Impact of Young Age on the Presentation of Saccular Intracranial Aneurysms: Population-Based Analysis of 4082 Patients

Impact of Young Age on the Presentation of Saccular Intracranial Aneurysms: Population-Based... Abstract BACKGROUND Formation and rupture of saccular intracranial aneurysms (sIAs) may have different pathobiologies in patients with younger age at first diagnosis of sIA disease. OBJECTIVE To study the phenotype of sIA disease and formation of new (de novo) sIAs in patients below 40 yr. METHODS A population-based cohort study was conducted in 613 young (<40 yr) sIA patients with first diagnosis between 1980 and 2014 and total angiographic follow-up of 3768 yr. RESULTS Of the 613 sIA patients <40 yr, 508 had aneurysmal subarachnoid hemorrhage (sIA-SAH) and 105 unruptured sIA(s) at first sIA diagnosis. Hypertension was 2 times less common among <40 than >40-yr-old patients (unruptured and ruptured). Smoking was very prevalent in <40-yr-old patients (33% in SAH, 68% unruptured). SAH patients <40 yr more often had family history of sIA, and lower PHASES scores (age omitted, P < .001). Ruptured sIAs were small (<7 mm) in 33% of 39 to 30 yr patients, in 44% of 29 to 20 yr patients, and 57% of <19 yr patients. Their shape was irregular in 90%, 94%, and 95%, respectively. Smoking history (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.2-7.0), family history for sIAs (HR 3.1, 95% CI 1.3-7.7), and age at presentation (HR .91 per year, 95% CI .85-.98) were risk factors for de novo sIA formation, diagnosed in 4% even after 20 yr (median 11.8 yr). CONCLUSION Smoking and family history are risk factors for sIA formation and aneurysmal SAH at young age. Young aneurysmal SAH patients had lower PHASES scores and often rupture from a small sIA, suggesting need for more aggressive management. Cerebrovascular, Intracranial aneurysm, Subarachnoid hemorrhage, Young age, Familial disease, Vascular diseases ABBREVIATIONS ABBREVIATIONS ACom anterior communicating aSAH aneurysmal subarachnoid hemorrhage CI confidence interval CT computed tomography HR hazard ratio MRI magnetic resonance imaging SAH subarachnoid hemorrhage sIAs saccular intracranial aneurysms Unruptured saccular intracranial aneurysm (sIA) is a relatively common disease (2%-3% prevalence).1 Asymptomatic unruptured sIAs are diagnosed increasingly frequently due to improved availability of magnetic resonance imaging (MRI) scans. Although sIAs may rupture causing devastating hemorrhage with mortality of 30% to 50%,2 most sIAs never rupture.3 The pathobiology of sIA formation and rupture need to be elucidated in order to focus follow-up efforts and therapy to those patients at risk of developing sIAs or at risk of sIA rupture. Formation and rupture of sIAs are multifactorial processes affected by genetic background (ethnicity, gender, family history)4-7 and multiple acquired risk factors (smoking, hypertension, stimulant abuse).8,4 Formation of sIAs occurs mostly at specific locations in the cerebral arteries, and location affects the risk of rupture.9,10 How the formation of sIAs in different locations is affected by patient-related risk factors is not well known. In addition to patient-related risk factors, aneurysm-related factors that reflect unstable wall and predict rupture (size and shape) are known11,12 and used to guide clinical decisions. Unruptured sIAs are mostly diagnosed at the fifth decade of life or later (>40 yr old),13 and are exceedingly rare in children and young adults.14 This suggests that sIAs form during lifetime due to the effect that exposure to risk factors has on the cerebral artery wall. Formation and rupture of sIAs may have different pathobiology in patients who develop disease manifestations at a young age compared to the middle-aged population. These patients may require different thresholds for follow-up or intervention than the middle-aged population. The phenotype of patients who develop sIA(s) at a young age is incompletely known, because modern clinical series that characterize these patients are few (Table 1). TABLE 1. Angiographically verified intracranial aneurysm cohorts of 25 or more young patients (0-20 yr) published since 2004* in English. Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  IA, intracranial aneurysm; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; IVH, intraventricular hemorrhage; ICA, internal carotid artery; ICA bif, internal carotid artery bifurcation; ACA, anterior cerebral artery; MCA, middle cerebral artery; VBA, vertebral and basilar arteries; n.d, no data *PubMed was searched for English articles from 2004 through November 2014 on cohorts of pediatric or adolescent patients carrying intracranial aneurysms with the following keywords: (aneurysm OR aneurysms OR aneurysmal) AND (intracranial OR “subarachnoid haemorrhage” OR SAH) AND (child OR children OR childhood OR pediatric OR adolescent). Inclusion criteria were angiographically verified intracranial aneurysm, minimum cohort size 25 cases and cohort collected after 1980. View Large TABLE 1. Angiographically verified intracranial aneurysm cohorts of 25 or more young patients (0-20 yr) published since 2004* in English. Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  IA, intracranial aneurysm; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; IVH, intraventricular hemorrhage; ICA, internal carotid artery; ICA bif, internal carotid artery bifurcation; ACA, anterior cerebral artery; MCA, middle cerebral artery; VBA, vertebral and basilar arteries; n.d, no data *PubMed was searched for English articles from 2004 through November 2014 on cohorts of pediatric or adolescent patients carrying intracranial aneurysms with the following keywords: (aneurysm OR aneurysms OR aneurysmal) AND (intracranial OR “subarachnoid haemorrhage” OR SAH) AND (child OR children OR childhood OR pediatric OR adolescent). Inclusion criteria were angiographically verified intracranial aneurysm, minimum cohort size 25 cases and cohort collected after 1980. View Large We characterized the phenotype of Eastern Finnish patients who developed intracranial aneurysm at a young age, and investigated the hypothesis that the risk factors and phenotype of those patients differ from that of other sIA patients. In addition, we studied the significance of known patient-related and aneurysm-related risk factors for rupture in young sIA patients. METHODS We conducted a population-based study of the characteristics of patients diagnosed with sIAs before the age of 40 yr. This study was approved by the Ethics Committee of the Kuopio University Hospital (KUH) and the Ministry of Social Affairs and Health of Finland. Catchment Population of Kuopio University Hospital During the study period from 1980 to 2014, Neurosurgery of Kuopio University Hospital was the only neurosurgical service provider for the KUH catchment area in Eastern Finland.13,15 The population decreased from 863 726 in 1980 to 841 713 in 2014. Cases of subarachnoid hemorrhage (SAH) or Unruptured IAs in the Kuopio University Hospital Area All patients with acute SAH have been acutely admitted to the KUH for diagnostic angiography, if not moribund or very aged. Similarly, patients with unruptured sIAs in computed tomography (CT) or MRI scans in other KUH catchment area hospitals were admitted to KUH for diagnostic angiography, unless excluded due to advanced age or serious preexisting medical conditions. Patients with angiographically confirmed sIAs were entered into Kuopio Intracranial Aneurysm Database (http://kuopioneurosurgery.fi/database/) after informed consent (in Finnish) was obtained.15 The database is run by a full-time nurse, who interviews new cases and codes variables with detailed information, including family history. The criterion for sIA family is at least 2 affected first-degree relatives. Clinical data from follow-up angiographies (digital subtraction angiography, magnetic resonance angiography or CT angiography) and outpatient clinical visits is included in the database.13,15 Basic Study Population The basic study population included 4082 sIA patients, and their stratification is shown in Figure 1. The inclusion and exclusion criteria were as follows. Citizen of Finland and resident of the KUH catchment area at the time of first diagnosis of sIA disease between January 1, 1980 and October 28, 2014. Admission alive to the KUH and verification of sIA(s) by angiography. Fusiform aneurysms as well as saccular aneurysms with mycotic or traumatic etiology were excluded. FIGURE 1. View largeDownload slide Flowchart showing the number of patients fulfilling inclusion criteria and their subsequent stratification into subgroups. FIGURE 1. View largeDownload slide Flowchart showing the number of patients fulfilling inclusion criteria and their subsequent stratification into subgroups. Statistical Analysis The variables are presented in Table 2. Discrete variables were expressed in proportions and continuous variables in medians and ranges. The 4 age groups (0-19; 20-29; 30-39; ≥40 yr) were compared using the Chi-square test, Fisher exact test or Kruskal–Wallis test when appropriate. Multivariable Cox regression analysis was used to analyze de novo sIA formation with the following variables: sex, age at presentation of sIA disease, smoking history, hypertension, family history for sIAs. The validity of proportional hazards assumption was verified using Schönfeld's residuals. The date of the imaging study confirming the first de novo sIA formation was used in the time-to-event variable calculation in Cox regression (Table, Supplemental Digital Content 1) and Kaplan–Meier estimate. Kaplan–Meier curves were plotted to visualize the effect of different risk factors on de novo sIA formation. P-values less than .05 were considered significant. SPSS statistical software (SPSS Inc, IBM, Armonk, New York) was used. TABLE 2. Characteristics of 4082 sIA Patients   Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084    Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084  sIA, saccular intracranial aneurysm; sIA-SAH, subarachnoid hemorrhage from ruptured sIA; APCKD, autosomal polycystic kidney disease. *Statistically significant P-value. View Large TABLE 2. Characteristics of 4082 sIA Patients   Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084    Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084  sIA, saccular intracranial aneurysm; sIA-SAH, subarachnoid hemorrhage from ruptured sIA; APCKD, autosomal polycystic kidney disease. *Statistically significant P-value. View Large RESULTS Main Results Between 1980 and October 2014, 508 patients were diagnosed with sIA-SAH and 105 patients with an unruptured sIA at an age younger than 40 yr. The 613 sIA patients were divided into age groups below 20 yr (n = 28); 20 to 29 yr (n = 132); and 30 to 39 yr (n = 453; Table 2, Tables, Supplemental Digital Content 2 and 3). sIA-SAH was very rare in patients younger than 20 yr, but increased in frequency between 20 and 30 yr, and more so between 30 and 40 yr (Figure 2). Unruptured sIAs showed a similar trend (Figure 2). We identified a total of 299 unruptured sIAs in patients younger than 40 yr: 145 unruptured sIAs in context of SAH from another sIA; 109 as incidental findings; and 45 by screening sIA families. FIGURE 2. View largeDownload slide Number of patients diagnosed with aSAH or unruptured sIA at different ages is shown separately for sporadic sIAs A and for patients with family history B. In order to visualize how sIA cases accumulate with increasing age in sporadic sIA patients C and in patients with family history D, we plotted the cumulative percentage of diagnosed sIAs against age at diagnosis. These graphs demonstrate that although the number of diagnosed sIAs increases after the age of 30, a significant portion of sIAs is diagnosed between the age of 20 to 30 yr. This observation supports the practice of starting MRA screening at the age of 20 to 30 yr when screening for sIAs is indicated overall. FIGURE 2. View largeDownload slide Number of patients diagnosed with aSAH or unruptured sIA at different ages is shown separately for sporadic sIAs A and for patients with family history B. In order to visualize how sIA cases accumulate with increasing age in sporadic sIA patients C and in patients with family history D, we plotted the cumulative percentage of diagnosed sIAs against age at diagnosis. These graphs demonstrate that although the number of diagnosed sIAs increases after the age of 30, a significant portion of sIAs is diagnosed between the age of 20 to 30 yr. This observation supports the practice of starting MRA screening at the age of 20 to 30 yr when screening for sIAs is indicated overall. Median angiographic follow-up time after the primary sIA diagnosis was 3.47 (range 0-32.8) yr and total follow-up time 3768 yr. Familial and Multiple sIAs Young adults (20-29 yr) and adults (30-39 yr) with unruptured sIAs or aneurysmal SAH (aSAH) at diagnosis had more often positive family history unrelated to ADPKD than patients >40 (Table 2), suggesting that family history is more important for sIA formation in young patients than after 40 yr of age. Patients who suffered aSAH at a young age did not have more often multiple aneurysms than other aSAH patients (Table 2). Interestingly, patients diagnosed with unruptured sIAs at a young age had more often multiple sIAs than young patients presenting with hemorrhage (32% vs 19%). Of those patients who developed multiple sIAs after being diagnosed with first sIA at an age younger than 40 yr, 32% had positive family history. De Novo sIA Formation in Young sIA Patients De novo sIAs were discovered in 4% (22/613) of the studied young sIA patients. Most (13/22) of those patients with de novo sIA formation were 30 to 39 yr of age at diagnosis of first sIA. Of adolescent (≤19 yr) sIA patients, 14% (4/28) had developed denovo sIAs during follow-up, whereas 4% (5/132) of the young adult sIA patients and 3% (13/453) of adult sIA patients had developed de novo sIAs. Median time to de novo sIA discovery was 11.8 yr after the primary sIA diagnosis. The selection of patients into long-term follow-up was based on an individual assessment. Of the patients alive at 12 mo after initial sIA diagnosis, 67% (n = 18) of 0 to 19 yr, 53% (n = 70) of 20 to 29 yr, 48% (n = 191) of 30 to 39 yr, and 38% (n = 1130) of ≥40 yr had undergone angiographic follow-up ≥5 yr. None of the de novo sIAs were discovered after 3 yr of follow-up. Of the de novo sIAs detected, 9% had been found after 5 yr of follow-up, 27% after 10 yr of follow-up, 59% after 15 yr of follow-up, and 82% after 20 yr of follow-up. Interestingly, 18% of the de novo sIAs were found more than 20 yr from initial diagnosis. Risk Factors for sIA Formation Differ in Young and Older sIA Patients Family history for sIA was clearly more common among patients diagnosed with unruptured sIAs at young age than in older (>40 yr) unruptured sIA patients (Table 2). Smoking was very common among young patients diagnosed with unruptured sIAs (68%), more so than among older unruptured sIA patients (Table 2). Diagnosed hypertension was, however, significantly less common among young unruptured sIA patients than among older ones (Table 2). In univariate analysis (Fisher’s exact test), family history (13/22) associated with de novo sIA formation in young sIA patients (P = .001). Smoking history (13/22) showed a trend towards association with de novo sIA formation (P = .072), but was not a significant factor. Interestingly hypertension (3/22) was not associated with denovo sIA formation in this series (P = 1.000). Hypertension was 2 times less common in patients younger than 40 yr at diagnosis than among older patients (Table 2). In Cox regression analysis including sex, age at presentation of sIA disease, family history, hypertension, and known smoking history, family history (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.3-7.7), smoking history (HR 2.8, 95% CI 1.2-7.0), and age at presentation (HR .91 per year, 95% CI .85-.98) were independent significant risk factors for denovo sIA formation (Table, Supplemental Digital Content 1, Figure 3.). FIGURE 3. View largeDownload slide Kaplan–Meier cumulative hazard curves for 3 risk factors of de novo sIA formation: A, smoking history, B, family history of IA disease, and C, age at first sIA diagnosis. Years of follow-up represent the time interval between the initial diagnosis and subsequent diagnosis of de novo sIA at follow-up angiography, or the last follow-up angiography available. FIGURE 3. View largeDownload slide Kaplan–Meier cumulative hazard curves for 3 risk factors of de novo sIA formation: A, smoking history, B, family history of IA disease, and C, age at first sIA diagnosis. Years of follow-up represent the time interval between the initial diagnosis and subsequent diagnosis of de novo sIA at follow-up angiography, or the last follow-up angiography available. Risk Factors for sIA Rupture Differ in Young and Older sIA Patients Of the known risk factors for aSAH, smoking was more frequent among young SAH patients than in older ones, whereas hypertension was less common (Table 2.). PHASES scores (age omitted) of patients that had suffered aSAH at the age of 29 to 20 yr or <20 yr were significantly lower than those of patients who had suffered aSAH at ≥40 yr (P < .001). PHASES scores of aSAH patients of 30 to 39 yr of age did not significantly differ from older patients. Gender distribution of aSAH patients diagnosed at 30 to 39 yr was male dominated (1.7:1), whereas unruptured sIA patients diagnosed at 30 to 39 yr had equal gender distribution (1:1). In this age group (30 to 39 yr), anterior communicating (ACom) sIAs counted for 36% of ruptured sIAs, but they were less frequent in females, which may in part explain the male-dominated gender distribution (Table, Supplemental Digital Content 2). The ACom location was clearly underrepresented in unruptured sIAs in patients younger than 40 yr compared to aSAH patients of the same age, suggesting a high rupture tendency in sIAs at this location. There was no such mismatch with the frequency of middle cerebral artery bifurcation sIAs (Table, Supplemental Digital Content 2). Acom and middle cerebral artery bifurcations were the most frequent sites of ruptured sIAs in young adults and adults, whereas in adolescents most ruptured sIAs (44%) were located at the internal carotid artery bifurcation (Table, Supplemental Digital Content 2). The median size of ruptured sIAs was 6.0 mm in adolescents, and 7.0 and 8.0 mm in young adults and adults, respectively. In adolescents, 57% of the ruptured sIAs were smaller than 7 mm, and 44% and 33% in young adults and adults, respectively (Table, Supplemental Digital Content 2). Of the ruptured sIAs, 95% had an irregular surface in angiography in the adolescent population, and 94% and 90% in young adults and adults, respectively. DISCUSSION Population-based series describing the characteristics of young sIA patients are very few (Table 1). We report the phenotype of sIA patients and sIAs diagnosed before the age of 40 yr in a large population-based cohort collected during 34 yr in Eastern Finland. Key Results Risk Factors for sIA Formation Differ in Young and Older sIA Patients In our population-based cohort, overall risk of de novo formation in young sIA patients was 4%, similar to the only prior population-based study of young sIA patients.14 In Cox regression, smoking, family history, and young age were significant risk factors for de novo sIA formation in young patients. Hypertension did not seem to be a significant risk factor in our cohort of young sIA patients, unlike in prospective follow-up cohort studies of older patients both in our population-based registry15,16 and in other cohorts,17 in which both hypertension and smoking are clearly risk factors for sIA formation. Smoking, however, was very frequent in our cohort and was a risk factor for sIA formation. Family history was clearly more common in young sIA patients than among sIA patients overall, with the exception of adolescent sIA patients. Although this observation might have been caused by active MRA screening of family members of sIA patients, it nevertheless suggests that family background may be a more important risk factor in young sIA patients than in older ones. In young patients, formation of multiple sIAs was associated with family history, supporting the interpretation that family history predisposes to sIA formation. Multiplicity of sIAs or family history did not associate with rupture, suggesting that the possible inherent wall weakness predisposing to sIA formation is separate from the sIA wall degeneration predisposing to rupture. Risk Factors for sIA Rupture Differ in Young and Older sIA Patients Patients who experienced aneurysmal SAH at a very young age (<30 yr) had lower PHASES scores than older aneurysmal SAH patients, suggesting that either at least a subpopulation of sIAs in young patients may be more prone to rupture, or risk factors not included in PHASES are particularly important in young sIA patients. More than 50% of ruptured sIAs in adolescent patients (≤19 yr) were small (<7 mm), supporting the interpretation that a subpopulation of sIAs in young patients is more prone to rupture than sIAs in general. The observation that irregular shape, which associates with unstable sIA wall and rupture,11,18 was most frequent in the youngest patients with ruptured sIAs and decreased with increasing age suggests that unstable sIA wall is associated with young age at disease onset. This hypothesis is supported by the unusually high rate of ruptured ICA bifurcation sIAs in adolescent patients compared to the relatively low rupture rate of ICA bifurcation sIAs in older patients, as demonstrated in our recent study on the characteristics of ruptured aneurysms in our population-based registry.18 Interpretation In our cohort, patients who experienced aneurysmal SAHs at a young age (<40 yr) often had small sIAs and low cumulative risk factor burden (PHASES), apart from smoking. This, together with the long life expectancy of young patients, justifies a more active approach to their treatment and follow-up. New de novo sIAs were found even after 20 yr of follow-up, demonstrating the need for long, if not lifelong, follow-up for patients diagnosed with sIAs at an age younger than 40 yr. In our cohort family history was a risk factor for de novo sIA formation, suggesting that especially young sIA patients with family history should have long-term follow-up, with possibly shorter intervals than otherwise indicated, since sIAs in young patients seem to be more prone to rupture overall (lower PHASES and smaller size). Smoking was the other significant risk factor for de novo sIA formation, underlining the importance of patient education and antismoking measures in young patients. Limitations In our current cohort, the timing of follow-up angiographies was determined on an individual basis instead of a rigid follow-up protocol. This may have influenced our results, especially the estimate of when de novo sIAs are likely to be detected in young patients. However, this issue also demonstrates the need for a predetermined follow-up protocol for young sIA patients. Generalizability Finnish ethnicity, a suspected risk factor for aneurysmal SAH,4 is a factor to be considered when applying our results to other populations. It may well be that the age of onset of aneurysm formation, rupture, or de novo aneurysm formation is different in different populations. Nevertheless, our study in the Finnish population demonstrates significant differences in patients with disease onset at a young age compared to sIA patients overall. CONCLUSION Smoking and family history are risk factors for de novo sIA formation and aSAH at young age. Young aSAH patients had lower PHASES scores and often rupture from a small sIA, suggesting more aggressive management. Lifelong follow-up is indicated because of late occurring de novo sIA formation. Disclosures This study was supported by Petri Honkanen Foundation, Maire Taponen Foundation, Yrjö Jansson Foundation, Päivikki and Sakari Sohlberg Foundation, Emil Aaltonen Foundation, North Savo Regional Fund of Finnish Cultural Foundation, University of Eastern Finland, Kuopio University Hospital, the Finnish Medical Foundation and Academy of Finland. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol . 2011; 10( 7): 626- 636. Google Scholar CrossRef Search ADS PubMed  2. Karamanakos PN, von Und Zu Fraunberg M, Bendel S et al.   Risk factors for three phases of 12-month mortality in 1657 patients from a defined population after acute aneurysmal subarachnoid hemorrhage. World Neurosurg . 2012; 78( 6): 631- 639. Google Scholar CrossRef Search ADS PubMed  3. Korja M, Lehto H, Juvela S. Lifelong rupture risk of intracranial aneurysms depends on risk factors: a prospective Finnish cohort study. Stroke . 2014; 45( 10): 1958- 1963. Google Scholar CrossRef Search ADS PubMed  4. Greving JP, Wermer MJH, Brown RD Jr et al.   Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol . 2014; 13( 1): 59- 66. Google Scholar CrossRef Search ADS PubMed  5. Broderick JP, Brown RD, Sauerbeck L et al.   Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms. Stroke . 2009; 40( 6): 1952- 1957. Google Scholar CrossRef Search ADS PubMed  6. Ronkainen A, Hernesniemi J, Puranen M et al.   Familial intracranial aneurysms. Lancet . 1997; 349( 9049): 380- 384. Google Scholar CrossRef Search ADS PubMed  7. Gaál EI, Salo P, Kristiansson K et al.   Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure. PLoS Genet . 2012; 8( 3): e1002563. doi: 1.1371/journal.pgen.1002563 Google Scholar CrossRef Search ADS PubMed  8. Feigin VL, Rinkel GJE, Lawes CMM et al.   Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke . 2005; 36( 12): 2773- 2780. Google Scholar CrossRef Search ADS PubMed  9. Weir B, Disney L, Karrison T. Sizes of ruptured and unruptured aneurysms in relation to their sites and the ages of patients. J. Neurosurg . 2002; 96( 1): 64- 70. Google Scholar CrossRef Search ADS PubMed  10. Bijlenga P, Ebeling C, Jaegersberg M et al.   Risk of rupture of small anterior communicating artery aneurysms is similar to posterior circulation aneurysms. Stroke . 2013; 44( 11): 3018- 3026. Google Scholar CrossRef Search ADS PubMed  11. Morita A, Kirino T, Hashi K et al.  ; UCAS Japan Investigators. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med . 2012; 366( 26): 2474- 2482. Google Scholar CrossRef Search ADS PubMed  12. Wiebers DO, Whisnant JP, Huston J 3rd et al.  ; International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet . 2003; 362( 9378): 103- 110 CrossRef Search ADS PubMed  13. Huttunen T, von und zu Fraunberg M, Frösen J et al.   Saccular intracranial aneurysm disease: distribution of site, size, and age suggests different etiologies for aneurysm formation and rupture in 316 familial and 1454 sporadic eastern Finnish patients. Neurosurgery . 2010; 66( 4): 631- 638. Google Scholar CrossRef Search ADS PubMed  14. Koroknay-Pál P, Lehto H, Niemelä M, Kivisaari R, Hernesniemi J. Long-term outcome of 114 children with cerebral aneurysms. J. Neurosurg Pediatr . 2012; 9( 6): 636- 645. Google Scholar CrossRef Search ADS PubMed  15. Lindgren AE, Kurki MI, Riihinen A et al.   Hypertension predisposes to the formation of saccular intracranial aneurysms in 467 unruptured and 1053 ruptured patients in Eastern Finland. Ann Med.  2014; 46( 3): 169- 176. Google Scholar CrossRef Search ADS PubMed  16. Lindgren AE, Räisänen S, Björkman J et al.   De Novo Aneurysm Formation in Carriers of Saccular Intracranial Aneurysm Disease in Eastern Finland. Stroke . 2016; 47( 5): 1213- 1218. Google Scholar CrossRef Search ADS PubMed  17. Wermer MJH, van der Schaaf IC, Velthuis BK, Algra A, Buskens E, Rinkel GJE. Follow-up screening after subarachnoid haemorrhage: frequency and determinants of new aneurysms and enlargement of existing aneurysms. Brain . 2005; 128( 10): 2421- 2429. Google Scholar CrossRef Search ADS PubMed  18. Lindgren AE, Koivisto T, Björkman J et al.   Irregular Shape of Intracranial Aneurysm Indicates Rupture Risk Irrespective of Size in a Population-Based Cohort. Stroke . 2016 47( 5): 1219- 26. Google Scholar CrossRef Search ADS PubMed  19. Agid R, Souza MPS, Reintamm G, Armstrong D, Dirks P, TerBrugge KG. The role of endovascular treatment for pediatric aneurysms. Childs Nerv Syst . 2005; 21( 12): 1030- 1036. Google Scholar CrossRef Search ADS PubMed  20. Lv X, Jiang C, Li Y, Yang X, Wu Z. Endovascular treatment for pediatric intracranial aneurysms. Neuroradiology . 2009; 51( 11): 749- 754. Google Scholar CrossRef Search ADS PubMed  21. Sharma BS, Sinha S, Mehta VS, Suri A, Gupta A, Mahapatra AK. Pediatric intracranial aneurysms-clinical characteristics and outcome of surgical treatment. Childs Nerv Syst . 2007; 23( 3): 327- 333. Google Scholar CrossRef Search ADS PubMed  22. Vaid VK, Kumar R, Kalra SK, Mahapatra AK, Jain VK. Pediatric intracranial aneurysms: an institutional experience. Pediatr Neurosurg . 2008; 44( 4): 296- 301. Google Scholar CrossRef Search ADS PubMed  23. Mehrotra A, Nair AP, Das KK, Srivastava A, Sahu RN, Kumar R. Clinical and radiological profiles and outcomes in pediatric patients with intracranial aneurysms. J Neurosurg Pediatr . 2012; 10( 4): 340- 346. Google Scholar CrossRef Search ADS PubMed  24. Garg K, Singh PK, Sharma BS et al.   Pediatric intracranial aneurysms—our experience and review of literature. Childs Nerv Syst . 2014; 30( 5): 873- 883. Google Scholar CrossRef Search ADS PubMed  25. Aryan HE, Giannotta SL, Fukushima T, Park MS, Ozgur BM, Levy ML. Aneurysms in children: review of 15 years experience. J Clin Neurosci . 2006; 13( 2): 188- 192. Google Scholar CrossRef Search ADS PubMed  26. Hetts SW, Narvid J, Sanai N et al.   Intracranial aneurysms in childhood: 27-year single-institution experience. AJNR . 2009; 30( 7): 1315- 1324. Google Scholar CrossRef Search ADS PubMed  27. Kakarla UK, Beres EJ, Ponce FA et al.   Microsurgical treatment of pediatric intracranial aneurysms: long-term angiographic and clinical outcomes. Neurosurgery . 2010; 67( 2): 237- 249 Google Scholar CrossRef Search ADS PubMed  28. Fulkerson DH, Voorhies JM, Payner TD et al.   Middle cerebral artery aneurysms in children: case series and review. J Neurosurg Pediatr . 2011; 8( 1): 79- 89. Google Scholar CrossRef Search ADS PubMed  29. Takemoto K, Tateshima S, Golshan A et al.   Endovascular treatment of pediatric intracranial aneurysms: a retrospective study of 35 aneurysms. J Neurointerv Surg . 2014; 6( 6): 432- 438 Google Scholar CrossRef Search ADS PubMed  30. Kalani MYS, Elhadi AM, Ramey W et al.   Revascularization and pediatric aneurysm surgery. J Neurosurg Pediatr . 2014; 13( 6): 641- 646 Google Scholar CrossRef Search ADS PubMed  Supplemental digital content is available for this article at www.neurosurgery-online.com. Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

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Copyright © 2017 by the Congress of Neurological Surgeons
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Abstract

Abstract BACKGROUND Formation and rupture of saccular intracranial aneurysms (sIAs) may have different pathobiologies in patients with younger age at first diagnosis of sIA disease. OBJECTIVE To study the phenotype of sIA disease and formation of new (de novo) sIAs in patients below 40 yr. METHODS A population-based cohort study was conducted in 613 young (<40 yr) sIA patients with first diagnosis between 1980 and 2014 and total angiographic follow-up of 3768 yr. RESULTS Of the 613 sIA patients <40 yr, 508 had aneurysmal subarachnoid hemorrhage (sIA-SAH) and 105 unruptured sIA(s) at first sIA diagnosis. Hypertension was 2 times less common among <40 than >40-yr-old patients (unruptured and ruptured). Smoking was very prevalent in <40-yr-old patients (33% in SAH, 68% unruptured). SAH patients <40 yr more often had family history of sIA, and lower PHASES scores (age omitted, P < .001). Ruptured sIAs were small (<7 mm) in 33% of 39 to 30 yr patients, in 44% of 29 to 20 yr patients, and 57% of <19 yr patients. Their shape was irregular in 90%, 94%, and 95%, respectively. Smoking history (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.2-7.0), family history for sIAs (HR 3.1, 95% CI 1.3-7.7), and age at presentation (HR .91 per year, 95% CI .85-.98) were risk factors for de novo sIA formation, diagnosed in 4% even after 20 yr (median 11.8 yr). CONCLUSION Smoking and family history are risk factors for sIA formation and aneurysmal SAH at young age. Young aneurysmal SAH patients had lower PHASES scores and often rupture from a small sIA, suggesting need for more aggressive management. Cerebrovascular, Intracranial aneurysm, Subarachnoid hemorrhage, Young age, Familial disease, Vascular diseases ABBREVIATIONS ABBREVIATIONS ACom anterior communicating aSAH aneurysmal subarachnoid hemorrhage CI confidence interval CT computed tomography HR hazard ratio MRI magnetic resonance imaging SAH subarachnoid hemorrhage sIAs saccular intracranial aneurysms Unruptured saccular intracranial aneurysm (sIA) is a relatively common disease (2%-3% prevalence).1 Asymptomatic unruptured sIAs are diagnosed increasingly frequently due to improved availability of magnetic resonance imaging (MRI) scans. Although sIAs may rupture causing devastating hemorrhage with mortality of 30% to 50%,2 most sIAs never rupture.3 The pathobiology of sIA formation and rupture need to be elucidated in order to focus follow-up efforts and therapy to those patients at risk of developing sIAs or at risk of sIA rupture. Formation and rupture of sIAs are multifactorial processes affected by genetic background (ethnicity, gender, family history)4-7 and multiple acquired risk factors (smoking, hypertension, stimulant abuse).8,4 Formation of sIAs occurs mostly at specific locations in the cerebral arteries, and location affects the risk of rupture.9,10 How the formation of sIAs in different locations is affected by patient-related risk factors is not well known. In addition to patient-related risk factors, aneurysm-related factors that reflect unstable wall and predict rupture (size and shape) are known11,12 and used to guide clinical decisions. Unruptured sIAs are mostly diagnosed at the fifth decade of life or later (>40 yr old),13 and are exceedingly rare in children and young adults.14 This suggests that sIAs form during lifetime due to the effect that exposure to risk factors has on the cerebral artery wall. Formation and rupture of sIAs may have different pathobiology in patients who develop disease manifestations at a young age compared to the middle-aged population. These patients may require different thresholds for follow-up or intervention than the middle-aged population. The phenotype of patients who develop sIA(s) at a young age is incompletely known, because modern clinical series that characterize these patients are few (Table 1). TABLE 1. Angiographically verified intracranial aneurysm cohorts of 25 or more young patients (0-20 yr) published since 2004* in English. Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  IA, intracranial aneurysm; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; IVH, intraventricular hemorrhage; ICA, internal carotid artery; ICA bif, internal carotid artery bifurcation; ACA, anterior cerebral artery; MCA, middle cerebral artery; VBA, vertebral and basilar arteries; n.d, no data *PubMed was searched for English articles from 2004 through November 2014 on cohorts of pediatric or adolescent patients carrying intracranial aneurysms with the following keywords: (aneurysm OR aneurysms OR aneurysmal) AND (intracranial OR “subarachnoid haemorrhage” OR SAH) AND (child OR children OR childhood OR pediatric OR adolescent). Inclusion criteria were angiographically verified intracranial aneurysm, minimum cohort size 25 cases and cohort collected after 1980. View Large TABLE 1. Angiographically verified intracranial aneurysm cohorts of 25 or more young patients (0-20 yr) published since 2004* in English. Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  Article  Study period Country  Patients males/ females  Familial IA disease  Mean age at diagnosis (range)  SAH ICH IVH n/N (%)  Patients with multiple aneurysms (2 or more)  Etiology of aneurysms  ICA ICA bif  MCA  ACA  VBA  Giant aneurysms  Saccular  Fusiform  Dissecting  Traumatic  Mycotic  A. Population-based series  Koroknay-Pal et al 201214  1937-2009 Finland  114 3:2  14/114 (12%)  14.5 (3 mos-18)  89/114 (78%)  13/114 (11%)  101/130 (78%)  13/130 (10%)  n.d.  10/130 (10%)  –  56/130 (43%) 36/130 (28%)  17/130 (13%)  43/130 (33%)  14/130 (11%)  16/130 (12%)  B. Institutional series (from 80’s onwards)  Agid et al 200519  1992-2004 Canada  33 16/17  n.d.  1.2 (1 day-17)  9/33 (27%) 3/33 (9%)  3/33 (9%)  17/37 (46%)  12/37 (32%)  7/37 (19%)  5/37 (14%)  5/37 (14%)  15/37 (41%) 8/37 (22%)  5/37 (14%)  6/37 (16%)  11/37 (30%)  11/37 (30%)  Lv et al 200920  1998-2005 China  25 20/5  n.d.  11.4 (4-17)  11/25 (44%)  0/25 (0%)  7/25 (28%)  18/25 (72%)  –  –  –  1/25 (4%) 0/25 (0%)  5/25 (20%)  4/25 (16%)  15/25 (60%)  17/25 (68%)  Sharma et al 200721  1995-2005 India  55 38/17  n.d  13.3 (7 mos-18)  43/55 (78%) 12/55 (22%) 7/55 (13%)  9/55 (16%)  63/67 (94%)  4/67 (6%)  –  1/67 (1%)  2/67 (3%)  37/67 (55%) 21/67 (31%)  12/67 (18%)  10/67 (15%)  8/67 (12%)  13/67 (19%)  Vaid et al 200822  1991-2007 India  27 14/13  n.d.  13.2 (5-18)  23/27 (85%)  3/27 (11%)  33/33 (100%)  –  –  –  3/33 (9%)  10/33 (30%) 6/33 (18%)  11/33 (33%)  4/33 (12%)  8/33 (24%)  7/33 (21%)  Mehrotra et al 201223  1991-2011 India  57 26/31  n.d.  12.7 (4-18)  50/57 (88%) 7/57 (12%)  11/57 (19%)  n.d.  2/73 (3%)  n.d.  6/73 (8%)  2/73 (3%)  25/73 (34%) 18/73 (25%)  18/73 (25%)  9/73 (12%)  21/73 (29%)  14/73 (19%)  Garg et al 201424  2001-2013 India  62 45/17  n.d.  13.5 (42 days-18)  36/62 (58%) 8/62 (13%) 8/62 (13%)  8/62 (13%)  n.d.  n.d.  10/62 (16%)  2/62 (3%)  2/62 (3%)  38/74 (51%) 17/74 (23%)  9/74 (12%)  15/74 (20%)  13/74 (18%)  11/74 (15%)  Aryan et al 200625  1989-2004 USA  50 n.d.  n.d  1.3 (5 mos-19)  35/54 (65%)  4/50 (8%)  n.d.  n.d.  n.d.  11/54 (20%)  2/54 (4%)  16/54 (30%)  10/54 (19%)  15/54 (28%)  13/54 (24%)  12/54 (22%)  Hetts et al 200926  1981-2008 USA  77 37/40  n.d.  12 (3 mos-18)  25/77 (32%)  12/77 (16%)  47/105 (45%)  31/105 (30%)  –  15/105 (14%)  12/105 (11%)  54/105 (51%)  18/105 (17%)  11/105 (10%)  22/105 (21%)  11/105 (10%)  Kalarla et al 201027  1989-2005 USA  48 28/20  n.d.  12.3 (8 mos-18)  8/48 (17%) 3/48 (6%)  15/48 (31%)  32/72 (45%)  28/72 (39%)  –  7/72 (10%)  5/72 (7%)  31/72 (43%)  14/72 (18%)  9/72 (13%)  17/72 (24%)  16/72 (22%)  Fulkerson et al 201128  1990-2010 USA  28 12/16  1/28 (4%)  14 (5-18)  19/28 (68%) 2/28 (7%) 1/28 (4%)  1/28 (4%)  14/30 (47%)  6/30 (20%)  5/30 (17%)  5/30 (17%)  –  9/30 (30%)  7/30 (23%)  7/30 (23%)  6/30 (20%)  n.d.  Takemoto et al 201329  1995-2012 USA  31 20/11  n.d.  14.4 (4 mos-20)  15/31 (48%)  4/31 (13%)  15/35 (43%)  17/35 (49%)  –  1/35 (3%)  2/35 (6%)  13/35 (37%) 1/35 (3%)  5/35 (14%)  7/35 (20%)  10/35 (29%)  11/35 (31%)  Kalani et al 201430  1989-2013 USA  27 19/8  n.d.  11.5 (1-17)  5/27 (19%)  n.d.  10/29 (34%)  19/29 (66%)  n.d.  n.d.  n.d.  7/29 (24%)  14/29 (48%)  2/29 (7%)  6/29 (21%)  14/29 (48%)  IA, intracranial aneurysm; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; IVH, intraventricular hemorrhage; ICA, internal carotid artery; ICA bif, internal carotid artery bifurcation; ACA, anterior cerebral artery; MCA, middle cerebral artery; VBA, vertebral and basilar arteries; n.d, no data *PubMed was searched for English articles from 2004 through November 2014 on cohorts of pediatric or adolescent patients carrying intracranial aneurysms with the following keywords: (aneurysm OR aneurysms OR aneurysmal) AND (intracranial OR “subarachnoid haemorrhage” OR SAH) AND (child OR children OR childhood OR pediatric OR adolescent). Inclusion criteria were angiographically verified intracranial aneurysm, minimum cohort size 25 cases and cohort collected after 1980. View Large We characterized the phenotype of Eastern Finnish patients who developed intracranial aneurysm at a young age, and investigated the hypothesis that the risk factors and phenotype of those patients differ from that of other sIA patients. In addition, we studied the significance of known patient-related and aneurysm-related risk factors for rupture in young sIA patients. METHODS We conducted a population-based study of the characteristics of patients diagnosed with sIAs before the age of 40 yr. This study was approved by the Ethics Committee of the Kuopio University Hospital (KUH) and the Ministry of Social Affairs and Health of Finland. Catchment Population of Kuopio University Hospital During the study period from 1980 to 2014, Neurosurgery of Kuopio University Hospital was the only neurosurgical service provider for the KUH catchment area in Eastern Finland.13,15 The population decreased from 863 726 in 1980 to 841 713 in 2014. Cases of subarachnoid hemorrhage (SAH) or Unruptured IAs in the Kuopio University Hospital Area All patients with acute SAH have been acutely admitted to the KUH for diagnostic angiography, if not moribund or very aged. Similarly, patients with unruptured sIAs in computed tomography (CT) or MRI scans in other KUH catchment area hospitals were admitted to KUH for diagnostic angiography, unless excluded due to advanced age or serious preexisting medical conditions. Patients with angiographically confirmed sIAs were entered into Kuopio Intracranial Aneurysm Database (http://kuopioneurosurgery.fi/database/) after informed consent (in Finnish) was obtained.15 The database is run by a full-time nurse, who interviews new cases and codes variables with detailed information, including family history. The criterion for sIA family is at least 2 affected first-degree relatives. Clinical data from follow-up angiographies (digital subtraction angiography, magnetic resonance angiography or CT angiography) and outpatient clinical visits is included in the database.13,15 Basic Study Population The basic study population included 4082 sIA patients, and their stratification is shown in Figure 1. The inclusion and exclusion criteria were as follows. Citizen of Finland and resident of the KUH catchment area at the time of first diagnosis of sIA disease between January 1, 1980 and October 28, 2014. Admission alive to the KUH and verification of sIA(s) by angiography. Fusiform aneurysms as well as saccular aneurysms with mycotic or traumatic etiology were excluded. FIGURE 1. View largeDownload slide Flowchart showing the number of patients fulfilling inclusion criteria and their subsequent stratification into subgroups. FIGURE 1. View largeDownload slide Flowchart showing the number of patients fulfilling inclusion criteria and their subsequent stratification into subgroups. Statistical Analysis The variables are presented in Table 2. Discrete variables were expressed in proportions and continuous variables in medians and ranges. The 4 age groups (0-19; 20-29; 30-39; ≥40 yr) were compared using the Chi-square test, Fisher exact test or Kruskal–Wallis test when appropriate. Multivariable Cox regression analysis was used to analyze de novo sIA formation with the following variables: sex, age at presentation of sIA disease, smoking history, hypertension, family history for sIAs. The validity of proportional hazards assumption was verified using Schönfeld's residuals. The date of the imaging study confirming the first de novo sIA formation was used in the time-to-event variable calculation in Cox regression (Table, Supplemental Digital Content 1) and Kaplan–Meier estimate. Kaplan–Meier curves were plotted to visualize the effect of different risk factors on de novo sIA formation. P-values less than .05 were considered significant. SPSS statistical software (SPSS Inc, IBM, Armonk, New York) was used. TABLE 2. Characteristics of 4082 sIA Patients   Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084    Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084  sIA, saccular intracranial aneurysm; sIA-SAH, subarachnoid hemorrhage from ruptured sIA; APCKD, autosomal polycystic kidney disease. *Statistically significant P-value. View Large TABLE 2. Characteristics of 4082 sIA Patients   Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084    Patients with unruptured sIA at first diagnosis  Patients with first sIA-SAH on admission    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr    0 to 19 yr  20 to 29 yr  30 to 39 yr  ≥40 yr      n = 6  n = 18  n = 81  n = 1150    n = 22  n = 114  n = 372  n = 2319      N (%)  N (%)  N (%)  N (%)  P-value  N (%)  N (%)  N (%)  N (%)  P-value  Family History for sIAs  1 (17%)  7 (39%)  38 (47%)  238 (21%)  .000*  5 (23%)  34 (30%)  71 (19%)  302 (13%)  .000*  APCKD  –  –  2 (3%)  16 (1%)  .687  –  3 (3%)  8 (2%)  16 (1%)  .005*  Patients with multiple sIAs  3/6 (50%)  4/18 (22%)  27/81 (33%)  313/1150 (27%)  .256  5/22 (23%)  15/114 (13%)  78/372 (21%)  503/2319 (22%)  .255  Gender (females)  4 (67%)  11 (61%)  41 (51%)  662 (58%)  .411  11 (50%)  53 (47%)  140 (38%)  1333 (58%)  .000*  Male to Female Ratio  1:2  1:1.6  1:1  1:1.4    1:1  1.2:1  1.7:1  1:1.4    History of smoking          .000*          .007*   Current  2 (33%)  10 (56%)  50 (62%)  323 (28%)    4 (18)  38 (33%)  102 (27%)  495 (21%)     Former    1 (6%)  8 (10%)  123 (11%)    –  6 (5%)  17 (5%)  129 (6%)    Hypertension  –  –  17 (21%)  481 (43%)  .000*  1 (5%)  8 (7%)  58 (16%)  791 (35%)  .000*  De novo sIAs  1 (17%)  –  5 (6%)  9 (1%)  .001*  3 (14%)  5 (4%)  8 (2%)  11 (1%)  .000*   Multiple De novo sIAs  –  –  2 (40%)  1 (11%)  .525  1 (33%)  3 (60%)  3 (38%)  –  .022   Family history for sIAs  –  –  4 (80%)  2 (22%)  .136  1 (33%)  3 (60%)  5 (63%)  2 (18%)  .109   History of smoking  –  –  4 (80%)  5 (56%)  1.000  2 (67%)  5 (100%)  2 (25%)  6 (55%)  1.000   Hypertension  –  –  1 (20%)  4 (50%)  .301  –  1 (20%)  1 (13%)  5 (46%)  .084  sIA, saccular intracranial aneurysm; sIA-SAH, subarachnoid hemorrhage from ruptured sIA; APCKD, autosomal polycystic kidney disease. *Statistically significant P-value. View Large RESULTS Main Results Between 1980 and October 2014, 508 patients were diagnosed with sIA-SAH and 105 patients with an unruptured sIA at an age younger than 40 yr. The 613 sIA patients were divided into age groups below 20 yr (n = 28); 20 to 29 yr (n = 132); and 30 to 39 yr (n = 453; Table 2, Tables, Supplemental Digital Content 2 and 3). sIA-SAH was very rare in patients younger than 20 yr, but increased in frequency between 20 and 30 yr, and more so between 30 and 40 yr (Figure 2). Unruptured sIAs showed a similar trend (Figure 2). We identified a total of 299 unruptured sIAs in patients younger than 40 yr: 145 unruptured sIAs in context of SAH from another sIA; 109 as incidental findings; and 45 by screening sIA families. FIGURE 2. View largeDownload slide Number of patients diagnosed with aSAH or unruptured sIA at different ages is shown separately for sporadic sIAs A and for patients with family history B. In order to visualize how sIA cases accumulate with increasing age in sporadic sIA patients C and in patients with family history D, we plotted the cumulative percentage of diagnosed sIAs against age at diagnosis. These graphs demonstrate that although the number of diagnosed sIAs increases after the age of 30, a significant portion of sIAs is diagnosed between the age of 20 to 30 yr. This observation supports the practice of starting MRA screening at the age of 20 to 30 yr when screening for sIAs is indicated overall. FIGURE 2. View largeDownload slide Number of patients diagnosed with aSAH or unruptured sIA at different ages is shown separately for sporadic sIAs A and for patients with family history B. In order to visualize how sIA cases accumulate with increasing age in sporadic sIA patients C and in patients with family history D, we plotted the cumulative percentage of diagnosed sIAs against age at diagnosis. These graphs demonstrate that although the number of diagnosed sIAs increases after the age of 30, a significant portion of sIAs is diagnosed between the age of 20 to 30 yr. This observation supports the practice of starting MRA screening at the age of 20 to 30 yr when screening for sIAs is indicated overall. Median angiographic follow-up time after the primary sIA diagnosis was 3.47 (range 0-32.8) yr and total follow-up time 3768 yr. Familial and Multiple sIAs Young adults (20-29 yr) and adults (30-39 yr) with unruptured sIAs or aneurysmal SAH (aSAH) at diagnosis had more often positive family history unrelated to ADPKD than patients >40 (Table 2), suggesting that family history is more important for sIA formation in young patients than after 40 yr of age. Patients who suffered aSAH at a young age did not have more often multiple aneurysms than other aSAH patients (Table 2). Interestingly, patients diagnosed with unruptured sIAs at a young age had more often multiple sIAs than young patients presenting with hemorrhage (32% vs 19%). Of those patients who developed multiple sIAs after being diagnosed with first sIA at an age younger than 40 yr, 32% had positive family history. De Novo sIA Formation in Young sIA Patients De novo sIAs were discovered in 4% (22/613) of the studied young sIA patients. Most (13/22) of those patients with de novo sIA formation were 30 to 39 yr of age at diagnosis of first sIA. Of adolescent (≤19 yr) sIA patients, 14% (4/28) had developed denovo sIAs during follow-up, whereas 4% (5/132) of the young adult sIA patients and 3% (13/453) of adult sIA patients had developed de novo sIAs. Median time to de novo sIA discovery was 11.8 yr after the primary sIA diagnosis. The selection of patients into long-term follow-up was based on an individual assessment. Of the patients alive at 12 mo after initial sIA diagnosis, 67% (n = 18) of 0 to 19 yr, 53% (n = 70) of 20 to 29 yr, 48% (n = 191) of 30 to 39 yr, and 38% (n = 1130) of ≥40 yr had undergone angiographic follow-up ≥5 yr. None of the de novo sIAs were discovered after 3 yr of follow-up. Of the de novo sIAs detected, 9% had been found after 5 yr of follow-up, 27% after 10 yr of follow-up, 59% after 15 yr of follow-up, and 82% after 20 yr of follow-up. Interestingly, 18% of the de novo sIAs were found more than 20 yr from initial diagnosis. Risk Factors for sIA Formation Differ in Young and Older sIA Patients Family history for sIA was clearly more common among patients diagnosed with unruptured sIAs at young age than in older (>40 yr) unruptured sIA patients (Table 2). Smoking was very common among young patients diagnosed with unruptured sIAs (68%), more so than among older unruptured sIA patients (Table 2). Diagnosed hypertension was, however, significantly less common among young unruptured sIA patients than among older ones (Table 2). In univariate analysis (Fisher’s exact test), family history (13/22) associated with de novo sIA formation in young sIA patients (P = .001). Smoking history (13/22) showed a trend towards association with de novo sIA formation (P = .072), but was not a significant factor. Interestingly hypertension (3/22) was not associated with denovo sIA formation in this series (P = 1.000). Hypertension was 2 times less common in patients younger than 40 yr at diagnosis than among older patients (Table 2). In Cox regression analysis including sex, age at presentation of sIA disease, family history, hypertension, and known smoking history, family history (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.3-7.7), smoking history (HR 2.8, 95% CI 1.2-7.0), and age at presentation (HR .91 per year, 95% CI .85-.98) were independent significant risk factors for denovo sIA formation (Table, Supplemental Digital Content 1, Figure 3.). FIGURE 3. View largeDownload slide Kaplan–Meier cumulative hazard curves for 3 risk factors of de novo sIA formation: A, smoking history, B, family history of IA disease, and C, age at first sIA diagnosis. Years of follow-up represent the time interval between the initial diagnosis and subsequent diagnosis of de novo sIA at follow-up angiography, or the last follow-up angiography available. FIGURE 3. View largeDownload slide Kaplan–Meier cumulative hazard curves for 3 risk factors of de novo sIA formation: A, smoking history, B, family history of IA disease, and C, age at first sIA diagnosis. Years of follow-up represent the time interval between the initial diagnosis and subsequent diagnosis of de novo sIA at follow-up angiography, or the last follow-up angiography available. Risk Factors for sIA Rupture Differ in Young and Older sIA Patients Of the known risk factors for aSAH, smoking was more frequent among young SAH patients than in older ones, whereas hypertension was less common (Table 2.). PHASES scores (age omitted) of patients that had suffered aSAH at the age of 29 to 20 yr or <20 yr were significantly lower than those of patients who had suffered aSAH at ≥40 yr (P < .001). PHASES scores of aSAH patients of 30 to 39 yr of age did not significantly differ from older patients. Gender distribution of aSAH patients diagnosed at 30 to 39 yr was male dominated (1.7:1), whereas unruptured sIA patients diagnosed at 30 to 39 yr had equal gender distribution (1:1). In this age group (30 to 39 yr), anterior communicating (ACom) sIAs counted for 36% of ruptured sIAs, but they were less frequent in females, which may in part explain the male-dominated gender distribution (Table, Supplemental Digital Content 2). The ACom location was clearly underrepresented in unruptured sIAs in patients younger than 40 yr compared to aSAH patients of the same age, suggesting a high rupture tendency in sIAs at this location. There was no such mismatch with the frequency of middle cerebral artery bifurcation sIAs (Table, Supplemental Digital Content 2). Acom and middle cerebral artery bifurcations were the most frequent sites of ruptured sIAs in young adults and adults, whereas in adolescents most ruptured sIAs (44%) were located at the internal carotid artery bifurcation (Table, Supplemental Digital Content 2). The median size of ruptured sIAs was 6.0 mm in adolescents, and 7.0 and 8.0 mm in young adults and adults, respectively. In adolescents, 57% of the ruptured sIAs were smaller than 7 mm, and 44% and 33% in young adults and adults, respectively (Table, Supplemental Digital Content 2). Of the ruptured sIAs, 95% had an irregular surface in angiography in the adolescent population, and 94% and 90% in young adults and adults, respectively. DISCUSSION Population-based series describing the characteristics of young sIA patients are very few (Table 1). We report the phenotype of sIA patients and sIAs diagnosed before the age of 40 yr in a large population-based cohort collected during 34 yr in Eastern Finland. Key Results Risk Factors for sIA Formation Differ in Young and Older sIA Patients In our population-based cohort, overall risk of de novo formation in young sIA patients was 4%, similar to the only prior population-based study of young sIA patients.14 In Cox regression, smoking, family history, and young age were significant risk factors for de novo sIA formation in young patients. Hypertension did not seem to be a significant risk factor in our cohort of young sIA patients, unlike in prospective follow-up cohort studies of older patients both in our population-based registry15,16 and in other cohorts,17 in which both hypertension and smoking are clearly risk factors for sIA formation. Smoking, however, was very frequent in our cohort and was a risk factor for sIA formation. Family history was clearly more common in young sIA patients than among sIA patients overall, with the exception of adolescent sIA patients. Although this observation might have been caused by active MRA screening of family members of sIA patients, it nevertheless suggests that family background may be a more important risk factor in young sIA patients than in older ones. In young patients, formation of multiple sIAs was associated with family history, supporting the interpretation that family history predisposes to sIA formation. Multiplicity of sIAs or family history did not associate with rupture, suggesting that the possible inherent wall weakness predisposing to sIA formation is separate from the sIA wall degeneration predisposing to rupture. Risk Factors for sIA Rupture Differ in Young and Older sIA Patients Patients who experienced aneurysmal SAH at a very young age (<30 yr) had lower PHASES scores than older aneurysmal SAH patients, suggesting that either at least a subpopulation of sIAs in young patients may be more prone to rupture, or risk factors not included in PHASES are particularly important in young sIA patients. More than 50% of ruptured sIAs in adolescent patients (≤19 yr) were small (<7 mm), supporting the interpretation that a subpopulation of sIAs in young patients is more prone to rupture than sIAs in general. The observation that irregular shape, which associates with unstable sIA wall and rupture,11,18 was most frequent in the youngest patients with ruptured sIAs and decreased with increasing age suggests that unstable sIA wall is associated with young age at disease onset. This hypothesis is supported by the unusually high rate of ruptured ICA bifurcation sIAs in adolescent patients compared to the relatively low rupture rate of ICA bifurcation sIAs in older patients, as demonstrated in our recent study on the characteristics of ruptured aneurysms in our population-based registry.18 Interpretation In our cohort, patients who experienced aneurysmal SAHs at a young age (<40 yr) often had small sIAs and low cumulative risk factor burden (PHASES), apart from smoking. This, together with the long life expectancy of young patients, justifies a more active approach to their treatment and follow-up. New de novo sIAs were found even after 20 yr of follow-up, demonstrating the need for long, if not lifelong, follow-up for patients diagnosed with sIAs at an age younger than 40 yr. In our cohort family history was a risk factor for de novo sIA formation, suggesting that especially young sIA patients with family history should have long-term follow-up, with possibly shorter intervals than otherwise indicated, since sIAs in young patients seem to be more prone to rupture overall (lower PHASES and smaller size). Smoking was the other significant risk factor for de novo sIA formation, underlining the importance of patient education and antismoking measures in young patients. Limitations In our current cohort, the timing of follow-up angiographies was determined on an individual basis instead of a rigid follow-up protocol. This may have influenced our results, especially the estimate of when de novo sIAs are likely to be detected in young patients. However, this issue also demonstrates the need for a predetermined follow-up protocol for young sIA patients. Generalizability Finnish ethnicity, a suspected risk factor for aneurysmal SAH,4 is a factor to be considered when applying our results to other populations. It may well be that the age of onset of aneurysm formation, rupture, or de novo aneurysm formation is different in different populations. Nevertheless, our study in the Finnish population demonstrates significant differences in patients with disease onset at a young age compared to sIA patients overall. CONCLUSION Smoking and family history are risk factors for de novo sIA formation and aSAH at young age. Young aSAH patients had lower PHASES scores and often rupture from a small sIA, suggesting more aggressive management. Lifelong follow-up is indicated because of late occurring de novo sIA formation. Disclosures This study was supported by Petri Honkanen Foundation, Maire Taponen Foundation, Yrjö Jansson Foundation, Päivikki and Sakari Sohlberg Foundation, Emil Aaltonen Foundation, North Savo Regional Fund of Finnish Cultural Foundation, University of Eastern Finland, Kuopio University Hospital, the Finnish Medical Foundation and Academy of Finland. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol . 2011; 10( 7): 626- 636. Google Scholar CrossRef Search ADS PubMed  2. Karamanakos PN, von Und Zu Fraunberg M, Bendel S et al.   Risk factors for three phases of 12-month mortality in 1657 patients from a defined population after acute aneurysmal subarachnoid hemorrhage. 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Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: Jun 9, 2017

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