Reversible Cerebral Vasoconstriction Syndromes (RCVS)

Reversible Cerebral Vasoconstriction 

Syndromes (RCVS) 

Aneesh B. Singhal, M.D. 

Associate Professor of Neurology 

Harvard Medical School 

Stroke Service, Mass. General Hospital

Cerebral Arteriopathies 

• Cause stroke and vascular headache 

• Overall, the most common cause of stroke 

– 20% to 50% in older adults (LAA and SVD) 

– 30% to 40% in young adults 

– > 50% in children 

[1] Baltimore-Washington Cooperative Young Stroke Study. 

[2] Helsinki Young Stroke Registry. 

[3] International Pediatric Stroke Study. 

[4] Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke. 2006

Patients (mostly women): rTCH ± stroke/seizure 

A 

D 

B C 

E 

? PACNS CSF, vasculitis labs, brain biopsy negative 

Some treated with empiric steroids / cyclophosphamide 

F

Nomenclature: 1960s – 2000s 

• Call or Call-Fleming syndrome 

• Postpartum angiopathy 

• Eclampsia associated vasoconstriction 

• Migraine ‘angiitis’ 

• Thunderclap HA with reversible ‘vasospasm’ 

• Drug induced ‘angiitis’ 

• CNS ‘pseudovasculitis’ 

• Benign angiopathy of the CNS (BACNS) 

‘RCVS’ includes all of the above

Key Elements for Diagnosis 

1. Severe, acute, recurrent ‘thunderclap’ 

headache with or without additional neurologic 

signs or symptoms 

2. DSA / CTA/ MRA : multifocal vasoconstriction 

3. No evidence for aneurysmal SAH 

4. Normal CSF (protein

MGH and Cleveland Clinic Data

Characteristic 

Clinical Features 

CCF 

(n=55) 

MGH 

(n=84) 

Mean age (yrs) 43 +/- 11 42+/-12 0.65 

Female 80% 82% 0.75 

Caucasian 76% 82% 0.52 

Associated Trigger 

(?) 

Postpartum 4% 12% 0.12 

Idiopathic 45% 29% 0.042* 

Drugs 36% 61% 0.005* 

Migraine 24% 50% 0.002* 

P


Clinical Features 

CCF 

(n=55) 

MGH 

(n=84) 

Any HA at onset 95% 95% 0.99 

Thunderclap 84% 86% 0.99 

Recurrent TCH 74% 87% 0.06 

Focal deficits 38% 46% 0.34 

Onset seizures 16% 18% 0.82 

Presented

Laboratory and Imaging Features 


CCF 

(n=55) 

MGH 

(n=84) 

CSF performed 80% 77% 0.71 

CSF protein


Brain Imaging 

CCF 

(n=55) 

MGH 

(n=84) 

First CT or MRI normal 57% 55% 0.83 

Any CT / MRI abnormal 79% 73% ns 

Lesion Patterns 

Cortical surface SAH 23% 42% 0.022* 

Ischemic stroke 38% 40% 0.75 

Lobar hemorrhage 23% 18% 0.49 

P


Follow-up Imaging 

CCF 

(n=55) 

MGH 

(n=84) 

F/up CTA, MRA, DSA 60% 70% 0.21 

F/up TCD only 35% 30% 0.55 

Full Reversibility 76% 73% 0.69 

Partial Reversibility 21% 26% 0.61 

No Reversibility 2.4% 1.5% 0.99 

Median F/up (days) 66 

(27,152) 

56 

(30,94) 

P 

0.35

Cerebral Angiography 

‘beading’ 

‘sausage-on-a-string’ 

RCVS: Brain Imaging 

Diffusion-MRI 

symmetric infarcts 

watershed regions 

FLAIR-MRI 

vasogenic edema 

(posterior leukoencephalopathy 

)

RCVS: Brain Imaging

RCV, RPLS, ICH, ICA-dissection

Brain Hemorrhage in RCVS 

Hemorrhages are common, more so in women, and 

frequently assoc. with vasoconstrictive drugs 

Types 

1. Small non-aneurysmal cortical surface SAH 

2. Parenchymal ICH – lobar (single or multiple) 

3. Subdural hemorrhage 

CT and FLAIR 

Cortical SAH 

GRE-MRI 

Cortical SAH 

CT 

Lobar ICH 

GRE-MRI 

Cerebellar ICH

Pathophysiology 

TCH 

RCVS 

PRES 

overlapping clinical, imaging features… 

?shared pathophysiology 

endothelium, perivascular nerves, serotonin, epinephrine

• Migraine 

Differential Diagnosis 

• Thunderclap headache (TCH) 

– aneurysmal SAH, intracerebral hemorrhage, 

CVST, pituitary apoplexy, viral encephalitis, 

vertebral or carotid dissection, PCA embolus 

• Similar angiographic abnormalities 

– Primary angiitis of the CNS (PACNS) 

– Moyamoya disease 

– FMD 

– Intracranial atherosclerosis

Distinguishing RCVS from PACNS 

Feature RCVS PACNS 

Headache Recurrent TCH Insidious, chronic 

Infarct pattern ‘Watershed’ Small, scattered 

Lobar H’rrge Common Rare 

Cortical SAH Common Rare 

Reversible edema Common - 

Angiogram Sausage on a 

string (smooth) 

Irregular, notched, 

ectasia

Diagnostic Approach 

1. Clinical Recognition (rTCH) 

2. Brain Imaging (lesion patterns) 

3. Angiography (‘sausage-string’) 

RCVS: an “instantly recognizable” condition

RCVS Treatment Options 

1. Simple observation !! 

2. IV fluids, pain management, laxatives 

3. Avoid precipitants e.g. vasoconstrictive drugs 

4. Avoid blood pressure modulation 

5. Ca ++ channel blockers (nimodipine, verapamil, Mg) 

6. Short course of steroids (best avoided!!) 

7. Fulminant cases: balloon angioplasty, IA nicardipine


Treatment and Outcomes 

CCF 

(n=55) 

MGH 

(n=84) 

Ca Channel Blockers 87% 46%

Regression: predictors of poor outcome 

Factor All Patients 

P Value 

MGH Cohort 

P Value 

Age 0.61 0.95 

Female 0.87 0.74 

CaCB 0.27 0.98 

Steroids 0.09 < 0.001 

MGH of 23 patients who received steroids, 11 

(48%) had new symptoms and new infarcts 

within 2-6 days after steroid initiation

CTA before IA treatment (PPD 20) 

Singhal et al., New Eng J Med 2009

CTA after IA treatment 


Final MRI 6 Days After Admission 


Autopsy: no evidence for inflammation 

Distal left MCA


• Group of conditions characterized by reversible 

segmental constriction-dilatation of cerebral arteries 

• ~90% have recurrent ‘thunderclap’ headaches 

• Brain MRI can be normal or show ischemic stroke, 

ICH, cSAH, or reversible brain edema (PRES) 

• Usually a self-limited condition with benign outcome 

• Angiographic reversal occurs within days to weeks 

• Pathophysiology: ?abnormal cerebral vascular tone 

Singhal et al., Arch Neurol 2011; Calabrese et al., Ann Int Med 2007; 

Ducros et al., Brain 2007; Chen et al., Ann Neurol 2008, 2010

Next Steps 

International Collaboration 

Validate provisional diagnostic criteria 

Define relationships with PRES and TCH 

Clarify whether drugs can precipitate RCVS 

Pathophysiology – biomarkers, autoregulation 

Investigate treatments e.g. nimodipine 

What’s first, headache or vasoconstriction? 

Why ‘segmental’? Why prolonged?

Stroke attributed to 

‘vasospasm’ for centuries 

1950s: Pathological entities 

- Carotid athero 

- Atrial fibrillation 

- Lacunar 

‘Vasospasm’ not implicated 

- except SAH 

- except rare migraine 

1971, 1975: Salpetrierre Conf. 

1988: Call-Fleming Syndrome 

C. Miller Fisher, MD

M. Akif Topcuoglu, MD (circa 2002)

Hemorrhages in 1 st week, Infarcts in 2 nd week

Additional Slides 

- Pathophysiology 

(BHI, endothelium/p-v nerves, drugs) 

- Migraine vs. RCVS 

- RCVS vs. PACS

Pathophysiology

Pathophysiology of RCVS 

- ‘migrainous vasospasm’ 

- ‘mechanical’: catheter-induced vasospasm 

- ‘angiographic dye’ - bradykinin 

- sympathomimetic (ergot, amphetamine, cocaine) 

- endothelin-1, nitric oxide, substance P, CGRP 

- female reproductive hormones 

- serotonin 

- calcium

A B 

C 

(A) Headframe used for bedside TCD examination. 

Breath Holding Index 

%(V apnea-V baseline) 

V baseline x t apnea 

Normal = 1.2 ± 0.6 

(B) Representative CT-angiogram showing multifocal segmental stenosis 

(“beading”) of the bilateral middle cerebral arteries, basilar, posterior 

cerebral, and superior cerebellar arteries. 

(C) TCD spectrum showing elevated mean flow velocity in the left MCA.

TCD response to Apnea (breath-hold) 

Percentage Change of CBFV (%) 

20 

15 

10 

5 

0 

-5 

-10 

-15 

-20 

Control Migraine RCVS 

BH start Min BH end

Perivascular nerves 

smooth muscle cells 

endothelial cells

Perivascular Nerves 

• Perivascular nerves release various 

neurotransmitters and peptides, including 5-HT (Reinhard 

et al., Science, 1979, 206: 85) 

• Perivascular nerves contain catecholamines, but 

vasoconstriction from norepinephrine is poor across 

species, including humans (Bevan et al., Stroke, 1998, 29: 212.) 

• Interestingly, perivascular sympathetic nerves take 

up serotonin both in vitro and during the early phase 

of subarachnoid hemorrhage (Szabo et al., Stroke, 1992, 23: 54.)

Endothelium 

• Modulates vascular caliber by producing and 

releasing EDRFs such as NO, PGI2, EDHF 

• Cerebrovascular endothelial dysfunction might 

be related to vasoconstriction in RCVS-PRES? 

• Increased plasma levels of soluble antiangiogenic 

factors (sFlt1, endoglin) documented 

in pre-eclampsia and may underlie the 

endothelium dysfunction. 

(Levin et al. NEJM 2004, 2006; Singhal et al, NEJM 2009)

Hypothesis 

• Raphe nuclei in the brainstem, projections to 

peri-vascular nerves 

– trigeminovascular system and serotonergic pathways 

• Increased serotonin, NE levels in nerve endings 

• Might explain the headache, hyper-reflexia, 

segmental vasoconstriction, depression in RCVS 

• Distal capillary bed - serotonergic effects may 

explain edema, overlap with PRES 

• In addition, endothelial dysfunction might be 

related to vasoconstriction in RCVS-PRES? 

– soluble anti-angiogenic factors (sFlt1, endoglin) 

• (Levin et al. NEJM 2004, 2006; Singhal et al, NEJM 2009)

Spectrum - disorders of cerebrovascular tone? 

Headache, vasoconstriction-vasodilatation 

Stroke 

Ischemic 

ICH 

cSAH 

Dissection 

TCH 

Other 1° Headaches 

Hypertensive enceph. 

Eclampsia 

Porphyria 

Head trauma 

Post-CEA 

Sympathomimetic drugs 

Serotonergic drugs 

- etc - 

Edema 

(PRES)

Inter-relationship between RCVS & PRES 

4 postpartum patients with RCV & PRES 

A 

B 

C D D 

Singhal AB, Arch Neurol 2004;61:411-6 

b 

A 

B 

C

RCVS and Drugs/Meds 

Ergot derivatives (bromocryptine, ergotamine, lisuride) 

Nasal decongestants (ephedrine, phenylpropanolamine) 

Diet pills (metabolife, ephedra supplements, ma huang) 

Cocaine, amphetamines, LSD, marijuana 

Cyclosporin A 

Erythropoetin, RBC transfusion, Hypercalcemia 

Licorice 

Intravenous immune globulin 

Sumatriptan 

SSRIs, in combination with other vasoactive drugs 

Hormonal – OCPs

RCVS and serotonergic drugs 

Drugs and ICH: epidemiological studies controversial 

•Hemorrhagic Stroke Project: PPA in diet pills, ephedra 

• Korean Study: PPA in cold remedies 

• Mexican study: sympathomimetics 

Association of drugs with RCVS remains anecdotal

Serotonin – central role in RCVS? 

Sumatriptan: 5-HT 1B,D receptors 

Cocaine, amphetamines: sympathomimetic + serotonergic actions 

Diet pills: stroke, “carcinoid” heart & lung lesions (NEJM 1997) 

Subarachnoid hemorrhage: ? neuronal serotonin uptake/release 

Migraine related stroke: ?serotonergic mechanisms 

Head injury: ? release of serotonin from brain, platelets 

Porphyria: liver tryptophan pyrrolase is haem-dependant; haem 

deficiency in porphyria elevates 5-HT levels (Nature 1983) 

Serotonin Syndrome: assoc. with migrainous stroke (Headache 1997)

Serotonin – further evidence 

• SSRIs associated with digit ischemia 

• serotonin implicated in Raynaud’s phenomenon 

• sumatriptan and Prinzmetal’s angina, MI 

• sumatriptan and mesenteric ischemia 

• Diet pills: sympathomimetic + serotonergic 

effects, reversible cardiac valvular lesions and 

pulmonary hypertension (carcinoid syndrome) 

• Abilify and stroke

Serotonergic meds common…but 

RCVS is relatively uncommon 

Idiosyncratic reaction? 

Transient effect? 

‘Tip of the iceberg’? 

Genetic polymorphisms? 

Genetic variation of SERT 

Genetic variation of 5-HT receptors 

Genetic variation affecting other regulatory proteins

RCVS and Migraine

RCVS and Migraine 

Is RCVS simply a severe migraine attack? 

Several differences between migraine and RCVS… 

- Migraine has vascular and neuronal basis 

- Angiogram in migraine invariably normal 

- Migraine is a primary headache disorder; while 

headache in RCVS may be ‘symptomatic’ 

- Migraine recurs for years, RCVS rarely recurs 

- Only 25% of pts with RCVS have prior migraine 

Singhal AB, Neurology 2002

Other Headaches and ‘Vasospasm’ 

IHS classification v.2: ‘Other Primary Headaches’ 

4.1 Primary stabbing headache 

4.2 Primary cough headache 

4.3 Primary exertional headache 

4.4 Primary headache associated with sexual activity 

4.5 Hypnic headache 

4.6 Primary thunderclap headache 

4.7 Hemicrania continua 

4.8 New persistent daily headache

Neurology 2006: 67:2164 

• Prospectively recruited 56 patients with 

recurrent TCH of unknown etiology 

• MR-angiography in all; repeated if abnormal 

• RCVS in 39% [MCA 100%, ACA, PCA ~50%, basilar 9%] 

• Ischemic stroke in 7% (14% Pv, 3% Pn) 

• Pv and Pn showed no difference in 

demographics and headache characteristics 

except for higher rate of Valsalva-like triggers 

(exertion, defecation)

RCVS vs. aSAH

RCVS-SAH (n=35) vs. aSAH (n=515) 

• Univariate analysis: 

younger (43±12 vs. 55±14 years; p

RCVS (n=35) vs. aSAH (n=515) 

• RCVS 

– Acute and multi-focal vasoconstriction 

– Small, cortical surface bleeds 

– Early infarcts, parenchymal bleeds, RPLS 

– Associated condition: pregnancy, drugs 

• Vasospasm in aSAH 

– Usually delayed, and affects 1-2 arteries 

– TCH not recurrent 

– Delayed infarction 

– Evidence for ruptured aneurysm 

Muelschlagel & Singhal, ISC 2011

RCVS vs. PACNS

RCVS versus PACNS 

• 1950s: Primary angiitis of the CNS (PACNS) 

uniformly poor outcome; requires prompt 

immunosuppressive therapy 

• Until late 2000s: RCVS under-recognized 

(variable nomenclature - Call’s, BACNS, PPA, 

vasospasm in eclampsia, TCH, migraine, drugs) 

• 1950s-2000s: patients with RCVS misinterpreted 

as having PACNS due to overlapping features 

such as headache, cerebral angiographic 

abnormalities, and ischemic stroke 

patients with RCVS exposed to the risks of brain 

biopsy, chronic immunosuppressive therapy

Angio positive in 70 cases; biopsy positive in 31 cases 

18 patients with positive angio, negative biopsy

RCVS vs PACNS: MGH cases, 1993-2009 

Clinical Characteristic RCVS 

(n=84) 

PACNS 

(n=35) 

P value 

Age in years, Mean ± SD 42 ± 12 49 ± 16 0.02 

Female 82% 31% < 0.001 

Depression or Anxiety 38% 11% 0.004 

Prior Chronic Migraine 43% 14% 0.003 

Thunderclap Headache (TCH) at 

Onset 

Associated Condition 

• No identifiable factor 

• Miscellaneous 

• Postpartum 

• Vasoactive drugs 

SSRI 

Illicit drugs 

Imitrex 

Sympathomimetics 

86% 6%


Characteristic RCVS 

(n=84) 

PACNS 

(n=35) 

P value 

Hemiplegia or aphasia 32% 51% n.s. 

Hemianopia / cortical blindness 41% 26% n.s. 

Seizures 18% 17% n.s. 

Hypertensive (≥140, ≥ 90mmHg) 45% 32% n.s. 

ESR, mm/ hour, mean (SD) 23 (22) 31 (23) n.s. 

CSF results abnormal 

WBC (corrected for RBC) 

Protein (mean, SD) 

Pathology available 

Positive histology 

24% 

2.5 (3.5) 

50 (43) 

13% 

0% 

70% 

19.5 (28.4) 

86 (124) 

77% 

33% 


Brain Imaging 

Initial Brain MRI Results 

Normal scan 

Infarct 

Parenchymal hemorrhage* 

Subarachnoid hemorrhage* 

RPLS 

Mass lesion 

New Lesion on F/up (n=76) 

New lesion present 

Infarct 

Parenchymal hemorrhage 

Subarachnoid hemorrhage 

RPLS 


(n=84) 

20% 

33% 

14% 

35% 

34% 

0% 

39% 

26% 

7% 

13% 

11% 

PACNS 

(n=35) 

0% 

91% 

3% 

3% 

0% 

6% 

40% 

40% 

3% 

0% 

0% 

P value 

0.006 


Brain Imaging RCVS 

(n=84) 

Lesion Pattern 

Single 

Symmetric 

Borderzone/watershed 

Hemispheric lesions 

Superficial 

Deep 

Brainstem 

Cerebellum 

‘Dot’ sign on FLAIR 

33% 

45% 

83% 

86% 

55% 

0% 

24% 

70% 

PACNS 

(n=35) 

3% 

18% 

9% 

27% 

97% 

97% 

18% 

21% 

P value 

0.001 

0.03 

Brain Lesion Topography in RCVS 

1. No parenchymal lesion 

All had recurrent 

‘thunderclap’ headaches 

(Ducros: MRI normal in 70%) 

2. Reversible brain edema: 

FLAIR-positive, ADCnegative,posteriorpredominant, 

grey-white 

matter lesions (i.e. 

‘reversible posterior 

leukoencephalopathy 

syndrome’)

Brain lesion topography in RCVS 

3. MCA/PCA/ACA watershed infarcts

Lesion patterns in PACNS 

1. Punctate, widely distributed infarcts; deep plus superficial regions


2. Diffuse, symmetric subcortical 

white matter hyperintensities 

with additional discrete infarcts


3. Single, hyperintense, mass lesion 

(one patient, normal angiogram, positive pathology) 

Molloy, Calabrese & Singhal; Arth Rheum 2008 

Note: In the MGH series, PACNS was never associated with 

normal MRI scans. ICH was rare. It is likely that literature 

reports of PACNS are confounded by RCVS.

Distinguishing RCVS from PACNS 

Clinical differences can be ‘diagnostic’ 

symptom onset acute in RCV, insidious in vasculitis 

Clinical distinction can be difficult especially in the 

acute stages (i.e., before the tempo of the disease 

is established, and without serial vascular imaging). 

Neuroimaging (lesion topography) may be helpful, 

but should be used in conjunction with the clinical 

features and lab. results to discriminate between 

these conditions.

Comparison of CTA and DSA Findings

Advanced MRI for Cerebral Arteriopathy? 

• Küker W et al., Vessel wall contrast enhancement: a diagnostic sign of 

cerebral vasculitis. Cerebrovasc Dis. 2008;26(1):23-9. 

• Swartz RH et al., Intracranial arterial wall imaging using high-resolution 

3-tesla contrast-enhanced MRI. Neurology. 2009;72(7):627-34.

A B C 

D 

E 

Brain biopsy positive PACNS immunosuppression 

F

To study the phenomena of disease 

without books is to sail an uncharted 

sea, while to study books without 

patients is not to go to sea at all 

The value of experience is not in 

seeing much, but in seeing wisely 

-Osler

Cerebral Arteriopathies 

1. Large or Medium-Sized Arteries 

a. Atherosclerosis 

b. Cerebral artery dissection 

c. Reversible cerebral vasoconstriction syndromes 

d. Genetic or Inherited: Moyamoya, Sickle, Fabry’s, FMD 

e. Inflammatory: Takayasu, Anti-phospholipid antibody-associated 

f. Infectious: TB, Herpes zoster, syphilis, bacterial, HIV 

2. Small Vessel Disease 

a. Inflammatory: PACNS, Giant-cell, Amyloid, PAN, SLE, Behcet’s, 

Scleroderma, Churg-Strauss, Degos’, Eale’s, Susac, Spatz-Lindenbergh 

b. Infectious: Herpes zoster, Cysticercosis 

c. Genetic or Inherited: CADASIL, HERNS, COL4A1 mutation

Illustrative Case 

46 year male: acute, 10/10 post coital headache 

CT-A : MCA, PCA, SCA, PICA, basilar ‘beading’ 

Vasculitis labs negative, CSF normal (no SAH, 0 WBC)


Recurrent 10/10 ‘thunderclap’ headaches 

Developed cortical blindness 

MRI: symmetric MCA and PCA ‘watershed’ infarcts 

DWI ADC FLAIR


MR angio - severe multifocal vasoconstriction 

TCDs - diffusely elevated blood flow velocities 

3 weeks later: 

Deficits resolve; TCD velocities normalize 

MRA shows resolution of vasoconstriction.

Illustrative Case # 2 

57 y woman. Recurrent TCH while bathing. 

A B

PACNS – Typical Angiographic features 

Left - CTA shows eccentric, irregular, 'notched' appearance of the left 

middle cerebral artery 

Middle - Digital subtraction angiogram shows irregular ‘notched’ 

appearance of the distal branches of the left anterior cerebral artery. 

Right - Digital subtraction angiogram shows irregular ‘notched’ 

appearance of the basilar artery and PICA.

RCVS – Typical Angiographic features 

Top left - CT angiogram shows 

‘sausage on a string’ 

appearance in the bilateral A2 

segment and distal branches of 

the anterior cerebral arteries. 

Top Right - CT angiogram 

shows symmetrical ‘sausage 

on a string’ appearance of 

bilateral middle cerebral 

arteries. 

Bottom left - Digital 

subtraction angiogram shows 


appearance of the A2 and 

distal branches of the anterior 

cerebral arteries. 

Bottom right - Digital 

subtraction angiogram shows 


appearance of the anterior and 

middle cerebral arteries.

Treatment vs Poor Outcome 

All Patients (n=139; of which 15 (11%) had mRS 4-6) 

Treatment O.R. 95% C.I. P Value 

CaCB (64%) 0.83 0.27 - 2.47 0.47 

Steroids (53%) 2.67 0.80 - 8.82 0.08 

MGH Cohort (n=84, of which 12 (14%) had mRS 4-6) 

Treatment O.R. 95% C.I. P Value 

CaCB (49%) 1.06 0.31-3.59 0.59 

Steroids (27%) 7.6 2.01 - 28.7 0.003 

(CCF 48 (87%) received both steroids and CaCB)

Reversible Cerebral Vasoconstriction Syndromes (RCVS)

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