Background Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by extensive arterial aneurysms. The successful clipping of intracranial aneurysms in patients with LDS has been reported in a limited number of patients but endovascular treatment of intracranial aneurysms in LDS has never before been described. The first successful cases of endovascular management of five intracranial aneurysms in two patients with LDS are reported.
Clinical presentation The first patient was an asymptomatic 45-year-old woman with LDS and two incidentally discovered, unruptured wide necked aneurysms (6×5 mm and 4×2 mm) arising from the ophthalmic segment of the left internal carotid artery. Both aneurysms were successfully embolized via Neuroform stent assisted coiling. The second patient was an asymptomatic middle 40s woman with LDS found to have an unruptured anterior communicating artery aneurysm (7×4 mm) as well as two ophthalmic segment aneurysms (2.5×3.7 mm and 2.9×3.5 mm). All three aneurysms were successfully embolized via Neuroform stent assisted coiling in two staged procedures. There were no periprocedural complications in either patient. Long term follow-up imaging demonstrated durable embolization in all aneurysms in both patients.
Conclusion This is the first reported case series of endovascular management of intracranial aneurysms in the setting of LDS. The endovascular approach was safe, effective and durable in all aneurysms in both patients, and should be considered when treating patients with LDS and intracranial aneurysms.
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Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by extensive arterial aneurysms as well as other phenotypic phenomena.1 The mutation linked to LDS is a missense in transforming growth factor β receptor (TGFβR) type I or II, which has downstream effects on elastin production and vascular structural integrity.2 The neurological manifestations of this disorder include Chiari I malformation, craniosynostosis, hydrocephalus and, most importantly to the neurosurgeon, intracranial aneurysms.1–4 While the aggressive nature of the arteriopathy in LDS makes correct diagnosis and timely intervention essential, surgical outcomes for the aortic manifestations of the syndrome are usually more favorable than comparable connective tissue disorders.1 ,5 The successful surgical clipping of intracranial aneurysms in patients with LDS has been reported in three patients.6 ,7 We report the first successful cases of endovascular management of five intracranial aneurysms in two patients with LDS.
Case No 1
An asymptomatic 45-year-old woman with a strong family history of aortic aneurysms carried a suspected diagnosis of Marfan's syndrome. Several family members had suffered ruptured intracranial aneurysms. She underwent genetic testing which demonstrated a TGFβR mutation, and was given the diagnosis of LDS. A routine MRI/MR angiography (MRA) of the brain revealed two incidental saccular wide necked aneurysms arising from the left internal carotid artery (ICA) just distal to the origin of the ophthalmic artery. One aneurysm (6×5 mm) arose from the superior surface of the ICA and was directed slightly laterally, while the second (4×2 mm) was located on the inferior surface, directed slightly medially (figure 1A,B). Mild diffuse vascular luminal irregularity, consistent with the patient's underlying collagen vascular disease, was also seen.
The patient underwent elective stent assisted coil embolization of both aneurysms under general anesthesia, after 5 days of premedication with aspirin and clopidogrel. The left ICA was selectively catheterized with a 6 French Envoy catheter (Codman Inc, Massachusetts, USA). An Excelsior SL-10 microcatheter (Boston Scientific, Natick, Massachusetts, USA) and Synchro-2 microwire (Boston Scientific) were advanced into the lumen of the inferior ophthalmic segment aneurysm and a primary coiling was attempted. This was unsuccessful due to the aneurysm's broad neck. The microcatheter was left in place, and a 4.5 mm×20 mm Neuroform stent was positioned within the cavernous and supraclinoid ICA with the aid of an exchange wire. The stent was deployed to appose the inferior and superior aneurysm necks, jailing the microcatheter within the inferior aneurysm lumen. Six GDC 360 coils (Stryker, Kalamazoo, Michigan, USA) were then deployed within the aneurysm. The jailed microcatheter was then removed and used to catheterize the superior aneurysm through the wall of the Neuroform device. Once accessed, four GDC 360 coils were deployed within this second aneurysm. Final angiographic runs were obtained, revealing complete obliteration of the aneurysms (figure 2A). There were no periprocedural complications, and the patient was observed overnight and discharged the following day.
Angiography 15 months after the initial endovascular treatment demonstrated continued obliteration of both aneurysms, and patency of the parent artery (figure 2B). A new 2 mm aneurysm of the ophthalmic segment of the right ICA was also noted (not shown), and the patient opted for further imaging surveillance of this lesion, with contrast enhanced post-coiling technique MRA every 12 months.
Case No 2
An asymptomatic middle 40s woman also had a family history of aneurysms and as part of genetic testing was diagnosed with LDS. Screening MRA disclosed an anterior communicating artery aneurysm measuring 7×4 mm, and two left-sided ophthalmic segment aneurysms measuring 2.5×3.7 mm and 2.9×3.5 mm (figure 3A,B). Prior neurosurgical consultation at another institution had recommended surgical clipping; however, she was interested in endovascular treatment.
The patient underwent staged elective procedures in the treatment of her multiple aneurysms. In the first session, the anterior communicating artery aneurysm was treated with stent assisted coil embolization, and a stent was placed (without coil embolization) in the ophthalmic segment of the ICA, spanning the two smaller aneurysms. Under general anesthesia after 5 days of premedication with aspirin and clopidogrel, the left ICA was catheterized with a 6 F Envoy catheter. An Excelsior SL-10 microcatheter and Synchro-2 microwire were navigated into the right A2 segment. The microwire was removed and, with the aid of an exchange microwire, a 3.5×20 mm Neuroform stent was deployed across the aneurysm neck. The aneurysm was catheterized through the stent wall, and five GDC coils were deployed.
The microcatheter and microwire were then navigated into the left M2 segment, and exchanged for a 4.5×30 mm Neuroform stent. The stent was deployed across the necks of both ophthalmic segment aneurysms. Final arteriogram revealed complete obliteration of the anterior communicating artery aneurysm from the circulation (figure 4A) and good placement of the ICA sent (figure 4B).
Coil embolization of the two ophthalmic segment aneurysms was performed 1 year later. Under general anesthesia, the proximal left ICA was catheterized with a 6 F Envoy catheter. Both aneurysms were selectively catheterized through the stent walls with a microcatheter and microwire, and embolization was performed with GDC coils (one standard and one UltraSoft coil in the first larger aneurysm and a single DeltaPlush coil in the second). Due to the small size and difficult visualization of the position of the single coil in the smaller aneurysm, a second 4.5×20 mm Neuroform stent was placed within the previous stent to ensure that no herniation into the parent vessel would occur. Final angiography showed complete obliteration of both aneurysms (figure 4C). There were no periprocedural complications in either of the two procedures, and the patient was observed overnight and discharged the following day for both procedures.
One year after the second embolization, contrast enhanced MRA (figure 4D) demonstrated continued complete obliteration of all aneurysms. As with patient No 1, we plan continued surveillance with contrast enhanced post-coiling technique MRA every 12 months.
To our knowledge, the two cases presented here are the first examples of endovascular treatment of cerebral aneurysms associated with LDS. The genetic basis of LDS has recently been elucidated.2 The syndrome results from autosomal dominant missense mutations in TGFβR types I or II. These mutations are associated with increased phosphorylation and activity of Smad2, an intracellular mediator and promoter of TGFβ activity. The abnormal activity of TGFβ is thus enhanced by the overabundance of phosphorylated Smad2, and indeed the increase in immunohistochemically detected phosphorylated Smad2 is seen in a variety of collagen vascular disorders in which TGFβ plays a role.8 ,9 While the many effects of such increased signaling are poorly understood, an interaction between fibrillin and other vascular wall components with TGFβ signaling has been demonstrated in animal models.10 ,11 This provides additional evidence for the vascular consequences of increased TGFβ activity.
Histopathological analysis of aortic aneurysms in patients with LDS has shown decreased production and abnormal fragmentation of elastin, as well as abnormal collagen deposition in the tunica media.12 Compared with patients with Marfans syndrome, the aortas of LDS patients showed diffuse, rather than cystic, medial degeneration. In addition, significantly more abnormal collage deposition was seen in LDS patients. Although the significance of these differences is not known, it is postulated that the diffuse nature of the medial degeneration as well as high collagen concentration is responsible for the more aggressive nature of the arterial aneurysms and dissections observed in LDS.9
To our knowledge, this is the first report of the successful treatment of intracranial aneurysms in LDS via the endovascular approach. The above cases illustrate how intracranial stenting provided safe scaffolding for aneurysm coiling without the need for balloon remodeling or extensive microcatheter manipulation within the aneurysms. Because LDS is a rare entity, and intracranial aneurysms from LDS even rarer, the optimal neurosurgical management of LDS patients has yet to be established. Previous reports6 ,7 have noted a hesitancy to treat these aneurysms from an endovascular approach or to use temporary clipping in the open surgical approach due to the friability of the abnormal vessels and their propensity toward vasospasm and/or catastrophic vascular injury. These complications have been seen in the endovascular13–15 and surgical16 treatment of neurovascular pathology in patients with Ehlers–Danlos syndrome IV which is a similar TGFβ connective tissue disorder. However, treatment strategies for aortic manifestations of LDS have included open surgery, endovascular or hybrid approaches with good results, suggesting that the treatment of intracranial aneurysms in this syndrome may be safer than those in patients with Ehlers–Danlos syndrome IV.5 ,17
These concerns shaped the endovascular strategies used to treat these two patients. The advantages of stent assisted coiling in LDS patients remain theoretical. The authors hypothesize that in the diseased vasculature of LDS patients, balloon assisted coiling is to be avoided due to the risk of accidental intraluminal pressure increase and arterial rupture.18 It is postulated that stent assistance provides beneficial flow diversion effects,19 which may further reduce the rate of aneurysm formation in the diseased segments of these two patients' carotid arteries.
Advantages and disadvantages of primary coiling versus stent assistance were discussed with both patients prior to treatment. Both patients expressed a strong interest in maximizing treatment durability. Although the anatomy of the ICA aneurysms in patient No 1 did not demand stent usage, we chose this option for two reasons. The relatively small size as well as orientation of the aneurysms relative to the parent vessel suggested that repeat access might be needed for primary coiling. In aneurysms presumed highly fragile, we hoped to avoid more than one placement of the microcatheter. Similarly, we hoped to minimize the likelihood of recurrence by exploiting flow diversion and remodeling advantages provided by stents. As the aneurysms were fairly proximal, we judged the additional risk of stent placement to be modest and merited.
For patient No 2, the end hole anatomy of the anterior communicating artery aneurysm was deemed to raise the risk of recurrence. Also, to achieve a durable treatment with primary coiling, we felt tight coil packing of the neck would be necessary, an approach we were reticent to use in the presumed very fragile aneurysm. As with patient No 1, we also hoped to exploit flow diversion advantages by stent assistance. The ICA aneurysms in patient No 2 were quite small and we felt delayed treatment following ICA stent placement was best to avoid stent migration during coiling in the difficult access aneurysms. Also, pleased with the successful treatment of the larger more worrisome anterior communicating artery aneurysm, we simply did not wish to push our luck. The delay of 1 year was chosen based on the patient's schedule, as she was traveling from out of state to our center for treatment. The use of a stent in the ICA was chosen as a way to treat a challenging blister aneurysm and for potential diversion advantages. Our understanding of the LDS disease process did not dictate deviation from a standard antiplatelet regimen.
The diseased state of LDS blood vessels has led some authors to recommend open surgical clipping in all intracranial aneurysms in LDS and employ alternatives to traditional methods of proximal aneurysmal control, such as adenosine induced temporary cardiac arrest,6 ,7 as this avoids temporary clipping and further arterial manipulation. While these reports were successful, many other centers do not have the required experience with such complicated microsurgical and neuroanesthetic techniques to perform this procedure safely. In contrast, the two patients we report above were successfully treated with a careful stent coiling technique, which is more widely available in centers around the world.
Stent-assisted coiling has been successfully employed to treat intracranial aneursysms in Loeys-Dietz syndrome patients.
The results were durable and without complication.
These patients should be offered endovascular treatment as an option.
This is the first case series of endovascular management of intracranial aneurysms in LDS wherein two patients with a total of five aneurysms were successfully treated with stent assisted coil embolization. Durable results were shown with at least 1 year of follow-up imaging. This report furthers the literature linking LDS and intracranial aneurysms, and demonstrates the safety and efficacy of the endovascular approach to their treatment in this unique patient population.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.