Marta Skowronska

Rationale and Design of INTERSTROKE: A Global Case-Control Study of Risk Factors for Stroke

Stroke is a major global health problem. It is the third leading cause of death and the leading cause of adult disability. INTERHEART, a global case-control study of acute myocardial infarction in 52 countries (29,972 participants), identified nine modifiable risk factors that accounted for >90% of population-attributable risk. However, traditional risk factors (e.g. hypertension, cholesterol) appear to exert contrasting risks for stroke compared with coronary heart disease, and the etiology of stroke is far more heterogeneous. In addition, our knowledge of risk factors for stroke in low-income countries is inadequate, where a very large burden of stroke occurs. Accordingly, a similar epidemiological study is required for stroke, to inform effective population-based strategies to reduce the risk of stroke. Methods: INTERSTROKE is an international, multicenter case-control study. Cases are patients with a first stroke within 72 h of hospital presentation in whom CT or MRI is performed. Proxy respondents are used for cases unable to communicate. Etiological and topographical stroke subtype is documented for all cases. Controls are hospital- and community-based, matched for gender, ethnicity and age (±5 years). A questionnaire (cases and controls) is used to acquire information on known and proposed risk factors for stroke. Cardiovascular (e.g. blood pressure) and anthropometric (e.g. waist-to-hip ratio) measurements are obtained at the time of interview. Nonfasting blood samples and random urine samples are obtained from cases and controls. Study Significance: An effective global strategy to reduce the risk of stroke mandates systematic measurement of the contribution of the major vascular risk factors within defined ethnic groups and geographical locations.

Acute Ischemic Stroke Care and Outcome in Centers Participating in the Polish National Stroke Prevention and Treatment Registry

Background and Purpose— Significant intercenter variability in quality of care and stroke outcomes was found in many countries. The aim of the study was to compare the acute ischemic stroke care and outcomes in centers participating in the Polish National Stroke Prevention and Treatment Registry. Methods— The World Health Organization Stepwise Approach to Stroke Surveillance–based questionnaire was used to collect data on patients admitted to participating centers between December 1, 2001, and July 31, 2002. To ensure data quality, only centers reporting representative sample of patients were analyzed. Ischemic stroke patient characteristics, in-hospital care, and early outcomes (adjusted for case mix) were compared for participating centers. Results— There were 26 of 48 centers that met inclusion criteria, with a total of 8736 patients (52% women; mean age 71 years, with a range among institutions from 68 to 75 years). Significant differences between centers were observed for distribution of risk factors and in-hospital care. The rates for death and poor outcome (defined as a Rankin score ≥3 or death) ranged from 8.0% to 31.8% and from 44.2% to 74.7%, respectively. After adjusting for case mix, the death or poor outcome prognoses remained significantly different between centers. Conclusions— The observed significant differences between Polish stroke centers indicate the need for improvement of patient education, effective stroke risk factor control, and standardized in-hospital care.

Lack of experience of intravenous thrombolysis for acute ischaemic stroke does not influence the proportion of patients treated

Objectives: To determine the eligibility of patients with ischaemic stroke admitted to the 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, for intravenous thrombolysis; to identify the major exclusions and assess whether organisational changes in the in-hospital stroke pathway and informative campaign in the local community and medical services can increase the number of patients treated; and to establish whether lack of previous experience with thrombolytic treatment or trials is predictive of the low proportion of patients treated. Methods: A survey of the database of patients with stroke admitted during the first 30 months after the introduction of intravenous thrombolysis for acute ischaemic stroke was conducted to search for all eligible patients. This included patients admitted within 2 h of symptom onset (assuming a 1 h door-to-needle time), age <80 years, National Institute of Health Stroke Scale (NIHSS) Score of 5–22, seizures at onset, platelet count >100 000/ml, glycaemia 50–400 mg/dl and international normalised ratio (INR) <1.6. The number of eligible patients was compared with the number actually treated. Results: 745 patients with acute ischaemic stroke were admitted during the study period. 18.4% were admitted within 2 h of symptom onset, 71% were aged <80 years, 55.4% had an NIHSS score between 5 and 22, 96.1% had INR <1.6, 98.9% had a platelet count >100 000/ml, 99.4% had blood glucose concentrations of 50–400 mg/dl and 97.4% had no seizures at onset. After adjusting for all inclusion criteria, 7.1% of the patients were found to be potentially eligible and 8.7% were actually treated (p = 0.25). Of the 65 treated patients, 63.1% were independent after 3 months, 16.9% died and none had a symptomatic intracranial haemorrhage. Conclusions: The proportion of patients with ischaemic stroke treated with intravenous thrombolysis in a previously inexperienced centre was not lower than in other centres and in countries where this treatment has been provided for a longer period of time. The number of patients treated was higher than that estimated mainly owing to organisational changes introduced in our centre, allowing treatment of those admitted between 2 and 3 h after symptom onset.

Ten years of stroke programmes in Poland: where did we start? Where did we get to?

Risk factors and a high stroke mortality rate are a heavy stroke burden on Central and Eastern European countries. The 1995 Helsingborg Declaration outlined the aim of the coming decade was to improve patient care. In Poland it led to the foundation of the National Stroke Prevention and Treatment Programme, (1998-2008) which later became part of the National Cardiovascular Disease Prevention and Treatment Programme. The aim: Improve acute and postacute management Implement innovative therapies Develop poststroke rehabilitation, and Monitor epidemiology. Establishing and equipping stroke units has raised their number from three to 111. Thrombolysis for stroke and carotid angioplasty and stenting procedures were supported and supervised. The needs in poststroke rehabilitation were assessed and services have improved due to the support of the programme. Continuous monitoring of patient care proved that the mortality and disability rates have decreased and the quality of treatment has improved.

Transcranial Sonography in Manganese-Induced Parkinsonism Caused by Drug Abuse

Transcranial sonography (TCs) is suitable to detect the accumulation of trace metals in the basal ganglia [1], and may be useful as a simple and safe technique in many neurodegenerative diseases [2–4]. Although the exact nature of basal ganglia hyperechogenicity is unclear, many studies have demonstrated an association between hyperechogenicity and iron accumulation [5]. In addition to iron, TCs hyperechogenicity has been associated with other trace metals, like copper and manganese [1]. Manganese accumulation in the brain can be caused by exposure to aerosolized manganese, as in miners and welders [6]. Manganese intoxication has also been described in cases of intravenous methcathinone (ephedrone) abuse. Homemade ephedrone is produced from tablets containing pseudoephedrine. The pseudoephedrine is oxidized with potassium permanganate, and then the solution is usually administered intravenously [7]. T1-weighted magnetic resonance imaging (MrI) hyperintensity in the basal ganglia, principally in the globus pallidus (Gp) (part of the lenticular nucleus, Ln), is distinctive in cases of manganese toxicity [7, 8] and has been described both after chronic occupational exposure and in methcathinone users. Although TCs studies of patients with brain manganese accumulation caused by aerosolized manganese have been performed, there are no TCs studies of manganese accumulation caused by ephedrone abuse. We would like to present such a study.

Peripheral Blood MCEMP1 Gene Expression as a Biomarker for Stroke Prognosis.

Background and Purpose— A limitation when making early decisions on stroke management is the lack of rapid diagnostic and prognostic testing. Our study sought to identify peripheral blood RNA biomarkers associated with stroke. The secondary aims were to assess the discriminative capacity of RNA biomarkers for primary stroke type and stroke prognosis at 1-month. Methods— Whole-blood gene expression profiling was conducted on the discovery cohort: 129 first-time stroke cases that had blood sampling within 5 days of symptom onset and 170 control participants with no history of stroke. Results— Through multiple regression analysis, we determined that expression of the gene MCEMP1 had the strongest association with stroke of 11 181 genes tested. MCEMP1 increased by 2.4-fold in stroke when compared with controls (95% confidence interval, 2.0–2.8; P=8.2×10−22). In addition, expression was elevated in intracerebral hemorrhage when compared with ischemic stroke cases (P=3.9×10−4). MCEMP1 was also highest soon after symptom onset and had no association with stroke risk factors. Furthermore, MCEMP1 expression independently improved discrimination of 1-month outcome. Indeed, discrimination models for disability and mortality that included MCEMP1 expression, baseline modified Rankin Scale score, and primary stroke type improved discrimination when compared with a model without MCEMP1 (disability Net Reclassification Index, 0.76; P=3.0×10−6 and mortality Net Reclassification Index, 1.3; P=1.1×10−9). Significant associations with MCEMP1 were confirmed in an independent validation cohort of 28 stroke cases and 34 controls. Conclusions— This study demonstrates that peripheral blood expression of MCEMP1 may have utility for stroke diagnosis and as a prognostic biomarker of stroke outcome at 1-month.

Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN).

BACKGROUND Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an neurodegeneration with brain iron accumulation (NBIA) subtype with mutation of C19orf12. Optic atrophy is one of the core symptoms in almost all MPAN cases, but the detailed ophthalmologic features of MPAN patients have not yet been described. METHODS All consecutive symptomatic, gene proven MPAN patients underwent a detailed ophthalmological examination: best corrected visual acuity (BCVA), slit lamp examination, dilated fundus examination, tonometry, optical coherent tomography (OCT) and electrophysiological examinations. The total thickness of the macula (Mth) and the retinal nerve fiber layer (RNFL) were measured separately. RESULTS Six males aged 18 to 21years were examined. Dilated fundus examination revealed complete optic disc paleness in 5 patients. In all patients, the Mth was normal. The total RNFL was thin in five patients. The latencies of PVEP were prolonged in all patients except one. In all cases, the ERG latencies and amplitudes were normal under both scotopic and photopic conditions. One patient, carrying different mutation and with different disease course, had a normal optic nerve head, normal RNFL thickness and PVEP latencies. CONCLUSIONS Optic nerve atrophy seems to be genotype-dependent in MPAN patients but is typical for the disease. This phenomenon, together with normal ERG examination, is most distinctive for MPAN.

Mitochondrial protein associated neurodegeneration – Case report

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. We present the case of a 31-year-old woman with mitochondrial protein associated neurodegeneration (MPAN). MPAN is a new identified subtype of NBIA, caused by mutations in C19orf12 gene. The typical features are speech and gait disturbances, dystonia, parkinsonism and pyramidal signs. Common are psychiatric symptoms such as impulsive or compulsive behavior, depression and emotional lability. In almost all cases, the optic atrophy has been noted and about 50% of cases have had a motor axonal neuropathy. In the MRI on T2- and T2*-weighted images, there are hypointense lesions in the globus palidus and substantia nigra corresponding to iron accumulation.

Transcranial sonography in mitochondrial membrane protein-associated neurodegeneration

Introduction Although the nature of basal ganglia hyperechogenicity in transcranial sonography (TCS) examinations remains unclear, many studies have shown associations between hyperechogenicity and iron accumulation. The role of iron in basal ganglia hyperechogenicity raises interest in the use of TCS in forms of neurodegeneration with brain iron accumulation (NBIA). Here we analyzed TCS and magnetic resonance imaging (MRI) findings among patients affected by one type of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN).

Thrombolysis for stroke in Poland: first 2 years of experience

Since the National Institute of Neurological Diseases and Stroke (NINDS) trial results were published in 1995, the number of countries in which recombinant tissue plasminogen activator (rt-PA, alteplase) is approved for acute stroke treatment is constantly increasing (1). It had been licensed for use by the European Agency for the Evaluation of Medicinal Products (EMEA) in 2002 on a temporary basis until 2005, now prolonged to 2007 (2). Alteplase will receive long-term approval provided that results of the monitoring study – Safe Implementation of Thombolysis in Stroke-Monitoring Study (SITS-MOST) will prove its safety and efficacy, and a trial of use within the time window from 3 to 4 5 h – European– Australasian Acute Stroke Study III (ECASS III) will be performed. On 11 November 2003 the drug was temporarily approved in Poland under the same conditions as in the EMEA countries. The health service in Poland, similar to other countries of Central and Eastern Europe, is seriously underfunded. Therefore, the use of thrombolysis, being a rather expensive treatment. is limited. The National Programme for Prevention and Treatment of Cardiovascular Diseases – POLKARD is one of the healthcare programmes of the Polish Ministry of Health. It was established in 2003 to support and fund the introduction and monitoring of new methods in the prevention and treatment of cardiovascular diseases, i.e. stroke. Implementation of thrombolysis for acute ischaemic stroke is one of the main goals. Now a few centres not included in POLKARD have funding from the National Health Fund (Narodowy Fundusz Zdrowia [NFZ]). In Poland, thrombolysis is implemented according to EUSI guidelines and SITS protocol (3, 4). Additionally, three centres treat patients in the randomised, controlled trial of rt-PA administered within 6 h of onset and in patients aged over 80 – the Third International Stroke Trial: Thrombolysis (IST-3) (5). POLKARD has agreed to reimburse the cost of rt-PA also for IST-3. In addition, the 2nd Department of Neurology of the Institute of Psychiatry and Neurology and the Department of Neurology of the Military Medical Institute in Warsaw, since 2005, have been awarded research grants from the Polish Ministry of Education and Science to support IST-3 in Poland. Before thrombolysis was approved in Poland a project to develop a stroke unit network was introduced. It was launched in 1997 when there were only three stroke units in Poland. Up to 2003, this programme was supported by the National Programme of Prevention and Treatment of Stroke and, after that date, by POLKARD. We estimate that 130 stroke units will cover the needs for stroke care. As the vast majority of stroke patients are treated in neurological departments, in 2003 we asked all 222 departments to answer a questionnaire on accessibility to the services necessary for a stroke unit. We surveyed the availability of CT/MRI scanning, ECG monitoring, laboratory tests, resuscitation devices and staff trained in stroke medicine, enquiring about availability 7 days a week/24 h a day. We also sought information on access to Doppler sonography, echocardiography, electrocardiography, chest X-ray, rehabilitation facilities and availability of a consulting neurosurgeon, anaesthetist, cardiologist, vascular surgeon and specialist in medical rehabilitation (4, 6). The units were divided into four categories: A (fulfilling all criteria), B (provisionally fulfilling), C (not fulfilling) and departments not having a stroke unit. We have received 194 completed questionnaires (response ratio 87 4%). In 2003, there were 20 class A stroke units, 56 B and 14 C (7). The situation is changing rapidly and there are now 58 class A stroke units. Thrombolytic treatment supported by POLKARD and NFZ is possible only in class A stroke units. According to the POLKARD registry (conducted by Prof. H. Kwiecinski at the Medical University of Warsaw), from autumn 2003 to the end of 2005, 339 cases were treated in 21 centres. There are substantial differences between centres in the number of patients treated according to the current license (range 2–93). Clinicians are also obliged to participate in the SITS registry since 2003 (the National Coordinator is Prof. A. Czlonkowska). To the end of 2005, 160 cases were registered. Only 15 centres are participating in SITS, 11 actively reporting patients and four not reporting. Also, some cases from SITS centres were not registered. Over the same time period, 91 patients were recruited in IST-3 in three active centres (the National Coordinators are Prof. A. Czlonkowska and Dr A. Kobayashi). Thrombolysis is a challenge for many neurologists in Poland. Contrary to what happens in many western countries, clinical trials with very early treatment of Correspondence: Prof. Anna Czlonkowska , 2nd Department of Neurology, Institute of Psychiatry and Neurology, Ul. Sobieskiego 9, 02-957 Warsaw, Poland. Tel: 14822 4582537; Fax: 14822 8424023; email: czlonkow@ipin.edu.pl 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland