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Background Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. Aims Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. Methods Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core Results From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89–3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0–1, OR 2.33, 95% CI 1.13–5.94, p = 0.032) or clinical mismatch criteria (mRS 0–1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. Conclusion Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase.

Background and Purpose: Perfusion imaging is used for patient selection in clinical practice and trials. Postprocessing and definitions of tissue viability are nevertheless not standardized. We compared the lesion volumes generated with two well-recognized perfusion tissue definitions in a single-center phase 2 thrombolysis study. Methods: We analyzed perfusion imaging data from the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study using two popular tissue viability thresholds (ischemic core definition: (1) cerebral blood volume 2 seconds; penumbra definitions: (1) mean transit time > 145% of contralesional hemisphere or (2) relative delay time < 2 seconds). We compared volumes of core and penumbra, mismatch ratio, percentage, and volume of penumbra salvaged at 24 hours. Results: We included 73 (tenecteplase = 36, alteplase = 37) patients who had analyzable perfusion lesions at baseline. Significant differences were found in core volumes using the two thresholds (33 ± 37 mL vs. 26 ± 32 mL, P < .001), as was mismatch ratio (2.5 ± .9 vs. 4.2 ± 3.7, P < 0.001). The volume of penumbra salvaged at 24 hours (30 ± 19 mL vs. 35 ± 26 mL, P = .043) differed significantly, although the percentages of penumbra salvaged did not (P= .2). No difference was found between the two thrombolytic agents in the percentages of penumbra salvaged using either threshold. Conclusion: Two commonly used tissue definitions generated significantly different lesion volumes and mismatch ratios. Threshold selection may have significant impact on patient selection for trials or reperfusion therapies.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

Background and Purpose— Both intracerebral hemorrhage (ICH) and brain edema have been attributed to reperfusion after intravenous thrombolysis. We explored the interaction of recanalization and core size for imaging outcomes (ICH and vasogenic brain edema). Methods— In patients with anterior circulation occlusion given intravenous thrombolysis 2 s and relative cerebral blood flow 2 s). CT and CT angiography at 24 hours were reviewed for ICH (European Cooperative Acute Stroke Study [ECASS]-2 definition), early vasogenic edema (third International Stroke Trial [IST-3] criteria), and recanalization (thrombolysis in myocardial infarction 2–3). Independent effects of recanalization, core volume and potential interactions on edema, ICH and day 90 outcomes were estimated by logistic regression. Results— In 123 patients, there was a trend for recanalization to be associated with H1/2 ICH (odds ratio [OR], 2.3 [0.97–5.5]; P =0.06) but not with PH1/2 ICH (OR, 1.7 [0.33–8.8]; P =0.5), any edema, or significant brain edema (OR, 1.45 [0.4–4.9]; P =0.55). Ischemic core (>50 mL) was associated with any ICH (OR, 4.0 [1.6–9.5]; P =0.003), edema (OR, 5.4 [2–14]; P P P =0.8), after controlling for recanalization. There was no significant interaction of recanalization and large core for any adverse outcomes. Conclusions— Large ischemic core was associated with poorer outcomes and both early vasogenic brain edema and ICH, but recanalization on 24-hour CT angiography was associated with clinically favorable outcome. There was no significant interaction of recanalization and large core volume for any outcomes. The association of hemorrhage or brain edema with post-thrombolysis reperfusion is unclear.

Background and Purpose— We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage. Methods— Venous blood samples from a subgroup of participants in the Alteplase–Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24±3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1, d -dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann–Whitney tests for between-group differences. Results— Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia ( P =0.002), prolonged prothrombin time ( P =0.011), hypoplasminogenaemia ( P =0.001), and lower factor V ( P =0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours ( P =0.011), whereas only minor hypoplasminogenaemia ( P =0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen ( P P =0.002) compared with alteplase. Conclusions— In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01472926.

Introduction Debate exists as to whether wake-up stroke (WUS) (i.e. symptoms first noted on waking) differs from stroke developing while awake [awake onset stroke (AOS)]. Unknown onset stroke (UOS) with unclear symptom onset time is infrequently studied. Aims This study aimed to examine differences in stroke characteristics and outcomes in these three groups. Methods The stroke registry database from Halifax Infirmary, Canada, was interrogated for hospitalised stroke patients between 1999–2011. Information was available on demographics, stroke characteristics, and functional status at discharge and six months (modified Rankin score [mRS]). Results Of 3890 patients, 65% had AOS, 21% WUS and 14% UOS. UOS patients were significantly older, more commonly female and living alone than AOS patients, with no difference between AOS and WUS. UOS rates increased from 10 to 16% of patients during the study period ( P < 0·0001). UOS but not WUS had a higher stroke severity than AOS. Intracerebral hemorrhage was less common (9 vs. 13%) and lacunar stroke more common (23 vs. 19%) in WUS compared to AOS. In UOS left hemisphere location was more likely, and lacunar stroke less common. Excellent outcomes were slightly lower for WUS. UOS had significantly higher rates of in-hospital mortality (23 vs. 16%, P < 0·0001) and poorer functional outcome six months after stroke (mRS < 3 in 26% of UOS and 46% of AOS, P = 0·02). Conclusion WUS has lower rates of ICH but similar stroke severity and outcomes to AOS. UOS prevalence appears to be increasing, with higher stroke severity and worse prognosis.

Objective:To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase.Methods:Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs).Results:From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0–1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02–7.84, p = 0.05).Conclusions:Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA.

Background: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. Methods: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core Results: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P =0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P =0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0–1: odds ratio, 1.77; 95% confidence interval, 0.89–3.51; P =0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P P =0.032) than those treated with alteplase. Conclusions: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion–defined target mismatch. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01472926. URL: https://www.anzctr.org.au . Unique identifier: ACTRN12608000466347.

Background The steep, time-dependent loss of benefit from reperfusion in clinical trials is consistent with loss of penumbra over the early hours of ischemia, as observed in animal models. Human imaging studies, however, show persistent penumbra for up to 48 h. We investigated core and penumbra volumes and collateral status in relation to time after stroke onset within the first 6 h. Methods Using data from three multimodal computer tomography-based studies in acute ischemic stroke patients 15 ml, mismatch ratio > 1.8). Patients were grouped by onset to imaging time (Results Analysis included 144 subjects. Across time epochs, neither proportions of penumbra (59%, 64%, 75% at 4. 5 h, respectively, p = 0.4) nor poor collaterals (15/56 (27%), 14/47 (30%), 4/15 (27%) at 4.5 h, p = 0.9) differed significantly. Penumbra proportion was not clearly related to time to imaging ( R2 = 0.003; p = 0.5) but a trend for divergent effects by collateral status was seen (slight increase in penumbra over time with good collaterals versus reduced with poor, interaction = 0.08). The proportion of patients with target mismatch did not vary by time (56%, 74%, and 67% at 4.5 h, p = 0.09). Conclusions In a cross-sectional sample imaged within 6 h, neither the proportions of penumbral tissue nor “target mismatch” varied by time from onset. A trend for reducing penumbra proportion only among those with poor collaterals may have pathophysiological and therapeutic importance.

Background and aims Intravenous Immunoglobulin (IVIG) is used to treat a variety of immunologically mediated neurological conditions.The Association of British Neurologists (ABN) published guidelines in 2005 for use of IVIG in neurological conditions. 1 These guidelines outline different indications for prescribing IVIG with research evidence and guidelines for monitoring patients on treatment. Our audit aimed to compare our practice in Aberdeen Royal Infirmary for the period of August 2010 to July 2011 to the ABN guidelines. We gathered data on indications of use of IVIG and 9 monitoring guidelines. Results A total of 36 Patients received IVIG and complete data were available for analysis for 32 patients. Indications for treatment included: Guillain–Barre Syndrome (GBS) (n=10), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (n=8), Myasthenia Gravis (n=5), Multiple Sclerosis (MS) and Paraprotein associated neuropathy (n=2), Limbic encephalitis, Multifocal Motor Neuropathy (MMN), other CNS inflammation, Polyneuropathy, Organomegaly, Endocrinopathy, M–protein and Skin changes (POEMS) syndrome, and other demyelinating neuropathy (not CIDP) (n=1). In most of these patients other immunosuppressive treatments had been contraindicated or tried and failed, apart from the MMN group. In terms of the monitoring guidelines, we found that all patients had routine blood tests prior to the first infusion, but in nine patients pre–treatment IgA levels were not performed. 18 Patients received more than one infusion and of these ten did not have regular further pre–treatment blood tests. Informed consent was documented in only 5 patients. Out of 14 patients who had documented improvement after the first IVIG infusion, and received further infusions, four had no documented clinical deterioration prior to subsequent infusions. Only five out of the 18 patients on regular treatment had documentation on consideration of reduction in treatment dose and frequency. Intravenous Hydrocortisone and Chlorpheneramine were given as prophylaxis for allergic reactions in 17 patients before the infusion with no documented prior side effects. No patient information sheets or signed consent forms were used. The cost of IVIG was just under £0.5 million during the audit year. Outcomes We presented these results locally and designed a protocol that includes written consent forms and patient information sheets (1). We agreed on annual consultant review dates (considering dose and frequency reduction, need for continuing IVIG use or alternative treatments) and monitoring of blood tests. We also discussed the judicious use of pre–treatment intravenous Chlorpheneramine and Hydrocortisone and consideration of oral treatment due to cost benefits where appropriate. We aim to implement the authorised protocol and close the audit cycle by repeating this in 2014.

We report a case of a twenty three year old female presenting with status epilepticus due to a rare mutation in a nuclear gene causing mitochondrial dysfunction. She had previously been investigated for an inherited ataxia without a definitive diagnosis being made. She presented as an emergency with focal seizures that rapidly evolved into intractable status epilepticus. Despite prolonged, aggressive treatment in Intensive Care Unit, she remained encephalopathic with persisting seizures. Her younger sister who also has milder symptoms with ataxia visited our hospital on the day of acute admission and revealed some useful information that led us investigate and confirm the diagnosis in our patient. Her younger sister who was a medical student told us that she had been investigated elsewhere and was confirmed to have an autosomal recessive mutation in a nuclear gene named POLG. We tested and confirmed the same POLG mutation in our patient. POLG is a nuclear gene located on long arm of chromosome 15 that encodes the catalytic subunit of mitochondrial DNA polymerase gamma. The defects in this enzyme are associated with disorders of mitochondrial DNA maintenance. POLG mutation has several phenotypes with onset between early childhood to late adulthood. Typical clinical features include ataxia, neuropathy, epilepsy, ophthalmoplegia, myopathy and in some cases liver failure. Liver failure has been associated with treatment with Sodium valproate and this should be avoided in these patients. Prognosis is poor in the presence of epilepsy with mortality rates to be reported to be nearly 80%. After extensive discussions with the family, local ethics team, and medical director, our patient was palliated in the local palliative care hospital where she died peacefully. A clinical intuition is needed for referring these patients to genetic testing and the diagnosis is crucial to inform us the prognosis. We discuss her presentation, management and our patient9s phenotype Mitochondrial Spino–Cerebellar Ataxia and Epilepsy (MSCAE).