Review

Diagnosis and clinical features of common optic neuropathies

Valérie Biousse, Nancy J Newman

Disorders of the optic nerves (optic neuropathies) are some of the most common causes of visual loss, and can Lancet Neurol 2016; 15: 1355–67
present in isolation or with associated neurological or systemic symptoms and signs. Several optic neuropathies— Neuro-Ophthalmology Unit,
especially inflammatory optic neuropathies—are associated with neurological disorders and thus are often diagnosed Emory Eye Center, Emory
University, Atlanta, GA, USA
and treated by neurologists. The mechanisms underlying optic neuropathies are diverse and typically manifest with
(Prof V Biousse MD,
decreased visual acuity, altered colour vision, and abnormal visual field in the affected eye. Diagnosis is made on the Prof N J Newman MD)
basis of clinical history and clinical examination, of which several aspects are particularly important, including the Correspondence to:
mode of onset of visual loss, the presence of pain with eye movements, the visual acuity, and the retention of colour Prof Valérie Biousse,
vision. Advances in optic nerve imaging—particularly retinal digital photography, optical coherence tomography, and Neuro-Ophthalmology Unit,
Emory Eye Center, Emory
MRI techniques—have revolutionised the diagnosis and follow-up of patients with an optic neuropathy. Furthermore,
University, Atlanta, GA 30322,
improvement and generalisation of some ancillary tests, such as diagnostic antibodies for neuromyelitis optica, USA
allows better phenotyping of the heterogeneous inflammatory optic neuropathies. vbiouss@emory.edu

Introduction Funduscopic examination

Disorders of the optic nerve can present as an isolated
occurrence of visual loss or as part of a wider neurological
disorder. The causes of optic neuropathy are diverse, and
differ for every neurological disease for which optic
neuropathy is often the presenting sign. The clinical
characteristics of optic neuritis in multiple sclerosis, for
example, differ greatly from those of the infectious
neuroretinitis associated with cat-scratch disease. Optic
neuropathy is a common sign of mitochondrial diseases
and numerous neurodegenerative disorders, such as
Charcot-Marie-Tooth disease and Friedreich’s ataxia.
Nutritional deficiencies severe enough to induce
neurological deficits, such as vitamin B12 or thiamine
deficiencies, can also be associated with optic neuropathies.
The diagnosis of an optic neuropathy only establishes
the location of the damage responsible for the visual
loss.1,2,3 An optic neuropathy cannot be considered a
disease in itself; the neurologist has to classify the optic
neuropathy according to its presumed mechanism,
before attempting to make a specific aetiological
diagnosis with ancillary testing.1,2,4,5 Knowledge of the
deficits that typically suggest an optic neuropathy and
recognition of the characteristics of the different causes
help clinicians narrow down a broad differential
diagnosis and execute an efficient diagnostic
assessment.1,2,4,5,6 Over the past 20 years, major advances
in optic nerve imaging have revolutionised the diagnostic
approach to neuropathies.7–9 Large cohort studies and
clinical trials, and the discovery of antibodies, such as
aquaporin-4 antibodies, have also advanced knowledge
about these conditions.10–13 This Review describes the
clinical features of common optic neuropathies, with an
emphasis on the latest methods of diagnosis.
Visualising the optic nerve
The past decade has seen great improvements in
imaging modalities of the optic nerve. Retinal digital
photography,7 optical coherence tomography (OCT),8
and new MRI techniques9 have enabled better
visualisation of the optic nerve.
Funduscopy remains the fastest and easiest way to
clinically assess the optic nerve; direct visualisation of the
optic nerve head using an ophthalmoscope or using
slit-lamp biomicroscopy with specific lenses is routinely
done in hospital settings and in eye clinics.14 However,
it is well established that most physicians without
ophthalmology training are not confident using an
ophthalmoscope15 and interpreting the findings. In a
recent study16 investigating the overdiagnosis of
idiopathic intracranial hypertension, examination of the
ocular fundus was often misinterpreted in obese patients
with headaches: 20% of care providers who were
consulted for headaches did not attempt ophthalmoscopy,
and 44% of those who examined the ocular fundus
misinterpreted the optic nerve appearance as
papilloedema. These numbers are consistent with the
results of the FOTO-ED study,7,17 in which health-care
providers in an emergency department performed
ophthalmoscopy in only 12% of patients presenting with
a chief complaint of headache, and misinterpreted
ophthalmoscopic findings in nearly all cases. This
difficulty with reliably diagnosing or ruling out
papilloedema in patients presenting with headache is
concerning. Easy and immediate access to brain imaging,
and insufficient training in ophthalmoscopy in many
medical schools, often lead clinicians to skip the
examination of the ocular fundus when assessing a
patient with headache.17
Non-mydriatic retinal fundus photography
Non-mydriatic retinal fundus photography is becoming
an attractive alternative to conventional funduscopic
examination with an ophthalmoscope (figure 1).7
Major technological advances allow high-quality digital
photography of the posterior pole of the eye without
pharmacological dilation of the pupils; these photographs
can be obtained outside of an eye clinic or even in a
hospital setting by non-specialised personnel. The
photographs can easily be examined on a computer,
tablet, or smartphone and remotely transmitted for

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 Review

an ophthalmologist’s interpretation if necessary.15,18 Optical coherence tomography

Several studies have shown that such non-mydriatic
fundus cameras can be safe and efficient in various
clinical settings, including emergency departments.18–21
Educational intervention studies showed that medical
students not only prefer to learn how to interpret ocular
fundus photographs than to use an ophthalmoscope, but
are also more accurate when interpreting fundus
photographs than when performing ophthalmoscopy.22,23
Such cameras are becoming smaller, more portable, less
expensive, and more readily available. Devices mounted
on smartphone cameras are becoming more reliable and
user-friendly. The introduction of fundus photography
into medical education is likely to better prepare the
rising generations of clinicians, and should improve the
performance of visualisation of the ocular fundus by
See Online for appendix non-ophthalmologists.14,15,22,23
Superior
A Vein B C
Rim
Temporal Nasal
Optical coherence tomography (OCT) has become
increasingly used in ophthalmology and neurology.8,10 It
is a non-invasive technology that functions in a similar
way to ultrasound, using the reflection of near-infrared
light, instead of sound, to create two-dimensional,
cross-sectional images of the retina and optic nerve.8
OCT is routinely used to quantify structural changes of
ocular tissues over time. Patients with optic neuropathy
develop axonal loss, which results in thinning of the
retinal nerve fibre layer, comprised of ganglion cell axons
that coalesce to form the optic nerve, and ultimately loss
of the ganglion cell layer as the ganglion cells undergo
retrograde death.8,10 The thickness of the peripapillary
retinal nerve fibre layer measured around the optic nerve
head and the thickness of the ganglion cell layer
measured at the macula can be used to assess various
optic neuropathies, such as optic neuritis or compressive
optic neuropathies (figure 2, appendix pp 5–6).8,10,24,25
OCT is an objective way to detect even subtle progressive
axonal loss, and can also be used to quantify and
follow-up disc oedema (appendix p 7).8

Cup Orbital imaging

Artery Orbital imaging is the only available technique to
Inferior visualise the retro-ocular portion of the optic nerve.
Orbital MRI, as long as it is done with the appropriate
D E methods and sequences, provides excellent imaging of
the intraorbital and intracranial portions of the optic
nerve.1,9,26 Contrast and fat-suppression methods are
necessary to adequately examine the optic nerve. Fat
suppression is especially important because fat is a
predominant component of the orbits and appears bright
on T1-weighted MRI sequences, as do most optic nerve
lesions.1,9,26 The routinely obtained brain MRI without
specific orbital views does not allow for proper
examination of the optic nerves, and is often misleading
and interpreted as normal in patients with optic
neuropathy (appendix p 4).1,5,9,26

Recognising an optic neuropathy

There are numerous mechanisms of optic neuropathy
(panel 1) and the correct diagnosis is most often made
on the basis of clinical history and clinical examination.1
Optic neuropathies generally result in decreased visual
Figure 1: Optic nerve appearance on funduscopic examination and with fundus photography acuity, altered colour vision, and abnormal visual field
(A) Healthy right optic nerve. The edges of the nerve are flat and well delimited; there is a small central cup with a
in the affected eye. A relative afferent pupillary defect is
pink rim; the arteries exiting the nerve head and the veins entering the nerve have a normal calibre and appearance
with the expected artery-to-vein thickness ratio of 2:3. The peripapillary retina is normal. (B) Swollen right optic always present when the optic neuropathy is unilateral
nerve. The edges of the nerve are elevated and faint; the central cup cannot be seen; the small vessels are obscured or asymmetric. The optic nerve head can appear normal
at the edge of the nerve. Peripapillary changes with a few high-water marks and yellow exudates are detected in the acute stage, when the posterior part of the optic
temporal to the nerve. (C) Atrophic right optic nerve. The edges of the nerve are flat and well delimited, but the
nerve is involved (retrobulbar optic neuropathy), or
nerve is diffusely pale in colour. (D) Retinal photography obtained with a non-mydriatric fundus camera.
This photograph of the posterior pole of the right eye was obtained without pharmacological dilation of the pupil might be swollen when the optic nerve head is involved
by a nurse in the triage area of an emergency department. The optic nerve, macula, and vascular arcades are easily (anterior optic neuropathy) (figure 1B). In all cases, the
visualised and are normal. (E) Comparison of the fundus photograph with the view obtained with a standard optic nerve becomes pale (figure 1C), usually 4–6 weeks
ophthalmoscope. The circle at the bottom of the figure represents the magnification of the optic nerve seen
through a standard ophthalmoscope. Although part of the optic nerve is well seen, the examiner needs to
after the acute stage, and OCT shows progressive loss of
manipulate the ophthalmoscope and follow the edges of the optic nerve head carefully, to ensure that no the retinal ganglion cell layers (figure 2).1–6,8 An exception
disc oedema is present. to this typical presentation occurs in patients with

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glaucomatous optic neuropathy, in whom the nerve Knowledge of the deficits typically suggestive of optic
does not swell and ultimately becomes cupped with the neuropathy and recognition of the characteristics of
rim remaining pink (appendix pp 2–3).1 Several clinical various causes of optic neuropathy help narrow a broad
characteristics are particularly helpful in establishing differential diagnosis.1,2,4,6
the mechanism of the optic neuropathy (table): (1) the
mode of onset of visual loss (acute or subacute in
ischaemic and inflammatory neuropathies,6 and A
Right eye Left eye
progressive in compressive5 or toxic1 optic neuropathies);
(2) the presence of pain with eye movements (highly
suggestive of an inflammatory mechanism);6 (3) visual
acuity (preserved until late in papilloedema and in
glaucoma);1 (4) colour vision (often relatively spared in
ischaemic optic neuropathies and usually abnormal in
inflammatory optic neuropathies);6 and (5) the optic
disc appearance (variable in inflammatory optic
neuropathies, swollen in all cases of anterior ischaemic
optic neuropathy, preferentially involving the
papillomacular bundle—the bundle of retinal ganglion
cells that carry visual impulses from the macula to the
optic nerve—with pallor of the optic nerve in toxic,
metabolic, or inherited optic neuropathies, uniformly
B
cupped—enlargement of the cup or central depression RNFL thickness analysis: optic disc cube 200 × 200 Right eye Left eye
in the optic disc—in glaucoma, sometimes progressively
cupped—but ultimately always with pallor of the RNFL thickness map μm 47 Average thickness 50
350
nerve—in compressive and hereditary optic 57 52
Quadrants
neuropathies, and the presence of associated retinal S S
48 T N 44 43 T N 50
changes in, for example, neuroretinitis).1 175 I I
Imaging of the optic nerve is often helpful in the 38 53
differential diagnosis of an optic neuropathy, especially 47 61 64 Clock hours 58 53 44
49 41
to show optic nerve inflammation, infiltration, or 0 49
43
43
51
RNFL thickness deviation 47 51
compression (appendix p 4).1,2,4,23 Dedicated MRI of the 46 44 46 49
orbits with or without contrast, and with fat-suppression 39 34 43 46
41 70
methods is the most sensitive test.1,9,26 Additionally, a Diversified:
Right eye distribution
brain MRI accompanying the orbital MRI allows for 200 Left eye of normals
detection of cerebral lesions, which might reveal an
μm

100 95%
underlying neurological disorder, such as multiple 5%
1%
sclerosis (panel 2, figure 4).10 0
Offset (–0·24; 0·27) mm 0 30 60 90 120 150 180 210 240 Offset (0·27; 0·33) mm
Electrophysiological testing is often not necessary for
l

r
ra

r
l

l
rio

sa

rio

ra
po

the diagnosis of optic neuropathy,1 although visual

po
Na
pe

fe
m

m
In
Su
Te

Te

evoked responses can be obtained to confirm optic

RNFL TSNIT normative data Symmetry
neuropathy when the diagnosis is unclear1–3,27 or to
identify subclinical optic neuropathy in patients with 200 200

suspected multiple sclerosis or a neuromyelitis optica

μm

spectrum disorder.10
Optic neuropathies and maculopathies have overlapping
presentations1–3 and can be difficult to differentiate even
for the ophthalmologist. Both can cause central visual loss
and dyschromatopsia. Many chronic maculopathies are
associated with mild optic nerve pallor.1,2,3 When the
macula appears normal on funduscopic examination, it
can be difficult to differentiate an optic neuropathy from a
maculopathy. In these cases, autofluorescence imaging of
the macula and OCT, as well as electroretinography, are
particularly helpful in distinguishing maculopathies from
optic neuropathies.1–3
Many optic neuropathies are misdiagnosed, resulting in
delay in appropriate clinical management (appendix p 4).1,2
100 100
0 0
0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Temporal Superior Nasal Inferior Temporal Temporal Superior Nasal Inferior Temporal
Figure 2: Bilateral optic atrophy on fundus photographs and optical coherence tomography (OCT)
This patient had severe bilateral optic neuropathy from compression of his optic chiasm and intracranial optic
nerves by a recurrent pituitary adenoma. (A) Both optic nerves are diffusely pale on the fundus photographs,
suggesting bilateral optic atrophy with severe retinal ganglion cell loss. (B) Spectral domain OCT of the optic
nerves allows objective measurement of the peripapillary RNFL thickness in each eye. This protocol shows the OCT
results for each eye side by side. The average RNFL thickness (shown in the small red circles) in this patient is
severely reduced, and measured at 47 μm in the right eye and 50 μm in the left eye (normal range is 85–105 μm).
These measurements can be repeated over time and provide an objective way to monitor progression in
compressive optic neuropathy, in addition to measures of visual function. The bottom graphs show the patient’s
RNFL thickness in each quadrant of each optic nerve (as the dashed black line), which can be compared with the
expected range of values in the general normal population (in green); the other colours (yellow and red) indicate
abnormal values (thinner RNFL) compared with the general population. RNFL=retinal nerve fibre layer.

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Panel 1: Case studies

Case 1: isolated optic neuritis
A woman aged 32 years had one episode of painful unilateral visual loss typical of
unilateral retrobulbar optic neuritis that recovered spontaneously within 6 weeks. She
had no neurological symptoms and no previous episodes of optic neuritis. Her brain MRI
was abnormal and showed lesions suggestive of demyelinating disease (figure 3), so her
risk of developing clinically definite multiple sclerosis within 15 years was estimated at
about 70%, with the risk being highest within the first few years after initial assessment.
Case 2: optic neuritis and neuroretinitis from cat-scratch disease
A man aged 20 years presented with subacute visual loss in the left eye. He complained of
mild left periorbital pain. He had no neurological or systemic symptoms. Visual acuity
was 20/20 in the right eye, with normal colour vision, and 20/50 in the left eye with
mildly decreased colour vision. There was a small left relative afferent pupillary defect, and
central depression in the left eye on the visual field test. Funduscopic examination
showed mild disc oedema in the left eye (figure 4A). The retina was normal. The right-eye
fundus examination was normal (figure 4A). MRI of the brain and orbits with or without
contrast showed mild enhancement of the intraorbital portion of the left optic nerve.
No other abnormalities were detected in the brain. The patient had kittens at home, and
the diagnosis of cat-scratch disease secondary to infection with Bartonella henselae was
confirmed by serology. He did not receive any treatment and his visual function improved
spontaneously. When seen 2 weeks after initial consultation, the disc oedema in the left
eye had improved and he had developed a left macular star consistent with neuroretinitis
(figure 4B). At that time, an asymptomatic white retinal lesion was noted in the right eye Figure 3: MRI of a patient with isolated optic neuritis and a high risk of
(figure 4B, small arrow). It subsequently resolved spontaneously. Cat-scratch disease is developing multiple sclerosis
Axial fluid attenuated inversion recovery MRI showing multiple periventricular
one of the most common causes of neuroretinitis, in which anterior optic neuritis is
white matter-hyperintense lesions highly suggestive of multiple sclerosis.
associated with retinal inflammatory lesions. It often improves spontaneously.
Neuroretinitis is usually secondary to systemic infectious or inflammatory systemic
disorders. Unlike idiopathic optic neuritis, it is not associated with multiple sclerosis. hypertension typically have headaches associated with
tinnitus and papilloedema, and no specific cause for the
Papilloedema and idiopathic intracranial increased intracranial pressure (appendix pp 7–8).28,30 The
hypertension diagnostic criteria have been revised several times,
Increased intracranial pressure can result from numerous reflecting technological improvements in non-invasive
mechanisms and typically presents with headache and brain imaging, and a better understanding of CSF
bilateral disc oedema (called papilloedema), sometimes dynamics (appendix p 17).31–35 Although the patho-
with associated neurological symptoms and signs.1,28 physiology of idiopathic intracranial hypertension
Although papilloedema does not usually cause decreased remains unknown, there is a strong association with
visual acuity until late in its course, it is a common cause obesity and recent weight gain.28,30 The prognosis of
of optic neuropathy that requires quick investigation and idiopathic intracranial hypertension is often good, but
treatment.1,28 Untreated raised intracranial pressure many patients develop permanent visual field loss from
results in chronic papilloedema, with subsequent damage chronic papilloedema and are disabled by chronic
of optic nerve axons, progressive concentric visual field headache, with a poor quality of life.28,30,36 Several studies
loss and, ultimately, permanent severe visual loss with have identified factors associated with an increased risk
secondary optic atrophy28,29 (appendix p 9). Papilloedema of visual loss, including black ethnicity, male sex,
can occur with raised intracranial pressure regardless of morbid obesity, fulminant onset, anaemia, uncontrolled
cause, and should therefore prompt urgent testing for a hypertension, and visual field defects at presentation.28,30,37
life-threatening disorder (panel 3). This evaluation should Management of idiopathic intracranial hypertension is
include brain imaging, ideally MRI with and without aimed at preserving visual function and relieving
contrast, often with magnetic resonance venography, symptoms, such as headache; it varies on the basis of the
followed by a lumbar puncture with measurement of CSF patients’ characteristics and symptoms, and should be
opening pressure and CSF analysis, if the MRI rules out aggressive when visual loss is present.28–30 Weight loss is
an intracranial mass or hydrocephalus.1 always necessary and hyperbaric surgery might be
Idiopathic intracranial hypertension is a condition needed in morbidly obese patients.28,30,38 Acetazolamide is
characterised by elevated intracranial pressure of commonly prescribed (1–4 g/day) to decrease the
unknown cause, occurring most commonly in young intracranial pressure and improve symptoms of
obese women.28,30 Patients with idiopathic intracranial intracranial hypertension; its use is supported by the

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results of the Idiopathic Intracranial Hypertension Right eye Left eye

Treatment Trial.39 In severe forms of idiopathic
intracranial hypertension, when visual loss worsens A
despite medical treatment, more aggressive treatment is
recommended, including CSF shunting procedures,
optic nerve sheath fenestration, or endovascular stenting
of stenosed intracranial transverse venous sinuses,
although no clinical trial has validated or compared these
treatment modalities.28,30,37

Optic neuritis
Inflammatory optic neuritis is the most common optic
neuropathy in young patients.1,4,6,11,13,40 It can occur in
isolation, in association with various infectious (panel 2,
figure 4, appendix pp 10–11) and non-infectious
inflammatory disorders, or most often in demyelinating
B
disorders, such as multiple sclerosis.1,4,11–13,40 Optic
neuritis is the heralding event of multiple sclerosis in at
least 20% of cases, and it occurs in more than 50% of
patients with multiple sclerosis at some point in the
course of their disease.10,12,40 When optic neuritis occurs
as an isolated event, it is referred to as idiopathic optic
neuritis, although in many cases, so-called idiopathic
optic neuritis is a clinically isolated syndrome indicating
multiple sclerosis or a neuromyelitis optica spectrum
disorder.10–13,40,41

Idiopathic optic neuritis

Idiopathic optic neuritis most often affects young
women.10–13,41 Patients with unilateral optic neuritis present
with acute or subacute painful monocular visual loss.
Central vision typically deteriorates over days and pain
with eye movement is a frequent early symptom. On
examination, there is decreased visual acuity and colour
vision, and central visual field loss. A relative afferent
pupillary defect is present if the optic neuritis is unilateral
or asymmetrical.1,11,13 In typical optic neuritis associated
with multiple sclerosis, optic disc oedema is found in a
third of patients (in those with anterior optic neuritis or
papillitis), whereas two-thirds have a normal optic
nerve (patients with retrobulbar or posterior optic
neuritis).1,10–13,40,41 In all patients, some optic nerve head
pallor develops 4–6 weeks after onset of visual loss.1,10,11,40
Spontaneous resolution of symptoms almost always
begins within 1 month, and visual outcome is good in
most patients regardless of treatment.10–13,40 The Optic
Neuritis Treatment Trial (ONTT)41–43 included 389 patients
with acute isolated optic neuritis and showed that, at
10-year follow-up, visual acuity was at least 20/40 in 92%
of the affected eyes of patients with typical idiopathic
optic neuritis. Visual function, however, usually does not
completely return to normal, with many patients having
persistent visual field defects, abnormal colour vision,
and decreased contrast sensitivity, despite excellent
visual acuity.10,42,43
Assessment of the patient with suspected optic neuritis
is dependent on the clinical presentation.1,2,4,11–13 A brain
Figure 4: Optic neuritis and neuroretinitis from cat-scratch disease
(A) Fundus photographs at the time of visual loss. The right eye is normal; the left optic nerve is moderately
swollen and the retina is normal. (B) Fundus photographs 2 weeks after initial visual loss. The right optic nerve is
still normal, but there is a new white retinal lesion in the right macula (short arrow). The left optic disc oedema is
improved and there are exudates in the left macula consistent with a macular star (long arrow).
MRI is obtained in patients with isolated optic neuritis to
look for abnormalities suggestive of multiple sclerosis,
such as white matter periventricular lesions that are
3 mm in diameter or larger and ovoid in shape (figure 3).
Various blood tests and serological tests are also often
obtained to investigate for infectious or inflammatory
disorders, depending on the patient’s characteristics.
Additionally, CSF analysis might be useful in these
patients, especially when the optic neuritis is not typical
of multiple sclerosis or when the MRI shows lesions that
are not typical of multiple sclerosis.13,44 However, in most
patients, optic neuritis remains idiopathic or is associated
with multiple sclerosis.4,10–13,40
In patients with typical isolated optic neuritis, the risk of
multiple sclerosis is best predicted by the results of the
brain MRI (figure 3).10–13,40,41 In the ONTT, patients with a
normal baseline brain MRI had an estimated 25% risk of
developing multiple sclerosis at 15 years, whereas those
with at least one typical demyelinating lesion on the MRI
had a risk of about 70%.41 In patients with normal brain
MRI, the ONTT showed that the risk of multiple sclerosis
was lower in men and in patients with disc oedema.41
The ONTT also identified a subgroup of patients with
optic neuritis who had a normal MRI and never developed

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Papilloedema Optic neuritis Non-arteritic anterior Compressive or Toxic or nutritional Hereditary neuropathy
ischaemic optic neuropathy infiltrative neuropathy neuropathy
Age Any age <40 years >50 years 30–50 years for Any age <40 years
meningioma;
childhood for glioma
Laterality Bilateral Unilateral Unilateral Unilateral Bilateral Bilateral
Pain Headache (raised Orbital pain frequent Pain infrequent Absent Absent Absent
intracranial pressure)
Visual loss Acuity preserved until Rapidly progressive, acuity Acute, acuity variable Progressive Slowly progressive Subacute (Leber hereditary
late rarely spared optic neuropathy), progressive
(dominant optic atrophy)
Colour vision Preserved until late Abnormal Variably spared Abnormal Affected early Abnormal
Visual field Peripheral constriction Central defect Altitudinal defect Variable Cecocentral Cecocentral or central scotoma
scotoma
Optic disc Disc oedema Normal (two-thirds of cases) Disc oedema, segmental or not; Variable Normal or Pseudo-oedema in Leber
(acute stage) or disc oedema (a third of small cup-to-disk ratio hyperaemic hereditary optic neuropathy
cases)
Optic disc Pale swelling Temporal pallor Segmental pallor Pallor Pallor, cupping Pallor, cupping
(advanced stage)
Visual prognosis Reversible if treated Good Variable, 15% risk for the other Variable Might improve Poor
early eye within 5 years
Systemic diseases Any cause of raised Risk of development of Hypertension (51%), diabetes Neurofibromatosis or Poor nutrition or Mitochondrial diseases,
intracranial pressure multiple sclerosis mellitus (24%), malignancy peripheral DIDMOAD
giant cell arteritis to be ruled out neuropathy

DIDMOAD=diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

Table: Clinical characteristics of common optic neuropathies (adapted from Biousse V, Newman NJ. Neuro-Ophthalmology Illustrated1)

multiple sclerosis in the 15 years of follow-up; these
patients had atypical features of optic neuritis such as
absence of pain, severe visual loss or no light perception at
all, severe optic disc swelling, peripapillary haemorrhages,
or retinal exudates.41 The presence of oligoclonal bands in
the CSF of patients with a normal brain MRI was
associated with an increased risk of multiple sclerosis.13,44
However, CSF analysis is recommended only in patients
with atypical optic neuritis, if an infectious or systemic
inflammatory disease is suspected.4,11–13,44
OCT is now being increasingly used in patients with
optic neuritis.8,10 Numerous studies8,10,11,13 have shown that
the thinning of the retinal nerve fibre layer observed
within 3–6 months of an acute episode of optic neuritis
correlates with decreases in visual function, represented
by measures of high-contrast visual acuity, visual field
mean deviation, and colour vision. Increased thinning of
the retinal nerve fibre layer also correlates with poor visual
outcome, suggesting that OCT might be useful in
predicting persistent visual dysfunction following an
episode of optic neuritis. Notably, some studies8,10 have
also shown that subclinical axon loss occurs in patients
with multiple sclerosis, even in eyes without a clinical
history of acute optic neuritis. Segmentation of the retinal
layers permits the selective examination of the ganglion
cell layer complex, allowing for the assessment of neuronal
loss in patients with multiple sclerosis (appendix p 5).10
This capacity of OCT to identify subclinical axonal and
neuronal loss can facilitate early intervention and
improved long-term visual outcomes. OCT is already used
to monitor disease progression in patients with optic
neuritis and multiple sclerosis or neuromyelitis optica
spectrum disorder in research and clinical settings.8,10
The optimal treatment of acute idiopathic optic neuritis
was clarified by the findings of the ONTT, which showed
that intravenous methylprednisolone given 1–2 weeks
after symptom onset speeds recovery of visual function
and decreases the risk of multiple sclerosis within the
first 2 years of follow-up, especially in patients considered
to be at high risk of multiple sclerosis by MRI
criteria.11–13,42,43,45,46 However, treatment with intravenous
methylprednisolone (1 g per day for 3 days followed by an
oral taper) had no proven effect on long-term visual
outcome or long-term risk of developing multiple
sclerosis.41–43 The ONTT also showed that treatment with
oral prednisone (1 mg/kg per day) alone actually increased
the short-term risk of recurrent optic neuritis and, for this
reason, should be avoided.42 However, high-dose oral
corticosteroids have not shown this detrimental effect
and can be considered in the treatment of acute
demyelinating optic neuritis.47 Recommendations vary in
different countries for whether or not to offer long-term
immunomodulatory therapy to patients with a first
episode of optic neuritis if the brain MRI suggests a high
risk of multiple sclerosis.11–13 These patients should be
carefully followed up to determine disease progression
and need for long-term treatment.
Neuroretinitis
Neuroretinitis characterises a small subgroup of patients
with anterior optic neuritis associated with retinal
exudates (figure 4, appendix p 11).1 In most cases,

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neuroretinitis is due to an infection such as cat-scratch
disease (panel 2, figure 4) or syphilis, or to a non-infectious
inflammatory disorder such as sarcoidosis (appendix
pp 10–11). Neuroretinitis is not associated with a
subsequent risk of multiple sclerosis.48
Neuromyelitis optica
Neuromyelitis optica is a recurring inflammatory disorder
of the CNS distinct from multiple sclerosis.49 Previously
known as Devic’s disease, it typically presents with bilateral
optic neuritis and transverse myelitis, and has a poor
prognosis, especially if untreated.49 Over the past decade, it
has become recognised that most patients with
neuromyelitis optica have serum antibodies against the
water channel aquaporin-4 (termed AQP4-IgG, or
neuromyelitis optica antibodies) that are highly specific for
neuromyelitis optica.50–53 The incorporation of AQP4-IgG
serology into the diagnostic criteria for neuromyelitis
optica has expanded the clinical and radiological spectrum
of neuromyelitis optica, now better defined as neuro-
myelitis optica-spectrum disorder (appendix p 18).50–54
Isolated optic neuritis is a common presenting sign of
neuromyelitis optica in which optic neuritis is often
severe, recurrent, or bilateral (appendix p 19). Visual
acuity is worse in patients with neuromyelitis optica and
there is more profound retinal nerve fibre layer thinning
on optical coherence tomography than in patients with
multiple sclerosis. Relapse rates are higher in
neuromyelitis optica than in multiple sclerosis, and the
long-term prognosis of neuromyelitis optica is poor. Over
10 years, at least 60% of patients with neuromyelitis
optica are legally blind in one eye, compared with the
typical patient with optic neuritis, who has an
approximate 3% risk of legal blindness in this
timeframe.12,49,51 In relapsing neuromyelitis optica,
about 55% of patients develop a second event within
1 year and 78% within 3 years; nearly 50% of patients
require ambulatory assistance after 10 years.49,51
Serology testing for AQP4-IgG in patients with isolated
optic neuritis allows for early diagnosis of neuromyelitis
optica, the treatment of which differs greatly from that of
other causes of optic neuritis.4,11–13,55 Indeed, although the
likelihood of finding AQP4-IgG antibodies in patients with
isolated optic neuritis is low (about 5%), the result can
have important prognostic and therapeutic implications.12
Knowledge of the antibody status should prompt
aggressive treatment with escalatory high-dose intravenous
methylprednisolone and plasma exchange, especially
when a subsequent attack ensues.12,46,50 The distinction
between multiple sclerosis and neuromyelitis optica is
crucial because of the poorer visual prognosis of
neuromyelitis optica and the differential response of these
conditions to immunomodulatory therapy. For example,
interferon beta, glatiramer acetate, natalizumab, and
fingolimod routinely given to patients with multiple
sclerosis or presumed multiple sclerosis might have a
deleterious effect on the relapse rates of neuromyelitis
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Review
Panel 2: Differential diagnosis of an optic neuropathy
(only broad mechanisms of diseases are listed)
• Glaucoma
• Raised intracranial pressure (papilloedema)
• Inflammatory
• Idiopathic inflammatory optic neuritis (associated with
multiple sclerosis)
• Neuromyelitis optica
• Systemic inflammatory and autoimmune diseases
• Infectious diseases
• Vascular
• Anterior or posterior
• Arteritic or non-arteritic
• Post-radiation therapy
• Compressive or infiltrative
• Neoplastic
• Non-neoplastic
• Paraneoplastic
• Toxic
• Nutritional
• Hereditary
• Traumatic
• Optic nerve head drusen
• Congenitally anomalous optic nerve
Glaucoma is by far the most common cause of optic
neuropathy and a leading cause of blindness; inflammatory
optic neuritis is the most common subacute optic
neuropathy in young people; non-arteritic anterior ischaemic
optic neuropathy is the most common acute optic
neuropathy in patients older than 50 years.
optica, showing that the immunological differences of
these disorders have therapeutic implications.51,55 For
disease prevention, the consensus is that patients with
neuromyelitis optica should be treated with immuno-
suppressive drugs such as azathioprine, mycophenolic
acid, or rituximab, although scientific evidence from well
designed clinical trials is still scarce.12,51,55
Anti-myelin oligodendrocyte glycoprotein (MOG)
antibodies
Recent reports have highlighted the association of
anti-MOG antibodies with relapsing and bilateral optic
neuritis, and with acute disseminated encephalomyelitis
and transverse myelitis.56 Patients with MOG
antibody-associated demyelination can have a unique
clinical, radiological, and therapeutic profile. Indeed,
MOG-associated optic neuritis is often associated with
disc oedema, and seems to be responsive to steroid
treatment, with a good overall visual outcome (appendix
p 19).56 However, MOG antibody detection is not
standardised across centres, commercial testing for
MOG antibodies is not yet available in most countries,
and it is still unclear whether anti-MOG antibodies are
pathogenic.
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Panel 3: Causes of raised intracranial pressure (papilloedema)
• Intracranial mass
• Neoplasm
• Abscess, or subdural empyema
• Vascular cause (large ischaemic stroke; intracerebral,
subdural, or extradural haematoma; large vascular
malformation)
• Obstructive hydrocephalus
• Meningeal process
• Infectious meningitis
• Inflammatory meningitis (granulomatosis,
autoimmune diseases)
• Carcinomatous meningitis
• Subarachnoid haemorrhage
• Traumatic brain injury
• Toxic brain oedema
• Carbon monoxide poisoning
• Venous sinus obstruction
• Cerebral venous sinus thrombosis
• Internal jugular vein thrombosis or compression
• Cerebral venous sinus stenosis
• Dural fistula
• Superior vena cava syndrome
• Pulmonary hypertension
• Idiopathic intracranial hypertension
Ischaemic optic neuropathy
Ischaemic optic neuropathies are classified into the more
common anterior ischaemic optic neuropathy (AION), in
which the optic nerve head is affected and visibly swollen,
and the rarer posterior ischaemic optic neuropathy (PION)
in which the posterior part of the optic nerve is ischaemic.
Ischaemic optic neuropathies are further classified as
non-arteritic and arteritic (most often associated with
giant cell arteritis).1,57,58 Non-arteritic AION is the most
common cause of acute optic neuropathy in patients
older than 50 years.57,58 However, AION can occur at any
age,59,60 and should be differentiated from other causes of
optic neuropathies, such as anterior inflammatory optic
neuritis (table).1,6
The diagnosis of ischaemic optic neuropathy is
primarily clinical and relies on demonstration of painless
acute or subacute visual loss, with visual field defects and
a relative afferent pupillary defect when the optic
neuropathy is unilateral or asymmetric (table). Patients
with AION always have disc oedema acutely, whereas the
optic disc appears normal acutely in PION; in both AION
and PION, optic disc pallor develops 4–6 weeks after
onset of visual loss.57 The main risk factor for non-arteritic
AION is a small, crowded (congenitally small) optic disc
with a small or non-existent cup (called disc-at-risk;
appendix p 12), but other optic disc anomalies that crowd
the optic nerve head, such as optic nerve head drusen
and papilloedema, can also underlie non-arteritic
AION.1,57,58,61 About two-thirds of patients with non-
1362
arteritic AION also have at least one cardiovascular risk
factor, but there is no increased risk of cerebrovascular
disease in patients with non-arteritic AION.57,58,62 Because
AION is a disease involving very small branches of the
posterior ciliary arteries, the pathophysiology involves
local atheromatous disease or hypoperfusion in addition
to a predisposed anomalously crowded optic nerve
head.57,58 AION is not an embolic disease, and patients
should not be evaluated in the same way as those with
retinal or cerebral ischaemia.57,58 Instead, patients with
AION should be asked about untreated obstructive sleep
apnoea63 or exposure to specific drugs, such as nasal
vasoconstrictors,57 amiodarone,64 or phosphodiesterase
type 5 (PDE5) inhibitors,65,66 all of which have been
associated with acute AION. Because patients usually
have a disc-at-risk in both eyes, it is not uncommon to
see bilateral non-arteritic AION, usually sequentially
rather than simultaneously.57,58 The risk of involvement of
the second eye is around 15% 5 years after initial
diagnosis (appendix p 12).67 Non-arteritic PION is
exceedingly rare and should be diagnosed by exclusion of
other diseases.1,57,68
No proven treatment for ischaemic optic neuropathy
exists, but it is essential to rule out giant cell arteritis
when assessing a patient with AION or PION.1,58 Giant
cell arteritis should always be considered in all patients
with AION or PION, and blood tests looking for an
inflammatory syndrome (including complete blood
count, platelets, erythrocyte sedimentation rate, and
C-reactive protein) need to be obtained as soon as
possible in patients older than 50 years.1,57 Abnormal
results should prompt treatment with high-dose steroids
in patients in whom there is high clinical suspicion; a
temporal artery biopsy is subsequently obtained when
the diagnosis of giant cell arteritis is suspected.69–72
Perioperative ischaemic optic neuropathy includes
both AION and PION precipitated by various surgeries,
often with severe bilateral vision loss.57 Ocular surgeries
such as cataract surgery or intravitreal injections of
drugs can rarely precipitate acute AION, probably as a
result of elevated intraocular pressure.73 Non-ocular
surgeries, especially coronary artery bypass grafting and
spinal fusion surgery with the patient in the prone
position for a long period, can also rarely (prevalence
of <0·3%) be complicated by severe visual loss from
AION or PION. AION represents the majority of cases
associated with cardiac surgery, whereas PION is more
often seen after spinal surgery.57 The causes of
perioperative ischaemic optic neuropathies are poorly
understood, and the contributing factors are probably
multifactorial and different in these surgical
procedures.57,74–76
Compressive optic neuropathy
Compression of the optic nerve produces progressive
unilateral optic neuropathy, with monocular, painless,
progressive visual loss in most cases (appendix p 20).1
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The correct diagnosis of compression is often delayed
(panel 2, appendix p 4). Common causes include
unrecognised pituitary tumours, meningiomas,5
craniopharyngiomas, and ophthalmic or internal carotid
artery aneurysms (appendix p 14).1 Occasionally, the
intracranial optic nerve might be compressed or
infiltrated by inflammatory orbital disorders such as
Graves’ disease, by other neoplasms (usually
metastases), or by infectious lesions (such as
mucormycosis in patients with diabetes mellitus)
involving the orbital apex. These patients can present
with rapidly progressive optic neuropathies and rapid
assessment and treatment are necessary.1
Toxic or nutritional optic neuropathy
Toxic and nutritional optic neuropathies often both
present in the same patient and have similar clinical
presentation, including progressive, symmetric central
visual loss, decreased colour vision, cecocentral scotomas
(central scotomas that connect to the normal blind spot),
and ultimately optic disc pallor.1 Very few definitely
proven cases of optic nerve damage caused by a single
recognised toxic agent or a deficiency of an identified
nutrient have been described.77 The underlying
mechanism of optic nerve injury might be similar in
some of these metabolic optic neuropathies, but the
pathogenesis remains unknown in most cases, often
with multifactorial, potentially synergistic factors
involved.77,78 Not all patients given even high doses of any
of the purportedly toxic agents will necessarily get optic
nerve damage.78 For vitamin B12 deficiency and at least
some toxic agents, including methanol, ethambutol, and
linezolid, the final common pathway probably involves
mitochondrial injury, with selective damage to the
papillomacular bundle.77,78
Methanol
Methanol ingestion can induce acute severe irreversible
bilateral toxic optic neuropathy, typically with initial
optic nerve oedema followed by pallor and cupping.
Methanol poisoning is a life-threatening disease that
presents with nausea, vomiting, abdominal pain, visual
loss, and hallucinations associated with acidosis; visual
loss, which occurs in about 50% of patients, often
enables an early diagnosis.75,78
Ethambutol
Ethambutol, an antibacterial agent commonly used to
treat tuberculosis and other chronic Mycobacterium
infections is toxic for the optic nerve in up to 6% of treated
patients;77,79–81 toxic effects of ethambutol usually take a few
months to develop, although this time can vary widely
from 2 to 12 months.77,80,81 Given the large number of
patients worldwide needing ethambutol for treatment of
tuberculosis or Mycobacterium infection, the annual
worldwide incidence of ethambutol optic neuropathy is
estimated to be at least 100 000 patients (estimate based
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Review
on the number of new cases of tuberculosis and
Mycobacterium avium reported each year to WHO).80
Patients develop bilateral insidious, progressive, painless
visual loss with cecocentral visual field defects that can
initially mimic a bitemporal hemianopia, and then
progresses to profound visual loss with large central
scotomas.1,77 Because the ocular toxicity is dose dependent
and duration dependent, early recognition of toxic optic
neuropathy and prompt cessation of the drug is important
to prevent further deterioration of vision. Recovery is
inconsistent and often delayed, and can take up to
6 months after discontinuation of the drug; up to 50% of
patients have permanent visual loss.77,79–81 Several risk
factors for optic nerve toxicity have been suggested,
including the duration of treatment (>2 months), age
older than 65 years, low bodyweight, daily dose greater
than 15–20 mg/kg, and abnormal glomerular filtration
rate.81 HIV-positive patients on antiretroviral therapy
might be especially vulnerable to toxic effects of
ethambutol via a multiple-hit effect. One of the postulated
mechanisms of ethambutol toxicity is associated with the
chelating effects of ethambutol on various mitochondrial
metal-containing enzymes; mitochondrial function is
also targeted by some antiretroviral therapies, resulting in
enhanced toxicity on the vulnerable optic nerves of
HIV-infected patients receiving treatment.77,81
Linezolid
Linezolid (an oxazolidinone antibiotic) is a powerful
antibiotic typically used for severe bacterial infections,
including tuberculosis. Although usually well tolerated
when used for up to 28 days as classically prescribed,
there are numerous reports of bilateral optic neuropathy
associated with peripheral neuropathy in patients with
chronic refractory infections receiving this antibiotic for
long periods of time.77,82 Patients develop progressive
bilateral visual loss with optic nerve hyperaemia. Visual
function usually improves after discontinuation of
the drug.77,82
Amiodarone
Amiodarone, an antiarrhythmic drug, has been
associated with bilateral or sequential anterior optic
neuropathy mimicking AION,64 although causation is
controversial.57 Patients develop painless subacute
monocular visual loss with disc oedema acutely, and
subsequent optic nerve pallor.57,64 Severe visual loss
develops and the optic neuropathy is bilateral in more
than two-thirds of patients. Discontinuation of the
drug can halt the visual loss, although the long half-
life of this medication (>100 days) can result in
prolonged effects.57,64
Phosphodiesterase type 5 (PDE5) inhibitors
PDE5 inhibitors, including sildenafil, tadalafil, and
vardenafil, which are drugs commonly used in the
treatment of erectile dysfunction, have been associated
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 Review
with an increased risk of AION.65 Numerous cases of
AION occurring after the use of these erectile
dysfunction drugs have been reported, including a few
cases with recurrent or sequential AION after repeated
use of the drug.65 One study66 suggested a two-times
increase in the risk of AION after using PDE5 inhibitors.
Although this association remains controversial,65 it is
recommended to enquire about the use of PDE5
inhibitors in all patients with AION, and consider
counselling against their use in these patients.
Tobacco and alcohol
Tobacco-alcohol optic neuropathy is most confusing in
regard to the overlap of toxic and nutritional optic
neuropathies; it is commonly diagnosed, but poorly
understood.78 Multiple factors contribute to visual loss
in patients who are alcoholics and smoke (usually cigar
or pipe smokers), and other aetiologies such as
malnutrition, vitamin deficiencies, and mitochondrial
optic neuropathies should be also investigated in this
patient population.78,83 Toxic and nutritional effects
might contribute synergistically to this optic neuropathy,
with direct toxicity from alcohol perhaps not being a
causal factor.78
Nutritional deficiency
Nutritional deficiency can result in bilateral, progressive,
painless optic neuropathy with cecocentral scotomas.
Pernicious anaemia leading to B12 deficiency is the most
typical cause, but other nutritional deficiencies, such as
those of thiamine (B1), folate, and copper can also affect
the optic nerves, especially in combination with other
deficiencies.1 The increased use of bariatric surgery for
morbid obesity has resulted in increased prevalence of
nutrient deficiencies, including those responsible for
optic neuropathy.1,38
Hereditary optic neuropathy
Genetic studies have facilitated the diagnosis and
furthered our understanding of inherited diseases of the
optic nerve. Although numerous hereditary, mostly
neurological, disorders are associated with optic nerve
dysfunction, optic neuropathy can be the sole manifest-
ation in genetic disorders affecting mitochondrial
metabolism.84,85
Leber hereditary optic neuropathy (LHON)
LHON is a maternally inherited isolated optic neuropathy
due to mitochondrial DNA mutations, with those at
positions 11778, 3460, and 14484 accounting for about
90% of patients worldwide. The 11778 locus is the most
commonly mutated and is associated with the worst
prognosis.84,85 Testing for these mutations is done on
blood and is commercially available.85
LHON presents as bilateral or sequential subacute
painless optic neuropathies affecting men more often
than women, typically between the ages of 15 and 35 years,
1364
although genetically confirmed patients, both men or
women, can experience visual loss at any age.84,85 Visual
acuity loss is usually severe (20/200 or worse) and
irreversible, with large central scotomas.84,85 Although
there is no true disc oedema in LHON, the optic disc
often appears hyperaemic with telangiectatic vessels
acutely (appendix p 15). The affected optic nerve eventually
becomes pale, but unlike other causes of optic neuropathy,
this change can take several months to become apparent.
Spontaneous visual improvement can occur, especially in
patients affected during early childhood and those with
the 14484 mutation.84–86 The presence of a LHON mutation
does not necessarily lead to vision loss.84,85 Although
environmental factors such as nutritional deficiencies,
exposure to agents stressing mitochondrial function
(such as ethambutol), cigarette smoking, and possibly
heavy alcohol intake increase the risk of visual loss in
patients with LHON mutations, the determinants of their
penetrance are poorly understood.86,87 The relative amount
of mutated mitochondrial DNA in tissues (heteroplasmy),
other mitochondrial abnormalities, or nuclear DNA
influences can affect disease penetrance.84,85 The high
susceptibility of men (with a 25–50% risk of vision loss in
men with a mutation, compared with a <10% risk in
women) remains unexplained, although it has been
suggested that an X-linked genetic modifier might be
involved.84,85
Attempts at therapy in LHON have remained largely
ineffective, although the free radical scavenger idebenone
has shown some beneficial effect on patients with recent
visual loss.85,88,89 Symptomatic treatment with low visual
aids and genetic counselling are important, and factors
that might stress mitochondrial function such as tobacco
use and heavy alcohol intake should be avoided.86,88 Gene
therapy is a promising treatment strategy for LHON. In
ongoing phase 3 gene therapy trials, viral vectors with
wild-type mitochondrial DNA sequences are delivered
directly into the eyes of patients with LHON via
intravitreal injection, with the goal of incorporation and
expression by the retinal ganglion cells and stabilisation
or improvement of vision.90,91
Autosomal dominant optic neuropathy
This neuropathy—also called dominant optic atrophy—is
clinically characterised by symmetrical, insidious onset of
visual loss in the first decade of life, cecocentral scotomas,
and wedges of temporal disc atrophy with cupping of the
nerve similar to that seen in glaucoma (appendix p 16).1,85
Visual loss is variable even within families, and ranges
from subtle visual loss to 20/200. Patients typically lose
one line of visual acuity on the Snellen visual acuity chart
per decade, and many patients retain fairly good visual
acuity during their lifetime.84,85 The disorder is most
commonly due to mutations in the OPA1 gene that codes
for an inner mitochondrial membrane protein.84,85
Therefore, despite being an autosomal dominant disease
associated with nuclear gene mutations, dominant optic
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atrophy is a mitochondriopathy similar to LHON and
other hereditary optic neuropathies.84,85 Both LHON and
dominant optic atrophy share the same characteristic
pathological features, with selective degeneration of the
retinal ganglion cell layer, particularly the papillomacular
bundle, leading to progressive optic nerve degeneration
and central visual loss. Numerous pathogenic OPA1
mutations have been described, but these account for
only about 50–60% of dominant optic atrophy cases
worldwide.84,85
Remarkable advances in the molecular diagnosis of the
inherited and degenerative optic neuropathies have
allowed for a better understanding of the pathogenesis of
these disorders, regardless of their pattern of inheritance
or their clinical manifestations as mono-symptomatic or
multisystem disorders. For example, some forms of
Charcot-Marie-Tooth disease, Friedreich’s ataxia, and
other neurodegenerative diseases with a final common
pathway of mitochondrial dysfunction, perhaps not
surprisingly, have a high prevalence of subclinical optic
neuropathies.84,85 However, no proven effective treatment
for dominant optic atrophy exists and management is
still limited to symptomatic treatment (visual aids and
genetic counselling).85
Conclusion and future directions
The diagnosis and management of optic neuropathies
have greatly improved over the past decade. The
widespread use of non-mydriatic fundus photography
offers unique opportunities for non-ophthalmologists to
incorporate ocular funduscopic examination into their
clinical practice. Advances in imaging techniques such as
OCT allow for detection of subtle changes in patients with
neurological disorders, such as multiple sclerosis or
compressive lesions of the optic nerve. Diagnostic criteria
are evolving, with inclusion of refined laboratory and
imaging testing, even resulting in the emergence of newly
defined clinical entities. Improvement and generalisation
of ancillary testing such as that for neuromyelitis optica or
MOG antibodies will allow more accurate phenotype
characterisation of various forms of inflammatory optic
neuritis and subsequent reclassification of this
heterogeneous group of optic neuropathies. New
treatment strategies are being developed with improved
visual outcomes, and gene therapy could change the
future management of inherited optic neuropathy.
Ongoing clinical trials for idiopathic intracranial
hypertension, ischaemic optic neuropathy, and Leber
hereditary optic neuropathy will hopefully provide new
avenues for the management of these devastating causes
of visual loss. Correct identification of the different causes
of optic neuropathy is essential in order to offer
appropriate medical care and counselling. Collaboration
between ophthalmologists and neurologists is now more
important than ever, with the ophthalmologist confirming
the diagnosis of optic neuropathy and characterising eye
findings associated with specific neurological disorders,
www.thelancet.com/neurology Vol 15 December 2016
Review
Search strategy and selection criteria
References for this Review were identified by searches of
PubMed done between June 1, 2016, and Sept 1, 2016, with
the terms “optic neuropathy”, “optic atrophy”, “papilledema”,
“idiopathic intracranial hypertension”, “pseudotumor
cerebri”, “optic neuritis”, “multiple sclerosis”, “neuromyelitis
optica”, “ischemic optic neuropathy”, “toxic optic
neuropathy”, “optic nerve imaging”, “optical coherence
tomography”, and “retinal photography”. Additional
references were identified by a manual search of journals and
relevant articles. Only articles published in English and in
French, and those published up to Aug 30, 2016, were
reviewed. Priority was given to the most recent references.
The final reference list was generated on the basis of
originality and relevance to the topics covered in the Review.
and the neurologist better equipped at interpreting
neuroimaging results and providing appropriate
management and specific treatment.
Contributors
Both authors contributed equally to the conception, design, literature
search, and writing of this Review.
Declaration of interests
VB and NJN are consultants for GenSight Biologics. NJN is a consultant
for Santhera Pharmaceuticals. VB and NJN are supported in part by an
unrestricted departmental grant (Department of Ophthalmology) from
Research to Prevent Blindness Inc, New York, by NIH/NEI core grant
P30-EY06360 (Department of Ophthalmology, Emory University School
of Medicine), and by NIH/NINDS (RO1NSO89694).
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