Hemorrhagic Manifestations of Reversible Cerebral ... · and reversible constriction of cerebral arteries, may be associated with ischemic and hemorrhagic strokes. The aim of The

Hemorrhagic Manifestations of Reversible CerebralVasoconstriction Syndrome

Frequency, Features, and Risk FactorsAnne Ducros, MD, PhD; Ursula Fiedler, MD; Raphael Porcher, PhD; Monique Boukobza, MD;

Christian Stapf, MD; Marie-Germaine Bousser, MD

Background and Purpose—Reversible cerebral vasoconstriction syndrome (RCVS), characterized by severe headachesand reversible constriction of cerebral arteries, may be associated with ischemic and hemorrhagic strokes. The aim ofthis study was to describe the frequency, patterns, and risk factors of intracranial hemorrhages in RCVS.

Methods—We analyzed prospective data on 89 consecutive patients with RCVS, of which 8 were postpartum and 46 usedvasoactive substances. Standard bivariate and multivariate statistical tests were applied to compare patients with andwithout hemorrhage.

Results—Thirty patients (34%), of which 5 were postpartum and 12 used vasoactive substances, developed at least 1 typeof intracranial hemorrhage, including cortical subarachnoid (n�27), intracerebral (n�11), and subdural hemorrhage(n�2). Patients with hemorrhage had an older age (46.6 versus 41.6 years, P�0.049) and were more frequently females(90% versus 51%, P�0.0017) or were migrainers (43% versus 19%, P�0.022) than those without hemorrhage.Multivariate testing identified 2 independent risk factors of hemorrhage in RCVS: female gender (OR, 4.05; 95% CI,1.46 to 11.2) and migraine (OR, 2.34; 95% CI, 1.06 to 5.18). Patients with hemorrhage had a greater risk of persistentfocal deficits (30% versus 2%, P�0.0002), cerebral infarction (13% versus 2%, P�0.039), posterior reversibleencephalopathy syndrome (17% versus 3%, P�0.041) at the acute stage, and of inability to resume normal activities at6 months (27% versus 0%, P�0.0001).

Conclusion—In RCVS, women and migrainers seem to be at higher risk of intracranial hemorrhage. Overall, intracranialhemorrhages are frequent in RCVS and are associated with a more severe clinical spectrum. (Stroke. 2010;41:2505-2511.)

Key Words: female gender � intracerebral hemorrhage � migraine � reversible cerebral vasoconstriction syndrome� subarachnoid hemorrhage � subdural hematoma

Reversible cerebral vasoconstriction syndrome (RCVS) ischaracterized by severe headaches, often thunderclap

headaches, with or without focal deficits and seizures, and amultifocal constriction of cerebral arteries, which resolvespontaneously within 3 months.1 This syndrome has a femalepreponderance and a mean age of onset of approximately 42years.1–3 RCVS presumably involves a transient disturbancein the control of cerebral arterial tone leading to segmentalmultifocal constrictions with alternating segmental dilatationsgiving the characteristic “sausage on a string” angiographicaspect.1 Although RCVS may be spontaneous, more than halfof the cases occur in special circumstances such as postpar-tum or after an exposure to sympathomimetic or seroto-ninergic substances.1,3–6 Once considered rare,7 RCVS hasbeen increasingly reported during the last 10 years,1 presum-ably due to the routine use of CT or MR angiography in

patients presenting with acute headache2 and/or stroke and tothe greater awareness of this syndrome.1–3 However, RCVSremains a poorly understood syndrome and is viewed com-pletely differently by headache specialists who consider it asa painful but benign syndrome and by stroke specialists whoview it mostly as a rare cause of stroke. Indeed, stroke is themost severe manifestation1–3,7 and may lead to permanentsequelae and even death.5,6 Recent reports and case serieshave suggested that intracranial hemorrhages may be frequentin RCVS3,5,8–12 and harbor different patterns, including cor-tical subarachnoid hemorrhages (cSAHs), intracerebral hem-orrhages (ICHs), and subdural hemorrhages (SDHs), butdetailed description of these hemorrhagic manifestations andof their risk factors is lacking so far.

We analyzed the frequency, clinical and radiological fea-tures, and risk factors of intracranial hemorrhages in a largeprospective cohort of 89 patients with RCVS.

Received November 7, 2009; final revision received June 17, 2010; accepted June 17, 2010.From the Emergency Headache Center (A.D., U.F.), Head and Neck Clinic, Lariboisiere Hospital, Paris, France; the Department of Neurology (A.D.,

U.F., C.S., M.-G.B.), Head and Neck Clinic, Lariboisiere Hospital, Paris, France; the Department of Biostatistics (R.P.), Saint Louis Hospital; and theDepartment of Neuroradiology (M.B.), Head and Neck Clinic, Lariboisiere Hospital, Paris, France; all from the APHP (Assistance Publique des Hopitauxde Paris) and the Universite Paris Diderot, Paris, France.

Correspondence to Anne Ducros, MD, PhD, Centre d’Urgences Cephalees, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris Cedex 10, France.E-mail [email protected]

© 2010 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.109.572313

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Subjects and MethodsIn a predefined prospective protocol,3 we recruited consecutivepatients with a diagnosis of RCVS based on the following criteria:(1) unusual, recent, severe headaches of progressive or sudden onsetwith or without focal neurological deficit and/or seizures; (2)imaging evidence of cerebral vasoconstriction with at least 2narrowings per artery on 2 different arteries, assessed by MRangiography (MRA), CT angiography, and/or transfemoral angiog-raphy (TfA); and (3) disappearance of arterial abnormalities assessedby a control angiography in �3 months.

From January 2004 to January 2008, 89 patients (61 women)fulfilling all 3 study criteria were recruited including 30 patientsthrough our stroke unit admitting approximately 1000 patients peryear and 59 through our emergency headache clinic receivingapproximately 7500 outpatients per year coming from the great Parisarea (10 million inhabitants). Patients with RCVS representedapproximately 0.26% (95% CI, 0.21% to 0.31%) of our overallrecruitment. Approximately 115 patients per year present to theclinic with thunderclap headaches as their chief complaint and allundergo an extensive workup, including cerebral and vascularimaging.

All patients orally agreed to participate in a descriptive follow-upstudy. We followed the French legislation stipulating that observa-tional studies do not require formal review by the institutional ethicscommittee but that any investigation or study requires that patientsgive their informed consent. This consent may be oral, like here.Detailed medical history, clinical, radiological, and biological datawere collected as previously described.3 When present, migraine wasdiagnosed according to the International Classification of HeadacheDisorders.13 The first 67 patients were the basis of a previouspublication.3 The 89 patients included 8 postpartum women and 46vasoactive substance users. Clinical symptoms included severeheadaches (89), transient focal deficits (14), persistent focal deficits(10), seizures (4), and blood pressure (BP) surges (29). Acuteinvestigations included cerebral CT scan (86); 1.5-T MRI withdiffusion-weighted imaging, fluid-attenuated inversion recovery, T1,and gradient-echo weighted images (89); 2-dimensional time-of-flight cerebral MRA (88); cervical and transcranial Doppler (86);TfA (57); complete blood workup (89), urine analysis for drugs (62);and cerebrospinal fluid analysis (CSF; 78). All 89 patients had anangiogram showing “string and beads.” CSF was abnormal in 47patients; 22 had an elevated white blood cell count (mean, 11/mm);30 elevated red blood cell count (mean, 2377/mm); and 30 elevatedprotein levels (mean, 59 mg/L).

Symptomatic analgesic treatment (mostly paracetamol) was usedin all patients without standard protocol. Nimodipine was used in 82patients with intravenous infusion (1 to 2 mg/h adapted to BP)followed by oral administration in 15 patients and direct oraladministration in 67 patients (30 to 60 mg every 4 hours, adapted toBP). Duration of treatment ranged from 4 to 8 weeks.

Clinical follow-up visits were performed within 3 to 6 weeks afterhospital discharge and then at 3 and 6 months after headache onset.Follow-up angiogram (73 MRA, 16 TfA) demonstrated the revers-ibility of arterial narrowings in all 89 patients.

Statistical AnalysisResults are expressed as mean and SD or counts and percent.Marginal association between patient characteristics and hemorrhagewas assessed by a Student t test for quantitative variables and aFisher exact test for qualitative variables. Multiple logistic regressionwas used to determine variables independently associated with eachoutcome. Variables associated with hemorrhage at a 0.15 level wereconsidered in the multiple models. A backward stepwise procedurewas used for variable selection with s probability value cutoff at0.05. First-order interactions between selected variables were thentested. Validity of the logistic regression model was checked usingthe goodness-of-fit test.14 Internal validation was performed bybootstrapping,15,16 with random generation of 200 samples from theoriginal data (drawn with replacement) on which the whole variableselection procedure was applied and the performance measures of the

derived model calculated. Discriminative ability of the models wasevaluated by the C index (identical to the area under the receiveroperating characteristics curve)17 and calibration by the calibrationslope.18 The models estimated in each bootstrap sample were thenevaluated in the original sample, and the differences between theperformance on the bootstrap sample and the original sample weretaken as a measure of overoptimism. The final model performanceswere corrected by this overoptimism and regression coefficientsestimates multiplied by the calibration slope. All tests were 2-sided.Analyses were carried out using R statistical software (The RFoundation for Statistical Computing, Vienna, Austria).

ResultsFrequency and Subtypes ofHemorrhagic ComplicationsAmong 89 patients with RCVS, 30 had an intracranialhemorrhage (34%) and 5 had a cerebral infarction (6%).Stroke occurred in 14 of the 89 patients (16%). One of the 59patients without hemorrhage had an infarction. Thirteen ofthe 30 patients with hemorrhagic RCVS had a stroke: ICHwith infarction (2), ICH without infarction (9), and infarctionwith cSAH (2).

All 30 patients with a hemorrhage underwent cerebral CTand MRI scans with MRA, and 27 also had TfA. Bydefinition, all 30 patients had angiographically proven mul-tifocal vasoconstriction, which resolved within 12 weeks asassessed by MRA (28) and/or TfA (8). Angiograms, MRI,and blood tests showed no other cause of hemorrhage.

Three varieties of hemorrhages were observed: cSAH in 27patients (30%), ICH in 11 (12%), and SDH in 2 (2%). Ninepatients had overlapping bleeding locations (Table 1). MRIT2* showed no microbleeds.

Among the 27 cSAHs (Figure 1), 24 were restricted to afew hemispheric sulci, unilaterally (10) or bilaterally (14).One SAH was visible in some sulci of the right cerebellarlobe. The last 2 SAH were more diffuse, lying over bothhemispheres and in the perimesencephalic cisterns. SAH wasvisible on both CT and MRI in 14 patients and only on MRIin 13 patients.

Ten patients had a single ICH and 1 had bilateral frontalhematomas. All 12 ICHs were visible on both CT and MRI.Sites of bleeding included various lobar regions in 6 patientsfor 7 ICH, basal ganglia in 4 patients, and thalamus in 1(Figure 2).

The 2 SDHs were acute and associated with other bleedingtypes (Figure 2).

Demographic Characteristics and Risk Factors inPatients With Hemorrhagic RCVSTable 2 presents the main demographic characteristics, vas-cular risk factors, and potential precipitating factors forRCVS in patients with and without hemorrhage. None had ahistory of recent head trauma. Bivariate analysis suggestedthat hemorrhagic manifestations were more frequent in olderpatients, females, and migrainers. This association entirelyrelied on migraine without aura, but only very few patientshad migraine with aura (Table 1). Multivariable analysisshowed only 2 independent factors associated with a higherrisk of bleeding in RCVS: female gender (OR, 4.05; 95% CI,1.46 to 11.2) and a history of migraine (OR, 2.34; 95% CI,

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1.06 to 5.18). No significant interaction was found betweengender and migraine (P�0.20).

Clinical Features and Associated Lesions inPatients With Hemorrhagic RCVSAcute very severe headache was the presenting symptom inall 30 patients, of whom 24 had the typical RCVS pattern ofmultiple recurrent thunderclap headaches (Tables 1 and 3).Eighteen subjects reported headache triggers, the most fre-

quent being bending down followed by sexual activity,physical exercise, coughing, sneezing, defecation, urination,and bathing.

Two patients had focal seizures with secondary generali-zation in 1 case. Six patients had a total of 14 episodes oftransient focal deficits, consistent with transient ischemicattacks in 4 patients (11 episodes) and with positive aura-likevisual symptoms in 2 patients. Nine patients had a persistentfocal deficit lasting �24 hours, which revealed an ICH in 7

Figure 1. cSAH in RCVS. A, CT showing a rightfrontal SAH. B, Fluid-attenuated inversion recoverysequence showing bilateral posterior cortical SAH.C–D, Case report: a 36-year-old woman wasstarted on bromocriptine 2 days after an uncompli-cated vaginal delivery. On Day 4 after delivery, shehad a thunderclap headache lasting 15 minutes.CT, MRI (C), and CSF analysis done a few hourslater were normal. The same day, she had 9 addi-tional short-lasting thunderclap headaches. Thenext day, repeat MRI showed a left temporalcSAH. D, Nimodipine was started and no otherthunderclap headache occurred. On Day 2 afterheadache onset, TfA showed diffuse arterial vaso-constriction. Control MRA at 2.5 months wasnormal.

Table 1. Different Patterns of Intracranial Hemorrhages in RCVS: Clinical and Radiological Features

Different Types ofIntracranial Hemorrhages

Isolated cSAH(n�18)

cSAH�ICH(n�7)

Isolated ICH(n�3)

SAH�SDH(n�1)

SAH�ICH�SDH(n�1)

Headache

Recurrent thunderclap 18 2 2 1 1

Single acute headache … 5 1 … …

Seizures 1 1 … … …

PRES 5 … … … …

Persistent focal deficit 1 6 2 … …

Related to ICH … 5 2 … …

Related to infarction 1 1 … … …

Cerebral infarction 2 2 … … …

Transient focal deficit 5 … 1 … …

Cervical artery dissection 2 2 … … …

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and a cerebral infarction in 2. Among the 11 patients with anICH, 4 had isolated headaches, 4 a single sudden headacheconcomitant to a focal deficit, and 3 initially had isolatedheadaches and developed a few days later a persistent focaldeficit.

Among the 9 subjects who had a systolic BP �160 mm Hgand/or a diastolic BP �90 mm Hg during the acute stage ofRCVS, 7 patients had BP surges only during the peak ofthunderclap headaches, and 2 had permanently elevated BP.

Five patients (17%) had MRI fluid-attenuated inversionrecovery sequence hyperintensities consistent with a posteriorreversible encephalopathy syndrome (PRES; Table 1). Fourpatients (13%), including 1 with PRES, developed a cerebralinfarction. Four patients, including 2 with PRES and 1 withinfarction, had a cervical artery dissection (unilateral vertebralartery dissection in 3 subjects and 4 vessels dissection in 1).

Patients with hemorrhage had a significantly higher fre-quency of persistent focal deficits (30% versus 2%), cerebralinfarction (13% versus 2%), and PRES (17% versus 3%) thanpatients without hemorrhage.

Temporal Profile of Vasoconstriction andIntracranial HemorrhageTable 4 presents the average delay of hemorrhages, ischemicevents, and diagnosis of vasoconstriction after headacheonset. Vasoconstriction was diagnosed concomitantly to hem-orrhage in 15 patients and after hemorrhage in 14 patients. In4 of these 14 patients, angiogram was available only a fewdays later. In the remaining 10 patients, early MRA (6), TfA(1), or both MRA and TfA (3) were normal, and vasocon-

striction was visible on a second angiogram (5 MRA, 5 TfA).Vasoconstriction was diagnosed before hemorrhage in 1patient with normal CT and CSF at Day 1, vasoconstrictionon TfA at Day 3, and cSAH on MRI at Day 4.

Hemorrhages, PRES, and seizures were mainly diagnosedwithin the first week, whereas ischemic events occurredmainly during the second week, often after the cessation ofthunderclap headaches (Figure 3).

Five patients (17%) with hemorrhage had a normal initialbrain imaging. One woman had both normal MRI and CSFthe day after her first thunderclap headache, but she subse-quently developed cSAH diagnosed on a repeat MRI at Day2, after 9 additional thunderclap headaches (Figure 1C).Another woman had both normal CT and CSF at Day 2 after3 thunderclap headaches but later developed bilateral corticaland perimesencephalic SAH diagnosed by CT and MRI atDay 5, after a fourth thunderclap headache. Three patientshad initial normal CT scans performed respectively at Days 0,1, and 3 after headache onset but later developed an ICHdiagnosed by a repeat imaging at Day 3 for the first 2 patientsand at Day 8 for the third patient (Figure 2D).

Clinical Outcome in Patients With Hemorrhagic RCVSAt 3 months of follow-up, the median modified Rankin Scalescore was 0 and the mean modified Rankin Scale was 1, 2patients remained severely disabled (modified Rankin Scale 3and 4), and 12 patients (40%) were unable to return to priorprofessional activities. There were no deaths.

At 6 months of follow-up, 8 patients with hemorrhagicRCVS were still unable to resume work because of persistent

Figure 2. ICH in RCVS. A, Right occipital ICH onCT. B, CT at Day 4 after headache onset showinga bilateral frontal ICH with mild frontal SAH in awoman who had 2 thunderclap headaches (Days 0and 3) and acute persistent aphasia at Day 3 andwho had an initial normal CT at Day 1. C, CT atDay 0 showing a deep right ICH in a woman witha single thunderclap headache immediately fol-lowed by a left hemiplegia, D, CT performed atDay 8 after headache onset showing a left internaloccipital ICH associated with a SDH and a mildcSAH in a woman who reported 6 thunderclapheadaches and who had at Day 3 both normalCT and CSF analysis.




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deficits (5) or marked asthenia (3), which was significantlyhigher than in patients without hemorrhage (27% versus 0%,P�0.0001).

DiscussionHemorrhagic manifestations were present in 34% of ourpatients with RCVS. Stroke, with both infarction and ICH,

has long been known as the most severe manifestation ofRCVS.1,5–7 However, its estimated incidence ranges from 6%to 7% in prospective studies recruiting acute headache pa-tients2 to 54% in a retrospective series including in-hospitalpatients,1 with ICH in 0% to 25% and infarctions in 6% to31%.1–3,7,19 This discrepancy presumably reflects recruitmentbiases and lack of standardized diagnostic workup. In ourcohort, recruitment bias is likely to be less marked because ofour dual recruitment based on both a stroke unit and anemergency headache center. Stroke occurred in 16% of our

Table 2. Intracranial Hemorrhages in RCVS: Associated Demographic Characteristics and Risk Factors

Variable

RCVS WithIntracranial Hemorrhage

(n�30)

RCVS WithoutIntracranial Hemorrhage

(n�59)

BivariateAnalysis

P

Multivariate Analysis

OR (95% CI)† P

Age, years, mean�SD 46.6�11.0 41.6�11.6 0.049

Age, years, range 26–63 19–70

No. Percent No. Percent

Sex, female 27 90 34 58 0.0017 4.05 (1.46–11.2) 0.007

Cardiovascular risk factors

Current smoker 9 30 30 53 0.11

History of hypertension 3 10 7 12 �0.99

Diabetes 2 7 0 0 0.11

Hypercholesterolemia 4 13 8 14 �0.99

Migraine 13 43 11 19 0.022 2.34 (1.06–5.18) 0.036

Migraine without aura 13 43 11 19 0.022

Migraine with aura 1 3 2 3 �0.99

Precipitant of RCVS

None 13 43 21 36 0.50

Postpartum* 5 19 3 9 0.46

Substance use 12‡ 40 34§ 58 0.12

*Percentages are given for women.†ORs and their 95% CIs are corrected for overoptimism.‡Substances used alone or in combination: selective serotonin reuptake inhibitors (SSRIs) (9), nasal decongestants (3), cannabis (2),

triptans (2), and interferon-� (1).§Substances used alone or in combination: SSRIs (7), cannabis (21), nasal decongestants (8), interferon-� (1), massive alcohol

intake (7), cocaine (4), and nicotine patches (1).

Table 3. Hemorrhagic RCVS: Clinical Features andAssociated Lesions

No. of Patients

RCVS WithIntracranialHemorrhage

(n�30)

RCVS WithoutIntracranialHemorrhage

(n�59) BivariateAnalysis

PNo. Percent No. Percent

Recurrent thunderclapheadache

25 83 56 95 0.11

Single acute headache 5 17 3 5 0.11

Transient focal deficit 6 20 8 14 0.54

Focal deficit �24 hours 9 30 1 2 0.0002

Seizures 2 7 2 3 0.60

Cerebral infarction 4 13 1 2 0.042

Elevated BP* 9 30 20 34 0.82

PRES 5 17 2 3 0.041

Dissection 4 13 3 5 0.22

Unable to work at6 months

8 27 0 0 �0.0001

*Systolic blood pressure (BP) �160 and/or diastolic blood pressure�90 mm Hg during the acute phase of RCVS. The mean maximal systolic/di-astolic BP was 153�36/82�16 mm Hg in the 30 patients with hemorrhageand 155�36/86�15 mm Hg in the 59 patients without hemorrhage.

Table 4. Mean Delay From Headache Onset to Other Featuresin Hemorrhagic RCVS

Delay From Headache Onset toNo. ofCases

Mean�SD,Days

Range,Days

Diagnosis* of ICH 11 2.2�2.5 0–8

In patients with a focal deficit 7 1.1�1.7 0–4

In patients without focal deficit 4 4�2.9 3–8

Diagnosis* of PRES 5 4�1.9 1–6

Diagnosis* of cSAH 27 4.6�4.3 0–20

First seizure 2 5�0 5

Diagnosis* of SDH 2 5.5�3.5 3–8

Last thunderclap headache 24 6.4�3.5 1–17

Diagnosis* of cerebral infarction 4 9.5�6.6 2–15

First angiogram 30 5�4.2 0–20

Showing vasoconstriction 20 5.7�4.8 0–20

Without visible vasoconstriction 10 3.4�2 0–6

Second angiogram showingvasoconstriction

10 8.2�4.2 1–15

Diagnosis* of vasoconstriction 30 6.6�4.7 0–20

*Diagnosis based on neuroimaging.




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89 patients and ICH was twice as frequent as infarction (12%versus 6%). Moreover, our data further establish that cSAH(30%) is the most frequent type of hemorrhagic manifestationof RCVS,3,4,8,10,11 whereas SDH seems less frequent.10,12

Despite the increasing number of published patients withhemorrhagic RCVS,3–5,7–12 some are still reluctant to attributean intracranial hemorrhage to RCVS and rather consider thearterial narrowings as a consequence of hemorrhage. Thisseems very unlikely in the present series for several reasons:first, the absence of other causes of hemorrhage at anextensive and repeated workup; second, the unusual prevail-ing pattern of bleeding, that is, mild localized cSAH, rarelyseen in other conditions; third, the clinical presentation withrecurrent thunderclap headaches in �80% of patients; fourth,the angiographic pattern of widespread segmental vasocon-striction and vasodilatation involving brain arteries wellremote from the site of bleeding; and fifth, the similarity ofangiographic changes in RCVS with and without intracranialhemorrhage.

The exact mechanisms of bleeding in RCVS remainunknown, but our data further illustrate the dynamic nature ofthis syndrome with headache and hemorrhages usually pre-ceding ischemic complications.3 Our finding that up to 17%of patients with hemorrhagic RCVS initially presented withisolated headaches and normal brain imaging, and onlysubsequently developed cSAH, ICH, and/or SDH after a fewdays of recurrent severe headaches, suggests that the abnor-mal vascular process starts before hemorrhage. The co-occurrence in 17% of our patients of PRES, a transientvasogenic cerebral edema related to small vessel dysfunctionwith acute disruption of the blood–brain barrier,4 and cSAHsuggests that the abnormal process initially affects very smallcortical arteries. We previously hypothesized that arterialabnormalities first involve small distal arteries and thenprogress toward medium- and large-sized vessels, whichcould explain the high rate of normal early angiograms (up to33%) in RCVS.3 Serial MRA and transcranial Dopplerstudies in a large cohort of RCVS cases showed that vaso-constriction affecting first segments of large arteries wasmaximal 18 to 22 days after headache onset, similar to thetiming of headache resolution.19,20 Moreover, marked vaso-

constriction could persist weeks after headache resolution,suggesting that vasoconstriction is not directly causing head-ache.19 We now suggest that segmental vasodilatation couldplay an important role at the initial stage of RCVS, triggeringthunderclap headaches by abrupt stretching of vessel wallsand causing hemorrhages by small vessel rupture or reperfu-sion injuries, whereas small vessel segmental constrictionremains asymptomatic (no or rare small vessel infarction). Ina second stage, vasoconstriction of second and first segmentsof major cerebral arteries becomes the major problem causingmainly watershed infarction.1–3,6

Risk factors for hemorrhagic RCVS have not been inves-tigated before. We found that female gender and a history ofmigraine were 2 independent predictors of intracranial hem-orrhages during RCVS. By contrast, a history of arterialhypertension and BP surges during RCVS were not associ-ated with the risk of hemorrhage. The female preponderanceof RCVS has long been described,1–3,7 and we have previ-ously shown that RCVS was more severe in females than inmales.3 Identifying migraine, especially without aura, as anindependent risk factor favoring hemorrhages is somewhatsurprising given the fact that prior studies did not single outmigraine as a risk factor for RCVS overall.2,3 Larger studiesare needed to re-evaluate migraine as a risk factor for RCVS,for hemorrhages during RCVS, or for both.

Our study, conducted in a single tertiary care center, is notfree of bias. Detailed clinical and imaging information wasprospectively collected, but timing of interviews and inves-tigations did not follow a standardized protocol. Observers ofthe neuroimaging data were not blinded to the clinical statusof the patients or to the hypotheses of the study. Despite theseconstraints, our study shows that hemorrhagic RCVS is notbenign; patients seem to have a higher risk of subsequentinfarction than those without hemorrhage, emphasizing theneed for close monitoring. Furthermore, one fourth are stillunable to work at 6 months of follow-up. There is no establishedtreatment of RCVS. Discontinuation of vasoactive medicationsin secondary forms seems logical.1,3 We used nimodipine inmost cases without any proof that it improved the course of thesyndrome more than simple bed rest.

The proportion of RCVS among intracranial hemorrhagesin the general population is as yet unknown but may be easilyunderestimated. Prospective studies are needed to address thisissue using a standardized workup in patients with cSAH,ICH, or SDH without other obvious cause and in patients withthunderclap headaches with normal findings on initial brainimaging and spinal tap.

ConclusionOur results indicate that intracranial hemorrhages affect onethird of all RCVS cases and are far more frequent thanischemic events. RCVS should be considered as a differentialdiagnosis in patients with any type of spontaneous intracra-nial hemorrhage and especially with localized cortical SAH.The diagnosis of RCVS may be difficult when initial brainand vascular imaging are normal, requiring repeated investi-gations. Women and migrainers may be at particularly highrisk for hemorrhagic manifestations. Studies of cerebral bloodflow at the acute stage and of cerebrovascular reactivity at a

Figure 3. Estimated event probability of cSAH, ICH, and ische-mic manifestations over time in the 30 patients with hemor-rhagic RCVS.




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distance of RCVS could help to understand the mechanismsunderlying this poorly understood syndrome.

DisclosuresNone.

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27

Abstract 5

28 Stroke Vol. 4, No. 1

52

Stroke November 2010

Original Contributions

可逆性脑血管收缩综合征出血的发生率、特征及危险因素Hemorrhagic Manifestations of Reversible Cerebral Vasoconstriction Syndrome

Frequency, Features, and Risk FactorsAnne Ducros, MD, PhD; Ursula Fiedler, MD; Raphael Porcher, PhD; Monique Boukobza, MD; Christian Stapf, MD;

Marie-Germaine Bousser, MD

背景和目的：可逆性脑血管收缩综合征 (Reversible cerebral vasoconstriction syndrome，RCVS) 常常表现为严重

的头痛和脑动脉可逆性收缩，且可能与缺血性和出血性卒中相关。本研究的目的在于揭示可逆性脑血管收缩

综合征伴发颅内出血的发生率、类型和危险因素。

方法：我们对 89 例患有可逆性脑血管收缩综合征的患者进行了前瞻性研究，其中有 8 例患者为产后发病，有

46 例患者应用了血管活性物质。应用标准双变量和多变量统计检验方法对发生出血和未发生出血的患者进行

统计分析。

结果：有 30 例患者 ( 占 34%) 出现了至少一种类型的颅内出血，包括皮层蛛网膜下腔出血 (n=27)、大脑半

球出血 (n=11) 和硬脑膜下出血 (n=2)，这 30 例患者中有 5 例为产后，12 例患者应用了血管活性物质。出血

的患者与未出血的患者相比有以下特征，年龄多较大 (46.6 岁比 41.6 岁，P=0.049)，多为女性 (90% 比 51%，

P=0.0017)，或合并有偏头痛 (43% 比 19%，P=0.022)。多变量统计检验显示有 2 个独立的危险因素与可逆性

脑血管收缩综合征伴发出血相关，即女性 (OR, 4.05; 95% CI, 1.46-11.2) 和合并偏头痛 (OR, 2.34; 95% CI, 1.06-5.18)。出血的患者在急性期出现持续的局灶神经功能缺失、脑梗死、可逆性后部白质脑病的危险性更高 ( 分别

为 30% 比 2%，P=0.0002 ；13% 比 2%，P=0.039 ；17% 比 3%，P=0.041)，并且在发病后 6 个月内不能恢复正

常 (27% 比 0%，P<0.0001)。结论：在可逆性脑血管收缩综合征的患者中，女性与合并偏头痛的患者有更高的伴发颅内出血的风险。总之，

颅内出血在可逆性脑血管收缩综合征患者中是较为常见的，并且与一些严重的临床表现相关联。

关键词：女性，颅内出血，偏头痛，可逆性脑血管收缩综合征，蛛网膜下腔出血，硬脑膜下血肿

(Stroke. 2010;41:2505-2511.　吉林大学第一医院神经内科　孙欣译吴江董铭校 )

From the Emergency Headache Center (A.D., U.F.), Head and Neck Clinic, Lariboisière Hospital, Paris, France; the Department of Neurology (A.D., U.F., C.S., M.-G.B.), Head and Neck Clinic, Lariboisière Hospital, Paris, France; the Department of Biostatistics (R.P.), Saint Louis Hospital; and the Department of Neuroradiology (M.B.), Head and Neck Clinic, Lariboisière Hospital, Paris, France; all from the APHP (Assistance Publique des Hoˆpitaux de Paris) and the Universite´ Paris Diderot, Paris, France.

Correspondence to Anne Ducros, MD, PhD, Centre d’Urgences Ce´phale´es, Hoˆpital Lariboisie`re, 2 rue Ambroise Pare´, 75475 Paris Cedex 10, France. E-mail [email protected]

© 2010 American Heart Association, Inc.

可逆性脑血管收缩综合征 (Reversible cerebral vasoconstriction syndrome，RCVS) 表现为剧烈的头

痛和多灶性脑血管收缩，头痛通常被患者描述为霹

雳样，伴或不伴有局灶神经功能缺失和癫痫发作，

这些伴随症状多在 3 个月内自愈 [1]。这一综合征以

女性患者居多，且多在 42 岁左右起病 [1-3]。可逆性

脑血管收缩综合征被认为是一种短暂的脑血管功能

的紊乱，从而形成了血管的节段性的扩张，在血管

造影时形成特征性的“香肠串样”的改变 [1]。尽管

可逆性脑血管收缩综合征可能是自发性的，但是一

半以上的病例显示该病常继发于特定的情况下，例

如产后或应用拟交感神经药物及 5- 羟色胺物质 [1,3-6]。

可逆性脑血管收缩综合征一度被认为是一种罕见的

疾病 [7]，但近 10 年来对该病的报道有所增加 [1]，这

是由于对在临床上表现为剧烈头痛 [2]、和 / 或表现为

卒中的患者常规进行头部 CT 血管造影或 MR 血管

造影，以及对该病认识的提高有直接关系 [1-3]。尽管

如此，可逆性脑血管收缩综合征始终是一种尚未被

充分了解的疾病，头痛的专科医生把该病看作是一

种完全不同类型的、尽管伴有疼痛但却是一种良性的

疾病；而卒中的专科医生则把该病看作是一种导致卒

中的特殊病因。实际上，卒中是该病的最严重的表现

形式 [1-3,7]，并且可能会遗留后遗症或导致患者死亡 [5,6]。

近期的研究和病例报道提示颅内出血可能在可逆性

53

Ducros et al Hemorrhages in RCVS

脑血管收缩综合征中是较为常见的 [3,5,8-12]，并且可表

现为不同类型，包括皮层蛛网膜下腔出血 (cSAHs)、大脑内出血 (ICHs) 和硬脑膜下出血 (SDHs)。但迄今

为止，尚无对这些颅内出血的临床特征及危险因素

的详细阐述。

我们通过前瞻性的研究分析了 89 例可逆性脑

血管收缩综合征患者颅内出血的临床和影像学特征，

并对其危险因素进行了分析。

对象和方法按照前瞻性研究的实验设计方案 [3]，我们连续

的纳入了明确诊断为可逆性脑血管收缩综合征的患

者，其纳入标准如下：(1) 突然发生的或进展性的罕

见的剧烈头痛，伴或不伴有局灶神经功能的缺失和

/ 或癫痫发作；(2)CTA、MRA 或经股动脉血管造影

(TfA) 显示有 2 根不同动脉各存在至少 2 处由脑血管

收缩导致的狭窄；(3) 应用相同血管造影方法显示动

脉的异常在 3 个月内消失。

从 2004 年 1 月到 2008 年 1 月，研究共纳入了

大巴黎地区 ( 共有约 1000 万居民 ) 符合上述 3 个标

准的患者 89 例 ( 其中 61 例为女性 )，其中 30 例患

者来自卒中单元 ( 每年大约收治 1000 例患者 )，另

外 59 例来自临床头痛急诊 ( 每年约 7500 例门诊患

者就诊 )。可逆性脑血管收缩综合征患者占总患者人

数的 0.26%(95% CI, 0.21%-0.31%)。每年约有 115 例

患者以霹雳样头痛为主诉前来就诊，对于这些患者

我们均进行包括血管成像在内的各项完善的检查。

对于所有患者均获得其知情同意。我们遵守法

国立法规定，即观察性研究不需要通过伦理委员会

的正式检查，但是所有的调查研究均需征得患者本

人的同意。这一许可可以是非书面的。按前文所述

收集患者详细的医疗史、临床、影像和生物学检查

数据 [3]。在发病时，按国际头痛疾病分类方法对偏

头痛患者进行诊断 [13]。最初的 67 例患者是基于先

前已发表的研究 [3]。在 89 例患者中有 8 例女性患者

为产后，有 46 例应用了血管活性物质。临床表现包

括剧烈的头痛 (89 例 )，短暂的局灶神经功能缺失 (14例 )，持续的局灶神经功能缺失 (10 例 )，癫痫发作 (4例 ) 和血压升高 (29 例 )。检查项目包括头部 CT 扫

描 (86例 )，1.5T MRI灌注成像、液体反转恢复 (FLAIR成像 )、T1和梯度回波加权成像 (89例 )，MRA(88例 )，经颅多普勒 (86 例 )，TfA(57 例 )，血液检查 (89 例 )，药物的尿液分析 (62)，脑脊液分析 (78 例 )。所有 89例患者的血管成像均表现出“串珠样”改变。47 例

患者脑脊液存在异常，22 例患者白细胞计数升高 ( 平均 11/mm)，30 例患者红细胞计数升高 ( 平均 2377/mm)，30 例患者蛋白水平升高 ( 平均 59 mg/L)。

针对所有患者均给予对症镇痛治疗 ( 一般为对

乙酰氨基酚 )。15例患者先应用尼莫地平静脉注射 (根据血压调整速度为 1-2 mg/ 小时 )，然后改为口服给

药，67 例患者直接口服尼莫地平 ( 根据血压调整剂

量为每 4 小时 30-60 mg)。疗程为 4-8 周。

分别于患者出院后 3-6 周和发病后 3-6 个月进行

跟踪随访。所有的 89 例患者跟踪随访的血管造影检

查 (73 例 MRA，16 例 TfA) 显示其血管狭窄均为可

逆性改变。

数据分析

结果用均数和标准差或频数和百分数表达。在

分析评价患者各特征表现与出血是否有关系时，计

量资料用 t 检验，计数资料用 Fisher 精确检验法。

多元逻辑回归用来确定多个相关变量与结果之间的

关系。与出血相关的因素在 0.15 水平可以纳入多元

模型。假设检验的检验水准均为 0.05。一阶相互作用

用于已选的变量检验。用拟合优度检验来分析逻辑回

归模型 [14]。从原始数据中按实验设计好的方法 [15,16]，

随机抽取 200 例样本。利用 C 指数 [17] 和校准斜率来

分析模型 [18]。用有代表性的样本评价模型再推论到

原始数据，样本和总体之间的差异可能由于抽样误

差引起。用校正斜率估计的回归系数修正最后的模

型。所有的测试是双向的，应用统计软件进行分析。

结果出血的发生率和亚型

89 例可逆性脑血管收缩综合征患者中，有 30例发生了颅内出血 (34%)，5 例发生了脑梗死 (6%)。89 例患者中 14 例发生了卒中 (16%)。59 例没有出

血的患者中有 1 例发生了梗死。30 例发生出血的患

者中有 13 例发生了卒中：包括脑出血合并脑梗死 (2例 )，脑出血不合并脑梗死 (9 例 )，脑出血合并皮层

蛛网膜下腔出血 (2 例 )。所有出血的 30 例患者均进行了 CT 和 MRA 扫

描，有 27 例行 TfA 检查。30 例患者血管造影均有

证据显示存在多灶性的血管收缩，而在 12 周内，通

过 MRA(28 例 ) 和 / 或 TfA(8 例 ) 检查发现上述改变

消失。血管造影、MRI 和血液检查均未发现其他导

致出血的原因。

研究中共发现了三种类型的出血，包括：皮层

54


表 1　可逆性脑血管收缩综合征颅内出血的不同类型：临床和影像学特征 cSAH cSAH+ICH ICH SAH+SDH SAH+ICH+SDH颅内出血的类型 (n=18) (n=7) (n=3) (n=1) (n=1)头痛　反复发作的霹雳样头痛 18 2 2 1 1　单纯急性头痛 … 5 1 … …

癫痫发作 1 1 … … …

可逆性后部白质脑病 5 … … … …

持续的神经功能缺失 1 6 2 … …

　脑出血相关 … 5 2 … …

　梗死相关 1 1 … … …

脑梗死 2 2 … … …

短暂神经功能缺失 5 … 1 … …

颈动脉夹层 2 2 … … …

cSAH ：皮层蛛网膜下腔出血；ICH ：脑出血；SDH ：硬脑膜下出血。

图 1　可逆性脑血管收缩综合征伴发皮层蛛网膜下腔出

血。A)CT 显示右侧额部蛛网膜下腔出血。B)FLAIR 序

列显示双侧后部皮质内蛛网膜下腔出血。C-D) 病例报

道：36 岁女性患者，阴道分娩后 2 天开始应用溴隐亭。

分娩后第 4 天，突发霹雳样头痛，持续 15 分钟。几小

时后的 CT、MRI(C) 和 CSF 均为正常。当天，患者又

继发了 9 次短暂霹雳样头痛。第二天，复查 MRI 显示

左侧颞叶皮层蛛网膜下腔出血。D) 应用尼莫地平治疗

后患者再未出现头痛。首发头痛后 2 天，TfA 显示弥漫

性血管收缩。2 个半月后复查 MRA 显示正常。

蛛网膜下腔出血 27 例 (30%)，脑出血 11 例 (12%) 和硬脑膜下血肿 2 例 (2%)。9 例患者为多发的出血 ( 表1)。MRI T2 成像未发现微出血。

在 27 例皮层蛛网膜下腔出血的患者中 ( 图 1)，有 24例患者的出血局限在单侧 (10例 )或双侧 (14例 )半球的脑沟内。其中有 1 例蛛网膜下腔出血的部位

是在右侧小脑半球的脑沟内。另外有 2 例蛛网膜下

腔出血较为弥散，位于双侧大脑半球和中脑环池。

有 14 例蛛网膜下腔出血患者通过 CT 和 MRI 均可诊

断，另外 13 例患者则是通过 MRI 诊断的。

10 例患者为一侧大脑半球出血，而有 1 例为双

侧额叶血肿。所有 12 处出血在 CT 和 MRI 上均可见。

55


6 例患者出现了 7 处不同脑叶的出血，有 4 例患者

出现了基底节出血，1 例为丘脑出血。

有 2 例蛛网膜下腔出血患者为急性起病且并发

了其他的出血类型。

可逆性脑血管收缩综合征出血患者的人口学特征和

危险因素

表 2 显示了伴或不伴有出血的可逆性脑血管收

缩综合征患者的主要人口学特征、血管危险因子和

潜在的危险因素。所有患者近期均无脑外伤史。双

变量分析结果显示年龄较大、女性及偏头痛患者更

易发生出血。而偏头痛的患者中大部分患者是没有

先兆的，只有少数患者伴有先兆 ( 表 1)。多变量分

析结果显示有 2 个独立的危险因素与可逆性脑血管

收缩综合征伴发出血高度相关，即女性 (OR, 4.05; 95% CI, 1.46-11.2) 和偏头痛病史 (OR, 2.34; 95% CI, 1.06-5.18)。但二者之间无关联。

可逆性脑血管收缩综合征出血患者的临床表现和相

关机能障碍

所有发生出血的 30 例患者均有急骤的剧烈头

痛，其中有 24 例可逆性脑血管收缩综合征患者伴有

的典型的反复发作的霹雳样头痛 ( 表 1 和表 3)。有

18 例患者有头痛触发诱因，多为性行为、体育锻炼、

咳嗽、打喷嚏、排便、排尿和沐浴。

2 例患者伴有局灶性的癫痫发作，其中有 1 例

患者继发大发作。6 例患者伴发 14 起短暂性局灶神

经功能缺失，包括 4 例患者发生的短暂性脑缺血发

作 ( 共 11 起 ) 和 2 例患者伴发的视觉先兆。9 例患

者出现了 >24 小时的持续的神经功能的缺失，其中

有 7 例为出血，2 例为脑梗死。在 11 例脑出血患者中，

有 4 例单纯表现为头痛，4 例为突发头痛伴发局灶

性神经功能缺失，另外 3 例患者在发病初期仅表现

为头痛，几天后进展为持续的局灶性神经功能缺失。

在可逆性脑血管收缩综合征发病的急性期，有

9 例患者收缩压≥ 160 mmHg，且 / 或舒张压≥ 90 mmHg，其中有 7 例患者仅是在霹雳样头痛的高峰

期血压有波动样升高，另外 2 例患者为持续的血压

升高。

5 例患者 (17%)MRI 扫描的 FLAIR 序列显示高

密度，这与可逆性后部白质脑病的改变一致 ( 表 1)。有 4 例患者 (13%)，包括 1 例可逆性后部白质脑病

患者进展为脑梗死。有 4 例患者，包括 2 例可逆性

后部白质脑病和 1 例脑梗死患者伴有颈动脉夹层 ( 其

图 2　可逆性脑血管收缩综合征伴发脑出血。A)CT 显示右侧枕叶脑出血。B) 女性患者突发头痛后

4 天 CT 显示双侧额叶脑出血伴轻微额叶皮质蛛网

膜下腔出血，而发病第 1 天 CT 正常。患者共发生

2 次头痛，分别发生于起病当天和第 3 天，第 3 天

出现失语。C) 女性患者突发霹雳样头痛，随后即

出现左侧偏瘫，发病当天行 CT 示深部脑出血。D)女性患者发生 6 次霹雳样头痛，发病 3 天 CT 和

CSF 均为正常，发病后 8 天 CT 示左侧枕叶出血伴

硬脑膜下血肿和轻微皮层蛛网膜下腔出血。

56


表 2　可逆性脑血管收缩综合征 (RCVS) 颅内出血：相关人口统计学特征和危险因素有颅内出血的无颅内出血的双变量分析　　　　　　多元分析

变量 RCVS (n=30) RCVS (n=59) P OR(95% CI)† P年龄，岁，均数±标准差 46.6±11.0 41.6±11.6 0.049 年龄，岁，范围 26–63 19–70 数量百分比数量百分比性别，女 27 90 34 58 0.0017 4.05(1.46-11.2) 0.007心血管危险因素　吸烟 9 30 30 53 0.11 　高血压病史 3 10 7 12 >0.99 　糖尿病 2 7 0 0 0.11 　高胆固醇血症 4 13 8 14 >0.99 　偏头痛 13 43 11 19 0.022 2.34(1.06-5.18) 0.936　无先兆偏头痛 13 43 11 19 0.022 　有先兆偏头痛 1 3 2 3 >0.99 RCVS 的促发因素　无 13 43 21 36 0.50 　产后 * 5 19 3 9 0.46 药物应用 12‡ 40 34§ 58 0.12 * 女性计算百分比†ORs 及其 95% 可信区间用于校正抽样误差。‡ 单一或复合用药：选择性 5 羟色胺再吸收抑制剂 (SSRIs) (9)，解鼻充血剂 (3)，大麻 (2)，阿米替林 (2)，α- 干扰素 (1)。§ 单一或复合用药：SSRIs (7)，大麻 (21)，解鼻充血剂 (21)，α- 干扰素 (1)，大剂量乙醇 (7)，可卡因 (4)，烟碱 (1)。

表 3　可逆性脑血管收缩综合征 (RCVS) 出血：临床特征和

相关的神经功能缺损有颅内出血的无颅内出血的双变量

RCVS (n=30) RCVS (n=59) 分析

患者数量数量百分比数量百分比 P反复发作的剧烈头痛 25 83 56 95 0.11单次急性头痛 5 17 3 5 0.11短暂的局灶性病变 6 20 8 14 0.54局灶性病变 >24 小时 9 30 1 2 0.002癫痫发作 2 7 2 3 0.60脑梗死 4 13 1 2 0.42血压增高 * 9 30 20 34 0.82可逆性后部白质脑病 5 17 2 3 0.041夹层 4 13 3 5 0.226 个月内不能工作 8 27 0 0 <0.0001*RCVS 急性期收缩压 (BP) ≥ 160 mmHg 和 / 或舒张压 ≥ 90 mmHg。在 30 名颅内出血的 RCVS 中平均最大收缩 / 舒张压

为 153±36/82±16 mmHg，在 59 名无颅内出血的 RCVS 中为

155±36/86±15 mmHg。

中有 3 例为单侧椎动脉夹层，有 1 例为 4 根血管均

有夹层 )。与未发生出血的患者相比，发生出血的患者表

现为持续性神经功能缺失的比例 (30% 比 2%)、发生

脑梗死的比例 (13% 比 2%) 以及可逆性后部白质脑

病的比例 (17% 比 3%) 较高。

血管收缩征象和颅内出血

表 4 显示的是头痛发生后诊断出血、缺血和血

管收缩的平均时间。有 15 例患者发生出血时即诊断

了血管收缩，而 14 例患者未在出血发生当时作出

诊断。14 例患者中有 4 例患者的血管造影在几天后

才显示出血管收缩。其余 10 例患者早期 MRA(6)、TfA(1) 或二者 (3) 均为正常。其血管收缩在第二次的

血管造影检查中才体现出来 (5 例 MRA，5 例 TfA)。有 1 例患者在出血前即诊断为血管收缩，患者第 1天 CT 和 CSF 检查为正常，第 3 天通过 TfA 发现血

管收缩，第 4 天 MRI 发现皮层蛛网膜下腔出血。

表 4　有颅内出血的可逆性脑血管收缩综合征 (RCVS) 患者

从头痛开始到其他症状发生的平均时间均数±标准差范围

从头痛开始病例数天数天数

诊断 * 脑出血 11 2.2±2.5 0-8　有局灶性症状 7 1.1±1.7 0-4　无局灶性症状 4 4±2.9 3-8诊断 * 可逆性后部白质脑病 5 4±1.9 1-6诊断 * 蛛网膜下腔出血 27 4.6±4.3 0-20首次癫痫发作 2 5±0 5诊断 * 硬脑膜下血肿 2 5.5±3.5 3-8最后一次剧烈头痛 24 6.4±3.5 1-17诊断 * 脑梗死 4 9.5±6.6 2-15首次血管造影 30 5±4.2 0-20　显示血管收缩 20 5.7±4.8 0-20　未显示血管收缩 10 3.4±2 0-6第二次血管造影显示血管收缩 10 8.2±4.2 1-15诊断 * 血管收缩 30 6.6±4.7 0-20* 诊断依靠神经影像学。

57


出血、可逆性后部白质脑病和癫痫发作通常发

生在 1 周内，而缺血性事件通常发生在第 2 周，多

在剧烈头痛停止后 ( 图 3)。有 5 例出血患者 (17%) 最初的大脑成像为正常。

1 例女性患者在霹雳样头痛首次发生 1 天内的 MRI和 CSF 均为正常，当天患者又再发了 9 次霹雳样头

痛，第二天复查 MRI 则提示继发了皮层蛛网膜下腔

出血 ( 图 1C)。另 1 例女性患者在发生 3 次霹雳样

头痛后的第二天 CT 和 CSF 检查仍未发现异常，但

在第 5 天发生第 4 次霹雳样头痛后行 CT 和 MRI 检查发现双侧皮质和中脑环池周围的蛛网膜下腔出血。

有 3 例患者分别在头痛发生后的当天、第 1 天和第

3 天初次行 CT 扫描时均为正常，然而 3 例患者中的

前 2 例在第 3 天，最后 1 例患者在第 8 天均发现发

生脑出血 ( 图 2D)。

可逆性脑血管收缩综合征伴发出血患者的临床转归

在最初的 3 个月，改良的 Rankin 评分中位值为

0 分，平均值为 1 分。有 2 例患者遗留严重功能缺

失 ( 改良的 Rankin 评分为 3 分和 4 分 )，有 12 例患

者 (40%)丧失了从事先前工作的能力。但无一例死亡。

发病后 6 个月，8 例患者因持续的神经功能缺

失 (5 例 ) 或明显的无力 (3 例 ) 仍无法重新工作。这

一比例较未发生出血的患者显著升高 (27% 比 0%，

P<0.0001)。

讨论研究中有 34% 的可逆性脑血管收缩综合征发生

了出血。众所周知，长期以来卒中 ( 包括脑出血和

脑梗死 ) 为可逆性脑血管收缩综合征最为严重的表

现 [1,5-7]。据估计，在前瞻性研究纳入的急性头痛患

者中其发生率为 6%-7%[2]，而在回顾性研究包括住

院患者的情况下其发生率为 54%[1]，其中脑出血占

0%-25%，脑梗死占 6%-31%[1-3,7,19]。这一偏差可能

是由于纳入研究对象的偏倚和缺乏诊断标准。在我

们的研究中，产生纳入对象偏倚的可能性较小，因

为我们同时纳入了卒中单元和头痛急诊中心的患者。

在我们的研究中，89 例患者卒中的发生率为 16%，

脑出血的发生率是脑梗死 2 倍 (12% 比 6%)。而且，

研究数据显示，可逆性脑血管收缩综合征伴随的出

血类型中，皮层蛛网膜下腔出血是最为常见的 ( 占30%)[3,4,8,10,11]，而硬脑膜下血肿最为少见 [10,12]。

尽管可逆性脑血管收缩综合征伴随出血的报道

日益增多 [3-5,7-12]，一些学者仍宁可认为由出血导致

了动脉的狭窄，也不愿将颅内出血归因于可逆性脑

血管收缩综合征。这种观点对于本研究中的病例很

可能是错误的，原因有以下几点：第一，经过多重

和反复的检查，没有其他原因能够导致出血；第二，

少量的局灶性的皮层蛛网膜下腔出血在其他情况下

是非常罕见的；第三，有 80% 的患者反复发生霹雳

样头痛；第四，血管造影显示出的包括脑动脉在内的

广泛性节段性血管收缩和血管舒张距出血发生的部位

较远；最后，伴和不伴有颅内出血的可逆性脑血管收

缩综合征患者的脑血管造影改变没有明显区别。

可逆性脑血管收缩综合征患者出血的确切机制

仍不清楚，但是我们的研究进一步证实了这一综合

征的动态变化，即头痛和出血常在缺血之前发生 [3]。

研究结果显示至少有 17% 的伴随出血的可逆性脑血

管收缩综合征患者在发病初期常表现为独立的头痛，

且大脑成像未见异常，仅在反复发生的剧烈头痛后

几天才进展为皮层蛛网膜下腔出血、脑出血、和 /或硬脑膜下血肿，提示在出血前已经出现了血管的

异常。研究中有 17% 的患者合并有可逆性后部白质

脑病，这是一种短暂的因小血管功能障碍和畸形血

脑屏障破坏所导致的血管源性脑水肿 [4]，而皮层蛛

网膜下腔出血则提示最初的异常影响了皮层小动脉。

我们最初假设动脉的异常首先累及远端的末梢血管，

接下来累及中等及大血管，这一假设能够解释为什

么可逆性脑血管收缩综合征早期血管造影检查正常

比例较高 ( 至少为 33%)[3]。应用 MRI 序列和经颅多

普勒研究可逆性脑血管收缩综合征病例，发现血管

收缩对大血管的影响最长可以发生在头痛发生后的

18-22 天，这与头痛缓解的时间相一致 [19,20]。此外，

明显的血管收缩可以持续到头痛缓解几周之后，提

图 3　30 例可逆性脑血管收缩综合征出血患者随时间的延长，发生

皮层蛛网膜下腔出血、脑出血和缺血事件的可能性。

天数

事件发生的可能性

皮层蛛网膜下腔出血

缺血事件

( 短暂性脑缺血发作和脑梗死 )

脑出血

58


示血管收缩并非是头痛的直接原因 [19]。我们提出节

段性的血管舒张在可逆性脑血管收缩综合征的早期

可能起到了重要作用，血管壁突发的伸缩导致了霹

雳样头痛，小血管的破裂或再灌注损伤导致了出血，

而小血管节段性的收缩可以没有任何症状 ( 没有或

罕有小血管梗死 )。在第二阶段，重要的脑血管出现

节段性的收缩成为问题的关键，从而最终导致了分

水岭梗死 [1-3,6]。

长期以来，对可逆性脑血管收缩综合征伴随出

血的危险因素从未进行过探讨。我们发现女性和偏

头痛病史是可逆性脑血管收缩综合征伴随颅内出血

的独立危险因素。相对而言，高血压和血压波动与

出血无关。以往的报道中也曾多次提及可逆性脑血

管收缩综合征患者中女性居多 [1-3,7]，我们发现可逆

性脑血管收缩综合征的患者中，女性患者较男性患

者病情更为严重 [3]。我们的研究发现偏头痛，尤其

是没有先兆的偏头痛，是可逆性脑血管收缩综合征

发生出血的独立危险因素，这是在以往的研究中从

未提及的 [2,3]。但仍需要进一步研究证实偏头痛究竟

是可逆性脑血管收缩综合征还是其伴随出血的危险

因素，或二者皆是。

我们的研究由一个第三方的护理中心监督，但

是仍不能避免偏倚。我们按时收集临床和影像学信

息，但是能否定时进行随访和观察并没有标准协定。

研究者在分析影像学数据时已经知晓了患者的临床

信息和研究假设。尽管存在以上因素，我们的研究

仍显示出伴有出血的可逆性脑血管收缩综合征并非

一种良性疾病，没有出血的患者则存在患梗死的较

高的风险，因此需要更密切的监护。并且，有四分

之一的患者在发病 6 个月时仍不能恢复工作。目前

尚无确切的治疗可逆性脑血管收缩综合征的方法。

停用血管活性药物似乎是合理的 [1,3]。我们应用尼莫

地平进行治疗，但是尚无任何证据显示其较单纯卧

床更为有效。

可逆性脑血管收缩综合征占一般人群颅内出血

的比率目前尚未统计，但很容易被低估。更进一步

的前瞻性研究应着眼于此，对无其他原因的皮层蛛

网膜下腔出血、脑出血或硬脑膜下血肿的患者，以

及那些起病初期大脑成像和腰椎穿刺正常的霹雳样

头痛的患者应进行更详细的检查。

结论我们的研究结果表明约有三分之一的可逆性脑

血管收缩综合征患者发生颅内出血，且其发生率高

于缺血性事件。对于伴有任何类型自发性颅内出血，

特别是局灶性皮层蛛网膜下腔出血的可逆性脑血管

收缩综合征患者应对其行鉴别诊断。在疾病早期，

当最初的大脑和血管成像均为正常时，可逆性脑血

管收缩综合征的诊断是较为困难的，需要对患者进

行反复的检查。女性和有偏头痛病史的患者存在较

高的出血风险。对于急性期脑血流的和脑血管反应

性的研究将有助于理解可逆性脑血管收缩综合征的

潜在机制。

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3. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syn-drome. A prospective series of 67 patients. Brain. 2007;130:3091–3101.

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