REVIEW

Emerging Concepts in Glaucoma and Review of

the Literature
Antonio Greco, MD,a Maria Ida Rizzo, MD,b Armando De Virgilio, MD,b Andrea Gallo, MD,c Massimo Fusconi, MD,a
Marco de Vincentiis, MDa
a
Department of Sense Organs, bDepartment of Surgical Science, and cDepartment of Medico-Surgical Sciences and Biotechnologies,
Sapienza University, Rome, Italy.

ABSTRACT
Glaucoma is the most commonly acquired optic neuropathy. It represents a public health challenge because
it causes an irreversible blindness. Emerging evidence indicates that the pathogenesis of glaucoma depends
on several interacting pathogenetic mechanisms, which include mechanical effects by an increased intraocular pressure, decreased neutrophine-supply, hypoxia, excitotoxicity, oxidative stress, and the involvement of autoimmune processes. In particular, alterations in serum antibody proles have been described.
However, it is still unclear whether the autoantibodies seen in glaucoma are an epiphenomenon or causative. Oxidative stress appears to be a critical factor in the neurodestructive consequences of mitochondrial
dysfunction, glial activation response, and uncontrolled activity of the immune system during glaucomatous
neurodegeneration. In addition, hearing loss has been identied in association with glaucoma. A higher
prevalence of antiphosphatidylserine antibodies of the immunoglobulin G class was seen in normal-tension
glaucoma patients with hearing loss in comparison with normal-tension glaucoma patients with normacusis.
This nding suggests a similar pathological pathway as a sign for generalized disease.
2016 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2016) -, --KEYWORDS: Antiphospholipid antibodies; Dual sensory loss; Glaucoma; Immune system; Normal-tension glaucoma;
Oxidative stress; Retinal ganglion cells

Glaucoma is the second leading cause of blindness globally, after cataracts. It presents an even greater public
health challenge than cataracts because the blindness it
causes is irreversible.1 Numerous interesting studies
investigate the involvement of immunological mechanisms. Wax et al,2 in 1998, detected antibodies against
endogenous antigens such as heat shock protein 60 in the
serum of normal-tension glaucoma patients. Recently,
glaucoma patients were found to develop antibody alterations against specic retina and optic nerve proteins.3 In
the experimental autoimmune glaucoma model, Grus and
Gramlich3 demonstrated that an immunization with these
Funding: None.
Conict of Interest: None.
Authorship: All authors had access to the data and a role in writing the
manuscript.
Requests for reprints should be addressed to Maria Ida Rizzo, MD,
Department of Surgical Science, Sapienza University, Viadotto Gronchi 13,
Roma 00139, Italy.
E-mail address: mariaidarizzo@gmail.com
0002-9343/$ -see front matter 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2016.03.038

proteins causes retinal ganglion cell loss in an autoimmune

context. Despite these results, it is still unclear whether the
changes in antibody patterns have a causal connection with
glaucoma development or are epiphenomena of the
disease.3,4

TYPES AND SYMPTOMS

Glaucoma is an eye disease that steals vision: the
progressive visual eld loss typically begins with an arcuate
Bjerrum scotoma in the central visual eld and ends with
total blindness of the eye.4-7 The demise of retinal ganglion
cells is accompanied by morphologic changes of the retina.
The cupping of the optic nerve head is the most prominent
(Figures 1 and 2).
The 2 main types of glaucoma are open-angle and
angle-closure. These are marked by an increase in
intraocular pressure. Well-marked symptoms are observed
only in acute angle-closure glaucoma. All other forms of
chronic glaucoma are largely asymptomatic. The only signs
are gradually progressive visual eld loss and optic nerve

The American Journal of Medicine, Vol -, No -,

2016

changes. This is the main reason the disease accomplishes

ETIOPATHOGENESIS AND IMMUNE SYSTEM
its destruction to a far extent unnoticed. Fifty percent of all
INVOLVEMENT
patients live without diagnosis until advanced illness.5
Glaucoma is a multifactorial optic neuropathy characterized
Normal-tension glaucoma is a form of glaucoma in
by progressive destruction of retinal ganglion cells and their
which damage occurs to the optic nerve without eye
axons. Mller cells play a key role in the maintenance of
pressure exceeding the normal range (12-22 mm Hg).
retinal ganglion cell bodies in the
Secondary glaucoma refers to
retina. These specialized macroany form of glaucoma in which
glial cells are critically important
CLINICAL SIGNIFICANCE
there is an identiable cause of
for controlling the extracellular
increased eye pressure (traumatic
 Glaucoma is a multifactorial optic
environment, maintaining the
glaucoma, uveitic glaucoma, drugdegenerative neuropathy characterized
extracellular glutamate and ion
induced glaucoma, advanced cases
balance, and buffering oxidative
by loss of retinal ganglion cells. The
of cataract or diabetes, and others).
stress.
pathogenesis is a combination of
To diagnose glaucoma caused
For decades, a permanent
vascular, genetic, anatomical, and imby autoimmunity, the physician
raised
intraocular pressure over
mune factors.
rst excludes all other causes of
21
mm
Hg was considered the
glaucoma.10
 Features are visual eld defects until
sole trigger for the onset of

irreversible blindness occurs, cupping of

the optic disks, and elevation of intraocular pressure.

glaucoma. However, approximately one-third of all primary

open-angle patients did not at any
time have a pathologically
The World Health Organization re A subset of patients has glaucomatous
elevated ocular pressure (normalports that glaucoma affects approxchange despite normal intraocular
tension glaucoma). This raises
imately
60 million
people
pressure.
the question of what, if not the
worldwide.1 Glaucoma disproporintraocular pressure, is respontionately affects women and
 Hearing disorders can be associated.
sible for the destruction of retinal
Asians.11,12 Asian people appear to
 Early detection is the key to protecting
ganglion cells.15-20
be at increased risk for angle-closure
the vision.
glaucoma. People of Japanese
Apoptosis is accepted as an
important component of glaucomadescent are at higher risk for normaltous neurodegeneration.4,21,22 The
tension glaucoma. Other high-risk
initiation of programmed cell death of retinal ganglion cells via
groups include: people over 60 years of age (6 times more
likely to get glaucoma), family members of those already
tumor suppressor protein p53 and through the activation of the
diagnosed, steroid users, diabetics, high myopia, hypertension,
death receptor CD95 in autoreactive conditions is
central corneal thickness <5 mm, and eye injury.
documented.23,24
For the year 2020 it is expected that approximately 80
Neurotransmitters such as dopamine, serotonin, and
million people will suffer from glaucoma, which is anticiglutamate have the potential to drive retinal ganglion cells
into programmed cell death. Excitatory mechanisms are
pated to result in 11.2 million cases of bilateral blindness.13,14

EPIDEMIOLOGY AND RISK

FACTORS

Figure 1 Glaucomatous excavation of the optic nerve: Loss of optic nerve tissue results in excavation or cupping of the optic
nerve head, which is best viewed by direct ophthalmoscopy. (A) Vertical cup-to-disk (C:D) ratio within the normal range. (B)
Glaucomatous cupping has an increased C:D ratio. From: Adatia FA, Damji KF. Can Fam Physician. 2005;51(9):1229-1237.8

Greco et al

Glaucoma

Figure 2 Optic nerve head shows loss of axons

(cupping) due to chronic glaucoma (hematoxylin and
eosin; 31). From: Read RW, Zamir E, Rao NA, et al.
Nongranulomatous Inammation: Uveitis, Endophthalmitis, Panophthalmitis, and Sequelae. In: Tasman W,
Jaeger EA, eds. Duanes Clinical Ophthalmology. Baltimore: Lippincott Williams & Wilkins; 2004, 1-13.9

suggested as a cause for the triggering of apoptosis.25-29

Regarding the potential excitotoxicity of glutamate, it is
noteworthy that glutamate transporters and receptors are
downregulated in glaucomatous eyes following astrocyte
activation.30,31
Anyway, homeostasis and survival of the retinal ganglion
cells depend on a well-balanced function of the immune
system. On the one hand, the immune system eliminates
pathogens and cell debris to maintain the homeostasis of the
central nervous system and, on the other hand, many of the
well-known neurodegenerative incidents that are caused by
misdirected immune processes within the central nervous
system are also detectable in glaucoma.32
Antibodies against endogenous antigens such as heat
shock proteins (HSPs) are found in the serum of normaltension glaucoma patients.2 HSPs are components of
cellular defense mechanisms and are upregulated under
pathophysiological conditions. HSP60 promotes the induction of apoptosis,33 whereas HSP27 has neuroprotective
effects. Rats immunized with HSP27 show an elevated rate
of apoptosis in the retinal ganglion cells, where the loss is
focused near the area centralis. Normal-tension glaucoma
patients display the worst damage in the same retinal area.34
In animal models, experimental elevation of intraocular
pressure leads to increased expression of Toll-like receptor
family (TLR) 2, 3, and 4 and of HSP27, HSP60, and
HSP72, as well as the characteristic TLR signaling cascade
adapter proteins and kinases. These ndings were conrmed
by proteomic analysis of glaucomatous donor eyes. This
supports the hypothesis that TLR contribute to the activation
of the innate immune system in glaucoma. The increased
HSP expression seems to stimulate the immune system even
further.35,36 Tumor necrosis factor alpha and its receptors
have been shown to be upregulated in the retinae of
glaucoma patients.37,38

3
Several authors documented peculiarities in the antibody
repertoire: antibodies against neuron-specic g-enolase, a
key enzyme for glycolysis39; antiglycosaminoglycans
antibodies and neurolament protein40,41; a subgroup of
antiphospholipid antibodies, called antiphosphatidylserine
antibodies.42-44 Autoreactive antibodies can be not only
destructive, but also protective. Recent ndings support the
hypothesis that these antibodies contribute to the clearance
of cellular damage and promote repair. A decreased
reactivity of naturally occurring and perhaps protective
autoantibodies may therefore lead to a loss of immune
protection and consequently, an increased risk of developing
glaucoma.45
Chronic tissue stress and age-dependent factors appear to
be critical in the failure of regulation of immune activity as
well as the increase of neuronal susceptibility to injury in
glaucoma. Mitochondrial dysfunction and the resultant
oxidative stress are directly involved in neuronal damage,
but may also facilitate dysregulation of immune activity
during glaucomatous neurodegeneration. Similarly, chronic
activity response and the accompanying dysfunction of
neurosupportive glia under glaucomatous stress may initiate
potentially neurotoxic inuences, as well as affect immunoregulatory functions.46
It is evident that glial antigen presentation is stimulated in
glaucomatous tissues, along with the loss of normal
immunosuppression due to neuronal loss and glial
dysfunction. Oxidative stress stimulates the antigenpresenting ability of glial cells in glaucoma. Many factors
evident in glaucoma, including an increase in antigenicity
due to increased protein expression and posttranslational
protein modications, an increase in highly antigenic stress
proteins, and an increase in the exposure of proteins due to
cell death, may further contribute to failure in the control of
immune activity in glaucoma. In addition, chronic tissue
stress in glaucomatous eyes may lead to increased contact of
the retina and optic nerve head tissues with systemic
immune cells due to alterations in perivascular barriers.47
Thus, oxidative stress appears to be a critical factor placed
at the glia/mitochondria/immune system intersection during
glaucomatous neurodegeneration (Figure 3).

DUAL SENSORY LOSS

Normal-tension glaucoma and hearing loss have a high
coincidence. Patients with normal-tension glaucoma are
reported to have elevated concentrations of antiphospholipid
antibodies with a coincidence of progressive sensorineural
hearing loss. The elevated levels may indicate an association
with similar systemic autoimmune processes.44
An interesting study performed inner-ear diagnostic tests
in some of these normal-tension glaucoma patients and found
that 67% had pathological audiograms (progressive sensorineural hearing loss in 32% and presbycusis in 35%).
Interestingly, a higher prevalence of antiphosphatidylserine
antibodies of the immunoglobulin G class was seen in
normal-tension patients with hearing loss in comparison with

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2016

Figure 3 Oxidative stress appears to be a critical factor in the neurodestructive consequences of

mitochondrial dysfunction, glial activation response, and uncontrolled activity of the immune system
during glaucomatous neurodegeneration. From: Tezel G. The role of glia, mitochondria, and the immune
system in glaucoma. Invest Ophthalmol Vis Sci. 2009;50:1001-1012.47

normal-tension patients with normacusis. This nding suggests a similar pathological pathway as a sign for generalized
disease. This is not surprising because antiphospholipid
antibodies increase with age. Antiphosphatidylserine antibodies can induce apoptosis, which results in occlusion of
small vessels by thromboemboli in the inner ear and eye.44
Antiphosphatidylserine immunoglobulin M antibodies
seem to coincide with an acute event, such as sudden
sensorineural hearing loss, whereas antibodies against
phosphatidylserine immunoglobulin G are detectable in the
prolonged sequel, such as in patients with progressive
sensorineural hearing loss and normal-tension glaucoma.48
The coincidence of hearing and vision loss is more
frequent than expected by the prevalence of individual disorders. With regards to demographic changes and an aging
population, in future, it is probable that the incidence of
combined hearing and vision impairments will increase,
representing not only a particular challenge for doctors and
nurses but also a high burden for the private environment of
the patients. Therefore, it is of particular importance to
diagnose and to treat hearing and vision loss (dual sensory
loss) as early as possible.45 One of the most common sensory
impairments of elderly people is hearing loss, and glaucoma
is one of the leading causes of blindness worldwide.
During the last years, knowledge about the molecular
biological background of hearing loss and glaucoma has

continuously increased, but it is currently still at the level of

laboratory and animal experiments. Therefore, it remains to
be seen whether and to what extent a real therapy for the
underlying genetic and immunological factors may be
feasible in the future.

DIAGNOSIS
Diagnosis of glaucoma is not always easy. Careful
evaluation of the optic nerve continues to be essential. Early
detection through regular and complete eye examinations is
the key to protecting vision. A complete eye examination
includes 5 common tests to detect glaucoma: tonometry,
ophthalmoscopy, perimetry, gonioscopy, and pachymetry.
Ophthalmoscopy (Figure 1)8 is fundamental to all types
of glaucoma. It examines the shape and color of the optic
nerve. Normal-tension glaucoma is diagnosed by observing
the optic nerve for signs of damage. A nerve that is cupped
or is not a healthy pink color is a cause for concern. With a
vertical cup-to-disk (C:D) ratio of 0.6 or greater, glaucoma
should be suspected. Often, glaucoma affects the
eyes asymmetrically; one cup appears larger than the other.
Thus >0.2 asymmetry between the C:D ratios of both eyes
should also suggest glaucoma.
The diagnosis of autoimmune glaucoma is a diagnosis
of exclusion.10 The physician rst excludes all other

Greco et al

Glaucoma

causes (such as elevated intraocular pressure in highpressure glaucoma; ischemia, migraine, systemic
nocturnal hypotension, or sleep apnea in the case of
normal-tension glaucoma). A complicating factor is that
any given autoimmune disease is heterologous, varying
from patient to patient with regard to the course of disease, the severity, and the underlying dysfunction of the
immune system.

5
Table 1

Features Suggesting a Nonglaucomatous Diagnosis*

History

Young Age

Examination

Rapid onset
Rapid progression
Headache (other than typical migraine)
Other neurologic symptoms
Loss of visual acuity or visual eld out of
proportion to cupping
Severe dyschromatopsia
Afferent pupillary defect without signicant
asymmetry of cupping
Ocular motility or other neurologic defects
Atypical visual eld: temporal > nasal, respect of
vertical meridian, inferior altitudinal defect,
central scotoma
Pallor of preserved rim

HISTOPATHOLOGY
The optic nerve damage manifests histopathologically as
loss of nerve bers and ganglion cells with cupping of the
optic nerve head (Figure 2).9
The site of damage to nerve bers is the scleral lamina
cribrosa, where there is local blockage of axonal transport.
Early cup size increase prior to denite eld loss results
from loss of nerve bers, not from damage to astrocytic glial
cells of the nerve head.49

Visual eld

Optic disk

*From: Moster ML, Kay MD. Glaucoma: the neuro-ophthalmologic

differential diagnosis. J Curr Glaucoma Pract. 2008;2:33-38.50

PROGNOSIS
DIFFERENTIAL DIAGNOSIS
Glaucomatous optic neuropathy is the most commonly acquired optic neuropathy encountered in clinical practice.
While it has clinical features that overlap with nonglaucomatous optic neuropathies, including the presence of
vision loss, visual eld loss, and optic disc cupping, there
are distinct features in each condition. Nonglaucomatous
optic nerve disorders must be differentiated from their
glaucomatous brethren because their underlying pathophysiological mechanisms are often part of systemic disease
processes that have the potential to impact mortality
(Tables 1 and 2).51,52
The 3 clinical features to identify glaucoma patients,
namely visual eld defects, cupping of the optic disks, and
elevation of intraocular pressure may be seen in patients
with neuro-ophthalmologic disorders as well. In Moster and
Kays50 experience, the most confusing issue leading to the
misdiagnosis of glaucoma in neuro-ophthalmologic patients
is the nonrealization that cupping may occur in neuroophthalmologic disease. In a series of patients with nonglaucomatous optic atrophy, 20% had cupping and in 6%
this was typical for glaucoma. When looked at more carefully, it turns out that in addition to cupping, the rim of the
optic disk is most often pale in neurologic disease. Rarely
does the cupping extend to completely obliterate the rim in
neurologic disease. Nonglaucomatous cupping has been
described to varying degrees in patients with compressive
lesions of the visual pathway, optic neuritis, toxic optic
neuropathy, radiation optic neuropathy, and neurodegenerative disease.50
Patients with acute glaucoma usually present to an
emergency department with unbearable pain, nausea, and
vomiting. Differential diagnosis with intracranial hypertension must be immediate, but it is easy because the eye is
congested and sore in acute glaucoma.

The prognosis depends on the timeline of diagnosis and

treatment. Some may have high eye pressure for years and
never develop damage, while others can develop nerve
damage at a relatively low pressure. Untreated glaucoma can
lead to permanent damage of the optic nerve and resultant
visual eld loss, which over time can progress to blindness.
Glaucoma is a silent thief of sight because the loss of
vision often occurs gradually over a long period of time, and
symptoms occur only when the disease is quite advanced.
Once lost, vision cannot normally be recovered, so treatment
is aimed at preventing further loss.
If the condition is detected early enough, it is possible to
arrest the development or slow the progression with medical

Table 2

Glaucomatous Optic Neuropathy*

Characteristics often noted when observing the glaucomatous

optic disc include:8,9,44-49
 Neuroretinal rim tissue that does not respect the ISNT rule.
 Notching of the rim.
 Verticalization of the optic cup.
 An acquired optic pit.
 Baring of a circumlinear vessel.
 Vessel bayoneting at the optic rim (indicating bean-pot
cupping).
 Nasalization of vessels.
 Disc hemorrhage (Drance hemorrhage).
 Abnormally large or atypical pattern of peripapillary atrophy
(beta zone atrophy).
 Nerve not exhibiting rim pallor.
ISNT rule (that normal eyes show a characteristic conguration for
disc rim thickness of inferior  superior  nasal  temporal) widely used
for clinical evaluation of the optic nerve head.
*From: Hutchinson JK, Gurwood AS, Myers MD. 18th Annual Glaucoma Report. Optic neuropathies: glaucomatous vs non-glaucomatous.
Rev Optom. 2012;149:58.51

6
and surgical means. Therapeutic lowering of the intraocular
pressure leads to a slowing of disease progression in a
subgroup of normal-tension glaucoma patients also.26,27,53

TREATMENTS AND NEUROPROTECTION

The only currently approved treatment is aimed at lowering
intraocular pressure, the most signicant risk factor known
to date.54 Reducing the intraocular pressure leads, even in
patients with normal-tension glaucoma, to an alleviation of
the disease process.5,21,25,55 Intraocular pressure reduction is
by eye drops or systemic application of glaucoma
medications. These include carbonic anhydrase inhibitors,
beta-blockers, cholinergic agonists, alpha-2 adrenoceptor
agonists, and prostaglandins.15,16,26,56,57 Laser therapy
(argon laser trabeculoplasty/cyclolaser ablation) or surgical
procedures (trabeculectomy/iridotomy/ltering surgery) for
ensuring an adequate aqueous humor outow are seen as
nal option.
In the secondary glaucoma, the type of treatment will
depend on the underlying cause.
In any case, glaucoma is not curable, and vision lost
cannot be regained. With medication or surgery, or both, it
is possible to halt further loss of vision.
Cannabinoid receptor agonists including tetrahydrocannabinol have been investigated for their potential role as
effective glaucoma treatments and neuroprotection.58
Neuroprotection is useful to save retinal ganglion cells
from glaucomatous injury or to repair neurons that have
been damaged. Inhibitors of glutamate, such as aminoguanidine or memantine, have been studied as neuroprotective agents, where memantine has been shown to be
protective against retinal ganglion cell loss in animal
models.59 Brimonidine, an alpha2-adrenergic receptor
agonist, may not only lower intraocular pressure but also
serve an additional, separate purpose of providing
neuroprotection.60
Nanotechnology applications are being developed for
several ocular diseases using a variety of nanosuspensions,
liposomes, dendrimers, nanoparticles, ocular inserts, implants, and hydrogels.61

CONCLUSIONS
Glaucoma is a devastating disease that affects millions of
people worldwide. Emerging evidence indicates that the
pathogenesis of glaucoma depends on several interacting
pathogenetic mechanisms, which include mechanical effects
by an increased intraocular pressure, decreased neutrophinesupply, hypoxia, excitotoxicity, oxidative stress, and the
involvement of autoimmune processes. Oxidative stress
appears to be a critical factor in the neurodestructive consequences of mitochondrial dysfunction, glial activation
response, and uncontrolled activity of the immune system
during glaucomatous neurodegeneration.4,47,48,62
In particular, autoimmune antibodies seem to play an
important role in the etiopathogenesis of some

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2016

glaucomatous patients; therefore, further studies may be

necessary to investigate possible therapeutic options.

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