Atkins2011 PDF

Handbook of Clinical Neurology, Vol.
102 (3rd series)

Neuro-ophthalmology
C. Kennard and R.J. Leigh, Editors
# 2011 Elsevier B.V. All rights reserved
Chapter 6
Lesions of the optic nerve

EDWARD J. ATKINS, NANCY J. NEWMAN * AND VALERIE BIOUSSE
Departments of Ophthalmology, Neurology, and Neurological Surgery, Neuro-ophthalmology Unit, Emory Eye Center,
Emory University School of Medicine, Atlanta, GA, USA
INTRODUCTION which is composed of unmyelinated retinal ganglion

cell axons and astrocytes; (2) the intraorbital segment
The optic nerves are unique central nervous system
(25–30 mm), which begins at the lamina cribrosa,
structures in terms of surrounding anatomy, size, loca-
passes through the annulus of Zinn, and extends to
tion, and blood supply; therefore, they are uniquely
the optic foramen; (3) the intracanalicular segment
vulnerable to every pathological process that can
(5–10 mm), which traverses the bony confines of the
affect the central and peripheral nervous systems,
optic canal in the lesser wing of the sphenoid; and
including inflammation, ischemia, compression, infil-
(4) the intracranial segment (10–15 mm), which runs
tration, toxic or hereditary metabolic dysfunction,
posteromedially above the cavernous sinus, and below
trauma, and mechanical damage (Table 6.1). The optic
the frontal lobe to join the optic chiasm. The optic nerve
nerve is the only part of the central nervous system
diameter increases from about 1.6 mm where it exits
that can be directly visualized with an ophthalmo-
the eye, to 3.5 mm in the orbit, and to 4.5 mm in the
scope; however, a damaged optic nerve has only a
intracranial space. The total length of the optic nerve
few possible appearances: (1) normal; (2) swollen; or
is approximately 5–5.5 cm. The blood supply also varies
(3) pale, regardless of the underlying cause of optic
by segment, with the optic disc supplied by anastomos-
neuropathy (Fig. 6.1).
ing arterioles arising from the posterior ciliary arteries,
the intraorbital segment supplied by perforating
ANATOMY OF OPTIC NERVE LESIONS
branches of the ophthalmic artery, and the intracanali-
The optic nerve is also known as cranial nerve II, cular and intracranial portions supplied by pial branches
but, unlike the other paired cranial nerves, it is not part of the ophthalmic, internal carotid, anterior cerebral,
of the peripheral nervous system. The optic nerves are and anterior communicating arteries (van Overbeeke
central nervous system white-matter tracts, each con- and Sekhar, 2003).
taining about 1.2 million retinal ganglion cell axons
(Mikelberg et al., 1989). Unlike peripheral nervous TOPICAL DIAGNOSIS OF OPTIC
system structures, the optic nerves are covered by all NERVE LESIONS
three meningeal layers, and are surrounded by a cuff
Localization to the optic nerve
of cerebrospinal fluid (CSF). Optic nerve fibers are
ensheathed with myelin produced by oligodendrocytes, The cardinal features of optic neuropathies are: (1) an
whereas the myelin of peripheral nerve fibers is pro- abnormality in visual sensory function (often unilateral
duced by Schwann cells. This is an important distinc- but may be bilateral); (2) a relative afferent pupillary
tion, as damaged axons of the central nervous system defect (RAPD) if unilateral; and (3) a change in the
are not as capable of regeneration as are those in the appearance of the optic nerve. Acquired optic neuro-
peripheral nervous system and optic nerve damage pathies can result in any kind of visual field defect,
can lead to irreversible blindness. but central, cecocentral, arcuate, or altitudinal defects
The optic nerve can be divided into four anatomical are most common. A monocular visual field defect
segments: (1) the intraocular segment, or the optic disc, helps to localize the lesion to the right or left optic
*Correspondence to: Nancy J. Newman, MD, Neuro-ophthalmology Unit, Emory Eye Center, 1365-B Clifton Road, NE, Atlanta,
Georgia 30322, USA. Tel: 404-778-5360, Fax: 404-778-4849. E-mail: OPHTNJN@emory.edu
160 E.J. ATKINS ET AL.
Table 6.1 vessels, and disc hyperemia. More severe optic disc
Categories of optic nerve lesions edema manifests with intraretinal hemorrhages, retinal
nerve fiber layer infarcts (cotton-wool spots), and hard
Inflammatory exudates.
Demyelination
Infection Optic atrophy
Systemic diseases
Ischemic Chronic optic neuropathies ultimately produce pale,
Arteritic anterior ischemic optic neuropathy atrophic optic discs, regardless of the cause. Irrevers-
Nonarteritic anterior ischemic optic neuropathy ible damage to the optic nerve results in optic disc
Compressive/infiltrative pallor in 4–6 weeks; therefore, the appearance of disc
Neoplasm pallor indicates that the injury occurred at least 4–6
Inflammation
weeks earlier. A key clinical point is that optic disc
Vascular
swelling may not develop if optic atrophy was already
Nutritional/toxic
Hereditary present prior to an acute insult (“dead axons don’t
Traumatic swell”). Ophthalmoscopic findings may be subtle, and
Direct asymmetry in disc color may be the only clue to early
Indirect optic atrophy. In this setting, measurement of the reti-
Mechanical nal nerve fiber layer thickness with optical coherence
Papilledema (" intracranial pressure) tomography (OCT) is helpful and shows decreased
Glaucoma (" intraocular pressure) average retinal nerve fiber layer thickness (Fig. 6.2A)
(Frohman et al., 2008). Optic atrophy may develop as
a result of injury at any point along the visual pathways
nerve anterior to the chiasm. The presence of a RAPD between the retinal ganglion cells and the lateral genic-
helps to distinguish optic nerve lesions from maculopa- ulate nucleus, including: (1) intraocular disease that
thies and other causes of monocular central vision loss damages the retinal ganglion cells, the nerve fiber layer,
(Sandbach and Newman, 2001). or the optic disc; (2) intraorbital, intracanalicular, or
intracranial optic nerve damage; and (3) the optic chiasm
or optic tract.
Optic disc edema
Although specific characteristic features of optic
Acute optic neuropathies may initially manifest with atrophy may have some localizing value, it is usually
swollen optic discs if the locus of pathology involves impossible to determine retrospectively the presumed
the anterior optic nerve. If the pathological process is mechanism of optic nerve injury in patients presenting
retrobulbar or posterior, the optic discs will appear with isolated optic atrophy. Helpful findings include:
normal acutely. Optic disc edema may result from (1) diffuse pallor, with a clear peripapillary nerve
any process that disrupts rapid axonal transport in the fiber layer, as seen in primary optic atrophy (atrophy
optic nerve. Stasis or congestion of axoplasmic flow with no prior disc edema) (Fig. 6.2B); (2) irregularity
often occurs anteriorly or at the level of the lamina of the peripapillary nerve fiber layer with associated
cribrosa, leading to optic disc swelling which is visible retinal pigment epithelium disruption, as seen in
by ophthalmoscopy. Early optic disc edema can be sub- secondary optic atrophy (atrophy with prior disc
tle and is characterized by blurring of the peripapillary edema) (Fig. 6.2C); (3) “bow-tie” optic atrophy
nerve fiber layer, obscuration of peripapillary blood from degeneration of axons of the retinal ganglion
Fig. 6.1. Optic nerve appearance: (A) normal; (B) swollen; (C) pale.
LESIONS OF THE OPTIC NERVE 161
RNFL THICKNESS AVERAGE ANALYSIS
Microns 107 89
49 113
300 27 106 S
37 68 32 T N 78
200 OD
33 61 I
100 59 139
161 120 Signal Strength (Max 10) 10
0
0 20 40 60 80 100 120 140 160 180 200 220 240
35 33
34 28
TEMP SUP NAS INF TEMP 40 30 S
Microns 38 43 40 N T 35
300 OS 41 33 I
52 28
38 39 Signal Strength (Max 10) 10
200
Analysis Confidence Low

100 OD (N = 3) OS (N = 3) OD-OS
Imax/Smax 1.52 1.54 −0.03
0 Smax/Imax 0.66 0.65 0.01
0 20 40 60 80 100 120 140 160 180 200 220 240 Smax/Tavg 3.62 1.07 2.55
TEMP SUP NAS INF TEMP Imax/Tavg 5.49 1.64 3.84
Smax/Navg 1.49 0.95 0.54 100%
Microns Max-Min 153.00 34.00 119.00 Normal 95%

Smax 117.00 38.00 79.00 distribution 5%
300 Percentiles
Imax 177.00 58.00 119.00 1%
Savg 89.00 33.00 56.00 0%
200
Iavg 120.00 39.00 81.00
Avg.Thickness 79.93 36.65 43.28
100
Patient/Scan Information
0
0 20 40 60 80 100 120 140 160 180 200 220 240
TEMP SUP NAS INF TEMP
OD OS Scan Type Fast RNFL Thickness (3.4)

Scan Date 2/10/2009
A Scan Length 10.87 mm
B C D E
Fig. 6.2. Patterns of optic nerve pallor and atrophy. (A) Optical coherence tomography (OCT) with moderately decreased aver-
age peripapillary retinal nerve fiber layer (RNFL) in the right eye (OD) (average thickness 79.93 mm) and markedly decreased
average RNFL thickness in an atrophic nerve left eye (OS) (average thickness 36.65 mm) as indicated on the last row of the table.
(B) Primary optic atrophy; (C) secondary optic atrophy; (D) “bow-tie” optic atrophy; (E) optic disc cupping.
cells located nasal to the fovea as seen in optic tract disease and their clinical entities (see Table 6.1).
lesions (Fig. 6.2D); and (4) optic disc cupping with a Narrowing of the differential diagnosis depends on
normal-appearing neuroretinal rim, as seen in further clues yielded from a complete neuro-ophthalmic
glaucomatous optic neuropathy (Fig. 6.2E) (Trobe examination and on a number of historical and clinical
et al., 1980). factors (Table 6.2). These factors include patient charac-
teristics (age, gender, race, family history), the tempo of
optic nerve dysfunction (acute, subacute, chronic, pro-
DIFFERENTIAL DIAGNOSIS OF
gressive), the presence or absence of other neurological
LESIONS OF THE OPTIC NERVE
or ocular findings (pain, proptosis, ocular motility dys-
Determination of the etiology of an optic neuropathy can- function), and on the results of appropriate ancillary
not be made on the appearance of the optic disc alone. testing (Van Stavern and Newman, 2001). For example,
Once pathology has been localized to the optic nerve, an acute optic neuropathy in an otherwise healthy
the best approach is to consider the main categories of 25-year-old white woman will most often be secondary
Table 6.2
162
Historical and clinical features of common optic neuropathies
Acute disc
Laterality Visual acuity Pain Visual field appearance Age (years) Gender Typical course
Inflammatory
Idiopathic Unilateral Decreased Present Central defects Normal (2/3) or 20–30 More females Worsens over days
demyelinating swollen (1/3) to weeks, then
optic neuritis recovers
Inflammatory/ Unilateral Decreased Present Central defects Normal or swollen Variable Either Rapidly progressive
infectious optic
neuritis
Ischemic
Nonarteritic anterior Unilateral Decreased Absent Altitudinal Disc edema with > 50 Either May worsen over
ischemic optic disc at risk in days, then
neuropathy unaffected fellow stabilize
E.J. ATKINS ET AL.

eye
Compressive/
infiltrative
Optic nerve sheath Unilateral Decreased Absent Variable Swollen 30–40 More females Slowly progressive
meningioma
Optic glioma Unilateral Variable Absent Variable Variable Childhood Either Often stable
Nutritional/toxic
B12 deficiency/ Bilateral Decreased Absent Cecocentral Temporal pallor Variable Either Slowly progressive
ethambutol (late)
Hereditary
Leber’s hereditary Initially Decreased Absent Cecocentral Pseudoedema, 15–35 More males Worsens over
optic neuropathy unilateral circumpapillary several months,
telangiectasia then stabilizes
Dominant optic Bilateral Decreased Absent Cecocentral Excavated temporal 5–10 Either Slowly progressive
atrophy wedge of pallor (one line/decade)
Traumatic
Indirect optic nerve Unilateral Decreased Variable Altitudinal Normal Variable Either Stable deficit
injury
Mechanical
Papilledema Bilateral Preserved Absent Nasal defects; Swollen Variable Either May cause
constriction progressive visual
field loss
Primary open-angle Bilateral Preserved Absent Nasal defects; Cupping; intact Variable Either Progressive visual
glaucoma constriction neuroretinal rim field loss
to acute idiopathic inflammatory optic neuritis, whereas a nerve damage and even to loss of central vision over
similar presentation in a 60-year-old hypertensive woman days (Thambisetty et al., 2007).
will most likely be secondary to nonarteritic anterior
ischemic optic neuropathy (NAION) (Newman, 1996). Pathogenesis
Papilledema is secondary to axoplasmic flow stasis as
PAPILLEDEMA pressure from the intracranial compartment is trans-
Clinical presentation mitted to the optic nerves and to the back of the globes.
Papilledema is an emergency, since it represents a syn-
Papilledema refers to optic disc swelling from raised drome of increased intracranial pressure which may be
intracranial pressure. Other causes of disc swelling secondary to an intracranial mass lesion, hydrocephalus,
are called “disc edema” as opposed to “papilledema.” or venous sinus thrombosis. Subarachnoid blood, menin-
Papilledema is most often bilateral, but may be asym- gitis, or proteinaceous CSF can also block the arachnoid
metrical. Unlike other causes of optic neuropathy villi, causing increased intracranial pressure.
resulting in disc edema (such as anterior ischemic optic
neuropathies (AIONs) or anterior optic neuritis), cen- Idiopathic intracranial hypertension
tral visual acuity is initially normal in papilledema.
Patients can have the symptoms of raised intracranial Idiopathic intracranial hypertension (IIH) is sometimes
pressure, including headache, nausea, vomiting, and still called by the older names “benign intracranial
pulsatile tinnitus. Visual symptoms can include tran- hypertension” or “pseudotumor cerebri.” These older
sient binocular visual obscurations which last for a names should be abandoned, since it is a syndrome of
few seconds and which are often triggered by changes increased intracranial pressure that can cause intolera-
in posture, and binocular horizontal diplopia secondary ble symptoms and can result in blindness; therefore,
to cranial nerve VI dysfunction. The visual field is also the condition is not benign. The term “pseudotumor”
initially normal, but the physiological blind spot may erroneously suggests that the pathology is related in
increase in size, and progressive visual field constric- some way to mass effect. It is “idiopathic” in that
tion can develop. Central visual loss develops later in there is no known underlying cause. Symptoms of IIH
cases of chronic, untreated papilledema. are those of elevated intracranial pressure, namely
headache (90%), transient visual obscurations (70%),
pulsatile tinnitus (60%), and diplopia (40%) (Ball and
Ophthalmoscopic appearance
Clarke, 2006). Papilledema is the principal diagnostic
The findings of very early papilledema are blurring of sign. Diagnostic criteria require: (1) symptoms and signs
the peripapillary nerve fiber layer and disc hyperemia. that are only those of generalized intracranial hyper-
There is mild disc elevation with some obscuration tension or papilledema; (2) documented elevated intra-
of optic disc borders. At this stage there is no visual cranial pressure measured in the lateral decubitus
dysfunction. As the papilledema worsens, there is position ( 25 cm H2O); (3) normal CSF composition;
peripapillary obscuration of vessels and flame-shaped (4) no evidence of hydrocephalus, mass, structural, or
retinal nerve fiber layer hemorrhages may appear. vascular lesion on magnetic resonance imaging (MRI)
With further progression, the optic discs become or contrast-enhanced computed tomography (CT) for
larger, and thus so do the physiological blind spots. typical patients (young, obese women), and MRI and
Nonspecific minor defects may be present on visual MR venography for atypical patients (men, children,
field testing, but visual acuity and color vision remain thinner, older) (Bruce et al., 2009); and (5) no other iden-
normal. Marked papilledema is characterized by cup- tified cause of intracranial hypertension (Friedman and
less, elevated optic nerve heads with obscuration Jacobson, 2002). The MRI in patients with IIH may
of major blood vessels and engorgement of retinal reveal an asymptomatic empty sella from chronically
veins. Curvilinear choroidal folds may appear, and raised intracranial pressure in more than 50% of cases.
the number of retinal nerve fiber layer hemorrhages High-dose vitamin A derivatives, long-term tetracy-
increases. With chronic papilledema, elevated pale cline antibiotics, oral contraceptives, obstructive sleep
optic discs and constricted visual fields are seen. apnea, chronic renal disease, and some inflammatory
Eventually optic nerve fibers die, resulting in severely conditions are common causes of secondary intra-
constricted visual fields with secondary optic atrophy, cranial hypertension. A brain imaging study must be
although central visual acuity is usually still preserved performed to exclude a secondary cause of elevated
until very late in the course of the disease (Frisén, intracranial pressure. Nowadays, all patients should
1982) (Figs 6.3 and 6.4). In rare cases papilledema have MRI, and MR venography should also be consid-
can be a fulminant process progressing to severe optic ered to rule out venous obstruction.
Fig. 6.3. Papilledema: (A) mild; (B) moderate; (C) severe.
Treatment of papilledema sufficient. If there are intolerable symptoms, or if there

is severe or rapidly progressive visual loss, or if visual
The primary treatment of papilledema is treatment of
loss does not respond to more conservative measures,
any underlying cause of raised intracranial pressure.
then repeat lumbar puncture and surgical management
Treatment of patients with IIH, and indeed, of any
with CSF shunting procedures or optic nerve sheath
patient with elevated intracranial pressure and papill-
fenestration is recommended (Fig. 6.5) (Ball and
edema, requires close monitoring and good communi-
Clarke, 2006).
cation, since often patients are co-managed by a
neurologist, ophthalmologist, primary care physician,
INFLAMMATORY OPTIC
and neurosurgeon. Treatments are aimed at prevention
NERVE LESIONS
of visual loss and alleviation of persistent headache.
There are no clinical trials that provide evidence-based Optic neuropathies associated with pain are most often
treatment guidelines for IIH. The presence and degree inflammatory and are called “optic neuritis.” Anterior
of symptoms of raised intracranial pressure, and the optic neuritis is sometimes referred to as “papillitis”
degree and progression of visual loss determine man- (because it involves the papilla and produces disc
agement. If there is only mild visual loss, and tolerable edema). In almost all cases of optic neuritis a good-
symptoms, then diagnostic lumbar puncture, weight quality MRI of the orbits with contrast and fat suppres-
loss, and medical therapy with acetazolamide are likely sion demonstrates enhancement of the optic nerve.
Fig. 6.4. Visual fields in papilledema: (A) mild (Humphrey 24–2 Swedish interactive threshold algorithm (SITA) standard
visual fields showing enlarged blind spots, both eyes (OU)); (B) moderate (Humphrey 24–2 SITA standard visual fields showing
greater enlargement of blind spots with early constriction superiorly, left eye (OS)); (C) severe (Goldmann visual fields showing
constriction with small preserved islands of central vision, OU). OD, right eye.
Idiopathic intracranial hypertension
Evaluate the severity of IIH

Severity/tolerance of headache
Diplopia [with nerve palsy]
Visual function, visual acuity, visual field testing
Evaluate and correct the predisposing factors

Careful follow-up [visual acuity, normal visual fields]
No headache or diplopia Headaches, ± diplopia, ± tinnitus Visual loss

No visual loss No visual loss Visual field defects
Normal visual fields Normal visual fields
No treatment Medical treatment Mild Severe

Careful follow-up “Repeat Lumbar puncture
Acetazolamide” ± Repeat Lumbar puncture
± Surgical treatment (immediate decrease in ICP)
CSF shunting procedure
Surgical treatment
No or mild
Headaches and diplopia
headaches
CSF shunting procedure Optic nerve sheath

>> Optic nerve sheath fenestration >> CSF
fenestration shunting procedure
In all cases with overweight, weight loss is essential, bariatric surgery sometimes recommended in
morbid obesity
ICP: intracranial pressure
“ Although there is no clinical trial evaluating the treatment of idiopathic intracranial hypertension,
acetazolamide is commonly prescribed [between 1 and 2 grams a day] to decrease CSF production.
Fig. 6.5. Management of idiopathic intracranial hypertension (IIH) algorithm. CSF, cerebrospinal fluid; ICP, intracranial pres-
sure. (Reproduced from Biousse and Newman (2009), with permission.)
Many inflammatory and infectious disorders can cause with a pronounced decrease in color vision. Both the
an optic neuritis (Table 6.3). The most common cause pain and the visual loss can be either mild or severe.
of optic neuritis is “isolated optic neuritis,” also called If it is a clinically isolated syndrome there should be
“idiopathic” or “demyelinating” optic neuritis. no other systemic or neurological symptoms.
On examination there is always a RAPD (if it is
Idiopathic demyelinating optic neuritis unilateral or asymmetrical). In the acute phase, fundus
examination shows a normal optic nerve in retrobulbar
Idiopathic inflammatory demyelinating optic neuritis is
optic neuritis (two-thirds of cases) or a swollen optic
the most common cause of optic neuropathy in the
nerve in anterior optic neuritis (one-third of cases).
young. Most patients are women (3:1 female-to-male
The macula and retina are normal with no exudates or
ratio) between 25 and 45 years of age, but optic neuritis
hemorrhages. Optic disc pallor develops 4–6 weeks
can occur in children and in older patients as well. It is
after onset. Visual field abnormalities are variable,
one of the clinically isolated demyelinating syndromes
but most often a central scotoma is present. Depending
suggestive of multiple sclerosis (MS). Isolated acute
on the quality of imaging, 50–90% of patients with
optic neuritis is often the first sign of MS, and many
optic neuritis show enhancement of the optic nerve
patients with MS develop optic neuritis during the
on orbital MRI; however, this finding is nonspecific
course of their disease.
(Fig. 6.6A).
The natural history of optic neuritis has been clari-
CLINICAL FEATURES OF IDIOPATHIC OPTIC NEURITIS
fied by a number of recent studies (Atkins et al.,
Idiopathic optic neuritis is usually rapidly progressive 2006). Among these, the Optic Neuritis Treatment Trial
over a few days. It is typically unilateral but can be (ONTT) is the largest (Beck et al., 1992), but several
bilateral, especially in children. It is characterized by clinical trials involving immunomodulatory drugs have
pain with eye movements in more than 90% of cases, also contributed to our understanding of the natural
and by variably decreased central visual acuity, usually history of optic neuritis (CHAMPS Study Group, 2001;
Table 6.3 diminished intensity of light, and Uhthoff phenomenon
Causes of inflammatory optic nerve lesions (a transient exacerbation of vision loss with heat or
exercise) (Optic Neuritis Study Group, 2004).
Demyelination
Idiopathic optic neuritis TREATMENT OF IDIOPATHIC OPTIC NEURITIS
Multiple sclerosis
Neuromyelitis optica (Devic’s disease) Acute treatment options for acute idiopathic optic
Acute disseminated encephalomyelitis (ADEM) neuritis include intravenous methylprednisolone or
Optic neuritis following vaccination observation alone. In the ONTT, a 3-day course of
Infection (*most common infectious causes) high-dose (1 g/day) methylprednisolone followed by an
Bacterial: syphilis*, cat-scratch disease (Bartonella 11-day course of low-dose (1 mg/kg/day) prednisone
henselae)*, Lyme disease, any bacterial meningitis, sped up visual recovery by a few weeks to a month;
Mycoplasma pneumoniae, tuberculosis, Whipple disease
however, the treatment had no effect on the final visual
Viral: herpes zoster*, herpes simplex, human
outcome (Beck et al., 1993). In patients with an abnor-
immunodeficiency virus, Epstein–Barr virus, adenovirus,
Coxsackie virus, cytomegalovirus, West Nile virus, mal baseline MRI, treatment with intravenous steroids
hepatitis A and B virus, measles, mumps, rubella may delay the onset of MS within the first 2 years
Parasitic: toxoplasmosis*, cysticercosis, toxocariasis, following an episode of optic neuritis, but has no effect
intraocular nematode infection on the long-term risk of MS. In the ONTT, the probabil-
Fungal: cryptococcosis*, aspergillosis, mucormycosis, ity of recurrence of optic neuritis in either eye was 35%
candidiasis, histoplasmosis at 10 years. Treatment with low-dose oral cortico-
Inflammation steroids was associated with a doubling of the risk of
Isolated: orbital pseudotumor, idiopathic recurrent optic recurrent optic neuritis, a risk maintained even at
neuritis, “autoimmune optic neuritis” 10-year follow-up (Volpe, 2008). A report of the Qual-
Part of other inflammatory disorders: sarcoidosis, systemic
ity Standard Committee of the American Academy of
lupus erythematosus, Sjögren’s syndrome, polyarteritis
nodosa, Wegener’s granulomatosis, inflammatory bowel
Neurology supported the use of high-dose intravenous
disease, other vasculitides, bee and wasp stings, Behçet’s steroids in patients requiring more rapid visual recov-
disease ery, but did not recommend low-dose oral corticoster-
Paraneoplastic disease oids in conventional doses of 1 mg/kg per day for
Small cell lung cancer with CRMP-5 antibodies patients with acute isolated optic neuritis (Kaufman
et al., 2000).
Comi et al., 2001; Kappos et al., 2007). Spontaneous
PROGNOSIS FOR MULTIPLE SCLEROSIS AFTER
visual recovery begins within 3 weeks in approximately
IDIOPATHIC OPTIC NEURITIS
80% of patients and continues for up to 1 year. If at
least some improvement does not occur within 5 weeks, Several older studies had emphasized the risk of devel-
the diagnosis of idiopathic optic neuritis should be oping MS following an episode of isolated optic neuri-
questioned. In the ONTT, at 1-year follow-up almost tis (Atkins et al., 2006). Since the advent of MRI,
all patients had visual acuity in the affected eye of subsequent studies have shown that brain MRI is the
better than 20/40 and half of patients had visual acuity most powerful predictor of development of MS in
of at least 20/20. Nevertheless, a majority of patients patients with acute idiopathic optic neuritis (Atkins
continued to complain of permanent visual dysfunc- et al., 2006). The 15-year cumulative probability of
tion, including impaired contrast sensitivity, decreased developing MS after an episode of idiopathic optic
color vision, difficulty with motion perception, neuritis is 25% with no lesions on MRI, 65% with 1–2
Fig. 6.6. Magnetic resonance imaging in optic neuritis. (A) T1 postcontrast image with fat suppression showing left optic nerve
enhancement (arrow); (B) T2 fluid-attenuated inversion recovery image showing a single typical multiple sclerosis lesion in the
corpus callosum; (C) temporal pallor of the optic nerve 3 months after optic neuritis.
lesions on MRI, and 78% with 3 or more lesions on infection are most often present, prompting further
MRI (Optic Neuritis Study Group, 2008). For patients investigations, including MRI, CSF studies, and blood
with no brain lesions on MRI at onset, the risk of devel- tests, to help elucidate the underlying cause. Infection
oping future MS was greatest in the first 5 years, and with Bartonella henselae (cat-scratch disease), toxo-
if MS did not develop in the first 10 years the risk plasmosis, and others can cause an isolated infection
during the period between 10 and 15 years was only of the optic nerve, but there is usually both optic disc
2%. The presence of oligoclonal bands is an indepen- and retinal involvement (see section on neuroretinitis,
dent risk factor that increases almost by twofold the below). Monocular or bilateral optic neuritis can be
risk of having a second attack in all patients, regardless caused by syphilis which should systematically be
of MRI findings; however, this is clinically relevant considered, particularly when there is associated intra-
only for those patients with a normal baseline MRI ocular inflammation. Antibiotic therapy is associated
(Tintoré et al., 2008). with recovery, but relapse is common. Lyme disease
Several important studies with disease-modifying may rarely cause anterior optic neuritis with disc
therapies have defined the risk of developing MS fol- edema. Meningitis and encephalitis can be compli-
lowing a clinically isolated syndrome, and evaluated cated by optic neuritis either as a direct effect of the
the extent to which early intervention with disease- infectious organism or from a secondary vasculitis.
modifying therapies can decrease the risk of progres- For example, optic neuritis has been reported in asso-
sion to clinically definite MS (Coyle, 2008). Results of ciation with herpes virus infection, and in meningitis
the CHAMPS, ETOMS, and BENEFIT studies suggest from West Nile virus infection (Garg and Jampol,
that patients with optic neuritis and abnormal baseline 2005). Tuberculosis and cryptococcus are classical
MRI (“high-risk patients”) should be considered for causes of chronic meningitis, in which case optic nerve
interferon-beta therapy (CHAMPS Study Group, 2001; involvement may be the primary manifestation.
Comi et al., 2001; Kappos et al., 2007). The PRECISE Sarcoidosis affects the optic nerve in about 5% of
study suggested that glatiramer acetate could also be cases and can present with clinical features similar to
considered as an early treatment option (Coyle, 2008). those of isolated optic neuritis. The granulomatous infil-
The CHAMPIONS study even suggested that such tration of sarcoid sometimes produces a nodular appear-
treatment should be initiated early after the first occur- ance to the optic disc and intraocular inflammation is
rence of optic neuritis (CHAMPIONS Study Group, common. MRI with gadolinium enhancement usually
2006). shows areas of enhancement and nerve thickening that
At present, MRI continues to be the most impor- may be generalized, nodular, or meningeal, and there
tant paraclinical modality for assessing the risk of may be other T2 signal abnormalities elsewhere on
future MS and for monitoring disease progression MRI. Corticosteroid treatment often results in visual
in patients with acute demyelinating optic neuritis recovery, but relapsing vision loss following a short
(Fig. 6.6B, C). However, newer imaging strategies, course of corticosteroids suggests sarcoidosis.
including magnetization transfer MRI, diffusion tensor Optic neuritis is a rare manifestation of other
MRI, and OCT, are being used alone and in combination systemic inflammatory or connective tissue diseases
for earlier detection of clinical impairment, monitoring (see Table 6.3) and usually occurs in the setting of an
disease progression, predicting disability, and ascertain- established diagnosis. The mechanisms and presenta-
ing the effects of experimental neuroprotective therapies tions of optic nerve involvement vary with the disorder.
(Glisson and Galetta, 2009). OCT in particular can Optic nerve involvement occurs very rarely in patients
provide rapid, reproducible, high-resolution images of with systemic lupus erythematosus and visual loss
retinal anatomy, and is increasingly being used to model may be due to either vasculitis or ischemia secondary
the axonal and neuronal degeneration that is now recog- to antiphospholipid antibody syndrome. Optic neuritis
nized as part of the disease process that contributes to may also be a symptom of Sjögren’s syndrome, in the
permanent disability in MS (Frohman et al., 2008). setting of additional features of the sicca syndrome.
Inflammation in the sinus and parasinus areas can
extend to the optic nerve in Wegener’s granulomatosis,
Causes of optic neuritis other than
and other orbital signs are a clinical clue. Optic neuritis
primary demyelination
is also a complication of Behçet’s disease, which should
Although most cases of inflammatory optic neuritis are be considered in the right clinical setting along with
idiopathic or demyelinating in origin, other inflamma- other manifestations of Behçet’s. There is a higher than
tory and infectious conditions need to be considered expected incidence of optic neuritis in inflammatory
in the differential diagnosis (see Table 6.3). In these bowel disease, possibly reflecting coincidence of auto-
conditions other symptoms and signs of underlying immune diseases (Fadil et al., 2007).
BILATERAL OPTIC NEURITIS of NMO (Wingerchuk et al., 2006). Bilateral or recur-
rent optic neuritis and chronic relapsing inflammatory
Bilateral inflammatory optic neuritis may be due to
optic neuropathy are clinical phenotypes associated
demyelination, infectious causes, systemic connective
with NMO-IgG positivity, but which may not fulfill
tissue disease, and other local or systemic inflamma-
the diagnostic criteria for NMO. Visual loss in patients
tory conditions (see Table 6.3). Postviral optic neuritis
with NMO is the result of a failure to recover from
is often bilateral, and has been associated with measles,
the initial attack or subsequent relapses. Preventing
mumps, chickenpox, influenza, and Epstein–Barr virus.
relapses is therefore an important goal, and patients
Postviral optic neuritis typically follows the clinical
with NMO-IgG seropositivity at the initial presentation
infection by 1–3 weeks. It also can occur as a postvacci-
are at high risk for developing future episodes of recur-
nation phenomenon. It is more common in children
rent optic neuritis (Fig. 6.7).
than adults and an immune-mediated process is likely.
Unfortunately, there is currently no evidence from
Visual recovery is usually excellent, even with no treat-
clinical trials to guide treatment or to prevent relapses in
ment. Corticosteroids may or may not hasten recovery,
NMO. Treatment is different from that for MS, and
but this treatment is reasonable to consider, particularly
interferon-beta therapy does not have a role in treating
in cases of bilateral severe visual loss. Some consider
NMO. Acute, severe attacks in patients with NMO may
this a forme fruste of acute disseminated encephalitis.
require plasma exchange to hasten recovery. Some advo-
Paraneoplastic optic neuritis has been described, usu-
cate therapy with corticosteroids followed by mainte-
ally in association with paraneoplastic encephalo-
nance therapy with long-term immunosuppressive
myelitis or retinitis and small cell lung cancer, and
therapy (Giovannoni, 2008).
the presence of the CRMP-5 antibody (Bataller and
Dalmau, 2004).
NEURORETINITIS
On occasion there can be signs of both optic nerve and
NEUROMYELITIS OPTICA
retinal involvement in a variant of optic neuritis known
Neuromyelitis optica (NMO) is a rare but important as “neuroretinitis.” Although initially the appearance of
cause of bilateral or recurrent optic neuritis which the optic nerve is suggestive of an anterior optic neuri-
is clinically and pathologically distinct from MS (see tis with disc edema, after about 1–3 weeks a macular
Table 6.3). In NMO, there is antibody-mediated loss star develops which may persist after the disc swelling
of the aquaporin-4 water channel protein on astrocytes, resolves (Fig. 6.8). The presence of a macular star is
which may cause secondary demyelination in the cen- characteristic of neuroretinitis, and these patients are
tral nervous system, including the optic nerves. Patients not at risk for MS. Neuroretinitis is most commonly
presenting with recurrent or bilateral optic neuritis, or caused by cat-scratch disease, an infection with Barto-
who have poor recovery from unilateral isolated optic nella henselae, but has been associated with other
neuritis, should be tested for NMO-IgG. NMO-IgG infectious causes (see Table 6.3). This disorder is usually
positivity is included in the revised diagnostic criteria self-limited, but it can be treated with an antibiotic
Fig. 6.7. T1 postcontrast magnetic resonance image showing an enhancing lesion of the spine extending for more than
five consecutive spinal levels (arrows), and optic atrophy 5 months after optic nerve demyelination in neuromyelitis optica
(Devic’s disease).
ISCHEMIC OPTIC NERVE LESIONS
Anterior ischemic optic neuropathy
AION results from ischemic damage to the anterior
portion of the optic nerve, which is primarily supplied
by the posterior ciliary artery circulation. Since the ante-
rior portion of the optic nerve is visible as the optic disc,
AION always presents with optic disc edema acutely.
AION is generally divided into two types: arteritic AION
(or AAION), resulting from ischemia secondary to vas-
culitis (usually giant cell arteritis (GCA)) (Melson et al.,
2007), and NAION, resulting from ischemia secondary
to noninflammatory small-vessel disease (Luneau et al.,
2008) (Table 6.4).
ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY
Although many different systemic diseases have been

associated with AION, the crucial initial diagnostic
Fig. 6.8. Macular star in neuroretinitis. step is differentiating AAION caused by GCA from
NAION. GCA is the most common primary vasculitis
with good CSF and intraocular penetration such as in adults, affecting individuals over the age of 50 and
doxycycline or ciprofloxacin according to an infec- causing rapid, irreversible vision loss in up to 14–20%
tious disease specialist’s recommendations. Sarcoido- of cases. AAION is the most common ophthalmic man-
sis, syphilis, toxoplasmosis, tuberculosis, or Lyme ifestation of GCA. In the patient with AION, suspicion
disease may also cause neuroretinitis, and vitreous for GCA is raised by older age, and the presence of
cells and retinal infiltrates are sometimes present on systemic symptoms such as headache, scalp tenderness,
examination. A recurrent idiopathic form of neurore- jaw claudication, muscle ache, fatigue, and weight
tinitis has been described (Purvin and Chioran, 1994). loss. Premonitory visual symptoms include transient
monocular visual loss or diplopia, but eye pain is not
ORBITAL INFLAMMATORY SYNDROME always present. On examination, chalky-white optic
disc swelling, bilateral involvement, and concurrent
Orbital inflammatory syndrome (also called orbital
signs of retinal or choroidal circulation ischemia, such
inflammatory pseudotumor) presents with painful
as cotton-wool spots or retinal infarction, are sugges-
visual loss, proptosis, and ophthalmoplegia related to
tive of an arteritic etiology (Fig. 6.9). An elevated eryth-
inflammation of the orbital contents. The clinical man-
rocyte sedimentation rate, C-reactive protein, platelet
ifestations vary based on the orbital structure involved:
count, and fibrinogen level are ancillary tests sugges-
inflammation of the optic nerve sheath results in
tive of GCA. Delayed or absent filling of the choroidal
perineuritis (often in association with optic neuritis),
circulation on fluorescein angiography also supports
inflammation of the posterior sclera results in posterior
the diagnosis (Melson et al., 2007).
scleritis, inflammation of the extraocular muscles pro-
The natural history of AAION in the patient with
duces myositis, inflammation of the orbital fat induces
GCA is progressive severe visual loss and involvement
proptosis, and inflammation of the lacrimal gland
of the second eye within days or weeks. Visual loss
produces dacryoadenitis. More than one orbital struc-
ture is usually involved, explaining the various clinical
manifestations of this syndrome. CT or MRI shows Table 6.4
thickening and enhancement of orbital tissues. Systemic Ischemic optic nerve lesions
steroid therapy usually results in rapid improvement in
symptoms, and repeat MRI shows resolution of the Anterior (AION)
mass lesion and extraocular muscle enlargement (Bhatti, Arteritic (AAION)
Nonarteritic (NAION)
2007). Steroid dependence or steroid resistance should
Posterior (PION)
prompt an orbital biopsy because many specific inflam- Arteritic
mations (such as Wegener’s granulomatosis) and neo- Nonarteritic
plasms (mostly lymphoma and metastases) can mimic Radiation optic neuropathy
idiopathic orbital inflammation (see Table 6.3).
can be affected. Fundoscopy reveals disc edema
acutely, often with peripapillary flame-shaped retinal
hemorrhages. By 4–6 weeks the optic disc edema
resolves and diffuse or segmental pallor with secondary
atrophy develops. The appearance of the optic disc in the
contralateral eye is almost always one of a “disc at risk,”
meaning that there is a small-diameter crowded optic
disc with a small or absent physiological cup (Fig. 6.10)
(Luneau et al., 2008).
Pathogenesis of NAION
Small-vessel circulatory insufficiency of the optic nerve
head is the most widely accepted pathophysiology of
NAION, but the location of the associated vasculopathy
and mechanism of ischemia remain uncertain. Patients
with a small cup-to-disc ratio (disc at risk) are predis-
posed to NAION. In normal eyes there is ample room
Fig. 6.9. Fundus appearance in anterior ischemic optic neu- for the optic nerve to exit the eye; however, in patients
ropathy from giant cell arteritis with chalky-white optic disc with structurally small scleral openings there is no
swelling. margin of safety to accommodate swelling. If swelling
occurs for any reason within the confines of a crowded
from GCA requires emergency intervention to prevent small optic disc, it may contribute to a compartment
irreversible severe visual loss. High doses of steroids syndrome, in which mild swelling induces a vicious
must be instituted immediately. There is anecdotal cycle of disc edema and peripapillary hemorrhages
evidence to suggest that early use of high-dose intrave- (Hayreh and Zimmerman, 2007). Optic nerve head
nous steroids may allow for some improvement in the ischemia/hypoxia may then cause secondary axoplasmic
involved eye in addition to better protection for the flow stasis within the optic nerve. Caucasians are sig-
fellow eye. Temporal artery biopsy must be obtained nificantly more predisposed to develop the disease than
to confirm the diagnosis, but it should not delay the Black or Hispanic people, and this is most likely
initiation of steroids. Biopsies are likely to remain posi- because Caucasians tend to have smaller cup-to-disc
tive even after 14 days of steroid therapy (Melson et al., ratios with more crowding of optic nerve head axons.
2007; Fraser et al., 2008). Other optic nerve anomalies causing crowding, such
as optic disc drusen and papilledema, are also asso-
NONARTERITIC ANTERIOR ISCHEMIC OPTIC ciated with NAION (Atkins et al., 2010).
NEUROPATHY
Vasculopathic risk factors
NAION is an acute optic neuropathy presumably result-
ing from small-vessel infarction of the anterior optic Diabetes, hypertension, and hypercholesterolemia are
nerve. NAION represents 95% of all AION, and is the well-known risk factors for ischemic small-vessel
most common cause of acute optic neuropathy in peo- disease. Arteriosclerosis or lipohyalinosis is often sus-
ple over the age of 50, affecting somewhere between pected in the pathogenesis of NAION, but no histo-
2 and 10 individuals per 100 000 (approximately 1500– pathological confirmation is available to date. In the
6000 new cases per year in the USA). The mean age Ischemic Optic Neuropathy Decompression Trial, 60%
of onset is in the range of 57–67 years, but it can occur of NAION patients had at least one vasculopathic risk
at any age (Preechawat et al., 2007). Symptoms include factor, 47% had hypertension, and 24% had diabetes
acute, unilateral, usually painless visual loss that can (Ischemic Optic Neuropathy Decompression Trial
evolve over several hours to several days. Visual acuity Research Group, 1995). Another study also showed that
varies from 20/20 to no light perception, but remains hypertension was present in up to 49% and diabetes in
better than 20/200 in about two-thirds of patients. up to 26% of patients with NAION (Hayreh et al.,
Because it is an optic neuropathy, a RAPD is invariably 1994). Association with other vascular risk factors has
present in unilateral forms. An arcuate or altitudinal been inconsistent. Tobacco smoking does not appear
defect, particularly in the inferior region of the visual to be an independent risk factor (Hayreh et al., 2007).
field, is most common; however, as is often the case NAION has not been associated with ipsilateral carotid
with optic neuropathies, any region of the visual field artery stenosis, and embolic AION is extremely rare
Fig. 6.10. Nonarteritic anterior ischemic optic neuropathy. (A) Disc at risk with small cup-to-disc ratio compared to normal and
large cup-to-disc ratio. (Reproduced from Biousse and Newman (2009), with permission.) (B) Superior disc edema;
(C) superior segmental atrophy; (D) inferior arcuate/altitudinal visual field defect.
(Fry et al., 1993). Sleep apnea, generalized hypoper- The visual acuity does not appear to worsen once the
fusion, vasospasm, microembolization from a remote disc edema has resolved (Hayreh and Zimmerman,
source, failure of autoregulation, severe anemia, and 2007). Compared with GCA patients with AION,
nocturnal hypotension are all included among the patients with NAION may have relatively good pre-
potential, but unproven, contributory pathogenetic fac- served visual acuity, with up to 56% of patients retain-
tors for NAION. Some drugs have been associated with ing acuity of 20/60 or better. Recurrence of NAION
the development of NAION, including amiodarone in the affected eye is rare, and occurs in less than 5%
(Murphy and Murphy, 2005) and erectile dysfunction of cases (Newman et al., 2002). A likely pathological
agents (Lee and Newman, 2005), but no definite causal explanation for the low rate of recurrence is that the
relationship has been established. atrophy of the optic nerve that follows NAION relieves
crowding of the nerve.
In the Ischemic Optic Neuropathy Decompression
Clinical course
Trial, approximately 15% of patients developed NAION
In most cases of NAION, vision worsens progressively in the fellow eye within 5 years (Newman et al., 2002).
over 2 weeks, and then remains stable over time. Presumably the other eye is exposed to the same risk
factors for small-vessel disease, and also has the same (2) have hypotensive episodes (such as those on chronic
structural vulnerability inherent in small cup-to-disc hemodialysis). High-grade carotid stenosis may be an
ratios. In the Ischemic Optic Neuropathy Decompres- additional predisposing risk factor. The visual loss is
sion Trial, risk of fellow eye involvement was related usually severe, anterior or posterior (i.e., with or without
to poor baseline visual acuity in the first eye and to disc edema), and onset may be acute or subacute.
diabetes, but not to age, gender, smoking history, or Endogenous vasoconstrictors released during acute
aspirin use (Newman et al., 2002). In younger patients, hypotensive episodes may play a role (Hayreh, 2004).
the risk of fellow eye involvement seems to be higher Spine surgery with maintenance of the prone position
than in older patients, with 35% involvement of the for several hours is a reported cause of bilateral PION,
second eye within 7 months (Preechawat et al., 2007). as is coronary artery bypass surgery (Newman, 2008).
There is no definite evidence that NAION is associated
with an increased risk of subsequent myocardial or Radiation optic neuropathy
cerebral infarction, but no sufficiently large studies
In 10–15% of cases where the optic nerve has been
have been done. Given that 60% of NAION patients
exposed to 50 Gy of radiation or more, a radiation-
have at least one vascular risk factor, the risk of other
induced optic neuropathy can occur. The threshold for
systemic vascular events should still be considered
radiation-induced optic neuropathy is lower in diabetics
and vascular risk factors should be managed according
and in patients receiving chemotherapy. Transient acute
to evidence-based guidelines. There is no proven treat-
swelling of the optic nerve can occur during the
ment for NAION, and even antiplatelet agents for the
radiation therapy, and this acute form is responsive to
secondary prophylaxis of fellow eye involvement remain
steroids. However, most cases of radiation-induced
controversial (Atkins et al., 2010).
optic neuropathy are delayed, occurring 1–8 years later.
The discs may initially appear normal at the time
Posterior ischemic optic neuropathy
of onset of visual loss, but eventually become pale.
The posterior optic nerve can be selectively affected by Enhancement of the optic nerves on MRI is characteris-
ischemia, since it has a distinct blood supply separate tic (Fig. 6.11). For the delayed-onset type of radiation-
from that of the anterior portion of the optic nerve. The induced optic neuropathy there is no proven effective
syndrome of posterior ischemic optic neuropathy (PION) treatment. Corticosteroids, anticoagulants, and hyper-
includes acute visual loss and, if unilateral, a RAPD. baric oxygen are advocated by some, but results are
PION is often bilateral. There is no associated disc not convincing (Danesh-Meyer, 2008).
edema, but optic atrophy eventually develops. PION
generally occurs in either the perioperative setting
or in the setting of GCA or other vasculitides, and
laboratory investigations for GCA must be obtained
(Newman, 2008). Orbital imaging is indicated, since
the differential diagnosis includes compressive and
infiltrative optic neuropathies; however, the onset of
visual loss is more abrupt in PION, and there should
be no associated ophthalmoplegia. Nonarteritic PION
can rarely occur in patients who share the common
vascular risk factors seen in NAION (Sadda et al.,
2001), but the disc at risk is not a factor. Nonarteri-
tic PION should not be mistaken for retrobulbar
optic neuritis, since PION occurs in older age groups
and there is no pain with eye movements and no
enhancement of the optic nerve on imaging.
Ischemic optic neuropathy in the setting

of hemodynamic compromise
Ischemic lesions of the optic nerve can be due to sys-
temic hypotension, anemia, blood loss, or a combina- Fig. 6.11. T1 postcontrast magnetic resonance image with fat
tion of these. The usual clinical setting is in anemic suppression showing optic nerve enhancement in radiation-
patients who have discs at risk and who: (1) experience induced optic neuropathy extending from the prechiasmal
hemorrhage either from surgical procedures, or from segment (arrow) to the posterior intraorbital segment
spontaneous gastrointestinal or uterine bleeding, or (arrowhead).
COMPRESSIVE AND INFILTRATIVE or infiltrative optic neuropathy include meningiomas,
OPTIC NERVE LESIONS optic gliomas, hemangiomas, lymphangiomas, dermoid
cysts, other malignancies (e.g., metastatic carcinomas,
Compressive lesions of the optic nerve can be unilateral
lymphoma, sarcoma, multiple myeloma), and arachnoid
or bilateral, anterior or posterior, neoplastic or inflam-
cysts of the optic nerve sheath. Inflammatory compres-
matory, infiltrating or noninfiltrating, and with or with-
sive and infiltrative lesions of the orbit include thyroid
out disc edema (Table 6.5). The earliest abnormalities
ophthalmopathy, orbital abscess, sarcoidosis, and idio-
on examination include an ipsilateral RAPD and
pathic orbital inflammatory syndrome. Mechanical
decreased color vision. These findings may be present
lesions such as an orbital vascular malformation can also
even when visual acuity is only minimally reduced and
compress the optic nerve (Table 6.5).
they provide objective evidence that the visual com-
Compressive and infiltrative optic neuropathies may
plaints are not related to an ocular cause. The optic disc
present with progressive visual loss, proptosis, signs
may be normal, swollen, or pale as for other causes of
of orbital congestion, and limitation of ocular motility.
optic neuropathy. When there is bilateral compression
In some cases, however, unilateral disc edema can
(such as from an intracranial mass), the optic disc pal-
be present with normal visual acuity and no signs of
lor may be difficult to recognize initially. Any type of
orbital disease. This more subtle presentation is particu-
visual field defect may be present; however, temporal
larly common in patients with optic nerve sheath menin-
hemianopic defects, a central scotoma that extends into
giomas and orbital hemangiomas. Transient monocular
the periphery temporally, or a junctional scotoma are
visual loss in only certain positions of gaze (gaze-
strongly suggestive of a compressive lesion. CT is still
evoked transient visual loss) can also occur with orbital
useful for bony orbital or paranasal sinus processes,
lesions.
but MRI with contrast and dedicated orbital views with
fat suppression is required whenever there is suspicion
THYROID EYE DISEASE
of an intracranial compressive or infiltrative lesion.
Thyroid eye disease can rarely cause compression of
Orbital compressive and infiltrative the optic nerve, and may be associated with disc
optic neuropathies swelling. Visual loss is usually bilateral, symmetrical,
gradual, and preceded by signs of orbital congestion.
Orbital compressive and infiltrative optic neuropathies
Symptoms of vision loss and diplopia from restricted
can be due to neoplastic or inflammatory causes. They
ocular motility are often more pronounced in the morn-
can be difficult to classify, since with some types of
ing, since more orbital congestion is present after a
pathology (such as sclerosing orbital pseudotumor) there
night’s sleep. The extraocular muscles become enlarged
is actually a mass effect within the orbit, with a compres-
and the fat is inflamed, resulting in compression of the
sive/infiltrative process contributing to the optic nerve
optic nerve, usually at the orbital apex. Visual fields
dysfunction, even though the underlying disease process
may show central scotomas combined with arcuate
is inflammatory. If disc edema is present, it usually
defects. Treatment options include steroids, orbital
indicates that the compressive or infiltrative lesion is
decompression surgery, and radiation therapy.
located within the orbit. Causes of orbital compressive
OPTIC NERVE SHEATH MENINGIOMA
Table 6.5
Primary optic nerve sheath meningiomas surround the
Causes of compressive/infiltrative optic neuropathy optic nerve, and often cause disc swelling by impairing
Compressive axonal transport and interfering with pial blood supply
Neoplastic: meningioma (optic nerve sheath, sphenoid wing), to the optic nerve. Affected patients are usually middle-
pituitary tumor, intraorbital tumor (hemangioma, aged women. Patients present with unilateral, slowly
lymphangioma, metastasis), craniopharyngioma progressive, painless visual loss, and may have mild
Non-neoplastic: ophthalmic artery aneurysm, pituitary proptosis, diplopia, transient visual obscurations, or gaze-
apoplexy, dolichoectatic internal carotid artery, thyroid evoked amaurosis. On examination there is decreased
eye disease, mucocele, orbital pseudotumor, orbital color vision, a RAPD, visual field defects of any type,
hemorrhage, Paget’s disease, fibrous dysplasia
and optic disc edema that eventually evolves into optic
Infiltrative
atrophy. Because the central retinal vein is chronically
Neoplastic: optic nerve glioma (pilocytic astrocytoma),
metastatic carcinoma, sinonasal tumors, lymphoma, compressed, optociliary shunt veins can occasionally
leukemia, meningeal carcinomatosis, germinoma be seen on fundoscopy (Fig. 6.12). CT or MRI shows
Non-neoplastic: sarcoidosis either focal or diffuse optic nerve enlargement. An
important distinguishing feature on CT or MRI is the
pathway gliomas occur in the setting of neurofibroma-
tosis type 1. The clinical presentation is determined by
the size, location, and extent of the tumor, but 90%
of the lesions are symptomatic by the second decade.
Children often present with a sensory strabismus (i.e.,
the poorly seeing eye will turn in or turn out) or with
proptosis. The diagnosis should be suspected in any
young child who presents with decreased visual acuity
and evidence of an optic neuropathy with either disc
swelling or pallor. Orbital MRI is the diagnostic test
of choice, and there is usually mild enhancement with
“kinking” and enlargement of the optic nerve with
increased T2 signal surrounding the nerve (Fig. 6.14).
Optic gliomas are true neoplasms of the benign juvenile
pilocytic astrocytoma type in most cases. Treatment is
controversial, and in many cases visual symptoms
remain stable for years with no treatment.
Fig. 6.12. Optociliary shunt vessels (arrow) and optic nerve
pallor. Intracranial compressive and infiltrative
optic neuropathies
fact that it is the optic nerve sheath around the nerve Meningiomas, pituitary tumors, pituitary apoplexy,
that is abnormal, not the optic nerve itself. This results aneurysms, and chiasmal gliomas are the most common
in the so-called tram track sign which refers to two parasellar lesions that may cause intracranial optic nerve
bright or dense linear streaks seen parallel to the optic and chiasmal compression or infiltration. Other less
nerve from calcification of the meningioma on CT, common compressive and infiltrative lesions affecting
and enhancement of the sheath with a normal intra- the intracranial optic nerves include local (usually para-
dural optic nerve on MRI (Fig. 6.13). Because the clin- nasal sinuses and skull base) and metastatic carcinomas,
ical course can be so indolent, observation alone is lymphoma, and leukemia (see Table 6.5). The frequency
suggested in patients with good visual function. In of primary and secondary orbital tumors varies between
patients with progressive visual loss, radiation therapy children and adults (Table 6.6).
is the treatment of choice. Biopsy is not performed Posterior compressive lesions located in the poste-
because of the risk of visual loss. Surgical debulking rior orbit, in the optic canal, or intracranially along
is only performed when there is severe visual loss, the prechiasmal segment of the optic nerve do not
major proptosis, or intracranial extension.
OPTIC NERVE GLIOMA
Optic nerve gliomas represent 65% of all intrinsic optic

nerve tumors. Approximately one-third of all optic
Fig. 6.13. T1 postcontrast magnetic resonance image with fat

suppression showing a right optic nerve sheath meningioma Fig. 6.14. T1 postcontrast magnetic resonance image of an
with enhancement of the optic nerve sheath (arrowhead), optic nerve glioma showing enlarged left optic nerve which
but with no enhancement of the optic nerve itself. is mildly enhancing.
Table 6.6 insidious unilateral dimming or blurring of vision; on
Orbital tumors in children and adults examination they will have a RAPD and decreased
color vision. Enlargement of the cup in the affected
Children eye is common in compressive optic neuropathies, but,
Primary: dermoid, epidermoid, capillary hemangioma, unlike glaucoma, these patients have a pale optic nerve
lymphangioma, optic nerve glioma, rhabdomyosarcoma, and they complain of decreased visual acuity with
Langerhans cell histiocytosis, granulocytic sarcoma
decreased color vision. In all cases where patients com-
(chloroma)
plain of progressive dimming of vision and a RAPD
Secondary: retinoblastoma, neuroblastoma, leukemia (acute
lymphogenous leukemia), Burkitt’s lymphoma, Ewing’s is present, even if the fundus appears normal, neuroim-
sarcoma aging must be obtained. In addition to regular clinical
Adults and visual field examination, OCT can be useful for
Primary: meningioma, fibrous histiocytoma, cavernous the follow-up of these patients (Danesh-Meyer et al.,
hemangioma, neurofibroma, schwannoma, optic nerve 2008).
glioma (pilocytic astrocytoma), metastatic carcinoma, Any type of visual field defect may be present, but
sinonasal tumors, lymphoma, leukemia, meningeal lesions that affect the anterior angle of the chiasm and
carcinomatosis, germinoma the prechiasmal segment of the optic nerve may produce
Secondary: metastases (breast, lung, melanoma, squamous a distinct visual field defect consisting of a central
cell carcinoma), lacrimal gland tumors, lymphoid tumors
defect and decreased visual acuity in the ipsilateral
eye, and a superotemporal defect with preserved visual
acuity in the contralateral eye (junctional scotoma)
produce disc swelling; therefore they may easily be (Fig. 6.15).
missed if a careful examination along with visual field Occasionally, posterior optic neuropathies due to
testing and neuroimaging is not obtained. Patients may pituitary apoplexy, aneurysms, mucoceles, and fibrous
have well-preserved visual acuity, but still complain of dysplasia may have a rapidly progressive course which
Fig. 6.15. Goldmann visual fields in a prechiasmal junctional compressive lesion from a pituitary tumor, with a central scotoma
on the side of the lesion (OS: left eye) and a contralateral superior defect (OD: right eye).
can be confused with retrobulbar optic neuritis or PION. RAPD is not typically present. The differential diag-
Neuroimaging should be obtained in all such cases and nosis also includes hereditary optic neuropathies and
treatment is specific to the disease process. There gener- bilateral compressive or infiltrative lesions of the
ally is a role for surgical decompression or reduction optic nerve, and in all cases neuroimaging should be
of the size of the mass lesion through medical or radia- obtained. Some suspected toxicities or deficiencies
tion therapy. Visual recovery following decompression may be confirmed through serum and urine analysis,
depends on how long symptoms have been present, on and serum B12 levels should always be obtained. Visual
the degree of optic atrophy, and on the severity of the loss may be reversible if the offending toxin is
visual loss before treatment. Recent studies have sug- removed, or if the deficient vitamin is replenished.
gested a role for measuring retinal nerve fiber thickness Even when there is severe loss of the nerve fiber layer
with OCT in predicting visual recovery in patients with and marked temporal optic disc pallor, visual recovery
compressive optic neuropathies from pituitary tumors may be dramatic. With certain toxins (most notably
(Danesh-Meyer et al., 2008). ethambutol), visual recovery may be delayed for
6–12 months after discontinuation of the medication.
TOXIC AND NUTRITIONAL DEFICIENCY
OPTIC NERVE LESIONS Specific nutritional causes
Toxic and nutritional optic neuropathies are relatively The most common cause of vitamin B12 deficiency is
uncommon in the USA, but in the past this form of optic pernicious anemia. Gastric surgery and infection with
neuropathy was far more common, and physicians have Diphylobothrum latum (fish tapeworm) can also inter-
recognized visual loss from toxic and nutritional causes fere with absorption, but dietary B12 deficiency is only
for centuries. In most cases the pathogenesis remains found in strict vegans. Optic nerve lesions have been
unknown. The cause is complex and multifactorial, but identified in patients with vitamin B12 deficiency on post-
there is likely a shared metabolic mechanism of optic mortem examination. In primate models, optic nerve
nerve injury. Other unknown factors must influence lesions precede both the anemia and the spinal cord
expression, since not all patients treated with known lesions. Therefore it is not surprising that, in humans,
toxic agents or with long-standing nutritional deficien- optic neuropathy may be the presenting symptom.
cies will suffer optic nerve damage. A thorough history If the serum B12 level is normal, and the clinical suspi-
is the most effective means of establishing exposure to cion remains high, additional testing of homocysteine
toxins or identifying possible nutritional deficiencies, and methylmalonic acid levels should be performed,
and toxic and nutritional optic neuropathies generally since these are more sensitive markers of deficiency,
share a similar clinical profile (Table 6.7). and will be elevated if there is dysfunction in the
The clinical presentation includes slowly progres- metabolic pathway of vitamin B12. Visual loss may be
sive, bilateral, painless, symmetrical central visual reversible with intramuscular injections of vitamin B12
loss, reduced perception of color, central or cecocen- if administered prior to the onset of optic atrophy.
tral scotomas on visual field testing with sparing of Although there is no proof that thiamine, folate, pyri-
the peripheral visual field, and optic disc pallor which doxine, riboflavin, or niacin deficiencies cause optic
corresponds to loss of nerve fibers in the papilloma- neuropathy, in patients who are generally malnourished
cular bundle. Since the process is usually bilateral, a and who have visual loss it seems reasonable to replace
all vitamins in which they may be deficient.
Table 6.7 Specific toxic causes

Nutritional/toxic optic neuropathies In the past, many authors have included extensive lists
of agents thought to be toxic to the optic nerve, but there
Nutritional
are very few agents with proven optic nerve toxicity.
B12 deficiency
Toxic
Methanol METHANOL
Ethylene glycol Methanol toxicity causes life-threatening systemic
Ethambutol
symptoms and severe irreversible visual loss; therefore
Amiodarone
it is not typical of the classical clinical picture of toxic
Linezolid
Combined nutritional/toxic optic neuropathy. Postmortem examinations have
Tobacco–alcohol amblyopia (cigars) shown that early demyelinating retrobulbar optic nerve
lesions progress to necrotic lesions. Metabolic acidosis
can be severe, but is not the cause of the optic neuro- experience visual symptoms, the medication should be
pathy. The lack of a pupillary light response indicates discontinued, and should only be prescribed to those
a poor prognosis for visual recovery. Treatment of eth- who are capable of promptly reporting a change in
anol poisoning is emergency, since there is a chance of visual function.
life- and vision-saving reversal of symptoms with the
administration of ethanol, which interferes with the AMIODARONE
metabolism of methanol.
Amiodarone is a cardiac antiarrhythmic medication that
may produce an optic neuropathy characterized by
ETHYLENE GLYCOL
insidious, bilateral, slowly progressive visual loss with
Ethylene glycol is the active ingredient in antifreeze, prolonged disc swelling (Fig. 6.16). Amiodarone’s asso-
and toxicity resembles methanol toxicity. There is a ciation with optic neuropathy remains somewhat con-
higher incidence of mortality in ethylene glycol poison- troversial (Murphy and Murphy, 2005). Some cases
ing than in methanol poisoning, and a lower frequency appear indistinguishable from NAION. Other cases
of visual loss, but when it does occur it can be equally have a more insidious bilateral onset with slow progres-
severe. sion to eventual severe visual loss suggestive of a direct
toxic effect. After discontinuation of the medication,
ETHAMBUTOL the disc swelling resolves, and visual acuity and visual
fields stabilize, but usually over a prolonged period of
Ethambutol toxic neuropathy has been well described in
months. In patients who have visual loss while taking
humans, and good animal models exist. The biological
amiodarone, consideration should be given to the
basis for the toxicity is not completely understood,
benefit of discontinuation versus the risk of continuing
but is presumably related to its mechanism of action
the drug based on their cardiac status.
as a chelating agent of copper and zinc, which could
adversely affect human mitochondrial enzymes. The
LINEZOLID
toxicity of ethambutol is dose- and duration-dependent,
with vision loss occurring in patients who have been on Linezolid is an antimicrobial effective against Gram-
the drug for at least 2 months, with 7 months of expo- positive bacteria. Several cases of linezolid-associated
sure being the average. Renal dysfunction, diabetes optic neuropathy have been reported, usually in asso-
mellitus, liver damage, poor nutrition, and tobacco or ciation with a peripheral neuropathy. Linezolid optic
alcohol use may be additional risk factors. Clinically, neuropathy usually presents with bilateral disc edema,
there is insidious progression of bilateral symmetrical typically after more than 5 months of prolonged treat-
central visual loss along with initially normal-appearing ment. Like other metabolic optic neuropathies, the visual
optic nerves. Visual field testing usually shows bilateral loss is bilateral with central scotomas. Disc edema
central scotomas, often with a bitemporal predomi- resolves and vision usually improves after discontinua-
nance. Once ethambutol is discontinued, slow improve- tion of the drug. The mechanism of toxicity to the optic
ment over several months may occur in up to half of nerve may be impairment of mitochondrial protein
patients. As soon as patients on ethambutol begin to synthesis (Rucker et al., 2006).
Fig. 6.16. Amiodarone toxic optic neuropathy with bilateral disc edema. OD, right eye; OS, left eye.
Combined nutritional–toxic optic or pedigrees. Many molecularly confirmed patients
nerve lesions are outside the common age range, do not exhibit the
classical fundus findings, and do not know of any
Combined nutritional–toxic deficiencies are presumed
family members with visual loss (Newman, 1996).
to have played a role in endemic optic neuropathy
Therefore, the diagnosis of hereditary optic neuropa-
reported under conditions of deprivation (e.g., Cuba
thy should be considered in any patient with unex-
in the 1990s, and Southeast Asia during World War II)
plained, sequential or bilateral, painless, central
(Newman, 1996). Most nutritional optic neuropathies
visual loss, regardless of age, tempo, gender, family
appear to be exacerbated by tobacco use. Tobacco–
history, or fundus appearance.
alcohol amblyopia is an often invoked but poorly
understood disease. It historically has been attributed
Monosymptomatic hereditary
to the toxic effects of tobacco smoking alone, to the
optic neuropathies
combined effects of tobacco and alcohol, to nutritional
deficiency, and to combined toxic and nutritional LEBER’S HEREDITARY OPTIC NEUROPATHY
influences. More recent work has suggested that the
Leber’s hereditary optic neuropathy (LHON) is a mater-
tobacco–alcohol amblyopia syndrome may in fact
nally inherited optic neuropathy that occurs predomi-
simply reflect a nutritional optic neuropathy. Convinc-
nantly in otherwise healthy young adults, although it can
ing cases of pure tobacco amblyopia are still encoun-
occur at any age. Both men and women can be affected,
tered, particularly in middle-aged and elderly men
but men are affected about eight times more frequently
who smoke pipes and cigars; however, the history of
than women. Painless visual loss occurs in one eye, and
epidemic optic neuropathies suggests combined influ-
in most cases is followed by painless visual loss in the
ences of nutritional deficiencies and toxic effects
other eye within 1 month. Visual loss can also be bilateral
of tobacco (Newman, 1996). Early vitamin supplemen-
and simultaneous in up to half of cases. Visual acuity
tation and smoking cessation have been anecdotally
typically deteriorates over a 3–6-month period to a nadir
associated with visual recovery.
of 20/200 or worse. The rate of deterioration is slower
than in demyelinating optic neuritis, but faster than in
HEREDITARY OPTIC NERVE LESIONS compressive lesions. In some cases with specific muta-
tions, spontaneous recovery of vision can occur even
The hereditary optic neuropathies are disorders in
years later. At onset there is marked loss of color vision,
which the underlying cause of optic nerve dysfunction
and central or cecocentral defects are seen on visual field
appears to be inherited, based on familial expression
testing, with preservation of the peripheral visual field
and/or genetic analysis. Genetic analysis has facilitated
in most cases. During the acute phase of visual loss, the
the diagnosis of hereditary optic neuropathies, broad-
funduscopic appearance may be normal, or the triad
ened our view of the clinical phenotypes, and furthered
of: (1) hyperemia and “pseudoedema” of the optic disc;
our understanding of inherited optic nerve disease.
(2) peripapillary telangiectatic engorged microvessels
There are monosymptomatic syndromes in which visual
(Fig. 6.17); and (3) absence of leakage on fluores-
loss is the primary manifestation, and multisympto-
cein angiography, may be seen. The presence of retinal
matic syndromes with widespread involvement of other
hemorrhages or exudates should suggest an alternate
organ systems (Table 6.8). Molecular genetic techni-
diagnosis. The telangiectatic vessels eventually disappear,
ques can help establish the diagnosis in atypical patients
the pseudoedema resolves, and ultimately the optic nerve
pallor and loss of the retinal nerve fiber layer develop,
Table 6.8 predominantly in the papillomacular bundle.
The mitochondrial DNA mutations at positions 11778,
Hereditary optic neuropathies
3460, and 14484 are the three mutations considered pri-
Monosymptomatic mary in LHON. The 11778 mutation accounts for approx-
Leber’s hereditary optic neuropathy (LHON) imately 3 of every 4 cases overall, but its frequency can
Dominant optic atrophy (OPA1) range from as low as 31% to as high as 90% in distinct
Multisymptomatic populations. The 3460 mutation accounts for 8–15% of
Leber’s plus cases, and the 14484 mutation for 10–15%, although these
OPA1 plus
percentages can also vary depending on ethnic origin.
Wolfram syndrome (DIDMOAD)
Recessive optic atrophy (OPA3)
(Newman, 2008). Among the three primary LHON muta-
tions, one phenotypic distinction is that patients with
DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, and the 14484 mutation have a substantially greater chance
deafness. for spontaneous recovery of vision (up to 70%) and for
Fig. 6.17. Leber’s hereditary optic neuropathy with pseudoedema, hyperemia, and telangiectasia of the right eye (OD), and
optic nerve pallor of the left eye (OS: previously affected eye).
having better final visual acuities. On the other hand, prevalence of 1:50 000. Usual onset is in the first
only about 4% of patients with the 11778 mutation decade of life, but it is often imperceptible in child-
improve. Good visual outcome strongly correlates with hood, and the mild degree of visual dysfunction slowly
age younger than 20 years at onset. progresses, with an estimated loss of one line on
Since LHON is a maternally inherited mitochondro- the Snellen visual acuity chart per decade. DOA is
pathy involving extranuclear DNA, only female family clinically characterized by symmetrical, insidious visual
members pass on the risk of the disease to all of their loss, decreased color vision, cecocentral scotomas,
offspring. However, the presence of a primary LHON and wedges of temporal optic disc atrophy, often with
mutation does not necessarily mean that a patient a triangular, excavated appearance (Fig. 6.18). Visual
will lose vision, and only about 20% of patients with loss is variable even within families, and ranges from
pathogenic LHON mutations become symptomatic. The 20/20 to 20/200, but usually not worse. Other neuro-
determinants of expression in LHON are poorly under- logical abnormalities are uncommon, although pedi-
stood, as is the specificity for optic nerve dysfunction. grees exist with prominent deafness. The majority of
Other contributing genetic factors may include: (1) the DOA pedigrees have an abnormality of the OPA1 gene
relative quantity of mutant mitochondrial DNA in indi- localized on chromosome 3 (Eiberg et al., 1994). Muta-
viduals and in specific tissues (heteroplasmy); (2) the tions in the OPA1 protein affect mitochondrial integrity
presence of other mitochondrial DNA abnormalities; and presumably lead to insufficient energy supply in
and (3) nuclear DNA influences. Intrinsic and extrinsic the highly energy-dependent neurons of the optic nerve,
environmental factors may also play a role in expres- likely causing blindness by compromising axonal trans-
sion, including systemic illness, nutritional deficiencies, port to and from the retinal ganglion cells. So far over
and toxic exposures. Tobacco use, environmental tox- 100 different missense and nonsense mutations, dele-
ins, and metabolic stress all place excess demands on tions, and insertions in the OPA1 gene have been found
compromised mitochondrial function and may tip the in affected families. A positive molecular genetic test
balance towards phenotypic expression. Therefore, it helps confirm the diagnosis, but a negative result does
is reasonable to counsel the at-risk patient to avoid not rule it out, since our current molecular diagnostics
agents that may stress mitochondrial function. Since can only identify approximately half of cases.
cardiac arrhythmias may be associated with LHON,
obtaining an electrocardiogram for all patients is essen-
Multisymptomatic hereditary
tial. There is no definitive treatment for LHON. Some
optic neuropathies
have suggested that idebenone may be helpful, and
others have suggested various vitamin or enzyme thera- LEBER’S-PLUS SYNDROMES
pies, but none has been proven effective.
Some patients with LHON also have cardiac conduction
abnormalities, minor neurological abnormalities, or dis-
DOMINANT OPTIC ATROPHY
ease clinically indistinguishable from MS. Several
Dominant optic atrophy (DOA), or Kjer’s disease, is "Leber’s-plus" pedigrees are described with maternally
the most common hereditary optic neuropathy, with a related members with LHON-like optic neuropathy
Fig. 6.18. Typical optic nerve appearance in dominant optic atrophy with temporal wedge of pallor and excavated appearance
temporally in both eyes. OD, right eye; OS, left eye.
plus more severe neurological manifestations, includ- Moderate to severe bilateral visual loss manifests within
ing dystonia and basal ganglia lesions, encephalopathic the first decade of life, but usually does not progress
episodes, spasticity, and psychiatric disturbance. after childhood. The identification of methylglutaconic
aciduria (Costeff syndrome) in several pedigrees led
OPA1-PLUS SYNDROME
to the mapping of the OPA3 gene on chromosome 19.
A syndrome of autosomal-dominant optic atrophy and
This syndrome consists of a combination of autosomal- cataracts has been described with mutations in the
dominant optic atrophy with progressive external OPA3 gene localized on chromosome 19 (Reynier
ophthalmoplegia, peripheral neuropathy, ataxia, deaf- et al., 2004).
ness, and ragged red fibers. The clinical features are
similar to those of the mitochondrial encephalomyo-
pathies associated with multiple mitochondrial DNA TRAUMATIC OPTIC NERVE LESIONS
deletions, suggesting mitochondrial DNA instability in Clinical assessment
critical tissues together with a second mechanism
directly linked to OPA1 dysfunction (Amati-Bonneau Visual loss is common after traumatic brain injury, but
et al., 2008). its diagnosis can be delayed. Patients may be uncon-
scious and unable to provide a clinical history, and
may be unaware of their visual loss at the time. Exami-
WOLFRAM SYNDROME
nation can be limited by lack of cooperation, physical
The autosomal-recessive optic neuropathies are a less injuries, sedative medications, and decreased level of
common, more heterogeneous group of disorders. They consciousness. The traumatic event may seem minimal
are frequently associated with systemic and neurological in relation to the visual loss, and the patient may be
abnormalities, and visual loss is typically severe. Genetic otherwise neurologically intact. A careful examination
analysis has yet to define adequately most of these combined with appropriate neuroimaging should eluci-
diseases. One particular phenotype, Wolfram syndrome, date the nature of the visual loss and guide initiation
or DIDMOAD (diabetes insipidus, diabetes mellitus, of optimal management (Atkins et al., 2008).
optic atrophy, and deafness), may prove, in some
cases, to represent a disorder of mitochondrial function Direct traumatic optic neuropathy
caused by defects in either mitochondrial or nuclear
DNA. Linkage analysis has suggested localization of In most cases, traumatic visual loss is related to direct ocu-
the Wolfram gene to the short arm of chromosome 4 lar injury and occurs in the setting of severe head trauma
in some families, but not in others. associated with loss of consciousness. Ocular trauma such
as hyphema or ocular penetrating injuries and foreign
body may require urgent ophthalmological treatment. Less
OPA3 SYNDROMES
common is unilateral or bilateral visual loss with normal
Complicated autosomal-recessive infantile optic atrophy ocular appearance, suggesting trauma to the optic nerve
or Behr’s syndrome begins in early childhood and is or intracranial visual pathways. Traumatic optic neuropa-
associated with variable pyramidal tract signs, ataxia, thy has traditionally been separated into direct and indi-
mental retardation, urinary incontinence, and pes cavus. rect. Direct traumatic optic neuropathy refers to direct
injury of the optic nerve causing functional and anato- suggest that very-high-dose steroids may actually prove
mical disruption. Direct optic nerve injury is often the harmful in this setting, especially if given more than
result of projectile injuries or penetrating stab wounds 8 hours after injury (Steinsapir, 2006).
to the orbit. The intraocular and intraorbital segments
of the optic nerve typically are involved. This form GLAUCOMA
of optic nerve injury is less common because of protec-
The term “glaucoma” refers to a group of diseases that
tion by the bony orbital walls.
have a characteristic pattern of optic nerve head cup-
ping with associated visual field loss; intraocular pres-
Indirect traumatic optic neuropathy
sure is usually elevated. Glaucoma is by far the most
Indirect traumatic optic neuropathy refers to the trans- common optic neuropathy, affecting more than 100
mission of force distant from the optic nerve, preserv- million people worldwide. It should not be missed by
ing ocular and cerebral tissue plane integrity, but neurologists evaluating a patient with an abnormal
indirectly causing optic nerve dysfunction. Indirect optic nerve or visual field defects. The clue to the diag-
traumatic optic neuropathy is suggested when the nosis is the enlargement of the central cup within the
neuro-ophthalmological examination shows: (1) unilat- optic nerve, classically a vertical elongation, with pres-
eral decreased visual acuity; (2) unilateral decreased ervation of the normal color of the rim of peripheral
color vision; (3) an ipsilateral RAPD; (4) a normal- optic nerve surrounding the cup (Fig. 6.19). Glaucoma
appearing fundus or mild optic nerve edema acutely; is important in the differential diagnosis of optic neuro-
and (5) no apparent intraocular pathology. The affected pathies and requires aggressive treatment by an
optic nerve becomes pale 4–6 weeks after injury (optic ophthalmologist.
nerve pallor at the time of trauma suggests pre-existing
optic neuropathy). The diagnosis of traumatic optic CONCLUSION
neuropathy is clinical and neuroimaging is only useful
As experts on the central nervous system, neurologists
to rule out compression of the optic nerve by a bone
are expected to be familiar with the many conditions
fragment or hemorrhage (Atkins et al., 2008).
that can result in visual loss arising from lesions of the
optic nerve. Since the optic nerve contains approximately
Treatment of traumatic optic nerve lesions
38% of the axons entering or leaving the brain, neurolo-
Although spontaneous visual recovery can rarely occur gists will frequently encounter patients with complaints
after direct traumatic optic neuropathy, surgical of neurogenic visual impairment. In this chapter, we
decompression of the optic nerve may be performed have highlighted the importance of being able to identify
when there is an orbital fracture and compression of the historical and clinical features that will enable neu-
the optic nerve by a bone fragment on imaging. Orbital rologists to narrow down the broad differential
hemorrhages with compartment syndrome presenting
with acute proptosis, chemosis, and elevated intra-
ocular pressure require emergent decompression
(Atkins et al., 2008).
Management of indirect traumatic optic neuropathy
is controversial. Some investigators have proposed pre-
vention of delayed visual loss through optic canal
decompression. Others have argued that the early use
of high-dose corticosteroids may prevent swelling and
compression of the optic nerve within the intracanalicu-
lar space. Still others have argued that close observation
may be the best option, since proposed treatments are
not completely benign, and spontaneous recovery can
occur (Atkins et al., 2008). The International Optic
Nerve Trauma Study, published in 1999, compared the
visual outcomes of traumatic optic neuropathy treated
within 7 days of injury with variable uncontrolled doses
of corticosteroids, optic canal decompression, or obser-
vation alone, and no significant difference between any Fig. 6.19. Glaucomatous cupping of the disc with vertical
of the treatment options was found (Levin et al., 1999). elongation of the cup, but with preservation of the neuro-
More recent animal and human spinal cord studies retinal rim.
diagnosis of optic nerve lesions. We have repeatedly Eiberg H, Kjer B, Kjer P et al. (1994). Dominant optic atro-
emphasized the clinical examination findings that are phy (OPA1) mapped to chromosome 3q region. I. Linkage
classic for the various types of optic neuropathy, and analysis. Hum Mol Genet 3: 977–980.
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diagnosis of multiple sclerosis. Int Rev Neurobiol 79:
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393–422.
examination alone, however, can be difficult, especially
Fraser JA, Weyand CM, Newman NJ et al. (2008). The treat-
when bilateral optic neuropathies are present. Specific ment of giant cell arteritis. Rev Neurol Dis 5: 140–152.
ancillary tests, especially new imaging modalities, help Friedman DI, Jacobson DM (2002). Diagnostic criteria
further localization and differential diagnosis. for idiopathic intracranial hypertension. Neurology 59:
1492–1495.
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Handbook of Clinical Neurology, Vol.

102 (3rd series)

Lesions of the optic nerve

INTRODUCTION which is composed of unmyelinated retinal ganglion

Analysis Confidence Low

Microns Max-Min 153.00 34.00 119.00 Normal 95%

TEMP SUP NAS INF TEMP

OD OS Scan Type Fast RNFL Thickness (3.4)

A Scan Length 10.87 mm

E.J. ATKINS ET AL.

Fig. 6.3. Papilledema: (A) mild; (B) moderate; (C) severe.

Treatment of papilledema sufficient. If there are intolerable symptoms, or if there

Evaluate the severity of IIH

Evaluate and correct the predisposing factors

No headache or diplopia Headaches, ± diplopia, ± tinnitus Visual loss

No treatment Medical treatment Mild Severe

CSF shunting procedure Optic nerve sheath

ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY

Although many different systemic diseases have been

Ischemic optic neuropathy in the setting

OPTIC NERVE GLIOMA

Optic nerve gliomas represent 65% of all intrinsic optic

Fig. 6.13. T1 postcontrast magnetic resonance image with fat

Table 6.7 Specific toxic causes

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