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Data on infarcts in new territory (INT) in patients undergoing endovascular stroke treatment for acute large-vessel occlusions are sparse. Aim of this study was to assess the prevalence, risk factors, and clinical relevance of INT. For this purpose, all patients in a single-center prospective registry who underwent endovascular stroke treatment and received pre- and post-interventional diffusion-weighted imaging were included (N = 259). Using an established scoring system, INT were classified according to size (I-III, ≤2 mm, >2 mm ≤20 mm, >20 mm) and likelihood of being related to the intervention (A, high likelihood; B, low likelihood). Additionally, a new type of infarct, that occurred in a territory distal to the occlusion, but was initially not hypoperfused, was defined as an infarct in initially not hypoperfused territory (IINHT). A total of 180 INT and 38 IINHT were observed in 32.8% (N = 85/259) of patients. In most patients, INT were angiographically occult (90.2%), and 13 patients had INT/IINHT larger than 2 cm (type III). Absence of protection during stent-retrieval and a cardio-embolic stroke origin were associated with higher incidence of INT/IINHT, whereas pretreatment with IV tPA showed no association, even when different bolus timing was considered. INT/IINHT were associated with lower rates of functional independence with increasing size type after adjusting for confounders ( adjusted Odds Ratio per size group increase 0.63, 95% confidence interval 0.46–0.86). In conclusion, INT and IINHT are not rare, are associated with poor outcome with increasing size, and they may serve as a surrogate endpoint for safety evaluation of new devices and endovascular techniques. Further research on associated factors is warranted.

Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non-motor impairment, often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood-brain barrier in animals. We assessed the safety and pharmacokinetics (PK) of TLN in patients with PD. We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with TLN. The maximum suitable dose of TLN was determined by dose escalation in three patients. All three patients tolerated the predetermined maximal dose of 720 mg. Subsequently, these and nine additional patients received weekly infusions at the maximum suitable dose of 720 mg TLN over two months (1 patient stopped prematurely). PK were determined for the additional nine patients as a secondary outcome measure. Cmax was reached 4 h after infusion start for all but one participant, who reached Cmax after 1 h, while the median plasma half-life was reached at 12.6 h. All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behavior, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used as further secondary outcomes as well as assessing the Levodopa-Equivalent Daily Dose (LEDD). Overall, 304 adverse events (mean: 25.33; 6-75 events per patient) occurred, 267 of which were mild (mean: 22.25; 3-72 events per patient). 23 were considered related to the study treatment (0-8 events per patient). Very mild-to-severe acute infusion reactions at the second, third, or fourth administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when TLN administration was resumed at a very low rate. Beyond the fourth administration, infusions could be given at increased rates up to 370 ml/h, and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after TLN following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease -11.09; 95% Confidence Interval [CI]; -18, -4.1; p = 0.006), the Parkinson's disease Questionnaire-39 (PDQ-39) summary index (mean decrease -2.91; 95% CI; -4.4, -1.4; p = 0.005), and the Non-Motor Symptoms Questionnaire (NMS-Quest) (mean decrease -4.27; 95% CI; -6.5, -2.1; p = 0.009). No statistically significant improvements were seen in the Montreal Cognitive Assessment (MoCA) (mean decrease -0.73; 95% CI; -2.1, 0.62; p = 0.255), Epworth Sleepiness Scale (mean increase 0.09; 95% CI; -2.6, 2.8; p > 0.999), Beck Depression Inventory (BDI) (mean decrease -1.27; 95% CI; -3.8, 1.3; p = 0.257), and the Starkstein Apathy Scale (mean increase 0.36; 95% CI; -1.6, 2.4; p = 0.822). Dopaminergic medications remained stable during the study (LEDD mean increase 8.18; 95% CI; -7.7, 24; p = 0.423). While clinical improvements indicate a benefit associated with TLN treatment, the trial design does not allow for definite conclusions regarding efficacy. A randomized, placebo-controlled trial will be required to corroborate our exploratory findings. TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD. The NEON trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04976127 and in the Swiss National Clinical Trials Portal (SNCTP000004631).

Background and PurposeData on the management of large vessel occlusion in patients with anterior circulation acute ischemic stroke (AIS) due to underlying intracranial stenosis are scarce. The aim of this retrospective study was to compare endovascular treatment and outcome in AIS patients with and without underlying stenosis of the M1 segment.Materials and MethodsA total of 533 acute stroke patients with an isolated M1 occlusion who underwent mechanical thrombectomy between 02/2010 and 08/2017 were included. Underlying intracranial atherosclerotic stenosis (ICAS) was present in 10 patients (1.9%), whereas 523 patients (98.1%) had an embolic occlusion without stenosis.ResultsThere was no difference in age, admission National Institutes of Health Stroke Scale, risk factors, Alberta stroke program early CT score or collaterals between the groups. Procedure time (155 vs 40 min, P = 0.001) was significantly longer in the ICAS group where rescue stent-angioplasty was performed in all patients. There was no statistical difference in final modified thrombolysis in cerebral infarction score between both groups (70 vs 88%, P = 0.115). Favorable outcome (modified Rankin Scale ≤ 2) at 90 days was less frequent in patients with ICAS than in the embolic group (0 vs 49.4%, P = 0.004). The mortality rate tended to be higher in the ICAS group (44.4 vs 19.4%, P = 0.082).ConclusionIn patients with AIS, rescue therapy with stent placement to treat underlying ICAS of the M1 segment is technically feasible; however, in our study, a significantly lower rate of favorable outcome was observed in these patients compared to those with thromboembolic M1 occlusions.Level of EvidenceLevel 3, non-randomized controlled study.

Recent studies suggest a paradoxical association between smoking status and clinical outcome after intravenous thrombolysis (IVT). Little is known about relationship between smoking and stroke outcome after endovascular treatment (EVT). We analyzed data of all stroke patients treated with EVT at the tertiary stroke centre of Berne between January 2005 and December 2015. Using uni- and multivariate modeling, we assessed whether smoking was independently associated with excellent clinical outcome (modified Rankin Scale (mRS) 0-1) and mortality at 3 months. In addition, we also measured the occurrence of symptomatic intracranial hemorrhage (sICH) and recanalization. Of 935 patients, 204 (21.8%) were smokers. They were younger (60.5 vs. 70.1 years of age, p<0.001), more often male (60.8% vs. 52.5%, p = 0.036), had less often from hypertension (56.4% vs. 69.6%, p<0.001) and were less often treated with antithrombotics (35.3% vs. 47.7%, p = 0.004) as compared to nonsmokers. In univariate analyses, smokers had higher rates of excellent clinical outcome (39.1% vs. 23.1%, p<0.001) and arterial recanalization (85.6% vs. 79.4%, p = 0.048), whereas mortality was lower (15.6% vs. 25%, p = 0.006) and frequency of sICH similar (4.4% vs. 4.1%, p = 0.86). After correcting for confounders, smoking still independently predicted excellent clinical outcome (OR 1.758, 95% CI 1.206-2.562; p<0.001). Smoking in stroke patients may be a predictor of excellent clinical outcome after EVT. However, these data must not be misinterpreted as beneficial effect of smoking due to the observational study design. In view of deleterious effects of cigarette smoking on cardiovascular health, cessation of smoking should still be strongly recommended for stroke prevention.

Anemia is associated with worse outcome in stroke, but the impact of anemia with intravenous thrombolysis or endovascular therapy has hardly been delineated. The aim of this study was to analyze the role of anemia on infarct evolution and outcome after acute stroke treatment. 1158 patients from Bern and 321 from Los Angeles were included. Baseline data and 3 months outcome assessed with the modified Rankin Scale were recorded prospectively. Baseline DWI lesion volumes were measured in 345 patients and both baseline and final infarct volumes in 180 patients using CT or MRI. Multivariable and linear regression analysis were used to determine predictors of outcome and infarct growth. 712 patients underwent endovascular treatment and 446 intravenous thrombolysis. Lower hemoglobin at baseline, at 24h, and nadir until day 5 predicted poor outcome (OR 1.150-1.279) and higher mortality (OR 1.131-1.237) independently of treatment. Decrease of hemoglobin after hospital arrival, mainly induced by hemodilution, predicted poor outcome and had a linear association with final infarct volumes and the amount and velocity of infarct growth. Infarcts of patients with newly observed anemia were twice as large as infarcts with normal hemoglobin levels. Anemia at hospital admission and any hemoglobin decrease during acute stroke treatment affect outcome negatively, probably by enlarging and accelerating infarct growth. Our results indicate that hemodilution has an adverse effect on penumbral evolution. Whether hemoglobin decrease in acute stroke could be avoided and whether this would improve outcome would need to be studied prospectively.

Background and Purpose Mechanical thrombectomy is an effective recanalization technique in acute ischemic stroke patients with large vessel occlusions; however, it is unclear to what extent stent retriever thrombectomy may be applicable to occlusions of smaller peripheral cerebral vessels. The outcome of patients with isolated M2 occlusions treated with the Mindframe Capture low profile (LP) stent retriever was reviewed. Material and Methods A retrospective review of prospectively collected data on all consecutive patients treated for isolated M2 occlusions between June 2013 and December 2017 using the Mindframe Capture LP was performed. Technical aspects of the recanalization procedure, recanalization rate, complication rate, and clinical outcome were analyzed. Results Mechanical thrombectomy with the Mindframe Capture LP was performed in 38 patients (median age 79 years) with an isolated M2 occlusion. The median National Institutes of Health Stroke Scale (NIHSS) score on admission was 7.5 (interquartile range, IQR 5–12) and successful reperfusion modified Thrombolysis in Cerebral Infarction (mTICI 2b or 3) was achieved in 28 patients (74%). A compensated/adjusted modified Rankin Scale (mRS) 0–2 at 3 months was observed in 65% when taking pre-stroke disability into account. Symptomatic intracranial hemorrhage (sICH) occurred in 1 patient (2.6%). Asymptomatic intracranial hemorrhage (aICH) was noted in 8 patients (21%) and a small subarachnoid hemorrhage (SAH) in the immediate vicinity of the target vessel was apparent in 8 patients (21%). Conclusion The Mindframe Capture LP is a technically effective thrombectomy device for the treatment of isolated M2 occlusions. The lower profile of the device is advantageous when targeting peripheral intracranial occlusions.

ObjectiveA reperfusion quality of thrombolysis in cerebral infarction (TICI)≥2b has been set as the therapeutic angiography target for interventions in patients with acute ischaemic stroke. This study addresses whether the distinction between TICI2b and TICI3 reperfusions shows a clinically relevant difference on functional outcome.MethodsA systematic literature review and meta-analysis was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria to test the primary hypothesis that TICI2b and TICI3 reperfusions are associated with different rates of modified Rankin Scale (mRS) ≤2 at day 90. Secondary endpoints included rates of haemorrhagic transformations, mortality and excellent functional outcome (mRS ≤1). Summary estimates of ORs (sOR) with 95% CI were calculated using the inverse variance heterogeneity model accounting for multiple true effect sizes.ResultsFourteen studies on 2379 successfully reperfused patients were included (1131 TICI3, 1248 TICI2b). TICI3 reperfusions were associated with higher rates of functional independence (1.74, 95% CI 1.44 to 2.10) and excellent functional outcomes (2.01, 95% CI 1.60 to 2.53), also after including adjusted estimates. The safety profile of patients with TICI3 was superior, as demonstrated by lower rates of mortality (sOR 0.59, 95% CI 0.37 to 0.92) and symptomatic intracranial haemorrhages (sOR 0.42, 95% CI 0.25 to 0.71).ConclusionTICI3 reperfusions are associated with superior outcome and better safety profiles than TICI2b reperfusions. This effect seems to be independent of time and collaterals. As reperfusion quality is the most important modifiable predictor of patients’ outcome, a more conservative definition of successful therapy and further evaluation of treatment approaches geared towards achieving TICI3 reperfusions are desirable.

Background and purposeAcute basilar artery occlusion (BAO) is a devastating disease with a high rate of mortality and morbidity, and early recanalization is crucial to achieve a good prognosis. The best treatment strategy for BAO combined with a proximal stenosis (tandem occlusion) is not yet clear. Our study aimed to evaluate whether and how vertebrobasilar tandem occlusions can be treated effectively and safely compared with isolated BAO.Materials and methodsFifty-two patients with acute vertebrobasilar occlusive stroke treated with mechanical thrombectomy were identified in a prospective database from March 2010 to September 2016. We retrospectively analysed the clinical, technical, and functional outcomes of the patients.ResultsOf the 52 patients, 15 presented with a tandem occlusion, 14 with a single intracranial occlusion due to an underlying stenosis, and 23 with a single embolic BAO. Successful recanalization was achieved in all of the patients with tandem occlusions (modified Thrombolysis in Cranial Infarction 2b/3) and in 35 of 37 patients with a single BAO (with and without stenosis). A favourable outcome was achieved (modified Rankin Scale ≤2) in 8 of the 15 patients with a tandem occlusion compared with 4 of the 14 patients with a single BAO with underlying stenosis and 5 of the 23 patients with isolated embolic BAO (p=0.18).ConclusionsWe suggest that endovascular treatment of vertebrobasilar tandem occlusions is safe and feasible, with a high rate of good outcome.

PurposeStent retrievers apply mechanical force to the intracranial vasculature. Our aim was to evaluate the safety and efficacy of the long Solitaire 4 × 40 mm stent retriever for large vessel occlusion in stroke patients.MethodsWe conducted a retrospective analysis of all patients treated for acute ischemic large vessel occlusion stroke with the Solitaire 2 FR 4 × 40 device between May and October 2016 at our institution. Patient-specific data at baseline and at discharge were documented. Reperfusion was graded with the thrombolysis in cerebral infarction (TICI) classification. Postinterventional angiograms and follow-up cross-sectional imaging were used to evaluate complications.ResultsTICI 2b/3 recanalization was achieved in 20 of 23 patients (87.0%), in 17 patients with the first retriever pass. NIHSS improved from a mean score at presentation of 16 (range 4–36) to 11 (range 0–41) at discharge. Mean mRS score at discharge was 3 (range 0–6) and 3 (range 0–6) at 90 days post-treatment. No infarcts in other territories were observed. One patient showed a (reversible) vasospasm in the postinterventional angiogram and another a small contrast extravasation in follow-up imaging.ConclusionThe Solitaire 2 FR 4 × 40 stent retriever is a safe and efficient device for large vessel occlusion acute ischemic stroke with a high recanalization rate and a low peri- and postinterventional complication rate together with a good clinical outcome. Despite potentially higher friction and shearing forces, no increased incidence of visible damage to the vessel wall was observed.

Background: Administration of intra-arterial (IA) thrombolysis may help to improve reperfusion during or after incomplete mechanical thrombectomy (MT) in large-vessel occlusions (LVO) stroke patients. However, data on its safety and efficacy is scarce. Methods: Consecutive acute ischemic stroke patients of a prospective registry presenting with anterior circulation LVO stroke were analyzed (N = 1017). Patients who received additional IA Urokinase during or after MT (+/- intravenous tPA) were compared to those treated with MT (+/- intravenous tPA) only. Primary safety measures included asymptomatic and symptomatic intracranial hemorrhage (aICH and sICH) according to PROACT-II criteria, and all-cause mortality. Primary efficacy endpoints were angiographic reperfusion and Thrombolysis in Cerebral Infarction (TICI) improvement, together with functional independence at day 90 (defined as modified Rankin Scale [less than or equal to]2). Endpoints were assessed using multivariate logistic regression analyses adjusting for confounders underlying case selection. Results: Additional IA Urokinase was administered in 102 of 1017 patients (10.0%). The most common reason for administering IA Urokinase was incomplete reperfusion (TICI<3) after MT (52.9%). After adjusting for baseline characteristics underlying case selection, IA Urokinase did not increase the risk of aICH (0.51, 95%-CI 0.29-0.92), sICH (aOR 0.95, 95%-CI 0.39-2.32) or 3-month mortality (0.71,95%-CI 0.40-1.26). In approximately two-thirds of patients treated with IA Urokinase, early reperfusion improvement was observed, with around one-third being TICI-grade tangible. Correspondingly, patients treated with IA Urokinase had higher rates of functional independence after adjusting for the selection bias favoring poor TICI cases in the IA Urokinase group (aOR 1.90, 95%-CI 1.10-3.30). Discussion/Conclusion: In selected patients, adjunctive treatment with IA Urokinase during or after MT seems to be safe, without an increased risk of intracranial bleedings. Additionally, IA Urokinase harbors the potential to improve the reperfusion status of patients undergoing endovascular interventions and may thus improve outcomes.