Single versus multiple fraction stereotactic radiosurgery for medium-sized brain metastases (4-14 cc in volume): reducing or fractionating the radiosurgery dose?

Background and purpose: Stereotactic radiosurgery (SRS) of brain metastases (BM) and resection cavities is a widely used and effective treatment modality. Based on target lesion size and anatomical location, single fraction SRS (SF-SRS) or multiple fraction SRS (MF-SRS) are applied. Current clinical recommendations conditionally recommend either reduced dose SF-SRS or MF-SRS for medium-sized BM (2-2.9 cm in diameter). Despite excellent local control rates, SRS carries the risk of radionecrosis (RN). The purpose of this study was to assess the 12-months local control (LC) rate and 12-months RN rate of this specific patient population. Materials and methods: This single-center retrospective study included 54 patients with medium-sized intact BM (n=28) or resection cavities (n=30) treated with either SF-SRS or MF-SRS. Follow-up MRI was used to determine LC and RN using a modification of the "Brain Tumor Reporting and Data System" (BT-RADS) scoring system. Results: The 12-month LC rate following treatment of intact BM was 66.7% for SF-SRS and 60.0% for MF-SRS (p=1.000). For resection cavities, the 12-month LC rate was 92.9%% after SF-SRS and 46.2% after MF-SRS (p=0.013). For intact BM, RN rate was 17.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). For resection cavities, RN rate was 28.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). Conclusion: Patients with intact BM showed no statistically significant differences in 12-months LC and RN rate following SF-SRS or MF-SRS. In patients with resection cavities the 12-months LC rate was significantly better following SF-SRS, with no increase in the RNFS.

Velocity and pattern of growth of intracranial meningiomas.

OBJECTIVE: The authors' aim was to assess the velocity and pattern of growth of meningiomas and to correlate the kinetics of tumor growth with their previously reported two-item radiological risk stratification and CNS WHO grade (5th edition, 2021). METHODS: The authors performed a serial volumetric analysis of meningiomas diagnosed radiologically at their institution between 2003 and 2015. The primary endpoint was velocity of diametric expansion (VDE), which represents the slope of the linear regression of the mean tumor diameter against time. For the secondary analysis, they categorized the growth patterns as linear or exponential by fitting time-volume curves to a linear and exponential function. Three radiological risk categories based on T2-weighted iso/hyperintensity and absence of calcifications were compared: low risk (T2-weighted hypointense), intermediate-risk (T2-weighted iso/hyperintense with calcifications), and high-risk (T2-weighted iso/hyperintense without calcifications) tumors. RESULTS: For the entire cohort of 240 meningiomas, the median (IQR) VDE was 0.33 (0.00-0.71) mm/year. Distribution of VDE differed significantly among radiological risk categories (0.49 vs 0.35 vs 0.05 mm/year, p < 0.001). High-risk and intermediate-risk tumors more frequently tended to grow exponentially compared to low-risk tumors (43.8% vs 37.0% vs 8.3%, p = 0.067). The authors found no correlation of growth velocity with CNS WHO grade in their cohort (1.30 mm/year for CNS WHO grade 1 vs 4.01 mm/year for CNS WHO grade 2, p = 0.185). CONCLUSIONS: A radiological risk assessment using two parameters-T2-weighted signal iso/hyperintensity and absence of calcifications-allows estimation of growth velocity and characteristics of untreated intracranial meningiomas. Only high-risk tumors exhibit the potential for rapid growth. However, rapid tumor growth does not indicate a higher CNS WHO grade per se.

Perfusion Abnormalities on 24-Hour Perfusion Imaging in Patients With Complete Endovascular Reperfusion.

BACKGROUND: Perfusion abnormalities in the infarct and salvaged penumbra have been proposed as a potential reason for poor clinical outcome (modified Rankin Scale score >2) despite complete angiographic reperfusion (Thrombolysis in Cerebral Infarction [TICI3]). In this study, we aimed to identify different microvascular perfusion patterns and their association with clinical outcomes among TICI3 patients. METHODS: University Hospital Bern's stroke registry of all patients between February 2015 and December 2021. Macrovascular reperfusion was graded using the TICI scale. Microvascular reperfusion status was evaluated within the infarct area on cerebral blood volume and cerebral blood flow perfusion maps obtained 24-hour postintervention. Primary outcome was functional independence (90-day modified Rankin Scale score 0-2) evaluated with the logistic regression analysis adjusted for age, sex, and 24-hour infarct volume from follow-up imaging. RESULTS: Based on microvascular perfusion findings, the entire cohort (N=248) was stratified into one of the 4 clusters: (1) normoperfusion (no perfusion abnormalities; n=143/248); (2) hyperperfusion (hyperperfusion on both cerebral blood volume and cerebral blood flow; n=54/248); (3) hypoperfusion (hypoperfusion on both cerebral blood volume and cerebral blood flow; n=14/248); and (4) mixed (discrepant findings, eg, cerebral blood volume hypoperfusion and cerebral blood flow hyperperfusion; n=37/248). Compared with the normoperfusion cluster, patients in the hypoperfusion cluster were less likely to achieve functional independence (adjusted odds ratio, 0.3 [95% CI, 0.1-0.9]), while patients in the hyperperfusion cluster tended to have better outcomes (adjusted odds ratio, 3.3 [95% CI, 1.3-8.8]). CONCLUSIONS: In around half of TICI3 patients, perfusion abnormalities on the microvascular level can be observed. Microvascular hypoperfusion, despite complete macrovascular reperfusion, is rare but may explain the poor clinical course among some TICI3 patients, while a detrimental effect of hyperperfusion after reperfusion could not be confirmed.

Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial.

BACKGROUND: Whether hemorrhagic transformation (HT) modifies the treatment effect of early compared with late initiation of direct oral anticoagulation in people with ischemic stroke and atrial fibrillation is unknown. METHODS: This is a post hoc analysis of the ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation). The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days. Secondary outcomes were the individual components, 30- and 90-day functional outcome. We estimated outcomes based on HT, subclassified as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on prerandomization imaging (core laboratory rating) using adjusted risk differences between treatment arms. RESULTS: Overall, 247 of 1970 participants (12.5%) had HT (114 HI 1, 77 HI 2, 34 PH 1, 22 PH 2). For the primary outcome, the estimated adjusted risk difference (early versus late) was -2.2% (95% CI, -7.8% to 3.5%) in people with HT (HI: -4.7% [95% CI, -10.8% to 1.4%]; PH: 6.1% [95% CI, -8.5% to 20.6%]) and -0.9% (95% CI, -2.6% to 0.8%) in people without HT. Numbers of symptomatic intracranial hemorrhage were identical in people with and without HT. With early treatment, the estimated adjusted risk difference for poor 90-day functional outcome (modified Rankin Scale score, 3-6) was 11.5% (95% CI, -0.8% to 23.8%) in participants with HT (HI: 7.4% [95% CI, -6.4% to 21.2%]; PH: 25.1% [95% CI, 0.2% to 50.0%]) and -2.6% (95% CI, -7.1% to 1.8%) in people without HT. CONCLUSIONS: We found no evidence of major treatment effect heterogeneity or safety concerns with early compared with late direct oral anticoagulation initiation in people with and without HT. However, early direct oral anticoagulation initiation may worsen functional outcomes in people with PH. REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT03148457.

Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial.

Importance: Whether infarct size modifies the treatment effect of early vs late direct oral anticoagulant (DOAC) initiation in people with ischemic stroke and atrial fibrillation is unknown. Objective: To assess whether infarct size modifies the safety and efficacy of early vs late DOAC initiation. Design, Setting, and Participants: Post hoc analysis of participants from the multinational (>100 sites in 15 countries) randomized clinical Early Versus Later Anticoagulation for Stroke With Atrial Fibrillation (ELAN) trial who had (1) acute ischemic stroke, (2) atrial fibrillation, and (3) brain imaging available before randomization. The ELAN trial was conducted between October 2017 and December 2022. Data were analyzed from October to December 2023 for this post hoc analysis. Intervention: Early vs late DOAC initiation after ischemic stroke. Early DOAC initiation was within 48 hours for minor or moderate stroke or on days 6 to 7 for major stroke; late DOAC initiation was on days 3 to 4 for minor stroke, days 6 to 7 for moderate stroke, and days 12 to 14 for major stroke. Main Outcomes and Measures: The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, extracranial bleeding, systemic embolism, or vascular death within 30 days. The outcome was assessed according to infarct size (minor, moderate, or major) using odds ratios and risk differences between treatment arms. Interrater reliability for infarct size between the core laboratory and local raters was assessed, and whether this modified the estimated treatment effects was also examined. Results: A total of 1962 of the original 2013 participants (909 [46.3%] female; median [IQR] age, 77 [70-84] years) were included. The primary outcome occurred in 10 of 371 participants (2.7%) with early DOAC initiation vs 11 of 364 (3.0%) with late DOAC initiation among those with minor stroke (odds ratio [OR], 0.89; 95% CI, 0.38-2.10); in 11 of 388 (2.8%) with early DOAC initiation vs 14 of 392 (3.6%) with late DOAC initiation among those with moderate stroke (OR, 0.80; 95% CI, 0.35-1.74); and in 8 of 219 (3.7%) with early DOAC initiation vs 16 of 228 (7.0%) with late DOAC initiation among those with major stroke (OR, 0.52; 95% CI, 0.21-1.18). The 95% CI for the estimated risk difference of the primary outcome in early anticoagulation was -2.78% to 2.12% for minor stroke, -3.23% to 1.76% for moderate stroke, and -7.49% to 0.81% for major stroke. There was no significant treatment interaction for the primary outcome. For infarct size, interrater reliability was moderate (κ = 0.675; 95% CI, 0.647-0.702) for local vs core laboratory raters and strong (κ = 0.875; 95% CI, 0.855-0.894) between core laboratory raters. Conclusions and Relevance: The treatment effect of early DOAC initiation did not differ in people with minor, moderate, or major stroke assessed by brain imaging. Early treatment was not associated with a higher rate of adverse events, especially symptomatic intracranial hemorrhage, for any infarct size, including major stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03148457.

Ultrasound intima-media thickness cut-off values for the diagnosis of giant cell arteritis using a dual clinical and MRI reference standard and cardiovascular risk stratification.

Objectives: To derive segmental cut-off values and measures of diagnostic accuracy for the intima-media thickness of compressed temporal artery segments for the diagnosis of giant cell arteritis (GCA) on the patient level. To examine the influence of cardiovascular risk. Methods: Retrospectively, patients evaluated for GCA with an ultrasound of the temporal arteries and an MRI of the head, including a T1-fatsat-black blood (T1-BB) sequence, were identified and classified based on cardiovascular risk and a dual reference standard of T1-BB on the segmental level and the clinical diagnosis on the patient level. Intima-media thickness of the common superficial temporal artery (CSTA), frontal and parietal branches (FB, PB) were measured by compression technique. Statistically and clinically optimal (specificity of approx. 90% for the patient level) cut-offs were derived. Diagnostic accuracy was evaluated on the patient level. Results: The population consisted of 144 patients, 74 (51.4%) with and 70 (48.6%) without GCA. The statistically optimal cut-offs were 0.86 mm, 0.68 mm and 0.67 mm for the CSTA, the FB and PB, respectively. On the patient level sensitivity and specificity were 86.5 and 81.4%. Clinically optimal cut-offs were 1.01 mm, 0.82 mm and 0.69 mm and showed a sensitivity of 79.7% and a specificity of 90.0%. For patients without high cardiovascular risk, statistically optimal cut-offs showed a sensitivity of 89.6% and a specificity of 90.5%. Conclusion: Newly derived ultrasound intima-media thickness cut-offs with a dual reference standard show high diagnostic accuracy on the patient level for the diagnosis of GCA, particularly in patients without high cardiovascular risk.

Incidence, Risk Factors, and Clinical Implications of Subarachnoid Hyperdensities on Flat-Panel Detector CT following Mechanical Thrombectomy in Patients with Anterior Circulation Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Flat-panel detector CT immediately after mechanical thrombectomy can detect complications, including early hemorrhagic transformation and subarachnoid hyperdensities. The clinical significance of subarachnoid hyperdensities in patients undergoing mechanical thrombectomy remains unclear. MATERIALS AND METHODS: We studied 223 patients who underwent mechanical thrombectomy for anterior circulation stroke who had flat-panel detector CT performed immediately after the procedure and had follow-up imaging within 24 hours. Subarachnoid hyperdensity severity was categorized into 5 grades (subarachnoid hyperdensities, 0: absent to subarachnoid hyperdensities, IV: extensive). Baseline and procedural characteristics as well as outcome measures were analyzed using group comparisons and multivariable logistic regression analyses. RESULTS: Overall, 100/223 (45%) patients showed subarachnoid hyperdensities on immediate postinterventional flat-panel detector CT. The factors associated with an increased subarachnoid hyperdensity risk were the following: medium-vessel occlusion or distal-vessel occlusion compared with a large-vessel occlusion, a more distal device position, a higher number of device passes, a larger volume of contrast applied, worse final reperfusion expanded TICI, and after receiving IV thrombolysis. The occurrence of subarachnoid hyperdensity grades II-IV was independently associated with worse functional outcomes (adjusted OR for mRS, 3-6: 2.2; 95% CI 1.1-4.3), whereas patients with subarachnoid hyperdensity grade I had outcomes similar to those in patients without subarachnoid hyperdensities. CONCLUSIONS: Our study identified risk factors for subarachnoid hyperdensities, most of which reflect increasingly challenging procedures or more peripheral recanalization attempts. The presence of subarachnoid hyperdensity grades II-IV was associated with poorer outcomes, suggesting the need for personalized strategies to reduce its incidence and severity or potentially improve recovery after subarachnoid hyperdensities.

CT brain perfusion patterns and clinical outcome after successful cardiopulmonary resuscitation: A pilot study.

AIM: CT perfusion is a valuable tool for evaluating cerebrovascular diseases, but its role in patients with hypoxic ischaemic encephalopathy is unclear. This study aimed to investigate 1) the patterns of cerebral perfusion changes that may occur early on after successful resuscitation, and 2) their correlation with clinical outcome to explore their value for predicting outcome. METHODS: We conducted a retrospective analysis of perfusion maps from patients who underwent CT brain perfusion within 12 h following successful resuscitation. We classified the perfusion changes into distinct patterns. According to the cerebral performance category (CPC) score clinical outcome was categorised as favourable (CPC 1-2), or unfavourable (CPC 3-5). RESULTS: A total of 87 patients were included of whom 33 had a favourable outcome (60.6% male, mean age 60 ± 16 years), whereas 54 exhibited an unfavourable outcome (59.3% male, mean age 60 ± 19 years). Of the patients in the favourable outcome group, 30.3% showed no characteristic perfusion changes, in contrast to the unfavourable outcome group where all patients exhibit changes in perfusion. Eighteen perfusion patterns were identified. The most significant patterns for prediction of unfavourable outcome in terms of their high specificity and frequency were hypoperfusion of the brainstem as well as coexisting hypoperfusion of the brainstem and thalamus. CONCLUSION: This pilot study identified various perfusion patterns in patients after resuscitation, indicative of circulatory changes associated with post-cardiac-arrest brain injury. After validation, certain patterns could potentially be used in conjunction with other prognostic markers for stratifying patients and adjusting personalized treatment following cardiopulmonary resuscitation. Normal brain perfusion within 12 h after resuscitation is predictive of favourable outcome with high specificity.

Post-stroke cognitive impairment remains highly prevalent and disabling despite state-of-the-art stroke treatment.

BACKGROUND: State-of-the-art stroke treatment significantly reduces lesion size and stroke severity, but it remains unclear whether these therapeutic advances have diminished the burden of post-stroke cognitive impairment (PSCI). AIMS: In a cohort of patients receiving modern state-of-the-art stroke care including endovascular therapy, we assessed the frequency of PSCI and the pattern of domain-specific cognitive deficits, identified risk factors for PSCI, and determined the impact of acute PSCI on stroke outcome. METHODS: In this prospective monocentric cohort study, we examined patients with first-ever anterior circulation ischemic stroke without pre-stroke cognitive decline, using a comprehensive neuropsychological assessment ⩽10 days after symptom onset. Normative data were stratified by demographic variables. We defined PSCI as at least moderate (<1.5 standard deviation) deficits in ⩾2 cognitive domains. Multivariable regression analysis was applied to define risk factors for PSCI. RESULTS: We analyzed 329 non-aphasic patients admitted from December 2020 to July 2023 (67.2 ± 14.4 years old, 41.3% female, 13.1 ± 2.7 years of education). Although most patients had mild stroke (median National Institutes of Health Stroke Scale (NIHSS) 24 h = 1.00 (0.00; 3.00); 87.5% with NIHSS ⩽ 5), 69.3% of them presented with PSCI 2.7 ± 2.0 days post-stroke. The most severely and often affected cognitive domains were verbal learning, episodic memory, executive functions, selective attention, and constructive abilities (39.1%-51.2% of patients), whereas spatial neglect was less frequent (18.5%). The risk of PSCI was reduced with more years of education (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23-0.99) and right hemisphere lesions (OR = 0.47, 95% CI = 0.26-0.84), and increased with stroke severity (NIHSS 24 h, OR = 4.19, 95% CI = 2.72-6.45), presence of hyperlipidemia (OR = 1.93, 95% CI = 1.01-3.68), but was not influenced by age. After adjusting for stroke severity and depressive symptoms, acute PSCI was associated with poor functional outcome (modified Rankin Scale > 2, F = 13.695, p < 0.001) and worse global cognition (Montreal Cognitive Assessment (MoCA) score, F = 20.069, p < 0.001) at 3 months post-stroke. CONCLUSION: Despite modern stroke therapy and many strokes having mild severity, PSCI in the acute stroke phase remains frequent and associated with worse outcome. The most prevalent were learning and memory deficits. Cognitive reserve operationalized as years of education independently protects post-stroke cognition.

Applied deep learning in neurosurgery: identifying cerebrospinal fluid (CSF) shunt systems in hydrocephalus patients.

BACKGROUND: Over the recent decades, the number of different manufacturers and models of cerebrospinal fluid shunt valves constantly increased. Proper identification of shunt valves on X-ray images is crucial to neurosurgeons and radiologists to derive further details of a specific shunt valve, such as opening pressure settings and MR scanning conditions. The main aim of this study is to evaluate the feasibility of an AI-assisted shunt valve detection system. METHODS: The dataset used contains 2070 anonymized images of ten different, commonly used shunt valve types. All images were acquired from skull X-rays or scout CT-images. The images were randomly split into a 80% training and 20% validation set. An implementation in Python with the FastAi library was used to train a convolutional neural network (CNN) using a transfer learning method on a pre-trained model. RESULTS: Overall, our model achieved an F1-score of 99% to predict the correct shunt valve model. F1-scores for individual shunt valves ranged from 92% for the Sophysa Sophy Mini SM8 to 100% for several other models. CONCLUSION: This technology has the potential to automatically detect different shunt valve models in a fast and precise way and may facilitate the identification of an unknown shunt valve on X-ray or CT scout images. The deep learning model we developed could be integrated into PACS systems or standalone mobile applications to enhance clinical workflows.

The analysis of association between single features of small vessel disease and stroke outcome shows the independent impact of the number of microbleeds and presence of lacunes.

The impact of small vessel disease (SVD) on stroke outcome was investigated either separately for its single features in isolation or for SVD sum score measuring a qualitative (binary) assessment of SVD-lesions. We aimed to investigate which SVD feature independently impacts the most on stroke outcome and to compare the continuous versus binary SVD assessment that reflects pronouncement and presence correspondingly. Patients with a first-ever anterior circulation ischemic stroke were retrospectively investigated. We performed an ordered logistic regression analysis to predict stroke outcome (mRS 3 months, 0-6) using age, stroke severity, and pre-stroke disability as baseline input variables and adding SVD-features (lacunes, microbleeds, enlarged perivascular spaces, white matter hyperintensities) assessed either continuously (model 1) or binary (model 2). The data of 873 patients (age 67.9 ± 15.4, NIHSS 24 h 4.1 ± 4.8) was analyzed. In model 1 with continuous SVD-features, the number of microbleeds was the only independent predictor of stroke outcome in addition to clinical parameters (OR 1.21; 95% CI 1.07-1.37). In model 2 with the binary SVD assessment, only the presence of lacunes independently improved the prediction of stroke outcome (OR 1.48, 1.1-1.99). In a post hoc analysis, both the continuous number of microbleeds and the presence of lacunes were independent significant predictors. Thus, the number of microbleeds evaluated continuously and the presence of lacunes are associated with stroke outcome independent from age, stroke severity, pre-stroke disability and other SVD-features. Whereas the presence of lacunes is adequately represented in SVD sum score, the microbleeds assessment might require another cutoff and/or gradual scoring, when prediction of stroke outcome is needed.

Magnetic resonance imaging in acute meningoencephalitis of viral and unknown origin: frequent findings and prognostic potential.

Background: Magnetic resonance imaging (MRI) findings in meningoencephalitis have mainly been described in terms of their diagnostic value rather than their prognostic potential, except for herpes simplex virus (HSV) encephalitis. The aims of our study were to describe frequency and anatomic locations of MRI abnormalities specific to limbic, circadian and motor systems in a cohort of meningoencephalitis patients, as well as to investigate the prognostic value of these MRI findings. Methods: A secondary, selective analysis of a retrospective database including all meningitis, meningoencephalitis and encephalitis cases treated between 2016 and 2018 in the University hospital of Bern, Switzerland was performed. Patients with meningitis of any cause, bacterial or autoimmune causes of encephalitis were excluded. Results: MRI scans and clinical data from 129 meningoencephalitis cases found that the most frequent causes were tick-borne encephalitis (TBE, 42%), unknown pathogens (40%), VZV (7%), and HSV1 (5%). At discharge, median modified Rankin Score (mRS) was 3 (interquartile range, IQR, 1), 88% of patients had persisting signs and symptoms. After a median of 17 months, median Glasgow Outcome Score (GOS) was 5 (IQR 1), 39% of patients still had residual signs or symptoms. All patients with HSV, 27% with TBE and 31% of those with meningoencephalitis of unknown etiology had fluid-attenuated inversion recovery (FLAIR) and to a lesser extent diffusion-weighted imaging (DWI) lesions in their initial MRI, with highly overlapping anatomical distribution. In one fifth of TBE patients the limbic system was affected. Worse outcome was associated with presence of DWI and/or FLAIR lesions and lower normalized apparent diffusion coefficient (ADC) signal intensities. Conclusion: Presence of FLAIR lesions, restricted diffusion as well as the extent of ADC hypointensity in initial MRI are parameters which might be of prognostic value regarding the longterm clinical outcome for patients with meningoencephalitis of viral and of unknown origin. Although not described before, affection of limbic structures by TBE is possible as shown by our results: A substantial proportion of our TBE patients had FLAIR signal abnormalities in these regions.

Cerebral small vessel disease and stroke: Linked by stroke aetiology, but not stroke lesion location or size.

BACKGROUND: Cerebral small vessel disease (SVD) has previously been associated with worse stroke outcome, vascular dementia, and specific post-stroke cognitive deficits. The underlying causal mechanisms of these associations are not yet fully understood. We investigated whether a relationship between SVD and certain stroke aetiologies or a specific stroke lesion anatomy provides a potential explanation. METHODS: In a retrospective observational study, we examined 859 patients with first-ever, non-SVD anterior circulation ischemic stroke (age = 69.0±15.2). We evaluated MRI imaging markers to assess an SVD burden score and mapped stroke lesions on diffusion-weighted MRI. We investigated the association of SVD burden with i) stroke aetiology, and ii) lesion anatomy using topographical statistical mapping. RESULTS: With increasing SVD burden, stroke of cardioembolic aetiology was more frequent (ρ = 0.175; 95 %-CI = 0.103;0.244), whereas cervical artery dissection (ρ = -0.143; 95 %-CI = -0.198;-0.087) and a patent foramen ovale (ρ = -0.165; 95 %-CI = -0.220;-0.104) were less frequent stroke etiologies. However, no significant associations between SVD burden and stroke aetiology remained after additionally controlling for age (all p>0.125). Lesion-symptom-mapping and Bayesian statistics showed that SVD burden was not associated with a specific stroke lesion anatomy or size. CONCLUSIONS: In patients with a high burden of SVD, non-SVD stroke is more likely to be caused by cardioembolic aetiology. The common risk factor of advanced age may link both pathologies and explain some of the existing associations between SVD and stroke. The SVD burden is not related to a specific stroke lesion location.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Adaptation of the Concept of Brain Reserve for the Prediction of Stroke Outcome: Proxies, Neural Mechanisms, and Significance for Research.

The prediction of stroke outcome is challenging due to the high inter-individual variability in stroke patients. We recently suggested the adaptation of the concept of brain reserve (BR) to improve the prediction of stroke outcome. This concept was initially developed alongside the one for the cognitive reserve for neurodegeneration and forms a valuable theoretical framework to capture high inter-individual variability in stroke patients. In the present work, we suggest and discuss (i) BR-proxies-quantitative brain characteristics at the time stroke occurs (e.g., brain volume, hippocampus volume), and (ii) proxies of brain pathology reducing BR (e.g., brain atrophy, severity of white matter hyperintensities), parameters easily available from a routine MRI examination that might improve the prediction of stroke outcome. Though the influence of these parameters on stroke outcome has been partly reported individually, their independent and combined impact is yet to be determined. Conceptually, BR is a continuous measure determining the amount of brain structure available to mitigate and compensate for stroke damage, thus reflecting individual differences in neural resources and a capacity to maintain performance and recover after stroke. We suggest that stroke outcome might be defined as an interaction between BR at the time stroke occurs and lesion load. BR in stroke can potentially be influenced, e.g., by modifying cardiovascular risk factors. In addition to the potential power of the BR concept in a mechanistic understanding of inter-individual variability in stroke outcome and establishing individualized therapeutic approaches, it might help to strengthen the synergy of preventive measures in stroke, neurodegeneration, and healthy aging.

Split-brain syndrome after subarachnoid haemorrhage.

We present the case of a patient with extensive ischaemia of the corpus callosum (CC) including all its anatomical subdivisions, caused by a ruptured aneurysm of the anterior cerebral artery (ACA). This resulted in subarachnoid haemorrhage (SAH) and subsequently in cerebral vasospasm. The aneurysm was coiled, the vasospasm treated with repetitive intra-arterial spasmolysis and the patient then received intensive neurorehabilitative care. The case is an example of ischaemic infarction, which happens rarely in the CC after SAH, and even more rarely affects the CC along its entire length. The case is further remarkable for the resulting nearly complete and isolated split-brain syndrome: CC disconnection syndromes are only exceptionally seen after vascular callosal damage because they are most often overshadowed by symptoms resulting from coaffected adjacent brain areas.

Small vessel disease burden and risk of recurrent cerebrovascular events in patients with lacunar stroke and intracerebral haemorrhage attributable to deep perforator arteriolopathy.

INTRODUCTION: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. PATIENTS AND METHODS: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months. RESULTS: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aORshift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. DISCUSSION/CONCLUSION: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

Can we forecast poor outcome in herpes simplex and varicella zoster encephalitis? A narrative review.

Herpes simplex virus (HSV) and varicella zoster virus (VZV) are among the most commonly diagnosed infectious causes of sporadic encephalitis worldwide. Despite treatment, mortality and morbidity rates remain high, especially for HSV encephalitis. This review is intended to provide an overview of the existing scientific literature on this topic from the perspective of a clinician who is confronted with serious decisions about continuation or withdrawal of therapeutic interventions. We performed a literature review searching two databases and included 55 studies in the review. These studies documented or investigated specifically outcome and predictive parameters of outcome of HSV and/or VZV encephalitis. Two reviewers independently screened and reviewed full-text articles meeting the inclusion criteria. Key data were extracted and presented as a narrative summary. Both, HSV and VZV encephalitis have mortality rates between 5 and 20% and complete recovery rates range from 14 to 43% for HSV and 33 to 49% for VZV encephalitis. Prognostic factors for both VZV and HSV encephalitis are older age and comorbidity, as well as severity of disease and extent of magnetic resonance imaging (MRI) lesions on admission, and delay in treatment initiation for HSV encephalitis. Although numerous studies are available, the main limiting factors are the inconsistent patient selection and case definitions as well as the non-standardised outcome measures, which hampers the comparability of the studies. Therefore, larger and standardised observational studies applying validated case definitions and outcome measures including quality of life assessment are required to provide solid evidence to answer the research question.