Impact of serum neurofilament light on clinical decisions in a tertiary multiple sclerosis clinic.

BACKGROUND AND OBJECTIVES: Serum neurofilament light (sNfL) is a biomarker for neuro-axonal damage in multiple sclerosis (MS). Clinical implementation remains limited. We investigated the impact of implementation on clinical decisions using questionnaires at the MS Center Amsterdam, a tertiary outpatient clinic. METHODS: sNfL assessments were added to routine clinical practice (August 2021-December 2022). Before and after the results, clinicians filled in questionnaires on context of testing, clinical decisions, certainty herein, expectation of magnetic resonance imaging (MRI) activity, urgency, and motivation to receive the sNfL result and perceived value of sNfL. RESULTS: sNfL was assessed in 166 cases (age 41 ± 12 years, 68% female, 64% disease-modifying therapy (DMT) use) for the following contexts: "DMT monitoring" (55%), "new symptoms" (18%), "differential diagnosis" (17%), and "DMT baseline" (11%). Clinical decisions changed in 19.3% of cases post-disclosure, particularly in context "new symptoms" (38%) and with higher sNfL levels (ß = 0.03, p = 0.04). Certainty increased (p = 0.004), while expectation of MRI activity decreased with disclosure of low sNfL levels (p = 0.01). Motivation was highest in context "differential diagnosis" (p < 0.001); perceived value and urgency were highest in context "new symptoms" (p = 0.02). CONCLUSION: In this study, sNfL implementation had considerable impact on clinical decision-making and certainty herein. Standard implementation may complement patient care but warrants caution and more exploration in diverse clinical settings.

Serial quality of life assessment around screening for familial intracranial aneurysms: a prospective cohort study.

INTRODUCTION: Screening for intracranial aneurysms (IAs) is cost-effective in first-degree relatives of aneurysmal subarachnoid haemorrhage (aSAH) patients, but its psychosocial impact is largely unknown. PATIENTS AND METHODS: A consecutive series of persons aged 20-70 years visiting the University Medical Centre Utrecht for first screening for familial IA was approached between 2017-2020. E-questionnaires were administered at six time points, consisting of the EQ-5D for health-related quality of life (QoL), HADS for emotional functioning and USER-P for social participation. QoL outcomes were compared with the general population, and between participants with a positive and negative screening for IA. Predictors of QoL outcomes were assessed with linear mixed effects models. RESULTS: 105 participants from 75 families were included; in 10 (10%) an IA was found. During the first year after screening we found no negative effect on QoL, except for a temporary decrease in QoL six months after screening in participants with a positive screen (EQ-5D -11.3 [95%CI:-21.7 to -0.8]). Factors associated with worse QoL were psychiatric disease (EQ-5D -10.3 [95%CI:-15.1 to -5.6]), physical complaints affecting mood (EQ-5D -8.1 [95%CI:-11.7 to -4.4]), and a passive coping style (EQ-5D decrease per point increase on the Utrecht Coping List -1.1 [95%CI:-1.5 to -0.6]). DISCUSSION AND CONCLUSION: We did not find a lasting negative effect on QoL during the first year after screening for familial IA. Predictors for a worse QoL were psychiatric disease, physical complaints affecting mood, and a passive coping style. This information can be used in counselling about familial IA 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.

Comparison of Rupture Risk of Intracranial Aneurysms Between Familial and Sporadic Patients.

Background and Purpose A much higher rupture rate for patients with familial intracranial aneurysms (IA) compared with patients with sporadic IA has been reported in a study with highly selected familial aneurysms using sporadic patients from other populations a controls. We aimed to validate these findings in a large independent series of Dutch patients with familial and sporadic IA. Methods We conducted a secondary analysis of our institutional cohort of patients who were screened for IAs between 1994 and 2016. We assessed the incidence of aneurysmal subarachnoid hemorrhage between familial, defined as ≥2 affected first-degree relatives with aneurysmal subarachnoid hemorrhage and unruptured IA (UIA), and sporadic patients with UIA with Cox regression analysis. Results We identified 62 familial IA patients with 91 UIA and 412 sporadic IA patients with 542 UIA. Despite familial aneurysms being smaller and more often located at low risk sites than sporadic IA, 3 familial patients had aneurysmal subarachnoid hemorrhage (0.77 ruptures per 100 aneurysm-years [95% CI, 0.20-2.09]) compared with 7 sporadic patients (0.51 ruptures per 100 aneurysm-years [95% CI, 0.22-1.01]). As compared to sporadic UIA, familial UIA seems to have a 3-fold higher risk of rupture (hazard ratio, 2.9 [95% CI, 0.6-14]). Conclusions Our results suggest a slightly increased risk of aneurysm rupture for familial compared with sporadic IA, although we were not able to demonstrate this with statistical significance. However, the rupture risk seems less strongly increased than found in a previous study. Based on our results, we recommend to treat familial UIA more aggressively.

Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome.

BACKGROUND AND PURPOSE: We systematically reviewed the literature on epidemiology, risk factors, presumed cause, clinical course, and outcome of perimesencephalic hemorrhage. METHODS: PubMed, Embase, and the Cochrane Library were searched until March 2016. Quality assessment was done by 2 authors independently. Pooled prevalence ratios and pooled odds ratios with 95% confidence intervals were calculated for data extracted from case-control studies. RESULTS: We included 208 papers. The incidence of perimesencephalic hemorrhage is ≈0.5 per 100.000 person-years, men are more often affected, and no risk factors were confirmed. Two decision analyses both found that a single, high-quality computed tomography angiography is the preferred diagnostic approach. Short-term complications, such as hydrocephalus or cranial nerve palsies, are rare, and usually transient, with the exception of acute symptomatic hydrocephalus necessitating treatment in 3% of patients. Lacunar infarcts in the brain stem were convincingly described in 4 patients only. Fatal rebleeding after installment of anticoagulation in the initial days after the hemorrhage was described in 1 patient. At long-term follow-up, death related to the hemorrhage has not been reported, disability is found in 0% to 6%, and neuropsychological sequelae are suggested. CONCLUSIONS: A single, high-quality computed tomography angiography is the preferred diagnostic strategy. Short-term complications are rare and often transient. Long-term outcome is excellent with respect to disability and death, but high-quality studies focused at neuropsychological sequelae are needed.

Additional Relevant Intracranial Findings in Persons Screened with MR for Intracranial Aneurysms.

BACKGROUND: Radiological screening for intracranial aneurysms (IAs) may identify other relevant intracranial findings. We investigated their prevalence on MR in persons screened for IAs. METHODS: We included all persons who were screened for the presence of IAs with brain MRI/MRA between 1996 and 2022 because of a family history of aneurysmal subarachnoid haemorrhage (aSAH) or autosomal dominant polycystic kidney disease (ADPKD). We reviewed radiology reports of initial and repeated brain MR to identify additional intracranial findings that needed follow-up or treatment, or carried a risk of becoming symptomatic. RESULTS: We included 766 persons (positive family history of aSAH: n = 681; ADPKD: n = 85) who had 1446 MRI/MRAs. At initial screening, 49 additional relevant intracranial findings were reported in 47 persons (6.1%, 95% CI 4.7-8.1%). Of all included persons, 338 (44%) underwent one (n = 154) or more (n = 184) follow-up screenings (total MRI/MRAs at follow-up: n = 680). In 15/338 persons (4.4%, 95% CI 2.7-7.2%), 16 new additional relevant findings were reported at a median follow-up duration of 10 years (IQR 5-12). CONCLUSIONS: Persons who are counselled for screening for IAs should be informed that there is a six percent chance of identifying an additional finding that requires follow-up or treatment, or may become symptomatic. Additionally, after 10-year follow-up screening there is a four percent chance of identifying a new additional relevant finding. The impact of such findings on quality of life needs further study.

Drivers of healthcare costs in patients with ischaemic stroke: a hospital-based retrospective cohort study.

OBJECTIVES: To evaluate how costs of healthcare can be reduced, there is an increasing need to gain insight into the main drivers of such costs. We evaluated drivers of costs of predefined subgroups of patients who had a stroke by linking cost registration with clinical data. METHODS: We retrospectively selected 555 consecutive patients with ischaemic stroke participating between June 2011 and December 2016 in the Dutch Parelsnoer Initiative. Patient characteristics and costs of healthcare activities during hospital admission and the first 3 months after discharge were linked. Patients were divided in subgroups based on age, severity of stroke, stroke subtype, discharge destination and functional outcome. Unit cost per healthcare activity was based on 2018 rates for mutual service in euros. Mean total costs per subgroup were calculated. Multivariate analysis was performed to identify factors associated with costs. RESULTS: Number of admitted days was the main driver of total hospital costs (range 82%-93%) in all predefined subgroups of patients. Second driver was radiological diagnostic investigations (range 2%-9%). Highest costs were observed in patients with a younger age at the time of admission, a higher modified Rankin Scale at the time of discharge and a nursing home as discharge destination. The distribution of costs over the different healthcare activities was associated with stroke subtype; for example, in patients with a cardiac embolism most costs were spent on cardiology-related healthcare activities. CONCLUSION: The number of admitted days was the most important driver of costs in all subgroups of patients with ischaemic stroke. This implicates that to reduce healthcare costs for patients who had a stroke, focus should be on reducing length of hospital stay.

Screening for intracranial aneurysms in persons ⩾35 years with hypertension and atherosclerotic disease who smoke(d).

INTRODUCTION: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. PATIENTS AND METHODS: Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. RESULTS: IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%-7.3%). Median 5 year risk of rupture assessed with the PHASES score was 0.9% (IQR: 0.7%-1.3%). During a median follow-up of 57 months (IQR: 39-83 months) no patients suffered from aSAH. Aneurysmal growth was detected in one patient for whom preventive treatment was advised. IA risk at screening ranged between 1.6% and 13.4% with predictors being age, female sex and current smoking. DISCUSSION AND CONCLUSION: IA prevalence in persons ⩾35 years with hypertension and atherosclerotic vascular disease who smoke(d) was 5%. Given the very small proportion of IA that needed preventive treatment, we currently do not advise screening for Caucasian persons older than 35 years of age who smoke and have hypertension in general. Whether screening may be effective for certain subgroups (e.g. women older than 50 years of age) or other ethnic populations should be the subject of future studies.

Aneurysm Prevalence and Quality of Life During Screening in Relatives of Patients With Unruptured Intracranial Aneurysms: A Prospective Study.

BACKGROUND AND OBJECTIVES: Screening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives (FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening is also effective for FDRs of patients with UIA is unknown. We determined the yield of screening in such FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, identified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL). METHODS: In this prospective cohort study, we included FDRs, aged 20-70 years, of patients with UIA without a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 participating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magnetic resonance angiography between 2017 and 2021. We determined UIA prevalence and developed a prediction model for UIA risk at screening using multivariable logistic regression. QoL was evaluated with questionnaires 6 times during the first year after screening and assessed with a linear mixed-effects model. RESULTS: We detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI 3.2-7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2-4 mm), and the median 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%-0.9%). All UIAs received follow-up imaging, and none were treated preventively. After a median follow-up of 24 months (IQR 13-38 months), no UIA had changed. Predicted UIA risk at screening ranged between 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcohol consumption (c-statistic: 0.76; 95% CI 0.65-0.88). At all survey moments, health-related QoL and emotional functioning were comparable with those in a reference group from the general population. One FDR with a positive screening result expressed regret about screening. DISCUSSION: Based on the current data, we do not advise screening FDRs of patients with UIA because all identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. A longer follow-up should determine the risk of aneurysm growth requiring preventive treatment.

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.

The Dutch Parelsnoer Institute Cerebrovascular Disease Initiative: a retrospective study of the effects of integrating clinical care and research on costs and quality of care in patients with ischaemic stroke.

INTRODUCTION: The Dutch Parelsnoer Institute (PSI) is a collaboration between all university medical centres in which clinical data, imaging and biomaterials are prospectively and uniformly collected for research purposes. The PSI has the ambition to integrate data collected in the context of clinical care with data collected primarily for research purposes. We aimed to evaluate the effects of such integrated registration on costs, efficiency and quality of care. METHODS: We retrospectively included patients with cerebral ischaemia of the PSI Cerebrovascular Disease Consortium at two participating centres, one applying an integrated approach on registration of clinical and research data and another with a separate method of registration. We determined the effect of integrated registration on (1) costs and time efficiency using a comparative matched cohort study in 40 patients and (2) quality of the discharge letter in a retrospective cohort study of 400 patients. RESULTS: A shorter registration time (mean difference of -4.6 min, SD 4.7, p=0.001) and a higher quality score of discharge letters (mean difference of 856 points, SD 40.8, p<0.001) was shown for integrated registration compared with separate registration. Integrated registration of data of 300 patients per year would save around €700 salary costs per year. CONCLUSION: Integrated registration of clinical and research data in patients with cerebral ischaemia is associated with some decrease in salary costs, while at the same time, increased time efficiency and quality of the discharge letter are accomplished. Thus, we recommend integrated registration of clinical and research data in centres with high-volume registration only, due to the initial investments needed to adopt the registration software.

Difference in Aneurysm Characteristics between Patients with Familial and Sporadic Aneurysmal Subarachnoid Haemorrhage.

OBJECT: Patients with familial intracranial aneurysms (IA) have a higher risk of rupture than patients with sporadic IA. We compared geometric and morphological risk factors for aneurysmal rupture between patients with familial and sporadic aneurysmal subarachnoid hemorrhage (aSAH) to analyse if these risk factors contribute to the increased rupture rate of familial IA. METHODS: Geometric and morphological aneurysm characteristics were studied on CT-angiography in a prospectively collected series of patients with familial and sporadic aSAH, admitted between September 2006 and September 2009, and additional patients with familial aSAH retrieved from the prospectively collected database of familial IA patients of our center. Odds ratios (OR) with corresponding 95% confidence intervals (95% CI) were calculated to compare the aneurysm characteristics between patients with familial and sporadic aSAH. RESULTS: We studied 67 patients with familial and 184 with sporadic aSAH. OR's for familial compared with sporadic aSAH were for oval shape 1.16(95%CI:0.65-2.09), oblong shape 0.26(95%CI:0.03-2.13), irregular shape 0.83(95%CI:0.47-1.49), aspect ratio ≥ 1.6 0.94(95%CI:0.54-1.66), contact with the perianeurysmal environment (PAE) 1.15(95%CI:0.56-2.40), deformation by the PAE 1.05(95%CI:0.47-2.35) and for dominance of the posterior communicating artery (PCoA) in case of PCoA aneurysms 1.97(95% CI:0.50-7.83). CONCLUSIONS: The geometric and morphological risk factors for aneurysm rupture do not have a higher prevalence in familial than in sporadic aSAH and thus do not explain the increased risk of IA rupture in patients with familial IA. We recommend further search for other potential risk factors for rupture of familial IA, such as genetic factors.

Circadian fluctuations in onset of perimesencephalic hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs more often during working hours and in the evening, and thus at times of relatively high blood pressure, with an even distribution over the days of the week in most studies. Perimesencephalic hemorrhage (PMH) is a non-aneurysmal subset of subarachnoid hemorrhage (SAH) without known circadian fluctuation. We studied the time and day of onset in a large series of patients with PMH. For all 249 PMH patients included in our SAH-database we analyzed the time (categorized in 2- and 6-h intervals) and day of onset by calculating rate ratios (RRs) with corresponding 95 % confidence intervals (CIs) for time and day, with the afternoon and Saturday as reference. The risk of PMH was lower between 2-4 AM (RR 0.14; 95 % CI 0.03-0.63), 4-6 AM (RR 0.21; 95 % CI 0.06-0.75) and 6-8 AM (RR 0.07; 95 % CI 0.01-0.54). A tendency towards higher risks in the morning and afternoon was observed. Analyzing the time of onset in 6-h intervals also showed a lower risk (RR 0.35; 95 % CI 0.21-0.58) during night hours (12-6 AM). The risk of PMH was evenly distributed over the days of the week. PMH occurs less often during night hours. The pattern of PMH during the day shows similarities to that seen in aSAH, although the differences over the day are not statistically significant, as they are in aSAH. The occurrence of PMH is evenly distributed over the days of the week, as it is in aSAH.