Clinical Characteristics,Reperfusion Therapy And Circadian Rhythm Analysis In Acute Stage Of Wake-up Stroke

Part Ⅰ Clinical characteristics of wake-up strokeObjective To compare the clinical characteristics of wake-up stroke(WUS)and non-WUS in our center.The clinical characteristics of WUS and non-WUS patients with responsible vessels in anterior circulation and posterior circulation were compared respectively.The clinical characteristics of patients with good and poor prognosis in WUS were compared,and independent predictors of good prognosis in WUS were identified.Method Patients with acute ischemic stroke(AIS)admitted to Stroke Center of our hospital from January 2019 to December 2019 were collected.All stroke patients within 24 hours after onset entered the stroke green channel in our hospital,and the tests of urgent routine blood,coagulation function,blood glucose,liver,and kidney function,etc.,were obtained.Patients with definite onset time and within the time window of intravenous thrombolysis,non-contrast brain computed tomography(CT)was performed urgently to exclude any intracranial hemorrhage.After communication and intravenous thrombolysis in patients without contraindications,bridging CT angiography(CTA)and CT perfusion(CTP).Patients with unknown onset time or late presenting were examined by CT,CTA,and CTP.Clinical data of enrolled patients were collected,including:(1)Demographic characteristics,personal and family history,and other medical history;(2)The Berlin questionnaire assessed the risk of Obstructive sleep apnea(OSA);(3)The last normal time,the time of discovery and the time of treatment;(4)Baseline assessment data including National Institutes of Health Stroke Scale(NIHSS)score,blood pressure and rapid blood glucose,etc.;(5)Data of fasting blood test in the next day;(6)The Trial of Org 10172 in Acute Stroke Treatment(TOAST)classification;(7)Treatment programs;(8)The safety of treatment:intracranial hemorrhage(ICH)and symptomatic ICH(sICH);(9)Prognosis:The modified Rankin Scale(mRS)and NIHSS scores were obtained at 7d,discharge,and 90d.Patients were divided into the WUS group and the non-WUS group,among which the non-WUS group was divided into the Onset Witnessed Stroke(OWS)group and the Daytime Unwitnessed Stroke(DUS)group according to the different time of discovery.The data of the three groups were compared and analyzed.Result1.The clinical characteristics of WUS compared with OWS and DUS,respectively.When compared with OWS group,the proportion of patients at high risk for OSA were more in the WUS group,and the last normal time to emergency room was longer,baseline NIHSS and the fibrinogen levels were higher.And the WUS group had a lower rate of intravenous thrombolysis,a higher rate of thrombectomy and conservative treatment.The ICH rate and sICH rate within 24h were higher,and the average hospital stay of WUS was longer,In terms of prognosis,the WUS group had higher mRS at 90 d,lower rates of excellent prognosis(mRS 0-1)and good prognosis(mRS 0-2)at 90d.When compared with DUS group,WUS group were younger,and the proportion of patients at high risk for OSA were more.And in WUS group,the time from the last normal time to witness and from witness to the emergency were both longer,the baseline NIHSS was lower,fewer patients with atrial fibrillation,the perfusion lesion,infarction core and ischemic penumbra were all smaller in CTP;and the 90d mortality was lower.2.The clinical characteristics of WUS compared with OWS and DUS when the responsible lesions were in the anterior circulation,respectively.When compared with OWS group,patients in WUS group had longer last normal time to emergency room,higher baseline NIHSS score,shorter time from registering to one-stop CT examination,lower Alberta stroke program early CT score(ASPECTS),higher fibrinogen in urgent laboratory examination.Treatment decisions were also different between the two groups,WUS group had lower rate of intravenous thrombolysis,higher rate of thrombectomy and conservative treatment.In WUS group,the ICH and sICH rate within 24h were higher,and the average hospital stay was longer.While in terms of prognosis,in WUS group the mRS at 90d was higher,and the rates of excellent prognosis(mRS 0-1)and good prognosis(mRS 0-2)at 90d were lower.When compared with DUS group,WUS patients were younger,and the proportion of high-risk OSA patients was higher.And in WUS group,the time from the last normal time to witness and from witness to the emergency were both longer;the baseline NIHSS was lower;fewer patients with previous history of atrial fibrillation;the perfusion lesion,infarction core and ischemic penumbra were smaller in CTP;and the 90d mortality was lower.3.The clinical characteristics of WUS compared with OWS when the responsible lesions were in the posterior circulation.When compared with OWS group,patients in WUS group had longer time from the last normal time to emergency,shorter time from registering to one-stop CT examination,lower Basilar Artery on Computed Tomography Angiography(BATMAN)score,higher total cholesterol level and longer average hospital stay.In terms of prognosis,the rate of good prognosis(mRS 0-2)was lower in WUS group.4.Comparison of good and poor prognosis in WUS.Univariate analysis showed that the lower baseline NIHSS score,the smaller perfusion lesion,infarction core and ischemic penumbra,and without ICH were predictive factors for good prognosis.Multivariate analysis showed that lower NIHSS were independent associated with good outcome(OR 0.813,95%CI:0.736-0.898,P<0.001).Using ROC analysis,the cutoff value of NIHSS score for predicting prognosis was 8.5(specificity 0.75,sensitivity 0.787,AUC 0.829,95%CI 0.746-0.913,P<0.001).Conclusion Compared with OWS,WUS patients in our center showed more severe baseline neurological deficits,longer hospital stays and relatively poor prognosis.While compared with DUS,baseline neurological deficits were milder and mortality was lower.Multivariate analysis showed that low NIHSS score was an independent predictor of good prognosis of WUS,and the cutoff value wasPart Ⅱ Reperfusion treatment of wake-up strokeObjective The purpose of this study was to evaluate the efficacy of reperfusion therapy in wake-up stroke(WUS)patients with tissue-window,compared with patients within time-window.Method This retrospective study was conducted of the medical records of all AIS patients who received intravenous(Ⅳ)recombinant tissue plasminogen activator(rt-PA)or endovascular thrombectomy(EVT)at Stroke Center of First Affiliated Hospital of Soochow University between January 2018 and November 2019.Large-artery atherosclerosis(LAA)and cardioembolism(CE)patients were recruited,whose etiological types were classified according to the Trial of Org 10172 in Acute Stroke Treatment(TOAST)classification.Patients were categorized into two groups:those with clear description of presence of focal neurologic symptoms on morning awakening were characterized as WUS Group;those with clear description of onset of focal neurologic symptoms during waking time and reperfusion therapy was administrated within time-window were characterized as non-WUS Group.Patients in the two groups were further divided into rt-PA subgroup and EVT subgroup.All WUS patients received Ⅳ rt-PA or EVT therapy were selected by tissue-window(perfusion lesion-core mismatch ratio>1.8,the volume of ischemic penumbra>15 ml and infract core<70 ml).The enrolled patients were further investigated for baseline characteristics,imaging parameters,treatment protocols,clinical and safety outcomes.Statistical analysis was performed to compare the two groups.Result A total of 235 patients were included,45 in WUS group and 190 in non-WUS group.WUS patients had a less prevalence of hypertension than Non-WUS patients(62.2%vs 76.8%,P=0.044).WUS patients were less prescribed with Ⅳ rt-PA than Non-WUS patients(51.3%vs 68.4%,P=036).The median door to needle time(DNT)was longer in WUS group than that in non-WUS group(80.04[64-106]min vs 63.7[40-78.5]min,P=0.002).There was no other statistically significant difference in the remaining clinical variables between groups.On ordinal regression shift analysis,reperfusion therapy was associated with a nonsignificant shift toward a better mRS category at 90 d.Independent predictors of mRS 0-1 at 90 days on logistic regression were age,baseline NIHSS score,and infarct core volume.Independent predictors of mRS 0-2 at 90 days on logistic regression were age,baseline NIHSS score,intracerebral hemorrhage(ICH),and infarct core volume.Mortality was predicted by higher baseline NIHSS score,history of diabetes,and greater infarct core volume.There was no difference in outcome of reperfusion therapy between patients with WUS and non-WUS even after adjusting for these variables.Conclusion WUS patients may be suitable for reperfusion therapy after tissue-window evaluation based on advanced imaging.The tissue-window criteria used in this study,which were implemented in the MIStar software,can guide effective reperfusion therapy.Part III Circadian rhythm in acute stage of wake-up strokeObjective Whether wake-up stroke(WUS)is differentiated from stroke that occur during daytime(non-WUS)by a distinct pathophysiology process remains unclear.Epidemiological studies have demonstrated a circadian distribution of AIS,with a higher frequency in the morning and a lower frequency during sleep.This distribution may be attributed to the circadian rhythmicity of some cardiovascular parameters,including morning increases in fibrinolytic activity,platelet aggregation,plasma viscosity,and endothelial dysfunction.The changes in these parameters in the morning may be advantageous in healthy individuals,but could be implicated in precipitating an ischemic event in susceptible individuals.We hypothesize that differences in circadian rhythm exist between WUS and non-WUS patients.The study aims to investigate the circadian rhythm of WUS patients within 24 h from symptom onset for comparison with those of non-WUS patients and healthy volunteers.Method This was a single-center,exploratory study,with a prospective,cross-sectional,and observational design.Patients with a first-time stroke and without clinical sleep disorders are considered for inclusion in the study and are divided into WUS and non-WUS groups according to time of symptom onset or observation.Meanwhile,age-and sex-matched healthy volunteers without sleep disorders are recruited.Circadian rhythmicity was examined by evaluating the serum concentrations of melatonin and cortisol,the relative expression levels of clock genes,blood pressure and heart rates.Participants are asked to maintain their normal nocturnal sleep patterns during the study period.Daytime naps are not allowed.Patients,as well as volunteers,are exposed to the natural and conventional fluorescent light during the awake time,and the lights are turned off between 20:00 and 22:00 depending upon individual sleeping habits.All participants are instructed to wear activity bracelet monitors and eye masks while sleeping.During the overnight sampling period,a pen-sized dim flashlight is used to avoid light-induced inhibition of melatonin secretion.Peripheral blood samples are taken at 6-h intervals for a total of four times.Blood pressure and heart rate parameters were collected every 2 hours.The concentrations of serum melatonin and cortisol in peripheral blood samples,as well as the relative expressions of whole blood clock genes CLOCK,BMAL1,two Cryptochrome genes(CRY 1,2)and three Period genes(PER 1,2,3)were detected.Baseline data of the three groups of participants were compared.The rhythmicity of diurnal data with multiple timepoints will be determined using the MetaCycle R package.The generalized estimation equation was used to compare the rhythmicity among the three groups.Kruskal-Wallis single-factor ANOVA test was used to analyze the difference of the expression of the same parameter at a certain time point among the three groups,and further pairwise comparison was made.Result A total of 28 participants were eventually included in the study,including 8 in the WUS group,9 in the non-WUS group,and 11 in the Control group.There were no statistically significant differences at sleep parameters and baseline demographic characteristics among the three groups.The rhythmicity statistics of different circadian rhythm markers showed rhythmicity expression of serum cortisol(P=0.001)and PER3 gene(P=0.019)in the WUS group,and rhythmicity expression of serum melatonin(P=0.001),serum cortisol(P=0.002)and PER3 gene(P=0.015)in the non-WUS group.Whereas in Control group,all the parameters showed rhythmicity except BMAL1 gene(P=0.289).Phase analysis showed that the phase time of serum melatonin and cortisol was similar in non-WUS group and Control group,while the phase shift of WUS group were both delay about 3 h.The circadian rhythm was disappeared in both WUS and non-WUS group.In the WUS group,the nocturnal increase of systolic and diastolic blood pressure lasted for a longer time,and the phase showed a trend of backward shift.In the analysis of heart rates,it was found that the circadian rhythm of heart rates disappeared both in WUS group and non-WUS group,but the mean heart rates in the WUS group was significantly higher than that in the non-WUS and Control group(P<0.001).Conclusion In this exploratory study,it was found that the rhythm markers in the WUS group showed circadian rhythm disorder,which was manifested as the disappearance of circadian rhythm or backward phase shift.Circadian rhythm disturbance may be associated with the occurrence of WUS.