- Email: [email protected]
Primary Hemorrhagic Neurovascular Diseases in Tibetans: A Retrospective Observational Study
Accepted Manuscript Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study Anqi Xiao, MD, Ruiqi Chen, MD, Hao Li, MD, Lu Ma, MD, Sen Lin, MD, Xin Hu, MD, Chao You, MD PII:
S1878-8750(16)30841-5
DOI:
10.1016/j.wneu.2016.09.015
Reference:
WNEU 4555
To appear in:
World Neurosurgery
Received Date: 4 July 2016 Revised Date:
5 September 2016
Accepted Date: 6 September 2016
Please cite this article as: Xiao A, Chen R, Li H, Ma L, Lin S, Hu X, You C, Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Xiao
ACCEPTED MANUSCRIPT
Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study Anqi Xiao1* MD, Ruiqi Chen1* MD, Hao Li1 MD, Lu Ma1 MD, Sen Lin1 MD, Xin Hu1 MD and Chao You1 MD
RI PT
1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; *These authors contributed equally to the manuscript
Corresponding author at all stages of refereeing, publication and post-publication:
SC
Chao You
Address: No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China
M AN U
Email: [email protected]
Key words: Primary hemorrhagic neurovascular diseases (PHNVDs), Ethnic, aneurysmal subarachnoid hemorrhage (aSAH), spontaneous intracerebral hemorrhage (sICH), arteriovenous malformation (AVM)
TE D
Abbreviations list:
aSAH=aneurysmal subarachnoid hemorrhage; AVM=Arteriovenous Malformation; BLAs= Blood
EP
Blister-like Aneurysms; CI= Confidence Intervals; CT=Computed Tomography; CTA=Computed Tomography Angiography; DSA=Digital Subtraction Angiography; HE=Hematoma Evacuation;
AC C
ICA=Internal Carotid Artery; IHM=Intra-hospital Mortality; MRI=Magnetic Resonance Imaging; PHNVDs
=Primary
hemorrhagic
neurovascular
diseases;
hemorrhage; WCH =West China Hospital of Sichuan University;
sICH=spontaneous
intracerebral
2 Xiao
ACCEPTED MANUSCRIPT
Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study Abstract:
RI PT
Background: Although there have been many studies on primary hemorrhagic neurovascular diseases (PHNVDs) in different populations, a study focusing on PHNVDs in Tibetan people was still lacking. This study aimed to explore the notable characteristics of Tibetan PHNVDs
SC
by comparing the most three common PHNVDs (aneurysmal subarachnoid hemorrhage,
between Tibetan and Han patients.
M AN U
spontaneous intracerebral hemorrhage and arteriovenous malformation) in our institution
Methods: In this retrospective observational study, the hospital information system (HIS) was utilized to access the records of patients with PHNVDs. A total of 249 Tibetan patients
TE D
and 2,093 corresponding contemporary Han patients were recruited from January 2012 to January 2016. Sociodemographic information and clinical data on each PHNVD subtype were collected and compared between two races.
EP
Results: For Tibetan patients, significantly higher incidence (p<0.05) of rebleeding and
AC C
cerebral infarction was observed in all three PHNVD subtypes. In aneurysmal subarachnoid hemorrhage group, Tibetan patients had significantly higher incidence of blood blister-like aneurysms (BLAs) (19.6% (19/97) vs 3.2% (34/1071), p<0.001). In spontaneous intracerebral hemorrhage group, Tibetan patients got a significantly higher incidence of brainstem hemorrhage in subtentorial area (10.8% vs 5.1%, p=0.035). Conclusions: For Tibetan PHNVDs, a high incidence of BLAs in aSAH, a tendency toward brainstem hemorrhage in subtentorial sICH, and a high rate of infarction and rebleeding in all
3 Xiao
ACCEPTED MANUSCRIPT three subtypes were all recognized.
Key Words: Primary hemorrhagic neurovascular diseases (PHNVDs), Ethnic, aneurysmal subarachnoid
hemorrhage
(aSAH),
spontaneous
intracerebral
hemorrhage
(sICH),
RI PT
arteriovenous malformation (AVM)
Introduction:
SC
Primary hemorrhagic neurovascular diseases (PHNVDs) have been a challenge for
M AN U
neurosurgeons due to their high rates of morbidity and mortality. Although there have been many studies on PHNVDs in different populations, the research focusing on Tibetan people was still lacking. In China, Han people are the majority of the population (over 1.2 billion). Although Tibetans only have 7.8 million people, they are the largest human race living in the
TE D
Himalaya plateau area, with an especially high-altitude atmosphere with low pressure and thin oxygen levels. Due to their different living environment and customs, the diet of Tibetans is composed of high-fat and high-salt food, increasing the risk of hypertension, hyperlidemia,
EP
and therefore hemorrhagic stroke1-3. Until now, few studies of PHNVDs in Tibetans were
AC C
published since a national survey explored the high incidence of stroke in the Tibet area 20 years ago4. As the largest medical center of West China area, the West China Hospital of Sichuan University (WCH) accepts a large number of PHNVD patients from different regions of western China, including the Tibetan plateau. In our study, we analyzed and compared the medical data for three common PHNVDs (aneurysmal subarachnoid hemorrhage, spontaneous intracerebral hemorrhage and arteriovenous malformation) in Tibetan and Han people in WCH from January 2012 to January 2016 to explore the notable characteristics of
4 Xiao
ACCEPTED MANUSCRIPT these PHNVDs in Tibetans for clinical doctors.
Materials and Methods
RI PT
Study design and Participants: In this retrospective observational study, the hospital information system (HIS) was utilized to access the records of patients with PHNVDs in our institute from January 2012 to January
SC
2016. The study patients were selected by their stated race as either “Tibetan” or “Han.” The
M AN U
diagnosis of the selected patients was confirmed by two neurosurgeons and one neuroradiologist, who reviewed their inpatient medical records and imaging data. In total, 254 PHNVD Tibetan patients meeting the criteria were enrolled, including 97 with aneurysmal subarachnoid hemorrhage (aSAH), 102 with spontaneous intracerebral
TE D
hemorrhage (sICH), 50 with arteriovenous malformation (AVM), 3 with Cavernous hemangioma and 2 with Moyamoya diseases. Due to an insufficient sample size, patients with cavernous hemangioma and Moyamoya disease were excluded from our study.
EP
Correspondingly, 2,093 Han PHNVD patients were enrolled, consisting of 1071 aSAHs, 826
AC C
sICHs and 196 AVMs for the comparison analysis. Data Collection:
Sociodemographic data and individual risk factors (history of hypertension, diabetes, coronary artery disease, dyslipidemia, hemoglobin, tobacco use, alcohol use, prior stroke, and peripheral vascular disease) were collected, as was information on each PHNVD subtype as follows: Aneurysmal subarachnoid hemorrhage (aSAH): Number and location of the aneurysms based
5 Xiao
ACCEPTED MANUSCRIPT
on computed tomography angiography (CTA) and Digital subtraction angiography (DSA). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical treatment
RI PT
Spontaneous intracerebral hemorrhage (sICH): Location of the hematoma based on computed tomography (CT) and magnetic resonance imaging (MRI). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical
SC
treatment
M AN U
Arteriovenous malformation (AVM): Spetzler-Martin AVM grading scale based on an imaging examination (DSA). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical treatment Treatment:
TE D
Surgery: Surgery was classified as craniotomy or interventional treatment. For aSAH patients, craniotomy indicated aneurysm-clipping surgery, and interventional treatment included endovascular coiling and cerebral artery stenting. For sICH patients, craniotomy indicated
EP
hematoma evacuation (HE) or HE plus decompressive craniectomy. There was no
AC C
interventional treatment for sICH patients. For AVM patients, craniotomy indicated the surgical removal of AVM lesions, and interventional treatment indicated the endovascular embolization of AVM.
Non-surgical: Non-surgical treatment was defined as medication therapy or radiation therapy (such as Gamma Knife for AVM). For patients who experienced multiple treatment methods, if they underwent any craniotomy or interventional treatment, they were analyzed in the surgical group. Otherwise, the patients
6 Xiao
ACCEPTED MANUSCRIPT would belong to the non-surgical group. Complications and intra-hospital mortality:
Complications such as rebleeding, infarction, hydrocephalus, and epilepsy were analyzed.
RI PT
Rebleeding was defined as any increase in the hematoma volume after admission on imaging examination (CT or MRI). Infarction was confirmed by an imaging examination during hospitalization (CT or MRI). Hydrocephalus was defined as an apparent radiological
SC
expansion of the ventricular system. Epilepsy was recorded according to the daily patient
M AN U
record or the results of electroencephalography. Intra-hospital mortality (IHM) was defined as death due to all causes during hospitalization. Statistical analysis:
Univariable analyses were conducted using the Chi-square test or Fisher exact tests, Student t
TE D
tests, and Mann–Whitney U tests, as appropriate. The Chi-square test or Fisher exact tests were used to compare the complications and IHM between Tibetan and Han PHNVD patients. Significance was defined as P<0.05 and 95% confidence intervals (CI) was used. All
AC C
EP
statistical analyses were performed using SPSS 19.0 (IBM, Armonk, New York, USA).
Results:
Among the 249 Tibetan PHNVD patients admitted from January 2012 to January 2016, 97 were aSAH, 102 were sICH, and 50 were AVM. 2,093 corresponding contemporary Han PHNVD patients were enrolled, including 1,071 aSAHs, 826 sICHs, and 196 AVMs. Compared to the Han subjects, the Tibetan cohort had higher proportion of males, tobacco smokers, hypertension and hypercholesterolemia (p<0.001). They also tended to have a
7 Xiao
ACCEPTED MANUSCRIPT
higher hemoglobin level (p<0.001). The two populations did not differ in age, gender, admission delay in hours, history of diabetes mellitus, coronary artery disease, or prior stroke
RI PT
(p>0.05) (Table 1).
The mean age of the Tibetan aSAH cohort (n=97) was 53.4±17.6 years old, with 42.3% (n=41) male and 85.6% (n=83) having a single aneurysm. Of which, 94.0% (n=78) located in
SC
the anterior circulation. The mean age of the Han aSAH cohort (n=1071) was 51.2±19.3
M AN U
years old, with 44.6% (478) being male and 85.5% (n=916) having a single aneurysm; 94.4% (n=865) of which had aneurysms located in the anterior circulation. The two cohorts did not differ significantly in age, gender and locations of aneurysms (p>0.05) (Table 2). Further, 19.6% (n=19) of the aneurysms in Tibetan group were blister-like aneurysms (BLAs), which
TE D
is defined as a special subtype of cerebral aneurysm characterized by the hemispherical fragile thin wall with a predilection to non-branching dorsal part of the internal carotid artery (ICA). However, the ratio of BLAs was 3.2% in Han group, which was significantly lower
AC C
EP
compared with that in Tibetan group (p<0.001).
Among the 1071 Han aSAH patients, 92% (n=985) underwent surgical treatment. Of the 97 Tibetan patients, 82.5% (n=80) belonged to the surgical group. The ratio of surgical treatment in Han group was significantly higher than that in Tibetan group (p=0.003). The incidence of infarction and rebleeding in Tibetan patients was significantly higher than that in Han patients in both the surgical and non-surgical groups (p<0.001). For other complications such as hydrocephalus and epilepsy, the Tibetan and Han patients did not differ significantly (p>0.05).
8 Xiao
ACCEPTED MANUSCRIPT
The IHM of Tibetan patients in surgical and non-surgical groups was also significantly higher (p<0.001) than for Han patients (Table 3).
RI PT
In the sICH cohort, there were 102 Tibetan patients and 826 Han patients with a mean age 54.4±18.3 years old and 51.2±17.1 years old, respectively. The mean hematoma volume was 36.25±16.59ml in Tibetan group and 34.72±21.42ml in Han group. The two groups did not
SC
differ significantly in age and the volume of hematoma (p>0.05). In our study, males
M AN U
represented a significantly higher proportion in Tibetan patients compared with Han patients (73.5% vs 54.5% p<0.001). In Tibetan group, 84.3% (n=86) of the hematoma located in the supratentorial area, including 28 in lobe, 44 in basal ganglia and 14 in thalamus. In Han group, 79.4% of the hematoma found in supratentorial region, including 205 in lobe, 346 in
TE D
basal ganglia and 105 thalamus. The two groups did not differ significantly (p>0.05) in the distribution of hematomas in supratentorial locations. However, the location of the hematomas varied in subtentorial region, with a brainstem hemorrhage more likely to be seen
EP
in Tibetan patients (10.8% vs 5.1%), whereas Han patients had a higher likelihood of a
AC C
cerebellum hemorrhage (11% vs 5.1%). The differences between the two groups were statistically significant (p<0.05).
A total of 31 Tibetan sICH patients (30.4%) underwent surgical treatment. Among the 826 Han patients, 33.7% (n=278) belonged to the surgical group. Two groups did not differ significantly in the ratio of surgical treatment (p=0.583). Infarction and rebleeding were the dominant complications in both groups. The incidence of infarction and rebleeding was
9 Xiao
ACCEPTED MANUSCRIPT
significantly higher (p<0.001) in the Tibetans than in the Han group in both the surgical and non-surgical groups. The incidence of other complications such as hydrocephalus and epilepsy did not differ significantly between either group (p>0.05). The IHM for the Tibetan
RI PT
patients was significantly longer than that for the Han patients in both the surgical and non-surgical groups (35.5% vs 15.1%, p=0.009; 28.2% vs 17.1%, p=0.037) (Table 4).
SC
In the AVM cohort, the mean age of the Tibetan and Han patients was 22.7±12.9 years old
M AN U
and 29±13.6 years old, respectively. The mean age of patients in Han group was significantly higher than that in Tibetan group (p=0.034). Meanwhile, the study revealed a predominance of males in the Tibetan patients, whose proportion was significantly higher than that in the Han group (78% vs 55.6%, p<0.05). In Tibetan group, the Number of patients with
TE D
Spetzler-Martin scale from I to V was 16 (32%), 21 (42%), 8 (16%), 4 (8%), 1(2%), respectively. In Han group, 46 (22.8%), 100 (51%), 27 (13.8%), 17(8.7%), 6 (3.1%) had the Spetzler-Martin scale from I to V. No significant difference (p>0.05) was found in the
AC C
EP
Spetzler-Martin scale grades between the Tibetans and Hans in this cohort.
Among the 196 Han AVM patients, 91.8% (n=180) underwent surgical treatment. For the 50 Tibetan patients, 86% (n=43) belonged to the surgical group. Two groups did not differ significantly in the ratio of surgical treatment (p=0.321). Epilepsy was the most common complication, without a significant difference in incidence between the Tibetans and Hans. However, infarction and rebleeding occurred more frequently in Tibetan patients than in Han patients, and there was a significant difference within the surgical group (p<0.001) (Table 5).
10 Xiao
ACCEPTED MANUSCRIPT
Discussion: Although many related studies on neurovascular diseases are documented, localized studies
RI PT
of patients in the Tibetan plateau area remain scarce in the field of PHNVD. Living in one of the highest elevation areas (called the “Roof of the World”) of the world (average altitude >4500 m, 14800 ft), the native Tibetan people are the representative race of the
SC
plateau area. With an abundant source of admission information on Tibetan patients living
M AN U
throughout the area and coming to our hospital, the largest medical center in southwest China, we retrospectively analyzed three common PHNVDs in Tibetans, including aSAH, sICH and AVM. We questioned whether these PHNVDs presented any differences in their incidence and clinical profiles for native Tibetans compared to contemporary Han patients.
TE D
aSAH
In our study, there were two interesting observations in aSAH cohort. First was the high incidence of blood blister-like aneurysms (BLAs) in Tibetan group compared with Han
EP
group(19.6% VS 3.2%). More interestingly, BLAs in Tibetan cohort count for 51.9% (14/27)
AC C
of all the ICA aneurysms, which was significantly higher than the reports of previous researches5, 6. Thus, we believe that BLAs have a high incidence rate in Tibetan aSAH patients. To date, there are no known mechanisms to explain the formation of BLAs. Some previous studies have suggested that some of the risk factors for BLAs may include hypertension, hemodynamics, atherosclerosis, and abnormal vascular anatomy. Based on their high incidence of BLAs, this study of high-altitude native Tibetan patients may help reveal a possible mechanism for the formation of BLAs. The second observation in aSAH
11 Xiao
ACCEPTED MANUSCRIPT
cohort was the high incidence of infarction and rebleeding in the Tibetan groups in both surgical and non-surgical patients. Based on the literature, the incidence of infarction and rebleeding in aSAH patients ranges from 3%-6% and 4%-13.6%, respectively9-15, similar to
RI PT
the incidence of our Han patients involved, but significantly lower than in the Tibetan patients. Thus, we concluded that Tibetan aSAH patients were more likely to suffer infarction and rebleeding than were Han patients.
SC
ICH
M AN U
In the sICH cohort, no significant differences were found in the locations of supratentorial hematomas in the two races. However, in the posterior fossa, the predominant site of hemorrhage was not consistent between the Tibetan and Han patients. The Tibetan patients had a higher incidence of brain stem hemorrhage, whereas the Han patients suffered a higher
TE D
proportion of cerebellum hemorrhages. In our study, a gender tendency toward males seemed to be more prominent in the Tibetan group with 73.5% male patients compared to 54.5% in the Han group. Although a higher susceptibility to sICH in men was fully recognized in
EP
previous studies16, an unusually high male proportion in the Tibetans aroused our attention.
AC C
The reasons for this phenomenon may be related to the higher status of men in Tibetan society and their living habits. Generally, Tibetan men have more medical recourse than women do and are more likely to engage in unhealthy habits like eating a high-fat diet, drinking alcohol and smoking tobacco, all of which have been shown to be risk factors for hemorrhagic stroke. Among the complications of sICH, a high incidence of infarction and rebleeding was also found in the Tibetan patients during hospitalization. The incidence rates were significantly higher than in the Han patients in both the surgical and nonsurgical groups.
12 Xiao
ACCEPTED MANUSCRIPT
According to the literature, the incidence of infarction in sICH is approximately 17%-22.9%17, far lower than the rate exhibited in our Tibetan patients (59.8%). For rebleeding complications in sICH, the incidence rate was 25.5% in the Tibetans involved, which is
RI PT
within the range reported earlier (18%-38%)18-21. AVM
In AVM cohort, no difference was seen in the Spetzler-Martin scale grades between the
SC
Tibetan and Han patients. The mean age of the Tibetan patients was younger than that of the
M AN U
Han group and that presented in previous studies. Although there is the lack of a definitive number of cases, it is possible that AVM rupture tends to occur more frequently in younger Tibetans. Among all complications, infarction and rebleeding in the Tibetans had the highest incidence, reaching 24% and 18%, respectively, which was significantly higher than the rates
TE D
for the Han patients in both the surgical and non-surgical treatment groups. In contrast, based on Carlos J. Ledezma’s earlier study 22, 23, the incidence rates of infarction and rebleeding in AVM were only 1.19% and 6.5%, respectively, similar to the complication rate findings from
AC C
HYPOSIS
EP
our Han AVM patients (2% and 5.1%, respectively).
Based on our research, a high incidence of infarction and rebleeding in the Tibetan patients was found for the three PHNVDs above. Because of a lack of earlier research focused on PHNVD in the Tibetan population, no feasible theories explaining the distinctive disease pathogenesis in this group have been proposed to date. We propose some hypothesis as follows. As for cerebral infarction, we put forward the “hemoglobin, blood viscosity, tiny thrombosis and infarction” hypothesis. From our baseline information, we showed that the
13 Xiao
ACCEPTED MANUSCRIPT
hemoglobin levels in the Tibetan patients were significantly higher than those in their contemporary Han patients. High hemoglobin levels are widely believed to be risk factors for high blood viscosity24-26. Several studies have proved the mechanism of high blood viscosity
RI PT
contributing to cerebral infarction on the basis of tiny thrombosis formation in the cerebral circulation system27-30. Thus, we consider the association of high hemoglobin levels, increased blood viscosity and tiny thrombosis formation might be the mechanisms leading to
SC
the high incidence of cerebral infarction in the Tibetan PHNVD patients. As for rebleeding,
M AN U
although multiple factors might contribute to rebleeding, we believe hypertension should be the important one. Exposure to hypoxia at high altitude is increasingly being recognized as a risk factor for hypertension reveled by some researches31-34. According to a cross-sectional study by Cuomu Mingji, et al. a significant correlation between altitude and the prevalence of
TE D
hypertension was observed among inhabitants of Tibet35. In our clinical observation of these Tibetan PHNVD patients, some of the patients showed a very high blood pressure of over 200/140 mmHg on admission. Furthermore, over half of the high blood pressure cases seen in
EP
the Tibetan PHNVD patients required multiple antihypertensive drugs. However, for the lack
AC C
of relative literatures, we believe that further studies should be performed to elucidate the exact pathway leading to this high risk of infarction and rebleeding. LIMITATIONS
Our study has some limitations. First, the study design was a nonrandomized, retrospective observational study covering only a single medical center. Second, the sample size of the Tibetan patients was limited, and we excluded cavernous hemangioma and Moyamoya disease patients to make sure that the cases in each subtype of PHNVDs had direct
14 Xiao
ACCEPTED MANUSCRIPT
comparability with the Han patient cases. Finally, all of the data that we collected were based on the inpatient records and images without any patient follow-up; thus, the long-term
RI PT
prognoses for the subjects remain uncertain.
Conclusions:
To date, research focusing on PHNVDs in the Tibetan population is still limited. Our study
SC
primarily explored the clinical characteristics of three common PHNVD subtypes, aSAH,
M AN U
sICH, and AVM, in Tibetan patients. In our research, a high incidence of BLAs in aSAH, a tendency toward brainstem hemorrhage in subtentorial sICH, and a high rate of infarction and rebleeding in Tibetan PHNVDs were all recognized. We believe that our findings will be a very valuable resource for clinicians seeking to gain an understanding of PHNVD in high
TE D
altitude patients. To gain further insight into PHNVD in the Tibetan plateau population, more prospective studies on PHNVD in Tibetan patients will be performed.
AC C
EP
Acknowledgements: None
Funding: This work was supported by the National Key Technology R&D Program for the 12th Five-year Plan of P.R China [grant numbers2011BAI08B05].
Reference: 1 Foroughi M, Akhavanzanjani M, Maghsoudi Z, Ghiasvand R, Khorvash F, Askari G. Stroke and nutrition: a review of studies. Int J Prev Med. 2013; 4(Suppl 2):S165-179. 2 He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, et al. Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study. BMJ. 2003; 327(7418):777-782.
15 Xiao
ACCEPTED MANUSCRIPT
3 Sasaki S, Zhang XH, Kesteloot H. Dietary sodium, potassium, saturated fat, alcohol, and stroke mortality. Stroke. 1995; 26(5):783-789.
4 Xue GB, Yu BX, Wang XZ, Wang GQ, Wang ZY. Stroke in urban and rural areas of China. Chin Med J (Engl). 1991; 104(8):697-704.
5 Gonzalez AM, Narata AP, Yilmaz H, Bijlenga P, Radovanovic I, Schaller K, et al. Blood blister-like aneurysms: single center experience and systematic literature review. Eur J Radiol. 2014; 83(1):197-205. 6 Szmuda T, Sloniewski P, Waszak PM, Springer J, Szmuda M. Towards a new treatment paradigm for ruptured
RI PT
blood blister-like aneurysms of the internal carotid artery? A rapid systematic review. J Neurointerv Surg. 2016; 8(5):488-494.
7 Ishikawa T, Nakamura N, Houkin K, Nomura M. Pathological consideration of a "blister-like" aneurysm at the superior wall of the internal carotid artery: case report. Neurosurgery. 1997; 40(2):403-405; discussion 405-406.
8 Meling TR, Sorteberg A, Bakke SJ, Slettebo H, Hernesniemi J, Sorteberg W. Blood blister-like aneurysms of the
SC
internal carotid artery trunk causing subarachnoid hemorrhage: treatment and outcome. J Neurosurg. 2008; 108(4):662-671.
9 Brinjikji W, Lanzino G, Cloft HJ, Siddiqui AH, Boccardi E, Cekirge S, et al. Risk Factors for Ischemic IntrePED Study. AJNR Am J Neuroradiol. 2016.
M AN U
Complications following Pipeline Embolization Device Treatment of Intracranial Aneurysms: Results from the 10 Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke. 2013; 44(2):442-447.
11 Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg. 2002; 97(4):771-778.
12 Kallmes DF, Hanel R, Lopes D, Boccardi E, Bonafe A, Cekirge S, et al. International retrospective study of the
TE D
pipeline embolization device: a multicenter aneurysm treatment study. AJNR Am J Neuroradiol. 2015; 36(1):108-115. 13 Kassell NF, Torner JC. Aneurysmal rebleeding: a preliminary report from the Cooperative Aneurysm Study. Neurosurgery. 1983; 13(5):479-481.
14 Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, Parra A, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol. 2005; 62(3):410-416.
EP
15 Ohkuma H, Tsurutani H, Suzuki S. Incidence and significance of early aneurysmal rebleeding before neurosurgical or neurological management. Stroke. 2001; 32(5):1176-1180. 16 Gokhale S, Caplan LR, James ML. Sex differences in incidence, pathophysiology, and outcome of primary
AC C
intracerebral hemorrhage. Stroke. 2015; 46(3):886-892. 17 Prabhakaran S, Gupta R, Ouyang B, John S, Temes RE, Mohammad Y, et al. Acute brain infarcts after spontaneous intracerebral hemorrhage: a diffusion-weighted imaging study. Stroke. 2010; 41(1):89-94. 18 Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997; 28(1):1-5. 19 Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke. 1998; 29(6):1160-1166. 20 Fujitsu K, Muramoto M, Ikeda Y, Inada Y, Kim I, Kuwabara T. Indications for surgical treatment of putaminal hemorrhage. Comparative study based on serial CT and time-course analysis. J Neurosurg. 1990; 73(4):518-525. 21 Li Q, Zhang G, Huang YJ, Dong MX, Lv FJ, Wei X, et al. Blend Sign on Computed Tomography: Novel and Reliable Predictor for Early Hematoma Growth in Patients With Intracerebral Hemorrhage. Stroke. 2015; 46(8):2119-2123.
22 Jordan JA, Llibre JC, Vazquez F, Rodriguez R, Prince JA, Ugarte JC. Predictors of hemorrhagic complications
16 Xiao
ACCEPTED MANUSCRIPT from endovascular treatment of cerebral arteriovenous malformations. Interv Neuroradiol. 2014; 20(1):74-82.
23 Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery. 2006; 58(4):602-611; discussion 602-611.
24 Luneva OG, Brazhe NA, Fadyukova OE, Akhalaya MY, Baizhumanov AA, Parshina EY, et al. Changes in plasma membrane viscosity and hemoporphyrin conformation in erythrocyte hemoglobin under the conditions of ischemia and reperfusion of rat brain. Dokl Biochem Biophys. 2005; 405:465-467.
RI PT
25 McClain BL, Finkelstein IJ, Fayer MD. Dynamics of hemoglobin in human erythrocytes and in solution: influence of viscosity studied by ultrafast vibrational echo experiments. J Am Chem Soc. 2004; 126(48):15702-15710. 26 Herrmann A, Muller P. Correlation of the internal microviscosity of human erythrocytes to the cell volume and the viscosity of hemoglobin solutions. Biochim Biophys Acta. 1986; 885(1):80-87.
27 Ott EO, Lechner H, Aranibar A. High blood viscosity syndrome in cerebral infarction. Stroke. 1974; 5(3):330-333.
SC
28 Jan KM, Chien S, Bigger JT, Jr. Observations on blood viscosity changes after acute myocardial infarction. Circulation. 1975; 51(6):1079-1084.
29 Grotta J, Ackerman R, Correia J, Fallick G, Chang J. Whole blood viscosity parameters and cerebral blood flow. Stroke. 1982; 13(3):296-301.
M AN U
30 Li RY, Cao ZG, Li Y, Wang RT. Increased whole blood viscosity is associated with silent cerebral infarction. Clin Hemorheol Microcirc. 2015; 59(4):301-307.
31 Brito J, Siques P, Leon-Velarde F, De La Cruz JJ, Lopez V, Herruzo R. Chronic intermittent hypoxia at high altitude exposure for over 12 years: assessment of hematological, cardiovascular, and renal effects. High Alt Med Biol. 2007; 8(3):236-244.
32 Ashraf MZ. Hypertension at high altitude: the interplay between genetic and biochemical factors in the setting of oxidative stress. Hypertens Res. 2016; 39(4):199-200.
TE D
33 Norboo T, Stobdan T, Tsering N, Angchuk N, Tsering P, Ahmed I, et al. Prevalence of hypertension at high altitude: cross-sectional survey in Ladakh, Northern India 2007-2011. BMJ Open. 2015; 5(4):e007026. 34 Raina SK, Chander V, Prasher CL, Raina S. Prevalence of Hypertension in a Tribal Land Locked Population at High Altitude. Scientifica (Cairo). 2016; 2016:3589720.
35 Mingji C, Onakpoya IJ, Perera R, Ward AM, Heneghan CJ. Relationship between altitude and the prevalence
AC C
EP
of hypertension in Tibet: a systematic review. Heart. 2015; 101(13):1054-1060.
ACCEPTED MANUSCRIPT Table 1: Sociodemographic information of Tibetan and Han PHNVD patients Tibetan
Han
(n=249)
(n=2093)
P value General information 0.242 49.1(19.8)
155(62.2)
1037(49.5)
17.78±16.51
15.36±13.37
0.094
Hypertension, n (%)
135(54.2)
837(40)
<0.001
Diabetes mellitus, n (%)
30(12.0)
251(12)
0.938
Coronary artery disease, n (%)
37(14.9)
268(12.8)
0.658
Prior hemorrhagic stroke, n (%)
6(2.4)
42(2)
0.851
Current smoking, n (%)
85(34.1)
536(25.6)
<0.001
Current drinking, n (%)
78(31.3)
603(28.8)
0.452
Hyperlipidemia, n (%)
45(18.1)
203(9.7)
<0.001
Men, n (%) Admission delay in hours
158.7(14.2)
AC C
EP
Mean(SD)
TE D
Hemoglobin, g/L
SC
47.6(15.1)
M AN U
Mean(SD)
RI PT
Age, y
131.6(21.4)
<0.001
<0.001
ACCEPTED MANUSCRIPT Table 2: Number and location of aneurysms in Tibetan and Han patients Tibetan
Han
N=97
N=1071
Multiple, n (%)
14(14.4)
155(14.5)
Single
83
916
Aneurysm
P value
263(24.6)
ACOM, n (%)
18(18.6)
227(21.2)
ACA, n (%)
7(7.2)
51(4.8)
MCA, n (%)
15(15.5)
125(11.7)
PCOM, n (%)
11(11.3)
199(18.6)
BA, n (%)
4(4.1)
RPCA, n (%)
1(1)
RI PT
27(27.8)
SC
ICA, n (%)
0.889
M AN U
32(3)
19(1.8)
0.553
0.631 0.411
0.348
0.101 0.754 0.895
Multiple indicates the number of aneurysms greater than or equals to 2. Single indicates the number of aneurysms equals to 1.
ICA indicates iternal carotid artery aneurysm; ACOM indicates anterior communicating artery aneurysms; ACA
TE D
indicates anterior cerebral artery aneurysms; MCA indicates middle cerebral artery aneurysms; PCOM indicates posterior communicating artery aneurysms; BA indicates basilar artery aneurysms; RPCA indicates remaining
AC C
EP
posterior circulation arteries
ACCEPTED MANUSCRIPT Table 3: Complications and intra-hospital mortality between Tibetan and Han patients in aSAH Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=86)
(n=17) 6(35.3)
P value
P value
(n=985)
(n=80)
Infarction, n (%)
76(7.7)
36(45)
<0.001
6(7)
Rebleeding, n (%)
35(3.6)
11(13.8)
<0.001
5(5.8)
3(17.6)
<0.001
Hydrocephalus, n (%)
42(4.3)
4(5)
0.980
5(5.8)
1(5.9)
0.578
Epilepsy, n (%)
26(2.6)
2(2.5)
0.773
4(4.7)
1(5.9)
0.688
IHM, n (%)
46(4.7)
9(11.2)
0.022
7(8.1)
6(35.3)
0.007
AC C
EP
RI PT
SC
TE D
M AN U
IHM indicates intra-hospital mortality
<0.001
ACCEPTED MANUSCRIPT Table 4: Complications and intra-hospital mortality between Tibetan and Han patients in sICH Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=548)
(n=71) 42(59.2)
P value
P value
(n=278)
(n=31)
35(12.6)
19(61.3)
<0.001
39(7.1)
Rebleeding, n (%)
39(14)
11(35.5)
<0.001
43(7.8)
15(21.1)
<0.001
Hydrocephalus, n (%)
6(9.3)
4(12.9)
0.753
31(5.7)
5(7)
0.842
Epilepsy, n (%)
16(5.8)
1(3.2)
0.864
21(3.8)
4(5.6)
0.685
IHM, n (%)
42(15.1)
11(35.5)
0.009
94(17.1)
20(28.2)
0.037
AC C
EP
TE D
M AN U
IHM indicates intra-hospital mortality
<0.001
RI PT
SC
Infarction, n (%)
ACCEPTED MANUSCRIPT Table 5: Complications and intra-hospital mortality between Tibetan and Han patients in AVM Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=16)
(n=7) 1(14.3)
P value
P value
(n=180)
(n=43)
3(1.7)
7(16.3)
<0.001
1(6.25)
Rebleeding, n (%)
9(5)
8(18.6)
0.006
1(6.25)
1(14.3)
0.735
Hydrocephalus, n (%)
2(1.1)
1(2.3)
0.908
1(6.25)
1(14.3)
0.735
49(27.2)
12(27.9)
0.920
4(25)
2(28.6)
0.736
6(3.3)
1(2.3)
0.884
1(6.25)
0(0)
0.664
IHM, n (%)
AC C
EP
TE D
M AN U
IHM indicates intra-hospital mortality
0.735
RI PT
Epilepsy, n (%)
SC
Infarction, n (%)
ACCEPTED MANUSCRIPT Three interesting characters of Primary hemorrhagic neurovascular diseases in Tibetans were observed, A high rate of infarction and rebleeding was found in aSAH, sICH and AVM
A high incidence of BLAs was found in aSAH.
A tendency toward brainstem hemorrhage in subtentorial was found in sICH
AC C
EP
TE D
M AN U
SC
RI PT
S1878-8750(16)30841-5
DOI:
10.1016/j.wneu.2016.09.015
Reference:
WNEU 4555
To appear in:
World Neurosurgery
Received Date: 4 July 2016 Revised Date:
5 September 2016
Accepted Date: 6 September 2016
Please cite this article as: Xiao A, Chen R, Li H, Ma L, Lin S, Hu X, You C, Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Xiao
ACCEPTED MANUSCRIPT
Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study Anqi Xiao1* MD, Ruiqi Chen1* MD, Hao Li1 MD, Lu Ma1 MD, Sen Lin1 MD, Xin Hu1 MD and Chao You1 MD
RI PT
1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; *These authors contributed equally to the manuscript
Corresponding author at all stages of refereeing, publication and post-publication:
SC
Chao You
Address: No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China
M AN U
Email: [email protected]
Key words: Primary hemorrhagic neurovascular diseases (PHNVDs), Ethnic, aneurysmal subarachnoid hemorrhage (aSAH), spontaneous intracerebral hemorrhage (sICH), arteriovenous malformation (AVM)
TE D
Abbreviations list:
aSAH=aneurysmal subarachnoid hemorrhage; AVM=Arteriovenous Malformation; BLAs= Blood
EP
Blister-like Aneurysms; CI= Confidence Intervals; CT=Computed Tomography; CTA=Computed Tomography Angiography; DSA=Digital Subtraction Angiography; HE=Hematoma Evacuation;
AC C
ICA=Internal Carotid Artery; IHM=Intra-hospital Mortality; MRI=Magnetic Resonance Imaging; PHNVDs
=Primary
hemorrhagic
neurovascular
diseases;
hemorrhage; WCH =West China Hospital of Sichuan University;
sICH=spontaneous
intracerebral
2 Xiao
ACCEPTED MANUSCRIPT
Primary hemorrhagic neurovascular diseases (PHNVDs) in Tibetans: a retrospective observational study Abstract:
RI PT
Background: Although there have been many studies on primary hemorrhagic neurovascular diseases (PHNVDs) in different populations, a study focusing on PHNVDs in Tibetan people was still lacking. This study aimed to explore the notable characteristics of Tibetan PHNVDs
SC
by comparing the most three common PHNVDs (aneurysmal subarachnoid hemorrhage,
between Tibetan and Han patients.
M AN U
spontaneous intracerebral hemorrhage and arteriovenous malformation) in our institution
Methods: In this retrospective observational study, the hospital information system (HIS) was utilized to access the records of patients with PHNVDs. A total of 249 Tibetan patients
TE D
and 2,093 corresponding contemporary Han patients were recruited from January 2012 to January 2016. Sociodemographic information and clinical data on each PHNVD subtype were collected and compared between two races.
EP
Results: For Tibetan patients, significantly higher incidence (p<0.05) of rebleeding and
AC C
cerebral infarction was observed in all three PHNVD subtypes. In aneurysmal subarachnoid hemorrhage group, Tibetan patients had significantly higher incidence of blood blister-like aneurysms (BLAs) (19.6% (19/97) vs 3.2% (34/1071), p<0.001). In spontaneous intracerebral hemorrhage group, Tibetan patients got a significantly higher incidence of brainstem hemorrhage in subtentorial area (10.8% vs 5.1%, p=0.035). Conclusions: For Tibetan PHNVDs, a high incidence of BLAs in aSAH, a tendency toward brainstem hemorrhage in subtentorial sICH, and a high rate of infarction and rebleeding in all
3 Xiao
ACCEPTED MANUSCRIPT three subtypes were all recognized.
Key Words: Primary hemorrhagic neurovascular diseases (PHNVDs), Ethnic, aneurysmal subarachnoid
hemorrhage
(aSAH),
spontaneous
intracerebral
hemorrhage
(sICH),
RI PT
arteriovenous malformation (AVM)
Introduction:
SC
Primary hemorrhagic neurovascular diseases (PHNVDs) have been a challenge for
M AN U
neurosurgeons due to their high rates of morbidity and mortality. Although there have been many studies on PHNVDs in different populations, the research focusing on Tibetan people was still lacking. In China, Han people are the majority of the population (over 1.2 billion). Although Tibetans only have 7.8 million people, they are the largest human race living in the
TE D
Himalaya plateau area, with an especially high-altitude atmosphere with low pressure and thin oxygen levels. Due to their different living environment and customs, the diet of Tibetans is composed of high-fat and high-salt food, increasing the risk of hypertension, hyperlidemia,
EP
and therefore hemorrhagic stroke1-3. Until now, few studies of PHNVDs in Tibetans were
AC C
published since a national survey explored the high incidence of stroke in the Tibet area 20 years ago4. As the largest medical center of West China area, the West China Hospital of Sichuan University (WCH) accepts a large number of PHNVD patients from different regions of western China, including the Tibetan plateau. In our study, we analyzed and compared the medical data for three common PHNVDs (aneurysmal subarachnoid hemorrhage, spontaneous intracerebral hemorrhage and arteriovenous malformation) in Tibetan and Han people in WCH from January 2012 to January 2016 to explore the notable characteristics of
4 Xiao
ACCEPTED MANUSCRIPT these PHNVDs in Tibetans for clinical doctors.
Materials and Methods
RI PT
Study design and Participants: In this retrospective observational study, the hospital information system (HIS) was utilized to access the records of patients with PHNVDs in our institute from January 2012 to January
SC
2016. The study patients were selected by their stated race as either “Tibetan” or “Han.” The
M AN U
diagnosis of the selected patients was confirmed by two neurosurgeons and one neuroradiologist, who reviewed their inpatient medical records and imaging data. In total, 254 PHNVD Tibetan patients meeting the criteria were enrolled, including 97 with aneurysmal subarachnoid hemorrhage (aSAH), 102 with spontaneous intracerebral
TE D
hemorrhage (sICH), 50 with arteriovenous malformation (AVM), 3 with Cavernous hemangioma and 2 with Moyamoya diseases. Due to an insufficient sample size, patients with cavernous hemangioma and Moyamoya disease were excluded from our study.
EP
Correspondingly, 2,093 Han PHNVD patients were enrolled, consisting of 1071 aSAHs, 826
AC C
sICHs and 196 AVMs for the comparison analysis. Data Collection:
Sociodemographic data and individual risk factors (history of hypertension, diabetes, coronary artery disease, dyslipidemia, hemoglobin, tobacco use, alcohol use, prior stroke, and peripheral vascular disease) were collected, as was information on each PHNVD subtype as follows: Aneurysmal subarachnoid hemorrhage (aSAH): Number and location of the aneurysms based
5 Xiao
ACCEPTED MANUSCRIPT
on computed tomography angiography (CTA) and Digital subtraction angiography (DSA). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical treatment
RI PT
Spontaneous intracerebral hemorrhage (sICH): Location of the hematoma based on computed tomography (CT) and magnetic resonance imaging (MRI). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical
SC
treatment
M AN U
Arteriovenous malformation (AVM): Spetzler-Martin AVM grading scale based on an imaging examination (DSA). Complications and intra-hospital mortality with different therapeutic options, including surgery and non-surgical treatment Treatment:
TE D
Surgery: Surgery was classified as craniotomy or interventional treatment. For aSAH patients, craniotomy indicated aneurysm-clipping surgery, and interventional treatment included endovascular coiling and cerebral artery stenting. For sICH patients, craniotomy indicated
EP
hematoma evacuation (HE) or HE plus decompressive craniectomy. There was no
AC C
interventional treatment for sICH patients. For AVM patients, craniotomy indicated the surgical removal of AVM lesions, and interventional treatment indicated the endovascular embolization of AVM.
Non-surgical: Non-surgical treatment was defined as medication therapy or radiation therapy (such as Gamma Knife for AVM). For patients who experienced multiple treatment methods, if they underwent any craniotomy or interventional treatment, they were analyzed in the surgical group. Otherwise, the patients
6 Xiao
ACCEPTED MANUSCRIPT would belong to the non-surgical group. Complications and intra-hospital mortality:
Complications such as rebleeding, infarction, hydrocephalus, and epilepsy were analyzed.
RI PT
Rebleeding was defined as any increase in the hematoma volume after admission on imaging examination (CT or MRI). Infarction was confirmed by an imaging examination during hospitalization (CT or MRI). Hydrocephalus was defined as an apparent radiological
SC
expansion of the ventricular system. Epilepsy was recorded according to the daily patient
M AN U
record or the results of electroencephalography. Intra-hospital mortality (IHM) was defined as death due to all causes during hospitalization. Statistical analysis:
Univariable analyses were conducted using the Chi-square test or Fisher exact tests, Student t
TE D
tests, and Mann–Whitney U tests, as appropriate. The Chi-square test or Fisher exact tests were used to compare the complications and IHM between Tibetan and Han PHNVD patients. Significance was defined as P<0.05 and 95% confidence intervals (CI) was used. All
AC C
EP
statistical analyses were performed using SPSS 19.0 (IBM, Armonk, New York, USA).
Results:
Among the 249 Tibetan PHNVD patients admitted from January 2012 to January 2016, 97 were aSAH, 102 were sICH, and 50 were AVM. 2,093 corresponding contemporary Han PHNVD patients were enrolled, including 1,071 aSAHs, 826 sICHs, and 196 AVMs. Compared to the Han subjects, the Tibetan cohort had higher proportion of males, tobacco smokers, hypertension and hypercholesterolemia (p<0.001). They also tended to have a
7 Xiao
ACCEPTED MANUSCRIPT
higher hemoglobin level (p<0.001). The two populations did not differ in age, gender, admission delay in hours, history of diabetes mellitus, coronary artery disease, or prior stroke
RI PT
(p>0.05) (Table 1).
The mean age of the Tibetan aSAH cohort (n=97) was 53.4±17.6 years old, with 42.3% (n=41) male and 85.6% (n=83) having a single aneurysm. Of which, 94.0% (n=78) located in
SC
the anterior circulation. The mean age of the Han aSAH cohort (n=1071) was 51.2±19.3
M AN U
years old, with 44.6% (478) being male and 85.5% (n=916) having a single aneurysm; 94.4% (n=865) of which had aneurysms located in the anterior circulation. The two cohorts did not differ significantly in age, gender and locations of aneurysms (p>0.05) (Table 2). Further, 19.6% (n=19) of the aneurysms in Tibetan group were blister-like aneurysms (BLAs), which
TE D
is defined as a special subtype of cerebral aneurysm characterized by the hemispherical fragile thin wall with a predilection to non-branching dorsal part of the internal carotid artery (ICA). However, the ratio of BLAs was 3.2% in Han group, which was significantly lower
AC C
EP
compared with that in Tibetan group (p<0.001).
Among the 1071 Han aSAH patients, 92% (n=985) underwent surgical treatment. Of the 97 Tibetan patients, 82.5% (n=80) belonged to the surgical group. The ratio of surgical treatment in Han group was significantly higher than that in Tibetan group (p=0.003). The incidence of infarction and rebleeding in Tibetan patients was significantly higher than that in Han patients in both the surgical and non-surgical groups (p<0.001). For other complications such as hydrocephalus and epilepsy, the Tibetan and Han patients did not differ significantly (p>0.05).
8 Xiao
ACCEPTED MANUSCRIPT
The IHM of Tibetan patients in surgical and non-surgical groups was also significantly higher (p<0.001) than for Han patients (Table 3).
RI PT
In the sICH cohort, there were 102 Tibetan patients and 826 Han patients with a mean age 54.4±18.3 years old and 51.2±17.1 years old, respectively. The mean hematoma volume was 36.25±16.59ml in Tibetan group and 34.72±21.42ml in Han group. The two groups did not
SC
differ significantly in age and the volume of hematoma (p>0.05). In our study, males
M AN U
represented a significantly higher proportion in Tibetan patients compared with Han patients (73.5% vs 54.5% p<0.001). In Tibetan group, 84.3% (n=86) of the hematoma located in the supratentorial area, including 28 in lobe, 44 in basal ganglia and 14 in thalamus. In Han group, 79.4% of the hematoma found in supratentorial region, including 205 in lobe, 346 in
TE D
basal ganglia and 105 thalamus. The two groups did not differ significantly (p>0.05) in the distribution of hematomas in supratentorial locations. However, the location of the hematomas varied in subtentorial region, with a brainstem hemorrhage more likely to be seen
EP
in Tibetan patients (10.8% vs 5.1%), whereas Han patients had a higher likelihood of a
AC C
cerebellum hemorrhage (11% vs 5.1%). The differences between the two groups were statistically significant (p<0.05).
A total of 31 Tibetan sICH patients (30.4%) underwent surgical treatment. Among the 826 Han patients, 33.7% (n=278) belonged to the surgical group. Two groups did not differ significantly in the ratio of surgical treatment (p=0.583). Infarction and rebleeding were the dominant complications in both groups. The incidence of infarction and rebleeding was
9 Xiao
ACCEPTED MANUSCRIPT
significantly higher (p<0.001) in the Tibetans than in the Han group in both the surgical and non-surgical groups. The incidence of other complications such as hydrocephalus and epilepsy did not differ significantly between either group (p>0.05). The IHM for the Tibetan
RI PT
patients was significantly longer than that for the Han patients in both the surgical and non-surgical groups (35.5% vs 15.1%, p=0.009; 28.2% vs 17.1%, p=0.037) (Table 4).
SC
In the AVM cohort, the mean age of the Tibetan and Han patients was 22.7±12.9 years old
M AN U
and 29±13.6 years old, respectively. The mean age of patients in Han group was significantly higher than that in Tibetan group (p=0.034). Meanwhile, the study revealed a predominance of males in the Tibetan patients, whose proportion was significantly higher than that in the Han group (78% vs 55.6%, p<0.05). In Tibetan group, the Number of patients with
TE D
Spetzler-Martin scale from I to V was 16 (32%), 21 (42%), 8 (16%), 4 (8%), 1(2%), respectively. In Han group, 46 (22.8%), 100 (51%), 27 (13.8%), 17(8.7%), 6 (3.1%) had the Spetzler-Martin scale from I to V. No significant difference (p>0.05) was found in the
AC C
EP
Spetzler-Martin scale grades between the Tibetans and Hans in this cohort.
Among the 196 Han AVM patients, 91.8% (n=180) underwent surgical treatment. For the 50 Tibetan patients, 86% (n=43) belonged to the surgical group. Two groups did not differ significantly in the ratio of surgical treatment (p=0.321). Epilepsy was the most common complication, without a significant difference in incidence between the Tibetans and Hans. However, infarction and rebleeding occurred more frequently in Tibetan patients than in Han patients, and there was a significant difference within the surgical group (p<0.001) (Table 5).
10 Xiao
ACCEPTED MANUSCRIPT
Discussion: Although many related studies on neurovascular diseases are documented, localized studies
RI PT
of patients in the Tibetan plateau area remain scarce in the field of PHNVD. Living in one of the highest elevation areas (called the “Roof of the World”) of the world (average altitude >4500 m, 14800 ft), the native Tibetan people are the representative race of the
SC
plateau area. With an abundant source of admission information on Tibetan patients living
M AN U
throughout the area and coming to our hospital, the largest medical center in southwest China, we retrospectively analyzed three common PHNVDs in Tibetans, including aSAH, sICH and AVM. We questioned whether these PHNVDs presented any differences in their incidence and clinical profiles for native Tibetans compared to contemporary Han patients.
TE D
aSAH
In our study, there were two interesting observations in aSAH cohort. First was the high incidence of blood blister-like aneurysms (BLAs) in Tibetan group compared with Han
EP
group(19.6% VS 3.2%). More interestingly, BLAs in Tibetan cohort count for 51.9% (14/27)
AC C
of all the ICA aneurysms, which was significantly higher than the reports of previous researches5, 6. Thus, we believe that BLAs have a high incidence rate in Tibetan aSAH patients. To date, there are no known mechanisms to explain the formation of BLAs. Some previous studies have suggested that some of the risk factors for BLAs may include hypertension, hemodynamics, atherosclerosis, and abnormal vascular anatomy. Based on their high incidence of BLAs, this study of high-altitude native Tibetan patients may help reveal a possible mechanism for the formation of BLAs. The second observation in aSAH
11 Xiao
ACCEPTED MANUSCRIPT
cohort was the high incidence of infarction and rebleeding in the Tibetan groups in both surgical and non-surgical patients. Based on the literature, the incidence of infarction and rebleeding in aSAH patients ranges from 3%-6% and 4%-13.6%, respectively9-15, similar to
RI PT
the incidence of our Han patients involved, but significantly lower than in the Tibetan patients. Thus, we concluded that Tibetan aSAH patients were more likely to suffer infarction and rebleeding than were Han patients.
SC
ICH
M AN U
In the sICH cohort, no significant differences were found in the locations of supratentorial hematomas in the two races. However, in the posterior fossa, the predominant site of hemorrhage was not consistent between the Tibetan and Han patients. The Tibetan patients had a higher incidence of brain stem hemorrhage, whereas the Han patients suffered a higher
TE D
proportion of cerebellum hemorrhages. In our study, a gender tendency toward males seemed to be more prominent in the Tibetan group with 73.5% male patients compared to 54.5% in the Han group. Although a higher susceptibility to sICH in men was fully recognized in
EP
previous studies16, an unusually high male proportion in the Tibetans aroused our attention.
AC C
The reasons for this phenomenon may be related to the higher status of men in Tibetan society and their living habits. Generally, Tibetan men have more medical recourse than women do and are more likely to engage in unhealthy habits like eating a high-fat diet, drinking alcohol and smoking tobacco, all of which have been shown to be risk factors for hemorrhagic stroke. Among the complications of sICH, a high incidence of infarction and rebleeding was also found in the Tibetan patients during hospitalization. The incidence rates were significantly higher than in the Han patients in both the surgical and nonsurgical groups.
12 Xiao
ACCEPTED MANUSCRIPT
According to the literature, the incidence of infarction in sICH is approximately 17%-22.9%17, far lower than the rate exhibited in our Tibetan patients (59.8%). For rebleeding complications in sICH, the incidence rate was 25.5% in the Tibetans involved, which is
RI PT
within the range reported earlier (18%-38%)18-21. AVM
In AVM cohort, no difference was seen in the Spetzler-Martin scale grades between the
SC
Tibetan and Han patients. The mean age of the Tibetan patients was younger than that of the
M AN U
Han group and that presented in previous studies. Although there is the lack of a definitive number of cases, it is possible that AVM rupture tends to occur more frequently in younger Tibetans. Among all complications, infarction and rebleeding in the Tibetans had the highest incidence, reaching 24% and 18%, respectively, which was significantly higher than the rates
TE D
for the Han patients in both the surgical and non-surgical treatment groups. In contrast, based on Carlos J. Ledezma’s earlier study 22, 23, the incidence rates of infarction and rebleeding in AVM were only 1.19% and 6.5%, respectively, similar to the complication rate findings from
AC C
HYPOSIS
EP
our Han AVM patients (2% and 5.1%, respectively).
Based on our research, a high incidence of infarction and rebleeding in the Tibetan patients was found for the three PHNVDs above. Because of a lack of earlier research focused on PHNVD in the Tibetan population, no feasible theories explaining the distinctive disease pathogenesis in this group have been proposed to date. We propose some hypothesis as follows. As for cerebral infarction, we put forward the “hemoglobin, blood viscosity, tiny thrombosis and infarction” hypothesis. From our baseline information, we showed that the
13 Xiao
ACCEPTED MANUSCRIPT
hemoglobin levels in the Tibetan patients were significantly higher than those in their contemporary Han patients. High hemoglobin levels are widely believed to be risk factors for high blood viscosity24-26. Several studies have proved the mechanism of high blood viscosity
RI PT
contributing to cerebral infarction on the basis of tiny thrombosis formation in the cerebral circulation system27-30. Thus, we consider the association of high hemoglobin levels, increased blood viscosity and tiny thrombosis formation might be the mechanisms leading to
SC
the high incidence of cerebral infarction in the Tibetan PHNVD patients. As for rebleeding,
M AN U
although multiple factors might contribute to rebleeding, we believe hypertension should be the important one. Exposure to hypoxia at high altitude is increasingly being recognized as a risk factor for hypertension reveled by some researches31-34. According to a cross-sectional study by Cuomu Mingji, et al. a significant correlation between altitude and the prevalence of
TE D
hypertension was observed among inhabitants of Tibet35. In our clinical observation of these Tibetan PHNVD patients, some of the patients showed a very high blood pressure of over 200/140 mmHg on admission. Furthermore, over half of the high blood pressure cases seen in
EP
the Tibetan PHNVD patients required multiple antihypertensive drugs. However, for the lack
AC C
of relative literatures, we believe that further studies should be performed to elucidate the exact pathway leading to this high risk of infarction and rebleeding. LIMITATIONS
Our study has some limitations. First, the study design was a nonrandomized, retrospective observational study covering only a single medical center. Second, the sample size of the Tibetan patients was limited, and we excluded cavernous hemangioma and Moyamoya disease patients to make sure that the cases in each subtype of PHNVDs had direct
14 Xiao
ACCEPTED MANUSCRIPT
comparability with the Han patient cases. Finally, all of the data that we collected were based on the inpatient records and images without any patient follow-up; thus, the long-term
RI PT
prognoses for the subjects remain uncertain.
Conclusions:
To date, research focusing on PHNVDs in the Tibetan population is still limited. Our study
SC
primarily explored the clinical characteristics of three common PHNVD subtypes, aSAH,
M AN U
sICH, and AVM, in Tibetan patients. In our research, a high incidence of BLAs in aSAH, a tendency toward brainstem hemorrhage in subtentorial sICH, and a high rate of infarction and rebleeding in Tibetan PHNVDs were all recognized. We believe that our findings will be a very valuable resource for clinicians seeking to gain an understanding of PHNVD in high
TE D
altitude patients. To gain further insight into PHNVD in the Tibetan plateau population, more prospective studies on PHNVD in Tibetan patients will be performed.
AC C
EP
Acknowledgements: None
Funding: This work was supported by the National Key Technology R&D Program for the 12th Five-year Plan of P.R China [grant numbers2011BAI08B05].
Reference: 1 Foroughi M, Akhavanzanjani M, Maghsoudi Z, Ghiasvand R, Khorvash F, Askari G. Stroke and nutrition: a review of studies. Int J Prev Med. 2013; 4(Suppl 2):S165-179. 2 He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, et al. Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study. BMJ. 2003; 327(7418):777-782.
15 Xiao
ACCEPTED MANUSCRIPT
3 Sasaki S, Zhang XH, Kesteloot H. Dietary sodium, potassium, saturated fat, alcohol, and stroke mortality. Stroke. 1995; 26(5):783-789.
4 Xue GB, Yu BX, Wang XZ, Wang GQ, Wang ZY. Stroke in urban and rural areas of China. Chin Med J (Engl). 1991; 104(8):697-704.
5 Gonzalez AM, Narata AP, Yilmaz H, Bijlenga P, Radovanovic I, Schaller K, et al. Blood blister-like aneurysms: single center experience and systematic literature review. Eur J Radiol. 2014; 83(1):197-205. 6 Szmuda T, Sloniewski P, Waszak PM, Springer J, Szmuda M. Towards a new treatment paradigm for ruptured
RI PT
blood blister-like aneurysms of the internal carotid artery? A rapid systematic review. J Neurointerv Surg. 2016; 8(5):488-494.
7 Ishikawa T, Nakamura N, Houkin K, Nomura M. Pathological consideration of a "blister-like" aneurysm at the superior wall of the internal carotid artery: case report. Neurosurgery. 1997; 40(2):403-405; discussion 405-406.
8 Meling TR, Sorteberg A, Bakke SJ, Slettebo H, Hernesniemi J, Sorteberg W. Blood blister-like aneurysms of the
SC
internal carotid artery trunk causing subarachnoid hemorrhage: treatment and outcome. J Neurosurg. 2008; 108(4):662-671.
9 Brinjikji W, Lanzino G, Cloft HJ, Siddiqui AH, Boccardi E, Cekirge S, et al. Risk Factors for Ischemic IntrePED Study. AJNR Am J Neuroradiol. 2016.
M AN U
Complications following Pipeline Embolization Device Treatment of Intracranial Aneurysms: Results from the 10 Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke. 2013; 44(2):442-447.
11 Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg. 2002; 97(4):771-778.
12 Kallmes DF, Hanel R, Lopes D, Boccardi E, Bonafe A, Cekirge S, et al. International retrospective study of the
TE D
pipeline embolization device: a multicenter aneurysm treatment study. AJNR Am J Neuroradiol. 2015; 36(1):108-115. 13 Kassell NF, Torner JC. Aneurysmal rebleeding: a preliminary report from the Cooperative Aneurysm Study. Neurosurgery. 1983; 13(5):479-481.
14 Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, Parra A, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol. 2005; 62(3):410-416.
EP
15 Ohkuma H, Tsurutani H, Suzuki S. Incidence and significance of early aneurysmal rebleeding before neurosurgical or neurological management. Stroke. 2001; 32(5):1176-1180. 16 Gokhale S, Caplan LR, James ML. Sex differences in incidence, pathophysiology, and outcome of primary
AC C
intracerebral hemorrhage. Stroke. 2015; 46(3):886-892. 17 Prabhakaran S, Gupta R, Ouyang B, John S, Temes RE, Mohammad Y, et al. Acute brain infarcts after spontaneous intracerebral hemorrhage: a diffusion-weighted imaging study. Stroke. 2010; 41(1):89-94. 18 Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997; 28(1):1-5. 19 Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke. 1998; 29(6):1160-1166. 20 Fujitsu K, Muramoto M, Ikeda Y, Inada Y, Kim I, Kuwabara T. Indications for surgical treatment of putaminal hemorrhage. Comparative study based on serial CT and time-course analysis. J Neurosurg. 1990; 73(4):518-525. 21 Li Q, Zhang G, Huang YJ, Dong MX, Lv FJ, Wei X, et al. Blend Sign on Computed Tomography: Novel and Reliable Predictor for Early Hematoma Growth in Patients With Intracerebral Hemorrhage. Stroke. 2015; 46(8):2119-2123.
22 Jordan JA, Llibre JC, Vazquez F, Rodriguez R, Prince JA, Ugarte JC. Predictors of hemorrhagic complications
16 Xiao
ACCEPTED MANUSCRIPT from endovascular treatment of cerebral arteriovenous malformations. Interv Neuroradiol. 2014; 20(1):74-82.
23 Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery. 2006; 58(4):602-611; discussion 602-611.
24 Luneva OG, Brazhe NA, Fadyukova OE, Akhalaya MY, Baizhumanov AA, Parshina EY, et al. Changes in plasma membrane viscosity and hemoporphyrin conformation in erythrocyte hemoglobin under the conditions of ischemia and reperfusion of rat brain. Dokl Biochem Biophys. 2005; 405:465-467.
RI PT
25 McClain BL, Finkelstein IJ, Fayer MD. Dynamics of hemoglobin in human erythrocytes and in solution: influence of viscosity studied by ultrafast vibrational echo experiments. J Am Chem Soc. 2004; 126(48):15702-15710. 26 Herrmann A, Muller P. Correlation of the internal microviscosity of human erythrocytes to the cell volume and the viscosity of hemoglobin solutions. Biochim Biophys Acta. 1986; 885(1):80-87.
27 Ott EO, Lechner H, Aranibar A. High blood viscosity syndrome in cerebral infarction. Stroke. 1974; 5(3):330-333.
SC
28 Jan KM, Chien S, Bigger JT, Jr. Observations on blood viscosity changes after acute myocardial infarction. Circulation. 1975; 51(6):1079-1084.
29 Grotta J, Ackerman R, Correia J, Fallick G, Chang J. Whole blood viscosity parameters and cerebral blood flow. Stroke. 1982; 13(3):296-301.
M AN U
30 Li RY, Cao ZG, Li Y, Wang RT. Increased whole blood viscosity is associated with silent cerebral infarction. Clin Hemorheol Microcirc. 2015; 59(4):301-307.
31 Brito J, Siques P, Leon-Velarde F, De La Cruz JJ, Lopez V, Herruzo R. Chronic intermittent hypoxia at high altitude exposure for over 12 years: assessment of hematological, cardiovascular, and renal effects. High Alt Med Biol. 2007; 8(3):236-244.
32 Ashraf MZ. Hypertension at high altitude: the interplay between genetic and biochemical factors in the setting of oxidative stress. Hypertens Res. 2016; 39(4):199-200.
TE D
33 Norboo T, Stobdan T, Tsering N, Angchuk N, Tsering P, Ahmed I, et al. Prevalence of hypertension at high altitude: cross-sectional survey in Ladakh, Northern India 2007-2011. BMJ Open. 2015; 5(4):e007026. 34 Raina SK, Chander V, Prasher CL, Raina S. Prevalence of Hypertension in a Tribal Land Locked Population at High Altitude. Scientifica (Cairo). 2016; 2016:3589720.
35 Mingji C, Onakpoya IJ, Perera R, Ward AM, Heneghan CJ. Relationship between altitude and the prevalence
AC C
EP
of hypertension in Tibet: a systematic review. Heart. 2015; 101(13):1054-1060.
ACCEPTED MANUSCRIPT Table 1: Sociodemographic information of Tibetan and Han PHNVD patients Tibetan
Han
(n=249)
(n=2093)
P value General information 0.242 49.1(19.8)
155(62.2)
1037(49.5)
17.78±16.51
15.36±13.37
0.094
Hypertension, n (%)
135(54.2)
837(40)
<0.001
Diabetes mellitus, n (%)
30(12.0)
251(12)
0.938
Coronary artery disease, n (%)
37(14.9)
268(12.8)
0.658
Prior hemorrhagic stroke, n (%)
6(2.4)
42(2)
0.851
Current smoking, n (%)
85(34.1)
536(25.6)
<0.001
Current drinking, n (%)
78(31.3)
603(28.8)
0.452
Hyperlipidemia, n (%)
45(18.1)
203(9.7)
<0.001
Men, n (%) Admission delay in hours
158.7(14.2)
AC C
EP
Mean(SD)
TE D
Hemoglobin, g/L
SC
47.6(15.1)
M AN U
Mean(SD)
RI PT
Age, y
131.6(21.4)
<0.001
<0.001
ACCEPTED MANUSCRIPT Table 2: Number and location of aneurysms in Tibetan and Han patients Tibetan
Han
N=97
N=1071
Multiple, n (%)
14(14.4)
155(14.5)
Single
83
916
Aneurysm
P value
263(24.6)
ACOM, n (%)
18(18.6)
227(21.2)
ACA, n (%)
7(7.2)
51(4.8)
MCA, n (%)
15(15.5)
125(11.7)
PCOM, n (%)
11(11.3)
199(18.6)
BA, n (%)
4(4.1)
RPCA, n (%)
1(1)
RI PT
27(27.8)
SC
ICA, n (%)
0.889
M AN U
32(3)
19(1.8)
0.553
0.631 0.411
0.348
0.101 0.754 0.895
Multiple indicates the number of aneurysms greater than or equals to 2. Single indicates the number of aneurysms equals to 1.
ICA indicates iternal carotid artery aneurysm; ACOM indicates anterior communicating artery aneurysms; ACA
TE D
indicates anterior cerebral artery aneurysms; MCA indicates middle cerebral artery aneurysms; PCOM indicates posterior communicating artery aneurysms; BA indicates basilar artery aneurysms; RPCA indicates remaining
AC C
EP
posterior circulation arteries
ACCEPTED MANUSCRIPT Table 3: Complications and intra-hospital mortality between Tibetan and Han patients in aSAH Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=86)
(n=17) 6(35.3)
P value
P value
(n=985)
(n=80)
Infarction, n (%)
76(7.7)
36(45)
<0.001
6(7)
Rebleeding, n (%)
35(3.6)
11(13.8)
<0.001
5(5.8)
3(17.6)
<0.001
Hydrocephalus, n (%)
42(4.3)
4(5)
0.980
5(5.8)
1(5.9)
0.578
Epilepsy, n (%)
26(2.6)
2(2.5)
0.773
4(4.7)
1(5.9)
0.688
IHM, n (%)
46(4.7)
9(11.2)
0.022
7(8.1)
6(35.3)
0.007
AC C
EP
RI PT
SC
TE D
M AN U
IHM indicates intra-hospital mortality
<0.001
ACCEPTED MANUSCRIPT Table 4: Complications and intra-hospital mortality between Tibetan and Han patients in sICH Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=548)
(n=71) 42(59.2)
P value
P value
(n=278)
(n=31)
35(12.6)
19(61.3)
<0.001
39(7.1)
Rebleeding, n (%)
39(14)
11(35.5)
<0.001
43(7.8)
15(21.1)
<0.001
Hydrocephalus, n (%)
6(9.3)
4(12.9)
0.753
31(5.7)
5(7)
0.842
Epilepsy, n (%)
16(5.8)
1(3.2)
0.864
21(3.8)
4(5.6)
0.685
IHM, n (%)
42(15.1)
11(35.5)
0.009
94(17.1)
20(28.2)
0.037
AC C
EP
TE D
M AN U
IHM indicates intra-hospital mortality
<0.001
RI PT
SC
Infarction, n (%)
ACCEPTED MANUSCRIPT Table 5: Complications and intra-hospital mortality between Tibetan and Han patients in AVM Surgical Complications
Han
Conservative
Tibetan
Han
Tibetan
(n=16)
(n=7) 1(14.3)
P value
P value
(n=180)
(n=43)
3(1.7)
7(16.3)
<0.001
1(6.25)
Rebleeding, n (%)
9(5)
8(18.6)
0.006
1(6.25)
1(14.3)
0.735
Hydrocephalus, n (%)
2(1.1)
1(2.3)
0.908
1(6.25)
1(14.3)
0.735
49(27.2)
12(27.9)
0.920
4(25)
2(28.6)
0.736
6(3.3)
1(2.3)
0.884
1(6.25)
0(0)
0.664
IHM, n (%)
AC C
EP
TE D
M AN U
IHM indicates intra-hospital mortality
0.735
RI PT
Epilepsy, n (%)
SC
Infarction, n (%)
ACCEPTED MANUSCRIPT Three interesting characters of Primary hemorrhagic neurovascular diseases in Tibetans were observed, A high rate of infarction and rebleeding was found in aSAH, sICH and AVM
A high incidence of BLAs was found in aSAH.
A tendency toward brainstem hemorrhage in subtentorial was found in sICH
AC C
EP
TE D
M AN U
SC
RI PT