Embolization techniques of spontaneous direct carotid-cavernous fistulae: a single-center experience.

PURPOSE: Spontaneous direct carotid-cavernous fistula (CCF) are usually caused by a ruptured carotid cavernous aneurysm. We studied treatment of spontaneous direct CCFs in a single-center cohort of a high-volume tertiary referral center, reporting anatomical details, technical approaches of treatment, and outcomes. METHODS: Adult patients with a spontaneous direct CCF treated between 2010-2022 with follow-up MRI and/or DSA imaging available were retrospectively analyzed. We studied age, sex, clinical presentation, angiographic findings, treatment techniques, outcomes, and complications. RESULTS: Out of 80 patients with CCFs, twelve patients were treated for a non-traumatic direct CCF (15%) in 13 sessions. Median age was 65 years. Two patients had an underlying connective tissue disorder. In 10 cases, the direct CCF was caused by a ruptured cavernous carotid aneurysm. The direct CCFs were treated by endovascular transarterial embolization (10 cases), transvenous embolization (1 case), or surgery (1 case). Selective closure of the shunt was possible in 10 patients. Two patients were treated with parent vessel occlusion (PVO; one endovascular; one surgical, with bypass). Complications occurred in 2 / 12 patients (17%), with permanent morbidity in two patients (17%): trigeminal neuralgia after PVO and new infarct after surgical PVO and bypass. Selective closure of CCF resulted in no morbidity. There was no mortality in our series. CONCLUSION: Spontaneous direct CCFs are caused by rupture of a cavernous carotid aneurysm in most cases. Selective closure of the shunt, usually feasible transarterially with coils, achieves good results. Reconstructive endovascular techniques are preferred to minimize treatment related neurological complications.

Posterior condylar canal dural arteriovenous fistula: anatomical, symptomatological, and therapeutic considerations in comparison with hypoglossal canal dural arteriovenous fistula.

BACKGROUND: Posterior condylar canal dural arteriovenous fistulas (dAVFs) are extremely rare. METHODS: We report a case series and literature review of posterior condylar canal dAVFs and discuss similarities and differences between posterior condylar and hypoglossal canal dAVFs with respect to the related vascular anatomy, angioarchitecture of the fistula, presentation, and treatment. RESULTS: Four cases of posterior condylar canal dAVF were identified at our institutions and six cases were identified in the literature. Posterior condylar canal dAVFs were predominantly frequent in relatively young women. All patients presented with pulsatile tinnitus. There was no history of hemorrhage as there was no cortical venous reflux. This is different from hypoglossal canal dAVFs which can present with myelopathy or hemorrhage from cortical venous reflux. Transvenous embolization was safe and eliminated the symptoms. Palliative transarterial embolization can be an option to mitigate the symptoms, although there is a potential risk of cranial nerve palsy or lateral medullary stroke. CONCLUSIONS: Posterior condylar canal dAVFs are generally benign lesions. However, intolerable tinnitus may require intervention. Transvenous embolization is effective and safe.

Risk factor management matters more than pharmaceutical cyclooxygenase-2 inhibition in the prevention of de novo intracranial aneurysms.

BACKGROUND AND PURPOSE: Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2-PGE2-NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients. METHODS: The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses. RESULTS: De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level. CONCLUSION: For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition.

Use of antihypertensive medication and formation of de novo intracranial aneurysms.

BACKGROUND AND PURPOSE: Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation. METHODS: The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors. RESULTS: Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty-five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty-three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84-3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93-0.98) and smoking history (HR: 5.53, 95% CI: 2.77-11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59-9.29) for de novo sIA formation. CONCLUSIONS: Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.

Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage.

BACKGROUND: Persons with a positive family history of aneurysmal subarachnoid hemorrhage are at increased risk of aneurysmal subarachnoid hemorrhage. Preventive screening for intracranial aneurysms (IAs) in these persons is cost-effective but not very efficient. We aimed to develop and externally validate a model for predicting the probability of an IA at first screening in persons with a positive family history of aneurysmal subarachnoid hemorrhage. METHODS: For model development, we studied results from initial screening for IA in 660 prospectively collected persons with ≥2 affected first-degree relatives screened at the University Medical Center Utrecht. For validation, we studied results from 258 prospectively collected persons screened in the University Hospital of Nantes. We assessed potential predictors of IA presence in multivariable logistic regression analysis. Predictive performance was assessed with the C statistic and a calibration plot and corrected for overfitting. RESULTS: IA were present in 79 (12%) persons in the development cohort. Predictors were number of affected relatives, age, smoking, and hypertension (NASH). The NASH score had a C statistic of 0.68 (95% CI, 0.62-0.74) and showed good calibration in the development data. Predicted probabilities of an IA at first screening varied from 5% in persons aged 20 to 30 years with two affected relatives, without hypertension who never smoked, up to 36% in persons aged 60 to 70 years with ≥3 affected relatives, who have hypertension and smoke(d). In the external validation data IA were present in 67 (26%) persons, the model had a C statistic of 0.64 (95% CI, 0.57-0.71) and slightly underestimated IAs risk. CONCLUSIONS: For persons with ≥2 affected first-degree relatives, the NASH score improves current predictions and provides risk estimates for an IA at first screening between 5% and 36% based on 4 easily retrievable predictors. With the information such persons can now make a better informed decision about whether or not to undergo preventive screening.

Sex Difference and Rupture Rate of Intracranial Aneurysms: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. METHODS: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. RESULTS: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89-1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58-0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07-1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02-1.90). CONCLUSIONS: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women.

Finnish flow diverter study: 8 years of experience in the treatment of acutely ruptured intracranial aneurysms.

BACKGROUND: Flow diversion of acutely ruptured intracranial aneurysms (IAs) is controversial due to high treatment-related complication rates and a lack of supporting evidence. We present clinical and radiological results of the largest series to date. METHODS: This is a nationwide retrospective study of acutely ruptured IAs treated with flow diverters (FDs). The primary outcome was the modified Rankin Scale (mRS) score at the last available follow-up time. Secondary outcomes were treatment-related complications and the aneurysm occlusion rate. RESULTS: 110 patients (64 females; mean age 55.7 years; range 12-82 years) with acutely ruptured IAs were treated with FDs between 2012 and 2020 in five centers. 70 acutely ruptured IAs (64%) were located in anterior circulation, and 47 acutely ruptured IAs (43%) were blister-like. A favorable functional outcome (mRS 0-2) was seen in 73% of patients (74/102). Treatment-related complications were seen in 45% of patients (n=49). Rebleeding was observed in 3 patients (3%). The data from radiological follow-ups were available for 80% of patients (n=88), and complete occlusion was seen in 90% of aneurysms (79/88). The data from clinical follow-ups were available for 93% of patients (n=102). The overall mortality rate was 18% (18/102). CONCLUSIONS: FD treatment yields high occlusion for acutely ruptured IAs but is associated with a high risk of complications. Considering the high mortality rate of aneurysmal subarachnoid hemorrhage, the prevention of rebleeding is crucial. Thus, FD treatment may be justified as a last resort option.

Difference in Rupture Risk Between Familial and Sporadic Intracranial Aneurysms: An Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVES: We combined individual patient data (IPD) from prospective cohorts of patients with unruptured intracranial aneurysms (UIAs) to assess to what extent patients with familial UIA have a higher rupture risk than those with sporadic UIA. METHODS: For this IPD meta-analysis, we performed an Embase and PubMed search for studies published up to December 1, 2020. We included studies that (1) had a prospective study design; (2) included 50 or more patients with UIA; (3) studied the natural course of UIA and risk factors for aneurysm rupture including family history for aneurysmal subarachnoid haemorrhage and UIA; and (4) had aneurysm rupture as an outcome. Cohorts with available IPD were included. All studies included patients with newly diagnosed UIA visiting one of the study centers. The primary outcome was aneurysmal rupture. Patients with polycystic kidney disease and moyamoya disease were excluded. We compared rupture rates of familial vs sporadic UIA using a Cox proportional hazard regression model adjusted for PHASES score and smoking. We performed 2 analyses: (1) only studies defining first-degree relatives as parents, children, and siblings and (2) all studies, including those in which first-degree relatives are defined as only parents and children, but not siblings. RESULTS: We pooled IPD from 8 cohorts with a low and moderate risk of bias. First-degree relatives were defined as parents, siblings, and children in 6 cohorts (29% Dutch, 55% Finnish, 15% Japanese), totaling 2,297 patients (17% familial, 399 patients) with 3,089 UIAs and 7,301 person-years follow-up. Rupture occurred in 10 familial cases (rupture rate: 0.89%/person-year; 95% confidence interval [CI] 0.45-1.59) and 41 sporadic cases (0.66%/person-year; 95% CI 0.48-0.89); adjusted hazard ratio (HR) for familial cases 2.56 (95% CI 1.18-5.56). After adding the 2 cohorts excluding siblings as first-degree relatives, resulting in 9,511 patients, the adjusted HR was 1.44 (95% CI 0.86-2.40). DISCUSSION: The risk of rupture of UIA is 2.5 times higher, with a range from a 1.2 to 5 times higher risk, in familial than in sporadic UIA. When assessing the risk of rupture in UIA, family history should be taken into account.

Endovascular Intervention Versus Surgery in Ruptured Intracranial Aneurysms in Equipoise: A Systematic Review.

Background and Purpose- The benefits of endovascular intervention over surgery in the treatment of ruptured aneurysms of anterior circulation remains uncertain. Recently, published studies did not find superiority of endovascular intervention, challenging earlier evidence from a clinical trial. The earlier evidence also had a higher than average proportion of patients in good clinical status, leading to uncertainty about external validity of earlier trials. Methods- We performed a systematic review of studies after 2005 under a protocol published in the International Prospective Register of Systematic Reviews. Primary outcomes were posttreatment rebleeding and adverse events (procedural complications). Secondary outcomes were dependency at 3 to 6 and 12 months, delayed cerebral ischemia, and seizures. Results- Rebleeding was more frequent after endovascular intervention (Peto OR, 2.18 [95% CI, 1.29-3.70]; 3104 participants; 15 studies; I2=0%, Grading of Recommendations, Assessment, Development and Evaluation: very low certainty of evidence). Fewer adverse events were reported with the endovascular intervention (RR, 0.71 [95% CI, 0.53-0.95]; 1661 participants; 11 studies; I2=14%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence). Three to six months dependency (RR, 0.82 [95% CI, 0.73-0.93]; 4081 participants; 18 studies; I2=15%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence) and 12-month dependency (RR, 0.76 [95% CI, 0.66-0.86]; 1981 participants; 10 studies; I2=0%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence) were lower after endovascular intervention. Conclusions- This study found consistent results between recent studies and the earlier evidence, in that endovascular intervention results in lower chance of dependency compared with surgery for repair of ruptured anterior circulation aneurysms. A lower proportion of patients in good clinical status in this review supports the application of the earlier evidence. Registration- URL: https://www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42018090396.

Periodontitis and gingival bleeding associate with intracranial aneurysms and risk of aneurysmal subarachnoid hemorrhage.

Oral bacteria DNA has been found in intracranial aneurysms (IA) and a high prevalence of periodontitis was reported in IA patients. We investigated whether periodontitis associates with IA formation and aneurysmal subarachnoid hemorrhage (aSAH). First, we compared in a case-control setting the prevalence of periodontal disease in IA patients (42 unruptured IA, 34 ruptured IA) and in age- and gender-matched controls (n = 70) from the same geographical area (Health 2000 Survey, BRIF8901). Next, we investigated whether periodontitis at baseline associated with aSAH in a 13-year follow-up study of 5170 Health 2000 Survey participants. Follow-up data was obtained from national hospital discharge and cause of death registries. Univariate analysis, logistic regression, and Cox-regression were used. Periodontitis (≥ 4mm gingival pocket) and severe periodontitis (≥ 6mm gingival pocket) were found in 92% and 49% of IA patients respectively and associated with IAs (OR 5.3, 95%CI 1.1-25.9, p < 0.000 and OR 6.3, 95%CI 1.3-31.4, p < 0.001, respectively). Gingival bleeding had an even stronger association, especially if detected in 4-6 teeth sextants (OR 34.4, 95%CI 4.2-281.3). Severe periodontitis in ≥ 3 teeth or gingival bleeding in 4-6 teeth sextants at baseline increased the risk of aSAH during follow-up (HR 22.5, 95%CI 3.6-139.5, p = 0.001 and HR 8.3, 95%CI 1.5-46.1, p = 0.015, respectively). Association of periodontitis and gingival bleeding with risk of IA development and aSAH was independent of gender, smoking status, hypertension, or alcohol abuse. Periodontitis and gingival bleeding associate with increased risk for IA formation and eventual aSAH. Further epidemiological and mechanistic studies are indicated.

Procedural Clinical Complications, Case-Fatality Risks, and Risk Factors in Endovascular and Neurosurgical Treatment of Unruptured Intracranial Aneurysms: A Systematic Review and Meta-analysis.

Importance: The risk of procedural clinical complications and the case-fatality rate (CFR) from preventive treatment of unruptured intracranial aneurysms varies between studies and may depend on treatment modality and risk factors. Objective: To assess current procedural clinical 30-day complications and the CFR from endovascular treatment (EVT) and neurosurgical treatment (NST) of unruptured intracranial aneurysms and risk factors of clinical complications. Data Sources: We searched PubMed, Excerpta Medica Database, and the Cochrane Database for studies published between January 1, 2011, and January 1, 2017. Study Selection: Studies reporting on clinical complications, the CFR, and risk factors, including 50 patients or more undergoing EVT or NST for saccular unruptured intracranial aneurysms after January 1, 2000, were eligible. Data Extraction and Synthesis: Per treatment modality, we analyzed clinical complication risk and the CFR with mixed-effects logistic regression models for dichotomous data. For studies reporting data on complication risk factors, we obtained risk ratios (RRs) or odds ratios (ORs) with 95% CIs and pooled risk estimates with weighted random-effects models. Main Outcomes and Measures: Clinical complications within 30 days and the CFR. Results: We included 114 studies (106 433 patients with 108 263 aneurysms). For EVT (74 studies), the pooled clinical complication risk was 4.96% (95% CI, 4.00%-6.12%), and the CFR was 0.30% (95% CI, 0.20%-0.40%). Factors associated with complications from EVT were female sex (pooled OR, 1.06 [95% CI, 1.01-1.11]), diabetes (OR, 1.81 [95% CI, 1.05-3.13]), hyperlipidemia (OR, 1.76 [95% CI, 1.3-2.37]), cardiac comorbidity (OR, 2.27 [95% CI, 1.53-3.37]), wide aneurysm neck (>4 mm or dome-to-neck ratio >1.5; OR, 1.71 [95% CI, 1.38-2.11]), posterior circulation aneurysm (OR, 1.42 [95% CI, 1.15-1.74]), stent-assisted coiling (OR, 1.82 [95% CI, 1.16-2.85]), and stenting (OR, 3.43 [95% CI, 1.45-8.09]). For NST (54 studies), the pooled complication risk was 8.34% (95% CI, 6.25%-11.10%) and the CFR was 0.10% (95% CI, 0.00%-0.20%). Factors associated with complications from NST were age (OR per year increase, 1.02 [95% CI, 1.01-1.02]), female sex (OR, 0.43 [95% CI, 0.32-0.85]), coagulopathy (OR, 2.14 [95% CI, 1.13-4.06]), use of anticoagulation (OR, 6.36 [95% CI, 2.55-15.85]), smoking (OR, 1.95 [95% CI, 1.36-2.79]), hypertension (OR, 1.45 [95% CI, 1.03-2.03]), diabetes (OR, 2.38 [95% CI, 1.54-3.67]), congestive heart failure (OR, 2.71 [95% CI, 1.57-4.69]), posterior aneurysm location (OR, 7.25 [95% CI, 3.70-14.20]), and aneurysm calcification (OR, 2.89 [95% CI, 1.35-6.18]). Conclusions and Relevance: This study identifies risk factors for procedural complications. Large data sets with individual patient data are needed to develop and validate prediction scores for absolute complication risks and CFRs from EVT and NST modalities.

Predictors of primary autograft cranioplasty survival and resorption after craniectomy.

OBJECTIVECraniectomy is a common neurosurgical procedure that reduces intracranial pressure, but survival necessitates cranioplasty at a later stage, after recovery from the primary insult. Complications such as infection and resorption of the autologous bone flap are common. The risk factors for complications and subsequent bone flap removal are unclear. The aim of this multicenter, retrospective study was to evaluate the factors affecting the outcome of primary autologous cranioplasty, with special emphasis on bone flap resorption.METHODSThe authors identified all patients who underwent primary autologous cranioplasty at 3 tertiary-level university hospitals between 2002 and 2015. Patients underwent follow-up until bone flap removal, death, or December 31, 2015.RESULTSThe cohort comprised 207 patients with a mean follow-up period of 3.7 years (SD 2.7 years). The overall complication rate was 39.6% (82/207), the bone flap removal rate was 19.3% (40/207), and 11 patients (5.3%) died during the follow-up period. Smoking (OR 3.23, 95% CI 1.50-6.95; p = 0.003) and age younger than 45 years (OR 2.29, 95% CI 1.07-4.89; p = 0.032) were found to independently predict subsequent autograft removal, while age younger than 30 years was found to independently predict clinically relevant bone flap resorption (OR 4.59, 95% CI 1.15-18.34; p = 0.03). The interval between craniectomy and cranioplasty was not found to predict either bone flap removal or resorption.CONCLUSIONSIn this large, multicenter cohort of patients with autologous cranioplasty, smoking and younger age predicted complications leading to bone flap removal. Very young age predicted bone flap resorption. The authors recommend that physicians extensively inform their patients of the pronounced risks of smoking before cranioplasty.

Determinants of Gadolinium-Enhancement of the Aneurysm Wall in Unruptured Intracranial Aneurysms.

BACKGROUND: Recent studies suggest that gadolinium-enhancement of the aneurysm wall may reflect aneurysm wall inflammation, which might increase the risk of aneurysm growth or rupture. OBJECTIVE: To determine the prevalence of gadolinium-enhancement and its determinants in patients with predominantly small (<7 mm) unruptured intracranial aneurysms. METHODS: We performed 3 T MRI aneurysm wall imaging in patients with ≥1 unruptured aneurysm. With Poisson regression analysis, we calculated crude and adjusted risk ratios (RRs) with 95% confidence intervals (CI) to assess determinants of gadolinium-enhancement. RESULTS: Gadolinium-enhancement was observed in 25/79 patients (32%; 95% CI: 21%-42%) and 26/89 aneurysms (29%; 95% CI: 20%-39%). With aneurysms 1.0-2.9 mm as reference, RRs were 4.6 (95% CI: 0.6-36.5) for 3.0 to 4.9 mm, 9.4 (95% CI: 1.3-67.2) for 5.0 to 6.9 mm, and 14.8 (95% CI: 2.1-104.6) for ≥7.0 mm. With internal carotid artery as reference, RRs adjusted for aneurysm size were 3.6 (95% CI: 1.1-11.4) for posterior communicating artery and 3.0 (95% CI: 1.0-8.6) for middle cerebral artery. RRs were 0.8 (95% CI: 0.4-1.8) for acetylsalicylic acid use, 0.9 (95% CI: 0.5-1.8) for statin use, 1.4 (95% CI: 0.7-2.8) for hypertension, 0.9 (95% CI: 0.4-1.8) for previous smoking, 0.9 (95% CI: 0.3-2.6) for never smoking, and 1.4 (95% CI: 0.7-2.7) for irregular aneurysm shape. CONCLUSION: Approximately one-third of patients had gadolinium-enhancement. Because aneurysm size is the strongest determinant of gadolinium-enhancement and also an established predictor for aneurysm growth and rupture, prospective studies with serial imaging need to investigate if gadolinium-enhancement predicts aneurysm growth and rupture.

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

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.

Neurofibromatosis type 1 is not associated with subarachnoid haemorrhage.

BACKGROUND: The prevalence of intracranial aneurysms (IAs) has been proposed to be elevated in the patients with neurofibromatosis type 1 (NF1). Our aims were to determine the prevalence of NF1 in a large Finnish population based cohort of IA patients and, on the other hand, the occurrences of subarachnoid haemorrhage and unruptured intracranial aneurysms in a nationwide population-based cohort of NF1 patients and its matched ten-fold control cohort. METHODS: The Kuopio IA Database (www.kuopioneurosurgery.fi) includes all ruptured and unruptured IA cases admitted to the Kuopio University Hospital (KUH) from its defined Eastern Finnish catchment population since 1980. In this registry-based study, we cross-linked the Kuopio IA database with the Finnish national registry covering all hospital diagnoses. The NF1 diagnoses of the 4543 patients with either saccular of fusiform IA were identified from 1969 to 2015 and verified from patient records. Our second approach was to analyze the occurrence of aneurysmal subarachnoid haemorrhage (aSAH) and unruptured IAs in a nationwide population-based database of 1410 NF1 patients and its ten-fold matched control cohort (n = 14030) using national registry of hospital diagnoses between 1987 and 2014. RESULTS: One NF1 patient was identified among the 4543 IA patients. Three verified IA cases (one unruptured IA and two aSAH cases) were identified in the cohort of 1410 NF1 patients, with similar occurrences in the control cohort. CONCLUSIONS: We found no evidence in our population-based cohorts to support the conception that NF1 is associated with IAs. Our results indicate that the incidence of aSAH is not elevated in patients with NF1. Further studies are required to confirm that there is no association between NF1 and unruptured IAs.

ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms.

OBJECTIVE: To develop a risk score that estimates 3-year and 5-year absolute risks for aneurysm growth. METHODS: From 10 cohorts of patients with unruptured intracranial aneurysms and follow-up imaging, we pooled individual data on sex, population, age, hypertension, history of subarachnoid hemorrhage, and aneurysm location, size, aspect ratio, and shape but not on smoking during follow-up and family history of intracranial aneurysms in 1,507 patients with 1,909 unruptured intracranial aneurysms and used aneurysm growth as outcome. With aneurysm-based multivariable Cox regression analysis, we determined predictors for aneurysm growth, which were presented as a risk score to calculate 3-year and 5-year risks for aneurysm growth by risk factor status. RESULTS: Aneurysm growth occurred in 257 patients (17%) and 267 aneurysms (14%) during 5,782 patient-years of follow-up. Predictors for aneurysm growth were earlier subarachnoid hemorrhage, location of the aneurysm, age >60 years, population, size of the aneurysm, and shape of the aneurysm (ELAPSS). The 3-year growth risk ranged from <5% to >42% and the 5-year growth risk from <9% to >60%, depending on the risk factor status. CONCLUSIONS: The ELAPSS score consists of 6 easily retrievable predictors and can help physicians in decision making on the need for and timing of follow-up imaging in patients with unruptured intracranial aneurysms.

Irregular Shape of Intracranial Aneurysm Indicates Rupture Risk Irrespective of Size in a Population-Based Cohort.

BACKGROUND AND PURPOSE: Size and shape of saccular intracranial aneurysms (sIA) reflect the condition of the sIA wall and were risk factors for rupture in previous follow-up studies. We investigated how well size or shape identify rupture-prone sIAs. METHODS: In a population-based registry, we investigated the characteristics of ruptured sIAs treated in a single neurosurgical center (1980-2014). In addition to univariate analysis, logistic regression was used in multivariate analysis, and sensitivity and specificity of size or shape were calculated using receiver operating characteristic curves. RESULTS: Ruptured sIAs were on average larger than unruptured sIAs (median, 7 versus 4 mm; P<0.000), but location and patient background affected the size at rupture. Of the ruptured sIAs, 38% were smaller than 7 mm and 18% were smaller than 4 mm. Of those sIAs that had ruptured at a small (<7 mm) size, 87% had an irregular shape. In multivariate analysis, irregular shape had the strongest association with presentation as ruptured sIA (odds ratio, 7.1; 95% confidence interval, 6.0-8.3), with better sensitivity (91%) and specificity (76%), in contrast to smoking (odds ratio, 0.7; 95% confidence interval, 0.6-0.9; sensitivity, 28%; specificity 57%) and Population, Hypertension, Age, Size of sIA, Earlier SAH from another sIA, Site of sIA score (odds ratio, 1.5; 95% confidence interval, 1.4-1.6). CONCLUSIONS: Irregular or multilobular shape is strongly associated with rupture in sIAs of all sizes and independent of location and patient background. Especially sIAs with irregular shape should be considered as high rupture risk lesions, even if small in diameter and in nonsmoking patients with low PHASES scores.

De Novo Aneurysm Formation in Carriers of Saccular Intracranial Aneurysm Disease in Eastern Finland.

BACKGROUND AND PURPOSE: Formation of new (de novo) aneurysms in patients carrying saccular intracranial aneurysm (sIA) disease has been published, but data from population-based cohorts are scarce. METHODS: Kuopio sIA database (http://www.uef.fi/ns) contains all unruptured and ruptured sIA patients admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We studied the incidence and risk factors for de novo sIA formation in 1419 sIA patients with ≥5 years of angiographic follow-up, a total follow-up of 18 526 patient-years. RESULTS: There were 42 patients with a total of 56 de novo sIAs, diagnosed in a median of 11.7 years after the first sIA diagnosis. The cumulative incidence of de novo sIAs was 0.23% per patient-year and that of subarachnoid hemorrhage from a ruptured de novo sIA 0.05% per patient-year. The risk of de novo sIA discovery per patient-year increased with younger age at the first sIA diagnosis: 2.2% in the patients aged <20 years and 0.46% in the patients aged between 20 and 39 years. In Cox regression analysis, smoking history and younger age at the first sIA diagnosis significantly associated with de novo sIA formation, but female sex, multiple sIAs, and sIA family did not. CONCLUSIONS: Patients aged < 40 years at the first sIA diagnosis are in a significant risk of developing de novo sIAs, and they should be scheduled for long-term angiographic follow-up. Smoking increases the risk of de novo sIA formation, suggesting long-term follow-up for smokers. Antismoking efforts are highly recommended for sIA patients.

Hypertension predisposes to the formation of saccular intracranial aneurysms in 467 unruptured and 1053 ruptured patients in Eastern Finland.

OBJECTIVE: Hypertension associates with subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) when compared to matched controls or general population. Few series compare hypertension in unruptured sIA versus sIA-SAH, so its impact on the sIA disease remains uncertain. METHODS: Kuopio sIA Database ( www.uef.fi/ns ) contains all cases of unruptured and ruptured sIAs admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We compared the age-adjusted incidence of drug-treated hypertension in 467 unruptured and 1053 ruptured sIA patients admitted to Kuopio University Hospital from 1995 to 2007, using the national registry of prescribed medicines. RESULTS: Antihypertensive medication was more frequent in the unruptured (73% versus 62%) with higher age-adjusted incidence. At sIA diagnosis, the sIA-SAH group had more often untreated hypertension (29% versus 23%). The size of unruptured sIAs increased with age at sIA diagnosis, independently of hypertension. Multiple sIAs, familial sIA, and sIA-SAH were not associated with hypertension in multivariate analysis. Results indicate that drug-treated hypertension associates with the formation of sIAs rather than their growth or rupture. CONCLUSION: Hypertension is highly prevalent in the carriers of unruptured sIAs when compared to those with ruptured sIA. Hypertension may associate with the sIA formation, and may predispose to the rupture of sIA if untreated.

Induction of hyaluronan cables and monocyte adherence in epidermal keratinocytes.

Hyaluronan attached to cell surface can form at least two very different structures; a pericellular coat close to plasma membrane and hyaluronan chains coalesced into "cables" that can span several cell lengths. The hyaluronan in cables, induced by many inflammatory agents, can bind leukocytes, whereas that in the pericellular coat does not contribute to leukocyte binding. Therefore, this structural change seems to have a major role in inflammation. In the present study we checked whether cells of squamous epithelium, like epidermal keratinocytes, can form hyaluronan cables and bind leukocytes. In addition, we checked whether hyaluronan synthesis is affected during the induction of cables. Control keratinocytes expressed pericellular hyaluronan as small patches on plasma membrane. But when treated with inflammatory agents or stressful conditions (tunicamycin, interleukin-1beta, tumor necrosis factor-alpha, and high glucose concentration), hyaluronan organization changed into cable-like structures that avidly bound monocytes. Simultaneously, the total amount of secreted hyaluronan was slightly decreased, and the expression levels of hyaluronan synthases (Has1-3) and CD44 were not significantly changed. The results show that epidermal keratinocytes can form cables and bind leukocytes under inflammatory provocation and that these effects are not dependent on stimulation of hyaluronan secretion.