Pathophysiology of carotid-cavernous fistulas in vascular Ehlers-Danlos syndrome: a retrospective cohort and comprehensive review

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Abstract

Background

Vascular Ehlers-Danlos syndrome (vEDS) is a rare condition characterized by connective tissue fragility. Direct spontaneous carotid-cavernous fistula (sCCF) is reportedly pathognomonic of vEDS. We conducted this study to understand the possible mechanisms of occurrence of sCCF in this subset of patients.

Methods

We conducted a retrospective analysis of a monocentric vEDS cohort along with a literature review regarding sCCF in this condition.

Results

Of 133 patients regularly followed in our centre between 2000 and 2017, 13 (9.8%) had a diagnosis of direct sCCF (92.3% female, median age 33.0 years, interquartile range (IQR) [26.0–39.5]). There were 7 Glycine missense and 6 splice-site variants but no variant leading to haploinsufficiency. The literature search identified 97 vEDS patients with direct sCCF (79.4% female, 7.2% sex not reported, median age 31.0 years, IQR [24.0–39.0]). Increased carotid circumferential wall stress, higher carotid distensibility and lower carotid intima-media thickness could contribute to a higher risk for direct sCCF in vEDS. There is no predictive factor for the occurrence of sCCF apart from female sex in vEDS.

Conclusions

In vEDS, anatomical and pathophysiological features of the intra-cavernous internal carotid artery make it prone to shunting in the cavernous sinus, due either to a spontaneous rupture or to a spontaneous dissection with pseudoaneurysm formation. Direct sCCF in seemingly healthy young individuals should be highly suggestive of vEDS and prompt further investigation.

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Most cited references 82

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The 2017 international classification of the Ehlers-Danlos syndromes.

Fransiska Malfait, Clair Francomano, Peter K. Byers … (2017)

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

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Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

M. Pepin, U Schwarze, A Superti-Furga … (2000)

Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.

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Classification and treatment of spontaneous carotid-cavernous sinus fistulas.

G T Tindall, Saori I. Braun, S C Tindall … (1985)

An anatomical-angiographic classification for carotid-cavernous sinus fistulas is introduced and a series of 14 patients with spontaneous carotid-cavernous sinus fistulas is reviewed to illustrate the usefulness of such a classification for patient evaluation and treatment. Fistulas are divided into four types: Type A are direct high-flow shunts between the internal carotid artery and the cavernous sinus; Type B are dural shunts between meningeal branches of the internal carotid artery and the cavernous sinus; Type C are dural shunts between meningeal branches of the external carotid artery and the cavernous sinus; and Type D are dural shunts between meningeal branches of both the internal and external carotid arteries and the cavernous sinus. The anatomy, clinical manifestations, angiographic evaluation, indications for therapy, and therapeutic options for spontaneous carotid-cavernous sinus fistulas are discussed.

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Author and article information

Contributors

Salma Adham: salma.adham@aphp.fr

Denis Trystram: d.trystram@ch-sainte-anne.fr

Juliette Albuisson: juliette.albuisson@aphp.fr

Valérie Domigo: v.domigo@ch-sainte-anne.fr

Anne Legrand: anne.legrand@aphp.fr

Xavier Jeunemaitre: xavier.jeunemaitre@aphp.fr

Michael Frank: +33 (0)1 56 09 50 41 , michael.frank@aphp.fr

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 25 June 2018

Publication date PMC-release: 25 June 2018

Publication date Collection: 2018

Volume: 13

Electronic Location Identifier: 100

Affiliations

[1 ]GRID grid.414093.b, Hôpital Européen Georges Pompidou, Département de Génétique, Centre de Référence des Maladies Vasculaires Rares, , Hôpital Européen Georges Pompidou, AP-HP, ; 20-40 rue Leblanc, 75908 Paris Cedex 15, France

[2 ]ISNI 0000 0001 2188 0914, GRID grid.10992.33, Sorbonne Paris Cité, Faculté de Médecine, , Université Paris Descartes, ; Paris, France

[3 ]ISNI 0000 0001 2200 9055, GRID grid.414435.3, Service d’imagerie morphologique et fonctionnelle, , Centre hospitalier Sainte-Anne, ; Paris, France

[4 ]ISNI 0000 0004 1788 6194, GRID grid.469994.f, INSERM, U894, IMA-BRAIN, , DHU NeuroVasc Sorbonne Paris Cité, ; Paris, France

[5 ]ISNI 0000 0004 0495 1460, GRID grid.462416.3, INSERM, U970, , Paris centre de Recherche Cardiovasculaire – PARCC, ; Paris, France

Article

Publisher ID: 842

DOI: 10.1186/s13023-018-0842-2

PMC ID: 6019721

PubMed ID: 29940997

SO-VID: a9eb2b53-1beb-4c63-86a8-1cbb1fa5191b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 December 2017

Date accepted : 13 June 2018

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: vascular ehlers-danlos syndrome,rare vascular disease,genetics,carotid-cavernous fistula,neurology,neuroophthalmology,pathophysiology

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: vascular ehlers-danlos syndrome, rare vascular disease, genetics, carotid-cavernous fistula, neurology, neuroophthalmology, pathophysiology

Pathophysiology of carotid-cavernous fistulas in vascular Ehlers-Danlos syndrome: a retrospective cohort and comprehensive review

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Annual Reviews: Coronavirus Research

Most cited references 82

The 2017 international classification of the Ehlers-Danlos syndromes.

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

Classification and treatment of spontaneous carotid-cavernous sinus fistulas.

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