Fatigue after spontaneous intracerebral haemorrhage: prevalence and associated factors.

BACKGROUND: Fatigue is a major complaint in stroke survivors, but data focusing on intracerebral haemorrhage (ICH) survivors are scarce. In a cohort of spontaneous ICH survivors, we assessed the long-term prevalence of fatigue and its associated factors. METHODS: We included consecutive 1-year ICH survivors from the prospective, observational, single-centre Prognosis of Intracerebral Haemorrhage (PITCH) study. We evaluated fatigue (defined as a score ≥ 4 in Chalder Fatigue Scale); the severity of neurological, depressive, and anxiety symptoms; and functional disability 1, 3, and 6 years after ICH. We performed univariable and multivariable models to evaluate clinical factors and brain magnetic resonance imaging (MRI) small vessel disease (SVD) markers associated with fatigue. RESULTS: Of 255 1-year ICH survivors, 153 (60%) underwent fatigue screening and were included in this study. Seventy-eight patients (51%) reported fatigue at 1-year, 56/110 (51%) at 3-year, and 27/67 (40%) at 6-year follow-up. Patients with fatigue exhibited more severe concomitant depressive/anxiety symptoms, but the severity of depressive symptoms was the only clinical factor significantly associated with 1-year fatigue in multivariable analysis (adjusted odds ratio 1.4 for one-point increase; 95% confidence interval 1.2-1.6). Patients with severe cortical atrophy at baseline had increased risk of fatigue at 1-year follow-up compared to patients with mild/no cortical atrophy (adjusted odds ratio 2.5; 95% confidence interval 1.1-5.8). CONCLUSIONS: Fatigue after ICH is frequent and long-lasting, and it is associated with cortical atrophy (but not with other MRI markers of cerebral SVD). The link between fatigue and depressive symptoms may represent a potential therapeutic target.

Brush Sign on pre-treatment imaging is associated with good functional outcome in stroke patients treated with mechanical thrombectomy: A prospective monocentric study.

BACKGROUND: The Brush Sign (BrS) is a radiological biomarker (MRI) showing signal decrease of subependymal and deep medullary veins on paramagnetic-sensitive magnetic resonance sequences. Previous studies have shown controversial results regarding the prognostic value of BrS. We aimed to assess whether BrS on T2*-weighted sequences could predict functional prognosis in patients treated with mechanical thrombectomy (MT). METHODS: We included all consecutive patients with large artery occlusion related stroke in anterior circulation treated with MT between February 2020 and August 2022 at Reims University Hospital. Multivariable logistic regression models were used to investigate factors associated with BrS and its impact on outcomes. RESULTS: Of the 327 included patients, 124 (37,9%) had a BrS on baseline MRI. Mean age was 72 ± 16 years and 184 (56,2 %) were female. In univariate analysis, BrS was associated with a younger age (67 vs 74; p<0.001), a higher NIHSS score (16(10-20) vs 13(8-19); p = 0.047) history of diabetes (15.3% vs 26.1 %; p = 0.022) and a shorter onset to MRI time (145.5 (111.3-188.5) vs 162 (126-220) p = 0.008). In multivariate analyses, patients with a BrS were younger (OR:0.970 (0.951 - 0.989)), tend to have a higher NIHSS score at baseline (OR:1.046 (1.000 - 1.094) and were less likely to have diabetes (OR: 0.433; 0.214-0.879). The presence of BrS was independently associated with functional independence (OR: 2.234(1.158-4,505) at 3 months but not with mortality nor with symptomatic intracerebral hemorrhage. CONCLUSION: BrS on pre-treatment imaging could be considered as a biomarker of physiological adaptation to cerebral ischemia, allowing prolonged viability of brain tissue and might participate in the therapeutic decision.

Impact of Day 1 carotid patency on outcome in dissection-related tandem occlusions treated with mechanical thrombectomy.

BACKGROUND: The clinical benefit of mechanical thrombectomy(MT) for stroke patients with tandem occlusion is similar to that of isolated intracranial occlusions. However, the management of cervical internal carotid artery(ICA) occlusion during the MT, particularly in the setting of carotid dissection, remains controversial. We aimed to investigate the clinical impact of cervical ICA patency at day 1 on 3-month functional outcome. METHODS: We collected data from the Endovascular Treatment in Ischemic Stroke, a prospective national registry in 30 French centers performing MT between January 2015 and January 2022. Inclusion criteria were consecutive tandem occlusions related to cervical ICA dissection treated with MT. Tandem occlusions of other etiology, isolated cervical ICA occlusions without intracranial thrombus and patients without day-1 ICA imaging were excluded. Primary endpoint was the 3-month functional outcome. Secondary endpoints included intracranial hemorrhage(ICH), excellent outcome, mortality and early neurological improvement. A sensitivity analysis was performed in patients with intracranial favorable recanalization after MT. RESULTS: During the study period, 137 patients were included of which 89(65%) presented ICA patency at day 1. The odds of favorable outcome did not significantly differ between patients with patent and occluded ICA at day 1(68.7 vs 59.1%;aOR=1.30;95%CI 0.56-3.00,p=0.54). Excellent outcome, early neurological improvement, mortality and ICH were also comparable between groups. Sensitivity analysis showed similar results. CONCLUSION: ICA patency at day 1 in patients with tandem occlusions related to dissection did not seem to influence functional outcome. Endovascular recanalization of the cervical ICA including stenting might not be systematically required in this setting.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Endovascular Thrombectomy Outcomes with and without Intravenous Thrombolysis for Large Ischemic Cores Identified with CT or MRI.

Background Whether intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) provides additional benefits in patients with acute ischemic stroke (AIS) and a large infarct core (LIC) remains unclear. Purpose To examine whether treatment with IVT before EVT is beneficial in patients with LIC identified with CT or MRI (Alberta Stroke Program Early CT score 0-5). Materials and Methods This retrospective study included consecutive adult patients diagnosed with AIS due to large vessel occlusion (LVO) and LIC treated with EVT who were enrolled in the ETIS (Endovascular Treatment in Ischemic Stroke) Registry in France between January 2015 and January 2022. The primary outcome measure was a favorable outcome (modified Rankin Scale [mRS] score 0-3) at 90 days. Secondary outcomes included functional independence (mRS score 0-2) at 90 days, improvement in degree of disability (ordinal shift in mRS score toward a better outcome) at 90 days, early neurologic improvement at 24 hours, and successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b or higher). Safety outcomes included symptomatic intracerebral hemorrhage within 24 hours and mortality at 90 days. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to assess the treatment effect of IVT adjusted for baseline variables. Results Of 1408 patients (mean age, 68.3 years ± 15.4 [SD]; 789 men), 654 (46.4%) were treated with IVT prior to EVT. In the IPTW-adjusted data set, IVT plus EVT was associated with a higher rate of favorable outcome at 90 days (odds ratio [OR], 1.24 [95% CI: 1.05, 1.46]; P = .01), functional independence at 90 days (OR, 1.47 [95% CI: 1.22, 1.77]; P < .001), improvement in degree of disability at 90 days (common OR, 1.30 [95% CI: 1.13, 1.49]; P < .001), early neurologic improvement (OR, 1.26 [95% CI: 1.07, 1.49]; P = .005), and successful reperfusion (OR, 1.43 [95% CI: 1.14, 1.79]; P = .002) than EVT alone. Rates of brain hemorrhage within 24 hours and mortality at 90 days were similar between groups. Conclusion In patients with AIS due to LVO with LIC identified with CT or MRI, treatment with IVT before EVT appeared to provide a clinical benefit over EVT alone. Clinical trial registration no. NCT03776877 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kallmes and Rabinstein in this issue.

Fatty acid photodecarboxylase is an ancient photoenzyme that forms hydrocarbons in the thylakoids of algae.

Fatty acid photodecarboxylase (FAP) is one of the few enzymes that require light for their catalytic cycle (photoenzymes). FAP was first identified in the microalga Chlorella variabilis NC64A, and belongs to an algae-specific subgroup of the glucose-methanol-choline oxidoreductase family. While the FAP from C. variabilis and its Chlamydomonas reinhardtii homolog CrFAP have demonstrated in vitro activities, their activities and physiological functions have not been studied in vivo. Furthermore, the conservation of FAP activity beyond green microalgae remains hypothetical. Here, using a C. reinhardtii FAP knockout line (fap), we showed that CrFAP is responsible for the formation of 7-heptadecene, the only hydrocarbon of this alga. We further showed that CrFAP was predominantly membrane-associated and that >90% of 7-heptadecene was recovered in the thylakoid fraction. In the fap mutant, photosynthetic activity was not affected under standard growth conditions, but was reduced after cold acclimation when light intensity varied. A phylogenetic analysis that included sequences from Tara Ocean identified almost 200 putative FAPs and indicated that FAP was acquired early after primary endosymbiosis. Within Bikonta, FAP was retained in secondary photosynthetic endosymbiosis lineages but absent from those that lost the plastid. Characterization of recombinant FAPs from various algal genera (Nannochloropsis, Ectocarpus, Galdieria, Chondrus) provided experimental evidence that FAP photochemical activity was present in red and brown algae, and was not limited to unicellular species. These results thus indicate that FAP was conserved during the evolution of most algal lineages where photosynthesis was retained, and suggest that its function is linked to photosynthetic membranes.

Long-term neuropsychiatric symptoms in spontaneous intracerebral haemorrhage survivors.

OBJECTIVE: Neuropsychiatric (NP) symptoms are prominent features of cognitive decline, but they have been understudied in patients with spontaneous intracerebral haemorrhage (ICH). In ICH survivors, we aimed at assessing NP symptoms prevalence and profiles, and their influence on long-term outcomes. METHODS: We analysed data from consecutive 6-month ICH survivors enrolled in the Prognosis of Intracerebral Haemorrhage study. We performed NP evaluation using the Neuropsychiatric Inventory Questionnaire. Patients underwent long-term clinical follow-up after ICH (median follow-up time 7.2 years, IQR 4.8-8.2). RESULTS: Out of 560 patients with ICH, 265 survived at 6 months. NP evaluation 6 months after ICH was feasible in 202 patients. NP symptoms were present in 112 patients (55%), and in 36 out of 48 patients (75%) with post-ICH dementia. Affective symptoms were present in 77 patients (38%), followed by vegetative symptoms (52 patients, 26%) and hyperactivity (47 patients, 23%). Apathy and hyperactivity were associated with post-ICH dementia and cerebral amyloid angiopathy MRI profile (all p<0.05). Apathy and hyperactivity prevailing over affective symptoms at 6-month follow-up were associated with higher risks of developing new-onset dementia (HR 5.40; 95% CI 2.27 to 12.84), while presence or severity of NP symptoms were not. CONCLUSION: NP symptoms were present in more than half of 6-month ICH survivors, with higher prevalence and severity in patients with post-ICH dementia. Distinctive NP profile might be associated to cognitive status and inform on long-term dementia risk.

Long-term functional decline of spontaneous intracerebral haemorrhage survivors.

OBJECTIVE: To identify in patients who survived 6 months after a spontaneous intracerebral haemorrhage (ICH) baseline characteristics and new clinical events associated with functional decline. METHODS: In a single-centre study, we prospectively included 6-month survivors with a modified Rankin Scale (mRS) score 0-3. We defined functional decline by a transition to mRS 4-5. We evaluated associations of baseline characteristics and new clinical events with functional decline, using univariate and multivariable models. RESULTS: Of 560 patients, 174 (31%) had an mRS score 0-3 at 6 months. During a median follow-up of 9 years (IQR 8.1-9.5), 40 (23%) converted to mRS 4-5. Age, diabetes mellitus, ICH volume and higher mRS scores at 6 months were independently associated with functional decline. Among baseline MRI markers, presence of strictly lobar cerebral microbleeds (CMBs), and mixed lobar and deep CMBs were independently associated with functional decline. When new clinical events occurring during follow-up were added in multivariable models, age (cause-specific HR (CSHR): 1.07; 95% CI: 1.03 to 1.11), ICH volume (CSHR: 1.03; 95% CI: 1.01 to 1.06), mRS score at 6 months (CSHR per 1 point increase 1.61, 95% CI 1.07 to 2.43), occurrence of dementia (CSHR: 3.81, 95% CI: 1.78 to 8.16) and occurrence of any stroke (CSHR: 4.29, 95% CI: 1.80 to 10.22) remained independently associated with transition to mRS 4-5. INTERPRETATION: Almost one-fourth of patients with spontaneous ICH developed a functional decline over time. Age, ICH volume, higher mRS score at 6 months and new clinical events after ICH are the major determinants.

Use of MRI to predict symptomatic haemorrhagic transformation after thrombolysis for cerebral ischaemia.

BACKGROUND AND OBJECTIVE: Predictors of symptomatic haemorrhagic transformation (s-HT) of cerebral ischaemia after intravenous recombinant tissue-plasminogen activator (rt-PA) were identified in studies using CT scans. We evaluated whether MRI can identify other predictors. METHOD: We analysed predictors of s-HT in a cohort of consecutive patients who received intravenous rt-PA for cerebral ischaemia after MRI at baseline. We used receiver operating characteristic curves considering an area under the curve (AUC) of 0.70 or higher as indicating acceptable discrimination. RESULTS: Of 944 patients, 49 patients (5.2%) developed s-HT. Clinical factors independently associated with s-HT were age (adjusted OR (adjOR) 1.03 for 1 year increase; 95% CI 1.01 to 1.05), excessive alcohol consumption (adjOR 3.13; 95% CI 1.32 to 7.42), recent transient ischaemic attack (adjOR 2.88; 95% CI 1.04 to 7.95) and baseline national institutes of health stroke scale score (adjOR 1.06 for 1 point increase; 95% CI 1.02 to 1.10). MRI predictors were vascular hyperintensities (adjOR 3.89; 95% CI 1.50 to 10.08), old infarcts (adjOR 2.01; 95% CI 1.11 to 3.66) and volume of diffusion-weighted imaging (DWI) abnormality (adjOR 1.02 for 1 cm3 increase; 95% CI 1.01 to 1.03). The only variable with an acceptable discrimination was volume of DWI abnormality (AUC 0.72; 95% CI 0.64 to 0.79), a value of 4 cm3 predicting s-HT with a 78% sensitivity and 58% specificity. Variables that can be assessed only with MRI did not predict s-HT. CONCLUSION: Although the volume of DWI abnormality predicts s-HT, other imaging characteristics that can only be assessed with MRI were not significantly associated with s-HT. Trial registration number NCT01614080.

Five-Year Risk of Major Ischemic and Hemorrhagic Events After Intracerebral Hemorrhage.

Background and Purpose- We aimed to determine incidences and predictors of major vascular events in intracerebral hemorrhage (ICH) survivors. Methods- We did a prospective observational cohort study in patients with spontaneous ICH from the Prognosis of Intracerebral Hemorrhage cohort in Lille, France. We studied incidences and predictors of long-term vascular events (cerebral and extracerebral, ischemic and hemorrhagic) in patients alive at 30 days with a prespecified subgroup analysis according to ICH location. We performed multivariable analyses (competing risk analyses, with death during follow-up as a competing event). Results- From the 560 patients with spontaneous ICH enrolled between November 2004 and March 2009, we included 310 patients (median age, 70 years). Eighty-two patients presented at least 1 major vascular event leading to an incidence rate of 20.0% (95% CI, 15.7-24.7) at 5 years after ICH. In the overall cohort, ischemic events were more frequent than hemorrhagic events. However, the incidence strikingly differed according to ICH location: deep ICH was associated with future ischemic events (subhazard ratio, 1.85; 95% CI, 1.01-3.40), whereas lobar ICH with hemorrhagic events (subhazard ratio, 2.38; 95% CI, 1.17-4.86). In deep ICH, the incidence of ischemic events at 5 years was 6× higher than the incidence of hemorrhagic events. Conclusions- ICH survivors are at high risk of both cerebral and extracerebral vascular events. The ischemic or hemorrhagic risk profile varies according to the index ICH location with a stronger ischemic risk in deep ICH. Secondary prevention, tailored on ICH location, should target not only cerebral recurrences but also extracerebral vascular events.

Stroke mimics and chameleons.

PURPOSE OF REVIEW: A stroke mimic is a situation in which a diagnosis of stroke at admission is not confirmed, and a stroke chameleon is a situation in which a stroke is revealed by clinical symptoms that are not usual in stroke. The objective of this review is to identify the most frequent clinical situations in which stroke mimics and chameleons are encountered and consequences for the patient. RECENT FINDINGS: The safety profile of intravenous thrombolysis (IVT) in patients who have stroke mimics is excellent, and intracranial hemorrhages are rare. Modern neuroimaging techniques help identifying most mimics. For stroke chameleons the role of imaging may be less important, especially when the clinical presentation is not suggestive of a brain disorder that request immediate neuroimaging. Education of health providers to identify such situations is crucial. SUMMARY: Stroke mimics account for up to 25% of admissions for probable strokes. The proportion of patients with stroke mimics decreases with use of MRI at baseline. Mimics cannot always be ruled out in emergency. The problem with mimics is that stroke facilities are not properly used, and patients may receive IVT. However, thrombolysis is usually well tolerated in mimics and we should not spend much time in all patients to improve diagnostic accuracy, knowing that the time lost is harmful in all patients, and will only prevent treating one mimic out of 100 patients. The problem with chameleons is more serious, because patients are not identified, and are not properly treated.

Role of Cerebral Microbleeds for Intracerebral Haemorrhage and Dementia.

PURPOSE OF REVIEW: Cerebral microbleeds (CMB)-small round or ovoid lesions detected in hyposignal on blood-sensitive MRI sequences-are promising radiological biomarkers of cerebral small vessel disease. Their relations with ischaemic or haemorragic stroke and their potential contribution to dementia have been extensively addressed. This article reviews recent research on the clinical significance of CMB that remains to be determined. RECENT FINDINGS: The presence, burden and location of CMB allow to obtain a more accurate estimate of intracerebral haemorrhage and ischaemic stroke risk. Most studies evaluating the association between CMB and dementia are hampered by methodological limitations and show conflicting results. CMB mainly reflect the severity of the underlying small vessel disease and should not be interpreted independently of the others neuroimaging biomarkers or the clinical setting. Future large prospective longitudinal studies and randomized controlled trials in various settings are required to determine whether specific therapies are beneficial in case of incidental findings.

A Selaginella moellendorffii Ortholog of KARRIKIN INSENSITIVE2 Functions in Arabidopsis Development but Cannot Mediate Responses to Karrikins or Strigolactones.

In Arabidopsis thaliana, the α/ß-fold hydrolase KARRIKIN INSENSITIVE2 (KAI2) is essential for normal seed germination, seedling development, and leaf morphogenesis, as well as for responses to karrikins. KAI2 is a paralog of DWARF14 (D14), the proposed strigolactone receptor, but the evolutionary timing of functional divergence between the KAI2 and D14 clades has not been established. By swapping gene promoters, we show that Arabidopsis KAI2 and D14 proteins are functionally distinct. We show that the catalytic serine of KAI2 is essential for function in plants and for biochemical activity in vitro. We identified two KAI2 homologs from Selaginella moellendorffii and two from Marchantia polymorpha. One from each species could hydrolyze the strigolactone analog GR24 in vitro, but when tested for their ability to complement Arabidopsis d14 and kai2 mutants, neither of these homologs was effective. However, the second KAI2 homolog from S. moellendorffii was able to complement the seedling and leaf development phenotypes of Arabidopsis kai2. This homolog could not transduce signals from exogenous karrikins, strigolactone analogs, or carlactone, but its activity did depend on the conserved catalytic serine. We conclude that KAI2, and most likely the endogenous signal to which it responds, has been conserved since the divergence of lycophytes and angiosperm lineages, despite their major developmental and morphogenic differences.