2025 Volume 19 Issue 1 Article ID: cr.2025-0026
Objective: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by mutations in the genes encoding transforming growth factor β (TGF-β). LDS is often associated with arterial tortuosity, aortic aneurysm, hypertelorism, and bifid uvula. Patients with LDS are at increased risk for vascular events due to aortic or cerebral aneurysms. We present the 1st reported instance of a carotid-cavernous fistula (CCF) in a patient with LDS.
Case Presentation: A 50-year-old male with LDS due to a pathogenic TGFBR2 variant presented with a 9-month history of bilateral tinnitus, right-sided exophthalmos, and conjunctival chemosis. Imaging revealed a direct Barrow type A CCF between the ventral wall of the internal carotid artery and the right cavernous sinus. The patient underwent transarterial embolization of the CCF using coils and 1 vial of ethylene vinyl alcohol copolymer. Postoperatively, the patient showed marked clinical improvement, with the resolution of pulsatile tinnitus and a gradual reduction of right-sided exophthalmos.
Conclusion: This case illustrates the successful endovascular management of a direct carotid-cavernous fistula in a patient with LDS. Careful pre-interventional imaging to rule out aortic aneurysm and meticulous catheter handling are necessary to achieve successful embolization.
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by mutations in genes of the transforming growth factor β (TGF-β) signaling pathway.1) LDS is often associated with arterial tortuosity, aortic aneurysm, hypertelorism, and bifid uvula.1,2) Patients with LDS are at increased risk for vascular events due to aortic or cerebral aneurysms.1,3) We present a 50-year-old male LDS patient due to a pathogenic TGFBR2 variant who developed a direct carotid-cavernous fistula (CCF) without a previous history of trauma. The patient was managed by transarterial embolization of the CCF.
A 50-year-old male patient with LDS due to a pathogenic TGFBR2 variant presented with a 9-month history of bilateral tinnitus and exophthalmos of the right eye. He underwent multiple aortic interventions in the past, including valve-sparing aortic root replacement, thoracic endovascular aortic repair following Stanford type B aortic dissection, open thoracoabdominal aortic surgery, and coil embolization of a left gastric artery aneurysm. On clinical examination, the patient presented right-sided exophthalmos, conjunctival chemosis, and bilateral hearing loss, which was more pronounced in the left ear.
Magnetic resonance imaging (MRI) demonstrated a dilated right cavernous sinus with early arterial filling on time-resolved MRA as well as exophthalmos of the right eye (Fig. 1). Digital subtraction angiography (DSA) confirmed a direct Barrow type A CCF, between the right cavernous sinus and the ventral wall of the internal carotid artery (ICA) at the petrocavernous junction (Fig. 2). This supported the theory of a primary rupture of the arterial wall, instead of secondary rupture of an aneurysm arising from the intracavernous portion of the ICA. The fistula drained via the ipsilateral inferior petrosal sinus (IPS), the superior ophthalmic vein, and the intercavernous sinus. The intraocular pressure (IOP) measurement revealed values within the normal range (20 mmHg on the right and 18 mmHg on the left).
The patient was subsequently scheduled for an endovascular treatment of the right CCF in general anesthesia. Due to an inherent vessel wall weakness with increased periprocedural risk and preceding aortic interventions, a transvenous approach was attempted first. However, due to a severe stenosis between the IPS and the cavernous sinus, transvenous approach had to be aborted (Fig. 2A).
For the transarterial approach, via transfemoral approach an 8-Fr guiding catheter (Cerebase; Cerenovus, Johnson & Johnson, Irvine, CA, USA) was placed in the proximal cervical segment of the right ICA. In the setting of pronounced vessel tortuosity, an intermediate catheter (Vecta71; Stryker, Kalamazoo, MI, USA) was navigated into the distal cervical ICA for better support and to mitigate the risk of a dissection. Two microcatheters (Echelon-10; Medtronic, Minneapolis, MN, USA) were then navigated via the ICA into the right cavernous sinus. Loose coiling of the cavernous sinus was performed, with a total of 11 coils (Target; Stryker) to provide a scaffold. The catheter was positioned at the inferior border of the cavernous sinus to effectively occlude the inflow into the cavernous sinus and 1 vial of ethylene vinyl alcohol copolymer (Onyx Liquid Embolic System; Medtronic) was carefully injected through 1 of the catheters into the cavernous sinus (Fig. 3). Given the large size of the internal carotid artery (9 mm), balloon protection was not used. Instead, meticulous care was taken to prevent off-target embolization into the ICA territory. A complete occlusion of the arterio-venous shunt was demonstrated on the final run (Fig. 3). Postoperatively, the patient demonstrated significant improvement in his symptoms. The pulsatile tinnitus subsided, and his right-sided exophthalmos began to resolve over the following weeks.
LDS is a connective tissue disorder with cardiovascular and neurovascular manifestations. It is characterized by pathogenic variants in 1 of 6 different genes encoding for various components of the TGF-β signaling pathway leading to excess TGF-β activity. TGF-β is a ubiquitous cytokine in most mammalian cells and plays an important role in proliferation and cellular differentiation.1) Patients with LDS suffer from aortic dissection at diameters previously not considered as thresholds for surgery.
Neurovascular hallmarks of LDS include tortuous head and neck vessels, intracranial aneurysms, dural ectasia, Arnold-Chiari type I malformation, hydrocephalus, and craniosynostosis.4) Cases of arterio-venous malformation (AVM) and dural arteriovenous fistula (dAVF) have also been reported in LDS. Aoki et al. reported successful embolization of a tentorial dAVF (Lawton type 1, Borden type 2) draining to the vein of Galen.5,6) Abdelhadi et al. described a case of recurrent coronary artery fistula due to a heterozygous mutation in the gene encoding TGFB3 linked to LDS.7) This could suggest that certain variants of LDS can have a higher propensity to develop systemic arteriovenous fistula.7) To our knowledge, a CCF has not been reported in a patient with LDS.
There are frequently reported cases of association of CCF with Ehlers-Danlos syndrome (EDS) but not with Marfan syndrome (MFS).8) Adham et al. reported higher risk for direct CCF in EDS due to increased carotid circumferential wall stress, higher carotid distensibility, and lower carotid intima-media thickness.9) Patients with LDS similar to EDS can have fragile vessel walls in both the cavernous sinus and the arterial wall of the ICA. This could predispose to rupture of the fragile arterial wall, resulting in direct spontaneous CCF. In the reported case, the fistulous point was located at the ventral wall of the ICA at the petrocavernous junction (Fig. 2), supporting the theory of a primary rupture of the arterial wall.
Endovascular embolization has been established as the 1st-line therapy for management of CCF. More than 80% of patients who undergo endovascular treatment for direct and indirect CCFs have been reported to have a complete cure.10) On the other hand, there are several reported cases of LDS that underwent successful intervention without complications.11) Aoki et al. particularly described repeated manipulation of the intermediate catheter and microcatheters in an attempt to navigate through a tortuous vertebral artery that did not result in dissection.6) Levitt et al. also reported successful coil embolization of aneurysms in 2 patients with LDS.12) Therefore, these facts indicate that endovascular treatment in LDS is more feasible than in vascular EDS. Thus, it is important to distinguish among these hereditary connective tissue disorders by utilizing both clinical and molecular diagnostic tools. Although the arteries in patients with LDS may generally tolerate catheter manipulation without issue, it is essential to be cautious when arteries are highly tortuous. On the other hand, aortic dissection is another common concern in patients with LDS. Therefore, comprehensive imaging of the aorta and major chest arteries should be acquired before any intervention. In general, it is advisable to adhere to standard procedural protocols when treating LDS patients, including ultrasound-guided vascular access, maintenance of stable arterial blood pressure, and administration of intravenous heparin to mitigate the risk of thromboembolic events.
This case illustrates the successful endovascular management of a direct carotid-cavernous fistula in a patient with LDS. Careful pre-interventional imaging to rule out aortic aneurysm and meticulous catheter handling are necessary to achieve successful embolization.
The authors declare no conflicts of interest.