Progress in Retinal and Eye Research 57 (2017) 26e45

Contents lists available at ScienceDirect

Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/prer

Primary angle closure glaucoma: What we know and what we dont

know
Xinghuai Sun a, b, e, *, 1, Yi Dai a, b, 1, Yuhong Chen a, b, 1, Dao-Yi Yu c, d, 1,
Stephen J. Cringle c, d, 1, Junyi Chen a, b, 1, Xiangmei Kong a, b, 1, Xiaolei Wang a, b, 1,
Chunhui Jiang a, b, 1
a
Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, China
b
Key Laboratory of Myopia of State Health Ministry (Fudan University) and Key Laboratory of Visual Impairment and Restoration of Shanghai, China
c
Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia
d
Lions Eye Institute, The University of Western Australia, Perth, Australia
e
State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, China

a r t i c l e i n f o a b s t r a c t

Article history: Primary angle-closure glaucoma (PACG) is a common cause of blindness. Angle closure is a fundamental
Received 8 August 2016 pathologic process in PAGC. With the development of imaging devices for the anterior segment of the
Received in revised form eye, a better understanding of the pathogenesis of angle closure has been reached. Aside from pupillary
18 November 2016
block and plateau iris, multiple-mechanisms are more common contributors for closure of the angle such
Accepted 7 December 2016
Available online 28 December 2016
as choroidal thickness and uveal expansion, which may be responsible for the presenting features of
PACG. Recent Genome Wide Association Studies identied several new PACG loci and genes, which may
shed light on the molecular mechanisms of PACG. The current classication systems of PACG remain
Keywords:
Primary angle closure glaucoma
controversial. Focusing the anterior chamber angle is a principal management strategy for PACG.
Nomenclature Treatments to open the angle or halt the angle closure process such as laser peripheral iridotomy and/or
Pathogenesis iridoplasty, as well as cataract extraction, are proving their effectiveness. PACG may be preventable in the
Diagnosis early stages if future research can identify which kind of angles and/or persons are more likely to benet
Treatments from prophylactic treatment. New treatment strategies like adjusting the psychological status and
balancing the sympathetic-parasympathetic nerve activity, and innovative medicines are needed to
improve the prognosis of PACG.
In this review, we intend to describe current understanding and unknown aspects of PACG, and to
share the clinical experience and viewpoints of the authors.
2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.1. Clinical classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2. Epidemiological classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.3. Pathogenic classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3.1. Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

* Corresponding author. Department of Ophthalmology, Shanghai Eye, Ear, Nose

and Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road,
Shanghai 200031, China.
E-mail address: xhsun@shmu.edu.cn (X. Sun).
1
Percentage of work contributed by each author in the production of the
manuscript is as follows:Sun X 40%, Dai Y 15%, Chen Y 10%, Yu DY 10%, Cringle S 5%,
Chen J 5%, Kong X 5%, Wang X 5 %, Jiang C 5%.

http://dx.doi.org/10.1016/j.preteyeres.2016.12.003
1350-9462/ 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45 27

3.2. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3.3. What we want to know . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.1. Anatomical risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.2. Important parameters relevant to PACG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.3. Mechanism of angle closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.4. Dynamic behavior of the uvea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.5. Where we will be going . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
4.6. Genetics of PACG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5. Clinical characteristics and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.1. Natural course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2. What we want to know . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.3. Angle assessment and its innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.4. Optic nerve damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.5. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.6. Controversies in PACG diagnostic criterion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6. Clinical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.1. Medical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.1.1. Reopening appositional angle closure and preventing synechial closed angle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.1.2. Agents for IOP reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
6.1.3. What new agents for PACG we need . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.2. Laser therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.2.1. Laser peripheral iridotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.2.2. Argon laser peripheral iridoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
6.2.3. What we need to think about LPI/ALPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.2.4. Selective laser trabeculoplasty (SLT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.3. Surgical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.3.1. Shallow anterior chamber after filtering surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.3.2. Lens extraction with/without goniosynechialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Competing interests statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

1. Introduction classied in different ways, based on clinical presentation, natural

history, anatomy and etiology, etc. Each classication has its ad-
Glaucoma is the leading cause of irreversible blindness world- vantages and value in practice. Currently, however, we still need to
wide. It is estimated that bilateral blindness was present in 4.5 work out a comprehensive and widely-accepted classication sys-
million people with primary open angle glaucoma (POAG) and 3.9 tem for both clinical and research purposes.
million people with primary angle closure glaucoma (PACG) in
2010, rising to 5.9 million and 5.3 million people in 2020. Compared 2.1. Clinical classication
with the rates of blindness in POAG, population based studies show
that PACG on average carries a three-fold increased risk of severe, A classical classication of PACG is based on clinical presenta-
bilateral visual impairment (Quigley and Broman, 2006; Friedman tion. PACG can be classied according to the timing or suddenness
et al., 2012; Tham et al., 2014). of onset into acute PACG or chronic PACG. The clinical course of
Our understanding of PACG has been considerably improved in acute PACG can be further divided into preclinical, attack (including
the last two decades as the harmfulness of the disease is better acute, subacute or intermediate attacks), intermittent, chronic
recognized worldwide. With regard to the clinical course and progression, and absolute stages according to the symptom and
pathogenic mechanisms, PACG is a different kind of glaucoma signs (Ji et al., 1966; Salmon, 1993). In the acute attack stage of
compared with POAG. Angle closure is the primary fundamental PACG, the iris quickly and completely covers the entire trabecular
problem in PACG, while elevated intraocular pressure (IOP) is sec- meshwork, leading to a sudden, symptomatic elevation of IOP. If it
ondary to angle closure. To some extent, PACG is a preventable does not remit spontaneously or under medical intervention, it will
disease if the angle closure process can be halted in the early stages. enter the chronic stage. In subacute attack, the symptoms are less
Treatments to open the angle such as laser peripheral iridotomy severe and the IOP may recover spontaneously.
(LPI) and/or iridoplasty, as well as cataract extraction, are proving By contrast, in chronic PACG, the iris slowly covers the trabec-
their effectiveness. However, there is still huge gap between cur- ular meshwork portion by portion, leading to peripheral anterior
rent knowledge and clinical management of PACG. synechiae (PAS). The PAS may be discrete or multi-centered at the
beginning, then gradually expand and fuse together (Sun et al.,
2. Nomenclature 1994; Wright et al., 2016) (Fig. 1). The IOP is gradually elevated
over a long period of time. This process is often painless and
PACG is characterized by elevated intraocular pressure (IOP) as a asymptomatic because the eyes have enough time to accommodate
result of mechanical obstruction of the trabecular meshwork by to the elevated IOP.
either apposition of the peripheral iris to the trabecular meshwork This classication is clear to understand and useful in helping
or by a synechial closed angle (Yanoff and Duker, 2014). It can be clinicians choose an appropriate treatment for different clinical
28 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45

Fig. 1. A schematic drawing and representative gonioscopic images to show the different shapes of PAS and angle closure in chronic PACG. Most grading systems that are used
clinically appear to simply judge approximate angle opening in degrees or in Grades 1e4 in four cardinal positions which gives limited information. The use of a schematic diagram
with essentially three concentric rings describing Schwalbe's line, scleral spur and iris insertion with the contact between iris and corneoscleral junction in the black hash line giving
a nice descriptive record of the state of the angle. It may also include a description of the iris conguration, i.e. whether there is bombe present, a straight insertion, a plateau iris or a
concave iris.

presenting cases. However, the clinical presentation of acute and 2002). Then, 180 degree of posterior trabecular meshwork not
chronic PACG may sometimes overlap, which makes diagnosis seen on gonioscopy in primary gaze without indentation, or simply
more challenging. Unlike POAG, PACG does not require glaucoma- 180 or more iridotrabecular contact (ITC), has been widely
tous optic nerve damage in this denition. accepted (Thomas et al., 2003a,b; Shen et al., 2008; Liang et al.,
2011). However, there is still debate that this slightly more liberal
threshold is still likely to exclude many people who have primary
2.2. Epidemiological classication
PAS or appositional angle closure (Foster et al., 2002, 2006).
Glaucomatous optic neuropathy has been dened in this
Since POAG is dened as an acquired optic neuropathy associated
scheme using three levels of evidence. The highest level of certainty
with characteristic structural damage to the optic nerve and visual
requires optic disc abnormalities (CDR or CDR asymmetry >97.5th
eld loss, the difference in the denition of PACG and POAG makes it
percentile for the normal population, or a neuroretinal rim width
difcult to compare prevalence and study risk factors in epidemio-
reduced to <0.1 CDR between 11 and 1 o'clock or 5 to 7 o'clock) and
logical glaucoma research. Hence, the International Society of
visual eld defect compatible with glaucoma. It also makes provi-
Geographic and Epidemiologic Ophthalmology (ISGEO) developed a
sion for some eyes in which visual eld testing or disc evaluation
scheme for diagnosis of glaucoma in 2002 (Foster et al., 2002). Since
are not possible. In the second level of evidence, if the subject could
then, it has gradually become a standard denition of PACG in
not satisfactorily complete visual eld testing but had a CDR or CDR
population based epidemiological studies. In this scheme, 3 cate-
asymmetry >99.5th percentile for the normal population, glau-
gories were classied: (1) Primary angle closure suspect (PACS): an
coma was diagnosed solely on the structural evidence. Lastly, if the
eye in which appositional contact between the peripheral iris and
optic disc could not be examined because of media opacity (and
posterior trabecular meshwork is considered possible. (2) Primary
hence, a eld test was also not possible), an IOP exceeding the
angle closure (PAC): an eye with an occludable angle and features
99.5th percentile of the normal population, or evidence of previous
indicating that trabecular obstruction by the peripheral iris has
glaucoma ltering surgery, may be taken as sufcient for a diag-
occurred. The optic disc does not have glaucomatous damage. (3)
nosis of glaucoma. The 97.5th percentile for vertical CDR has been
PACG: PAC together with evidence of glaucomatous optic neuropa-
proposed as a useful tool to assist in the diagnosis of glaucoma in
thy. Therefore, it is a continuum from PACS, to PAC, to PACG, ac-
population studies. In practice, vertical CDR 0.7 has been re-
cording to the ISGEO protocol of primary angle closure diseases.
ported to be the 97.5th percentile value of the study population in
Many population-based surveys have adopted the ISGEO clas-
many epidemiological studies. However, this criterion is nonspe-
sication. In practice, a key issue is the denition of occludable
cic in the diagnosis of PACG. Liang et al. reported in the Handan
angle, which is considered as a diagnostic threshold. It was initially
Eye Study (HES) with 5480 subjects in a rural Chinese population
dened as
270 of the posterior (usually pigmented) trabecular
that four (4/32) cases of PACG identied by the HES expert group
meshwork not seen on gonioscopy, in keeping with several popu-
did not meet the ISGEO denition for glaucoma because the cup/
lation studies (Arkell et al., 1987; Salmon et al., 1993; Foster et al.,
disc ratio was not greater than 0.7; and 23 (23/51) cases that met
1996, 2000). Later studies have shown that it is too stringent as
the ISGEO denition of PACG were not found to have glaucoma
at least half of those who had PAS and glaucomatous optic neu-
using the HES consensus process (Liang et al., 2011).
ropathy were excluded from being dened as PACG (Foster et al.,
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
2.3. Pathogenic classication
One of the deciencies with the above classication systems is
that they do not identify the mechanism responsible for angle
closure. The classication, devised by Ritch and colleagues, is based
on anatomic levels of obstruction to aqueous ow in primary and
secondary angle closure glaucoma (ACG) (Ritch and Lowe, 1996). In
their scheme, angle closure in ACG may be due to forces acting at
four anatomic levels: Level I, the iris, including pupillary block, non-
pupillary block/angle crowding mechanisms, and contraction of
brin in angle secondary to other ocular diseases, etc. Level II, the
ciliary body, including plateau iris conguration and iridociliary
cysts. Level III, the lens, including thick, anteriorly positioned and
subluxed lens. Level IV, vectors posterior to the lens, including
aqueous misdirection, choroidal effusion, and space-occupying le-
sions etc. However, in many ACG patients multiple levels may
simultaneously or consecutively play a role. To mix primary and
secondary ACG into one classication system also makes it
confusing in the diagnosis and treatment. Recently, Ng and col-
leagues suggested that in view of angle closure can recur following
peripheral iridotomy in up to 58% of cases, the mechanism of angle
closure could be classied into pupillary block, plateau iris syn-
drome, lens disproportion, and ciliary block (Ng et al., 2012).
Further studies are needed to test whether combining the classical
classication of PACG with concise pathogenic subgrouping is
feasible in clinical practice.
With the development of imaging devices for the anterior
segment of the eye, some causes of angle closure, such as lens
subluxation, spherical lens, and ciliary cysts could be detected and
differentiated from conventional PACG. The denition and classi-
cation of PACG may become more concise as we get to know more
about the pathogenesis of angle occlusion.
3. Epidemiology
With the world's population aging, glaucoma prevalence and
morbidity can be expected to increase. As a potentially preventable
disease, epidemiological studies on PACG are especially warranted.
It is estimated that the number of people aged 40e80 years with
PACG worldwide was 20.17 million in 2013, and predicted to in-
crease to 23.36 million in 2020 and 32.04 million in 2040. Asia
accounts for about 77% of worldwide PACG cases (Tham et al.,
2014). Advancing age and female gender are two major predis-
posing factors for the development of PACG (Foster et al., 1996,
2000; Yamamoto et al., 2005; He et al., 2006a,b; Liang et al., 2011).
3.1. Prevalence
The prevalence of PACG varies across geographic regions and
ethnic groups. In the past 15 years, there has been a rapid emer-
gence of more than 20 population-based prevalence studies on
glaucoma, particularly from Asia. Two studies in African and Latin
American regions provide rst-hand epidemiologic data on PACG in
these regions (Budenz et al., 2013; Sakata et al., 2007). According to
a recent analysis (Tham et al., 2014), the prevalence of PACG is
highest in Asia (1.09%). This result is consistent with previous PACG
reviews (Quigley and Broman, 2006). The prevalence of PACG in
Latin America and the Caribbean (0.85%) and Africa (0.60%) is
higher than those in Europe (0.42%) and North America (0.26%).
In most population based studies, POAG is the most common
type of glaucoma. However, the higher prevalence of PACG among
Eskimos, Chinese and Mongolians has long been acknowledged. In
1971, Clemmesen and Alsbirk reported high rates of PACG in
Greenlandic Inuit (Clemmesen and Alsbirk, 1971). Since then,
several studies have shown that PACG prevalence in Eskimos (also
29
called Inuit, who are anthropologically linked to the Sino-
Mongolian people) is about 20e40 times higher than among Cau-
casians (Arkell et al., 1987; Alsbirk, 1992). Recently, two studies
from Northeast Asia, Hovsgol, Mongolia (1.4% vs. 0.5%) and Harbin,
China (1.6% vs. 0.7%), have shown that the prevalence of PACG is
higher than that of POAG, further suggesting that Sino-Mongolian
people are more susceptible to PACG than POAG (Foster et al.,
1996; Qu et al., 2011). From an evolutionary perspective on Sino-
Mongolian people, it is postulated that shallow anterior chambers
may have evolved as an anatomical adaptation to resist corneal
freezing in northeast Asia during the last Ice Age (Casson, 2008).
Among all the Asian epidemiologic studies, the Meiktila Eye
Study in Myanmar, South Asia, reported the highest prevalence of
PACG (2.5%) (Casson et al., 2007). The prevalence of POAG was also
relatively high (2.0%) in this study. The Singapore Malay Eye Study
reported the lowest prevalence (0.12%) of PACG in the Malay pop-
ulation of Singapore, Southeast Asia, while 1.1% of Chinese Singa-
poreans had PACG (Shen et al., 2008).
Recently, a systemic review showed that of those over 40 years
old in European derived populations, 0.4% are estimated to have
PACG (Day et al., 2012). As a rst glaucoma prevalence study in
Latin America, PACG prevalence was reported to be 0.7% in the
southern region of Brazil (Sakata et al., 2007). Both are higher than
previous estimates (0.1%e0.25%) (Congdon et al., 1992; Quigley and
Broman, 2006). Further studies are needed to address the roles of
genetics and epigenetic changes in the prevalence of PACG in
different geographic regions and ethnic groups.
On the other hand, hospital based studies from China as well as
other Asian countries showed that PACG is the most common type
of glaucoma in a particular hospital/clinic, though the proportion of
POAG is rising. The clinical data from our hospital reveals that PACG
accounted for 50e55%, while POAG accounted for 25e35% of all
glaucoma patients (approximately 60,000 visits/year) in our out-
patient department in the past 5 years (unpublished data). How-
ever, hospital-based studies are subject to the bias that acute ACG is
more likely to cause symptoms than POAG. Those patients are
therefore more likely to seek medical assistance, so the hospital
based studies may tend to overestimate the incidence of PACG.
Meanwhile, for ophthalmologists who are practicing in PACG high-
risk areas, it is important to be competent in handling emergency
cases of PACG attack.
3.2. Incidence
The prevalence of disease represents the frequency of existing
cases in a dened population at a given point of time, while inci-
dence is the rate of occurrence of new cases arising in a specied
population in a given period (Bonita et al., 2006). Longitudinal
incidence studies are helpful to understand the natural history and
the causes of the disease. However, data on the incidence rate of
PACG are limited.
In respect of the natural history of PACS progressing to PACG,
Alsbirk et al. reported that among a high risk cohort of Greenland
Eskimos (shallow chamber at the limbus), 8% of normal (angles
open on gonioscopy) and 35% of PACS progressed to PAC or PACG
over 10 years (Alsbirk, 1992). Recently, Thomas et al. reported that
22% of PACS progressed to PAC over 5 years in a population based
study from south India (Thomas et al., 2003a,b), and 28.5% of PAC
progressed to PACG during the same period (Thomas et al.,
2003a,b). Yip et al. reported that the 6-year incidence of occlud-
able angles (PACS) in a high risk Mongolian population (central
anterior chamber depth <2.53 mm) was 20.4%. Narrower angle was
identied as the main risk factor for progression of PACG (Yip et al.,
2008).
30 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
3.3. What we want to know
PACG carries a heavier burden of visual morbidity than POAG
(Foster et al., 2002). Screening and prophylactic treatment of PACS
and PAC may form a feasible population-level intervention. How-
ever, less than 35% cases developed PAC or PACG after 5e10 years
follow-up. Why do most cases not develop PAC or PACG without
any intervention? Taking into account cost-effective management,
more information about the PACG incidence with the adoption of
prophylactic interventions is required before population-based
intervention approach could be considered. Randomized
controlled clinical trials are needed not only to assess the long-term
efcacy of treatments to open the angle, but also to explore factors
associated with a low risk of progressing to angle closure or angle
closure glaucoma in this high risk population. As we move forward
in the big data age, big data analysis may bring new approaches to
better recognize the epidemiology of PACG.
4. Pathogenesis
PACG has its characteristic anatomy features and unique path-
ological process, which makes it completely different from POAG. A
crowded anterior segment and narrow anterior chamber angle are
the basic anatomic features for PACG. The progression that the
anterior chamber angle develops from narrow to become closed is
quite complicated and involves many different factors (Fig. 2). With
the development of imaging devices for the anterior segment,
better understanding of the pathogenesis of angle closure has been
reached. However, there are still many questions remaining to be
answered.
4.1. Anatomical risk factors
PACG eyes usually have the following anatomical features: small
cornea, shallow anterior chamber, thick lens, anterior lens position,
and short axial length (AL) (Lowe, 1970; Lee et al., 1984; Marchini
et al., 1998). However, some angle closures are not fully explained
by these anatomical risk factors. With the increasing use of new
anterior chamber assessment techniques such as ultrasound bio-
microscopy (UBM) and OCT, anterior segment parameters can be
precisely measured. Quantitative measurements revealed that the
position of the ciliary processes is another one of the most
Fig. 2. Schematic illustration for proposed PACG pathogenesis. AC: anterior chamber; AL: axial length; ACW: anterior chamber width; CP: ciliary process.
important differences between patient's angle closure eyes and
normal eyes (Fig. 3). The ciliary processes are rotated more ante-
riorly in patients with PACG (Marchini et al., 1998). The trabecular
to ciliary process distance (TCPD), which is the length of a line
perpendicular to the iris connecting a point on the trabecular
meshwork 500 mm from the scleral spur to the ciliary process,
seems a useful measure of ciliary body rotation and relative ciliary
block (Man et al., 2015). Greater iris curvature, larger iris volume
and a thicker iris are independently associated with narrow angles
as well (Wang et al., 2010). Iris thickness was shown to be likely to
play a role in the development of angle closure and ultimately PACG
(Wang et al., 2013). Smaller ACA (anterior chamber area) and ACV
(anterior chamber volume) were independently associated with
the presence of narrow angles, even after controlling for other
known ocular biometric parameters, such as anterior chamber
depth (ACD) and AL (Wu et al., 2011). Anterior chamber width
(ACW), which was dened as the horizontal scleral spur-to-spur
distance, could be a novel risk indicator for angle closure. Non-
gpiur et al. found ACW was associated with narrow angle, inde-
pendently of age, gender and AL, in two different studies of
Singapore populations (Nongpiur et al., 2010). ACV was calculated
to be 25% lower in PACG patients than normal people (Congdon
et al., 1997). These fundamental anatomical characteristics of
PACG are partially because the position or the size of lens is out of
proportion to the eyeball (Lowe, 1970; Phillips, 1972). The lens is
thought be play a crucial role in the pathogenesis of angle closure
disease either because of an increase in its thickness or a more
anterior position resulting in angle crowding and a greater pre-
disposition to pupillary block (Marchini et al., 1998; Nongpiur et al.,
2011). Lens vault (LV), dened as the perpendicular distance be-
tween the anterior pole of the crystalline lens and a horizontal line
joining the 2 scleral spurs, was described independent ocular
parameter associated with angle closure. For the purpose of
screening, LV has better performance than other various parame-
ters of lens, such as lens position, (LP, dened as ACD1/2 lens
thickness (LT)), relative lens position (dened as LP/AL), and LT-to-
AL ratio, and even better than ACD and AL (Nongpiur et al., 2011).
The thickness of lens increases with age and makes the narrow
anterior chamber angle even more crowded, which might be a
reasonable explanation for why most PACG happens in patients
older than 40 years.
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45 31

Fig. 3. UBM images to show different types of narrow angles. Upper left: relative pupillary block with iris bombe. Upper right: ciliary choroid detachment with complete closed
angels after the acute attack. Middle left: Plateau iris. Middle right: anterior rotated ciliary body with closed angle and small lens to ciliary body distance. Lower left: ciliary body
cyst with narrow angle. Lower right: thick iris with Plateau iris.

4.2. Important parameters relevant to PACG
The eye is an optical organ with a unique arrangement of optical
media and blood supply. It is important to appreciate some
anatomic and physiological parameters which are highly relevant
to understanding the pathogenesis of PACG. Fig. 4 schematically
illustrates and estimates some of these critical parameters.
The cornea and the sclera are dense connective tissues designed
to provide structural integrity of the globe and to protect the inner
components of the eye from physical injury. The ocular rigidity is of
the order of 0.77 mmHg/ml meaning tiny changes in intraocular
volume could induce signicant increase in IOP (Collins and Van
der Werff, 1980). The cornea covers the anterior 1/6th of the total
surface area of the globe, while the sclera covers the remaining 5/
6ths (Kaufman and Alm, 2003). The volume of the anterior chamber
and posterior chamber are approximately 250 ml and 60 ml

Fig. 4. Important parameters relevant to PACG. A schematic drawing to show some critical parameters including ocular rigidity, volume distributions and aqueous and blood ow in
the normal eye.
32 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
respectively which are a relatively small fraction of the total
intraocular volume (6000 ml) (Collins and Van der Werff, 1980). The
iris is the anterior portion of the uvea forming a delicate and
movable diaphragm between the anterior and posterior chambers
(Hogan et al., 1971). The lens is suspended in the anterior of the eye
by a band of inelastic microbrils, the zonules. To meet the high
demands of neural retina and avascular tissues in the anterior
segments such as lens and cornea, the ocular circulation is unique
and complex with high intraocular blood ow rate (~850 ml/min).
The uvea, including the iris and ciliary body has a rich blood
vasculature and uveal blood pressure (systolic ~75 mmHg and
diastolic ~35 mmHg) is higher than normal IOP (~15 mmHg).
Aqueous outow rate is about 2 ml per minute. Intraocular contents
such as aqueous humor, vitreous and tissues are relatively incom-
pressible and are bounded by the relatively rigid cornea and sclera.
Therefore, input and output uid including aqueous and blood have
to be dynamical balanced in order to maintain IOP in the normal
range. Such delicate balance can be disturbed by pathological
changes in the iris and choroid as pathogenic factors of PACG.
4.3. Mechanism of angle closure
The anterior chamber angle closes due to two types of forces:
the forces that push the iris forward and the forces that pull the iris
against the trabecular meshwork. Thus, the classical mechanisms of
PACG could be mainly divided to two types: pupillary block and
non-pupillary block. Pupillary block is the main common known
mechanism of PAC. It mainly due to the proximity between the lens
and the posterior face of the iris generates an increase in aqueous
ow resistance, thus generates the pressure difference between the
posterior chamber and anterior chamber and force the peripheral
iris to bow anteriorly (Tarongoy et al., 2009; Quigley et al., 2003).
Non pupillary block factors include thick peripheral iris, anteriorly
located peripheral iris, anteriorly rotated ciliary body and plateau
iris. About half of the PACG in Chinese patients (54.8%) was caused
by multiple mechanisms, one third (38.1%) was caused by pure
pupillary block and less than 10% (7.1%) was caused by pure non-
pupillary block mechanisms (Wang et al., 2000). Plateau iris was
dened by anteriorly directed ciliary body, absent ciliary sulcus,
steep iris root from its point of insertion followed by a downward
angulation, at iris plane and irido-angle contract (Kumar et al.,
2009). Plateau iris is found in about one third of Asian PACG eyes
with a patent LPI (Kumar et al., 2008, 2009). Quantitative analysis
suggested majority of eye have more than one mechanism under-
lying angle closure including pupillary block and plateau iris
conguration (Shabana et al., 2012). The other major mechanism is
ciliary block due to a combination of resistance between ciliary
process and lens equator (Chandler et al., 1968; Weiss and Shaffer,
1972; Shaffer, 1973, Shaffer and Hoskins 1978; Luntz and
Rosenblatt, 1987). With ageing the distance between lens equator
and ciliary body decreases as lens grows. The ciliolenticular gap
reducing will cause ciliary ow resistance increasing and hence
ciliary block. Furthermore, small changes in lens position, such as
lax lens zonules, and ciliary body, such as supraciliary swelling or
ciliary edema (Liebmann et al., 1998; Trope et al., 1994), may lead
lens in contact with ciliary processes and worsen ciliary block. In
these circumstances, the aqueous humor ow direction is more
from posterior ciliary processes passing through anterior vitreous,
traversing the anterior hyaloid to enter the posterior chamber be-
tween iris and lens, which creates a force to push the lens the ciliary
processes anteriorly (Ng et al., 2012) (Fig. 6).
The question remaining unanswered is why some angle closure
eyes develop an acute disease while others develop a chronic dis-
ease. Earlier studies already revealed signicant differences of
anterior segment parameters between acute and chronic PACG
(Sun et al., 1994). Further evidence of signicant biometric differ-
ences between acute and chronic PACG were reported as ultra-
sound biomicroscopy was used for biometric measurement of the
eyes. Chronic PACG is characterized by a less-crowded anterior
segment compared to the acute PACG (Marchini et al., 1998). The
pattern of chronic angle closure appears to mainly be creeping
closure or zipper up. Sihota et al. reported a narrower trabecular
iris angle and shorter ciliary process distance in acute PACG than in
chronic PACG (Sihota et al., 2005). Acute PACG eyes show the
greatest deviation from normal than chronic PACG eyes do on
regards of lens thickness, ACD and corneal diameter (Sihota et al.,
2000). Compared to the fellow eyes of APAC, affected eyes have
shallower ACD, more anterior lens position (Lim et al., 2006) and
greater lens vault when assessed by AS-OCT (Lee et al., 2014), but
these parameters of APAC eyes were already affected by acute
attack.
Clearly, smaller ocular biometry is a risk factor for the acute
primary angle closure. However, there could be other physiological
factors triggering the acute attack, since not all narrow angles
would have acute attacks throughout the life time of the patient,
even for nanophthalmos. Pupil dilation is a common mechanism
causing acute attack, which often happens in eyes in the dark or
with the use of certain medicines. The angle width generally
decreased with increased pupil diameters, and appositional closure
could be developed when the pupil is mid dilated (Leung et al.,
2007). But Woo et al. reported that angle narrowing in the eyes
in dark is not related to increased iris-lens touch and occurs
promptly on pupillary dilation and is caused by a combination of
iris shortening, increased iris thickness and increased iris convexity
(Woo et al., 1999). Another mechanism more recently proposed for
acute PACG in anatomically predisposed eyes has been choroidal
expansion causing a forward movement of the lens and iris, since
the position of the plane of the iris-lens diaphragm may vary quite
quickly as choroidal blood volume and aqueous production uc-
tuate (Phillips, 1972) (Fig. 6). However, there was no signicant
change in lens position, lens vault, relative lens position or axial
length in eye with acute attacks compared to 2 weeks later, which
did not demonstrate any evidence of lens movement in patients
presenting with acute PACG (Yang et al., 2005). Thus, whether
choroidal expansion was a trigger factor of acute attack remains
controversial.
4.4. Dynamic behavior of the uvea
To move beyond anatomy alone, dynamic or physiologic
changes in the anterior segment may play an important role. With
advances of imaging techniques, the structure changes of anterior
segment including the geometrics of angle, iris, cornea and lens as
well as the choroid can be determined noninvasively (Arora et al.,
2012). These clinical data provide valuable information to further
understand the pathogenesis of PACG and may allow the devel-
opment of new and targeted strategies to manage different stages
of PACG. Recently, the possible role of dynamic behavior of the
uvea, including the iris and choroid, in the development of PACG
requires consideration.
The dynamic processes leading to changes in iris and choroid
volume could have a more signicant and mechanistic effect on its
surrounding structures than a mere anatomical observation
(Quigley, 2009; Quigley et al., 2009), such as changes of iris volume
during mydriasis (Aptel and Denis, 2010; Quigley et al., 2009).
Signicant changes in iris volume have been observed using these
imaging devices and postulated to be a major pathogenic factor for
PACG (Aptel et al., 2012; Baskaran et al., 2013; Mak et al., 2013;
Oyster, 2000; Quigley, 2009; Seager et al., 2014). The iris volume
increase per millimeter of pupil dilation was reported to be an
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
independent predictor of angle narrowing in darkness (Aptel et al.,
2012). It was found that the iris cross-sectional area decreases after
physiologic or pharmacologic pupil dilation regardless of anterior
chamber angles, but with a smaller decrease in narrow-angle pa-
tients (Quigley et al., 2009). This suggests angle closure eyes lose
less iris volume as the pupil enlarges, which might be explained by
different uid movement in and out of the iris stroma between
angle closure glaucoma patients and normal people. However, the
iris volume was found to increase signicantly after pupil dilation
in the narrow-angle eyes, whereas it decreased signicantly in the
open-angle eyes (Aptel and Denis, 2010). Recently, our group found
that the iris thickness at different part changed differently with
aging. When the iris was evenly divided into 4 different regions, iris
thickness at the area close to the angle seemed to get thickening
with aging, while the area at the middle to pupil got thinning and
the rest regions remained unchanged (Table 1, Fig. 5). Beside the
change of iris thickness, the change of iris microvasculature could
affect the iris volume as well (Yang et al., 2015), which is possibly in
accordance with the change of choroid vessels. Hence the mecha-
nisms involved in iris volume change as well as the consequence
from the iris volume change could well be an important pathogenic
factor in PACG.
The iris has some specic features relevant to uid exchange
with the aqueous humor and iris volume changes. The anterior
surface of the iris is not covered with endothelium at or soon after
birth, and a modication of the stroma composed of a relatively
dense meshwork of melanocytes and broblasts with associated
collagen forms the anterior surface of the iris (Freddo, 1996; Hogan
et al., 1971; Tousimis and Fine, 1959; Vrabec, 1952). This meshwork
of cells does not form a continuous, impermeable sheet that over-
lies the anterior iris surface but allows aqueous humor to pass
freely into the iris stroma (Freddo, 1996; Oyster, 2000). However,
the process of uid and molecules exchange between blood vessels,
stroma and aqueous humor has not been delineated, although it is
known that the stroma of the iris is a sponge-like layer composed of
an interwoven, collagenous framework in a matrix of hyaluronidase
sensitive substance (Tasman and Jaeger, 2005). There does not
appear to be any apparent diffusion barrier between the interstitial
spaces of the iris and the anterior chamber. Therefore, aqueous
ow, iris vasculature and ciliary body vasculature may offer
different roles to keep a certain concentration gradient of each
molecule in the aqueous humor. Previous studies have supported
the pathway that plasma constituents might diffuse from the ciliary
body stroma into the iridial stroma and, nally, into the anterior
chamber (Freddo et al., 1990; Raviola and Butler, 1985). Also, some
molecules can selectively be transported through the iris endo-
thelium (Raviola and Butler, 1985). Therefore, the roles of the iris
microvasculature, particularly its endothelium, need to be further
explored. Recent studies of the iris vasculature found that the iris
has a high density of microvasculature and an unusual pattern of
vascular distribution. This consists of abundant relatively large
vessels in the middle of the iris stroma supplying the microvascu-
lature located in the supercial side of the stroma and pupil edge.
Within a short distance, large diameter of capillary and relatively
long spindle shaped endothelial cells in different orders of iris
vasculature are present. All these ndings suggest that the iris has
high blood ow rate and a capability for nutrient and waste
Table 1
Changes of iris thickness with aging in different regions.
Region 1(close to angle) 2 3 4(close to pupil)
b 0.258 0.088 0.224 0.061
P 0.016 0.415 0.037 0.574
33
Fig. 5. Representative OCT image of iris segmentation in Table 1.
exchange between the blood stream and the iris stroma (Yang et al.,
2015a,b,c).
Choroidal expansion could be another important factor which
inuences the progression of shallow anterior chamber in eyes
with PAC (Quigley et al., 2003), as UBM and OCT have provided
some insights suggesting a possible role of uvea in the pathogenesis
of PACG. Approximately 15% of PACG demonstrated uveal effusion
on UBM (Kumar et al., 2008). Uveal effusion was not only observed
in affected acute PACG eye (58%) but also in unaffected fellow eyes
(23%) or chronic PAC eyes (9%) (Sakai et al., 2005). Choroidal
thickness changes have been studied in different types of PACS and
PACG (Arora et al., 2012) as well as the fellow eye of acute PAC
patients (Zhou et al., 2013). It was observed that angle closure eyes
had signicantly thicker choroidal thickness than open angle eyes
and normal eyes by using OCT (Arora et al., 2012; Huang et al.,
2013a). Furthermore, the sub-foveal choroid thickness was found
to be signicantly thicker in the fellow eyes in patients with uni-
lateral acute PAC (APAC) compared with the eyes of normal in-
dividuals (Zhou et al., 2013, 2014).
Increased choroidal thickness/volume could very likely be a
critical pathogenic factor although its exact role has still not been
identied. It is expected that increased choroidal volume could
induce signicant changes in the anterior segment. Fig. 6 illustrates
a proposed mechanism of choroidal volume changes induced PACG.
The area of choroid is about 1000 mm2 which is at least 7 times
larger than the area of the iris. The area of iris in Asians is smaller
than Caucasians (Seager et al., 2014). Therefore, a small amount of
choroidal volume changes may cause massive alterations of iris and
lens because of the relatively rigid sclera and cornea and incom-
pressible intraocular contents including large volume of the vitre-
ous and small volume of aqueous in the posterior chamber. The iris
diaphragm and lens could move forward and change their position
and shape (Fig. 6 B2 and B3) from their initial position (Fig. 6 B1)
resulting in pupil block and angle closure.
Some interesting questions need to be addressed: why choroidal
volume can be changed which may help us to understand the
pathogenic roles in PACG. The choroid has very high blood ow rate
per unit volume in the human body, with a circulation volume
10e20 times that of cerebral cortex (Bill and Sperber, 1990).
Choroidal over-perfusion may cause increased choroidal thickness.
There are multiple hypotheses proposed such as synthesis of
osmotically active molecules, vascular permeability, uid ux from
the anterior chamber to the choroid, movement of uid across the
RPE, and changes in the tone of non-vascular smooth muscle from
experimental models (Nickla and Wallman, 2010). Recently, we are
focusing on other major control sites of the choroidal circulation.
The vortex vein system is the drainage pathway for the choroidal
circulation and serves an important function in the effective
34 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45

Fig. 6. Possible explanation of mechanism of choroidal volume changes induced PACG. If the volume of the choroid expands this would lead to a forward displacement of the lens
and iris. This in turn may lead to closure of the angle and a dramatic rise in IOP.

drainage of the exceptionally high blood ow from the choroidal very likely to be a control site for the choroidal circulation. In
circulation (Alm and Bill, 1987). As there are only 4e6 vortex veins, addition, there is rich innervation in the choroid and vortex vein
a large volume of blood must be drained from many choroidal veins system.
into each individual vortex vein. The choroid plays a vital role in Given the incidence of venous pathology is about ten times
sustaining the outer retina's high metabolic demands (Smith et al., higher than arterial disease. It is important to study the very sig-
1985; Yu and Cringle, 2001, 2002). In addition to the choroidal nicant but undervalued vortex vein system of the eye. We need to
outow, the vortex vein system also drains the anterior portion of develop clinical assays to evaluate the vortex vein system and
the eye. A high volume of blood ows through numerous choroidal determine the role in choroidal thickness changes and PACG.
veins before converging into a larger, sometimes slightly dilated
vessel called an ampulla, before entering the sclera to exit through a
4.5. Where we will be going
vortex vein (Hogan et al., 1971; Kaufman and Alm, 2003; Potter
et al., 1984). The entire drainage pathway from the choroid to the
In respect of the pathogenic mechanism of PACG, there are still
vortex vein is dened as the vortex vein system. The ow patterns
many phenomena we are not able to explain. We don't know why
and hemodynamic forces could be signicantly non-uniform in the
some people with narrow angle morphology develop PAS and
different regions of the geometrically complex vortex vein system.
others not. We are not able to determine which patients with
Functionally, the vortex vein system has a role in maintaining an
shallow chamber and narrow angle will later develop the acute
optimal choroidal blood volume which is exposed to the positive
attack. Given each PACG patient has bilaterally crowded anterior
extruding pressure within the eye as well as an abrupt drop in
segment anatomy, either pupillary block or non-pupillary block
extravascular pressure in the region where the draining vessels
exist, and choroidal expansion does play a role, but why most acute
leave the eye and enter the orbit. The vortex vein system must also
attacks occur unilaterally is not known. Sometimes the acute attack
cope with passing through tissues of different rigidity and signi-
could occur on one eye shortly after the other eye, but rarely occurs
cant pressure gradient as it transverses from the intraocular to the
on both eyes simultaneously, except when the cause is iatrogenic
extraocular compartments. However, little is known about how the
medicine, such as mydriatic eye drops. Furthermore, emotion upset
vortex vein system works under such complex situations in both
or stress is more often just before acute attack of PACG for many
physiological and pathological condition. The vortex vein system
patients clinically. Then what is the mechanism behind that? How
endothelium had not previously been studied in detail, nor were
could psychological status possibly affect the development of PACG,
the endothelial phenotypes known at specic sites within the
seeing that anxiety and depression more commonly exist in glau-
vortex vein system (Tan et al., 2013; Yu et al., 2013, 2014a, Yu et al.,
coma patients than in the general population? (Kong et al., 2014,
2014b). We studied the endothelial intracellular cytoskeleton pro-
2015; Lim et al., 2016). It was suggested by literature that psycho-
teins, cell shape, and nuclei position, along with smooth muscle cell
physiological stress may play a part in the precipitation of acute
distribution in different regions of the vortex vein system in human
PACG because IOP can be affected by the emotional state (Shily,
donor eyes (Yu et al., 2013). The different regions studied were the
1987). We might need to consider PACG as partly a systemic dis-
choroidal veins, pre-ampulla, ampulla, post-ampulla, scleral
ease instead of only looking at the eyeballs in future studies.
entrance, intra-scleral channel, scleral exit and extra-scleral vortex
vein. The endothelium and smooth muscle cells in the vessel wall
were studied for f-actin and nuclei distribution, and the 4.6. Genetics of PACG
morphology of the cells. Remarkable regional differences of endo-
thelial phenotype and smooth muscle cells distribution has been The heritability of narrow angle was reported as high as 60% and
demonstrated in the vortex vein system (Tan et al., 2013; Yu et al., siblings of PACG patients have been estimated to be at 7 times more
2013) suggesting that distinct hemodynamic changes occur and are likely to have narrow angles than the general population
(Amerasinghe et al., 2011). Although family history was found to be
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
a consistent risk factor, attempts at tting the inheritance into a
certain genetic pattern did not succeed convincingly (Lowe, 1972).
These facts support that PACG is a complex heterogeneous disease.
The molecular mechanisms leading to PACG are poorly understood.
Recently, Vithana et al. conducted a genome wide association study
(GWAS) to determine the genetic variants underlying susceptibility
to PACG (Vithana et al., 2012). The study found a genome-wide
signicant association between PACG and three genetic markers:
rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213
located between PCMTD1 and ST18 on Chromosome 8q. The
contribution of the two single nucleotide polymorphisms (SNPs) in
PLEKHA7 and COL11A1 were conrmed in a large PACG cohort in
China (Chen et al., 2014) and patients from Australia and Nepal
(Awadalla et al., 2013). PLEKHA7 (pleckstin homology domain-
containing family A member 7) located on Chromosome 11, is an
adherens junction protein, which was found to be expressed within
PACG-related structures (iris ciliary body, and choroid) and blood-
eaqueous barrier (BAB) structures (posterior iris epithelium, non-
pigmented ciliary epithelium, iris and ciliary body
microvasculature) (Lee et al., 2014). COL11A1 encodes one of the
two alpha chains of type XI collagen. Both COL11A1 and PLEKHA7
were shown to confer higher risk for PACG with acute attacks rather
than chronic PACG (Chen et al., 2014), although the three genetic
susceptibility loci did not found to underlie any major phenotypic
diversity in terms of disease severity of progression (Wei et al.,
2014). More recently, rs1401999 within ABCC5 (ATP binding
cassette subfamily C member 5) was found to contribute to the
normal variation of ACD, a quantitative trait of anatomical risk
factor for PACG, through a GWAS. Importantly, the association of
rs1401999 was PACG was demonstrated as well, by using case-
control cohorts from multiple populations across Asia (Nongpiur
et al., 2014). In addition, SNPs on other candidate genes, including
HGF (hepatocyte growth factor) (Awadalla et al., 2013), HSP70
(heat-shock protein 70) (Ayub et al., 2010), MFRP (membrane type
frizzled related protein) (Wang et al., 2008), MMP9 (matrix
metalloproteinase-9) (Wang et al., 2008), and eNOS (endothelial
nitric oxide synthase) (Ayub et al., 2010), were found to be genetic
biomarkers for PACG as well. However, they have not yet been
consistently replicated across different population, their contribu-
tion to pathogenesis of PACG remained to be conrmed (Shastry,
2013; Rong et al., 2016; Chen et al., 2016). Recently, Khor et al.
observed signicant evidence of disease association at ve new
genetic loci, including EPDR1 (ependymin related 1) rs3816415,
CHAT (choline O-acetyltransferase) rs1258267, GLIS3 (GLIS family
zinc nger 3) rs736893, FERMT2 (fermitin family member 2)
rs7494379, and DPM2-FAM102A (dolichyl-phosphate mannosyl-
transferase subunit 2, regulatory- family with sequence similarity
102 member A) rs3739821, upon meta-analysis of patients from 24
countries across Asia, Australia, Europe, North America, and South
America (Khor et al., 2016).
Nevertheless, the detailed pathogenic function of these genes in
PACG was still unknown. The clinical presentation of PACG varied
and the occurrence of PACG can by inuenced by mood, weather,
living habits and other environmental factors, which suggest PACG
is a genetically complex disease. What we don't know is whether
these associated genes are the real causal genes and how they could
cause PACG to develop. Future functional studies will aim to vali-
date the role of PLEKHA7 and COL11A1 in PACG pathogenesis.
5. Clinical characteristics and diagnosis
5.1. Natural course
According to the clinical presentation and progress of the dis-
ease, Ji and colleagues rstly put forward a staging method of acute
35
PACG (Ji et al., 1966), which has been widely accepted and applied
in the clinical diagnosis and treatment in China. The staging system
was as follows (Fig. 7):
1) Preclinical stage: just like PACS. When one eye had acute attack,
the other eye could be diagnosed as preclinical cause. Because
PACG is bilateral disease, the healthy eye is also at risk of
attack.
2) Attack stage: there are two types. Mild attacks are present with
slight symptoms such as colored halos, cloudy vision, soreness
of the root of the nose and mild eye congestion, with small IOP
spikes due to incomplete angle closure. After pilocarpine usage
or good rest like sleep during which parasympathetic nerve is
excited leading to physiological miosis, the mild attack can
relieve. Acute attack is present with sudden IOP elevation usu-
ally above 70 mmHg due to complete angle closure. The patient
complains of sharp vision loss and intense eye pain, sometimes
accompanied with systemic symptoms like severe forehead
ache above the affected eye and nausea and vomiting. The
attacked eye appeared marked conjunctiva hyperemia, corneal
edema, a medium-sized unreactive pupil, very at chamber,
together with triple sign (pigmented precipitates, irregular iris
atrophy, and glaucomecken), even occulent exudate in the
anterior chamber.
3) Intermittent stage: After attack, no matter mild or acute, angle is
partly open again, usually more than half of the angle is open,
and IOP could be maintained in a normal range. But the eye still
is in a dangerous condition and likely to have attack again.
4) Chronic stage: the IOP is progressively elevated and the optic
nerve is damaged because angle closed usually more than half
circumference.
5) Absolute stage: the eyeball loses visual function and usually
with refractory eye pain.
Different from acute PACG, chronic PACG is a gradual, often
clinically silent, closure of the angle resulting in increased IOP and
eventual glaucomatous optic nerve damage. The chronic PACG
natural course was more like that of POAG. Ocular anatomic dif-
ferences exist between acute and chronic PACG cases. The acute
cases have a less deep anterior chamber, thicker lens, shorter axis
and more narrow entrance of chamber angle than those of the
chronic cases. Moreover, acute cases are more common for females
and chronic cases are more common for males (Sun et al., 1994).
5.2. What we want to know
Even though most of the acute PACG patients have typical pre-
sentation, however, part of the cases shows atypical manifestations.
Some of the chronic PACG patients have acute attack when they
suffered emotional stimuli or other induced factors. So, the clinical
course of PACG is multiple and complicated, it is not reliable to
judge it only based on the clinical presentations. Furthermore, the
extent of the closed angle is an index for us to evaluate the state of
the illness, but patients with the same range of closed angle might
have different IOP levels and manifestations. Are there different
patterns of angle closure in acute and chronic PACG? The rela-
tionship between closed angle and clinical presentations need in
depth studies and new reliable indexes need to be investigated.
5.3. Angle assessment and its innovation
Gonioscopy remains the most important diagnostic method for
assessing the presence of angle closure. With gonioscopy exami-
nation, pupillary block could be manifested as iris bowing into a
convex shape, appositional contact with the trabecular meshwork,
36 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45

Fig. 7. The developing process of Acute PACG.

and eventually peripheral anterior synechiae (PAS). Indentation
gonioscopy in particular is an essential technique for assessing
appositional angle closure (Fig. 8) and PAS (Fig. 1). The static angle
should be examined rst, and then do dynamic indentation
gonioscopy, which could help to determine the extent of PAS and
differentiate plateau iris conguration from pupillary block.
Notably, gonioscopy is highly subjective, and the ndings may
vary with the amount of light or mechanical compression of the eye
used during the examination. Quantitative studies of the anterior
segment structures therein could provide objective measurements,
including UBM and anterior segment OCT (AS-OCT) (Dorairaj et al.,
2012). With tissue resolution of approximately 50 mm and pene-
tration depth of 5 mm, UBM is capable of imaging the posterior
chamber and ciliary body, which could not be examined by
gonioscopy. However, it is difcult to differentiate appositional
angle closure from PAS using just UBM and also patients require
examination in the supine position. AS-OCT is a noncontact optical
signal acquisition and processing device that provides magnied,
high-resolution cross-sectional images of ocular tissues. Since AS-
OCT can visualize the entire anterior chamber, all the essential
parameters for detection of angle closure can be examined in a
single scan. Slit lamp OCT (SL-OCT) has the potential to provide
valuable quantitative and spatial information regarding dynamic
changes of the angle conguration (Leung et al., 2008). Using OCT,
details of anterior chamber drainage angle including Schlemm's
canal and trabecular meshwork could be visualized and analyzed
(Asrani et al., 2008; Hong et al., 2013, 2014). Recently, swept-source
OCT (SS-OCT) is specically designed for anterior segment imaging.
It allows 360-degree imaging of the angle and iris. Both the scleral
spur and the Schwalbe's line can be identied. Using this SS-OCT,
the trabecular meshwork width (Tun et al., 2013), iridocorneal
angle width (Tun et al., 2014), iris volume (Mak et al., 2013; Tun
et al., 2014) and PAS (Lai et al., 2013) could be evaluated. But to
date, none of the above imaging methods provides sufcient in-
formation about the anterior chamber angle anatomy to be
considered a substitute for gonioscopy (Smith et al., 2013). At
present, new generation of imaging devices need to be explored for
more convenient and comprehensive methods, not only
morphology but also structural mechanics about angle closure. It
will greatly improve the accuracy and efciency of angle exami-
nations in epidemiological and clinical studies.
5.4. Optic nerve damage
Glaucomatous optic neuropathy is the characteristic of POAG.
However, the patterns of optic nerve damage are different in PACG.
At the early stage of PACG such as preclinical stage or intermittent
stage or PACS and PAC, there is no detectable optic nerve damage.
Even after episodes of acute attack, the eyeball might present a
pale disc with diffuse eld depression instead of a cupping disc

Fig. 8. Schematic drawings and representative images on gonioscopy. Left column: appositional angle closure in static gonioscopy. Right column: angle remains open with
pigmentation in dynamic indentation gonioscopy.
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
(Douglas et al., 1975). The possible reason is that acute attack is
equivalent to the ischemia of optic disc caused by a very high IOP. As
the disease progresses, eyes with PACG tends to have a lower PSD
(pattern standard deviation) with a more diffuse eld loss, while
POAG eyes are more likely to have localized defect in the superior
Hemield (Fig. 9) (Gazzard et al., 2002). It is in agreement with
ndings that inferotemporal rim loss is more common in POAG eyes
(Nouri-Mahdavi et al., 2011). There is greater asymmetry of visual
eld loss between eyes, as measured by AGIS scores and mean
defect, in PACG than in POAG (Wang et al., 2008). At the late stage of
PACG, the characteristic of visual eld defect also differs from POAG.
PACG had more severe defect of the central visual eld, while the
damage of superior and the inferior hemield in PACG are similar to
POAG. (Han et al., 2009) The eyes with a central visual eld island
tend to have the central retinal vessel trunk in the temporal optic
disc region (Huang et al., 2013b). Using OCT angiography, the per-
ipapillary microvasculature could be detected, and the data shows
that uniform reduction of vessel density is found in PACG while a
regional reduction is usually found in POAG (Wang et al., 2015,
2016). Chronic PACG is also different from acute PACG. The abnor-
mally shaped rim width (alteration of ISN'T rule), bared circum-
lunar vessel, vessel bayonetting, rim width narrower than the
temporal sector, and zone beta (nasal and super temporal sectors)
were detected more frequently in chronic PACG (Uhm et al., 2005).
Further studies are needed to investigate whether all these struc-
tural changes have corresponding characteristic changes of visual
function between PACG and POAG.
5.5. Differential diagnosis
In some cases, PACG should be differentiated from other ocular/
systemic diseases. During acute attack of PACG, pain, hyperemia
and cellulose-like exudation is found in some cases, while
cellulose-like exudation is commonly found in iridocyclitis, then it
could be misdiagnosed as iridocyclitis. However, the following
points could help to distinguish: the normal depth anterior
chamber and normal IOP could not be found in PACG but in irido-
cyclitis. Many patients suffer headache, nausea and vomiting dur-
ing acute attack of PACG, if ignored the symptoms of the eyes, they
would be misdiagnosed as migraine, cerebrovascular accident, or
gastroenteritis and so on. After antispasmodics such as atropine
were misused, the situation would become more dangerous.
Angle closure glaucoma resulting from the uveitis such as Vogt-
Koyanagi-Harada (VKH) or some kinds of medicine usage should
also be noted. They all show acute onset, vision loss, shallow
Fig. 9. Visual eld patterns of PACG and POAG. Left column: a more diffuse eld loss in PACG. Right column: localized defect in the superior hemield in POAG.
37
anterior chamber and headache. Uveal effusion could cause swollen
of ciliary body and ciliary detachment, which might cause anterior
rotation of ciliary body, anterior movement of lens and then result
in secondary pupil block and angle closure. Usually, VKH affects
both eyes, presents a small pupil and typical fundus changes, and
sometimes is accompanied by systemic symptoms such as tinnitus
or hair loss. Generally, PACG would not have acute attack of both
eyes at the same time, while secondary angle closure glaucoma
could affect both eyes simultaneously. And the PACG eyes have
characteristic parameters such as short axial length while VKH eyes
do not. On the other hand, given the causal phenomenon between
uveal effusion and angle closure, it may enlighten the idea that the
role of vascular dysregulation in PACG is worth paying attention to.
5.6. Controversies in PACG diagnostic criterion
To diagnose PACG with the requirement of glaucomatous optic
neuropathy remains controversial. First, the current ISGEO protocol
(optic disc abnormalities and visual eld defect) may not be sen-
sitive enough to detect glaucomatous optic neuropathy in PACG
patients as described above (Liang et al., 2011). Besides, quite a few
patients could be present with occludable angle, PAS, and raised
IOP during visits, OCT examination may already detect inferotem-
poral RNFL bundles thinning, but their visual eld (with standard
examination program) is within normal range, it will be classied
as PAC according to the ISGEO protocol. But we think it should be
diagnosed as early stage of chronic PACG.
Second, PACG could cause damage to the eye in addition to
glaucomatous optic neuropathy. In patients suffering from serious
acute attack of PACG, the optic disc may become swollen and later
in chronic stage the disc may show similar signs to ischemic optic
neuropathy. Simultaneously, signs of iris ischemic atrophy and
glaucomecken may arise from acute attack. It is an ophthalmic
emergency and the prognosis is often poor, but it could not be
classied as PACG according to the ISGEO denition. Even in very
early stage of chronic PACG, appositional and synechial closed angle
is causing damage to trabecular meshwork and deteriorating
outow facility. Since it is well recognized that angle closure is a
fundamental pathologic process, in some recent literature, angle
closure disease (Sinota, 2011; Walland and Thomas, 2011) was
named in order to separate from the ISGEO denition of PACG.
Recently, we investigated peripapillary retinal perfusion in eyes
after an attack of acute PACG one month later by optical coherence
tomography angiography (OCT-A). These eyes had a lower peri-
papillary retinal ow index (0.083 0.012 vs. 0.093 0.011;
38 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
P 0.001) and vessel density (79.3 8.2 vs. 85.6 4.9; P 0.001)
than those of the fellow normal eyes, showing the damaged retinal
circulation after acute attack (Fig. 10, Table 2). OCT-A is a sensitive
way to detect vascular changes in PACG eyes. The above evidence
suggests that the ISGEO denition of PACG may not be suitable in
clinical practice at the present time.
Third, the mechanism of optic nerve damage caused by PACG is
different from that of POAG. The typical development of PACG is
angle closure, IOP elevation and then optic nerve damage. While in
many POAG (including NTG), IOP could be within the normal range
and vascular factors are considered to be important factors leading
to typical optic neuropathy. Moreover, although both are consid-
ered to be a chronic pathologic process, studies show that the
patterns of glaucomatous damage in chronic PACG are different
from those in POAG (Nouri-Mahdavi et al., 2011). Evidence suggests
that the pathological changes of optic nerve head (ONH) in PACG
and POAG are different. The latter one was reported to have some
innate abnormality, such as laminar cribrosa defect (Tatham et al.,
2014; Kimura et al., 2014), or peripapillary vascular abnormality
(Flammer et al., 2002; Jonas et al., 2015; Tobe et al., 2015) in the
pathogenesis of POAG, especially NTG. Our recent study using OCT-
A also showed that acute PAC eyes had lower peripapillary vessel
density compared with normal eyes (56.43 5.84 vs. 65.98 2.03,
P < 0.001), while POAG eyes had the lower vessel density in the
inferior temporal quadrant in the peripapillary region
(46.75 11.80 vs. 59.65 7.63, P < 0.001) (Fig. 10, Table 2). More-
over, unlike POAG, the ONH in PACG has no sign of innate abnor-
mality before IOP elevation, and may tolerate much higher IOP.
Therefore, copying the diagnostic algorithm on optic nerve damage
of POAG to PACG in ISGEO protocol may be inappropriate. The
further modication of current ISGEO protocol about PACG is
needed before it could be adopted more as a glaucoma guideline in
clinical practice.
6. Clinical management
Management of PACG differs considerably from that used in
POAG cases because of the fundamentally different mechanisms of
the two diseases (Friedman et al., 2012). Unlike POAG, PACG to
some extent is a preventable disease. Except IOP lowering, the
management to protect the anterior chamber angle and keep its
drainage function is unique for PACG. It is very important since the
angle of PACG is original with normal drainage function. Focusing
the anterior chamber angle is a principal management strategy for
PACG. Choice of management is dependent on the stage of the
disease. As for PACS and PAC, the aim is to modify the anterior
segment conguration preventing angle closure and IOP elevation.
As for PACG, the aim is to protect those yet not closed angle, and to
lower the IOP to prevent the worsening of glaucomatous optic
Fig. 10. OCT-A images of the peripapillary area in normal eyes (A), acute attack of PACG (B) and POAG (C).
neuropathy and visual eld loss.
6.1. Medical treatment
6.1.1. Reopening appositional angle closure and preventing
synechial closed angle
Cholinergic agonist, pilocarpine, is the rst-line drug for treating
PACG. It contracts the pupillary sphincter, pulling the peripheral iris
away from the trabecular meshwork and therefore reopening the
drainage angle. Pilocarpine is still widely used in Asian countries, as
it is inexpensive and effective for patients with PACG. However,
pilocarpine agents have not been shown to lower IOP in these eyes
which had whole angle closed because of permanent synechial
formation. In addition, frequently used pilocarpine may cause some
complications like synechial miosis, ciliary muscle spasm to induce
malignant glaucoma and tear the peripheral retina in some cases
(Pape and Forbes, 1978; Beasley and Fraunfelder, 1979; Stocker,
1947).
For acute attack cases, topical steroids are also important that
can control the inammation of the anterior segment, restrain the
formation of PAS, and protect the structure and function of angle
drainage.
6.1.2. Agents for IOP reduction
Agents used in POAG to reduce IOP, such as beta-adrenergic
antagonists, alpha2-adrenergic agonist and carbonic anhydrase
inhibitors (CAIs) by reducing aqueous production, prostaglandin
analogues (PGAs) by enhancing intraocular uid outow, are also
used in cases of PACG.
In a randomized trial (Kim et al., 2011), the effects of brimoni-
dine and of brimonidine/timolol xed combination (BTFC) on the
pupil and angle structures were assessed in both normal subjects
and POAG patients. Results showed that brimonidine and BTFC
caused miosis and widening of most of the anterior chamber angle
parameters without changing the anterior chamber depth. The ef-
fects of BTFC on the angle were likely to be greater than those
resulting from the pilocarpine. Another investigation showed that
adrenergic alpha2 agonists inhibit the contraction of cholinergi-
cally innervated bovine ciliary muscle (Kubo and Suzuki, 1992).
The main mechanism of PGAs for IOP reduction is increasing
uveoscleral outow (Toris et al., 1993). However, they have no ef-
fects on the aqueous humor production (Ziai et al., 1993). Studies
have shown PGAs are effective at lowering IOP in chronic PACG
(Aung et al., 2000; Hung et al., 2000). No correlation was found
between efcacy of PAGs and the extent of synechial closed angle
(Aung et al., 2005). A report found that even in eyes with 360 de-
grees of PAS, latanaprost is still effective in lowering IOP (Kook
et al., 2005).
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45 39

Table 2
Peripapillary retinal perfusion in three groups.

Characteristics Normal APAC POAG P valuea Post hocb

(a) (N 20) (b) (N 20) (c) (N 20)

Gender (male: female) 9:11 10:10 10:10 0.935 /

BCVA (log MAR) 0.20 0.04 0.22 0.21 0.13 0.14 <0.001 a>c;b>a
OPP (mmHg) 46.7 6.6 47.2 9.2 49.8 8.2 0.490 /
VF
MD (dB) 1.24 1.05 7.70 5.90 8.41 3.51 <0.001 a>c, a>b
PSD (dB) 1.92 0.42 5.16 3.57 10.11 4.97 <0.001 a<b, a<c
Structural assessments
RNFL thickness (mm) 111.2 7.4 115.5 33.9 81.7 10.8 <0.001 a>c, b > c
GCC thickness (mm) 97.8 6.3 91.4 9.3 76.3 7.3 <0.001 a>c, b > c
Peripapillary vessel density
Whole 65.98 2.03 56.43 5.84 54.00 6.29 <0.001 a>b, a>c
Nasal 62.47 3.26 53.40 4.78 53.44 7.16 <0.001 a>b, a>c
Inferior nasal 66.77 3.41 58.08 8.67 51.94 7.68 <0.001 a>b, a>c
Inferior tempo 70.40 2.05 59.65 7.63 46.75 11.80 <0.001 a>b > c
Superior tempo 70.00 2.94 58.81 9.76 58.36 9.94 <0.001 a>b, a>c
Superior nasal 65.61 3.95 54.45 7.74 56.36 8.44 <0.001 a>b, a>c
Tempo 65.61 2.38 57.94 6.08 54.30 11.31 <0.001 a>b, a>c

APAC, acute primary angle closure; BCVA, best-corrected visual acuity; OPP, ocular perfusion pressure; VF, visual eld; MD, mean deviation; PSD, pattern standard deviation;
RNFL, retinal nerve ber layer; GCC, ganglion cell complex.
Numbers displayed are mean standard deviation.
a
All calculated by the Kruscal-Wallis test, except the values in bold, which was calculated by Chi-square test.
b
Multiple comparisons among the three groups.

6.1.3. What new agents for PACG we need 6.2.2. Argon laser peripheral iridoplasty
With the miotic effects, pilocarpine can also cause ciliary muscle For patients undergoing acute attacks of angle closure, Argon
contraction resulting in anterior chamber shallowing, anterior laser peripheral iridoplasty (ALPI) has been used as initial treat-
movement of the lens-iris diaphragm and increasing thickness of ment to open the drainage angle prior to LPI and can achieve rapid
the lens (Abramson et al., 1972; Wilkie et al., 1969). These effects efcacy (Lam et al., 1998). Other indications of ALPI include plateau
increase the risk of severe ciliary block and other side effect. The iris conguration or in eyes with an enlarged or intumescent lens,
question is which miotic agents are best for PACG? The aim is to use the angle remains appositionally closed or occludable following LPI.
miotic agents to pull the peripheral iris away from the trabecular
meshwork by contraction of the pupillary sphincter and keep open
the drainage angle. Ciliary muscle contraction should be avoided. A
special subtype of miotic agents, which act only on the pupillary
sphincter but not the ciliary muscle, needs to be developed even
though research already goes several decades about muscarinic
receptor subtypes of cholinergic receptor (Gupta et al., 1994; Gil
et al., 2001; Luo et al., 2001). Furthermore, the role of brimoni-
dine on angle structure in PACG and the possible mechanism of
PGAs effective in IOP reduction on whole closed angle are inter-
esting topics to be further investigated.

6.2. Laser therapy

6.2.1. Laser peripheral iridotomy

Although many anatomic mechanisms may result in angle
closure, virtually majority eyes with angle closure possess a
component of relative pupillary block. LPI successfully eliminates
the relative pupillary block component of the angle closure process.
Iridotomy can be accomplished by incisional surgery or laser.
Because of the safety and effectiveness, LPI has become a preferred
alternative treatment for incisional surgery. It is recommended as
prophylactic treatment for all occludable angles (Schwartz et al.,
1986). It is generally accepted that LPI should be performed
immediately after the termination of acute attack with medical
therapy. For chronic PACG, LPI should be performed in these eyes to
eliminate pupillary block and the progression of PAS. LPI is
commonly used as a prophylactic treatment, but evidence is lacking
as to its efcacy in preventing all PACG. A study of Asian eyes
showed that a high proportion (58.1%) of eyes with APAC developed
Fig. 11. Representative images of laser treatments. Left column: LPI; Right column: LPI
increased IOP on long-term follow-up after resolution of the acute combined with ALPI. (The top left gure shows classical glaucomecken. The lower
attack, despite the presence of a patent LPI (Aung et al., 2001) right gure shows anterior rotation of ciliary body and anterior lens capsule abutting
(Fig. 11). the enlarged ciliary process.).
40 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
However, the clinical efcacy of ALPI in these indications remains to
be determined.
Recently, some randomized, controlled clinical trials explored
the efcacy and safety of ALPI in the treatment of eyes with syne-
chial PAC or PACG. One research found that there were no signi-
cant difference in IOP, medications, need for surgery, or visual
function between groups of ALPI with/without LPI at the 1-year
visit (Sun et al., 2010). Narayanaswamy et al. compared the effec-
tiveness of ALPI with PGA therapy (Travoprost 0.004%) in PAC or
PACG, and found ALPI was associated with higher failure rates and
lower IOP reduction compared with PGA therapy (Narayanaswamy
et al., 2016). These results suggest that ALPI might have little role in
PAC/PACG eyes.
6.2.3. What we need to think about LPI/ALPI
Some authors suggest that all patients with chronic PACG should
receive LPI as the initial treatment (Ritch, 1981; Quigley, 1981;
Gieser and Wilensky, 1984). But for some advanced stage eyes
with whole or almost whole angle closed, the possibility of
reducing IOP after LPI is remote and the IOP spike after LPI may
cause further harm to the already fragile optic nerve. For these
patients the question is whether or not it is necessary to select LPI
as the initial treatment? Further studies are mandated since there is
little evidence regarding this topic. For some cases with thicker and
darker iris, LPI can induce severe inammation and iris pigment
spread to cause a signicant IOP spike, even resulting in corneal
endothelial decompensation (Wang et al., 2013). Iridotomy by laser
or incisional surgery should be selected according to the iris char-
acteristic by UBM. So incisional surgical iridotomy may be more
suited for these eyes because it excises a small piece of peripheral
iris which is then taken out of the eyeball.
A study on angle-closure mechanism in Chinese PACG patients
found that 38.1% patients had pure pupillary block (Wang et al.,
2000). Another study which compared anterior segment parame-
ters in Chinese and Japanese subjects with angle closure, found that
comparing with Chinese, Japanese angle-closure eyes have smaller
and more crowded anterior segment with thicker lenses (Ho et al.,
2015). These ndings support the notion that non-pupil block
mechanisms may play more of a role in the pathogenesis of angle
closure in some Asian populations. Therefore, we need to further
address whether ALPI with LPI should be performed as the standard
treatment of Asian PACG patients?
Laser parameters used for PACS treatments need to be quanti-
tatively studied. We still don't have clear or quantitative indications
of optimized laser treatment for PACS. In fact, there are suspected of
excessive laser treatment for PACS (He et al., 2006a,b; Nolan et al.,
2000).
6.2.4. Selective laser trabeculoplasty (SLT)
SLT is an effective method of lowing IOP for POAG and ocular
hypertension. Its efcacy in the treatment of PACG or PAC was
explored in recent years. In a case control study (Ali Aljasim et al.,
2016), effectiveness of SLT in PAC/PACG (with an opening of the
angle for at least 180 ) was compared with POAG. The results
showed that the safety and efcacy of SLT was equivalent in PAC/
PACG and POAG. In another randomized clinical trial
(Narayanaswamy et al., 2015), the IOP-lowering efcacy of SLT was
assessed with that of prostaglandin analog (PGA; travoprost,
0.004%) in PAC/PACG eyes, found that there were no differences
between the SLT and PGA groups in the absolute value or in the
percentage of IOP reduction. These ndings support the notion that
SLT could be a therapeutic option in eyes with angle closure, but the
overall long-term therapeutic effectiveness needs further
evaluation.
6.3. Surgical management
The mainstay of PACG therapy is largely surgical. Incisional
surgery for PACG is typically required when laser and/or medical
therapy fail to control the IOP. There is at present no consensus on
the best approach to the surgical management of PACG. Once LPI is
performed and IOP is still not optimally controlled, the surgical
options for PACG are diverse. These include trabeculectomy, angle
widening procedures, such as lens extraction with/without gonio-
synechialysis, and combined cataract with ltering surgery.
6.3.1. Shallow anterior chamber after ltering surgery
Trabeculectomy, which is the most common procedure of
glaucoma surgery, is also effective for ACG (Salmon, 1993). Trabe-
culectomy has been shown to have an overall success rate of 68% in
terms of IOP control (Sharif and Selvarajah, 1997).
The biggest risk of the ltering surgery for PACG was the shallow
or at anterior chamber post-operation. Flat anterior chamber with
hypertension is malignant glaucoma, which is special complication
with PACG surgery. Even though we had management strategy like
ciliary muscle spasmolysis (e.g. Atropine drops), vitreous tapping,
laser cutting posterior capsule and anterior vitreous limiting
membrane in intraocular lens (IOL) eyes, lens extraction, and vit-
rectomy, some eyes still had tragic results. For these cases, modied
or innovated management will be developing to solve this special
problem based on the mechanism of malignant glaucoma from
PACG.
Flat anterior chamber with hypotony is often accompanied by
choroidal effusions or detachment in PACG. By UBM, ciliary
detachment often observed in PACG, especially in the eyes of acute
PACG. Ciliary-Choroidal detachment due to serous effusions in the
supra-cyclochoroidal space is a frequent occurrence after trabecu-
lectomy, especially in association with a sudden decrease of IOP.
However, with the use of adjunctive antimetabolites during tra-
beculectomy, prolonged hypotony may lead to prolonged or
persistent ciliary-choroidal detachment (WuDuun et al., 2005).
Severe ciliary-choroidal detachments cause a shallow anterior
chamber, retinal detachment, complicated cataract, even choroidal
hemorrhage. According to the recognition of ciliary-choroidal ef-
fusions and the potential joint space of ciliary-choroid, trabecu-
lectomy combined with prophylactic sclerotomy is developed by
the author to control IOP in glaucoma patients with high risk of
surgical complications and provides a promising intervention to
prevent intra and postoperative severe ciliary-choroidal effusion.
The process of operation: followed by a scleral ap 4 mm by 5 mm
with half of the full scleral thickness, then a 3 mm incision was
made through the full thickness of the sclera, across the posterior
margin of the scleral bed, and perpendicular to the limbus until the
ciliary-choroid underneath was exposed. The anterior half of the
scleral incision (about 1.5 mm) was covered by the scleral ap and
the posterior half was not covered (Fig. 12). The cutting edges of the
scleral incision were cauterized to keep it open as long as possible
postoperatively. After the sclerotomy, a standard trabeculectomy
was performed (unpublished data).
A 3 mm incision sclerotomy (black arrow) was made through
the full thickness of the sclera across the posterior margin of the
scleral bed perpendicular to the limbus until the ciliary-choroid
underneath was exposed. The anterior half of the scleral incision
(about 1.5 mm) was covered by scleral ap and the posterior half
was not covered.
The sclerotomy across the boundary of the posterior scleral bed
worked as a drainage passage from supra-cyclochoroidal space to
the subconjuntival space and could drain ciliary-choroidal effusion,
even hemorrhage outside the globe at the earliest stage without
resistance of the scleral ap. This immediate drainage lowers the
 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45 41

Fig. 12. Schematic drawing of sclerotomy and operation photos.

pressure of the supra-cyclochoroidal space which reduces or avoids
severely massive ciliary-choroidal effusion and explosive choroidal
haemorrhage. Trabeculectomy combined with prophylactic ante-
rior sclerotomy within scleral bed should be a safe and effective
technique in high risk eyes of PACG.
6.3.2. Lens extraction with/without goniosynechialysis
A thicker lens is considered to play an essential role in the
pathogenesis of angle closure by causing a decrease ACD, resulting
in angle crowding (George et al., 2003). Lens extraction offers yet
another approach to treating angle closure. Lens removal is asso-
ciated with deepening of the anterior chamber and widening of the
angle (Hayashi et al., 2000). Removal of the lens may also decrease
the possibility of recurrent angle closure (Roberts et al., 2000).
There is increasing evidence regarding the effectiveness of lens
extraction for PACG (Tham et al., 2009). A recent RCT research
showed that clear-lens extraction showed greater efcacy and was
more cost-effective than laser peripheral iridotomy, and should be
considered as an option for rst-line treatment (Azuara-Blanco
et al., 2016).
Combining goniosynechialysis with lens extraction has the ad-
vantages of angle widening and IOP-lowering effect (Shao et al.,
2015). However, irreversible damage to the trabecular meshwork
may occur in areas of synechial closure. This may explain why
goniosynechialysis appeared to be less effective in angle closure of
longer duration. In order to be effective, it must be performed
before there is irreversible histological change in the trabecular
meshwork. But how can we decide which duration of angle closure/
closed is better indication for goniosynechialysis? This is a question
remaining to be answered since there are no function evaluated
methods for angle drainage at present, although we can speculate it
from the angle morphology by gonioscopy, AS-OCT or UBM.
7. Conclusion and future directions
PACG, a common cause of blindness, develops due to angle
closure. Though it is estimated that the rate of bilateral blindness in
PACG remains high (22.6% in 23.36 million patients) in 2020
(Quigley and Broman, 2006), treatments to open the angle are
proving their effectiveness. PACG is a more IOP-dependent disease
compared with POAG. While there is now evidence available to
guide us in setting target IOPs when treating POAG, there is no
consensus on what IOP levels are required to prevent progression of
glaucomatous optic neuropathy in PACG. Moreover, given the cost
effective management and diverse health care systems in different
countries, future studies will need to identify which kind of angles

Fig. 13. Illustration of investigating visual pathway function in vivo by functional magnetic resonance imaging. A. Using hemield checkerboard to localize lateral geniculate body
and visual cortex for further observation of brain activation. B. Using active and passive viewing condition to explore visual cortical response.
42 X. Sun et al. / Progress in Retinal and Eye Research 57 (2017) 26e45
and/or persons are more likely to benet from the prophylactic
treatment.
Our understanding of the pathogenesis of PACG has been
improved in recent years. Scientic progress is propelled by
improved observation technology. Astonishing improvements in
medical imaging allow us to reveal the untold information of PACS
and PACG. Numerous imaging techniques such as UBM and AS-OCT
and OCT-A have been widely used in clinical examination of
different stages of PACG patients to quantitatively determine the
relationship between the angle, iris, lens and choroid geographi-
cally and dynamically. These clinical studies will help us to further
exploit knowledge of pathogenesis of PACG, challenge our tradi-
tional concepts and stimulate further basic scientic research. For
example, we have demonstrated the volume changes of the choroid
and iris in PACG. Why do such volume changes occur and how to
modulate these changes? To address these questions, we have to
further study on endothelium, microvasculature, extracellular
matrix and innervation within the uveal tissues. It is expected that
the answers to these questions will help us to improve clinical
management of PACG.
PACG also is a typical psychosomatic disease. Currently what we
know about PACG is just within the eyeball. With the development
of functional magnetic resonance imaging and cognitive ap-
proaches, future research may investigate the entire visual pathway
and brain function, the relationship among psychological status,
neurotransmitter, and neural circuits, and their roles in the path-
ogenic mechanism on occurrence and progression of PACG (Zhang
et al., 2016) (Fig. 13). IOP regulation system is another important
eld, which may be closely related with the onset and relief of
attacks in PACG. Given the dopamine activity in the central nervous
system, recent study on dopamine D3 receptor modulating intra-
ocular pressure is promising (Leggio et al., 2016). Hopefully, new
treatment strategies like adjusting the psychological status and
balancing the sympathetic-parasympathetic nerve, and innovative
medicines based on these researches may develop to improve the
prognosis of PACG.
Competing interests statement
There are no competing interests.
Acknowledgements
Supported in part by the key project of the National Natural
Science Foundation of China (No. 81430007), Special Scientic
Research Project of Health Professions (No. 201302015), National
Major Scientic Equipment program (No. 2012YQ12008003), Sci-
ence and Technology Commission of Shanghai Municipality (No.
16411962000).
We are grateful to Hongfang Yang, Xueli Chen, Xinxin Hu, and
Yingying Zheng, for their assistance with illustrations.
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