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Descriptive Study of Aneurysmal and Nonaneurysmal Subarachnoid Hemorrhage and the Role of Confirmative Digital Subtraction Angiography in Patients with Nonaneurysmal Subarachnoid in Puerto Rico
Journal Pre-proof Descriptive study of aneurysmal and non-aneurysmal subarachnoid hemorrhage and the role of confirmative DSA in non-aneurysmal subarachnoid patients in Puerto Rico Gabriel Flores, Caleb Feliciano, Natalie Amaral-Nieves, Aixa de Jesús, Consultant PII:
S1878-8750(19)32724-X
DOI:
https://doi.org/10.1016/j.wneu.2019.10.104
Reference:
WNEU 13575
To appear in:
World Neurosurgery
Received Date: 25 June 2019 Revised Date:
16 October 2019
Accepted Date: 17 October 2019
Please cite this article as: Flores G, Feliciano C, Amaral-Nieves N, de Jesús A, Descriptive study of aneurysmal and non-aneurysmal subarachnoid hemorrhage and the role of confirmative DSA in non-aneurysmal subarachnoid patients in Puerto Rico, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.104. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Descriptive study of aneurysmal and non-aneurysmal subarachnoid hemorrhage and the role of confirmative DSA in non-aneurysmal subarachnoid patients in Puerto Rico
Gabriel Flores, Corresponding author [email protected] Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico Medical Sciences Campus Box 365067 San Juan, PR 00936-5067
Caleb Feliciano [email protected] Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico – Medical Sciences Campus
Natalie Amaral-Nieves [email protected] School of Medicine University of Puerto Rico – Medical Sciences Campus
Aixa de Jesús, Consultant Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico – Medical Sciences Campus
Key-words: Subarachnoid hemorrhage, perimesencephalic, DSA, CTA Short title: Subarachnoid Hemorrhage in Puerto Rico and the Need for a Confirmatory DSA
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Abbreviation list: 1) Spontaneous Subarachnoid Hemorrhage-SSAH 2) Subarachnoid Hemorrhage-SAH 3) Arteriovenous Malformations-AVMs 4) Perimesencephalic Subarachnoid Hemorrhage- PM-SAH 5) Diffuse Subarachnoid Hemorrhage-d-SAH 6) Digital Subtraction Angiography-DSA 7) CT Angiography-CTA 8) Posterior Inferior Cerebellar Artery-PICA 9) Middle Cerebral Artery-MCA 10) Electronic Medical Records-EMR 11) World Federation of Neurosurgical Society-WFNS
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Abstract: Background- Cerebrovascular disease is the fifth cause of mortality in Puerto Rico. Currently, there is no descriptive study for the presentation of spontaneous subarachnoid hemorrhage (SSAH) in our institution. Therefore, our primary aim is to make a retrospective analysis of adult patients with SSAH and assess the need for a DSA after an initially aneurysm-negative CTA in non-aneurysmal SAH, specifically perimesencephalic SAH (PM-SAH). Methods- Medical records of 324 adult patients with aneurysmal and non-aneurysmal SAH treated at the Puerto Rico Medical Center from 2015 to 2018 were retrospectively analyzed. Demographics, past medical history, clinical characteristics and imaging information was extracted. Results- Acute hydrocephalus, mortality at 30 days, prevalence of diffuse SAH pattern, Fisher and WFNS grades >2 on initial exam were higher in the aneurysmal SAH sub-group. Patients with non-aneurysmal SAH had a significantly higher prevalence of Chronic Kidney Disease and Diabetes Mellitus. 100% of the non-aneurysmal PM SAH with an initial aneurysmnegative CTA were subsequently confirmed by DSA. Conclusions- Patients in the aneurysmal SAH sub-group correlated with an increased disease burden. Furthermore, this study shows that in our population, patients with non-aneurysmal PM-SAH with a low Fisher and WFNS grade and with comorbid Diabetes Mellitus and Chronic Kidney Disease, may not need a DSA after a negative initial CTA.
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Introduction Spontaneous subarachnoid hemorrhage (SSAH) is very serious condition that may arise as a result of ruptured cerebral aneurysms, arteriovenous malformations (AVMs), cerebrovascular dissection, vasculitis or other vasculopathy, that grants urgent neurosurgical evaluation. It is important to specify that SSAH from AVMs may be related to intranidal and flowrelated aneurysms (1). Other etiologies for SSAH may be more benign such as PM-SAH, also known as pretruncal nonaneurysmal subarachnoid hemorrhage, or reversal cerebral vasoconstrict syndrome (2). Aneurysm growth and rupture have associated risk factors such as female sex, hypertension, smoking, use of vascular active or toxic drugs or medications, aneurysm size, location, and shape (3,4). Even though most SSAH are caused by ruptured aneurysms, up to 15% of SSAH have no known bleeding source (4,5). These are known as non-aneurysmal SAH and are associated with better neurological outcomes than aneurysmal SAH (aSAH). Furthermore, diffuse-SAH (d-SAH) has been linked to more aggressive disease course, more complications, longer hospital stays and higher economic burden for patients when compared to PM-SAH. Non-aneurysmal SAH can be classified depending on the bleeding pattern confirmed by initial computed tomography without contrast (CT); PM-SAH and diffuse SAH (d-SAH) (5,6). PM-SAH are characterized by bleeding PM-SAH are characterized by bleeding in the prepontine, interpeduncular, crural, ambient and quadrigeminal cisterns that may spread to the basal parts of the sylvian fissures (7). On the other hand, d-SAH are characterized by having blood that exceeds the limits mentioned above. The imaging strategy in a patient that presents with symptoms suggestive of SSAH varies among institutions. Digital Subtraction Angiography (DSA) has been advocated as the gold standard due to its ability to identify smaller pathologies in posterior circulation, multiple aneurysms and ability for better surgical planning. However, some prefer CT-Angiography (CTA) due to the cost effectiveness and less invasive study in cases such as PM-SAH (8). However, some advocate that a DSA should be mandatory because they report close to 3% risk of having an aneurysm in PM-SAH (9). This study aims to further assess this controversy. Cerebrovascular disease and strokes are the fifth cause of mortality in Puerto Rico (10). However, there are no descriptive study about SSAH in Puerto Rico. We describe our experience with aSAH and non-aneurysmal SAH. Moreover, we describe the yield of a follow-up DSA after initial negative CTA on PM-SAH pattern.
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Materials and Methods A retrospective review of electronic medical records (EMR) of patients who had spontaneous subarachnoid hemorrhage (SSAH) from November 2015 to May 2018 was done in order to obtain demographic information such as age, gender, initial neurological exam and past medical history. Past medical history included history of hypertension, diabetes, smoking status, use of alcohol and chronic kidney disease and were collected by ICD-10 codes. Mortality at 30 days and whether there was development of acute hydrocephalus at 72 hours with requirement of ventriculostomy was also extracted from the records. These patients could have SSAH associated with intracranial hemorrhage (ICH) and intraventricular hemorrhage (IVH) and could be due to aneurysmal or non-aneurysmal causes. Patients who were younger than 18 years, who suffered from traumatic SAH, brain contusions or traumatic acute subdural hematoma (ASDH) and/or with a World Federation of Neurosurgical Society (WFNS) grade of 5 at initial exam were excluded from the study. The initial head CT without contrast, CTA, subsequent DSA images and reports were extracted from a software storage imaging from our institution in order to review the pattern of bleeding and to assess whether they were positive or negative for brain aneurysms by our Neuroendovascular surgery service and expert neuroradiologists at our institution. The data collected from the DSA reports included the dimensions (dome height and dome diameter), location of aneurysm and the presence of multiple brain aneurysms. For patients to be included in the study the CTA must had been done before a DSA. Descriptive analysis was performed in both groups (aSAH vs non-aneurysmal SAH) to describe demographic and clinical characteristics of the patients. Comparison between the groups was performed using Chi-square or Fisher exact tests for the categorical variables and t-test for continuous variables, as appropriate. A two-sided p-value < 0.05 was considered as statistically significant. Specificity, sensitivity, positive predictive value and negative predictive value with their corresponding 95% confidence value was estimated in order to compare CTA and DSA as an imaging tool in SAH. Analysis was completed using R (version 3.4.4). Approval for Protocol A0230119 was obtained from the University of Puerto Rico – Medical Sciences Campus Institutional Review Board.
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Results Aneurysmal SAH A total of 216 patients had aneurysmal SAH. The median age was 61 years (IQR: 52.8-70.1) with a gender ratio of 2.33:1 (female:male). The most common pattern of SAH was diffuse (75%) compared to perimesencephalic (0.9%). Only two patients with PM-SAH had a positive initial CTA for aneurysm. A DSA was later used to confirm the presence of aneurysms in these two patients.In the initial neurological exam, patients in the aneurysmal SAH sub-group had a WFNS grade of 2 or more (87.5%) and Fisher grade of 2 or more (99.1%). Only two patients required lumbar puncture to rule out SAH. Acute hydrocephalus at 72 hours with requirement of ventriculostomy was 27.3% with a prevalence of chronic hydrocephalus of 4.6%. Mortality rate at 30 days was 23.1%. First DSA study confirmed 97.7% of aSAH, follow-up DSA study improved yield to 100%. Results are exposed in Table 1. Aneurysm characteristics The location of the aneurysms was more prevalent in the anterior circulation (89.4%) when compared to the posterior circulation (10.6%). Three of the aneurysms were classified as mycotic in the corresponding locations; posterior inferior cerebellar artery (PICA), pericallosal segment of anterior cerebral artery (ACA) and middle cerebral artery (MCA) M4 segment. Meanwhile, one aneurysm was classified as a vertebral VA dissecting aneurysm. The incidence of aneurysmal rupture based on location was comparable between anterior communicating artery (26.4%) and posterior communicating arteries (26.4%) followed by MCA segment M2 (15.3%). The average dimensions via DSA for ruptured aneurysms were 4.74 ± 2.27mm for dome height and 5.01 ± 2.85 mm for dome diameter Differences in size were not statistically significant when comparing anterior versus posterior aneurysms. Non-aneurysmal SAH A total of 108 patients had non-aneurysmal SAH, with a mean age of 60.1 years (IQR 52.8-67.4) with a gender ratio of 1.5:1 (female:male). The most common pattern of SAH was perimesencephalic (52.8%) compared to diffuse (26.9%). In the initial neurological exam, patients in Non-aneurysmal SAH sub-group had a WFNS grade of 1 (76.9%) and Fisher grade of 2 and 3. Acute hydrocephalus at 72 hours with requirement of ventriculostomy was 9.3% with a prevalence of chronic hydrocephalus of 1.9%. Mortality rate at 30 days was 6.5%. Even though all DSA proved to be negative for aneurysms in
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this sub-group, there were other pathologies found; one arteriovenous malformation (AVM), six patients with vasculitis and three patients with cerebral atherosclerosis. Mortality rate at 30 days in patient with PM-SAH 1.8% (N=1/57), a death related to cardiovascular complications. Results are in Table 2. Comparison Acute hydrocephalus, mortality at 30 days, prevalence of diffuse SAH pattern and Fisher and WFNS grades > 2 in initial exam were higher in the aneurysmal SAH sub-group than in the non-aneurysmal. Patients with non-aneurysmal SAH had a higher prevalence of Chronic Kidney Disease and Diabetes Mellitus when compared to the non-aneurysmal SAH sub-group. All of the variables mentioned above were statistically significant (p-value < 0.05). 100% of the non-aneurysmal PM-SAH with an initial CTA negative for aneurysm had a subsequent confirmation by DSA. In addition, only 10 cases of non-aneurysmal PMSAH had second follow-up DSA which reported normal cerebral angiogram. In aneurysmal PM-SAH, 2 patients had an initial CTA positive for aneurysm which was further confirmed by DSA. Results are in Table 3. Diagnostic Test Characteristics For initial head CT, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.94 (95% CI: 0.88-0.97), 0.99 (95% CI: 0.94-1.00), 0.99 (95% CI: 0.95-1.00) and 0.93 (95% CI: 0.86-0.97), respectively. Meanwhile, for DSA, the sensitivity, specificity, positive predictive value and negative predictive value were 0.98 (95% CI: 0.0.94-0.99), 1.00 (95% CI: 0.96-1.00), 1.00 (95% CI: 0.98-1.00) and 0.96 (95% CI: 0.89-0.98), respectively. Results are in Tables 4.
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Discussion This study demonstrated differences between non-aneurysmal SAH and aneurysmal SAH as very distinct etiologies for SSAH with dissimilar demographic characteristics, clinical presentation and outcomes. In general, non-aneurysmal SAH exhibits a less aggressive clinical course compared to aSAH in terms mortality, acute and shunt dependent hydrocephalus. These results are comparable to Konczalla J et al (5,11). In the aneurysmal SAH sub-group the median age, prevalence of hypertension and diabetes were higher compared to RCS of England, National Study of Subarachnoid Hemorrhage (12). Also, the initial WFNS and the amount of blood on Head CT were more severe compared to the aforementioned study. This dissimilarity could be associated to higher prevalence of pre-existing medical conditions in our studied population. The anatomic location of ruptured aneurysms was more common in the anterior cerebral circulation, and anterior communicating artery, posterior communicating arteries and MCA M2 arteries were the more common sites, which is comparable with previous studies (12, 13). Literature has reported that aneurysmal size less 7mm represents a lower risk for the ruptured of aneurysm, on the contrary in our study the average size for ruptured aneurysm was 5.01mm (14). This inconsistency may support the hypothesis that unruptured aneurysms are different than ruptured aneurysms. Furthermore, it is important to emphasize that studies have shown that post rupture morphology should not be used as a measure of risk of rupture (15). Non-aneurysmal SAH sub-group showed a more benign clinical course. Furthermore, there was higher incidence of PM-SAH pattern, better neurological status, lower incidence of acute and chronic hydrocephalus, and lower rate of mortality. These results are comparable with literature (5,11). In addition, our non-aneurysmal SAH sub-group had higher prevalence of Diabetes Mellitus, similar to Mensing L, et al (16). This result may support the hypothesis of the pathogenesis of PM-SAH is secondary to capillary leak, and could correlate with Diabetes Mellitus as risk factor due to its relation of microvascular complications (7, 17) In our current study, all patients in the PM-SAH pattern in the non-aneurysmal SAH sub-group had a negative initial CTA for aneurysms which was later confirmed by follow-up DSA. Only in one case was found an incidental AVM not associated with PM-SAH pattern. In ten cases of PM-SAH pattern a second DSA follow-up was done and only one case showed radiographic vasospasm. Our findings suggest that a CTA is high yield study to rule out aneurysms or other vascular pathology in patients
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with PM-SAH pattern. These results are comparable with previous studies that show DSA follow-up detection rates of 0.78% to 1.5% for aneurysms, and concluded no use of initial DSA or follow-up angiographic imaging in patients with PM-SAH with a negative CTA (8,18). On the contrary, another study advocated that patients with PM-SAH should continue to undergo DSA even after negative CTA, as they found aneurysms as the causative agent in 3% of patients with initial negative CTA (9). In our Institution, the sensitivity, specificity, PPV and NPV for DSA had higher values throughout when compared to CTA as expected. Compared to other study, our sensitivities for both imaging tools were slight lower compared to a CTA between 99.2% and for DSA at 100% (9). However, in our study for aSAH sub-group a second DSA follow-up improve sensitivity to 100% and for non-aneurysmal PM-SAH the yield for aneurysmal detection after first follow-up and second follow-up DSA was 0%. The retrospective nature of our data is a limitation to the study. A strength of our study is that all CTAs and DSAs were performed and analyzed by the same facility which decreases the presence of different practices in our study. Due to the great diversity that currently exists in the diagnostic management of SAH patients, more studies are needed to further assess this controversy. As a result, studies such as a meta-analysis necessary to begin to establish a standard of practice.
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Conclusions Patients in the aneurysmal SAH sub-group had a higher incidence of diffuse bleeding pattern, higher mortality at 30 days, higher incidence of hydrocephalus with subsequent shunt placement, higher Fisher and WFNS grades at initial neurological exam. Patients in the non-aneurysmal sub-groups had a higher prevalence of Chronic Kidney Disease and Diabetes Mellitus. 100% of patients in the non-aneurysmal sub-group who had a PM-SAH had a negative initial CTA for aneurysms which was confirmed by a follow-up DSA. As a result, it can be concluded that in our population, patients with non-aneurysmal PMSAH who had low Fisher and WFNS grading and have pre-existing Diabetes Mellitus and Chronic Kidney Disease, do not need a follow-up DSA after a negative initial CTA.
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Acknowledgements Special thanks to Department of Neurosurgery of the University of Puerto Rico. Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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References (1) Redekop G, Terbrugee, K, Montanera, W, Willinsky, R. Arterial aneurysms asscoaited with cerebral arteriovenous malformations: classification, incidence, and risk of hemorrhage. J Neurosurg. 1998;539-546. https://doi.org/10.3171/jns.1998.89.4.0539 (2) Elhadi A.M, Zabramski J.M, Almefty K.K, Mendes G.A, Nakaji P, McDougall C.G, Albuquerque F.C, Preul M.C, Spetzler R.F. Spontaneous subarachnoid hemorrhage of unknown origin: hospital course and long-term clinical and angiographic followup. J Neurosurg. 2015;122:663-70. doi: 10.3171/2014.10.JNS14175. (3) Feigin V.L, Rinkel G, Lawes C, Algra A, Bennett D.A, Van Gijn J, Anderson C.S. Risk Factors for Subarachnoid Hemorrhage An Updated Systematic Review of Epidemiological Studies. Stroke. 2005; 36:2773-2780. doi:10.1161/01.STR.0000190838.02954.e8. (4) Tominari S, Morita A, Ishibashi T, Yamazaki T, Takao H, Murayama Y, et al. Unruptured Cerebral Aneurysm Study Japan Investigators. Prediction model for 3-year rupture risk of unruptured cerebral aneurysms in Japanese patients. Ann Neurol. 2015; 77:1050–1059. doi: 10.1002/ana.24400. (5) Konczalla J, Platz J, Schuss P, Vatter H, Seifert V, Güresir E. Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients. BMC Neurol. 2014; 14:140. doi:10.1186/1471-2377-14-140. (6) Coelho L. G, Costa J. M, & Silva E. I. Non-aneurysmal spontaneous subarachnoid hemorrhage: perimesencephalic versus non-perimesencephalic. Hemorragia subaracnóidea espontânea não aneurismática: perimesencefálica versus não perimesencefálica. Rev Bras Ter Intensiva. 2016; 28: 141–146. doi:10.5935/0103-507X.20160028. (7) van Gijn J, van Dongen K. J, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology.1985;35:493. DOI: 10.1212/WNL.35.4.493. (8) Kalra V.B, Wu X, Forman H.P, Malhotra A. Cost-Effectiveness of Angiographic Imaging in Isolated Perimesencephalic Subarachnoid Hemorrhage. Stroke. 2014; 45:3576-3582. https://doi.org/10.1161/STROKEAHA.114.006679.
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(9) Heit J.J, Pastena G.T, Nogueira R.G, Yoo A.J, Leslie-Mazwi T.M, Hirsch J.A, Rabinov J.D. Cerebral Angiography for Evaluation of Patients with CT Angiogram-Negative Subarachnoid Hemorrhage: An 11-year Experience. Am J Neuroradiol. 2016; 37:297-304. doi.org/10.3174/ajnr.A4503. (10) Institute of Health Metrics and Evaluation. Puerto Rico. http://www.healthdata.org/puerto-rico. Accessed 8 June 2019. (11) Konczalla J, Schmitz J, Kashefiolasl S, Senft C, Seifert V, Platz J. Aneurysmal Subarachnoid Hemorrhage in 173 Patients: A Prospective Study of Long-term Outcome. Eur.J.Neurol. 2015;22:1329-1336. doi:10.1111/ene.12762. (12) The Royal College of Surgeons of England. National Study of Subarachnoid Hemorrhage. https://www.rcseng.ac.uk//media/files/rcs/standards-and-research/research/national-study-of-subarahnoid-haemorrhage-final-report-2006.pdf.; 2006 Accessed 5 May 2019 (13) Korja M, Kivisaari R, Rezai B, Lehto H. Size and Location of Ruptured Intracranial Aneurysms: Consecutive Series of 1993 Hospital-admitted Patients. J Neurosurg. 2017; 127:748-753. doi: 10.3171/2016.9.JNS161085. (14) Harbaugh R.E, The International Study on Unruptured Intracranial Aneurysms (ISUIA): New Prospective Data. Neurosurgery.2003;53. doi.org/10.1227/01.neu.0000309249.94601.9b. (15) Skodvin TO,Johnsen LH, Gjertsen O, Isaksen JG, Sorteberg A. Cerebral Aneurysm Morphology Before and After Rupture: Nationwide Case Series of 29 Aneurysms. Stroke. 2017; 48:880-886. doi: 10.1161/STROKEAHA.116.015288 (16) Mensing LA, Vergouwen MDI, Laban KG, Ruigrok YM, Velthuis BK, Algra A, Rinkel GJE. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke. 2018; 49:1363-1370. doi: 10.1161/STROKEAHA.117.019843. (17) Fowler M.J. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 2008; 26:77-82. doi.org/10.2337/diaclin.26.2.77. (18) Potter C.A, Fink K.R, Ginn, A.L & Haynor D.R. Perimesencephalic Hemorrhage: Yield of Single versus Multiple DSA Examinations--A Single-Center Study and Meta-Analysis. Radiology.2016;281:858-864.
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Variable Gender Female Male Hypertension Diabetes Mellitus Chronic Kidney Disease Smoker Acute Hydrocephalus Chronic Hydrocephalus Alcohol
n
%
152 64 188 51 7 55 59 10 8
70.4 29.6 87.0 23.6 3.2 25.5 27.3 4.6 3.7
Mortality at 30 days 50 23.1 SAH Perimesencephalic 2 0.9 Cistern 4 1.9 Diffuse 162 75.0 Comorbid ICH or IVH 46 21.3 None, positive LPH 2 0.9 Fisher Grading Scale 1 2 0.9 2 57 26.4 3 102 47.2 4 55 25.5 WFNS Grade 1 45 20.8 2 68 31.5 3 27 12.5 4 76 35.2 CTA Positive 116 53.7 Negative 7 3.2 No Study 93 43.1 Localization Anterior 194 89.8 Posterior 22 10.2 More than 1 aneurysm 39 18.1 First DSA Positive 211 97.7 Table 1: Descriptive Analysis for Aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination.
VARIABLE
N
(%)
GENDER FEMALE MALE HYPERTENSION
65 43 96
60.2 39.8 88.9
DIABETES MELLITUS
37
34.3
CHRONIC KIDNEY DISEASE
13
12.0
SMOKER
23
21.3
ACUTE HYDROCEPHALUS
10
9.3
CHRONIC HYDROCEPHALUS
2
1.9
MISCELLANEOUS ALCOHOL MORTALITY AT 30 DAYS
4
3.7
7
6.5
SAH PERIMESENCEPHALIC 57 52.8 CONVEXITY 13 12.0 CISTERN 4 3.7 DIFFUSE 29 26.9 ICH OR IVH 5 4.6 FISHER GRADING SCALE 1 0 0 2 78 72.2 3 25 23.1 4 5 4.6 WFNS GRADE 1 83 76.9 2 13 12.0 3 3 2.8 4 9 8.3 CTA POSITIVE* 1 1.0 NEGATIVE 96 88.9 NO STUDY 11 10.2 DSA POSITIVE† 10 9.3 NEGATIVE 98 90.7 Table 2: Descriptive Analysis for Non-aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. DSA demonstrated negative for aneurysm*. One patient with incidental AVM, six patients with vasculitis and three patients with cerebral atherosclerosis†. All were negative for aneurysms.
NON-ANEURYSMAL SAH CHARACTERISTIC
ANEURYSMAL SAH
N
%
N
%
p-value
59.9
10.5
59.9
15.3
1
Female
65
60.2
152
70.4
0.066
Hypertension
96
88.9
188
87.0
0.633
Diabetes mellitus
37
34.3
51
23.6
0.042*
Chronic kidney disease
13
12.0
7
3.2
0.003*
Smoker
23
21.3
55
21.3
0.408
Acute hydrocephalus
10
9.3
59
27.3
<0.001*
Chronic hydrocephalus
2
1.9
10
4.6
0.350
Age (mean, sd)
Alcohol 4 3.7 8 3.7 1 Mortality at 30 days 7 6.5 50 23.1 <0.001* SAH <0.001* Perimesencephalic 57 52.8 2 0.9 Convexity 13 12.0 0 0 Cistern 4 3.7 4 1.9 Diffuse 29 26.9 162 75.0 ICH or ICV 5 4.6 46 21.3 None, positive LPH 0 0 2 0.9 Fisher grading scale <0.001* 1 0 0 2 0.9 2 78 72.2 57 26.4 3 25 23.1 102 47.2 4 5 4.6 55 25.5 WFNS grade <0.001* 1 83 76.9 45 20.8 2 13 12.0 68 31.5 3 3 2.8 27 12.5 4 9 8.3 76 35.2 Table 3: Comparative analysis between the Aneurysmal vs Non-aneurysmal sub-groups. Patients were compared in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. Statistical significance was established with at p-value < 0.05.
CTA
Neurovascular DSA
Test characteristics Estimate 95% CI Estimate 95% CI Sensitivity 0.94 0.88 – 0.97 0.98 0.94 – 0.99 Specificity 0.99 0.94– 1.00 1.00 0.96 – 1.00 Positive predictive value 0.99 0.95– 1.00 1.00 0.98 – 1.00 Negative predictive value 0.93 0.86 – 0.97 0.96 0.89 – 0.98 Table 4: Analysis for CTA and Digital Subtraction Angiography as imaging studies for SAH patient
Variable
n
%
Female
152
70.4
Male
64
29.6
Hypertension
188
87.0
Diabetes Mellitus
51
23.6
Chronic Kidney Disease
7
3.2
Smoker
55
25.5
Acute Hydrocephalus
59
27.3
Chronic Hydrocephalus
10
4.6
Alcohol
8
3.7
Mortality at 30 days
50
23.1
Perimesencephalic
2
0.9
Cistern
4
1.9
Diffuse
162
75.0
Comorbid ICH or IVH
46
21.3
None, positive LPH
2
0.9
1
2
0.9
2
57
26.4
3
102
47.2
4
55
25.5
1
45
20.8
2
68
31.5
3
27
12.5
Gender
SAH
Fisher Grading Scale
WFNS Grade
4
76
35.2
Positive
116
53.7
Negative
7
3.2
No Study
93
43.1
Anterior
194
89.8
Posterior
22
10.2
More than 1 aneurysm
39
18.1
First DSA Positive
211
97.7
CTA
Localization
Table 1: Descriptive Analysis for Aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination.
VARIABLE
N
(%)
FEMALE
65
60.2
MALE
43
39.8
HYPERTENSION
96
88.9
DIABETES MELLITUS
37
34.3
CHRONIC KIDNEY DISEASE
13
12.0
SMOKER
23
21.3
ACUTE HYDROCEPHALUS
10
9.3
CHRONIC HYDROCEPHALUS
2
1.9
4
3.7
7
6.5
PERIMESENCEPHALIC
57
52.8
CONVEXITY
13
12.0
CISTERN
4
3.7
DIFFUSE
29
26.9
ICH OR IVH
5
4.6
1
0
0
2
78
72.2
3
25
23.1
4
5
4.6
83
76.9
GENDER
MISCELLANEOUS ALCOHOL MORTALITY AT 30 DAYS
SAH
FISHER GRADING SCALE
WFNS GRADE 1
2
13
12.0
3
3
2.8
4
9
8.3
POSITIVE*
1
1.0
NEGATIVE
96
88.9
NO STUDY
11
10.2
10
9.3
98
90.7
CTA
DSA POSITIVE† NEGATIVE
Table 2: Descriptive Analysis for Non-aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. DSA demonstrated negative for aneurysm*. One patient with incidental AVM, six patients with vasculitis and three patients with cerebral atherosclerosis†. All were negative for aneurysms.
NON-ANEURYSMAL SAH CHARACTERISTIC
ANEURYSMAL SAH
N
%
N
%
p-value
59.9
10.5
59.9
15.3
1
Female
65
60.2
152
70.4
0.066
Hypertension
96
88.9
188
87.0
0.633
Diabetes mellitus
37
34.3
51
23.6
0.042*
Chronic kidney disease
13
12.0
7
3.2
0.003*
Smoker
23
21.3
55
21.3
0.408
Acute hydrocephalus
10
9.3
59
27.3
<0.001*
Chronic hydrocephalus
2
1.9
10
4.6
0.350
Alcohol
4
3.7
8
3.7
1
Mortality at 30 days
7
6.5
50
23.1
<0.001*
Age (mean, sd)
SAH
<0.001*
Perimesencephalic
57
52.8
2
0.9
Convexity
13
12.0
0
0
Cistern
4
3.7
4
1.9
Diffuse
29
26.9
162
75.0
ICH or ICV
5
4.6
46
21.3
None, positive LPH
0
0
2
0.9
Fisher grading scale
<0.001*
1
0
0
2
0.9
2
78
72.2
57
26.4
3
25
23.1
102
47.2
4
5
4.6
55
25.5
WFNS grade
<0.001*
1
83
76.9
45
20.8
2
13
12.0
68
31.5
3
3
2.8
27
12.5
4
9
8.3
76
35.2
Table 3: Comparative analysis between the Aneurysmal vs Non-aneurysmal sub-groups. Patients were compared in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. Statistical significance was established with at p-value < 0.05.
CTA Test characteristics
Neurovascular DSA
Estimate
95% CI
Estimate
95% CI
Sensitivity
0.94
0.88 – 0.97
0.98
0.94 – 0.99
Specificity
0.99
0.94– 1.00
1.00
0.96 – 1.00
Positive predictive value
0.99
0.95– 1.00
1.00
0.98 – 1.00
Negative predictive value
0.93
0.86 – 0.97
0.96
0.89 – 0.98
Table 4: Analysis for CTA and Digital Subtraction Angiography as imaging studies for SAH patient
Abbreviation list: 1) Spontaneous Subarachnoid Hemorrhage-SSAH 2) Subarachnoid Hemorrhage-SAH 3) Arteriovenous Malformations-AVMs 4) Perimesencephalic Subarachnoid Hemorrhage- PM-SAH 5) Diffuse Subarachnoid Hemorrhage-d-SAH 6) Digital Subtraction Angiography-DSA 7) CT Angiography-CTA 8) Posterior Inferior Cerebellar Artery-PICA 9) Middle Cerebral Artery-MCA 10) Electronic Medical Records-EMR
World Federation of Neurosurgical Society-WFNS
Conflicts of interest The authors declare that this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors that could be construed as a potential conflict of interest.
S1878-8750(19)32724-X
DOI:
https://doi.org/10.1016/j.wneu.2019.10.104
Reference:
WNEU 13575
To appear in:
World Neurosurgery
Received Date: 25 June 2019 Revised Date:
16 October 2019
Accepted Date: 17 October 2019
Please cite this article as: Flores G, Feliciano C, Amaral-Nieves N, de Jesús A, Descriptive study of aneurysmal and non-aneurysmal subarachnoid hemorrhage and the role of confirmative DSA in non-aneurysmal subarachnoid patients in Puerto Rico, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.104. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Descriptive study of aneurysmal and non-aneurysmal subarachnoid hemorrhage and the role of confirmative DSA in non-aneurysmal subarachnoid patients in Puerto Rico
Gabriel Flores, Corresponding author [email protected] Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico Medical Sciences Campus Box 365067 San Juan, PR 00936-5067
Caleb Feliciano [email protected] Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico – Medical Sciences Campus
Natalie Amaral-Nieves [email protected] School of Medicine University of Puerto Rico – Medical Sciences Campus
Aixa de Jesús, Consultant Section of Neurosurgery Department of Surgery School of Medicine University of Puerto Rico – Medical Sciences Campus
Key-words: Subarachnoid hemorrhage, perimesencephalic, DSA, CTA Short title: Subarachnoid Hemorrhage in Puerto Rico and the Need for a Confirmatory DSA
1
Abbreviation list: 1) Spontaneous Subarachnoid Hemorrhage-SSAH 2) Subarachnoid Hemorrhage-SAH 3) Arteriovenous Malformations-AVMs 4) Perimesencephalic Subarachnoid Hemorrhage- PM-SAH 5) Diffuse Subarachnoid Hemorrhage-d-SAH 6) Digital Subtraction Angiography-DSA 7) CT Angiography-CTA 8) Posterior Inferior Cerebellar Artery-PICA 9) Middle Cerebral Artery-MCA 10) Electronic Medical Records-EMR 11) World Federation of Neurosurgical Society-WFNS
2
Abstract: Background- Cerebrovascular disease is the fifth cause of mortality in Puerto Rico. Currently, there is no descriptive study for the presentation of spontaneous subarachnoid hemorrhage (SSAH) in our institution. Therefore, our primary aim is to make a retrospective analysis of adult patients with SSAH and assess the need for a DSA after an initially aneurysm-negative CTA in non-aneurysmal SAH, specifically perimesencephalic SAH (PM-SAH). Methods- Medical records of 324 adult patients with aneurysmal and non-aneurysmal SAH treated at the Puerto Rico Medical Center from 2015 to 2018 were retrospectively analyzed. Demographics, past medical history, clinical characteristics and imaging information was extracted. Results- Acute hydrocephalus, mortality at 30 days, prevalence of diffuse SAH pattern, Fisher and WFNS grades >2 on initial exam were higher in the aneurysmal SAH sub-group. Patients with non-aneurysmal SAH had a significantly higher prevalence of Chronic Kidney Disease and Diabetes Mellitus. 100% of the non-aneurysmal PM SAH with an initial aneurysmnegative CTA were subsequently confirmed by DSA. Conclusions- Patients in the aneurysmal SAH sub-group correlated with an increased disease burden. Furthermore, this study shows that in our population, patients with non-aneurysmal PM-SAH with a low Fisher and WFNS grade and with comorbid Diabetes Mellitus and Chronic Kidney Disease, may not need a DSA after a negative initial CTA.
3
Introduction Spontaneous subarachnoid hemorrhage (SSAH) is very serious condition that may arise as a result of ruptured cerebral aneurysms, arteriovenous malformations (AVMs), cerebrovascular dissection, vasculitis or other vasculopathy, that grants urgent neurosurgical evaluation. It is important to specify that SSAH from AVMs may be related to intranidal and flowrelated aneurysms (1). Other etiologies for SSAH may be more benign such as PM-SAH, also known as pretruncal nonaneurysmal subarachnoid hemorrhage, or reversal cerebral vasoconstrict syndrome (2). Aneurysm growth and rupture have associated risk factors such as female sex, hypertension, smoking, use of vascular active or toxic drugs or medications, aneurysm size, location, and shape (3,4). Even though most SSAH are caused by ruptured aneurysms, up to 15% of SSAH have no known bleeding source (4,5). These are known as non-aneurysmal SAH and are associated with better neurological outcomes than aneurysmal SAH (aSAH). Furthermore, diffuse-SAH (d-SAH) has been linked to more aggressive disease course, more complications, longer hospital stays and higher economic burden for patients when compared to PM-SAH. Non-aneurysmal SAH can be classified depending on the bleeding pattern confirmed by initial computed tomography without contrast (CT); PM-SAH and diffuse SAH (d-SAH) (5,6). PM-SAH are characterized by bleeding PM-SAH are characterized by bleeding in the prepontine, interpeduncular, crural, ambient and quadrigeminal cisterns that may spread to the basal parts of the sylvian fissures (7). On the other hand, d-SAH are characterized by having blood that exceeds the limits mentioned above. The imaging strategy in a patient that presents with symptoms suggestive of SSAH varies among institutions. Digital Subtraction Angiography (DSA) has been advocated as the gold standard due to its ability to identify smaller pathologies in posterior circulation, multiple aneurysms and ability for better surgical planning. However, some prefer CT-Angiography (CTA) due to the cost effectiveness and less invasive study in cases such as PM-SAH (8). However, some advocate that a DSA should be mandatory because they report close to 3% risk of having an aneurysm in PM-SAH (9). This study aims to further assess this controversy. Cerebrovascular disease and strokes are the fifth cause of mortality in Puerto Rico (10). However, there are no descriptive study about SSAH in Puerto Rico. We describe our experience with aSAH and non-aneurysmal SAH. Moreover, we describe the yield of a follow-up DSA after initial negative CTA on PM-SAH pattern.
1
Materials and Methods A retrospective review of electronic medical records (EMR) of patients who had spontaneous subarachnoid hemorrhage (SSAH) from November 2015 to May 2018 was done in order to obtain demographic information such as age, gender, initial neurological exam and past medical history. Past medical history included history of hypertension, diabetes, smoking status, use of alcohol and chronic kidney disease and were collected by ICD-10 codes. Mortality at 30 days and whether there was development of acute hydrocephalus at 72 hours with requirement of ventriculostomy was also extracted from the records. These patients could have SSAH associated with intracranial hemorrhage (ICH) and intraventricular hemorrhage (IVH) and could be due to aneurysmal or non-aneurysmal causes. Patients who were younger than 18 years, who suffered from traumatic SAH, brain contusions or traumatic acute subdural hematoma (ASDH) and/or with a World Federation of Neurosurgical Society (WFNS) grade of 5 at initial exam were excluded from the study. The initial head CT without contrast, CTA, subsequent DSA images and reports were extracted from a software storage imaging from our institution in order to review the pattern of bleeding and to assess whether they were positive or negative for brain aneurysms by our Neuroendovascular surgery service and expert neuroradiologists at our institution. The data collected from the DSA reports included the dimensions (dome height and dome diameter), location of aneurysm and the presence of multiple brain aneurysms. For patients to be included in the study the CTA must had been done before a DSA. Descriptive analysis was performed in both groups (aSAH vs non-aneurysmal SAH) to describe demographic and clinical characteristics of the patients. Comparison between the groups was performed using Chi-square or Fisher exact tests for the categorical variables and t-test for continuous variables, as appropriate. A two-sided p-value < 0.05 was considered as statistically significant. Specificity, sensitivity, positive predictive value and negative predictive value with their corresponding 95% confidence value was estimated in order to compare CTA and DSA as an imaging tool in SAH. Analysis was completed using R (version 3.4.4). Approval for Protocol A0230119 was obtained from the University of Puerto Rico – Medical Sciences Campus Institutional Review Board.
2
Results Aneurysmal SAH A total of 216 patients had aneurysmal SAH. The median age was 61 years (IQR: 52.8-70.1) with a gender ratio of 2.33:1 (female:male). The most common pattern of SAH was diffuse (75%) compared to perimesencephalic (0.9%). Only two patients with PM-SAH had a positive initial CTA for aneurysm. A DSA was later used to confirm the presence of aneurysms in these two patients.In the initial neurological exam, patients in the aneurysmal SAH sub-group had a WFNS grade of 2 or more (87.5%) and Fisher grade of 2 or more (99.1%). Only two patients required lumbar puncture to rule out SAH. Acute hydrocephalus at 72 hours with requirement of ventriculostomy was 27.3% with a prevalence of chronic hydrocephalus of 4.6%. Mortality rate at 30 days was 23.1%. First DSA study confirmed 97.7% of aSAH, follow-up DSA study improved yield to 100%. Results are exposed in Table 1. Aneurysm characteristics The location of the aneurysms was more prevalent in the anterior circulation (89.4%) when compared to the posterior circulation (10.6%). Three of the aneurysms were classified as mycotic in the corresponding locations; posterior inferior cerebellar artery (PICA), pericallosal segment of anterior cerebral artery (ACA) and middle cerebral artery (MCA) M4 segment. Meanwhile, one aneurysm was classified as a vertebral VA dissecting aneurysm. The incidence of aneurysmal rupture based on location was comparable between anterior communicating artery (26.4%) and posterior communicating arteries (26.4%) followed by MCA segment M2 (15.3%). The average dimensions via DSA for ruptured aneurysms were 4.74 ± 2.27mm for dome height and 5.01 ± 2.85 mm for dome diameter Differences in size were not statistically significant when comparing anterior versus posterior aneurysms. Non-aneurysmal SAH A total of 108 patients had non-aneurysmal SAH, with a mean age of 60.1 years (IQR 52.8-67.4) with a gender ratio of 1.5:1 (female:male). The most common pattern of SAH was perimesencephalic (52.8%) compared to diffuse (26.9%). In the initial neurological exam, patients in Non-aneurysmal SAH sub-group had a WFNS grade of 1 (76.9%) and Fisher grade of 2 and 3. Acute hydrocephalus at 72 hours with requirement of ventriculostomy was 9.3% with a prevalence of chronic hydrocephalus of 1.9%. Mortality rate at 30 days was 6.5%. Even though all DSA proved to be negative for aneurysms in
3
this sub-group, there were other pathologies found; one arteriovenous malformation (AVM), six patients with vasculitis and three patients with cerebral atherosclerosis. Mortality rate at 30 days in patient with PM-SAH 1.8% (N=1/57), a death related to cardiovascular complications. Results are in Table 2. Comparison Acute hydrocephalus, mortality at 30 days, prevalence of diffuse SAH pattern and Fisher and WFNS grades > 2 in initial exam were higher in the aneurysmal SAH sub-group than in the non-aneurysmal. Patients with non-aneurysmal SAH had a higher prevalence of Chronic Kidney Disease and Diabetes Mellitus when compared to the non-aneurysmal SAH sub-group. All of the variables mentioned above were statistically significant (p-value < 0.05). 100% of the non-aneurysmal PM-SAH with an initial CTA negative for aneurysm had a subsequent confirmation by DSA. In addition, only 10 cases of non-aneurysmal PMSAH had second follow-up DSA which reported normal cerebral angiogram. In aneurysmal PM-SAH, 2 patients had an initial CTA positive for aneurysm which was further confirmed by DSA. Results are in Table 3. Diagnostic Test Characteristics For initial head CT, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.94 (95% CI: 0.88-0.97), 0.99 (95% CI: 0.94-1.00), 0.99 (95% CI: 0.95-1.00) and 0.93 (95% CI: 0.86-0.97), respectively. Meanwhile, for DSA, the sensitivity, specificity, positive predictive value and negative predictive value were 0.98 (95% CI: 0.0.94-0.99), 1.00 (95% CI: 0.96-1.00), 1.00 (95% CI: 0.98-1.00) and 0.96 (95% CI: 0.89-0.98), respectively. Results are in Tables 4.
4
Discussion This study demonstrated differences between non-aneurysmal SAH and aneurysmal SAH as very distinct etiologies for SSAH with dissimilar demographic characteristics, clinical presentation and outcomes. In general, non-aneurysmal SAH exhibits a less aggressive clinical course compared to aSAH in terms mortality, acute and shunt dependent hydrocephalus. These results are comparable to Konczalla J et al (5,11). In the aneurysmal SAH sub-group the median age, prevalence of hypertension and diabetes were higher compared to RCS of England, National Study of Subarachnoid Hemorrhage (12). Also, the initial WFNS and the amount of blood on Head CT were more severe compared to the aforementioned study. This dissimilarity could be associated to higher prevalence of pre-existing medical conditions in our studied population. The anatomic location of ruptured aneurysms was more common in the anterior cerebral circulation, and anterior communicating artery, posterior communicating arteries and MCA M2 arteries were the more common sites, which is comparable with previous studies (12, 13). Literature has reported that aneurysmal size less 7mm represents a lower risk for the ruptured of aneurysm, on the contrary in our study the average size for ruptured aneurysm was 5.01mm (14). This inconsistency may support the hypothesis that unruptured aneurysms are different than ruptured aneurysms. Furthermore, it is important to emphasize that studies have shown that post rupture morphology should not be used as a measure of risk of rupture (15). Non-aneurysmal SAH sub-group showed a more benign clinical course. Furthermore, there was higher incidence of PM-SAH pattern, better neurological status, lower incidence of acute and chronic hydrocephalus, and lower rate of mortality. These results are comparable with literature (5,11). In addition, our non-aneurysmal SAH sub-group had higher prevalence of Diabetes Mellitus, similar to Mensing L, et al (16). This result may support the hypothesis of the pathogenesis of PM-SAH is secondary to capillary leak, and could correlate with Diabetes Mellitus as risk factor due to its relation of microvascular complications (7, 17) In our current study, all patients in the PM-SAH pattern in the non-aneurysmal SAH sub-group had a negative initial CTA for aneurysms which was later confirmed by follow-up DSA. Only in one case was found an incidental AVM not associated with PM-SAH pattern. In ten cases of PM-SAH pattern a second DSA follow-up was done and only one case showed radiographic vasospasm. Our findings suggest that a CTA is high yield study to rule out aneurysms or other vascular pathology in patients
5
with PM-SAH pattern. These results are comparable with previous studies that show DSA follow-up detection rates of 0.78% to 1.5% for aneurysms, and concluded no use of initial DSA or follow-up angiographic imaging in patients with PM-SAH with a negative CTA (8,18). On the contrary, another study advocated that patients with PM-SAH should continue to undergo DSA even after negative CTA, as they found aneurysms as the causative agent in 3% of patients with initial negative CTA (9). In our Institution, the sensitivity, specificity, PPV and NPV for DSA had higher values throughout when compared to CTA as expected. Compared to other study, our sensitivities for both imaging tools were slight lower compared to a CTA between 99.2% and for DSA at 100% (9). However, in our study for aSAH sub-group a second DSA follow-up improve sensitivity to 100% and for non-aneurysmal PM-SAH the yield for aneurysmal detection after first follow-up and second follow-up DSA was 0%. The retrospective nature of our data is a limitation to the study. A strength of our study is that all CTAs and DSAs were performed and analyzed by the same facility which decreases the presence of different practices in our study. Due to the great diversity that currently exists in the diagnostic management of SAH patients, more studies are needed to further assess this controversy. As a result, studies such as a meta-analysis necessary to begin to establish a standard of practice.
6
Conclusions Patients in the aneurysmal SAH sub-group had a higher incidence of diffuse bleeding pattern, higher mortality at 30 days, higher incidence of hydrocephalus with subsequent shunt placement, higher Fisher and WFNS grades at initial neurological exam. Patients in the non-aneurysmal sub-groups had a higher prevalence of Chronic Kidney Disease and Diabetes Mellitus. 100% of patients in the non-aneurysmal sub-group who had a PM-SAH had a negative initial CTA for aneurysms which was confirmed by a follow-up DSA. As a result, it can be concluded that in our population, patients with non-aneurysmal PMSAH who had low Fisher and WFNS grading and have pre-existing Diabetes Mellitus and Chronic Kidney Disease, do not need a follow-up DSA after a negative initial CTA.
7
Acknowledgements Special thanks to Department of Neurosurgery of the University of Puerto Rico. Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
8
References (1) Redekop G, Terbrugee, K, Montanera, W, Willinsky, R. Arterial aneurysms asscoaited with cerebral arteriovenous malformations: classification, incidence, and risk of hemorrhage. J Neurosurg. 1998;539-546. https://doi.org/10.3171/jns.1998.89.4.0539 (2) Elhadi A.M, Zabramski J.M, Almefty K.K, Mendes G.A, Nakaji P, McDougall C.G, Albuquerque F.C, Preul M.C, Spetzler R.F. Spontaneous subarachnoid hemorrhage of unknown origin: hospital course and long-term clinical and angiographic followup. J Neurosurg. 2015;122:663-70. doi: 10.3171/2014.10.JNS14175. (3) Feigin V.L, Rinkel G, Lawes C, Algra A, Bennett D.A, Van Gijn J, Anderson C.S. Risk Factors for Subarachnoid Hemorrhage An Updated Systematic Review of Epidemiological Studies. Stroke. 2005; 36:2773-2780. doi:10.1161/01.STR.0000190838.02954.e8. (4) Tominari S, Morita A, Ishibashi T, Yamazaki T, Takao H, Murayama Y, et al. Unruptured Cerebral Aneurysm Study Japan Investigators. Prediction model for 3-year rupture risk of unruptured cerebral aneurysms in Japanese patients. Ann Neurol. 2015; 77:1050–1059. doi: 10.1002/ana.24400. (5) Konczalla J, Platz J, Schuss P, Vatter H, Seifert V, Güresir E. Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients. BMC Neurol. 2014; 14:140. doi:10.1186/1471-2377-14-140. (6) Coelho L. G, Costa J. M, & Silva E. I. Non-aneurysmal spontaneous subarachnoid hemorrhage: perimesencephalic versus non-perimesencephalic. Hemorragia subaracnóidea espontânea não aneurismática: perimesencefálica versus não perimesencefálica. Rev Bras Ter Intensiva. 2016; 28: 141–146. doi:10.5935/0103-507X.20160028. (7) van Gijn J, van Dongen K. J, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology.1985;35:493. DOI: 10.1212/WNL.35.4.493. (8) Kalra V.B, Wu X, Forman H.P, Malhotra A. Cost-Effectiveness of Angiographic Imaging in Isolated Perimesencephalic Subarachnoid Hemorrhage. Stroke. 2014; 45:3576-3582. https://doi.org/10.1161/STROKEAHA.114.006679.
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(9) Heit J.J, Pastena G.T, Nogueira R.G, Yoo A.J, Leslie-Mazwi T.M, Hirsch J.A, Rabinov J.D. Cerebral Angiography for Evaluation of Patients with CT Angiogram-Negative Subarachnoid Hemorrhage: An 11-year Experience. Am J Neuroradiol. 2016; 37:297-304. doi.org/10.3174/ajnr.A4503. (10) Institute of Health Metrics and Evaluation. Puerto Rico. http://www.healthdata.org/puerto-rico. Accessed 8 June 2019. (11) Konczalla J, Schmitz J, Kashefiolasl S, Senft C, Seifert V, Platz J. Aneurysmal Subarachnoid Hemorrhage in 173 Patients: A Prospective Study of Long-term Outcome. Eur.J.Neurol. 2015;22:1329-1336. doi:10.1111/ene.12762. (12) The Royal College of Surgeons of England. National Study of Subarachnoid Hemorrhage. https://www.rcseng.ac.uk//media/files/rcs/standards-and-research/research/national-study-of-subarahnoid-haemorrhage-final-report-2006.pdf.; 2006 Accessed 5 May 2019 (13) Korja M, Kivisaari R, Rezai B, Lehto H. Size and Location of Ruptured Intracranial Aneurysms: Consecutive Series of 1993 Hospital-admitted Patients. J Neurosurg. 2017; 127:748-753. doi: 10.3171/2016.9.JNS161085. (14) Harbaugh R.E, The International Study on Unruptured Intracranial Aneurysms (ISUIA): New Prospective Data. Neurosurgery.2003;53. doi.org/10.1227/01.neu.0000309249.94601.9b. (15) Skodvin TO,Johnsen LH, Gjertsen O, Isaksen JG, Sorteberg A. Cerebral Aneurysm Morphology Before and After Rupture: Nationwide Case Series of 29 Aneurysms. Stroke. 2017; 48:880-886. doi: 10.1161/STROKEAHA.116.015288 (16) Mensing LA, Vergouwen MDI, Laban KG, Ruigrok YM, Velthuis BK, Algra A, Rinkel GJE. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke. 2018; 49:1363-1370. doi: 10.1161/STROKEAHA.117.019843. (17) Fowler M.J. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 2008; 26:77-82. doi.org/10.2337/diaclin.26.2.77. (18) Potter C.A, Fink K.R, Ginn, A.L & Haynor D.R. Perimesencephalic Hemorrhage: Yield of Single versus Multiple DSA Examinations--A Single-Center Study and Meta-Analysis. Radiology.2016;281:858-864.
10
Variable Gender Female Male Hypertension Diabetes Mellitus Chronic Kidney Disease Smoker Acute Hydrocephalus Chronic Hydrocephalus Alcohol
n
%
152 64 188 51 7 55 59 10 8
70.4 29.6 87.0 23.6 3.2 25.5 27.3 4.6 3.7
Mortality at 30 days 50 23.1 SAH Perimesencephalic 2 0.9 Cistern 4 1.9 Diffuse 162 75.0 Comorbid ICH or IVH 46 21.3 None, positive LPH 2 0.9 Fisher Grading Scale 1 2 0.9 2 57 26.4 3 102 47.2 4 55 25.5 WFNS Grade 1 45 20.8 2 68 31.5 3 27 12.5 4 76 35.2 CTA Positive 116 53.7 Negative 7 3.2 No Study 93 43.1 Localization Anterior 194 89.8 Posterior 22 10.2 More than 1 aneurysm 39 18.1 First DSA Positive 211 97.7 Table 1: Descriptive Analysis for Aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination.
VARIABLE
N
(%)
GENDER FEMALE MALE HYPERTENSION
65 43 96
60.2 39.8 88.9
DIABETES MELLITUS
37
34.3
CHRONIC KIDNEY DISEASE
13
12.0
SMOKER
23
21.3
ACUTE HYDROCEPHALUS
10
9.3
CHRONIC HYDROCEPHALUS
2
1.9
MISCELLANEOUS ALCOHOL MORTALITY AT 30 DAYS
4
3.7
7
6.5
SAH PERIMESENCEPHALIC 57 52.8 CONVEXITY 13 12.0 CISTERN 4 3.7 DIFFUSE 29 26.9 ICH OR IVH 5 4.6 FISHER GRADING SCALE 1 0 0 2 78 72.2 3 25 23.1 4 5 4.6 WFNS GRADE 1 83 76.9 2 13 12.0 3 3 2.8 4 9 8.3 CTA POSITIVE* 1 1.0 NEGATIVE 96 88.9 NO STUDY 11 10.2 DSA POSITIVE† 10 9.3 NEGATIVE 98 90.7 Table 2: Descriptive Analysis for Non-aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. DSA demonstrated negative for aneurysm*. One patient with incidental AVM, six patients with vasculitis and three patients with cerebral atherosclerosis†. All were negative for aneurysms.
NON-ANEURYSMAL SAH CHARACTERISTIC
ANEURYSMAL SAH
N
%
N
%
p-value
59.9
10.5
59.9
15.3
1
Female
65
60.2
152
70.4
0.066
Hypertension
96
88.9
188
87.0
0.633
Diabetes mellitus
37
34.3
51
23.6
0.042*
Chronic kidney disease
13
12.0
7
3.2
0.003*
Smoker
23
21.3
55
21.3
0.408
Acute hydrocephalus
10
9.3
59
27.3
<0.001*
Chronic hydrocephalus
2
1.9
10
4.6
0.350
Age (mean, sd)
Alcohol 4 3.7 8 3.7 1 Mortality at 30 days 7 6.5 50 23.1 <0.001* SAH <0.001* Perimesencephalic 57 52.8 2 0.9 Convexity 13 12.0 0 0 Cistern 4 3.7 4 1.9 Diffuse 29 26.9 162 75.0 ICH or ICV 5 4.6 46 21.3 None, positive LPH 0 0 2 0.9 Fisher grading scale <0.001* 1 0 0 2 0.9 2 78 72.2 57 26.4 3 25 23.1 102 47.2 4 5 4.6 55 25.5 WFNS grade <0.001* 1 83 76.9 45 20.8 2 13 12.0 68 31.5 3 3 2.8 27 12.5 4 9 8.3 76 35.2 Table 3: Comparative analysis between the Aneurysmal vs Non-aneurysmal sub-groups. Patients were compared in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. Statistical significance was established with at p-value < 0.05.
CTA
Neurovascular DSA
Test characteristics Estimate 95% CI Estimate 95% CI Sensitivity 0.94 0.88 – 0.97 0.98 0.94 – 0.99 Specificity 0.99 0.94– 1.00 1.00 0.96 – 1.00 Positive predictive value 0.99 0.95– 1.00 1.00 0.98 – 1.00 Negative predictive value 0.93 0.86 – 0.97 0.96 0.89 – 0.98 Table 4: Analysis for CTA and Digital Subtraction Angiography as imaging studies for SAH patient
Variable
n
%
Female
152
70.4
Male
64
29.6
Hypertension
188
87.0
Diabetes Mellitus
51
23.6
Chronic Kidney Disease
7
3.2
Smoker
55
25.5
Acute Hydrocephalus
59
27.3
Chronic Hydrocephalus
10
4.6
Alcohol
8
3.7
Mortality at 30 days
50
23.1
Perimesencephalic
2
0.9
Cistern
4
1.9
Diffuse
162
75.0
Comorbid ICH or IVH
46
21.3
None, positive LPH
2
0.9
1
2
0.9
2
57
26.4
3
102
47.2
4
55
25.5
1
45
20.8
2
68
31.5
3
27
12.5
Gender
SAH
Fisher Grading Scale
WFNS Grade
4
76
35.2
Positive
116
53.7
Negative
7
3.2
No Study
93
43.1
Anterior
194
89.8
Posterior
22
10.2
More than 1 aneurysm
39
18.1
First DSA Positive
211
97.7
CTA
Localization
Table 1: Descriptive Analysis for Aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination.
VARIABLE
N
(%)
FEMALE
65
60.2
MALE
43
39.8
HYPERTENSION
96
88.9
DIABETES MELLITUS
37
34.3
CHRONIC KIDNEY DISEASE
13
12.0
SMOKER
23
21.3
ACUTE HYDROCEPHALUS
10
9.3
CHRONIC HYDROCEPHALUS
2
1.9
4
3.7
7
6.5
PERIMESENCEPHALIC
57
52.8
CONVEXITY
13
12.0
CISTERN
4
3.7
DIFFUSE
29
26.9
ICH OR IVH
5
4.6
1
0
0
2
78
72.2
3
25
23.1
4
5
4.6
83
76.9
GENDER
MISCELLANEOUS ALCOHOL MORTALITY AT 30 DAYS
SAH
FISHER GRADING SCALE
WFNS GRADE 1
2
13
12.0
3
3
2.8
4
9
8.3
POSITIVE*
1
1.0
NEGATIVE
96
88.9
NO STUDY
11
10.2
10
9.3
98
90.7
CTA
DSA POSITIVE† NEGATIVE
Table 2: Descriptive Analysis for Non-aneurysmal Sub-Group. Patients were analyzed in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. DSA demonstrated negative for aneurysm*. One patient with incidental AVM, six patients with vasculitis and three patients with cerebral atherosclerosis†. All were negative for aneurysms.
NON-ANEURYSMAL SAH CHARACTERISTIC
ANEURYSMAL SAH
N
%
N
%
p-value
59.9
10.5
59.9
15.3
1
Female
65
60.2
152
70.4
0.066
Hypertension
96
88.9
188
87.0
0.633
Diabetes mellitus
37
34.3
51
23.6
0.042*
Chronic kidney disease
13
12.0
7
3.2
0.003*
Smoker
23
21.3
55
21.3
0.408
Acute hydrocephalus
10
9.3
59
27.3
<0.001*
Chronic hydrocephalus
2
1.9
10
4.6
0.350
Alcohol
4
3.7
8
3.7
1
Mortality at 30 days
7
6.5
50
23.1
<0.001*
Age (mean, sd)
SAH
<0.001*
Perimesencephalic
57
52.8
2
0.9
Convexity
13
12.0
0
0
Cistern
4
3.7
4
1.9
Diffuse
29
26.9
162
75.0
ICH or ICV
5
4.6
46
21.3
None, positive LPH
0
0
2
0.9
Fisher grading scale
<0.001*
1
0
0
2
0.9
2
78
72.2
57
26.4
3
25
23.1
102
47.2
4
5
4.6
55
25.5
WFNS grade
<0.001*
1
83
76.9
45
20.8
2
13
12.0
68
31.5
3
3
2.8
27
12.5
4
9
8.3
76
35.2
Table 3: Comparative analysis between the Aneurysmal vs Non-aneurysmal sub-groups. Patients were compared in terms of comorbid conditions, mortality at 30 days, pattern of bleeding, incidence of hydrocephalus at 72 hours and grading scale upon initial neurological examination. Statistical significance was established with at p-value < 0.05.
CTA Test characteristics
Neurovascular DSA
Estimate
95% CI
Estimate
95% CI
Sensitivity
0.94
0.88 – 0.97
0.98
0.94 – 0.99
Specificity
0.99
0.94– 1.00
1.00
0.96 – 1.00
Positive predictive value
0.99
0.95– 1.00
1.00
0.98 – 1.00
Negative predictive value
0.93
0.86 – 0.97
0.96
0.89 – 0.98
Table 4: Analysis for CTA and Digital Subtraction Angiography as imaging studies for SAH patient
Abbreviation list: 1) Spontaneous Subarachnoid Hemorrhage-SSAH 2) Subarachnoid Hemorrhage-SAH 3) Arteriovenous Malformations-AVMs 4) Perimesencephalic Subarachnoid Hemorrhage- PM-SAH 5) Diffuse Subarachnoid Hemorrhage-d-SAH 6) Digital Subtraction Angiography-DSA 7) CT Angiography-CTA 8) Posterior Inferior Cerebellar Artery-PICA 9) Middle Cerebral Artery-MCA 10) Electronic Medical Records-EMR
World Federation of Neurosurgical Society-WFNS
Conflicts of interest The authors declare that this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors that could be construed as a potential conflict of interest.