Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

Quantitative measurement of cortical superficial siderosis in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease affecting the small arteries in the brain with hallmark depositions of amyloid-ß in the vessel wall, leading to cognitive decline and intracerebral hemorrhage (ICH). An emerging MRI marker for CAA is cortical superficial siderosis (cSS) as it is strongly related to the risk of (recurrent) ICH. Current assessment of cSS is mainly done on T2*- weighted MRI using a qualitative score consisting of 5 categories of severity which is hampered by ceiling effects. Therefore, the need for a more quantitative measurement is warranted to better map disease progression for prognosis and future therapeutic trials. We propose a semi-automated method to quantify cSS burden on MRI and investigated it in 20 patients with CAA and cSS. The method showed excellent inter-observer (Pearson's 0.991, P < 0.001) and intra-observer reproducibility (ICC 0.995, P < 0.001). Furthermore, in the highest category of the multifocality scale a large spread in the quantitative score is observed, demonstrating the ceiling effect in the traditional score. We observed a quantitative increase in cSS volume in two of the 5 patients who had a 1 year follow up, while the traditional qualitative method failed to identify an increase because these patients were already in the highest category. The proposed method could therefore potentially be a better way of tracking progression. In conclusion, semi-automated segmenting and quantifying cSS is feasible and repeatable and may be used for further studies in CAA cohorts.

Evolutionary algorithms and decision trees for predicting poor outcome after endovascular treatment for acute ischemic stroke.

Despite the large overall beneficial effects of endovascular treatment in patients with acute ischemic stroke, severe disability or death still occurs in almost one-third of patients. These patients, who might not benefit from treatment, have been previously identified with traditional logistic regression models, which may oversimplify relations between characteristics and outcome, or machine learning techniques, which may be difficult to interpret. We developed and evaluated a novel evolutionary algorithm for fuzzy decision trees to accurately identify patients with poor outcome after endovascular treatment, which was defined as having a modified Rankin Scale score (mRS) higher or equal to 5. The created decision trees have the benefit of being comprehensible, easily interpretable models, making its predictions easy to explain to patients and practitioners. Insights in the reason for the predicted outcome can encourage acceptance and adaptation in practice and help manage expectations after treatment. We compared our proposed method to CART, the benchmark decision tree algorithm, on classification accuracy and interpretability. The fuzzy decision tree significantly outperformed CART: using 5-fold cross-validation with on average 1090 patients in the training set and 273 patients in the test set, the fuzzy decision tree misclassified on average 77 (standard deviation of 7) patients compared to 83 (±7) using CART. The mean number of nodes (decision and leaf nodes) in the fuzzy decision tree was 11 (±2) compared to 26 (±1) for CART decision trees. With an average accuracy of 72% and much fewer nodes than CART, the developed evolutionary algorithm for fuzzy decision trees might be used to gain insights into the predictive value of patient characteristics and can contribute to the development of more accurate medical outcome prediction methods with improved clarity for practitioners and patients.

Evaluation of the yield of post-clipping angiography and nationwide current practice.

BACKGROUND: Surgical treatment of intracranial saccular aneurysms aims to prevent (re)hemorrhage by complete occlusion of the aneurysmal lumen. It is unclear whether routine postoperative imaging, to assess aneurysmal occlusion, is necessary since intraoperative assessment by the neurosurgeon may be sufficient. We assessed routine clinical protocols for post-clipping imaging in the Netherlands and determined whether intraoperative assessment of aneurysm clippings sufficiently predicts aneurysm residuals. METHODS: A survey was conducted to assess postoperative imaging protocols in centers performing clipping of intracranial aneurysms in the Netherlands (n = 9). Furthermore, a retrospective single-center cohort study was performed to determine the predictive value of intraoperative assessment of aneurysm occlusion in relation to postoperative digital subtraction angiography (DSA) findings, between 2009 and 2017. RESULTS: No center performed intraoperative DSA in a hybrid OR, routinely. Respectively, four (44.4%), seven (77.8%), and three (33.3%) centers did not routinely perform early postoperative imaging, late follow-up imaging, or any routine imaging at all. Regarding our retrospective study, 106 patients with 132 clipped aneurysms were included. There were 23 residuals ≥ 1 mm (17.4%), of which 10 (43.5%) were unexpected. For the presence of these residuals, intraoperative assessment showed a sensitivity of 56.5%, a specificity of 86.2%, a positive predictive value of 46.4%, and a negative predictive value of 90.4%. CONCLUSIONS: There is lack of consensus regarding the post-clipping imaging strategy in the Netherlands. Since intraoperative assessment is shown to be insufficient to predict postoperative aneurysm residuals, we advocate routine postoperative imaging after aneurysm clipping unless this is not warranted on the basis of patient age, clinical condition, and/or comorbidity.

Comparison of CTA- and DSA-Based Collateral Flow Assessment in Patients with Anterior Circulation Stroke.

BACKGROUND AND PURPOSE: Collateral flow is associated with clinical outcome after acute ischemic stroke and may serve as a parameter for patient selection for intra-arterial therapy. In clinical trials, DSA and CTA are 2 imaging modalities commonly used to assess collateral flow. We aimed to determine the agreement between collateral flow assessment on CTA and DSA and their respective associations with clinical outcome. MATERIALS AND METHODS: Patients randomized in MR CLEAN with middle cerebral artery occlusion and both baseline CTA images and complete DSA runs were included. Collateral flow on CTA and DSA was graded 0 (absent) to 3 (good). Quadratic weighted κ statistics determined agreement between both methods. The association of both modalities with mRS at 90 days was assessed. Also, association between the dichotomized collateral score and mRS 0-2 (functional independence) was ascertained. RESULTS: Of 45 patients with evaluable imaging data, collateral flow was graded on CTA as 0, 1, 2, 3 for 3, 10, 20, and 12 patients, respectively, and on DSA for 12, 17, 10, and 6 patients, respectively. The κ-value was 0.24 (95% CI, 0.16-0.32). The overall proportion of agreement was 24% (95% CI, 0.12-0.38). The adjusted odds ratio for favorable outcome on mRS was 2.27 and 1.29 for CTA and DSA, respectively. The relationship between the dichotomized collateral score and mRS 0-2 was significant for CTA (P = .01), but not for DSA (P = .77). CONCLUSIONS: Commonly applied collateral flow assessment on CTA and DSA showed large differences, indicating that these techniques are not interchangeable. CTA was significantly associated with mRS at 90 days, whereas DSA was not.

Assessment of Collateral Status by Dynamic CT Angiography in Acute MCA Stroke: Timing of Acquisition and Relationship with Final Infarct Volume.

BACKGROUND AND PURPOSE: Dynamic CTA is a promising technique for visualization of collateral filling in patients with acute ischemic stroke. Our aim was to describe collateral filling with dynamic CTA and assess the relationship with infarct volume at follow-up. MATERIALS AND METHODS: We selected patients with acute ischemic stroke due to proximal MCA occlusion. Patients underwent NCCT, single-phase CTA, and whole-brain CT perfusion/dynamic CTA within 9 hours after stroke onset. For each patient, a detailed assessment of the extent and velocity of arterial filling was obtained. Poor radiologic outcome was defined as an infarct volume of ≥70 mL. The association between collateral score and follow-up infarct volume was analyzed with Poisson regression. RESULTS: Sixty-one patients with a mean age of 67 years were included. For all patients combined, the interval that contained the peak of arterial filling in both hemispheres was between 11 and 21 seconds after ICA contrast entry. Poor collateral status as assessed with dynamic CTA was more strongly associated with infarct volume of ≥70 mL (risk ratio, 1.9; 95% CI, 1.3-2.9) than with single-phase CTA (risk ratio, 1.4; 95% CI, 0.8-2.5). Four subgroups (good-versus-poor and fast-versus-slow collaterals) were analyzed separately; the results showed that compared with good and fast collaterals, a similar risk ratio was found for patients with good-but-slow collaterals (risk ratio, 1.3; 95% CI, 0.7-2.4). CONCLUSIONS: Dynamic CTA provides a more detailed assessment of collaterals than single-phase CTA and has a stronger relationship with infarct volume at follow-up. The extent of collateral flow is more important in determining tissue fate than the velocity of collateral filling. The timing of dynamic CTA acquisition in relation to intravenous contrast administration is critical for the optimal assessment of the extent of collaterals.

Whole brain CT perfusion in acute anterior circulation ischemia: coverage size matters.

INTRODUCTION: Our aim was to compare infarct core volume on whole brain CT perfusion (CTP) with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. METHODS: In total, 40 acute ischemic stroke patients with non-contrast CT (NCCT) and CTP imaging of anterior circulation ischemia were included. Imaging was performed using a 320-multislice CT. Average volumes of infarct core of all simulated partial coverage sizes were calculated. Infarct core volume of each partial brain coverage was compared with infarct core volume of whole brain coverage and expressed using a percentage. To determine the optimal starting position for each simulated CTP coverage, the percentage of infarct coverage was calculated for every possible starting position of the simulated partial coverage in relation to Alberta Stroke Program Early CT Score in Acute Stroke Triage (ASPECTS 1) level. RESULTS: Whole brain CTP coverage further increased the percentage of infarct core volume depicted by 10% as compared to the 8-cm coverage when the bottom slice was positioned at the ASPECTS 1 level. Optimization of the position of the region of interest (ROI) in 3 cm, 4 cm, and 8 cm improved the percentage of infarct depicted by 4% for the 8-cm, 7% for the 4-cm, and 13% for the 3-cm coverage size. CONCLUSION: This study shows that whole brain CTP is the optimal coverage for CTP with a substantial improvement in accuracy in quantifying infarct core size. In addition, our results suggest that the optimal position of the ROI in limited coverage depends on the size of the coverage.

Dynamic 320-section CT angiography in cranial arteriovenous shunting lesions.

Novel 320-section CT scanning equipment enables dynamic noninvasive angiographic imaging of the entire cranial vasculature (4D-CTA). We describe this technique and demonstrate its potential in arteriovenous shunting lesions. 4D-CTA imaging resulted in a correct diagnosis, lesion classification, and treatment-strategy selection in 3 patients, compared with CA. We think that 4D-CTA can further reduce the need for CA, sparing the patient the discomfort and risk associated with an invasive procedure.

Association between MRI parameters and the MS severity scale: a 12 year follow-up study.

BACKGROUND: Several magnetic resonance imaging (MRI) parameters are known to be associated with short-term outcome in multiple sclerosis (MS) patients. MS-related disability typically progresses over decades, stressing the need for longer follow-up studies. Until now, these studies are relatively sparse and, therefore, the predictive value of MRI parameters for clinical disability remains largely unknown. OBJECTIVE: To assess the predictive value of brain MRI parameters, which are obtained during the first 3.3 years of the study for overall disease severity as measured by the MS Severity Score (MSSS) after 12.2 years follow-up. METHODS: Forty-six MS patients were included in the study. MRI parameters included both lesion loads and atrophy measures. Average and change parameters were calculated for MRI parameters and subsequently used as independent variables in regression models, while MSSS was the dependent variable. RESULTS: Follow-up (FU) was obtained in 43/46 patients (94%) and median expanded disability status scale (EDSS) score increased significantly from 2.5 to 4.0. At last FU median MSSS was 4.3 (range 2.2-6.9). In univariate analyses, both change and cross-sectional T1-hypointense lesion load and ventricular atrophy measures were associated with MSSS. A multiple regression model included the change parameter of hypointense T1-lesion load (BHLL). This model explained 20% of variance in MSSS, which increased to 34% when type of disease (relapsing remitting or secondary progressive), age, and sex were entered additionally. CONCLUSION: MRI measures of axonal loss are associated with higher overall disease severity in MS patients.

Giant intracranial aneurysm in a ten-year-old boy with parry romberg syndrome. A case report and literature review.

SUMMARY: Parry-Romberg syndrome (PRS) is a rare acquired syndrome consisting of progressive hemiatrophy of the face.We present a child with PRS and progressive neurological deficit caused by a giant intracranial aneurysm and reviewed the literature concerning all intracranial abnormalities in patients with PRS.A literature search identified 27 articles reporting on 88 patients ith PRS and intracranial abnormalities. Ipsilateral brain calcification and hemiatrophy are the most prominent features on CT scan and hyperintense white matter lesions are most frequently seen on T2-weighted MRI. Although lacking precise prevalence data, intracranial abnormalities are not uncommon in patients with PRS. We found three other PRS patients with intracranial aneurysms. Our case and literature search suggests a possible association between PRS and intracranial aneurysms. We consider this association important for clinical practice and recommend including intracranial vascular diseases in the differential diagnosis when dealing with a PRS patient with neurological symptoms.