Pathophysiology 18 (2011) 81–92

Optic neuritis: A mechanistic view

Erik V. Burton a , Benjamin M. Greenberg a , Elliot M. Frohman a,b,∗
a Department of Neurology, University of Texas Southwestern Medical Center at Dallas, United States
b Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, United States
Received 28 February 2010; received in revised form 16 March 2010; accepted 8 April 2010

Abstract
Acute demyelinating optic neuritis is a condition of the optic nerves characterized by inflammation, demyelination, and neurodegeneration.
Optic neuritis is a relatively common demyelinating event, strongly associated with multiple sclerosis. A number of clinical, radiographic,
retinal imaging, and electrophysiologic techniques have provided significant insight into the pathologic and pathophysiologic mechanisms of
optic neuritis and its related disorder multiple sclerosis. The development of validated biomarkers within the anterior visual system has paved
the way for novel investigations aimed at characterizing the processes of axonal loss and neurodegeneration, neuroprotection, and perhaps
even neurorestoration strategies.
© 2010 Elsevier Ireland Ltd. All rights reserved.

Keywords: Multiple sclerosis; Visual evoked potentials; Optical coherence tomography pupil light reflex; Optic neuritis; Retinal nerve fiber layer; Macular
volume

1. Introduction ropathy (AION) [9] and Leber’s hereditary optic neuropathy

The optic nerve is a simple, well-defined white-matter
tract emanating from single-ordered neurons within the reti-
nal macular zone. It is commonly affected in demyelinating
disorders, such as acute demyelinating optic neuritis (ON),
and has well-defined clinical outcome measures. Optic neuri-
tis is an inflammatory condition of the afferent visual system
that may be associated with a variety of autoimmune or
infectious etiologies [1–6]. When associated with swelling
of the optic disc it is referenced as papillitis or anterior optic
neuritis; when the disc appears normal it is referred to as
retrobullbar optic neuritis. Optic neuritis is strongly associ-
ated with multiple sclerosis (MS), though it may be idiopathic
or associated with numerous other conditions including neu-
romyelitis optica (NMO) [7,8]. There exists a number of
conditions which may result in ON (Table 1) and a number of
conditions from which ON must be differentiated clinically
and pathologically including anterior ischemic optic neu-
∗ Corresponding author at: Department of Neurology, University of Texas
Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX
75235, United States. Tel.: +1 214 645 0555; fax: +1 214 645 0556.
E-mail address: elliot.frohman@utsouthwestern.edu (E.M. Frohman).
(LHON).
Optic neuritis is a frequent “forme fruste” of MS. It is
estimated that 40% of patients with MS experience ON as
their first clinical demyelinating event, while up to 80% of
patients with MS experience ON at some point during the
course of their illness [10,11]. A number of studies includ-
ing the optic neuritis treatment trial (ONTT) have looked at
other factors associated with the risk of developing MS in
the setting of isolated ON (Table 2) [12–14]. The high asso-
ciation of ON and MS, coupled with evidence from clinical
trials demonstrating reduction in risk of progression and dis-
ability among selected patients with early disease modifying
therapy, underscores the importance of early and accurate
diagnosis and management.
As a common demyelinating event strongly associated
with MS, assessment of the afferent visual system in ON
has provided significant insights into the pathophysiology of
MS in general. Essentially all of the cardinal pathologic fea-
tures of MS brain and spinal cord pathology are recapitulated
within the anterior visual system including demyelination,
axonal and neuronal degeneration, and astrogliosis [15–18].
Here we present a broad review of ON including the clinical
characteristics and anatomic considerations with particular

0928-4680/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pathophys.2010.04.009
82 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92

Table 1 ON may also present in chronic and subclinical (occult)

Causes of optic neuritis. forms.
Idiopathic The optic neuritis treatment trial assessed the benefits of
Multiple sclerosis corticosteroid treatment on visual recovery in ON, and the
Neuromyelitis optica (Devic’s)
Viral infections (measles, mumps, varicella)
relationship between ON and MS. Data on 457 patients,
Mycoplasma aged 18–46 years, with ON was collected. Patients typi-
Postviral, postvaccine cally experienced a decline in vision over a 7–10-day period
Mononucleosis with a highly variable degree of visual acuity (VA) loss [12].
Herpes zoster Some patients experienced little change in central vision and
Contiguous inflammation of the meninges, orbits, and sinuses
Granulomatous inflammation (sarcoidosis, Wegener’s,
retained a VA of 20/20 or better while no light perception
tuberculosis, syphilis) vision was present in only 3% of participants at presen-
Intraocular inflammation tation. A progression of vision loss beyond 2 weeks was
unusual in this study, and typical cases exhibited at least
some recovery within 30 days of symptom onset [22,23].
emphasis on the pathology and pathophysiology of ON and A number of additional historic features are strongly asso-
the clinical, electrophysiologic, neuroimaging, and retinal ciated with ON in addition to reduced VA (Table 2). In the
imaging correlates. ONTT, 92% of patients reported concomitant pain, partic-
ularly with eye movements [12]. Flashes of light may be
associated with ON and may be induced by eye movement or
2. Clinical characteristics of optic neuritis certain sounds, a phenomenon referred to as Moore’s light-
ning streaks [24–26].
Optic neuritis is very frequently the initial clinical man- Clinical findings in ON apart from reduced VA com-
ifestation of MS, and is one of the most common clinical monly include a relative afferent papillary defect (RAPD),
events during the course of that illness [10,11]. There is a gen- which is almost invariably present in the affected eye, unless
der predilection for women, who are three times as likely as the fellow optic nerve is affected pathologically such that
men to develop ON. The incidence of ON in persons at high light transmission is slowed (as with demyelination) rela-
risk for developing MS is approximately 3–5/100,000 per tively symmetrically. Central and cecocentral (a central field
year [19–21]. In lower-risk regions the incidence is approx- depression extending into the blind spot) visual field defects
imately one per 100,000 per year [19–21]. While the acute are common in patients with ON. Other variations include
form of ON is most commonly recognized by the clinician, arcuate defects, unilateral nasal and temporal hemianopsias,
quadrant defects, and diffuse field depression (48%) [27].
Table 2
Funduscopic examination was normal in approximately two-
Features of typical and non-typical optic neuritis. thirds of patients with classic ON (hence the adage, ‘the
Typical optic neuritis Non-typical optic neuritis
patient sees nothing and the physician sees nothing’) in the
ONTT, while in the remainder the optic disc appears swollen,
Unilateral (rarely bilateral) Bilateral and sequential
optic neuritis
as in anterior ON (papillitis) [12]. Pallor of the optic disc is not
Young Caucasian women (3F:1M)a Absence of light present acutely after ON, but rather takes weeks to months in
perception order to become manifest, and is explained by the process of
Acute to subacute onset (stabilization Progression of vision loss astrogliosis within the optic nerve head in conjunction with
by 2 weeks) beyond 2 weeks axonal loss [28].
Variable reduced acuity (better than Poor recovery
no light perceptiona )
A number of retinal and clinical features are suggestive of
Reduced color vision Absence of periocular non-typical ON (Table 2) [14]. Patients with atypical features
pain (such as hemorrhage) on presentation had a lower risk of
Recovery begins by day 30 (>90%) Severe papillitis developing MS, particularly when a baseline brain MRI scan
Periocular pain, particularly with eye Peripapillary hemorrhage was normal [13,14].
movement (>90%)a
Moore’s lightning streaks Retinal exudates
Visual recovery occurred rapidly following ON in most
Uhthoff’s phenomena Insidious onset patients in the ONTT and continued for up to a year in
RAPD (if unilateral) the affected eye [29,30]. The mean VA in the affected eye
Central visual field deficit at one year following onset of ON was 20/15, with 90%
No papillitis in 2/3a of patients having VA better than 20/40 [23]. Even fol-
Normal retina (except retinal venous
sheathing)a
lowing severe visual loss (no light perception or finger
Optic disc pallor (4–6 weeks from counting only) 49% of such patients regained VA 20/20
onset) or better. Though marked improvement in high contrast
MRI variable(at least one T2 lesiona ) VA abnormalities was typical, abnormalities on low-contrast
Non-typical features are associated with a low risk of developing MS. sensitivity, color perception, and visual field analyses per-
a Typical features associated with high risk for developing MS.
sisted in approximately 30% of affected eyes and in 14–19%
 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92 83

Table 3
Imaging and evoked potential changes reflecting pathophysiologic mechanisms in optic neuritis and their associated clinical changes.
Pathophysiology Imaging and evoked potential changes reflecting pathophysiology Clinical features associated with pathophysiology
Inflammation Gadolinium enhancement Reversible visual deficits
Increased optic nerve thickness Pain
Increased RNFL thickness Retinal venous sheathing
Decreased VEP amplitude and conduction block

Demyelination Decreased MTR Uhthoff’s phenomena

Prolonged VEP latency and conduction block Moore’s lightning streaks
Increased MD Potentially reversible visual deficits
Decreased FA

Neurodegeneration
Axonal loss Decreased optic nerve thickness Fixed visual deficit
Decreased RNFL thickness
Decreased MTR
Atrophy
Increased MD
Decreased FA
Decreased VEP amplitude
Neuronal loss Decreased macular volume Fixed visual deficit
Cortical atrophy
Decreased cortical MTR
Decreased VEP amplitude

Repair
Remyelination Increased MTR Visual recovery
Normalization of VEP latency
Adaptation fMRI changes Improved visual function
Adapted from Kolappan et al. [41].
RNFL: retinal nerve fiber layer; VEP: visual evoked potential; MTR: magnetization transfer ratio; MD: mean diffusivity; FA: fractional anisotropy; fMRI:
functional magnetic resonance imaging.

of contralateral eyes (suggesting occult optic neuropathy)
[31–34].
Additional diagnostic evaluation is generally unnecessary
in the setting of typical ON as other etiologies were unlikely
in the ONTT [12]. A more aggressive assessment should be
considered when non-typical features of ON are present and
may include testing for lupus, Lyme disease, sarcoid, syphilis,
West Nile virus, human immunodeficiency virus, ehrlichio-
sis, Leber’s optic neuropathy, and neuromyelitis optica [22].
To determine risk of progression to MS, oligoclonal banding
in the CSF was strongly predictive but not independent of
MRI and is of limited utility when the clinical course and
imaging features are typical for demyelinating disease [35].
The risk of developing MS following an event of ON
can be estimated reliably, with MRI having been established
as the most important predictor. Approximately 50–70%
of patients with ON will have periventricular white-matter
abnormalities consistent with demyelination on an initial
MRI scan [29,36–38]. In 115 patients with clinically iso-
lated ON, 70% of the patients had abnormal brain lesions
demonstrated by MRI and 27% had spinal cord lesions [37].
According to the ONTT, the cumulative risk of developing
MS following optic neuritis was 50% by 15 years. In patients
with no white-matter lesions the risk of developing MS was
approximately 25%. The presence of even one white-matter
lesion, however, raises the risk of developing clinically def-
inite MS to 72%. The risk of developing MS after 5 years
in those patients with normal initial MRI’s remained low but
in those with MRI lesions the risk remained significant. Of
those individuals with lesions on an initial MRI, male sex,
optic disc swelling, poor vision, and no pain were associated
with a lower risk for development of MS [39].
Many of the clinical characteristics of ON have partic-
ularly strong correlations with underlying pathologic and
pathophysiologic changes (Table 3).
3. Anatomy of the afferent visual system
The retina consists of a number of neuronal components
including photoreceptors, bipolar cells, and ganglion cell
neurons and their axons, which form the retinal nerve fiber
layer (RNFL), the most superficial layer of the retina. The
RNFL consists of unmyelinated axons that later become
myelinated after passing posteriorly through the lamina cri-
bosa to form the optic nerves. Optic nerve axons from the
nasal hemiretina represent greater than 50% of the optic nerve
axons and decussate in the chiasm to join the contralateral
axons of the temporal hemiretina to form the optic tract. Most
optic tract axons terminate in the lateral geniculate nucleus
84 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92
(LGN). Neurons of the LGN project to the primary visual
cortex via the optic radiations. This three-neuron pathway to
the primary visual cortex forms the retino-geniculo-calcarine
pathway for vision.
A minority of the optic nerve axons are organized into
two other principal retinal projections. These include the
retino-mesencephalic system, in which axons project via the
brachium of the superior colliculus to innervate the nucleus
of the optic tract (NOT) for mediation of the pupillary light
reflexes, and the retino-hypothalamic tract (innervating the
suprachiasmatic nucleus) involved in circadian rhythm regu-
lation, neuroendocrine reflex arcs, and mood states.
4. Imaging and electrophysiology of optic neuritis
Inflammation, demyelination, axonal transection,
astrogliosis, and atrophy, along with limited repair and
plasticity, are prominent pathologic features of ON and its
related condition MS. These pathologic features are the
primary cause of neurologic deficits in ON and MS and
correlate with specific clinical findings [17,40]. Techniques
such as visual evoked potentials (VEPs), T1 gadolinium
enhanced and non-enhanced magnetic resonance imaging
(MRI), magnetization transfer imaging (MTI), magnetic
resonance spectroscopy (MRS), diffusion tensor imaging
(DTI), optical coherence tomography (OCT), and scanning
laser polarimetry (GDx) provide important information
regarding structure and function in ON [41] (Table 3).
Visual evoked potentials (VEPs) measure cortically gen-
erated potentials via repetitive visual stimulation. Visual
evoked potentials provide information about electric trans-
mission of frequency-coded messages along ganglion cell
axons within the afferent visual system and are frequently
abnormal following ON [42,43]. Whole field VEP and
multifocal VEP (mfVEP) have been used clinically and
experimentally in the evaluation of ON and MS, and correlate
with a number of pathologic and clinical findings. Electro-
physiologic testing, such as VEP, is of limited clinical utility
but is often considered useful when there is paucity of data
to confirm a diagnosis of MS [44]. The mfVEP may be use-
ful in some selected patients when the distinction between
optic nerve and retinal disease is in question, or evidence of
subclinical optic nerve dysfunction is sought [45].
Optic nerve MRI has recently been utilized to study the
natural history of ON in vivo. It can potentially differentiate
among various pathologic components of ON, but ultimately
the specificity is modest at best. MRI of the optic nerve is
challenging owing to the small size of this targeted struc-
ture, errors associated with subject mobility, and confounding
influence of surrounding anatomic structures including fat,
bone, CSF, and vascular pulsations. A number of techniques
have been developed to overcome these limitations such as fat
suppression, fast sequencing, 3D acquisition, surface coils,
and high field MRI [46–50]. These include short-tau inversion
recovery (STIR), selective partial inversion recovery (SPIR),
and fat suppressed fast spin echo sequences (fsFSE), which
reduce T2 hyperintensity of the optic nerve. Combinations
of sequences with fast fluid attenuation inversion recovery
(FLAIR) can reduce CSF signal, and three Tesla scanning
and surface coils improve sensitivity and spatial resolution
[47,49,50]. STIR was shown in one study to detect lesions
in 84% of patients with symptomatic ON. Individuals with
longer lesions and/or optic canal involvement had slow or
poor visual recovery [51]. STIR and SPIR sequences are lim-
ited by long acquisition times. Nevertheless, combinations
of sequences with FLAIR protocols have been shown to be
superior to simple STIR and SPIR sequences in detecting
optic neuritis [46]. Newer techniques such as DTI, MTI, and
MRS provide additional information on optic nerve structural
architecture [52–63].
Retinal imaging provides information about the patho-
phyiology of ON and MS and correlates with certain
functional, radiographic, and physiologic changes [64–74].
The retina is unique in that the RNFL is composed of unmyeli-
nated axons with an admixture of glia (approximate 80/20%
composition). There are a number of techniques that are use-
ful in the evaluation of the RNFL along with other retinal
structures, such as OCT, laser polarimetry (GDx), and Heidel-
berg retinal tomography (HRT). With OCT, high-resolution
images of the internal retinal structures are generated by an
optical beam scanned across the retina [65].
5. Pathophysiology of inflammation in optic neuritis
The earliest pathologic findings in MS include inflamma-
tion with lymphocytic infiltration of the leptomeninges and
Virchow–Robin spaces [16], as well as perivenular infiltrates
of lymphocytes, plasma cells, and macrophages [75,76].
Analogously, retinal venous sheathing or periphlebitis may
be visualized in ON, and may be associated with increased
risk of conversion to MS [77–79]. The presence of vascular
inflammation, lesions and other pathologic changes early in
the retina, a structure free of myelin and oligodendrocytes,
suggests that vascular changes may be a primary event in
demyelinating diseases such as ON and MS.
Inflammation is not confined to the retina and optic nerves
but may involve any portion of the afferent visual system
including the optic chiasm and optic tracts. Optochiasmatic
arachnoiditis may be a prominent and early finding in MS,
and may be grossly visualized [80]. Involvement of the
retrochiasmal pathways including the optic tracts and radia-
tions is seen in 13% of idiopathic inflammatory optic neuritis
and are often associated with subclinical changes in visual
function [81,82]. In addition to inflammation and lesions
within the optic nerves, chiasm, and tracts, the lateral genic-
ulate nucleus (LGN) and visual cortex are not infrequently
involved [83,84].
Inflammation culminates in early demyelination. Ini-
tially the outer lamellae of myelin are stripped away by
macrophages in a successive fashion. The result is a ‘bare-
 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92
Fig. 1. Axial (A) and coronal (B) T1 weighted gadolinium enhanced MR images of acute left optic neuritis (arrows).
naked’ axon that may later be partially remyelinated or,
instead, be invested by proliferating astrocytes (gliosis)
[75,76]. It is gliosis in proximity to demyelinated axons that
gives the optic disk its pale white or grey color.
A number of clinical findings in the early stage of ON may
be associated with inflammation in addition to demyelina-
tion, including reduced visual acuity and visual field defects,
along with corresponding changes in electrophysiology and
imaging metrics [85,86]. Evaluation of the afferent visual
system by these objective methods provides key insights into
the pathophysiologic underpinnings of inflammation and its
impact upon the integrity of visual system function.
Cortically generated potentials via visual stimulation in
VEPs have been observed to be persistently delayed follow-
ing optic neuritis, even following visual recovery [42,43].
In MS and ON, the VEP P100 latency is characteristically
delayed, typically with preserved waveform amplitude. How-
ever, in early or severe ON, the P100 amplitude may be
reduced, temporally dispersed (due to axons firing at vary-
ing velocities secondary to variability in demyelination), or
associated with complete conduction block (severe attenua-
tion or absent amplitude). Acute reduction in amplitude, as
well as complete conduction block, is likely related to active
inflammation and blood brain/nerve barrier breach, and is
associated with corresponding changes in visual function.
With resolution of the acute stage of ON the VEP ampli-
tude often normalizes, while the P100 latency often remains
delayed [85]. Visual field defects identified in optic neuritis
are highly variable and correspond anatomically to lesions
within the afferent visual system, and have the potential to be
correlated to abnormalities on mfVEP [87,88].
Gadolinium enhancement (Fig. 1) is identified in approx-
imately 90% of optic nerves during the acute phase of
optic neuritis [89]. Enhancement is a sensitive finding in
acute ON, is absent in chronic optic neuropathy (with some
important conspicuous exceptions such as with sarcoid and
neoplasm’s), and is thought to be a vascular phenomenon
resulting from breach in the integrity of the blood brain/nerve
85
barrier which permits the extravasation of gadolinium. Optic
nerve enhancement on MRI is associated with impaired visual
acuity, desaturation of color perception, eye pain, an RAPD,
and delayed P100 latency and reduced amplitude on VEP test-
ing [85,86]. Occasionally, inflammation of the optic chiasm
may produce an expanded region of enhancement, whereas
some patients may have focal leptomeningeal enhancement
along the chiasm [90–92]. Length of the enhancing portion
of the optic nerve also correlates with the severity of visual
impairment [93]. Resolution of enhancement occurs over the
following month after symptom inception and is associated
with improvements in visual systemic metrics including VEP
amplitude, and to lesser degree VEP latency. Collectively,
these findings suggest that acute inflammation is associated
with blood brain/nerve barrier compromise, and results in
reversible conduction block [85].
6. Pathophysiology of demyelination in optic neuritis
Histopathologic features of demyelination within the optic
nerves, chiasm, and optic tract parallel those of the brain.
Demyelination occurs early in ON and in association with
acute inflammation with macrophage ingestion of myelin.
Demyelination may include the entire cross-section of the
nerve over several centimeters or may be more limited in
distribution. The entire nerve and optic chiasm may show
features of demyelination and chronically appear structurally
smaller than normal (likely the result of myelin and axonal
loss). Remyelination occurs, albeit sparsely in the acute MS
plaque [94].
Once a demyelinated plaque forms in ON or MS the lesion
may become one of three types: a chronic inactive plaque,
a chronic active plaque, or a shadow plaque [15,18,94–96].
Chronic inactive plaques are characterized by complete or
near-complete absence of myelin and are often found in
the optic nerve and chiasm of patients with stable disease
(particularly in those with disease duration of 20–30 years)
86 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92
[15]. Chronic active plaques are associated with ongoing
demyelination and inflammation in conjunction with promi-
nent axonal transection [17]. When substantial remyelination
occurs, which does not begin until 1 month or more following
the onset of demyelination, it becomes known as a shadow
plaque [95,96].
Demyelinated axons have impaired ability to transmit
action potentials due to disruption of saltatory conduction
via the nodes of Ranvier. This may result in complete or
intermittent conduction block or slowed conduction. As men-
tioned above, these changes have been confirmed by VEP
P100 latency analysis, which were delayed following ON and
remained delayed following visual recovery [42,43]. Delayed
latency is strongly associated with demyelination follow-
ing optic neuritis, while changes in amplitude correlate with
inflammation in conjunction with axonal loss [85]. Demyeli-
nation can be highly restricted to a focal area of the visual
system and as such may not be identified by standard VEP
techniques. As such, mfVEP has been established as a more
sensitive detection strategy than conventional VEP in patients
with MS [97].
Demyelinated axons are thermolabile such that small
physiologic changes in core body temperature are associated
with changes in nerve conduction properties, most typi-
cally characterized by slowing or complete block. This likely
accounts for the so-called Uhthoff’s phenomena (reversible
and typically stereotyped and recurrent clinical symptoms)
though a number of other physiologic changes have been
implicated (e.g. exercise, infection, and psychologic stress)
[98–100]. In 1889 Uhthoff reported on the reversible blur-
ring of vision in MS patients following exercise [101]. The
most widely accepted physiologic mechanism for this clinical
finding is reversible conduction block in partially demyeli-
nated axons with reduced safety threshold [102] for certain
metabolic and physiologic changes including small changes
in temperature [103], blood pH, calcium, sodium, and potas-
sium [104,105]. A number of studies using VEPs have
confirmed that small elevations in body temperature result in
impaired conduction in demyelinated axons, and that changes
in conduction are associated with new or worsening visual
deficits, albeit temporarily [106–110]. Likewise active cool-
ing may improve conduction and result in reversal (often
rapidly) of visual deficits [111,112].
In addition to impaired conduction, demyelinated axons
have abnormally increased (described as ephaptic electric
discharges) excitability resulting in a number of clinical phe-
nomena in MS and ON, such as the perception phosphenes
upon eye movements in dim lighting conditions (Moore’s
lightning streaks) [24–26].
7. Neuroradiologic correlates of optic neuritis
Changes on conventional MRI studies including T2 hyper-
intensities are non-specific and may be associated with a
number of pathologic processes including demyelination,
axonal loss, inflammation, and gliosis. Alternately, atrophy
and T1 hypointensities within the CNS strongly correlate
with axonal and neuronal loss in MS. Newer MRI techniques
such as DTI and MTI may improve our ability to sensitively
and specifically detect changes in tissue architecture within
the brain and optic nerve of MS patients [52–55].
MTI measures the rapid transfer of magnetization between
two pools of protons, those bound in macromolecules such
as myelin and axons, and free protons such as those in the
extracellular space. Magnetic transfer ratio (MTR) is the mea-
surement of this effect and is an indirect measure of integrity
of macromolecular structure which is in greater concentra-
tion in white versus grey matter [63]. MTR is significantly
reduced in affected optic nerves and is inversely correlated
with VEP latency, consistent with demyelination [60,61].
MTR trends upward (generally signifying improved tissue
structure and perhaps remyelination) after reaching a nadir at
approximately 8 months following ON [113,114]. However,
some evidence suggests that MTR may also correlate with
axonal and neuronal atrophy [61] limiting its specificity.
DTI has shown dynamic changes in early and remote
ON [57]. DTI describes the diffusion properties of water
molecules in tissue along various planes. In geometrically
ordered tissue (such as the optic nerve) water motion is
facilitated along axons, whereas it is impeded perpendicular
to the main axis of the tract, thereby resulting in direc-
tional selectivity diffusion characteristic. The metric of this
directional selectivity is calculated as anisotropy, and mea-
sured as fractional anisotropy (FA) (again increased along
ordered pathways). The FA is reduced in the context of tis-
sue damage, which disrupts the organized and directional
movement of water along the direction of axons (so-called
axial diffusivity). The perpendicular impedence (so-called
radial diffusivity) to diffusion is reduced with demyelination
(because of less integrity and loss of tissue barriers), which
increases mean diffusivity (MD) (i.e. water can move more
freely as a consequence of reduced tissue organization). In
addition to these important correlates of myelin disruption,
evidence also suggests that there is a relationship between
DTI metrics and axonal loss [62].
8. Neurodegeneration in optic neuritis
Classically described as an inflammatory demyelinating
process with relative sparing of axons, Trapp et al. demon-
strated extensive axonal transection as a consistent feature
in MS lesions [17]. We now recognize that axonal injury
and atrophy represent prominent and early pathologic fea-
tures of MS and ON [18,115,116]. Atrophy is the result of
a combination of demyelination and axonal loss. White mat-
ter is composed of about 50% axons, 25% myelin, with glia
and other tissue elements comprising the remainder of this
tissue compartment. Given these proportions, axonal degen-
eration would appear to prominently contribute to the process
of white-matter atrophy in MS [48].
 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92
Thinning of the RNFL, which consists of axons devoid of
myelin, occurs following ON but also in MS patients without
a history of ON [71], and appears to correlate with cerebral
atrophy and disease-related disability in MS [69]. Transec-
tion of axons has been demonstrated in acute and chronic
MS lesions, leading to both Wallerian as well as a dying
back degeneration [18]. Axonal densities are reduced in the
optic nerves and tracts (30–45% reduction) of SPMS patients
[69].
The lateral geniculate nucleus (LGN) and visual cortex are
frequently affected subsequent to ON, secondary to reduced
transmission mechanisms in addition to trans-synaptic degen-
erative changes. In MS patients, there is significant neuronal
cell body atrophy noted in the LGN, particularly within the
parvocellular layers, as well as similar changes in the pri-
mary visual cortices [84]. The pathologic changes in the
LGN and visual cortex may be a consequence of primary
demyelination and inflammation, as a consequence of Wal-
lerian degeneration secondary to lesions of the connecting
white-matter tracts or as a result of trans-synaptic degen-
eration due to lesions in an anatomically linked remote
region [84]. Evangelou et al. investigated the anterior visual
pathways of eight postmortem cases of MS and found that
in addition to significant atrophy and axonal loss in the
optic nerve and tract, there was also a selective atrophy of
smaller neurons (parvocellular layer of LGN) consistent with
trans-synaptic degeneration. This suggests an increased sus-
ceptibility of smaller axons to MS related injury [117], as
has also been suggested by studies of achromatic [118] and
chromatic [119] contrast sensitivity, VEP [120], temporal fre-
quency discrimination [121] and pupillary light reflex metrics
[122].
Though VEP amplitude can be acutely reduced in early
ON, reductions are also observed in chronic ON and correlate
with both a reduction in RNFL thickness (implying axonal
loss) and macular volume (signifying loss of ganglion cell
neurons) [123].
MRI measures of brain and spinal cord atrophy corre-
late well with disability in MS [124,125]. A study evaluating
optic nerve atrophy in patients with unilateral optic neuri-
tis demonstrated significant reduction in cross-sectional area
(11.2 mm2 ) of affected eyes compared to fellow (12.9 mm2 )
and control (12.8 mm2 ) eyes, with the degree of atrophy
correlating to disease duration thereby suggesting ongoing
axonal loss following ON [126]. Additional studies have cor-
related visual dysfunction with the degree of atrophy [127].
Other studies have corroborated some of these findings [128].
Trip et al. found that optic nerve area was reduced by 30%
in patients with incomplete recovery following unilateral ON
and that RNFL thickness and macular volume reduction cor-
related significantly with optic atrophy [74]. Visual evoked
potential amplitude correlated with optic nerve atrophy, while
latency did not, suggesting that optic nerve atrophy on MRI
is a function of axonal loss [123].
MTI and DTI provide insight into the natural history
of ON in vivo and can partially differentiate among vari-
87
ous pathologic changes including axonal loss and neuronal
degeneration. While MTR correlates well with demyelina-
tion in white matter, it was also shown to correlate well
with thinning of the RNFL, suggesting that MTR is reduced
by axonal loss as well as by demyelination [61]. MTR has
also been shown to be reduced in the visual cortex of indi-
viduals having had optic neuritis (at least 6 months prior
to imaging), further supporting trans-synaptic degeneration
as a significant etiology of neuronal and axonal atrophy
[129].
Trip et al. showed that DTI measures of MD were
increased and FA was decreased in optic nerves affected by
ON and that these changes correlated with VEP amplitude
signifying axonal loss [62]. DTI parameters such as FA of
the optic nerve appear to correlate with functional, structural,
and physiologic tests of vision [57]. An additional study of
optic radiation specific damage showed that FA and perpen-
dicular diffusivity (MD) correlated well with OCT measures
of retinal injury and visual disability [72]. These findings,
in addition to MTI changes, underscore the importance of
trans-synaptic changes that may occur in MS and ON as a
source of disability. Mechanisms of trans-synaptic changes
are important for normal development as well as disability
and/or recovery in MS and ON and may represent a target for
neuroprotective drugs.
9. Retinal imaging and optic neuritis
The retina is unique in that the most superficial layer, the
RNFL, contains axons and glia in the absence of myelin.
Axonal loss in the RNFL has consistently been demonstrated
early in MS and following optic neuritis [64,68,73,130]. Reti-
nal axonal loss on red-free photography may be seen in eyes
with a history of acute optic neuritis (AON) associated with
corresponding visual field changes. Visual confirmation of
nerve fiber layer loss during fundoscopy or retinal photog-
raphy requires a reduced thickness of approximately 50% in
the RNFL (Fig. 2) [131].
Advancements in the application of OCT has facilitated
objective analysis of neurodegeneration and axonal loss in
the anterior visual system [132]. With OCT, high-resolution
images of the internal retinal structures are generated by an
optic beam scanned across the retina (Fig. 3). It is noninvasive
and can sensitively and rapidly measure changes in the retina
that are a consequence of MS and may provide an additional
means of monitoring therapeutic response to neuroprotective
agents [133,134].
Multiple groups have reported reduction in RNFL thick-
ness in eyes with a prior history of ON [64,73,130,135]. The
RNFL thickness is 110–120 ␮m by the age of 15 years. Fol-
lowing ON, about 75% of patients sustain a 10–40 ␮m loss
of RNFL thickness that appears to be unaffected by corti-
costeroid or disease modifying therapy [64]. Measurements
of RNFL correlate with high- and low-contrast visual acu-
ity (more sensitively with the latter), visual field changes,
88 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92

Fig. 2. Fundus appearance of eyes following left optic neuritis in a subject with multiple sclerosis. To the left side of the illustrations we see the normal retina
and optic disc of the unaffected right eye and the corresponding nerve fiber layer pattern corresponding to an average retinal nerve fiber layer (RNFL) thickness
of 106.4 ␮m. To the right side of the illustration we see the affected eye with optic disc pallor most prominent to the temporal segment and the corresponding
nerve fiber layer pattern of thinning corresponding to an average RNFL thickness of 60.9 ␮m with arrows indicating the thinning associated with the temporal
pallor. These changes had associated abnormalities in visual function including decreased high contrast visual acuity and low-contrast visual acuity.

brain atrophy, and subtype of MS [68]. Reductions in
RNFL thickness and macular volume are significantly cor-
related with reductions in visual function [64,66,68,73] as
well as measures of disability (EDSS and MSSS) in MS
[69–70,136].
RNFL thinning in eyes not previously affected by an attack
of ON has been reported in RRMS, SPMS and PPMS. This
is least evident in the RRMS and most prominent in SPMS
[66,137].
10. Recovery and plasticity in optic neuritis
Recovery has been demonstrated following ON in many
clinical parameters including high contrast VA. Remyelina-
tion is a reparative process in MS whereby myelin is laid down
around demyelinated axons. When effective, axonal con-
duction and neurologic function is restored. Unfortunately
the process is incomplete and variable with the majority of
lesions failing to have functionally significant remyelination.

Fig. 3. High-resolution OCT image of normal human macula. NFL, nerve fiber layer; IPL, inner plexiform layer; OPL, outer plexiform layer; RPE, retinal
pigment epithelium; ONL, outer nuclear layer; INL, inner nuclear layer; IS, inner segment; OS, outer segment; ELM, external limiting membrane; GCL,
ganglion cell layer.
 E.V. Burton et al. / Pathophysiology 18 (2011) 81–92
Chronic inactive lesions, which are often located in the optic
nerves and chiasm, are associated with complete or near-
complete absence of myelin and depopulation of oligoden-
droglia from the center of the lesion. Chronic inactive lesions
may have some degree of preservation of demyelinated
axons though there may be a prominent reduction in axonal
density. Early recovery of vision following ON has been cor-
related with reduced conduction block and corresponding
improvement in VEP amplitude, however, latency typically
remains prolonged. MTR, which correlates inversely with
VEP latency, may improve after reaching a nadir 8 months
following ON suggestive of remyelination [113,114].
Functional MRI (fMRI) is a method of measuring brain
activity that takes advantage of oxygenated and deoxy-
genated states of hemoglobin, having different MRI signals
where functionally activated brain regions have increased
oxygen requirements. fMRI has been used extensively and
has been employed to demonstrate cortical plasticity in MS
[59]. Numerous studies have demonstrated reduced activa-
tion within the visual cortex in ON corresponding to reduced
neuronal input. Neural plasticity has been demonstrated in
ON with increased activation in areas outside the visual
cortex in addition to correlation with VEP latency, sug-
gesting an association with demyelination within the optic
nerve. Reorganization has been localized to the lateral occip-
ital cortex and is associated with visual recovery [56,138].
Further evidence for plasticity has been found in the LGN
[83].
Proton MR spectroscopy (MRS) is another method of
characterizing the pathophysiologic changes in the brain.
MRS of the brain has been very helpful in providing cell spe-
cific measures of neuronal damage. Additional MRS changes
provide evidence for repair involving non-neuronal brain
cells [139].
11. Conclusions
Optic neuritis can now be sensitively characterized both
structurally and functionally with the application of new
technologies including MRI of the afferent visual pathways,
RNFL thickness and macular volume measurements by OCT,
and evoked potentials (conventional and mfVEP). Notwith-
standing these important and powerful advancements, ON
remains a clinical diagnosis. Further, conventional brain MRI
sequences continue to play a significant role in the evalua-
tion of isolated ON in determining risk of MS [14,140]. VEP
has limited clinical utility (beyond the acumen of the experi-
enced neurologist) but is useful in evaluating for occult optic
neuropathy. Retinal imaging is non-specific but does pro-
vide evidence of early axonal and neuronal degeneration, and
may reveal further evidence of occult optic neuropathy in the
appropriate clinical settings.
The application of optic nerve MRI has been particularly
useful in understanding the temporal profile of inflamma-
tion, demyelination, axonal loss, gliosis, and neuronal loss
89
in ON, and correlates with clinical measures of visual func-
tion, evoked potentials, and retinal imaging. The newer MTI
and DTI techniques have provided insight into the pro-
cesses of axonal loss and demyelination in ON and MS, and
future application may enhance our ability to render prognos-
tic predictions, correlate to certain clinical features such as
Uhthoff’s phenomena, and ultimately help monitor response
to novel treatments. Future imaging techniques including
higher magnetic field strength scanners, surface coils, and
fast acquisition methods, will improve spatial resolution and
reduce noise while MR spectroscopy may provide useful
information regarding cell specific changes in ON.
VEP and mfVEP techniques have provided complimen-
tary information regarding the physiologic changes seen in
MRI, while retinal imaging has yielded direct evidence of
axonal loss via RNFL thickness measures and neuronal loss
via macular volume, both supporting early neurodegeneration
in ON and MS. Future studies correlating physiologic decay
in action potential propagation in ON eyes with structural
changes utilizing MTR, DTI, and OCT would provide further
insight into ON and Uhthoff’ phenomena. Such character-
ization would provide an objective means for quantifying
Uhthoff’s phenomena and response to various interventions
such as body surface cooling and potassium channel block-
ade.
Ultimately it would appear that ON is a good model
for understanding multiple sclerosis, as it is a very com-
mon clinical syndrome and the organization of the afferent
visual apparatus has been systematically characterized. Opti-
cal coherence tomography is potentially a useful technique
for monitoring the effects of neuroprotective therapies using
RNFL thickness for axonal loss and macular volume for neu-
ronal loss. Magnetization transfer ratio, DTI, and VEP are
sensitive measures of pathologic changes ON and in com-
bination with OCT may be effective for evaluation of repair
such as with remyelination.
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