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

Salma Adham, Denis Trystram, Juliette Albuisson, Valérie Domigo, Anne

Legrand, Xavier Jeunemaitre, Michael Frank

► To cite this version:

Salma Adham, Denis Trystram, Juliette Albuisson, Valérie Domigo, Anne Legrand, et al. Pathophysiology of carotid-cavernous fistulas in vascular Ehlers-Danlos syndrome: a retrospective cohort and comprehensive review. Orphanet Journal of Rare Diseases, 2018, 13 (1), pp.100. 10.1186/s13023-018-0842-2. [hal-03671156](https://hal.science/hal-03671156)

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

Salma Adham<fnref n="1" />,², Denis Trystram³,⁴, Juliette Albuisson<fnref n="1" />,²,<fnref n="5" />, Valérie Domigo³,⁴, Anne Legrand<fnref n="1" />,²,<fnref n="5" />, Xavier Jeunemaitre<fnref n="1" />,²,<fnref n="5" /> and Michael Frank<fnref n="1" />,<fnref n="5" />*

**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.

**Keywords:** Vascular Ehlers-Danlos syndrome, Rare vascular disease, Genetics, Carotid-cavernous fistula, Neurology, Neuroophthalmology, Pathophysiology

**Background**

Vascular Ehlers-Danlos syndrome (vEDS, OMIM #130050) is a rare inherited connective tissue disorder with a prevalence estimated at 1/150000. It is an autosomal dominant transmitted disorder caused by diverse mutations in the COL3A1 gene which encodes the pro-alpha1 chain of type

III procollagen [1–3]. Vascular EDS is characterized by connective tissue fragility leading to life-threatening complications in seemingly healthy young adults. Easy bruising, thin and translucent skin, acrogeria and characteristic facial features may be a hint for clinicians. Intestinal and uterine fragility are classical features of vEDS, but generalized arterial fragility dominates the clinical picture with spontaneous dissections, aneurysms and arterial ruptures [2].

It is therefore unsurprising that vEDS has been associated with the development of spontaneous direct carotid-cavernous fistula (sCCF). Carotid-cavernous fistula (CCF) is an abnormal communication between the

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BMC

<footnote>* Correspondence: michael.frank@aphp.fr</footnote>

<footnote n="1">¹Hôpital 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</footnote>

<footnote n="5">⁵INSERM, U970, Paris centre de Recherche Cardiovasculaire – PARCC, Paris, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
high-pressure carotid arterial system and the low-pressure cavernous venous system (CS). In direct CCF, internal carotid artery (ICA) wall disruption allows high-pressure blood to move into the CS, resulting in short-circuiting of the ICA arterial blood into the venous system of the CS. The most common symptoms are swelling of the eye, chemosis, pain, ophthalmoplegia and bruit [4]. Direct sCCF is rare in the general population as most direct fistulas are posttraumatic but seems to be more common in vEDS patients and especially in females.

We report in this article a series of 13 molecularly proven vEDS patients diagnosed with direct sCCF along with a review on literature regarding direct sCCF occurring in vEDS patients. The possible mechanisms of occurrence in this subset of patients are discussed.

# Methods

## Study population

Since 2000, all molecularly proven vEDS patients followed in our department are systematically monitored clinically, biologically and by means of imaging (Doppler ultrasound, MR-Angiogram and/or CT-scan) at regular time intervals.

Patients with vEDS regularly followed in the French National Reference Centre for rare vascular diseases between 2000 and 2017 were included in this retrospective cohort study. Probands and relatives were diagnosed with vEDS based on clinical presentation, physical examinations, radiological findings and confirmation of a pathogenic variant in the COL3A1 gene. Genetic testing was performed in compliance with the French legislation on genetic diagnostic tests (French bioethics law no. 2004–800) and written informed consent was given by all patients. A retrospective review of medical records for this study was approved by an ethical standards committee, the Comité de Protection des Personnes Ile-de-France 2 (IRB 00001072). Medical history was reviewed to identify patients suffering from direct sCCF. Patients’ characteristics were reported only for the patients with fistulas.

## Statistical analysis

A statistical analysis was performed with the XLStat software (Addinsoft, version 2017.4). To analyse patients’ characteristics, time-independent qualitative variables were compared using Chi-square test or Fisher’s exact test whenever the count was insufficient. Quantitative variables were reported using parametric descriptive statistics. A *P* value < 0.05 was considered significant.

## Literature review

A literature search was performed via computer literature searches. Articles were identified through a systematic PubMed search and by a review of their respective

references. Available articles in English or in French regarding direct sCCF in vEDS patients were included.

# Results

## Study population

Since 2000, our centre has followed 148 molecularly proven vEDS patients. We identified 15 individuals either with variants leading to haploinsufficiency (n = 12) or with non-Glycine missense variants within the triple helix and non-Glycine missense variants or in-frame insertions-deletions in the N- or C-terminal part of the protein (n = 3). None of these 15 patients had a history of direct sCCF. Of 133 patients known to have either Glycine missense or splice-site and in-frame insertions-deletions variants in the COL3A1 gene, there were 79 (59.4%) females, 90 (67.7%) Glycine missense variants, 55 (41.4%) patients with a history of digestive event and 66 (49.6%) patients with a history of acute arterial event.

Among these 133 patients, we identified 13 (9.8%) individuals who suffered from direct sCCF diagnosed between January 1985 and September 2014 (Table 1). There were 7 (53.8%) Glycine missense variants and 6 (46.2%) splice-site variants (OR 0.52 with a 95% confidence interval (CI) [0.14, 2.02], *P* 0.349). There were 12 (92.3%) females and 1 (7.7%) male (OR 0.11 with a 95% confidence interval (CI) [0.002–0.760], *P* 0.014). The median age at molecular diagnosis was 32.0 years, interquartile range (IQR) [28.0–39.0]. The median age at time of direct sCCF diagnosis was 33.0 years, IQR [26.0–39.5].

Direct sCCF was the first symptomatic vascular complication reported in 9 (69,2%) patients (cases 1 to 5, 7 to 9 and 11). Of 13 patients, 5 (38.5%) had already been diagnosed with vEDS 44.0 months, IQR [7.0–60.5], before the occurrence of the fistula (cases 5, 6, 8, 12 and 13). Occurrence of a direct sCCF led to vEDS molecular diagnosis in less than 15 months in 4 (30.8%) patients (cases 4, 7, 9 and 11, median diagnosis time 7.5 months, IQR [6.0–9.0]). Molecular diagnosis of vEDS was delayed to 79.5 months, IQR [49.5–166.5], after the sCCF in the 4 (30.8%) remaining patients (cases 1 to 3, case 10).

Data regarding the previous ICA status was not available in 4 (30.8%) patients (cases 2, 4, 8 and 10). No previously known aneurysm or dissection of the ICA was found in the medical history or in the radiological reports of 3 (23.0%) patients (cases 3, 9 and 13). Imaging during the systematic follow-up described a dysplastic aspect of the petrous ICA (probably secondary to a dissection) a few months before the ipsilateral sCCF diagnosis in one patient (case 6). Imaging at the time of the sCCF described an aspect of ICA dissection ipsilateral to the fistula in 4 (30.8%) patients (cases 1, 5, 7 and 12). Another patient (case 11) was diagnosed with cavernous ICA dissection and petrous aneurysm rupture leading to an ipsilateral fistula a few weeks later. Overall, there was
<table><caption>**Table 1** Case series</caption><thead><tr><th>Case no.</th><th>Age (years)</th><th>Sex</th><th>sCCF side</th><th>Treatment</th><th>Outcome</th><th>IMT (mm)</th><th>COL3A1 variant cDNA</th><th>Protein</th><th>Type</th></tr></thead><tbody><tr><td>1</td><td>34</td><td>F</td><td>Left</td><td>ICA sacrifice</td><td>Alive</td><td>0.383</td><td>c.665G&gt;A</td><td>p.(Gly222Asp)</td><td>Glycine</td></tr><tr><td>2</td><td>30</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.354</td><td>c.2735G&gt;A</td><td>p.(Gly912Asp)</td><td>Glycine</td></tr><tr><td>3</td><td>13</td><td>F</td><td>Left</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.339</td><td>c.951+1G&gt;A</td><td>p.?</td><td>Splice</td></tr><tr><td>4</td><td>21</td><td>F</td><td>Left</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.372</td><td>c.2553+1G&gt;A</td><td>p.?</td><td>Splice</td></tr><tr><td>5</td><td>33</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.394</td><td>c.1662+1G&gt;A</td><td>p.?</td><td>Splice</td></tr><tr><td>6</td><td>42</td><td>F</td><td>Left</td><td>ICA sacrifice</td><td>Alive</td><td>0.387</td><td>c.3441_3485dup</td><td>p.(Lys1150_Gly1164dup)</td><td>Duplication</td></tr><tr><td>7</td><td>27<br>31</td><td>F</td><td>Right<br>Left</td><td>CCF closure (embolization)</td><td>Died aged 38</td><td>0.319</td><td>c.2222G&gt;A</td><td>p.(Gly741Asp)</td><td>Glycine</td></tr><tr><td>8</td><td>38</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.503</td><td>c.2095G&gt;C</td><td>p.(Gly699Arg)</td><td>Glycine</td></tr><tr><td>9</td><td>25</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>NR</td><td>c.898-1G&gt;C</td><td>p.?</td><td>Splice</td></tr><tr><td>10</td><td>36</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.435</td><td>c.2293G&gt;C</td><td>p.(Gly252Arg)</td><td>Glycine</td></tr><tr><td>11</td><td>28</td><td>M</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>NR</td><td>c.[1347+ 1G&gt;A];[=]</td><td>p.?</td><td>Splice</td></tr><tr><td>12</td><td>49</td><td>F</td><td>Right</td><td>CCF closure (embolization)</td><td>Alive</td><td>0.417</td><td>c.755G&gt;T</td><td>p.(Gly252Val)</td><td>Glycine</td></tr><tr><td>13</td><td>41</td><td>F</td><td>Left</td><td>Died before treatment</td><td>Died aged 41</td><td>NR</td><td>c.826G&gt;A</td><td>p.(Gly276Ser)</td><td>Glycine</td></tr><tr><th>Case no.</th><th>Age at molecular diagnosis (years)</th><th>1st vascular event</th><th>Age at 1st vascular event (years)</th><th>Acute arterial events (other than sCCF)</th><th>1st digestive event</th><th>Age at 1st digestive event (years)</th><th></th><th></th><th></th></tr><tr><td>1</td><td>38</td><td>sCCF</td><td>34</td><td>Yes</td><td>Incisional hernia</td><td>32</td><td></td><td></td><td></td></tr><tr><td>2</td><td>35</td><td>sCCF</td><td>30</td><td>Yes</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>3</td><td>32</td><td>sCCF</td><td>13</td><td>Yes</td><td>Postoperative adhesive intestinal obstruction</td><td>25</td><td></td><td></td><td></td></tr><tr><td>4</td><td>22</td><td>sCCF</td><td>21</td><td>No</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>5</td><td>28</td><td>sCCF</td><td>33</td><td>Yes</td><td>Intestinal perforation</td><td>21</td><td></td><td></td><td></td></tr><tr><td>6</td><td>38</td><td>AR</td><td>33</td><td>Yes</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>7</td><td>28</td><td>sCCF</td><td>27</td><td>Yes</td><td>Diverticulitis</td><td>26</td><td></td><td></td><td></td></tr><tr><td>8</td><td>32</td><td>sCCF</td><td>38</td><td>Yes</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>9</td><td>25</td><td>sCCF</td><td>25</td><td>Yes</td><td>Occlusion on paresis</td><td>25</td><td></td><td></td><td></td></tr><tr><td>10</td><td>45</td><td>AVF</td><td>24</td><td>Yes</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>11</td><td>28</td><td>sCCF</td><td>28</td><td>No</td><td>–</td><td>–</td><td></td><td></td><td></td></tr><tr><td>12</td><td>49</td><td>AR</td><td>48</td><td>Yes</td><td>Sigmoiditis</td><td>48</td><td></td><td></td><td></td></tr><tr><td>13</td><td>40</td><td>ADO</td><td>21</td><td>Yes</td><td>–</td><td>–</td><td></td><td></td><td></td></tr></tbody></table>

sCCF spontaneous carotid-cavernous fistula, F female, ICA internal carotid artery, IMT intima-media thickness, M male, NR not reported, ADO arterial dissection and occlusion, AR arterial rupture, AVF arteriovenous fistula

no aneurysm or dissection of the contralateral ICA or in the other cerebral arteries reported on imaging at time of sCCF imaging diagnosis.

A patient (case 7) developed a sCCF during pregnancy, a second patient (case 2) developed a sCCF 2 years after her second pregnancy, a third one (case 10) developed a
sCCF 3 years after her first pregnancy and a fourth pa-
tient (case 1) developed a sCCF 5 years after her second
pregnancy. The patient reported as case 12 developed a
sCCF 12 years after a second pregnancy. The median
age of pregnancy in these 9 patients was 29.0 years, IQR
[28.0–30.0], and the median age of occurrence of their
fistula was 30.0 years, IQR [25.0–30.0] (P 0.888).

Most patients (76.9%) were treated by selective occlusion
of the fistula (cases 2 to 5 and 7 to 12). Sacrifice of the ICA
to achieve occlusion of the sCCF was necessary in 2
(15.4%) patients (cases 1 and 6), and one (7.7%) patient
(case 13) died before treatment of the sCCF. A contralateral
sCCF occurred in a patient (case 7) 5 years after the first
sCCF embolization. All patients are still alive, except for
case 7 who died of a ruptured aortoiliac dissection 11 years
after the first sCCF embolization and 6 years after the
contralateral embolization, and case 13 who died of a
ruptured splenic dissection 1 month after sCCF diagnosis.

Literature review

A literature search was performed on July, 2017, using
PubMed. Abstracts were reviewed by a single reviewer
and full-text articles were obtained for the studies meeting
the eligibility criteria. Reference lists were also examined
for additional relevant studies not identified through the
initial search. Inclusion criteria were English-language and
French-language full-text publications published since the
1950s, regarding vEDS patients diagnosed with sCCF.

We identified 51 articles [4–54], mainly case reports,
describing 101 direct CCF in 97 vEDS patients (Table 2).
There were 77 (79.4%) females and 13 (13.4%) males.
Sex was not reported for 7 (7.2%) individuals [21, 40].
Median age at direct CCF diagnosis was 31.0 years, IQR
[24.0–39.0] (one missing value [34]). Pepin et al. re-
ported an overall mean age of 30.9 years in 27 patients.
Five (5.2%) patients [18, 40, 46, 47, 50] experienced a
direct sCCF recurrence on the contralateral ICA
2.5 years, IQR [2.0–3.5] after the first fistula. Of 97 pa-
tients, 4 (4.1, 75.0% male) were diagnosed either with a
direct CCF following minor trauma [7, 11, 14] or with
an iatrogenic direct CCF after placement of a Fogarty
balloon into the cavernous segment of the ICA [28].

Death was reported for 20 (20.6%) patients [4, 6, 7, 9–
12, 19, 21, 23, 24, 26, 32, 43, 44, 47, 49, 51], of which 14
(70.0%) died in the course of sCCF management [4, 7, 9,
11, 12, 19, 23, 24, 32, 43, 44, 49, 51]. COL3A1 variants
were reported in 9 patients. There were 5 Glycine mis-
sense variants [5, 8, 18, 51, 53] and 4 splice-site variants
[8, 29, 45, 51]. In the other patients, vEDS diagnosis was
made either on relevant clinical examination, imaging
and medical history [6, 7, 9, 10, 12, 15, 19, 27, 28, 30, 31,
33, 34, 39, 42, 46–50, 52], histological findings [6, 9, 24,
27, 32, 43, 44, 47] or on fibroblast culture [8, 15, 36, 38,
40, 43, 44]. Imaging described marked tortuosity or

dysplastic aspect or ectasia of the ICA segment in the
neck [6, 10, 19, 26, 39, 49], sometimes associated with
an aneurysm rupture of the intracranial ICA segment
into the CS [8, 15, 19]. Aneurysms of the ICA without
rupture were also reported [12, 30, 51], sometimes asso-
ciated with images of dissection [33, 46, 52].

Discussion

Classification of CCF is based on aetiology (traumatic
versus spontaneous), blood flow velocity (high versus
low) and anatomy (direct versus dural, or ICA versus
ECA). According to the Barrow classification, there are
4 types of CCF [55]. Type A or direct CCF is a high-flow
direct shunt due to a posttraumatic or ruptured
aneurysm which results in short-circuiting of the ICA
arterial blood into the venous system of the CS. Type B,
C and D are low-flow lesions and grouped under the
common definition of dural or indirect CCF. In the gen-
eral population, direct CCF represents 75% of all CCF
and is mostly posttraumatic (0.2–0.3% of craniofacial
trauma) [56] or associated with surgical complications,
while spontaneous dural (indirect) low-flow CCF are
mostly found in postmenopausal hypertensive females
[57]. Direct sCCF only accounts for 10% of all spontan-
eous CCF [58]. The intracavernous ICA is prone to
spontaneous shunting due to the amount and direction
of ligaments in relation to the adventitia, the conform-
ation and mobility of the siphon (horizontal segment),
and the inextensibility of the dura [59, 60]. Direct sCCF
can be found in patients with intracavernous ICA aneu-
rysms, but only 2 to 9% of intracavernous ICA aneu-
rysms are complicated with a direct CCF [61]. The
rupture of a persistent trigeminal artery-associated
aneurysm has also been associated with the development
of CCF [62, 63]. Though direct sCCF seems to be rare in
healthy individuals, it appears to be a significant compli-
cation in patients with collagenopathies such as vEDS
[40, 46, 64]. Spontaneous CCF does not seem to associ-
ate with other rare vascular diseases such as Marfan dis-
ease or Loeys-Dietz syndrome [65].

Vascular EDS is a rare heritable disease mainly character-
ized by vascular manifestations such as rupture, dissection or
aneurysm affecting large or medium-sized arteries. Cervico-
cerebral arteries can be affected with disorders such as intra-
cranial aneurysm, carotid artery dissection or direct CCF
[64–66]. In our tertiary referral centre, subjects with direct
CCF represent 9.8% of vEDS patients and all fistulas were
spontaneous. Posttraumatic direct CCF seems to be rare
in vEDS patients and occurs mostly in males [7, 11, 14].

The median age of our patients at direct sCCF diagno-
sis, 33.0 years, IQR [26.0–39.5], is quite similar to previ-
ous data reported in vEDS population [46, 54, 64], and
considerably lower than patients free from vEDS who
experience CCF [55]. These results are also concordant
<table><caption>**Table 2** Literature review</caption><thead><tr><th>Authors</th><th>Age (years)</th><th>Sex</th><th>CCF side and type</th><th>COL3A1 variant</th></tr></thead><tbody><tr><td>François P et al. Bull Soc Ophtalmol Fr 1955 [16]</td><td>52</td><td>F</td><td>Right - NR</td><td>NR</td></tr><tr><td rowspan="3">Graf CJ et al. Arch Neurol 1965 [19]</td><td>24</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>26</td><td>M</td><td>Left - Direct</td><td>NR</td></tr><tr><td>37</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Bannerman RM et al. Br Med J 1967 [6]</td><td>37</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Schoolman A et al. J Neurosurg 1967 [47]</td><td>39<br>3 weeks later</td><td>F</td><td>Left - Direct<br>Right - Direct</td><td>NR</td></tr><tr><td>Julien I et al. Presse Med 1971 [25]</td><td>50</td><td>F</td><td>Right - Direct</td><td>NR</td></tr><tr><td>Maugery G et al. Bull Soc Ophtalmol Fr 1972 [37]</td><td>17</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Farley MK et al. Ophthalmology 1983 [12]</td><td>22</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Guiolet M et al. Bull Soc Ophtalmol 1984 [20]</td><td>31</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Dany F et al. J Mal Vasc 1986 [9]</td><td>29</td><td>F</td><td>Right - Direct</td><td>NR</td></tr><tr><td>Lach B et al. J Neurosurg 1987 [32]</td><td>43</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Peaceman AM et al. Obstet Gynecol 1987 [42]</td><td>27</td><td>F</td><td>NR - NR</td><td>NR</td></tr><tr><td>Fox R et al. J Neurol Neurosurg Psychiatry 1988 [15]</td><td>20</td><td>M</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Halbach VV et al. Neurosurgery 1990 [21]</td><td>22<br>19</td><td>F<br>NR</td><td>Left - Direct<br>NR - Direct</td><td>NR</td></tr><tr><td rowspan="4">Pope FM et al. Br J Neurosurg 1991 [44]</td><td>22</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>25</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>45</td><td>F</td><td>Right - NR</td><td>NR</td></tr><tr><td>27</td><td>F</td><td>Left - NR</td><td>NR</td></tr><tr><td>Schievink WI et al. J Neurosurg 1991 [46]</td><td>17<br>20</td><td>F</td><td>Left - Direct<br>Right - Direct</td><td>NR</td></tr><tr><td>Kashiwagi S et al. Surg Neurol 1993 [27]</td><td>22</td><td>M</td><td>Left - Direct</td><td>NR</td></tr><tr><td rowspan="6">North NK et al. Ann Neurol 1995 [40]</td><td>17</td><td>F</td><td>NR - NR</td><td>NR</td></tr><tr><td>27</td><td>NR</td><td>NR - NR</td><td>NR</td></tr><tr><td>32</td><td>NR</td><td>NR - NR</td><td>NR</td></tr><tr><td>24</td><td>NR</td><td>NR - NR</td><td>NR</td></tr><tr><td>28</td><td>NR</td><td>NR - NR</td><td>NR</td></tr><tr><td>28<br>33</td><td>NR</td><td>NR - NR<br>Contralateral - NR</td><td>NR</td></tr><tr><td>Forlodou P et al. Neuroradiology 1996 [14]</td><td>40</td><td>F</td><td>Right - Traumatic, direct</td><td>NR</td></tr><tr><td rowspan="3">Debrun GM et al. Surg Neurol 1996 [10]</td><td>39</td><td>F</td><td>Right - NR</td><td>NR</td></tr><tr><td>39</td><td>F</td><td>Left - NR</td><td>NR</td></tr><tr><td>39</td><td>F</td><td>Left - NR</td><td>NR</td></tr><tr><td>Pollack JS et al. Arch Ophthalmol 1997 [43]</td><td>33</td><td>F</td><td>Right - Direct</td><td>NR</td></tr><tr><td>Bashir Q et al. Interv Neuroradiol 1999 [7]</td><td>50</td><td>F</td><td>Left - Traumatic, direct</td><td>NR</td></tr><tr><td>Koh J-H et al. Circulation 1999 [30]</td><td>21</td><td>F</td><td>Left - Direct</td><td>NR</td></tr><tr><td>Horowitz MB et al. AJNR Am J Neuroradiol 2000 [23]</td><td>18<br>40</td><td>F<br>F</td><td>Left - Direct<br>Right - Direct</td><td>NR<br>NR</td></tr><tr><td>Kanner AK et al. J Neurosurg 2000 [26]</td><td>33</td><td>F</td><td>Left - Direct</td><td>NR</td></tr></tbody></table>
<table><caption>**Table 2** Literature review (Continued)</caption><thead><tr><th>Authors</th><th>Age (years)</th><th>Sex</th><th>CCF side and type</th><th>COL3A1 variant</th></tr></thead><tbody><tr><td rowspan="2">Chuman H et al. J Neuroophthalmol 2002 [8]</td><td>57</td><td>M</td><td>Left – Direct</td><td>IVS8+5G>A</td></tr><tr><td>48</td><td>F</td><td>Left – Direct</td><td>c.544G>S</td></tr><tr><td>Favrole P et al. La Lettre du Neurologue 2003 [13]</td><td>32</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td>Mitsuhashi T et al. Neurol Med Chir (Tokyo) 2004 [38]</td><td>30</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Desal HA et al. Neuroradiology 2005 [11]</td><td>48</td><td>F</td><td>Left – Traumatic</td><td>NR</td></tr><tr><td>Jindal R et al. Eur J Vasc Endovasc Surg Extra 2005 [24]</td><td>30</td><td>F</td><td>Right – Direct (pregnancy)</td><td>NR</td></tr><tr><td>Hollands JK et al. Neuroradiology 2006 [22]</td><td>34</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td>Usinskiene J et al. Cardiovasc Intervent Radiol 2006 [49]</td><td>25</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Van Overmeire O et al. Interv Neuroradiol 2006 [4]</td><td>45</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td rowspan="2">Yang JH et al. J Korean Med Sci 2007 [51]</td><td>48</td><td>F</td><td>Left – Direct</td><td>c.2195G>T</td></tr><tr><td>36</td><td>F</td><td>Left – Direct</td><td>c.3221_3235dup</td></tr><tr><td>Zilocchi M et al. AJR Am J Roentgenol 2007 [52]</td><td>20</td><td>F</td><td>NR – Direct</td><td>NR</td></tr><tr><td>Drera B et al. J Derm Sci 2011 [53]</td><td>32</td><td>F</td><td>NR – NR</td><td>c.1655A>G</td></tr><tr><td>Khan A et al. J Neurointervent Surg 2012 [28]</td><td>20</td><td>M</td><td>Right – Traumatic, direct</td><td>NR</td></tr><tr><td>Mammen S et al. Neurol India 2012 [35]</td><td>27</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Gauthier CE et al. J Mal Vasc 2013 [17]</td><td>25</td><td>F</td><td>NR – Direct</td><td>NR</td></tr><tr><td rowspan="2">Girardin M et al. Ann Dermatol Venereol 2013 [18]</td><td>32</td><td>F</td><td>Right – Direct</td><td>p.(Gly912Asp)</td></tr><tr><td>34</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td rowspan="2">Wang Q et al. J Neurol Surg A Cent Eur Neurosurg 2013 [50]</td><td>37</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td>39</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Ananth AL et al. Semin Pediatr Neurol 2014 [5]</td><td>17</td><td>F</td><td>Left – Direct</td><td>c.3158G>A</td></tr><tr><td>Kim JG et al. J Korean Neurosurg Soc 2014 [29]</td><td>46</td><td>F</td><td>Right – Direct</td><td>c.1662+1G>A</td></tr><tr><td>Pepin M et al. NEJM 2014 [54]</td><td>Mean age 30.9</td><td>22F, 5 M</td><td>NR – NR</td><td>NR</td></tr><tr><td>Tanaka T et al. Neurol Med Chir (Tokyo) 2014 [48]</td><td>37</td><td>F</td><td>Left – Direct</td><td>NR</td></tr><tr><td>Kojima A et al. Interv Neuroradiol 2015 [31]</td><td>59</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Linfante I et al. J Neurointervent Surg 2015 [34]</td><td>NR</td><td>M</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Liang JW et al. Neurology 2016 [33]</td><td>25</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Nakagawa I et al. J Neurol Intervent Surg 2016 [39]</td><td>24</td><td>M</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Ohlsson M et al. Neuroradiology 2016 [41]</td><td>33</td><td>F</td><td>Right – Direct</td><td>NR</td></tr><tr><td>Samaraweera APR et al. Neurology 2016 [45]</td><td>40</td><td>F</td><td>Right – Direct</td><td>c.1347+1G>A</td></tr><tr><td>Masson-Roy J et al. Can J Neurol Sci 2017 [36]</td><td>39</td><td>F</td><td>Left – Direct</td><td>NR</td></tr></tbody></table>

CCF carotid-cavernous fistula, F female, M male, NR not reported

with the median age (31.0 years, IQR [24.0–39.0]) of the patients identified in the literature review. In our series, it is remarkable that 9 patients (69.2%) experienced a direct sCCF as their first vascular event, prompting further investigations for vEDS molecular diagnosis in 4 patients only. Notably, direct sCCF has recently been included in the 2017 classification for vEDS as a major diagnosis criterion [2]. As direct sCCF in young patients seems to be pathognomonic of vEDS, genetic testing of the COL3A1 gene should be mandatory in such patients.

The type of pathogenic variant identified within the COL3A1 gene encoding the pro-alpha1 chain of type III procollagen in vEDS patients who experienced sCCF is another interesting finding. The natural course of vEDS depends on the type of COL3A1 variant, and there are

more severe clinical and phenotypical presentations in Glycine missense and splice-site variants than in variants leading to haploinsufficiency [67]. Our 13 patients presented either with heterozygous Glycine missense or splice-site variants of exons encoding a triple helix sequence. The literature review identified 9 patients with available pathogenic variants within the COL3A1 gene, and all were unsurprisingly either Glycine missense [5, 8, 18, 51, 53] or splice-site variants [8, 29, 45, 51]. Therefore, it seems reasonable to hypothesize there might be a strong association between these variants and the occurrence of sCCF, while haploinsufficiency does not associate with fistulas. However, the total number of pathogenic variants identified in our patients or reported in the literature (22/97, 22.7%) is
too small to confirm this genotype-phenotype correl-
ation. As the genetic test is now mandatory to con-
firm clinical diagnosis, the presence of pathogenic
COL3A1 variants should be systematically reported in
future articles related to sCCF.

In vEDS patients, spontaneous rupture of a tortuous
ICA emerging from the petrous bone into the CS can
result in a direct fistula with [8, 15, 19] or without
[6, 10, 19, 26, 39, 49] a previous known intracranial
ICA aneurysm. Another mechanism could be a spon-
taneous dissection of the ICA with pseudoaneurysm
formation [68]. Spontaneous ICA dissection leading to
direct sCCF is described in 5 of our patients (cases 1, 6, 7,
11 and 12) and in the literature review [33, 46, 52]. Intra-
cranial arteries have a histological constitution that report-
edly differs from diameter-matched extracranial arteries.
They have a decreased amount of elastic fibers in the
media and adventitia layers, along with thinner collagen fi-
bers and no external elastic lamina [69]. It is well known
that vEDS leads to vascular complications due to struc-
tural weakness of the artery wall secondary to type III col-
lagen defects. Therefore, arterial ruptures can also occur
on previously non-aneurysmal arteries as we found in 3
patients (cases 5, 9 and 13). Notably, direct sCCF in vEDS
patients do not systematically result from aneurysm
rupture or dissection of the cavernous ICA and cannot be
exclusively described as a complication of an aneurysm or
dissection of the cavernous ICA. An explanation for such
spontaneous ruptures in seemingly healthy arteries can be
found in Boutouyrie et al. [70] who demonstrated an
increased carotid circumferential wall stress and a higher
carotid distensibility in vEDS patients compared with
healthy individuals. Moreover, vEDS patients are known
to have lower IMT [70] and lower diastolic-systolic arterial
stiffening than healthy control individuals [71]. Impair-
ment of type III collagen generates a lower carotid stiff-
ness and an abnormally low IMT, leading to higher wall
stress and risk of arterial rupture. As direct sCCF is prob-
ably due to a sudden increase of the ICA intraluminal
pressure [72], the previous findings explain why vEDS are
at high risk for direct sCCF.

The male to female ratios in our study (0.08) and
literature review (0.15) stress the fact that female vEDS
patients seem to be more at risk than males for direct
sCCF. In comparison, there was a 0.79 male to female
ratio in our non-sCCF vEDS patients. In addition to po-
tential sex differences in IMT, sex differences in ICA
anatomy could account for a higher prevalence of
fistulas in females. Though gathering evidence in vEDS
patients is challenging, inferring results from the general
population is a first step in understanding the female
predominance for sCCF in vEDS. Differences between
males and females in various segments of the vascular
system have been reported [73–75], as well as in intracranial

arterial bifurcations and more specifically of the ICA
[76, 77], suggesting the involvement of a physiological
or an anatomical factor. First of all, sex differences in
ICA can be found in the diameter of the parent ICA
and its largest and smallest branches, with a signifi-
cantly larger diameter in male vessels than in female
vessels [77, 78]. Secondly, the study of ICA maximum
wall shear stress shows a 50% higher stress in the
female bifurcation compared with the male bifur-
cation [77]. As females have smaller ICA, their vessel
walls are exposed to higher blood flow velocity, and
this shear stress is reflected through a higher pressure
drop in the female bifurcation compared with the
male bifurcation. Vessel morphology and more specifically
vessel curvature is also an interesting factor to take into
account to determine hemodynamic patterns. Healthy
females reportedly have higher mean curvature of their
intracranial ICA than males (P 0.04) with a general ten-
dency to a more curved ICA [79]. Only 20.5% of males
have their peak curvature located within the CS, in com-
parison with as much as 45.1% of females. Therefore, we
hypothesize that anatomical differences account for an
irregular blood-flow pattern—which in turn accounts for
the alteration of the arterial wall—due to higher shear
forces in female intracranial ICA, and lead to more ICA
ruptures and fistulas in female vEDS patients. Finally, evi-
dence regarding lower IMT in healthy females compared to
males can be found in the literature [80–82]: sex is signifi-
cantly correlated with carotid artery IMT (P 0.001), as fe-
males have significantly lower IMT than age matched
males [82]. However, due to the rarity of vEDS, there is no
available evidence in the literature regarding IMT differ-
ences between male and female vEDS patients. Moreover,
as carotid IMT is measured on the extracranial part of the
carotid artery 1 cm beneath the bifurcation, the IMT profile
of proximal ICA might not be translatable into structural
fragility of the cavernous ICA. Nonetheless, assuming that
IMT difference between healthy male and female individ-
uals might also be found in vEDS males and females could
account for the overwhelming prevalence of direct sCCF in
female vEDS patients.

Another appealing and complementary hypothesis for
the frequent occurrence of direct sCCF in vEDS females
could be the decrease of wall thickness due to sex hor-
mones, and in particular the role of oestrogens on arterial
wall remodelling. An arteriovenous fistula model in rats re-
veals a significant decrease in wall thickness of the proximal
and distal aorta in castrated male rats receiving oestrogens
[83]. These results are consistent with the findings of a pre-
vious study: neointima formation is reduced by 60% in rats
treated daily by oestrogens before and after balloon injury
of carotid artery [84]. The role of oestrogens in spontan-
eous rupture of carotid-cavernous aneurysm has also been
suspected during pregnancy in healthy females free from
pregnancy-induced hypertension [85, 86]. We could not
find evidence of oestrogen taking in oral-contraceptives for
example in our female vEDS patients who experienced
direct sCCF, but it is noteworthy that the median age of
pregnancy in these patients is quite similar to the median
age of occurrence of their sCCF. These results lead us to
think that collagen fragility, IMT and anatomy differences
are not the only factors predisposing to the rupture
of arteries in vEDS females.

Conclusions

Patients with vEDS have greater risk than healthy indi-
viduals to develop direct sCCF due to their fragile ves-
sels walls. Direct sCCF may occur spontaneously by
rupture of the ICA, secondary to the rupture of an ICA
aneurysm or by dissection of the ICA. The type of vari-
ant at the COL3A1 gene associates with the occurrence
of fistulas, as only Glycine missense and splice-site vari-
ants were identified in our sCCF patients. Female vEDS
patients evidently seem more at risk for direct sCCF
than males. We hypothesize that this sex difference is
essentially linked to ICA anatomical and possible IMT
differences between females and males but might also be
amplified by hormonal differences. These hypotheses call
for further investigations in vEDS patients.

Finally, direct sCCF can be the first symptomatic event
in a previously non-diagnosed vEDS individual: in one
third of our patients, the occurrence of a fistula led to
the molecular diagnosis of vEDS. As sCCF seems to be
highly suggestive and possibly pathognomonic of vEDS,
type III collagen deficiency should be suspected in young
patients and especially in females presenting with a dir-
ect sCCF.

Abbreviations

CCF: Carotid-cavernous fistula; CI: Confidence interval; CS: Cavernous sinus;
ECA: External carotid artery; EDS: Ehlers-Danlos syndrome; ICA: Internal carotid
artery; IMT: Intima-media thickness; IQR: Inter quartile range; sCCF: Spontaneous
carotid-cavernous fistula; vEDS: Vascular Ehlers-Danlos syndrome

Availability of data and materials

The datasets used during the current study are available from the
corresponding author on reasonable request.

Authors’ contributions

SA carried out study concept and design, acquisition of data, analysis and
interpretation of data. DT carried out critical revision of manuscript for
intellectual content. JA carried out critical revision of manuscript for
intellectual content. VD carried out critical revision of manuscript for
intellectual content. AL carried out critical revision of manuscript for
intellectual content. XJ carried out critical revision of manuscript for
intellectual content. MF carried out study concept and design, and critical
revision of manuscript for intellectual content. All authors read and approved
the final manuscript.

Ethics approval and consent to participate

Approval from an ethical standards committee to conduct this study based
on medical records was received by the Comité de Protection des Personnes
lle-de-France 2 (IRB 00001072).

**Consent for publication**

Not applicable.

Competing interests

The authors declare that they have no competing interests.

**Publisher’s Note**

Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.

Author details

¹Hôpital 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.

²Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Paris, France. ³Service d'imagerie morphologique et fonctionnelle, Centre hospitalier Sainte-Anne, Paris, France. ⁴INSERM, U894, IMA-BRAIN, DHU NeuroVasc Sorbonne Paris Cité, Paris, France. ⁵INSERM, U970, Paris centre de Recherche Cardiovasculaire - PARCC, Paris, France.

Received: 21 December 2017 Accepted: 13 June 2018

Published online: 25 June 2018

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