Disparities in Stroke Risk: Learning from Strokes in Little Folks

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Disparities in Stroke Risk: Learning from Strokes in Little Folks

Multiple Mechanisms

Causing Arteriopathies in

Childhood Stroke

Heather J. Fullerton, MD, MAS

Associate Professor of Neurology & Pediatrics

Director, Pediatric Stroke & Cerebrovascular Disease Center

University of California, San Francisco


Cerebral Arteriopathies

• Have emerged as the most common

cause of childhood arterial ischemic stroke

(AIS)

• Ganeson et al (Ann Neurol 2003): 78% of

previously healthy children with AIS had a

large vessel arteriopathy


Arteriopathies predict recurrent stroke

0.00 0.20 0.40 0.60 0.80 1.00

Kaplan-Meier survival estimates, by abvascim_x_occl

Normal vascular imaging, n=30

Abnormal vascular imaging, n=22

0 1 2 3 4

Time (years) from index stroke

P


What are these arteriopathies?


Childhood Arteriopathies

• Heterogeneous, difficult to classify,

multifactorial

Genetic

Inflammatory Environmental


Genetic: Williams Syndrome

• Deletion 7q11.23

• “Elfin” facial features

• Mental retardation

• Supravalvular aortic

stenosis

• Pulmonary/peripheral/

visceral A. stenosis

• Cervical/cerebral

artery stenosis


Genetic?: FMD/Vascular Web

• Sporadic or familial (AD with

decreased penetrance in

males)

• Pathology (non-inflammatory):

– Smooth muscle hyperplasia

– Elastic fiber destruction

– Fibrous tissue proliferation

– 95% involves media

• Women > men

• 95% cervical ICA

• Beading in 80-90%

• Less often tubular or web

• Healton, Stroke, 1998


Congenital: PHACES syndrome

• Posterior fossa

malformations

• Large facial

Hemangiomas

• Arterial anomalies

• Cardiac anomalies

– Aortic coarctation

• Eye abnormalities

• Sternal cleft


Inflammatory: Vasculitis

Genetic component? Polymorphisms associated with giant cell arteritis


Multifactorial: Moyamoya

• Genetic: primary form (can

be AD w/ low penetrance);

secondary forms: Downs, NF-

1, TS, primoridal dwarfism,

ACTA2 mutations (Milewicz,

2009)

• Environmental: cranial

irradiation

• Inflammatory?:

pathology shows smooth cell

prolif w/ localization of

macrophages & T cells


Mutifactorial: Arterial Dissection

• Environmental:

trauma, infection

• Genetic: Ehlers

Danlos type IV,

TGFBR2 (Pezzini, et al, J

Neurol Neurosurg Psych 2011)


Distribution of Arteriopathies:

population-based cohort in NorCal

Kaiser Pediatric Stroke Study

1993-2004

n=52

“Idiopathic”

Moyamoya

Vasculitis

Dissection

Fullerton, Pediatrics, 2007


Focal Cerebral Arteriopathy

• Distal ICA, M1, A1

• Monophasic disease

• Initial progression,

nonprogression after

6 months

• Improvement or

stabilization; rarely

normalization

• Chabrier & Sebire, J Child

Neurol 1998; Danchaivijitr,

Ann Neurol 2006

Acute 2 months 12 months

Courtesy of G. DeVeber


What could cause this focal

arterial stenosis in children?

• Trauma? • Infection?


Trauma (past 1 week) is a

Risk Factor for Childhood Stroke

12%

10%

8%

6%

4%

2%

0%

Cases Controls

10% of cases (n=97) vs. 0.3% of controls (n=291)

OR 39 (95% CI 5.1-298, p


Intracranial Dissection FCA

• 4 cases from IPSS: imaging c/w FCA, but

autopsy (n=3) or wall imaging (n=1) c/w dissection

Noma

Dlamini,

et al, J

Child

Neurol

2011


Focal Cerebral Arteriopathy and

• Post-varicella Arteriopathy

(PVA)

– FCA with h/o chicken pox in past

12 months

– Case reports of AIS after VZV

infection

– Pathology: focal vasculitis with

vessel wall infiltration of virus and

lymphocytes

– Association studies:

– Sebire & Chabrier, Ann Neurol

1999; case-control: OR 18

– Lanthier & deVeber, Neurology

2005

Infection

• Other viruses associated with

cerebral arteriopathies (case

reports):

– Herpes viruses:

• HSV-1, EBV, CMV

– Enterovirus

– HIV


Minor Infection (prior 4 weeks) is a

Risk Factor for Childhood Stroke

35%

30%

25%

20%

15%

10%

5%

0%

Cases Controls

32% of cases vs. 8% of controls

OR 7.9 (95% CI 3.7-16.8, p


Minor Infections in Prior 4 weeks

Urinary tract infection

Tonsillitis

Pneumonia

Pharyngitis

Acute otitis media

Upper respiratory

Acute gastroenteritis

p=0.16

p=0.44

p=0.06

p


Infection is an Independent Risk Factor for

Focal Cerebral Arteriopathy in IPSS

(n=525)

Demographics

Age group

0-4 years

P value

5-9 years 1.76 (0.94-3.30) 0.076

10-14 years 1.41 (0.70-2.81) 0.334

15-19 years 0.99 (0.40-2.42) 0.980

Recent Infection

Upper respiratory infection* 2.82 (1.29-6.22) 0.010

*includes sinusitis and otitis media

Odds Ratio (95% CI)

reference

LeFond, Circulation, 2009


But childhood infections are

common, stroke is rare

• Unlikely to be a “stroke bug”

• “Multiple hits”

– Other environmental factors

• Trauma, diet/nutrition

– Genetic susceptibility

• Polymorphisms/mutations affecting immune

function

• (Aleksandra Mineyko & Adam Kirton, in press)


Summary: Childhood Arteriopathies

• Common in children with ischemic stroke

• Heterogeneous (FCA most common)

• Multifactorial

• Strongest predictor of recurrence


Vascular effects of Infection in

Pediatric Stroke (VIPS) Study

• NIH funded, prospective, 30 centers, 140+

cases enrolled

• Explore the associations between

infection, inflammation, arteriopathy, and

stroke recurrence

• Long-term goal: 2ary stroke prevention

– Anti-thrombotics, immunosuppressants?


We still know so little…


VIPS Study

• Members of the IPSS Enrolling Patients in VIPS:

• Australia: Drs. Mark Mackay; Canada: Drs. Gabrielle deVeber,

Adam Kirton, Peter Humphreys, Anthony Chan, Jerome Yager,

Mubeen Rafay; Chile: Marta Hernandez Chavez; China: Drs. Li-

Ping Zou, Virginia Wong; Georgia: Gordana Vlahovic Kovacavich;

Phillipines: Marilyn Tam; United Kingdom: Noma Dlamini, Fenella

Kirkham, Finbar O’Callaghan; United States: Drs. Ann Yeh,

Rebecca Ichord, Kate Lefond, Neil Friedman, Warren Lo, Tim

Bernard, Neil Goldenberg, Jennifer Armstrong-Wells, Stephen

Ashwal, Steve Pavlakis, Christine Fox, Michael Dowling, Susan

Benedict, James Bale, Jessica Carpenter, Michael Rivkin, Lori

Jordan.

• Pis and Co-investigators:

• Gabrielle DeVeber, Heather Fullerton, Mitch Elkind, Max

Wintermark, Jim Barkovich, Nancy Hills, David Glidden

• VIPS Core Staff: Katherine Sear, Maria Kuchherzki, Michelle

Salinardi, Cerys Starkey, Khin Liu


International Pediatric Stroke Study

• Members of the IPSS Enrolling Patients:

• Australia: Drs. Mark Mackay and Paul Monagle; Canada: Drs.

Gabrielle deVeber and Guillaume Sebire; People’s Republic of

China: Dr. Virginia Wong; Germany: Dr. Ulrike Nowak-Gottl;

Republic of Georgia: Dr. Nana Tatishvili; Malaysia: Dr. Imam

Hussain; United Kingdom: Dr. Vijeya Ganesan; United States: Drs.

Ann Yeh, Geoff Heyer, Rebecca Ichord, Kate Lefond, Neil Friedman,

Warren Lo, Max Wiznitzer, Khaled Zamel, Tim Bernard, Stephen

Ashwal and Chalmer McClure, Steve Pavlakis, Marcel Deray, Ziad

Khatib, Meredith Golomb, Li Kan, Donna Ferriero, Heather Fullerton,

Yvonne Wu, Norma Lerner, Shalu Lamba, Michael Dowling, Susan

Benedict.

• Senior scientists serving the IPSS in advisory capacities:

• Anthony Chan, Deborah Hirtz, Collin Hovinga, Fenella Kirkham,

John Lynch, Karin Nelson, Harry Whelan, Andy Willan.

• IPSS Study Coordinators: Marianne Sofronas, Elisa Wilson, Jeff

Templeton


Stroke Sciences Group

• Clay Johnston, MD PhD

• Yvonne Wu, MD MPH

• Nancy Hills, PhD

Acknowledgements

UCSF Pediatric Stroke &

Cerebrovascular Center

• Chris Dowd, MD; Van Halbach, MD;

Randy Higashida, MD

• Michael Lawton, MD; Nalin Gupta, MD PhD

• Jim Barkovich, MD

• James Huang, MD

• Patrick McQuillen, MD

KPMCP DOR

• Stephen Sidney, MD,

MPH

• Barbara Rowe, RN

• Mike Sorel, MPH

KP patients & providers

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