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This is an author produced version of a paper
published in Cephalalgia : an international journal of
headache. This paper has been peer-reviewed but
does not include the final publisher proof-corrections
or journal pagination.
Citation for the published paper:
Per-Olof Grände, Anders Lundgren,
Hjalmar Bjartmarz, Mats Cronqvist
"Segmental cerebral vasoconstriction: successful
treatment of secondary cerebral ischaemia with
intravenous prostacyclin."
Cephalalgia : an international journal of headache
2010 30, 890 - 895
http://dx.doi.org/10.1177/0333102409352909
Access to the published version may require journal
subscription.
Published with permission from: SAGE Publications

Segmental cerebral vasoconstriction: successful treatment of
secondary cerebral ischaemia with intravenous prostacyclin
Per-Olof Grände1, Anders Lundgren2 Hjalmar Bjartmarz3 and Mats Cronqvist4
Department of Anaesthesia and Intensive Care1, department of Neurology2, department of
Neurosurgery3 and department of Neuroradiology4, University Hospital of Lund, Sweden

Department of Anaesthesiology and Intensive Care1, Department of Neurology2, Department
of Neurosurgery3 and Department of Radiology4, Lund University Hospital, Sweden

Correspondence: P.O. Grände, Department of Anaesthesia and Intensive Care, Lund
University Hospital, SE-221 85 Lund, Sweden
E-mail: per-olof.grande@med.lu.se

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Abstract
We describe a 23-year old male patient who presented with spontaneous intermittent and
increasing attacks of severe, left-sided thunderclap headache combined with rapidly
progressive muscle weakness and dysphasia, including gradual loss of consciousness.
Subsequent CT, MRI and DSA showed progressive brain ischaemia and oedema within the
left cerebral hemisphere with strict ipsilateral segmental arterial vasoconstriction. Despite
extensive medical care, including steroids, the patient deteriorated rapidly. However, the
clinical course changed dramatically within 15 h after the start of an intravenous infusion of
prostacyclin at a dose of 0.9 ng/kg/min, with an almost complete recovery of consciousness
and speech. In addition the patho-physiological alterations seen on MRI and DSA (including
DWI/ADC) shortly before prostacyclin treatment were clearly reduced when the patient was
examined 3–4 days later and he continued to recover thereafter. Although not fully
compatible, our case had several clinical characteristics and radiological findings reminiscent
of those of the “segmental reversible vasoconstriction syndrome”, sometimes called the CallFleming syndrome.
Key words: prostacyclin, dysphasia, segmental reversible cerebral vasoconstriction,
thunderclap headache, cerebral ischemia, Call-Fleming syndrome.

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Introduction
This case report describes the treatment with prostacyclin of a 23-year-old male patient who
presented with spontaneously developed attacks of rapidly progressive intermittent left-sided
thunderclap headache. The symptoms developed almost a year after an accidental fall from
the fourth floor resulting in a left-sided subdural haematoma and a fracture of the C5 vertebra.
The subdural haematoma had been acutely evacuated without replacing the bone flap. Apart
from paraplegia the patient had recovered within a few weeks after the trauma. There was no
indication of alcohol abuse, drug problems, previous episodes of cerebral vasculitis and
recurrent headaches or family history of migraine in this previously healthy man. Except from
taking anti-depressant (Fluoxetin, 20 mg), he used no pharmacological drugs.
The diagnosis remained unclear, but the symptoms showed similarities with those attributed
to the “segmental reversible cerebral vasoconstriction syndrome”, also called Call-Fleming
syndrome (CFS) (1-4). Our patient worsened dramatically with dysphasia and loss of
consciousness Radiological examinations including Magnetic Resonance Imaging (MRI)
showed severe segmental cerebral vasoconstriction and progressive ischaemia, indicating
focal cerebral hypoperfusion. He was now given synthetic prostacyclin (epoprostenol sodium,
Flolan®; GlaxoSmithKline) on the basis of its feature of improving a compromised
microcirculation in the brain as well as in other organs of the body (5, 6). To our knowledge,
prostacyclin infusion has not been used previously as a treatment of cerebral vasoconstrictor
syndromes.

Methods and material
Digital Subtraction Angiography (DSA) and Magnetic Resonance Image (MRI)
protocols
A Philips Integris 5000 bi-plane unit (Philips Medical Systems, Best, the Netherlands) was
used for all DSA. Routine protocols for morphological and functional MRI were done using a
Siemens Allegra 3 Tesla and a Philips Gyroscan 3T MR-unit. Diffusion-weighted imaging
(DWI) including apparent diffusion coefficient maps (ADC) and MR-perfusion (MRP) were

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performed using standard practice and techniques. MRP maps of relative regional cerebral
blood volume (rCBV), relative regional cerebral blood flow (rCBF), mean transit time (MTT)
were done with the Lund perfusion program (LUPE) (7), and colour-coded after
normalisation to the relative rCBF and rCBV values of the cerebellum (8). The arterial input
function (AIF) was determined from an artery on the unaffected side.
Clinical course
Approximately 10 months after the accident, the patient suddenly developed intermittent
severe left-sided headache. After one week of daily recurrence of thunderclap headache at
intervals, which were resistant to various types of analgesics (paracetamol, naproxen and
tramadol), he was referred from his domestic hospital to the Neurological Department and
later on to the neuro-intensive unit of our hospital. He had been treated with ciprofloxacin for
2 days because of a urinary infection.
On arrival at our hospital, the patient was normally oriented and adequate, but showed
episodes of recurrent severe left-sided headache accompanied by intermittent slight
dysphasia. A computed tomography (CT) and subsequent CT angiography (CTA) of the brain
were both normal except from sinusitis. There were no signs of vasculitis, vascular dissection,
cerebral aneurysm or dural sinus thrombosis. A urine culture was positive for E. coli and
antibiotic was changed to trimetroprim + sulfametoxazol. No indication of systemic or CNS
infection were found. To exclude a concealed epileptogenic origin of the dysphasia, the
patient was given a bolus dose of fosfenytoin (750 mg) and daily treatment with
carbamazepin.
The attacks of headache and dysphasia became gradually more prominent and his right arm
became weaker. A CT scan (2 days after the initial one) showed signs of brain swelling and
oedema, and patchy areas of hypo-attenuation within the white and cortical matter in the left
frontal and parietal lobes. The EEG showed a slower pattern on the left side. At this stage, it
was unclear wheather the lesions were of inflammatory, infectious or ischemic origin.

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Prednisolon therapy, 50 mg/day, was initiated as a potential adjuvant and was given for 5
days.
On day 7 after arrival at our hospital, a selective digital subtraction angiography (DSA) of the
anterior and posterior cerebral vascularity was done. The arteries of the right cerebral and
cerebellar hemisphere were normal. On the left side, there was segmental and acute narrowing
of multiple branches of the proximal, distal anterior and middle cerebral arteries (ACA and
MCA) (Fig. 1 a), and in the left posterior cerebral artery (PCA). MRI including DWI of the
brain showed brain swelling and large areas of hyperintense lesions (partially hypointense on
ADC maps) in the left frontal and parietal lobes corresponding to mainly cytotoxic oedema
reflecting acute ischaemia and to a lesser extent vasogenic oedema (Fig. 2 a, b and c). A
lumbar puncture (LP) showed normal cerebrospinal fluid (CSF)

On day 9 after admission the right arm was fully paralysed, the patient became almost
completely dysphasic, followed by unconsciousness. Intravenous prostacyclin infusion was
started in the afternoon at a dose of 0.9 ng/kg/min. The next morning, approximately 15 h
after the start of the prostacyclin treatment, the patient was fully awake and well oriented. His
speech was close to normal, only mild dysphasia remained, and he could now move his right
arm slightly.
An MRI including DWI and MRP 3 days after the start of prostacyclin treatment revealed a
reduction of the brain swelling. The hyperintense lesions, including both vasogenic and
cytotoxic oedema, showed no progression. The DWI and ADC patterns were significantly
reduced, indicating that the pre-existing brain ischaemia was partially reversible (Fig. 2 d, e
and f to be compared with Fig. 2 a, b and c). MRP showed secondary hyperperfusion in the
areas distal to the previously demonstrated segmental vascular stenoses on DSA (Fig. 2 g). In
addition, the periodic recurrent headache was less severe at this stage. Prostacyclin was
discontinued gradually for about 10 hours.

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Follow-up DSA 4 days after the start of the prostacyclin treatment showed a significant
reduction of the segmental stenoses with almost complete normalisation of the previously
narrowed vessels within the left ACA, MCA and PCA branches (Fig. 1 b).
The craniotomy was then covered with a cranioplastic operation using the removed bone flap.
The headache disappeared successively over the following weeks. An MRI done 1 month
later showed smaller areas of permanent brain infarctions (Fig. 3 a and b). At a next visit 2
months after leaving hospital, the motor function of his right arm was not normalized, but had
improved significantly and his speech and mental status were normal.
Blood analysis in terms of haemoglobin, creatinin, urea, anti-thrombin concentrations and
liver tests (bilirubin, GT ALAT and ASAT) were normal throughout the entire hospital stay.
CRP and leukocytes as markers for vasculitis were normal or slightly above normal (highest
values 40 g/L and 11 × 109/L, respectively). The CSF analysis showed normal levels of cells
(poly 0.4 x106/L, mono 4x106/L), protein 0.5 g/L, glucose 3.3 g/L and no IgG production. The
patient had a normal blood pressure (range 120/70–95/60 mm Hg) throughout the whole
hospital stay and there was no epileptogenic activity on EEG.

Discussion
Prostacyclin is an endogenous substance controlled by cAMP and produced in the endothelial
cells of the vascular wall. It is important for maintenance of an adequate microcirculation (5,
6, 9). It is a vasodilator with anti-aggregatory, anti-adhesive and anti-inflammatory effects,
and may reduce vasospasm after subarachnoid haemorrhage (10). The balance between
prostacyclin and the vasoconstrictor and pro-aggregatory substance thromboxane A2 is
disturbed in favour of thromboxane A2 under patho-physiological conditions (11), but can be
re-established by infusion of prostacyclin. Prostacyclin has been shown to improve perfusion
in the penumbra zone of the traumatised human brain (6) and to reduce the contusion volume
in the traumatized rat brain (12). Based on these considerations, prostacyclin was given to our
patient with the purpose of improving the cerebral circulation. Both the clinical and
radiological symptoms were significantly reduced after the start of prostacyclin treatment.

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The comprehensive picture showed some similarities with the “segmental reversible cerebral
vasoconstriction syndrome” known as Call-Fleming syndrome (CFS) (1-4). The sudden onset
of episodes of severe thunderclap headache and later-developing segmental narrowing in
patches of cerebral microvessels in our patient are compatible with that syndrome. However,
the symptoms are often bilateral, which was not the case in this patient. CFS has been related
to precipitating factors such as migraine, porphyria, pregnancy and the use of vasoactive
drugs and drugs of abuse, but it may also appear spontaneously, as was the case in our patient
(2,3, 13 -14). The pathophysiological mechanisms are still poorly understood. The course of
CFS is often benign, but there have been reports of cases with focal cerebral ischaemia
sometimes leading to stroke or cerebral haemorrhage, resulting in permanent sequelae and
even death (1-4, 13, 14). Steroid treatment has not been shown to be effective (14), as was the
case in our patient. There is no established standard treatment that can reverse the syndrome.
One case report described beneficial effects of intravenous use of the calcium channel
antagonist Nimodipine (14), a finding that was not, however, confirmed in a subsequent larger
study (3). Another case report indicated beneficial effects of the phosphodiesterase inhibitor
Milrinone given intra-arterially (15).
In our patient, prostacyclin was given at an infusion rate compatible with endogenous
production and it is safe without any side effects (16). The well-known features of
prostacyclin (5,6,10) are compatible with the improvement in cerebral circulation that was
apparent in this patient (Fig. 1 a, b), but we cannot exclude the possibility that the
improvement occurred independently of prostacyclin treatment. However, this is less likely
because, firstly, the progressive scenario of severe deterioration stopped almost immediately
and, secondly, the improvement regarding consciousness, dysphasia and arm weakness
appeared very soon after the start of the prostacyclin infusion. It is unlikely that normalisation
of consciousness and speech within 15 h after the start of prostacyclin from a phase of
deterioration can be explained by a spontaneous healing process only. In addition, there was a
dramatic and rapid reversibility towards normalization of the radiological alterations noted on

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DSA and MRI shortly after the start of the prostacyclin infusion (Fig. 2 d-f), and improved
perfusion on MRP (Fig. 2 g), indicating that the ischaemia was partially reversible.
The craniotomy may have been a precipitating factor, as the headache and the vascular
alterations occurred on the left side of the brain. On the other hand, there were no signs of
headache during the first 10 months after the craniotomy, and the headache did not disappear
immediately after the craniotomy was restored.

Cerebral vasculitis is an improbable differential diagnosis due to the normal CSF analysis
(2,17), the acute onset of the apoplectic headache at intervals, focal neurological symptoms
absence of vasculitis markers, and no fever. Further, there was an aggravation of symptoms
despite the start of steroid treatment.
The signs of ischaemia on the MR images, the reduced consciousness, the right-sided paresis
and the dysphasia (the patient was right-handed) can most likely be related to the cerebral
vascular alterations seen in the left hemisphere – especially as the patient was improved
regarding the dysphasia and consciousness relative to improvement of the cerebral circulation.
In summary: The present case report describes the use of prostacyclin infusion therapy in a
young patient who spontaneously developed recurrent thunderclap headache, followed by
fluctuating and progressive neurological deterioration combined with unilateral segmental
vasoconstriction and secondary cerebral ischaemia. It seems reasonable to believe that
prostacyclin had a favourable effect on the clinical and radiological course.

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References
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cerebral segmental vasoconstrictotion. Stroke 1988; 19:1159-70.
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12) Bentzer P, Mattiasson G, Mc Intosh TK, Wieloch T and Grände PO. Infusion of
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Legends
Fig. 1. a. Left common carotid angiogram, lateral projection, showing segmented and acute
narrowing of multiple branches of the proximal and distal anterior and middle cerebral
arteries (ACA and MCA) (see arrows) 4 days before prostacyclin. b. Corresponding image 3
days after the start of prostacyclin infusion, illustrating a dramatic reduction and a partial
normalisation of the previously narrowed vessels within the ACA and MCA territories (see
arrows).
Fig. 2. An MR scan (axial T2W) 2 days before prostacyclin (a) and corresponding DWI (b1200) image (b) showing brain swelling and large areas of hyperintense lesions in the left
parietal lobe, and hypointensity on ADC (c) corresponding to acute cytotoxic oedema, i.e.
ischemia. Corresponding axial T2W (d) and DWI/ADC (e, f) 3 days after the start of
prostacyclin treatment reveal a reduction in the hyperintense lesions and in brain oedema. An
MRP; a cerebral blood flow (rCBF) measurement 3 days after start of prostacyclin illustrates
the increased perfusion in the previously ischemic region due to secondary hyperperfusion
(g). No new ischemic lesions were found. The corresponding MRP image before prostacyclin
treatment is lacking.
Fig. 3. Follow-up MR done almost 4 weeks after ictus. Axial T2W (a) and DWI (b) images
show minimal areas of permanent brain infarction and no acute ischaemia. The craniotomy
has been covered by a bone implant, with an underlying and small postoperative subdural
haematoma.

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Fig 1a,b

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13

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Figurerna kommer i ordning Fig 1a och b på en sida, Fig 2a-d på nästa sida, Fig 2 e-g nästa sida
samt Fig 3a-b sista sidan

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