An often unrecognized cause of thunderclap headache: reversible cerebral vasoconstriction syndrome
Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Abstract
Thunderclap headache (TCH) can have several causes of which subarachnoid hemorrhage (SAH) is most common and well known. A rare cause of TCH is the reversible cerebral vasoconstriction syndrome (RCVS) which is characterized by a reversible segmental vasoconstriction of the intracranial vessels. We describe two patients with TCH due to RCVS and the probable precipitating factor, namely, cannabis and an anti-migraine drug. In RCVS, cerebrospinal fluid examination is (near) normal, in contrast to SAH and (primary) cerebral vasculitis. Brain MRI may be normal or shows infarction. MRA can demonstrate vasoconstriction of the great arteries, but a normal MRA does not rule out the diagnosis. Caliber changes on cerebral angiography cannot adequately differentiate between RCVS and vasculitis. Calcium-channel antagonists may be a good therapy and repeated transcranial Doppler ultrasonography can be a reliable non-invasive investigation to monitor the effect of treatment and demonstrate reversibility of the vasoconstriction.
BRIEF REPORT
An often unrecognized cause of thunderclap headache: reversible
cerebral vasoconstriction syndrome
K. Koopman AE L. K. Teune AE M. ter Laan AE
M. Uyttenboogaart AE P. C. Vroomen AE J. De Keyser AE
G. J. Luijckx
Received: 23 June 2008 / Accepted: 31 August 2008 / Published online: 23 September 2008
O The Author(s) 2008. This article is published with open access at Springerlink.com
Abstract Thunderclap headache (TCH) can have several
causes of which subarachnoid hemorrhage (SAH) is most
common and well known. A rare cause of TCH is the
reversible cerebral vasoconstriction syndrome (RCVS)
which is characterized by a reversible segmental vaso-
constriction of the intracranial vessels. We describe two
patients with TCH due to RCVS and the probable precip-
itating factor, namely, cannabis and an anti-migraine drug.
In RCVS, cerebrospinal fluid examination is (near) normal,
in contrast to SAH and (primary) cerebral vasculitis. Brain
MRI may be normal or shows infarction. MRA can dem-
onstrate vasoconstriction of the great arteries, but a normal
MRA does not rule out the diagnosis. Caliber changes on
cerebral angiography cannot adequately differentiate
between RCVS and vasculitis. Calcium-channel antago-
nists may be a good therapy and repeated transcranial
Doppler ultrasonography can be a reliable non-invasive
investigation to monitor the effect of treatment and dem-
onstrate reversibility of the vasoconstriction.
Keywords Thunderclap headache
Reversible cerebral vasoconstriction syndrome
Vasospasm
Introduction
Thunderclap headache (TCH) is often associated with a
subarachnoid hemorrhage (SAH). However, TCH can also
be the first sign of several other neurological conditions,
some of which are less well known [1]. The term primary
TCH can be used when all other potential conditions have
been eliminated by diagnostic testing. A rare cause of TCH
is the reversible cerebral vasoconstriction syndrome
(RCVS) [2]. This syndrome is characterized by a reversible
segmental vasoconstriction of the intracranial blood vessels
[2-5]. It is important to recognize this syndrome and dis-
tinguish RCVS from other conditions such as primary
angiitis of the central nervous system (PACNS), to choose
proper treatment [3, 4, 6]. Here, we present two patients
with TCH due to RCVS and discuss the clinical features of
this often unrecognized syndrome.
Case 1
A 46-year-old man with a history of radical extirpated
melanoma was transferred to our hospital under the sus-
picion of cerebral vasculitis. One week before, he
presented with spontaneous acute severe headache, fol-
lowed a few days later by progressive confusion and a mild
left-sided hemiparesis. Magnetic imaging resonance (MRI)
of the brain showed ischemic lesions bilateral occipital and
right parietal. MR angiography (MRA) showed no abnor-
mality; however, on second review the examination was
without gadolinium and of poor quality and therefore not
reliable. Patient did not use any medication, smoked 20
cigarettes and 3-4 times cannabis a day. The admission
blood pressure was 184/89 and the following day 154/90.
On neurological examination, he appeared confused and
K. Koopman (&) L. K. Teune M. Uyttenboogaart
P. C. Vroomen J. De Keyser G. J. Luijckx
Department of Neurology, University Medical Center
Groningen, University of Groningen, Hanzeplein 1,
9700 RB Groningen, The Netherlands
e-mail: k.koopman@neuro.umcg.nl
M. ter Laan
Department of Neurosurgery, University Medical Center
Groningen, University of Groningen, Groningen,
The Netherlands
123
J Headache Pain (2008) 9:389-391
DOI 10.1007/s10194-008-0068-0
scored 15 of 30 items on the mini-mental state examina-
tion. There was a hemiparesis MRC grade 4 on the left
side. Ancillary laboratory investigations in serum (includ-
ing blood count, serum electrolytes, liver, renal and thyroid
function tests, erythrocyte sedimentation rate, C-reactive
protein level, antinuclear and antineutrophil cytoplasmic
antibody tests, complement C1q, C3 and C4, lupus anti-
coagulant, rheumatoid factor) and cerebrospinal fluid
(CSF) showed no abnormalities. Selective catheter cerebral
angiography showed multiple caliber changes in the
intracranial blood vessels (Fig. 1). Transcranial Doppler
ultrasonography (TCD) examination showed increased
intracranial blood flow velocities among others of medial
cerebral artery (154 cm/s), and anterior cerebral artery
(168 cm/s). Because of the acute presentation with TCH,
normal CSF examination and the findings on TCD the
diagnosis RCVS was established. Calcium-channel antag-
onist nimodipine 60 mg six times daily was started. Few
days after treatment was started, the clinical condition
improved. A follow-up TCD showed a normalization of
blood flow velocities (medial cerebral artery: 94 cm/s and
anterior cerebral artery: 90 cm/s). The follow-up MRI
showed reduction in size of the hyperintense lesions. The
patient was transferred to a rehabilitation center and dis-
charged home after 3 weeks under good clinical condition.
Case 2
A 48-year-old woman presented at the emergency depart-
ment with spontaneous acute severe headache. She had a
history of migraine, but did not recognize this type of
headache as her migraine headache. She frequently used
sumatriptan and 1 week before admission, because of
severe attacks, she had used sumatriptan daily with tem-
porally good response. On examination, the blood pressure
was 140/88 and neurological examination was normal. SAH
was ruled out by CT scan and CSF examination was com-
pletely normal. Following day, she became confused with
behavioral changes. Brain MRI/MRA revealed no abnor-
malities. TCD showed increased blood flow velocities over
the medial cerebral artery (109 cm/s) and anterior cerebral
artery (108 cm/s). Under the suspicion of RCVS, calcium
antagonist verapamil 120 mg twice daily was started.
Within a day, the patient improved clinically and TCD after
4 days showed normal blood flow velocities of medial
cerebral artery (80 cm/s) and anterior cerebral artery
(66 cm/s). She was discharged at home without any com-
plaints and was strongly advised not resume any triptans.
Discussion
These cases highlight the recognition of RCVS as a cause
of TCH. It is important to realize that TCH is a symptom
rather than a diagnosis and can be caused by several acute
(neurological) conditions as cerebral venous thrombosis,
ischemic stroke, dissection, acute hypertension, vasospasm
and infection [1].
The RCVS was first described by Call et al. in 1988 [2]
and is characterized by a reversible segmental vasocon-
striction of the intracranial vessels. It is most common in
women aged 20-50 years. The striking presenting feature
of RCVS is TCH, followed immediately, or after a symp-
tom free interval, by seizures, neurological deficits or
encephalopathy [2-5]. RCVS can occur spontaneously or
in association with pregnancy, migraine, sexual activity,
certain prescribed or illicit drugs (selective serotonin re-
uptake inhibitors, triptans, cannabis, cocaine and ecstasy)
[3-5, 7-10]. Concerning the patients in our case, the fre-
quent use of cannabis in the first patient and sumatriptan in
the second patient were probably the precipitating factors.
Fig. 1 Cerebral angiography:
multiple caliber changes in the
intracranial vessels
390 J Headache Pain (2008) 9:389-391
123
MRI findings in RCVS can be normal or showing
ischemic lesions, especially in posterior circulation and
watershed areas. CSF is normal in 80-90% of the patients,
as it was in our patients [3-6].
MR angiography can demonstrate vasoconstriction in
the proximal parts of the great cerebral arteries. However, a
normal MRA examination does not rule out the diagnosis.
In a series of 44 RCVS patients, 6 had a normal MRA
while on cerebral angiography there were signs of vaso-
constriction [7]. In the first patient MRA was inconclusive
but cerebral infarction was seen on MRI and cerebral
angiography showed multiple alterations. MRA in the
second patient did not show vasospasm; the reason might
be that this patient had only mild vasospasm.
Cerebral angiography can show multiple alterations of
the cerebral blood vessel caliber. These findings are often
associated with cerebral vasculitis or PACNS but these
patients present in general with gradually progressive
neurological symptoms, encephalopathy and CSF is
abnormal in 80-90% [1, 6, 11].
TCD is not specific for the initial diagnosis of RCVS,
but (repeated) TCD can be a reliable non-invasive inves-
tigation to monitor vasospasm. Normalization of cerebral
blood flow velocities is often seen within 12 weeks [5, 12].
In our patients there was also normalization of cerebral
blood flow velocities.
The exact pathophysiology underlying the reversible
vasoconstriction is unknown. The International Classifica-
tion of Headache Disorders-II classified RCVS as a
secondary headache disorder, in contrast to primary TCH.
Alternatively, Chen et al. suggested that primary TCH, or
TCH elicited by, e.g., physical stress and RCVS are dif-
ferent spectra of the same disorder. Their study showed
vasospasm in 39% of the patients with recurrent primary
TCH [13]. This suggests that RCVS may have a higher
incidence than reported earlier.
The sympathetic nervous system may play a role in the
pathogenesis of TCH. This is suggested by the fact that
TCH has been associated with factors elevating sympa-
thetic tone, such as adrenergics and physical stress [14].
Furthermore, proximal parts of the intracranial vessels are
strongly innervated by sympathetic afferents, which mod-
ulate vascular tone. Vasoconstriction in RCVS is most
common in these large- and medium-sized vessels [1, 4].
In RCVS, there is no established therapy. A few small
observational studies and case reports described a good
effect of calcium-channel antagonists in the treatment of
the vasospasm of intracranial vessels [3, 15]. In summary,
TCH is a symptom which can be caused by several (neu-
rological) conditions. A normal brain CT scan and CSF
examination can exclude a SAH but are not sufficient to
establish ``primary TCH''. A rare cause of TCH is RCVS.
The exact cause of RCVS is unknown but among others
associated with substance and medication use. Sometimes,
this syndrome can be difficult to distinguish from PACNS
on cerebral angiography and can be a pitfall. The acute
presentation with TCH and the normal CSF examination
are in favor of RCVS. Calcium-channel antagonists like
nimodipine may be a good therapy and repeated TCD can
be a reliable non-invasive investigation to monitor the
effect of treatment and demonstrate the reversibility.
Conflict of interest None.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
1. Schwedt TJ, Matharu MS, Dodick DW (2006) Thunderclap
headache. Lancet Neurol 5:621-631
2. Call GK, Fleming MC, Sealfon S et al (1988) Reversible cerebral
segmental vasoconstriction. Stroke 19:1159-1170
3. Bernstein RA (2006) Reversible cerebral vasoconstriction syn-
dromes. Curr treat Options Cardiovasc Med 8:229-234
4. Singhal AB (2004) Cerebral vasoconstriction syndromes. Top
Stroke Rehabil 11:1-6
5. Calabrese LH, Dodick DW, Schwedt TJ et al (2007) Narrative
review: reversible cerebral vasoconstriction syndromes. Ann
Intern Med 146:34-44
6. Koopman K, Uyttenboogaart M, Luijckx GJ et al (2007) Pitfalls
in the diagnosis of reversible cerebral vasoconstriction syndrome
and primary angiitis of the central nervous system. Eur J Neurol
14:1085-1087
7. Ducros A, Boukobza M, Porcher R et al (2007) The clinical and
radiological spectrum of reversible cerebral vasoconstriction
syndrome: a prospective series of 67 patients. Brain 130:3091-
3101
8. Noskin O, Jafarimojarrad E, Libman RB et al (2006) Diffuse
cerebral vasoconstriction (Call-Fleming syndrome) and stroke
associated with antidepressants. Neurology 67:159-160
9. Moussouttas M (2004) Cannabis use and cerebrovascular disease.
Neurologist 10:47-53
10. Valenca MM, Valenca LP, Bordini CA et al (2004) Cerebral
vasospasm and headache during sexual intercourse and mastur-
batory orgasms. Headache 44:244-248
11. Calabrese LH (1995) Vasculitis of the central nervous system.
Rheum Dis Clin North Am 21:1059-1076
12. Chen SP, Fuh JL, Chang FC et al (2008) Transcranial color
Doppler study for reversible cerebral vasoconstriction syndromes.
Ann Neurol 63:751-757
13. Chen SP, Fuh JL, Lirng JF et al (2006) Recurrent primary
thunderclap headache and benign CNS angiopathy: spectra of the
same disorder? Neurology 67:2164-2169
14. Lu SR, Liao YC, Fuh JL et al (2004) Nimodipine for treatment of
primary thunderclap headache. Neurology 62:1414-1416
15. Dodick DW (2003) Reversible segmental cerebral vasoconstric-
tion (Call-Fleming syndrome): the role of calcium antagonists.
Cephalalgia 23:163-165
J Headache Pain (2008) 9:389-391 391
123
Introduction
Thunderclap headache (TCH) is often associated with a subarachnoid hemorrhage (SAH). However, TCH can also be the first sign of several other neurological conditions, some of which are less well known [1]. The term primary TCH can be used when all other potential conditions have been eliminated by diagnostic testing. A rare cause of TCH is the reversible cerebral vasoconstriction syndrome (RCVS) [2]. This syndrome is characterized by a reversible segmental vasoconstriction of the intracranial blood vessels [2–5]. It is important to recognize this syndrome and distinguish RCVS from other conditions such as primary angiitis of the central nervous system (PACNS), to choose proper treatment [3, 4, 6]. Here, we present two patients with TCH due to RCVS and discuss the clinical features of this often unrecognized syndrome.
Case 1
A 46-year-old man with a history of radical extirpated melanoma was transferred to our hospital under the suspicion of cerebral vasculitis. One week before, he presented with spontaneous acute severe headache, followed a few days later by progressive confusion and a mild left-sided hemiparesis. Magnetic imaging resonance (MRI) of the brain showed ischemic lesions bilateral occipital and right parietal. MR angiography (MRA) showed no abnormality; however, on second review the examination was without gadolinium and of poor quality and therefore not reliable. Patient did not use any medication, smoked 20 cigarettes and 3–4 times cannabis a day. The admission blood pressure was 184/89 and the following day 154/90. On neurological examination, he appeared confused and scored 15 of 30 items on the mini-mental state examination. There was a hemiparesis MRC grade 4 on the left side. Ancillary laboratory investigations in serum (including blood count, serum electrolytes, liver, renal and thyroid function tests, erythrocyte sedimentation rate, C-reactive protein level, antinuclear and antineutrophil cytoplasmic antibody tests, complement C1q, C3 and C4, lupus anticoagulant, rheumatoid factor) and cerebrospinal fluid (CSF) showed no abnormalities. Selective catheter cerebral angiography showed multiple caliber changes in the intracranial blood vessels (Fig. 1). Transcranial Doppler ultrasonography (TCD) examination showed increased intracranial blood flow velocities among others of medial cerebral artery (154 cm/s), and anterior cerebral artery (168 cm/s). Because of the acute presentation with TCH, normal CSF examination and the findings on TCD the diagnosis RCVS was established. Calcium-channel antagonist nimodipine 60 mg six times daily was started. Few days after treatment was started, the clinical condition improved. A follow-up TCD showed a normalization of blood flow velocities (medial cerebral artery: 94 cm/s and anterior cerebral artery: 90 cm/s). The follow-up MRI showed reduction in size of the hyperintense lesions. The patient was transferred to a rehabilitation center and discharged home after 3 weeks under good clinical condition.
Case 2
A 48-year-old woman presented at the emergency department with spontaneous acute severe headache. She had a history of migraine, but did not recognize this type of headache as her migraine headache. She frequently used sumatriptan and 1 week before admission, because of severe attacks, she had used sumatriptan daily with temporally good response. On examination, the blood pressure was 140/88 and neurological examination was normal. SAH was ruled out by CT scan and CSF examination was completely normal. Following day, she became confused with behavioral changes. Brain MRI/MRA revealed no abnormalities. TCD showed increased blood flow velocities over the medial cerebral artery (109 cm/s) and anterior cerebral artery (108 cm/s). Under the suspicion of RCVS, calcium antagonist verapamil 120 mg twice daily was started. Within a day, the patient improved clinically and TCD after 4 days showed normal blood flow velocities of medial cerebral artery (80 cm/s) and anterior cerebral artery (66 cm/s). She was discharged at home without any complaints and was strongly advised not resume any triptans.
Discussion
These cases highlight the recognition of RCVS as a cause of TCH. It is important to realize that TCH is a symptom rather than a diagnosis and can be caused by several acute (neurological) conditions as cerebral venous thrombosis, ischemic stroke, dissection, acute hypertension, vasospasm and infection [1].
The RCVS was first described by Call et al. in 1988 [2] and is characterized by a reversible segmental vasoconstriction of the intracranial vessels. It is most common in women aged 20–50 years. The striking presenting feature of RCVS is TCH, followed immediately, or after a symptom free interval, by seizures, neurological deficits or encephalopathy [2–5]. RCVS can occur spontaneously or in association with pregnancy, migraine, sexual activity, certain prescribed or illicit drugs (selective serotonin reuptake inhibitors, triptans, cannabis, cocaine and ecstasy) [3–5, 7–10]. Concerning the patients in our case, the frequent use of cannabis in the first patient and sumatriptan in the second patient were probably the precipitating factors.
MRI findings in RCVS can be normal or showing ischemic lesions, especially in posterior circulation and watershed areas. CSF is normal in 80–90% of the patients, as it was in our patients [3–6].
MR angiography can demonstrate vasoconstriction in the proximal parts of the great cerebral arteries. However, a normal MRA examination does not rule out the diagnosis. In a series of 44 RCVS patients, 6 had a normal MRA while on cerebral angiography there were signs of vasoconstriction [7]. In the first patient MRA was inconclusive but cerebral infarction was seen on MRI and cerebral angiography showed multiple alterations. MRA in the second patient did not show vasospasm; the reason might be that this patient had only mild vasospasm.
Cerebral angiography can show multiple alterations of the cerebral blood vessel caliber. These findings are often associated with cerebral vasculitis or PACNS but these patients present in general with gradually progressive neurological symptoms, encephalopathy and CSF is abnormal in 80–90% [1, 6, 11].
TCD is not specific for the initial diagnosis of RCVS, but (repeated) TCD can be a reliable non-invasive investigation to monitor vasospasm. Normalization of cerebral blood flow velocities is often seen within 12 weeks [5, 12]. In our patients there was also normalization of cerebral blood flow velocities.
The exact pathophysiology underlying the reversible vasoconstriction is unknown. The International Classification of Headache Disorders-II classified RCVS as a secondary headache disorder, in contrast to primary TCH. Alternatively, Chen et al. suggested that primary TCH, or TCH elicited by, e.g., physical stress and RCVS are different spectra of the same disorder. Their study showed vasospasm in 39% of the patients with recurrent primary TCH [13]. This suggests that RCVS may have a higher incidence than reported earlier.
The sympathetic nervous system may play a role in the pathogenesis of TCH. This is suggested by the fact that TCH has been associated with factors elevating sympathetic tone, such as adrenergics and physical stress [14]. Furthermore, proximal parts of the intracranial vessels are strongly innervated by sympathetic afferents, which modulate vascular tone. Vasoconstriction in RCVS is most common in these large- and medium-sized vessels [1, 4].
In RCVS, there is no established therapy. A few small observational studies and case reports described a good effect of calcium-channel antagonists in the treatment of the vasospasm of intracranial vessels [3, 15]. In summary, TCH is a symptom which can be caused by several (neurological) conditions. A normal brain CT scan and CSF examination can exclude a SAH but are not sufficient to establish “primary TCH”. A rare cause of TCH is RCVS. The exact cause of RCVS is unknown but among others associated with substance and medication use. Sometimes, this syndrome can be difficult to distinguish from PACNS on cerebral angiography and can be a pitfall. The acute presentation with TCH and the normal CSF examination are in favor of RCVS. Calcium-channel antagonists like nimodipine may be a good therapy and repeated TCD can be a reliable non-invasive investigation to monitor the effect of treatment and demonstrate the reversibility.
Acknowledgements
Conflict of interest
None.
Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.