Clinical Usefulness of the Measurement of Optic Nerve
Head Blood Flow in Myopic Normal-Tension Glaucoma
Tetsuya
Sugiyama, Hajime Nakamura, Emiko Shimizu, Kazuaki Miyamoto, Ryozo Yamada
Tetsuya Sugiyama,
Hajime Nakamura, Emiko Shimizu, Kazuaki Miyamoto, Ryozo Yamada, Nakano Eye Clinic of Kyoto Medical
Co-operative, Kyoto, Japan
Correspondence to: Tetsuya Sugiyama, MD, PhD, Nakano Eye Clinic
of Kyoto Medical Co-operative, 2, Jurakumawari-higashimachi, Nakagyo-ku, Kyoto
604-8404, Japan
Email: tsugiyama@kyo-con.or.jp
Telephone: +81-75-801-4151
Fax:
+81-75-822-7423
Received: December 24,
2014
Revised: January 25, 2015
Accepted: January 25, 2015
Published online: June 1, 2015
ABSTRACT
AIM: Diagnosis of glaucoma is often
difficult in patients with myopic changes in the optic nerve head. We
investigated the clinical usefulness of measuring blood flow in myopic optic
nerve heads for the diagnosis of normal-tension glaucoma.
METHODS: Forty eyes, including 20 with
normal-tension glaucoma and 20 without glaucoma, of 40 patients with myopic
optic nerve heads (oval and tilting to the temporal side with crescent
peripapillary atrophy) and visual field defects were evaluated. Blood flow in
the optic nerve head was assessed by laser speckle flowgraphy, and the mean
blur rates for the entire optic nerve head and for its vessels and tissue were
analyzed. The mean deviation and the circumpapillary retinal nerve fiber layer
thickness were determined using the Humphrey Field Analyzer and optical
coherence tomography, respectively. The mean blur rates were compared between
the two groups, and their correlation with the mean deviation and circumpapillary
retinal nerve fiber layer thickness were verified using simple regression
analyses.
RESULTS: The mean blur rates for the entire
optic nerve head and for its tissue were significantly lower in glaucomatous
eyes than in nonglaucomatous eyes, and both values correlated with the mean
deviation only in the former group. The mean blur rate for the optic nerve head
tissue did not depend on the circumpapillary retinal nerve fiber layer
thickness in glaucomatous and nonglaucomatous eyes.
CONCLUSION: Blood flow in the optic nerve head,
particularly the tissue, may be useful for the differential diagnosis of
normal-tension glaucoma in patients with myopia.
© 2015 ACT. All
rights reserved.
Key words: Normal-tension glaucoma; Optic nerve head; Blood flow;
Myopic disc; Mean deviation
Sugiyama T,
Nakamura H, Shimizu E, Miyamoto K, Yamada R. Clinical Usefulness of the
Measurement of Optic Nerve Head Blood Flow in Myopic Normal-Tension Glaucoma. International Journal of Ophthalmic Research 2015; 1(1): 11-18
Available from: URL: http://www.ghrnet.org/index.php/ijor/article/view/993
INTRODUCTION
Glaucoma is the second leading cause of blindness according to global
surveys[1]. It is a group of optic neuropathies characterized by the
death of retinal ganglion cells and loss of axons in the optic nerve head (ONH)[2],
which results in a characteristic ONH appearance and corresponding visual field
defects[3]. Although increased intraocular pressure (IOP) is the
most critical risk factor[4], a number of previous studies suggested
that other factors may be involved in the pathogenesis of this glaucoma,
particularly normal-tension glaucoma (NTG)[5-7]. Other risk factors
reportedly include myopia[8-11] and dysregulation of ocular blood
flow[12,13]. Myopia has been reported to aggravate abnormalities in
ocular hemodynamics in patients with glaucoma[14,15].
On the other
hand, myopic changes in eyes with glaucoma affect the appearance of the ONH and
cause additional retinal nerve fiber layer defects (RNFLDs) as assessed by
optical coherence tomography (OCT)[16-18]. Consequently, the
differential diagnosis of glaucoma, particularly NTG, is often difficult in
patients with high myopia[19]. Even though the OCT system for the
diagnosis of glaucoma has been improved lately[20,21], it does not
always overcome the abovementioned limitation[22,23]. Therefore,
another reliable parameter is required for the differential diagnosis of
glaucoma in myopic ONHs.
Measurement of
ocular blood flow using laser speckle flowgraphy (LSFG), which was developed
and is clinically used in Japan, is noninvasive and completed within several
seconds[24-27]. Compared with other laser-based techniques (i.e.,
laser Doppler velocity and flowmetry), LSFG measurements cover a larger field
and enable two-dimensional observation of the overall hemodynamic condition of
the ONH tissue and vessels. ONH circulation measured using LSFG is reported to
be significantly poorer in myopic eyes with glaucoma than in those without
visual field defects[28,29].
The present
study aimed to verify whether blood flow in the ONH correlates with visual
field defects and whether its measurement is useful for the differential
diagnosis of glaucoma in patients with myopia and visual field defects.
MATERIALS
AND METHODS
Subjects
The procedures of this study followed the tenets of the Declaration of
Helsinki and were approved by the Institutional Review Board of Nakano Eye
Clinic. Japanese adults with myopic ONHs and a refractive error of more than −3
diopters were enrolled in this study. A myopic ONH was diagnosed from its oval
shape and tilt to the temporal side with crescent peripapillary atrophy.
Inclusion criteria: patients with any ocular diseases except myopia, NTG, and
mild cataract; those with advanced-stage NTG and/or diabetes; those who were
taking systemic medications that could affect the ocular blood flow; and those
with a history of smoking were excluded. NTG was diagnosed from all of the
following findings: (1) presence of glaucomatous ONH changes (cupping
enlargement, rim thinness etc.) and glaucomatous visual field defects confirmed
by an accurately performed visual field test using the 30-2 Swedish interactive
threshold algorithm (SITA) program of the Humphrey Field Analyzer (HFA, Carl
Zeiss Meditec, Dublin, CA), according to the Anderson-Patella classification[30],
as well as by Goldmann perimetry; (2) an abnormal decrease in the
circumpapillary retinal nerve fiber layer thickness (cpRNFLT); (3) a normal
open angle as determined by gonioscopy; (4) absence of a history of IOP more
than 21 mmHg; and (5) absence of a history of systemic disease (including
intracranial diseases) that can cause visual field defects. Consequently, 20
eyes of 20 patients diagnosed with NTG and 20 eyes of 20 age-matched controls
with no diagnosis of glaucoma despite the presence of visual field defects
indicative of other causes were included in this cross-sectional study. The
worse eyes were selected if both eyes were applicable for this study. Figure 1
shows a representative patient with NTG (A) and a patient without glaucoma (B).
Nine out of 20 patients with NTG were using anti-glaucoma eyedrops (3:
tafluprost, 3: timolol, 2: latanoprost, 1: carteolol).
Assessment of
ONH blood flow
The principles of LSFG-NAVI (Softcare Co., Ltd., Fukuoka, Japan),
illustrated in Figure 2, have been described in detail elsewhere[27].
Briefly, this instrument comprises a fundus camera equipped with a diode laser
(wavelength, 830 nm) and an ordinary charge-coupled device (CCD) camera
(750×360 pixels). The mean blur rate (MBR) represents the blurring of the
speckle pattern formed by the interference of a laser scattered by blood cells
moving in the ocular fundus. A previous study suggested that absolute MBR
values for the ONH correlate with capillary blood flow (CBF) and linearly
change with it, indicating the quantifiability of these values at least under
certain conditions, i.e., in the absence of large topographical or color
differences in the ONH induced by races, diseases, etc., which affect
absorption and reflection of the laser beam[31]. LSFG measurements
were conducted a month after the withdrawal of all anti-glaucoma eyedrops in
patients who were using them. The measurement time of the day was set between 1
p.m. and 4 p.m. After the pupil was dilated with 0.4% tropicamide (Midrin-M,
Santen Pharmaceutical Co. Ltd., Osaka, Japan) and subjects kept sitting
position for more than 15 minutes, MBR images were continuously acquired at the
rate of 30 frames per second over 4 s. The LSFG Analyzer software (Softcare
Co., Ltd.) synchronized all captured MBR images with each cardiac cycle, and
the averaged MBR of a heartbeat was displayed as a composite map. After the
margin of the ONH was identified using a round band, the software segmented out
the vessels using the automated definitive threshold (Figure 2A and 2B) and
analyzed the mean MBR for the entire ONH (MA), that for the ONH large vessels
(MV), and that for the ONH tissue (MT).
Measurement of
clinical parameters
IOP was measured using the Goldmann applanation tonometer just before
blood flow measurement. The mean deviation (MD) was obtained by the SITA
strategy of the 30-2 program of the HFA. CpRNFLT was assessed using the Retina
Scan (RS-3000, Nidek, Co., Ltd., Gamagori, Japan) OCT device. Cup/disc ratio
was obtained by the stereo fundus camera (nonmyd WX, Kowa, Company, Ltd.,
Nagoya, Japan) and its software (VK-2 WX, Kowa). To reduce inter-examiner
variability, 3 data of cup/disc ratio by different examiners was averaged for each
subject.
Statistical
analysis
Each result is expressed as the mean ± standard deviation (SD).
Statistical comparisons between the two groups were evaluated by Student’s
t-test for unpaired data or Fisher exact test. Differences were considered
statistically significant at p<0.05. Correlations between two
parameters, including ONH blood flow, MD, and cpRNFLT, were verified by simple
regression analyses.
RESULTS
The demographic characteristics of patients with and without glaucoma
are shown in Table 1. There were no significant differences in ages, gender
distribution, refractive errors, visual acuity, and IOP between the two groups,
whereas there were significant differences in the cup/disc ratio, MD, and
cpRNFLT.
The MBR values
for the two groups are shown in figure 3. MA and MT were significantly lower in
the NTG group than in the nonglaucoma group, while there was no significant
difference in MV between the two groups. In addition, the overlap of MT in the
two groups was relatively small compared to that of MA (Figure 4).
There were
significant correlations between MA and MD and between MT and MD only in the
NTG group (Figures 5 and 6). On the other hand, there was no correlation
between MT and cpRNFLT in both groups, although MA correlated with cpRNFLT only
in the NTG group (Figures 7 and 8). In addition, MD correlated with cpRNFLT in
both groups (Figure 9).
In addition,
no significant correlations were found between refractive error and MBR values
(MA, MV and MT) in both groups (data not shown).
DISCUSSION
In the present study, we compared ONH blood flow between myopic
glaucomatous eyes and myopic nonglaucomatous eyes to verify whether the
measurement of this parameter is useful for the differential diagnosis of
glaucoma in eyes with myopic ONHs and visual field defects. The results
revealed that the ONH blood flow, particularly in the ONH tissue, was
significantly poorer in glaucomatous myopic ONHs than in nonglaucomatous myopic
ONHs. Furthermore, it correlated with MD in the glaucomatous myopic eyes, but
not in the nonglaucomatous myopic eyes. Blood flow in the ONH tissue of the
glaucomatous myopic eyes was not associated with cpRNFLT.
We used LSFG
for assessment of ONH blood flow in the current study because its validity and
reproducibility have been previously demonstrated[31,32]. In
addition, our recent studies suggested that absolute MBR values for the ONH
correlated with CBF, indicating the quantifiability of these values in the
absence of large topographical and color differences in the ONH[31,33].
This condition was probably observed in the present study because we compared
MBR values among eyes with myopic ONHs, which have similar topographical and
color appearances.
According to
our results, MA and MT were significantly lower in myopic glaucomatous eyes
than in myopic nonglaucomatous eyes, whereas MV did not show any difference,
suggesting a selective decrease in blood flow in the ONH tissue, not the ONH
large vessels, in glaucomatous eyes. A similar result was reported only for MA
in previous studies, which compared myopic glaucomatous eyes with myopic
control eyes[28,29]. In addition, the current study indicated a
relatively small overlap of MT distribution in the glaucomatous and
nonglaucomatous eyes, compared to that of MA. Furthermore, myopic glaucomatous
eyes showed a strong correlation between MA and MD (p=0.0014, r
=0.66), similar to the findings in previous studies (p<0.001, =0.58 or 0.63)[28,29], and
between MT and MD. In addition, there was a significant correlation between MA
and cpRNFLT, as reported in previous studies[28,29], while MT showed
no correlation with cpRNFLT. Therefore, MT may be relatively independent of a
decrease in cpRNFLT, at least in a certain stage of glaucoma, suggesting, for
the first time as per our knowledge, that a decreased MT can be a potential
critical parameter for the development of glaucoma, apart from a decreased
cpRNFLT.
Significant
correlations between cpRNFLT and MD were detected not only in myopic
glaucomatous eyes but also in myopic nonglaucomatous eyes, suggesting that
cpRNFLT is also a critical parameter, though reduced ONH blood flow is not such
a critical parameter in nonglaucomatous eyes. Myopic nonglaucomatous eyes in
the current study showed various types of optic nerve hypoplasia; one of the
representative types is superior segmental optic nerve hypoplasia (SSOH). A
recent study also suggested that LSFG measurements, in addition to the analysis
of cpRNFLT, may be useful to differentiate SSOH and NTG because of differences
in ONH hemodynamics caused by different pathophysiologies between the two
conditions[34].
The
significant intergroup differences in MD and cpRNFLT were possibly related to
the difference in ONH blood flow in this study. Nevertheless, the decreased ONH
blood flow may be involved in the pathology of glaucoma in myopic eyes because
a significant correlation between MD and ONH blood flow was found only in
glaucomatous eyes.Furthermore, it remains unclear whether the difference in ONH
blood flow caused or resulted from glaucomatous impairment in ONH.
This study had
several limitations. First was the small sample size. The results in the
current study should be verified in a multicenter study in the future. Second,
MD could not be matched between the two groups. If MD was matched, the results
of this study would be more justified. Third, this study included no normal
controls since it did not seem proper to compare MBR values between ONHs with
normal or abnormal configuration. Fourth, we did not use the data from multiple
measurements of blood flow and IOP in the day. Instead, we standardized the
measurement time of the day to avoid diurnal fluctuation. Fifth, we could not
examine the correlation between cpRNFLT and blood flow in each quadrant of the ONH
because all patients had tilted discs, which made accurate division into
superior, inferior, temporal, and nasal quadrants difficult.
In conclusion,
assessment of blood flow in the ONH tissue, in addition to the evaluation of
cpRNFLT, may be useful for the differential diagnosis of NTG in patients with
myopic ONHs. Further studies with a larger sample size and MD-matched groups
are needed to verify the present conclusions.
ACKNOWLEDGMENTS
The authors thank the editors at Editage, a devision of Cactus
Communications, for English language editing.
CONFLICT OF INTERESTS
The author has no conflicts of interest to declare.
REFERENCES
1 Resnikoff
S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti
SP. Global data on visual impairment in the year 2002. Bull World Health Organ
2004; 82: 844-851.
2. Quigley
HA. Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust N Z J Opthalmol 1995; 23: 85-91.
3. Hitchings
RA, Spaeth GL. The optic disc in glaucoma II: correlation of the appearance of
the optic disc with the visual field. Br J Ophthalmol 1977;
61: 107-113.
4. Kass
MA, Hart WM Jr, Gordon M, Miller JP. Risk factors favoring
the development of glaucomatous visual field loss in ocular hypertension.
Surv Ophthalmol 1980; 25: 155-162.
5. Richler
M, Werner EB, Thomas D. Risk factors for progression of visual field defects in
medically treated patients with glaucoma. Can J Ophthalmol 1982; 17: 245-248.
6. Araie
M, Sekine M, Suzuki Y, Koseki N. Factors contributing to the progression of
visual field damage in eyes with normal-tension glaucoma. Ophthalmology
1994; 101: 1440-1444.
7. Daugeliene
L, Yamamoto T, Kitazawa Y. Risk factors for visual field damage progression in
normal-tension glaucoma eyes. Graefes Arch Clin Exp
Ophthalmol 1999; 237: 105-108.
8. Mastropasqua
L, Lobefalo L, Mancini A, Ciancaglini M, Palma S. Prevalence of myopia in open
angle glaucoma. Eur J Ophthalmol 1992; 2: 33-35.
9. Mitchell
P, Hourihan F, Sandbach J, Wang JJ. The relationship between glaucoma and
myopia: the Blue Mountains Eye Study. Ophthalmology 1999;
106: 2010-2015.
10. Suzuki
Y, Iwase A, Araie M, Yamamoto T, Abe H, Shirato S, Kuwayama Y, Mishima HK, Shimizu
H, Tomita G, Inoue Y, Kitazawa Y; Tajimi Study Group. Risk factors for
open-angle glaucoma in a Japanese population: the Tajimi Study. Ophthalmology
2006; 113: 1613-1617.
11. Marcus
MW, de Vries MM, Junoy Montolio FG, Jansonius NM. Myopia as a risk factor for
open-angle glaucoma: a systematic review and meta-analysis. Ophthalmology 2011;
118: 1989-1994.
12. Gasser
P. Ocular vasospasm: a risk factor in the pathogenesis of low-tension glaucoma.
Int Ophthalmol 1989; 13: 281-290.
13. Flammer
J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK. The impact
of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21: 359-393.
14. Galassi
F, Sodi A, Ucci F, Harris A, Chung HS. Ocular haemodynamics in glaucoma
associated with high myopia. Int Ophthalmol 1998; 22:
299-305.
15. Németh
J, Michelson G, Harazny J. Retinal microcirculation correlates with ocular wall
thickness, axial eye length, and refraction in glaucoma patients. J Glaucoma
2001; 10: 390-395.
16. Leung
CK, Mohamed S, Leung KS, Cheung CY, Chan SL, Cheng DK, Lee AK, Leung GY, Rao
SK, Lam DS. Retinal nerve fiber layer measurements in myopia: An optical
coherence tomography study. Invest Ophthalmol Vis Sci 2006; 47: 5171-5176.
17. Kim
MJ, Lee EJ, Kim TW. Peripapillary retinal nerve fibre layer thickness profile
in subjects with myopia measured using the Stratus optical coherence
tomography. Br J Ophthalmol 2010; 94: 115-120.
18. Kang
SH, Hong SW, Im SK, Lee SH, Ahn MD. Effect of myopia on the
thickness of the retinal nerve fiber layer measured by Cirrus HD optical
coherence tomography. Invest Ophthalmol Vis Sci 2010; 51: 4075-4083.
19. Melo
GB, Libera RD, Barbosa AS, Pereira LM, Doi LM, Melo LA Jr. Comparison of optic
disk and retinal nerve fiber layer thickness in nonglaucomatous and
glaucomatous patients with high myopia. Am J Ophthalmol 2006; 142: 858-860.
20. Kim
NR, Lee ES, Seong GJ, Kang SY, Kim JH, Hong S, Kim CY. Comparing the ganglion
cell complex and retinal nerve fibre layer measurements by Fourier domain OCT
to detect glaucoma in high myopia. Br J Ophthalmol 2011; 95: 1115-1121.
21. Shoji
T, Sato H, Ishida M, Takeuchi M, Chihara E. Assessment of glaucomatous changes
in subjects with high myopia using spectral domain optical coherence
tomography. Invest Ophthalmol Vis Sci 2011; 52: 1098-1102.
22. Witmer
MT, Margo CE, Drucker M. Tilted optic disks. Surv Ophthalmol 2010; 55: 403-428.
23. Chang
RT, Singh K. Myopia and glaucoma: diagnostic and therapeutic challenges. Curr
Opin Ophthalmol 2013; 24: 96-101.
24. Tamaki
Y, Araie M, Kawamoto E, Eguchi S, Fujii H. Non-contact, two-dimensional
measurement of tissue circulation in choroid and optic nerve head using laser
speckle phenomenon. Exp Eye Res 1995; 60: 373–384.
25. Tamaki
Y, Araie M, Tomita K, Nagahara M, Tomidokoro A, Fujii H. Real-time measurement
of human optic nerve head and choroid circulation, using the laser speckle
phenomenon. Jpn J Ophthalmol 1997; 41: 49–54.
26. Sugiyama
T, Araie M, Riva CE, Schmetterer L, Orgul S. Use of laser speckle flowgraphy in
ocular blood flow research. Acta Ophthalmol 2010; 88: 723–729.
27. Sugiyama
T. Basic technology and clinical applications of the updated model of laser
speckle flowgraphy to ocular diseases. Photonics 2014; 1: 220-234.
28. Yokoyama
Y, Aizawa N, Chiba N, Omodaka K, Nakamura M, Otomo T, Yokokura S, Fuse N,
Nakazawa T. Significant correlations between optic nerve head microcirculation
and visual field defects and nerve fiber layer loss in glaucoma patients with
myopic glaucomatous disk. Clin Ophthalmol 2011; 5: 1721-1727.
29. Aizawa
N, Kunikata H, Shiga Y, Yokoyama Y, Omodaka K, Nakazawa T. Correlation between
structure/function and optic disc microcirculation in myopic glaucoma, measured
with laser speckle flowgraphy. BMC Ophthalmol 2014; 14: 113.
30. Anderson
DR, Patella VM. Automated static perimetry. 2nd ed. St
Louis: Mosby, 1999: 121-190.
31. Takahashi
H, Sugiyama T, Tokushige H, Maeno T, Nakazawa T, Ikeda T, Araie M. Comparison
of CCD-equipped laser speckle flowgraphy with hydrogen gas clearance method in
the measurement of optic nerve head microcirculation in rabbits. Exp Eye Res
2013; 108:10-15.
32. Aizawa
N, Yokoyama Y, Chiba N, Omodaka K, Yasuda M, Otomo T, Nakamura M, Fuse N,
Nakazawa T. Reproducibility of retinal circulation measurements obtained using
laser speckle flowgraphy-NAVI in patients with glaucoma. Clin Ophthalmol 2011;
5:1171-1176.
33. Aizawa
N, Nitta F, Kunikata H, Sugiyama T, Ikeda T, Araie M, Nakazawa T. Laser speckle
and hydrogen gas clearance measurements of optic nerve circulation in albino
and pigmented rabbits with or without optic disc atrophy. Invest Ophthalmol Vis
Sci 2014; 55: 7991-7996.
34. Aizawa
N, Kunikata H, Omodaka K, Nakazawa T. Optic disc microcirculation in superior
segmental optic hypoplasia assessed with laser speckle flowgraphy. Clin Exp
Ophthalmol 2014; 42: 702-704
Peer reviewers: Nader Hussein Bayoumi,
Associate Professor, Ophthalmology Department, Faculty of Medicine, Alexandria
University, Egypt; Barbara Cvenkel,
Department of Ophthalmology, University Medical Centre, Medical Faculty,
University of Ljubljana, Slovenia; Elie Beit-Yannai, PhD, Clinical Biochemistry
and Pharmacology Department, The faculty of Health Sciences, Ben-Gurion
University of the Negev, POB 653, Beer-Sheva, Israel.
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