Reversible Cerebral Vasoconstriction Syndromes (RCVS)

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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


Characteristic

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

Characteristic

CCF

(n=55)

MGH

(n=84)

CSF performed 80% 77% 0.71

CSF protein


Characteristic

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


Characteristic

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


Characteristic

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

Singhal et al., New Eng J Med 2009


Final MRI 6 Days After Admission

Singhal et al., New Eng J Med 2009


Autopsy: no evidence for inflammation

Distal left MCA


RCVS

• 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%


RCVS vs PACNS: MGH cases, 1993-2009

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%


RCVS vs PACNS: MGH cases, 1993-2009

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

RCVS

(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


RCVS vs PACNS: MGH cases, 1993-2009

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


Lesion patterns in PACNS

2. Diffuse, symmetric subcortical

white matter hyperintensities

with additional discrete infarcts


Lesion patterns in PACNS

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)


Illustrative Case

Recurrent 10/10 ‘thunderclap’ headaches

Developed cortical blindness

MRI: symmetric MCA and PCA ‘watershed’ infarcts

DWI ADC FLAIR


Illustrative Case

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

‘sausage on a string’

appearance of the A2 and

distal branches of the anterior

cerebral arteries.

Bottom right - Digital

subtraction angiogram shows

‘sausage on a string’

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)

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