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Major review

Optic disk hemorrhage in health and disease

M. Reza Razeghinejad, MDa,b,*, M. Hossein Nowroozzadeh, MDb

a
Glaucoma Service, Wills Eye Institute, Philadelphia, PA, USA
b
Poostchi Eye Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

article info abstract

Article history: Optic disk hemorrhage occurs in all age groups from neonates to the elderly. Optic disk
Received 30 December 2016 hemorrhage is best known for its association with visual field loss and progression in pa-
Received in revised form 31 March tients with glaucoma; however, it may occur in conjunction with other ocular or systemic
2017 conditions as well as in healthy individuals. It may also be the first sign of a sight-threatening
Accepted 3 April 2017 condition. Variations in the shape, location, and size of the optic disk hemorrhage, as well as
Available online 8 April 2017 associated ocular and systemic signs or symptoms, may help determine the underlying
pathology. We address the epidemiology, demographics, pathophysiology, clinical pre-
Keywords: sentations and implications, differential diagnoses, and management of eyes with optic disk
glaucoma hemorrhage in diseased and healthy subjects.
hemorrhage ª 2017 Elsevier Inc. All rights reserved.
optic disk
retinal diseases

1. Introduction thus, it may be difficult to detect clinically. ODHs more

commonly occur with glaucoma or ocular hypertension;
The term “glaucoma hemorrhagicum” was first introduced in however, they may be detected in apparently normal eyes.
1876 by Albert Emmerich to describe the association between Therefore, careful ocular and systemic evaluations are
optic disk hemorrhage (ODH) and glaucoma.A More than a required to ensure the correct diagnosis from the list of dis-
century later, Drance and Begg47 revisited this finding with eases that cause ODH.
their study of a splinter hemorrhage on the disk rim in a pa-
tient with a new visual field defect. ODH is classified based on
the location or shape of the hemorrhage. With respect to
2. Prevalence and incidence
location, ODHs are divided into 4 types: within the cup base,
cup margin, disk margin, or peripapillary. Regarding the
In large population-based studies, the prevalence of ODH has
shape, a classic ODH is a flame-shaped or splinter oriented
ranged from 0% to 1.4% in healthy individuals and from 4.2%
radially at the border of the optic nerve head or a dot hem-
to 17.6% in patients with glaucoma (Table 1).8,44,56,62,169,174,182
orrhage.62 ODHs may be detected in all age groups from neo-
The highest rate for ODH has been reported in glaucomatous
nates to the elderly. ODH is typically a highly localized and
Japanese subjects, which may be a result of the relatively
temporary event with no dramatic-associated symptoms;
higher prevalence of normal-tension glaucoma (NTG), the

* Corresponding author: M. Reza Razeghinejad, MD, Wills Eye Institute, 840 Walnut Street, Suite 1140, Philadelphia, PA 19107, USA
E-mail address: razeghinejad@yahoo.com (M.R. Razeghinejad).
0039-6257/$ e see front matter ª 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.survophthal.2017.04.001
Table 1 e Demographic details of population-based studies of optic disk hemorrhage
Authors Number of Method of ODH Age R/L Prevalence Unilateral/ Prevalence in Factors ODH prevalence in
subjects detection (years) ODH (%) bilateral different age associated glaucomatous/
groups (%) with ODH healthy
patients (%)
Eye Subject 30e39 40e49 50e59 60e69 70e79 >80
62
Healey et al 3654 Funduscopy and >49 22/34 0.8 1.4 45/5 0.2 (30e69 years) 1.4 1.9 Increasing IOP, 13.8/1
fundus photo increasing
BP, diabetes
mellitus,
pseudoexfoliation,
high C/D ratio, and
migraine in
nonglaucomatous

s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
subjects
Jonas et al84 4570 Fundus photo >30 d 0.19 0.35 d 0.05 0.1 0.13 0.25 0.91 d Glaucoma, 5.7/0.07
older age
Yamamoto et al182 13,965 Fundus photo >40 55/41 0.3 0.6 84/4 d 0.2 0.5 0.8 1.1 d Female sex, 8.2/0.2
older age
Wang et al174 4378 Fundus photo >40 d 1.24 d d 0.5 0.5 0.6 1.1 (60e79 years) d Older age, 8.8
glaucoma
Sugiyama et al162 5967 Fundus photos >19 d 0.3 0.6 34/1 d Zone alpha 4.3/0.2
and beta,
female, older age
Bengtsson16 1496 Fundus photo >55 d 1.4 0.7 25/2 d d 0.3 0.7 1.4 d Older age d/0.7
Kim et al92 5612 Fundus photo >19 d d 0.42 d 0 0.52 0.52 0.56 1.27 2.09 Older age, 2.82/0.32
glaucoma
Tomidokoro et al169 2761 Fundus photo >40 d d 1.2 34/0 d 0.52 0.64 0.16 0.25 0.3 Older age, 14/0.4
glaucoma,
suspected
glaucoma
Park et al136 164,029 Fundus photo >20 120/113 0.07 0.14 219/7 0.08 0.18 0.2 0.27 0.56 d Older age, 5.66/0.5
glaucomatous
RNFL defect

d, data not available; BP, blood pressure; C/D ratio, cup/disk ratio; IOP, intraocular pressure; ODH, optic disk hemorrhage; RNFL, retinal nerve fiber layer.

785
786 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
most common type of glaucoma in Japan,152 that has the
strongest association with ODH.44,101
2.1. Healthy individuals
The prevalence of ODH in healthy individuals is substantially
lower than that in glaucomatous patients17,28,37,62,156; how-
ever, because of the relative rarity of glaucoma, most ODHs in
a given population are found in healthy individuals. For
example, in a population-based study from China, 20% of the
observed ODHs were detected in glaucomatous optic disks,
whereas 80% of the ODHs were detected in eyes with a normal
optic nerve head appearance.174 Before labeling a patient with
ODH as a healthy individual, ocular or systemic associates of
ODH must be excluded.
2.2. Ocular hypertension
The incidence of ODH in eyes with ocular hypertension lies
between those in normal and glaucomatous eyes.62 In the
Ocular Hypertension Treatment Study (OHTS),28 the cumula-
tive incidence of eyes with at least 1 ODH before primary
open-angle glaucoma (POAG) development was approxi-
mately 0.5% per year over 8 years of follow-up. The cumulative
incidence of 1 or more ODHs after POAG onset was approxi-
mately 2.5% per year.28 In the European Glaucoma Prevention
Study, 120 of 1077 participants developed POAG. Ten (8.33%) of
the 120 participants who developed POAG and 28 (2.93%) of the
957 who did not convert to POAG had ODH.123
2.3. Glaucoma
Glaucoma is the most important single entity attributed to
ODH. Among individuals with glaucoma, ODH occurs up to
four times more frequently in NTG than in POAG patients with
a baseline intraocular pressure (IOP) of >21 mm Hg.62,83,101,154
The reported ranges for the rates of ODH were 19.4% to 35.3%
and 4.2% to 17.6% for NTG and POAG, respectively.56,62,64,101,165
The prevalence of ODH in primary angle-closure glaucoma
(PACG) has been reported to be relatively lower (1.1%e5.7%)
than the prevalence of either NTG or POAG.54,111,154 The
Fig. 1 e A: Splinter- and B: blot-shaped optic disk hemorrhages.
reported incidence of ODH ranged from 0.11 to 0.46.64,124,165
The incidence of ODH substantially varies between studies
depending on the frequency of examination, duration of
follow-up, clinical examination protocols, methods for
detection and monitoring of ODH, study populations, and
systemic diseases or medications that have been reported to
be associated with ODH. ODHs are transient and recurrent;
thus, with a greater number of examinations and a longer
follow-up period, the probability of identifying an ODH in the
studied population increases.56
3. Clinical characteristics
3.1. Shape
In general, an ODH is divided into splinter or flame-shaped
and blot hemorrhages (Fig. 1). The splinter hemorrhage is a
thin superficial hemorrhage stretched radially on the disk
border, often along a vessel, and may resemble a vessel. The
reported mean width of splinter hemorrhages is 1.33 mm,
ranging from 0.05 to 4.0 mm.27 The papillary portion of
splinter ODHs typically resorbs sooner than the extrapapillary
portion. Therefore, partially resorbed splinter hemorrhages
may be identified as peripapillary hemorrhages.159 ODHs that
occur centrally on the disk are often rounded (blot-shaped)
and typically occur in healthy individuals.62 According to
previous population-based studies, approximately 75% of
ODHs are splinter shaped, and the remaining ODHs are
blot.62,169 Splinter ODHs tend to be identified more frequently
on the temporal side of the optic disk, with the largest pro-
portion identified in the inferotemporal quadrant, whereas
blot ODHs are evenly distributed across sectors.62,79
3.2. Size
A previous study reported that ODHs were larger in area and
longer in length in NTG than POAG groups.99 Thus, reports that
indicated a greater prevalence of ODH in NTG may be, at least in
part, a result of the greater area and length of ODH in the NTG,
which makes it more detectable because of both the larger size
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
and longer persistence. Compared with POAG patients, the
larger ODH in NTG patients may result from an involvement of
larger peripapillary vessels or the tamponade effect of IOP, in
which NTG patients have a relatively lower IOP with a milder
tamponade effect. A higher IOP in POAG patients would stop
bleeding earlier and consequently result in a smaller ODH.99
There is the possibility that the optic nerve head tissue in
NTG may be more susceptible to damage and bleeding than
POAG because of the associated biomechanical properties,
including the lamina cribrosa and blood vessels.90,98,113,150
3.3. Location
Previous studies have invariably denoted the inferotemporal
quadrant as the most frequent site for both primary and
recurrent ODHs in patients with glaucoma, followed by the
superotemporal quadrant.8,16,159,165 Approximately 2/3 of all
ODHs in each glaucoma subtype occur at the inferotemporal
disk margin.72 The superotemporal area is involved in 19.9%,
17.1%, and 7.5% of cases with POAG, PACG, and NTG, respec-
tively.72 Notably, the inferotemporal and superotemporal re-
gions of the disk margin are also the sites where the earliest
glaucomatous changes are evident. In comparison, the loca-
tions of ODH in healthy subjects are more widely distributed
around the disk.169 In addition to the presence of glaucoma
and its subtypes as the most important determinant for the
location of the ODH, other factors have been reported to play a
role. In a series of patients with POAG, a greater IOP was
associated with hemorrhages in the horizontal meridian
(29 vs 23 mm Hg for hemorrhages in the horizontal vs vertical
meridians, respectively; P ¼ 0.005).138 In addition, race affects
the location of ODHs. A study comparing 551 black and 611
white patients indicated that 96% of all ODHs in white patients
were detected in the inferotemporal sector of the optic disk,
whereas 60% and 30% of ODHs in black subjects were identi-
fied inferotemporally and inferonasally, respectively.156
3.4. Multiplicity of ODHs
Multiple ODHs have been reported in up to 70% of glaucom-
atous eyes with ODH.19,53 In a study of NTG patients, 72.2%
had 2 or more ODHs in the same eye, and 53.8% had 4 or more
hemorrhages.53 In individuals with ocular hypertension,
multiple hemorrhages were identified in approximately 30%
of eyes with ODH.41 Moreover, it has been reported that white
patients had a greater predilection for multiple ODHs than
black patients.156
3.5. Timing of the initial ODH
In one study 387 patients (387 eyes) with NTG and 205 patients
(205 eyes) with POAG were examined every 1e3 months for
3 years, followed by every 1e6 months for up to 15 years. Most
ODHs were identified in the first 5 years of follow-up in both
groups. Approximately half of all initial ODHs were detected
in the first year, and approximately 3 quarters were identified
by 3 years. At 5 years, the incidence began to plateau, with few
initial ODHs identified after this time.165 These findings sug-
gest that ODHs may be involved in the early, rather than late,
pathophysiological process of glaucoma.
787
3.6. Recurrent ODHs
The rate of second and more ODHs has been reported as up to
73%17,63,64,101,143,151,154; however, the observed frequency of
ODH depends on several factors, including the type and stage
of glaucoma, frequency of eye examination, detection
method, and studied population. With more frequent exami-
nations or a more sensitive method of examination, there is a
greater chance of detecting recurrent ODHs. Most recurrent
ODHs occur within 5e24 months after the original ODH.47
Recurrences are thought to affect whites more than
blacks,156 as well as NTG patients rather than other sub-
categories of glaucoma.64,101 Notably, most recurrent ODHs
are identified in the same quadrant of the optic disk as the
previously identified primary ODH,47,101 which is typically at
the vicinity of the border between localized retinal nerve fiber
layer (RNFL) defects and the adjacent healthy retina.163,164 The
reported number of ODHs per year was greater in eyes with an
ODH that accompanied an RNFL defect (0.35) compared with
eyes with an ODH and no RNFL defect (0.22, P ¼ 0.034).132
4. Optic disk hemorrhage detection
ODH detection is challenging because ODHs are transient.
Unless patients are photographed or have dilated ophthal-
moscopy at the time of hemorrhage, there is a high probability
that ODHs would be missed during a single or limited number
of examinations.63 In some cases, ODHs are subtle and may be
easily mistaken through the small pupil for a congested blood
vessel, dilated capillaries, or neovascularization. ODHs persist
for 2e62 weeks, with an average of 10e12 weeks. Approxi-
mately 90% of ODHs last for 4e8 weeks after their first pre-
sentation.72,101 Given the transient nature of ODHs, one
should be vigilant when distinguishing recurrent hemor-
rhages from a hemorrhage that has persisted. In glaucoma
practice, the typical follow-up interval for patients with stable
glaucoma is 6 months; thus, it is possible for an ODH to occur
between visits and go undetected. Sonnsjo and colleagues159
suggested that the probability of finding an ODH in cases of
early glaucoma followed with repeated examinations is 80%,
and the lack of ODH detection may be a result of sparse ex-
aminations.106 There are several methods for documenting an
ODH, including ophthalmoscopy, fundus photography, and
other imaging modalities.
4.1. Ophthalmoscopy
Ophthalmoscopy through an undilated pupil may be insuffi-
cient to detect cases of ODH when they are subtle or close to
vascular or pigmented tissues, particularly in elderly in-
dividuals who have miotic pupils and cataracts. Pupillary
dilation improves the quality of optic disk observation and
thus the chance of ODH detection. Among different methods
of ophthalmoscopy, the use of magnifying lenses in
conjunction with a slit lamp yields the clearest view of the
optic nerve head with optimal magnification and stereopsis.
The gonioscopic lens has been considered to have the best
resolution; however, noncontact condensing lenses (such as
the 90 D lens) are substantially more convenient to both the
788 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
examiner and patient and provide nearly the same quality
image in the hands of an experienced observer.
It is well established that optic disk examination, in terms
of glaucoma diagnostic accuracy, is a skill that improves with
experience.2 Compared with novice ophthalmologists, expert
glaucoma specialists tend to take their time observing disk
areas with the greatest likelihood of pathology rather than
aimlessly examining around the disk.129 Taken together,
slit-lampeassisted indirect ophthalmoscopy using high-
magnification lenses with dilated pupils in the hands of an
experienced ophthalmologist is considered the best clinical
method for ODH detection.
4.2. Fundus photography
The early manifest glaucoma trial116 data have indicated that
careful funduscopy is nearly as good as photographic assess-
ment for ODH detection; however, the OHTS advocates fundus
photography as a better option for ODH detection. Ninety
percent of photographically documented ODHs were missed
in clinical examinations.28 Fundus photography has several
advantages over ophthalmoscopy. In contrast to clinical ex-
aminations that require an expert ophthalmologist, fundus
photography may be easily performed by a technician.
Documentation and archiving of fundus photographs enables
consultation with experts for difficult cases at any time. A
comparison of successive images is particularly helpful in
distinguishing a recurrent hemorrhage from a persistent
hemorrhage. Fundus photography, however, is not available
in every ophthalmic office, entails greater costs, and may lead
to poor-quality images (2.9% of 28,396 photos in one study).182
Among the different techniques of fundus photography,
alternation flicker had the best sensitivity for ODH detection,
which was more dramatic for difficult cases.166
4.3. Optical coherence tomography
Optical coherence tomography (OCT) is not regarded as a
proper diagnostic tool for ODH detection; however, it is helpful
for evaluating the underlying pathophysiology of the hemor-
rhage. OCT may be used to easily locate an associated RNFL
loss after an episode of ODH and evaluate the relevance of
new ODHs to previous RNFL defects. OCT may also effectively
detect vitreopapillary traction associated with non-
glaucomatous ODH.69,85,179 OCT angiography enables the
noninvasive evaluation of the small vessels of the retina and
the optic nerve head and has the potential to further expand
our understanding of the background causes of ODH.65
4.4. Confocal scanning laser tomography
Compared with the classic fundus photography, confocal
scanning laser tomography (cSLO) produces higher resolution
images in different planes by reducing light scatter.168 The
standard cSLO, however, is equipped with a 670-nm red
laser,31 which cannot enhance the hemorrhage and has thus
failed to detect ODHs. Less than half of all photographically
detected ODHs were detected using a cSLO image, and the
cSLO was completely blinded to hemorrhages restricted to the
intrapapillary region.27 The recently introduced multicolor
cSLO incorporates 3 distinct wavelengths (blue reflectance,
488 nm; green reflectance, 515 nm; and infrared reflectance,
820 nm) and has been claimed to provide many advantages
compared with the standard fundus photography.168 The
value of this novel technique in ODH detection remains to be
determined.
5. Mechanisms of optic disk hemorrhage
development
The exact underlying pathophysiology of ODH remains un-
certain, and several different mechanisms and theories,
which can generally be categorized as mechanical or vascular,
have been proposed.
5.1. Mechanical
5.1.1. Alteration of the lamina cribrosa
The deformations or structural changes at the level of the lam-
ina cribrosa may cause mechanical disruption of the capillaries
secondary to stretching or degenerative changes, leading to an
ODH.113 High IOP has been identified as a major factor that may
alter the architecture of the lamina cribrosa.29,141 Impaired blood
supply to the lamina cribrosa may represent another factor that
can lead to structural changes, even within a statistically normal
range of IOP.45 The lamina cribrosa was thinner and prone to
more outward and radial deformation in eyes with ODH than
eyes without hemorrhage.113,131,132 Maximum alteration of the
lamina cribrosa was identified within a 1 clock-hour distance
from the location of ODH.113 Because of the inhomogeneous
microarchitecture of the lamina cribrosa, the peripheral part of
the lamina cribrosa is more prone to alterations, which may
explain the detection of most ODHs at the border of the optic
disk134; however, the previously described theory cannot explain
all cases of ODH. ODHs tend to occur more frequently in the
early (with less posterior bowing of the lamina cribrosa) than
late stages of glaucoma,6 as well as more frequently in NTG with
a predominance of shallow optic disk cupping than high IOP
glaucoma.101
5.1.2. Intraocular pressure and cerebrospinal fluid pressure
A population-based study conducted by Healey and col-
leagues62 indicates that the risk of ODH increases with
increasing IOP. A decreased incidence of ODH after reduction
of the IOP further suggests that it may be pressure related.64
Other studies have confirmed that IOP-reducing therapy
does not increase the frequency of ODH.38,160 Theoretically,
greater IOP fluctuations may cause transient mechanical
stresses on the optic nerve head vessels by increasing the
pressure difference across the vessel wall, which may be po-
tential mechanisms of ODH development; however, in clinical
practice, acute alterations in IOP do not appear to play an
important role in the development of ODH. During cataract
extraction by phacoemulsification, high absolute IOP and
large IOP fluctuations occur intraoperatively. The IOP
frequently exceeds 70 mm Hg. At times, the effective IOP may
decrease close to 0 mm Hg.178 Nevertheless, no statistically
significant change in the rate of ODH formation was identified
before and after phacoemulsification in a group of glaucoma
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
patients.22 One case report described a patient with a
controlled NTG who developed recurrent ODHs and glaucoma
progression likely because of decreased intracranial pressure
(ICP) after ventriculoperitoneal shunt surgery.32 It has been
suggested that the difference between the IOP and ICP rather
than the absolute IOP may determine the glaucomatous optic
neuropathy findings, including ODH. Normal values for IOP
and ICP are 10e21 mm Hg and 5e15 mm Hg, respectively.
Therefore, a small positive pressure gradient typically exists
across the lamina cribrosa from the intraocular compartment
to the retrolaminar portion. Providing a constant IOP and
lower ICP results in a greater gradient at the lamina cribrosa
and may lead to worse glaucomatous optic neuropathy.59 This
issue was assessed in an experimental study with monkeys.
Nine monkeys had lumboperitoneal shunts placed, 4 of which
had the shunts opened to achieve a lower ICP. Two of the 4
monkeys with reduced ICP had a bilateral increased cup/disk
ratio, and 1 monkey developed ODH. The 5 controls, as well as
1 monkey with a low ICP, did not develop evidence of optic
neuropathy.183 The conflicting role of the IOP in ODH devel-
opment may be addressed in future studies that simulta-
neously evaluate the IOP and ICP in patients with ODH.
5.1.3. Retinal nerve fiber layer loss
RNFL loss has been suggested as both the cause and result of
ODH. In a prospective study, NTG patients were divided into 2
groups (enlarged vs stable RNFL loss area). The frequencies of
ODH development and recurrent ODHs were 4 and 5 times
greater in the enlarged RNFL loss group. RNFL loss was
enlarged in the direction of ODH in 84%.128 In a study of 36
eyes of 36 glaucoma patients with ODH, 57.9% of the 19 eyes
with ODH that accompanied an RNFL defect had a vessel
filling defect or delayed filling on fluorescein angiography,
whereas none of the eyes with ODH not related to an RNFL
defect had these findings. The arteriovenous transit time was
more prolonged in the former group (2.79 vs 1.79 seconds,
respectively; P ¼ 0.02). Thus, the findings in the group with
RNFL defects indicated blood flow stasis.132 The loss of the
neuroretinal rim that supports the microvascular tissue may
lead to continued stress on the vessel walls and may result in
ODH and its recurrence.39,43,76
5.2. Vascular
5.2.1. Venous stasis/thrombosis
In some cases ODHs, particularly in NTG, may have a pathogenic
mechanism similar to a branch retinal vein occlusion that in-
volves the small vessels of the optic nerve head.95 The glau-
comatous changes in the lamina cribrosa may compress
adjacent veins and predispose them to thrombosis and occlu-
sion, similar to classic branch retinal vein occlusion at an arte-
riovenous crossing. In support of the idea, Sonnsjo and
colleagues161 found that the incidence of concurrent retinal
venous occlusion in cases with ODH (10.5%) was higher than that
in control subjects (1.3%). They proposed that the classic ODHs,
branch retinal vein occlusions, and central retinal vein occlu-
sions are various manifestations of the same vascular disease,
and the only difference is in the size or location of the involved
vessel.161
789
5.2.2. Arteriolar microinfarction
Considering the significant incidence of RNFL loss at the
location of the ODH and evidence of generalized vascular
disorders in ODH patients, such as hypertension and dia-
betes, microinfarction of the anterior optic nerve head has
been suggested as a mechanism for ODH formation. The lack
of pale edema of the disk associated with anterior ischemic
optic neuropathy has been justified by the small degree of
damage.15 In support of this, there is evidence of endothelial
proliferations in the vessels of glaucoma patients that are
thought to make them susceptible to infarction.107 Scanning
laser Doppler flowmetry of peripapillary blood vessels indi-
cated a reduced flow at the time of ODH108; however, ODHs
are not associated with cotton-wool spots, a marker of
ischemia,81 and the corresponding visual field defects are
absent or occur after several months,16,63 which argues
against this proposed ischemic mechanism for ODH.
5.2.3. Vascular dysregulation syndrome
Vascular dysregulation syndrome (VDS) is characterized by
vasospasm and insufficient venous dilation after exposure to
cold, physical, or emotional stress. It is mainly divided into
primary VDS (formerly referred to as vasospastic or Flammer
syndrome) and secondary VDS. The cause of primary VDS is
vascular endotheliopathy and dysfunction of the autonomic
nervous system, whereas secondary VDS occurs in the
context of other diseases, such as multiple sclerosis, retro-
bulbar neuritis, rheumatoid arthritis, fibromyalgia, and giant-
cell arteritis.52 In Switzerland, approximately 10% of women
and 3% of men exhibit the classic symptoms of primary VDS.52
The ocular findings include increased retinal venous pressure,
stiffer and irregular retinal vessels, disturbed autoregulation,
fluctuating visual field defects, and ODH in the absence of
glaucoma.52,57 These subjects are at increased risk for NTG,
retinal artery and vein occlusions, and anterior ischemic optic
neuropathy.52 Similar to glaucoma cases, they have higher
plasma concentrations of endothelin-1 and matrix
metalloproteinase-9, which cause vasoconstriction, loosening
of endothelial tight junctions, and breakdown of the basement
membrane, thereby resulting in ODH.103
5.2.4. Systemic vasculopathy
There are reports of increased nailfold hemorrhages in pa-
tients with glaucoma that support a link between hemor-
rhages as a sign of systemic vascular disease and glaucoma. In
a study by Park and colleagues,135 32% of patients with POAG
and 16% of patients with NTG had nailfold hemorrhages
compared with 3% of control subjects. The association be-
tween ODH and nailfold hemorrhage for glaucoma was sig-
nificant (odds ratio [OR] 66; 95% confidence interval [CI]
14.3e304.2; P < 0.01). Decreased levels of hyaluronic acid and
von Willebrand factor were identified in patients with glau-
coma compared with control subjects and were suggested as
laboratory confirmations of systemic vasculopathy in glau-
coma157; however, the association between the concurrent
incidence of ODH and nailfold hemorrhages in glaucomatous
eyes has been debated.137 Systemic vascular problems, as
indicated by nailfold hemorrhages, may be involved in the
pathophysiology of ODH in a subset of glaucoma patients.
790 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
5.2.5. Central retinal venous pressure
Under normal circumstances, the retinal venous pressure is
approximately equal to the IOP, whereas it is often increased in
glaucoma patients.1,126 It is suspected that in glaucoma venous
walls are thickened in response to higher shear forces, which
results in greater flow resistance in the veins and may explain
the higher rate of ODH and central retinal vein occlusion.125
Kim and colleagues91 compared the central retinal venous
pressure among fellow eyes of NTG patients with unilateral
ODH and NTG patients without ODH. The central retinal
venous pressure of either eye in NTG patients with unilateral
ODH was significantly lower than that of patients without ODH.
In a multivariable analysis, a low central retinal venous pres-
sure (OR, 0.88; 95% CI, 0.80e0.95; P ¼ 0.003) was associated with
ODH. The mechanism driving spontaneous venous pulsations
is not completely understood; however, the variation in the
pressure gradient along the retinal vein as it traverses the
lamina cribrosa has been proposed as a potential mecha-
nism.176 The absence of spontaneous venous pulsation is likely
a result of increased resistance in the central retinal vein at the
retrolaminar area.77 In a study of 52 patients with ODH and 11
individuals without ODH, the frequency of spontaneous venous
pulsation was not significantly different (63.5% and 59.5%,
respectively). In addition, there was no significant difference in
the frequency of spontaneous venous pulsation between the
single ODH group and the recurrent ODH group (58.1% vs 71.4%,
respectively).93 These findings argue against the theory of
increased resistance in the central retinal vein in ODH.
6. Differential diagnoses
The differential diagnoses of ODH may be divided into 2 major
groups: ocular and systemic diseases. A complete ocular ex-
amination, including a dilated ophthalmoscopic examination
and medical history, may help to determine the underlying
causative disorder. Glaucoma is the most important associate of
ODH and should be excluded in every case with a typical ODH.
6.1. Nonglaucomatous ocular diseases
6.1.1. Retinal diseases
Retinal vein occlusion may involve central or branch retinal
veins. A typical central retinal vein occlusion, in addition to
other manifestations, is associated with innumerable or
confluent dot- or flame-shaped peripapillary hemorrhages
and disk edema.140 Sectoral peripapillary hemorrhages and
disk edema may occur in branch retinal vein occlusion with
the occlusion site close to the disk.78
Multilayered optic disk hemorrhage is characterized by sub-
retinal, superficial retinal, and subhyaloid or vitreous hem-
orrhages in adolescents. It is typically accompanied by acute
visual symptoms of floaters or blurring. Subretinal hemor-
rhages are often located at the nasal disk with flame-shaped
ODHs at the superior hemidisk. Myopia with a crowded or
tilted disk is the main risk factor for this condition.75,153
Despite the dramatic clinical picture, the course is typically
benign, and the prognosis is generally favorable.75 In a series
of 16 patients with multilayered ODH, 9 patients were female,
and the mean age was 15 years. None of the patients had a
systemic disease or were on antiplatelet drugs or anticoagu-
lants. The extent of hemorrhage in patients with this condi-
tion is typically greater than that in patients with typical ODH;
however, 5 patients had a superficial flame-shaped ODH
located at the superotemporal and superonasal parts of the
disk, which could be confused with a classic ODH.75 Crowded
disks with hemorrhages may resemble papilledema; thus,
clinicians should be vigilant regarding this rare condition and
avoid costly and invasive diagnostic tests, such as lumbar
puncture or brain imaging. The suggested pathogenic mech-
anisms of multilayered ODH include a complicated posterior
vitreous detachment (PVD) and vitreopapillary traction.36
Posterior vitreous detachment may be associated with ODH. In
1 study, 8 healthy individuals with optic disk and peripapillary
hemorrhage, aged 11 to 42 years, with no or mild visual
symptoms, had an incomplete PVD.87 The posterior vitreous
body was separated from the retina; however, it remained
attached to the disk as a result of the tenacious vitreopapillary
attachments. All hemorrhages were at the superior or super-
onasal part of the optic disk. The optic disk component of the
hemorrhages resorbed within weeks; however, the retinal
component lasted longer (6 months).87 Jonas and Ritch re-
ported a case of partial PVD with ODH documented by OCT in
a healthy nonglaucomatous patient. The ODH was dot rather
than flame shaped.85 The acute symptoms of an impending
PVD, combined with a careful examination of the vitreoretinal
interface and the use of adjunctive imaging modalities, such
as OCT, enable the detection of a posterior vitreous traction as
the causative mechanism for an ODH.
Peripapillary intrachoroidal cavitation is characterized by an
asymptomatic, localized yellow-orange peripapillary eleva-
tion of the retinal pigment epithelium and retina. The most
common location of the lesion was the inferotemporal part of
the disk with a corresponding superior visual field defect that
mimicked a glaucomatous field defect.12,130 Recurrent ODH
over 2 years of follow-up was identified in a myopic patient
with peripapillary intrachoroidal cavitation. The mechanism
of stretch and damage to the peripapillary vessels and ODH
formation was potentially the entrance of extravasated fluid
within the peripapillary intrachoroidal cavitation into the
prelaminar tissue and aggravation of the prelaminar
schisis.114
Peripapillary subretinal hemorrhages may be small and close
to the optic disk in some patients and may resemble a typical
ODH. Symptomatic peripapillary subretinal hemorrhages are
occasionally identified in idiopathic choroidal neo-
vascularization, choroidal neovascularization secondary to
age-related macular degeneration, myopic degeneration,
angioid streaks, and polypoidal choroidal vasculopathy. The
condition has rarely been identified in association with other
peripapillary pathologies, such as choroidal osteoma, multi-
focal choroiditis, peripapillary pseudopodal pigment epithe-
lial and choroidal atrophy, punctate inner choroidopathy,
histoplasmosis, infectious chorioretinitis, optic disk drusen,
and congenital disk anomaly.3,20,26,67
6.1.2. Brain and optic nerve diseases
Optic disk drusen are in the differential of optic nerve head
elevation. The lumpy character of the optic disk swelling,
anomalous branching of vessels that are not buried in the disk
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
substance, highly reflective round structures with acoustic
shadowing in B-scan, and autofluorescence are among the
features that may facilitate the diagnosis of this condition.26,149
Three different patterns of peripapillary hemorrhages have
been reported in this condition: transient and clinically insig-
nificant small superficial ODHs; large ODHs that extend into the
vitreous humor with potential visual disturbances, which
typically resolve without a permanent visual deficit; and deep
peripapillary hemorrhages, which extend under the sur-
rounding retina and lead to permanent dysfunction and field
defects.144
Papilledema is characterized by disk swelling caused by
increased intracranial pressure. The swollen optic disk has
blurred margins associated with venous congestion, retinal
hard exudates, splinter ODH, and infarcts.177 In children, the
distribution pattern of retinal hemorrhage after increased ICP
is often peripapillary and invariably occurs adjacent to a
swollen optic disk.21 In a series of 100 children with papil-
ledema, 16 had retinal hemorrhages, 8 had superficial intra-
retinal peripapillary hemorrhage adjacent to a swollen optic
disk, and 8 had only a splinter ODH on a swollen disk.21
Terson syndrome is typically characterized as a subhyaloid,
peripapillary, or vitreous hemorrhage after an acute sub-
arachnoid hemorrhage. Isolated peripapillary and ODH may
occur rarely in this condition.49 The exact mechanism is not
established; however, it has been proposed that the abrupt
intracranial hemorrhage may cause an acute increase in the
intraocular venous pressure, which leads to the rupture of
peripapillary or retinal vessels. Terson syndrome may occur at
any age; however, it typically presents in individuals aged 30
to 50 years, and vision returns to normal in most cases once
the hemorrhage clears.49,120
Graves compressive optic neuropathy occurs in less than 5% of
patients with thyroid-related orbitopathy.88 Peripapillary
hemorrhages with optic disk swelling may be present in pa-
tients who experience more acute visual loss.40,170
Anterior ischemic optic neuropathy manifests with a charac-
teristic pale disk swelling, in which flame-shaped ODHs are a
frequent finding.60 In a series of 20 eyes, the most common
funduscopic findings were peripapillary splinter hemorrhages
(90%) and a sectorial swollen optic disk (60%).14
Optic neuritis presents with papillitis in one-third of pa-
tients may be associated with ODH. ODH was one factor that
conferred a low risk of developing clinically definite multiple
sclerosis in patients with optic neuritis and without lesions on
brain magnetic resonance imaging.24
Disk shape anomalies may predispose peripapillary vessels to
disrupt with trivial mechanical forces, such as vitreous trac-
tion.11,75 Hemorrhages may occur in the subretinal, intraretinal,
or subhyaloid/vitreous spaces.75 In addition, optic disk anom-
alies may occasionally cause peripapillary choroidal neo-
vascularization with associated hemorrhage.26,35
6.1.3. Trauma
Varma and colleagues172 reported a case of traumatic optic
neuropathy with ODH and no optic disk swelling. No
abnormal vascular finding was identified via fluorescein
angiography. Traumatic complete or partial PVD may lead to
classic ODH-like peripapillary hemorrhages.25,172 Traumatic
choroidal ruptures may occasionally be complicated by late-
791
onset neovascularization and associated hemorrhage that
extends to the optic nerve head.10 In a study on 22 eyes of 22
patients suffering from ocular contusion, however, no case of
ODH was identified, which implies that ODH is not a common
manifestation of ocular trauma.104
6.2. Systemic diseases
Optic nerve head changes imposed by glaucoma have been
suggested as the primary cause for ODH53,83,150; however, any
systemic disease with associated vasculopathy or coagulopathy
may further predispose patients to develop ODH.58 Systemic
conditions that affect the vasculature may be the cause of iso-
lated ODH in a normal eye or a predisposing factor for earlier
development of ODH in a glaucomatous patient.84,89
6.2.1. Hypertension
The classic hypertensive retinopathy encompasses a constel-
lation of retinal signs, including arterial narrowing/focal irreg-
ularities and retinal hemorrhages and/or exudates.180 In the
absence of these pathognomonic features, isolated ODH may
occur in hypertensive patients. In a population-based study
from Australia, 1.4% had ODH. After controlling for age and
gender, increasing systolic blood pressure was associated with
ODH (OR, 1.1 per 10 mm Hg; 95% CI, 1.0e1.3).62 In a study by Kim
and colleagues89 on NTG patients, systemic hypertension was
more frequent in cases with ODH, and a strong independent
association was identified between systemic hypertension and
ODH (hazard ratio [HR], 1.998; 95% CI, 1.094-3.651; P ¼ 0.024).
In another population-based study from India, however,
systolic blood pressure was significantly higher in individuals
with ODH, whereas no independent association was identified
between hypertension and ODH in a multiple regression anal-
ysis.84 In the Low-Pressure Glaucoma Treatment Study, a low
systolic blood pressure and low arterial ocular perfusion pres-
sure exhibited independent associations with the occurrence of
ODH.53 The identification of this contradictory association may
be rooted in the method of blood pressure measurement in this
study, which used the mean of multiple prospective measure-
ments of blood pressure during the follow-up period (rather
than a single cross-sectional type measurement) and included
hypotensive episodes from the overtreatment of systemic hy-
pertension,53 a condition that has the potential to cause a series
of complications, including stroke and reduction of ocular
perfusion pressure.13,122 Overall, these studies suggest that
disturbances in systemic blood pressure may lead to ODH in
both glaucomatous and normal patients. This association is
theoretically sensible because hypertension may cause
atherosclerosis and consequently thrombosis or mechanical
disruption of weakened vessel walls. The identification of an
ODH may necessitate an evaluation of systemic hypertension
and potentially its overtreatment.
6.2.2. Diabetes mellitus
Diabetes mellitus is a major cause of vasculopathy, and its
ocular hallmark is retinal hemorrhages.33 Studies have linked
diabetic vasculopathy to ODH. In a population-based survey,
ODH with and without diabetic retinopathy was identified in a
significantly greater percentage of diabetic patients compared
with nondiabetic subjects. Most individuals with ODH had
792 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
diabetic retinopathy; however, none of the individuals had
retinopathy-associated hemorrhages in field 1 images
(defined as 30 retinal photographs centered on the optic
disk).62 In another population-based study, 28.6% of patients
with ODH and 5.5% of individuals without ODH were diabetic;
however, there was no association between diabetes and ODH
in a multivariate model.84 Poinoosawmy and colleagues138
compared 62 patients with POAG and an ODH with 58
similar patients without an ODH and identified a higher inci-
dence of abnormal glucose tolerance (33.3% vs 9.4%, respec-
tively) or frank diabetes (14.6% vs 6.3%, respectively) in the
patients with ODH. This finding was corroborated by another
case-control study in which 29.2% of individuals in the ODH
group and none in the control group had diabetes (P ¼ 0.01).171
Diabetes appears to be a risk factor for the development of
isolated ODH, and well-designed meta-analyses have estab-
lished the association between diabetes and glau-
coma.23,184,185 Therefore, the identification of an ODH in a
diabetic patient may not necessarily be attributed to diabetic
vasculopathy, and further investigations to detect potential
associated glaucoma are warranted.
6.2.3. Hematologic disorders
Hemophilia is a bleeding disorder that may be associated with
ocular hemorrhages.66,119 ODH was reported in a case with
hemophilia A; however, the extent of hemorrhage was sub-
stantially greater than a typical ODH and involved both the
RNFL and subretinal space.173
Leukemic ophthalmopathy may present with retinal hemor-
rhages, and these hemorrhages may be limited to the peri-
papillary region.167 Up to 18% of acute leukemias and 16% of
chronic leukemias have leukemic infiltration of the optic
nerve, which causes optic disk edema and hemorrhage.100
6.2.4. Migraine
Migraine is associated with transient cerebral vasospastic
episodes that may result in impairments in the mechanisms
of autoregulation of blood flow and potential brain and optic
nerve ischemia.155 Both of these findings have been suggested
as the mechanisms of ODH development. There have been
mixed results regarding the association between migraine and
ODH. In a series of 137 patients of POAG, no association was
identified between ODH and migraine158; however, in a study
of NTG patients, a history of migraine (HR, 5.737; P ¼ 0.01) was
an independent risk factor for the development of ODH.53 In
the Blue Mountain Eye Study, there was a significant associ-
ation between migraine and ODHs only in healthy subjects
and not in glaucomatous patients.62
6.2.5. Systemic medications
Platelet aggregation inhibitors, Studies regarding glaucoma pa-
tients have shown an association between aspirin use and
ODH in glaucoma patients.22,158 This finding was supported by
a large population-based study, in which ODHs were identified
more in patients using platelet aggregation inhibitors (41/
2686; 1.53%) than the total population (285/32,918; 0.87%) (HR,
3.16; 95% CI, 1.97e5.06; P < 0.001).58 Kim and colleagues94
compared 54 glaucoma cases with ODH with 131 glaucoma
patients without ODH and reported there was no association
between ODH and aspirin use. Moreover, the population-
based Blue Mountain Eye Study reported the same results.62
In addition to its potential effect on the rate, aspirin use has
been associated with a greater area of ODH.99 The association
identified between aspirin and ODH may be attributed to an
actual increase in the risk of developing ODHs or producing
larger ODHs that may take longer to absorb. Regarding the
average time of 2 months for the resorption of an ODH, larger
ODHs may remain longer, which increases the possibility of
detection. Furthermore, patients who use aspirin are more
likely to have generalized vascular disease that, by itself, may
cause an ODH.58
Antihypertensive medications, One study reported a signifi-
cant association between the use of systemic b-blockers and
the development of ODH (HR, 5.585; 95% CI, 1.119e27.778; P ¼
0.007)53; however, the wide range of the CI and the lower limit
value of 1.119 imply a limited power of the study to effectively
explore this association. Other studies did not identify a sig-
nificant overrepresentation of ODH in subjects who use anti-
hypertensive agents.58,62
6.3. Newborns
Hemorrhages identified in healthy term newborns have varied
from isolated ODHs to hemorrhages that involve the macula.
The reported incidence of newborn fundus hemorrhages,
including ODH, substantially varied from 2.6% to 50%, which is
potentially a result of the different patient demographics,
time of first fundus examination, examiner specialty
(ophthalmologist vs pediatrician), and examination technique
(funduscopy vs fundus photography).48,55,145 Giles55 reported
that the incidence was reduced from 40% at 1 hour after de-
livery to 20% at 72 hours. The incidence was only 2.6% after 3
to 5 days in a group of healthy neonates.147
The 1-year results of the Newborn Eye Screen Test Study on
202 infants indicated a fundus hemorrhage at birth prevalence
of 20.3% (41/202). The hemorrhages were most commonly
optic nerve flame hemorrhages (48%) and white-centered
retinal hemorrhages (30%). Of 98 flame-shaped ODHs, 14
(14%), 31 (32%), 20 (20%), and 33 (34%) were located inferior,
nasal, superior, and temporal, respectively.30 Vaginal delivery
compared with cesarean section and vacuum-assisted vaginal
delivery increased the odds of fundus hemorrhage.30,175 It is
hypothesized that the passage of a baby’s head through the
birth canal causes an acute increase in the ICP, which is
aggravated by the use of instruments. This causes stasis of
blood flow in the central retinal vein, which subsequently
develops into an acute change in pressure of the central
retinal vein and may result in fundus hemorrhages.34
In addition to birth trauma, neonatal coagulopathies
associated with sepsis, shaken baby syndrome, and intracra-
nial hemorrhage are other mechanisms of newborn fundus
hemorrhage.148 Subdural and subarachnoid intracranial
hemorrhageeinduced fundus hemorrhages are peripapillary,
in some cases extensive, breaking into the vitreous. Moreover,
reabsorption may be delayed. Intraocular hemorrhages occur
simultaneously or within a few days in approximately 20% of
patients with subarachnoid hemorrhage.127 In shaken baby
syndrome, the reported incidence of fundus hemorrhage
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
varies from 65% to 89%. Fundus hemorrhages may involve the
optic disk; however, the hemorrhages are characteristically
intraretinal. In contrast to neonatal fundus hemorrhages that
resolve within days, these may last for several months or
years.110
7. Associations and risk factors
The pathogenesis of ODH has not been completely elucidated;
however, recognition of the associations and risk factors of
ODH may contribute to our understanding of the mechanisms
and an improved management of glaucoma.
7.1. Demographic factors
1. Sex: Conflicting results have been reported regarding the
association between ODH and gender. The ODH prevalence
in men was significantly higher than that in women via a
univariate analysis in a population-based study; however,
the difference was not significant via a multivariate logistic
regression analysis.136 Similarly, in a population-based
study from China, ODH was not associated with gender174;
however, in the Blue Mountain Eye Study, the prevalence of
ODHs was higher in women than men, and the difference
increased with age.8 A female preponderance of ODHs has
also been reported in several other studies.8,17,19,62,102,162,182
2. Age: There is solid evidence from many studies that ODH
occurrence increases with age (Table 1).16,62,99,174,182 In the
OHTS, the patients with ODH were older than the in-
dividuals without ODH (59.0 vs 55.2 years, P < 0.01).41 Jonas
and colleagues83 reported an OR of 1.48 for the 10-year in-
crease in age for the development of ODH (P ¼ 0.01). In the
Korean National Health and Nutrition Examination Sur-
vey,92 the prevalence of ODH increased with age and was
close to the value in the study by Jonas and colleagues83:
1.04-fold in 1 year and 1.54-fold in 10 years (P < 0.001).92
Kim and colleagues identified an association between a
greater area of ODH and older age.99 Optic nerve head
biomechanics, such as laminar and peripapillary scleral
connective tissue geometry, and material properties
(strength, stiffness, rigidity, compliance, and nutrient
diffusion capabilities) are affected by aging, which may
explain the susceptibility of the optic nerve to ODH in older
individuals.29 Aging also causes atherosclerosis, which
may be another risk factor for ODH.
3. Rural versus urban residential area: In the Korean National
Health and Nutrition Examination Survey, the prevalence
of ODH in rural areas was greater than that in urban areas.
The rural population was older and exhibited a significantly
higher systolic BP, BMI, hemoglobin A1C, and prevalence of
glaucoma.92 The older age, higher systolic BP, BMI, and
HbA1C, which are established risk factors for vascular
diseases and glaucoma, may explain the higher rate of ODH
in the rural population of this study. Furthermore, a
multivariate analysis did not identify an independent as-
sociation between ODH and residential area (P ¼ 0.3). In
contrast, in the Beijing Eye Study, ODH occurrence was
associated with urban regions, which may have been a
result of the older age of urban individuals.174 The present
793
literature does not support the residential area as an in-
dependent risk factor for ODH development.
4. Preferred sleeping position: In a study on NTG patients with
unilateral ODH, the frequencies of sleep position were as
follows: 23.5% no preferred lying position, 21% ODH
dependent-lateral decubitus position, 16.8%61 fellow eye
without ODH dependent-lateral decubitus, 22.7% supine,
1.7% prone, and 14.3% both lateral decubitus positions. The
preferred sleeping position was not associated with the
presence of unilateral ODH.97
5. Smoking: There are mixed reports regarding the associa-
tion between smoking and ODH. In the OHTS, a life-time
history of smoking at least 100 cigarettes28 as well as cur-
rent smoking in the early manifest glaucoma trial was
associated with a higher frequency of ODH.18 In a
population-based study, however, there was no difference
between subjects with and without ODH for smoking.169
6. Alcohol consumption: In a population-based study, alcohol
intake was classified based on the amount of alcohol and
the number of days of alcohol intake. The number of days
of alcohol use, rather than the amount, was associated
with ODH.136
7. Race: Nine hundred twenty-eight eyes of 551 African
descent and 1022 eyes of 611 European descent patients
with and without glaucomatous optic neuropathy were
followed for 13 years. ODH was more common in European
descent (4.8%) than African descent (1.1%; P < 0.001) in-
dividuals.156 The development of ODH was independent of
the size of the optic disk, which has been suggested to be
greater in those of African descent.83,86 This suggests that
the difference in the size of the optic disk among different
races may not be a reason for the development of ODHs.
7.2. Ocular factors
1. Cup/disk ratio: In hospital-based studies, the frequency of
ODH increased from an early stage of glaucoma to a me-
dium advanced stage and subsequently decreased toward a
far-advanced stage.81,86 The study by Jonas and col-
leagues86 on optic disk photographs of glaucomatous eyes
indicated that ODHs are unlikely to occur in disk regions or
eyes without a detectable neuroretinal rim. Therefore, it
may be reasonable to barely find ODH in nearly total cup-
ped optic disks. In the Blue Mountain Eye Study,62 ODHs
were more prevalent in eyes with greater vertical cup-disk
ratios after adjusting for age and gender only in subjects
without glaucoma. Similarly, in the OHTS, patients with
ODH had a greater cup/disk ratio than individuals without
ODH (0.45 vs 0.39, respectively, P < 0.01).41 A vascularized
substance is required for bleeding; thus, ODHs are less
likely to appear in an excavated disk than in a disk with a
pink neuroretinal rim.
2. IOP: ODHs tended to be detected in examinations when the
IOP was at a relatively lower level during a patient’s follow-
up. In a study of POAG patients over a follow-up of 9 years,
the IOP at the time of the first ODH was significantly (1.4 mm
Hg) lower than the average of the three previous visits.158 The
rate of ODH in NTG patients with a baseline IOP of <15 mm
Hg was higher than patients with an IOP >15 mm Hg115;
however, Miyake and colleagues124 identified a reduction in
794 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
the incidence of ODHs after trabeculectomy in a group of
POAG patients who had a mean IOP reduction of 43%, with no
change in the NTG group. The same results regarding NTG
were obtained in another study by Hendrickx and col-
leagues64 However, it should be noted that the IOP lowering
achieved with therapy in the NTG group was substantially
smaller (2.3 mm Hg) than that of POAG and glaucoma sus-
pects (5.5 mm Hg) in the study by Miyake and colleagues124
The effect of IOP on the development of ODH appears to be
complex. Chronic elevation of the IOP causes structural and
biomechanical changes on the optic nerve head, which have
been suggested to predispose eyes to ODH. IOP is typically
less than the intravascular pressure; therefore, lower IOPs
increase the hemodynamic pressure gradient between the
intravascular and intraocular spaces and may facilitate
hemorrhages in susceptible vessels. The beneficial effect of
IOP reduction on the frequency of ODH, and the occurrence of
ODH at lower IOPs, suggests that an ODH may be partially IOP
dependent or, at the very least, IOP sensitive.
3. Pseudoexfoliation: In the Blue Mountain Eye Study,62 a sig-
nificant association was identified between pseudoexfolia-
tion and ODHs, even in individuals without glaucoma. In
another population-based study, however, 85% of observed
ODHs were located in the eyes without pseudoexfoliation.16
4. Myopia: In a population-based study84 and early manifest
glaucoma trial,18 more ODHs were identified in myopic
patients, which conflicted with the results of another
population-based study.62
5. Peripapillary atrophy: Ahn and colleagues4 reported that
the area and extent of the peripapillary atrophy were
greater and more prevalent in glaucomatous eyes with
ODH, which is in concordance with other studies.94,142 Law
and colleagues112 reported that ODH was preceded by
peripapillary atrophy in a significant proportion (76%) of
their study population. In another study, the prevalence of
zone beta and alpha in nonglaucomatous eyes with ODH
was greater than that of eyes without ODH but not in
glaucoma patients.162 The zone beta of peripapillary atro-
phy is significantly correlated with the severity of glaucoma
and clinical features, such as neuroretinal rim loss,
decrease of retinal vessel diameter, and visual field de-
fects,80 as well as the absence of retinal pigment epithelium
and the thinning or absence of the choriocapillaris adjacent
to the disk.51 Therefore, these peripapillary vascular
changes may potentially lead to a vascular insufficiency at
the optic disk and ODH development.
6. Central corneal thickness: In a group of POAG, NTG, and
PACG patients, there was no significant difference between
the central corneal thickness of the eyes with recurrent
ODH and the fellow eyes without ODH for all types of
glaucoma.72 In the Beijing Eye Study, there was a statisti-
cally insignificant trend toward slightly smaller central
corneal thickness values in the hemorrhagic than non-
hemorrhagic groups.181 In the OHTS, eyes with recurrent
ODH had significantly thinner corneas (557 vs 554, respec-
tively, P < 0.01); however, the 3-micron difference may not
be clinically relevant.41
7. Pre-existing optic disk damage: In a prospective study, 50
eyes of patients with NTG and ODH were compared with 58
eyes of patients without ODH over 2 years of follow-up. The
highest incidence of ODH (78%) was identified in the infe-
rotemporal sector. The values for the rim area, rim volume,
mean RNFL thickness, and RNFL cross-section area in the
inferotemporal sector of the ODH group were significantly
smaller than the values in the same sector of the non-
hemorrhagic group.118 This finding is in accordance with
the study by Furalentto and colleagues,53 who showed that
the presence of rim loss increased the risk of ODH by
approximately 3-fold.
8. Antiglaucoma medication use: In a study of NTG patients,
there was no difference between timolol and brimonidine
in ODH development; however, greater recurrence of ODHs
was identified in individuals who received timolol.53
7.3. Systemic conditions
As previously discussed, diabetes and hypertension are the
two most common systemic associates of ODH. There are
some reports regarding the associations of systemic coagu-
lopathies or anticoagulant medications with ODH.22,89,158
There was no significant association between ODHs and a
history of stroke, angina, myocardial infarction, or smoking.62
8. Clinical implications
The positive predictive value of ODH for glaucoma varies in
different studies, including the Korean National Health and
Nutrition Examination Survey (41.4%; 12/29),92 Central India
Eye and Medical Study (64.7%; 11/17),84 Tajimi Study from
Japan (73.9%; 65/88),169 Beijing Eye Study (10%e20% depending
on the definition of glaucoma),174 and Blue Mountain Eye
Study (27.5%; 15/51).62 The highest positive predictive value
(73.9%) was identified in a report from Japan, where the most
patients suffer from NTG, which has more predilections for
ODH. The lowest value was identified in the Beijing study
(20%), where most patients have PACG, which has the lowest
rate of ODH.54,165 Therefore, the chance of having or devel-
oping glaucoma in a patient with ODH depends on the most
common type of glaucoma in the society in which the patient
originates.
In hospital-based studies, ODH has only rarely been iden-
tified in normal eyes, which suggests the high specificity of
ODH for glaucoma86; however, population-based studies have
demonstrated a lower ODH specificity for glaucoma.92 In the
Beaver Dam Eye Study102 and Blue Mountain Eye study,62 4.3%
and 30% of subjects with ODH had glaucoma, respectively.
8.1. Ocular hypertension
In OHTS, the risk of developing POAG after the occurrence of
an ODH was 6 times higher than not having an ODH; however,
after adjusting for baseline factors reported as predictive for
POAG and treatment assignment, the independent contribu-
tion of an ODH risk declined to 3.7-fold.41 The OHTS had
several limitations in this regard: 52% of individuals who
converted to glaucoma were detected based on the changes in
the fundus photos, whereas 25% were based on the changes in
the visual field. Approximately 90% of photographically
documented ODHs were missed in the clinical examination,
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
and all patients with an ODH were excluded at the time of
enrollment. Therefore, assuming the inclusion of ocular hy-
pertensive patients with an ODH at the outset, the use of a
precise examiner-independent objective test such as the OCT
to detect early glaucoma may have yielded different rates of
conversion to glaucoma.
In the European Glaucoma Prevention Study, 6 (8.33%) of
120 patients who developed POAG and 28 (2.93%) of 957 pa-
tients who did not convert to POAG had ODH. The HR for the
conversion to POAG for ODH was 1.97 (95% CI, 1.21e3.22).123 In
comparison, the HR for the conversion of ocular hypertensive
eyes to OAG in the OHTS (3.7) was greater.28 The median
follow-up was 96.3 months in the OHTS and 59 months in the
European Glaucoma Prevention Study. The longer follow-up
in the OHTS may explain this difference because the proba-
bility of developing an ODH may be greater during a longer
follow-up. Moreover, the longer follow-up enables the interval
between the observation of an ODH and the early signs of
glaucoma to be passed in more patients.
8.2. Open-angle glaucoma
Several reports have found a lack of correlation between ODH
and glaucoma progression.63,70 In contrast, most studies have
indicated progressive RNFL loss and optic nerve head changes
or visual field defect progression after ODH development in
glaucoma patients.5,46,50,72,76,121,139,154 Although Schor and
colleagues146 did not report faster glaucoma progression after
ODH development, other studies showed faster rate of visual
field defect deterioration.41,42 There are controversial reports
regarding the effect of recurrent ODHs on the rate of glaucoma
progression. Some authors have concluded that recurrent
ODHs result in more rapid glaucoma progression,96,109,133 in
contrast to other studies.39,143,154 One potential explanation
for the observed discrepancy may be a result of the different
methods of progression detection.
Definite glaucoma or preperimetric glaucoma patients with
ODH were approximately twice as likely to experience pro-
gression than individuals without ODH.121 Patients with
POAG, NTG, and ocular hypertension with ODHs exhibited
significantly greater progression of visual field defects and
changes in the optic nerve head, with a mean time interval to
progression of 16.8 and 23.8 months, respectively.154 The
structural test in this study was fundus photos. In NTG,46 the
mean time to progression in the visual field after ODH was
3.2 years. There is a delay between the ODH and visual field
progression; however, the location of ODHs has been closely
correlated with the location of RNFL defects.163 The progres-
sion was detected as early as 1 year after ODH using OCT.74
There was no significant change in the average thickness of
the RNFL measured by OCT 1 year after ODH; however, sig-
nificant RNFL loss occurred locally at the site of ODH.68 These
studies highlight the importance of the effect of the method
for detecting glaucoma progression in cases with ODH. Glau-
coma patients with ODH and a baseline visual field mean
deviation worse than 4.0 dB and age >68 years had an
approximately 270% and 200% increased risk, respectively, of
a fast rate of progression compared with individuals with a
mean deviation better than 4.0 dB and younger than
68 years.139 These results may suggest an association between
795
ODH and localized rapid deterioration, particularly in older
patients with a worse visual field. Figure 2 presents an optic
nerve head photograph, OCT, and visual field changes of a
patient with recurrent ODH.
8.3. Angle-closure glaucoma
The characteristics of ODH in PACG are most likely the same
as those of other forms of glaucoma.71 In a comparison of
glaucoma progression in groups of POAG, NTG, and PACG with
and without ODH, the ORs were 2.78 (95% CI, 1.38e5.59), 3.75
(95% CI, 1.07e13.21), and 4.50 (95% CI, 1.41e14.35), respec-
tively.72 The possibility of progression in the PACG group was
greater than that in the POAG and NTG groups.
8.4. Healthy subjects
In 1 study, the RNFL thickness was compared between sub-
jects with an ODH and an otherwise normal eye examination
(normal visual field and IOP) and a healthy control group
without ODH. The average RNFL thickness and the RNFL
thickness at 7:00, which was the most common location for
ODH, were significantly thinner in eyes with ODH. Significant
RNFL loss was present in the ODH eyes, which suggests that
these eyes were at risk for visual field loss.79 Similarly, in a
population-based study, the optic disks were compared be-
tween participants with and without ODHs using an HRT-II.
All parameters, including the disk area, cup area, rim area,
mean cup depth, height variation contour, and cup shape,
were similar, with the exception of the RNFL thickness, which
was thinner in subjects with ODHs.169 ODHs are rarely iden-
tified in normal eyes. The detection of an ODH typically in-
dicates the presence of RNFL loss if other causes of ODH have
been ruled out, even if the visual field is unremarkable.5e7,9,16
9. Management
9.1. Healthy individuals
The identification of an ODH in nonglaucomatous subjects
should be considered a warning sign that the affected subject
may be suffering from a systemic or ocular disease. Twelve
subjects with ODH and a normal IOP and visual field in the
Dalby population study were followed for 7 years. Two sub-
jects died, and half of the remaining subjects developed
glaucoma. The period of latency between the detection of the
ODH and the development of a glaucomatous visual field
defect was 2, 3, 5, 6, and 7 years.16 Sonnsjo and colleagues159
suggested that the ODH is the precursor of glaucoma and
that all healthy subjects with an ODH require long-term
follow-up. In a population-based study, the latency to glau-
comatous visual field defect development in patients who had
ODH was 12 years for subjects <70 years and 16 years for
subjects 70 years.16 Regarding the greater possibility of using
anticoagulants and vascular disease at an older age, which
have also been associated with ODH,22,158 the detection of
ODH in younger individuals compels more investigation for
glaucoma and long-term follow-up.
796 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
Fig. 2 e An open-angle glaucoma case with 3 optic disk hemorrhages over 6 years, as well as progressive nerve fiber layer
and visual field loss.
9.2. Ocular hypertension and glaucoma patients
The detection of an ODH in a patient with ocular hypertension
is an additional risk factor that must be considered in treat-
ment decisions. According to the OHTS, 86.7% of ocular
hypertension patients with ODH do not progress to glau-
coma.28 The low rate of conversion to glaucoma after ODH
development in the OHTS may be a result of the limited mean
follow-up time of 30 months, the lack of enrolling ocular
hypertensive patients with initial ODHs in the study, and the
failed identification of some ODHs. (The interval of the exam
was 6 months, and dilated funduscopy was performed every
12 months.) The OHTS indicated that the presence of at least 1
ODH increased the odds of pointwise progression by more
than 250%, compared with that of eyes without ODH.41 This is
a strong effect for justifying therapy in ocular hypertensive
patients with ODH.
Studies have suggested that IOP reduction by surgical or
medical therapy significantly decreases the frequency of ODH
in glaucoma.64,124 The cumulative probability of ODHs
decreased from 33.4% before surgery to 5.5% after surgery in the
POAG and 42.1% to 23.1% in the NTG group.64 The greater IOP
reduction in the POAG compared with that of NTG (8.5 vs 4 mm
Hg, respectively) may have been responsible for this difference.
Randomization to treatment in the OHTS28 with a mean IOP
reduction of 20% compared with that of the observation groups
did not affect the frequency of ODH, which may have been a
result of insufficient IOP reduction.
In some cases, the occurrence of ODH is interpreted as a
marker for insufficient IOP-lowering treatment.76,82,96,154 With
respect to the association between ODH and glaucoma pro-
gression, an intense IOP-lowering treatment is suggested in eyes
with ODH to prevent glaucoma progression,76,96,117,121,154
particularly in older subjects with a worse baseline visual
field.139 It has been suggested that a 35% reduction in the mean
IOP would be necessary to bring the slopes of visual field change
after ODH development close to zero.121 The suggested amount
of IOP reduction of 35% may not be achievable or beneficial to all
patients who present with ODH.121 Factors such as life expec-
tancy, patient preference, and potential side effects or compli-
cations of medical and surgical treatment should be taken into
account. Kono and colleagues105 reported NTG cases with ODH
that exhibited more progressive visual field changes in the
central 10-degree area than non-ODH cases. Therefore, NTG
patients with an ODH may benefit from checking the central
10-degree in addition to the standard 24-degree visual field.
9.3. Nonglaucomatous patients
ODHs in nonglaucomatous patients require treatment of the
baseline ocular or systemic condition (such as hypertension,
diabetes, increased ICP, diabetic retinopathy, and retinal vein
 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 7 8 4 e8 0 2
occlusion). Peripapillary choroidal neovascularization
warrants prompt treatment with anti-VEGF agents, photody-
namic therapy, or a combination of both approaches.20,26 The
clinician should be vigilant regarding a hemorrhagic posterior
vitreous detachment and should search for peripheral retinal
breaks or vitreomacular pathologies. Individuals with exten-
sive or bizarre hemorrhages should be evaluated for blood
dyscrasia or coagulopathies. Subjects on antiplatelets or
anticoagulants should be tested for drug overdose and
toxicity. Patients with no systemic issues require long-term
follow-up for the potential development of glaucoma.
9.4. Newborns
Fundus hemorrhage in healthy newborns presumably relates
to the birth process, and spontaneous absorption generally
occurs over time. In general, birth-related fundus hemor-
rhages resolve quickly (90% resorb within 2 weeks and 100%
within 4 weeks) and do not cause subsequent visual or
neurological deficits.48,73 In a series of 29 eyes of 17 neonates
with fundus hemorrhage, only 1 patient had premacular vit-
reous hemorrhage and developed myopic amblyopia when
examined at her third birthday.34 Other causes of neonatal
fundus hemorrhage, such as shaken baby syndrome, sepsis,
and intracranial hemorrhage, require a proper work up and
management of the baseline condition.
10. Conclusion
The detection of ODHs may be difficult because they are often
subtle and transient. Practitioners must be vigilant and look
for ODH when performing ophthalmoscopy, even in healthy
subjects. The transient appearance and recurrence of ODH
imposes difficulties in determining its true incidence and
limits the evaluation of predictive factors for its development.
ODH should not be related to glaucoma if the disk is swollen or
nonglaucomatous optic neuropathy or concomitant retinal
pathologies are present. Healthy subjects with an ODH may
benefit from long-term follow-up as some cases may convert
to glaucoma. In newborns with isolated ODH, the hemorrhage
is not typically extensive and does not cause visual deficits or
require intervention. ODH is not pathognomonic; however, it
is quite specific to glaucoma and nearly always heralds glau-
comatous change or progression. Glaucoma patients with
ODH have greater susceptibility to visual field progression;
thus, they must be followed more closely than usual and may
need to have lower IOPs. Prospective long-term studies on
healthy and glaucoma subjects and the use of OCT, OCT
angiography, and visual field may facilitate an understanding
of the mechanisms of ODH and glaucoma development and
progression.
11. Literature search
A literature search was performed using PubMed Medline
(1960 to June 2015), the Cochrane Library Database and Scopus
(1970 to June 2015), and EMBASE (1947 to June 2015) using the
following terms and their combinations: optic disk (or disc)
797
hemorrhage (or haemorrhage), peripapillary hemorrhage
(or haemorrhage), glaucoma, anticoagulants, hypertension,
diabetes mellitus, systemic vascular diseases, optic nerve
diseases, and retinal vascular occlusion. The reference lists
from the selected articles were reviewed to obtain additional
relevant articles not included in the electronic databases.
12. Disclosures
The authors have no financial conflicts with the material
presented.
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