This article was downloaded by: [Emory University]

On: 13 August 2015, At: 06:53

Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place,
London, SW1P 1WG

Expert Review of Ophthalmology

Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/ierl20

Clinical update in optic nerve disorders

a ab a ac
Nidhi Agarwal , Daren Hanumunthadu , Morteza Afrasiabi , Giulia Malaguarnera & Maria
ad
Francesca Cordeiro
a 1
Glaucoma and Retinal Neurodegeneration Research Group Visual Neuroscience, UCL
Institute of Ophthalmology, 11 – 43 Bath Street, London, EC1V 9EL, UK
b 2
Central Middlesex Hospital, Acton Lane, London NW10 7NS, UK
c 3
International Ph.D. programme in Neuropharmacology, University of Catania, 95123
Catania, Italy
d 4
Western Eye Hospital, Imperial College Healthcare Trust, Marylebone Road, London, NW1
5HQ, UK
Published online: 26 May 2015.
Click for updates

To cite this article: Nidhi Agarwal, Daren Hanumunthadu, Morteza Afrasiabi, Giulia Malaguarnera & Maria Francesca Cordeiro
(2015) Clinical update in optic nerve disorders, Expert Review of Ophthalmology, 10:2, 145-166

To link to this article: http://dx.doi.org/10.1586/17469899.2015.1003544

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Nidhi Agarwal1,
Daren
Hanumunthadu1,2,
Morteza Afrasiabi1,
Giulia Malaguarnera1,3
and Maria Francesca
Downloaded by [Emory University] at 06:53 13 August 2015
Cordeiro*1,4
1
Glaucoma and Retinal
Neurodegeneration Research Group
Visual Neuroscience, UCL Institute of
Ophthalmology, 11 – 43 Bath Street,
London, EC1V 9EL, UK
2
Central Middlesex Hospital, Acton
Lane, London NW10 7NS, UK
3 .
International Ph.D. programme in
Neuropharmacology, University of
Catania, 95123 Catania, Italy
4
Western Eye Hospital, Imperial College
Healthcare Trust, Marylebone Road,
London, NW1 5HQ, UK
Author for correspondence:
Tel.: +44 207 608 6938;
+44 207 608 6939
m.cordeiro@ucl.ac.uk
informahealthcare.com
Review
Clinical update in optic nerve
disorders
Expert Rev. Ophthalmol. 10(2), 145–166 (2015)
Optic nerve disorders lead to visual loss and can result: from multiple etiologies, including
optic neuritis, anterior ischemic optic neuropathy, glaucoma, Leber’s hereditary optic
neuropathy and dominant optic atrophy. The recent advances in imaging technologies often
supplement the history and clinical examination for identification of optic neuropathies.
Correlation between the structural and functional changes in eye is important to validate
these diagnostic techniques. Advancement in the understanding of disease process has led to
the development of new potential therapeutic targets that may enable apt management of
these conditions. Animal models play a crucial role in understanding the pathophysiology of
these disorders, identifying therapeutic targets and testing prospective drugs, which are vital
for providing better patient care. In this review, the authors aim to provide a clinical update
to the readers about these optic neuropathies in addition to the essential role played by
animal research in progressing their current state of knowledge.
KEYWORDS: animal models . anterior ischemic optic neuropathy . clinical examination . dominant optic atrophy
glaucoma . history . imaging technologies . Leber’s hereditary optic neuropathy . optic nerve disorders
. optic neuritis
The optic nerve functions at the inception of neuropathy, resulting in degeneration of optic
the channel for transmission of visual informa- nerve fibers [8]. Despite multiple differential
tion from the retina to the visual cortex. Visual diagnoses of optic nerve disorders, a proficient
loss is a common symptom encountered by the history and clinical examination can provide a
ophthalmologist and general physician and can good differential, which may then be confirmed
result from many optic nerve disorders (TABLE 1), using advanced investigations. Atypical presen-
including: optic neuritis (ON), anterior ische- tations or a poor history can be challenging,
mic optic neuropathy (AION) and open-angle although advances in imaging technologies have
glaucoma (OAG) (TABLE 2). ON represents steered more efficient and reliable diagnosis in
inflammation of the optic nerve and is the most such cases. These same imaging technologies
common etiology of optic neuropathy encoun- provide the opportunity for objective data that
tered in young adult patients [1]. AION is are reliable, reproducible and repeatable,
divided into arteritic-AION (A-AION) and thereby assisting in establishing guidelines for
non-arteritic AION (NA-AION); the former is monitoring the disease progression.
frequently associated with giant cell arteritis Animal models play a crucial role in under-
(GCA) [2] – an ophthalmic emergency with standing the disease pathophysiology and test-
unilateral visual loss in 48.8 and 31% bilater- ing diagnostic as well as preliminary
ally [3], while the latter is a more common form therapeutic strategies. The significance of the
of AION. Glaucoma is the most common cause latter is underscored by the recent potential
of irreversible blindness across the world, add- therapeutic breakthrough tested in a mouse
ing significantly to health care demands [4,5]. model of LHON [9]. In most scenarios, how-
Leber’s hereditary optic neuropathy (LHON) is ever, extrapolation of data acquired from ani-
the most common mitochondrial genetic dis- mal experiments is often challenging due to
ease [6] in which application of gene therapy differences in the anatomy and biological
with the aim to achieve potential vision has behavior of the tissue in question between dif-
progressed to human clinical trials [7]. Domi- ferent species and multi-factorial pathogenic
nant optic atrophy (DOA) on the other hand is mechanisms of these neuropathies. This leads
the most common form of inherited optic to unattainability of a single representative
10.1586/17469899.2015.1003544
2015 Informa UK Ltd ISSN 1746-9899 145
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

Table 1. Causes of optic neuropathy†.

Types of optic neuropathy Causes
Congenital anomalies Optic nerve hypoplasia, megalopapilla, congenital tilted disc syndrome, morning glory disc,
coloboma of optic disc, peripapillary staphyloma, optic disc pit, optic disc dysplasia,
papillorenal syndrome, optic disc drusen
Optic neuritis Typical ON – MS-associated ON, isolated ON; atypical ON – neuromyelitis-associated ON, ON
with systemic disorders like sarcoid, lupus, polyarteritis nodosa
Ischemic optic neuropathy Anterior (AION) or posterior (PION), arteritic (A-AION or A-PION) or non-arteritic (NA-AION or
NA-PION)
Glaucoma Congenital, open-angle glaucoma, angle closure glaucoma, normal tension glaucoma
Inherited optic neuropathy Leber hereditary optic neuropathy, dominant optic atrophy or Kjer’s
Compressive optic neuropathy Optic nerve sheath meningioma, pituitary tumors, Graves’ ophthalmopathy with optic nerve
compression
Infiltrative optic neuropathy Primary tumors infiltrating the optic nerve – optic glioma, ganglioglioma
Downloaded by [Emory University] at 06:53 13 August 2015

Nutritional and toxic optic neuropathy
Drugs associated with optic neuropathy
Infectious optic neuropathy
Traumatic optic neuropathy
†
The list is non-exhaustive.
ION: Ischemic optic neuropathy; MS: Multiple sclerosis; ON: Optic neuritis.
Adapted from [1,73,163].
Secondary tumors – optic nerve sheath meningioma, retinal tumors, distant metastasis
Deficiency of vitamin B1 (thiamine), B2 (riboflavin), B12 and folate; alcohol, carbon monoxide,
carbon tetrachloride, lead, mercury
Chloramphenicol, cyclosporine, cisplatin,
5-fluorouracil, amiodarone
Bacterial (Bartonella henselae, Treponema pallidum, Borrelia burgdorferi), viral (human
immunodeficiency virus, cytomegalovirus) and fungal (Cryptococcus neoformans, Aspergillus
fumigatus)

animal model. Successful application of gene therapy approach
in human clinical trials for ophthalmic conditions such as Leb-
er’s congenital amaurosis [10–13] and choroideremia [14] has also
been initiated in case of LHON, which is currently recruiting
subjects [15].
Presenting symptoms
Optic neuritis
History of onset of visual loss is of paramount importance to
guide the clinical diagnosis. A rapid onset (acute/subacute) is
highly indicative of ON, ION and also traumatic optic neurop-
athy, whereas a more gradual onset points toward a slow pro-
cess seen in compressive, toxic and nutritional etiologies. ON is
mainly unilateral in adults, whereas in children, it is more
likely to be bilateral [16]. It is the presenting symptom in 50%
of patients with multiple sclerosis (MS) and may occur in 80%
of these patients during the course of this condition [17]. Typi-
cal ON (following MS) presents as a subacute unilateral visual
loss that worsens over hours to days [18] and can be differenti-
ated on the basis of history from the sudden loss of vision that
accompanies AION. A characteristic feature of typical ON
affecting the optic disc (papillitis) is the presence of constant
mild-to-moderate periocular pain in 92.2% of the patients that
is exacerbated with ocular movements [18]. ON associated with
inflammation of optic nerve posterior to the orbit (retrobulbar
neuritis) is not always associated with pain [19]. A careful his-
tory of deterioration of vision on exposure to activities that
increase body temperature such as exercise; hot shower, espe-
cially in case of MS (Uhthoff’s phenomenon) [20]; impaired
depth perception, especially of moving objects (Pulfrich phe-
nomenon) [21] assists in narrowing down the differential diag-
nosis and thereby further investigations.
Anterior ischemic optic neuropathy
Both A-AION and NA-AION present with a classic history of
sudden painless deterioration of vision [2]. A crucial symptom
differentiating A-AION from NA-AION is Amaurosis fugax,
which is intermittent painless loss of vision and signifies
impending risk of developing visual loss [2]. Also, the presence
of systemic symptoms of GCA such as jaw claudication, neck
pain, scalp tenderness, headache, malaise, anorexia and weight
loss [22] clinches the diagnosis of A-AION, but the absence of
it as seen in 21.2% patients of occult GCA with ocular mani-
festations does not rule out the diagnosis [23].The vision loss in
NA-AION is usually discerned on waking up in the morning,
which may be associated with nocturnal hypotension [24]; how-
ever the Ischemic Optic Neuropathy Decompression Trial
(IONDT) did not confirm this observation [25]. These patients
often describe the visual deficit as blurred or clouded in the
affected area [26]. Although nocturnal hypotension is the most

146 Expert Rev. Ophthalmol. 10(2), (2015)

 Downloaded by [Emory University] at 06:53 13 August 2015

Table 2. Epidemiology of the most common causes of optic neuropathy.

Optic Age and sex Prevalence Age Sex Race Ref.
neuropathy adjusted
incidence
ON Minnesota (USA) – Minnesota (USA) Average age 36.3 ± F>M Caucasian [18,164–166]
5.1/100 000/year 115/100 000 12 years

informahealthcare.com
Sweden (Europe) –
1.4/100 000/year
Japan – 1.62/100 000/year
A-AION California (USA) – – 75.2 ± 5† F > M† Caucasians† [167,168]
0.36/100 000/year
NA-AION USA – 0.01–0.35/1000/year – >50 years age, but M > F in patients White > black [169–171]
(incidence observed between recent data suggest below 50 years of
18 and 44 years and above 23% patients to be age
75 years of age respectively) younger than 50
(Clinical Trials.gov identifier
NCT01260324)
China – 1/16,000/year
Recent data suggest the
incidence above sixth decade to
be 82/100 000/year
OAG Minnesota – 14.5/100 000/year Worldwide – mean >40 years of age and M > F (5) African > Europeans [5,31,172–174]
Barbados – 2.2% in the fourth prevalence of POAG prevalence increases (5)
decade and increases to 4.2% in between 40 and 80 years with increasing age
the seventh decade and above of age is 3.54% (5)
Incidence of definite glaucoma is
4.1% in eighth decade in a
population study from Australia,
Melbourne and Victoria
LHON – Netherland (Europe) – 22 ± 13.6 M>F m.11778 G > A – [51,58,175–178]
1/39 000 common in Northern
Finland (Europe) – Europeans and Asians,
1/50 000 and of carrier m.14484 T > C –
state is 1/9000 French Canadians
Point prevalence of visual
failure in North East
England is
3.22/100 000
Clinical update in optic nerve disorders

DOA North England – First two decades of [8,52,179,180]

1/25 000, life
Denmark – 1/10
000 (founder effect)
†
These figures represent the data for giant cell arteritis, which is the most common cause of A-AION.
Review

A-AION: Arteritic anterior ischemic optic neuropathy; DOA: Dominant optic atrophy; LHON: Leber’s hereditary optic neuropathy; NA-AION: Non-arteritic anterior ischemic optic neuropathy; OAG: Open-angle glaucoma.

147
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro
crucial precipitating factor of NA-AION, presence of risk fac-
tors such as diabetes mellitus, hypertension and sleep apnea
predispose to the development of NA-AION [27–29]. The fellow
eye involvement in patients with unilateral NA-AION was esti-
mated to be 14.7% after a mean follow-up period of
5.1 years [30].
Glaucoma
In ACG, rapid elevation of the intraocular pressure (IOP)
results in marked intermittent diminution of vision with excru-
ciating pain that radiates along the distribution of trigeminal
nerve, and these patients additionally complain of photophobia,
lacrimation, nausea and vomiting [31]. OAG on the other hand
is recognized as the ‘silent thief of sight’ as it is usually asymp-
tomatic with patients even unaware of a visual field (VF) defect
when almost 40% of the retinal ganglion cells (RGCs) have
been lost [32]. The combination of being the most common
Downloaded by [Emory University] at 06:53 13 August 2015
cause of irreversible blindness worldwide [5] with 50% patients
staying undetected and the increasing economic burden for
treatment [4] as the disease advances [33] makes glaucoma an
ideal candidate for mass screening programs. It is worthwhile
to mention the major drawbacks encountered with glaucoma
screening program that hinders its implementation include the
lack of a cost–effective and, more importantly, a sensitive and
specific diagnostic test for the early detection of glaucoma [34,35].
In recent years, the genetic basis of glaucoma has attracted a
lot of attention and subsequent research using linkage analysis,
genome-wide association studies has led to discovery of novel
genes that are associated with increased propensity to develop
glaucoma [36]. Myocilin [37], optineurin [38] and WD repeat
domain 36 [39] genes have been implicated in the development
of primary OAG (POAG) within the 20 linkage loci identi-
fied [40]. Missense mutation in the myocilin gene is associated
with 8% cases of juvenile onset POAG and 3–5% cases of
adult-onset POAG [41]. The clinical phenotype is severe in
patients harboring this mutation [42]. Similarly E50K mutation
in the optineurin gene has been linked to the development of
clinically severe form of normal tension glaucoma [38,43]. On
the other hand, mutation in the WD repeat domain
36 increases the individual’s risk of POAG rather than directly
causing it [39]. Genome-wide association studies have
highlighted the increased association of single-nucleotide poly-
morphisms rs4236601 (chromosome 7q31) [44], cyclin-
dependant kinase inhibitor 2B [45] and variant in the 14q23 [45]
with POAG and single-nucleotide polymorphisms
rs3213787 in the S1 RNA-binding domain 1 with normal ten-
sion glaucoma [46]. With the advent of sophisticated genetic
diagnostic tools, more genes are being implicated in the patho-
genesis of various forms of glaucoma, thereby enabling future
use of gene therapy approaches in these cases.
Leber’s hereditary optic neuropathy
LHON results from mutation in the mitochondrial genes that
code for the complex I subunit of the mitochondrial respiratory
chain [47] and is characterized by RGC death subsequent to
148
optic nerve damage [48–50]. A retrospective study conducted by
Mackey et al. estimated 97% of the patients with LHON to
harbor one of these three point mutations in their mitochon-
drial genes, that is, m.11778 G>A, m.14484 T>C and
m.3460 G>A [51]. LHON more commonly affects males, with
the likelihood of 50% males developing this condition as
opposed to only 10% females in presence of LHON causing
mutation [52]. The incomplete penetrance and male preponder-
ance can be explained by simultaneous inheritance of recessive
susceptibility allele (or nuclear modifier genes) on the
X-chromosome that can act in synergy with the primary muta-
tions [53–55]. Additionally, the presence of mitochondrial hap-
logroup J and K in association with the primary mutations
m.11778 G>A, m.14484 T>C and m. 3460 G>A respectively
have been linked to increase an individual’s risk for visual
impairment [56].With the background of maternal inheritance,
variable penetrance and male predominance (ibid), the patients
usually present with unilateral visual loss (78%) with sequential
involvement of the other eye within a median period of
8 weeks [57]. In both eyes, the visual loss reaches a nadir within
1–6 weeks (ibid). Patients harboring m.11778 mutation show a
slower development of visual impairment when compared to
mutation at m.14484 and m.3460 loci [58]. Simultaneous
involvement of both eyes has been reported in about 22% cases
of LHON. The presence of a positive family history is variable
(50–100%) depending on the underlying genetic mitochondrial
mutation. Visual improvement has been observed in 64,
22 and 15% of the patients harboring the mitochondrial muta-
tion at locus 14484, 11778 and 3460, respectively [58]. Addi-
tionally some patients of LHON report of periocular pain that
worsens with eye movement and Uhthoff’s phenomenon and
MS-like illness [57], all of which are also manifested in cases of
ON and hence needs careful evaluation.
Dominant optic atrophy
DOA results from mutation in specific nuclear genes that
encode proteins, which are associated with the mitochondrial
inner membrane [59]. A total of 60–80% of the patients with
DOA have mutation in the OPA1 gene (optic atrophy 1) [60]
and others may demonstrate mutation in other known genes
such as OPA3 [61] or the OPA4 [62], OPA5 [63] and OPA8 [64]
loci. Mutation of the OPA1 gene that encodes a dynamin-
related GTPase [65] causes a significant decline in ATP synthesis
by mitochondrial complex 1 with inhibition of mitochondrial
fusion in skin fibroblasts derived from DOA patients [66] and
also increases their susceptibility to apoptosis [67]. Majority of
cases with DOA present with insidious, slowly progressive and
symmetric impairment of vision with presence of intra and
inter-familial variability [8]. The clinical spectrum can vary
from the presence of unaffected members within the same fam-
ily harboring the same mutation to members showing severe
visual impairment [68]. There have been many case reports link-
ing R445H mutation in the OPA1 gene with clinical presenta-
tion of DOA in association with sensorineural deafness
(DOAD i.e., DOA with deafness) [69,70]. Mutation in the
Expert Rev. Ophthalmol. 10(2), (2015)

OPA1 gene, especially the missense mutation, have been associ-
ated with DOAplus syndrome, in which patients develop fea-
tures of DOA in association with extra-ocular manifestations
such as sensorineural deafness, ataxia, sensorimotor polyneurop-
athy and also chronic progressive external ophthalmoplegia and
proximal myopathy [68,71].
Clinical signs
Initial assessment of a patient with suspected optic neuropathy
must include examination of spatial vision (central visual acuity
[VA], contrast sensitivity), color vision, pupillary response,
optic disc and VF evaluation.
Visual acuity & contrast sensitivity
In the ON treatment trial (ONTT), the central VA measured
using high-contrast Bailey–Lovie chart was reduced in 89.5%
of patients and ranged from log MAR value of more than
Downloaded by [Emory University] at 06:53 13 August 2015
0.0 to 1.50 (75th percentile), with 15.6% patients among
them showing severe VA deficit ranging from finger counting
to no light perception [18]. 10.5% patients enrolled in ONTT
had a VA of 20/20 and better [18] and also 32% of patients
with NA-AION were observed to have normal VA within
2 weeks of onset of symptoms [72], indicating that the presence
of optic neuropathy does not always correlate with a decrease
in high-contrast VA (Snellen, Bailey–Lovie). Hence, it is not a
completely reliable indicator of the underlying visual deficit.
A more efficient way to gauge the presence of optic neuropathy
is to measure low-contrast sensitivity (Pelli–Robson letter
chart), as 98.2% of patients with ON demonstrated a deficit in
this parameter [18]. In patients of LHON, VA is reduced to fin-
ger counting and even no light perception [73]. As opposed to
this, VA in patients with DOA ranges from 20/20 to light per-
ception, with approximately 20% patients experiencing gradual
deterioration of vision with age [52].
Color vision
The presence of a mild-to-moderate deficit in VA and central
visual loss in association with reduced color vision is a sensitive
indicator of optic neuropathy. It assists in differentiating
pathologies of optic nerve from that affecting the macula, as in
the latter, VA is severely reduced with mild deficits in color
vision [74]. Both red–green and blue–yellow color deficits are
seen in cases of ON, with a slight preponderance of the former
in acute phase and the latter in chronic phase [75]. In subclini-
cal cases of ON associated with MS, pattern visual-evoked
potential, contrast sensitivity and color vision (using first
25 plates of Ishihara test) were shown to be abnormal in 81.8,
72.2 and 31.8% patients, thereby signifying the value of former
two tests in assisting in the early diagnosis of ON [76]. How-
ever, a recent study conducted on MS patients with 20/20 VA
(Snellen chart) demonstrated the presence of greater abnormal-
ity in color vision (70% patients) tested with Farnsworth
Munsell-100 Hue test as compared to pattern visual-evoked
potential (55%), thereby promoting the use of color vision test-
ing as a more sensitive indicator of subclinical ON in patients
informahealthcare.com
Clinical update in optic nerve disorders Review
with MS than pattern visual-evoked potential [17]. Some
patients with ION may have normal color perception, espe-
cially in the areas where their VF is intact [74]. In glaucoma sus-
pects with unilateral/bilateral IOP >21 mmHg or POAG in
the contralateral eye with normal optic disc and VF examina-
tion in the test eye in both cases, alterations in the perception
of color (blue–yellow > diffuse color defect > red–green)
occurred prior to the changes observed in VF or optic disc [77].
Thus, color vision testing may be a strong predictor for future
development of glaucoma and may be used as a valuable
follow-up test in these cases. Similarly, asymptomatic LHON
causing m.11778 mutation carriers demonstrated both blue–
yellow and red–green color deficit with preponderance of the
former, signifying early involvement of the papillomacular bun-
dle prior to development of clinically overt disease [78]. Initial
studies demonstrated tritanopia (blue–yellow defect) to be the
characteristic color deficit in patients with DOA [79,80]. How-
ever, subsequent studies found mixed color defect (red/green/
blue) in majority of the cases, with only few patients presenting
with tritanopia [81,82].
Relative afferent pupillary defect
Relative afferent pupillary defect (RAPD) is defined as the dif-
ference in the direct and consensual pupillary reaction observed
in the same eye in response to the swinging flash light test.
Reduction in the speed of the initial pupillary constriction or
presence of incomplete constriction signifies the presence of an
afferent defect on flashing light on the affected eye [83]. It is an
indicator of asymmetric optic nerve pathology and may be the
only objective sign present in cases with retrobulbar ON [84].
RAPD demonstrates a direct correlation with the grade of VF
defect, thereby correlating with the degree of RGC loss [85].
LHON has been associated with the phenomenon of ‘pupil
sparing’, meaning preserved pupillary function despite the pres-
ence of impaired visual function [86,87]. But this is not entirely
true as stated by Bremner et al., who demonstrated RAPD in
areas corresponding to visual deficits on the retina in LHON
patients and concluded that stimulation of the entire retinal
field enabled signals to be transmitted from the healthy periph-
eral retina in these patients giving a false-negative RAPD [88].
Though RAPD is present in LHON, the visual deficits super-
sede it by an average of 7.5 dB [88]. Structural–functional analy-
sis in glaucoma has revealed that 83% reduction in the
thickness of the retinal nerve fiber layer (RNFL) between the
two eyes as analyzed using optical coherence tomography
(OCT) was associated with the presence of RAPD with a sensi-
tivity and specificity of 72 and 100%, respectively [89]. A very
specific indicator suggesting the presence of RAPD in patients
with glaucoma was an inter-eye difference of 64% or more in
sensing brightness [89]. Another study conducted by
Tatham et al. demonstrated that a high absolute RAPD score,
as detected by quantitative infrared pupillometry, directly corre-
lated with the inter-eye difference in RGC count [90]. The
authors indicated that every 0.1 increase in the RAPD score
most likely corresponded to an inter-eye difference in RGC
149
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

Table 3. Fundus features of optic neuropathy.

Optic Optic disc Ref.
neuropathy
ON 2/3rd cases – normal disc (retrobulbar) [181]
1/3rd cases – swollen disc (papillitis)
5–6% cases may show OD or peripapillary hemorrhage
A-AION Cotton wool spots represent an associated retinal ischemia and may precede visual loss. Early stage [3,182]
(within 1 month of symptoms) – chalky-white edema of the whole OD (2/3rd cases) or sectoral (1/3rd
cases). Late stage (after 1 month) – OD atrophy is present with cupping showing characteristic rim pallor
NA-AION Early stage: OD edema (may be more prominent in one region than other) and in some cases may be [183]
associated with disc hyperemia. Splinter hemorrhage at disc margin present. Late stage (after 2–3 weeks):
OD edema resolves and pallor sets in that can be generalized or sectoral
OD smaller in diameter
OAG Notching of the OD rim (more at superior and inferior poles), optic cup:disc ratio is increased, residual [95,184]
neuroretinal rim is NOT pale, progressive cupping of the OD, presence of OD hemorrhage, parapapillary
retinal nerve fiber layer loss
Downloaded by [Emory University] at 06:53 13 August 2015

LHON Pre-symptomatic stage: pseudoedema of the (swelling of the nerve fiber layer around disc), [185–187]
circumpapillary telangiectatic microangiopathy
Acute stage: dilated, tortuous and telangiectatic circumpapillary retinal vessels. Hemorrhage in the nerve
fiber layer may be present. Some patients present with normal fundus in acute phase. Late stage: retinal
atrophy, involution of the retinal vasculature, pale OD. Some patients, in addition to above features, may
show presence of OD cupping
DOA Symmetrical pallor of the optic disc is characteristic – temporal pallor is more common than diffuse disc [82,188]
pallor. Other findings may include saucerization, temporal gray pigmentary crescent, optic disc cupping
(cup:disc ratio >0.5) and peripapillary atrophy
A-AION: Arteritic anterior ischemic optic neuropathy; DOA: Dominant optic atrophy; LHON: Leber’s hereditary optic neuropathy; NA-AION: Non-arteritic anterior ischemic
optic neuropathy; OAG: Open-angle glaucoma; OD: Optic disc; ION; Ischemic optic neuropathy.

count of about 35,000 cells [90]. Lankaranian et al. demon-
strated higher rates of RAPD detection using infrared pupill-
ometry in comparison to the swinging flashlight test or
magnifier-assisted swinging flashlight test [91]. Application of
infrared pupillometry for evaluation of RAPD in glaucoma
clinic can thus serve as a sensitive, specific and objective diag-
nostic tool [92] and requires further validation. More recently,
attention is being paid at dissecting the RGC subtypes that are
preferentially lost in glaucoma. Studies have demonstrated a
decrease in the post-illumination pupil response that is charac-
teristic of intrinsically sensitive photoreceptor RGCs in
advanced disease process [93,94], and this finding may have a
potential role in monitoring these cases.
Fundus examination
Examination of the optic disc may reveal abnormalities depend-
ing on the stage at which the patient is viewed by the
ophthalmologist (TABLE 3). Although pathological optic disc cup-
ping (ODC) is considered characteristic of glaucoma, it has
also been reported in cases of ON, A-AION and LHON, lead-
ing to misdiagnosis of glaucoma [95]. Zhang et al. in 2014 pre-
sented 12 cases with non-glaucomatous ODC (NGODC)
(4 patients: ON; 1: LHON; 1: neuromyelitis optica; 6: other
causes) and highlighted the crucial examination findings that
may clinically differentiate glaucomatous ODC from non-
glaucomatous ODC in decreasing order of significance, namely
pink color of the neuroretinal rim, focal rim loss, strong corre-
lation between ODC and degree of VF loss, presence of ODC
before detectable VF defect, high IOP and peripapillary
atrophy [96].
Visual field examination
Both baseline and follow-up examination of VF are paramount
in the management of optic neuropathies. TABLE 4 enumerates
the various VF defects detected in these cases. The peculiar fea-
ture of the central scotoma observed in ON is that it is cen-
tered on the fixation point with a characteristic sloping
border [97]. The central scotoma of ON can be differentiated
from the centrocecal scotoma seen in patients with AION as
the latter is not centered at the fixation point and has a charac-
teristic steep border [97]. LHON is characterized by the pres-
ence of cecocentral defect that progresses to central defect,
suggesting involvement of the papillomacular bundle [98]. The
defect in LHON may follow similar pattern between the two
eyes [98]. In glaucoma, the VF defects are generally present
between 5 and 30 from the fixation point and involve the
arcuate nerve fibers [99]. Characteristic pattern of VF damage
ranges from the development of paracentral scotomas that coa-
lesce to form arcuate scotoma, with respect to the horizontal
meridian [99]. With disease progression, the superior and infe-
rior arcuate scotoma may amalgamate to form a ring-shaped
scotoma that spares the central vision [99].

150 Expert Rev. Ophthalmol. 10(2), (2015)

 Clinical update in optic nerve disorders Review

Table 4. Visual field features of optic neuropathy.

Optic Visual field Ref.
neuropathy
ON Affected eye: central VF defect more prevalent than peripheral defect. Central VF defects include [97,189,190]
altitudinal (superior/inferior), central scotoma. Fellow eye: abnormality present in 68.7% cases at time
of presentation. VF defect is mainly central, but can also be diffuse or involve the peripheral rim)
A-AION VF defects in AION associated with GCA in descending order – [191]
Sectoral defect (respecting the horizontal meridian), only peripheral island of VF intact; altitudinal
defect (superior > inferior) – respecting the horizontal meridian
NA-AION Combination of absolute inferior nasal VF defect with a relative inferior altitudinal defect [192]

OAG Peripheral VF defect > central defect – nasal step scotoma (respecting the horizontal raphe), arcuate [184]
scotoma (superior or inferior), paracentral scotoma, diffuse defect
LHON Symptomatic eye: primarily paracentral VF defect (temporal > nasal) sparring the physiological blind [98]
spot in acute phase.
The defect encroaches the blind spot resulting in central scotoma. Asymptomatic eye: relative changes
Downloaded by [Emory University] at 06:53 13 August 2015

observed
DOA Characteristic cecocentral scotoma with some cases showing central or paracentral VF defects [81,82]
A-AION: Arteritic anterior ischemic optic neuropathy; AION: Anterior ischemic optic neuropathy; DOA: Dominant optic atrophy; GCA: Giant cell arteritis; LHON: Leber’s
hereditary optic neuropathy; OAG: Open-angle glaucoma; ON: Optic neuritis; NA-AION: Non-arteritic anterior ischemic optic neuropathy; VF: Visual field.

Further investigations patients at follow-up [104]. OCT evaluation of 60 eyes with

Further investigations may aid in the diagnosis of specific
causes of optic neuropathy, but should be guided by the history
and clinical examination. TABLE 5 summarizes investigations that
may be useful in different forms of optic nerve disorders. It is
important to remember that these investigations should not be
requested routinely. They may be useful in complicated cases
where the clinical presentation is unclear. Even in these cases, it
is paramount to consider the choice of investigations carefully.
Imaging
Imaging techniques, including OCT and MRI, can now be
applied in atypical presentations of optic nerve disorders to aid
diagnosis in difficult cases. The ability to correlate structural
and functional changes in vision not only improves diagnosis,
but also can assess response to treatment and provide quantita-
tive and reproducible data that can be applied in research.
Optical coherence tomography
Evaluation of the RNFL thickness using OCT can be applied
in the diagnosis and investigation of optic neuropathy. In acute
ON, for example, RNFL thickness appears to increase during
an acute episode of optic nerve swelling [100]. Conversely,
reduction in RNFL thickness appears to occur after these epi-
sodes; a study of 90 patients after an episode of ON showed a
mean 20% reduction in RNFL [101]. Spectral domain OCT
evaluation of both retinal thickness and RNFL appearance is
now used in the diagnosis of glaucoma, with significant struc-
ture–function relationships being found [102].
Both the RGC layer and inner plexiform layer seemed to be
thin in OCT studies in patients with MS, and these changes
were associated with an alteration in visual function [103]. Lon-
gitudinal studies of ON show thinning of the RGC layer in
LHON and 30 normal eyes to compare RNFL thickness in
quadrants showed a unique process of RNFL thickening and
thinning in eyes of patients with LHON [105]. Changes in the
different quadrants at different time points could be evaluated
with alteration in best-corrected VA. OCT investigation of
patients with DOA suggests that there may be significant thin-
ning of the RNFL [106,107]. It has recently been suggested, how-
ever, that the loss of macular RGCs may be an early event in
disease development with decrease in RNFL thickness present
in only severe cases [108].
OCT technology can be useful when clinical examination is
ambiguous. For example, spectral domain OCT can be useful
to help in differentiating between longstanding central retinal
artery occlusion and NA-AION. Evaluation of 76 patients with
AION using macular OCT within 4 months of developing
sudden loss of vision, decreased VA or RAPD showed that
eight patients had subretinal fluid with increased macular thick-
ness that appeared to correlate with reduction in VA [109].
While the application of OCT has been well applied in the
diagnosis of glaucoma, its application in other forms of optic
neuropathy has yet to be validated in individuals with the tar-
get disease and should be used with caution and in conjunction
with a full clinical evaluation.
Magnetic resonance imaging
MRI with gadolinium enhancement can allow visualization of
the acute inflammatory lesion in ON [110,111]. Diagnosis of MS,
in particular, requires identification of lesions that are dissemi-
nated both in time and in space using MRI (The McDonald Cri-
teria, 2010) [112]. This involves identification of more than one
T2-weighted lesion in at least two or four locations (juxtacortical,
periventricular, infratentorial and spinal cord) and identification

informahealthcare.com 151
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

Table 5. Further investigations to consider in different optic nerve disorders.

Optic nerve Investigations to consider Ref.
disorder
Optic neuritis Autoantibody screen (including ANA, ANCA, NMO-Ig) [193,194]
(in atypical Syphilis: VDRL, TPHA tests [195]
forms) Viral screen (including but not limited to hepatitis, human immunodeficiency virus, varicella zoster [196,197]
virus) [198,199]
Visual evoked potentials [200–202]
B1, B2, B12, folate [203–206]
Lumbar puncture (including detection of malignant cells,
CSF leukocytosis and electrolytes; viral PCR and bacteriology; autoantibody and oligoclonal bands)
A-AION Blood tests including full blood count, C-reactive protein, erythrocyte sedimentation rate [207–210]
Temporal artery biopsy [211,212]

NA-AION Stratification of vascular risk factors may include: [170,213]

HbA1c, cholesterol [214]
Hyperhomocysteinemia, [29]
Downloaded by [Emory University] at 06:53 13 August 2015

Overnight polysomnography to detect sleep apnea in suspected cases

OAG Electroretinogram [215,216]

LHON and Consideration of genetic testing with adequate provision of genetic counseling, for example, [57]
DOA LHON: four primary mutations: G11778A, G3460A, T14484C and T10663C [52]
DOA: mutations in OPA1 gene
A-AION: Arteritic anterior ischemic optic neuropathy; ANA: Anti-nuclear antibody; ANCA: Anti-neutrophil cytoplasmic antibody; DOA: Dominant optic atrophy;
LHON: Leber’s hereditary optic neuropathy; NA-AION: Non-arteritic anterior ischemic optic neuropathy; NMO-Ig: Neuromyelitis optica – immunoglobulin; OAG: Open-
angle glaucoma; VDRL: Venereal disease research laboratory; TPHA: Treponema pallidum hemagglutination test.

of a new T2 lesion/gadolinium-enhancing lesion that does not
cause clinical signs (asymptomatic) [112]. MRI is also useful in the
diagnosis of inflammation of the optic nerve sheath (perineuri-
tis) [113]. Imaging is also indicated when there is suspicion of infil-
trative disease (such as secondary to hematological disease,
including leukemia and myeloma) [114,115]. Interestingly, it is
noted that the OD or ON appeared to be grossly normal on
examination in these cases. Recently, masked evaluation of brain
MRIs of patients with MS and LHON concluded that lesion
appearance appeared to show strong similarity in these diseases,
suggesting not only that MRI may be useful in LHON diagnosis
but that there may be similarities in pathogenesis [116].
Future imaging technologies
There is considerable interest in the development of imaging
techniques that aid diagnosis of optic neuropathy. Detection of
apoptosing retinal cells (DARC) uses fluorescently labeled
Annexin V to observe apoptosing RGCs in vivo using scanning
laser ophthalmoscopy [117]. It is hoped that it could be used to
improve the diagnosis and follow-up of patients with glaucoma.
A Phase I clinical trial investigating the application of DARC
in both glaucoma and NA-AION is due to start in 2015. Eval-
uation of hyperspectral imaging techniques that determine oxy-
gen saturation have been investigated in optic nerve
pathology [118]. Hyperspectral imaging, for example, has been
used to assess the oxygen requirements associated with treat-
ment in patients with POAG and suggested that there is
reduced metabolic consumption in retinal tissues in treated
POAG patients compared with untreated individual with
POAG [119]. This technique could be developed to evaluate
both disease severity and the response to treatment. Adaptive
optics scanning laser ophthalmoscopy can investigate the disease
processes associated with retinal disease, including alterations in
blood flow [120]. This can help to understand the processes
underlying disease development and could be modified to help
investigate patients with suspected optic neuropathy. Adaptive
optics scanning laser ophthalmoscopy can produce high-
resolution images of retinal nerve fiber bundles in glaucoma
and could be applied in the evaluation of structural degenera-
tion associated with optic neuropathy [121].
Current treatment approaches for optic neuropathy
Current treatment approaches in the management of optic neu-
ropathy vary according to etiology. A summary of current prac-
tice is shown in TABLE 6, but there is considerable variation in
management practice worldwide.
The ONTT showed that 3-day treatment of intravenous
methylprednisolone followed by 11 days of oral prednisolone
hastened recovery of visual function in patients with ON [122].
The American Academy of Neurology emphasized the impor-
tance of intravenous methylprednisolone not only in hastening
recovery but also improving the quality of life, function of the
fellow eye and decreasing the risk to vision. Corticosteroids
administered early and aggressively are widely agreed to be
imperative in the management of patients with GCA in order
to prevent visual loss and stroke [123]. Indeed, it has been sug-
gested that corticosteroid treatment within 24 h can prevent
visual loss in 58% of cases compared with just 6% in those

152 Expert Rev. Ophthalmol. 10(2), (2015)

 Clinical update in optic nerve disorders Review

Table 6. Summary of current management approaches in different forms of optic nerve disorders.
Optic nerve Treatment Ref.
disorder
Optic neuritis Corticosteroid treatment: intravenous methylprednisolone (followed by oral prednisolone) hastens [122]
the speed of recovery of visual loss (ONTT)
A-AION High-dose corticosteroid therapy [127,217]

NA-AION Modulation of vascular risk factors (long term) to prevent fellow eye involvement [218]
Corticosteroid therapy (controversy over true treatment efficacy and adverse effects) [219–222]
Treatment of sleep apnea syndrome – Severe cases – nasal continuous positive airway pressure [29]
with mask during sleep;
Moderate cases – weight loss, positional treatment
OAG Medical – topical agents to reduce IOP (prostaglandin analogs, b-adrenergic antagonists, [133,223]
a-adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists)
Laser – for example, selective laser trabeculoplasty (shown to reduce 6.9–35.9% reduction in IOP); [224,225]
Surgery – trabeculectomy, drainage tubes,
Minimally invasive surgery [224,226]
Downloaded by [Emory University] at 06:53 13 August 2015

LHON Supportive treatments are currently the mainstay of treatment. These include: [52]
DOA low visual aids
Occupational therapy [227]

Various vitamins (B2, B3, B12, C, E, folic acid) and oxidants used (no proven efficacy) [228]

Low visual aids, occupational therapy, multidisciplinary approach in case of DOA-plus phenotypes [229]
ONTT: Optic Neuritis Treatment Trial; IOP: Intraocular pressure; DOA: Dominant optic atrophy.

where treatment began later [124]. There is significant debate,
however, upon the exact starting dose, route of administration
and total duration of treatment. A dose of 40–60 mg/day is
advocated in the majority of circumstances perhaps as a single
or divided dose [125,126]. A higher dose may be required if there
is evidence of significant visual loss [127]. Early institution of
therapy with intravenous methylprednisolone may be of bene-
fit, although the length of therapy required to deliver improved
visual outcome needs to be established [128,129]. Tapering of ste-
roids after treatment needs careful follow-up. Not only is there
a high risk of relapse in these patients, significant variation
exists that necessitates close monitoring to prevent visual
loss [130]. Also, prolonged treatment with corticosteroids may
have multiple systemic side effects that require monitoring.
The management of glaucoma has for many years been
based on IOP reduction, which has been shown to be effective
in most patients in preventing disease progression. However,
studies such as the ocular hypertension treatment study and
Early Manifest Glaucoma Trial, clearly showed that some
patients with well-controlled IOPs still progress in terms of VF
loss [131,132]. Current European Glaucoma Society guideline
recommends lowering of IOP toward a target pressure in the
management of patients with POAG [133]. This pressure,
however, varies in between the patients and depends on
pre-treatment IOP, pre-existing glaucoma damage, age, rate of
progression and also presence of risk factors such as exfoliation
syndrome [133]. It can be achieved by medication (preferably),
selective laser trabeculoplasty or surgery [133]. Multiple topical
drugs are now available; the choice is affected by side effects,
cost and local guidelines. Selective laser trabeculoplasty has
been found to deliver as much as a 20% reduction in IOP
with a 27% reduction in medications at 6 months and is now
an established treatment modality in medically uncontrolled
IOP [134,135]. Minimally invasive surgery is the term used for
new forms of surgical procedures that deliver reduction in IOP
without the requirement for penetrating surgery such as trabe-
culectomy [136]. The decreased risk of these techniques has been
said to be accompanied by a comparatively modest reduction
in IOP only [136]. A recent reduction in the rate of trabeculec-
tomy surgery in the UK may reflect changes in treatment prac-
tice among clinicians (perhaps due to increasing efficacy of
medical treatment), but may also reflect recent changes in refer-
ral practice [137,138]. The Collaborative normal tension glaucoma
study investigated the contribution of IOP in the management
of patients with normal tension glaucoma [139]. It revealed that
reduction of IOP is integral to its management, showing that a
IOP decrease of 30% led to a reduction in VF progression
whether it was achieved by medications or laser therapy [140].
The European Glaucoma Society guideline currently recom-
mends a target peak IOP of 8–15 mmHg or a 30% reduction
from baseline using medical and, if needed, surgical therapy for
normal tension glaucoma [133]. Glaucoma surgery, however,
may need intensive monitoring to ensure adequate pressure
reduction (laser trabeculoplasty appears to be less beneficial as
the filtration functions normally in these patients) [133]. Sys-
temic nocturnal arterial hypotension has been suggested to lead
to increased VF loss, particularly in normal tension glau-
coma [141–143]. Disruption in physiological variation in systemic

informahealthcare.com 153
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

Table 7. Future possible therapeutic approaches in the management of optic nerve disorders.
Possible future Comments Ref.
treatment approach
Neuroprotection There is no definitive clinical trial showing neuroprotection efficacy [230–232]
(maintenance of neuronal Several mitochondrial candidates are in early experimental studies only [134,233–236]
function to improve visual
function)
Gene therapy Investigated as a gene replacement strategy in LHON. [7,237]
Investigated in neuroprotective strategies that may deliver sustained visual outcomes [238–240]
compared with drug therapy
Cellular therapy Delivery of neuroregenerative therapy is currently being investigated in LHON, MS and [240–242]
glaucoma
Stem cell-mediated delivery of neurotrophic factors [243,244]
LHON: Leber’s hereditary optic neuropathy; MS: Multiple sclerosis.

blood pressure has been associated with decreased ocular blood identification of low-density lipoprotein receptor-related protein
Downloaded by [Emory University] at 06:53 13 August 2015

flow and consequent optic nerve head injury [144,145]. The
potential of blood pressure management in glaucoma deserves
further investigation. New approaches in the management of
optic nerve disorders are currently being investigated (TABLE 7).
Although there is much interest in these approaches, significant
research is required before they can be translated to the clinic.
Animal models
When investigating human diseases, the most applicable
research system is of course the clinical model. However, such
systems are either not always readily available or ethical for
research programs to utilize, making the use of animal models
imperative for analyzing the diseases. While animal physiology
can closely mirror that of a human, they also possess divergent
biological properties that arise at some juncture of the research
question, making it difficult to draw conclusions. Despite these
differences, there are numerous animal species that have been
developed into suitable models for studying the human diseases
of glaucoma, ON, NA-AION, LHON and DOA (TABLES 8 & 9).
Monkeys demonstrate phylogenetic proximity and high pro-
tein sequence conservation with humans, thereby promoting
their utility as an animal model of a disease [146]. Although their
retinal and optic nerve anatomy closely resembles that of the
human eyes, monkey research systems are expensive to acquire
and are also ethically challenging [146]. Hence, rats and mice are
frequently utilized as disease models with an added benefit of
easy accessibility to their eyes and optic nerve. Although there is
high evolutionary conservation between humans, mice and rats,
which makes them suitable for basic research into molecular
mechanisms [147] their retina has several differences from
humans, mainly the absence of macula and fovea, making it dif-
ficult to draw comparisons [148]. Advances in genetic studies have
allowed targeted manipulation of the mouse genome, thereby
enabling researchers to generate artificial disease systems to fur-
ther the understanding of human diseases [148]. Similar to mouse
model availability, rapid development and easy genetic manipu-
lation of the zebra fish makes it a suitable animal to explore the
genetics of glaucoma. Study of transgenic zebra fish led to
2 that is associated with myopia, increased IOP and other fac-
tors, which increase the risk of glaucoma [149]. Other animal
model systems such as pigs and minipigs in addition to being
more readily available, with the presence of many similarities
with humans, can also be subjected to electroretinography, OCT
and corneal topography imaging techniques. Three classes of
RGCs have been identified in pigs, which make them a suitable
model to investigate selective death of RGCs. The difficulty of
visualizing the lamina cribrosa due to the highly dense vasculari-
zation around the OD and their high expense are the major
drawbacks associated with their utilization [150].
In MS-associated ON, there is autoimmune-mediated degen-
eration of optic nerve myelin sheaths associated with inflamma-
tion that can manifest as visual loss [151]. The rodent models that
recapitulate some MS phenotypes are termed as experimental
autoimmune encephalomyelitis (EAE) and spontaneous EAE,
the former is induced by immunization or adoptive transfer of
myelin antigen-specific T cells, while the latter comprise of trans-
genic systems where the immune genes are modified to give rise
to spontaneous EAE. However, spontaneous EAE is unpredict-
able and often occurs at different times within mice of the same
line. Another technique is by continuous infusion of neuromyeli-
tis optica IgG and complement near the optic chiasm in mice
that results in ON. However, it is invasive and technically chal-
lenging; moreover, co-administration of complement and pres-
ence of complement inhibitory factor in mouse does not reflect
human ON in which complement is directly released into
serum [152].In the animal models of NA-AION described
in TABLE 9, only the microvessels of the optic nerve are damaged,
whereas in the high-intraocular pressure model, the damage is
both to the inner and outer retinal layer [153] as well as in the
transection and ON crush model, all structures in the optic nerve
are damaged [154,155]. Therefore, they may be useful models for
the evaluation of neuroprotective strategies focused on treatment
of RGCs [156]. The first animal model of LHON was developed
by Zhang and colleague by intravitreal injection of rotenone in
CBA/J mice [157] that causes mitochondrial complex I dysfunc-
tion. The mito-mouse model generated by Yokota et al., by

154 Expert Rev. Ophthalmol. 10(2), (2015)

 Downloaded by [Emory University] at 06:53 13 August 2015

Table 8. Animal models of glaucoma.

Animal Method Benefits Limitations Ref.
Model
Natural Beagles (dogs), Spontaneous Increased IOP, Expensive, [245,246]
New Zealand open angle, close angle, absence of lamina cribrosa (New Zealand
rabbits, macaque excavation of optic nerve head rabbits),
monkey partial myelinization of optic nerve

informahealthcare.com
Siamese cat PCG of OAG phenotype, moderate elevation in Further studies extending the application of [247]
IOP, mild-moderate buphthalmos, open to this spontaneous feline congenital glaucoma
slightly narrow iridocorneal angle as a model for human disease are awaited
Turkey PACG glaucoma Limited availability [248]

Quail PCG glaucoma phenotype, easy to maintain and Small cornea, [249]
handle in laboratory IOP measurement is challenging
Induced Rabbit a-chymotrypsin intra- Increases IOP, POAG Fluctuation in IOP, dependant on dose and [250]
ocular injection location of injection
Laser-induced outflow Temporary IOP elevation Narrow iridocorneal angle prevents [251]
obstruction adequate access of TM by laser beam
Rats and mice Multiple methods Increased IOP, Non-glaucomatous pathologies, [148,252,253]
RGC death, small eye size,
immunoreactivity to retinal cell types, retina shows absence of macula and fovea
accessible optic nerve,
genetic manipulation
Sheep, cow Topical glucocorticoids Consistently elevated IOP when on steroids, IOP reduces to normal without use of [254,255]
POAG phenotype steroids,
prolonged topical application can lead to
adverse effect like cataract and corneal ulcer
Monkey Autologous RBC or latex Clear optic disc with injection of latex Obscured optic disc after RBC injection [256,257]
microspheres injection microspheres
Laser-induced outflow IOP elevation seen in 70% of animal [258]
obstruction
Avian Light-induced outflow POAG, high IOP, prolonged pre-glaucoma period [259]
obstruction
Genetic Zebra fish Bugeye mutant and Lrp2 Eye enlargement with elevated IOP, Differences in TM and aqueous humor [260–262]
mutant decreased optomotor response (bugeye mutant), dynamics
Clinical update in optic nerve disorders

RGC death with rapid regeneration,

forward and reverse genetic approach possible,
easily adapted in lab, early development and
sexual maturity, needs small space
Cyp1b1: Cytochrome P450 1B1; EAAC-1: Excitatory amino-acid carrier 1; GLAST: Glutamate aspartate transporter; HSP: Heat-shock protein; IOP: Intraocular pressure; Lrp2: Lipoprotein receptor-related protein 2; Myoc:
Myocilin; NTG: Normal tension glaucoma; PACG: Primary angle closure glaucoma; PCG: Primary congenital glaucoma; POAG: Primary open-angle glaucoma; RBC: Red blood cell; RGC: Retinal ganglion cell;
Review

TM: Trabecular meshwork.

155
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

Ref.

[263]

[264]

[265]
[266]

[267]

[268]
introducing pathogenic G13997A mutation (equivalent

Cyp1b1: Cytochrome P450 1B1; EAAC-1: Excitatory amino-acid carrier 1; GLAST: Glutamate aspartate transporter; HSP: Heat-shock protein; IOP: Intraocular pressure; Lrp2: Lipoprotein receptor-related protein 2; Myoc:
to the human ND6 G14600A mutation), is a promising
model that shows clinical, biochemical and anatomical
hallmarks of human LHON in mice of 14–24 months

Myocilin; NTG: Normal tension glaucoma; PACG: Primary angle closure glaucoma; PCG: Primary congenital glaucoma; POAG: Primary open-angle glaucoma; RBC: Red blood cell; RGC: Retinal ganglion cell;
age [158]. In another study, mutant G11778A ND4 DNA
and asymmetric development of the disease

No IOP elevation or gross abnormality seen,

This model shows retinal neovascularization
that is not a feature of glaucoma. Variable

causes only moderate elevation of IOP was introduced into the murine mitochondria of the inner
retina, where the expression of the DNA resembled
human LHON [159]. Other allotropic expression of
mutant complex I subunit includes the model developed
by Qi and colleagues by injecting in the mouse rAVV-
delivered 11778 ND4 mutant [160] and by Ellouze and
colleagues with intravitreal injection of optimized mutant
11778 ND4 fusion gene with electroporation in rats [161].
However, generation of these models appear to be highly
Limitations

dependent on the mitochondrial targeting sequence,

recoded mitochondrial gene and the appended epitope
tag used for immunodetection.
Downloaded by [Emory University] at 06:53 13 August 2015

Expert commentary
POAG phenotype, gradual elevation of IOP, optic

aimed at preventing pressure-independent effect

Systematic evaluation of a patient presenting with symp-

anterior chamber structural abnormality present

system in glaucoma, study treatment strategies

Resembles pigmentary glaucoma and pigment

Improve understanding of the role of immune

RGC death through apoptosis, detachment of
dispersion syndrome, RGC death, optic nerve

toms suggestive of optic neuropathy is crucial for enabling

Histology and electron microscopy showed

the ophthalmologist to derive an appropriate diagnosis

NTG phenotype, RGC death, optic nerve
POAG phenotype, axonal degeneration,

and hence treatment. The clinical judgment can now be

supplemented but not replaced with the higher investiga-
tion tools (TABLE 4), advanced imaging tools such as OCT
as seen in human PCG cases.

and MRI that have made structural and functional corre-

RGC death and axonal loss

lation conceivable. Appropriate use of investigations can

on RGCs and their axons

help the clinician in atypical clinical presentations but

clearly should not be used in routine circumstances. The
nerve axonal loss

challenge of analyzing patients with atypical features, such

degeneration

degeneration

as LHON presenting as ON [162], and arriving at a correct

cells of TM
Benefits

diagnosis requires high levels of clinical suspicion, espe-

cially when the disease continues to progress despite
adequate management.
The burden of these conditions is enormous and con-
ducting screening programs for the same is a time-
consuming and expensive affair. So evaluation of simple,
a-1 subunit collagen

GLAST and EAAC-1

Cyp1b1 null mouse

Immunization with
HSP60 and HSP27
DBA/2J transgenic

Myoc, transgenic,
Table 8. Animal models of glaucoma (cont.).

less expensive, rapid, reproducible screening tests that

type I transgenic,

can be used for multiple conditions may assist diagnosis

at subclinical and early stage and hence aid efficient
transgenic
Method

management. Recent studies have underscored the sig-

nificance of testing color vision as a sensitive indicator
of subclinical disease in ON, glaucoma as well as
LHON, and thus its further exploration to standardize
the interpretation of test abnormalities can be incorpo-
rated into screening process.
Current therapy aims to either halt or slow down the
pathological process underlying these optic nerve condi-
Mouse

TM: Trabecular meshwork.

tions, thereby preventing further visual deterioration

Rat

(TABLE 5). With human trials commencing in gene therapy

for LHON, the situation with corticosteroids in ON is
Autoimmune

like that of catch-22, where studies have shown both ben-

glaucoma
Animal

efits and drawbacks and clinicians continue to use it as

Model

there are no other treatment agents available. Ongoing

research aims at exploring the avenue of neuroprotection,

156 Expert Rev. Ophthalmol. 10(2), (2015)

 Clinical update in optic nerve disorders Review

Table 9. Animal models of ON, NA-AION, LHON and DOA.

Disease Animal model Method Benefits Limitations Ref.
ON Rats Induced Prodromal phase; atonicity in Unpredictable penetrance and [151]
genetic tail; hind limb weakness; not specific to optic neuritis.
forelimb paralysis
2D2 transgenic Eyelid swelling. Partial or Only 35% phenotypically [151,269]
mice complete atrophy of the eye classified as optic neuritis.
HLA- Optic neuritis; limp tail and Specific to genetic background [151]
A3-2D1-TCR forelimb paralysis of other endogenous immune
transgenic mice factors and low penetrance
NA-AION Rat, primate Rose Bengal injection The model resembles the human Does not reflect the [270–272]
with use of fd-YAG AION, optic disc edema, RGC pathogenesis of NA-AION
laser or green argon death, optic nerve remodeling
laser
LHON CBA/J mice Rotenone-induced Quick and simple, reproduce the The causal role of toxins in [157]
Downloaded by [Emory University] at 06:53 13 August 2015

pathophysiologic phenotype – human LHON has not been

reduced RGC layer thickness, demonstrated
increased apoptosis, decreased
retinal metabolic capacity,
increased superoxide
Mice, Mitochondrial Mechanistic resemblance to The mutation can be fatal [159,160]
rats ND4 mutation LHON (ND4 mutation), it is technically [161]
demanding
Mice Mitochondrial Clinical, biochemical and [273,158]
ND6 mutation anatomical hallmarks of human
LHON when induced in animal
at 14 and 24 months
DOA Mice Heterozygous splice Features of DOA present – 50% Development of DOA phenotype [274,275]
site mutation in exon reduction in OPA1 protein level, is late in age and not uniform
10 of OPA1 gene. loss of RGCs, optic nerve gliosis,
Heterozygous reduction in optic nerve axons.
nonsense mutation in Features of DOA present – 50%
exon 8 of OPA1 gene reduction in OPA1 protein level,
impairment of visual function,
optic nerve myelination
abnormality
DOA: Dominant optic atrophy; LHON: Leber’s hereditary optic neuropathy; NA-AION: Non-arteritic anterior ischemic optic neuropathy; ND4: Mitochondrially encoded
NADH dehydrogenase 4, ND6: Mitochondrially encoded NADH dehydrogenase 6; ON: Optic neuritis.

remyelinating therapies and even neuroregeneration to provide
more efficient and effective therapeutic modalities. The role of
animal research is indispensable in understanding the molecular
mechanisms underlying these optic neuropathies as well as
screening of potential drugs to treat them. Availability of reliable
and reproducible animal data is essential, especially in a multifac-
torial condition such as glaucoma where translation of neuropro-
tective therapy from bench to clinic has been rather difficult.
Five-year view
Difficulties in diagnosis of optic neuropathy should be aided
by emerging techniques of investigation. These new techniques,
though promising, require validation for diagnosis in real
patients prior to instigation in the clinic. The challenge will be
to ensure that this is done rapidly across varying populations of
patients in order that these innovations can be delivered to the
clinic. The delivery of reproducible data on structural changes
associated with disease processes should help with formulation
of diagnostic criteria and should be particularly useful in a clin-
ical trial setting. Analysis of VF defects in particular using auto-
mated perimetry should benefit from the continuing research
in clinical tools that attempt to deliver reliable analysis of VF
and interpretation of symptom progression.
OCT technology, in particular, continues to deliver
improved resolution at increased retinal depths, thus delivering
huge amounts of information about structural changes associ-
ated with disease. An important caveat is to ensure that there is
significant association between these structural changes and
functional consequences for the patient – the maintenance of
visual function and quality of life. Evaluation of new imaging
techniques such as DARC, as well as other emerging technolo-
gies (including hyperspectral imaging and adaptive optics),

informahealthcare.com 157
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro

could improve our ability to diagnose optic neuropathy and
evaluate response to treatment. These new techniques could
help to define new structural endpoints that may be helpful in
order to deliver clinical trials in these conditions.
Current treatment approaches in the management of optic
neuropathy need further investigation. The variation in cortico-
steroid treatment in the management of ON deserves evalua-
tion. Appreciation of side effects of treatment could aid the
clinician in delivering patient-centered care. Research in neuro-
protection requires further evaluation in the future. The possi-
bility of harnessing promising treatment approaches across
different optic neuropathies should be considered and increase
the rate of drug discovery.
While many varied animal models of optic neuropathy exist,
no perfect models of these optic neuropathies exist. Although it
Downloaded by [Emory University] at 06:53 13 August 2015
is true that future validation of these animal models should aid
future research, corroboration in several models in different lab-
oratories can act to deliver proof of concept. New techniques
of imaging of RGC degeneration in vivo (including DARC)
can aid in the understanding of pathogenesis and facilitate
drug delivery.
Financial & competing interest disclosure
MF Cordeiro is an inventor on patent applications owned by University
College London and pertaining to Detection of Apoptosing Retinal cells.
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
. Visual loss associated with conditions affecting the optic nerve such as optic neuritis, anterior ischemic optic neuropathy, glaucoma and
Leber’s hereditary optic neuropathy can be diagnosed with a proficient history and clinical examination that can be confirmed using
advanced investigations.
. Presence of optic neuritis or non-arteritic anterior ischemic optic neuropathy does not always correlate with a decrease in high-contrast
visual acuity. A more efficient way to gauge the presence of optic neuropathy is to measure low-contrast sensitivity.
. Deficit in color vision may indicate subclinical optic neuritis; it may also be a strong predictor for future development of glaucoma and
may be used as a valuable follow-up test in these cases.
. Higher rates of relative afferent pupillary defect detection are seen using infrared pupillometry in comparison to the swinging flashlight
test or magnifier-assisted swinging flashlight test.
. Investigation of optic neuropathy may include blood tests (including inflammatory markers, serology and autoantibodies),
electrodiagnostics and imaging (such as OCT and MRI).
. New imaging techniques are currently evaluating optic nerve structure and function, including possible pathological processes mediated
by alteration in inflammation, blood flow and apoptosis.
. New treatment approaches in optic neuropathy are being investigated. These include neuroprotective strategies that aim to maintain
neuronal function despite retinal ganglion cell loss. Gene replacement therapy is currently being investigated in Leber’s hereditary optic
neuropathy. There are a range of cellular therapy approaches that aim to promote neuroprotection and neuroregeneration.
. Extrapolation of data acquired from animal experiments is often challenging owing to differences in the anatomy and biological
behavior of the tissues between different species and also multifactorial pathogenic mechanisms of these neuropathies.
. Many of the animal models currently used reflect in part the disease described, reproducing the phenotype but not the
pathophysiology. The validation of these models is necessary to develop new therapies for these disorders.

References
Papers of special note have been highlighted as:
. of interest
.. of considerable interest
1. Tosy AT, Mason DF, Miller DH. Optic
neuritis. Lancet Neurol 2014;13(1):83-99
. A comprehensive review covering all the
aspects of optic neuritis.
2. Hayreh SS. Anterior ischaemic optic
neuropathy. Differentiation of arteritic from
non-arteritic type and its management. Eye
Lond Engl 1990;4(Pt 1):25-41
3. Hayreh SS, Podhajsky PA, Zimmerman B.
Ocular manifestations of giant cell arteritis.
Am J Ophthalmol 1998;125(4):509-20
4. Quigley HA, Broman AT. The number of
people with glaucoma worldwide in
2010 and 2020. Br J Ophthalmol 2006;
90(3):262-7
5. Tham Y-C, Li X, Wong TY, et al. Global
prevalence of glaucoma and projections of
glaucoma burden through 2040:
a systematic review and meta-analysis.
Ophthalmology 2014;121(11):2081-90
6. Chinnery PF, Johnson MA, Wardell TM,
et al. The epidemiology of pathogenic
mitochondrial DNA mutations. Ann Neurol
2000;48(2):188-93
7. Lam BL, Feuer WJ, Abukhalil F, et al.
Leber hereditary optic neuropathy gene
therapy clinical trial recruitment: year 1.
Arch Ophthalmol 2010;128(9):1129-35
8. Kjer B, Eiberg H, Kjer P, et al. Dominant
optic atrophy mapped to chromosome 3q
region. II. Clinical and epidemiological
aspects. Acta Ophthalmol Scand 1996;
74(1):3-7
9. Guy J, Qi X, Koilkonda RD, et al.
Efficiency and safety of AAV-mediated gene
delivery of the human ND4 complex I

158 Expert Rev. Ophthalmol. 10(2), (2015)


subunit in the mouse visual system. Invest
Ophthalmol Vis Sci 2009;50(9):4205-14
. A study demonstrating successful
incorporation and expression of normal
human ND4 complex I subunit into the
mouse visual system that may be
translated in treatment of human subjects
with Leber’s hereditary optic neuropathy.
10. Bainbridge JWB, Smith AJ, Barker SS, et al.
Effect of gene therapy on visual function in
Leber’s congenital amaurosis. N Engl J Med
2008;358(21):2231-9
11. Cideciyan AV, Aleman TS, Boye SL, et al.
Human gene therapy for RPE65 isomerase
deficiency activates the retinoid cycle of
vision but with slow rod kinetics. Proc Natl
Acad Sci USA 2008;105(39):15112-17
Downloaded by [Emory University] at 06:53 13 August 2015
12. Simonelli F, Maguire AM, Testa F, et al.
Gene Therapy for Leber’s Congenital
Amaurosis is Safe and Effective Through
1.5 Years After Vector Administration. Mol
Ther 2010;18(3):643-50
13. Cideciyan AV, Jacobson SG, Beltran WA,
et al. Human retinal gene therapy for Leber
congenital amaurosis shows advancing
retinal degeneration despite enduring visual
improvement. Proc Natl Acad Sci USA
2013;110(6):E517-25
14. MacLaren RE, Groppe M, Barnard AR,
et al. Retinal gene therapy in patients with
choroideremia: initial findings from a
phase 1/2 clinical trial. Lancet 2014;
383(9923):1129-37
15. Safety Evaluation of Gene Therapy in Leber
Hereditary Optic Neuropathy (LHON)
Patients. Available from: https://clinicaltrials.
gov/ct2/show/NCT02064569
16. Boomer JA, Siatkowski RM. Optic neuritis
in adults and children. Semin Ophthalmol
2003;18(4):174-80
17. Gundogan F, Tas A, Oz O, et al. Color
vision versus pattern visual evoked potentials
in the assessment of subclinical optic
pathway involvement in multiple sclerosis.
Indian J Ophthalmol 2013;61(3):100
18. The clinical profile of optic neuritis:
experience of the optic neuritis treatment
trial. Arch Ophthalmol 1991;109(12):
1673-8
19. Fazzone HE, Lefton DR, Kupersmith MJ.
Optic neuritis: correlation of pain and
magnetic resonance imaging.
Ophthalmology 2003;110(8):1646-9
20. Guthrie TC, Nelson DA. Influence of
temperature changes on multiple sclerosis:
critical review of mechanisms and research
potential. J Neurol Sci 1995;129(1):1-8
informahealthcare.com
Clinical update in optic nerve disorders
21. Diaper CJ. Pulfrich revisited. Surv
Ophthalmol 1997;41(6):493-9
22. Salvarani C, Cantini F, Hunder GG.
Polymyalgia rheumatica and giant-cell
arteritis. The Lancet 2008;372(9634):
234-45
23. Hayreh SS, Podhajsky PA, Zimmerman B.
Occult giant cell arteritis: ocular
manifestations. Am J Ophthalmol 1998;
125(4):521-6
24. Hayreh SS, Podhajsky PA, Zimmerman B.
Nonarteritic anterior ischemic optic
neuropathy: time of onset of visual loss. Am
J Ophthalmol 1997;124(5):641-7
25. Characteristics of patients with nonarteritic
anterior ischemic optic neuropathy eligible
for the Ischemic Optic Neuropathy
Decompression Trial. Arch Ophthalmol
1996;114(11):1366-74
26. Miller NR, Arnold AC. Current concepts in
the diagnosis, pathogenesis and management
of nonarteritic anterior ischaemic optic
neuropathy. Eye Lond Engl 2014. [Epub
ahead of print]
27. Repka MX, Savino PJ, Schatz NJ, et al.
Clinical profile and long-term implications
of anterior ischemic optic neuropathy. Am J
Ophthalmol 1983;96(4):478-83
28. Mojon DS, Hedges TR, Ehrenberg B, et al.
Association between sleep apnea syndrome
and nonarteritic anterior ischemic optic
neuropathy. Arch Ophthalmol 2002;120(5):
601-5
29. Palombi K, Renard E, Levy P, et al.
Non-arteritic anterior ischaemic optic
neuropathy is nearly systematically
associated with obstructive sleep apnoea. Br
J Ophthalmol 2006;90(7):879-82
30. Newman NJ, Scherer R, Langenberg P,
et al. The fellow eye in NAION: report
from the ischemic optic neuropathy
decompression trial follow-up study. Am J
Ophthalmol 2002;134(3):317-28
31. Ramakrishan R, Krishnadas R, Robin AL,
et al. Diagnosis and Management of
Glaucoma. JP Medical Ltd; 2013. p. 682
32. Quigley HA, Dunkelberger GR, Green WR.
Retinal ganglion cell atrophy correlated with
automated perimetry in human eyes with
glaucoma. Am J Ophthalmol 1989;107(5):
453-64
33. Denis P, Lafuma A, Berdeaux G. Medical
predictive factors of glaucoma treatment
costs. J Glaucoma 2004;13(4):283-90
34. Nduaguba C, Lee RK. Glaucoma screening:
current trends, economic issues, technology,
and challenges. Curr Opin Ophthalmol
2006;17(2):142-52
Review
35. Maul EA, Jampel HD. Glaucoma screening
in the real world. Ophthalmology 2010;
117(9):1665-6
36. Fan BJ, Liu K, Wang DY, et al. Association
of polymorphisms of tumor necrosis factor
and tumor protein p53 with primary
open-angle glaucoma. Invest Ophthalmol
Vis Sci 2010;51(8):4110-16
37. Stone EM, Fingert JH, Alward WL, et al.
Identification of a gene that causes primary
open angle glaucoma. Science 1997;
275(5300):668-70
38. Rezaie T, Child A, Hitchings R, et al.
Adult-onset primary open-angle glaucoma
caused by mutations in optineurin. Science
2002;295(5557):1077-9
39. Hauser MA, Allingham RR, Linkroum K,
et al. Distribution of
WDR36 DNA sequence variants in patients
with primary open-angle glaucoma. Invest
Ophthalmol Vis Sci 2006;47(6):2542-6
40. Fan BJ, Wang DY, Lam DSC, et al. Gene
mapping for primary open angle glaucoma.
Clin Biochem 2006;39(3):249-58
41. Wiggs JL, Allingham RR, Vollrath D, et al.
Prevalence of mutations in TIGR/Myocilin
in patients with adult and juvenile primary
open-angle glaucoma. Am J Hum Genet
1998;63(5):1549-52
42. Fingert JH, Heon E, Liebmann JM, et al.
Analysis of myocilin mutations in
1703 glaucoma patients from five different
populations. Hum Mol Genet 1999;8(5):
899-905
43. Aung T, Rezaie T, Okada K, et al. Clinical
features and course of patients with
glaucoma with the E50K mutation in the
optineurin gene. Invest Ophthalmol Vis Sci
2005;46(8):2816-22
44. Thorleifsson G, Walters GB, Hewitt AW,
et al. Common variants near CAV1 and
CAV2 are associated with primary
open-angle glaucoma. Nat Genet 2010;
42(10):906-9
45. Fan BJ, Wang DY, Pasquale LR, et al.
Genetic variants associated with optic nerve
vertical cup-to-disc ratio are risk factors for
primary open angle glaucoma in a US
Caucasian population. Invest Ophthalmol
Vis Sci 2011;52(3):1788-92
46. Writing Committee for the Normal
Tension Glaucoma Genetic Study Group of
Japan Glaucoma Society. Meguro A,
Inoko H, Ota M, et al. Genome-wide
association study of normal tension
glaucoma: common variants in SRBD1 and
ELOVL5 contribute to disease susceptibility.
Ophthalmology. 2010;117(7):1331-8.e5
159
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro
47. Brown MD. The enigmatic relationship
between mitochondrial dysfunction and
Leber’s hereditary optic neuropathy.
J Neurol Sci 1999;165(1):1-5
48. Sadun A. Acquired mitochondrial
impairment as a cause of optic nerve
disease. Trans Am Ophthalmol Soc
1998;96:881-923
49. Sadun AA, Win PH, Ross-Cisneros FN,
et al. Leber’s hereditary optic neuropathy
differentially affects smaller axons in the
optic nerve. Trans Am Ophthalmol Soc
2000;98:223-32.discussion 232-5
50. Carelli V, Ross-Cisneros FN, Sadun AA.
Optic nerve degeneration and mitochondrial
dysfunction: genetic and acquired optic
neuropathies. Neurochem Int 2002;40(6):
573-84
Downloaded by [Emory University] at 06:53 13 August 2015
51. Mackey DA, Oostra RJ, Rosenberg T, et al.
Primary pathogenic mtDNA mutations in
multigeneration pedigrees with Leber
hereditary optic neuropathy. Am J Hum
Genet 1996;59(2):481-5
52. Yu-Wai-Man P, Griffiths PG, Hudson G,
et al. Inherited mitochondrial optic
neuropathies. J Med Genet 2009;46(3):
145-58
53. Ji Y, Jia X, Li S, et al. Evaluation of the
X-linked modifier loci for Leber hereditary
optic neuropathy with the
G11778A mutation in Chinese. Mol Vis
2010;16:416-24
54. Shankar SP, Fingert JH, Carelli V, et al.
Evidence for a novel x-linked modifier locus
for leber hereditary optic neuropathy.
Ophthalmic Genet 2008;29(1):17-24
55. Bu XD, Rotter JI. X chromosome-linked
and mitochondrial gene control of Leber
hereditary optic neuropathy: evidence from
segregation analysis for dependence on X
chromosome inactivation. Proc Natl Acad
Sci USA 1991;88(18):8198-202
56. Hudson G, Carelli V, Spruijt L, et al.
Clinical expression of Leber hereditary optic
neuropathy is affected by the mitochondrial
DNA-haplogroup background. Am J Hum
Genet 2007;81(2):228-33
57. Riordan-Eva P, Sanders MD, Govan GG,
et al. The clinical features of Leber’s
hereditary optic neuropathy defined by the
presence of a pathogenic mitochondrial
DNA mutation. Brain J Neurol 1995;
118(Pt 2):319-37
58. Spruijt L, Kolbach DN, de Coo RF, et al.
Influence of mutation type on clinical
expression of Leber hereditary optic
neuropathy. Am J Ophthalmol 2006;
141(4):676-82
160
59. Delettre C, Lenaers G, Pelloquin L, et al.
OPA1 (Kjer type) dominant optic atrophy:
a novel mitochondrial disease. Mol Genet
Metab 2002;75(2):97-107
60. Ferre M, Bonneau D, Milea D, et al.
Molecular screening of 980 cases of
suspected hereditary optic neuropathy with
a report on 77 novel OPA1 mutations.
Hum Mutat 2009;30(7):E692-705
61. Reynier P, Amati-Bonneau P, Verny C,
et al. OPA3 gene mutations responsible for
autosomal dominant optic atrophy and
cataract. J Med Genet 2004;41(9):e110
62. Kerrison JB, Arnould VJ, Ferraz Sallum JM,
et al. Genetic heterogeneity of dominant
optic atrophy, Kjer type: identification of a
second locus on chromosome 18q12.2-12.3.
Arch Ophthalmol 1999;117(6):805-10
63. Barbet F, Hakiki S, Orssaud C, et al.
A third locus for dominant optic atrophy
on chromosome 22q. J Med Genet 2005;
42(1):e1
64. Carelli V, Schimpf S, Fuhrmann N, et al.
A clinically complex form of dominant
optic atrophy (OPA8) maps on
chromosome 16. Hum Mol Genet 2011;
20(10):1893-905
65. Alexander C, Votruba M, Pesch UE, et al.
OPA1, encoding a dynamin-related GTPase,
is mutated in autosomal dominant optic
atrophy linked to chromosome 3q28. Nat
Genet 2000;26(2):211-15
66. Zanna C, Ghelli A, Porcelli AM, et al.
OPA1 mutations associated with dominant
optic atrophy impair oxidative
phosphorylation and mitochondrial fusion.
Brain J Neurol 2008;131(Pt 2):352-67
67. Olichon A, Landes T, Arnaune-Pelloquin L,
et al. Effects of OPA1 mutations on
mitochondrial morphology and apoptosis:
relevance to ADOA pathogenesis. J Cell
Physiol 2007;211(2):423-30
68. Amati-Bonneau P, Valentino ML,
Reynier P, et al. OPA1 mutations induce
mitochondrial DNA instability and optic
atrophy ‘plus’ phenotypes. Brain J Neurol
2008;131(Pt 2):338-51
69. Amati-Bonneau P, Odent S, Derrien C,
et al. The association of autosomal
dominant optic atrophy and moderate
deafness may be due to the R445H
mutation in the OPA1 gene. Am J
Ophthalmol 2003;136(6):1170-1
70. Amati-Bonneau P, Guichet A, Olichon A,
et al. OPA1 R445H mutation in optic
atrophy associated with sensorineural
deafness. Ann Neurol 2005;58(6):958-63
71. Hudson G, Amati-Bonneau P, Blakely EL,
et al. Mutation of OPA1 causes dominant
optic atrophy with external
ophthalmoplegia, ataxia, deafness and
multiple mitochondrial DNA deletions:
a novel disorder of mtDNA maintenance.
Brain J Neurol 2008;131(Pt 2):329-37
72. Hayreh SS, Zimmerman MB. Nonarteritic
anterior ischemic optic neuropathy: natural
history of visual outcome. Ophthalmology
2008;115(2):298-305.e2
73. Chan JW. Optic Nerve Disorders:
Diagnosis and Management. 2010 edition
Springer; New York: 2010. p. 284
74. Behbehani R. Clinical approach to optic
neuropathies. Clin Ophthalmol Auckl NZ
2007;1(3):233-46
75. Schneck ME, Haegerstrom-Portnoy G.
Color vision defect type and spatial vision
in the optic neuritis treatment trial. Invest
Ophthalmol Vis Sci 1997;38(11):2278-89
76. Van Diemen HAM, Lanting P, Koetsier JC,
et al. Evaluation of the visual system in
multiple sclerosis: a comparative study of
diagnostic tests. Clin Neurol Neurosurg
1992;94(3):191-5
77. Papaconstantinou D, Georgalas I,
Kalantzis G, et al. Acquired color vision and
visual field defects in patients with ocular
hypertension and early glaucoma. Clin
Ophthalmol Auckl NZ 2009;3:251-7
78. Quiros PA, Torres RJ, Salomao S, et al.
Colour vision defects in asymptomatic
carriers of the Leber’s hereditary optic
neuropathy (LHON)
mtDNA 11778 mutation from a large
Brazilian LHON pedigree: a case-control
study. Br J Ophthalmol 2006;90(2):150-3
79. Smith DP. Diagnostic criteria in cominantly
inherited juvenile optic atrophy. A report of
three new families. Am J Optom Arch Am
Acad Optom 1972;49(3):183-200
80. Kline LB, Glaser JS. Dominant optic
atrophy. The clinical profile. Arch
Ophthalmol 1979;97(9):1680-6
81. Votruba M, Fitzke FW, Holder GE, et al.
Clinical features in affected individuals from
21 pedigrees with dominant optic atrophy.
Arch Ophthalmol 1998;116(3):351-8
82. Puomila A, Huoponen K, Mäntyjärvi M,
et al. Dominant optic atrophy: correlation
between clinical and molecular genetic
studies. Acta Ophthalmol Scand 2005;
83(3):337-46
83. Wilhelm H. Neuro-ophthalmology of
pupillary function–practical guidelines.
J Neurol 1998;245(9):573-83
84. Bremner FD. Pupil assessment in optic
nerve disorders. Eye 2004;18(11):1175-81
Expert Rev. Ophthalmol. 10(2), (2015)

85. Lagrèze WD, Kardon RH. Correlation of
relative afferent pupillary defect and
estimated retinal ganglion cell loss. Graefes
Arch Clin Exp Ophthalmol Albrecht Von
Graefes Arch Für Klin Exp Ophthalmol
1998;236(6):401-4
86. Wakakura M, Yokoe J. Evidence for
preserved direct pupillary light response in
Leber’s hereditary optic neuropathy. Br J
Ophthalmol 1995;79(5):442-6
87. Nikoskelainen EK, Huoponen K,
Juvonen V, et al. Ophthalmologic findings
in leber hereditary optic neuropathy, with
special reference to mtDNA Mutations.
Ophthalmology 1996;103(3):504-14
88. Bremner FD, Shallo–Hoffmann J,
Riordan–Eva P, et al. Comparing Pupil
Function with Visual Function in Patients
Downloaded by [Emory University] at 06:53 13 August 2015
with Leber’s Hereditary Optic Neuropathy.
Invest Ophthalmol Vis Sci 1999;40(11):
2528-34
89. Chew SSL, Cunnningham WJ, Gamble GD,
et al. Retinal nerve fiber layer loss in
glaucoma patients with a relative afferent
pupillary defect. Invest Ophthalmol Vis Sci
2010;51(10):5049-53
90. Tatham AJ, Meira-Freitas D, Weinreb RN,
et al. Estimation of Retinal Ganglion Cell
Loss in Glaucomatous Eyes With a Relative
Afferent Pupillary Defect. Invest
Ophthalmol Vis Sci 2014;55(1):513-22
. A cross-sectional study demonstrating
high correlation between estimated RGC
count and the magnitude of relative
afferent pupillary defect in glaucoma.
91. Lankaranian D, Altangerel U, Spaeth GL,
et al. The usefulness of a new method of
testing for a relative afferent pupillary defect
in patients with ocular hypertension and
glaucoma. Trans Am Ophthalmol Soc
2005;103:200-8
92. Kalaboukhova L, Fridhammar V,
Lindblom B. Relative afferent pupillary
defect in glaucoma: a pupillometric study.
Acta Ophthalmol Scand 2007;85(5):519-25
93. Kankipati L, Girkin CA, Gamlin PD. The
Post-Illumination Pupil Response Is
Reduced in Glaucoma Patients. Invest
Ophthalmol Vis Sci 2011;52(5):2287-92
94. Feigl B, Mattes D, Thomas R, Zele AJ.
Intrinsically Photosensitive (Melanopsin)
Retinal Ganglion Cell Function in
Glaucoma. Invest Ophthalmol Vis Sci 2011;
52(7):4362-7
95. Piette SD, Sergott RC. Pathological
optic-disc cupping. Curr Opin Ophthalmol
2006;17(1):1-6
informahealthcare.com
Clinical update in optic nerve disorders
96. Zhang Y-X, Huang H-B, Wei S-H. Clinical
characteristics of nonglaucomatous optic
disc cupping. Exp Ther Med 2014;7(4):
995-9
97. Gerling J, Meyer JH, Kommerell G. Visual
field defects in optic neuritis and anterior
ischemic optic neuropathy: distinctive
features. Graefes Arch Clin Exp Ophthalmol
Albrecht Von Graefes Arch Für Klin Exp
Ophthalmol 1998;236(3):188-92
98. Newman NJ, Biousse V, Newman SA, et al.
Progression of visual field defects in leber
hereditary optic neuropathy: experience of
the LHON treatment trial. Am J
Ophthalmol 2006;141(6):1061-7
99. Miller NR, Walsh FB, Hoyt WF. Walsh
and Hoyt’s Clinical Neuro-ophthalmology.
Lippincott Williams & Wilkins; 2005. p.
1404
100. Kupersmith MJ, Mandel G, Anderson S,
et al. Baseline, one and three month
changes in the peripapillary retinal nerve
fiber layer in acute optic neuritis: relation to
baseline vision and MRI. J Neurol Sci
2011;308(1-2):117-23
101. Fisher JB, Jacobs DA, Markowitz CE, et al.
Relation of visual function to retinal nerve
fiber layer thickness in multiple sclerosis.
Ophthalmology 2006;113(2):324-32
102. Pollet-Villard F, Chiquet C, Romanet J-P,
et al. Structure-function relationships with
spectral-domain optical coherence
tomography retinal nerve fiber layer and
optic nerve head measurements. Invest
Ophthalmol Vis Sci 2014;55(5):2953-62
103. Walter SD, Ishikawa H, Galetta KM, et al.
Ganglion cell loss in relation to visual
disability in multiple sclerosis.
Ophthalmology 2012;119(6):1250-7
104. Syc SB, Saidha S, Newsome SD, et al.
Optical coherence tomography segmentation
reveals ganglion cell layer pathology after
optic neuritis. Brain J Neurol 2012;
135(Pt 2):521-33
105. Zhang Y, Huang H, Wei S, et al.
Characterization of retinal nerve fiber layer
thickness changes associated with Leber’s
hereditary optic neuropathy by optical
coherence tomography. Exp Ther Med
2014;7(2):483-7
106. Barboni P, Savini G, Parisi V, et al. Retinal
nerve fiber layer thickness in dominant
optic atrophy measurements by optical
coherence tomography and correlation with
age. Ophthalmology 2011;118(10):2076-80
107. Park SW, Hwang J-M. Optical coherence
tomography shows early loss of the inferior
temporal quadrant retinal nerve fiber layer
in autosomal dominant optic atrophy.
Review
Graefes Arch Clin Exp Ophthalmol
Albrecht Von Graefes Arch Klin Exp
Ophthalmol 2014; Epub ahead of print
108. Barboni P, Savini G, Cascavilla ML, et al.
Early macular retinal ganglion cell loss in
dominant optic atrophy: genotype-
phenotype correlation. Am J Ophthalmol
2014;158(3):628-36.e3
109. Hedges TR, Vuong LN,
Gonzalez-Garcia AO, et al. Subretinal fluid
from anterior ischemic optic neuropathy
demonstrated by optical coherence
tomography. Arch Ophthalmol 2008;
126(6):812-15
110. Youl BD, Turano G, Miller DH, et al. The
pathophysiology of acute optic neuritis.
An association of gadolinium leakage with
clinical and electrophysiological deficits.
Brain J Neurol 1991;114(Pt 6):2437-50
111. Hickman SJ, Toosy AT, Miszkiel KA, et al.
Visual recovery following acute optic
neuritis–a clinical, electrophysiological and
magnetic resonance imaging study. J Neurol
2004;251(8):996-1005
112. Miller DH, Chard DT, Ciccarelli O.
Clinically isolated syndromes. Lancet Neurol
2012;11(2):157-69
113. Fay AM, Kane SA, Kazim M, et al.
Magnetic resonance imaging of optic
perineuritis. J Neuro-Ophthalmol Off J
North Am Neuro-Ophthalmol Soc 1997;
17(4):247-9
114. Brown GC, Shields JA, Augsburger JJ, et al.
Leukemic optic neuropathy. Int
Ophthalmol 1981;3(2):111-16
115. Shimada Y, Shibuya M, Ohki R, et al.
Bilateral optic neuropathy associated with
multiple myeloma. J Neuro-Ophthalmol
Off J North Am Neuro-Ophthalmol Soc
2006;26(2):117-20
116. Matthews L, Enzinger C, Fazekas F, et al.
MRI in Leber’s hereditary optic neuropathy:
the relationship to multiple sclerosis. J
Neurol Neurosurg Psychiatry 2014; Epub
ahead of print
117. Normando EM, Turner LA, Cordeiro MF.
The potential of annexin-labelling for the
diagnosis and follow-up of glaucoma. Cell
Tissue Res 2013;353(2):279-85
. Review of the potential of use of
fluorescently labeled Annexin-V in in vivo
evaluation of retinal ganglion cell
apoptosis in glaucoma.
118. Khoobehi B, Beach JM, Kawano H.
Hyperspectral imaging for measurement of
oxygen saturation in the optic nerve head.
Invest Ophthalmol Vis Sci 2004;45(5):
1464-72
161
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro
119. Mordant DJ, Al-Abboud I, Muyo G, et al.
Oxygen saturation measurements of the
retinal vasculature in treated asymmetrical
primary open-angle glaucoma using
hyperspectral imaging. Eye Lond Engl 2014;
28(10):1190-200
120. Zhong Z, Petrig BL, Qi X, et al. In vivo
measurement of erythrocyte velocity and
retinal blood flow using adaptive optics
scanning laser ophthalmoscopy. Opt Express
2008;16(17):12746-56
121. Takayama K, Ooto S, Hangai M, et al.
High-resolution imaging of retinal nerve
fiber bundles in glaucoma using adaptive
optics scanning laser ophthalmoscopy. Am J
Ophthalmol 2013;155(5):870-81
122. Beck RW, Cleary PA, Anderson MM, et al.
A randomized, controlled trial of
Downloaded by [Emory University] at 06:53 13 August 2015
corticosteroids in the treatment of acute
optic neuritis. The Optic Neuritis Study
Group. N Engl J Med 1992;326(9):581-8
123. Myles AB, Perera T, Ridley MG.
Prevention of blindness in giant cell arteritis
by corticosteroid treatment. Br J Rheumatol
1992;31(2):103-5
124. González-Gay MA, Blanco R,
Rodrı́guez-Valverde V, et al. Permanent
visual loss and cerebrovascular accidents in
giant cell arteritis: predictors and response
to treatment. Arthritis Rheum 1998;41(8):
1497-504
125. Nesher G, Rubinow A, Sonnenblick M.
Efficacy and adverse effects of different
corticosteroid dose regimens in temporal
arteritis: a retrospective study. Clin Exp
Rheumatol 1997;15(3):303-6
126. Delecoeuillerie G, Joly P, Cohen de Lara A,
et al. Polymyalgia rheumatica and temporal
arteritis: a retrospective analysis of
prognostic features and different
corticosteroid regimens (11 year survey of
210 patients). Ann Rheum Dis 1988;47(9):
733-9
127. Hayreh SS, Zimmerman B. Visual
deterioration in giant cell arteritis patients
while on high doses of corticosteroid
therapy. Ophthalmology 2003;110(6):
1204-15
128. Chevalet P, Barrier JH, Pottier P, et al.
A randomized, multicenter, controlled trial
using intravenous pulses of
methylprednisolone in the initial treatment
of simple forms of giant cell arteritis: a one
year followup study of 164 patients. J
Rheumatol 2000;27(6):1484-91
129. Mazlumzadeh M, Hunder GG, Easley KA,
et al. Treatment of giant cell arteritis using
induction therapy with high-dose
glucocorticoids: a double-blind,
162
placebo-controlled, randomized prospective
clinical trial. Arthritis Rheum 2006;54(10):
3310-18
130. Alba MA, Garcı́a-Martı́nez A,
Prieto-González S, et al. Relapses in patients
with giant cell arteritis: prevalence,
characteristics, and associated clinical
findings in a longitudinally followed cohort
of 106 patients. Medicine (Baltimore) 2014;
93(5):194-201
131. Kass MA, Heuer DK, Higginbotham EJ,
et al. The Ocular Hypertension Treatment
Study: a randomized trial determines that
topical ocular hypotensive medication delays
or prevents the onset of primary open-angle
glaucoma. Arch Ophthalmol 2002;120(6):
701-13.discussion 829–30
132. Heijl A, Leske MC, Bengtsson B, et al.
Reduction of intraocular pressure and
glaucoma progression: results from the Early
Manifest Glaucoma Trial. Arch Ophthalmol
2002;120(10):1268-79
133. EGS Guidelines. Internet Available from:
www.eugs.org/eng/EGS_guidelines.Asp
[cited 2014 Aug 15]
134. Lee JWY, Gangwani RA, Chan JCH, Lai JS.
Prospective study on the efficacy of treating
normal tension glaucoma with a single
session of selective laser trabeculoplasty.
J Glaucoma 2015;24(1):77-80
135. Sayin N, Alkin Z, Ozkaya A, et al. Efficacy
of selective laser trabeculoplasty in medically
uncontrolled glaucoma. ISRN Ophthalmol
2013;2013:975281
136. Brandão LM, Grieshaber MC. Update on
Minimally Invasive Glaucoma Surgery
(MIGS) and New Implants. J Ophthalmol
2013;2013:705915
137. Fraser SG, Wormald RPL. Hospital Episode
Statistics and changing trends in glaucoma
surgery. Eye Lond Engl 2008;22(1):3-7
138. Whittaker KW, Gillow JT, Cunliffe IA. Is
the role of trabeculectomy in glaucoma
management changing? Eye Lond Engl
2001;15(Pt 4):449-52
139. Anderson DR. Normal tension glaucoma
study. collaborative normal tension
glaucoma study. Curr Opin Ophthalmol
2003;14(2):86-90
140. Comparison of glaucomatous progression
between untreated patients with
normal-tension glaucoma and patients with
therapeutically reduced intraocular pressures.
Collaborative Normal-Tension Glaucoma
Study Group. Am J Ophthalmol 1998;
126(4):487-97
141. Charlson ME, de Moraes CG, Link A,
et al. Nocturnal systemic hypotension
increases the risk of glaucoma progression.
Ophthalmology 2014;121(10):2004-12
142. Ramli N, Nurull BS, Hairi NN, et al. Low
nocturnal ocular perfusion pressure as a risk
factor for normal tension glaucoma. Prev
Med 2013;57(Suppl):S47-9
143. Kaiser HJ, Flammer J, Graf T, et al.
Systemic blood pressure in glaucoma
patients. Graefes Arch Clin Exp
Ophthalmol Albrecht Von Graefes Arch Für
Klin Exp Ophthalmol 1993;231(12):677-80
144. Emre M, Orgül S, Gugleta K, et al. Ocular
blood flow alteration in glaucoma is related
to systemic vascular dysregulation. Br J
Ophthalmol 2004;88(5):662-6
145. Fuchsjäger-Mayrl G, Wally B,
Georgopoulos M, et al. Ocular blood flow
and systemic blood pressure in patients with
primary open-angle glaucoma and ocular
hypertension. Invest Ophthalmol Vis Sci
2004;45(3):834-9
146. Bouhenni RA, Dunmire J, Sewell A, et al.
Animal models of glaucoma. J Biomed
Biotechnol 2012;2012:692609
. A detailed discussion of the different
animal models of glaucoma with their
associated advantages and disadvantages.
147. Carelli V, La Morgia C, Sadun A.
Mitochondrial dysfunction in optic
neuropathies: animal models and therapeutic
options. Curr Opin Neurol 2013;26:52-8
148. Levkovitch-Verbin H. Animal models of
optic nerve diseases. Eye Lond Engl 2004;
18(11):1066-74
149. Veth KN, Willer JR, Collery RF, et al.
Mutations in zebrafish lrp2 result in
adult-onset ocular pathogenesis that models
myopia and other risk factors for glaucoma.
PLoS Genet 2011;7(2):e1001310
150. Ruiz-Ederra J, Garcı́a M, Hernández M,
et al. The pig eye as a novel model of
glaucoma. Exp Eye Res 2005;81(5):561-9
151. Gupta A, Ding D, Lee RK, et al.
Spontaneous ocular and neurologic deficits
in transgenic mouse models of multiple
sclerosis and noninvasive investigative
modalities: a review. Invest Ophthalmol Vis
Sci 2012;53(2):712-24
152. Asavapanumas N, Ratelade J,
Papadopoulos MC, et al. Experimental
mouse model of optic neuritis with
inflammatory demyelination produced by
passive transfer of neuromyelitis
optica-immunoglobulin G. J
Neuroinflammation 2014;11:16
153. Grozdanic SD, Sakaguchi DS, Kwon YH,
et al. Functional characterization of retina
and optic nerve after acute ocular ischemia
Expert Rev. Ophthalmol. 10(2), (2015)

in rats. Invest Ophthalmol Vis Sci 2003;
44(6):2597-605
154. Berkelaar M, Clarke DB, Wang YC, et al.
Axotomy results in delayed death and
apoptosis of retinal ganglion cells in adult
rats. J Neurosci Off J Soc Neurosci 1994;
14(7):4368-74
155. Duvdevani R, Rosner M, Belkin M, et al.
Graded crush of the rat optic nerve as a
brain injury model: combining
electrophysiological and behavioral outcome.
Restor Neurol Neurosci 1990;2(1):31-8
156. Touitou V, Johnson MA, Guo Y, et al.
Sustained neuroprotection from a single
intravitreal injection of PGJ2 in a rodent
model of anterior ischemic optic
neuropathy. Invest Ophthalmol Vis Sci
2013;54(12):7402-9
Downloaded by [Emory University] at 06:53 13 August 2015
157. Zhang X, Jones D, Gonzalez-Lima F.
Mouse model of optic neuropathy caused
by mitochondrial complex I dysfunction.
Neurosci Lett 2002;326(2):97-100
158. Lin CS, Sharpley MS, Fan W, et al. Mouse
mtDNA mutant model of Leber hereditary
optic neuropathy. Proc Natl Acad Sci USA
2012;109(49):20065-70
. Study describing a novel model for
Leber’s hereditary optic neuropathy,
which reproduces the biological hallmark
of the disease.
159. Yu H, Ozdemir SS, Koilkonda RD, et al.
Mutant NADH dehydrogenase subunit
4 gene delivery to mitochondria by targeting
sequence-modified adeno-associated virus
induces visual loss and optic atrophy in
mice. Mol Vis 2012;18:1668-83
160. Qi X, Sun L, Lewin AS, et al. The mutant
human ND4 subunit of complex I induces
optic neuropathy in the mouse. Invest
Ophthalmol Vis Sci 2007;48(1):1-10
161. Ellouze S, Augustin S, Bouaita A, et al.
Optimized allotopic expression of the
human mitochondrial ND4 prevents
blindness in a rat model of mitochondrial
dysfunction. Am J Hum Genet 2008;83(3):
373-87
162. Hsu T-K, Wang A-G, Yen M-Y, et al.
Leber’s hereditary optic neuropathy
masquerading as optic neuritis with
spontaneous visual recovery. Clin Exp
Optom J Aust Optom Assoc 2014;97(1):
84-6
163. Gurwood AS, Muchnick BG. The optic
nerve in clinical practice.
Butterworth-Heinemann; 1997. p. 260
164. Rodriguez M, Siva A, Cross SA, et al. Optic
neuritis: a population-based study in
informahealthcare.com
Clinical update in optic nerve disorders
Olmsted county, Minnesota. Neurology
1995;45(2):244-50
165. Jin Y-P, de Pedro-Cuesta J, Söderström M,
et al. Incidence of optic neuritis in
Stockholm, Sweden 1990–1995: I. Age, sex,
birth and ethnic-group related patterns.
J Neurol Sci 1998;159(1):107-14
166. Wakakura M, Minei-Higa R, Oono S, et al.
Baseline features of idiopathic optic neuritis
as determined by a multicenter treatment
trial in Japan. Jpn J Ophthalmol 1999;
43(2):127-32
167. Johnson LN, Arnold AC. Incidence of
nonarteritic and arteritic anterior ischemic
optic neuropathy. Population-based study in
the state of Missouri and Los Angeles
County. California. J Neuro-Ophthalmol
Off J North Am Neuro-Ophthalmol Soc
1994;14(1):38-44
168. Liu NH, LaBree LD, Feldon SE, et al. The
epidemiology of giant cell arteritis: a 12-year
retrospective study. Ophthalmology 2001;
108(6):1145-9
169. Xu L, Wang Y, Jonas JB. Incidence of
nonarteritic anterior ischemic optic
neuropathy in adult Chinese: the Beijing
Eye Study. Eur J Ophthalmol 2007;17(3):
459-60
170. Lee MS, Grossman D, Arnold AC, et al.
Incidence of Nonarteritic Anterior Ischemic
Optic Neuropathy: increased Risk Among
Diabetic Patients. Ophthalmology 2011;
118(5):959-63
171. Preechawat P, Bruce BB, Newman NJ,
et al. Anterior Ischemic Optic Neuropathy
in Patients Younger than 50 Years. Am J
Ophthalmol 2007;144(6):953-60
172. Schoff EO, Hattenhauer MG, Ing HH,
et al. Estimated incidence of open-angle
glaucoma in Olmsted County, Minnesota.
Ophthalmology 2001;108(5):882-6
173. Leske M, Connell AS, Wu S, et al.
Incidence of open-angle glaucoma: the
Barbados eye studies. Arch Ophthalmol
2001;119(1):89-95
174. Mukesh BN, McCarty CA, Rait JL, et al.
Five-year incidence of open-angle glaucoma:
the visual impairment project.
Ophthalmology 2002;109(6):1047-51
175. Puomila A, Hämäläinen P, Kivioja S, et al.
Epidemiology and penetrance of Leber
hereditary optic neuropathy in Finland. Eur
J Hum Genet EJHG 2007;15(10):1079-89
176. Man PYW, Griffiths PG, Brown DT, et al.
The Epidemiology of Leber Hereditary
Optic Neuropathy in the North East of
England. Am J Hum Genet 2003;72(2):
333-9
Review
177. Jia X, Li S, Xiao X, et al. Molecular
epidemiology of mtDNA mutations in
903 Chinese families suspected with Leber
hereditary optic neuropathy. J Hum Genet
2006;51(10):851-6
178. Macmillan C, Kirkham T, Fu K, et al.
Pedigree analysis of French Canadian
families with T14484C Leber’s hereditary
optic neuropathy. Neurology 1998;50(2):
417-22
179. Thiselton DL, Alexander C, Morris A, et al.
A frameshift mutation in exon 28 of the
OPA1 gene explains the high prevalence of
dominant optic atrophy in the Danish
population: evidence for a founder effect.
Hum Genet 2001;109(5):498-502
180. Yu-Wai-Man P, Chinnery PF. Dominant
optic atrophy: novel opa1 mutations and
revised prevalence estimates. Ophthalmology
2013;120(8):1712-1712.e1
181. The clinical profile of optic neuritis.
Experience of the Optic Neuritis Treatment
Trial. Optic Neuritis Study Group. Arch
Ophthalmol 1991;109(12):1673-8
182. Melberg NS, Grand MG, Dieckert JP, et al.
Cotton-wool spots and the early diagnosis
of giant cell arteritis. Ophthalmology 1995;
102(11):1611-14
183. Hayreh SS, Zimmerman MB. Optic disc
edema in non-arteritic anterior ischemic
optic neuropathy. Graefes Arch Clin Exp
Ophthalmol Albrecht Von Graefes Arch Für
Klin Exp Ophthalmol 2007;245(8):1107-21
184. Weinreb RN, Khaw PT. Primary
open-angle glaucoma. The Lancet 2004;
363(9422):1711-20
185. Newman NJ, Lott MT, Wallace DC. The
clinical characteristics of pedigrees of Leber’s
hereditary optic neuropathy with the
11778 mutation. Am J Ophthalmol 1991;
111(6):750-62
186. Nikoskelainen E, Hoyt WF, Nummelin K.
Ophthalmoscopic findings in Leber’s
hereditary optic neuropathy. II. The fundus
findings in the affected family members.
Arch Ophthalmol 1983;101(7):1059-68
187. Ortiz RG, Newman NJ, Manoukian SV,
et al. Optic disk cupping and
electrocardiographic abnormalities in an
American pedigree with Leber’s hereditary
optic neuropathy. Am J Ophthalmol 1992;
113(5):561-6
188. Votruba M, Thiselton D, Bhattacharya SS.
Optic disc morphology of patients with
OPA1 autosomal dominant optic atrophy.
Br J Ophthalmol 2003;87(1):48-53
189. Keltner JL, Johnson CA, Spurr JO, et al.
Comparison of central and peripheral visual
field properties in the optic neuritis
163
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro
treatment trial. Am J Ophthalmol 1999;
128(5):543-53
190. Keltner JL, Johnson CA, Spurr JO, et al.
Baseline visual field profile of optic neuritis.
The experience of the optic neuritis
treatment trial. Optic Neuritis Study
Group. Arch Ophthalmol 1993;111(2):
231-4
191. Fakin A, Kerin V, Hawlina M. Visual fields
in giant cell arteritis (Horton’s disease).
Transl Neurosci 2011;2(4):325-30
192. Hayreh SS, Zimmerman B. Visual field
abnormalities in nonarteritic anterior
ischemic optic neuropathy: their pattern and
prevalence at initial examination. Arch
Ophthalmol 2005;123(11):1554-62
193. Montehermoso A, Cervera R, Font J, et al.
Association of antiphospholipid antibodies
Downloaded by [Emory University] at 06:53 13 August 2015
with retinal vascular disease in systemic
lupus erythematosus. Semin Arthritis
Rheum 1999;28(5):326-32
194. Lennon VA, Wingerchuk DM, Kryzer TJ,
et al. A serum autoantibody marker of
neuromyelitis optica: distinction from
multiple sclerosis. Lancet 2004;364(9451):
2106-12
195. Weinstein JM, Lexow SS, Ho P, et al.
Acute syphilitic optic neuritis. Arch
Ophthalmol 1981;99(8):1392-5
196. Azevedo AR, Simões R, Silva F, et al. Optic
neuritis in an adult patient with chickenpox.
Case Rep Ophthalmol Med
2012;2012:371584
197. Siddiqui J, Rouleau J, Lee AG, et al.
Bilateral optic neuritis in acute hepatitis C.
J Neuro-Ophthalmol Off J North Am
Neuro-Ophthalmol Soc 2009;29(2):128-33
198. Jayaraman M, Gandhi RA, Ravi P, et al.
Multifocal visual evoked potential in optic
neuritis, ischemic optic neuropathy and
compressive optic neuropathy. Indian J
Ophthalmol 2014;62(3):299-304
199. Weizer JS, Musch DC, Niziol LM, et al.
Multifocal visual evoked potentials for early
glaucoma detection. Ophthalmic Surg Lasers
Imaging Off J Int Soc Imaging Eye 2012;
43(4):335-40
200. Gratton SM, Lam BL. Visual loss and optic
nerve head swelling in thiamine deficiency
without prolonged dietary deficiency. Clin
Ophthalmol Auckl NZ 2014;8:1021-4
201. Golnik KC, Schaible ER. Folate-responsive
optic neuropathy. J Neuro-Ophthalmol Off
J North Am Neuro-Ophthalmol Soc 1994;
14(3):163-9
202. Sadun AA, Martone JF, Muci-Mendoza R,
et al. Epidemic optic neuropathy in Cuba.
164
Eye findings. Arch Ophthalmol 1994;
112(5):691-9
203. Van Oostenbrugge RJ, Twijnstra A.
Presenting features and value of diagnostic
procedures in leptomeningeal metastases.
Neurology 1999;53(2):382-5
204. Goldsmith P, Jones RE, Ozuzu GE, et al.
Optic neuropathy as the presenting feature
of HIV infection: recovery of vision with
highly active antiretroviral therapy. Br J
Ophthalmol 2000;84(5):551-3
205. Modvig S, Degn M, Horwitz H, et al.
Relationship between cerebrospinal fluid
biomarkers for inflammation, demyelination
and neurodegeneration in acute optic
neuritis. PLoS One 2013;8(10):e77163
206. Schmidt RM, Kuppe G, Kissig B, et al.
Research approaches on the diagnosis of
multiple sclerosis by CSF examination.
Schweiz Arch Für Neurol Psychiatr Zurich
Switz 1985;138(3):13-22
207. Lincoff NS, Erlich PD, Brass LS.
Thrombocytosis in temporal arteritis rising
platelet counts: a red flag for giant cell
arteritis. J Neuro-Ophthalmol Off J North
Am Neuro-Ophthalmol Soc 2000;20(2):
67-72
208. Costello F, Zimmerman MB, Podhajsky PA
, et al. Role of thrombocytosis in diagnosis
of giant cell arteritis and differentiation of
arteritic from non-arteritic anterior ischemic
optic neuropathy. Eur J Ophthalmol 2004;
14(3):245-57
209. Brittain GP, McIlwaine GG, Bell JA, et al.
Plasma viscosity or erythrocyte
sedimentation rate in the diagnosis of giant
cell arteritis? Br J Ophthalmol 1991;75(11):
656-9
210. Hayreh SS, Podhajsky PA, Raman R, et al.
Giant cell arteritis: validity and reliability of
various diagnostic criteria. Am J
Ophthalmol 1997;123(3):285-96
211. Cavazza A, Muratore F, Boiardi L, et al.
Inflamed temporal artery: histologic findings
in 354 biopsies, with clinical correlations.
Am J Surg Pathol 2014;38(10):1360-70
212. Breuer GS, Nesher R, Reinus K, et al.
Association between histological features in
temporal artery biopsies and clinical features
of patients with giant cell arteritis. Isr Med
Assoc J IMAJ 2013;15(6):271-4
213. Deramo VA, Sergott RC, Augsburger JJ,
et al. Ischemic optic neuropathy as the first
manifestation of elevated cholesterol levels
in young patients. Ophthalmology 2003;
110(5):1041-6.discussion 1046
214. Pianka P, Almog Y, Man O, et al.
Hyperhomocystinemia in patients with
nonarteritic anterior ischemic optic
neuropathy, central retinal artery occlusion,
and central retinal vein occlusion.
Ophthalmology 2000;107(8):1588-92
215. Pangeni G, Lämmer R, Tornow RP, et al.
On- and off-response ERGs elicited by
sawtooth stimuli in normal subjects and
glaucoma patients. Doc Ophthalmol Adv
Ophthalmol 2012;124(3):237-48
216. Forte R, Ambrosio L, Bonavolontà P, et al.
Pattern electroretinogram optimized for
glaucoma screening (PERGLA) and retinal
nerve fiber thickness in suspected glaucoma
and ocular hypertension. Doc Ophthalmol
Adv Ophthalmol 2010;120(2):187-92
217. Chan C, Paine M, O’Day J. Steroid
management in giant cell arteritis. Br J
Ophthalmol 2001;85(9):1061-4
Optic nerve decompression surgery for
218.
nonarteritic anterior ischemic optic
neuropathy (NAION) is not effective and
may be harmful. The Ischemic Optic
Neuropathy Decompression Trial Research
Group. JAMA 1995;273(8):625-32
219. Kinori M, Ben-Bassat I, Wasserzug Y, et al.
Visual outcome of mega-dose intravenous
corticosteroid treatment in non-arteritic
anterior ischemic optic neuropathy -
retrospective analysis. BMC Ophthalmol
2014;14:62
220. Rebolleda G, Perez-Lopez M, Casas-LLera P,
et al. Visual and anatomical outcomes of
non-arteritic anterior ischemic optic
neuropathy with high-dose systemic
corticosteroids. Graefes Arch Clin Exp
Ophthalmol Albrecht Von Graefes Arch Für
Klin Exp Ophthalmol 2013;251(1):255-60
221. Hayreh SS, Zimmerman MB. Non-arteritic
anterior ischemic optic neuropathy: role of
systemic corticosteroid therapy. Graefes
Arch Clin Exp Ophthalmol Albrecht Von
Graefes Arch Klin Exp Ophthalmol 2008;
246(7):1029-46
222. Yaman A, Selver OB, et al. Intravitreal
triamcinolone acetonide injection for acute
non-arteritic anterior ischaemic optic
neuropathy. Clin Exp Optom J Aust
Optom Assoc 2008;91(6):561-4
223. Weinreb RN, Aung T, Medeiros FA. The
pathophysiology and treatment of glaucoma:
a review. JAMA J Am Med Assoc 2014;
311(18):1901-11
224. AGIS Investigators. The Advanced
Glaucoma Intervention Study (AGIS): 11.
Risk factors for failure of trabeculectomy
and argon laser trabeculoplasty. Am J
Ophthalmol 2002;134(4):481-98
225. Wong MOM, Lee JWY, Choy BNK, et al.
Systematic review and meta-analysis on the
efficacy of selective laser trabeculoplasty in
Expert Rev. Ophthalmol. 10(2), (2015)

open-angle glaucoma. Surv Ophthalmol
2015;60(1):36-50
226. Lichter PR, Musch DC, Gillespie BW,
et al. Interim clinical outcomes in the
Collaborative Initial Glaucoma Treatment
Study comparing initial treatment
randomized to medications or surgery.
Ophthalmology 2001;108(11):1943-53
227. Newman NJ, Biousse V, David R, et al.
Prophylaxis for second eye involvement in
Leber hereditary optic neuropathy:
an open-labeled, nonrandomized multicenter
trial of topical brimonidine purite. Am J
Ophthalmol 2005;140(3):407-15
228. Pfeffer G, Horvath R, Klopstock T, et al.
New treatments for mitochondrial
disease-no time to drop our standards. Nat
Rev Neurol 2013;9(8):474-81
Downloaded by [Emory University] at 06:53 13 August 2015
229. Yu-Wai-Man P, Votruba M, Moore AT,
et al. Treatment strategies for inherited
optic neuropathies: past, present and future.
Eye 2014;28(5):521-37
230. Krupin T, Liebmann JM, Greenfield DS,
et al. A randomized trial of brimonidine
versus timolol in preserving visual function:
results from the Low-Pressure Glaucoma
Treatment Study. Am J Ophthalmol 2011;
151(4):671-81
231. Osborne NN. Recent clinical findings with
memantine should not mean that the idea
of neuroprotection in glaucoma is
abandoned. Acta Ophthalmol (Copenh)
2009;87(4):450-4
232. Quigley HA. Clinical trials for glaucoma
neuroprotection are not impossible. Curr
Opin Ophthalmol 2012;23(2):144-54
233. Huang C-C, Kuo H-C, Chu C-C, et al.
Rapid visual recovery after coenzyme
q10 treatment of leber hereditary optic
neuropathy. J Neuro-Ophthalmol Off J
North Am Neuro-Ophthalmol Soc 2002;
22(1):66
234. Kernt M, Arend N, Buerger A, et al.
Idebenone prevents human optic nerve head
astrocytes from oxidative stress, apoptosis,
and senescence by stabilizing BAX/Bcl-
2 ratio. J Glaucoma 2013;22(5):404-12
235. Fiebiger SM, Bros H, Grobosch T, et al.
The antioxidant idebenone fails to prevent
or attenuate chronic experimental
autoimmune encephalomyelitis in the
mouse. J Neuroimmunol 2013;262(1-2):
66-71
236. Sadun AA, Chicani CF, Ross-Cisneros FN,
et al. Effect of EPI-743 on the clinical
course of the mitochondrial disease Leber
hereditary optic neuropathy. Arch Neurol
2012;69(3):331-8
informahealthcare.com
Clinical update in optic nerve disorders
237. Lam BL, Feuer WJ, Schiffman JC, et al.
Trial end points and natural history in
patients with G11778A Leber hereditary
optic neuropathy: preparation for gene
therapy clinical trial. JAMA Ophthalmol
2014;132(4):428-36
238. Miyazaki M, Ikeda Y, Yonemitsu Y, et al.
Pigment epithelium-derived factor gene
therapy targeting retinal ganglion cell
injuries: neuroprotection against loss of
function in two animal models. Hum Gene
Ther 2011;22(5):559-65
239. Renwick J, Narang MA, Coupland SG,
et al. XIAP-mediated neuroprotection in
retinal ischemia. Gene Ther 2006;13(4):
339-47
240. Mansergh FC, Chadderton N, Kenna PF,
et al. Cell therapy using retinal progenitor
cells shows therapeutic effect in a
chemically-induced rotenone mouse model
of Leber hereditary optic neuropathy. Eur J
Hum Genet EJHG 2014;22(11):1314-20
241. Hedayatpour A, Ragerdi I, Pasbakhsh P,
et al. Promotion of remyelination by
adipose mesenchymal stem cell
transplantation in a cuprizone model of
multiple sclerosis. Cell J 2013;15(2):142-51
242. Jaramillo-Merchán J, Jones J, Ivorra JL,
et al. Mesenchymal stromal-cell transplants
induce oligodendrocyte progenitor migration
and remyelination in a chronic
demyelination model. Cell Death Dis
2013;4:e779
243. Johnson TV, Bull ND, Hunt DP, et al.
Neuroprotective effects of intravitreal
mesenchymal stem cell transplantation in
experimental glaucoma. Invest Ophthalmol
Vis Sci 2010;51(4):2051-9
244. Johnson TV, Martin KR, Tomarev SI.
Reply: platelet-derived growth factor-BB
may be involved in mesenchymal stem cell
secretome-induced neuroprotection of
retinal ganglion cells. Brain J Neurol 2014;
137(Pt 5):e277
245. Dawson WW, Brooks DE, Hope GM,
et al. Primary open angle glaucomas in the
rhesus monkey. Br J Ophthalmol 1993;77:
302-10
246. Kolker AE, Moses RA, Constant MA, et al.
THE DEVELOPMENT OF
GLAUCOMA IN RABBITS. Invest
Ophthalmol 1963;2:316-21
247. McLellan GJ, Betts DM, Sigle K, et al.
Congenital glaucoma in the Siamese cat - a
novel spontaneous animal model for
glaucoma research. ARVO Meet Abstr
2005;46(5):134
248. De Kater AW, Smyth JR, Rosenquist RC,
et al. The Slate turkey: a model for
Review
secondary angle closure glaucoma. Invest
Ophthalmol Vis Sci 1986;27(12):1751-4
249. Takatsuji K, Sato Y, Iizuka S, et al. Animal
model of closed angle glaucoma in albino
mutant quails. Invest Ophthalmol Vis Sci
1986;27(3):396-400
250. Gaasterland D, Tanishima T, Kuwabara T.
Axoplasmic flow during chronic
experimental glaucoma. Invest Ophthalmol
Vis Sci 1978;17(9):838-46
251. Johnson B, House P, Morgan W, et al.
Developing laser-induced glaucoma in
rabbits. Aust N Z J Ophthalmol 1999;
27(3-4):180-3
252. Carelli V, La Morgia C, Sadun AA.
Mitochondrial dysfunction in optic
neuropathies: animal models and therapeutic
options. Curr Opin Neurol 2013;26(1):52-8
253. Casson RJ, Chidlow G, Wood JPM, et al.
Definition of glaucoma: clinical and
experimental concepts. Clin Experiment
Ophthalmol 2012;40(4):341-9
254. Gerometta R, Podos SM, Danias J, et al.
Steroid-induced ocular hypertension in
normal sheep. Invest Ophthalmol Vis Sci
2009;50(2):669-73
255. Gerometta R, Podos SM, Candia OA, et al.
Steroid-induced ocular hypertension in
normal cattle. Arch Ophthalmol 2004;
122(10):1492-7
256. Quigley HA, Addicks EM. Chronic
experimental glaucoma in primates.
Production of elevated intraocular pressure
by anterior chamber injection of autologous
ghost red blood cells. Invest Ophthalmol
Vis Sci 1980;19(2):126-36
257. Weber AJ, Zelenak D. Experimental
glaucoma in the primate induced by latex
microspheres. J Neurosci Methods
2001;111:39-48
258. Gaasterland D, Kupfer C. Experimental
glaucoma in the rhesus monkey. Invest
Ophthalmol 1974;13(6):455-7
259. Lauber JK. Light-induced avian glaucoma as
an animal model for human primary
glaucoma. J Ocul Pharmacol 1987;3(1):
77-100
260. Stujenske JM, Dowling JE, Emran F. The
bugeye mutant zebrafish exhibits visual
deficits that arise with the onset of an
enlarged eye phenotype. Invest Ophthalmol
Vis Sci 2011;52(7):4200-7
261. Chen C-C, Yeh L-K, Liu C-Y, et al.
Morphological differences between the
trabecular meshworks of zebrafish and
mammals. Curr Eye Res 2008;33(1):59-72
262. Gray MP, Smith RS, Soules KA, et al. The
aqueous humor outflow pathway of
165
 Review Agarwal, Hanumunthadu, Afrasiabi, Malaguarnera & Cordeiro
zebrafish. Invest Ophthalmol Vis Sci 2009;
50(4):1515-21
263. Schuettauf F, Rejdak R, Walski M, et al.
Retinal neurodegeneration in the DBA/2J
mouse-a model for ocular hypertension.
Acta Neuropathol (Berl) 2004;107(4):352-8
264. Libby RT, Smith RS, Savinova OV, et al.
Modification of ocular defects in mouse
developmental glaucoma models by
tyrosinase. Science 2003;299(5612):1578-81
265. Senatorov V, Malyukova I, Fariss R, et al.
Expression of Mutated Mouse Myocilin
Induces Open-Angle Glaucoma in
Transgenic Mice. J Neurosci 2006;26(46):
11903-14
266. Mabuchi F, Lindsey JD, Aihara M, et al.
Optic nerve damage in mice with a targeted
type I collagen mutation. Invest
Downloaded by [Emory University] at 06:53 13 August 2015
Ophthalmol Vis Sci 2004;45(6):1841-5
267. Harada T, Harada C, Nakamura K, et al.
The potential role of glutamate transporters
in the pathogenesis of normal tension
glaucoma. J Clin Invest 2007;117(7):
1763-70
166
268. Wax MB, Tezel G, Yang J, et al. Induced
Autoimmunity to Heat Shock Proteins
Elicits Glaucomatous Loss of Retinal
Ganglion Cell Neurons via Activated T
Cell-Derived Fas-Ligand. J Neurosci Off J
Soc Neurosci 2008;28(46):12085-96
269. Bettelli E, Baeten D, Jäger A, et al. Myelin
oligodendrocyte glycoprotein-specific T and
B cells cooperate to induce a Devic-like
disease in mice. J Clin Invest 2006;116(9):
2393-402
270. Bernstein SL, Guo Y, Kelman SE, et al.
Functional and cellular responses in a novel
rodent model of anterior ischemic optic
neuropathy. Invest Ophthalmol Vis Sci
2003;44(10):4153-62
. Study describing a validated animal
model for non-arteritic anterior ischemic
optic neuropathy that can serve as a
useful model for evaluation of new
therapeutic approaches.
271. Chen CS, Johnson MA, Flower RA, et al.
A primate model of nonarteritic anterior
ischemic optic neuropathy. Invest
Ophthalmol Vis Sci 2008;49(7):2985-92
272. Chuman H, Maekubo T, Osako T, et al.
Rodent model of nonarteritic ischemic optic
neuropathy and its electrophysiological
evaluation. Jpn J Ophthalmol 2012;56(5):
518-27
273. Yokota M, Shitara H, Hashizume O, et al.
Generation of trans-mitochondrial mito-
mice by the introduction of a pathogenic
G13997A mtDNA from highly metastatic
lung carcinoma cells. FEBS Lett 2010;
584(18):3943-8
274. Alavi MV, Bette S, Schimpf S, et al.
A splice site mutation in the murine
Opa1 gene features pathology of autosomal
dominant optic atrophy. Brain J Neurol
2007;130(Pt 4):1029-42
275. Davies VJ, Hollins AJ, Piechota MJ, et al.
Opa1 deficiency in a mouse model of
autosomal dominant optic atrophy impairs
mitochondrial morphology, optic nerve
structure and visual function. Hum Mol
Genet 2007;16(11):1307-18
Expert Rev. Ophthalmol. 10(2), (2015)