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Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by cutaneous pigmentations, neurofibromas, Lisch nodules and neuroectodermal tumors. Supra-aortic vessel aneurysms may affect patients with NF-1 and can be associated with rupture, ischemic complications and compression symptoms. We describe a 48-year-old woman with NF-1 and an extracranial 3×5 cm right internal carotid artery aneurysm. After balloon test occlusion the patient was treated with parent artery sacrifice which led to significant shrinkage on follow-up MR and reduction of compression symptoms. The literature concerning internal carotid artery aneurysms associated with NF-1 is reviewed evaluating the possible therapeutic options.
Neurofibromatosis type 1 (NF-1), or von Recklinghausen's disease, is an autosomal dominant disorder linked to chromosome 17, affecting one in 3000 individuals 1,2. Its most frequent manifestations include cutaneous pigmentations, neurofibromas, and Lisch nodules, which result from abnormalities in neural crest-derived cell types 3,4. It is characterized by abnormal growth of neuroectodermal tumors throughout the body 5,6 but many non-neural crest-derived tissues, including bone, brain, and blood vessels, may also be affected in patients with NF-1 3. Two factors have recently been independently associated with increased mortality in affected children and young adults (< 30 years of age): soft-tissue malignancies and vascular disease 7,8, even though most individuals with NF-1-associated vascular lesions are asymptomatic 9.
NF-1 associated vascular lesions were classified already in 1945 by Reubi 10. The form of the disease usually associated with cerebral aneurysms has been called the intimal aneurysmal form 6 but overlap occurs among the different types that are thought to involve the same pathogenesis at different stages of maturation 11. Greene et al. 12 suggested that there are two primary types of vascular lesions associated with neurofibromatosis where the first type affects large vessels with perivascular neurofibromas or ganglioneuromas that are associated with degenerative changes in the adjacent vessel wall. The second type is present in small vessels and consists of nodular aggregates of smooth muscle cells that Greene believed represented mesodermal dysplasia. The most common clinical presentation for vascular involvement by neurofibromatosis is renal artery stenosis with consequent hypertension, but characteristic NF-1 vascular lesions have been described in the entire arterial tree 4,2,12,13. Cerebrovascular abnormalities include occlusion of major intracranial vessels, arteriovenous malformations, and intracranial aneurysms 6,12,14-16.
The gene responsible for neurofibromatosis type-1, NF1, encodes neurofibromin, which normally acts as a tumor-suppressor product through down regulation of reticular activating system induced signaling and by modulating epithelial-mesenchymal transformation and cell proliferation. A mutation involving NF1 results in an inactivated form of neurofibromin and an increase in cellular proliferation that underlies tumor formation 3,8,17 - most commonly malignant nerve sheath tumors, myelogenous leukemia, pheochromocytoma, and neurofibromas 2.
The pathogenetic mechanisms of these vascular lesions in NF-1 are not completely clear 8, however, loss of function of NF1 could contribute to the pathogenesis of vascular disease because this gene is normally expressed both in endothelial and vascular smooth muscle cells (VSMCs) and can regulate cell growth through Ras regulation 17.
In studies of genetically engineered mice, Xu et al. 17 found an apparent lack of vascular disease in uninjured animals despite a nearly complete loss of NF1 from vascular smooth muscle. This is consistent with the finding that vascular disease in NF-1 appears to develop over time 18,3 probably as the result of a pathological response to otherwise normal stress within the vasculature. The profound neointimal proliferation from injury that can be observed in NF-1 suggests that loss of NF1 or other perturbations that result in elevated Ras activity in vascular smooth muscle may sensitize the vasculature to minor traumas, including shear stress 17.
A 48-year-old woman had a two-year history of cough, hoarseness, swallowing difficulties and some recent episodes of amaurosis fugax. She had a few café-au-lait skin spots and fibromas as well as familiarity for NF-1 but felt no local pain and reported no previous trauma. At oral inspection, a pulsatile mass compressing the pharynx was seen, protruding from the right side. A neck MR investigation revealed a giant aneurysm of the right cervical internal carotid artery (ICA), measuring 4×3.2 cm in the transverse plane and 4.7 cm longitudinally (Figure (Figure1).1). A brain-MR study performed simultaneously showed no signs of ischemic brain lesions.
CT angiography confirmed the presence of a fusiform giant aneurysm that originated approximately 2 cm above the carotid bifurcation at the level of vertebrae C2-C3, extending to just below the skull base. It caused a compression of the naso- and oro-pharynx which was in concordance with the oral findings. A small calcification was present in the medial wall of the aneurysm but no thrombus was detected inside the dome (Figure (Figure22).
An angiography with test occlusion was performed using a Balt B-2 non-detachable balloon (Balt, Montmorency, France) positioned proximal to the aneurysm. No neurological deficit was found during 30 minutes of occlusion, during which time, clinical evaluation (including motor, sensitive language, and higher function testing) were performed every five minutes. The test showed a good right hemisphere perfusion through the anterior communicating artery and through the ipsilateral posterior communicating artery (Figure (Figure3)3) with no significant delay in the venous phase on the occluded side. Open vascular surgery was declined because of difficulties anticipated to be caused by aneurysm size and high position of the distal aneurysm limit. Stenting with coiling or insertion of a flow-diverter inside a long regular stent were discussed but ruled out because of the large aneurysm size requiring a stent length of approximately 8-10 cm to be able to anchor it properly proximally and distally.
The treatment was performed through an 8 Fr 80 cm Arrow Sheath Introducer (Teleflex Incorporated, Limerick, PA, USA). An 8 Fr Merci balloon guide catheter (Concentric Medical, Mountain View, CA, USA) was positioned just below the aneurysm. During proximal temporary occlusion of the ICA with the Merci balloon, two 20×7 mm Goldvalve detachable balloons (CathNet-Science, Paris, France) were placed distally and proximally to the aneurysm. Finally, HydroCoils (MicroVention, Tustin, CA, USA) and GDC-18 (Boston Scientific, Natick, MA, USA) were positioned proximally to the inferior balloon to ensure stability of the whole system (Figure (Figure4).4). The patient tolerated the treatment well without significant side-effects. She was put on a low dose of acetyl salicylic acid (Trombyl®, 75 mg daily; Pfizer AB, Sollentuna, Sweden) for three months to avoid any emboli emerging from the internal carotid artery above the occlusion.
One month after treatment, a CT perfusion was performed and no significant asymmetry or defect of perfusion were documented (Figure (Figure5).5). An MRI of the neck performed at the same time showed a change of signal within the aneurysm due to thrombosis, without any change in size. MR angiography showed complete aneurysmal exclusion.
An MRI of the neck performed five months after treatment showed a moderate reduction in aneurysm size.
Six months after treatment the patient still reported moderate dysphagia. Esophagography showed a slight slowdown in the oral and proximal pharyngeal swallowing phase; after a few months a second esophagography showed a complete normalization.
A neck MRI performed 20 months after treatment showed a marked reduction of aneurysm diameter, which now was measured to be 1.5×3.5 cm, and homogeneous signal intensity content in relation to fibrosis (Figure (Figure6).6). Clinically at the same time the patient had no visible pharyngeal protrusion, no remaining cough but still a slight but improved glossopharyngeal palsy. She worked full time and carried out her daily activities without limitations.
Lastly, 2.5 years after the treatment, she reports that her dysphagia has resolved almost completely and that she remains healthy with no impairments in daily life.
Aneurysms involving supra-aortic extracranial vessels have a number of serious risks such as rupture and local compression, but also a risk of brain embolization and stroke. Presenting symptoms may be different, including the presence of a palpable mass, supraclavicular pain, dysphagia, hoarseness, Horner's syndrome, transient ischemic attacks (TIA) or ischemic stroke 19. The patient in our report developed slow-onset symptoms but increasing swallowing difficulties made her seek care where a simple oral inspection revealed the mass that was later revealed as the giant ICA aneurysm.
Aneurysms of the extracranial portion of the ICA are extremely rare, accounting only for 0.5% to 1.9% of all carotid surgical treatments 20. As the presenting manifestation of NF-1 vasculopathy, ICA aneurysms are even rarer, predominantly affecting women in their fourth decade of life 21.
Although most patients with NF1-associated vascular lesions are asymptomatic 9, in cases of carotid artery aneurysms with symptoms like cerebral ischemia, mass effect or rupture, treatment is usually recommended. There are doubts, however, about the natural history of asymptomatic aneurysms as they are so uncommon, and therefore the indications for treatment are not clearly defined. While the diameter threshold to recommend treatment for adult asymptomatic aneurysms is proposed to be 2 cm, it is even more difficult to establish such threshold in pediatric patients because of the disease rarity 22,23.
Early surgical treatment may be preferred in children considering the serious risks of cerebral ischemia or rupture and the lack of experience from stents and covered stent grafts in the pediatric population. Open surgery may be a treatment option also in adults 21, but as the NF-1 related aneurysms discovered in adults often are of a significant size at the time of treatment, operative exposure is mostly considered challenging and risky. Reports on covered stent graft placement in the internal carotid artery in adults are few and reveal the risks of both thromboemboli and graft occlusion 24-26 requiring meticulous antithrombotic treatment 27. Endovascular techniques may also include filling the aneurysm with coils, glue 21 or Onyx 28 but more recently, stenting techniques using flow diverters have been proposed for the treatment of giant and large aneurysms. Flow diverters appear to be a promising tool even though the risks and the outcomes of such treatment are still not well known 29, especially in cases of a known underlying disease like NF-1. Finally, giant and large aneurysms of the internal carotid artery may be treated with parent vessel occlusion. Endovascular treatment by occlusion of the parent artery is a long-practiced, safe and effective treatment despite the obvious limitation and potential long-term complications of sacrificing the vessel 29. In the face of an underlying vasculopathy affecting the vessel wall, it may also be preferable not to leave too much foreign material in the vasculature and especially not directly in the aneurysm, be it coils, liquid embolics or different types of advanced stent constructs. There have been reports in the literature that NF-1 affected arteries are indeed more fragile with dissections and vessel wall degeneration in the elastic lamina and the media 2,30.
After passing a balloon occlusion test, our patient was treated with parent artery occlusion, trapping the aneurysm with two detachable balloons, positioned distal and proximal to the aneurysm. To secure the construct, coils were placed below the proximal balloon. The procedure was performed under flow-reversal achieved by an 8 French balloon guide catheter to avoid escape of small thromboemboli as well as of the detachable balloons. Before embarking on this treatment, other options were discussed but ruled out: open surgery because of the need for a very high exposure, different stent techniques mainly for anatomical-technical reasons. Finally coils or liquid embolics to fill the sac were excluded because of the risk for augmentation of the compression symptoms and because of the huge aneurysm size necessitating large amounts of foreign material in a diseased segment of the vasculature that harbored unpredictable vessel wall alterations.
Therapeutic carotid artery occlusion is a simple, safe, and effective treatment for large and giant carotid artery aneurysms in patients who can tolerate sacrifice of the vessel 31-33, which can be reliably tested by angiographic balloon test occlusion. The aim of therapeutic carotid artery occlusion is thrombosis of the internal carotid artery, including the aneurysm. In a clinical study De Gast et al. 34 evaluated aneurysm size and clinical symptoms midterm after therapeutic carotid artery occlusion in 39 patients with large or giant intracranial carotid artery aneurysms. Most aneurysms involuted totally or decreased substantially in size over time, particularly in the first year after carotid artery occlusion. Thrombosis of the aneurysm was assessed by typical signal changes in the aneurysmal lumen on MR scans over time, including loss of flow void and the appearance of T1-weighted hyperintensities.
Negative effects of parent vessel sacrifice include the increased risk for hemodynamic impairment in patients with a single carotid artery 29 as well as the risk for formation of flow-related de novo aneurysms in other, mainly contra-lateral arteries that now have to harbor an increased flow 35,36.
In our patient, the aneurysm gradually involuted and decreased in size as demonstrated on an MR performed 20 months after treatment where the size was approximately half of the original. Repeated esophagographies revealed normalized swallowing and clinically after 2.5 years she reports to be almost completely asymptomatic. Still, she is scheduled for another MR scan to be performed five years after treatment. In addition to controlling the treated aneurysm, the investigation will include MR angiography and MR perfusion to look for de novo aneurysms and signs of hemodynamic impairment. The need for life-long periodic assessments in NF-1 patients with vascular manifestations has been debated 2,30. The rarity of such vascular involvement in this particular disease has been argued to speak against long-term follow-up whereas the potential catastrophic consequences of a rupture or a major ischemic infarct to speak in favor of following the patients possibly for life. The problem of inactive neurofibromin is, however, also related to tumor formation, which is equally well-demonstrated by mutations in another gene, RASA1, (p120-RASGAP) 37. Such mutations increase the risk for a variety of fast-flow vascular anomalies as well as for tumor development 38. Even if the vascular malformations in such patients with mutations in RF1 or RASA1 may potentially be treated and cured, it has been argued that the patients still need long-term follow-up to disclose any potential appearance of tumors. We have together with the patient agreed on clinical and MR follow-ups at least five and ten years after treatment.
In conclusion, giant cervical internal carotid aneurysms associated with NF-1 can be safely treated with parent artery occlusion leading to an excellent result both radiologically and clinically.