R Shravani RCVS Grand Rounds final .ppt

Reversible Cerebral Vasoconstriction Syndrome

Shravani Reddy Nalla MDNeurology Residency PGY2

Grand Rapids Medical Education Partners

Disclosures

None

AGENDA

•Case Presentation•History •Clinical Diagnosis •Associated Conditions •Pathophysiology•Neuroimaging•Differential Diagnosis •Management

Chief complaint

32 y/o female G1P0 presents to Emergency room with

Altered Level of Consciousness

History

Initial Presentation❏ Patient developed -Severe Headache,

Holocephalic -Associated with nausea 3 hours prior to her presentation to ED

❏ Patient found Unresponsive ❏ Tongue bite ❏ Incontinent Urine ❏ On floor by the family❏ Another seizure in ED

Past History

❏ PMH: Migraine without aura

❏ PSH: Appendectomy

❏ Medications: Prenatal Vitamins, Tylenol

❏ Social history: No tobacco, alcohol or illicit drug use per Family

Physical Exam ❏ Blood Pressure : 202/135❏ Temperature: 37.C❏ Heart Rate : 110❏ Respiratory Rate : 24

Neuro Exam❏ Severe Distress,❏ Somnolent and Moaning❏ Follows simple verbal commands ❏ CN II-XII intact ❏ Motor- grossly equal strength in

all 4 extremities ❏ Sensory -Intact to all modalities ❏ Reflexes- 2+ all extremities

Labs ❏ Lactic Acid 8.1❏ HCO3 Arterial 10.2❏ pH Arterial 7.1❏ Sodium Arterial 138

❏ ALT 5850❏ AST 6450 ❏ Bilirubin 2.0

❏ Hg 7.2 ❏ Platelets 39❏ INR 1.8

❏ GFR 38❏ Creatinine 1.3

CT head

MRI DWI-ADC

MRI – T2 FLAIR

MRA

Further Investigations

❏ Hypercoagulable Panel:

Elevated Factor VIII,Elevated Protein C , Elevated Protein S

❏ ECHO Normal EF :No valvular abnormalities

❏ Serum Vasculitis labs:

ANA, p-ANCA, c-ANCA,Cryoglobulin, Complement levels,Rheumatoid factor, SSA/SSBALL above labs NORMAL

❏ CSF analysis: Clear fluid, RBC-3, WBC-0, protein-46, Glucose-60

❏ EEG:

Encephalopathic No epileptiform discharges

MRA 2 weeks later

Final Neurological Diagnosis

RCVS

HISTORY

History of RCVS• Stroke attributed to 'vasospasm' for centuries • 1950's pathological entities – Carotid atheroma, Lacunar, Afib• 1970s Dr.Fisher described an unusual case of postpartum women with

vasospasms• 1984 First Convincing Case report description A 39-year-old woman with acute onset severe headache, R hemiparesis R hemianopia and Seizures,• 1988 Call Fleming syndrome

1.M Serdaru. Et. al" Isolated benign cerebral vasculitis or migrainous vasospasm? "Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:73-762.Gregory K. Call, MD, Marie C. Fleming, MD .et.al "Reversible Cerebral Segmental Vasoconstriction" (Stroke 1988;19:1159-1170)

Initial Angiography

1.M Serdaru. Et. al" Isolated benign cerebral vasculitis or migrainous vasospasm? "Journal of Neurology, Neurosurgery, and Psychiatry 1984

Resolution on repeat Angiography 3 weeks later

1.M Serdaru. Et. al" Isolated benign cerebral vasculitis or migrainous vasospasm? "Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:73-76

Nomenclature

History

In 2007 review by Leonard Calabrese and colleagues proposed the name "Reversible Cerebral Vasoconstriction Syndrome“

Leonard H. Calabrese et, al “Narrative Review: Reversible Cerebral Vasoconstriction Syndromes” Ann Intern Med.

What is RCVS

• Comprise a group of diverse conditions, all characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden (thunderclap), severe headaches with or without associated neurologic deficits

• Usually Benign, self limiting condition

Leonard H. Calabrese et al. 2007

Key Elements for Diagnosis 1. Severe, acute, recurrent "thunderclap" headache with or without

additional neurologic signs or symptoms

2. No evidence of aneurysmal SAH

3. Normal or near Normal CSF analysis (protein<80, WBC<10)

4. DSA/MRA/CTA: multifocal vasoconstriction

The diagnosis may be 'confirmed' if:a. Reversibility is documented (typically <12 weeks)b. Autopsy – no mimics (PACNS, Athero, aSAH)Leonard H. Calabrese, David W. Dodick, Todd J. Schwedt, and Aneesh B. Singhal (Annals of Int Med 2007)

Data From 3 Large Case Series

1. Chen et al, (n=77), 2002-2009 (excluded hemorrhages)2. Ducros et al, (n=89), 2004- 2008 3. Singhal et al, (n=139), 1993-2009 (retrospective)

Clinical Features

• Thunderclap Headache (94 to 100%) -- Acute onset, peaks in less than a minute --Short lasting, typically 1-3 hours• Focal deficits (8 to 43%) - Transient or persistent • Seizure (1 to 17%)- Recurrent seizures are rare

Clinical FeaturesCharacteristics Chen et al (n=77) Ducros et al (n=89) Singhal et al (n=139)

Headaches at onset 100% 100% 95%

Recurrent thunderclap 100% 91% 78%

Any trigger for headaches 80% 75% --

Focal neurological deficit 8% 25% 43%

Seizures 1% 4% 17%

Blood pressure surge 46% 34% --

1. Aneesh B. Singhal, et al. “Reversible Cerebral Vasoconstriction Syndromes Analysis of 139 Cases”Arch Neurol. 2011;68(8):1005-1012.2. Ducros A, et, al “Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke 2010; 3. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010;

Timing of Clinical Features

Ducros A et al.. "The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome". 2007;130(Pt 12):3091–101. text

Epidemiology• True Incidence of RCVS remains uncertain • Age• Peak Incidence - 42 years• Range 10-72 years

• Males present on an average 10 years earlier than women

• Female to male ratio ranged from 2.6 : 1 in the French cohort to 8.6 : 1 in the Taiwan cohort

• Pediatric patients are occasionally seen and all of them have been boys Ducros et al. 2007; Chen et al. 2006a Liu et al. 2009; Kirton et al. 2006

Characteristics Chen et al (n=77) Ducros et al (n=89) Singhal et al (n=139)

Recruitment Prospective from headache clinic

Prospective from emergency headache center and stroke unit

Retrospective from an internal medicine dept and stroke unit

Duration 2002-2009 2004-2008 1993-2009

Mean age 47.7 years (10-76) 43.2 years (19-70) 42·5 years (13–69)

Sex distribution (M:F) 1:8·6 1:2·2 1:4·3

History of migraine 17% 27% 40%(headache)History of hypertension 25% 11% -Any precipitant for syndrome

8% 62% -

Postpartum 1% 13% 11%Vasoactive substances 3% 52% 42%

1. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010; 2. Ducros A, et, al “Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke 2010;3. Aneesh B. Singhal, et al. “Reversible Cerebral Vasoconstriction Syndromes Analysis of 139 Cases”Arch Neurol. 2011;68(8):1005-1012.

ASSOCIATED CONDITIONS

Predisposing Conditions

• Post-partum (±use of vasoactive drugs)

• Migraine

• Vascular disorders: Cervical artery dissection, fibromuscular dysplasia, carotid endarterectomy, unruptured intracranial aneurysm

• Catecholamine-secreting tumors: Pheochromocytoma, glomus tumors, bronchial carcinoid tumors

• Intracranial conditions: Neurosurgical procedures, head trauma, spinal subdural haematoma, CSF hypotension

• Others: Hypercalcaemia, porphyria

Precipitants

• Illicit drugs: cannabis, cocaine, ecstasy, amphetamines, LSD• Ergotamine and ergot derivatives • Sympathomimetic drugs: Adrenaline, pseudoephedrine, ephedrine,• Serotonergic drugs: Selective serotonin reuptake inhibitors, triptans• Dopaminergic drugs: Bromocriptine• Immunosuppressant drugs: Tacrolimus, cyclophosphamide, interferon-α• Blood products: Intravenous immunoglobulin, red blood cell transfusion• Miscellaneous: indomethacin, nicotine patches, erythropoietin, oralcontraceptive pills, ginseng, licorice, diet pills

Pathophysiology

Pathophysiology

• Key mechanism: Transient alteration in Cerebral Vascular tone

1. Sympathetic overactivity2. Oxidative stress3. Endothelial dysfunction

1. Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007 2.Ducros A, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of 67 patients. Brain 2007 3.Bain J, Segal D, Amin R, et al. Call-Fleming syndrome: headache in a 16-year-old girl. Pediatr Neurol 2013;49:130 –33.e1

Sympathetic Overactivity

• Supported by association with hypertensive surges, pheochromocytoma and after ingestion of sympathomimetic vasoactive substances

Endothelial Dysfunction

• Endothelial progenitor cells (EPCs) are biomarkers of vascular function • Patients with RCVS have reduced circulating CD34+KDR+ (EPCs)

Chen et al. “Reduced circulating endothelial progenitor cells in reversible cerebral vasoconstriction syndrome” The Journal of Headache and Pain 2014, 15:82

Oxidative stress

• Urine 8-iso-prostaglandin F2α is Potent vasoconstrictor and oxidative biomarker • 8-Iso-prostaglandin F2α is elevated in patients with RCVS.

Shih-Pen Chen "Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome" Free radical Biology of medicine Volume 61, August 2013, Pages 243–248

Pathophysiology

Pathophysiology

Second stage

Vasoconstriction of major cerebral arteries Causing mainly watershed infarction

Abrupt stretching of vessel walls

Triggering thunderclap headache Hemorrhages by small vessel rupture

Initial stage

Involves small distal arteries Segmental vasodilation - Important role

Anne Ducros et, al “Hemorrhagic Manifestations of Reversible Cerebral Vasoconstriction Syndrome” Stroke 2014

NEUROIMAGING

Neuroimaging Features in RCVS

CT/MRI Brain : Convexity Subarachnoid Hemorrhage,

Intracerebral Hemorrhage Cerebral Infarction Reversible Brain Edema

CTA/MRA Brain: "Sausage on a String" appearance of the circle of Willis arteries

and their branches Smooth, tapered narrowing abnormal dilated segments of 2nd and 3rd order branches of the cerebral arteries

Typical Neuroimaging Features of RCVS

Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. "Reversible cerebral vasoconstriction syndromes: analysis of 139 cases." Arch Neurol. 2011;68(8):1005–12

Typical Neuroimaging Features of RCVS

Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. "Reversible cerebral vasoconstriction syndromes: analysis of 139 cases." Arch Neurol. 2011;68(8)

Laboratory and Imaging features Characteristics Chen et al (n=77) Ducros et al (n=89) Singhal et al

(n=139)CSF performed 18% 88% 82% Protein conc >16 mg/dl 0% 12% 16% WBC >10 per µL 0% 8% 3%Initial CT or MRI normal -- 80% 55%Any abnormal CT or MRI 12% 37% 81% Subarachnoid Hemorrhage

-- 30% 34%

Intracerebral hemorrhage

-- 12% 20%

Ischemic stroke 8% 6% 39% PRES 9% 8% 38%Death 0% 0% 2%

1. Aneesh B. Singhal, et al. “Reversible Cerebral Vasoconstriction Syndromes Analysis of 139 Cases”Arch Neurol. 2011;68(8):1005-1012.2. Ducros A, et, al “Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke 2010; 3. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol 2010;

Follow up Imaging studies

Characteristics CCF (n=55) MGH (n=84)Full Reversibility 76% 73%Partial Reversibility 21% 26%No Reversibility 2.4% 1.5%Median f/u days 66 56


Transcranial Doppler Sonography

Chen et, al Transcranial Color Doppler Study for Reversible Cerebral Vasoconstriction Syndromes Ann Neurol 2008;63:751–757

Transcranial Doppler Sonography

Chen et, al Transcranial Color Doppler Study for Reversible Cerebral Vasoconstriction Syndromes Ann Neurol 2008;63:751–757

Perfusion Imaging

• Multifocal areas of hypoperfusion - often watershed zones• Corresponds to the evolution of arterial vasoconstriction,• Potentially be used to track treatment response

T.R. Miller, R. Shivashankar, M. Mossa-Basha, and D. Gandhi “Cerebral Vasoconstriction Syndrome, Part 2: Diagnostic Work-Up, Imaging Evaluation, and Differential Diagnosis” Published January 22, 2015 as 10.3174/ajnr.A4215

Catheter angiography

• Invaluable tool when diagnosis is equivocal and noninvasive imaging findings are normal.

• Better visualization of morphology of cerebral artery irregularities• Aid the diagnosis- Reversibility with IA vasodilator administration

T.R. Miller, R. Shivashankar, M. Mossa-Basha, and D. Gandhi “Cerebral Vasoconstriction Syndrome, Part 2: Diagnostic Work-Up, Imaging Evaluation, and Differential Diagnosis” Published January 22, 2015 as 10.3174/ajnr.A4215

COMPLICATIONS

Hemorrhage in RCVS • High risk : Women and Migrainers • Frequently associated with vasoconstrictive drugs • Types1. Small non aneurysmal cortical SAH

2. Parenchymal Lobar (single or multiple)

3. Subdural Hemorrhage

CT and FLAIR cortical SAH GRE Cortical SAH CT lobar ICH GRE cerebellar ICH


Hemorrhage in RCVS


Hemorrhage in RCVS


DIFFERENTIAL DIAGNOSIS

Differential Diagnosis

• Migraine • Thunderclap Headache --Aneurysmal SAH, Intracerebral Hemorrhage, CSVT, Pituitary apoplexy Viral Encephalitis, Vertebral and carotid artery dissection, PCA embolus • Similar Angiographic abnormalities --Primary angiitis of the CNS --Moyamoya disease --Fibromuscular dysplasia

--Intracranial atherosclerosis

RCVS vs Migraine Is RCVS simply a severe Migraine attack?• Migraine is Primary headache; Headache in RCVS is Symptomatic• Migraine has vascular and neuronal basis• Angiogram in Migraine is invariably normal • Migraine recurs for years whereas RCVS rarely recurs • Only 25% patients with RCVS have prior migraine

RCVS SAH Aneurysmal SAH No evidence of ruptured aneurysm or vascular malformation

Plausible target lesion identified

Diffuse and disproportionate extent of cerebral vasoconstriction relative to amount of SAH

Severity of vasospasm correlates with amount of hemorrhage

Sausage on string appearance of alternating areas of segmental vasoconstriction preferentially involving distal 2nd- and 3rd-order cerebral branches

Smooth, long segmental narrowing for proximal arteries at circle of Willis

Development of vasoconstriction in first 4–5 days after symptom onset, or persistence past 3 weeks

Development of vasospasm peaking between 4 and 14 days after hemorrhage

Variable

RCVS PACNS

Incidence ? 2.4/1,000,000

Age 40-60 40-60

Sex F>>M F=M

Onset Acute (sec to min) Typically subacute to chronic

Headache Often Thunderclap Dull aching

CSF analysis Normal or near normal Abnormal 80-90%

CT/MRI Normal in MajorityIf complicated show watershed infarcts, ICH, SAH , PRES

97% abnormal, infarction (53%)ICH, Gadolinium enhancing lesions (33.3%)

Neurovascular Imaging

Sausage on a string appearace Reversible

50-90% angiography positive String and bead appearanceMostly Irreversible

Brain biopsy Always negative Gold standard for diagnosis

Typical Angiographic features of RCVS

Singhal et,al Reversible Cerebral VasoconstrictionSyndromes and Primary Angiitis of the Central Nervous System: Clinical, Imaging, and Angiographic Comparison ANN NEUROL 2016

MANAGEMENT

Treatment

• Simple Observation!• Symptomatic treatment - IV fluids, Pain management, Laxatives• Avoid Precipitants e.g Vasoconstrictive Medications • Avoid Blood pressure modulation • Calcium Channel blockers- Verapamil, Nimodipine, Magnesium• Fulminant cases: Balloon angioplasty, IA Nicardipine

Case report of IA Nimodipine and Balloon Angioplasty• A case of 50 year old F with RCVS refractory to IV Nimodipine with

subsequent paraparesis • Use of balloon angioplasty as an adjunctive therapy to IA Nimodipine

Ioannidis et al Interv Neuroradiol. Reversible Cerebral Vasoconstriction Syndrome: Treatment with Multiple Sessions of Intra-Arterial Nimodipine and Angioplasty 2012 Sep; 18(3): 297–302.

Angiogram before IA therapy


Angiogram after IA therapy


Treatment


Prognosis

• 90-95% patients recover completely to near completely in days to weeks• <5% develop life threatening strokes • <1% mortality reported from large case studies • Recurrence is described, rate unknown

• Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of 67 patients. Brain 2007; 130: 3091–101.

• Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 2011; 68: 1005–12

• Chen SP, Fuh JL, Lirng JF, Chang FC, Wang SJ. Recurrent primary thunderclap headache and benign CNS angiopathy: spectra of the same disorder? Neurology 2006; 67: 2164–69.

Take Home Message • RCVS is group of conditions characterized by reversible cerebral constriction –

dilation of cerebral arteries • ~90% have recurrent thunderclap headaches • ~1/3rd of patients develop ischemic or hemorrhagic strokes or reversible brain

edema on brain imaging • Exclusion of CNS vasculitis and demonstrating reversibility is key to diagnosis • Sympathomimetics, serotonergic drugs, immunosuppressive as well as

postpartum status are important precipitants• Most important treatment principle is identification and removal of potential

precipitants

THANK YOU

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R Shravani RCVS Grand Rounds final .ppt