Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes.

Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of death-effector deoxyribonucleosides, which kill infectious foci-penetrating macrophages. However, the exact mechanisms whereby staphylococcal death-effector deoxyribonucleosides and coupled imbalances of intracellular deoxyribonucleotide species provoke immune cell death remain elusive. Here, we report that S. aureus systematically promotes an overload of deoxyribonucleotides to trigger mitochondrial rupture in macrophages, a fatal event that induces assembly of the caspase-9-processing apoptosome and subsequent activation of the intrinsic pathway of apoptosis. Remarkably, genetic disruption of this cascade not only helps macrophages coping with death-effector deoxyribonucleoside-mediated cytotoxicity but also enhances their infiltration into abscesses thereby ameliorating pathogen control and infectious disease outcomes in laboratory animals. Combined with the discovery of protective alleles in human CASP9, these data highlight the role of mitochondria-centered apoptosis during S. aureus infection and suggest that gene polymorphisms may shape human susceptibility toward a predominant pathogen.

Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.

OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. METHODS: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.

The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins.

Reversible S-palmitoylation of cysteine residues critically controls transient membrane tethering of peripheral membrane proteins. Little is known about how the palmitoylation machinery governs their defined localization and function. We monitored the spatially resolved reaction dynamics and substrate specificity of the core mammalian palmitoylation machinery using semisynthetic substrates. Palmitoylation is detectable only on the Golgi, whereas depalmitoylation occurs everywhere in the cell. The reactions are not stereoselective and lack any primary consensus sequence, demonstrating that substrate specificity is not essential for de-/repalmitoylation. Both palmitate attachment and removal require seconds to accomplish. This reaction topography and rapid kinetics allows the continuous redirection of mislocalized proteins via the post-Golgi sorting apparatus. Unidirectional secretion ensures the maintenance of a proper steady-state protein distribution between the Golgi and the plasma membrane, which are continuous with endosomes. This generic spatially organizing system differs from conventional receptor-mediated targeting mechanisms and efficiently counteracts entropy-driven redistribution of palmitoylated peripheral membrane proteins over all membranes.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Impact of Time to Treatment on Endovascular Thrombectomy Outcomes in the Early Versus Late Treatment Time Windows.

BACKGROUND: The impact of time to treatment on outcomes of endovascular thrombectomy (EVT) especially in patients presenting after 6 hours from symptom onset is not well characterized. We studied the differences in characteristics and treatment timelines of EVT-treated patients participating in the Florida Stroke Registry and aimed to characterize the extent to which time impacts EVT outcomes in the early and late time windows. METHODS: Prospectively collected data from Get With the Guidelines-Stroke hospitals participating in the Florida Stroke Registry from January 2010 to April 2020 were reviewed. Participants were EVT patients with onset-to-puncture time (OTP) of ≤24 hours and categorized into early window treated (OTP ≤6 hours) and late window treated (OTP >6 and ≤24 hours). Association between OTP and favorable discharge outcomes (independent ambulation, discharge home and to acute rehabilitation facility) as well as symptomatic intracerebral hemorrhage and in-hospital mortality were examined using multilevel-multivariable analysis with generalized estimating equations. RESULTS: Among 8002 EVT patients (50.9% women; median age [±SD], 71.5 [±14.5] years; 61.7% White, 17.5% Black, and 21% Hispanic), 34.2% were treated in the late time window. Among all EVT patients, 32.4% were discharged home, 23.5% to rehabilitation facility, 33.7% ambulated independently at discharge, 5.1% had symptomatic intracerebral hemorrhage, and 9.2% died. As compared with the early window, treatment in the late window was associated with lower odds of independent ambulation (odds ratio [OR], 0.78 [0.67-0.90]) and discharge home (OR, 0.71 [0.63-0.80]). For every 60-minute increase in OTP, the odds of independent ambulation reduced by 8% (OR, 0.92 [0.87-0.97]; P<0.001) and 1% (OR, 0.99 [0.97-1.02]; P=0.5) and the odds of discharged home reduced by 10% (OR, 0.90 [0.87-0.93]; P<0.001) and 2% (OR, 0.98 [0.97-1.00]; P=0.11) in the early and late windows, respectively. CONCLUSIONS: In routine practice, just over one-third of EVT-treated patients independently ambulate at discharge and only half are discharged to home/rehabilitation facility. Increased time from symptom onset to treatment is significantly associated with lower chance of independent ambulation and ability to be discharged home after EVT in the early time window.

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism.

BACKGROUND: A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk. OBJECTIVE: To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD). METHODS: We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. RESULTS: Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10-8 ). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, ß = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, ß = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, ß = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, ß = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers. CONCLUSIONS: The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Red Blood Cell Microparticles Limit Hematoma Growth in Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is the deadliest stroke subtype with no effective therapies. Limiting hematoma expansion is a promising therapeutic approach. Red blood cell-derived microparticles (RMPs) are novel hemostatic agents. Therefore, we studied the potential of RMPs in limiting hematoma growth and improving outcomes post-sICH. METHODS: sICH was induced in rats by intrastriatal injection of collagenase. RMPs were prepared from human RBCs by high-pressure extrusion. Behavioral and hematoma/lesion volume assessment were done post-sICH. The optimal dose, dosing regimen, and therapeutic time window of RMP therapy required to limit hematoma growth post-sICH were determined. We also evaluated the effect of RMPs on long-term behavioral and histopathologic outcomes post-sICH. RESULTS: RMP treatment limited hematoma growth following sICH. Hematoma volume (mm3) for vehicle- and RMP- (2.66×1010 particles/kg) treated group was 143±8 and 86±4, respectively. The optimal RMP dosing regimen that limits hematoma expansion was identified. RMPs limit hematoma volume when administered up to 4.5-hour post-sICH. Hematoma volume in the 4.5-hour post-sICH RMP treatment group was lower by 24% when compared with the control group. RMP treatment also improved long-term histopathologic and behavioral outcomes post-sICH. CONCLUSIONS: Our results demonstrate that RMP therapy limits hematoma growth and improves outcomes post-sICH in a rodent model. Therefore, RMPs have the potential to limit hematoma growth in sICH patients.

Early lowering of blood pressure after acute intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

OBJECTIVE: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH). METHODS: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect. RESULTS: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth. INTERPRETATION: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent. PROSPERO REGISTRATION NUMBER: CRD42019141136.

Greater Cognitive-Motor Interference in Individuals Post-Stroke During More Complex Motor Tasks.

BACKGROUND AND PURPOSE: Dual-task (DT) walking assessments allow for the simultaneous evaluation of cognitive and motor performance. During DT walking, individuals may experience interference in one or both tasks, known as cognitive-motor interference (CMI). The primary purpose of this study was to compare CMI between individuals post-stroke and healthy persons group during single- and dual-motor and cognitive tasks, using 2 distinct walking tasks. METHODS: Motor performance was quantified as the total time for the Timed Up and Go (TUG) and gait speed for the 90-second walk (90W). Cognitive performance was measured as the correct response rate (CRR) during serial 7 subtractions. Participants performed the motor and cognitive tasks in isolation for the single-task (ST) and simultaneously for DT conditions, TUG-DT and 90W-DT. A repeated-measures analysis of variance assessed group (poststroke and healthy) by condition (ST and DT) interactions for the TUG, 90W, and CRR. RESULTS: There were significant main effects of group and condition for both the TUG and the 90W (P < 0.05). There was also an interaction effect for the TUG, with individuals post-stroke demonstrating a larger decrement in TUG-DT performance compared with healthy persons (P < 0.05). Furthermore, a significant interaction effect was observed for the CRR, in which healthy individuals exhibited a greater decrement in performance from the ST to the 90W-DT (P < 0.05). DISCUSSION AND CONCLUSIONS: Individuals post-stroke were susceptible to greater motor interference during the more complex motor task, the TUG-DT. However, the only decrements observed in cognitive performance from the ST to DT occurred in healthy individuals during the 90W-DT.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A367).

Accuracy of transcranial Doppler in detecting intracranial stenosis in patients with sickle cell anemia when compared to magnetic resonance angiography.

BACKGROUND: Stroke, the most devastating consequence of sickle cell anemia (SCA), is associated with endothelial damage and intracranial artery stenosis. We aimed to assess transcranial Doppler (TCD) ultrasound accuracy in detecting intracranial stenosis when compared to magnetic resonance angiography (MRA). METHODS: Children with SCA and at least one TCD and MRA within 1 month were identified from a retrospectively collected database. Sensitivity and specificity were obtained to assess the overall accuracy of TCD mean flow velocity (mFV) ≥200 cm/s in detecting vessel stenosis of ≥50%. Multivariate analysis identified independent factors associated with MRA stenosis. RESULTS: Among 157 patients in the database, 64 had a TCD and MRA within 1 month (age 11.8 ± 5.3 years, 56% female, 20% with cerebral infarcts on MRI, 8 or 13% had mFV ≥200 cm/s and 20% or 21%, had intracranial stenosis ≥50% on MRA). TCD mFV ≥200 cm/s had a high specificity (95%) but low sensitivity (29%) to detecting intracranial stenosis. As a continuous variable, TCD mFV of 137.5 cm/s had maximal specificity (77%) and sensitivity (72%). After adjustment for age, hemoglobin level, transfusion status, hydroxyurea treatment, and vessel, for every increase in cm/sec on TCD, there was a 2% increase in the odds of ≥50% stenosis on MRA (p < 0.001). CONCLUSION: Our study reports TCD mFV is a positive predictor of MRA stenosis in SCA, independent of patient characteristics, including hemoglobin. A mFV ≥200 cm/s is highly specific but less sensitive in detecting stenosis ≥50%. Lower mFV cut points may be needed for the early detection of intracranial stenosis.

Effect of Primary Prophylactic Antiseizure Medication for Seizure Prevention Following Intracerebral Hemorrhage in the ERICH Study.

OBJECTIVES: Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of any stroke subtype and clinicians often administer prophylactic antiseizure medications (ASMs) as a means of preventing post-stroke seizures, particularly following lobar ICH. However, evidence for ASM efficacy in preventing seizures and reducing disability is lacking given limited randomized trials. Herein, we report analysis from a large prospective observational study that evaluates the effect of primary prophylactic ASM administration on seizure occurrence and disability following ICH. MATERIALS AND METHODS: Primary analysis was performed on 1630 patients with ICH enrolled in the ERICH study. A propensity score for administration of prophylactic ASM was developed and patients were matched by the closest propensity score (difference < 0.1). McNemar's test was used to compare occurrence of in-hospital seizure and disability, defined by modified Rankin Score (mRS) ≥ 3 at 3 months post ICH. RESULTS: Of the 815 matched pairs of patients treated with primary prophylactic ASM, there was no significant difference in seizure occurrence (p = 0.4631) or disability (p = 0.4653). Subset analysis of 280 matched pairs of patients with primary lobar ICH similarly revealed no significant difference in seizure occurrence (p = 0.1011) or disability (p = 1.00) between prophylactically treated and untreated patients. CONCLUSIONS: Although current guidelines do not recommend primary prophylactic ASM following ICH, clinical use remains widespread. Data from the ERICH study did not find an association between administering primary prophylactic ASM and preventing seizures or reducing disability following ICH, thus providing evidence to influence clinical practice and patient care.

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats.

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use.

How Well Do Neurochecks Perform After Stroke?

BACKGROUND: In the certification of stroke centers, the performance of serial nursing neurological assessments and reassessments, commonly known as neurochecks, is often cited as one of the most problematic standards. The role of neurochecks is to readily detect neurological change, but it is surprising that this practice has undergone relatively little scientific study. Their effectiveness in detecting worsening in acute ischemic stroke patients has not been well studied. Our objective was to investigate the sensitivity of neurochecks to detect neurological deterioration after acute ischemic stroke. We performed a retrospective chart review of patients with acute ischemic stroke who were admitted to a comprehensive stroke center over a 2-year period and who received intravenous thrombolysis. The incidence, reasons, and detection rates for neurological deterioration by neurochecks were collected during the first 72 hours of admission. RESULTS: A total of 231 patient records were reviewed. Over the first 72 hours of admission, each patient had a mean of 63±15 neurochecks. Neurological worsening as determined by a stroke neurologist was found in 62 (27%) patients. This deterioration was first detected by a scheduled neurocheck in 28 (45%) patients and was discovered by the nurse outside of a scheduled neurocheck in 16 (26%) patients. In 18 out of 62 (29%) patients, the worsening was not detected. CONCLUSIONS: Although neurochecks detected neurological deterioration in almost half of patients with acute stroke, a significant proportion of deteriorations were found outside scheduled assessments or remained undetected. This suggests that novel monitoring strategies are needed to readily identify worsening neurological status in acute stroke.

Withdrawal of Life-Sustaining Treatment Mediates Mortality in Patients With Intracerebral Hemorrhage With Impaired Consciousness.

BACKGROUND AND PURPOSE: Impaired level of consciousness (LOC) on presentation at hospital admission in patients with intracerebral hemorrhage (ICH) may affect outcomes and the decision to withhold or withdraw life-sustaining treatment (WOLST). METHODS: Patients with ICH were included across 121 Florida hospitals participating in the Florida Stroke Registry from 2010 to 2019. We studied the effect of LOC on presentation on in-hospital mortality (primary outcome), WOLST, ambulation status on discharge, hospital length of stay, and discharge disposition. RESULTS: Among 37 613 cases with ICH (mean age 71, 46% women, 61% White, 20% Black, 15% Hispanic), 12 272 (33%) had impaired LOC at onset. Compared with cases with preserved LOC, patients with impaired LOC were older (72 versus 70 years), more women (49% versus 45%), more likely to have aphasia (38% versus 16%), had greater ICH score (3 versus 1), greater risk of WOLST (41% versus 18%), and had an increased in-hospital mortality (32% versus 12%). In the multivariable-logistic regression with generalized estimating equations accounting for basic demographics, comorbidities, ICH severity, hospital size and teaching status, impaired LOC was associated with greater mortality (odds ratio, 3.7 [95% CI, 3.1-4.3], P<0.0001) and less likely discharged home or to rehab (odds ratio, 0.3 [95% CI, 0.3-0.4], P<0.0001). WOLST significantly mediated the effect of impaired LOC on mortality (mediation effect, 190 [95% CI, 152-229], P<0.0001). Early WOLST (<2 days) occurred among 51% of patients. A reduction in early WOLST was observed in patients with impaired LOC after the 2015 American Heart Association/American Stroke Association ICH guidelines recommending aggressive treatment and against early do-not-resuscitate. CONCLUSIONS: In this large multicenter stroke registry, a third of ICH cases presented with impaired LOC. Impaired LOC was associated with greater in-hospital mortality and worse disposition at discharge, largely influenced by early decision to withhold or WOLST.

Mechanical thrombectomy in isolated large vessel posterior cerebral artery occlusions.

PURPOSE: Mechanical thrombectomy (MT) in posterior circulation large vessel occlusion (LVO), including posterior cerebral artery (PCA), has not been validated since all five major MT trials excluded such patients. To evaluate the feasibility and preliminary safety and efficacy of MT in isolated PCA occlusion stroke patients with new-generation MT devices. METHODS: Endovascularly treated acute ischemic stroke (AIS) patients were identified from a prospectively collected database and their baseline characteristics were noted. Clinical outcomes were angiographic recanalization, a favorable clinical outcome at 3 months on modified Rankin Scale (mRS) and visual field (VF) deficit improvement on confrontation test, rate of intracranial hemorrhage (ICH), and mortality at 3 months. RESULTS: A total of 355 AIS patients underwent MT from January 2018 to December 2019. Isolated PCA MT was performed in 15 consecutive patients. The mean age was 64 ± 17 years, and 9(60%) were women. Median presentation NIHSS was 9 (interquartile range 5-15). MT devices used were stent retrievers in 6 patients and combined aspiration and stent retriever in 9 patients. Complete revascularization (TICI 2c or 3) was achieved in 12/15 patients. 3-month VF normalization was seen in 7/12 of the patients. Post-procedure symptomatic ICH occurred in 1/15 of patients. mRS score of 0-2 was achieved in 9/15 of patients but one patient was dead at 3 months post procedure. CONCLUSION: MT is feasible and can achieve successful reperfusion in isolated PCA occlusions and resulted in favorable motor and visual outcomes in this small series of ischemic stroke patients.

Do Carotid Plaque Ulcers Heal? Potential Detection of Carotid Artery Plaque Healing by Carotid Ultrasound Imaging.

OBJECTIVES: Carotid plaque ulcers confer an increased risk for stroke/ transient ischemic attacks in both symptomatic and asymptomatic carotid artery stenosis. Little is known about the healing rates of ulcers or the development of new ulcers. Carotid Duplex studies are noninvasive and easily repeatable tests to monitor progression of carotid stenosis and plaque morphology. Our aim was to determine the prevalence and healing rates of ultrasound-detected carotid plaque ulcers. METHODS: We retrospectively reviewed 5837 carotid Duplex studies performed in an outpatient ultrasound laboratory affiliated with the neurological department of an academic center. A total of 3215 patients underwent a first carotid ultrasound Duplex study, and 2622 follow-up studies were done. Carotid ulcer was defined as a 2 mm deep surface indentation in a carotid plaque with a well-defined back wall, as determined by multimodal ultrasound imaging techniques. RESULTS: The prevalence of carotid plaque ulcers among the 3215 patients with a first ultrasound study was 3% (82/3215). The mean follow-up was 42 ± 30 months, and the median number of follow-up studies was 6. Among patients with ulcers, follow-up studies were available in 65/82 patients. During the follow-up period, 28/65 (43%) ulcers healed. Among all 2622 follow-up studies, 45 patients developed a new ulcer. CONCLUSIONS: Duplex-detected carotid plaque ulcer prevalence is low. The carotid ulcers healed in approximately half of patients during follow-up. Factors associated with ulcer healing and development remain poorly understood.

Effect of Race-Ethnicity and CT Angiography on Renal Injury During Blood Pressure Treatment for Intracerebral Hemorrhage.

BACKGROUND: Lowering blood pressure intensively in acute intracerebral hemorrhage (ICH) is associated with adverse renal events; Blacks and Hispanics have a higher incidence of ICH and kidney disease than Whites. In addition, CT angiography (CTA), which may also be associated with acute kidney injury (AKI), is often done in acute ICH. Our objective was to investigate the relationship between aggressive BP management, CTA, race-ethnicity and the risk of developing AKI in patients presenting with ICH. METHODS: We retrospectively calculated the difference between the highest and lowest systolic blood pressure during the first 24 h of admission in patients with spontaneous ICH over 30 months. Creatinine (Cr) levels at admission were compared to the highest Cr level during the first 7 days after admission. AKI was defined as any > 50% increase of baseline Cr during the first 7 days. Logistic regression models were used to assess the association between race-ethnicity and CTA and AKI. We also analyzed the incidence of AKI stratified by race-ethnicity. RESULTS: A total of 394 patients were included (mean age ± SD 63 ± 14 years), 160 patients (41%) were women, 162 (41%) Hispanic, 39 (10%) White and 189 (48%) Black. Most of the patients underwent CTA (73%). The prevalence of AKI was (18%), but no difference was found in AKI incidence (19% in Blacks vs. 17% in Whites vs. 18% in Hispanics (p = 0.940). In fully adjusted models, AKI was not associated with race-ethnicity (p = 0.665) or CTA (p = 0.187). The stratified analysis by race-ethnicity did not change our findings. CONCLUSION: We found no association between race-ethnicity or CTA and AKI during the acute management of ICH in a real-life stroke population. Our findings suggest that CTA can be safely obtained in acute ICH, even in populations of diverse race-ethnicity who may be more prone to adverse kidney events. CTA did not contribute to developing AKI.

Infarct Recurrence in Intracranial Atherosclerosis: Results from the MyRIAD Study.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism. METHODS: This prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks. RESULTS: Amongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes. CONCLUSIONS: Despite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02121028.

What is the Role of Hyperosmolar Therapy in Hemispheric Stroke Patients?

The role of hyperosmolar therapy (HT) in large hemispheric ischemic or hemorrhagic strokes remains a controversial issue. Past and current stroke guidelines state that it represents a reasonable therapeutic measure for patients with either neurological deterioration or intracranial pressure (ICP) elevations documented by ICP monitoring. However, the lack of evidence for a clear effect of this therapy on radiological tissue shifts and clinical outcomes produces uncertainty with respect to the appropriateness of its implementation and duration in the context of radiological mass effect without clinical correlates of neurological decline or documented elevated ICP. In addition, limited data suggest a theoretical potential for harm from the prophylactic and protracted use of HT in the setting of large hemispheric lesions. HT exerts effects on parenchymal volume, cerebral blood volume and cerebral perfusion pressure which may ameliorate global ICP elevation and cerebral blood flow; nevertheless, it also holds theoretical potential for aggravating tissue shifts promoted by significant interhemispheric ICP gradients that may arise in the setting of a large unilateral supratentorial mass lesion. The purpose of this article is to review the literature in order to shed light on the effects of HT on brain tissue shifts and clinical outcome in the context of large hemispheric strokes, as well as elucidate when HT should be initiated and when it should be avoided.

Mechanical Thrombectomy for Large Vessel Occlusions in Cocaine Associated Acute Ischemic Stroke: Small Case Series and Review of the Literature.

INTRODUCTION: Cocaine through multifactorial pathogenetic mechanisms causes small and large vessel occlusions (LVO) leading to acute ischemic stroke. The optimal treatment for cocaine related LVO remains unknown. Mechanical thrombectomy (MT) poses a unique challenge, and successful MT are not widely reported. MATERIAL AND METHODS: We report three patients with no other risk factors and a common history of cocaine metabolites found on presentation drug screen who underwent MT for MCA occlusions with subsequent failed recanalization or vessel re-occlusion due to persistent thrombosis and severe vasospasm.Two patients initially had good revascularization but then developed severe vasospasm and reoccluded, and the remaining patient had persistent severe distal vasospasm. Rescue therapy either with balloon angioplasty with stent placement or intraarterial vasodilator was used in all patients and was ineffective. All patient had large hemispheric strokes and developed malignant cerebral edema requiring hemicraniectomy in two of them. We also did literature review and summarized previously reported cases of cocaine associated vasospasm in MT and other endovascular procedures. CONCLUSION: In this case series, cocaine induced vasospasm contributed to unsuccessful recanalization and reocclusion in patients undergoing MT with poor outcomes. Further studies are needed to ascertain strategies for improved outcomes in patients with LVO related to cocaine use.