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Ultrasonographic Evaluation of Optic Nerve Sheath Diameter among Healthy Chinese Adults
Ultrasound in Med. & Biol., Vol. 42, No. 3, pp. 683–688, 2016 Copyright Ó 2016 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.11.020
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Original Contribution ULTRASONOGRAPHIC EVALUATION OF OPTIC NERVE SHEATH DIAMETER AMONG HEALTHY CHINESE ADULTS LIJUAN WANG,* LIANGSHU FENG,* YAN YAO,y FANG DENG,* YUZHI WANG,* JIACHUN FENG,* and YINGQI XING* * Neuroscience Center, Department of Neurology, First Hospital of Jilin University, Jilin University, Changchun, China; and y Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China (Received 22 January 2015; revised 20 July 2015; in final form 23 November 2015)
Abstract—The aim of the work described here was to establish the range for optic nerve sheath diameter (ONSD) and potential factors influencing ONSD in healthy Chinese adults. Both ONSDs were measured twice in the sagittal and transversal planes by two observers. The final ONSD value for each participant was the average of 16 measurements of both eyes. The ONSD range (N 5 3680) among 230 participants was 2.65–4.30 mm. The upper ONSD limit was lower than those in previous studies in Caucasian and African samples. Simple linear regression analyses revealed that the ONSD was correlated with sex, body mass index and waistline and head circumference. After adjustment for potential confounds between these factors, sex (coefficient 5 0.225, p , 0.001) and body mass index (coefficient 5 0.042, p , 0.001) were independently associated with ONSD. Underweight women had the smallest ONSD. These results suggest that racial, sex, and body mass index differences should be noted when assessing ultrasonographic criteria. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Optic nerve sheath diameter, Ultrasonography, Cerebral pressure.
pressure changes as the intracranial subarachnoid space (Hansen and Helmke 1996; Hayreh 1968). Several studies have confirmed that increased ICP leads to enlarged optic nerve sheath diameter (ONSD) (Hansen and Helmke 1997; Liu and Kahn 1993). Precise measurements of ONSD by magnetic resonance imaging (MRI) can accurately predict raised ICP (Geeraerts et al. 2008). However, MRI is expensive and time consuming, and requires patient transport. For these reasons, other studies have used ultrasound to assess ONSD (B€auerle et al. 2013; Steinborn et al. 2011). Given its low cost, bedside administration and speediness, ultrasonographic ONSD is being widely applied in clinical settings and has been developed as a diagnostic tool for raised ICP (Blaivas et al. 2003; Bolesch et al. 2015; Geeraerts et al. 2007; Kimberly et al. 2008; Moretti and Pizzi 2011; Rajajee et al. 2011; Soldatos et al. 2009; Tsung et al. 2005). A recent metaanalysis revealed that ONSD ultrasonography provided adequate diagnostic accuracy for detecting raised intracranial hypertension, which helped physicians make clinical decisions (Dubourg et al. 2011). As the available data regarding normal ONSD are inconclusive, diagnostic standards for determining raised ICP through this
INTRODUCTION Measurements of intracranial pressure (ICP) are very important in situations in which raised ICP is associated with poor outcomes and high mortality (Juul et al. 2000). The gold standard for ICP monitoring includes invasive devices that are either intra-parenchymal or intra-ventricular. However, such invasive measurements are not routinely performed during emergencies because of a lack of neurosurgeons. Additionally, invasive methods are not always feasible because of contraindications (e.g., thrombocythemia and coagulopathy) or complications, including hemorrhaging and bacterial colonization (Ghajar 2000; Raboel et al. 2012). Thus, precise and non-invasive methods for estimating ICP are needed in clinical settings. The optic nerve is part of the central nervous system, and several studies have documented that the intra-orbital subarachnoid space, which surrounds the optic nerve, is subject to the same
Address correspondence to: Jiachun Feng or Yingqi Xing, Neuroscience Center, Department of Neurology, First Hospital of Jilin University, Xinmin Street 71, 130021, Changchun, China. E-mail: [email protected] 683
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measure are not completely unified. Well-established, normed values are required at the clinical level. A relatively wide range of normal ONSD values is observed because of inter-individual variation (B€auerle et al. 2012). However, most previous ultrasonographic measurements of ONSD are based on Caucasian participants and individuals of African descent. Only a few studies have described the relationship between individual characteristics and ONSD given such small sample sizes. One study assessing normal children reported a relationship between increased age and increased ONSD, with the greatest increase occurring during the first 2 mo of life (Ballantyne et al. 1999). However, perhaps because of the small sample sizes, it is not known whether ONSD increases with age among adults or how ONSD varies with other demographic and physiologic features such as race, sex, body mass index (BMI), blood pressure, head circumference and waistline. Therefore, a protocol used by an ONSD research group in 2013 sought to assess if the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP varies according to patient characteristics (Dubourg et al. 2013). Furthermore, no previous evaluation exists regarding ONSD among a healthy Chinese sample. Therefore, the goal of the present study was to establish normative values for ONSD among Chinese adults and investigate relationships between ONSD and specific demographic and physiologic characteristics. METHODS Participants The present study was performed between January 2013 and January 2014 at the First Hospital of Jilin University, which owns one of the four ultrasound training centers in China. The ethics committee of the First Hospital of Jilin University approved this study. All participants provided written informed consent. Healthy adults (age $ 18) were recruited by a convenience sampling procedure during routine examinations. All participants had no history of disease, including no ophthalmologic or neurologic complaints. Individuals were excluded if they had any disease history or had taken any medications during the preceding year that could affect ICP (e.g., carbonic anhydrase inhibitors, diuretics, glucocorticoids). The demographic/physiologic data collected were: age, sex, BMI, waistline, head circumference, systolic blood pressure (SBP) and diastolic blood pressure (DBP). Mean arterial blood pressure (MABP) was calculated as 1/3 3 systolic blood pressure 1 2/3 3 diastolic blood pressure. Measurements Ultrasound ONSD examinations were carried out in B-mode using a Philips iU22 (Andover, MA, USA) ultra-
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sound system and a 9- to 3-MHz linear array transducer. Individuals were examined in the supine position. A probe was placed softly on the closed upper eyelid with a thick layer of ultrasound gel. In line with previous protocols, ONSD was assessed 3 mm posterior to the point where the optic nerve entered the globe (Romagnuolo et al. 2005; Tayal et al. 2007). Two measurements were made for each ONSD. One measurement was performed in the sagittal plane (with the probe vertical), and one was performed in the transverse plane (with the probe horizontal) (Geeraerts et al. 2007; Moretti et al. 2009). Both eyes were examined twice, and the mean value of eight measurements was recorded. All participants were examined by two experienced observers (Y.X. and L.W.), who were blind to the ultrasonographic results. The final ONSD value for an individual was the average of the 16 measurements to minimize variability. Statistics All statistical analyses were performed using SPSS for Windows software Release 17.0 (SPSS, Chicago, IL, USA). Continuous variables are presented as means 6 SD, whereas categorical variables are reported as frequencies and percentages. Simple linear regression analyses were performed to determine associations between age, sex, BMI, waistline, head circumference, MABP and ONSD, respectively. To adjust for potential confounds, multiple regression analyses were carried out to determine independent factors associated with ONSD. A forward stepwise process was employed to select parameters, using p , 0.05 to include and p . 0.10 to exclude. Multiple comparisons of ONSD among different groups were carried out via least-significant-difference analyses. A two-tailed probability of p , 0.05 was used as the significance level. RESULTS Optic nerve sheath diameters of 230 individuals aged 18 to 80 y (mean: 43.2 6 15.9 y) were measured; 118 (51.3%) were male. Mean BMI was 22.6 6 3.5 kg/ m2 (range: 15.9–33.8 kg/m2). According to Chinese adult BMI classifications (Chen 2008), 35 (14 male, 21 female) participants were underweight. An acceptable BMI range (18.5–23.9 kg/m2) was observed among 114 volunteers (50 male, 64 female). Sixty-seven participants (43 male, 24 female) were deemed overweight (24 # BMI # 27.9 kg/m2). Another 14 volunteers (11 male, 3 female) were categorized as obese (BMI $ 28 kg/m2). ONSD measurements (N 5 3680) were conducted on all participants. The ONSD values ranged from 2.65 to 4.30 mm. The mean ONSD was
US evaluation of optic nerve sheath diameter d L. WANG et al.
Fig. 1. Distribution of mean ONSD measurements. ONSD 5 optic nerve sheath diameter.
3.458 mm (SD 5 0.2767), with 95% of participants in the range 3.420–3.493 mm. The ONSD distribution in this sample was considered normal (Fig. 1). Simple linear regression analyses revealed that ONSD was correlated with sex, BMI, waistline and head circumference (Table 1). After adjustment for potential confounds between these factors, sex (coefficient 5 0.225, p , 0.001) and BMI (coefficient 5 0.042, p , 0.001) were independently associated with ONSD (Table 1). Figure 2 illustrates how changes in ONSD were associated with sex and BMI. According to multiple linear regression results, participants were divided into different groups according to related sex and BMI variables (underweight, acceptable range, overweight, obesity). Mean ONSDs among these groups are listed in Table 2. Underweight women had the smallest ONSD (3.201 mm). Overweight men, obese men and obese women had the largest ONSD; there were no significant differences between these three overweight/obese groups (Table 3).
DISCUSSION This is the first study to assess a normative range of ultrasonographically measured ONSDs among a Chinese
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adult sample. To our knowledge, this is the largest study to examine specific relationships between demographic characteristics, physiologic characteristics and ultrasonographically measured ONSD. The ONSD measurement range (2.65–4.30 mm) in the present study was narrower than those in past studies. The mean ONSD value (3.458 mm) is consistent with results from two previous studies (Ballantyne et al. 2002; Soldatos et al. 2008). Ballantyne et al. assessed 67 adults in the United Kingdom, and the ONSD values ranged from 2.4 to 4.7 mm (mean 5 3.2–3.6 mm). Soldatos et al. examined 26 Greek adults with ONSDs ranging from 2.2 to 4.9 mm (mean 5 3.6 mm). However, other studies have reported higher mean values and ONSD ranges in Iran (4.6 mm, 3.8–5.4 mm) (Amini et al. 2013), Bangladesh (4.41 mm, 4.24– 4.83 mm) (Maude et al. 2013), and Italy (5.4 mm, 4.3– 7.6 mm) (B€auerle et al. 2012). The aforementioned findings are consistent with predictions suggesting a relatively wide inter-individual range in ONSD (B€auerle et al. 2012; Lagreze et al. 2007). Such differences between studies might be the result of ethnic/racial variability and/or genetic distinctions. Sonographic ONSD measurements for raised ICP have not been properly evaluated among heterogeneous patients, especially those from Asia. The present study is the first to provide an overview of a normative ONSD range within a sample of healthy Chinese adults. It is noteworthy that the upper ONSD limit in the present study was 4.3 mm, which is remarkably lower than values observed in several other countries. Because the present study had an upper limit of ultrasonographic ONSDs remarkably lower than those in studies in other countries, standard ONSDs might not be easily attainable across racial/ethnic groups. Therefore, the present results prompt an additional need to investigate ultrasonographic ONSD criteria for Chinese samples. If this sort of specificity is confirmed in future work, racial and ethnic characteristics should be noted when applying ultrasonographic criteria to determination of ONSD.
Table 1. Results of linear regression analyses Simple linear regression analysis
Multiple linear regression analysis
Variable
Coefficient
SE
t
p Value
Coefficient
SE
t
p Value
Sex Age Body mass index Waistline Head circumference MABP
0.240 0.001 0.038 0.012 0.033 0.004
0.033 0.001 0.005 0.002 0.009 0.003
7.273 0.990 8.379 6.769 3.821 1.401
,0.001 0.323 ,0.001 ,0.001 ,0.001 0.163
0.189 — 0.032 — — —
0.030 — 0.004 — — —
6.237 — 7.436 — — —
,0.001 — ,0.001 — — —
MABP 5 mean arterial blood pressure.
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Fig. 2. Associations between ONSD, sex and BMI. ONSD 5 optic nerve sheath diameter; BMI 5 body mass index.
The distribution of ONSDs in the present study was relatively normal. Conversely, a study sampling 136 healthy volunteers in Bangladesh reported a bimodal ONSD distribution. Again, racial/ethnic differences could account for differences in ONSD distributions between these studies. We argue that the relatively large sample size employed in the present study might reflect a more authentic distribution; therefore, future assessments of ONSD distributions should include larger samples. Few studies have observed significant factors associated with ultrasonographic ONSD measurements, perhaps because of smaller sample sizes. One study found sex differences in ONSD thickness (i.e., higher thickness in men than in women); however, this result was not statistically significant because of the small sample size (Garcia et al. 2004). A previous study confirmed that ONSD has a linear relationship with ICP (Hansen and Helmke 1997), and a linear covariate relationship between BMI and ICP has been observed elsewhere (Berdahl et al. 2012; Ren et al. 2012). However, whether ultrasonographically measured ONSD is correlated with BMI had not yet been confirmed. A study of 40 healthy Italian adults identified no correlation between ONSD and BMI
Table 2. Optical nerve sheath diameters of different groups Group
N
Mean (mm)
SD (mm)
Underweight men Normal weight men Overweight men Obese men Underweight women Normal weight women Overweight women Obese women
14 50 43 11 21 64 24 3
3.379 3.484 3.703 3.736 3.201 3.325 3.437 3.683
0.1237 0.2270 0.2983 0.2270 0.1224 0.2109 0.2007 0.1193
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(B€auerle et al. 2012). However, the authors speculated that because the maximum BMI value observed was 33.6 kg/m2, a possible association between higher BMI and ONSD could not be fully ruled out. The present study, with a relatively large sample size and a wide range of BMIs, observed sex- and BMI-related changes in ONSD. To our knowledge, this is the first study to reveal significant associations between sex, BMI and ultrasonographically measured ONSDs among healthy adults. The present study included 81 participants with BMIs higher than the normal population range; the maximum BMI was 33.8 kg/m2, which is significantly higher than the normal population value (according to the Chinese adult BMI classification, a BMI $ 24 is defined as higher than normal [Chen 2008]). The minimum ONSD values were measured within the female underweight group. One possible explanation for this difference could be related to nutritional factors influencing these groups. For instance, malnutrition can diminish physical development, which could lead to smaller ONSD values (Maude et al. 2013). The present findings revealed a variety of factors related to normal ultrasonographically measured ONSD. However, up to now, little had been known regarding potential factors affecting relationships between ONSD and raised ICP. Thus, such factors should be further investigated, especially when establishing more accurate diagnostic criteria for raised ICP. The lack of findings regarding an association between ONSD and age in the present study is compatible with previous research. Although some studies have reported significant increases in ONSD during the first year of life (Ballantyne et al. 1999; Helmke and Hansen 1996), others speculate much smaller increases in ONSD by the end of childhood (Maude et al. 2013). The lack of age differences in the relationship between ONSD and age is further highlighted by non-significant findings observed for waistline, head circumference and blood pressure (all biological/physiologic characteristics associated with age) in the present study. We should note a few limitations of the present study. Because our sample included healthy adults, ICP was presumed to be relatively normal based on patient histories. Second, although our study revealed a few related factors associated with ultrasonographic ONSD, future studies should strive toward examining other potential factors affecting this association. Third, more accurate ranges of normal ONSD still need to be confirmed. Therefore, large multicenter and multicultural samples should be addressed in future studies.
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Table 3. Mean differences in ONSDs during multiple comparisons among patients with different body mass indexes
Underweight men Normal weight men Overweight men Obese men Underweight women Normal weight women Overweight women Obese women
Underweight men
Normal weight men
Overweight men
Obese men
Underweight women
Normal weight women
Overweight women
Obese women
— 0.105 0.324* 0.357* 20.178* 20.055 0.058 0.306*
— 0.219* 0.252* 20.283* 20.159* 20.047 0.201
— 0.033 20.502* 20.378* 20.266* 20.018
— 20.535 20.411* 20.299* 20.051
— 0.124* 0.236* 0.484*
— 0.112* 0.361*
— 0.248
—
* p , 0.05.
CONCLUSIONS Ultrasonographic measurements of ONSD among normal Chinese adults were correlated with sex and BMI. The upper ONSD limit was lower than what has been observed among Caucasian samples and individuals of African descent. Therefore, we propose that ethnic/ racial, sex and BMI differences should be noted when devising ultrasonographic ONSD criteria. Overall, the present findings could be used as a basis for future investigations regarding non-invasive assessments of raised ICP.
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Dubourg J, Messerer M, Karakitsos D, Rajajee V, Antonsen E, Javouhey E, Cammarata A, Cotton M, Daniel RT, Denaro C, Douzinas E, Dubost C, Berhouma M, Kassai B, Rabilloud M, Gullo A, Hamlat A, Kouraklis G, Mannanici G, Marill K, Merceron S, Poularas J, Ristagno G, Noble V, Shah S, Kimberly H, Cammarata G, Moretti R, Geeraerts T. Individual patient data systematic review and meta-analysis of optic nerve sheath diameter ultrasonography for detecting raised intracranial pressure: Protocol of the ONSD research group. Syst Rev 2013;2:62. Garcia JP Jr, Garcia PT, Rosen RB, Finger PT. A 3-dimensional ultrasound c-scan imaging technique for optic nerve measurements. Ophthalmology 2004;111:1238–1243. Geeraerts T, Launey Y, Martin L, Pottecher J, Vigue B, Duranteau J, Benhamou D. Ultrasonography of the optic nerve sheath may be useful for detecting raised intracranial pressure after severe brain injury. Intensive Care Med 2007;33:1704–1711. Geeraerts T, Newcombe VF, Coles JP, Abate MG, Perkes IE, Hutchinson PJ, Outtrim JG, Chatfield DA, Menon DK. Use of T2weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure. Crit Care 2008;12:R114. Ghajar J. Traumatic brain injury. Lancet 2000;356:923–929. Hansen HC, Helmke K. The subarachnoid space surrounding the optic nerves: An ultrasound study of the optic nerve sheath. Surg Radiol Anat 1996;18:323–328. Hansen HC, Helmke K. Validation of the optic nerve sheath response to changing cerebrospinal fluid pressure: Ultrasound findings during intrathecal infusion tests. J Neurosurg 1997;87:34–40. Hayreh SS. Pathogenesis of oedema of the optic disc. Doc Ophthalmol 1968;24:289–411. Helmke K, Hansen HC. Fundamentals of transorbital sonographic evaluation of optic nerve sheath expansion under intracranial hypertension: II. Patient study. Pediatr Radiol 1996;26:706–710. Juul N, Morris GF, Marshall SB, Marshall LF. Intracranial hypertension and cerebral perfusion pressure: Influence on neurological deterioration and outcome in severe head injury. J Neurosurg 2000;92:1–6. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med 2008;15:201–204. Lagreze WA, Lazzaro A, Weigel M, Hansen HC, Hennig J, Bley TA. Morphometry of the retrobulbar human optic nerve: Comparison between conventional sonography and ultrafast magnetic resonance sequences. Invest Ophthalmol Vis Sci 2007;48:1913–1917. Liu D, Kahn M. Measurement and relationship of subarachnoid pressure of the optic nerve to intracranial pressures in fresh cadavers. Am J Ophthalmol 1993;116:548–556. Maude RR, Hossain MA, Hassan MU, Osbourne S, Sayeed KLA, Karim MR, Samad R, Borooah S, Dhillon B, Day NP, Dondorp AM, Maude RJ. Transorbital sonographic evaluation of normal optic nerve sheath diameter in healthy volunteers in Bangladesh. PloS One 2013;8:e81013. Moretti R, Pizzi B, Cassini F, Vivaldi N. Reliability of optic nerve ultrasound for the evaluation of patients with spontaneous intracranial hemorrhage. Neurocrit Care 2009;11:406–410.
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Moretti R, Pizzi B. Ultrasonography of the optic nerve in neurocritically ill patients. Acta Anaesthesiol Scand 2011;55:644–652. Raboel P, Bartek J, Andresen M, Bellander B, Romner B. Intracranial pressure monitoring: Invasive versus non-invasive methods—A review. Crit Care Res Pract 2012;2012:950393. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care 2011;15:506–515. Ren R, Wang N, Zhang X, Tian G, Jonas JB. Cerebrospinal fluid pressure correlated with body mass index. Graefes Arch Clin Exp Ophthalmol 2012;250:445–446. Romagnuolo L, Tayal V, Tomaszewski C, Saunders T, Norton HJ. Optic nerve sheath diameter does not change with patient position. Am J Emerg Med 2005;23:686–688. Soldatos T, Karakitsos D, Chatzimichail K, Papathanasiou M, Gouliamos A, Karabinis A. Optic nerve sonography in the diagnostic evaluation of adult brain injury. Crit Care 2008;12:R67.
Volume 42, Number 3, 2016 Soldatos T, Chatzimichail K, Papathanasiou M, Gouliamos A. Optic nerve sonography: A new window for the non-invasive evaluation of intracranial pressure in brain injury. Emerg Med J 2009;26: 630–634. Steinborn M, Fiegler J, Ruedisser K, Hapfelmeier A, Denne C, Macdonald E, Hahn H. Measurement of the optic nerve sheath diameter in children: Comparison between transbulbar sonography and magnetic resonance imaging. Ultraschall Med 2011. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head injury patients. Ann Emerg Med 2007;49:508–514. Tsung JW, Blaivas M, Cooper A, Levick NR. A rapid noninvasive method of detecting elevated intracranial pressure using bedside ocular ultrasound: Application to 3 cases of head trauma in the pediatric emergency department. Pediatr Emerg Care 2005;21: 94–98.
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.11.020
d
Original Contribution ULTRASONOGRAPHIC EVALUATION OF OPTIC NERVE SHEATH DIAMETER AMONG HEALTHY CHINESE ADULTS LIJUAN WANG,* LIANGSHU FENG,* YAN YAO,y FANG DENG,* YUZHI WANG,* JIACHUN FENG,* and YINGQI XING* * Neuroscience Center, Department of Neurology, First Hospital of Jilin University, Jilin University, Changchun, China; and y Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China (Received 22 January 2015; revised 20 July 2015; in final form 23 November 2015)
Abstract—The aim of the work described here was to establish the range for optic nerve sheath diameter (ONSD) and potential factors influencing ONSD in healthy Chinese adults. Both ONSDs were measured twice in the sagittal and transversal planes by two observers. The final ONSD value for each participant was the average of 16 measurements of both eyes. The ONSD range (N 5 3680) among 230 participants was 2.65–4.30 mm. The upper ONSD limit was lower than those in previous studies in Caucasian and African samples. Simple linear regression analyses revealed that the ONSD was correlated with sex, body mass index and waistline and head circumference. After adjustment for potential confounds between these factors, sex (coefficient 5 0.225, p , 0.001) and body mass index (coefficient 5 0.042, p , 0.001) were independently associated with ONSD. Underweight women had the smallest ONSD. These results suggest that racial, sex, and body mass index differences should be noted when assessing ultrasonographic criteria. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Optic nerve sheath diameter, Ultrasonography, Cerebral pressure.
pressure changes as the intracranial subarachnoid space (Hansen and Helmke 1996; Hayreh 1968). Several studies have confirmed that increased ICP leads to enlarged optic nerve sheath diameter (ONSD) (Hansen and Helmke 1997; Liu and Kahn 1993). Precise measurements of ONSD by magnetic resonance imaging (MRI) can accurately predict raised ICP (Geeraerts et al. 2008). However, MRI is expensive and time consuming, and requires patient transport. For these reasons, other studies have used ultrasound to assess ONSD (B€auerle et al. 2013; Steinborn et al. 2011). Given its low cost, bedside administration and speediness, ultrasonographic ONSD is being widely applied in clinical settings and has been developed as a diagnostic tool for raised ICP (Blaivas et al. 2003; Bolesch et al. 2015; Geeraerts et al. 2007; Kimberly et al. 2008; Moretti and Pizzi 2011; Rajajee et al. 2011; Soldatos et al. 2009; Tsung et al. 2005). A recent metaanalysis revealed that ONSD ultrasonography provided adequate diagnostic accuracy for detecting raised intracranial hypertension, which helped physicians make clinical decisions (Dubourg et al. 2011). As the available data regarding normal ONSD are inconclusive, diagnostic standards for determining raised ICP through this
INTRODUCTION Measurements of intracranial pressure (ICP) are very important in situations in which raised ICP is associated with poor outcomes and high mortality (Juul et al. 2000). The gold standard for ICP monitoring includes invasive devices that are either intra-parenchymal or intra-ventricular. However, such invasive measurements are not routinely performed during emergencies because of a lack of neurosurgeons. Additionally, invasive methods are not always feasible because of contraindications (e.g., thrombocythemia and coagulopathy) or complications, including hemorrhaging and bacterial colonization (Ghajar 2000; Raboel et al. 2012). Thus, precise and non-invasive methods for estimating ICP are needed in clinical settings. The optic nerve is part of the central nervous system, and several studies have documented that the intra-orbital subarachnoid space, which surrounds the optic nerve, is subject to the same
Address correspondence to: Jiachun Feng or Yingqi Xing, Neuroscience Center, Department of Neurology, First Hospital of Jilin University, Xinmin Street 71, 130021, Changchun, China. E-mail: [email protected] 683
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measure are not completely unified. Well-established, normed values are required at the clinical level. A relatively wide range of normal ONSD values is observed because of inter-individual variation (B€auerle et al. 2012). However, most previous ultrasonographic measurements of ONSD are based on Caucasian participants and individuals of African descent. Only a few studies have described the relationship between individual characteristics and ONSD given such small sample sizes. One study assessing normal children reported a relationship between increased age and increased ONSD, with the greatest increase occurring during the first 2 mo of life (Ballantyne et al. 1999). However, perhaps because of the small sample sizes, it is not known whether ONSD increases with age among adults or how ONSD varies with other demographic and physiologic features such as race, sex, body mass index (BMI), blood pressure, head circumference and waistline. Therefore, a protocol used by an ONSD research group in 2013 sought to assess if the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP varies according to patient characteristics (Dubourg et al. 2013). Furthermore, no previous evaluation exists regarding ONSD among a healthy Chinese sample. Therefore, the goal of the present study was to establish normative values for ONSD among Chinese adults and investigate relationships between ONSD and specific demographic and physiologic characteristics. METHODS Participants The present study was performed between January 2013 and January 2014 at the First Hospital of Jilin University, which owns one of the four ultrasound training centers in China. The ethics committee of the First Hospital of Jilin University approved this study. All participants provided written informed consent. Healthy adults (age $ 18) were recruited by a convenience sampling procedure during routine examinations. All participants had no history of disease, including no ophthalmologic or neurologic complaints. Individuals were excluded if they had any disease history or had taken any medications during the preceding year that could affect ICP (e.g., carbonic anhydrase inhibitors, diuretics, glucocorticoids). The demographic/physiologic data collected were: age, sex, BMI, waistline, head circumference, systolic blood pressure (SBP) and diastolic blood pressure (DBP). Mean arterial blood pressure (MABP) was calculated as 1/3 3 systolic blood pressure 1 2/3 3 diastolic blood pressure. Measurements Ultrasound ONSD examinations were carried out in B-mode using a Philips iU22 (Andover, MA, USA) ultra-
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sound system and a 9- to 3-MHz linear array transducer. Individuals were examined in the supine position. A probe was placed softly on the closed upper eyelid with a thick layer of ultrasound gel. In line with previous protocols, ONSD was assessed 3 mm posterior to the point where the optic nerve entered the globe (Romagnuolo et al. 2005; Tayal et al. 2007). Two measurements were made for each ONSD. One measurement was performed in the sagittal plane (with the probe vertical), and one was performed in the transverse plane (with the probe horizontal) (Geeraerts et al. 2007; Moretti et al. 2009). Both eyes were examined twice, and the mean value of eight measurements was recorded. All participants were examined by two experienced observers (Y.X. and L.W.), who were blind to the ultrasonographic results. The final ONSD value for an individual was the average of the 16 measurements to minimize variability. Statistics All statistical analyses were performed using SPSS for Windows software Release 17.0 (SPSS, Chicago, IL, USA). Continuous variables are presented as means 6 SD, whereas categorical variables are reported as frequencies and percentages. Simple linear regression analyses were performed to determine associations between age, sex, BMI, waistline, head circumference, MABP and ONSD, respectively. To adjust for potential confounds, multiple regression analyses were carried out to determine independent factors associated with ONSD. A forward stepwise process was employed to select parameters, using p , 0.05 to include and p . 0.10 to exclude. Multiple comparisons of ONSD among different groups were carried out via least-significant-difference analyses. A two-tailed probability of p , 0.05 was used as the significance level. RESULTS Optic nerve sheath diameters of 230 individuals aged 18 to 80 y (mean: 43.2 6 15.9 y) were measured; 118 (51.3%) were male. Mean BMI was 22.6 6 3.5 kg/ m2 (range: 15.9–33.8 kg/m2). According to Chinese adult BMI classifications (Chen 2008), 35 (14 male, 21 female) participants were underweight. An acceptable BMI range (18.5–23.9 kg/m2) was observed among 114 volunteers (50 male, 64 female). Sixty-seven participants (43 male, 24 female) were deemed overweight (24 # BMI # 27.9 kg/m2). Another 14 volunteers (11 male, 3 female) were categorized as obese (BMI $ 28 kg/m2). ONSD measurements (N 5 3680) were conducted on all participants. The ONSD values ranged from 2.65 to 4.30 mm. The mean ONSD was
US evaluation of optic nerve sheath diameter d L. WANG et al.
Fig. 1. Distribution of mean ONSD measurements. ONSD 5 optic nerve sheath diameter.
3.458 mm (SD 5 0.2767), with 95% of participants in the range 3.420–3.493 mm. The ONSD distribution in this sample was considered normal (Fig. 1). Simple linear regression analyses revealed that ONSD was correlated with sex, BMI, waistline and head circumference (Table 1). After adjustment for potential confounds between these factors, sex (coefficient 5 0.225, p , 0.001) and BMI (coefficient 5 0.042, p , 0.001) were independently associated with ONSD (Table 1). Figure 2 illustrates how changes in ONSD were associated with sex and BMI. According to multiple linear regression results, participants were divided into different groups according to related sex and BMI variables (underweight, acceptable range, overweight, obesity). Mean ONSDs among these groups are listed in Table 2. Underweight women had the smallest ONSD (3.201 mm). Overweight men, obese men and obese women had the largest ONSD; there were no significant differences between these three overweight/obese groups (Table 3).
DISCUSSION This is the first study to assess a normative range of ultrasonographically measured ONSDs among a Chinese
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adult sample. To our knowledge, this is the largest study to examine specific relationships between demographic characteristics, physiologic characteristics and ultrasonographically measured ONSD. The ONSD measurement range (2.65–4.30 mm) in the present study was narrower than those in past studies. The mean ONSD value (3.458 mm) is consistent with results from two previous studies (Ballantyne et al. 2002; Soldatos et al. 2008). Ballantyne et al. assessed 67 adults in the United Kingdom, and the ONSD values ranged from 2.4 to 4.7 mm (mean 5 3.2–3.6 mm). Soldatos et al. examined 26 Greek adults with ONSDs ranging from 2.2 to 4.9 mm (mean 5 3.6 mm). However, other studies have reported higher mean values and ONSD ranges in Iran (4.6 mm, 3.8–5.4 mm) (Amini et al. 2013), Bangladesh (4.41 mm, 4.24– 4.83 mm) (Maude et al. 2013), and Italy (5.4 mm, 4.3– 7.6 mm) (B€auerle et al. 2012). The aforementioned findings are consistent with predictions suggesting a relatively wide inter-individual range in ONSD (B€auerle et al. 2012; Lagreze et al. 2007). Such differences between studies might be the result of ethnic/racial variability and/or genetic distinctions. Sonographic ONSD measurements for raised ICP have not been properly evaluated among heterogeneous patients, especially those from Asia. The present study is the first to provide an overview of a normative ONSD range within a sample of healthy Chinese adults. It is noteworthy that the upper ONSD limit in the present study was 4.3 mm, which is remarkably lower than values observed in several other countries. Because the present study had an upper limit of ultrasonographic ONSDs remarkably lower than those in studies in other countries, standard ONSDs might not be easily attainable across racial/ethnic groups. Therefore, the present results prompt an additional need to investigate ultrasonographic ONSD criteria for Chinese samples. If this sort of specificity is confirmed in future work, racial and ethnic characteristics should be noted when applying ultrasonographic criteria to determination of ONSD.
Table 1. Results of linear regression analyses Simple linear regression analysis
Multiple linear regression analysis
Variable
Coefficient
SE
t
p Value
Coefficient
SE
t
p Value
Sex Age Body mass index Waistline Head circumference MABP
0.240 0.001 0.038 0.012 0.033 0.004
0.033 0.001 0.005 0.002 0.009 0.003
7.273 0.990 8.379 6.769 3.821 1.401
,0.001 0.323 ,0.001 ,0.001 ,0.001 0.163
0.189 — 0.032 — — —
0.030 — 0.004 — — —
6.237 — 7.436 — — —
,0.001 — ,0.001 — — —
MABP 5 mean arterial blood pressure.
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Fig. 2. Associations between ONSD, sex and BMI. ONSD 5 optic nerve sheath diameter; BMI 5 body mass index.
The distribution of ONSDs in the present study was relatively normal. Conversely, a study sampling 136 healthy volunteers in Bangladesh reported a bimodal ONSD distribution. Again, racial/ethnic differences could account for differences in ONSD distributions between these studies. We argue that the relatively large sample size employed in the present study might reflect a more authentic distribution; therefore, future assessments of ONSD distributions should include larger samples. Few studies have observed significant factors associated with ultrasonographic ONSD measurements, perhaps because of smaller sample sizes. One study found sex differences in ONSD thickness (i.e., higher thickness in men than in women); however, this result was not statistically significant because of the small sample size (Garcia et al. 2004). A previous study confirmed that ONSD has a linear relationship with ICP (Hansen and Helmke 1997), and a linear covariate relationship between BMI and ICP has been observed elsewhere (Berdahl et al. 2012; Ren et al. 2012). However, whether ultrasonographically measured ONSD is correlated with BMI had not yet been confirmed. A study of 40 healthy Italian adults identified no correlation between ONSD and BMI
Table 2. Optical nerve sheath diameters of different groups Group
N
Mean (mm)
SD (mm)
Underweight men Normal weight men Overweight men Obese men Underweight women Normal weight women Overweight women Obese women
14 50 43 11 21 64 24 3
3.379 3.484 3.703 3.736 3.201 3.325 3.437 3.683
0.1237 0.2270 0.2983 0.2270 0.1224 0.2109 0.2007 0.1193
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(B€auerle et al. 2012). However, the authors speculated that because the maximum BMI value observed was 33.6 kg/m2, a possible association between higher BMI and ONSD could not be fully ruled out. The present study, with a relatively large sample size and a wide range of BMIs, observed sex- and BMI-related changes in ONSD. To our knowledge, this is the first study to reveal significant associations between sex, BMI and ultrasonographically measured ONSDs among healthy adults. The present study included 81 participants with BMIs higher than the normal population range; the maximum BMI was 33.8 kg/m2, which is significantly higher than the normal population value (according to the Chinese adult BMI classification, a BMI $ 24 is defined as higher than normal [Chen 2008]). The minimum ONSD values were measured within the female underweight group. One possible explanation for this difference could be related to nutritional factors influencing these groups. For instance, malnutrition can diminish physical development, which could lead to smaller ONSD values (Maude et al. 2013). The present findings revealed a variety of factors related to normal ultrasonographically measured ONSD. However, up to now, little had been known regarding potential factors affecting relationships between ONSD and raised ICP. Thus, such factors should be further investigated, especially when establishing more accurate diagnostic criteria for raised ICP. The lack of findings regarding an association between ONSD and age in the present study is compatible with previous research. Although some studies have reported significant increases in ONSD during the first year of life (Ballantyne et al. 1999; Helmke and Hansen 1996), others speculate much smaller increases in ONSD by the end of childhood (Maude et al. 2013). The lack of age differences in the relationship between ONSD and age is further highlighted by non-significant findings observed for waistline, head circumference and blood pressure (all biological/physiologic characteristics associated with age) in the present study. We should note a few limitations of the present study. Because our sample included healthy adults, ICP was presumed to be relatively normal based on patient histories. Second, although our study revealed a few related factors associated with ultrasonographic ONSD, future studies should strive toward examining other potential factors affecting this association. Third, more accurate ranges of normal ONSD still need to be confirmed. Therefore, large multicenter and multicultural samples should be addressed in future studies.
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Table 3. Mean differences in ONSDs during multiple comparisons among patients with different body mass indexes
Underweight men Normal weight men Overweight men Obese men Underweight women Normal weight women Overweight women Obese women
Underweight men
Normal weight men
Overweight men
Obese men
Underweight women
Normal weight women
Overweight women
Obese women
— 0.105 0.324* 0.357* 20.178* 20.055 0.058 0.306*
— 0.219* 0.252* 20.283* 20.159* 20.047 0.201
— 0.033 20.502* 20.378* 20.266* 20.018
— 20.535 20.411* 20.299* 20.051
— 0.124* 0.236* 0.484*
— 0.112* 0.361*
— 0.248
—
* p , 0.05.
CONCLUSIONS Ultrasonographic measurements of ONSD among normal Chinese adults were correlated with sex and BMI. The upper ONSD limit was lower than what has been observed among Caucasian samples and individuals of African descent. Therefore, we propose that ethnic/ racial, sex and BMI differences should be noted when devising ultrasonographic ONSD criteria. Overall, the present findings could be used as a basis for future investigations regarding non-invasive assessments of raised ICP.
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