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Correlation between hyperhemoglobinemia and pseudosubarachnoid hemorrhage
Clinical Imaging 59 (2020) 8–12
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Pediatric Radiology
Correlation between hyperhemoglobinemia and pseudosubarachnoid hemorrhage Hongmei Lia, Abudusaimaiti Ayinuera, Jiankang Huangb, a b
T
⁎
Department of Neurology, Kashgar Prefecture Second People's Hospital, Kashgar, Xinjiang Uygur Autonomous Region, China Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Hyperhemoglobinemia Pseudo-subarachnoid hemorrhage Brain CT scan
Background and purpose: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular condition. Some cases present with typical signs of SAH on head computed tomography (CT), whereas other cases have a condition known as pseudo-SAH, with no bleeding actually present. In our clinical experience, we noted that cases of hyperhemoglobinemia often also had pseudo-SAH. Here we investigated the relationship between hyperhemoglobinemia and pseudo-SAH and explored the underlying mechanism. Methods: We retrospectively collected data for patients who were treated for hyperhemoglobinemia in our hospital and had available brain CT scans. An age-matched control group of patients with normal hemoglobin levels was used to compare the incidence of pseudo-SAH between individuals with elevated versus normal hemoglobin levels. Spearman correlation and logistic regression analyses were performed to identify correlations between pseudo-SAH and hemoglobin level as well as gender, history of chronic obstructive pulmonary disease, and smoking history. Results: The incidence of pseudo-SAH was significantly higher in hyperhemoglobinemia group than in the control group (12.5% vs. 1.6%, respectively, P < 0.001), and within the hyperhemoglobinemia group, it was significantly higher among those with a hemoglobin value ≥210 g/L than among those with a hemoglobin value < 210 g/L (29.2% vs. 8.8%, respectively, P < 0.001). Spearman correlation analysis and logistic regression analysis showed a significant correlation between pseudo-SAH and hyperhemoglobinemia but no significant correlation between pseudo-SAH and gender, COPD, or smoking history. Conclusion: Hyperhemoglobinemia may be a contributing factor to pseudo-SAH. Clinicians should be aware of this phenomenon and be careful to distinguish pseudo-SAH from SAH, particularly in patients with hyperhemoglobinemia.
1. Introduction Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that requires immediate treatment. Thus, accurate diagnosis of SAH is critical. Head computed tomography (CT) imaging is the first choice for diagnosis of SAH, offering a sensitivity as high as 95–98% for the detection SAH within 24 h of onset [1]. On head CT, SAH is generally characterized by high-density signals in the subarachnoid space. Of course, in clinical practice, special cases are also encountered. For example, head CT can show the characteristic signal of SAH but in the absence of bleeding. Spiegel et al. reported this phenomenon in 1986 [2], and later in 1998, Avrahami et al. defined this condition as pseudo-subarachnoid hemorrhage (pseudo-SAH) [3]. The incidence of pseudo-SAH is low in the clinical setting. Clinical
⁎
findings associated with pseudo-SAH are more commonly representative of hypoxic encephalopathy, intracranial infection, cardiopulmonary resuscitation, large-area cerebral infarction, etc. [4] (Table 1). Among cases of true SAH, the bleeding is distributed along the falx cerebri, the interhemispheric fissure or the medial frontal lobe. Thus, the high-density foci are intermittent and irregular, whereas the high-density foci of pseudo-SAH form a relatively uniform line indicating pooling in the basal cisterns. Also, in pseudo-SAH, there is no thick blood clot in the cerebral sulcus and no hematoma in the brain parenchyma. Pseudo-SAH patients do not have the typical manifestations associated with SAH, such as headache and meningeal irritation, and do not meet the performance criteria for diagnosis of SAH. Because blood and cerebrospinal fluid have unique appearances in different sequences of magnetic resonance imaging (MRI), the use of MRI
Corresponding author. E-mail address: [email protected] (J. Huang).
https://doi.org/10.1016/j.clinimag.2019.09.002 Received 20 November 2018; Received in revised form 6 August 2019; Accepted 3 September 2019 0899-7071/ © 2019 Elsevier Inc. All rights reserved.
Clinical Imaging 59 (2020) 8–12
H. Li, et al.
Table 1 Conditions with pseudo-SAH signs described in the literature. Conditions
Possible mechanism
Cardiac arrest Respiratory arrest Venous sinus thrombosis Anoxic–ischemic encephalopathy Meningitis
Loss of gray-white differentiation, narrowing and effacement of the subarachnoid spaces, and corresponding engorgement of superficial pial veins
Intracranial hypotension Cerebellar infarctions Bilateral subdural hematomas Iatrogenic causes
The presence of white blood cells, increased protein in the CSF surrounding the inflamed pial surface, and a subjacent cortex with edematous deeper cortical layers all contribute to production of the superficial brain hyperdensity Brain sagging may compress the basal cistern and the Sylvian fissures, and then subsequently compromise the CSF circulation then results in brain edema Secondary increased intracranial pressure from obstructive hydrocephalus Increased volume in the supratentorial compartment produces compression and effacement of the subarachnoid spaces, combined with the ensuing vascular congestion Intrathecal administration of contrast material or leakage of high-dose of intravenous contrast medium within the sub-arachnoid spaces
examination is helpful for distinguishing SAH and pseudo-SAH. It has been reported in the literature that application of the FLAIR sequence is more conducive to the diagnosis of pseudo-SAH [5], while the detection of blood in cerebrospinal fluid by lumbar puncture helps to identify SAH. We have treated several patients in our clinic who were referred to us by other hospitals as cases of SAH based on CT scanning and manifesting as sudden dizziness and headache. However, after lumbar puncture and re-examination of the head CT in our clinic, the diagnosis of SAH was excluded. We noted that all of these patients had hyperhemoglobinemia, and thus, questioned whether hyperhemoglobinemia can lead to pseudo-SAH signs. We searched for relevant studies in both the Chinese and English literature and found that a report of a single case by Sun et al. [6]. Their patient had hyperhemoglobinemia secondary to tetralogy of Fallot. Another patient reported by Yin et al. also had hyperhemoglobinemia secondary to congenital heart disease [7]. No case series or study on the relationship between hyperhemoglobinemia and pseudo-SAH was found though. Therefore, we recruited patients who were admitted to our hospital with hyperhemoglobinemia and underwent head CT examination. The clinical characteristics and imaging features of these cases were statistically analyzed and compared with those of patients with normal hemoglobin levels to analyze the correlation between hyperhemoglobinemia and pseudo-SAH.
contrast head CT scans. We ruled out true SAH based on each patient's medical history and signs on imaging. The exclusion was based not only on the results of CT scanning but also MRI findings. Each patient's medical history was used only for reference and not as the only evidence for exclusion. Lumbar puncture was performed to provide additional evidence, if the patients could not undergo MRI. If any bleeding was found in the images or CSF, the patient was considered to have true SAH.
2. Materials and methods
A total of 128 patients with hyperhemoglobinemia were screened, including 110 men (85.9%) with an average age of 59.2 ± 14.1 years and 18 women with an average age of 57.1 ± 14.0 years. One hundred twenty-eight patients were enrolled in the control group, including 103 men (80.5%) with an average age of 56.2 ± 13.6 years and 25 women with an average age of 56.3 ± 12.7 years. There were no significant differences in age and gender between the two groups. The occurrence of chronic obstructive pulmonary disease (COPD) was significantly higher in the high hemoglobin group (93.7%) than in the control group (10.6%), and the percentage of smokers was significantly higher in the high hemoglobin group (74.2%) than in the control group (24.2%; Table 2).
2.3. Statistical analysis Statistical analysis was performed using SPSS software (version 20; SPSS, Inc., Chicago, IL, USA). Measurement data are expressed as mean ± standard deviation (SD). The positive rates were compared between groups by chi-square test. The differences were considered significant if the P value was < 0.05. Correlations of classification data were analyzed based on Spearman correlation. The associations between classification data and related factors were analyzed by multivariate logistic regression analyses. An association was considered significant if P < 0.05. 3. Results 3.1. Basic and clinical characteristics of the patients
2.1. Study population We screened the electronic medical records system of our hospital for middle-aged and elderly patients who were treated for hyperhemoglobinemia between January 1, 2015 and June 31, 2016 in the Departments of Respiratory, Hypertension, Neurology, etc. with concurrent head CT examination. Hemoglobin ranges of 130–175 g/L and 115–150 g/L were considered normal for males and females, respectively. Patients were included if they were over 45 years old and had a hemoglobin level > 190 g/L. The control group included age- and gender-matched patients with normal hemoglobin levels who also underwent head CT scanning in our hospital during the same period and did not have SAH, brain trauma, cerebral infarction, or hypoxic encephalopathy.
3.2. Incidence of pseudo-SAH in patients with hyperhemoglobinemia Of the 128 patients enrolled in the hyperhemoglobinemia group, 16 patients had positive CT findings for pseudo-SAH, whereas only 2 patients of the 128 patients in the control group showed pseudo-SAH. Thus, the incidence of pseudo-SAH differed significantly between the groups (12.5% vs. 1.6% for the hyperhemoglobinemia vs. control groups, respectively, P < 0.001). We next divided the hyperhemoglobinemia group into two groups according to a hemoglobin cutoff of 210 g/L and observed that the incidence of pseudo-SAH was significantly higher among patients with a hemoglobin level > 210 g/L (7/24, 29.2%) than among patients with a hemoglobin level ≤ 210 g/L
2.2. Data collection The demographic characteristics, underlying diseases, main disease, routine blood test results, blood biochemistry results, and head CT images were extracted from the electronic medical records for all included patients. The images were reviewed by two experienced neurologists (Fig. 1). The chief radiologist of our department made the final assessment in case of disagreement. The images reviewed were non9
Clinical Imaging 59 (2020) 8–12
H. Li, et al.
Fig. 1. Head CT findings in a case of pseudo-SAH. In a 65-year-old male, plain CT scan showed increased signal intensity in the longitudinal fissure cistern, basal cistern and tentorium cerebellum.
Table 2 Comparison of basic and clinical characteristics of patients in the high and normal hemoglobin groups.
Gender (male), n (%) Age, years High blood pressure, n (%) Diabetes, n (%) COPD, n (%) Smoking history (> 20/day), n (%) Drinking history (> 80 g/day), n (%)
Hyperhemoglobinemia group (n = 128)
Normal control group (n = 128)
P value
110 (85.9) 58.9 ± 13.6 43 (33.5) 36 (28.1) 120 (93.7) 95 (74.2) 30 (23.4)
103 (80.5) 56.8 ± 12.7 46 (35.9) 33 (25.7) 14 (10.9) 31 (24.2) 33 (25.7)
0.316 0.423 0.793 0.778 0.000 0.000 0.772
10
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tissue. Given et al. reviewed the CT scans of 7 patients with diffuse cerebral edema and basal cell signals, and the absence of SAH was confirmed by lumbar puncture or autopsy [9]. Pseudo-SAH was reported to be caused by chronic hypoxemia in one study [10]. The most common cause of pseudo-SAH is hypoxic brain damage caused by cardiac arrest, and diffuse edema of the brain causes blurring of the gray matter boundaries. Increased intracranial pressure leads to hyperemia of the supratentorial venous system. Because of the cerebral edema and increased intracranial pressure, the cerebrospinal fluid in the subarachnoid space is reduced, the brain parenchymal attenuation is decreased due to edema, and the venous system is congested, leading to signs of pseudo-SAH. The relative difference in attenuation values of vessels as compared to adjacent parenchyma is an important factor. Additional studies have suggested that exudation of inflammatory substances such as proteins caused by inflammation of the brain may increase the density within the basal and subarachnoid spaces [9]. In our study, the incidence of pseudo-SAH was found to be lower in patients with hemoglobin values < 190 g/L. Therefore, we screened patients with a hemoglobin concentration of 190 g/L or more. Among the cases included in the present study, 16 patients were found to have pseudo-SAH, for an incidence of 12.5% among cases of hyperhemoglobinemia. Our study demonstrated that patients with hyperhemoglobinemia tend to have higher occurrence of COPD and smoking history compared with individuals with normal hemoglobin levels. In the present study, correlation analysis showed that pseudo-SAH was highly associated with hyperhemoglobinemia. Notably, this study was performed on patients with pseudo-SAH. Multiple regression analysis showed that there were no statistically significant associations between pseudo-SAH and COPD or smoking history, only a significant association with hyperhemoglobinemia. These results suggest that COPD and smoking are important causes of a secondary hemoglobin increase, but they have no direct correlation with pseudo-SAH. We also grouped patients with hyperhemoglobinemia based on a hemoglobin cut-off of 210 g/L and found that the incidence of pseudoSAH was significantly higher (~4 times higher) among those with a hemoglobin value > 210 g/L than in those with a hemoglobin level below the cut-off, suggesting that the development of this condition occurs is influenced by the hemoglobin concentration. Different from previous case reports, the mechanism of pseudo-SAH in patients with hyperhemoglobinemia is considered to be associated with increased red blood cell counts and hemoglobin in the blood and is characterized by a high signal in the subarachnoid space and increased blood viscosity on head CT. It was reported that secondary polycythemia may be associated with mimic intravascular enhancement and pseudo-subarachnoid hemorrhage [11]. Conversely, when the hemoglobin concentration is normal, pseudoSAH does not develop due to blood flow and volume effects and the surrounding gap phenomenon. Notably, the blood density on CT is positively correlated with hemoglobin concentration, and at a hemoglobin concentration of 242 ± 23 g/L or greater, CT shows similar cerebral vascular enhancement after contrast agent injection [12]. In the present study, the proportion of male patients relative to female patients (ratio, 6.1:1) was quite high in the hyperhemoglobinemia group. Another clinical retrospective study of 1886
Fig. 2. Incidence of pseudo-SAH among subgroups of hyperhemoglobinemia patients based on hemoglobin level ≤210 or > 210 g/L. HGBE: hyperhemoglobinemia.
(9/104, 8.8%; P < 0.001; Fig. 2). These results suggest that the incidence of pseudo-SAH increased with increasing hemoglobin level. 3.3. Correlation between hyperhemoglobinemia and pseudo-SAH We performed a Spearman correlation analysis to investigate the potential association of elevated hemoglobin values and signs of pseudo-SAH on head CT in all patients. The results identified a significant correlation between the hemoglobin level and pseudo-SAH (P < 0.001, Table 3). With pseudo-SAH as the dependent variable and hemoglobin value, smoking history, history of COPD, and gender as independent variables, logistic regression analysis showed a regressive relationship between pseudo-SAH and hemoglobin value (P = 0.005, odds ratio [OR] = 1.049, 95% confidence interval [CI]: 1.014–1.085), but no correlation of pseudo-SAH with smoking, COPD history, or gender (Table 4). 4. Discussion SAH is a serious neurological condition, and accurate, timely diagnosis is critical for successful treatment. However, when patients are misdiagnosed as having SAH when they in fact do not, they and their families suffer an unnecessarily increased mental and emotional burden as well as unnecessary medical expenses. Lumbar puncture or angiograms have their own complications. In addition, misdiagnosis can also delay the delivery of appropriate treatments. For example, among the patients with pseudo-SAH in our study, one patient presented with sudden vertigo to the local hospital, and head CT scanning indicated SAH. The patient was then transferred to our hospital, and after careful examination, a diagnosis of benign positional vertigo was determined. After treatment by manual reduction, the patient's symptoms were obviously relieved, and SAH was excluded based on the observation of normal cerebrospinal fluid after lumbar puncture. Yuzawa et al. reported in 2008 that the incidence of pseudo-SAH in patients with encephalopathy after resuscitation can be as high as 20% [8]. Some researchers believe that the development of pseudo-SAH is related to basal venous congestion and the decreased signal of adjacent brain
Table 3 Correlation analysis results for the association between hemoglobin value and pseudo-SAH.
Spearman's rho
Hemoglobin value
Pseudo-SAH
⁎⁎
Correlation coefficient Significant (two-tailed) N Correlation coefficient Significant (two-tailed) N
Correlation is significant at P < 0.01 (two-tailed). 11
Hemoglobin value
Pseudo-SAH
1.000 . 189 0.268⁎⁎ 0.000 189
0.268⁎⁎ 0.000 189 1.000 . 189
Clinical Imaging 59 (2020) 8–12
H. Li, et al.
Table 4 Logistic regression results for the associations of clinical factors with pseudo-SAH. B
a
Step 1
a
Hemoglobin Smoking COPD Gender Constant
0.048 0.744 −0.249 0.959 −12.822
S.E.
0.017 0.732 0.965 1.082 3.993
Wald
df
7.728 1.032 0.066 0.786 10.312
1 1 1 1 1
Sig
0.005 0.310 0.797 0.375 0.001
Exp (B)
1.049 2.104 0.780 2.609 0.000
95% CI of exp (B) Lower
Upper
1.014 0.501 0.118 0.313
1.085 8.840 5.172 21.744
Variables entered in step 1: hemoglobin, smoking, COPD, gender.
committee of Kashgar Prefecture Second People's Hospital, Kashgar, Xinjiang Uygur Autonomous Region, China.
hyperhemoglobinemia patients published by Ling et al. reported an even higher male to female ratio of 13:1 [13]. This gender disparity may be explained by considering that the frequency of smoking is significantly higher among men than women and smoking is an important factor for the development of COPD. However, we did not find a significant correlation between pseudo-SAH and smoking or COPD in our study. Thus, the mechanism responsible for the gender disparity in pseudo-SAH requires further study. The results of the present study indicate that hyperhemoglobinemia may cause pseudo-SAH, and that with a higher hemoglobin value, the incidence of pseudo-SAH also increases. At the same time, the incidence of pseudo-SAH among patients with hyperhemoglobinemia have certain implications for clinical work. Limitations of the present study include the small number of cases enrolled, and thus, studies in a larger sample size are needed. Also, the hyperhemoglobinemia patients in the present all had secondary hyperhemoglobinemia, and the incidence of primary hyperhemoglobinemia was low. Further clinical studies are needed to determine the potential effect of this factor. Lastly, the inclusion of only middle aged and elderly patients is another limitation of our study. This was because the incidence of secondary hyperHb is quite low in young patients, and CT scans were rarely available for patients with hyperHb < 45 years old. We will try to enroll younger patients in our future research. Due to the increased density of the cerebrovascular and venous sinus, pseudo-SAH caused by hyperhemoglobinemia is distributed according to the vascular anatomy, and the patient has no clinical symptoms or signs of SAH. When encountering this phenomenon, clinicians should review the patient's medical history and clinical symptoms and signs, and if necessary, perform a lumbar puncture to make a correct diagnosis and avoid unnecessary examinations and even application of inappropriate treatments.
Data availability statement The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request. Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Acknowledgements None. References [1] Latchaw RE, Silva P, Falcone SF. The role of CT following aneurysmal rupture. Neuroimaging Clin N Am 1997;7(4):693–708. [2] Spiegel SM, Fox AJ, Vinuela F, Pelz DM. Increased density of tentorium and falx: a false positive CT sign of subarachnoid hemorrhage. Can Assoc Radiol J 1986;37(4):243–7. [3] Avrahami E, Katz R, Rabin A, Friedman V. CT diagnosis of non-traumatic subarachnoid haemorrhage in patients with brain edema. Eur J Radiol 1998;28(3):222–5. [4] You JS, Park S, Park YS, Chung SP. Pseudo-subarachnoid hemorrhage. Am J Emerg Med 2008;26(4):1–2. [5] Ho AL, Sussman ES, Pendharkar AV, Iv M, Hirsch KG, Fischbein NJ, et al. Practical pearl: use of MRI to differentiate pseudo-subarachnoid hemorrhage from true subarachnoid hemorrhage. Neurocrit Care 2018:1–6. [6] Sun Xianyong SWXY. A case report of CT findings of hyperhemoglobinemia in brain. Chin J Med Imag 2014;22:320. [7] Yin Weiwei XHCW. A case of CT findings of high hemoglobinemia with CT enhancement. Chin J Radiol 2008;42:1265. [8] Yuzawa H, Higano S, Mugikura S, Umetsu A, Murata T, Nakagawa A, et al. Pseudosubarachnoid hemorrhage found in patients with postresuscitation encephalopathy: characteristics of CT findings and clinical importance. AJNR Am J Neuroradiol 2008;29(8):1544–9. [9] CA G, Burdette J, Elster A. Pseudo-subarachnoid hemorrhage: a potential imaging pitfall associated with diffuse cerebral edema. AJNR Am J Neuroradiol 2003;24(2):254–6. [10] Patzig M, Laub C, Janssen H, Ertl L, Fesl G. Pseudo-subarachnoid haemorrhage due to chronic hypoxaemia: case report and review of the literature. BMC Neurol 2014;14(1):1–5. [11] Javedan SP, Marciano F. Pseudo-enhancement from polycythemia. Neurology 2004;62(1):150. [12] Liu Hui ZXJ. CT findings and mechanism analysis of intracranial vascular density in patients with cyanotic congenital heart disease. Chin J Radiol 2012;46:300–3. [13] Z L. Clinical review of 1886 patients with hyperhemoglobinemia. J Chin Med 2013;32:142–3.
5. Conclusion Hyperhemoglobinemia may be a contributing factor to the development of pseudo-SAH, as a significant correlation was found between the incidences of these conditions. Clinicians should be aware of this phenomenon and seek to accurately identify pseudo-SAH in order to avoid unnecessary examinations (such as cerebral angiography) and the time required to perform the examinations and wait for the results, which may delay application of the best treatment. Ethical approval Ethical approval of the study was given by the medical ethics
12
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Pediatric Radiology
Correlation between hyperhemoglobinemia and pseudosubarachnoid hemorrhage Hongmei Lia, Abudusaimaiti Ayinuera, Jiankang Huangb, a b
T
⁎
Department of Neurology, Kashgar Prefecture Second People's Hospital, Kashgar, Xinjiang Uygur Autonomous Region, China Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Hyperhemoglobinemia Pseudo-subarachnoid hemorrhage Brain CT scan
Background and purpose: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular condition. Some cases present with typical signs of SAH on head computed tomography (CT), whereas other cases have a condition known as pseudo-SAH, with no bleeding actually present. In our clinical experience, we noted that cases of hyperhemoglobinemia often also had pseudo-SAH. Here we investigated the relationship between hyperhemoglobinemia and pseudo-SAH and explored the underlying mechanism. Methods: We retrospectively collected data for patients who were treated for hyperhemoglobinemia in our hospital and had available brain CT scans. An age-matched control group of patients with normal hemoglobin levels was used to compare the incidence of pseudo-SAH between individuals with elevated versus normal hemoglobin levels. Spearman correlation and logistic regression analyses were performed to identify correlations between pseudo-SAH and hemoglobin level as well as gender, history of chronic obstructive pulmonary disease, and smoking history. Results: The incidence of pseudo-SAH was significantly higher in hyperhemoglobinemia group than in the control group (12.5% vs. 1.6%, respectively, P < 0.001), and within the hyperhemoglobinemia group, it was significantly higher among those with a hemoglobin value ≥210 g/L than among those with a hemoglobin value < 210 g/L (29.2% vs. 8.8%, respectively, P < 0.001). Spearman correlation analysis and logistic regression analysis showed a significant correlation between pseudo-SAH and hyperhemoglobinemia but no significant correlation between pseudo-SAH and gender, COPD, or smoking history. Conclusion: Hyperhemoglobinemia may be a contributing factor to pseudo-SAH. Clinicians should be aware of this phenomenon and be careful to distinguish pseudo-SAH from SAH, particularly in patients with hyperhemoglobinemia.
1. Introduction Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that requires immediate treatment. Thus, accurate diagnosis of SAH is critical. Head computed tomography (CT) imaging is the first choice for diagnosis of SAH, offering a sensitivity as high as 95–98% for the detection SAH within 24 h of onset [1]. On head CT, SAH is generally characterized by high-density signals in the subarachnoid space. Of course, in clinical practice, special cases are also encountered. For example, head CT can show the characteristic signal of SAH but in the absence of bleeding. Spiegel et al. reported this phenomenon in 1986 [2], and later in 1998, Avrahami et al. defined this condition as pseudo-subarachnoid hemorrhage (pseudo-SAH) [3]. The incidence of pseudo-SAH is low in the clinical setting. Clinical
⁎
findings associated with pseudo-SAH are more commonly representative of hypoxic encephalopathy, intracranial infection, cardiopulmonary resuscitation, large-area cerebral infarction, etc. [4] (Table 1). Among cases of true SAH, the bleeding is distributed along the falx cerebri, the interhemispheric fissure or the medial frontal lobe. Thus, the high-density foci are intermittent and irregular, whereas the high-density foci of pseudo-SAH form a relatively uniform line indicating pooling in the basal cisterns. Also, in pseudo-SAH, there is no thick blood clot in the cerebral sulcus and no hematoma in the brain parenchyma. Pseudo-SAH patients do not have the typical manifestations associated with SAH, such as headache and meningeal irritation, and do not meet the performance criteria for diagnosis of SAH. Because blood and cerebrospinal fluid have unique appearances in different sequences of magnetic resonance imaging (MRI), the use of MRI
Corresponding author. E-mail address: [email protected] (J. Huang).
https://doi.org/10.1016/j.clinimag.2019.09.002 Received 20 November 2018; Received in revised form 6 August 2019; Accepted 3 September 2019 0899-7071/ © 2019 Elsevier Inc. All rights reserved.
Clinical Imaging 59 (2020) 8–12
H. Li, et al.
Table 1 Conditions with pseudo-SAH signs described in the literature. Conditions
Possible mechanism
Cardiac arrest Respiratory arrest Venous sinus thrombosis Anoxic–ischemic encephalopathy Meningitis
Loss of gray-white differentiation, narrowing and effacement of the subarachnoid spaces, and corresponding engorgement of superficial pial veins
Intracranial hypotension Cerebellar infarctions Bilateral subdural hematomas Iatrogenic causes
The presence of white blood cells, increased protein in the CSF surrounding the inflamed pial surface, and a subjacent cortex with edematous deeper cortical layers all contribute to production of the superficial brain hyperdensity Brain sagging may compress the basal cistern and the Sylvian fissures, and then subsequently compromise the CSF circulation then results in brain edema Secondary increased intracranial pressure from obstructive hydrocephalus Increased volume in the supratentorial compartment produces compression and effacement of the subarachnoid spaces, combined with the ensuing vascular congestion Intrathecal administration of contrast material or leakage of high-dose of intravenous contrast medium within the sub-arachnoid spaces
examination is helpful for distinguishing SAH and pseudo-SAH. It has been reported in the literature that application of the FLAIR sequence is more conducive to the diagnosis of pseudo-SAH [5], while the detection of blood in cerebrospinal fluid by lumbar puncture helps to identify SAH. We have treated several patients in our clinic who were referred to us by other hospitals as cases of SAH based on CT scanning and manifesting as sudden dizziness and headache. However, after lumbar puncture and re-examination of the head CT in our clinic, the diagnosis of SAH was excluded. We noted that all of these patients had hyperhemoglobinemia, and thus, questioned whether hyperhemoglobinemia can lead to pseudo-SAH signs. We searched for relevant studies in both the Chinese and English literature and found that a report of a single case by Sun et al. [6]. Their patient had hyperhemoglobinemia secondary to tetralogy of Fallot. Another patient reported by Yin et al. also had hyperhemoglobinemia secondary to congenital heart disease [7]. No case series or study on the relationship between hyperhemoglobinemia and pseudo-SAH was found though. Therefore, we recruited patients who were admitted to our hospital with hyperhemoglobinemia and underwent head CT examination. The clinical characteristics and imaging features of these cases were statistically analyzed and compared with those of patients with normal hemoglobin levels to analyze the correlation between hyperhemoglobinemia and pseudo-SAH.
contrast head CT scans. We ruled out true SAH based on each patient's medical history and signs on imaging. The exclusion was based not only on the results of CT scanning but also MRI findings. Each patient's medical history was used only for reference and not as the only evidence for exclusion. Lumbar puncture was performed to provide additional evidence, if the patients could not undergo MRI. If any bleeding was found in the images or CSF, the patient was considered to have true SAH.
2. Materials and methods
A total of 128 patients with hyperhemoglobinemia were screened, including 110 men (85.9%) with an average age of 59.2 ± 14.1 years and 18 women with an average age of 57.1 ± 14.0 years. One hundred twenty-eight patients were enrolled in the control group, including 103 men (80.5%) with an average age of 56.2 ± 13.6 years and 25 women with an average age of 56.3 ± 12.7 years. There were no significant differences in age and gender between the two groups. The occurrence of chronic obstructive pulmonary disease (COPD) was significantly higher in the high hemoglobin group (93.7%) than in the control group (10.6%), and the percentage of smokers was significantly higher in the high hemoglobin group (74.2%) than in the control group (24.2%; Table 2).
2.3. Statistical analysis Statistical analysis was performed using SPSS software (version 20; SPSS, Inc., Chicago, IL, USA). Measurement data are expressed as mean ± standard deviation (SD). The positive rates were compared between groups by chi-square test. The differences were considered significant if the P value was < 0.05. Correlations of classification data were analyzed based on Spearman correlation. The associations between classification data and related factors were analyzed by multivariate logistic regression analyses. An association was considered significant if P < 0.05. 3. Results 3.1. Basic and clinical characteristics of the patients
2.1. Study population We screened the electronic medical records system of our hospital for middle-aged and elderly patients who were treated for hyperhemoglobinemia between January 1, 2015 and June 31, 2016 in the Departments of Respiratory, Hypertension, Neurology, etc. with concurrent head CT examination. Hemoglobin ranges of 130–175 g/L and 115–150 g/L were considered normal for males and females, respectively. Patients were included if they were over 45 years old and had a hemoglobin level > 190 g/L. The control group included age- and gender-matched patients with normal hemoglobin levels who also underwent head CT scanning in our hospital during the same period and did not have SAH, brain trauma, cerebral infarction, or hypoxic encephalopathy.
3.2. Incidence of pseudo-SAH in patients with hyperhemoglobinemia Of the 128 patients enrolled in the hyperhemoglobinemia group, 16 patients had positive CT findings for pseudo-SAH, whereas only 2 patients of the 128 patients in the control group showed pseudo-SAH. Thus, the incidence of pseudo-SAH differed significantly between the groups (12.5% vs. 1.6% for the hyperhemoglobinemia vs. control groups, respectively, P < 0.001). We next divided the hyperhemoglobinemia group into two groups according to a hemoglobin cutoff of 210 g/L and observed that the incidence of pseudo-SAH was significantly higher among patients with a hemoglobin level > 210 g/L (7/24, 29.2%) than among patients with a hemoglobin level ≤ 210 g/L
2.2. Data collection The demographic characteristics, underlying diseases, main disease, routine blood test results, blood biochemistry results, and head CT images were extracted from the electronic medical records for all included patients. The images were reviewed by two experienced neurologists (Fig. 1). The chief radiologist of our department made the final assessment in case of disagreement. The images reviewed were non9
Clinical Imaging 59 (2020) 8–12
H. Li, et al.
Fig. 1. Head CT findings in a case of pseudo-SAH. In a 65-year-old male, plain CT scan showed increased signal intensity in the longitudinal fissure cistern, basal cistern and tentorium cerebellum.
Table 2 Comparison of basic and clinical characteristics of patients in the high and normal hemoglobin groups.
Gender (male), n (%) Age, years High blood pressure, n (%) Diabetes, n (%) COPD, n (%) Smoking history (> 20/day), n (%) Drinking history (> 80 g/day), n (%)
Hyperhemoglobinemia group (n = 128)
Normal control group (n = 128)
P value
110 (85.9) 58.9 ± 13.6 43 (33.5) 36 (28.1) 120 (93.7) 95 (74.2) 30 (23.4)
103 (80.5) 56.8 ± 12.7 46 (35.9) 33 (25.7) 14 (10.9) 31 (24.2) 33 (25.7)
0.316 0.423 0.793 0.778 0.000 0.000 0.772
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tissue. Given et al. reviewed the CT scans of 7 patients with diffuse cerebral edema and basal cell signals, and the absence of SAH was confirmed by lumbar puncture or autopsy [9]. Pseudo-SAH was reported to be caused by chronic hypoxemia in one study [10]. The most common cause of pseudo-SAH is hypoxic brain damage caused by cardiac arrest, and diffuse edema of the brain causes blurring of the gray matter boundaries. Increased intracranial pressure leads to hyperemia of the supratentorial venous system. Because of the cerebral edema and increased intracranial pressure, the cerebrospinal fluid in the subarachnoid space is reduced, the brain parenchymal attenuation is decreased due to edema, and the venous system is congested, leading to signs of pseudo-SAH. The relative difference in attenuation values of vessels as compared to adjacent parenchyma is an important factor. Additional studies have suggested that exudation of inflammatory substances such as proteins caused by inflammation of the brain may increase the density within the basal and subarachnoid spaces [9]. In our study, the incidence of pseudo-SAH was found to be lower in patients with hemoglobin values < 190 g/L. Therefore, we screened patients with a hemoglobin concentration of 190 g/L or more. Among the cases included in the present study, 16 patients were found to have pseudo-SAH, for an incidence of 12.5% among cases of hyperhemoglobinemia. Our study demonstrated that patients with hyperhemoglobinemia tend to have higher occurrence of COPD and smoking history compared with individuals with normal hemoglobin levels. In the present study, correlation analysis showed that pseudo-SAH was highly associated with hyperhemoglobinemia. Notably, this study was performed on patients with pseudo-SAH. Multiple regression analysis showed that there were no statistically significant associations between pseudo-SAH and COPD or smoking history, only a significant association with hyperhemoglobinemia. These results suggest that COPD and smoking are important causes of a secondary hemoglobin increase, but they have no direct correlation with pseudo-SAH. We also grouped patients with hyperhemoglobinemia based on a hemoglobin cut-off of 210 g/L and found that the incidence of pseudoSAH was significantly higher (~4 times higher) among those with a hemoglobin value > 210 g/L than in those with a hemoglobin level below the cut-off, suggesting that the development of this condition occurs is influenced by the hemoglobin concentration. Different from previous case reports, the mechanism of pseudo-SAH in patients with hyperhemoglobinemia is considered to be associated with increased red blood cell counts and hemoglobin in the blood and is characterized by a high signal in the subarachnoid space and increased blood viscosity on head CT. It was reported that secondary polycythemia may be associated with mimic intravascular enhancement and pseudo-subarachnoid hemorrhage [11]. Conversely, when the hemoglobin concentration is normal, pseudoSAH does not develop due to blood flow and volume effects and the surrounding gap phenomenon. Notably, the blood density on CT is positively correlated with hemoglobin concentration, and at a hemoglobin concentration of 242 ± 23 g/L or greater, CT shows similar cerebral vascular enhancement after contrast agent injection [12]. In the present study, the proportion of male patients relative to female patients (ratio, 6.1:1) was quite high in the hyperhemoglobinemia group. Another clinical retrospective study of 1886
Fig. 2. Incidence of pseudo-SAH among subgroups of hyperhemoglobinemia patients based on hemoglobin level ≤210 or > 210 g/L. HGBE: hyperhemoglobinemia.
(9/104, 8.8%; P < 0.001; Fig. 2). These results suggest that the incidence of pseudo-SAH increased with increasing hemoglobin level. 3.3. Correlation between hyperhemoglobinemia and pseudo-SAH We performed a Spearman correlation analysis to investigate the potential association of elevated hemoglobin values and signs of pseudo-SAH on head CT in all patients. The results identified a significant correlation between the hemoglobin level and pseudo-SAH (P < 0.001, Table 3). With pseudo-SAH as the dependent variable and hemoglobin value, smoking history, history of COPD, and gender as independent variables, logistic regression analysis showed a regressive relationship between pseudo-SAH and hemoglobin value (P = 0.005, odds ratio [OR] = 1.049, 95% confidence interval [CI]: 1.014–1.085), but no correlation of pseudo-SAH with smoking, COPD history, or gender (Table 4). 4. Discussion SAH is a serious neurological condition, and accurate, timely diagnosis is critical for successful treatment. However, when patients are misdiagnosed as having SAH when they in fact do not, they and their families suffer an unnecessarily increased mental and emotional burden as well as unnecessary medical expenses. Lumbar puncture or angiograms have their own complications. In addition, misdiagnosis can also delay the delivery of appropriate treatments. For example, among the patients with pseudo-SAH in our study, one patient presented with sudden vertigo to the local hospital, and head CT scanning indicated SAH. The patient was then transferred to our hospital, and after careful examination, a diagnosis of benign positional vertigo was determined. After treatment by manual reduction, the patient's symptoms were obviously relieved, and SAH was excluded based on the observation of normal cerebrospinal fluid after lumbar puncture. Yuzawa et al. reported in 2008 that the incidence of pseudo-SAH in patients with encephalopathy after resuscitation can be as high as 20% [8]. Some researchers believe that the development of pseudo-SAH is related to basal venous congestion and the decreased signal of adjacent brain
Table 3 Correlation analysis results for the association between hemoglobin value and pseudo-SAH.
Spearman's rho
Hemoglobin value
Pseudo-SAH
⁎⁎
Correlation coefficient Significant (two-tailed) N Correlation coefficient Significant (two-tailed) N
Correlation is significant at P < 0.01 (two-tailed). 11
Hemoglobin value
Pseudo-SAH
1.000 . 189 0.268⁎⁎ 0.000 189
0.268⁎⁎ 0.000 189 1.000 . 189
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Table 4 Logistic regression results for the associations of clinical factors with pseudo-SAH. B
a
Step 1
a
Hemoglobin Smoking COPD Gender Constant
0.048 0.744 −0.249 0.959 −12.822
S.E.
0.017 0.732 0.965 1.082 3.993
Wald
df
7.728 1.032 0.066 0.786 10.312
1 1 1 1 1
Sig
0.005 0.310 0.797 0.375 0.001
Exp (B)
1.049 2.104 0.780 2.609 0.000
95% CI of exp (B) Lower
Upper
1.014 0.501 0.118 0.313
1.085 8.840 5.172 21.744
Variables entered in step 1: hemoglobin, smoking, COPD, gender.
committee of Kashgar Prefecture Second People's Hospital, Kashgar, Xinjiang Uygur Autonomous Region, China.
hyperhemoglobinemia patients published by Ling et al. reported an even higher male to female ratio of 13:1 [13]. This gender disparity may be explained by considering that the frequency of smoking is significantly higher among men than women and smoking is an important factor for the development of COPD. However, we did not find a significant correlation between pseudo-SAH and smoking or COPD in our study. Thus, the mechanism responsible for the gender disparity in pseudo-SAH requires further study. The results of the present study indicate that hyperhemoglobinemia may cause pseudo-SAH, and that with a higher hemoglobin value, the incidence of pseudo-SAH also increases. At the same time, the incidence of pseudo-SAH among patients with hyperhemoglobinemia have certain implications for clinical work. Limitations of the present study include the small number of cases enrolled, and thus, studies in a larger sample size are needed. Also, the hyperhemoglobinemia patients in the present all had secondary hyperhemoglobinemia, and the incidence of primary hyperhemoglobinemia was low. Further clinical studies are needed to determine the potential effect of this factor. Lastly, the inclusion of only middle aged and elderly patients is another limitation of our study. This was because the incidence of secondary hyperHb is quite low in young patients, and CT scans were rarely available for patients with hyperHb < 45 years old. We will try to enroll younger patients in our future research. Due to the increased density of the cerebrovascular and venous sinus, pseudo-SAH caused by hyperhemoglobinemia is distributed according to the vascular anatomy, and the patient has no clinical symptoms or signs of SAH. When encountering this phenomenon, clinicians should review the patient's medical history and clinical symptoms and signs, and if necessary, perform a lumbar puncture to make a correct diagnosis and avoid unnecessary examinations and even application of inappropriate treatments.
Data availability statement The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request. Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Acknowledgements None. References [1] Latchaw RE, Silva P, Falcone SF. The role of CT following aneurysmal rupture. Neuroimaging Clin N Am 1997;7(4):693–708. [2] Spiegel SM, Fox AJ, Vinuela F, Pelz DM. Increased density of tentorium and falx: a false positive CT sign of subarachnoid hemorrhage. Can Assoc Radiol J 1986;37(4):243–7. [3] Avrahami E, Katz R, Rabin A, Friedman V. CT diagnosis of non-traumatic subarachnoid haemorrhage in patients with brain edema. Eur J Radiol 1998;28(3):222–5. [4] You JS, Park S, Park YS, Chung SP. Pseudo-subarachnoid hemorrhage. Am J Emerg Med 2008;26(4):1–2. [5] Ho AL, Sussman ES, Pendharkar AV, Iv M, Hirsch KG, Fischbein NJ, et al. Practical pearl: use of MRI to differentiate pseudo-subarachnoid hemorrhage from true subarachnoid hemorrhage. Neurocrit Care 2018:1–6. [6] Sun Xianyong SWXY. A case report of CT findings of hyperhemoglobinemia in brain. Chin J Med Imag 2014;22:320. [7] Yin Weiwei XHCW. A case of CT findings of high hemoglobinemia with CT enhancement. Chin J Radiol 2008;42:1265. [8] Yuzawa H, Higano S, Mugikura S, Umetsu A, Murata T, Nakagawa A, et al. Pseudosubarachnoid hemorrhage found in patients with postresuscitation encephalopathy: characteristics of CT findings and clinical importance. AJNR Am J Neuroradiol 2008;29(8):1544–9. [9] CA G, Burdette J, Elster A. Pseudo-subarachnoid hemorrhage: a potential imaging pitfall associated with diffuse cerebral edema. AJNR Am J Neuroradiol 2003;24(2):254–6. [10] Patzig M, Laub C, Janssen H, Ertl L, Fesl G. Pseudo-subarachnoid haemorrhage due to chronic hypoxaemia: case report and review of the literature. BMC Neurol 2014;14(1):1–5. [11] Javedan SP, Marciano F. Pseudo-enhancement from polycythemia. Neurology 2004;62(1):150. [12] Liu Hui ZXJ. CT findings and mechanism analysis of intracranial vascular density in patients with cyanotic congenital heart disease. Chin J Radiol 2012;46:300–3. [13] Z L. Clinical review of 1886 patients with hyperhemoglobinemia. J Chin Med 2013;32:142–3.
5. Conclusion Hyperhemoglobinemia may be a contributing factor to the development of pseudo-SAH, as a significant correlation was found between the incidences of these conditions. Clinicians should be aware of this phenomenon and seek to accurately identify pseudo-SAH in order to avoid unnecessary examinations (such as cerebral angiography) and the time required to perform the examinations and wait for the results, which may delay application of the best treatment. Ethical approval Ethical approval of the study was given by the medical ethics
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