RCVS is a common but underappreciated cause of TCH.

1. Reversible Cerebral
Vasoconstriction Syndrome
Shravani Reddy Nalla MD
Neurology Residency PGY2
Grand Rapids Medical Education Partners

2. Disclosures
None

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

4. Chief complaint
32 y/o female G1P0 presents to
Emergency room with
Altered Level of Consciousness

5. 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

6. 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

7. CT head

8. MRI DWI-ADC

9. MRI – T2 FLAIR

10. MRA

11. 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/SSB
ALL above labs NORMAL
❏ CSF analysis:
Clear fluid,
RBC-3,
WBC-0,
protein-46,
Glucose-60
❏ EEG:
Encephalopathic
No epileptiform
discharges

12. MRA 2 weeks later

13. Final Neurological Diagnosis
RCVS

14. HISTORY

15. 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;47:73-76
2.Gregory K. Call, MD, Marie C. Fleming, MD .et.al "Reversible Cerebral Segmental Vasoconstriction" (Stroke 1988;19:1159-1170)

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

17. 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

18. Nomenclature

19. 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.

20. 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

21. 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)

22. 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)

23. 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

24. Clinical Features
Characteristics 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;

25. 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

26. 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

27. 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.

28. ASSOCIATED CONDITIONS

29. 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

30. 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, oral
contraceptive pills, ginseng, licorice, diet pills

31. Pathophysiology

32. Pathophysiology
• Key mechanism: Transient alteration in Cerebral Vascular tone
1. Sympathetic overactivity
2. Oxidative stress
3. 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

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

34. 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

35. 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

36. Pathophysiology

37. 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

38. NEUROIMAGING

39. 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

40. 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

41. 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)

42. 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;

43. 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
Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. "Reversible cerebral vasoconstriction syndromes: analysis of 139 cases." Arch Neurol.
2011;68(8):1005–12

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

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

46. 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

47. 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

48. COMPLICATIONS

49. Hemorrhage in RCVS
• High risk : Women and Migrainers
• Frequently associated with vasoconstrictive drugs
• Types
1. 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
Anne Ducros et, al “Hemorrhagic Manifestations of Reversible Cerebral Vasoconstriction Syndrome” Stroke 2014

50. Hemorrhage in RCVS
Anne Ducros et, al “Hemorrhagic Manifestations of Reversible Cerebral Vasoconstriction Syndrome” Stroke
2014

51. Hemorrhage in RCVS
Anne Ducros et, al “Hemorrhagic Manifestations of Reversible Cerebral Vasoconstriction Syndrome” Stroke 2014

52. DIFFERENTIAL DIAGNOSIS

53. 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

54. 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

55. 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

57. 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 Majority
If 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 appearance
Mostly Irreversible
Brain biopsy Always negative Gold standard for diagnosis

58. 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

59. MANAGEMENT

60. 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

61. 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.

62. Angiogram before IA therapy
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.

63. Angiogram after IA therapy
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.

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

65. 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.

67. 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

68. THANK YOU