Background Cerebral aneurysm formation is one of the cerebrovascular complications of sickle cell disease.
Objective To report the clinical and imaging findings of intracerebral aneurysms and their treatment in pediatric and adult patients with sickle cell disease.
Methods Review of clinical data via chart abstraction and radiologic features at the University of Pennsylvania and Children's Hospital of Philadelphia from 2000 to 2014 and review of the literature since 1942.
Results Nineteen patients with aneurysms (2.7%) were found in 709 imaged patients, including 1.2% of imaged children and 10.8% of adults. A total of 44 aneurysms were detected (52.6% with multiple aneurysms, overall 2.3 per patient), 35 (79.5%) in the anterior circulation and 9 in the posterior circulation (20.4%). Thirty-eight unruptured aneurysms ranging in size from 2 to 6 mm and six ruptured aneurysms ranging in size from 3 to 9 mm in diameter were found. Of the patients with ruptured aneurysms, two were treated by stent-assisted coiling, two by clipping, and one patient with coiling. In the group without a rupture, one patient was treated by coil embolization and one patient with a peripheral middle cerebral artery aneurysm was treated by aneurysmectomy. Three pediatric patients with a previously normal MR angiogram demonstrated new aneurysm formation during the study.
Conclusions Adult patients with sickle cell disease have a high prevalence of aneurysm formation. Both pediatric and adult patients with sickle cell disease tend to develop multiple aneurysms with frequent involvement of atypical locations, in both anterior and posterior circulations.
- CT Angiography
- Magnetic Resonance Angiography
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Cerebrovascular diseases are common complications in patients with sickle cell disease. Ischemia and intracranial hemorrhage are the most common neurologic complications of sickle cell disease. Cerebral aneurysms have been described in patients with sickle cell disease and have been shown to have different distributions and prevalence than in the general population.1 There is a paucity of published information about cerebral aneurysms and their treatment in patients with sickle cell disease. Aside from two large case series that were published in the early nineties,2 ,3 the literature on this subject is primarily limited to case reports and small case series.4–26 This study aimed to investigate the clinical and imaging findings of intracerebral aneurysms and their treatment in pediatric and adult patients with sickle cell disease.
Methods and patients
A retrospective review of brain MR angiography (MRA), CT angiography (CTA), and cerebral angiograms in patients with sickle cell disease at our institutions from 2000 to 2014 was performed. A keyword search of the picture archiving and communications system identified patients with sickle cell anemia and cerebral aneurysms using related keywords. Inclusion criteria were (1) diagnosis of hemoglobinopathy, including HgbSS, HgbSC, and HgbS-β thalassemia, confirmed by a hematologist; (2) finding of a cerebral aneurysm on routine surveillance imaging or in the evaluation of subarachnoid hemorrhage; (3) imaging available for analysis. Departmental databases from the Sickle Cell Anemia Program and Stroke Program were queried to identify cases. Medical records and imaging were also reviewed to determine inclusion criteria and treatments received. The study was performed with approval of the institutional review board and was compliant with guidelines of the Health Insurance Portability and Accountability Act.
Imaging protocol and analysis
CTA was performed on various multidetector CT scanners (Siemens, Erlangen, Germany), and MRI was performed on 1.5 T or 3 T magnets (Siemens) in two institutions. The technical parameters of these various scanner models varied over the course of the 14 years. CTA imaging, in general, consisted of submillimeter collimation axial scanning after dynamic injection of intravenous contrast using a timed delay triggered from the aortic arch or common carotid arteries. MRI sequences varied among patients, but generally included precontrast T1-weighted, T2-weighted, fluid-attenuated inversion recovery, echo-planar spin-echo diffusion-weighted imaging, and either T2* gradient-echo susceptibility or susceptibility-weighted imaging, and three-dimensional (3D) time-of-flight MRA. Catheter angiography (DSA) was performed using dedicated biplane neuroangiographic units (Siemens, Germany) with transfemoral arterial access.
The vascular imaging studies (CTA, MRA and cerebral angiography) were reviewed and consensus reached by two board-certified neuroradiologists. For CTA and MRA, various visual assessments of available images, including source axial CTA and MRA data, multiplanar reformats, maximum intensity projections, and volume rendered images, were reviewed in various planes. DSA images were reviewed in multiple angiographic planes, and where available, 3D rendered images. Brain CT and MR images were also reviewed for pertinent findings by a board-certified diagnostic neuroradiologist and a second year neuroradiology fellow. For each patient, the location, number, and size of the cerebral aneurysms were recorded. Subarachnoid hemorrhage was diagnosed based on non-contrast head CT. In patients with multiple aneurysms, the ruptured aneurysm was determined based on the location of subarachnoid hemorrhage and aneurysm wall irregularity/nipple on cerebral angiogram. Occlusive vasculopathy was also diagnosed based on the finding of arterial stenosis and Moyamoya-type collaterals in each patient by visual qualitative assessments.
Patient demographics and aneurysm size, location, and type of treatment were evaluated using descriptive statistics. Mann–Whitney U test was used to compare the number of aneurysms in pediatric and adult populations, and also between male and female subjects. Fisher's exact test was performed to compare the distribution of posterior circulation aneurysms and also to compare the frequency of multiple aneurysm formation in pediatric and adult populations. Spearman’s rank correlation coefficient was obtained to investigate the correlation between age and number of aneurysms.
Demographics, characteristics, clinical features
A total of 709 patients with sickle cell disease had vascular imaging, with 19 patients demonstrating aneurysms (prevalence 2.7%). The mean age of patients (11 female, 8 male) at the time of initial diagnosis of an aneurysm was 29.4±17 years (range 12.9–53 years, median age 21 years). Fifteen (78.9%) patients had HgbSS, two (10.5%) had HgbSC, and two (10.5%) had HgbS-β-0 thalassemia. Of the 19 patients with aneurysms, seven of 598 were pediatric (<18 years of age) patients (prevalence 1.2%) and 12/111 were adults (prevalence 10.8%). The M:F ratio in children was 2.5:1 and in adults 1:4. The method of diagnosis was DSA in nine (47.4%), MRA in seven (36.8%), and CTA in two (10.5%), and both CTA and MRA in one (5.3%). In three patients who were imaged by MRA followed by DSA, the DSA results were similar; however, in one patient, DSA showed the presence of two additional 2 mm terminal internal carotid artery aneurysms.
In those with aneurysms, occlusive vasculopathy was present in seven (36.8%) patients (table 1) and two (10.5%) patients demonstrated bilateral internal carotid artery severe narrowing/occlusion with Moyamoya appearance. Of 17 patients who had MRI, six (35.3%) had white matter ischemic changes, and one (5.9%) had a hemorrhagic infarction.
Forty-four aneurysms were detected (2.3 aneurysms per patient), 35 (79.5%) located in the anterior circulation and nine in the posterior circulation (20.4%). Thirty-eight aneurysms were unruptured, ranging from 2 to 6 mm (mean diameter 3.3 mm, median diameter 3 mm, SD=1 mm). Six aneurysms, ranging from 3 to 9 mm in diameter (mean diameter 5.75 mm, median 5.75 mm, SD 2.8 mm), were ruptured. There was no significant difference between the number of aneurysms in male and female subjects (p=0.456). Ten of the 19 patients (52.6%) had multiple aneurysms. Seven paediatric patients with 10 aneurysms (1.4 aneurysm per patient) were detected, including seven (70%) in the anterior circulation and three (30%) in the posterior circulation. There was no significant difference between the frequency of anterior and posterior circulation aneurysms in pediatric and adult groups (p=0.328). Comparison of the multiplicity of aneurysms in adult and pediatric age groups showed 66.7% (8/12) in adult patients compared with 28.6% (2/7) in pediatric patients; however, the difference was not statistically significant (p=0.12). Similarly, there was no significant difference between the number of aneurysms in pediatric and adult patients (p=0.73); however, there was a moderate, statistically significant positive correlation between age and number of aneurysms (r=0.388, p=0.05).
Treatment choice, outcome and follow-up imaging
In patients with ruptured aneurysms, two were treated by stent-assisted coiling (figure 1), two by clipping, and one patient was primarily coiled. In the unruptured group, one patient was treated by coil embolization and one patient with a peripheral middle cerebral artery aneurysm was treated by aneurysmectomy (table 1). Follow-up imaging was available in 14 patients (mean 4, median 4, SD 2.3 years, table 1). Three pediatric patients (age range 12.9–17.5 years) showed new aneurysm formation during the course of the study. Patient No 6 developed a 3 mm distal basilar aneurysm in 2009, after multiple negative studies in 2002 and 2004. Patient No 7 developed a 4 mm petrous carotid aneurysm in 2014 after four negative MRA studies in 2001–2011. Finally, in patient No 4, the first MRA in 2000 showed no aneurysm, but a 7-year follow-up MRA in 2007 showed a 3 mm distal basilar aneurysm and a 3 mm cavernous aneurysm, and a second follow-up MRA in 2014 showed a stable distal basilar aneurysm, enlargement of the cavernous aneurysm from 3 to 5 mm, and a new 4 mm supraclinoid aneurysm (figure 2). None of the adult patients showed new aneurysm formation on follow-up studies.
In four patients with coiled aneurysms, follow-up imaging showed no residual filling in two patients. In one patient (No 5), a 7-year follow-up MRA showed 3 mm residual filling at the base of a coiled aneurysm which was the origin of the right superior cerebellar artery, unchanged when compared with immediate post-coiling cerebral angiogram. In another patient (No 12), a 1.5-year follow-up DSA demonstrated a 2 mm residual filling of the coiled aneurysm which was recoiled. An additional 1 year follow-up DSA in this patient showed no residual filling. One of the two patients with clipped aneurysms (No 10) had a 5-year follow-up DSA angiogram which demonstrated no new aneurysm and no recanalization of clipped aneurysms. Patient No 14 had no follow-up imaging; however, an immediate post-clipping angiogram demonstrated a 4 mm residual filling of a multicompartmental right supraclinoid aneurysm.
Anson et al2 observed 325 patients with sickle cell disease for 14 years and identified cerebral aneurysms in 10 patients, with a total number of 16 aneurysms and multiple aneurysms in three patients. Oyesiku et al3 reported 15 cases of patients with sickle cell disease with 30 aneurysms, nine (60%) of them with multiple aneurysms. Review of all case series and case reports published in English1–26 (table 2) shows a total of 56 patients with sickle cell disease with 105 cerebral aneurysms (1.87 aneurysms per patient) and 28 of these patients (50%) with multiple aneurysms. Thirty-four (32%) aneurysms were reported in the posterior circulation and 71 (68%) in the anterior circulation indicating a higher number of aneurysms in posterior circulation locations than in the overall intracranial aneurysm population.16 ,27 Of the above reported patients, four pediatric patients presented with a total of five aneurysms, three in the posterior circulation, two in the anterior circulation, and one patient with multiple aneurysms.2 ,14 ,16 ,17
In this study we showed that multiple cerebral aneurysm formation is frequent in patients with sickle cell disease who are diagnosed with cerebral aneurysms, a finding consistent with previous studies (table 2). Although we found a higher prevalence of aneurysms (2.3 aneurysms per patient compared with 1.8 in previous reports), this might be due to use of high-field MRA and high-resolution DSA in most of our patients, leading to diagnosis of more aneurysms. The overall prevalence of intracranial aneurysms in adult patients in this study (10.9%) is higher than for the population without comorbidity (3.2%) and even higher than in populations with autosomal dominant polycystic kidney disease (6.9%), or patients with a positive family history of intracranial aneurysm of subarachnoid hemorrhage (3.4%) in comparison with meta-analysis of prior large studies.27 The prevalence of intracranial aneurysms in pediatric patients in this study is similar to that in previous reports.16 ,28
Despite a higher percentage of multiple aneurysms in adult patients than in pediatric patients, the difference was not statistically significant, although this might be owing to our small sample size. We also found a high percentage of aneurysm formation in atypical locations such as bilateral mirror aneurysms of the posterior cerebral arteries (patient No 9), bilateral aneurysms of the A3 segment of the anterior cerebral arteries (patient No 14), basilar artery (between the origins of the superior cerebellar and posterior cerebral artery) (patient No 4), and superior cerebellar artery (patient No 16). We noted a higher distribution of posterior circulation aneurysms compared with published data in the overall population.29 The female/male predominance (11/8) in our study group is consistent with published data in the overall population.29
Most sickle cell-associated aneurysms in previous series were treated by clipping (table 2), mainly because they were reported before the wide use of endovascular treatment modalities (table 2). Most of the reported series that used an endovascular approach in patients with sickle cell disease do not have imaging follow-up. However, McQuaker et al18 reported on two patients with sickle cell disease who underwent coil embolization of cerebral aneurysms with a follow-up angiogram showing compaction of the coils with recanalization of a small portion of the aneurysm base. Among four patients who were coiled in our study, one patient showed residual filling on a follow-up angiogram which required additional coiling.
There is no report about development of additional aneurysms over time in patients with sickle cell disease; we demonstrated the development of de novo aneurysms in three pediatric patients, with one of them (patient No 4) developing three new aneurysms over the course of observation. Although new aneurysm formation was not seen in adult patients in this study, this may be at least partly secondary to differences in the duration and availability of follow-up studies in pediatric and adult patients. Further studies are needed to determine more exactly the time course and frequency of aneurysm development in patients with sickle cell disease. Another point to be noted is the difference in presentation with ruptured aneurysms between the pediatric and the adult patients. One of the seven adolescents presented with a ruptured aneurysm, while five of the 12 adult patients presented with rupture. This difference in presentation may be an indication that increasing age is a risk factor for rupture, and that early diagnosis and proactive treatment is possible as early as adolescence.
This study has several limitations. DSA, which is more sensitive for detection of small aneurysms, was not performed in all patients, and therefore the true prevalence of aneurysms in patients with sickle cell disease may be higher than reported in this study. In addition, we did not have information about the long-term hematologic parameters before aneurysm formation, which may play a role in aneurysm formation by affecting the hemodynamics in intracranial arteries. An ideal study will be a prospective study investigating a very large cohort of patients with sickle cell disease using high-resolution non-invasive vascular imaging over a long period of time to monitor aneurysm formation based on different hematologic parameters. Finally, because the overall number of patients was small, the relationship between different vascular abnormalities, such as arterial stenosis and Moyamoya to aneurysm formation, cannot be determined in this study.
Adult patients with sickle cell disease have a high prevalence of aneurysm formation. Both pediatric and adult patients with sickle cell disease who develop cerebral aneurysms tend to develop multiple aneurysms with frequent involvement of atypical locations, both in the anterior and posterior circulations.
Contributors All authors significantly contributed to the study design, analysis and interpretation of data, drafting of the work and have approved the final version of the manuscript.
Competing interests None.
Ethics approval Institutional review board committee of the Children's Hospital of Philadelphia.
Provenance and peer review Not commissioned; externally peer reviewed.