Clinical approach to optic neuropathies dove med press

Clinical Approach to Optic

Neuropathies

Raed Behbehani , MD FRCSC

Neuro-Ophthalmology Service, Department of Ophthalmology, Ibn Sina

Hospital, Kuwait City, Kuwait.

Correspondence or reprints request to Raed Behbehani, FRCSC,

Department of Ophthalmology, Ibn Sina Hospital, PO Box 1262, 130013

Safat, Kuwait.

E-mail: r_behbehani@Hotmail.com. Tel : (965) 483-4820 , Fax : (965)

241-7409

The author have no relevant financial interest in this article.

Keywords: optic neuropathy, optic neuritis, Non-arteritic anterior ischemic optic
neuropathy (NAION), Arteritic anterior ischemic optic neuropathy (AION),
Traumatic optic neuropathy, Leber's optic neuropathy, Dominant optic atrophy,
Recessive optic atrophy, Radiation optic neuropathy, optical coherence tomography,
multiple sclerosis.

Abstract

Optic neuropathy is a frequent cause of vision loss encountered by ophthalmologist.
The diagnosis is made on clinical grounds. The history often points to the possible
etiology of the optic neuropathy. A rapid onset is typical of demyelinating,
inflammatory, ischemic and traumatic causes. A gradual course points to
compressive, toxic/nutritional and hereditary causes. The classic clinical signs of
optic neuropathy are visual field defect, dyschromatopsia, and abnormal papillary
response. There are ancillary investigations that can support the diagnosis of optic
neuropathy. Visual field testing by either manual kinetic or automated static
perimetry is critical in the diagnosis. Neuro-imaging of the brain and orbit is essential
in many optic neuropathies including demyelinating and compressive. Newer
technologies in the evaluation of optic neuropathies include multifocal visual evoked
potentials and optic coherence tomography.

Diagnosis

History
The mode of onset of visual loss is an important clue to the etiology of the optic
neuropathy. Rapid onset is characteristic of optic neuritis, ischemic optic neuropathy,
inflammatory (non-demyelinating) and traumatic optic neuropathy. A gradual onset
over months is typical of compressive toxic/nutritional. A more protracted history
over years is seen in compressive and hereditary optic neuropathies. The
ophthalmologist should make an effort in eliciting history of associated symptoms
that can help refine the differential diagnosis. In a young patient, history of eye pain
associated with eye movement, prior history of neurological symptoms such as
paresthesia, limb weakness, and ataxia is suggestive of demyelinating optic neuritis.
These neurological complaints may have been misdiagnosed or dismissed by other
physicians. For example, chronic arm paresthesia is usually initially misdiagnosed as
"carpal tunnel syndrome". Diminution of vision following a rise in body temperature
such as following exercise or a hot shower is known as Uhthoff's phenomenon.
Although this symptom is usually associated with demyelinating optic neuropathy, it
has been reported in a variety of other optic neuropathies including Leber's
hereditary optic neuropathy, and optic neuropathy in sarcoidosis (Riordan-Eva,
Sanders et al. 1995; Haupert and Newman 1997).
In an elderly with signs of optic neuropathy, the presence of preceding transient
visual loss, diplopia, temporal pain, jaw claudications, fatigue, weight loss and
myalgias is strongly suggestive of arteritic ischemic optic neuropathy (AION) due to
giant cell arteritis (GCA). In children, history of recent flu-like illness or
vaccination days or weeks before vision loss points to a para-infectious or post-
vaccinial optic neuritis, respectively.
Symptoms such as diplopia and facial pain are suggestive of multiple cranial
neuropathies seen in inflammatory or neoplastic lesions of the posterior orbit or
parasellar region. Transient visual obscurations (periods of vision blackouts lasting
seconds caused by change in body position), transient diplopia and headache should
raise the suspicion of increased intra-cranial pressure.

The use of any medications should be carefully noted since some are either directly or
indirectly toxic to the optic nerve. These include drugs as ethambutol, amiodarone,
alcohol, and immunosuppressive medications such as methotrexate and cyclosporine.

History of diabetes, hypertension and hypercholesterolemia is common in patients with
non-arteritic ischemic optic neuropathy (NAION). Patients who are being treated for
or have history of malignancy may have infiltrative or para-neoplastic optic
neuropathy.
Inquiry into the patient's general health, eating and social habits (drinking, smoking)
is important in suspected toxic/nutritional optic neuropathy. A detailed family
history is important in diagnosing hereditary autosomal and mitochondrial optic
neuropathies.

Neuro-ophthalmic Examination
Acute or chronic vision loss can be caused by any diseases of the anterior visual
pathway including the retinal diseases. In many cases, the signs of retinopathy are
subtle and it is difficult to determine if the cause of vision loss is a retinopathy or
optic neuropathy. Therefore, it is important to establish the classic signs of optic
neuropathy; visual field defect, decreased color vision, and the presence of relative
afferent papillary defect (RAPD).
Visual acuity can be normal or impaired depending on whether the central visual
field is affected. In many cases, visual acuity is normal, yet the patient as a large
visual field defect that spares the central field. In the optic neuritis treatment trial,
11% of patients had a visual acuity of 20/20 or better (Beck, Trobe et al. 2003)
Color vision can be assessed by using the Ishihara color plates or the American
Optical Hardy-Ritter-Rand (AOHRR) pseudoisochromatic color plates. Most patients
with acquired optic neuropathy will have dyschromatopsia. However, some patients,
especially those with ischemic optic neuropathies may have normal color vision at
least in their intact visual field areas. When assessing color vision, it is important to
not only assess the number of plates recognized by each eye, but also the speed with
which they are recognized and the patients' subjective comparison between each eye.
Dyschromatopsia can also occur in macular disease but in this case the visual acuity
tends to be profoundly affected. A mild to moderate visual acuity loss in association
with dyschromatopsia is a sensitive indicator of optic neuropathy.
A RAPD can be detected by performing the swinging light-pupil test. In the presence
of bilateral symmetric optic neuropathy, a RAPD may be absent and the briskness of
pupillary constriction to light will reflect the degree of optic nerve dysfunction.
When checking for RAPD, it is important to use a very bright light in a dark room to
assess the full amplitude of pupillary response. A RPAD can be estimated
subjectively by asking the patient about the difference in brightness of light

presented in front of each eye.
Patients with optic neuropathy often have red color desaturation and a red-capped
bottle can be presented to each eye and the patient can be asked about the difference
in brightness of the red color. A positive response would be that the red color looks
"faded", "pink" or "washed out".

Fundus examination may show normal, swollen, pale or anamolous optic disc. The
optic disc is usually swollen in NAION and inflammatory (non-demyelinating) optic
neuritis. In demyelinating optic neuritis ,however, the optic disc is normal in 65% of
cases (retrobulbar neuritis). If disc swelling is present in demyelinating optic neuritis,
it is usually mild and diffuse in nature. Severe disc swelling with the presence of
hemorrhages and exudates is very atypical of demyelinating optic neuritis and should
point to an alternative etiology such as NAION, inflammatory, or infiltrative optic
neuropathy. In NAION, disc swelling can be sectoral or diffuse and typically
associated with peripaillary hemorrhages. A small cup-to-disc ratio (also called
disc at risk or congenitally anamolous) is seen in the other eye. Diffuse pallid or
"chalky white" swelling with cotton wool spots is usually seen in AION due to GCA.
Temporal pallor is seen in conditions that selectively affect the papillo-macular
bundle such as toxic/nutritional and hereditary optic neuropathies.
The ophthalmologist should always look for evidence of uveitis such as cells in the
anterior vitreous or signs of posterior uveitis such as retinal vasculitis, retinitis, and
choroiditis. This would indicate that the disc swelling is secondary to a uveitic
process.
A pale optic disc indicates long-standing optic neuropathy such as compressive,
hereditary, toxic/nutritional optic neuropathies. This can also occur as a sequel of
an acute inflammatory or ischemic optic neuropathy. Sectoral pallor with retinal
arteriole attenuation should point to a previous NAION. When optic atrophy is
present, it is possible to detect slit-like or wedge-shaped defects in the peripapillary
nerve fiber layer. The red-free ophthalmoscope is most useful to detect these subtle
changes.
Diffuse cupping with pallor occurs in the end stage following AION (Danesh-Meyer,
Savino et al. 2001). Occasionally, optic disc cupping is seen and the disc appearance
may resemble glaucomatous disc cupping. Pallor of the neuro-retinal rim is a specific
but insensitive sign of non-glaucomatous cupping. Cupping of the optic nerve head has
been described in congenital optic disc anamolies, compressive optic neuropathy from
large intra-cranial aneurysms or masses, hereditary optic neuropathy (dominant
optic atrophy, Leber's mitochondrial optic neuropathy), radiation optic neuropathy
and methanol poisoning (Trobe, Glaser et al. 1980; Trobe, Glaser et al. 1980;

Bianchi-Marzoli, Rizzo et al. 1995) The ophthalmologist should carefully consider
these underlying causes before resorting to the diagnosis of "low tension glaucoma".
An anamolous optic nerve indicates a congenital anamoly such as optic nerve
hypopolasia, optic nerve coloboma, morning-glory disc anamoly and optic nerve
drusen. These entities will not be discussed further and the discussion will be limited to
acquired optic neuropathies.

Investigations

Visual Field Testing

Visual filed testing is an integral component of the neuro-ophthalmic examination and
is critical in the diagnosis of optic neuropathy. Both manual kinetic or automated
static perimetry can be used. The visual field defects in optic neuropathies can take
several patterns including central, diffuse, arcuate, and altitudinal defect. The
pattern of visual filed defect is not specific of any etiology and almost any type of
field defect can occur with any optic neuropathy. However, altitudinal defects are
more common in ischemic optic neuropathies and central, or cecocentral defects
frequently accompany toxic/nutritional and hereditary optic neuropathies. A cental
scotoma affects central fixation and is due to a lesion in the fovea or
papillomacular bundle. A cecocentral sctoma extends from fixation towards the
blindspot and is due to invelvement of the papillomacular bundle arising from the
fovea towards the optic disc. A hemianopic defect indicates a lesion at or posterior
the chiasm. A junctional scotoma, defined as ipsilateral central field defect and
contralateral superotemporal field defect indicates a compressive lesion at the
junction of the optic nerve and the chiasm.

Contrast Sensitivity
Contrast sensitivity is usually reduced in patients with optic neuropathy. Testing
charts such as the perri-robson charts can be useful in patients with normal snellen

visual acuity. The sensitivity and specificity of this tool, however, is yet to be
determined.

Electrophysiological Tests
Visual evoked potential (VEP) can be abnormal in any optic neuropathy but it is no
substitute to a careful clinical examination. VEPs measure the cortical activity in
response to flash or pattern stimulus. They are abnormal in the presence of any
lesion along the anterior visual pathway. Although VEP is not necessary in the
diagnosis of optic neuropathy, it can be useful in patients with early or sub-clinical
optic neuropathy who may have normal pupillary responses and no discernible optic
disc changes on clinical examination. VEPs are used commonly in patients with
demyelinating disease to detect occult optic nerve dysfunction and to identify a second
site of involvement as part of the neurological assessment. Pettern ERG (PERG) can
be abnormal in dysfunction of the macula or retinal ganglion cells, which do not
contribute significantly to the full field ERG. Therefore, PERG can be useful in a
patient with abnormal VEP to identify a macular lesion. A more recent technology,
multifocal VEP, has been shown to be of useful values in detecting optic neuritis
patients at high-risk patients to develop clinically definite multiple sclerosis (Fraser,
Klistorner et al. 2006). Panfield eletroretinography can be useful to rule out
diffuse retinal diseases such as retinitis pigmentosa and multifocal
electroretinography can be useful to distinguish macular disease from optic
neuropathy.

Optical Coherence Tomography (OCT)
OCT is a new technology that uses low coherence light to penetrate tissue and a
camera to analyze the reflected image. By performing circular scans around the
optic nerve head, the peripapillary nerve fiber layer can be analyzed. This has been
useful in the follow up of patients with optic neuritis, traumatic optic neuropathy,
and Leber's hereditary optic neuropathy (Medeiros, Moura et al. 2003; Barboni,
Savini et al. 2005; Lim, Sellebjerg et al. 2005; Costello, Coupland et al. 2006;
Pro, Pons et al. 2006; Trip, Schlottmann et al. 2006). OCT can also be used to
document peripaillary nerve fiber layer thickening in subtle NAION cases and to
follow up resolution of disc edema (Savini, Bellusci et al. 2006).

Clinical approach to optic neuropathies dove med press

Specific Diagnosis

Acute Demyelinating Optic Neuritis

Because optic neuritis can be the initial manifestation of multiple sclerosis (MS), its
recognition is of important prognostic value. Optic neuritis is more common in females
with a peak age of onset between 30-40 years (Beck, Trobe et al. 2003) Magnetic
resonance imaging (MRI) of the brain is needed to detect the presence of white matter
lesions. The risk of developing clinically definite multiple sclerosis over 10 years is
56% if one or more baseline lesion 3mm diameter is found, whereas the risk in normal
MRI is 22% (Figure-1). The risk is low (5%) in males with severe disc edema with
peripaillary hemorrhages and normal MRI (Beck, Trobe et al. 2003). Initiating
treatment with beta-1a interferon should also be strongly considered in high-risk
patients since this has been found to decrease the risk of conversion to clinically
definite multiple sclerosis by 50% (Beck, Chandler et al. 2002).
Optic neuritis improves in 90% of cases over several weeks to near normal visual
acuity (Beck 1995). The use of intravenous steroids was found to hasten the visual
recovery but not the final visual outcome (Beck 1995). However, the early use of
steroids may be warranted to minimize axonal loss of the optic nerve, which has been
found to occur early in the disease (Arnold 2005; Trip, Schlottmann et al. 2005;
Costello, Coupland et al. 2006). Lack of improvement after about 4-6 weeks with or
without steroids is atypical of optic neuritis and should prompt searching for an
alternative causes such as inflammatory (sarcoid, vasculitis), infiltrative and
compressive. In such cases, the recommended additional investigations include spinal
tap, complete blood count, antinuclear antibodies (ANA), chest radiographs,
angiotensin converting enzyme levels (ACE), and anti-neutrophil cytoplasmic
antibodies (ANCA) (Lee, Lin et al. 2000).
Optic neuritis in children is classically thought to differ from adult optic neuritis by
frequent bilateral involvement and disc swelling, and more severe initial vision loss.
A history of viral infection or vaccination is common (Figure-2). Other neurological
manifestations may occur if there is concurrent acute disseminated encephalomyelitis
(Bangsgaard, Larsen et al. 2006). MRI of the brain and orbit is recommended to rule
out demyelination, and meningeal enhancement seen in infectious or non-infectious
meningitis. Contrary to the common notion that childhood optic neuritis is less likely
to be associated with multiple sclerosis (Lucchinetti, Kiers et al. 1997), a recent

report found an association with MS in 36% of patients with optic neuritis, especially
with bilateral involvement (Wilejto, Shroff et al. 2006).

Neuromyelitis Optica (Devic's disease)
When optic neuritis is preceded or followed by transverse or ascending myelopathy
often causing paraplegia, the condition is referred to as neuromyelitis optica (NMO).
This condition is more common in young patients with a predilection for Asians and
Africans (Cabre, Heinzlef et al. 2001; Nakashima, Fujihara et al. 2006). The visual
loss is often severe, bilateral and may precede or follow the myelopathy. The
interval between myelopathy and optic neuritis can be months to years. MRI of the
spine will show demyelination extending over 3 or more vertebral segments. There is
a debate about whether NMO is simply a sub-type of MS (Rubiera, Rio et al. 2006)
Although, lesions outside the optic nerve and spinal cord were considered incompatible
with NMO, the criteria of diagnosis have been revised recently to allow for the
presence of MRI brain lesion "not compatible with MS" (Pittock, Lennon et al. 2006;
Wingerchuk, Lennon et al. 2006). A serum marker, NMO Ig-G, has been found useful
to distinguish NMO from other related disorders such as MS (Lennon, Wingerchuk et
al. 2004).

Non-arteritic Ischemic Optic Neuropathy (NAION)

NAION can occasionally be confused with acute demyelinating optic neuritis. There
are some features that may help distinguishing the two conditions. The presence of
severe disc edema with hemorrhages is characteristic of NAION and atypical of optic
neuritis (Figure-3). Patients with NAION are usually over 50 year old and have
systemic vascular risk factors such as diabetes, hypertension, and smoking (Tsai, Liu
et al. 1998; McCulley, Lam et al. 2005). Nevertheless, NAION can occur in young
patients (below 45 years) and patients who lack any vascular risk factors. In young
patients, it has been associated with hypercholesterolemia and hyperhomocysteinemia
(Pianka, Almog et al. 2000; Deramo, Sergott et al. 2003). Visual acuity can be
normal or severely affected. The visual field defect is usually inferonasal arcuate
or altitudinal. The optic nerve head in the other eye is often has small cup-to-disc
ratio (0.1 or less) (Burde 1993; Feldon 1999). This optic nerve head configuration
seems to play a more important role than the systemic risk factors (Tsai, Liu et al.

1998). Recent reports have linked NAION to the sleep apnea syndrome (Mojon,
Hedges et al. 2002; Palombi, Renard et al. 2006), but it is unknown whether
treatment of sleep apnea can prevent NAION (Behbehani, Mathews et al. 2005) .
Visual acuity usually remains static or improves slightly in the vast majority of
patients with NAION (Arnold and Hepler 1994). In a small subset of patients, visual
acuity may actually worsen over the first few weeks (progressive NAION) (Sergott,
Cohen et al. 1989; Spoor, McHenry et al. 1993; Arnold and Hepler 1994). This
progressive phase may cause a diagnostic difficulty but it rarely lasts more than
3-4 weeks and is then followed by stabilization of visual function. Bilateral
simultaneous involvement is very unusual of NAION and but can occur during a
hypotensive episode such as blood loss or over-dosing of anti-hyprtensive medications
(Hayreh 1999). Recurrence in the same eye is uncommon with a risk of 5 % (Hayreh,
Podhajsky et al. 2001). The risk of later involvement in the follow eye within 5
years is 15% (Newman, Scherer et al. 2002).
In posterior ischemic optic neuropathy (PION) there is no disk swelling. PION can
occur in severe blood loss, hypotension, hemodialysis, anemia, and after long
surgeries , such as spinal surgeries, in which the patient is positioned prone (Buono,
Foroozan et al. 2003; Murphy 2003; Hayreh 2004). The visual loss is often
bilateral but can be asymmetrical. Pupillary responses to light will be sluggish,
which helps distinguish PION from cortical cause of vision loss.

Arteritic Ischemic Optic Neuropathy (AION)
In patients over 60 year old with features of ischemic optic neuropathy, the
ophthalmologist should strongly consider the possibility of giant cell arteritis
(GCA). Careful medical history should be obtained, inquiring about temporal pain,
jaw claudications, transient visual or diplopia, fever, weight loss, myalgias and
fatigue.(Hayreh, Podhajsky et al. 1998) Some patients may not have the
constitutional symptoms and have only visual symptoms (occult GCA) (Liu, Glaser et
al. 1994; Hayreh, Podhajsky et al. 1998). Other clinical features that may help
distinguishing patients with AION from NAION include cup-to-disk ratio of greater
than 0.2 in the other eye, early massive or bilateral simultaneous visual loss,
markedly pallid disk edema often described as "chalky-white" swelling in 68.7 % of
cases, and choroidal infarcts (Figure-4) (Hayreh, Podhajsky et al. 1998; Hayreh,
Podhajsky et al. 1998). Rarely, the optic disc can look normal (PION). (Sadda, Nee
et al. 2001) End-stage optic disc appearance of patients with AION is characterized
by marked cupping with pallor and should not be confused with glaucomatous cupping
(Danesh-Meyer, Savino et al. 2001) . The superficial temporal arteries should be

palpated and the pulse felt. Patients with GCA have a "cord-like" feel with reduced
pulses.
Laboratory evaluation should include complete blood count, erythrocyte
sedimentation rate (ESR), and C-reactive protein (CRP). ESR is elevated in GCA but
2-30% of patients with biopsy-proven GCA will have normal ESR (Brittain,
McIlwaine et al. 1991; Liu, Glaser et al. 1994; Hayreh, Podhajsky et al. 1997;
Salvarani and Hunder 2001). Elevated CRP was found to be more sensitive (97.5%)
than ESR (76%-86%) for the detection of GCA. ESR and CRP combined give the best
specificity (97.0%) and sensitivity (99%) for diagnosis (Hayreh, Podhajsky et al.

1997; Parikh, Miller et al. 2006). Thrombocytosis is another useful feature that can
complement ESR and CRP (Lincoff, Erlich et al. 2000; Costello, Zimmerman et al.
2004).
Steroid treatment should be instituted in patients who are considered at high risk to
have GCA based on the clinical and laboratory features. Untreated GCA will cause
visual loss in the fellow eye in about a third of cases with the risk highest in the first
4 weeks. Either oral (80-120 mg prednisone) or intravenous (1 gram
methyleprdnisolone) for 3-5 days followed by oral steroids can be used. There is no
evidence that either route of administration is more effective in preventing possible
early visual deterioration (Hayreh and Zimmerman 2003). There are reports of the
successful use of heparin if visual deterioration occurs despite being on steroid
treatment (Buono, Foroozan et al. 2004).
Definitive diagnosis of AION is established by temporal artery biopsy and
histopathological confirmation. Although the inflammation can be seen
histopathologically in the vessels for weeks despite steroid therapy, temporal artery
biopsy should be performed as soon as the patient is started on steroids to avoid
equivocal results. Jaw claudications and neck pain are significant indicators of a
positive temporal artery biopsy independent of the ESR and CRP (Hayreh, Podhajsky
et al. 1997) The odds ratio for a positive temporal artery biopsy was 9.0 times
greater with jaw claudications, 3.3 greater with neck pain, and 3.2 greater with an

elevated ESR and CRP (Hayreh, Podhajsky et al. 1997). Biopsy can be performed on
one side and if it is negative and the index of suspicion of GCA is high, a biopsy is
performed the contra-lateral side. Some authors advocate bilateral temporal
artery biopsies at the onset because an overall chance of discordance of 4-5%
(Danesh-Meyer, Savino et al. 2000; Pless, Rizzo et al. 2000).

Inflammatory (Non-demyelinating) Optic Neuropathy
This category comprises many entities in which the optic nerve is involved by either an
ocular or systemic inflammatory process. Optic disc swelling frequently occurs with
posterior uveitis and retinitis. Therefore, when evaluating optic disk swelling, it is
useful to look for evidence of anterior or posterior segment inflammation. Optic
neuropathy can also occur in the context orbital inflammatory disease (orbital
pseudotumor). MRI of the orbit will show inflammation of the optic nerve sheath
(optic perineuritis) (Fay, Kane et al. 1997).
The optic nerve can be involved in a variety of systemic auto-immune and infectious
disorders such as sarcoidosis, systemic lupus erythematosus, Behcet's disease
inflammatory bowel disease, Sjogren's syndrome Wegener's granulomatosis, syphilis,
Lyme disease and cat-scratch disease (Jabs, Miller et al. 1986; Wise and Agudelo
1988; Kansu, Kirkali et al. 1989; Belden, Hamed et al. 1993; Han, Lee et al. 2006).

Auto-immune optic neuropathy is a recurrent, steroid-responsive optic neuropathy.
The anti-nuclear antibody (ANA) and anticardiolipin antibody are frequently
positive (Kupersmith, Burde et al. 1988; Frohman, Turbin et al. 2003). The diagnosis
is made by performing a skin biopsy, which often shows evidence of vasculitis when
studied with immunoflorescence.
Chronic relapsing inflammatory optic neuropathy is another entity characterized by
recurrences and steroid-responsiveness. The syndrome can behave as granulomatous
optic neuropathy and may require long-term immunosuppressive therapy (Kidd, Burton
et al. 2003).
Some of the features should raise the suspicion of an inflammatory optic neuritis
include lack of spontaneous improvement of visual function after 30 days, or
exquisite steroid-responsiveness and steroid-dependency. In such cases, a spinal tap
and additional laboratory studies directed by the history and neuro-ophthalmic
examination are indicated (see discussion under demyelinating optic neuritis).

Infiltrative Optic Neuropathies
The optic nerve can be infiltrated in systemic malignancies such as lymphoma,
leukemia, multiple myeloma, and carcinoma.(Brown, Shields et al. 1981; Brazis,
Liesegang et al. 1990; Behbehani, Vacarezza et al. 2005; Shimada, Shibuya et al.
2006) The optic disc can be swollen or normal in appearance (Figure 5). MRI of the
brain and orbit may show meningeal and optic nerve enhancement. Spinal tap is
recommended in cases of suspected CNS malignancy but more than one spinal tap may

be needed to detect malignant cells (van Oostenbrugge and Twijnstra 1999) In case
of localized optic nerve infiltration with no evidence of systemic disease,
histopathological diagnosis may require direct optic nerve sheath biopsy (Behbehani,
Vacarezza et al. 2005).

Compressive Optic Neuropathy
In compressive optic neuropathy, visual loss is usually gradual and progressive.
Common causes include orbital and intracranial meningiomas, pituitary adenomas,
intracranial aneurysms, craniopharyngiomas, and gliomas of the anterior visual
pathway (Figure 6). Vision loss, however, can be fast and dramatic in pituitary
apoplexy, or ruptured aneurysm. Visual field testing aids in the localization of the
lesion and neuro-imaging with MRI of the brain and orbit is essential.
Compressive optic neuropathy can also occur in thyroid eye disease and can present
as asymmetric progressive visual loss. This will require prompt therapy (orbital
radiation, orbital decompression, high-dose systemic steroids).

Hereditary Optic Neuropathy
The hereditary optic neuropathies are a broad category including autosomally-
inherited diseases (dominant, recessive, x-linked) and diseases caused by inheritance of
defective mitochondrial genome. Mitochondrial dysfunction may be a final common
pathway among these disorders (Newman 2005; Atkins, Biousse et al. 2006).
Hereditary optic neuropathies can be isolated or associated with other neurological
signs and symptoms.
Patients with dominant optic neuropathy (Kjers' type) often present in the first
decade of life with bilateral symmetric visual loss. Visual acuity can range from
20/20 to 20/400 (Hoyt 1980; Das, Bendok et al. 2006). Visual field testing
frequently reveals bilateral central or cecocentral scotomas. In some cases, a
central hemianopic bitemporal visual field defect is found, which in the absence of
positive family history may erroneously lead to a search for a chiasmal lesion
(Manchester and Calhoun 1958). Patients will have color vision deficit along the
tritan (blue-yellow) axis. The optic disc will show temporal pallor and in some cases
severe excavation and cupping. There various responsible genetic mutations occur in
the OPA1 gene located on the chromosome 3 q region (Votruba 2004).

Recessive optic neuropathy is rare and tends to present in the first year of life
(Francois 1976). It can be associated with diabetes mellitus, diabetes inspidus, and
deafness (Wolfram syndrome) (Ajlouni, Jarrah et al. 2002). An X-linked optic
atrophy has also been described and the genetic mutation has been localized to
Xp11.4-Xp11.2 (OPA2) (Katz, Zhao et al. 2006). Optic neuropathy can also occur in
neurological conditions such as spinocerebellar degeneration, Friedriech's ataxia, and
olivo-ponto-cerebellar atrophy.
Leber's hereditary mitochondrial optic neuropathy (LHON) classically presents with
acute unilateral, painless, visual loss. However, some cases may stay asymptomatic
or have a chronic course (Kerrison 2005). Sequential bilateral involvement may
occur weeks or months later. Visual filed defects tend to be central or cecocentral
as the papillo-macular bundle is first and most severely affected (Barboni, Savini et
al. 2005). Fundoscopy may show disk swelling, thickening of the peripapillary retinal
nerve fiber layer and peripapillary retinal telangectatic vessels which do not leak
on flourescin angiography (Figure7). Occasionally, optic nerve pallor can be seen
initially. Because of the wide age range (6-80 year old) at which LHON may present,
it is frequently misdiagnosed (Ajax and Kardon 1998). Young patients are often
diagnosed as optic neuritis and older patients as ischemic or infiltrative optic
neuropathy. MRI may show optic nerve enhancement and white matter lesions, which
may add to the diagnostic difficulties (Paulus, Straube et al. 1993; Vaphiades and
Newman 1999) Therefore, a high index of suspicion is essential. Some patients may
spontaneously improve to normal or near normal visual acuity (Nakamura and
Yamamoto 2000)
LHON has 4 primary mitochondrial genome mutations; G11778A, G3460A and
T14484C and T10663C. The disease affects males more than females with a ratio of
2.5:1 for the G11778A and G3460A mutation and 6:1 ratio for the T14484C mutation
(Riordan-Eva, Sanders et al. 1995). The frequencies of mutation may vary across
different countries and newer mutations have been described worldwide (Zhadanov,
Atamanov et al. 2005; Houshmand, Mahmoudi et al. 2006). Some patients may
demonstrate neurological manifestations such as peripheral neuropathy, ataxia,
dystonia and cardiac conduction defects (Bower, Hawley et al. 1992; Murakami, Mita
et al. 1996; Watanabe, Mita et al. 2006) These patients fall in the spectrum
mitochondrial encephalomyelopathies and their clinical manifestations may vary
considerably (Gropman, Chen et al. 2004; Blakely, de Silva et al. 2005).

Toxic-Nutritional Optic Neuropathies
Optic nerve dysfunction can be caused by various drugs, toxins and nutritional

deficiencies. The most common offenders are ethambutol, amiodarone, methanol,
ethanol and tobacco (DeVita, Miao et al. 1987; Purvin, Kawasaki et al. 2006).
Similar to hereditary optic neuropathies, toxic-nutritional optic neuropathies are
also characterized by selective maculo-papillar bundle involvement, leading to
central or cecocentral scotomas.
Ethambutol causes optic neuropathy in 1% of patients using the anti-tuberculous
medication. . Although the dosage of 25mg/kg/day for 2 months followed by 15
mg/kg/day maintenance doses is considered safe, toxicity has been reported at below
this dosage (Tsai and Lee 1997) Patients with low zinc levels were found to be more
vulnerable to develop optic neuropathy (De Palma, Franco et al. 1989). The visual
symptoms usually start 2 to 8 months after the drug is started. Pupillary
abnormalities can be subtle, and visual evoked potential may be needed to confirm the
diagnosis The diagnosis is often made late when optic nerve pallor has already set in
and vision is severely affected. The drug should be stopped as soon as the diagnosis is
made, although in advanced cases vision continues to deteriorate even following drug
cessation.
The anti-arrhythmic drug amiodarone can cause bilateral optic neuropathy. Because
patients using this drug have systemic vascular risk factors, there is still
controversy whether patients affected may simply have NAION. Some of the clinical
features that may help distinguish this entity from NAION are the bilateral
simultaneous onset, the insidious nature of vision loss, and the protracted disc edema
which can last for months (Murphy and Murphy 2005; Purvin, Kawasaki et al.
2006). The disc edema in NAION usually resolves within 6-8 weeks.
Other medications which can cause toxic optic neuropathy include methotrexate,
cyclosporine, vincristine, cisplatin and chloramphenicol (Godel, Nemet et al. 1980;
Walter, Bertz et al. 2000; Wang, Arnold et al. 2000; Clare, Colley et al. 2005;
Weisfeld-Adams, Dutton et al. 2005).
Tobacco-alcohol amblyopia is a term used for a condition that may be due both the
toxic effect of the tobacco and a nutritional deficiency state. Because many patients
who abuse alcohol and tobacco do not get optic neuropathy, the mechanism is
unlikely to be a direct insult to the optic nerve. A more plausible mechanism is that
genetic and nutritional deficiency factors increase the susceptibility for optic
neuropathy for the effects of certain toxins. Deficiency of thiamine (B1), riboflavin
(B2), Folate , B 12 and B6 have all been associated with optic neuropathy (Rizzo and
Lessell 1993; Golnik and Schaible 1994; Sadun, Martone et al. 1994; Hsu, Miller et
al. 2002). Patients who follow high protein, ketogenic and low carbohydrate diet
are at risk for developing thiamin deficiency. Similarly, patients who have undergone
gastrointestinal surgery may develop optic neuropathy due interference with the

absorption of vitamin B12.

Radiation Optic Neuropathy (RON)
Patients with RON can present with vision loss, months or years following history of
radiation exposure to the brain or orbit. The risk increases in patients who had also
received chemotherapy (Kline, Kim et al. 1985). The mechanism of RON is ischemia
caused by endothelial cell injury from radiation. The optic disc is usually normal but
can be swollen. MRI of the orbit may show optic nerve enhancement with gadolinium
(Guy, Mancuso et al. 1990; Lessell 2004) Patients may also have radiation
retinopathy with retinal hemorrhages, cotton wool spots, exudates and macular
edema. Because many of those patients were treated for brain or orbital tumors,
recurrent tumor is initially the main consideration when patients become symptomatic.
There is no treatment of proven efficacy for RON. Hyperbaric oxygen, steroids,
antiplatelet drugs, and anticoagulants have all been used with limited success
(Barbosa, Carvalho et al. 1999; Danesh-Meyer, Savino et al. 2004; Boschetti, De
Lucchi et al. 2006) The visual prognosis is poor with 45% of eyes ending with no light
perception visual acuity (Lessell 2004)

Traumatic Optic Neuropathy
Traumatic optic neuropathy presents with typical signs and symptoms. Patients
usually had suffered craniofacial trauma but occasionally mild orbital or eye
injury (Hou and Murphy 2004; Nishi, Ueda et al. 2006). A RAPD is the main clue to
the diagnosis. CT scan of the orbit is recommended to detect any bony fractures,
fractures of the optic canal, and acute orbital hemorrhages. High-dose steroid
therapy was adopted as a treatment because of their beneficial effect in studies on
spinal cord injuries. Subsequently , however, it was shown that high-dose steroids
may be harmful to the optic nerve if started 8 hours after the injury (Steinsapir
2006). In a non-randomized trial, no clear benefit was found with either steroids or
surgical decompression of the optic canal (Levin, Beck et al. 1999). There are
anecdotal reports of beneficial outcome of surgery in cases of optic canal fracture

and optic nerve sheath hematoma (Jiang, Hsu et al. 2001; Wohlrab, Maas et al.
2002; Rajiniganth, Gupta et al. 2003).

Paraneoplastic Optic Neuropathy

Optic neuropathy can occur as a remote effect of both small cell and non-small cell
lung carcinoma (Asproudis, Nikas et al. 2005; Sheorajpanday, Slabbynck et al.
2006) Some patients may have a concurrent paraneoplastic cerebellar syndrome of
dysarthria and ataxia (Luiz, Lee et al. 1998; Thambisetty, Scherzer et al. 2001).
Patients often have bilateral disc swelling and progressive visual loss before the
diagnosis of the systemic malignancy is made. The collapsing response-mediating
protein (CRMP-5), has been found recently to be a useful marker in the diagnosis of
this condition in patients with lung carcinoma (Yu, Kryzer et al. 2001; Calvert
2006).

Conclusion
Optic neuropathy can be caused by demyelination, inflammation, ischemia,
infiltration, compression, and hereditary and toxic/nutritional causes. Careful
clinical evaluation is essential to rule in the diagnosis of optic neuropathy.
Recognition of same entities can not only alter the visual prognosis but also the
neurological prognosis. Some additional tests particularly visual field testing and
neuro-imaging are very useful in the clinical evaluation. The ophthalmologist should
be familiar with the various entities that can cause optic neuropathy. With careful
clinical evaluation and appropriate investigations, a specific diagnosis can be made in
most cases.

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Figure Legends

Figure-1: (A) Axial MRI of the brain (FLAIR sequence) showing the classic
periventricular white matter lesions seen in MS. (B) Sagittal MRI showing
peri-collosal white matter lesions also known as "Dawson's fingers"

Figure-2: An 11 year old boy with sudden onset of visual loss 2 weeks following a
viral upper respiratory tract infection. Bilateral disc swelling was seen in
the right (A) and left (B) disc. Visual acuity improved over 1 week
spontaneously from counting fingers to 20/20 in both eyes.
Figure-3: A 57 year old patient with history of hypertension, diabetes and
hypercholesterolemia and NAION in his right eye. There is pallid swelling of
the right disc with hemorrhage superiorly. The left optic disc has a cup to disc
ratio of 0.1 (not shown).
Figure-4: Disc swelling in GCA. Note pallid disc swelling with hemorrhages and an
adjacent area of choroidal infarction (arrow) (courtesy of Peter J Savino,
MD).
Figure 5: A 55 year old women with chronic disc swelling and optic neuropathy in the
right eye. MRI showed enhancement of the intracranial nerve. An extensive
work up, including a spinal tap, was negative. An optic nerve sheath biopsy
showed optic nerve lymphoma with no systemic involvement.
Figure 6: An axial contrast-enhanced MRI of the orbit showing enhancement of the
intra-orbital and intra-canalicular optic nerve in a lady with optic nerve
sheath meningioma in the right eye.
Figure-7: A 55 year old lady carrier of the 3460 G LHON mitochondrial mutation,
with bilateral disc swelling (top figure). Automated 24-2 perimetry (middle
figure) shows bilateral arcuate defects and 10-2 perimetry shows bilateral
central scotomas (bottom figure). The patient is a carrier the 3460 G LHON
mitochondrial mutation.

Table 1

Type of Optic Onset Pattern of Visual Ophthalmoscopi Additional
Neuropathy Field Loss c Findings Features
Demyelinating Acute Central,cecocentral,a 75% normal disc Neurological
signs of brain
rcuate (retrobulbar) stem
(diplopia,
ataxia,
weakness) or
spinal cord
involvement
(leg
weakness,
bladder
symptoms,
paresthesias)
Non-arteritic Acue Arcuate, altitudinal Swollen disc Crowded
Ischemic ( usually (anamalous)
sectoral) with disk ,
disc systemic
hemorrhages vascular risk
factors
(diabetes,
hypertension,
hyerlipedemia
)
Arteritic Acute Arcuate Pallid swelling Headache,
Ischemic of the disc jaw
claudications
, transient
visual loss
or diplopia,
myalgias,
fever, weight
loss, High
ESR and CRP
Inflammatory Acute, Arcuate, central, Swollen disc Features of
sub- cecocentral auto-immune
acute diseases (skin
rash,
arthritis,
Raynaud’s
phenomenon),
exquisite
responsivenes

s to systemic
steroids
Infiltrative Acute, Arcuate, hemianopic Normal or Systemic
subacute swollen disc malignancy
may be
present, MRI
may show
optic nerve
or meningeal
infiltration
Compressive Chronic Arcuate, hemianopic Normal or pale MRI will
disc show a
compressive
mass
Toxic/nutritio Acute, Central, cecocentral Normal or History of
nal subacute mildly swollen drug use
or disc (ethambutol,
chronic alcohol)
Hereditary Chronic Central, cecocentral Pale (dominant Onset in
(dominan and recessive) childhood
t and or mildly with positive
recessive swollen with family
) , acute peripapillary history,
or telengiectatic Mitochondria
subacute vessels l DNA
( Leber’s (Leber’s) testing may
) reveal
Leber’s
mutataion
Traumatic Acute Arcaute, central or Normal Head or
hemianopic facial
trauma
Radiation Acute Arcuate, hemianopic Normal History of
radiation to
the brain or
orbit, MRI
may show
enhancement
of the optic
nerve with
Gadolinium
Paraneoplasti Subacute Central Swollen disc Associated

c , chronic small-cell
lung
carcinoma,
CRMP-5
marker may
be positive,
paraneoplas
tic
cerebellar
syndrome

Clinical approach to optic neuropathies dove med press

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