Al Louzi2016

C H A P T E R
12
Pathophysiology of Optic
Neuritis
Omar Al-Louzi, Shiv Saidha
Division of Neuroimmunology and Neurological Infections, Johns Hopkins
Hospital, Baltimore, MD, USA
INTRODUCTION
The optic nerve, also termed cranial nerve II, is a distinct white mat-
ter tract extending from the posterior aspect of the ocular globe to the
optic chiasm. It forms the initial part of the afferent visual pathway
linking the retina to the brain. Optic neuritis (ON) is a term coined
to describe an inflammatory condition primarily involving the optic
nerve. Depending on the site of involvement, ON can also be referred
to as papillitis or anterior ON when there is evidence of associated
optic disc swelling. This is in distinction to retrobulbar ON, where
the disc often appears normal (Balcer, 2006). ON affects many people
worldwide and can result from many conditions producing an inflam-
matory reaction within the optic nerve, including, but not limited to,
autoimmune, infectious, and idiopathic etiologies (Burton, Greenberg,
& Frohman, 2011). Despite the fact that ON can be caused by a broad
category of disorders, a strong relationship exists between ON and
multiple sclerosis (MS). It is not surprising that essentially all of the
fundamental features of brain and spinal cord pathology in MS present
themselves in the anterior visual pathway during the course of ON.
In this sense, ON provides a general window and an exciting oppor-
tunity to examine some of the hallmark processes underlying what is
currently known about MS pathophysiology including inflammation,
demyelination, and neurodegeneration.
Multiple Sclerosis 281

http://dx.doi.org/10.1016/B978-0-12-800763-1.00012-9 © 2016 Elsevier Inc. All rights reserved.
282 12. PATHOPHYSIOLOGY OF OPTIC NEURITIS
ON IN RELATION TO THE RISK OF MS
In certain clinical circumstances, ON can be considered a harbinger

that heralds the diagnosis of MS. It is estimated that 25% of MS patients
suffer from ON as their initial disease manifestation and up to 70% of
patients experience it at least once throughout their disease course. Sev-
eral studies have examined the risk of developing MS in patients with
ON. Earlier population-based follow-up studies, relying solely on clini-
cal criteria for MS diagnosis, reported probabilities of developing MS
as low as 17% and as high as 39% 10 years after ON (Kurtzke, 1985).
The widespread availability of magnetic resonance imaging (MRI) has
made it possible to image clinically silent lesions attributable to the MS
disease process, thus facilitating an earlier and more accurate diagnosis
of MS. One study reported that MRI, as an investigation tool in patients
presenting with their first episode of acute ON, had a superior sensi-
tivity for detecting synchronous and clinically silent central nervous
system (CNS) lesions, outside of the affected optic nerve, that were
characteristic of MS, as compared to electrophysiological methods, such
as visual evoked potentials (VEPs) and somatosensory evoked poten-
tials (Frederiksen, Larsson, Olesen, & Stigsby, 1991). One of the prin-
cipal studies that helped advance our knowledge about ON treatment
and the relationship between MS and ON was the Optic Neuritis Treat-
ment Trial (ONTT) (Beck et al., 1992). This trial examined 457 patients
with acute ON and assessed the impact of oral versus intravenous cor-
ticosteroid therapy on visual function recovery. The investigators fol-
lowed a subset of 388 patients, who did not have probable or clinically
definite MS (CDMS) at the time of ON, and found that the cumulative
probability of developing CDMS was 30% after 5 years (Optic Neuritis
Study Group, 1997), 38% after 10 years (Optic Neuritis Study Group,
2003), and 50% after 15 years of the initial ON episode (Optic Neuritis
Study Group, 2008a). Importantly, the study also substantiated the evi-
dence that at the time of ON the presence of brain MRI abnormalities is
a strong predictor of future clinical events. Indeed, 25% of patients with
no baseline brain MRI lesions followed in the ONTT developed MS after
15 years of follow up compared with 72% of patients who had one or
more brain lesions. Consequently, MRI criteria have been developed in
order to more accurately prognosticate the risk of conversion to CDMS
in patients with ON and other clinically isolated syndromes (CISs)
(Swanton et al., 2007). Although clinical evidence of lesion dissemina-
tion in both space and time lies at the heart of establishing a diagnosis
of MS, MRI of the CNS can now replace some of the clinical criteria
enabling the clinician to diagnose MS at presentation in a subset of
patients with ON (Polman et al., 2011) (Table 1).
Epidemiology of ON in MS 283
TABLE 1 MRI criteria for MS diagnosis according to the 2010 revised McDonald criteria
requiring objective evidence of dissemination of CNS lesions in both space and time
Type of
dissemination MRI criteria
Space One or more lesions on a T2-weighted scan, with or without gadolinium

enhancement, visible in at least two out of the following four CNS locations:
• p eriventricular
• juxtacortical
• i nfratentorial
• s pinal cord
Time One or both of the following:
1. Presence of a new T2 and/or gadolinium-enhancing lesion(s) on
follow-up MRI, with reference to a baseline scan, regardless of the
timing of the baseline MRI.
2. An MRI scan demonstrating the simultaneous presence of
asymptomatic gadolinium-enhancing and nonenhancing lesions.
CNS, central nervous system; MRI, magnetic resonance imaging; MS, multiple sclerosis.
EPIDEMIOLOGY OF ON IN MS
Several community-based studies have estimated that the average

annual incidence rates for isolated ON range globally from 0.7 to 6.4 per
100,000 per year (Jin, de Pedro-Cuesta, Söderström, Stawiarz, & Link,
1998; Percy, Nobrega, & Kurland, 1972; Rodriguez, Siva, Cross, O’Brien, &
Kurland, 1995; Wakakura et al., 1995; Wikström, 1975). In general, ON
incidence patterns bear close resemblance to what is seen in MS overall.
ON occurs more commonly in women, as compared to men, with most
northern European and United States studies reporting a female-to-male
ratio of approximately 3:1 (Jin et al., 1998; Optic Neuritis Study Group,
1991; Rodriguez et al., 1995). Several studies have also reported that sea-
sonal and latitudinal patterns of ON and MS closely resemble each other,
with the occurrence of ON being greater during the spring months and
at higher latitudes (Jin, de Pedro-Cuesta, Söderström, Stawiarz, & Link,
2000; Taylor et al., 2010). Interestingly, racial factors might influence the
severity of an attack of ON. In the United States, studies have suggested
that an African–American ethnicity might be related to worse visual out-
comes (visual acuity and contrast sensitivity) following an episode of ON
(Kimbrough et al., 2014; Moss, Gao, Balcer, & Joslin, 2014). Similar forms
of severe ON have also been described in black South African, as well as
Japanese patients (Dean et al., 1994; Kuroiwa, Igata, Itahara, Koshijima, &
Tsubaki, 1975). According to the results of one study, a fewer proportion
of Japanese patients with ON had demyelinating lesions on brain MRI
(14%) in contrast to rates reported in the US (49%) (Wakakura et al., 1999),

suggesting that different etiologic factors might underlie a proportion of
ON cases in Japan, a country known for its low prevalence of classical MS
(Poser & Brinar, 2004).
THE AFFERENT VISUAL PATHWAY
The retina
The important role of the human visual sensory system is high-
lighted by the remarkably sophisticated organization of the afferent
visual pathway. This functional organization begins at the level of the
outer retina where two primary types of photoreceptors are located: the
rods and cones. Although the cell bodies of both the rods and cones are
present in the outer nuclear layer (ONL) of the retina, their topographi-
cal distribution is not uniform. The central depression in the human
macula, known as the fovea centralis, constitutes an area essentially
devoid of rods, and primarily composed of a compact arrangement
of cone cells imparting color perception and high acuity vision to the
eye. The photoreceptors project their processes to the outer plexiform
layer in order to synapse with neuronal elements in the neighboring
inner nuclear layer (INL). The INL, a retinal layer recognized to have
a complex architecture, harbors the cell bodies of bipolar, horizontal,
amacrine, and Müller cells. It is worth noting that Müller cells, a type
of specialized radial glia, serve a secondary, yet vital, role in the visual
pathway where they provide a support system for virtually all neuro-
nal components of the retina through their widely branching processes.
Ultimately, visual information is propagated to the retinal ganglion
cells (RGCs), whose cell bodies are located in the ganglion cell layer
(GCL). In turn, the axons of ganglion cells form bundles in the inner-
most retinal layer, the retinal nerve fiber layer (RNFL), which project
toward the optic disc where they coalesce to form the optic nerves. At
least three types of ganglion cells exist in the human retina: parasol,
midget, and small bistratified cells. Centrally in the macula, midget
cells constitute approximately 90%, parasol cells 5%, and small bistra-
tified cells about 1% of the RGCs, whereas in the periphery midget
cells make up about 40–45%, parasol cells 20%, and small bistratified
cells about 10% of the total RGCs. The parasol RGCs are character-
ized by the large size of their dendritic trees and cell bodies in contrast
to midget RGCs which have smaller dendritic trees and cell bodies.
All RGC axons are unmyelinated as they course through the RNFL.
They only acquire myelin as they pass posteriorly through the lamina
cribrosa where they exit the eye.
The afferent visual pathway 285
The optic nerve

The optic nerve comprises 0.87–1.2 million ganglion cell axons and
ranges in length from 5 to 6 cm. It is divided into four distinct segments:
intraocular, intraorbital, intracanalicular, and intracranial segments
(Bruesch & Arey, 1942). Embryologically, the optic nerve is considered an
extension of the diencephalon. Unlike other cranial and peripheral nerves,
the axons enclosed within the optic nerve are myelinated by oligoden-
drocytes. Therefore, the optic nerve represents a structure akin to white
matter tracts in the brain, potentially explaining the tendency for MS, a
disorder known for its propensity to affect widespread areas of the CNS
myelinated by oligodendrocytes, to affect the optic nerves. This involve-
ment manifests itself clinically, as discrete episodes of ON frequently seen
in the relapsing–remitting stages of the disorder, as well as subclinically
in the form of demyelinating optic nerve plaques seen at postmortem in
the striking majority (94–99%) of MS patients (Ikuta & Zimmerman, 1976;
Toussaint, Périer, Verstappen, & Bervoets, 1983).
The optic chiasm

The optic chiasm plays a pivotal role in the retinotopic representation
of visual input data and is located superior to the pituitary gland, anterior
to the pituitary stalk, and inferior to the hypothalamus. It is estimated that
at the level of the optic chiasm 53% of optic nerve axons, predominantly
originating from the nasal hemiretina, decussate to join the fibers from
the contralateral temporal hemiretina forming the optic tract (Kupfer,
Chumbley, & Downer, 1967). This decussation aims to combine visual input
information from the two halves of each retina that receive light from the
same portion of the visual field. The majority of optic tract axons synapse
in the lateral geniculate nucleus (LGN) of the thalamus.
The lateral geniculate nucleus (LGN) and optic radiations

The LGN serves as a relay station responsible for visual signal process-
ing through a highly complex synaptic organization. The LGN is composed
of a laminar structure partitioned into six separate laminae. Laminae 1
and 2 (the magnocellular layers) comprise neurons that principally receive
their input from the larger, faster conducting parasol RGC axons. On the
other hand, laminae 4–6 (the parvocellular layers) harbor smaller neu-
rons receiving afferent signals from the small diameter, slowly conducting
axons of midget RGCs. Neurons of the LGN project via the geniculocal-
carine fibers of the optic radiations to the primary visual cortex (V1). The
human optic radiations are composed of two main bundles: a temporal
branch carrying information from the contralateral superior homonymous
visual field (also termed Meyer’s loop), and a parietal branch carrying
information from the contralateral inferior homonymous visual field.
Visual cortex
The human primary visual cortex (V1) is located in the mesial aspect
of the occipital lobe where the superior and inferior banks of the calca-
rine fissure receive input signals from the parietal and temporal optic
radiations, respectively. A well-defined topographic map of the contra-
lateral homonymous visual hemifield exists in the primary visual cortex.
Macular representations synapse with neurons located posteriorly in the
occipital pole, while the periphery of the visual field is mapped more ante-
riorly. The vertical meridian representation lies medially in the calcarine
lips, whereas the horizontal meridian representation is located laterally
deep within the calcarine fissure (Horton & Hoyt, 1991). Collectively, the
human retino–geniculo–calcarine neuronal pathway maintains a distinct
retinotopic organization that is carried over to the visual cortex.
CLINICAL FEATURES OF OPTIC NEURITIS
Patient history
Acute demyelinating ON usually presents between the ages of 20 and
50 years and can be classified into typical and atypical forms based on
clinical features (Table 2). In its typical form, ON presents with subacute
visual loss associated with blurring of objects in the affected visual field.
The decline in visual acuity, although highly variable, is generally monoc-
ular and develops over a period of several days. Patients often report color
desaturation in the affected eye, particularly of red colors, that can persist
for months after the acute event (Schneck & Haegerstrom-Portnoy, 1997).
Periocular pain is another symptom seen in 92–94% of patients with ON
(Beck et al., 1992) and is usually exacerbated by eye motion. It can precede
the onset of visual symptoms in 40% of patients (Optic Neuritis Study
Group, 1991). Lesions in the intracanalicular and/or intracranial seg-
ments of the optic nerve, in the absence of orbital segment involvement,
are perhaps less likely to result in pain (Fazzone, Lefton, & Kupersmith,
2003). Patients may also report brief vertical flashes of light that can also
be induced by eye movements. This effect is often referred to as Moore’s
lightning streaks and is considered to be a subgroup of phosphenes (phe-
nomena characterized by the sensation of seeing light when no light is
actually entering the eye) seen in ON (Davis, Bergen, Schauf, McDonald,
& Deutsch, 1976). Other symptoms that can be experienced by patients
include the Pulfrich effect (a visual stereoillusion seen in unilateral ON
Clinical features of optic neuritis 287
TABLE 2 Features of typical versus atypical optic neuritis
Typical optic neuritisa Atypical optic neuritisb
Age (years) 20–50 >50 or <12
Symptomatic Unilateral in adults, more frequently Bilateral simultaneous or

side bilateral in children rapidly sequential
Visual loss Acute/subacute onset with stabilization Worsening of visual loss beyond
by 2 weeks 2 weeks or lack of recovery
within 1 month of onset
Pain Mild-to-moderate periocular pain Absence of periocular pain or

exacerbated by eye movement severe periocular pain waking
the patient from sleep
Fundoscopy Normal optic disc appearance in Presence of severe papillitis,

two thirds of cases, diffuse optic disc disc or peripapillary
swelling in one third hemorrhage, retinal exudate
Other MRI showing at least one T2 lesion Personal or family history of
compatible with demyelinating disease, systemic illness
Uhthoff’s phenomenon, Moore’s
lightning streaks, Pulfrich effect
a Typical features are associated with a high risk of developing MS.
b Absence of typical features or presence of atypical features should raise suspicion for alternative diagnoses (e.g.,
sarcoidosis, systemic lupus erythematosus, anterior ischemic optic neuropathy, Leber’s hereditary optic neuropathy,
syphilis, Lyme disease, paraneoplastic disease) (Balcer, 2001; Burton et al., 2011; Toosy, Mason, & Miller, 2014).
characterized by a false depth perception of moving objects due to dispa-

rate conduction between optic nerves) (O’Doherty & Flitcroft, 2007) and
Uhthoff’s phenomenon (a transient decline in visual acuity induced by
a rise in core body temperature, often experienced in hot weather condi-
tions, during exercise, or when taking a hot bath/shower).
Physical examination
Clinically, reduced visual acuity is a common, early sign of ON that
occurs with a variable spectrum of severity ranging from 20/20 vision or
better to an absence of light perception (Balcer, 2001). Reductions in low-
contrast visual acuity and color vision are also seen during the course of ON.
Furthermore, deficits in low-contrast vision can persist for many years after
the acute ON event (Talman et al., 2010). A relative afferent pupillary defect
(RAPD) is a consistent clinical sign seen in ON, unless the fellow optic nerve
is equally involved or previously pathologically affected resulting in dimi-
nution of the intereye difference. Fundoscopic examination is unrevealing
in approximately 65% of cases, with the remainder demonstrating evidence
of mild-to-moderate, diffuse papillitis, or optic disc swelling (Optic Neuritis
Study Group, 1991). The presence of severe papillitis, disc or peripapillary
hemorrhage, retinal exudate, and/or vitreous cells is uncommon and, not

only does it raise suspicion for other diagnoses, but was also found to be
associated with a lower risk of MS development 10 years after ON (Optic
Neuritis Study Group, 2003). Optic disc pallor following the initial insult
does not usually manifest itself acutely but rather takes several months to
become apparent (unless the affected eye had a previous history of ON),
and possibly reflects astrogliosis in response to axonal degeneration/loss
within the affected optic nerve head (Burton et al., 2011). Visual field loss,
as revealed by perimetry, is typical of ON and can be diffuse or focal. More-
over, variable patterns of focal visual field disturbances can be seen includ-
ing, but not limited to, central, centrocecal, paracentral, arcuate, altitudinal,
nasal step, and hemianopic defects (Keltner, Johnson, Spurr, & Beck, 1993;
Nevalainen et al., 2008).
Recovery
In most patients with typical ON, visual recovery is relatively quick and
occurs as early as the first few weeks after symptom onset (Beck, Cleary, &
Backlund, 1994). The affected eyes of patients enrolled in the placebo arm of
the ONTT had a median visual acuity of 20/60 at baseline which improved
to 20/25 by day 15 and to 20/20 by one month of follow up (Beck et al., 1994).
Failure of recovery to begin within the first 4 weeks following ON or further
worsening of visual acuity beyond two weeks of onset is uncommon and
suggestive of alternate diagnoses (Burton et al., 2011). The course of visual
recovery, however, can continue for up to one year after ON onset, with 90%
of patients demonstrating a 20/40 or better visual acuity at the one year time-
point (Beck & Cleary, 1993). Although the initial severity of visual loss was
predictive of the visual outcome after 6 months of follow up in the ONTT
(Beck et al., 1994), visual recovery was still pronounced in patients with severe
visual loss (20/200 acuity or worse) enrolled in the placebo group, of whom
57% regained better than 20/20 vision (Beck, 1993). Despite the remarkable
recovery of visual function at high contrast in the majority of affected eyes,
long-term deficits in visual acuity (particularly at the low contrast level), con-
trast sensitivity, and visual fields are not uncommon after the initial episode
of ON (Balcer, 2001; Optic Neuritis Study Group, 2008b), suggesting that
natural reparative mechanisms may not be capable of fully restoring baseline
visual function and quality-of-life measures in a subgroup of patients.
INFLAMMATION IN OPTIC NEURITIS
During the initial development of a prototypical MS lesion, it is believed

that activated CD4+ T cells with specificity for one or more self-antigens gain
access to the CNS by migrating through the luminal endothelial surface of
CNS venules (Noseworthy, Lucchinetti, Rodriguez, & Weinshenker, 2000).
Inflammation in optic neuritis 289
After recognition of target antigens on antigen-presenting cells, this process

is followed by a cascade of events that result in amplification of the immune
response and further recruitment of inflammatory cells to the CNS resulting
in a heterogeneous inflammatory infiltrate consisting of T cells, B cells, and
mononuclear cells of the monocyte/macrophage system within demyelin-
ating lesions (Brück et al., 1995). Similarly, the early phase of ON in MS is
dominated by inflammation; evidence of systemic T cell activation has been
identified early after the onset of clinically isolated ON associated with the
release of pro-inflammatory cytokines (Roed et al., 2005). The resulting optic
nerve lesion displays remarkable pathologic similarity to MS brain lesions
in human and animal studies (Allen, 1981; Guy, Fitzsimmons, Ellis, Beck, &
Mancuso, 1992).
It is important to note that inflammation in ON is not necessarily con-
fined to the optic nerves, but may also involve the retina and/or other
structures of the afferent visual system including the optic chiasm and optic
tracts (Plant et al., 1992). Retinal venous sheathing or periphlebitis has been
observed in a proportion of ON and MS patients ranging between 5% and
25% according to several studies (Engell, 2009; Lightman et al., 1987). This
ophthalmoscopic finding refers to visible cuffs of inflammatory cells sur-
rounding retinal veins analogous to cellular infiltrates seen around cere-
bral veins in prototypical MS lesions (Engell, Jensen, & Klinken, 1985). Yet
the importance of retinal involvement in ON, and MS overall, stems from
the fact that the retina itself is a structure devoid of myelin and oligoden-
drocytes. Not only does this finding suggest that retinal vascular changes
in ON could be the derivative of a primary event, but it also challenges the
central dogma that the presence of myelin is necessary for the instigation
and propagation of inflammation in MS. Furthermore, evidence suggests
that retinal periphlebitis may confer a greater risk of conversion to MS in
patients with ON (Lightman et al., 1987) and may be related to overall MS
severity in the absence of ON (Ortiz-Pérez et al., 2013).
The presence of inflammation during the acute phase of ON relates to some
extent with a number of symptoms experienced by patients, including the
reduction in visual acuity, visual field deficits, and periocular pain. The faster
visual recovery in ON patients receiving intravenous methylprednisolone
followed by oral prednisone, as compared to placebo, underscores the rela-
tionship between early optic nerve inflammation and the acute disturbance
in visual acuity (Beck et al., 1992). Moreover, cytokines released by immune
cells, whether locally or in the systemic circulation, may play an important
role in instigating transient conduction block in the optic nerve (Compston,
2004). Even in patients who have recovered from ON, acute cytokine release
secondary to lymphocytotoxicity may result in recrudescence of optic nerve
dysfunction and a decline in visual acuity (Moreau et al., 1996). Gradual reso-
lution of inflammation several weeks after ON onset occurs simultaneously
with the recovery of visual acuity (Hickman, Toosy, Jones, et al., 2004; Youl
et al., 1991).
DEMYELINATION IN OPTIC NEURITIS
Inflammation and demyelination occur congruently during the early

phase of ON. Spatially, both processes may involve the entire cross-section
of the nerve or may be more limited in their distribution (Burton et al.,
2011). In active MS lesions, the presence of activated T cells, microglia,
and macrophages results in a subsequent release of pro-inflammatory
cytokines, such as interleukin (IL)-1 β, IL-6, and tumor necrosis factor-α,
along with enhanced expression of inducible nitric oxide synthase. This
inflammatory milieu has been described to play a central role in promot-
ing in vitro demyelination and oligodendrocyte death (Di Penta et al.,
2013; Smith & Lassmann, 2002). The association between inflammation
and demyelination is not surprising given that macrophages are the pre-
dominant cell type responsible for myelin phagocytosis in MS lesions. In
fact, the identification of myelin degradation products in macrophages
(referred to as foamy macrophages) is perhaps the most reliable way of
recognizing active MS lesions (Noseworthy et al., 2000). The end result of
these processes which occur during the course of ON is that ganglion cell
axons are left either completely denuded of myelin or with a reduced con-
tent of surrounding myelin. As a consequence, these axons may no longer
be able to transmit action potentials as efficiently, needing to rely on mem-
brane conduction in place of more efficient saltatory conduction mecha-
nisms. Loss of saltatory conduction results in slowing, or even blocking,
of the propagation of action potentials conveying visual information from
ganglion cells to the LGN and therefore the development of some of the
ON symptoms observed, including reduced visual acuity and visual field
deficits.
Axonal demyelination is also closely related to other clinical phenom-
ena observed in ON patients. Studies have demonstrated that demy-
elinated axons are susceptible to physiologic increases of temperature
(as small as 0.5 °C) which often result in reversible conduction block
(Rasminsky, 1973). This effect is thought to explain the reversible blurring
of vision experienced by MS patients following exposure to hot ambient
conditions, such as during exercise, hot baths, and fever, which was orig-
inally reported by Uhthoff in 1889. Reciprocally, active cooling therapy
has been shown to be associated with improved conduction and modest
improvements in visual function of MS patients (Schwid et al., 2003).
The pathophysiological underpinnings of demyelination in ON may
not solely relate to the loss or reduction of the protective myelin insu-
lation. Attention has also been focused on the mechanisms of neuronal
plasticity following demyelinating injury in MS (Compston, 2004). This
is supported by evidence that suggests an important role for oligoden-
drocytes in dictating the distribution of neuronal sodium and potassium
channels along the axolemma (Mathis, Denisenko-Nehrbass, Girault, &
Demyelination in optic neuritis 291
Borrelli, 2001) and that of myelination in inducing clustering of Na(v)1.6

(the main sodium channel isoform in adults) at the nodes of Ranvier
(Kaplan et al., 2001). It follows that demyelination and oligodendrocyte
cell drop out could result in a variety of disturbances to this arrange-
ment, one of which appears to be redistribution of sodium channels
along the denuded axon (England, Gamboni, Levinson, & Finger, 1990).
In theory, such alterations could help restore, at least partially, some of
the conductive function of the nerve in the short term. However, the long-
term effects of such physiological derangements on axonal and neuronal
health remain to be fully elucidated.
Evidence from experimental and pathologic studies in humans sup-
ports the notion that remyelination does in fact occur in the adult ner-
vous system, albeit sparsely and incompletely. Although oligodendrocyte
numbers are variably reduced during active stages of myelin destruction,
demyelinating optic nerve injury triggers a wave of reparatory processes
in inactive lesions exemplified by oligodendrocyte proliferation, with
marked heterogeneity existing between individual MS patients (Lucchinetti
et al., 1999). In experimental animal studies, the proliferative oligo-
dendrocyte progenitor cell has been described as the most efficient
remyelinating cell in achieving successful myelin repair of demyelinating
lesions, including those of the optic nerve (Carroll, Jennings, & Mastaglia,
1990; Reynolds & Wilkin, 1993). The source of oligodendrocyte prolifer-
ation after demyelinating lesions in humans may relate to the presence
of a similar population of oligodendrocyte progenitor cells identified in
normal adult human white matter as well as in acute and chronic lesions
of MS patients (Scolding, Franklin, Stevens, Heldin, & Compston, 1998).
Although the availability of oligodendrocyte progenitor cells influences
the final number of oligodendrocytes in a demyelinating lesion, the mere
presence of oligodendrocytes does not appear to be the only factor nec-
essary for successful remyelination. Some oligodendrocytes that remain
morphologically preserved in acute MS lesions may show subtle, early
pathologic abnormalities suggesting that their myelinating potential could
have been compromised without overt cell death taking place (Rodriguez,
Scheithauer, Forbes, & Kelly, 1993).
Endogenous remyelination after ON appears to be most conspicuous
in optic nerve lesions developing early in the course of MS and, when
substantial remyelination takes place, it usually becomes morphologi-
cally apparent at least 1 month after the initial insult; a time interval that
coincides with clinical recovery after isolated typical ON (Prineas, Barnard,
Kwon, Sharer, & Cho, 1993). Plaques composed of thinly myelinated
axons (also known as shadow plaques) are thought to represent the out-
come of remyelination after a single previous episode of acute demyelin-
ation. In contrast, recurrent demyelinating optic nerve injury in the same
area of white matter may disrupt those reparative mechanisms, underlie
failure of remyelination, and result in permanently demyelinated axons

(Prineas, Barnard, Revesz, et al., 1993). This finding explains the conspicu-
ity of remyelination early in the course of MS and its absence in typical
chronic MS lesions which are more likely to have suffered repeated, tem-
porally distinct episodes of demyelination (Lucchinetti, Brück, Rodriguez,
& Lassmann, 1996). Endogenous remyelination in ON and in MS overall,
while helpful, is not without its limitations. Remyelinated axons tend to
have myelin sheaths that are thinner and have a shorter internodal length
compared with normal axons (Hanafy & Sloane, 2011). In effect, remy-
elinated axons demonstrate suboptimal axonal conduction velocities (Wu,
Williams, Delaney, Sherman, & Brophy, 2012). Ultimately, failure of com-
plete remyelination represents a paramount factor underlying persistent
visual disability following ON.
AXONAL AND NEURONAL DEGENERATION

IN OPTIC NEURITIS
Although MS has long been identified as an inflammatory demyelin-

ating disorder of the CNS, it is now widely accepted that axonal and
neuronal degeneration represent the principal pathological substrates of
disability in MS. The role of pathological axonal changes, including loss,
transection, and/or disturbed axonal transport, has been recognized as
a prominent and early feature of MS and ON contributing to permanent
disability (Kuhlmann, Lingfeld, Bitsch, Schuchardt, & Brück, 2002; Trapp
et al., 1998). Axonal loss, in conjunction with demyelination, culminates
in white matter atrophy of brain tissue during the course of MS. Similarly,
axonal degeneration in conjunction with demyelination following ON
results in a reduction of the cross-sectional area of the optic nerve, that is,
optic nerve atrophy.
Despite the uncertainty surrounding the cause(s) of neuronal injury in
MS, one of the ramifications of axonal transection and injury in MS is the
potential for subsequent retrograde neuronal degeneration, perceived as
a dying back phenomenon extending proximally from a point of injury
along the axon and resulting in pathological changes at the level of the
originating neuronal cell body. Conversely, axonal degeneration may also
proceed in an anterograde direction along the parts of the axon distal to
the point of injury, a phenomenon referred to as Wallerian degeneration.
The afferent visual pathway, due to its functional eloquence, provides an
excellent opportunity to study the neurodegenerative sequelae following
ON-related axonal injury. Rodent models of RGC axotomy have clearly
demonstrated that both anterograde and retrograde axonal degeneration
progress simultaneously following transection of unmyelinated ganglion
cell axons, suggesting a common pathogenic mechanism underlying this
Axonal and neuronal degeneration in optic neuritis 293
bidirectional axonal loss (Kanamori, Catrinescu, Belisle, Costantino, &

Levin, 2012). Histopathologic studies of human optic nerves have esti-
mated that axonal densities are reduced by approximately 45% in the
optic nerves of MS patients when compared to healthy controls, although
this reduction has not been explicitly linked to previous ON history
(Evangelou et al., 2001). Axonal degeneration seen after ON is not neces-
sarily restricted to the optic nerve, but may also extend anterogradely to
affect the optic tract and retrogradely to the RNFL. This is unsurprising
given that both of these structures harbor biological extensions of RGC
axons (Kerrison, Flynn, & Green, 1994). While axonal loss in the optic
nerve of MS patients probably reflects inflammation-induced axonal dam-
age, it may also represent postinflammatory neurodegeneration partially
due to unsuccessful remyelination, especially in the progressive subtypes
of the disease (Miller, Barkhof, Frank, Parker, & Thompson, 2002). In the
absence of inflammation, animal studies have demonstrated spontaneous
axonal degeneration in myelin-deficient mice indicating the importance of
local oligodendrocyte support in maintaining axonal well-being (Griffiths
et al., 1998). In MS patients, denuded axons may be more susceptible to
soluble or cellular immune mediators present in chronic demyelinating
lesions (Brück & Stadelmann, 2003). This is supported by the fact that
remyelinated lesions are less susceptible to axonal destruction, perhaps
due to the protective effects of myelin (Kuhlmann et al., 2002). Collec-
tively, these findings highlight the importance of the myelin-oligodendro-
cyte unit in preserving axonal integrity.
Not only is axonal injury integral to the functional deficit seen after
an ON episode, but there is also evidence to suggest that RGCs are par-
ticularly susceptible to the effects of retrograde axonal degeneration.
This has been clearly demonstrated in animal models showing marked
ganglion cell apoptosis in response to axonal transection, whether sec-
ondary to mechanical or inflammatory events (Cusato, Stagg, & Reese,
2001; Fairless et al., 2012). Postmortem human studies of MS patients
have also revealed significant RGC drop out and corresponding GCL
atrophy in 73–79% of MS eyes, of which the majority suffered from
optic nerve atrophy and/or gliosis (Green, McQuaid, Hauser, Allen, &
Lyness, 2010; Kerrison et al., 1994). These findings, while not confirma-
tory of the exact etiology of ganglion cell death, do provide grounds to
suspect that retrograde degeneration might be at play in the anterior
visual pathway of MS patients, whether secondary to clinically dis-
crete episodes of ON or subclinical demyelinating plaques in the optic
nerve which are almost ubiquitously present at postmortem (Ikuta &
Zimmerman, 1976; Toussaint et al., 1983).
Although retrograde neuronal degeneration after axonal damage has
been well-described, another intriguing question is whether this degener-
ation extends to the next cell in the chain of neuronal conduction adjacent
to the one that degenerates, a process known as trans-synaptic neurode-

generation. Perhaps one of the best known examples of anterograde trans-
synaptic degeneration in the visual pathway (i.e., atrophy and death of
neurons losing their afferent supply of impulses) is that of the LGN fol-
lowing lesions of the retina, optic nerve, and/or optic tract (Goldby, 1957).
Interestingly, neurodegeneration in the LGN can occur in disparate pat-
terns depending on the size of neurons involved, with the smaller neurons
of the parvocellular layers (laminae 4–6) being preferentially affected in
MS (Evangelou et al., 2001). It is also plausible for degeneration to progress
in the opposite direction; upstream from the primarily affected neuron to
the nerve cell providing it with impulses, that is, retrograde trans-synaptic
neurodegeneration. Early reports examining retrograde trans-synaptic
degeneration in the retina have described degeneration within the INL
occurring synchronously with anterograde trans-synaptic degeneration of
the LGN following a lesion of the optic chiasm in a primate (Van Buren,
1963). Surprisingly, the INL showed evidence of cystic changes that were
irregularly rounded, the larger of which contained fine strands of tissue
and debris (presumed to be the result of degeneration). These findings
have been recapitulated in human eyes with lesions in the optic nerve
and/or chiasm, further demonstrating a significant decrease in the cel-
lularity of the INL (Gills & Wadsworth, 1967). Similarly, more refined his-
topathologic postmortem examinations have revealed prominent atrophy
of the INL in 40% of MS eyes. A proportion of MS eyes examined also
demonstrated concomitant localized perivenular inflammatory infiltrates
that sometimes extended into the INL. Therefore, it remains to be eluci-
dated whether the INL pathology seen in MS eyes is a derivative of retro-
grade trans-synaptic neuronal degeneration or represents the aftermath of
primary retinal inflammatory events, that is, periphlebitis, culminating in
bipolar, amacrine, horizontal, and/or Müller cell loss in association with
INL atrophy.
IMAGING AND ELECTROPHYSIOLOGIC CORRELATES

OF OPTIC NEURITIS
Optical coherence tomography (OCT)

The classic structural changes in the posterior pole of the eye related to
ON, as visualized during fundoscopy, include papilledema acutely in one
third of cases which is followed gradually (over the course of months) by
optic disc pallor. Unlike most areas of the CNS, the unmyelinated nature
of the RNFL, and retina in general, presents a unique opportunity to study
axonal, neuronal, and glial changes following MS-related injury that are
not directly confounded by changes in myelin. It is estimated that losses
Imaging and electrophysiologic correlates of optic neuritis 295
(A) (C)
(B)
FIGURE 1 High-definition optical coherence tomography (OCT) images obtained using

a Cirrus HD-OCT device from the left eye of a 30-year-old healthy female. Panel A shows a
scanning laser ophthalmoscope image depicting the retinal area scanned. The depth-resolving
capacity of OCT enables the generation of cross-sectional images of the vitreoretinal
interface allowing clear demarcation of the different retinal layers (Panel B), and three-
dimensional reconstruction of the retina (Panel C). GCIP, ganglion cell + inner plexiform
layer; INL, inner nuclear layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RNFL,
retinal nerve fiber layer; RPE, retinal pigment epithelium.
of greater than 50% of the RNFL thickness are necessary for deficits to
become clinically apparent on fundoscopic examination and/or retinal
photography (Quigley & Addicks, 1982), indicating that physical exami-
nation techniques might be insensitive to early or mild retinal changes
resulting from optic nerve injury.
Advancements in ocular imaging have facilitated the objective analysis
of retinal axonal and neuronal degeneration in ON, and MS in general.
In particular, optical coherence tomography (OCT), an imaging technique
that relies on Michelson’s theory of interferometry of near infrared light,
enables the generation of high-resolution, three-dimensional images of
retinal architecture (Figure 1). Not only does this allow gross character-
ization of retinal morphology at a qualitative level, but it also provides
the capability to objectively and reproducibly quantify the thicknesses of
different retinal layers (Syc et al., 2010). OCT is noninvasive and, for most
patients, well tolerated, thus providing a way to sensitively and rapidly
capture changes in the retina that occur as a consequence of ON, as well
as to possibly monitor therapeutic responses to neuroprotective agents
(Frohman et al., 2008).
Concomitant with the early, inflammatory phase of ON, studies
using OCT have described that the thickness of the peripapillary RNFL
increases acutely after the event, with or without apparent clinical
swelling of the optic nerve (Figure 2) (Pro et al., 2006). Although direct
extension of the inflammatory lesion and/or blood-optic nerve barrier
breakdown to the laminar and prelaminar portions of the optic nerve
has been proposed as a pathobiologic explanation, another plausible
alternative is that the thickening can be attributed to secondary axonal
swelling and interstitial edema resulting from axonal blockade, partic-
ularly when the optic nerve lesion is remotely located from the optic
nerve head. This is perhaps supported by the findings from one study
showing that elevated RNFL thickness acutely after ON was related to
the length of the optic nerve lesion rather than its apparent location
(Kallenbach et al., 2010). After two to three months of the ON event,
ensuing reductions in the thickness of the peripapillary RNFL have
been reported both cross-sectionally and longitudinally, culminating in
an overall loss of thickness compared to the clinically unaffected eye
(Costello et al., 2008; Henderson et al., 2010; Parisi et al., 1999). This
observed rapid change in the peripapillary RNFL thickness from swell-
ing to atrophy can be explained by two coexisting factors: resolution of
the peripapillary RNFL edema (which would explain the drop in thick-
ness back to its presumed baseline value taking the clinically unaffected
eye as a surrogate), in conjunction with axonal degeneration with or
without gliosis (which would explain the eventual drop in thickness
below the presumed baseline value).
OCT imaging has also enabled in vivo characterization of the GCL
following MS-related ON. In line with experimental animal and post-
mortem human studies demonstrating ganglion cell loss following
MS-related optic nerve injury (Fairless et al., 2012; Green et al., 2010),
longitudinal studies have shown that the composite thickness of the
ganglion cell and inner plexiform layers (GCIP), ascertained using OCT,
declines in the early period following an ON event (Figure 3) (Syc et al.,
2012). Unlike the RNFL, however, the GCIP thickness is not confounded
acutely by the presence of swelling or edema, making it more suitable to
assess ganglion cell atrophy within the retina without needing to rely on
measures from the clinically unaffected eye as a surrogate for baseline
values. There is also evidence to suggest that the pathologic sequelae
from ON are not limited to the RNFL and GCL but may also extend to the
deeper retinal neuronal layers. Cross-sectionally, studies have described
(A)
(B)
(C)
(D)
FIGURE 2 RNFL thickening during the acute stage of ON as detected using OCT in a
34-year-old female diagnosed with unilateral, right-sided ON. (A) OCT fundus images illus-
trate blurring of the optic margins consistent with disc swelling in the clinically affected eye.
(B) Extracted RNFL tomograms from the region of the green circle seen in row A reveal con-
comitant RNFL thickening. (C and D) Spatial RNFL thickness graph and quadrant average
RNFL thickness values of regions around the same circle depict the profile of quantitative
RNFL thickening compared with the clinically unaffected eye. ILM, inner limiting mem-
brane; RNFL, retinal nerve fiber layer; NAS/N, nasal; INF/I, inferior; TMP/T, temporal;
SUP/S, superior; OCT, optical coherence tomography; ON, optic neuritis.
(A)
(B)
(C)
FIGURE 3 Changes in the composite thickness of the ganglion cell and inner plexiform
layers (GCIP) at baseline and 12 months after right-sided ON. (A) Central OCT B-scans dem-
onstrate qualitative thinning of the GCIP (bounded by the purple and yellow boundaries)
12 months after ON. (B) GCIP thickness maps of the macular region indicate a circumferen-
tial loss of GCIP thickness around the fovea. (C) Color-coded, sectoral GCIP thickness mea-
surements, within an annulus centered at the fovea, demonstrate a quantitative reduction in
GCIP thickness measurements to values below the first percentile (as indicated by the red
color) compared with an age-matched reference population.
that in eyes with a previous history of ON more pronounced ganglion

cell loss appears related to an increased thickness of the INL (Kaushik
et al., 2013). Qualitative changes in the INL, termed microcystic macular
edema (MME), have also been detected using OCT, more commonly in
MS eyes with a past history of ON (Gelfand, Nolan, Schwartz, Graves,
& Green, 2012; Saidha et al., 2012). The term “microcystic,” in this sense,
could be a misnomer as these lesions may not reflect true cystic pathol-
ogy. Their presence may also not be specific to the MS disease process
as similar findings have been seen in patients with other forms of optic
neuropathy (Sotirchos et al., 2013; Wolff et al., 2014). Interestingly, it is

plausible that MME may actually represent the in vivo, OCT correlate of
the INL pathology described by Van Buren in the early 1960s (Van Buren,
1963), although this remains to be determined. MS eyes with MME tend
to have an increased thickness of the INL and exhibit more pronounced
visual disability in terms of high and low contrast visual acuity. In the
absence of apparent MME, increased INL thickness in MS eyes with or
without a past history of ON might be associated with or even predic-
tive of inflammatory activity and lesion accumulation, thereby raising
the possibility that inflammation confined to this retinal layer could
be reflecting or even preceding global inflammatory events in the CNS
(Saidha et al., 2012).
Magnetic resonance imaging (MRI)

Advances in MRI technology have permitted a more thorough under-
standing of the pathophysiological underpinnings of inflammation in
ON. Perhaps the best known MRI correlate of inflammation during the
acute phase of ON is gadolinium enhancement (Figure 4). More specifi-
cally, enhancement within the optic nerve reflects a disruption in the integ-
rity of the blood–brain barrier at the level of the optic nerve resulting in
the extravasation of gadolinium into the surrounding tissue. This find-
ing is present in approximately 90–94% of ON cases (Rizzo, Andreoli, &
Rabinov, 2002). The relevance of optic nerve enhancement is highlighted
by its association with reduced visual acuity, dyschromatopsia, periocu-
lar pain, RAPD, and delayed P100 latency and reduced amplitude on VEP
testing of affected eyes (Youl et al., 1991). The presence versus absence
of optic nerve enhancement does not appear to be the only MRI predic-
tor of visual disability during the acute phase of ON, but studies have
also pointed to the fact that the length of the enhancing optic nerve seg-
ment also correlates with a more severe pattern of visual dysfunction
(Kupersmith, Alban, Zeiffer, & Lefton, 2002). Optic nerve enhancement typ-
ically resolves over the course of the first month after symptom onset and
its disappearance parallels the resolution of the clinical symptoms of ON.
Another measure with potential specificity towards detecting demy-
elination and axonal loss is magnetization transfer imaging (MTI). MTI
detects the shift of magnetization between two types of protons present
within biological systems: protons that are bound to macromolecules,
such as myelin and axons, and those that are free. The magnetization
transfer ratio (MTR) is affected by changes in myelin and axonal macro-
molecular structure. The MTR initially appears reduced after ON and its
recovery following the resolution of ON may reflect remyelination within
the injured optic nerve (Hickman, Toosy, Miszkiel, et al., 2004; Schmierer,
Scaravilli, Altmann, Barker, & Miller, 2004).
(A) (B)
(C)
FIGURE 4 Postcontrast T1-weighted MRI images illustrating right optic nerve enhance-
ment (blue arrows) seen on axial (Panel A), coronal (Panel B), and sagittal views (Panel C) in
a patient with active clinically isolated optic neuritis.
Diffusion tensor imaging (DTI) is an MRI technique that relies on char-

acterizing the three-dimensional diffusion of water to provide information
regarding the structural integrity of axons within white matter tracts or
changes in their permeability (Alexander, Lee, Lazar, & Field, 2007). When
applied to the optic nerve following ON, DTI measures provide in vivo
evidence of axonal disruption in the affected optic nerve that correlates
with visual dysfunction and abnormalities in VEPs (Naismith et al., 2010;
Trip et al., 2006) and may be associated with a worse visual outcome at
6 months (Naismith et al., 2012). Such DTI alterations, reflecting aberrant
patterns of water diffusion, could be attributed to myelin loss, axonal tran-
section, and/or degeneration secondary to the inflammatory demyelinat-
ing lesion associated with ON (Naismith et al., 2010). Quantitative DTI
biomarkers have also revealed that retinal injury and visual disability in
patients with previous ON is related to evidence of axonal damage in the

optic radiations, possibly representing an in vivo correlate of anterograde
trans-synaptic neurodegeneration (Kolbe et al., 2012; Reich et al., 2009).
Visual evoked potentials (VEPs)

Visual stimuli can result in (or “evoke”) cortically generated potentials
in the visual receiving areas of the occipital cortex after transmission of
the afferent signal from the retina via the LGN to the striate cortex. Such
responses can be recorded via scalp electrodes and are termed VEPs. Due
to the cortical overrepresentation of the macular region, conventional full-
field VEP is greatly influenced by the macular response (Klistorner et al.,
2008). In addition, it is prone to cancellation and distortion of its waveform
(Costello, 2013). More recent methodology has enabled the simultaneous
recording of VEPs from multiple regions of the visual field thus isolating
smaller groups of optic nerve axons and permitting a more refined topo-
graphic assessment (referred to as multifocal VEPs).
During the acute stage of ON, there is well-established evidence to
suggest that the amplitude of the VEP signal appears reduced (Halliday,
Mcdonald, & Mushin, 1972). Another hallmark finding on VEP testing
found in a high proportion of ON patients is delayed conduction of the
afferent signal which is thought to be a consequence of demyelinating injury
in the afferent visual pathway with subsequent loss of saltatory conduction
(Halliday, McDonald, & Mushin, 1973). VEP amplitude relates to the amount
of functioning fibers in the afferent visual pathway projecting to the striate
cortex. Hence, VEP amplitude reductions following ON may be a reflection
of two mutually nonexclusive pathophysiologic processes: inflammation
induced conduction block and/or axonal degeneration. Acutely, reduc-
tions in VEP amplitude appear related to gadolinium enhancement of the
affected optic nerve, an MRI marker reflecting a breach in the integrity of
the blood–optic nerve barrier and an imaging surrogate of active inflam-
mation (Youl et al., 1991). Moreover, reduced peripapillary RNFL thickness
(a structural measure of optic nerve integrity) following ON is not only
associated with reductions in VEP amplitude but also with prolongation of
VEP latency. This observation suggests a possible role for persistent demy-
elination in promoting axonal injury (Klistorner et al., 2008).
The resolution of the acute stages of ON is frequently accompanied by
normalization of the VEP amplitude. The improvement in VEP latency,
however, appears to be more limited (Youl et al., 1991). Recovery of VEP
amplitude following ON coincides with visual recovery and cessation of
gadolinium leakage, presumably due to resolution of the inflammatory
process and gradual reversal of the conduction block (Youl et al., 1991).
Generally, the recovery of VEP amplitudes does not appear to be com-
plete and long-term deficits could be attributed to underlying axonal
degeneration as well as slowing or dispersion of the signal corresponding

to persistent demyelination (Jones & Brusa, 2003).
CONCLUSIONS
ON is a clinical entity characterized by subacute visual loss accompa-

nied by pain on eye movement that is followed, in the majority of cases, by
spontaneous recovery. Due to its structural and functional transparency,
the afferent visual pathway provides an ideal model to study the mech-
anisms contributing to neurological disability in MS patients. Develop-
ments in retinal and optic nerve imaging have, therefore, permitted a more
thorough understanding of ON pathophysiology, including the interplay
between inflammation, demyelination, and neuroaxonal degeneration
within the confines of the visual pathway. Integration of these mechanis-
tic concepts into clinical trials is underway to help identify potential neu-
roprotective and neurorestorative therapies that could potentially reduce
visual disability following ON, as well as disability in general, in MS.
DISCLOSURES
Dr Al-Louzi reports no disclosures.

Dr. Shiv Saidha has received consulting fees from Medical Logix for
the development of Continuing Medical Education (CME) programs in
neurology, consulting fees from Axon Advisors LLC, Educational Grant
Support from Novartis & Teva Neurosciences, speaking honoraria from
the National Association of Managed Care Physicians, Advanced Studies
in Medicine and the Family Medicine Foundation of West Virginia, and
served on a scientific advisory board for Biogen-Idec and Genzyme. Dr
Saidha also receives research funding from the Race to Erase MS.
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C H A P T E R

Multiple Sclerosis 281

ON IN RELATION TO THE RISK OF MS

In certain clinical circumstances, ON can be considered a harbinger

Space One or more lesions on a T2-weighted scan, with or without gadolinium

Several community-based studies have estimated that the average

(14%) in contrast to rates reported in the US (49%) (Wakakura et al., 1999),

THE AFFERENT VISUAL PATHWAY

The optic nerve

The optic chiasm

The lateral geniculate nucleus (LGN) and optic radiations

CLINICAL FEATURES OF OPTIC NEURITIS

TABLE 2 Features of typical versus atypical optic neuritis

Typical optic neuritisa Atypical optic neuritisb

Age (years) 20–50 >50 or <12

Symptomatic Unilateral in adults, more frequently Bilateral simultaneous or

Pain Mild-to-moderate periocular pain Absence of periocular pain or

Fundoscopy Normal optic disc appearance in Presence of severe papillitis,

characterized by a false depth perception of moving objects due to dispa-

hemorrhage, retinal exudate, and/or vitreous cells is uncommon and, not

INFLAMMATION IN OPTIC NEURITIS

During the initial development of a prototypical MS lesion, it is believed

After recognition of target antigens on antigen-presenting cells, this process

DEMYELINATION IN OPTIC NEURITIS

Inflammation and demyelination occur congruently during the early

Borrelli, 2001) and that of myelination in inducing clustering of Na(v)1.6

failure of remyelination, and result in permanently demyelinated axons

AXONAL AND NEURONAL DEGENERATION

Although MS has long been identified as an inflammatory demyelin-

bidirectional axonal loss (Kanamori, Catrinescu, Belisle, Costantino, &

to the one that degenerates, a process known as trans-synaptic neurode-

IMAGING AND ELECTROPHYSIOLOGIC CORRELATES

Optical coherence tomography (OCT)

FIGURE 1 High-definition optical coherence tomography (OCT) images obtained using

that in eyes with a previous history of ON more pronounced ganglion

neuropathy (Sotirchos et al., 2013; Wolff et al., 2014). Interestingly, it is

Magnetic resonance imaging (MRI)

Diffusion tensor imaging (DTI) is an MRI technique that relies on char-

patients with previous ON is related to evidence of axonal damage in the

Visual evoked potentials (VEPs)

degeneration as well as slowing or dispersion of the signal corresponding

ON is a clinical entity characterized by subacute visual loss accompa-

Dr Al-Louzi reports no disclosures.

Rasminsky, M. (1973). The effects of temperature on conduction in demyelinated single

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