Peter J. Hand

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Distinguishing Between Stroke and Mimic at the Bedside The Brain Attack Study

Background and Purpose— The bedside clinical assessment of the patient with suspected stroke has not been well studied. Improving clinical skills may accelerate patient progress through the emergency department. We aimed to determine the frequency and nature of stroke mimics and to identify the key clinical features that distinguish between stroke and mimic at the bedside. Methods— Consecutive presentations to an urban teaching hospital with suspected stroke were recruited. A standard bedside clinical assessment was performed. The final diagnosis was determined by an expert panel, which had access to clinical features, brain imaging, and other tests. Univariate and multivariate analyses determined the bedside features that distinguished stroke from mimic. Results— There were 350 presentations by 336 patients. The final diagnosis was stroke in 241 of 350 (69%) and mimic in 109 (31%). The mimics included 44 events labeled “possible stroke or TIA.” Eight items independently predicted the diagnosis in patients presenting with brain attack: cognitive impairment and abnormal signs in other systems suggested a mimic, an exact time of onset, definite focal symptoms, abnormal vascular findings, presence of neurological signs, being able to lateralize the signs to the left or right side of the brain, and being able to determine a clinical stroke subclassification suggested a stroke. Conclusions— The bedside clinical assessment can be streamlined substantially. This has important implications for teaching less experienced clinicians how to assess the patient with suspected stroke.

Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months

Objective: To test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting. Methods: The existing “code stroke” model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday–Friday) from May 2012. Results: There were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43–75) minutes to 46 (24–79) minutes (p = 0.040). All of the effect came from the change in the in-hours DNT, down from 43 (33–59) to 25 (19–48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55–82) to 62 (44–95) minutes (p = 0.835). Conclusion: We demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of-hours.

Do Acute Diffusion- and Perfusion-Weighted MRI Lesions Identify Final Infarct Volume in Ischemic Stroke?

Background and Purpose— An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the “tissue-at-risk.” It is unclear which “semiquantitative” perfusion parameter most closely identifies final infarct volume. Methods— Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. “Semiquantitative” mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired ≥1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume. Results— Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient &rgr;=0.68), intermediate for CBFsq (&rgr;=0.55), and weakest for MTTsq (&rgr;=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch. Conclusions— Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. “DWI/PWI mismatch” does not identify lesion growth. Patients without “DWI/PWI mismatch” are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.

Retinal Signs and Stroke Revisiting the Link Between the Eye and Brain

Background and Purpose— The retinal and cerebral vasculature share similar anatomic, physiological, and embryological characteristics. We reviewed the literature, focusing particularly on recent population-based studies, to examine the relationship between retinal signs and stroke. Summary of Review— Hypertensive retinopathy signs (eg, focal retinal arteriolar narrowing, arterio-venous nicking) were associated with prevalent stroke, incident stroke, and stroke mortality, independent of blood pressure and other cerebrovascular risk factors. Diabetic retinopathy signs (eg, microaneurysms, hard exudates) were similarly associated with incident stroke and stroke mortality. Retinal arteriolar emboli were associated with stroke mortality but not incident stroke. There were fewer studies on the association of other retinal signs such as retinal vein occlusion and age-related macular degeneration with stroke, and the results were less consistent. Conclusion— Many retinal conditions are associated with stroke, reflecting possible concomitant pathophysiological processes affecting both the eye and the brain. However, the incremental value of a retinal examination for prediction of future stroke risk remains to be determined.

Dorsal root projections to nucleus cuneatus of the cat.

Following single, dorsal rhizotomies in 9 cats, axonal degeneration was traced ipsilaterally throughout nucleus cuneatus with the Nauta-Laidlaw and Fink-Heimer 1 silver stains. (1) Cytoarchitectonic differences permitted a division of the nucleus into a rostral ‘reticular’ region and a caudal ‘cell nest’ region. (2) Degeneration from each root was found at all rostrocaudal levels of the nucleus, but in unequal amounts. (3) Two patterns of degeneration were evidenced with the Nauta-Laidlaw technique: (A) focal; characterized by localized areas of degeneration and minimal intersegmental overlap which was found in the caudal ‘cell nest’ region, and (B) diffuse; exhibiting less discrete areas of degeneration and greater intersegmental overlap which was found predominantly in the rostral ‘reticular’ region, but was also notable in ventral portions of the caudal region. The two patterns were less evident with the Fink-Heimer 1 technique which stains more terminal and preterminal degenerating fibers; however, focal degeneration in the caudal region was still discernible from the less localized degeneration of the rostral region. (4) The extent and amount of degeneration from each root was related to both the size and the proximodistal position of its peripheral dermatome. (5) Terminal degeneration from all of the roots was arranged somatotopically: cranial roots terminated laterally, caudal roots medially, whereas distal dermatomes projected dorsally, proximal dermatomes ventrally. (6) The somatotopia is maintained in the rostral ‘reticular’ region, although some lateral skewing of the fibers occurs. (7) A ventrolateral region of asomatotopia was noted and discussed. (8) Some degeneration in other brain stem nuclei was noted. The variations in the disposition of dorsal root fibers in the cuneate nucleus augment anatomical and physiological findings, and support the division of the cuneate nucleus into rostral and caudal regions.

Cost-Effectiveness of Thrombolysis With Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke Assessed by a Model Based on UK NHS Costs

Background and Purpose— Thrombolytic therapy is licensed for use in highly selected patients with acute ischemic stroke. We aimed to model the health economic impact of limited use of thrombolytic therapy and to assess whether it was likely to be cost-effective when used more widely in the UK National Health Service (NHS). Methods— The authors formed a discussion panel to develop the decision-analysis model of acute stroke care. It consisted of Markov state-transition processes, with probabilities of different health states determined by certain key variables. The range of estimates of efficacy of recombinant tissue plasminogen activator (rt-PA) was taken from an update to a Cochrane systematic review of randomized trials of thrombolysis. Data on outcome after stroke were taken from our hospital-based stroke register, supplemented by data derived from relevant literature sources. Results— The model suggested that compared with standard care, if eligible patients were treated with rt-PA up to 6 hours, there was a 78% probability of a gain in quality-adjusted survival during the first year, at a cost of £13 581 per quality-adjusted life-year (QALY) gained. Over a lifetime, rt-PA was associated with cost-savings of £96 565 per QALY. However, the estimates were imprecise and highly susceptible to the assumptions used in the economic model; under several plausible assumptions, rt-PA was much less cost-effective than standard care, and under others, a great deal more cost-effective. Conclusions— The estimates of effectiveness and cost-effectiveness were imprecise. Although the benefits appeared promising, the data did not support the widespread use of thrombolytic therapy outside the terms of the current restricted license in routine clinical practice in the NHS. There is a case for new large-scale randomized trials comparing thrombolytic therapy with control up to 6 hours to determine more precisely the effects of rt-PA on short-term and long-term survival and its cost-effectiveness when used in a wider range of patients.

Efferent projections of the gracile nucleus in the cat

The efferent projections of different portions of the gracile nucleus in the cat were studied using both autoradiographic and degeneration tracing methods. The results suggest that there are two aspects to the functional organization of these projections. First, the somatotopic organization of the gracile n. (GR) is maintained, but inverted, by the topographic organization of its projections to VPL1. Fibers from the lateral portions of GR terminate medially in VPL1; fibers from the dorsal portions terminate ventrally. These fibers, especially those from the middle and caudal portions of GR, terminate in dense, precisely located groups of clusters. Dorsally located clusters in VPL1 (predominantly from middle-ventral portions of GR) are significantly smaller than ventrally located clusters (predominantly from middle-dorsal portions). The second aspect of this organization, involving the projections both to VPL1 and to other brain stem targets, is that some kind of functionally relevant sorting process appears to occur as fibers leave different portions of the gracile n. The afferent projections of the rostral (GRr) and middle-ventral portions (GRmv) of the gracile n. are different from those from the other portions of the nucleus. Projections to VPL1 from GRr are less dense, less likely to form clusters, less clearly topographically organized, and extend further rostrally and dorsally in VPL1 than those from the rest of GR. The clusters are small, like those from GRmv. Similarly, although all portions of GR project to several other brain stem regions, these projections appear to be derived preferentially from GRr and/or GRmv. These brain stem regions involve certain portions of the inferior olive, inferior and superior colliculi, red n., zona incerta, pretectum, thalamic posterior group and the H field of Forel. This dual organization of efferent connectivity is similar to that of the cuneate n.20, and is consistent with many of the differences in cytoarchitecture, afferent connectivity and response properties of cells within different portions of the dorsal column nuclei.

MR diffusion-weighted imaging and outcome prediction after ischemic stroke

Background: MR diffusion-weighted imaging (DWI) shows acute ischemic lesions early after stroke so it might improve outcome prediction and reduce sample sizes in stroke treatment trials. Previous studies of DWI and outcome produced conflicting results. Objective: To determine whether DWI lesion characteristics independently predict outcome in a broad range of patients with acute stroke. Methods: The authors recruited hospital-admitted patients with all severities of suspected stroke, assessed stroke severity on the NIH Stroke Scale (NIHSS), performed early brain DWI, and assessed outcome at 3 months (modified Rankin Scale). Clinical data and DWI lesion parameters were evaluated in a logistic regression model to identify independent predictors of outcome at 3 months and a previously described “Three-Item Scale” (including DWI) was tested for outcome prediction. Results: Among 82 patients (mean NIHSS 7.1 [±6.3 SD]), the only independent outcome predictors were age and stroke severity. Neither DWI lesion volume nor apparent diffusion coefficient nor the previously described Three-Item Scale predicted outcome independently. Comparison with previous studies suggested that DWI may predict outcome only in patients with more severe cortical ischemic strokes. Conclusions: Across a broad range of stroke severities, diffusion-weighted imaging (DWI) did not predict outcome beyond that of key clinical variables. Thus, DWI is unlikely to reduce sample sizes in acute stroke trials assessing functional outcome, especially where estimated treatment effects are modest.

Infection after acute stroke is associated with poor short-term outcome

Background –  We sought to explore the frequency, risk factors, and clinical consequences of post‐stroke infections (PSI).