl Cannabis, cocaine, ecstasy, amphetamines, LSD, binge drinkingl Selective serotonin reuptake inhibitorsl Nasal decongestantsphenylpropanolamine, pseudoephedrine, ephedrinel Ergotamine tartratel Metherginel Bromocriptine, lisuridel Triptansl

Isometheptinel Nicotine patchesl GinsengCatecholamine secreting tumoursl Phaeochromocytoma, bronchial carcinoid tumour, glomus tumoursExposure to immunosuppressants or blood productsl Tacrolimus (FK-506), cyclophosphamide, erythropoietin, intravenous

immunoglobulin, red blood cell transfusion, interferon aMiscellaneousl Hypercalcaemia, porphyria, head trauma, subdural spinal haematoma,

carotid endarterectomy, neurosurgical procedures, CSF hypotensionExtra or intracranial large artery disordersl Cervical dissection, unruptured intracranial aneurysm, dysplasia

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during the first week after delivery, usually

after a normal pregnancy.8, 9, 16 In 5070% 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 causesMany 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 thesearterial 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 1620% of reversible cerebral vaso-

constriction syndrome cases, no different

from the prevalence of migraine in the

general population.3, 14

Overlap with the posteriorreversible encephalopathysyndromeThe reversible cerebral vasoconstriction syn-

drome may complicate severe conditions such

as intravenous immunoglobulin therapy in

GuillainBarre 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, temporaloccipital 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 focalareas 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 emergingsecond 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:

N reversible cerebral vasoconstriction is afrequent if not a constant feature of theposterior reversible encephalopathy syn-drome

N 2030% of cases are normotensiveN normotensive cases have vasogenic

oedema that is more extensive thanhypertensive cases which suggests thathypertension may sometimes be a reac-tion to the increase in cerebral blood flowin some cases.21, 2326

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% ofthe former cases are associated with the

The headaches aresecondaryheadaches,symptomatic of the

vascular disorder;they have nothingto do with migraine

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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 SIGNSHeadacheHeadache 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

typevery 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 , 1 4

The headache is typically bilateral, with a

posterior onset rather than diffuse, of severeto 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 13 h (but ranges from a

few minutes to several days) and 5075% 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 , 1 4 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 alwayshave 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 vertebralartery dissection.3, 19

Focal deficits and seizuresThe 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 extensiveinvestigations 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 examinationThe 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 2530% of patients

have blood pressure surges during the

thunderclap headaches and some patients

also have a facial flush.

INVESTIGATIONSBrain CT and MRINon-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 wasa 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, 2729 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 , 3 0 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 angiographyAngiography 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 45 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

UltrasoundCervical 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 thethird 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 thanhalf of the patients with an excess of white

Figure 1

Cortical subarachnoid haemorrhage inreversible 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.

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blood cells (535/mm3) 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/mm3, it is better to repeat the lumbar

puncture after a few weeks to make sure it is

normal and exclude chronic meningitis.

Other investigationsBlood 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.

TEMPORALCLINICORADIOLOGICAL COURSEOne 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 78 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 , 1 4

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 calibrearteries.

DIAGNOSISThe diagnosis should be suspected in allpatients 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 temporoparietalinfarcts.

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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 DIAGNOSISThunderclap headache revealingsubarachnoid haemorrhageEvery 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 cerebralvasoconstriction 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 criteriafor acute reversible cerebral angiopathy and the criteria proposedin 2007 by Calabrese et al1, 2)

l Acute and severe headache (often thunderclap headache) with or without focalneurological deficits or seizures

l Monophasic course without new symptoms more than 1 month after clinical onsetl Segmental vasoconstriction of cerebral arteries demonstrated by angiography (MRA, CTA

or catheter)l Exclusion of subarachnoid haemorrhage due to a ruptured aneurysml Normal or near normal CSF (protein ,1 g/l, white cells ,15/mm3, normal glucose)l Complete 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.24, 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 ofvasospasm. 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 thunderclapheadacheBesides SAH, thunderclap headache may be

the presenting symptom of several other

vascular and non-vascular disorders.32, 33

N Other intracranial haemorrhages, notablycerebellar or intraventricular, are respon-sible for 510% of thunderclap head-aches, and the diagnosis is easily made byCT scan.

N Rarely infarcts, notably cerebellar infarcts,may present with an isolated thunderclapheadache with a normal CT scan withinthe first few hours, MRI (diffusionsequences) being much more sensitive.Some cerebellar infarcts present withpseudo SAH without even vertigo, andit may be difficult to examine patients forgait ataxia who are vomiting and have avery severe headache.

N Several other vascular disorders may

present with isolated thunderclap head-ache: cervical and intracranial arterialdissection, intracranial venous thrombo-sis, giant cell arteritis, pituitary apoplexyand some symptomatic but as yetunruptured aneurysms (although bleed-ing may be visible within the wall onMRI). A number of these causes have anormal CT brain scan and CSF, making itmandatory to perform brain MRI withcervical and cerebral angiography andvenography (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).

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N Finally, an isolated thunderclap headachemay 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

angiitisThe 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:

N Clinically, reversible cerebral vasocon-striction syndrome has an acute onsetfollowed by a monophasic course usuallywithout any new complications after4 weeks3; this can only be a retrospectivecriterion.

N Onset in the postpartum phase or afterexposure to vasoactive substances is very

suggestive of reversible cerebral vasocon-striction syndrome.

N In primary angiitis of the CNS, the onsetis more insidious, and the headache is notof the thunderclap type, but rathersubacute and progressive, then accom-panied by transient deficits, and even-tually multiple infarcts.

N MRI is often normal in reversible cerebralvasoconstriction syndrome (70%) but isabnormal in most cases of primaryangiitis of the CNS (90%) showing small,multiple, deep or superficial infarcts ofdifferent ages, with or without associatedwhite matter abnormalities.

N The CSF is markedly abnormal in mostcases of primary angiitis of the CNS(.95%) showing an inflammatory reac-tion, while it is normal (4080%) orshows only mild abnormalities in rever-sible cerebral vasoconstriction syndrome.

N Catheter angiography is frequently nor-mal in primary angiitis of the CNS while itis by definition always abnormal inreversible cerebral vasoconstriction syn-drome. Some aspects are suggestive ofangiitis and are not observed in reversiblecerebral vasoconstriction syndromes: irre-gular and asymmetrical arterial stenosesor multiple occlusions.2, 34

If there is persistent uncertainty it may be

best to wait a few days; reversible cerebral

vasoconstriction syndrome should stabiliseand 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

PROGNOSISThe eventual prognosis is determined by any

stroke which occurred in 69% of cases in the

prospective series.3 , 6 , 1 4 Higher percentages

have been reported in retrospective series and

literature reviews2 , 9 , 1 3 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 acutephase, one-third of the patients report

TABLE 3 Mean delay from headache onset to the other features ofreversible cerebral vasoconstriction syndrome (adapted from Ducros etal3)

Delay from headache onset to

No of days

(mean (SD) [range])Diagnosis of cerebral haematoma 1.7 (2) [04]Diagnosis of subarachnoid haemorrhage 5 (5) [020]First seizure 3 (1.4) [24]Posterior reversible encephalopathy syndrome 4 (1.9) [16]Last recurrent thunderclap headache 7.4 (5.6) [028]Transient neurological deficit 11.6 (4.9) [023]Symptoms of cerebral infarction 13.5 (2.1) [1215]Diagnosis of cerebral infarction* 12 (3) [915]

*Diagnosis of infarction may precede symptoms of infarction because anasymptomatic infarct was found in one patient who had a repeat MRI at day 9.

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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 amean of 3.2 years (range 2662 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 thunderclapheadaches 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.

TREATMENTSymptomatic 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 IndicationsCauses that may be detected by thisinvestigation

Non-contrast CT brain scan

(with visualisation of sinusesif symptoms suggest acutesinusitis)

All thunderclap headaches as first

investigation

Subarachnoid haemorrhage (90% within the

first 24 h), intracerebral haematoma,intraventricular haemorrhage, subduralhaematoma (rare cause of thunderclapheadache), some infarcts particularly in thecerebellum, hydrocephalus, tumours, acutesinusitis

CSF All CT normal thunderclap headaches Subarachnoid haemorrhage, meningitisESR and C reactive protein Age .60 years Giant cell arteritis (very rare cause of

thunderclap headache)MRI (diffusion, FLAIR,gradient-echo, sagittal T1, T1with gadolinium, cervical

FAT/SAT), MRA and MRV

All thunderclap headaches afternormal CT and normal or near normalCSF.

Intracranial venous thrombosis, dissection ofcervical arteries (extra or intracranial, carotid orvertebral), pituitary apoplexy, reversible cerebral

vasoconstriction syndrome, unruptured butsymptomatic aneurysm (eg, third cranial nervepalsy).

Fewer sequences if cervical andtranscranial Doppler shows abnormalitiessuggesting dissection or an increase inintracranial flow velocities suggestingreversible cerebral vasoconstrictionsyndrome

Acute infarct less than 3 h not visualised on CTscan, CSF hypotension, and better visualisationof all abnormalities previously seen on CT.

Catheter angiography Gold standard for subarachnoidhaemorrhage. Particularly if increasingheadaches, and occurrence/increase offocal deficits, unexplained after

CT scan, CSF analysis and completeMRI/MRA/MRV

Ruptured aneurysm in 85% of patients withsubarachnoid haemorrhage, intracranial venousthrombosis, dissection (cervical, intracranial),reversible cerebral vasoconstriction syndrome,

differential diagnosis of cerebral arteritis,unruptured but symptomatic aneurysm (thirdnerve palsy)

ESR, erythrocyte sedimentation rate; MRA, MR angiography; MRV, MR venography.

2Ducros, Bousser



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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 (12 mg/kg/h

with monitoring of blood pressure). More

often, nimodipine is given orally, the dosevarying from 60 mg every 48 h, for 4

12 weeks. The effect this has on the various

symptoms and complications is unclear.

Thunderclap headaches seem to stop within

4872 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, nimodipineshould 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

ACKNOWLEDGEMENTSThis article was reviewed by Keith Muir,

Glasgow, UK.

Competing interests: None.

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PRACTICE POINTS

l The reversible cerebral vasoconstriction syndrome is more frequent thanpreviously thought and affects patients of both genders, with a femalepreponderance.

l It is attributed to a transient disturbance in the control of cerebral vascular

tone leading to multifocal arterial constrictions and dilatations.l Some cases are spontaneous while others (60%) are secondary, mostly to

exposure to vasoactive substances and to the postpartum state.l The syndrome has a characteristic course; the onset is sudden followed by

a monophasic course, generally without new events after 1 month. Themain pattern is of recurrent thunderclap headaches.

l Cortical subarachnoid haemorrhage, intracerebral haemorrhage, seizuresand the reversible posterior encephalopathy syndrome are earlycomplications, occurring mainly within the first week.

l Ischaemic events, including transient ischaemic attacks and cerebralinfarction, occur later than any haemorrhagic strokes, mainly during thesecond week.

l

Diagnosis requires the demonstration of the characteristic string ofbeads on cerebral angiography, the definitive diagnosis being made whena later angiogram shows resolution or at least marked improvement of thearterial abnormalities after about 12 weeks.

l Nimodipine is the proposed treatment but in our experience does not seemvery effective; randomised trials are needed.

l Relapses do occur but are rare

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2Ducros, Bousser

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