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Familial occurrence and heritable disorders of connective tissue in cervical artery dissection

Supplementary Appendix

Contents

e-MethodsFigure e-1: Inclusion criteria Figure e-2: Recruiting centers for the present study Table e-1: Characteristics of patients with clinical suspicion of inherited disorders of connective tissue e-References

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e-Methods

Study population

CADISP-StudyStructure and methods of the CADISP-study have been described in detail previously.1-3 Between 2004 and 2009, as part of a multicenter effort comprising 22 centers in nine countries, we have included consecutive patients evaluated in a department of neurology with a diagnosis of CeAD. Patients were recruited both prospectively and retrospectively. Retrospective patients are participants who had a qualifying event before the beginning of the study in each center and were identified through local registries of CeAD patients. The vast majority of patients had a qualifying event between 1999 and 2009 (<4% before 1999). The primary aim of the CADISP consortium was to perform a genetic association study, currently under way, to identify genetic susceptibility factors of CeAD.1 All but two centers also participated in a clinical study including detailed screening of family history, putative risk factors, clinical and radiological characteristics, and three-month outcome, using a standardized questionnaire. The CADISP clinical study comprises a total of 983 patients with a diagnosis of CeAD, included in eight countries (Argentina, Belgium, Finland, France, Germany, Italy, Switzerland, Turkey) and 20 centers (Supplemental Figure 2). Of these, 62 patients in whom reliable information on family history was unavailable were excluded. Hence the present study comprised 921 CeAD patients.

Paris-Lariboisière/Zürich/Bern RegistryThe methods of the Paris-Lariboisière/Zürich/Bern Registry on CeAD patients have been described previously.4 The current study is based on the prospectively collected data of patients included at all three study centers between 1985 and 2013.

Variable definition

Arterial occlusion was defined by the absence of blood flow; stenosis, by a narrowing of the arterial lumen, regardless of the presence or absence of hemodynamic blood flow modifications; aneurysmal dilation, by a focal enlargement of the arterial lumen and external diameter.Hypertension was defined by a history of elevated blood pressure (systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg) diagnosed by the treating physician, or use of a blood pressure lowering therapy. In the Paris-Lariboisière/Zürich/Bern Registry, the older World Health Organization threshold for hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg) was used for patients included before 2000 (n=308). Body-mass index (BMI) was calculated as the ratio of weight (kg) to the square of height (m 2). For hypercholesterolemia we redefined the variable as having a total fasting cholesterol ≥6.20 mmol/L at admission. Indeed, the original definition differed between studies: fasting total cholesterol ≥6.20 mmol/L or LDL-cholesterol ≥4.1 mmol/L, measured within 48 hours after admission or diagnosed by the treating physician, or use of a cholesterol-lowering therapy in the CADISP study; fasting total cholesterol >5 mmol/L or use of a cholesterol-lowering therapy in the Paris-Lariboisière/Zürich/Bern registry. Migraine was defined according to the International Classification of Headache Disorders.5 An infection in the week preceding the dissection was defined by the presence of at least one typical symptom of infection, in combination with fever (temperature ≥38°C) or the presence of at least one typical symptom of infection with corresponding serological, cultural or radiological findings indicating an acute infection or the combination of at least two typical corresponding symptoms.6 In the Paris-Lariboisière/Zürich/Bern registry, infection in the previous month was recorded. The presence of a cervical trauma in the month preceding the dissection was ascertained.

Risk of CeAD in a first degree relative

The prevalence of CeAD has been estimated around 1/1000.7 For a CeAD patient, the probability of having a first degree relative who also suffers a CeAD by mere chance once in his lifetime is: P = k x

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1/1000, where k is the number of first degree relatives (e.g., for an individual with one sibling and two children, P = 5/1000). At a given timepoint, for instance when the CADISP questionnaire was administered, the probability for a CeAD patient of having a first degree relative who already suffered a CeAD by mere chance is P’ < P.

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Figure e-1: Inclusion criteria

CeAD patientsInclusioncriteria

Typical radiological aspect of dissection* in a cervical artery (carotid, vertebral)

Exclusioncriteria

Purely intracranial dissection Iatrogenic dissection after endovascular procedure Age <18 years at inclusion Monogenic disorder known to cause CeAD (e.g. vascular Ehlers-

Danlos syndrome), for the genetic study only

CeAD: Cervical Artery Dissection; * Mural hematoma, pseudoaneurysm, long tapering stenosis, intimal flap, double lumen, or occlusion > 2 cm above the carotid bifurcation revealing a pseudoaneurysm or a long tapering stenosis after recanalization

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Figure e-2: recruiting centers for the present study

Helsinki, Finland

Lille, France

Brussels ,Belgium

Amiens, France

Paris x 3, France

Dijon, France

Besançon, France

Basel, Switzerland

Ludwigshafen, Germany

Heidelberg, Germany

Brescia, Italy

Milano, Italy

Rome, Italy

Perugia, Italy

Leuven, Belgium

Monza, Italy

Bern, Switzerland

Zürich, Switzerland

Istanbul, Turkey

+ Cordoba, Argentina

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Table e-1: Characteristics of patients with clinical suspicion of inherited disorders of connective tissue

ID Country City CTD DCT known before CeAD

Other DCT criteria Gene with mutation

Age Sex CeAD location

CeAD type Cerebral ischemia

Putative risk factors of CeAD

VII France Paris vEDS suspicion

no extensive bruising, evocative facial appearance, acrogeria, tendon fragility, joint laxity (medium and small size joints), no arterial event since 2004; diverticulitis (age 36)

gDNA sequencing of COL3A1 negative, repeat loss of cell cultures for cDNA sequencing

24 F carotid (vertebral 4 years later)

occlusion ischemic stroke

migraine with aura

VIII France Paris vEDS suspicion

no thin translucent skin, characteristic facial appearance, at diagnostic work-up: silent dissection of mesenteric artery, and possibly of the coeliac trunc and right renal artery

gDNA sequencing and MLPA of COL3A1 negative; TGF-ßR2 sequencing ongoing

37 F carotid + vertebral

stenosis no migraine with aura; hypercholesterolemia; cervical trauma in previous month ; current smoker

IX Switzerland Zürich MFS suspicion

yes mitral valve prolapse, long fingers, increased arm span, pectus excavatum

not done 41 F carotid no information ischemic stroke

migraine without aura; hypercholesterolemia

X Switzerland Bern MFS suspicion

yes wrist and thumb sign, hindfoot deformity, positive family history

not done 35 M vertebral (bilateral)

aneurysm no migraine with aura; hypertension

CeAD: Cervical Artery Dissection; DCT: Disorder of Connective Tissue; MFS: Marfan syndrome; vEDS: vascular Ehlers-Danlos syndrome; gDNA: genomic DNA ; cDNA : complementary DNA

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e-References

1. Debette S, Metso TM, Pezzini A, et al. CADISP-genetics: an International project searching for genetic risk factors of cervical artery dissections. Int J Stroke 2009;4:224-230.2. Debette S, Metso T, Pezzini A, et al., for the CADISP Group. Do vascular risk factors increase the risk of cervical artery dissection? . submitted (personal communication).3. Debette S, Grond-Ginsbach C, Bodenant M, et al. Differential features of carotid and vertebral artery dissections: the CADISP study. Neurology 2011;77:1174-1181.4. von Babo M, De Marchis GM, Sarikaya H, et al. Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery. Stroke 2013;44:1537-1542.5. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:9-160.6. Grau AJ, Buggle F, Heindl S, et al. Recent infection as a risk factor for cerebrovascular ischemia. Stroke 1995;26:373-379.7. Grond-Ginsbach C, Debette S. The association of connective tissue disorders with cervical artery dissections. Curr Mol Med 2009;9:210-214.