Sari Atula

A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis

Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS). Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. Results Median change in BOD was 287 mm3 in the placebo group and 83 mm3 in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19–82) nmol/l to 110 (range 67–163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate. Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS. Trial registration number EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke

Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use. Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables. Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage. Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

Outcome by Stroke Etiology in Patients Receiving Thrombolytic Treatment. Descriptive Subtype Analysis

Background and Purpose— Treating ischemic stroke with thrombolytic therapy is effective and safe, but limited data exist on its efficacy and safety in different etiologic subtypes. Methods— Patients with acute ischemic stroke treated with intravenous thrombolysis between 1995 and 2008 at our hospital were classified according to the Trial of ORG 10172 in Acute Stroke Treatment criteria based on diagnostic evaluation. Clinical outcome of the stroke subtypes by 3-month modified Rankin Scale was compared by multivariate logistic regression. A good outcome was defined as modified Rankin Scale ≤2. Symptomatic intracranial hemorrhage was defined according to both National Institute of Neurological Disorders and Stroke and European Cooperative Acute Stroke Study criteria. Results— Of the 957 eligible patients, 41% (389) had cardioembolisms, 23% (217) large-artery atherosclerosis, and 11% (101) small-vessel disease (SVD). A good outcome was more common in SVD than in the other subtypes. Patients with SVD were more often male (64% versus 54%), had a lower baseline National Institutes of Health Stroke Scale score, lower mortality rate, and experienced no symptomatic intracranial hemorrhage. Patients with SVD had a prior stroke more often (20% versus 11%), whereas hypertension, diabetes, hypercholesterolemia, and transient ischemic attacks were equally distributed in all subtypes. Patients with SVD had a better outcome even after adjusting for baseline National Institutes of Health Stroke Scale and glucose level, age, and hyperdense artery sign (OR, 1.81; 1.01 to 3.23). In the adjusted multivariate model, other etiologic groups showed no significant correlation to good outcome. Conclusions— Patients with SVD were spared from bleeding complications and had the best outcome even after adjustment for confounding factors.

Stroke Mimics and Intravenous Thrombolysis

STUDY OBJECTIVE The necessity for rapid administration of intravenous thrombolysis in patients with acute ischemic stroke may lead to treatment of patients with conditions mimicking stroke. We analyze stroke patients treated with intravenous thrombolysis in our center to characterize cases classified as stroke mimics. METHODS We identified and reviewed all cases with a diagnosis other than ischemic stroke in our large-scale single-center stroke thrombolysis registry. We compared these stroke mimics with patients with neuroimaging-negative and neuroimaging-positive ischemic stroke results. RESULTS Among 985 consecutive intravenous thrombolysis-treated patients, we found 14 stroke mimics (1.4%; 95% confidence interval 0.8% to 2.4%), 694 (70.5%) patients with neuroimaging-positive ischemic stroke results, and 275 (27.9%) patients with neuroimaging-negative ischemic stroke results. Stroke mimics were younger than patients with neuroimaging-negative or -positive ischemic stroke results. Compared with patients with neuroimaging-positive ischemic stroke results, stroke mimics had less severe symptoms at baseline and better 3-month outcome. No differences appeared in medical history or clinical features between stroke mimics and patients with neuroimaging-negative ischemic stroke results. None of the stroke mimics developed symptomatic intracerebral hemorrhage compared with 63 (9.1%) among patients with neuroimaging-positive ischemic stroke results and 6 (2.2%) among patients with neuroimaging-negative ischemic stroke results. CONCLUSION Stroke mimics were infrequent among intravenous thrombolysis-treated stroke patients in this cohort, and their treatment did not lead to harmful complications.

Stroke Outcome in Clinical Trial Patients Deriving From Different Countries

Background and Purpose— Stroke incidence and outcome vary widely within and across geographical locations. We examined whether differences in index stroke severity, stroke risk factors, mortality, and stroke outcome across geographical locations remain after adjusting for case mix. Methods— We analyzed 3284 patients from the Virtual International Stroke Trials Archive (VISTA). We used logistic regression to examine the incidence of mild index stroke, functional, and neurological outcomes after accounting for age, medical history, year of trial recruitment, and initial stroke severity in the functional and neurological outcome analyses. We examined mortality between geographical regions using a Cox proportional hazards model, accounting for age, initial stroke severity, medical history, and year of trial recruitment. Results— Patients enrolled in the USA and Canada had the most severe index strokes. Those recruited in Austria and Switzerland had the best functional and neurological outcomes at 90 days (P<0.05), whereas those enrolled in Germany had the worst functional outcome at 90 days (P=0.013). Patients enrolled in Austria, Switzerland, Belgium, Netherlands, Finland, Germany, Greece, Israel, Spain, and Portugal had a significantly better survival rate when compared with those enrolled in USA and Canada. Patients enrolled in trials after 1998 had more severe index strokes, with no significant difference in outcome compared with those enrolled before 1998. Conclusion— We identified regional variations in index stroke severity, outcome, and mortality for patients enrolled in ischemic stroke clinical trials over the past 13 years that were not fully explained by case mix. Index stroke severity was greater in patients enrolled after 1998, with no significant improvement in outcomes compared to those enrolled before 1998.

Post-Thrombolytic Hyperglycemia and 3-Month Outcome in Acute Ischemic Stroke

Background: Treating hyperglycemia in acute ischemic stroke may be beneficial, but knowledge on its prognostic value and optimal target glucose levels is scarce. We investigated the dynamics of glucose levels and the association of hyperglycemia with outcomes on admission and within 48 h after thrombolysis. Methods: We included 851 consecutive patients with acute ischemic stroke treated with intravenous thrombolysis in the Helsinki University Central Hospital during 1998–2008. Outcome measures were unfavorable 3- month outcome (3–6 on the modified Rankin Scale), death, and symptomatic intracerebral hemorrhage (sICH) according to NINDS criteria. Hyperglycemia was defined as a blood glucose level of ≧8.0 mmol/l. Four groups were identified based on (a) admission and (b) peak glucose levels 48 h after thrombolysis: (1) persistent normoglycemia (baseline plus 48-hour normoglycemia), (2) baseline hyperglycemia (48-hour normoglycemia), (3) 48-hour hyperglycemia (baseline normoglycemia), and (4) persistent hyperglycemia (baseline plus 48-hour hyperglycemia). Results: 480 (56.4%) of our patients (median age 70 years; onset-to-needle time 199 min; National Institutes of Health Stroke Scale score 9), had persistent normoglycemia, 59 (6.9%) had baseline hyperglycemia, 175 (20.6%) had 48-hour hyperglycemia, while persistent hyperglycemia appeared in 137 (16.1%) patients. Persistent and 48-hour hyperglycemia independently predicted unfavorable outcome [odds ratio (OR) = 2.33, 95% confidence interval (CI) = 1.41–3.86, and OR = 2.17, 95% CI = 1.30–3.38, respectively], death (OR = 6.63, 95% CI = 3.25–13.54, and OR = 3.13, 95% CI = 1.56–6.27, respectively), and sICH (OR = 3.02, 95% CI = 1.68–5.43, and OR = 1.89, 95% CI = 1.04–3.43, respectively), whereas baseline hyperglycemia did not. Conclusions: Hyperglycemia (≧8.0 mmol/l) during 48 h after intravenous thrombolysis of ischemic stroke is strongly associated with unfavorable outcome, sICH, and death.

Does Time of Day Or Physician Experience Affect Outcome of Acute Ischemic Stroke Patients Treated with Thrombolysis? a Study from Finland:

Background Maintaining a steady thrombolysis service for treatment of acute ischemic stroke 24 h/7 days is challenging. Diurnal and seasonal variability of stroke onset affects the clinical outcome of these patients. Hypothesis We state that a 24 h/7 days availability of stroke-trained physicians ameliorates weekend effects and other seasonal, weekday, or non-office-hour-related influences on outcome of ischemic stroke patients treated with intravenous thrombolysis. Methods All consecutive ischemic stroke patients treated with thrombolysis at the Helsinki University Central Hospital were prospectively registered (n = 1581). Patients with basilar artery occlusion (n = 154) were excluded. Door-to-needle time, three-month clinical outcome as measured by the modified Rankin Scale dichotomized at 0 to 2 vs. 3 to 6, and symptomatic intracerebral hemorrhage were analyzed with logistic regression models adjusting for baseline variables. The treating physician was defined as experienced after 18 decisions made to give thrombolysis treatment. Results Door-to-needle time or clinical outcome did not differ with regard to time of day or season of presentation. Higher rates of symptomatic intracerebral hemorrhage occurred in spring (odds ratio 2.06, 95% confidence interval 1.03–4.11) and fall (odds ratio 2.08, 95% confidence interval 1.03–4.18). Physician experience reduced the door-to-needle time (odds ratio 0.40, 95% confidence interval 0.32–0.50) but was not associated with patient outcome (modified Rankin scale 3 to 6, odds ratio 1.22, 95% confidence interval 0.95–1.59) or symptomatic intracerebral hemorrhage (odds ratio 0.80, 95% confidence interval 0.51–1.27) rates. Conclusions Thrombolytic therapy can be delivered at a steady service level at all times. With proper training, less-experienced physicians can provide high quality thrombolysis, but experience translates into faster treatment.

Characteristics and Outcome of Ischemic Stroke Patients Who Are Free of Symptoms at 24 Hours following Thrombolysis

Background: A part of ischemic stroke patients score 0 on the National Institutes of Health Stroke Scale (NIHSS) within 24 h following thrombolysis. Their clinical characteristics and long-term outcome are poorly studied. We report a single-center assessment of such patients. Methods: The cohort comprises 874 consecutive patients from the Helsinki Stroke Thrombolysis Registry, out of whom 113 scored 0 on 24-hour NIHSS. We analyzed their baseline demographic, clinical and radiological characteristics and 3-month outcome (modified Rankin Scale, mRS). Associations between the study parameters were tested by multivariate analysis. Results: Patients with a 24-hour NIHSS score = 0 (n = 113) were younger than the rest of the population (n = 761; median: 65.6 vs. 71.5 years; p < 0.001), their NIHSS score on admission was lower (median: 5 vs. 10; p < 0.001), as was their glucose level (median: 6.2 vs. 6.7 mmol/l; p = 0.02). The onset-to-treatment time was similar in both groups (median: 120 vs. 115 min; p = 0.89). Patients with a 24-hour NIHSS score = 0 more often achieved an excellent outcome (mRS scores: 0–1; 81 vs. 31%; p < 0.001) and had lower mortality (1.8 vs. 11.8%; p < 0.01). One third of these patients had a brain infarction visible on 24-hour imaging. Lower baseline NIHSS score and younger age were independently associated with 24-hour NIHSS score = 0, which, in turn, was independently associated with excellent 3-month outcome. Conclusions: Patients with an NIHSS score = 0 at 24 h following thrombolysis are younger, have milder symptoms and have a lower glucose level on admission. They achieve more often excellent outcome and lower mortality. Still, 8% of them required help in daily activities or were dead at 3 months (mRS scores: 3–6).

Neuromyelitis optica and aquaporin-4 (AQP4) autoantibodies in consecutive optic neuritis patients in Southern Finland

Purpose:  To analyse the frequency of neuromyelitis optica (NMO) among consecutive optic neuritis (ON) patients in Southern Finland and the feasibility of Aquaporin‐4 (AQP4) autoantibody assay in the diagnosis of NMO.

Outcome of ischemic stroke patients with serious post-thrombolysis neurological deficits

To identify factors associated with favorable outcome in ischemic stroke patients having considerable post‐thrombolytic neurological deficits but without endovascular treatment.