stroke is the fourth leading cause of death and a major cause of adult disability .
relatively recent studies of survival in hypertensive patients have revealed that the incidence of stroke exceeded that of coronary events .
there are available data from observational studies suggesting that cerebrovascular events are not randomly distributed over time , but have a peculiar distribution along the day ( circadian variation with morning peak of occurrence ) , week ( circaseptan variation with higher frequencies in the last and first days of the week ) and even months of the year ( circannual or seasonal variation with predilection for the cold months ) .
regarding the ischemic stroke ( is ) , the earliest studies suggested a higher incidence in evening hours or during nocturnal sleep .
starting with the 1980s the studies more strongly indicate the morning higher occurrence of stroke with the lowest incidence during nighttime [ 69 ] , confirmed by the conclusions of the meta - analysis of elliot et al . in the last years
there were reports that showed a second peak , not so striking but evident , in the late afternoon [ 1113 ] .
there is an obvious similarity between cardiovascular events and cerebrovascular events regarding their diurnal variation with an increase during the morning hours after awaking and a decrease during the nocturnal sleep .
this pattern of diurnal variation is typical for myocardial infarction , angina ( stable , unstable , silent ) and sudden death .
this similarity suggests that cerebrovascular and cardiovascular events share common triggering factors . for the hemorrhagic stroke ( hs )
, the results of different studies show some differences , but the double - peak pattern is the most frequently reported [ 13,1618 ] .
the highest peak seems to be in the morning for some authors and   in the afternoon for others .
the most various patterns are reported regarding the subarachnoid hemorrhage ( sah ) , but all of them with the highest occurrence between 10.00 and 16.00 ( with or without any peak ) and the lowest during nighttime , suggesting the overlapping with the working hours .
although the temporal pattern of stroke occurrence has been recognized , at least for the circadian variation of the stroke onset , the reason underlying the temporal nature of stroke is not completely understood .
a constellation of exogenous cyclic factors such as temporal pattern in posture , physical activity , emotional stress and food behavior can influence the stroke occurrence .
there are also data suggesting that endogenous factors , all having demonstrated a temporal variation , such as blood pressure ( bp - with physiological nocturnal decrease and morning increase ) , autonomic system activity ( with activation of the sympathetic nervous system after the wake - up moment ) and hemostatic balance ( with increased platelet aggregability , hypercoagulability and hypofibrinolysis in the morning ) , can influence the susceptibility to stroke or can even have a triggering role .
their physiological diurnal rhythms ( related to the central and peripheral internal clock activity ) and moreover , the alterations of this rhythm , are the most important factors contributing to the stroke occurrence , even bigger than the trigger itself . the majority of available studies concerning the aspects of chronological variation refer to is , there are less reports available for sah and even hs , and only a few treating the three major types of stroke simultaneously .
the aims of our study are to investigate the existence of a circadian pattern in stroke occurrence , the relationship between this temporal pattern and the conventional vascular risk factors and the possible differences in the circadian variation among stroke types , in the cluj napoca area .
in the present retrospective , hospital  based study , we included a consecutive series of 1083 patients with stroke admitted through the emergency room to the neurology department i and ii of the district hospital of cluj napoca , between 1 january 2012 and 31 december 2012 ( which serves the population of cluj napoca city and of the surroundings ) .
the study is focused simultaneously on the three major types of stroke : ischemic stroke ( is ) , stroke caused by intracerebral hemorrhage ( hs ) and stroke caused by subarachnoid hemorrhage ( sah ) .
the diagnosis of is was defined according to updated world health organization criteria , as an episode of neurological dysfunction caused by central nervous system ( cns : cerebral , spinal or retinal ) infarction .
the evidence of cns infarction was defined as cns cells death attributable to ischemia , based on imaging or other objective evidence of cns focal ischemic injury in a defined vascular distribution , or on clinical evidence of cns focal ischemia injury based on symptoms persisting 24 hours or until death .
the diagnosis of hs was defined as rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system which is not caused by trauma .
the diagnosis of sah was defined as rapidly developing clinical signs of neurological dysfunction and/or headache caused by bleeding into the subarachnoid space , which is not secondary to a trauma . for each patient demographic data
( sex , age ) were recorded , date of onset and the daytime period or hour , where it was specified , risk factors and comorbidities : arterial hypertension , diabetes mellitus , hypercholesterolemia , coronary artery disease ( cad ) , atrial fibrillation ( af ) and smoking status .
based on the data available in the patient records , precise or approximate determination of the time of symptoms onset was possible for 925 cases and was assigned to 1 of 4 six - hours intervals : 00.0106.00 ( night ) , 06.0112.00 ( morning ) , 12.0118.00 ( afternoon ) and 18.0124.00 ( evening ) . for the remaining 158 patients the date of stroke onset could be determined ; it was treated as a separate category in the descriptive analysis and was randomly redistributed along the daytime for fourier curves analysis of circadian rhythm pattern .
the wake - up strokes ( the situation when the symptoms of stroke was first recognized to the wake - up moment ) were assigned equally between 00.0106.00 ( night ) and 06.0112.00 ( morning ) . according to the patients records , the number of wake - up stroke was 92 patients for
is ( 9.5% ) , 6 patients for ih ( 6.4% ) and none for sah .
the characteristics of the patients with stroke ( having is , sh or sah ) are shown in table i. men represent 47.18% ( 572 ) and women represent 52.81% ( 511 ) .
the women s average age is 72.26+/11.09 years , compared with the men s age 68.67+/11.26 years .
the total of 1083 patients were classified in the known three major types of stroke : 969 patients with is ( 89.47% ) , 94 patients with hs ( 8.68% ) and 20 patients with sah ( 1.85% ) .
figure 1 illustrates the distribution of all strokes and of each stroke type onset along the daytime concerning the four six - hours intervals convened .
it shows an evident peak during the morning hour ( corresponding to interval 06.0112.00 ) , followed by a slow decrease during afternoon ( 12.0118.00 ) , evening ( 18.0124.00 ) and nighttime ( interval 00.0106.00 ) for each type of stroke .
the percentage of occurrences during the four six - hour intervals for each type is described in table ii . using a fourier analysis for the detection of the hypothesized circadian rhythm pattern ( cosinor function ) , after the random distribution along the daytime of the patients with undetermined onset time
we analyzed the circadian variation in the condition of the presence / absence of the risk factors .
the presence of the risk factors regarding each stroke type is described in table iv . the pattern of diurnal variation of stroke types concerning the risk factors : hypertension , diabetes mellitus , hypercholesterolemia , coronary artery disease , atrial fibrillation , smoking status and previous stroke are shown in the figures 34 .
the diurnal variation related to the previous anti - aggregant medication is shown in figure 5 .
the situation of the anticoagulant medication is similar with that of the anti - aggregant medication and is not mentioned in the article .
the proportion between the three types of stroke found in our study is relatively close to that reported in literature .
overall the men s age is about 3.5 years lower than the age of women .
the difference is more obvious in younger categories , becoming the same after 65 years ( table i ) and reflecting the onset or worsening of vascular risk factors after menopause .
the results of this study are in accordance with the findings of the majority of previous reports available in literature , with the highest incidence of stroke occurrence during the morning ( 6.0112.00 ) and the minimum occurrence during the night ( 00.0106.00 ) for all stroke types ( is , hs and sah ) ( fig . 1 , table ii ) .
the spectral fourier analysis of the time of stroke onset has shown the existence of two cycles : one of 12-hours and one of 24-hours . analyzing the curves and indices of the two cycles ( fig .
2 , table iii ) we can speculate that the cycles are phase - shifted by approximately 90 degrees .
they suggest the possibility that initially the two cycles antagonize each other and after 12-hours they synchronize with a synergic effect .
the 24 cosinor curve analysis shows a hall - mark of the 12-hours cycle in their first part .
therefore we can speculate the existence of a protective mechanism against stroke in the 00.0106.00 interval .
the nocturnal sleep seems  to protect  against stroke despite the old traditional teaching that strokes are more likely to occur at night , but further studies are needed to confirm this hypothesis , maybe including persons working on night shifts and changing their sleep cycle .
some authors observed a single peak   in the morning , including elliot s meta - analysis , and others showing a double peak pattern of the circadian variation for all or for some of stroke types with a second small peak in the afternoon .
their methodology included the division of the 24-hour daytime in more than four intervals , ( six 4-hour , twelve 2-hour or even 24 1-hour ) , because the patients data from their stroke registries were more accurate and permitted an increased precision in the stroke onset time determination . in our study , this pattern with significant increase in stroke incidence during morning 
time was found even in the condition of an equal redistribution of the wake - up stroke number between the night and the morning interval , despite the consideration that the stroke concentration at the time of awakening was not due to the concentration of stroke occurrence , but to that of its recognition .
concerning is , in literature it was reported around 20%25% of the wake - up stroke as compared to our findings ( 9.5% ) .
the same circadian pattern for is , hs and sah suggests common triggers for all three types of stroke , the endogenous factors also having a known circadian variation .
the best studied triggers are the blood pressure ( bp ) and the coagulation status .
the bp has a well - known circadian variation with a nocturnal dip and a morning increase .
the loss of the physiological circadian pattern of bp ( non - dipper and reverse - dipper profile ) and the excessive morning bp surge at wake - up are accompanied by an increased risk of cerebrovascular events .
we obtained information only for the previous hypertension status , and in our findings the circadian pattern of stroke onset was almost the same in hypertensive and non - hypertensive patients with or without antihypertensive treatment ( fig .
the same situation is suggested for the other vascular risk factors ( dm , hypercholesterolemia , smoking status , af and cad ) with the same circadian variation in their presence or absence ( fig .
the hemostatic balance is inclined to a temporal prothrombotic status , with increased levels of the hematocrit , increased platelet aggregability , hypercoagulability and hypofibrinolytic activity .
we do not have information about the hemostatic status before the stroke and we could not analyze this aspect , but we recorded the situation of previous prophylactic anti - aggregant and anticoagulant medication , which did not modify the circadian pattern of stroke occurrence ( fig . 5 ) .
the two best known triggering factors , high morning bp and pro - thrombotic status in the morning , promote ischemic stroke and the latter prevents hemorrhagic stroke ( a conclusion of the studies that found the highest peak for hs and sah in the afternoon ) .
our study found one peak for hs in the morning with a relatively increased level of occurrence in the afternoon ( 12.0118.00 ) and evening ( 18.0124.00 ) as compared to night .
sah seems to have a similar situation but the number of sah cases was too small for a strong conclusion , reports in literature relating sah occurrence time to the working period of the day .
there are reports suggesting the modification of bp circadian rhythm post stroke ( with reduction of nocturnal bp decline ) the but we did not find a more impressive peak in the morning for the patients with previous stroke in comparison with the patients with the first - ever stroke ( fig .
the highest occurrence of stroke during morning hours has a sociological dimension as information , with practical implication for the admission , evaluation and treatment of stroke in emergencies departments / stroke units , requiring an increased level of awareness and availability during the morning interval .
another wide implication may be the prevention of stroke by treating the risk factors concerning their circadian variation .
a chrono - therapeutic approach may be useful for arterial hypertension ( started to develop in the last years ) , in the case of anticoagulant treatment   and possible in the case of antiplatelet treatment . in order to address this problem further studies with long - term investigations
to our knowledge , this is the first romanian study concerning the circadian variation of stroke onset .
our results show that all three type of stroke have a circadian variation with the highest peak in the morning and the lowest during nighttime .
this pattern of variation is present independently of the presence of vascular risk factors ( arterial hypertension , dm , hypercholesterolemia , cad , af and smoking status ) , of previous stroke and demographic aspects .
the triggering factors are common , the most important and studied being the diurnal rhythm of blood pressure and the hemostatic balance
. these findings may have therapeutic applicability ( regarding the acute intervention treatment like thrombolysis ) and implications for prophylaxis ( chrono - therapy of the risk factors ) .
 aims and background.the circadian pattern of stroke occurrence variation has been recognized with certain differences between authors and stroke types . the underlying reason may be related to exogenous factors ( cyclic physical activity , including sleep  awake cycles and assuming the up - right posture ) and endogenous factors , with their diurnal variation ( blood pressure , hemostatic balance , autonomic system activity ) . 
 the aims of the present study are to investigate the existence of a circadian variation of stroke and the possible differences between stroke subtypes in the cluj napoca area.materials and method.the stroke event data were acquired from the patient records of a consecutive series of 1083 patients admitted through the emergency room at neurology departments i and ii of the district hospital of cluj napoca , between 1 january 2012 and 31 december 2012 . the classifiable onset time 
 was assigned to one of four six - hour intervals : 00.0106.00 ( night ) , 06.0112.00 ( morning ) , 12.0118.00 ( afternoon ) and 18.0124.00 ( evening ) . 
 demographic data and vascular risk factors were recorded.results.all three stroke types ( ischemic stroke , hemorrhagic stroke and subarachnoid hemorrhage ) have shown a circadian variation regarding their occurrence , with the peak of incidence in the morning and the nadir during nighttime . this circadian pattern is independent by demographic factors and vascular risk factors.conclusion.our study confirmed the circadian variation of onset occurrence for all stroke subtypes . 
 some triggering factors promote ischemic stroke and prevent hemorrhagic stroke . the diurnal pattern of variation with the higher incidence in the morning and the lower in the night may lead to chrono - therapeutic and preventive approach ( chrono - therapy of the risk factors ) , which targets the period of the highest vulnerability after awaking . 
Aims and background
Materials and method
Results
Discussion
Conclusions