Transorbital Sonographic Evaluation of Normal Optic Nerve Sheath Diameter in Healthy Volunteers in Bangladesh
et al. (2013) Transorbital Sonographic Evaluation of Normal Optic Nerve Sheath Diameter
in Healthy Volunteers in Bangladesh. PLoS ONE 8(12): e81013. doi:10.1371/journal.pone.0081013
Transorbital Sonographic Evaluation of Normal Optic Nerve Sheath Diameter in Healthy Volunteers in Bangladesh
Rapeephan R. Maude 0
Md Amir Hossain 0
Mahtab Uddin Hassan 0
Sophie Osbourne 0
Katherine Langan Abu Sayeed 0
Mohammed Rezaul Karim 0
Rasheda Samad 0
Shyamanga Borooah 0
Bal Dhillon 0
Nicholas P. J. Day 0
Arjen M. Dondorp 0
Richard J. Maude 0
Friedemann Paul, Charite University Medicine Berlin, Germany
0 1 Mahidol-Oxford Tropical Medicine Research Unit , Rajthewi, Bangkok , Thailand , 2 Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford , United Kingdom , 3 Chittagong Medical College Hospital , Chittagong , Bangladesh , 4 College of Medicine and Veterinary Medicine, University of Edinburgh , Edinburgh , United Kingdom
Introduction: Measurement of optic nerve sheath diameter (ONSD) by ultrasound is increasingly used as a marker to detect raised intracranial pressure (ICP). ONSD varies with age and there is no clear consensus between studies for an upper limit of normal. Knowledge of normal ONSD in a healthy population is essential to interpret this measurement. Methods: In a prospective observational study, ONSD was measured using a 15 MHz ultrasound probe in healthy volunteers in Chittagong, Bangladesh. The aims were to determine the normal range of ONSD in healthy Bangladeshi adults and children, compare measurements in males and females, horizontal and vertical beam orientations and left and right eyes in the same individual and to determine whether ONSD varies with head circumference independent of age. Results: 136 subjects were enrolled, 12.5% of whom were age 16 or under. Median ONSD was 4.41 mm with 95% of subjects in the range 4.25-4.75 mm. ONSD was bimodally distributed. There was no relationship between ONSD and age ($4 years), gender, head circumference, and no difference in left vs right eye or horizontal vs vertical beam. Conclusions: Ultrasonographic ONSD in Bangladeshi healthy volunteers has a narrow bimodal distribution independent of age ($4 years), gender and head circumference. ONSD .4.75 mm in this population should be considered abnormal.
Funding: This research was a part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, supported by the Wellcome Trust of
Great Britain (Major Overseas ProgrammeThailand Unit Core Grant). The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Identification of elevated intracranial pressure (ICP) is
important in the assessment of a range of neurological diseases. It is a
predictor of poor prognosis including risk of death from brainstem
herniation. ICP is commonly measured by opening pressure on
lumbar puncture but this is invasive, unpleasant for the patient,
and contraindicated in many cases. Non-invasive detection of
raised ICP can be achieved by detection of specific signs e.g.
papilloedema on fundoscopy. This requires an experienced
examiner with an ophthalmoscope and the changes can appear
late requiring a sustained increase in ICP.[1,2] Computed
tomography (CT) and magnetic resonance imaging (MRI) of the
head can be used to infer ICP and determine the safety or
otherwise of lumbar puncture. These require the patient to be
moved, are frequently not available in resource-poor settings and
can be normal early in the presence of raised ICP.[3,4]_ENREF_2
Ultrasound measurement of the optic nerve sheath diameter
(ONSD) is a quick, non-invasive method of detecting raised ICP. It
is increasingly being used in emergency departments and intensive
care units.[5,6,7] The optic nerve sheath is a membrane covering
the optic nerve behind the eye and is continuous with the dura
mater over the brain. It distends when ICP is high due to
expansion of the underlying subarachnoid space and its diameter
can be reliably measured at its point of maximal distension 3 mm
posterior to the globe.
ONSD has been used as a clinical and research tool for a variety
of conditions to detect raised ICP. Its sensitivity for detecting
raised ICP is high[5,8] and ONSD varies almost concurrently with
ICP._ENREF_7 It is cheap and easy to train operators.
Ultrasound is known to be operator dependent. However, ONSD
ultrasound has been well evaluated and found to have low intra
and inter-operator variability.[10,11]_ENREF_9 ONSD can be
measured with the ultrasound beam in the vertical or horizontal
orientation and this varies between studies. The degree of normal
intra-individual variation in ONSD between left and right eyes is
thought to be minimal.[2,3,12]
There is no consensus as to the cut-off for an abnormal ONSD
indicating raised intracranial pressure. There is considerable
interindividual variation but no difference between male and
female children. Although 5 mm is most commonly used for
adults, different studies have used values up to 5.9 mm. In
children, ONSD has been shown to increase with age with most of
the increase in the first year of life. Threshold values of 4.0 mm
under 1 year and 4.5 mm in those 1 to 16 years of age [9,12] or
4 mm under 4 years and 5 mm in older children and adults
have been proposed._ENREF_8 It is not known whether ONSD
increases beyond childhood or how ONSD varies with
ethnicity or head circumference.
Knowledge of the normal range of ONSD in a healthy
population is essential to interpret this measurement as a marker
of intracranial pressure in clinical practice[5,13] and research.
Studies are currently underway in Bangladesh using ONSD to
detect raised intracranial pressure in adult severe malaria. To date,
however, there has been no evaluation of ONSD in a healthy
An observational study was performed to determine the normal
range of ONSD in healthy Bangladeshi adults and children,
compare measurements in males and females, horizontal and
vertical beam orientations and left and right eyes in the same
individual and to determine whether ONSD correlates with head
circumference independent of age.
Materials and Methods
The study was conducted in Chittagong Medical College
Hospital, Chittagong, Bangladesh. Chittagong Medical College
Ethical Committee and OXTREC, the University of Oxford
Tropical Research Ethics Committee (OXTREC reference 2412)
provided ethical approval for this study. Healthy relatives of
patients and hospital staff of all ages and both genders were
recruited if they provided written, informed consent. Written
informed consent was obtained from the next of kin, caretakers, or
guardians on behalf of children participating in the study.
Individuals were excluded if they had any chronic diseases, any
acute illnesses in the preceding 4 weeks or had taken any
medications in the preceding 4 weeks. Upon enrollment, basic
demographic data were collected and the head circumference
measured by a single observer using a purpose-designed
nonstretchable tape around the widest possible occipitofrontal
ONSD was measured 3 mm behind the retina. A single
investigator used a 15 MHz linear ultrasound probe (Accutome
B-Scan Plus, Accutome Inc., USA) oriented perpendicularly in the
vertical plane and at around 30 degrees in the horizontal plane on
the closed eyelids of both eyes of supine subjects. Ultrasound gel
was applied to the outside of each eyelid and recordings made in
the axial and longitudinal planes of the widest diameter visible.
Video of every ultrasound was recorded for later analysis by a
single blinded investigator. To determine ONSD, electronic
calipers were used to mark 3 mm perpendicularly behind the
retina. The ONSD was measured at the depth marker at right
angles to the optic nerve. This method has been described and
illustrated diagrammatically in detail elsewhere. Each video
was played three times and a single measurement made each time
from a randomly selected frame, giving 6 measurements of each
eye and 12 measurements in total per subject.
The study aimed to include 100 healthy Bangladeshi people.
Previous studies in healthy children found ranges of ONSD of 2.5
4.1 mm in 31 people in Africa and 2.14.3 mm in 102 people
in the UK with correlation with age. As it was not known to
what degree ONSD varies in Bangladeshi people, or how this
changes with age or skull size, it was not possible to perform a
precise sample size calculation. The UK study was used as a guide
to the approximate sample size required. With this sample size,
assuming an alpha of 0.05, two groups of equal size and a total
population of 158,000,000, a 10% difference in mean ONSD
between adults and children can be detected. Results from a
second smaller group of different healthy individuals recruited
concurrently from the same population for a separate study were
also included for comparison. In this group, videos were recorded
by a different investigator from the first group using the same
methodology except head circumference was not measured and
ONSD was recorded only in the horizontal plane. Results of this
study will be published separately. The same investigator
measured all ONSDs from the videos for both groups.
Statistical analysis was performed using GraphPad Prism 6
(GraphPad Software, Inc., USA). Mann Whitney U test was used
to compare unpaired ONSD between genders and observers,
Wilcoxon matched pairs signed rank test to compare left and right
eyes and horizontal and vertical measurements. Linear regression
was used to assess for correlations with age and head
circumference. One way analysis of variance and intraclass correlation
coefficient (CCI) were used to test for differences between the
repeated measures of ONSD within individuals. Mean values of
repeated measures were used for correlations and comparison
ONSD was measured in 106 healthy volunteers by the first
observer, and an additional 30 by the second observer. All those
asked agree to participate in the study. 17/136 (12.5%) subjects
were age 16 or under and 49.3% were male. All patients were of
Bangladeshi origin. The median (range) ONSD was 4.41 (4.24
4.83) mm and 95% of individuals had mean ONSD in the range
4.254.75 mm (figure 1). The distribution of ONSD in this study
was bimodal (figure 1). There was no difference in the
measurements in the two groups [median (range) 4.41 (4.24
4.83) vs 4.33 (4.244.75) mm, p = 0.52]. There was no difference
between the 6 repeated measures of ONSD in each eye (right eye
CCI = 0.897, F (4.432, 465.3) = 1.331, p = 0.254 and left eye
CCI = 0.897, F (4.595, 482.4) = 1.351, p = 0.2451).
There was no relationship between ONSD and age
(R2 = 0.0093, p = 0.27, figure 2) or ONSD and head
circumference (R2 = 0.011, p = 0.31, figure 3), and no difference in ONSD
between males and females (p = 0.47). There were also no
differences in individuals mean measurements taken in the
horizontal or vertical planes (p = 0.99), or between left and right
eyes (p = 0.12). The maximum difference between mean
measurements in horizontal and vertical planes was 0.093 mm and
between left and right eyes 0.13 mm.
The mean (95% CI) difference in individual ONSD
measurements from the overall mean for each subject was 0.19 (0.170.20)
mm. Repeating each measurement three times gave a mean
difference of 0.07 (0.060.08) mm from the overall mean for each
subject. The mean (95%) coefficient of variation of the multiple
ONSD readings for each individual was 1.19 (1.091.29) % and
the typical error of measurement 0.054 (0.0490.59) mm.
This study indicates the cut-off for the upper limit of normal
ONSD in Bangladeshi people $4 years old is 4.75 mm. The
normal range of ONSD was independent of age, gender,
ultrasound beam orientation, head circumference and observer.
The range of ONSD in this study (4.244.83 mm) was higher
and narrower than has usually been found previously. Examples
from previous studies include 2.54.1 mm in 50 UK adults,
2.14.3 mm in 102 UK children, 2.54.1 mm in 31 African
children, 2.94.3 mm in 20 German adults and 2.2
4.9 mm in 26 Greek adults. A study in Iran found similar values
to the present study with a mean of 4.6 mm in normal
subjects. The differences in normal range between studies
may be due to differences between ethnicities, although it is not
possible to exclude subtle differences in methodology as a
contributing factor. Examples might include variation in the angle
or positioning of the probe or differences in resolution. The
precision of measurement increases with increasing power of the
ultrasound probe used. This study used a relatively powerful
15 MHz probe which may have partially accounted for the
relatively narrow normal range found.
The distribution of ONSDs in this population was bimodal with
a cut-off between the two groups of 4.5 mm. This could not be
explained by differences between investigators, genders or ethnic
origin and warrants further investigation. Possible explanations
might include two genetically distinct subpopulations or
differences in nutrition in childhood, for example malnutrition causing
growth retardation and a smaller ONSD. A consequence of this is
that in those with ONSD,4.5 mm, an increase in ICP could
produce an ONSD within the normal distribution of the second
peak between 4.5 and 4.75 mm.
This study had several limitations. A direct measure of ICP was
not included thus it is not known how well ONSD above the
derived normal range predicts ICP. Previous studies have shown a
reliable linear relationship. The present study did not include
any volunteers under 4 years of age. Previously it has been shown
that ONSD increases with age under 4 years and most within the
first year of life.[2,12] Previous studies have also suggested a much
smaller increase in ONSD to the end of childhood, although this
was not corroborated by the present study. Each measurement was
made three times from the same video by the same observer. This
observer was not blinded to the other results from the same video
and this may have reduced the variability in these measurements
due to observer bias. As the two investigators measuring ONSD
did so in different patients, it was not possible to determine
interobserver variability in this study. However, there was no
difference in the median or range of observations by the two
investigators and previous studies have shown inter-observer
agreement to be high.[10,11]
Ultrasonographic measurements of ONSD in Bangladeshi
healthy volunteers have a narrow bimodal distribution. ONSD is
independent of age ($4 years), gender and head circumference.
ONSD.4.75 mm in this population should be considered
The authors would like to thank Md Hasanur Rahman, Md Safiqul
Mostafa Chowdhury, Sanjib Kanti Paul and Sumon Sharma for their
assistance in recruiting volunteers, as well as the volunteers themselves. In
addition, Dr Sue Lee for her advice regarding the statistical analysis.
Conceived and designed the experiments: RRM RJM. Performed the
experiments: RRM RJM. Analyzed the data: RRM RJM. Contributed
reagents/materials/analysis tools: RJM NPJD AMD. Wrote the paper:
RRM RJM. Analysed the ultrasound images: RRM. Performed the clinical
assessments and data entry: RRM RJM KL SO. Responsible for patient
care: MAH MUH MAS MRK RS. Provided advice and assisted with study
design: SB BD. Supervised the study: RJM NPJD AMD. Read and
approved the final manuscript: RRM MAH MUH SO KL MAS MRK RS
SB BD NPJD AMD RJM.
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