Neurocritical Care

, Volume 7, Issue 3, pp 203–210

Reversible Cerebral Vasoconstriction Syndrome Associated with Subarachnoid Hemorrhage

Authors

  • Brian L. Edlow
    • Department of NeurologyUniversity of Pennsylvania Medical Center
  • Scott E. Kasner
    • Department of NeurologyUniversity of Pennsylvania Medical Center
  • Robert W. Hurst
    • Department of Interventional NeuroradiologyUniversity of Pennsylvania Medical Center
  • John B. Weigele
    • Department of Interventional NeuroradiologyUniversity of Pennsylvania Medical Center
    • Neurocritical Care Program, Departments of Neurology, Neurosurgery, and Anesthesiology and Critical CareUniversity of Pennsylvania Medical Center
Original Paper

DOI: 10.1007/s12028-007-0058-0

Cite this article as:
Edlow, B.L., Kasner, S.E., Hurst, R.W. et al. Neurocrit Care (2007) 7: 203. doi:10.1007/s12028-007-0058-0

Abstract

Introduction

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare vasculopathy of unknown etiology. Ischemic stroke and intracerebral hemorrhage are well-documented sequelae, but subarachnoid hemorrhage is an uncommon complication of RCVS.

Methods and results

We report six cases of RCVS associated with subarachnoid hemorrhage. Two cases occurred in postpartum women, two in women with a history of migraines, one in a woman who recently stopped taking her anti-hypertensive medications, and one in a man after sexual intercourse. All six patients presented with the classic thunderclap headache. Two patients experienced generalized tonic-clonic seizures, and two patients had small ischemic infarcts. Segmental vasoconstriction was demonstrated on cerebral angiography in all six cases. Aneurysmal subarachnoid hemorrhage and other etiologies were excluded. Reversibility of the segmental vasoconstriction was confirmed by follow-up angiography in four patients and by transcranial Doppler sonography in two patients. All six patients had an excellent neurological outcome.

Conclusions

Reversible cerebral vasoconstriction syndrome may be associated with subarachnoid hemorrhage. RCVS should be included in the differential diagnosis of non-aneurysmal subarachnoid hemorrhage.

Keywords

Reversible cerebral vasoconstriction syndromeCall-Fleming syndromeSubarachnoid hemorrhageThunderclap headachePostpartum cerebral angiopathyBenign angiopathy of the central nervous system

Introduction

Reversible cerebral vasoconstriction syndrome (RCVS) was first described by Call and Fleming in 1988 [1]. The syndrome is defined by reversible segmental vasoconstriction of the medium and large caliber cerebral arteries. It is typically heralded by the acute onset of a severe “thunderclap” headache [2] and may be associated with focal cerebral ischemia or intraparenchymal hemorrhage. Neurological deficits range from mild to severe but usually improve as the vasculopathy resolves. While some cases are idiopathic [3], there appears to be an association with child birth [4], exertion [5], acute arterial hypertension [4, 611], and the administration of sympathomimetic [12], serotonergic [1315], and dopaminergic drugs [16].

The nomenclature used to describe cases of RCVS in the literature has varied, often depending on the clinical context. Reports in the neurology literature commonly use the labels “Call-Fleming Syndrome” or “benign angiopathy of the central nervous system,” whereas reports in the obstetrics and gynecology literature use the term “postpartum cerebral angiopathy.” Recently, a multidisciplinary group of authors adopted the term RCVS, an inclusive label that emphasizes the common clinical and radiographic findings shared by this diverse group of patients [17].

Despite an increasing number of published case reports in recent years, the pathophysiology of RCVS remains poorly understood. The diagnosis is one of exclusion and reversibility of the vasoconstriction is expected. While some authors have advocated for magnetic resonance angiography (MRA) or serial transcranial Doppler (TCD) imaging as non-invasive methods of vascular surveillance [4, 1821], cerebral angiography remains the gold standard for definitive diagnosis [6, 22].

A review of the literature reveals only six cases of subarachnoid hemorrhage (SAH) occurring in RCVS patients, with four occurring in the postpartum period [6, 7, 23, 24]. We report six cases of RCVS associated with SAH, with two occurring in postpartum women, two in women with a history of migraines, one in a woman who recently stopped taking her anti-hypertensive medications, and one in a man after sexual intercourse. All six cases began with the classic thunderclap headache, involved segmental constriction of the cerebral arteries, and shared the rare distinction of being associated with radiographically confirmed SAH.

Case Material

Demographic and Clinical Data

Demographic and clinical data are summarized in Table 1. The six patients in this series presented with acute thunderclap headaches that recurred throughout their hospital stays. Five out of the six patients were women, and age ranged from 25 to 52 years. Four patients had a history of migraine headaches and two had hypertension. In the patients with a history of migraine headaches, the thunderclap headache was either different in character, location, or severity from their usual migraines. One patient ingested sumatriptan after the initial radiographic workup for his thunderclap headache was normal; SAH was subsequently diagnosed on magnetic resonance imaging (MRI, patient 2).
Table 1

Patient demographics and clinical data

Patient #

Age (years)

Gender

Pertinent clinical history

Blood pressure at presentation (mmHg)

Neurological deficits and events

1

37

F

Thunderclap headache began on postpartum Day 8 after an uncomplicated pregnancy

174/90

Generalized Tonic/Clonic Seizure

2

29

M

History of migraine headaches; thunderclap headache began immediately after sexual intercourse; ingested sumatriptan after initial thunderclap headache

156/106

2 Generalized Tonic/Clonic Seizures

3

43

F

History of migraine headaches

120/60*

None

4

25

F

History of migraine headaches; thunderclap headache began immediately after full-term delivery; no signs or symptoms of pre-eclampsia during pregnancy

170/100

None

5

48

F

History of migraine headaches and hypertension; thunderclap headache began during valsalva

156/80

None

6

52

F

History of hypertension; discontinued anti-hypertensive medication 3 days prior to symptom onset; thunderclap headache awoke patient from sleep

151/112

Diplopia, decreased sensation in right arm

*  Blood pressure increased to 171/74 mmHg on day 2 of admission

Five patients presented to the hospital with acute arterial hypertension, and one developed acute arterial hypertension on day 2 of her admission. One patient had discontinued her anti-hypertensive medications three days prior to symptom onset. Three patients had no neurological deficits or symptoms except for recurrent headaches. Two patients experienced generalized tonic-clonic seizures but had normal neurological exams thereafter. One patient presented with diplopia and decreased sensation in the right upper extremity, with the latter symptom resolving by the time of discharge from the hospital.

Radiographic and Laboratory Data

Radiographic and laboratory data are summarized in Table 2. Subarachnoid hemorrhage was confirmed by a combination of head computed tomography (CT) scan (5 cases), MRI (6 cases), and cerebrospinal fluid analysis (2 cases). In all six cases, the subarachnoid blood was present in cortical sulci, suggesting hemorrhage from the distal cerebral vasculature rather than from the circle of Willis arteries. Segmental vasoconstriction was demonstrated on cerebral angiography in all six cases and follow-up angiography was performed in four cases to confirm reversibility of the vasoconstriction. Two patients were advised to undergo follow-up angiography in four to six weeks but did not do so. One patient was lost to follow-up (patient 6). The other patient (patient 4) declined follow-up angiography but had a follow-up MRI after seven months, which demonstrated hypointensity in the right frontal sulci consistent with chronic SAH. This patient continued to have weekly headaches after discharge and was found to have intermittent elevations in blood pressure on follow-up clinic visits. Both the hypertension and the headaches were well controlled after administration of a calcium channel blocker.
Table 2

Patient radiographic and laboratory data*

Patient #

CT

MRI

Lumbar puncture

Initial angiography

Follow-up angiography

1

Normal (Day 1) Left frontal subarachnoid hemorrhage (Day 5, Fig. 1C)

Left frontal subarachnoid hemorrhage (Day 3)

Tube 1: 3210 RBCs per microliter Tube 4: 64 RBCs per microliter (Day 1)

Diffuse segmental narrowing and irregularity of ACAs and MCAs bilaterally (Fig. 1A, B); irregularities in the left PCA and posterior inferior cerebellar artery; no evidence of intracranial aneurysm or arteriovenous malformation, and normal venous phase (Day 5)

Improvement of multiple areas of focal stenoses in the distribution of the MCAs and ACAs bilaterally with some areas of increased irregularity (Week 3, Fig. 1D)

2

Normal (Day 0, Day 2)

Right frontal subarachnoid hemorrhage (Day 8, Fig. 2A)

Normal (Day 0)

Diffuse segmental narrowing of the bilateral supraclinoid internal carotid arteries, the ACAs (A1 and A2 segments), the MCAs (M1 and M2 segments), the proximal posterior cerebral arteries, the posterior inferior cerebellar arteries, and the basilar artery (Fig. 2B); segmental narrowing in cortical branches of the anterior and posterior circulation; no evidence of aneurysm or arteriovenous malformation, and normal venous phase (Day 14)

Marked improvement in the segmental narrowing involving the proximal and cortical branches of both the anterior and posterior circulations bilaterally (Week 8, Fig. 2C)

3

Left fronto-parietal subarachnoid hemorrhage extending into the interhemispheric fissure (Day 0)

Left fronto-parietal subarachnoid hemorrhage extending into the inter-hemispheric fissure (Day 2, Fig. 3C)

Tube 4: 8700 RBCs per microliter (Day 1)

Smooth and intermittent narrowing of the distal ACAs and MCAs (Fig. 3A, B); no evidence of aneurysm or arteriovenous malformation, and normal venous phase (Day 0)

Reversal of the segmental narrowing in the ACAs and MCAs bilaterally (Week 7, Fig. 3D)

4

Right frontal subarachnoid hemorrhage (Day 4, Fig. 4A)

Right frontal subarachnoid hemorrhage (Day 4)

Not performed

Mild narrowing of the right supraclinoid ICA, the proximal right MCA, and the basilar artery (Fig. 4B, C); no evidence of aneurysm or arteriovenous malformation, and normal venous phase (Day 5)

Not performed; (TCD blood flow velocities normal on Day 9)

5

Normal (Day 0) Right fronto-temporal and parietal subarachnoid hemorrhage (Day 5)

Right fronto-temporal and parietal subarachnoid hemorrhage; bilateral small subcortical occipital lobe infarcts; (Day 3)

Tube 1: 34,000 RBCs per microliter Tube 4: 32,500 RBCs per microliter (Day 3)

Mild-moderate focal narrowing of ACAs, MCAs, and PCAs bilaterally; no evidence of arteriovenous malformation, and normal venous phase (Day 5)

All ACA, MCA and PCA branches widely patent bilaterally (Week 6)

6

Left frontal subarachnoid hemorrhage (Day 0)

Left frontal subarachnoid hemorrhage; left parietal and bilateral occipital infarcts (Day 1)

Tube 4: 38 RBCs per microliter (Day 1)

Extensive segmental narrowing of distal left ACA and PCA; no evidence of aneurysm or arteriovenous malformation, and normal venous phase (Day 1)

Not performed; (TCD blood flow velocities normal on Day 2)

*  The day that each test was performed after thunderclap headache onset (day 0) is indicated in parentheses

https://static-content.springer.com/image/art%3A10.1007%2Fs12028-007-0058-0/MediaObjects/12028_2007_58_Fig1_HTML.jpg
Fig. 1

(A) On cerebral angiogram, lateral view of left internal carotid artery injection demonstrates areas of left MCA and ACA narrowing (arrows). (B) Lateral view of right internal carotid artery injection demonstrates areas of right MCA narrowing (arrows). (C) Unenhanced CT scan demonstrates SAH over the convexity of the left frontal lobe (arrows). (D) Lateral view of left internal carotid artery injection demonstrates resolution of narrowing along left MCA branches (arrows), but new irregularities along an ACA branch (arrow head)

https://static-content.springer.com/image/art%3A10.1007%2Fs12028-007-0058-0/MediaObjects/12028_2007_58_Fig2_HTML.jpg
Fig. 2

(A) MRI FLAIR sequence demonstrates increased signal within sulci over the right frontal convexity (arrow), compatible with SAH. (B) Lateral view of right internal carotid artery injection demonstrates several areas of right MCA narrowing (arrows). (C) Lateral view of right internal carotid artery injection shows resolution of right MCA narrowing (arrows)

https://static-content.springer.com/image/art%3A10.1007%2Fs12028-007-0058-0/MediaObjects/12028_2007_58_Fig3_HTML.jpg
Fig. 3

(A) Oblique view of right internal carotid artery injection demonstrates segments of right MCA narrowing (arrows). (B) Oblique view of left internal carotid artery injection shows a segment of left ACA narrowing (arrow). (C) MRI FLAIR demonstrates increased signal in the interhemispheric fissure (arrow) and in the sulci of the left parietal lobe (arrow head), consistent with SAH. (D) Oblique view of right internal carotid injection shows resolution of right MCA narrowing (arrows)

https://static-content.springer.com/image/art%3A10.1007%2Fs12028-007-0058-0/MediaObjects/12028_2007_58_Fig4_HTML.jpg
Fig. 4

(A) Unenhanced CT scan demonstrates SAH over the convexity of the right frontal lobe (arrow). (B) Anterior-posterior (AP) view of right internal carotid artery injection demonstrates an area of narrowing (arrow). (C) AP view of left vertebral artery injection demonstrates mild basilar artery narrowing (arrow)

All patients had extensive serologic testing for markers of infectious or immunological disease. Rheumatoid Factor, anti-nuclear antibody, erythrocyte sedimentation rate, Lyme titer, and rapid plasma reagin were invariably normal or near normal. Lumbar puncture was performed in five out of six patients. Cerebrospinal fluid analysis was not consistent with infection or inflammation in any case.

Illustrative Case Reports

Case 1

A 37-year-old woman presented to a local Emergency Department (ED) 8 days after an uncomplicated delivery with sudden onset of a severe, throbbing, bifrontal headache that woke her from sleep. She denied aura, meningeal symptoms, or sensorimotor deficits. Her past medical history was notable for childhood meningitis, but no headaches. There had been no signs or symptoms of preeclampsia during her recent pregnancy. In the ED, the patient’s neurological examination was nonfocal, her blood pressure was 174/90 mmHg, and trace protein was noted on urinalysis.

An intravenous (IV) infusion of magnesium was started empirically to treat postnatal preeclampsia and IV lopressor was started for blood pressure control. Initial head CT was negative. A lumbar puncture was performed and the opening pressure was 24 cm H2O. Cerebrospinal fluid (CSF) glucose was 44 mg/dl and CSF protein was 34 mg/dl. The first tube of CSF contained 0 white blood cells (WBCs) and 3,210 red blood cells (RBCs) per microliter, while the fourth tube contained 1 WBC and 64 RBCs per microliter. There was no xanthocromia. MRI on hospital day 3 showed increased signal in the superior sulci of the left frontal lobe, suggesting SAH. The patient was transferred to our hospital for a cerebral angiogram, which demonstrated multiple areas of segmental narrowing and irregularity along the distribution of the anterior cerebral artery (ACA) and middle cerebral artery (MCA) bilaterally (Fig. 1A, B). Irregularities in the left posterior cerebral artery (PCA) and posterior inferior cerebellar artery were also noted. There was no evidence of intracranial aneurysm or arteriovenous malformation, and the venous phase of the angiogram was normal.

On the night after the angiogram, the patient had a generalized tonic-clonic seizure. Repeat head CT scan showed left frontal SAH (Fig. 1C). Treatment with phenytoin and amlodipine was started and the magnesium infusion was continued. Transcranial Doppler imaging on hospital day 6 was normal, but mean cerebral blood flow velocities were elevated in the MCAs bilaterally on hospital days 7 and 8 (right MCA = 108 cm/sec, left MCA = 105 cm/sec). Anti-nuclear antibody was negative, and erythrocyte sedimentation rate was normal (17 mm/hr). There were no further seizures and her headache gradually improved. She was discharged on Day 8 and was instructed to continue taking phenytoin, amlodipine, and lopressor. Three weeks later, the patient was asymptomatic and follow-up cerebral angiography showed interval improvement of multiple areas of focal stenoses in the distribution of the MCAs and ACAs bilaterally with some areas of increased irregularity (Fig. 1D).

Case 2

A 29-year-old man with a history of migraine headache presented to our ED with a severe occipital headache that began immediately after sexual intercourse. This thunderclap headache was similar in severity to the patient’s previous migraines but developed much more rapidly and differed in its location. There was no prior history of hypertension, seizures or head trauma. Initial blood pressure was 156/106 mmHg and his neurological exam was non-focal. Head CT scan and CSF analysis were normal. The headache was relieved by phenergan and oral morphine sulfate, and the patient was discharged home.

Over the next 6 days, the patient returned three times to the ED with persistent, severe occipital headaches. At each visit the neurological exam was normal and the blood pressure was elevated (151–173/79–97 mmHg). Prior to the third ED visit, the patient experienced a generalized tonic-clonic seizure. He then had a second seizure in the ED. Sumatriptan had been prescribed after the first ED visit, but this medication was discontinued because of a temporal association between seizure onset and sumatriptan ingestion. Laboratory evaluation was notable only for a white blood cell count of 16,400 cells per microliter. Repeat head CT scan showed no intracranial hemorrhage or mass lesion.

Two days after the last ED visit, an outpatient MRI and magnetic resonance venography (MRV) were performed for recurrent headaches, which were now associated with neck stiffness. Fluid-attenuated inversion recovery (FLAIR) images revealed abnormal T2 signal in the region of the right superior frontal sulcus, suggesting SAH (Fig. 2A). Diffusion-weighted imaging (DWI) was normal. The patient was seen in a neurology clinic twice over the next 3 days, where his blood pressure was recorded at 161/83 mmHg and 172/81 mmHg on successive visits. Three days later, cerebral angiography was performed and showed diffuse irregularity within the intracranial vessels with segmental narrowing of the bilateral supraclinoid internal carotid arteries, the ACAs (A1 and A2 segments), the MCAs (M1 and M2 segments), the proximal posterior cerebral arteries, the posterior inferior cerebellar arteries, and the basilar artery (Fig. 2B). Segmental narrowing was also observed in cortical branches of the anterior and posterior circulation. There was no evidence of aneurysm or arteriovenous malformation, and the venous phase of the angiogram was normal.

The patient was admitted to the hospital and started on nifedipine. The following day, cerebral blood flow velocities on TCD imaging were normal and his headache was remitting. Laboratory evaluation for systemic inflammatory disease was negative. The patient was discharged on a 6-week course of daily nifedipine. Six weeks later, a follow-up cerebral angiogram demonstrated marked improvement in the segmental narrowing involving the proximal and cortical branches of both the anterior and posterior circulation bilaterally (Fig. 2C). There was no evidence of hemodynamically significant stenosis. The frequency and severity of the patient’s headaches had decreased, and his blood pressure was now 124/70 mmHg.

Discussion

The clinical and radiographic features of these six cases are consistent with previous descriptions of RCVS. Each case involved recurrent thunderclap headache, segmental cerebral vasoconstriction, and excellent neurological outcome. The presence of SAH distinguishes these six cases from previous reports of RCVS.

The etiology of the SAH in these six RCVS patients is unclear. Several radiographic features make aneurysmal rupture an unlikely cause of the SAH. First, no aneurysms were detected on cerebral angiography in all cases. While cerebral angiography initially may not detect thrombosed aneurysms, neither MRI (6 cases) nor repeat angiography (4 cases) revealed a previously undetected aneurysm. Second, the subarachnoid blood in all six patients was superficial, and not near the circle of Willis branch points that are the classic sites of aneurysm formation. Finally, the time course of vasospasm onset in these cases is atypical for vasospasm related to aneurysmal SAH. Vasospasm was documented within one day of SAH in three patients (patients 3, 4, and 6), and within two days of hemorrhage in two patients (patients 1 and 5). Vasospasm related to aneurysmal SAH usually does not occur before day 4 [25]. While “ultraearly vasospasm” (vasospasm within the first 48 h of aneursymal rupture), may occur in up to 13% of patients with aneurysmal SAH [26], several clinical and radiographic features differentiate these six cases from the typical presentation of ultraearly vasospasm. In a recent meta-analysis that included 3,478 patients with aneurysmal SAH, ultraearly vasospasm was associated with intracerebral hematoma, intraventricular hemorrhage, declining neurological status, and unfavorable outcome [27]. None of these features were present in our patients.

In each case, clinical and radiological features excluded other known causes of non-aneurysmal SAH. These include trauma, rupture of cranial, spinal, or dural arteriovenous malformations (AVM), venous hemorrhage, perimesencephalic SAH, vasculitis, intracranial arterial dissection, dural arteriovenous fistulas, bleeding disorders, and cocaine use. While rupture of a small cerebral AVM in the setting of hypertension cannot be excluded definitively, this etiology is unlikely as conventional angiography was negative in all cases and AVM-related hemorrhages are not typically associated with segmental constriction of remote cerebral arteries. Animal models suggest that vasospasm itself may cause SAH [28], but human data supporting a causal link are lacking.

Differentiating SAH due to RCVS from other causes of SAH, especially aneurysmal SAH, is crucial, as the natural history and prognosis of RCVS is relatively favorable. In general, early onset of vasospasm, absence of intracranial aneurysms, and focal subarachnoid blood isolated exclusively to a small region over the cerebral convexities all help to distinguish RCVS-associated SAH from aneurysmal SAH. Angiographic evidence of an unruptured aneurysm in the setting of RCVS, especially when SAH is present, may complicate diagnosis. An association between RCVS and unruptured aneurysms has been reported [29, 30]. In patients with RCVS, it is unclear whether unruptured aneurysms are incidental findings or whether they are indicative of an underlying abnormality in vessel tone [30].

The pathophysiology of RCVS is unknown. Arterial hypertension is commonly observed during the acute phase of the disease, but it is not clear whether hypertension is a cause or an effect of the cerebral vasoconstriction. In animal models, arterial hypertension induced through renal artery clamping may cause segmental cerebral vasoconstriction and neurological deficits that rapidly reverse upon removal of the clamp [28]. In humans, RCVS shares angiographic similarities with hypertensive encephalopathy, perhaps suggesting a causal role of hypertension. It is also plausible that arterial hypertension is a compensatory reflex aimed at preserving cerebral blood flow in response to cerebral vasoconstriction. Reversible cerebral vasoconstriction syndrome is associated with medications that induce systemic hypertension and with medications that promote cerebral vasoconstriction but have little effect on systemic blood pressure.

A weakness of this case series is that two of the six patients (patients 4 and 6) did not undergo follow-up angiography, which is considered to be the gold standard test for confirming the diagnosis of RCVS. However, both patient 4 and patient 6 were followed with TCD imaging, which demonstrated normalization of the cerebral blood flow velocities over the course of their hospitalizations. Several published reports of RCVS have similarly relied upon normalization of blood flow velocities on TCD imaging to demonstrate that the vasoconstriction is reversible [10, 15, 18, 19, 24, 31]. Furthermore, the location and volume of the subarachnoid blood was not characteristic of aneurysmal rupture, the patients had no recurrent events in the short term, and other etiologies such as vasculitis, AVM rupture and venous sinus thrombosis were not consistent with the laboratory or radiographic data. RCVS was therefore considered to be the most likely diagnosis in both cases.

RCVS has recently become the focus of numerous reports, literature reviews and correspondences in neurology, internal medicine, and obstetrics and gynecology publications [17, 21, 22, 3135], leading to greater recognition of the syndrome. Frequent misdiagnosis and an inconsistent use of nomenclature may have led to an underestimation of the incidence of RCVS. As more cases of RCVS are recognized and reported, the full breadth of clinical presentations and the underlying pathophysiology of this unusual vasculopathy will become clearer. RCVS should be included in the differential diagnosis for non-aneurysmal SAH.

Acknowledgments

We would like to thank Natasha Wehrli for translating articles in French, and Benjamin Meyer for translating articles in Japanese.

Copyright information

© Humana Press Inc. 2007