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.

Dynamic functional connectivity of the EEG in relation to outcome of postanoxic coma.

OBJECTIVE: Early EEG contains reliable information for outcome prediction of comatose patients after cardiac arrest. We introduce dynamic functional connectivity measures and estimate additional predictive values. METHODS: We performed a prospective multicenter cohort study on continuous EEG for outcome prediction of comatose patients after cardiac arrest. We calculated Link Rates (LR) and Link Durations (LD) in the α, δ, and θ band, based on similarity of instantaneous frequencies in five-minute EEG epochs, hourly, during 3 days after cardiac arrest. We studied associations of LR and LD with good (Cerebral Performance Category (CPC) 1-2) or poor outcome (CPC 3-5) with univariate analyses. With random forest classification, we established EEG-based predictive models. We used receiver operating characteristics to estimate additional values of dynamic connectivity measures for outcome prediction. RESULTS: Of 683 patients, 369 (54%) had poor outcome. Patients with poor outcome had significantly lower LR and longer LD, with largest differences 12 h after cardiac arrest (LRθ 1.87 vs. 1.95 Hz and LDα 91 vs. 82 ms). Adding these measures to a model with classical EEG features increased sensitivity for reliable prediction of poor outcome from 34% to 38% at 12 h after cardiac arrest. CONCLUSION: Poor outcome is associated with lower dynamics of connectivity after cardiac arrest. SIGNIFICANCE: Dynamic functional connectivity analysis may improve EEG based outcome prediction.

Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy.

AIMS: We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. METHODS: The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n = 9), Alzheimer's disease (AD) (n = 11) and healthy control cases (n = 11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n = 31), AD patients (n = 27) and non-neurological controls (n = 67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85 years), and paired CSF and serum samples. RESULTS: ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50 years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P = 0.0008). CONCLUSIONS: Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

Cognitive functioning in patients with carotid artery occlusion; a systematic review.

INTRODUCTION: Patients with complete occlusion of the internal carotid artery (CAO) are vulnerable to cerebral hypoperfusion. Since cerebral hypoperfusion is associated with accelerated cognitive decline, patients with CAO may have an increased risk of cognitive impairment. We aimed to assess the prevalence and profile of cognitive impairment in patients with CAO and to explore the relation between hemodynamic impairment and cognitive functioning. METHODS: We systematically searched Medline and EMBASE for studies including patients with symptomatic or asymptomatic CAO subjected to cognitive testing that were published between 1980 and 2017. We did not include patients with carotid stenosis. We obtained data on type of study, patient characteristics, cerebral imaging and neuropsychological testing. In addition, we extracted data on potential causes of systemic hemodynamic impairment and the presence and stage of cerebral hemodynamic impairment. We assessed methodological quality of included studies with the Newcastle-Ottawa Scale. RESULTS: We found eight studies comprising 244 patients (mean age 61 years, 76% male, 93% symptomatic CAO). The proportion of patients with cognitive impairment ranged from 54 to 71% in four studies; in the other four studies patients with CAO performed worse on cognitive testing than controls, but results were not quantified. Impairment was reported in all cognitive domains. We found no data on the association between systemic hemodynamic impairment and cognitive functioning. Studies that assessed whether cerebral hemodynamic impairment was associated with cognitive functioning showed conflicting results. CONCLUSION: In patients with CAO, cognitive impairment is present in about half to two-thirds of patients and is not restricted to specific cognitive domains. The effect of systemic and cerebral hemodynamic impairment on cognitive functioning in patients with CAO deserves further study.

Brain imaging in comatose survivors of cardiac arrest: Pathophysiological correlates and prognostic properties.

INTRODUCTION: Hypoxic-ischemic brain injury is the main cause of death and disability of comatose patients after cardiac arrest. Early and reliable prognostication is challenging. Common prognostic tools include clinical neurological examination and electrophysiological measures. Brain imaging is well established for diagnosis of focal cerebral ischemia but has so far not found worldwide application in this patient group. OBJECTIVE: To review the value of Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) for early prediction of neurological outcome of comatose survivors of cardiac arrest. METHODS: A literature search was performed to identify publications on CT, MRI or PET in comatose patients after cardiac arrest. RESULTS: We included evidence from 51 articles, 21 on CT, 27 on MRI, 1 on CT and MRI, and 2 on PET imaging. Studies varied regarding timing of measurements, choice of determinants, and cut-off values predicting poor outcome. Most studies were small (n = 6-398) and retrospective (60%). In general, cytotoxic oedema, defined by a grey-white matter ratio <1.10, derived from CT, or MRI-diffusion weighted imaging <650 × 10-6 mm2/s in >10% of the brain could differentiate between patients with favourable and unfavourable outcomes on a group level within 1-3 days after cardiac arrest. Advanced imaging techniques such as functional MRI or diffusion tensor imaging show promising results, but need further evaluation. CONCLUSION: CT derived grey-white matter ratio and MRI based measures of diffusivity and connectivity hold promise to improve outcome prediction after cardiac arrest. Prospective validation studies in a multivariable approach are needed to determine the additional value for the individual patient.

[Ischemic stroke in young women]. / Herseninfarct bij jonge vrouwen.

- In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in women aged between 25-49 years the prevalence is higher than in men. Female-specific risk factors and disorders may explain this peak.- Pregnancy and the post-partum period are associated with physiological changes which can increase blood coagulation. Complications during pregnancy may also increase the risk of ischaemic stroke.- Migraine with aura and antiphospholipid syndrome are disorders which are also associated with an increased risk of ischaemic stroke. These disorders are more common in women compared to men. Furthermore, hormonal contraceptives containing oestrogen are also identified to increase the incidence of ischaemic stroke.- The acute treatment and secondary prevention of ischaemic stroke in young women is identical to that in elderly stroke patients, be it men or women, although thrombolysis and platelet aggregation inhibition in pregnant women should be approached with care.- Clinical outcomes after stroke for women under the age of 50 are worse compared to age-matched men.

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis.

BACKGROUND: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results. METHODS: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3. RESULTS: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1ß, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005). CONCLUSIONS: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1ß, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.

Outcome after intracranial haemorrhage from dural arteriovenous fistulae; a systematic review and case-series.

Dural arteriovenous fistulae (DAVFs) are a rare cause of intracranial haemorrhage. We aimed to investigate outcome of patients with intracranial haemorrhage from a DAVF. We performed a systematic literature search for studies reporting outcome after intracranial haemorrhage caused by a DAVF. We used predefined selection criteria and assessed the quality of the studies. In addition, we studied outcome in all patients with DAVF who had presented with intracranial haemorrhage at two university centers in the Netherlands, between January 2007 and April 2012. We calculated case fatality and proportions of patients with poor outcome (defined as modified Rankin Scale ≥ 3 or Glasgow Outcome Scale ≤ 3) during follow-up. We investigated mean age, sex, mid-year of study and percentage of patients with parenchymal haemorrhage as determinants of case fatality and poor outcome. The literature search yielded 16 studies, all but two retrospective and all hospital-based. Combined with our cohort of 29 patients the total number of patients with DAVF-related intracranial haemorrhage was 326 (58% intracerebral haemorrhage). At a median follow-up of 12 months case fatality was 4.7% (95% CI 2.5-7.5; 17 cohorts) and the proportion of patients with poor outcome 8.3% (95% CI 3.1-15.7; nine cohorts). We found no effect of mean age, sex, mid-year of the cohorts and percentage of patients with parenchymal haemorrhage on either outcome. Hospital based case-series suggest a relatively low risk of death and poor outcome in patients with intracranial haemorrhage due to rupture of a DAVF. These risks may be underestimated because of bias.

Antithrombotic treatment and intracerebral haemorrhage: between Scylla and Charybdis.

In patients who have intracerebral haemorrhage while on antithrombotic treatment, there is no evidence from randomised clinical trials to support decisions with regard to antithrombotic medication. In the acute phase, we advise stopping all antithrombotic treatment with rapid reversal of antithrombotic effects of oral anticoagulants. After the acute phase, we discourage restarting oral anticoagulants in patients with a lobar haematoma caused by cerebral amyloid angiopathy because of the high risk of recurrent bleeding. In these patients, even treatment with platelet inhibitors needs careful weighing of the risks of bleeding and ischaemic stroke. In patients with non-lobar intracerebral haemorrhage, we suggest considering restarting optimal antithrombotic treatment. This includes treatment with oral anticoagulants for patients with atrial fibrillation and/or mechanical valve prosthesis. After intracerebral haemorrhage during oral anticoagulant therapy in patients with atrial fibrillation, direct anticoagulants may be better than vitamin K antagonists, but we await confirmation of this from ongoing trials.

[Resumption of antithrombotic treatment after an intracerebral haemorrhage]. / Hervatten van antistolling na een hersenbloeding.

There is no evidence from randomised clinical trials with regard to the question if and when to resume antithrombotic medication in patients who have suffered an intracerebral haemorrhage and in whom medication continues to be indicated. It is unknown whether new oral anticoagulants are more suitable than vitamin K antagonists in this group of patients. Oral anticoagulants should probably not be resumed in patients with a lobar intracerebral haemorrhage caused by cerebral amyloid angiopathy. They can be considered in patients with a haemorrhage in subcortical regions of the brain, the brain stem or the cerebellum, provided that blood pressure levels are under control. Depending on the risk of a cardiac embolus, antithrombotic medication can be resumed from 1 to 10 weeks after the intracerebral haemorrhage. In patients with atrial fibrillation this risk can be calculated using the CHA2DS2-VASc score. In patients with a cardiac indication for antithrombotic medication the decision whether or not to resume medication should be made by a cardiologist and a neurologist in collaboration.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

BACKGROUND: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS: Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.

[Acute treatment of hypertension in intracerebral haemorrhage]. / Acute hypertensiebehandeling na een hersenbloeding.

Thus far no effective treatment for an intracerebral haemorrhage has been available. A randomized clinical trial recently showed that treatment of hypertension in the acute phase of spontaneous intracerebral haemorrhage with a target systolic blood pressure of 140 mmHg is safe and improves prognosis. The effect of blood pressure reducing therapy was small and not statistically significant for the primary outcome (mortality or severe morbidity). Moreover, this effect was shown in one trial only. Therefore the clinical relevance of these study results remains debatable. Considering all available arguments, in patients with a systolic blood pressure >150 mmHg in the first 6 hours after spontaneous intracerebral haemorrhage the Dutch Neurovascular Working Group recommends lowering the blood pressure to a target systolic level of 140 mmHg within 1 hour and maintaining this target level for 1 week. When this strategy is not chosen, we recommend that a systolic blood pressure >180 mmHg should be treated anyway, with a target level of 160 mmHg.

Measuring outcome after arterial ischemic stroke in childhood with two different instruments.

BACKGROUND: Assessment of outcome after childhood stroke is important both for clinical practice and for research purposes. The objective of this study was to compare two frequently used outcome measures. METHODS: In 40 children with arterial ischemic stroke (AIS), dichotomized outcome obtained from the Pediatric Stroke Outcome Measure (PSOM) was compared with a dichotomized modified Rankin Scale (mRS) combined with information on type of school attendance. In addition, we compared dichotomized outcome, obtained from the PSOM and the mRS combined with school attendance, with the results of pediatric quality of life (PedsQL) questionnaires and the impressions of the child's general functioning on a visual analogue scale (VAS) that was filled out by parents and investigators. RESULTS: In 35 children (88%), outcome classification was concordant between the two outcome measures. Five children had a poor outcome according to the PSOM and good outcome with the mRS including school performance. In these patients, mRS outcome classification agreed better with the impression of the investigators, as reflected by VAS scores ≥7.5. For both the PSOM and mRS in combination with school performance, patients with a good outcome had significantly higher PedsQL and VAS scores than those with a poor outcome (p values <0.01 for all comparisons). VAS scores of investigators and parents correlated significantly with PedsQL. CONCLUSIONS: In children with AIS, both PSOM and mRS combined with school type correlated significantly with quality of life and VAS scores of general functioning. The mRS combined with school type is easier to obtain than the PSOM, reflects function rather than deficits, includes an important measure of cognitive outcome, and corresponds better with the doctor's impression of outcome.

Arterial spin-labeling MR imaging measurements of timing parameters in patients with a carotid artery occlusion.

BACKGROUND AND PURPOSE: Arterial spin-labeling (ASL) with image acquisition at multiple delay times can be exploited in perfusion MR imaging to visualize and quantify the temporal dynamics of arterial blood inflow. In this study, we investigated the consequences of an internal carotid artery (ICA) occlusion and collateral blood flow on regional timing parameters. MATERIALS AND METHODS: Seventeen functionally independent patients with a symptomatic ICA occlusion (15 men, 2 women; mean age, 57 years) and 29 sex- and age-matched control subjects were investigated. ASL at multiple delay times was used to quantify regional cerebral blood flow (CBF) and the transit and trailing edge times (arterial timing parameters) reflecting, respectively, the beginning and end of the labeled bolus. Intra-arterial digital subtraction angiography and MR angiography were used to grade collaterals. RESULTS: In the hemisphere ipsilateral to the ICA occlusion, the CBF was lower in the anterior frontal (31 +/- 4 versus 47 +/- 3 mL/min/100 g, P < .01), posterior frontal (39 +/- 4 versus 55 +/- 2 mL/min/100 g, P < .01), and frontal parietal region (49 +/- 3 versus 61 +/- 3 mL/min/100 g, P = .04) than that in control subjects. The trailing edge of the frontal-parietal region was longer in the hemisphere ipsilateral to the ICA occlusion compared with that in control subjects (2225 +/- 167 versus 1593 +/- 35 ms, P < .01). In patients with leptomeningeal collateral flow, the trailing edge was longer in the anterior frontal region (2436 +/- 275 versus 1648 +/- 201 ms, P = .03) and shorter in the occipital region (1815 +/- 128 versus 2388 +/- 203 ms, P = .04), compared with patients without leptomeningeal collaterals. CONCLUSION: Regional assessment of timing parameters with ASL may provide valuable information on the cerebral hemodynamic status. In patients with leptomeningeal collaterals, the most impaired territory was found in the frontal lobe.

Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage.

BACKGROUND: In approximately 5% of patients with intracranial subarachnoid haemorrhage (SAH), the cause is another than a ruptured aneurysm or perimesencephalic haemorrhage. One of these causes is a spinal arteriovenous shunt (SAVS). The aim of this study was to investigate the characteristics of patients with SAVS who present with intracranial SAH without symptoms and signs suggesting a spinal cause. METHODS: We systematically reviewed the literature and searched the SAH database of the University Medical Center Utrecht, The Netherlands, for patients with SAVS presenting with intracranial SAH and studied the characteristics of patients with SAVS whose clinical presentation mimicked intracranial SAH caused by rupture of a saccular aneurysm. RESULTS: Thirty-five patients were identified after a review of the literature. In our SAH database, comprising 2142 patients included in the period 1985-2004, we found one patient (0.05%, 95 % CI 0.006- 0.3%). SAH due to SAVS occurred at any age (4-72 years). The SAVS was located at the craniocervical junction in 14 patients, at the cervical level in 11, and at the thoracolumbar level in the remaining 11 patients. The majority of patients (n = 26, 72%) had no disabling deficits at discharge or follow-up. CONCLUSION: Rupture of a SAVS presenting as intracranial SAH is rare and can occur at any age. The SAVS can be located not only at the craniocervical junction or cervical level but also in the thoracolumbar region. Most patients with SAVS presenting as intracranial SAH have a good recovery.

Familial occurrence of brain arteriovenous malformations: a systematic review.

BACKGROUND: Brain arteriovenous malformations (BAVMs) are thought to be sporadic developmental vascular lesions, but familial occurrence has been described. We compared the characteristics of patients with familial BAVMs with those of patients with sporadic BAVMs. METHODS: We systematically reviewed the literature on patients with familial BAVMs. Three families that were found in our centre were added. Age, sex distribution and clinical presentation of the identified patients were compared with those in population based series of patients with sporadic BAVMs. Furthermore, we calculated the difference in mean age at diagnosis of parents and children to study possible anticipation. RESULTS: We identified 53 patients in 25 families with BAVMs. Mean age at diagnosis of patients with familial BAVMs was 27 years (range 9 months to 58 years), which was younger than in the reference population (difference between means 8 years, 95% CI 3 to 13 years). Patients with familial BAVMs did not differ from the reference populations with respect to sex or mode of presentation. In families with BAVMs in successive generations, the age of the child at diagnosis was younger than the age of the parent (difference between means 22 years, 95% CI 13 to 30 years), which suggests clinical anticipation. CONCLUSIONS: Few patients with familial BAVMs have been described. These patients were diagnosed at a younger age than sporadic BAVMs whereas their mode of presentation was similar. Although there are indications of anticipation, it remains as yet unclear whether the described families represent accidental aggregation or indicate true familial occurrence of BAVMs.