twenty‐four‐hour and annual variation in onset of epistaxis in osler disease
TRANSCRIPT
TWENTY-FOUR-HOUR AND ANNUAL VARIATION IN ONSET OF
EPISTAXIS IN OSLER DISEASE
Haneen Sadick,1 Inigo Fleischer,1 Ulrich Goessler,1 Karl Hormann,1 and
Maliha Sadick2
1Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital ofMannheim, Mannheim, Germany2Department of Clinical Radiology, University Hospital of Mannheim, Mannheim,Germany
Osler disease is an autosomal dominant disorder of the fibrovascular tissue character-ized by arteriovenous malformations with multi-systemic haemorrhages. Recurrentepistaxis is the predominant symptom in more than 90% of patients. Recent studiesshowed circadian and seasonal patterns in the onset of nosebleeds, similar to acute car-diovascular events, such as myocardial infarction and stroke. The aim of this study wasto determine whether such patterns would also apply to the onset of epistaxis inpatients with Osler disease. In all, 110 patients with Osler disease who were undertreatment for recurrent epistaxis at the University Hospital of Mannheim wererequested to complete a questionnaire addressing the intensity and frequency of epi-staxis according to the classification of Bergler et al., as well as circadian and circannualrhythmicity in the occurrence of epistaxis according to visual analogue scales (VAS).More than half of the patients claimed to experience daily to weekly episodes of recur-rent epistaxis. The occurrence of epistaxis showed a biphasic 24 h pattern, with aprimary peak in the morning (05 : 00–8 : 00 h) and smaller secondary peaks in theevening (17 : 00–20 : 00 h and 21 : 00–00 : 00 h). No significant seasonal variationwas found in the onset of epistaxis. However, a slight tendency, with a peak inwinter months, was observed. Similar to other chronobiological studies on nosebleeds,this study showed that the 24 h pattern and seasonal tendency in the onset of epistaxiseven applied to patients with Osler disease. Further investigations are necessary todetermine the pathological mechanism underlying this phenomenon.
Keywords Circadian rhythm, Epistaxis, Osler disease, Seasonal variation
Submitted September 28, 2006, Returned for revision October 17, 2006, Accepted November 9,2006
The first two authors contributed to this article equally.Address correspondence to PD Dr. med. Haneen Sadick, Department of Otorhinolaryngology,
Head and Neck Surgery, University Hospital of Mannheim, Theodor-Kutzer-Ufer, 68135 Mannheim,Germany; Tel.: 0049 121 383 3965; Fax: 0049 621 383 3827; E-mail:. E-mail: [email protected]
Chronobiology International, 24(2): 357–364, (2007)Copyright # Informa HealthcareISSN 0742-0528 print/1525-6073 onlineDOI: 10.1080/07420520701284485
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INTRODUCTION
Many biological and pathophysiologic events seem to exhibit circadianand circannual patterns. Recent studies verify a circadian and circannualvariation in the occurrence of especially acute cardiovascular events, forexample, myocardial infarction, stroke, and acute aortic dissection, andcerebrovascular events like subarachnoid haemorrhage (Cohen et al.,1997; Fogelholm et al., 1995; Gallerani et al., 1996; Manfredini et al.,2005a, 2005b; Mehta et al., 2005a, 2005b; Sloan et al., 1992). These tem-poral patterns are presumed to be related to hypertensive blood pressurerhythms (Manfredini et al., 1996). Using hospital emergency care data,Manfredini et al. (2000a, 2000b) detected day-night variation in the occur-rence of acute epistaxis, with a primary peak in the morning and a smallerpeak in the evening, as well as seasonal variation. Based on these results,the authors sought to determine whether the occurrence of epistaxis exhi-bits 24 h and seasonal variation in patients with Osler disease. Oslerdisease, also known as hereditary hemorrhagic telangiectasia, is an autoso-mal dominant disorder of the fibrovascular tissue. It is characterized by theclassic triad of telangiectasia, recurrent epistaxis, and a family history of thedisorder (Bergler & Gotte, 1999; Byahatti et al., 1997; Osler, 1901;Weber,1907). Light and electron microscopic studies of the abnormal bloodvessels have shown that the defect in the vasculature consists of dilatedvenules with areas of endothelial discontinuity and degeneration(Bravermann et al., 1990; Jahnke, 1970). Due to the fragility of theblood vessels, mild trauma can instigate the onset of bleeding andinduce multi-systemic haemorrhages. Macroscopically, telangiectasia areseen within the nasal mucosa and the mucosa of the upper aerodigestivetract. Acute epistaxis is the most common clinical symptom in more than90% of the cases of Osler disease (Sadick et al., 2003, 2005, 2006).
PATIENTS AND METHODS
From January 2005 to May 2006, a total of 110 day-active patients withdiagnosed Osler disease were contacted. All were under treatment for epi-staxis at the Department of Otolaryngology, Head and Neck Surgery ofthe University Hospital of Mannheim, Germany, for many years, and allhad previously given written consent for their data to be entered in anOsler database. The patients were asked to complete a standardized ques-tionnaire asking for information about different parameters concerningthe onset of epistaxis. Questions addressed the intensity and frequencyof bleeding according to the criteria of Bergler et al. (2002). Both ofthese parameters were differentiated into three different grades depend-ing on the severity of bleeding (see Table 1). In addition, the patientswere asked to indicate the occurrence of their acute epistaxis during the
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day and night using a scale divided into six 4 h intervals: 01 : 00–04 : 00,05 : 00–08 : 00, 09 : 00–12 : 00, 13 : 00–16 : 00, 17 : 00–20 : 00, and21 : 00–00 : 00 h (see Figure 1). This was assessed using visual analoguescales (VAS) by dividing the day into 4 h time intervals. Seasonal variationin the pattern of epistaxis was also evaluated. Patients were asked todescribe whether the bleeding occurred more often in the spring,summer, autumn, or winter. Patients who experienced seasonal period-icity were then asked to specify the months of the year when most of theacute bleeding attacks were experienced. Questions concerning 24 h andseasonal patterns of bleeding allowed more than one answer. At the endof the questionnaire, patients had to specify whether they had any illnessesbesides Osler disease, whether they were on any medication, and whetherthey had any other hemorrhages besides nosebleeds. The study wasapproved by the Ethical Board of the University Hospital of Mannheimand was conducted according to the ethical standards of the journal(Touitou et al., 2006).
Out of 110 patients with Osler disease who were asked to fill in the stan-dardized questionnaire, 70 provided complete data. The other 40 patientsdid not give detailed answers and thus were excluded from the analysis.
TABLE 1 Intensity and frequency of epistaxis in Osler disease according to Bergler et al. (2002)
Intensity of bleeding Frequency of bleeding
Grade 1: slight stains on the handkerchief Grade 1: less than once a weekGrade 2: soaked handkerchief Grade 2: a few times a weekGrade 3: bowl or similar utensil necessary Grade 3: more than once a day
FIGURE 1 Circadian variation within a 24 h time period in the onset of epistaxis in patients with Oslerdisease. (Patients were allowed to give more than one answer.)
Epistaxis in Osler and Circadian Variation 359
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The study sample of 70 patients was made up of 40 male and 30 femalepatients with a mean age of 56.9 years (range from 8 to 85years, S.D.+ 18.5 years). The mean age of the male patients was 56.9(S.D.+ 16) years, and the mean age of the female patients was 56.4(S.D.+ 20) years. Twenty-five (36%) of the 70 patients claimed to sufferfrom hypertension. Fourteen hypertension patients were male and11 female. The mean age of this subgroup was 66.6 (S.D.+ 16) years. Ingeneral, all patients with Osler disease claimed to have primarily epistaxiswithout any other severe symptomatic hemorrhages.
The SAS program (SAS for Windows, Version 8.2) was used to assessthe data. The chi-square test was used to analyze the data for 24 h, seaso-nal, and annual variation. p values ,0.05 were considered statisticallysignificant.
RESULTS
The intensity of bleeding was heavy (grade 3) in 27 (38.5%) patients,moderate (grade 2) in 30 (43%) patients, and slight (grade 1) in 13(18.5%) patients. The frequency of bleeding was once per week or less in24 (34%) patients, more than twice per week in 32 (46%) patients, anddaily in 14 (20%) patients (see Table 2).
A 24 h distribution in the onset of epistaxis was claimed by 37 (53%)patients, with the major peak experienced in the morning between05 : 00–08 : 00 h by 54%, and a smaller secondary peak experienced inthe evening between 17 : 00–20 : 00 h by 46% and 21 : 00–00 : 00 h by41%. Epistaxis was least frequent in the afternoon between 13 : 00–17 : 00 h, occurring only in 8% of the patients during this time interval,and at night between 01 : 00–04 : 00 h, occurring only in 27% of thepatients during this time interval (see Figure 1). Altogether, a highly sig-nificant ( p ¼ 0.00837) 24 h variation was found in the onset of epistaxis.Variables such as age, sex, or risk factors, like the presence/absence ofhypertension, showed no influence on the 24 h variability of epistaxis. In
TABLE 2 Intensity and frequency of epistaxis in 70 patients with Osler disease
Intensity of bleeding Frequency of bleeding
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3
Patients (n) 13 30 27 24 32 14
Intensity of bleeding: Grade 1 ¼ slight stains on the handkerchief, Grade 2 ¼ soaked handkerchief,Grade 3 ¼ bowl or similar utensil necessary.
Frequency of bleeding: Grade 1 ¼ bleeding less than once a week, Grade 2 ¼ bleeding a few times aweek, Grade 3 ¼ bleeding more than once a day.
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the other 33 cases, the time of the onset of epistaxis could not be deter-mined precisely. A circannual variation in the onset of epistaxis was con-firmed in 27 of the 70 (38.5%) patients. The monthly distribution of theoccurrence of epistaxis showed a major peak in winter and a secondarypeak in autumn; the nadir occurred in spring and summer. Althoughthese results failed to show statistical significance, a weak trend, withexcess in the winter months, was observed ( p ¼ 0.269; see Figure 2).
DISCUSSION
Through this study, it was demonstrated for the first time that the epi-staxis of Osler disease occurs during specific time spans of the day andnight, the early morning hours between 05 : 00–08 : 00 h and theevening hours between 17 : 00–20 : 00 and 21 : 00–00 : 00 h. Thenumber of patients experiencing epistaxis at the time of the primarypeak in themorning and the secondary peak in the evening was statisticallysignificantly greater than those experiencing epistaxis between 09 : 00–12 : 00 h, 13 : 00–17 : 00 h, and 01 : 00–04 : 00 h. The occurrence of epi-staxis in the cohort of patients with Osler disease follows a statistically sig-nificant biphasic circadian variation. Seasonal distribution in the onset ofepistaxis was not verified by the statistical analysis, although a weak ten-dency with an excess of epistaxis was observed in the winter months.These findings are similar to those described previously with hypertensivepatients (Brennan et al., 1982), though in the present study, the annualpattern in the onset of epistaxis was not statistical significant.
Overall, the results of this study correlate well with those described byManfredini et al. (2000b). In their study, the data of more than 1000patients who presented to the hospital emergency ward for nose bleeds
FIGURE 2 Monthly distribution in the onset of epistaxis. Histograms represent the percentage of totalevents occurring in each month of the year. The dark histograms indicate the months representing theseason of the year, giving also the standard deviation (I) in the occurrence of epistaxis in that season.
Epistaxis in Osler and Circadian Variation 361
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were analyzed for temporal patterns. Manfredini et al. (2000b) foundhighly significant biphasic circadian rhythm in the time of occurrence ofnosebleeds, with the primary peak in the morning at 08 : 00 h, a smallersecondary peak in the evening at 20 : 00 h, and nocturnal nadir. The find-ings of the current and Manfredini et al. study demonstrate that the onsetof epistaxis in patients with or without Osler disease is subject to a chron-obiological pattern. Similar biphasic cycles have been described in cardio-vascular events, such as angina pectoris, myocardial infarction, stroke, andsubarachnoid haemorrhages (Cohen et al., 1997; Fogelholm et al., 1995;Gallerani et al. 1996; Manfredini et al., 1996; Sloan et al., 1992; Smolenskyet al., 2005), which are presumably related to hypertensive blood pressurerhythms (Fogelholm et al., 1995; Manfredini et al., 1996).
The findings of this study are very interesting and surprising, as theprinciple pathomechanism of epistaxis in Osler disease differs from theevent of acute “non-Osler-related” nosebleed. Osler disease is a disorderwith its own pathophysiologic entity. It is an autosomal dominant multi-systemic disorder of the vessel enlargement phase of angiogenesis(Sadick et al., 2006). The typical clinical characteristics are severe hemor-rhages, which are primarily seen in the form of nosebleed in more than90% of the patients due to a localized abnormality within the bloodvessels (Jahnke, 1970). Light and electron microscopic studies of theabnormal blood vessels have shown the defect of the vasculature consistsof dilated postcapillary venules connecting directly to arterioles withoutan intervening capillary bed and with areas of endothelial discontinuityand degeneration (Bravermann et al., 1990; Jahnke 1970). Due to the fra-gility of the blood vessels, even mild trauma can instigate the onset ofbleeding. Keeping this pathomechanism in mind, one would not initiallyexpect a biphasic circadian rhythm in the onset of epistaxis in Oslerdisease. Therefore, the occurrence of epistaxis in Osler disease is thoughtto be independent of the pathomechanism underlying acute epistaxis,which is presumably related also to the blood pressure rhythm (Fogelholmet al., 1995; Manfredini et al., 1996). The fact that the onset of epistaxis isindependent of hypertension might be explained by the fact that acute epi-staxis is not only caused by arterial but also venous bleedings. As the venoussystem is anatomically and functionally separated from the arterial bed bythe interposing capillary system, blood pressure changes in the arterial dis-trict do not seem to have amajor influence on venous pressure. Rhythmicityin local factors, such as dryness of the nasal mucosa, microtrauma to thenasal mucosa, or prevalence of upper respiratory infections during thecolder seasons seemingly are more likely to contribute to the temporalvariations in the onset of epistaxis. In our study, the 24 h temporalpattern in the onset of epistaxis in Osler patients does seem to be dependenton the blood pressure rhythm as only 25 of the 70 Osler patients whoshowed circadian variation in bleeding episodes had hypertension.
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Another interesting aspect is the fact that different studies in literaturecould indicate time-dependent variations in the physiology of blood coagu-lation. Animal data illustrated a much shorter blood clotting time with highlevels of the coagulation factors II, VII, and IX during the animal’s restingperiod. Moreover, the coagulation activity showed rhythmic variationswith a significant peak around the time of the light-to-dark transition(Bertolucci et al., 2005; Labrecque & Soulban, 1991). In what way thecircadian rhythm of blood coagulation also has an influence on the 24 hvariation in onset of epistaxis in Osler disease still needs to be investigated.
In summary, this study of patients with Osler disease established forthe first time a 24 h pattern in the onset of epistaxis. Nonetheless, thesample size of the patient cohort was small compared to the study ofManfredini et al. (2000b), in which more than 1000 patients were enrolled.Moreover, only a limited proportion of patients (37 of 70) claimed byrecall, in the form of answers to a questionnaire, a circadian distributionof events. A larger, prospective, population-based study is required toconfirm and extend these findings based on patient recall. Moreover,further investigations are also necessary to determine the influence ofdifferent variables, such as blood pressure rhythm, vessel structure, orblood coagulation factors, on the circadian and circannual variation inthe onset of epistaxis in Osler disease.
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