Michal Karlinski

Intravenous alteplase in ischemic stroke patients not fully adhering to the current drug license in Central and Eastern Europe

Background The current European license for alteplase in acute ischemic stroke excludes from treatment large groups of patients. Nevertheless, in everyday practice, many patients receive off-label thrombolysis at the physicians discretion. Aim Our aim was to evaluate safety and effectiveness of intravenous alteplase in patients not fully adhering to the drug license compared with those treated strictly according to the license in Central and Eastern Europe. Methods We analyzed the data contributed to Safe Implementation of Thrombolysis in Stroke registry from nine countries between February 2003 and February 2010. Statistical analysis included multivariate logistic regression. Results Of 5594 consecutive patients, 1919 patients (34·3%) not fully adhered to the license. The most frequent deviations were: time-to-treatment >3 h (13·1%), use of intravenous antihypertensives (8·3%), age >80 years (7·3%), oral anticoagulation (4·2%), a previous stroke with concomitant diabetes (3·9%), and previous stroke <three-months (2·7%). The off-label group showed a significantly higher rate of symptomatic intracranial haemorrhage, which was not confirmed in the multivariate analysis. License nonadherence significantly increased the risk of death or dependency (odds ratio 1·26; 95% confidence interval: 1·08–1·48), with a trend for increased mortality (odds ratio 1·17; 95% confidence interval: 0·97–1·42). Isolated time-to-treatment >3 h was an independent predictor of unfavorable outcome (odds ratio 1·32; 95% confidence interval: 1·01–1·71). Conclusion Our findings show that patients not fully adhering to the European license are not at increased risk of symptomatic intracranial haemorrhage but achieve less favorable outcome. Some contraindications appear more redundant than others. However, the final conclusions about safety and effectiveness should be based on the results of ongoing randomized trials.

Hyperperfusion Syndrome after Carotid Endarterectomy and Carotid Stenting

Background: Hyperperfusion syndrome (HS) is a relatively rare but possibly serious complication of carotid revascularization procedures. Impaired cerebral autoregulation and postrevascularization changes in cerebral blood flow are the main mechanisms involved in the development of HS. Most up-to-date studies addressing this issue are retrospective and tend to concentrate on carotid endarterectomy (CEA), neglecting carotid stenting (CAS). Our aim was to compare the frequency of clinical signs of HS and hyperperfusion detected by transcranial Doppler (TCD) in patients undergoing CAS or CEA due to carotid stenosis. Methods: In this prospective observational study, we evaluated 61 patients scheduled for routine CAS or CEA. Each patient was examined by a neurologist before and after the revascularization procedure to assess the clinical status. Severe headache, ocular or facial pain, confusion, visual disturbances, epileptic seizures or any focal deficits not caused by cerebral ischemia were considered clinical signs of HS. Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), and pulsatility index were measured by TCD once before and twice after the intervention (within 6 h after and 2-5 days after the procedure). Hyperperfusion was defined as a >100% increase in the middle cerebral artery (MCA) blood velocity, evaluated separately for PSV and MV after the procedure compared with the baseline value. Cerebrovascular reactivity (CVR) was evaluated with a TCD acetazolamide test before the intervention. Results: CAS (n = 33) and CEA (n = 28) patients were included in the study. There was no difference between the groups in the frequency of clinical signs of HS (21.2 vs. 21.4%) and ratio of TCD hyperperfusion (12.1 vs. 14.3%). In the CAS group, ipsilateral MCA velocity significantly increased directly after the intervention and 2-5 days later, while it increased in the CEA group only 2-5 days after the intervention. The sensitivity and specificity of hyperperfusion, defined by MV, for HS signs were 38.5 and 93.8%, respectively, whereas those defined by PSV were 30.8 and 89.6%, respectively. The sensitivity and specificity of impaired CVR (<25%) for HS signs were 63.6 and 73.5%, respectively. Conclusions: There is no difference in the frequency of HS clinical signs and hyperperfusion detected by TCD between patients after CAE and CAS. Clinical signs suggested HS does not always correspond with TCD hyperperfusion. However, both the CVR test and TCD measurements of MCA velocity can help identify patients at high risk for HS.

Early neurological worsening in patients with Wilson's disease

BACKGROUND Early neurological worsening during treatment initiation for Wilsons disease (WD) is an unresolved problem. Our aim was to establish the frequency and outcome of early neurological worsening in patients with WD. METHODS We analyzed 143 symptomatic patients diagnosed with WD between 2005 and 2009. Early neurological deterioration was based on worsening on the Unified Wilsons Disease Score Scale, scored at baseline through 6 months or occurrence of new neurological symptoms. Reversibility of worsening was followed up to 24 months. RESULTS Early neurological worsening was observed in 11.1% (16/143) and involved only patients with neurological signs at diagnosis. Mean time to worsening from treatment initiation was 2.3 ± 1.9 months. Neurological deterioration was completely reversible in 53% (8/15) and partially in 13% (2/15) of patients over 9.2 ± 5.2 months. Patients who experienced early deterioration had significantly more severe baseline neurological deficit, higher prevalence of thalamic (66% vs 29%) and brain stem (73% vs 33%) lesions seen on baseline magnetic resonance imaging, and more often used concomitant dopamine receptor antagonists (46% vs 5%). Disease duration, treatment type (d-penicillamine or zinc sulfate), type of neurological manifestations, initial copper metabolism results, and liver function parameters did not differ between evaluated groups. CONCLUSIONS Neurological worsening at the beginning of anti-copper therapy may occur in over 10% of WD patients. Special attention should be paid to those with severe initial neurological manifestations, advanced brain injury and using dopamine receptor antagonists. Type of anti-copper therapy did not show clear association with early neurological worsening.

Role of Preexisting Disability in Patients Treated With Intravenous Thrombolysis for Ischemic Stroke

Background and Purpose— Little is known about the effect of thrombolysis in patients with preexisting disability. Our aim was to evaluate the impact of different levels of prestroke disability on patients’ profile and outcome after intravenous thrombolysis. Methods— We analyzed the data of all stroke patients admitted between October 2003 and December 2011 that were contributed to the Safe Implementation of Treatments in Stroke–Eastern Europe (SITS-EAST) registry. Patients with no prestroke disability at all (modified Rankin Scale [mRS] score, 0) were used as a reference in multivariable logistic regression. Results— Of 7250 patients, 5995 (82%) had prestroke mRS 0, 791 (11%) had prestroke mRS 1, 293 (4%) had prestroke mRS 2, and 171 (2%) had prestroke mRS ≥3. Compared with patients with mRS 0, all other groups were older, had more comorbidities, and more severe neurological deficit on admission. There was no clear association between preexisting disability and the risk of symptomatic intracranial hemorrhage. Prestroke mRS 1, 2, and ≥3 were associated with increased risk of death at 3 months (odds ratio, 1.3, 2.0, and 2.6, respectively) and lower chance of achieving favorable outcome (achieving mRS 0–2 or returning to the prestroke mRS; 0.80, 0.41, 0.59, respectively). Patients with mRS ≥3 and 2 had similar vascular profile and favorable outcome (34% versus 29%), despite higher mortality (48% versus 39%). Conclusions— Prestroke disability does not seem to independently increase the risk of symptomatic intracranial hemorrhage after thrombolysis. Despite higher mortality, 1 in 3 previously disabled patients may return to his/her prestroke mRS. Therefore, they should not be routinely excluded from thrombolytic therapy.

Deep venous thrombosis in acute stroke patients.

Deep venous thrombosis (DVT) is a complication of stroke. Our aim was to determine the frequency of DVT in patients with acute stroke, risk factors for its development, and its influence on the 3-month outcome. A total of 323 consecutive patients with acute stroke were enrolled. We performed ultrasound imaging within 7 days after stroke. Deep venous thrombosis was found in 8.7% of patients, only in those with ischemic stroke. Patients with DVT were more frequently female (71.4% vs 49.5%), had prestroke Modified Rankin scale (mRS) 3 to 5 (42.9% vs 15.3%), elevated C-reactive protein (CRP) serum level (65.4% vs 32.5%), and a trend toward elevated serum fibrinogen level (85.7% vs 70.1%; P = .08). In a multivariate analysis, elevated CRP (odds ratio [OR] 3.15) and prestroke disability (OR 2.89) were independent risk factors for DVT. Deep venous thrombosis occurs in <10% of patients with acute stroke and does not significantly affect the 3-month outcome. Prestroke dependency and elevated CRP level at baseline are independent risk factors for DVT.

Temporal trends in vascular risk factors and etiology of urban Polish stroke patients from 1995 to 2013

BACKGROUND Despite estimates about general trends in stroke epidemiology worldwide, there are only a few reports of detailed longitudinal data and none of them reflects the economic transition that occurred in Central and Eastern Europe over the last two decades. The aim of this study was to investigate long term trends in risk factors and their pre-stroke control as well as acute stroke clinical presentation and etiology in Polish urban setting. METHODS This is a retrospective registry-based analysis of consecutive acute stroke patients from a highly urbanized area (Warsaw, Poland) admitted to a single stroke center between 1995 and 2013. Patients were divided into four time periods: 1995-1999 (n=529), 2000-2004 (n=1253), 2005-2009 (n=1320) and 2010-2013 (n=871). RESULTS During the study period 3973 first-ever stroke patients were admitted. The proportion of ischaemic strokes (88.2% to 90.9%) and male patients (45.2% to 46.2%) remained stable throughout the whole study period. Admitted patients became older (72, 73, 74 and 76years, consecutive time periods), were more likely to be diagnosed with hypertension (from 61.1% to 72.8%) and disable (84.3% to 67.4%) prior to stroke. There was an increase in pre-stroke use of antihypertensives in patients with hypertension (from 77.8% to 90.5%), antiplatelets in patients with coronary artery disease (from 33.9% to 56.5%), vitamin K antagonists in patients with atrial fibrillation (from 6.3% to 39.8%) and statins (from 7.6% to 26.3%). There was a decrease in mean stroke severity (9, 11, 8 and 6 points on the National Institutes of Stroke Scale) on admission and the proportion of strokes attributed to small-vessel disease (22.0%, 20.0%, 10.6% and 8.3%). CONCLUSIONS Over the last two decades the profile of urban Polish stroke patients has changed significantly and it can be attributed to marked economic improvement in Poland since 1990s. Increasing age and better management of pre-existing vascular risk factors were accompanied by decreasing stroke severity and lower proportion of strokes attributed to small-vessel disease.

The accuracy of prehospital diagnosis of acute cerebrovascular accidents: an observational study.

Introduction Time to treatment is the key factor in stroke care. Although the initial medical assessment is usually made by a non-neurologist or a paramedic, it should ensure correct identification of all acute cerebrovascular accidents (CVAs). Our aim was to evaluate the accuracy of the physician-made prehospital diagnosis of acute CVA in patients referred directly to the neurological emergency department (ED), and to identify conditions mimicking CVAs. Material and methods This observational study included consecutive patients referred to our neurological ED by emergency physicians with a suspicion of CVA (acute stroke, transient ischemic attack (TIA) or a syndrome-based diagnosis) during 12 months. Referrals were considered correct if the prehospital diagnosis of CVA proved to be stroke or TIA. Results The prehospital diagnosis of CVA was correct in 360 of 570 cases. Its positive predictive value ranged from 100% for the syndrome-based diagnosis, through 70% for stroke, to 34% for TIA. Misdiagnoses were less frequent among ambulance physicians compared to primary care and outpatient physicians (33% vs. 52%, p < 0.001). The most frequent mimics were vertigo (19%), electrolyte and metabolic disturbances (12%), seizures (11%), cardiovascular disorders (10%), blood hypertension (8%) and brain tumors (5%). Additionally, 6% of all admitted CVA cases were referred with prehospital diagnoses other than CVA. Conclusions Emergency physicians appear to be sensitive in diagnosing CVAs but their overall accuracy does not seem high. They tend to overuse the diagnosis of TIA. Constant education and adoption of stroke screening scales may be beneficial for emergency care systems based both on physicians and on paramedics.

Carotid intima media thickness and blood biomarkers of atherosclerosis in patients after stroke or myocardial infarction

Aim To test if circulating levels of markers of inflammation, endothelial function, and chronic infections, as well as association between these markers and carotid intima media thickness (CIMT), depend on the stage of atherosclerosis expressed as a history of a major vascular event. Methods The associations were analyzed separately in 75 healthy controls, 79 patients 3-6 months after the first-ever non-cardioembolic ischemic stroke (IS), and 37 patients 3-6 months after the first-ever myocardial infarction (MI). Data were collected prospectively in 2005. We measured high sensitivity C-reactive protein (hs-CRP), procalcitonin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), serum level of immune complexes (IC), and identified antibodies against Herpes simplex virus type 1 (HSV), Cytomegalovirus, Chlamydia pneumonia, and Helicobacter pylori. Correlations with CIMT were determined using Pearson R and verified after adjustment for age, sex, hypertension, diabetes, and statin therapy. Results Median ICAM-1 concentration was significantly lower in controls than in post-IS patients (188 μg/L vs 215 μg/L), and significantly lower in post-IS patients than in post-MI patients (215 μg/L vs 260 μg/L). Control patients also had significantly lower IC level (0.03 U/L) and HSV antibody index (6.0) compared to both post-IS (0.6 U/L, 9.6) and post-MI (0.4 U/L, 9.2) patients. CIMT was correlated with age (Pearson R = 0.38, P = 0.001) in the control group, immune complexes (R = 0.26, P = 0.023) in the post-IS group, and with hs-CRP (R = 0.40, P = 0.017) in the post-MI group. These correlations were confirmed using multiple regression analysis. Conclusions Our study supports linear correlations between CIMT and IC and hs-CRP levels. However, these associations seem to depend on the type of vascular burden.

Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event

Background and Purpose— According to the European license, alteplase can be given no sooner than 3 months after previous stroke. However, it is not known whether past history of stroke influences the effect of treatment. Our aim was to evaluate safety and functional outcome after intravenous thrombolysis administered in everyday practice to patients with previous stroke ⩽3 months compared with those with first-ever stroke. Methods— We analyzed consecutive cases treated with alteplase between October 2003 and July 2014 contributed to the Safe Implementation of Thrombolysis for Stroke–Eastern Europe registry from 12 countries. Odds ratios were calculated using unadjusted and adjusted logistic regression. Results— Of 13 007 patients, 11 221 (86%) had no history of stroke and 249 (2%) experienced previous stroke ⩽3 months before admission. Patients with previous stroke ⩽3 months had a higher proportion of hypertension and hyperlipidemia. There were no significant differences in outcome, including symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study (unadjusted odds ratio 1.27, 95% confidence interval: 0.74–2.15), and being alive and independent at 3 months (odds ratio 0.81, 95% confidence interval: 0.61–1.09). Conclusions— Patients currently treated with alteplase, despite a history of previous stroke ⩽3 months, do not seem to achieve worse outcome than those with first-ever stroke. Although careful patient selection was probably of major importance, our findings provide reassurance that this group of patients may safely benefit from thrombolysis and should not be arbitrarily excluded as a whole. Further studies are needed to identify the shortest safe time lapse from the previous event to treatment with alteplase.

Optical coherence tomography as a marker of neurodegeneration in patients with Wilson’s disease

Wilson’s disease (WD) is an inherited autosomal recessive disorder that leads to pathological copper accumulation in different organs. Optical coherence tomography (OCT) is proposed as a marker of neurodegeneration in many neurological diseases. Thinning of the total retinal nerve fiber layer (RNFL) and macular thickness (Mth) examined by OCT was detected in patients with WD, especially those with brain magnetic resonance imaging changes. The aim of this study was to evaluate the relationship between OCT parameters and the progression of neurological signs measured by the Unified Wilson’s Disease Rating Scale (UWDRS) in patients with WD. Consecutive patients with WD admitted to the Department of Neurology underwent OCT to assess the thickness of the macula and total RNFL. Patients also had neurologic assessments according to the UWDRS part III. Patients were divided into two groups based on the presence (UWDRS+) and absence (UWDRS−) of neurological symptoms. Fifty-eight patients (34 females, 24 males) were enrolled. Mean duration of treatment was 9 years (standard deviation [SD], ±10.8). The mean UWDRS score at the time of study was 8.4 (range 1–52; SD ±13.9) points. Total RNFL as well as macula thickness were significantly decreased in the UWDRS+ group versus the UWDRS− group. A significant negative correlation was found between OCT parameters (RNFL and Mth measurements) and neurological impairment according the UWDRS scale. This study confirms that OCT may be a useful tool for measuring the degree of neurodegeneration in patients with WD, and may play role in monitoring disease progression.