Thomas M. Hemmen

A Modified National Institutes of Health Stroke Scale for Use in Stroke Clinical Trials Preliminary Reliability and Validity

Background and Purpose— The National Institutes of Health Stroke Scale (NIHSS) is accepted widely for measuring acute stroke deficits in clinical trials, but it contains items that exhibit poor reliability or do not contribute meaningful information. To improve the scale for use in clinical research, we used formal clinimetric analyses to derive a modified version, the mNIHSS. We then sought to demonstrate the validity and reliability of the new mNIHSS. Methods— The mNIHSS was derived from our prior clinimetric studies of the NIHSS by deleting poorly reproducible or redundant items (level of consciousness, face weakness, ataxia, dysarthria) and collapsing the sensory item into 2 responses. Reliability of the mNIHSS was assessed with the certification data originally collected to assess the reliability of investigators in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA (recombinant tissue plasminogen activator) Stroke Trial. Validity of the mNIHSS was assessed with the outcome results of the NINDS rtPA Stroke Trial. Results— Reliability was improved with the mNIHSS: the number of scale items with poor &kgr; coefficients on either of the certification tapes decreased from 8 (20%) to 3 (14%) with the mNIHSS. With the use of factor analysis, the structure underlying the mNIHSS was found identical to the original scale. On serial use of the scale, goodness of fit coefficients were higher with the mNIHSS. With data from part I of the trial data, the proportion of patients who improved ≥4 points within 24 hours after treatment was statistically significantly increased by tPA (odds ratio, 1.3; 95% confidence limits, 1.0, 1.8;P =0.05). Likewise, the odds ratio for complete/nearly complete resolution of stroke symptoms 3 months after treatment was 1.7 (95% confidence limits, 1.2, 2.6) with the mNIHSS. Other outcomes showed the same agreement when the mNIHSS was compared with the original scale. The mNIHSS showed good responsiveness, ie, was useful in differentiating patients likely to hemorrhage or have a good outcome after stroke. Conclusions— The mNIHSS appears to be identical clinimetrically to the original NIHSS when the same data are used for validation and reliability. Power appears to be greater with the mNIHSS with the use of 24-hour end points, suggesting the need for fewer patients in trials designed to detect treatment effects comparable to rtPA. The mNIHSS contains fewer items and might be simpler to use in clinical research trials. Prospective analysis of reliability and validity, with the use of an independently collected cohort, must be obtained before the mNIHSS is used in a research setting.

Efficacy of site-independent telemedicine in the STRokE DOC trial: a randomised, blinded, prospective study

BACKGROUND To increase the effective use of thrombolytics for acute stroke, the expertise of vascular neurologists must be disseminated more widely. We prospectively assessed whether telemedicine (real-time, two-way audio and video, and digital imaging and communications in medicine [DICOM] interpretation) or telephone was superior for decision making in acute telemedicine consultations. METHODS From January, 2004, to August, 2007, patients older than 18 years who presented with acute stroke symptoms at one of four remote spoke sites were randomly assigned, through a web-based, permuted blocks system, to telemedicine or telephone consultation to assess their suitability for treatment with thrombolytics, on the basis of standard criteria. The primary outcome measure was whether the decision to give thrombolytic treatment was correct, as determined by central adjudication. Secondary outcomes were the rate of thrombolytic use, 90-day functional outcomes (Barthel index [BI] and modified Rankin scale [mRS]), the incidence of intracerebral haemorrhages, and technical observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00283868. FINDINGS 234 patients were assessed prospectively. 111 patients were randomised to telemedicine, and 111 patients were randomised to telephone consultation; 207 completed the study. Mean National Institutes of Health stroke scale score at presentation was 9.5 (SD 8.1) points (11.4 [8.7] points in the telemedicine group versus 7.7 [7.0] points in the telephone group; p=0.002). One telemedicine consultation was aborted for technical reasons, although it was included in the analyses. Correct treatment decisions were made more often in the telemedicine group than in the telephone group (108 [98%] vs 91 [82%], odds ratio [OR] 10.9, 95% CI 2.7-44.6; p=0.0009). Intravenous thrombolytics were used at an overall rate of 25% (31 [28%] telemedicine vs 25 [23%] telephone, 1.3, 0.7-2.5; p=0.43). 90-day functional outcomes were not different for BI (95-100) (0.6, 0.4-1.1; p=0.13) or for mRS score (0.6, 0.3-1.1; p=0.09). There was no difference in mortality (1.6, 0.8-3.4; p=0.27) or rates of intracerebral haemorrhage after treatment with thrombolytics (2 [7%] telemedicine vs 2 [8%] telephone, 0.8, 0.1-6.3; p=1.0). However, there were more incomplete data in the telephone group than in the telemedicine group (12%vs 3%, 0.2, 0.1-0.3; p=0.0001). INTERPRETATION The authors of this trial report that stroke telemedicine consultations result in more accurate decision making compared with telephone consultations and can serve as a model for the effectiveness of telemedicine in other medical specialties. The more appropriate decisions, high rates of thrombolysis use, improved data collection, low rate of intracerebral haemorrhage, low technical complications, and favourable time requirements all support the efficacy of telemedicine for making treatment decisions, and might enable more practitioners to use this medium in daily stroke care.

Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) Final Results

Background and Purpose— Induced hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke. Methods— Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33°C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not. Results– In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator. Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT). Baseline demographics and risk factors were similar between groups. Mean age was 65.5±12.1 years and baseline National Institutes of Health Stroke Scale score was 14.0±5.0; 32 (55%) were male. Cooling was achieved in all patients except 2 in whom there were technical difficulties. The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4). At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant). Symptomatic intracranial hemorrhage occurred in 4 patients (68); all were treated with tissue plasminogen activator <3 hours (1 received hypothermia). Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant). Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (P=0.001). The pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (P=0.32). Conclusion— This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke.

A Pilot Dose-Escalation Safety Study of Tenecteplase in Acute Ischemic Stroke

Background and Purpose— Recombinant tissue-type plasminogen activator (rtPA) is the only approved treatment in acute ischemic stroke. However, intracerebral hemorrhage (ICH) occurs in 6.4% of patients treated with rtPA and limits its use. Tenecteplase (TNK) is a modified form of rtPA, with longer half-life and greater fibrin specificity. Patients after myocardial infarction had fewer systemic hemorrhages when treated with TNK compared with rtPA. This open-label, dose-escalation safety study was conducted to develop initial experience with TNK in the treatment of ischemic stroke. Methods— Eligible patients were treated with an intravenous bolus infusion of TNK within 3 hours of stroke onset. The dose escalation was conducted in tiers of 25 patients, starting at 0.1 mg/kg, to a planned maximum of 0.6 mg/kg. The primary endpoint was symptomatic intracranial hemorrhage within 36 hours of treatment. All patients were followed-up for 3 months. Results— Eighty-eight (88) patients were treated in 4 dosing tiers. In the first 3 tiers (0.1, 0.2, 0.4 mg/kg) of 25 patients each, no symptomatic and 2 (8%), 8 (32%), and 7 (28%) asymptomatic ICHs occurred. Enrollment into the fourth tier at 0.5 mg/kg was closed after 2 of 13 patients (15%) had symptomatic and 3 (23%) had asymptomatic ICHs. Overall, modified Rankin scores at 3 months were similar to those of historical controls treated with rtPA and not significantly different between treatment groups. Conclusions— TNK doses of 0.1 to 0.4 mg/kg are safe in ischemic stroke. Future trials are needed to compare the effect of TNK on neurological outcome and safety as compared with rtPA.

Induced Hypothermia for Acute Stroke

Induced hypothermia is one of the most promising neuroprotective therapies. Technological limitations and homeostatic mechanisms that maintain core body temperature have impeded the clinical use of hypothermia. Recent advances in intravascular cooling catheters and successful trials of hypothermia for cardiac arrest and neonatal asphyxia renewed interest in hypothermia for stroke, resulting in early phase clinical trials and plans for further development. This review elaborates on the clinical implications of hypothermia research in stroke and technical and logistical issues associated with the application of hypothermia.

Therapeutic Hypothermia for Brain Ischemia Where Have We Come and Where Do We Go

Mild hypothermia is an established neuroprotectant in the laboratory, showing remarkable and consistent effects across multiple laboratories and models of brain injury. At the clinical level, mild hypothermia has shown benefits in patients who have experienced cardiac arrest and in some pediatric populations experiencing hypoxic brain insults. Its role, however, in stroke therapy has yet to be established. Translating preclinical data to the clinical arena presents unique challenges with regard to cooling in patients who are generally awake and may require additional therapies, such as reperfusion. We review the state of therapeutic hypothermia in ischemic and hemorrhagic stroke and provide an outlook for its role in stroke therapy.

Identification of Nonischemic Stroke Mimics Among 411 Code Strokes at the University of California, San Diego, Stroke Center

BACKGROUND Code Stroke systems are widely used to expedite emergency treatment of patients with stroke. Code Stroke for mimic patients-those without a stroke cause-wastes resources. We investigated how many times a Code Stroke was initiated for patients who did not have a stroke appropriate for thrombolysis. METHODS We conducted a retrospective review of the discharge diagnoses of all patients who presented to our emergency department as a Code Stroke. A patient was considered a stroke mimic if a stroke code was activated, but none of the first 3 International Classification of Diseases, Ninth Revision codes on discharge were transient ischemic attack-related or ischemic stroke-related. RESULTS A total of 411 patients presented to the emergency department as Code Stroke. In all, 104 (25.3%) were discharged without a diagnosis of stroke or transient ischemic attack. The diagnoses in this group were intracranial hemorrhage in 19 patients, subarachnoid hemorrhage 6, subdural hematoma 3, old deficit 11, hypotension 11, seizure 10, intoxication 8, hypoglycemia 7, mass lesion 6, migraine 5, and other 18. In all, 33 of 307 eligible patients (10.7%) were treated with tissue-type plasminogen activator. None of the patients with a stroke mimic received tissue-type plasminogen activator. In 44 of 104 stroke mimics (42.3%), the acute disease was caused by a severe neurologic condition other than ischemic cerebrovascular disease. Only 60 of 411 stroke codes (14.6%) were initiated for patients without a severe and acute neurologic condition. CONCLUSIONS In our community, 25.5% of all Code Strokes were initiated for stroke mimics. Most mimic patients had an illness likely to benefit from urgent neurologic evaluation.

Endovascular therapeutic hypothermia for acute ischemic stroke: ICTuS 2/3 protocol

Therapeutic hypothermia improves neurological outcome after out-of-hospital cardiac arrest or neonatal hypoxic–ischemic injury. Although supported by preclinical evidence, therapeutic hypothermia for acute stroke remains under study. In the Intravascular Cooling in the Treatment of Stroke (ICTuS) trial, awake stroke patients were successfully cooled using an endovascular cooling catheter and a novel antishivering regimen. In the ICTuS-L study, the combination of endovascular hypothermia and thrombolysis proved feasible; while hypothermia was associated with no increased risk of bleeding complications, there was an increased association with pneumonia. Despite efforts to expedite, cooling began on average six-hours after stroke onset. We designed a novel Phase 2/3 trial to further test the safety of combined thrombolysis and endovascular hypothermia and to determine if the combination shows superiority compared with thrombolysis alone. ICTuS 2 (n = 400) will assess four hypotheses, and if milestones are met, ICTuS 3 (n = 1200) will begin as a seamless continuation for a total sample of 1600 patients. The ICTuS 2 milestones include (1) target temperature reached within six-hours of symptom onset; (2) no increased risk of pneumonia; (3) no increase in signs/symptoms of fluid overload due to chilled saline infusions; and (4) sufficient recruitment to complete the trial on time. The ICTuS 2/3 protocol contains novel features–based on the previous ICTuS and ICTuS-L trials – designed to achieve these milestones. Innovations include scrupulous pneumonia surveillance, intravenous chilled saline immediately after randomization to induce rapid cooling, and a requirement for catheter placement within two-hours of thrombolysis. An Investigational Device Exemption has been obtained and an initial group of sites initiated.

Translational Stroke Research: Vision and Opportunities

See related article, p 2341 Stroke risk and poststroke disability have steadily decreased in the United States over the past 2 decades because of improved prevention and access to reperfusion therapies for acute ischemic stroke, such as tPA (tissue-type plasminogen activator; alteplase) and endovascular thrombectomy. Despite the efficacy and safety of thrombolysis and thrombectomy, not all patients who receive the treatment improve to full, independent recovery, and most patients are ineligible for treatment. Additionally, there are no efficacious treatments to improve long-term outcomes for patients after the acute phase of ischemic stroke or to reduce brain injury induced by acute intracerebral hemorrhage. Therefore, development of new therapies for both acute and chronic stroke is sorely needed. Stroke occurs because of a variety of vascular pathologies and injury mechanisms, some of which are difficult to model in animals. With the exception of reperfusion therapy, preclinical research end points do not generally reflect clinical outcomes. Pharmacodynamics, pharmacokinetics, and target engagement in the human brain need to be further developed and optimized for stroke interventions so that drug level in brain tissue, time to initiation, and duration of treatment can be accurately measured in clinical trials. Many variables, such as heterogeneity of vascular pathologies, patient demographics, and a host of comorbid conditions, as well as the lack of validated biomarkers to stratify patient populations, limit the ability of typical stroke clinical trials to detect a treatment effect. To address these gaps, the National Institute of Neurological Disorders and Stroke organized and sponsored the workshop Translational Stroke Research: Vision and Opportunities, which was held in Bethesda, Maryland, on November 1 to 2, 2016. The workshop gathered over 180 registered participants from academia, industry, the Food and Drug Administration, and other public and private funding agencies. …

Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2)

Background and Purpose— Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients. Methods— Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1. Results— Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36–1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56–7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63–6.98). Conclusions— Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator–treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.