Introduction As part of an institutionally approved research protocol, patients with cerebral berry aneurysm were enrolled in a clinical trial designed to evaluate the safety of the new moldable liquid embolic agent Neucrylate AN.
Methods Twelve patients with aneurysms judged to be suboptimal for treatment by standard endovascular or surgical approaches were treated with Neucrylate AN. The agent was injected during temporary balloon occlusion at the neck of the aneurysm. The immediate angiographic percentage of aneurysm occlusion and periprocedural adverse events were assessed for each patient. Six-month follow-up angiographic studies were obtained for nine of the 12 patients.
Results Ten of the 12 aneurysms treated (83%) were large to giant (>1.0 cm in diameter), nine (75%) were wide-necked (dome/neck ratio <2.0) and three (25%) were dissecting aneurysms. There were four (33%) periprocedural neurological events. Immediate aneurysm occlusion of >90% was obtained in nine of the 12 cases (75%). There were five recurrences (55.5%) at 6 months.
Conclusion This preliminary clinical series shows that it is feasible to achieve a high percentage of immediate aneurysm occlusion with limited patient morbidity and mortality in the setting of morphologically challenging aneurysms. These preliminary data support larger trials assessing the safety and efficacy of this agent.
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Endovascular coiling of aneurysms has become a well-accepted method of treatment.1–4 Endovascular aneurysm therapy has continued to evolve with improved coil designs, the use of adjunctive devices such as temporary balloon occlusion catheters and stents, as well as the availability of a liquid agent.5–14 Despite these improvements, therapeutic complications and aneurysm remnants and recurrences remain an issue.15–21
We have developed a rapidly solidifying cyanoacrylate-based embolic agent, Neucrylate AN (VALOR Medical Inc, San Diego, California, USA) which can be introduced into an aneurysm lumen.22–24 Intitial benchtop in vitro studies with this agent have shown that it can be reproducibly and rapidly deployed into an aneurysm lumen under temporary neck occlusion conditions without significant risk of downstream embolization.23 Furthermore, animal model studies have demonstrated permanence of the implant with a relatively minimal inflammatory response.24
Materials and methods
The study was conducted with export license approval from the FDA and IRB approval from the host institution, the University of Tehran in Iran. Patients who presented with ruptured or unruptured aneurysms, who were judged by the evaluating neurointerventional surgeon to be suboptimal for treatment by standard endovascular or open surgical techniques due to aneurysm morphology or poor clinical grade, were included in the study. Patients were excluded if they or their families could not give informed consent, if there was a history of allergy to cyanoacrylate or if there was an inability to undergo cerebral angiography.
Following physical evaluation (and, in some patients, CT or MR scanning), patients were evaluated by catheter angiography. A single physician (RSP) performed all the surgeries.
After diagnostic cerebral angiography, patients received a 4000 unit bolus of heparin. A continuous heparin flush perfused the dead space of the guiding catheters throughout the procedure (heparin 6000 units/l), the same protocol followed at the institution for endovascular coiling. No patient received antiplatelet agents during or after therapy. A microcatheter with appropriate curve was placed beyond the aneurysm. Using a 300 cm guidewire, an exchange was performed, replacing the microcatheter with a balloon microcatheter (Hyperglide or Hyperform, EV 3 Endovascular Inc, Plymouth, Minnesota, USA). A microcatheter (Excelsior SL 10, Target Therapeutics, Fremont, California, USA) was then positioned into the middle portion of the aneurysm. Small aliquots of contrast agent were injected gently into the aneurysm while inflating the balloon. At the point of occlusion, the balloon size and volume were noted. The balloon was then deflated, allowing flowing blood to flush all contrast agent from the aneurysm.
Using standard non-ionic catheter hygiene, the microcatheter was flushed with dextrose 5% in water. The balloon was subsequently re-inflated to the predetermined size and volume. Neucrylate AN was then introduced into the aneurysm over 1–3 min until it conformed itself to that part of the balloon at the aneurysm neck. After a 10 s pause, with the balloon still inflated and with continued suction on the microcatheter, the microcatheter was pulled back from the aneurysm and removed completely from the patient while still continuing suction. After an additional pause of 10–20 s (longer with larger aneurysms), the balloon was deflated and the balloon microcatheter was removed. Post-procedure angiography was performed and, if needed, further treatment with an additional injection of Neucrylate under balloon occlusion conditions was performed.
Follow-up angiography to assess recurrence of the aneurysm and parent artery patency was performed at 6 months.
Aneurysm size, location, clinical presentation and follow-up are shown in table 1.
The age range of the patients (six men, six women) was 26–77 years (mean 57 years). Four patients had a history of subarachnoid hemorrhage. Three patients presented with cranial nerve dysfunction related to their aneurysm and two presented with stroke related to their aneurysm.
Ten of the 12 aneurysms treated (83%) were large to giant (>1.0 cm) and nine (75%) were wide-necked (dome/neck ratio <2.0) (figure 1). Three of the aneurysms (25%) were dissecting aneurysms.
Technical success was achieved in all 12 cases. Immediate aneurysm occlusion of >90% occurred in 9 of the 12 cases (75%). Follow-up angiography at 6 months was performed in nine patients; five patients (55.5%) showed evidence of recurrence.
There were four periprocedural neurological deficits (33%). One of these completely resolved at 6 weeks, another had completely resolved at 6 months, one was improved at 6 months and one, which was secondary to an intraprocedure balloon rupture and subsequent hemispheric stroke, resulted in a periprocedural death (8.3%) (figure 2). The details of these complications are discussed further below.
Neucrylate AN is a recently developed liquid embolic agent which has shown promise in benchtop and animal model testing for the treatment of cerebral aneurysms.23 24 The current pilot study was primarily designed to test the safety and secondarily to test the effectiveness of this agent in a human cohort. By design, the aneurysms treated in this study were those which were judged by the study investigators to be suboptimal for treatment by either conventional endovascular or open surgical methods. Because of this selection criterion, a high percentage of aneurysms treated in this study were large to giant and wide-necked; 25% of the aneurysms treated were dissecting aneurysms. Despite the challenging morphology of the aneurysms treated, the technical success rate of successfully instilling Neucrylate into the aneurysm lumen was 100%. Additionally, the immediate >90% occlusion rate was 75%. While Neucrylate infusion times were not specifically tracked for the purpose of this study, in no case did infusion times exceed 3 min. Thus, the agent shows promise in significantly reducing procedure times and therefore patient and operator radiation dose compared with existing endovascular methods.
Nine of the 12 patients had 6 month follow-up angiographic studies, five of whom (55.5%) showed some evidence of aneurysm recurrence. In none of the five patients who demonstrated recurrence did the Neucrylate mass change size or shape but, rather, in each case the entire solidified agent moved towards the dome of the aneurysm. Pretreatment MRI studies were available in four of the five patients with recurrence. In all four of these patients the pretreatment MRI demonstrated lamellated clot within the aneurysm (figure 3). The increased risk of aneurysm recurrence or regrowth in the setting of intraluminal clot has been described with other endovascular devices.25 26
Four patients suffered neurological deterioration during or immediately after treatment. In one of these patients postoperative CT scanning showed a definite loss of the device into branches of the anterior choroidal artery which originated from the aneurysm. Similarly, although the cause of neurological deterioration in two other patients was not definitely proven, occlusion of choroidal vessels arising from the base of the aneurysms was highly suspected. Therefore, as with other endovascular methods, understanding the branch anatomy in relationship to the aneurysm is also critically important with Neucrylate.
When treating with Neucrylate, the balloon microcatheter is used to create a smooth interface at the neck of the aneurysm in the hope of recreating normal laminar flow. However, intraprocedural balloon rupture is a catastrophic phenomenon. Balloon rupture allows contrast in the balloon to come into contact with the polymerizing agent, thereby disrupting it and leading to a high likelihood of downstream embolization. This complication occurred in the one patient in this series who died. In that patient a 4 mm balloon had been overinflated to 7 mm in order to provide optimal neck coverage. The balloon ruptured upon overinflation resulting in downstream embolization of Neucrylate material which led to a massive hemispheric infarction and subsequent death (figure 2).
This study has several limitations. The number of patients treated was small. Availability of sophisticated imaging such as three-dimensional angiography at the treatment facility was limited. Additionally, there was an inherent selection bias towards large wide-necked aneurysms in this study which makes generalization of the results to the average pool of aneurysms difficult.
Despite these limitations, this initial pilot study shows that treatment of even morphologically challenging aneurysms with Neucrylate is technically feasible and has a reasonable safety margin. Additionally, we believe that, in the majority of cases, treatment with this investigational agent removed apparent pathological flow dynamics such as swirling flow seen with angiography. This factor is rarely discussed in most current literature and in relation to other commercially available devices. In the future we hope to study the change in aneurysm flow dynamics provided by Neucrylate deposition.27–29
This pilot study of patients with aneurysm treated with Neucrylate shows promise for the application of this agent in the treatment of aneurysms. Further trials will be necessary to fully evaluate the efficacy of this agent.
The authors thank Joseph Horton and Jeffrey Sunshine for their critical suggestions and review of the manuscript.
Linked article 004317.
Competing interests CWK is a shareholder and Chief Medical Officer in Valor Medical Inc. RSP is a shareholder in Valor Medical Inc. The other authors have no competing interests.
Ethics approval This study was conducted with the approval of the University of Tehran.
Provenance and peer review Not commissioned; externally peer reviewed.
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