CASE REPORT
A Case of Spontaneous Carotid-cavernous Fistula in a Patient with Vascular Ehlers-Danlos Syndrome
2024 Volume 11 Pages 345-352
Details
2024 Volume 11 Pages 345-352
Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder that is characterized by vascular lesions mainly caused by vascular fragility, such as spontaneous carotid-cavernous fistula (sCCF). We experienced a patient who presented with sCCF but suffered postoperative multiple vascular arteriopathy complications caused by undiagnosed vEDS. A 39-year-old woman who had no physical and medical characteristics indicating vEDS was referred to our hospital due to sudden onset of headache and pulsatile tinnitus. Digital subtraction angiography revealed direct sCCF of the left internal carotid artery. Internal trapping with coils was performed using the bilateral transfemoral artery approach, and complete occlusion of the high-flow fistula was achieved. At the end of the procedure, left femoral angiography via the sheath revealed extravasation from the puncture site. Hemostasis using an Angio-Seal hemostasis device under proximal balloon protection standby was immediately performed, and complete hemostasis was achieved. Postoperative abdominal computed tomography (CT) revealed a huge retroperitoneal hematoma. To improve the patient's hypovolemic shock conditions, hypervolemic therapy was administered, and her vital signs normalized. Approximately 10 days after the treatment, abdominal CT revealed pseudoaneurysm at the bilateral puncture sites and dissection of the left external iliac artery. Based on the clinical events, vEDS was strongly suspected. The genetic test revealed collagen type III alpha 1 chain gene abnormality, which led to a definite diagnosis. The symptoms improved, and follow-up CT showed spontaneous healing of both vascular arteriopathies with no recurrence. Attention should be paid to the risk of vascular arteriopathy complications during the perioperative period in patients with vEDS.
Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder characterized by vascular lesions, such as spontaneous carotid-cavernous fistula (sCCF) and vascular dissection, mainly due to connective tissue weakness.1) vEDS is a type IV EDS, accounting for 5%-10% of all cases of EDS; it has an incidence of only 1/90000-1/200000.2) Abnormalities in the collagen type III alpha 1 chain (COL3A1) gene encoding type III procollagen, which forms the vascular wall, gastrointestinal tract, and uterus,3) associated with vEDS can cause rupture of the internal organs, arteries, or uterus before or after delivery, resulting in various serious clinical symptoms other than those of the central nervous system. Among all types of EDS, vEDS is considered to have the poorest prognosis.3)
sCCF in vEDS was changed from minor diagnostic criteria in the old classification4) to major criteria in the recent classification.2) The intracranial vascular arteriopathy complications of vEDS include sCCF, vascular dissection, aneurysm, and rupture, with sCCF being the most frequent. The frequency of sCCF was previously reported to be 2.4%,5) but it has increased to 9.8%,1) partly due to improved diagnostic rates. Moreover, sCCF is more common in women (79.4%) than in men among patients with vEDS.1)
Surgical intervention for vEDS carries a high risk of dissection or rupture due to inherent vascular fragility.6) Endovascular treatment was previously reported to cause mortality as high as 58%;7) however, a recent review reported a mortality of 0% with the subsequent advances in endovascular treatment techniques and improvement in device performance.1)
We herein describe a patient who presented with sCCF but suffered postoperative multiple arteriopathy complications caused by undiagnosed background vEDS.
A 39-year-old woman presented to our satellite hospital with sudden onset of headache, vomiting, and pulsatile tinnitus without any specific cause. She had a history of two pregnancies and vaginal deliveries, both of which were uneventful. Furthermore, she had undergone traumatic anterior cruciate ligament reconstruction surgery 5 years ago, but she had no medical or family history suggesting vEDS. Head computed tomography (CT) revealed no intracranial abnormal lesions, whereas head magnetic resonance (MR) angiography showed abnormal high-intensity signals in the bilateral cavernous sinuses, predominantly on the left, the posterior intercavernous sinus, and the left superficial middle cerebral vein (Fig. 1A, B). Transfemoral digital subtraction angiography (DSA) showed a direct fistula in the cavernous portion of the left internal carotid artery (ICA). Normal blood flow distal to the fistula was poor. Blood flow to the left cerebral hemisphere was provided by collateral blood circulation via the anterior and posterior communicating arteries and was thought to be sufficient to maintain normal brain function. The shunt flow drained into the bilateral inferior petrosal sinuses, predominantly on the left, and into the left pterygoid venous plexus (Fig. 1C, D). There were no feeders from other territories, such as the bilateral extracranial carotid arteries, contralateral ICA, or vertebral artery. The patient was referred to our hospital for further examination and treatment on the 8th day after onset.
Preoperative imaging of the spontaneous carotid-cavernous fistula. A, B: Preoperative magnetic resonance angiography revealing arterialized flow signals in the bilateral cavernous sinuses, posterior intercavernous sinus, and left superficial middle cerebral vein. C, D: Preoperative left internal carotid angiography revealing a fistula in the cavernous sinus, with early visualization of the bilateral cavernous sinuses predominantly on the left. The intracranial arteries distal to the fistula are poorly visualized, indicating that the fistula orifice is large. The shunt flow drains into the bilateral inferior petrosal sinuses, predominantly on the left, and into the left pterygoid venous plexus. E, F: Preoperative four-dimensional computed tomography angiography showing the high-flow CCF. Detailed identification of the orifice was difficult, but it seemed to be large.
Physical examination on admission revealed left-sided pulsatile tinnitus, but the patient's headache and vomiting had disappeared. Neurological examination revealed no abnormalities, and there were no characteristic facial features or skin or joint abnormalities suggestive of vEDS. At this point, we did not suspect vEDS.
Although it was difficult to understand the detailed structure of the fistula using four-dimensional CT angiography in the outpatient setting, the orifice of the fistula was predicted to be large (Fig. 1E, F). Endovascular therapy (EVT) was planned, and oral administration of aspirin at 100 mg/day was initiated 3 days before the procedure. The treatment plan was to preserve the ICA if the orifice was small but perform ICA parent artery occlusion otherwise.
II. TreatmentUnder local anesthesia, an 8-Fr-long sheath was placed in the right femoral artery and a 4-Fr-long sheath in the left femoral artery through anterior wall punctures. During the insertion of the left sheath into the femoral artery, the guidewire exhibited an inversion behavior; thus, the guidewire was removed, and repuncture was performed. Sheath angiography performed immediately after the puncture revealed extravasation from the puncture site of the left external iliac artery (Fig. 2A). After several minutes of observation, the extravasation naturally disappeared; thus, the procedure was continued (Fig. 2B). An anticoagulant was intravenously administered with a 4000-U heparin bolus, and the activated clotting time was maintained at approximately 250 s.
Intraoperative distal subtraction angiography (DSA) findings. A: Left common iliac angiography showing extravasation (arrow) from the puncture site of the left external iliac artery. B: After several minutes, the extravasation spontaneously disappeared. C: Intraoperative left vertebral angiography during balloon test occlusion of the orifice of the fistula using the TransForm microballoon catheter (white arrows) showing incomplete occlusion of the shunt. D1: Intraoperative fluoro A-P view showing the coils in the left carotid artery. D2: Postoperative left common carotid angiography A-P view showing complete occlusion of the fistula. E: Left sheath angiography showing recurrence extravasation (arrow) from the left external iliac artery. F: Left external iliac artery angiography from the balloon catheter showing complete hemostasis.
An 8-Fr balloon guide catheter (Optimo EPD; Tokai Medical Products, Aichi, Japan) was passed into the left cervical ICA. Left internal carotid angiography revealed no changes compared with the initial DSA finding. Based on the preoperative hemodynamics, the balloon occlusion test was not conducted as the patient was expected to demonstrate ischemic tolerance even after occlusion of the ICA on the affected side.
An Excelsior 1018 microcatheter (Stryker, Kalamazoo, MI, USA) was placed in the ophthalmic segment of the left ICA. Then, a TransForm 4 × 11-mm microballoon catheter (Stryker) was positioned at the orifice of the fistula. To determine the size of the orifice, left ICA and left vertebral arteriography with a TransForm microballoon inflated in the orifice. However, complete occlusion of the shunt was not achieved (Fig. 2C). Based on these results, ICA parent artery occlusion was planned as the orifice was suspected to be too large to preserve the ICA.
The Excelsior 1018 microcatheter was advanced proximal to the ophthalmic artery bifurcation across the fistula, and internal trapping was performed using a total of 26 target coils (Stryker) (Fig. 2D1). Left common carotid angiography confirmed complete occlusion of the fistula with the left ICA (Fig. 2D2). After right internal carotid and left vertebral angiography had confirmed collateral blood flow to the left cerebral hemisphere, the procedure was apparently completed. However, the patient complained of lower abdominal and left femoral pain after the removal of the guide catheter. Subsequently, she went into shock.
A huge subcutaneous hematoma was found at the left femoral puncture site. Left femoral sheath angiography revealed extravasation from the left external iliac artery (Fig. 2E). After referral to a radiologist and vascular surgeon, a 5-Fr Lutonix drug-coated balloon catheter (Medicon, Tokyo, Japan) was navigated from the right femoral artery to the left external iliac artery for standby proximal flow control. The left sheath was then removed from the left femoral artery, and a hemostasis device (6 Fr Angio-Seal; MicroVention TERUMO, Tustin, CA, USA) was used to achieve complete hemostasis. After contrast-enhanced imaging through the balloon catheter confirmed the disappearance of the extravasation from the left external iliac artery, the balloon catheter was removed and the puncture site closed using a second Angio-Seal device (Fig. 2F).
III. Postoperative coursePostoperative abdominal CT revealed a huge hematoma extending from the left femoral subcutaneous tissue to the retroperitoneal cavity and perisplenic area. The patient's vital signs indicated hypovolemic status. Therefore, postoperative antithrombotic drugs were not administered. To improve the hypovolemic shock condition, the patient was managed with large volume infusion and transfusion of 4 units of red blood cells. Her blood pressure gradually stabilized the day after EVT, and follow-up contrast-enhanced abdominal CT performed 2 days after EVT revealed no evidence of active contrast leakage or hematoma growth. Head MR imaging 8 days after EVT showed scattered asymptomatic high-diffusion-weighted signals in the left cerebral hemisphere. However, the findings of the CCF had disappeared. Contrast-enhanced lower extremity CT 10 days after EVT revealed a new vascular dissection in the left common iliac artery and new pseudoaneurysms in the bilateral external iliac arteries in the vicinity of the puncture site (Fig. 3A). To manage these pseudoaneurysms, compression therapy using an echo probe was performed for approximately 1 h, which successfully reduced the aneurysms. After consultation with the vascular surgeon, a policy of intensive follow-up was planned.
Postoperative bilateral iliac artery imaging. A: Contrast-enhanced lower extremity computed tomography (CT) 10 days after endovascular therapy (EVT) showing two vascular dissections (arrowheads) in the left common iliac artery and pseudoaneurysms (arrows) in the bilateral external iliac arteries at the puncture site. B: Contrast-enhanced lower extremity CT 18 days after EVT showing morphologic changes in the known dissection of the left common iliac artery (arrowheads) and size reduction of the bilateral external iliac artery pseudoaneurysms (arrows). C: Contrast-enhanced lower extremity CT 60 days after EVT showing improvement of the bilateral external iliac artery pseudoaneurysms but also a stenotic change in the left common iliac artery dissection (arrow). D: Lower extremity magnetic resonance (MR) angiography 1 year after EVT showing improvement of the left common iliac artery stenosis but also the formation of a new dissection-like stenosis (arrow) on the proximal side of the right external iliac artery. E: Lower extremity MR angiography 2.5 years after EVT showing a clear dissection (arrow) on the central side of the right external iliac artery.
Based on the clinical course, vEDS was suspected and genetic testing was conducted with the patient's consent to determine the definitive diagnosis. We submitted the patient's blood samples to the genetic laboratory of the Kazusa DNA Research Institute (Kisarazu, Chiba, Japan). About 1 month later, the genetic test revealed abnormalities in the COL3A1 gene. Contrast-enhanced lower extremity CT performed on postoperative day 18 showed angiographic change in the left common iliac artery dissection and reduction in the size of the bilateral external iliac artery pseudoaneurysms (Fig. 3B). The clinical course was uneventful; thus, the patient was discharged home without neurological deficits or symptom after EVT. Periodic follow-up examinations with ultrasonography, contrast-enhanced CT, ankle-brachial index, and MR angiography were planned for vascular arteriopathy monitoring. Approximately 2 months after the EVT, contrast-enhanced lower extremity CT revealed that the bilateral external iliac artery pseudoaneurysms had disappeared, but the left common iliac artery dissection had become a stenotic lesion (Fig. 3C). As there were no symptoms, follow-up was continued. Approximately 1 year after the EVT, lower extremity MR angiography showed improvement of the left common iliac artery stenosis; however, a new dissection-like stenosis had appeared in the proximal right external iliac artery, which was located proximal to the vascular puncture (Fig. 3D). Approximately 30 months after the EVT, lower extremity MR angiography showed a clear dissection on the proximal side of the right external iliac artery (Fig. 3E), As the lesion was asymptomatic, intensive follow-up examination was continued.
The patient in this case did not meet the diagnostic criteria for vEDS until the postoperative onset of bleeding from the complicating arteriopathy. The characteristic findings of vEDS include thin skin with visible blood vessels, easy bleeding, birdlike face, and fragile intestinal tract and uterus. However, none of these were observed in the patient. Internal trapping using a transarterial approach was employed to occlude the fistula as the fistula orifice was suspected to be too large to close with ICA preservation. In this case, the balloon occlusion test was not conducted before parent artery occlusion but might have caused immediate vascular complications. Fortunately, the right ICA, which had been occluded with an Optimo and Transform balloon, did not suffer vascular injury.
Intraoperative puncture site bleeding was observed, but this was initially thought to be intra-abdominal bleeding from a high-level puncture beyond the inguinal ligament, a basic complication to be avoided. However, subsequent perioperative imaging studies reported new delayed vascular arteriopathy, which led to the suspicion of vEDS and conduct of confirmatory genetic testing. vEDS is associated with puncture site hemorrhage during EVT as well as intracranial hemorrhage, cardiac rupture, aortic and peripheral artery rupture and dissection, splenic artery rupture, retroperitoneal hematoma, other vascular complications, and unexplained artery rupture at a site not directly affected by endovascular treatment, often described as "remote vascular catastrophes." 8) Even after the initial vascular complication, serial hemorrhagic complications may occur, and the timing and location of such complications are difficult to determine.8)
In our case, delayed formation of pseudoaneurysms and dissections in the common iliac artery and external iliac artery occurred, which were the access routes for the guidewire and catheter but not directly punctured. However, contrast images at the end of the treatment detected no abnormality. Regardless of the presence or absence of intraoperative bleeding complications, it is always recommended to be aware of the possibility of various vascular events to occur in the perioperative period in patients with vEDS, even in remote locations unaffected by the treatment. vEDS is associated with a 22% risk of morbidity and 5.6% risk of mortality based on angiography.7) Fortunately, in our patient, no complications occurred from the preoperative DSA performed by the previous hospital. But if vEDS is suspected before surgery, a noninvasive examination, such as MR angiography or CT angiography, seems safer.
Cases of endovascular treatment of sCCF associated with vEDS reported after 2000, including this case, are summarized in Table 1.10-26) The mean age of the patients was 38.3 (range: 21-59) years, and 83.3% of them were women. The transarterial approach was employed in 38.8% of the cases, the transvenous approach in 44.4%, and the combination of the transarterial and transvenous approaches in 16.6%. The direct cervical carotid artery puncture approach was also selected in some cases. The transvenous approach is often employed if vEDS has already been diagnosed or strongly suspected based on the patients' clinical course and physical examination.
Summary of spontaneous carotid cavernous fistula in patients who had vascular Ehlers–Danlos syndrome since 2000
| Case No. | Author (year) | Age (years) /Sex | Genetic mutation | Diagnosis period | Treatment | Complications (period) | Recur-rence | Follow-up/outcome |
|---|---|---|---|---|---|---|---|---|
| M: male, F: female, N/A: not available, Pre-OP: preoperative period, Post-OP: postoperative period, TAE: transarterial embolization, TVE: transvenous embolization, DP: direct puncture, SOV: trans-superior ophthalmic vein approach, POD: postoperative day, FA: femoral artery, CIA: common iliac artery, EIA: external iliac artery, Y: year, M: month, W: week, D: day | ||||||||
| 1 | Chuman et al. (2002) 10) | 57/M | COL3A1 | Post-OP | TVE | Colon rupture (POD 3) | No | 1 Y/Good |
| 2 | Desal et al. (2005) 11) | 48/F | N/A | Pre-OP | TAE | None | N/A | 7 D/Dead (POD 7) |
| 3 | Hollands et al. (2006) 12) | 34/F | N/A | Pre-OP | TAE+TVE (DP) | None | No | 6 M/Good |
| 4 | Van Overmeire et al. (2006) 13) | 45/F | COL3A1 | Pre-OP | TVE | Intra-abdominal hemorrhage (POD 0) | N/A | 10 D/Dead (POD 10) |
| 5 | Usinskiene et al. (2006) 14) | 25/F | N/A | Pre-OP | TVE | Intra-abdominal hemorrhage (POD 3) | N/A | 3 D/Dead (POD3) |
| 6 | Mammen et al. (2012) 15) | 27/F | N/A | Pre-OP | TAE | Right FA dissection (POD 0) | No | 9 M/Good |
| 7 | Wang et al. (2013) 16) | 39/F | N/A | Pre-OP | TAE | None | Yes | 2 Y/Good |
| 8 | Asai et al. (2013) 17) | 41/F | COL3A1 | Post-OP | TAE | Puncture site hemorrhage (POD 0), splenic artery aneurysm (POD 3) | No | 2 Y/Good |
| 9 | Kim et al. (2014) 18) | 46/F | COL3A1 | Pre-OP | TVE | None | No | 6 M/Good |
| 10 | Tanaka et al. (2014) 19) | 37/F | N/A | Pre-OP | TVE (SOV) | None | No | 18 M/Good |
| 11 | Nakagawa et al. (2014) 20) | 24/M | COL3A1 | Pre-OP | TVE (DP) | None | No | 6 M/Good |
| 12 | Kojima et al. (2015) 21) | 59/F | COL3A1 | Post-OP | TAE | None | No | 21 M/Good |
| 13 | Sato et al. (2018) 22) | 21/F | N/A | Pre-OP | TVE | None | No | 1 Y/Good |
| 14 | Masson-Roy et al. (2017) 23) | 39/F | N/A | Pre-OP | TAE | None | No | 3 M/Good |
| 15 | Ito et al. (2019) 24) | 48/M | N/A | Pre-OP | TAE+TVE (DP) | None | No | 3 M/Good |
| 16 | Uchiyama et al. (2023) 25) | 22/F | COL3A1 | Pre-OP | TVE (DP) | None | No | 3 M/Good |
| 17 | See et al. (2024) 26) | 48/F | N/A | Pre-OP | TAE+TVE | Intra-abdominal hemorrhage (POD 5) | No | 10 W/Good |
| 18 | Present case | 39/F | COL3A1 | Post-OP | TAE | Puncture site hemorrhage, intra-abdominal hemorrhage (POD 0), left CIA/EIA pseudoaneurysm, right EIA dissection (POD 10) | No | 2.5 Y/Good |
A diagnosis of vEDS was made after treatment in 22.2% of the cases, indicating the difficult preoperative diagnosis of vEDS among sCCF cases. Therefore, it is important to consider sCCF in young women with no history of trauma, as in the present case, who may have vEDS in the background.
Celiprolol (Selectol; Nippon Shinyaku, Kyoto, Japan), a vasodilatory β1-blocker, has been reported to reduce cardiovascular and other serious events by stimulating collagen production in patients with vEDS whose vessels are vulnerable to mechanical stress.9) Therefore, celiprolol administration may be useful before surgery in patients with vEDS. In the present case, we did not use celiprolol as vEDS was not suspected preoperatively and the patient fell into shock immediately after the curative operation. However, it could have been considered once the patient's condition had stabilized after surgery and a diagnosis of vEDS was made to prevent delayed bleeding events.
In view of the above, if vEDS has been diagnosed preoperatively, we recommend avoiding diagnostic and operative procedures that require arterial puncture. We should opt for the transvenous approach with surgical exposure for the direct insertion of an intravascular sheath to minimize the risk of vascular injuries. It may have also been necessary to administer preoperative celiprolol for the prevention of vascular events in treated and nontreated sites.
The mode of inheritance of vEDS is autosomal dominant. The natural history of vEDS depends on the type of COL3A1 mutation, and patients with missense or splice mutations of glycine have severe courses, including CCF.1) Therefore, the possibility of vEDS should be considered, particularly in young women with CCF but no history of trauma, and the vessels should be protected regardless of the treatment method. If a patient can wait for intervention based on the CCF symptoms, preoperative genetic testing should be conducted to establish a detailed plan for intraoperative and postoperative management. Notably, genetic testing should be considered earlier if vEDS is suspected after treatment as it takes about 1 month from the actual submission of the specimen for genetic test until the results are known. Moreover, the genetic counseling team should be asked to assist in providing information when conducting genetic testing, and the psychological follow-up of the individual and blood relatives should be taken into account. The patient in this case has been treated for 2.5 years, including her lower extremity vascular arteriopathy. She is currently a stable outpatient. However, close follow-up is necessary based on the presence of the missense mutation of glycine.
Sufficient attention should be given to the possibility of vEDS in young women with sCCF but no history of trauma. Also, genetic testing should be conducted as early as possible, even in the absence of any characteristic physical findings or family history of vEDS. The treatment planning for vEDS must consider the potential for vascular complicative arteriopathy, such as pseudoaneurysms and dissections, in remote locations other than the puncture site during both EVT and the perioperative period.
Consent to publish this paper has been obtained from the patient.
The authors declare no conflicts of interest to declare.
