Hrev_master Abstract Wake-Up Stroke (WUS) is defined as a stroke with the unclear onset of symptoms and subsequent neurological deficits which perceived upon awakening. WUS patients are often excluded from acute fibrinolytic and reperfusion therapy due to the unknown exact time of symptoms onset. This study aimed to evaluate patients with and without WUS characteristics and associated risk factors at two tertiary hospitals. First, we prospectively evaluated consecutive patients with stroke symptoms and determined stroke sub groups by using Computed Tomography (CT) scan. Next, demographic and clinical characteristics including past medical and drug consumption history as well as cardiac function index (ejection fraction), LDL (mg/dl) level and hematologic parameters: hemoglobin (Hb); hematocrit (Hct); platelet (Plt) were assessed. Results: 510 patients (56.1% men and 43.9% women) with aver- aged age of 70 and 72 years were studied, respectively. Of 510 patients, 405 (79.4%) had non-WUS stroke (known-onset stroke) and 105 (20.6%) had WUS strokes (unknown-onset stroke). The WUS occurrence most likely was observed in ischemic stroke compared to hemorrhagic one. No significant differences were found between patients from both groups regarding stroke risk fac- tors. However, hypertension and family history were more com- mon in patients with WUS (p>0.05). Moreover, individuals with a previous cerebrovascular accident in WUS group were almost sim- ilar to non-WUS counterparts. No differences also detected in case of hematologic characteristics, heart function index and LDL lev- els between study groups (p>0.05). Together, wake-up stroke occurs in approximately 20% of stroke subjects. In this study, patients with WUS had more hypertension and family history. Introduction Stroke or Cerebrovascular Accident (CVA) is a well-known medical emergency with high mortality rates conceived as the sec- ond leading cause of death and disability worldwide.1 Long-term and serious disability are important outcomes in patients with stroke.2 Two main broad categories of stroke include ischemic and hemorrhagic strokes which have somewhat different etiology, clin- ical course and treatment strategies.3 The recent epidemiologic study revealed that ischemic stroke is more common compared to hemorrhagic type. In 2013, around 6.9 million people had an ischemic stroke while 3.4 million people had a hemorrhagic stroke.4 Hemorrhagic stroke is also divided into two sub-types including Intracranial Hemorrhage (ICH) and Subarachnoid Hemorrhage (SAH).5 Although there is evidence-based develop- ment in acute stroke therapy as well as organized care in stroke units, determination of onset time is a critical step in stroke man- agement.6 Notably, the onset of stroke symptoms is a vital determi- nant of eligibility for receiving thrombolytic therapy.7 However, certain beginning time of stroke cannot be determined particularly in patients who develop stroke during sleeping and they often awaken with neurologic deficits such as aphasia and decreased consciousness.8 This type of stroke is known as Wake Up Stroke (WUS) or unclear-onset stroke.9 It has been estimated that WUS approximately accounts for 25% of all stroke incidence.10,11 However, the big challenge in WUS treatment is the time interval between stroke onset, hospital arrival and subsequent limited inter- ventions. As t-PA (tissue-plasminogen activator) is a time-depen- dent therapeutic strategy that should be performed till 3 to 4.5 hours following stroke symptoms onset, patients with WUS have not been included in thrombolytic treatment due to a higher risk of probable hemorrhagic complications.12 However, a subset of these patients received empirical or reperfusion therapy based on imag- ing criteria.13 In the present study, we sought to evaluate WUS prevalence and related effective factors in patients who referred to Emergency Care Journal 2020; volume 16:8834 Correspondence: Aysa Rezabakhsh,Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail: aysapharma.rezabakhsh@gmail.com Tel.:+98-4133352078 - Fax:+98-4136581558 Key words: Wake Up Stroke; Risk Factors; Familiar History; Hematologic Characteristics. Conflict of interest All authors declare there is no conflict of interest regarding the article publication. Contributions: ESH analyzed and interpreted the data; SSV conceived and designed the experiments; RR contributed reagents, materials, analysis tools or data; NK performed the experiments; AR wrote the paper. Ethics approval and consent to participate: The manuscript does not contain any individual person's data in any form. Received for publication: 19 January 2020. Accepted for publication: 27 May 2020. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2020 Licensee PAGEPress, Italy Emergency Care Journal 2020; 16:8834 doi:10.4081/ecj.2020.8834 [Emergency Care Journal 2020; 16:8834] [page 79] Evaluation of stroke related risk factors in wake up and non-wake up stroke patients Elyar Sadeghi-Hokmabadi,1 Samad Shams Vahdati,2 Reza Rikhtegar,1 Nazila Karzad,1 Aysa Rezabakhsh3 1Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences; 2Emergency Medicine Research Team, Tabriz University of Medical Sciences; 3Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Non -co mmerc ial us e o nly [page 80] [Emergency Care Journal 2020; 16:8834] emergency department of Imam-Reza and Razi hospitals, affiliated to Tabriz University of Medical Sciences. Materials and Methods Study Sample and design We included all consecutive patients in our cross-sectional study with stroke or stroke-related symptoms who referred to Imam-Reza and Razi hospitals emergency department from April- May 2015 until April-May 2016. The stroke patients were classi- fied to WUS and non-WUS groups. Moreover, the patients who received anti-hypertension drugs (controlled hypertension) or without any hypertension history were included while the patients without brain organic lesion (such as seizure, electrolyte imbal- ance, infections, etc.) as well as the patients who had un-controlled hypertension (without receiving any anti-hypertension medica- tions) were excluded from the study. Discrimination of stroke subtypes CT scan is the first neuro-imaging technique used to identify patients with suspected ischemic or hemorrhagic strokes. These subtypes of strokes were determined by CT scan and the ratio of ischemic and hemorrhagic strokes was precisely estimated. Based on CT scan findings, hyperintensity appearance in cerebrovascular was detected at SAH and ICH while these features were not seen in an ischemic stroke condition. Comparison of stroke-related risk factors In the present study, different risk factors related to the stroke occurrence such as hypertension, hyperlipidemia, diabetes melli- tus, smoking, alcohol consumption as well as drug history was evaluated by appropriate designed questioner and then comparison was conducted between WUS and non-WUS groups. Determination of hematologic profiles and a cardiac function index By using IDEXX ProCyte Dx® hematology analyzer, blood parameters including levels of Hb, Hct and Plt were measured. Moreover, low-density lipoprotein cholesterol (LDL-C), as one of the key biomarker for hyperlipidemia, was measured with a com- mercial kit according to the manufacturer’s introduction (Cat no: PT10041, Pars Azmun Co; Iran). Also, the cardiac ejection fraction was evaluated by echocardiography imaging under supervision of an expert cardiologist. Statistical analysis After data collection, we used SPSS software ver.17.0.1 (SPSS Inc., Chicago, IL, USA) for statistical analysis. For a description of demographic variables, mean ± Standard Deviation (SD) and fre- quency percent were used. To analyze differences between quanti- tative values, we used the independent t-test. Qualitative values also were analyzed by Chi-square or Mann-Whitney U test when appropriated. P value <0.05 was considered statistically signifi- cant. Ethical considerations Ethical approval for the current study was achieved from Faculty of Medicine of Tabriz University of Medical Sciences with ref number of 93/1-9/17 and ethical code of 5/4/10687. Informed consent was obtained from all individuals participated in the cur- rent study. Results Of 510 subjects evaluated during the timeframe of the study (one year), 316 and 194 patients from Imam Reza and Razi hospi- tal emergency department were included, respectively. Of the total 510 patients, 405 (79.4%) had non-WUS (known-onset stroke) and 105 (20.6%) had WUS (unclear-onset stroke). It seems that non- WUS is more common compared to the WUS (p<0.05, Table 1). According to our results, the minimum and maximum ages for WUS were 35 and 81 years old, and the calculated median reached 72 years old. While the minimum and maximum age for non-WUS patients were 17 and 92 years old with median of 70 years old. Interestingly, within the WUS candidates, 59 patients (56.19%) were male and 46 (43.8%) were female. Similar results were also obtained from non-WUS group. The number of male and female patients were 227 (56.04%) and 178 (43.95%), respectively. In this study, the percentage of ischemic stroke incidence was 85.29%. As our data showed, there was no significant differences in demo- graphic characteristics such as age and gender (p>0.05, Table 1). As shown in Table 1, there are also no significant differences regarding the previous CVA in the WUS and non-WUS (p=0.66; Table 1). Regarding stroke sub-types, 333 patients (76.6%) of non- WUS and 102 patients (23.4%) of WUS caused by ischemic attacks (the number of total patients was 435) (p<0.001, Table 2). There were no remarkable differences between two genders. In the case of hemorrhagic stroke sub-type (the number of total patients were 75), 66 patients (97.1%) of non-WUS and 2 patients (2.9%) of WUS had ICH (p<0.001, Table 2) while 6 patients (85.7%) of non-WUS and one patient (14.3%) of WUS showed SAH (p<0.001, Table 2). Because of the relatively small size of the sub- arachnoid population, p-value was not significant but the occur- rence of SAH in females was more than male patients. Previous CVA was considered as one of the key risk factors for stroke inci- dence. Table 3 exhibited well-established risk factors involved in stroke occurrence. As shown, 388 patients (76.1%) had high blood pressure experience in their medical history (Table 3). Moreover, 117 (22.9%), 77 (15.1%) and 48 (9.4%) patients had ischemic heart diseases, atrial fibrillation, and heart failure, respectively. It seems that the history of cardiovascular disorders plays an impor- tant role in subsequent stroke incidence. Other important risk fac- tors in the occurrence of stroke are hyperlipidemia and diabetes mellitus (as a metabolic disorder). Our data showed 175 (34.3%) and 143 (28%) of patients had hyperlipidemia and type 1 diabetes, respectively. According to our results, smoking and alcohol con- sumption had a lower role as stroke risk factors. However, 105 patients (20.6%) had a smoking history in their life span and just 9 patients (1.8%) were alcohol consumers. According to recent data, there were no statistically significant differences between the two groups (p>0.05; Table 3). However, the percentage of hypertension and familiar history risk factors in the occurrence of WUS were higher than non-WUS (hypertension: 77.03 vs. 72.38, p=0.37; familiar history: 12.34 vs. 6.8, p=0.13). In the next step, we evalu- ated the effect of antiplatelet, anti-coagulants and contraceptive drugs consumption. Our results showed no significant differences between non-WUS and WUS in relation to drug consumption (p>0.05; Table 3). As outlined in Table 4, neither hematologic characteristics (Hb, Ht, Plt) nor cardiac function index (EF) and LDL as lipid profile did not differ significantly between two groups (p>0.05; Table 4). Article Non -co mmerc ial us e o nly Discussion In the present study, we found that 20% of included patients had WUS. Following CT scan imaging to determine stroke sub- types, demographic characteristics and related risk factors analyses were done. Next, important hematologic items along with heart function index and LDL-C were measured as well. Due to WUS importance, the main purpose of this study was the determination of WUS prevalence and major leading risk factors in patients who hospitalized at two tertiary hospitals. In line with previous studies, there are minor demographic and clinical differences between patients with WUS and non-WUS.14,15 Controversially, other stud- ies demonstrated that WUS had greater severity at admission and poor prognosis at discharge.16 First, our findings showed both known-onset and WUS had almost the same prevalence in men and women and its occurrence most likely observed at older ages (aver- age age: 70-72 years old). In accordance with our results, it has been reported that the average age of stroke occurrence was 67.58 Article Table 2. Comparison of Stroke Sub -types in Patients with Non-Wake Up and Wake Up Strokes. Stroke sub- types Total Patients with non-wake up stroke Patients with wake up stroke P value Male (%) Female(%) Ischemic 435 333 (76.6%) 102 (23.4%) <0.001 57.7% 42.3% Intracranial 68 66 (97.1%) 2 (2.9%) <0.001 Hemorrhage (ICH) 48.5% 51.5% Sub-Arachnoid 7 6 (85.7%) 1 (14.3%) <0.001 Hemorrhage 28.6% 71.4% (SAH) Table 1. Comparison of Demographic Characteristics and Cerebrovascular Accident History in in Patients with Non-Wake Up and Wake Up Strokes. Demographic Characteristics Patients with non-wake up stroke Patients with wake up stroke P value Number of patients 405 105 _ Gender Male Female Male Female 56.04 % 43.95 % 56.16 % 43.80 % 0.53 Age (Median) 70 72 0.97 Non- cerebrovascular damage 300 (74.07%) 78 (74.28%) _ Cerebrovascular damage (≤3 months) 19 (4.69%) 7 (6.66%) _ Cerebrovascular damage (>3 months) 86 (21.23%) 20 (19.04%) _ Table 3. Comparison of Past Medical and Social History in Patients with Non-Wake Up and Wake Up Strokes. Past medical and social history Patients with non-wake up stroke (%) Patients with wake up stroke (%) P value High blood pressure (hypertension) 72.38 77.03 0.37 Diabetes mellitus type 1 35.23 26.17 0.06 Atrial fibrillation 16.19 14.81 0.76 Smoking 21.9 20.24 0.83 Alcohol consumption 3.8 1.23 0.09 Family history 6.8 12.34 0.136 Anti- platelet 31.42 27.65 0.46 Anti- coagulants 2.85 6.91 0.17 Contraceptives 0 0.98 0.58 Table 4. Comparison of Hematologic parameters and Heart Function Index in Patients with Non-Wake up and Wake up Strokes. Hematologic parameters and Heart Function Index Patients with non-wake up stroke Patients with wake up stroke P value Levels of Hemoglobin (Hb) 13.92 ± 5.93 13.5 ± 1.98 0.48 Levels of Hematocrit (Hct) 41.31±5.11 40.89±5.19 0.45 Platelet (Plt) 257480±102036 246500±82700 0.30 Low-Density Lipoproteins (LDL, mg/dl) 102.1±33.71 102.8±33.15 0.06 Heart ejection fraction 49.39±8.59 48.8±8.49 0.60 [Emergency Care Journal 2020; 16:8834] [page 81] Non -co mmerc ial us e o nly [page 82] [Emergency Care Journal 2020; 16:8834] ± 15.2 and 68.88 ± 15.4% in known and unknown onset strokes, respectively.17 Although the risk of stroke occurrence increases with aging (≥65 years old), our results showed that it could be rarely seen in early ages (non-WUS: 35 years old, WUS: 17 years old). It has been proven that the most common sub-type of stroke is an ischemic form which accounts for 87% of all strokes.18 Our results also declared ischemic stroke had a higher occurrence in both WUS and non-WUS patients compared with hemorrhagic sub-type (p<0.001). Moreover, a large number of clinical findings demonstrated an early-morning high occurrence of ischemic strokes.19,20 Albeit, Bornstein et al. reported some risk factors effect on stroke incidence, they could not find significant differences between WUS and non-WUS groups.16,21 Recently, a prospective cohort study revealed that there is a reverse relationship between the level of education and stroke occurrence. In better words, lower level of education is tightly associated with increased stroke occur- rence thereby it could be considered as possible risk factor of stroke. To note, this association attenuates during older ages but persists. Together, most of the risk factors involved in the stroke can be managed by changing their lifestyle.22 Moreover, sleep dis- order is another indispensable risk factor which is increasingly associated with stroke. To prevent primary and reoccurrence stroke, it should be address to the sleep disorders before and after stroke. In fact, sleep disorders following stroke can affect related consequence and can interfere in recovery process in the patients.23-25 Our data indicated that the number of WUS patients with hypertension was more than non-WUS group. It is notewor- thy to mention that cardiovascular disorders play an important role in subsequent stroke incidence. Interestingly, we reported a famil- iar history supposed another important risk factor.26,27 Presumably, it would be helpful to provide prospective treatment protocol to manage WUS patients. We also evaluated the effect of short- and long-term CVA in both subgroups. But appreciable differences were not observed between WUS and non-WUS patients. Furthermore, we observed stroke patients with anticoagulant, antiplatelet or contraceptive drugs history but the significant differ- ences could not be detected between patients with WUS and non- WUS. However, the percentage of patients with anti-platelet con- sumption was higher than other medications. Although the antiplatelet and anticoagulant therapies are prescribed recently in patients who had prior stroke attacks other protective approaches should be also considered.28 Eventually, the hematologic panel along with cardiac ejection fraction and LDL level was evaluated. The results did not show a remarkable increase in WUS rate in comparison with non-WUS subjects. Therefore, hematologic char- acteristics, cardiac functional indices, and lipid profiles changes are not proper diagnostic criteria for WUS differentiation. Despite less available data in this field, Yilmaz et al. recently demonstrated that the Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW) also had no significant increase in patients with the acute ischemic stroke while the WBC and Neutrophil–Lymphocyte ratio (N/L) ratio was considerably high in comparison with the control group. Additionally, they noted that WBC and N/L ratio could be helpful for an earlier diagnosis with acute ischemic stroke especially in children.29 Based on our data, cardiac ejection frac- tion ratio was decreased non-significantly in WUS patients. As above-mentioned, cardiovascular disorders history have a critical role in ischemic stroke occurrence. 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